DSra^, Acquisitions Unit
National Institutes of Health
Buiidirig 10
Betfiesda, Maryland 20014
ISflBB Office of the
Director Pa^Ject Seports
Ths Di^ecter's Beport ««—»—.—— — -— «««.-u,-*.„ J&sland
Bis-ect IfealHlEiS— »«.»—.— .-»-»»».^ — «*,»« «««..».«,» Wlpf
Collaberative ReBearch«— »«—»-«. — -,»- ..««.. S^slaod
SgJia^aioJ.©^ feffiBch-* — «<..«....••..»«.....». — .«.« K«r2asid
Bi^setricG Brunch— .-—"—.—»— —«——»..„,«...,« Ooldatela
SsAsaia-axal Prsgs^iaS"— • — — ~-»^— — .-« .—»„.
I. Hesearcli Grafts— >-<> — ......._...,«. _^_.
H. Field Xa:tfesti^ti«sis snd Pilot^ Projects-*— Se^r
IIX. S-radamts t!?raiaing Gj^nts— — « — — — ^-.-^ Seger
I?.. Sfe^cis^ 1?ra.ine€@Mp Ppogsss — — — ^rt^in
7I« Eerier aad Agpro^al ©f GsasxtS"* — «««——.«- Seger
r
clinical Research - 1959
Clinical Direccor's Report — — — — — — -~» Shy
Medical Neurology Branch
Summary-—- — — _-,-»---.. -_.« — >_„ „ gj^y
Individual Project Report-
Serial No» Title Principal Invest igetor
1(c) Amino Acid Metabolism in Normal
and Epileptogenic Cerebral Cortex
In Vitro- — ~ — --— — — _- Tower
Peters
2(c) Electrolyte and Energy Metabolism in
Normal and Epileptogenic Cerebral Cortex
in Vitro? Tower
Peters
3(c) The Metabolic Significance of
'Y-'Ainino'Wityric Acid in Neural
Tissue— — ——«——- -_-._-_—. McKhann
4(c) Clinical Evaluation of Various Mino
Acids and Related Compounds in Control
Seisures, including Studies of their
Metabolism in Vivo^ — — -— — Tower
5(c) Anticonvulsant Drugs and Cerebral
Electrolyte Metaboiisn— — — — Smith
6(c) Con5)arative Biochemistry of Smooth
Muscle and Striated b&iscle Horvath
7(c) Distribution of Actia and Tropomyosin
in Normal and Diseased Mtiscle— — — — — Horvath
8(c) Alterations of Actomyosin Tensile Strength
and of Muscle Proteins in Neuromuscular
Diseases—---- — Horvath
9(c) The Surface-Chemical Behavior of Urine
in Relation to its Surface-Active
Macromolecular Constituents— — Curtis
Curtis
McKhann
Sporn
Dingman
I\?herret£
Shy
Haase
Serial No. Title Principal Invest: igaiior
10(c) Physio-Chemical Studies of Human
Cerebrospinal Fluid >»_..
11(c) The Relation of PyridoKine (Vitamin Eg)
to Certain Seizure States—-—--" '
12(c) Isolation, Fractionation,, characterisation
and MetabolisiE (Synthesis, Turnover, etc*)
of Ribonucleic Acids in Brain------- --
13(c) Cerebral Protein Metabolisia and Turnover
in Tissue Slices incubated in vitro ----.
14(c) The Histopathological and Ghaaical
Investigations of Keurosiuscular
Disorders------------ — — —
15(c) The Physiology and Pharmacology in
Kjyasthenia Gravis-— — -».-
16(c) Clinical Pathological Correlative Study
of the Hervous System in Orthostatic
Hypotension — ---- — --- — ■- — • -__-
17(c) A study of naturally occurring choline
esters . — —
18(c) A study of uaiscle cholinesterase and
its inhibitors- ~—
19(c) A study to dete^sdne the effects of
depolarising drags on miscla ensymes-------
20(c) The localization of muscle fibers in a
single motor unit;' -~ — — — .-_—
21(c) The action of neuroBUSCular blocking
drugs on directly stimulated innervated
and denervated jauscle— — Irwin
Shy
Drager
Shy
Irwin
Irwin
Irwin
Irwin
Serial Ko. Title Principal Invest igator
22(c) Blood and tissue cholinesterases in
neuromuscular blockade—- — - — » — - Irwin
23(c) Slmll Changes in Eighteen Cases of
Dystrophia Myontonica------ • ■ -_-— _ m chiro
Caughey
31(c) Thyroid function and neuromuscular
disease------------------- — Engel
32(c) Studies of the Chroaosomal Constitution of:
1) Human subjects with various disorders.
2) Local tissue abnormalities-^---- • Altrocchi
Krooth
33(c) Pathological Study of Intramuscular
Motor and Sensory Herve Endings in the
Normal and in Neuromuscular Diseases---- - Haase
34(c) The use of a Konoamine Gsidase Inhibitor
(JB-5i6) as an Aati-convulsant Medication
Centrencephalic Seizures--- ~- — ---------- Prockup
Smith
35(c) A Study of Progressive Parenchymatous
Degeneration of the Central Nervous System Smith
i>rager
Electroencephalography and Clinical Neurophysiology
Branch
Summary-----^'--— — --- — -» .„_ Ajmone-Marsan
Individual Project Report
36(c) A Seizure Atlas (Clinical-Electroencephalo-
graphic Correlations)—--- — - --------, Ajmone-Marsan
37(c) Depth electrography in epileptic patients — — Ajmone-Marsan
38(c) Electrocorticographic studies in temporal
lobe epilepsy and in focal cerebral
seisures"----—- — ■ ■ • — Ajmone-Marsan
Serial NOo Title Princj
39(c) Unitary analysis of tha res-ponse elicited
in the visual cortes of cat- — ~-- — ----- — _-„_
40(c) i-Iicroelectrode investigations of the mechanisms
of the electrically induced epileptifoairm
seizure ("efterdischarge")-- ' —
41(c) Effects of corticofugal and corticopetal
impulses upon single elements of the lateral
geniculate nuceleus — ■t — -- —
42(c) Thalamocortical mechanisms. A cosparison
between specific, association and non-specific
systems -__„„_ __^ „„_„ „ —
Surgical Neurology Branch
SuEsnary------ ~ .--__ ._-_---
43(c) Epileptogenic Mechanisms in the Brain of Man
and Other Primates- -•
44(c) Functional Representation in the Temporal Lobe
of Man and Higher Primates-- —
45(c) Effect of Radio Frequency Energy en Primate Brain
Mechaaisras-"-- _-_--_ __--_ -_- — _
46(c) Effect of Destructive Lesions upon the Function
and Structure of the Human Central Nervous
System--- .----«.-_--— -_.-_ -___ — .
47(c) A Study of the Functional Matomy and Pathology
of the Human Visual System----- — ---- — .- --
■48(c) Studies of Involuntary Movements------' — --------
49(c) Some Aspects of Amygdaie- Amygdala
Connections ■- •-- -_»--
50(c) Effects of Nucleus Amygdaliformis Stimulation— --
pal Invest igato r
Widen
Ajmohe-Marsai-
Gerin
^'Jiden
Ajmone-Mars an
Morrillo
Baldwin
Baidvjin
Bald^v-in
Baldwin
Van Bur en
Van Buren
Van Buren
Horris
Norris
Sarial HOo Title Principal Investigator
51(c) The Recruiting Responses -. .- i^±
52(c) Cortical Intracellular Potentials in
Epileptic Cortes — . . i^±
53(c) Cortical Intracellular Potentials in Response
to a Single Cortical Stimulus- ---„-„„_ cliou
54(c) Study of Inhibitory Intemeurones of the
Cerebral Cortes----- — —_--___— — ,.„«- — __„ ii
55(c) Synaptic Activation of Kerve Cells in the
Primary Visual Cortes — ------------------ — -. i,±
56(c) Synaptic Activation of Cortical Nerve Cells- Li
57(c) Elestrical Activity of Individual Glia
Cells in Tissue Culture Material-—- Li
Klatzo
58(c) Electrical Activity of Individual Neuronal
Elements in Tissue Culture---- — ■ — ------»-- Li
Klatso
59(c) Study on Morphological Changes due to
EKposure to Radio- frequency Energy- » Klatso
60(c) Study on Piaocytosis and Uptake of
Proteins and Neutral Red Dye in Vitro--- — -- Klatso
61(c) Study of Regeneration in the Central
Nervous System------ — ------- — - — „_-„„-»„ Ortis-Galvan
62(c) Histocheaical and Electrophysiological
Observations on the Muscle Fibers Grown
in Vitro---- ■ — ------^ -----» Engel
63(c) A New Method for Quantitative Study of
Precipitin Reaction--------- — -— — Miquel
54(c) Study of the Effects of Hypothermia on
Injured and Normal Brain Tissue------------- Laskowski
65(c) Investigation of the Etiology, Pathology
and Clinical Manifestations of Cerebral
Palsy and Allied Conditions; Also of the
Epilepsy During Childhood— —--—---- — - Dekaban
Serial KOo TiSle Principal Investigator
66(c) Mate3niai Condition During Pregnancy
and the Course of Birth in Reiatioa
to Neurological Abnormalifcies in the
Infants and Pathologic Lesiotis in
Products of Abortion-"--- — ---■ — --=-.»----- Dekaban
67(c) Pathological Lesions in the Central islervous
System Occurring During Prenatal, Intranatal
and Early Postnatal Life — .--«..----- — .„-„„ Dekabsn
68(c) The Incidence and the T;fpe of the Central
Nervous System Abnormalities Eucouatered
in Offspring Bom to Diabetic Mothers----- — Dekaban
Baird
69(c) Measurements of EKtemal and Internal
Orbital Distance in Males and Females
froEi Birth .to Adulthood---------------- — --- Dekaban
70(c) Preparation of the Horizons of the Noriiial
Development of the QJS in Mice and
Espex'imental Production of Congenital
Malformations of the CNS-----------' -■ Dekaban
71(c) Effect of "fear-provoking" Stismxli on
Visual Discrimination in Priiaates- — ------- Lansdell
72(c) Psychological Evaluation of Temporal Lobe
Disease — - — .--- — _-_--_-„-_-_„- „-----.--^„- Lansdell
73(c) Body Temperature in Ghimpanaees ^aith
Bilateral TeiJiporal Lobe Daraager- — ----------- Blevins
74(c) Fluothaae Studies----- — --- — ------ — --„,._„„- Hall
75(c) Hypothenaia in Neuroanesthasiology — ■ — - Pritchard
76(c) Succinyl Choline in Awake Cranietoiay--------- Pritchard
77(c) The Effect of Hj^ertonic Urea Solution on
Intracranial Pressure-- — ----. — -..--„_--„-„_ Pritchard
Ophthalmology Branch
SusHBary---- -_-------_-_-_-=-- -_----_--o._--_-™^-__„„„„ -^q^ Salliaana
78(c) Basic Factors in Refraction Anomalies-------- van Alpen
serial HOo Title Principal Invesfcigafcor
79(c) Insffiinological Relations in Ocular
Tissues— — — — van Alpen
80(c) Clinical Glaucoma Study— — ■ — Okun
von Sallman
81(c) Simultaneous Occurrence of Primary Malig-
nant Melanoma of the Eye and Skin—- Paton
Thomas
82(c) Intraocular Angiography- Cohan
83(c) Thyroid Hormone Turnover in Uveitis O'Rourke
84(c) Detection of Ocular Tumor by Isotope
Tracer Methods O'Rourke
85(c) Study on a Possible Second Aqueous Outflou
Pathway in the Eye-— ■ — Macri
86(c) Anatomy of the Venous Circulation of the Cat
Eye and the Aqueous Outflow Channels in the
Cat, Rabbit end Itonkey- — — — - Macri
87(c) Study on the Pharmacodynamics of Various
Agents Affecting Intraocular Pressure Macri
88(c) A Study of the Proteins of the Lens Resnik
89(c) An Investigation of the Enzyme Systems
Present in Cornea and Other Collagenous
Tissues- — -- — Kuhlman
90(c) An Investigation of the En33^atic Systems
Present in the Aqueous Humor--- Kuhlman
91(c) Studies on Central Nervous System Control
of Intraocular Pressurso (Anatomy of
Posterior Ciliary Slerves) von Sallman
Grimes
92(c) An Unusual Self- Inflicted Eye Injury- — --- — Copenhaver
93(c) Angioid Streaks and Sickle Cell Anemia—-— Paton
Serial Ho<, Title Principal Investigator
94(c) fhe Study ei Neural Mechanisms in the
Regulation of Intraocular Pressure in
the Cat • — Lele
95(c) Design and Construction of Ophthalmic
Instruments ■ • Gunkel
96(c) Functional Studies in Retinal Anomalies and
Diseases (Electroretinography, Adaptometry,
and Perimetric Light Sense Studies)- — Copenhaver
Gunkel
Goodman
Dodt
97(c) ERG Reactions of Pure-Cone Mammalian
Retinae Tansley
Copenhaver
98(c) Electrophysiology of the Eye- — pourtes
99(c) Studies on the Corneal Endothelium- — von Saliman
Caravaggio
100(c) Eye Changes in a Familial Type of Dyskera-
tosis of the Conjunctiva and the Oral
lyfiicosa— " — > — - — — - — — — von Saliman
Paton
101(c) Nutritional Cataracto Tryptophane
Deficiency Cataract in Guinea Pigs-- von Saliman
Reid
102(c) Study of Ocular Toxoplasmosis and Its
Therapy — Kaufman
103(c) Electron Microscope Studies on Biopsies
of Human Muscle Diseases- Wanko
Shy
104(c) Electron Microscopic Studies on Tissues
of the Eye, such as Epithelium, Fibers and
Capsule of the Lens, Epithelium of the
Ciliary Body, the Optic Nerve and the
Conjunctiva ■ ■■ -----< — - Wanko
Basic Research
Introduction »--»«— Livingston
Laboratory of Heuroanatomical Sciences
Summary- __----_- windle
Individual Project Reports
Serial NOo Title Principal Investigator
NINDB-KA-DR-1 Aspects of Experimental
Neuroembryology ■ — --- Guth
NlNDB-NA-DR-3 Histogenesis in the Embryonic
Maamelian Nervous System- — ---- — Miale
Sidman
NINDB-NA-DR-4 Regeneration in the Spinal Cord Campbell
Feringa
Windle
NINDB-NA-DR-6 The Functional Role and Specificity of
the Sympathetic Nervous System in the
Regulation of Pupillary Function Guth
NINDB-NA-DR-7 Heterogeneous Reinnervation of the
Diaphragm- — — " Guth
NINDB-NA-DR-9 Histological Studies of the Nervous
System of Macaca ^&llatta after
Asphyxia Neonatorum windle
NINDB-NA-DR-21 Psychological and Histopathological
Deficits of Asphyxia Neonatorum in
Guinea Pigs _--_--—_ Bailey
Windle
NINDB-NA-DR-23 Regeneration of Peripheral Nerves
Over Long Gaps — -— — Campbell
Feringa
NINDB-NA-DR-24 Histological Study of the Nervous
System of the Macaca Mulatta after
Asphyxiation with Nitrogen Gas- ■-- Windle
NlNDB-WA-NC-1 Ultrastructure of Nervous system-------- Palay
Serial HOo Title PriacipGl Investigator
NINDB-NA-NC-6 Relationship Between Neurosecretion
and Milk Ejection------ — •^-— Brighttnan
NINDB-NA-KC-7 Species Differences in Chollnesterase
Activity of the Central Nervous System---- Brightman
KIHDB-NA-NC-8 Metabolism of the Nervous System:
Quantitative and Cyfcochemical Studies-- — - Aibers
WINDB-NA-EP-1 Pathogenetic al Eacfcors in the Development
of Myelopathies--- •---- « Csnmermeyer
NINDB-NA-EP-4 Introduction of a New Chemical Fixative
for Tissues- — Malm
NINDB-NA-FN-1 A Study of the Auditory Afferent and
Efferent Systems--— — RasarJEsen
NINDB-NA-FN-5 The Comparative Anatomy of the Efferent
Cochlear Bundle in Selected Submaamalian
Vertebrates; an Sxperiraental study--—"-- Boerd
NIKDB-NA-FN-6 Further Studies on the Efferent Component
of the Vestibular Nerve- -_~-- Gacek
NIWDB-NA-FN-7 An Experimental Study of the Ascending and
Descending Fiber Connections Between
Corpus Geniculatum Mediale and Auditory
Cortex----' — —-.«.---• — » — .--- -. — - — RasmuEsen
NINDB-NA-PP-1 Ecological Study of Bhesus Monkeys on Cayo
Santiago, Puerto Rico — Koford
KIlWB-NA-PP-2 Normal Reproductive Function in the
Rhesus Monkey-- ■--- — -_-«---„ Jacobson
Vollmati
NINDB-NA-PP-3 Maturation in Infant Rhesus Monkeys and
Care Required for Rearing Them--- Jacobson
NINDB-NA-PP-4 The Intrinsic Nerve Supply to the
Endometrium in Cat and Monkey-— --------- Jairofason
Serial No<. Title Principal Invesfcigator
NINDB-NA-PP-5 Neurological Evaluation and Electro-
encephalographic Studies in the
Monkey (Macaca ISnlatta) Asphyxiated
at Birth- — de Arellano
NINDB-NA-PP-6 Psychological Effects of Asphyxia
Neonatorum in Rhesus Monkeys- -— — - saxon
NINDB-NA-PP-7 Evoked Potential Evidence for
Connections from the Cerebellar
Hemispheres to the Sigmoid Gyri • — Combs
S^sson
NINDB-NA-PP-8 ^&lltiple Alpha-rhythm Cortical Responses
Resulting from Single Shock Cerebellar
Stinnilation— ----- — -— — --— — — Combs
Dennery
NINDB-l?A-PP-9 An Evoked Potential Study of Connections
Between the Diencephalon and the Si@&oid
Gyri — ■ Dennery
Combs
NINDB-NA-PP-iO Physiological Studies of Fetal and
Newborn Monkeys — - — - — - — ---—__- Dawes
NINDB-NA-PP-11 Tests of Ovulation in the Monkey- Vollman
NINDB-NA-PP-12 Responses of Fetal and Newborn Monkey
to Asphyxiation and Resuscitation— — - — Windle
and Staff
Laboratory of Biophysics
Summary--- ->_._.-._. _ ...... Cole
NINDB-B-1 Ionic Permeabilities of the Squid Giant
Axon Membraneo Experiment and Analysis— Moore
Taylor
NINDB-B-2*^^ Ionic Permeabilities of Nerve Membranes;
Theoretical Investigations—-- FitsHugh
Chandler
KINDB-B-3 X Studies of Acetylcholinesterase
Inhibition and Nerve Activity——— Whitcomb
Serial NOo Title Frincipal Investigator
NINDB-B-5 Ionic Permeabilities of Nodal
Membrane- --»- — . ttoore
del Castillo
Laboratory of Neurophysiology
Summary-- — ~--- — — - — Marshall
NINDB-NP-SS-5 The Mechanism of Nerve Excitation— Tasaki
Teorell
Franck
SpyropouloE
NINDB-NP-SC-3 Generation of Impulses in Nerve Cells-- Frank
Fuortes
NINDB~NP-SC-6 Augmentation of Signal to Noise
Ratio ■ — Frank
NIHDB-NP-SC-7 The Effect of Anosia on Motoneuron
Meaabrane Potential— Nelson
NINDB-NP-SC-8 Generation of Impulses in the Mauthner
Cell of the Goldfish- — Oikawa
NIMH-NF-BS-i Vestibular Influences on Spinal
Mechanisms—-— — — Gemandt
Laboratory &i Neurochemistry
Section on Lipid Chemistry
Summary ~~«~^~. »-»-- , — -— — -—»—.« __« Brady
NINDB-NC-1 Biosynthesis of Sphingolipids — — Brady
NINDB-NC-6 Biosynthesis of Aromatic Compounds— Brady
NIKDB-NC-7 Metabolism of Inositol- — Agranoff
NINDB-HC-13 The Effect of Sphingosine on Blood
Coagulation— ■»- — Hecht
NINDB-NC-14 Enzymatic Synthesis of Fatty Acids- — — Brady
NINDB-NC-15 Biosynthesis of Cholesterol Agranoff
NINDB-NC-16 Role of Redox Reactions in Excitation— Brady
Spyropouios
ANNUAL REPORT
Calendar Year 1959
National Institute of Neurological Diseases and Blindness
National Institutes of Health
The Director's Report
The 1959 Annual Report of the National Institute of Neurological
Diseases and Blindness contains the Director's Report; the Reports of
the Chief of the Extramural Programs Branch, Dr. Gordon Ho Seger; the
Annual Report of the Clinical Director, Dr. G. Milton Shy; the Annual
Report of Basic Research, Dr. Robert B. Livingston; the Annual Report
of Collaborative Research, Dr. Richard L. Masland; and summary reports
of branch and laboratory chiefs.
The Annual Report also brings notification of the request of
the Director of Basic Research for reassignment. At the completion of
three years as Director of Basic Research, Dr. Robert B. Livingston,
in accordance with a previous commitment j, feels that a change of
leadership is desirable at this time.
Since these individual reports include comprehensive
commentaries on the total 1959 program, the Director's report will
confine itself in the main to new trends and developments and to
events of special importance in the overall program during the year.
DEVELOPMENT OF THE OVERSEAS RESEARCH PROGRAM
In September 1959, the overseas program of the Institute
received increased emphasis as Dr. Pearce Bailey relinquished his
position as Director of the NINDB to become Director of International
Neurological Research, a newly created Institute post. His decision
highlights the recognition of the tremendous opportunity which exists
for the establishment of a closely knit and carefully coordinated
worldwide program of attack against disorders of the nervous system.
Dr. Bailey has established headquarters in Antwerp, where he will
maintain close liaison with the World Federation of Neurology which
also has headquarters in that city. The objectives of his mission
have been summarized as follows:
The primary mission of this overseas assignment is to
strengthen the NINDB-NIH program for the diagnosis, prevention,
treatment or rehabilitation of crippling neurological and sensory
disorders. A special focus shall be placed upon research promising
to supply clues to the basis of serious neurological and sensory
disorders that are prevalent in the United States,
In his overseas assignments Dr. Bailey will give attention
to two immediate aims. The first is to survey, evaluate, and report
on international scientific talent and facilities for research and
training in neurological disorders. The second is to study and
develop methods for the application of this potential to the
organization of promising collaborative projects in international
geographical clinical pathology. Many scientists now believe that
the discovery of clues to the treatment of obscure metabolic
diseases and certain other disorders of the nervous and sensory
systems depends upon international studies of their nature and
frequency in relationship to genetic and environmental factors in
diverse geographic regions and populations throughout the world.
This mission is concerned with the development of such collaborative
undertakings. The objective is not to undertake general solicita-
tion of individual research grant applications.,
Certain methods are directed toward the strengthening of the
total international research effort as follows:
1. The implementation of a program for the dissemination
and exchange of medical and scientific news related
to neurological and sensory disorders.
2. The initiation of a program for establishing a
full-time technical staff at the WFN secretariat in
Antwerp ,
3. The organization of international neurological
4. Establishment of a liaison and working relationship
with the World Health Organization, UNESCO, and
other international bodies.
5. Establishment of a liaison between NINDB and overseas
investigators.
6. Giving technical advice and aid to foreign countries
desiring to organize more effective research and
training programs in neurological and sensory diseases.
7. Seek contributions and support of countries other
than the United States Co an international research
effort in neurological and sensory disorders.
The program of the World Federation of Neurology has moved
ahead rapidly during the closing months of 1959. Problem commissions,
comprising men of international stature in various fields of
neurology, have been formed, and meetings of these commissions have
already taken place for the discussion of important areas of concern.
New personnel have been recruited for a full=time central staff in !?I.
the WFN, and this organization is planning a leading role in the
development of a cooperative comparative study of the geographic
neuropathology of cerebrovascular diseases. The WFN has been
recognised as a nongovernmental agency in official relations with
the World Health Organization.
DIGEST OF EXTRAMURAL PROGRAMING HIGHLIGHTS
The Institute has continued its cautious development and
strengthening of broad cooperative and collaborative programs. In
fact, 1959 marks the first year of actual study of patients within
the collaborative project for the study of cerebral palsy and other
sensory and motor disabilities of childhood. During the year,
approximately 5,000 women and 2,500 children have been observed
under this program. The study is showing increasing strength and
cohesiveness as individuals from within the collaborating institu-
tions meet regularly with the central staff for purposes of protocol
development, methodology testing;, and quality control.
The central staff for this project, which in January 1959
numbered 67 , has been strengthened to a full complement of 104.
Facilities for the storage of serum specimens have been developed
to accommodate over 120,000 vials. Facilities for neuropathological
examination of specimens also have been established.
Further extension of this program in the immediate future
will depend upon efforts to strengthen the so-called extensive
phase of the project=-those methods which may obtain less detailed
information from large groups of women and their offsprings
Through such a mechanism some indication of the representativeness
of the experience in the collaborating institutions and increased
data for statistical analysis will be obtained.
Two important cooperative studies of cerebrovascular diseases
have also reached the stage where findings are becoming available.
Seven institutions are collaborating in a study of the effectiveness
of anticoagulants in the treatment of cerebrovascular diseases.
Initial reports of the study of 600 cases have been prepared, and
it is evident that this group will provide significant facts for the
rapid and accurate evaluation of the effectiveness of this means of
therapy in various types of cerebrovascular diseases.
Twenty-two different institutions are cooperating in a study
of intracranial aneurysms^ and the records of well over 1,000 cases
are now in hand. An overall mortality rate of 40 percent highlights
the extreme seriousness of this disease, and indicates that our
presently available therapeutic measures still fall far short of
the desirable„ It is encouraging, however, that important advances
in neurosurgical techniques, including the improvement of anesthetic
agents and the use of hypothermia, are greatly reducing the mortality
of surgical procedures for aneurysms as well as for intracranial
ttmors.
Another important cooperative venture is concerned with the
development of accurate screening techniques for the early diagnosis
of glaucoma^ Four institutions are working together toward the
development of a reliable mass screening technique, and an evaluation
of methods now available. The increasing effectiveness of these
glaucoma detection methods, and the availability of drug therapy,
are greatly reducing the impact of this important cause of blindness.
The improvement of surgical techniques for the treatment of retinal
detachment J, and for cataract removals are reducing blindness from
these causes. Improved diagnostic and therapeutic measures for
toxoplasmosis are expected to reduce the toll of blindness from
certain types of uveitis.
The year 1959 has shown an important and growing emphasis
in problems of speech and hearing. Expenditures in these two areas
increased by over 60 'percent. The development of accurate techniques
of audiometry is greatly improving our ability to distinguish between
those forms of communications defects which result from hearing loss
from those which are attributable to abnormalities of the higher
brain centers. Basic researeh is also increasing our knowledge of
the mechanisms of hearing and of hearing loss. Similarly, the newer
techniques of neurophysiology are providing important new information
regarding the speech mechanisms and the disturbances of coordination
and movement which underlie certain forms of speech disorder.
Significant increases in the NINDB training program are now
beginning to provide trained personnel to undertake badly needed
research in this important and long-neglected field-=a field
which is a very large factor in special disabilities of children
of school age.
The above special programs highlight the overall steady
growth of the grants program. At the end of December 1958, there
were 913 active research grants; at the end of December 1959,
1,107. Grant support amounted to $10,844,100 in fiscal year 1958;
$16,855,000 in fiscal year 1959.
In 1959 continued emphasis on the training of scientists
has provided an increased reserve of manpower to carry forward the
country's research programs of the future^ Programs in clinical
neurology and ophthalmology have not enlarged, although moderate
budget increases have been allocated. Increases in the clinical
specialties have occurred in pediatric neurology--a reflection of
heightened recognition of the serious gap in trained personnel for
this important area of clinical neurological research--and in
otolaryngology, another area of serious neglect. It is a source
of great satisfaction to record the continuing growth of the
important training programs in sensory physiology and of other
basic sciences supportive of neurological research. The objective
of these specialized programs is to provide this form of training
for clinicians interested in broadening their research resources,
and for Ph.D.'s in basic science wishing to prepare themselves for
careers in medical research. Expenditures in these important areas
have almost tripled during 1959.
MAJOR OPPORTUNITIES FOR NEUROLOGICAL RESEARCH
At this particular point in timej, it is apparent that the
development of certain new techniques has opened a wide vista for
research in neurological disorders. The opportunity now exists to
exploit special techniques of physics and chemistry which have only
recently become available. The prevention and cure of neurological
disorders will be hastened to the extent that we find the means and
resources to encourage the prompt application of these techniques
to the solution of our problems.
The first important research area is the general range of
neurochemistry. In a number of important neurological conditions,
there is strong reason to believe that the fundamental basis of
the disorder lies in some abnormality of general body metabolism,
or of the enzyme systems of certain selected individual cells. In
this category, one might mention amyotrophic lateral sclerosis,
Parkinsonism, some forms of "idiopathic" epilepsy, myasthenia
gravis, and certain forms of neuropathy. Increased knowledge of
tissue metabolism, and the search for specific abnormalities of
metabolites either by microchemistry, histochemistry, or in vitro
analysis, provide avenues through which our ability to cure such
important diseases as these listed above may be achieved.
Closely related is the study of molecular biology and
cytogenetics. Important new techniques and discoveries in these
fields lend hope that the solution of such conditions as the
hereditary ataxias, muscular dystrophy, the leukodystrophies, the
lipoidoses, as well as of the inborn errors of metabolism with
generalized disturbances, may achieve solution.
A second major opportunity lies in the field of immunology.
This expanding field now includes not only the study of the immune
reaction itself, but the use of the immune response and of anti-
bodies as a tool for biochemical analysis. Of outstanding concern
in this area is the problem of multiple sclerosis and some of the
acute encephalomyelitides to which it bears a close relationship.
It is probable that certain of the infectious neuritides are also
influenced by inflammatory reactions and sensitivity responses.
The search for an infectious agent in multiple sclerosis, and the
elucidation of the immune responses of the central nervous system
and their experimental nullification are important avenues toward
the solution of these major neurological diseases.
The search for new clues toward finding the cause and
prevention of neurological diseases can be greatly strengthened
by broad scale epidemiological investigations, which represent
the third area where expanded activities are needed. Such
epidemiological investigations are pertinent to the problem of
cerebrovascular diseases, multiple sclerosis, and amyotrophic
lateral sclerosis. Closely related is the increasing concern over
environmental health hazards. Under NINDB direction, such hazards
were high-pointed this year through the investigation of an out-
break of "Minimata disease"--now shown to be the result of mercury
poisoning, presumably because of improper disposition of industrial
wastes. To what extent less dramatic disorders are being brought
about is not evident.
7 -
For the strongest possible development of programs in these
important areas, it is urgent and essential to bring well-trained
nonmedical specialists into medical research. Solution of this
type of medical problem is most likely to develop when basic
scientists with great skill in the techniques of physics and
chemistry can be provided an opportunity for stable working
conditions in close relationship with clinicians having broad
knowledge of the problems of neurological disorder. It would
appear that three measures would be required if this ideal is to
be achieved.
The first requires continued development and expansion of
training programs in the basic sciences underlying neurological
research. The second requires the establishment of a mechanism
whereby stable support for both medical and nonmedical investiga-
tors can be assured. The final measure envisages the establishment
of centers within which a multidisciplinary attack against various
disease entities can be mounted. The productivity of the Clinical
Center, National Institutes of Health, is a clear example of the
gains to be reached when one establishes a research environment of
this sort.
INTRAMURAL RESEARCH
The direct intramural research program remained approximately
stationary in 1959. Those expansions which have taken place have
been exclusively in the collaborative research area housed off
c£unpus in rental facilities at Silver Spring. There is at this
time no additional clinical or laboratory space for basic or
clinical research expansion at NINDB, The only exception lies in
additional construction of neurosurgical operating facilities,
expected to be completed in 1960,
The productiveness of the direct intramural research program
is strikingly presented in the reports of the Directors of Basic
Research and Clinical Research.
The intramural program continues to demonstrate the tremendous
achievements which result from bringing together within one institu-
tion a group of scientists representing many branches of knowledge
and skill, but working closely together toward the solution of
fundamental problems of medical science. Within the clinical
research area, there have been three major centers of emphasis.
The first is an overall study of epilepsy and the convulsive
process. This broad study includes careful analyses of chemical
disorders and changes in normal and epileptic brain tissue, and
changes of excitability brought about by alterations in amino acid
levels in brain tissue. It includes clinical evaluation of seizure
patterns, which correlate closely with electroencephalographic
observations, and is valuable in demonstrating the focus of origin
of the seizure in patients with focal epilepsy. The epileptic
process is being studied by means of the microelectrode technique,
through which scientists are demonstrating the character of the
electrical discharges associated with the seizure. Results of
surgical therapy, particularly centering on temporal lobectomy,
complete the range of this broad study of convulsive disorders.
The second large area of activity relates to muscle disorders.
Starting with basic classification of muscle disease, by both
clinical and neuropathological examination, studies include detailed
investigation of muscle chemistry, using the newer techniques of
immunochemistry, and correlating chemistry with the production of
specific lesions by specific antibodies. Special pathological
studies include the observation of degenerating tissue, the study
of the distribution of neural fibers and motor endplates, in normal
and abnormal muscle, and the study of the process of regeneration by
the use of tritivmi- labeled thymidine. Finally, the study of neuro-
muscular conduction has led to the development of new therapeutic
agents in myasthenia gravis, which offers some promise of Improving
our armamentarium for that disease.
The study of eye diseases encompasses a particularly broad
program. Basic physiological investigations are concerned with the
nature of impulse initiation- -the chemical and physical phenomena
which accompany response to light stimulus. Such investigations
are carried out in varying selected animal species from Llmulus to
tree squirrel and humans, both normal volunteers and diseased.
No less than five broad programs are concerned with the
study of Intraocular tension and the mechanisms altering fluid
transfer. The chemistry and pathology of the cornea, and similar
studies of the lens, are closely related to concern with cataract
and opacities. Finally, the study of inflammatory processes in the
eye, the diagnosis and treatment of toxoplasmosis and other forms
of uveitis, is Included in this broad range of investigations.
These brief svmmarles can give merely the shallowest glimpse of
the program, the depth, breadth, and intensity of which can be
appreciated only through perusal of the detailed reports of the
Individual Investigators,
Review of the basic science program also attests to its
breadth of view. This year has seen important new advances in our
knowledge of the nature of the nerve impulse, and the mechanism
of synaptic transmission. In the area of neurochemistry, our
knowledge of the routes of synthesis of important complex lipids
of the nervous system is rapidly extending. From the Laboratory
of Neuroanatomical Sciences come new observations on the complex
developmental processes of the nervous system, the processes of
nerve regeneration, and the intricate pathways concerned with
coordination and with hearing.
The Perinatal Laboratory in Puerto Rico this year reached
the stage where an adequate number of animals were available for
a broadened program of study of the physiology of pregnancy, and
of the developmental processes of the nervous system in primates.
A broader utilization of this important facility will be possible
from now on.
Although this program, as outlined above, is proving
extremely productive, it will be less inspiring in the future
unless ways are found for developing within the Institute broader
programs to capitalize on the new developments in neurochemistry,
immunology, and epidemiology, discussed in this report. The
creation of additional research facilities and office space,
within which the various activities of this Institute can be
closely coordinated and interrelated, could be a most important
measure in strengthening the overall program and increasing the
efficient utilization of its critically short manpower.
RUSSIAN MISSION TO NINDB
During 1959, this Institute continued to contribute to the
Russian exchange program through serving as host to the Russian
mission visiting the United States.
Three Soviet scientists working in the area of research on
the nervous system visited this country under the provision of a
January 1958 agreement between the United States and the Union of
Soviet Socialist Republics to exchange missions in different fields
of medical sciences. They made a 30-day survey of U.S. research
developments in the physiology and pharmacology of the nervous
system. They spent three days visiting the National Institute of
Neurological Diseases and Blindness before visiting research centers
throughout the country.
10
The members of the group were; Dr. Sergey Viktorovich
Anichkov, Professor, Head of the Department of Pharmacology,
Sanitary -Hygiene Medical Institute at Leningrad, and spokesman
for Pharmacology achievements In the U.S.S.R. ; Dr. Vladimir
Sergeyevich Ruslnov, Head, Department of Physiology and Pathology
of the Nervous System, Institute of Neurosurgery of the U.S.S.R.
Academy of Medical Sciences; and Dr, Vaslliy Vasll'yevlch Zakusov,
Director of the Institute of Pharmacology and Chemotherapy of the
U.S.S.Ro Acadenqr of Medical Sciences.
At the end of their tour, they said their inqiression of
neurological research in this country was that the United States
is doing more work in the subcortical areas and the U.S.S.R, is
doing more with the cerebral cortex. They suggested that perhaps
new findings might be made if the emphasis were reversed.
They indicated a great interest in the work this country
is doing on the electronic investigation of single cells and
said their work related more to the effect of drugs on the body
as a whole.
All three scientists indicated that they were glad to
know that we were conducting not only applied but basic research
relating to the pharmacology of the central nervous system.
However, they said that they had observed that most of the search
for new drugs in this country is done by industry rather than
universities.
During the course of their stay, they visited the research
facilities of a number of medical institutions which Included;
Johns Hopkins University^ Baltimore; the Neurological Institute,
New York; Cornell University, New York; University of Utah
College of Medicine; U.C.L.A. School of Medicine; Washington
University School of Medicinej St. Louis; University of Wisconsin,
Madison; Harvard Medical School, Boston; Massachusetts Institute
of Technology, Boston.
The group received publicity and press coverage at most
every point of their tour. A final j well-attended press
conference arranged by NINDB, was held March 7 at the Shelburne
Hotel, New York City.
- 11
They expressed the hope that their visit had strengthened
the friendly feelings between the scientists and the peoples of
the two countries and expressed deep thanks for the many individuals
who had been kind to them during their stay.
INFORMATION
The Information Office of NINDB is engaged in producing
materials to support and implement a broad program of public and
professional information and education. This past year, the work
has included the preparation and distribution of press releases,
press conference materials, exhibits, radio and television broad-
casts, films, nonperiodical publications, speeches, and articles.
The office has also arranged press conferences, press interviews,
and picture stories. It has edited many manuscripts and has
answered inquiries of all types.
Among the publications completed in 1959 are: "Little
Strokes--Hope Through Research," "Brain-Damaged Children and The
Collaborative Project," and "Highlights of Progress in Research
on Neurological and Sensory Disorders." Nearing completion are
four other publications: "Parkinsonism," "Cerebral Palsy,"
"Cataracts and Glaucoma," and "Mongolism."
The Information Office also prepares reports, articles, and
speeches to fill requests from individual Congressmen, Congressional
Committees, the Department, Public Health Service, the National
Advisory Council, and voluntary health agencies. In 1959, these
included: the neurology section of the Senate Documents on Inter-
national Chronic Neurological Disorders (Epidemiology) and
International Research; background statements on disorders of
vision, cerebrovascular diseases, hearing and speech, neurological
disorders of childhood, and the Collaborative Project; in addition,
statements were prepared on the problem, progress, and the potential
gains for epilepsy, blindness, cerebral palsy and mental retardation,
and cerebrovascular diseases.
Interviews were arranged and press releases distributed to
scientific journals and the press. Included were: the Associated
Press, United Press International, New York Times, Medical News,
Life, Time, Newsweek, Parade, Saturday Review, Scope, and Science
Service as well as professional journals. Detailed arrangements
were also made for 17 Institute lectures.
12
During 1959, the Information Office replied to approximately
1,000 letters including Congressional inquiries; mailed out several
thousand individual pamphlets (not including bulk orders) ; and
replied to more than 2^000 telephone inquiries from the public.
Finally, the Information Office edited and cleared many articles
and scientific manuscripts, and gave assistance in the construction,
revision, and refurbishing of three scientific exhibits and the
revision of the amyotrophic lateral sclerosis film for the
Epidemiology Branch. Five NINDB exhibits appeared at 21 showings
to professional and scientific groups.
MEETINGS AND SYMPOSIA
During the calendar year, 1959, a number of important
meetings and symposia were held under NINDB auspices. Among these
were the following: a three=day conference on Neuromechani sms of
the Auditory and Vestibular Systems (June 11-13); a conference on
Postgraduate Training in Otolaryngology (May 14); conferences on
Glaucoma (April 13), Uveitis (September 18), Research in Otopathol-
ogy (October 19), a Cooperative Study on Aneurysms (December 9);
and planning conferences on Cerebrovascular Diseases (December 8),
and Drug Therapy Research (September 16).
NINDB also cooperated in sponsoring a number of conferences.
Among these were: The Second International Symposium on Myasthenia
Gravis held in Los Angeles, April 18-19, and co-sponsored by NINDB
and the Myasthenia Gravis Foundations, Inc.; an International
Symposium on the Encephalitides held in Antwerp, May 10-14, and
sponsored by WFN, Centre Interuniversitaire de Recherches Neuro-
pathologiques , and the NINDB; a Geomedical Conference, under the
auspices of the WFN Commission on Biometry and Genetics, held in
Copenhagen in June and sponsored by WFN^ NINDB, and the Danish
Multiple Sclerosis Society,
The proceedings of most of these meetings are now in press.
In additions ii" 1959, three books were published which summarized
the proceedings of previous NINDB S3anposia. These ares The Process
of Aging in the Nervous System, Allergic Encephalomyelitis, and
The Biology of Myelin, In addition, members of the NINDB staff have
published books on Neurology of Infancy and Neurochemistry of
Epilepsy; Seizure Mechanisms and Management.
AOTmL BEPORP
Calendar Year^ 1959
Direct Training
MTIOML JmSHmSE OF NSUROIOIICAX DISEASES AUD BLIKDKESS
HATiOML xmsumms of eeaiieh
Funds under tMs activity ($50,(XX)) provide for the support
of the in-sea^ice tKitniiig prograia of the Institute. This progrjja
aakes 11^ possiMe for the Institute to secure qualified staff for soaae
of its operations "by training younger scientf^sts in particular skills
aecessasy to carry on ce^ftain progxsaaa operations.
In cooperation with the Ccramtmicahle Disease Center in
Atlanta, Georgia, the Institute is presently supporting training in the
■br03-d-<*oncepts of epidemiology. Basic training and experience in the
field of the more acute and widespread cosmauni cable diseases offer an
introduction to the more coErpies and protracted epidemiological problems
of neu3ro3.i£^ical eind seaaoiy disorders and chronic diseases.
Training is obtained in universities eind other appropriate
institutions in order to suppleiaent already acquired esgerience and
acadesaic training where special needs exist in the total neurology
researdi prograsn.
Short-tersa courses, generally of a specific tedbnical nature,
are also undertsiken in this activity.
The follcwiiig is a list of personnel who received training
under this activity during the calendar year 1959:
^se Institute Purpose
Dr. Milton Alter Colussbia Presbyterian Med. Training in neuro-
Center, Ke»^ fork. logical disorders
Br. asraard Agranoff Institute for Cellular
CSi^Eistxy, Munich, Seraany To study the mechanisms
involved in the
foHaation of
acetylcholine and in
the relationship
between acetylcholine
and certain important
lipid factions of the
nerve membrane »
Dr. John Van Buren
Dr. Asao Hirano
Dr. Anthony Fons
Dr. Harry »feEseson
Dr. Captaine ThGrnpsaa
Dr. C. Spyropoulos
Mr. BclKirt Wlpf
J5rSo Ronica Sdssartz
Dr« Ifeiry Marijues
Mr. Jeraa® Kera
Miss Dorofchy Starr
Mrs. Shirley Chim Wong
Mr. Roljert Bawlss
Mrs. Blanche Vlnceat
Mr. Soberfc Ravles
Albert Cantu
fostltistg
l^lburg Clinic, GesBaisy
Ccsfflsxini cable Disease
Center^ Atlanta, Ga.
Varian. Associates ^
Instrument Div.j
Palo Alto, Calif.
Indiana University,
Bloaaington, Indiaaa
Friden Inc. School^
Rocbgeter, ^w York
Walter Reed Anay Medical
Center, Washlngtcm, D. C.
Uo S. Sept. of Agrictiltm'e
Graduate School
JJIHj, Bethesda, Md.
tl. S. Dept. of AgricusJlturs
Graduate School
Km, Bethesda, Md.
U. S. Itept. of Agriculture
Graduate School
Wm, Bethesda, Mdo
U. S. fept. of As^cultiare
Graduate School
Georgetc^m Chiv.,
Washl^gtoUy D. C.
^ruining in stereotosic
techniques --
Tt&IoLd^ in epidesaiology
and statistics.
Leetiires and laboratory
sessioas in Huclear
Ma^ietio Kesoiasace -
Slectron ParaisKignetic
Resonance Spectroscopy „
American Society for
Public Adiaiaistration
Course
Trainiiis in the pro-
gKUisaing of the data
processing models of
the JViden Flesowrl!;®r.
Coarse in Application of
HistocheH)ist:i^ to
Bithology .,
Course in Introductory
Virology. General
revieB" of aaiaal viruses
infecting husaans, ^th
emi&sasls on the
iabortxtosry properties
of these viruses »
Introductory course In
EtBosan Genstlcse
Course in General
Bacteriology »
Course in Basic prlac
of laboratory aniaal
ciir®o
Calendar Year, 195y
Collaborative Resssarch
Hatlcaal Institute of Ksurologlcal
Diseases and Blindness
national Institutes of Health
©le function of the Collaborative Research Program of tlie
Institute is to conduct a collaboxutive prograia of research,
wherein the Institute serves as the planning and integrating axis
for prosrsoai^d research on institutioiml^ geographic, and
disciplinary levels, end includes laboratory and other professional
research and services such as epid^oiology, biometry, neuropathology.
and virology.
Persoonel 19&} Budget I960
tfcdt Positions Personal Serv. 7l3i500
°"~~~ Other Objects 1*20,500
C© 17 Contracts 260,000
Projo SerVo 20
BiCBsetrics 3^ TOTAL
IntezBational 0 »=«—_—»
Yirology 7
Keuro^tho 6
Kuru 5
Epideaaiology _ 1$
KJTAL 1^
At the present tiiue, the major emphasis of the collaborative
program is the study of perinatal factors in relaticaa to cerebral
palsy and other defects of the nervous ^stemo Ho»ev®r, ther®
are several Independent activitiess aad thsy are covered in mor®
detail in the individual reports of the Branch Chiefs of Epidem-
iology and Biometry o
Further studies of Kuru continue to en^hasize the devastating
potential of this disorder » Although this condition is clearly
limited to an ethnic groirp in New Guinea, several other conditions
showing a very close pathological similarity have been observed In
other parts of the world « There appears to be a strong familial
ftictor sxiggestlng a genetic basis^, but this has not been entirely
established on the basis of present knowledge » Detailed population
studies eire in progress. In addition^ continuing efforts to
determine toxic or infectious agents ajpe in progress, and are being
combined with intensive studies of the chemical and pathological
(dianges of this baaoar and destructive disorder c
- 2 -
In general, the yesultB of th^ coHsixMfatlve rmseaTth area
contlime to dasonatrate the S!ni:&t2s.l advantages for r^saarch asd
scientific developBent which steia ftcsa a close eollaljctmtion
hetveen maobers cf the Public Eealth Service and i^ftil^erslty and
research c®aterB throix^hoiit the world.
The Problga
An imderstanding of Tshen &nd hcv hrain daiaage takes pl&ce
is essential in the effort to achieve the eventual prevention of
cerebral palsy, mental retardation and related dlso3rd££'s of
Inffancy and childhood. ^Phe soia'ce of the daasage is no» belisred
to lie in the period surrounding hlrfch««freffl conception throu^
labor and delivery and mitil about (»ie month after birth «
Xt is estimated that there are apipirosis^t«2y four and a
half Billion laentally retarded arsons in this countxy^ About
one third of these are childx%n and the disor^L&r afflicts about
126,000 children each year. In addition, acxe 550,000 persoos
are afflicted vith cerebral ^Isy, two to five percent of cur
school children are reported to have speech disordere, four
percent have hearing int^airssent, and ao^ 35^000 school children
are legally blind.
In an att^srpt to find the answers to these l^rge xsaticmal
probi€sa3, a collabceative research ^ogrjjn related to cerebral
palsy, Bsental retardation and other defects in childx^n tiae
officially begun Januaa^ 1959* after tvo and a half years of
intensive preparation.
fhis is the first large-scale effort to collect inforaatic«2
on all factors whidx mlsht c<sjeeivably relate to these neuro-
logical disorders and l^e first research progs^exs ever isidertaken
to collect and analyze this infomsation before ratl^gr than after
such disorders develop. 'Shs WMB is serving as coordinates and
central laboratory for tdfte project <.
. 3 -
AcccB^plishmettts IMs fe.st Year
de central services tor the coUaTsox^tive pexlziatal
project have heen eacpantitipg this past year and vill coatinize
to expand diiring 19^. ^ere have been two najor objectives:
first, to tt^go jk strong and closely Imit organization of the
coUahorators and the central office; and second, to refine
the data collection procedure.
To tniild a veil laait organization, snail vorking sub-
ccsaaittees have been established in special areas of the stiidy.
Sbese have included obstetrical, pediatric, and neurolc^cal
eastsoinatiaas; psydiological testing; and intervievisg. Tbs
Bsesabers of the subcotaiiittees have voxked closely at Bethesdi
vith the central staff, ?jad in some instances, have serv^ as
staff monbers for the developosent of certain fiicets of the
pro^ct. !Shis association has not only Increased the actieUL
participation of the collaborators in the central planning,
but has aided in coordinating the total v^cogfim.
In addition to the active working sessicHis, thirty-five
i&eetings Involving principal investigators in various areas
of the study iave been held this year. Plans have beeai reArleved>
protocols established, and policy decisions w&As regarding the
scientific de\'-elops!aent of the project.
Eeco^ilsing the iaportance tc the study of accurate and
cooiplete reporting, the reliability and validity of protocols
imve been further develofped suad tested during the past year.
A carefully refined jaotocol for listing accuKite and detailed
fssaily health and socio-ecoi»xiic data has been voiced out. A
series of obstetrical e^minations has been critically revievred,
end the obstetriral subcooslttee Txba established procedures to
achieve accurate recording of these essential data, A detailed
protocol for the exiuaination of the placenta has been developed,
and a cw.mtQl for placental esamlnatiQa is nag available. The
manual is acccsaj^mied by koda<±rcgae slides depicting the
characteristic changes to be rep<a?ted.
A protocol for the neurological examination of the nevboxti
infant has been developed and has been subjected to a test<>rete6t
analysis. On the basis of these findings, in^ortant changes in
the procedure have been reccssEwnded, A training film daatmstrating
the technique of the ex^iminatica of the netrbom has nov been con^
pleted. Also, a rigorous pretest of the developoaeixtal examination
for the eight -jBonth old Infiant has resulted in various procedural
changes.
A procedure has been established for the collection of
blood specijaens frcan the pregnaxit vcaan for virus stydi«So A
coidroom is now eqiiipg«5d at NIH and blood specimens from patients
studied this ysar are baing carefully flied for future virus
studies o Uoder contract, antigens of 8«as Uo Tsnown viruses are
being pi^paredo More than tlape@=<n»rtera of these are now available
and it is anticipated that within the next six months, antigens
for all th«s© agsnts rfill b« cm hando Tbe t«eun of sciantiats
responsible fear conducting the serological Bt\idi»s is now in
trainingo
In addition to the 5500 mothers and 4200 babies stuidied
in the pr«^est phase of th« pxo^ct, 3300 mothers and 1800 babies
had been studies this year in the final study series as of
October !» Ttm project also ecvleagea the study of other groups
of woosn end thsir offspriiig not delivered in the collaborating
institutionso This will aid in det«nnlziing the repp89«ntativ«ni*s8
of ths pregnancy exp®ri@nc® in the collaborating institutions and
will broaden th© statistical base of the project by bringing into
it additional numbers of damaged cases o
In December, 1958;, arrangements wer« mada with the Ccliasbia
Ifaiversity School of Public Health dnd Administrative Medicine to
e3i^Xor« the n@«ds and methods of this 'eartensive phase* of the
collaborating project » In January ^ a conference of scoe twenty
outstandifig investigators vas held tc outline th« ne«ds and methods
of this jgii&se of the study. Since then^ a smaU voxMng ccmmittec
has been forn^ vhich is concerned vith the further development
of these methodologies » To date, two ongoing protests have evoivedc
ISie Columbia Iftiiverslty group is now studying the
methodology for case finding in the New York area« Their objective
is to determine methods of detecting cases of cerebral palsy^ mental
retardation^, blindness, deafness and other neurological disabilities j
and relating the findings in these patients to ths prior recordM
events of pregnancy and labor <- This 8t\»3y will also aid in
coM.«ctlng accrued figures of prevaienca and incideac®, and in
evaluating the sample being collected at th® New YorlE Medical
College and Colxxobia ISiiversity School of Medicine ^
In another study, with the Kaiser Foundation and the
Ifeiversity of California at BertE«l«yj, women receiving prepaid
medical care are participating in a study similar to the
collaborative project but with less d/ttailed observatiouo This
will ssOce possible a larger sample, approximately 8^,000 waaen a
yearo
/ 1 fanc e_^
As J. result of tibsse activities, and under the surveyanco
of the planning eisamlttee, a w«ll»?oimdad total ^proemm is evolving.
Its objective is to evaliut« tkose ftLctors in i^^gnant wcaaen which
infiv^nce the bealth of their children and interfere with the
acMevCTsent of their full pot^nttillty.
The follotflsg table indicates the Buppott for the colIabor°o
ating perinatal project; grants awarded are on the attached sheet t
i2^ i2^ i^
Bxfcr.iEwral $3,^52,058 $1^,203,122 $3,732,73^
Sntraaunl 700^000 l,l6l,000 1,200,000
Totals $1*,152,058 $5,36»t,122 $i^,932,73^
r
P
9
A
H"
►*
4
»-|
H
M
H
^
^
a
a»
2
f-fc
3
w
?*•
-
'■i?
e»
■j>
§«
f
pfe
ss ^
er
I ;? ^ 9 f f i
■^
®
eo
r'
3
H'
'^
4
<§
O
t
®
^-^
^^
c^
H-
(A
c
*^
^
OJ
fi^
o
«
^
ts
}^
ta.
^*
S--"
«^
«i m
*d
^
•^
^
4^' 4^
CO M3
ro
ro
H
O
<*^
:..
\.
^
H
jp'
H»
H
^'*
■■^^
^.^.^
' >p
<.J1
^ol
'•jr,
vn
■^■c
vO
■>o
CO
vo
JS
V,
so
ro
®
H 5
0^
O
18
IBS-
03 H
^ I
8
|fV>
ro iM5
■"--Ij.:
ru
'3B \n
u>
■■■ a\
VO
t-^"
■«
- *-
dv
PO
o
■•u>
O'
?
•e*--^*
*d «
/-.
Cji Co
i:5>
o
OS
H
J?-
03
&
S
a?
CO
H
O
03
(V) U)
-J
ON
8 ^
Pv.
-~3
H
CD
M
ON
CD
ro
00
00
5
H
§
B
-■=1
^
^
c>
-&*
*-
-4
0^
%
S
ON
■^
^
le
■te
<!8
■vO
1
'P
^
■^
CO
W
o\
^■i.
Vft
<«
VJJ
OA
4^
®
%
^-
"4 --i
CBP-2
AlfNUAL REPdfT
Calendar Year 1959
Epxdessiolo^ Bremcli
Uationai Institute of Heiirological
IDiseasea arbd Blindness
National Institutes of H@altb
In general, the basic pxo^rain of this Brancli is still concerned
wi-yi tiie frequency, geographic distribution, and popxHation selectivity
of neurological and sense organ diseases o Nxuaeyous genetic and
definitive epidemiologic studies have been developed in conjunction
vith this basic prograa. The nature of the disorders under study and
the need to define the inhe3rf.tance factors of the affected "hosts" has
resulted in s baeoed and diversified genetics program and a recent
reconmiendation for the foa^sal organization of the Section of Genetics
vithin the Branch. Several ne^r activities of genetic© per-soimei are
dependent on cytological sjsd bioeheailcal labora'cory facilities. Since
these facilities are not available at our present q.uarters, labos'atoxy
space has been tsiapojpairily provided by other prograsss at NIH on a
coopeyative research basis. The resultant displacement and the constant
Hovement of our personnel between an office in Silver Spring and
laboratojcy, library and conference facilities in Bethesda has resulted
in considerable disj?uption of our program. Any success s^gistered
dviring the year has been made in spite of this diffictilty; but the
probable gain in recruitaasnt and research potential should be eonsidexed
if the space policy met the baeic needs vhich ax« so obvious to our
staff.
Our part in the investigations of several localized epidemics
of acute neurologic disease in -which toxic agents have been incriainated,
has focused our attention on the need, for en organised program in
esperimental and clinical neurotoxicology. However, here too, the lack
of a suitable laboratory facility has resulted in dispersion of so many
facets of otar investigations, thit schedules and coimtiitments, so often
dependent on outsit resovirces, have been difficvilt to meet) outbreaks
which we believe could hs-ve been solved proisgptly by our personnel have
suffered because of the lack of appropriate research facilities.
Our interest in geographic isolates and particularly the lew
cost but productive research of the genetic and neurological conditions
of phenomenal incidence on Guam continues. Long-term epid'Kaiologic
and genetic follow-up studies as well as detailed clinical, pathological
and anliuropological investigations aiaong the Chatsjorros are unSer way.
In cooperation with the CocEaission on Bioaietry and Genetics of
the World Federation of Keurology, the Branch is developing standardized
procedxires and reporting methods for population cos^arisons of morbidity
from neurological diseases. International saortality statistics are
also being evaluated in coopesation with the Biocie-trics Branch,
®P-2 ™ 2 - NlffiJB - Epidemiology Bsranch
Since proTslen^ of nomenclature and classification are basic in snoyMdity
surveys, the Branch is cooperating in efforts to sin5)lif^ the Nei^opologic
Section of iJas AMA Stanfiai^d Nomenclature and the International List of
Siseases and Causes of Dea-ai. Part of this effort is concerned with the
development of a useful classification systea for out-patient services.
Tbs relatively siaall p3?ofessional staff of this Biranch reps^sents
an unusual combination of scientific disciplines 'whose activities are
widely distributed geographically. Half of its professional staff are
in the field; others provide laboratojpy and administrative support for
the distant operations as well as dl2?ect field, clinical, and labora-
tosy research locally aiBi teaching responsibilities at N.I. H. In
addition, the staff provides many siippoiftive functions for the Office
of the Mrector, as well as the usual evaluation of reports and
axjplications for grants and fellowships.
The Branch maiatains a cooperative field investi^tion and
teaching program with the Spidenjiology Branch, CoaBiunicable Disease
Center. Before coiapleting his tour of duty in June, 1959y Br. Howard D.
Siedler, an Epidemic Intelligence Service Officer assigned by CBC to
this Branch, con^leted his x"eport on •Qie recent polion^relitis and
aseptic meningitis epidemic in Washington, D. C He ^ilso cosapleted
reports on -Uie investigation of smaltiple sclerosis prevalence in Duxbury,
Massachusetts, and a report on an investigation of congenital anomaliee
in Mexandria, Virginia. His field evaluation of multiple sclerosis
prevalence in Paroington, Blaine, failed to disclose anytMng out of the
ordinary. Other projects in which he was engaged included the collaboxa-
tive study on the possible teratogenic effects of Asian Influenza, and
also "Minamata" disease. The Asian Infliienza study is nearing
eompletionj preliiainary results fail to show any effect of l^e virus on
the incidence of presiaturity, abortions or neonatal deaths. The
teratogenic effect, if any, must await refined statistical analysis of
data ^lich are still being collected.
Dr. Siedler 's replacecsent from the Coaammieable Disease Center,
Dr. Stanley Faro, continues the Asian Influenza sttiidyj he has been
en^ged particvilarly in the neurotoxicological effects of alkyl mercury
con5)ound3 as part of the Mincuaata Disease study. There is reason to
believe ihat these conpotsnds, conteminatlng shellfish in Minaajata Bay,
Japan, nay have been responsible for the epideiaic of serious neurologic
disease in that community. Efforts are being made in cooperation with
other Laboratories in the Public Health ServLis to detexraine ^Jh&th&r the
possibility of a similar -ttoeat exists in the vicinity of waterways
close to United States vinyl chloride production plants using Bsrcury
compounds as catalysts. Dr. Faro is also en^ged in developing survey
procedures for a new study on the geographic distribution of uveitis.
Dr. Robert S. Krooth who was stationed on Guaia has coEg)leted
several reports on his worii on dia;^iysial aclasia, Paxfeinsonism and
aiayotrophic lateral sclerosis in the Marianas. The population on Guam
ORP-2 - 3 - NEiBB - Epidemiology Brancii
«md nei^boffing IslaEds still provides a wealth of cliaical inforeaation
and expes'ieace. At i3s.e same time, patJiological and other specimens are
available on short notice toT cooperative research activities at UIH,
CDC, and for the collalxsratoffs in various universities in the United
States and abroad. The island is at a crossroads of 1±te Western Pacific
aod provides imusual oppoaftunities in standard epidemiologic practice
for our field workers as velio The excellent cooperation of the Govern-
ment of Guam and the Havy Hospital facility continues. It is proposed
that the facilities of this reseasrch center be expanded for further use
of all Institutes of the National Institutes of Health.
In cooperation with other laboratories at N3DS, Br* Krooth is
studying the excretion sate of beta-isoaainobutyric acid in gout, the
jE«lationship of phenylthiom'ea tasting to thyroid disease, and is
applying ■^te technique of tissue culture to saetabolis problems in
selected ^netic diseases. In con;3^Juaction with Dr. Harold FvOHiaer,
RISR, member of tlie Branch are pursuing studies 'which li^ve demonstrated
abnormalities in collagen forsmtioa of aiayotrophic lateral sclerosis
patients .
On Guam, Ur, ICrooth was followed by Br. Asao Hi3?axio, a hi^tly
skilled neurologist and neiiropathologist, vibo has joined our research
center as a Visiting Scientist, le is parfcicularly concerned with
determining the nature of recently described nexirof ibriUary changes in
postaiorteia specimens of aasyotrophic lateml sclerosis and Parkinsonism
on Guam, and he will continue the genetic folio-%f--up studies of patients
and controls in the large registry on the Island.
Dr. Milton Alter who is con^leting a year of t3:aining in clinical
neurology at the Neurological Institute in Eew York has reported the
resvilts of a eoaiparative study of isultiple sclerosis prevalence in
Halifax, Hova Scotia, Canada; and Charleston, South Carolina, United
States. The prevalence is 2.5 tissss greater in Halifax and, for the
white populations alone, about 2 tisaes as ^eat in Halifax. There is
no apparent reason for the geographic difference. Dr. Alter has also
participated in descriptive studies of the epidemiology and genetics
of myasiaxenla ^avis and is reporting an uniastjal set of twins, one of
whom had myas-Qienia gravis .
Dr. Anthony Fens is developing survey procedures for a descriptive
study of cerebral vascular disease in the population of Rochester,
Minnesota. Records of the Mayo Clinic, the cooperating unit in this
Investigation, provide excellent coverage of diagposed cerebral vascular
disorders. Dr« Fons also plans a study on the prognosis of sub-
arachnoid hemorrhage prior to the present surgical era to provide
baseline data for comparison \7ith the surgical procedures now being
recoimsended.
CRp-2 ' k ' HIM)B - Epidemiology Branch
A neuyologie section ahoiild "be ready for organization at the end
of tMa year*. 13ie proposed head for the Section will "be available in
i960 ai^ in the interim, the Branch Chief will continue in this
activity.
Difficulties in recruiting an epidesniologist with training in
ophthalmology have again delayed -yae p3Poposed study on phlycteaulosis
in the Alaskan native papulation and the developaaeat of an ophtbalsjologic
epideniioloQr prograia.
Dr. Htinos Myrianthopoulos, geneticist, continues in his
investi^tions of Parkinsonism^ schizophrenia, and eas^rotTOphic lateral
sclearosis. The Parkinsonism study ia an attenipt t^ detesmine whether
there is a genetic laechaniss ia ■aie sensitivity or resistance to the
developiaent of Paricinsonisai hy phenothiazine ataraxic compcunds In
cooperation with the LahojE^tory of Blood Pxt^ucts, MS, t>se association
of hlood gi*ou!ps in patients with amyotrophic lates-al sclerosis is "being
evaluated. Dr. Myriaa-aLopoulos ia also carrying on a project with "the
cooperation of the Neurology Service, Clinical Center, to study the
existence of congenital anomalies in offspring of patients vith myotonic
dystrophy; there is reason to helieve that such anoiaalies appear more
frequently in the offspring of such patients than wotild be expected by
chance. He is also ptirsuing several other studies as follows: peroneal
teuscixLar atrophy (the question of penetrance and detection of the
genetic carrier state by nerve conduction velocity tests }j incidence and
prevalence of Tay-Sachs disease Mimng the Jewish and aon-Jewish popula-
tion of the United States from mortality statistics, and with Dr. Kowley
he has conpleted a repeal on a study of Hiantington's chorea in monosy-
gotic twins.
Ia addition to sevemL of the preceding studies in which he
participates, Dr. Kurland. is responsible for continuing the study with
the Kational Research Council and the Veterans Adiainistration on the
natural history of acute retrobulbar" neiaritis and saultiple sclerosis.
Data now available indicate that only about 8 per cent of patients witfei
retrobulbar neuritis develop ssultiple sclerosis 10 - 15 years after the
bout of acute optic neviritis.
(»P-2 • 5 - IJ2HDB * Epidemiology Breuach
The future program of the Branch is, ia large laeasare,
depeKdent on the orgssizatlonail structure of the lastitut©, the
sectional de^elojaaent which has teeaa reeojffiaeMed ^ad the assigEtnent
of space suitable for the cos&ined field laTestigatioas assd laboratory
programs in the Branch » If our space and organizaticaal Heeds ax^e met,
we csta suaticlpate an appraciable extension of our research, particularly
as this relates t=o geographic distribution and the clarificaticaa of the
role of eaviroim^Btal and inherited factors in the etiology of neuro-
logical and ophthaiiaological disorders » Our staff of experienced
epidezaiologists end geneticists will be prepared to e:q)lore, expeditiously,
situations of unusual incidence saad particularly geographic isolates of
disease as these are disccveredo
The close relationship of genetics and epidemiology in this
Branch provides unique ojrporfcunities for the simultaneous s-feudy of
populations, the individual patient, and biochemical factors in diseasec
It is prc^KJsed to clarify the interpl^ of envirosaent and heredity in
chronic disease and to assess the genetic endowment of populations as
these relate to disease predispositionu Tfee genetics program can be
e;^pected to provide in^ortasat contributions through the estimation of
gene frequencies and mutation rafees, the detection of heterozygous
carrier states, the elucidation of ^e seieeti'^e advante^e of genotypes
and the biochemical aud cyfeologie nature of tolierited disease « The
epideaiologic investigations ha-pe demonstrated a need for eas experimental
and clinical neurotoxicologic program in t-he Branch « FurtheRSore, our
field studies can be escpected to help complete descriptions of clinical,
disease since broad population studies ©re likely to uncover subclinical,
miniaal ®ttd atypical cases said unusual fasailisl aggregates yiiich are nos
obvious In standard clinical procedures.
In closing, it is difficult to reconcile the many disruptive
morsres and unsuited facilities assigned to the Branch with the tremeJEdous
cost and effort represented in the training eM ea5>erience of 'fehe
scientists vho form the nucleus of our exterjsive and soms^rtiat usaique
program. If ve are to attain the cosffplete fulfiliiaeat of the scientific
achie'^wsents of which we are cspable, the logistic supporfc of the
adntlaistrstive leaders of this Institute and of the lf.I»Ho is
essential.
OEP-2 wmm - Epidemiology B:eaneh
PUBLICATIOHS
Published or in Trese
1. Kurland; Leonsurd T.: "Hie Xacidenee and Prevalence of Convulsive
Htsar^isra in A Saall Urban CoaBmmity» Epilq?0ia, June, 1959
2. Sngel, Kingj KurlaM, Leonard T-j and Klatzo, Igor; An Inherited
Disease Similar to Aa^otrophic Lateyaa Sclerosis With A Pattern
of Posterior Colvmin Involveisent. An Intersjj^date Fo:Kia? Brain,
Vol. 82, Pea-b II, 1959, PP 203-220. ~™.
3. Kurland, Leoaaafcl T., and Alter, Stilton; The Current Status of •&€
Epidemiology and G€sietics of ISyasthenia Gravis. Accepted for
publication in Syn^siuia of the Second International Congress for
t^sthffinia Gravis »
k. Deacon, Walter S.; Aleissandeg', Leoj Siedler, Eovfai'd D.; and Kurland,
Leonard 7.t Multiple Sclesosis in A Snail Kew England CossEiuaity.
Accepts foi' Publication in Hev Englajed Joxignal of Medicine.
5. Fullmer, H. M.j Siedler, H.. D.j KSrooth, R. S.j and Kta-land, L. T.t
Desmal Changes in Patients Affected ^rith Amyotrophic lateral
Scleifosls. Submitted to Keurology for publication.
6. Maekay, R, P. aM Myeianthopoulos, H. C: Multiple Sclerosis in
Twins and Their Relatives. Preliminary R^ort On A Genetic and
Clinical Study, Arch. Heurol. Psychiat. 8O: 667-67)^, Beceaiber, I958,
7. %3?iQnthopoulos, N. C. and Maclmy, E. P.: Multiple Sclerosis in
Twins and Their Relatives: Genetic Analysis of Family Histories.
Accepted for publication by the American Journal of Human Genetics .
8. Jlyrlenthopoulos, N. C. and Pleper, S.: The ABO and SH Blood Groirps
Among the Chamorros of Guam. Aei. J. Phys. Anthrop«, June, 1959 «
9. MyarlantSiopoulos, H. C. and Bcwley, P.: Monozygotic Twins Concordant
for Huntington's Chorea. Acc^ted for publication by Heurologyo
10. lityriantljopoulos, H. C. and Stevens, H.; Genetic Counseling in
Medicine. Med. Ann. District of Columbia 28:256, 258, December,
1958. --— — ■ -~ —
11. Myrlanthopoulos, H. C.j Genetics and Public Health. Accepted for
publication by Public Health Reports.
12. Siedler, Howard D.j Kalter, Seymour S.j Thrupp, Laurie D.; Utz, John
Poj Pinucane, Daniel L.j and Parrott, Robert H.j Outbreak for
Type III Paralytic Poliomyelitis in Washington, Do C. in 1957.
Accepted for publication in the Aatericaa Journal of Hygiene-
mP'2 ISINDB - Epidemiology Branch
Ft^blisheti or In Press - 2
13= Sietiler, Hoxrard D.j McGou^, Thomas F.s Excess Congenital
ABonialies in AlesaMria, Virginia, Accepted for publication in
Public Health Reports .
1^!-, Pieper, Sejsuel J. asA Fields^ Williaia S.: Failux-e of Asiyotrophic
La-b«ral Sclerosis to Bespons to Intratiiecal Steroid and Vitasain B
Thes'apy. Heigology-y Vol= 9, lo. 8^ August 1959- -^
^^^SjU^ibli^'^^Jata)
15- Alter, Miitoni .Allison, R. S.; Taltert, 0. B.j K-<5rl0.nd, L. T.; and
God^n, J. 0.: Geographic Distribution of f^fultiple Sclerosis; A
Cotsparison of Pr^^'alence in Claarlesten, Soiith Carolixia, U.S.A. >
and Halifax: Comity, lova Scotia^ Caasda. To Toe -publx&hed..
l6» &ootli; P.ob©rfc S.: AEijotror^ic lateral Sclerosis and Cer-tain
Helated Ps-ofelsss on t^ Island of Guam.
17 «■ IJroo"^, Bobert S*: Soutlieast Asia Trip Report,
l8o OkiHsliS; ^iige<5| McAlpin©;, PoBglasj KurLasd. Leonard T,, et al;
Ths PrevBleaee of Multiple Sclerosis in lfos*tliGrn and Soutaem
JapaBj \ Description of SwevQjs In iSa;^oro. oa the Island of
HolJkaMo, sM ESsmssioto tm the Island of ICjmsM. To be pnblisiied,
19 <■ Alter, Miton, and I'albsrfc, Bheet. Msrasthenia. Gravis in One Meiaber
of A l^lonozjsotie TvdssMp. To be publislied.
American Spiaesaologic Society, April, 1959. 'Br- Kurland.
Cbaiiisan, GoKaaissioa on Biometxy and Genetics, World Feaeration
of ^«urology, Jiane, 1959- Dr* Eurlondo
Co33siL?.ting Etitor, World learolo©'-, Jime, 1959, Dr. Km-land..
Assn. of Military SiJrgeoas, Jime, 1959. Dr. Kurland
Cliaieai Assists,tit Professor, Heurology Sepaxtiaeat, George-torn
Uaiv€>rsity, iJsshington, U. C-, October, 1959= Br,, iCurland
CX?P-2 WnBB ' Epidemiolo^ Branch
PHS-NIH
Individual Project Report
Calendar Year 1959
1. Project Title; Investigations of CbamotroB on the Island of Guam
Princip al Investigators; Leonard T = Kurland
Hobert S= Krool^
Asao Hix=aQO
Samuel Jc L. Pieper
Jose Torres
Other Investigators; James H. Pert, \iaeriGan Hed Cross
Ho Eldon Sutton, Department of Huaan Genetic
Univ. of Michigan Medical School
Oliver Smithies, University of Toronto
Medical School
Coopeffating Units; Departiaent of Easmn Genetics, University of
Michigan Medical School
Connau^t Medical Kesearclx I^bosatorit^s,
University of Toronto
Man Years; Total » 3 3./^
Professional - 1 l/U
Other - 2
Project Pescription;
The pheaoiaenal incidence of s€vei?al disorders among t3iae ChsmoiTos of
Guam offers, in this rmique and isolated setting, an eatcelleaat oppor*
tunity res' clinical, genetic and spiteHdologie investigations » Major
emphasis continues on aiayotrophie lateral sclerosis j other st'adies are
uMerway to delineate an organic 'brain syntoome yesetabling ParkinsorAiSiE..
Jakob-Creutzfeld-t disease and presenile dementia « Diaphysial aclasia,
gout anfl d-iabetss also appear to "be unduly pi:^valent amel px^limia&ry
studies of -^ese cliEorders are undenmyo
Aiayotrophie I^tes'al ScleT-osis
A registry v!b.s compiled of the immediate relatives of a ©roup of
proven eases of aayotrophic lateral sclerosis,, and -Uae iEusediate
relatives of control persons kno^m to be free of the disease but matchec
to each patient by age, sex^ and village of residence. A genetic
analysis was then performed on this registry to determine whether MB
was occurring with escceptional frequency among the relatives of affecte.:
The analysis revealed, that 1^e patients had about ten times as 5mny
living affected relatives as one would expect if there were no fasaily
concentration of the disease » Moreover, the patients had si^iificantly
Project 1 .» 2 - Nn®B • Epidemiology Brancsli
fewer living relatives than the controls, and the living relatives of
patients averaged significantly yoimger than the living irelatives of
controls. It was possible to show that the patients had fewer living
relatives in age g^roups where the mortality from AIS is hi#i, suggesting
that members of the patients' families may have been selectively
eliminated by the disease o
Neurc^athologlc studies to date, perforiEed in collabo??ition with
Dr. Nathan Malamud of the Langley Porter Institute for Neiarcrosychiatric
Research, have revealed in both AIS and Parkinsonism patients, a neuro-
fibrillmfy change which is unaccompanied by senile plaqties and xitoich is
widely distributed in the brain. This finding is preliminary and is
receiving fur^er study »
Cooperative studies on tbe bir^efcoiaistry of ALS and Pa^tinson's
disease Includss
a) Tirine chromatography for amino acids
b) starch gel electrophoresis of the seriaa proteiiis
c) starch gel electrophoresis of -Oie ces?ebrospinal fluid roteinc
yi'ih. respect to amino acid ehroisato^sphy and electroplioresis of
the serum proteins, the restslt revealed no essential difference between
patients and controls « The data on the cerebrospinal fluid i^rotein is
not yet available.. These investigations have yielded, as a by»productj
some interesting biochemical data bearing on the anthropology of the
CSiamorros of Guam. Detailed l-amunogenetic studies ■'.^ere performed on
100 Chamoawtss and the rate of isonieotinic hydra zidg inactivation was
determined on 20 of these people to help furtdaer cbaracterizo the
Chamorros as a people.
The high prevalence of ALS offers a uniciue facility for therapeutic
studies = Baseline life expect;ancy and profession of disease rates
are available. Trends of new lirugs are readily accepted by -the affected
popxilation and their families* Among recent trials report.sd are the
unsuccessful tests of intrathecal cortisone and vitamin Bjg ^y
SA Surgeon Samuel Pieper and Dc. Wil3.iaa Fields, Baylor University «
The us^of the Guam Research Center in other investigations are
described in Project No. 2, "Darmal Changes in Patients With AmyotropMc
Lateral Sclerosis."
Parfeinsonisai
The incidence imy be Mg^ but is still uncertain for an organic
brain syjidrome characfcerized by increased rigidity and tremosr but
differing from the usual Park.i:ason'.s disease in its earlier age at onset,
its more rapid course, and frequently observed dementia. There are
numerous instances of family history of ALS in these cases mid of
"Parkinsonism" in ancestors of ALS patients. The interrelationship of
PSfoJect 1 - 3 •» . NIMDB - EpMesaiology BJfan^li
these aisord«TS and of presenile dausntia and Jakob^Creutzfeldt disease
is being intensively studied by Bar, Asao Hi?ano, Visiting Scientist
assigtieS. to the Research Center on Gnaiae
fii genetic study of "Parkinsonism", with l8 patients and l3 coats,'olG
on the registfy, has also been developed. Hers, however, tJse x^stdts
were more equivocal than in ^e AIS cases, due partly to i^ie small sais^le
SiSSo
'She Paxtinsonisa ajid ALS registries are being continued for 5
years to acciJiaulate further esperience on the genetics of tfcese diseases o
A study of the effect of artene on t^e aysdiaftokineeis of
Parkinson's disease was coi!5>leted. A haaa. punch counter yraz ussd to
recoM the sa^iBaum number of voluntary thiaab ia3ve!2sents over a 30- second
intervals No effect of orally administered artene on the patieats'
scoj«8 -w^as noted over several laon'i^, or on tlis hourly scog€;s folloving
a single parenteral, dose. Similar results vere obtained with
dextroasphetasine, atjropine, and a placebo ( aeetylsalicylie acia)o
Diaphyseal Aclasia
Genetic studies were eararied out on diaphysial aclasis, a xare
disease, due to an autosomal dominant gene, and cm-,racteriz©d by multiple
usually benign osteochondromata. 21 living cases of this disease,
involving 7 faiailies were collected on Guam, reflecting a prevalence
which is almost certain to be far ^»eater than any previously noted., A
number of interesting findings have been obtained from tbe dsta^,
including the sudden appearance within families of tumors at unique
sites o The X-ray films on the patients are now being reviewed at the
lational Institutes of Health.
Otfeer Disorders
Prsliainary clinical and statistical studies on gout and diabetes
were also started en Guam in cooperation with interested Eiember'S of
•aie NIH Staff,
PART Bo
Pieper, Saeiuel J. aM Fields, William S»t Failure of suayo trophic
latesal sclerosis to respond to int:^s.theeal steroid and vitaMn
B^ therapy > Setirology, Vol. 9, Efo. 8, Aijgust 1959 »
PAST A»
^0 Frojiect 'ntle: Barsml changes in patients affectei wltfe
aE^othropMc lateral sclerosis
PriBcipa,! Investigator: Dr^ He Fullmer
Other lE-vestigators : PTo He Siedier
BTo K« So Krooth
Sr. Lo T. KurlaM (NIHPB)
Mas-Years t Total - 1 l/k£
Professional - 1/2
Other - 1
Project Bescriptioa:
A large jsusaber of skin, biopsies aat skin froia patients with
ALS aM from coatrols ■uere staiaed by the peracetic aeid-aMe'-.y e
fuchsiB"Haliai xaetbod recently developed by Fuirunerc The
ffiajority of ALS patie»ts shoved cha^iges lu, the dermis of their
skljEo fhe moss specific of these chaiiges involve the size
acd morphology of coilageR fibers o It is believed that the
patieats have 'ix)th aa increased rate of elaboration aiA axt
increased rate of destructi-on of coilageso
The coasges noted were not uniformly present over the whole
iKtegument^ anl seemed correlatei w.lih the clinical severity
of the disease^ It is not at present knows whether they
reflect another facet of the basic »iiseaae process, or whether
they are purely secosdary to the muscle atrophy 5, neuronal
■degeiaerationj, etc. Investigations on this last point are
contiatiing^
Biblications other than abstracts from this project:
Fulljaer^, So Mo, Siedler^ Ho D., Krooth^ Ro So, a^ Kurlemi^ Lo Tc
(l959)o A Senaal cosaaective tissue (Sisorter ia aisyotrophic
lateral sclerosis o Preseated at meeting of American Acafteaiy of
Neurology ant submitted for publication in neurology ..
iJiaxTldiial Fro,}ect. Bepcsrt
CaaeMar Year I959
TP^ Ao
3<, Project Title: The ABO aM Kb. BIoqA Groups Aiaong the
Chamorros of Guam
Principal Investigator: No J^riantJiopoulos
Other laves ti^^ator: Samuel J<, Lo Fieper
Mam -Years : Total - 2/32
Pirofessional - 202
Project BescriptiOG:
A study to detersaine the pfeenotypic and geaotypic frequeiaeies
of the ABO aM Rb. groups axLcng the Shaajorros of Guaac,, wltb
enrphssis on anthropologic aad genetic iarpllcations <>
fhe low frequency of Rh negative blood smong the Chamorros
casts some douht on the hypothesis that aaDyotro|^,e lateral
sclerosis oa Guam -was introduced from Spain ahout I7OO0
PMg B.
Myriaathopoiaos^ K. C. aad Pieper, S«s, Jr, IJhe ABO and RE BlooA
Groups Among the Chisaaaorros of Guam vith Reference to some
Ajithropoligie osA Geaetic Problems ia the Area.
Accepted for puhlieation "oy the American Journal of Physical
Anthropology J June 1959 *
XBQlvidual Project Heoort
Gslern^ir Yeax' 1959
?mJ! Ac
k.. Project Titles The Association of Blood Groups to .Aa^otropM.c
Lateral Sc3.sr<3sis
Pri,:aeipal Investigator: H. Mys^-anthopoxilos
Other lavestigatoys: ?. Schmidt, I£BP
IjeonaxcL T. ICurland
Cooperating Units: Laboratory of Blood and Blood Products,
Division of Biologic Standards
Man-Years: Total - U/32
Professional - l}-/32
Project Descifiption;
'\ pilot study to detenain® if the3r« exists any selection for a
specific blood type ainong patients? with a motor neurone disease.
Preijent Status o The nsedieal facilities of the -Army, Navy, Air Force
and Veterans Administration, the Guam Research Center, and vaaxxy
practicing neiirologists are participating in this project "by providing
blood and saliva specimens for analysis. Specimens from about
400 cases anci controls have been (collected «
Hone
Calendar Year 195;
5c Project Title: The Effect of Climate snd Othar EnviroaBxeatal
factors in the Prognosis of Multiple Sclerosis.-
One Aspect of A Broader Iix-vestigatiOEi of the
latural History of !&ilt-lple Sclerosis (Ool-
laborative Pit5,jeet)
Priacipjil Ixf^^estigator: Leonard To Kuxlasjd
Othei Investigators: Gilbert Beebe aM Deaa Hefageri, Follow-up
Agency ,5 Hatioiaal Research Council
J» F, Kiirtzkej, Cbief^ Meurology Servlce^-
Vo Aa Hospital^ Ooatesvlllep Pemasylvauia
Thomas Auth^, Heuroiogy Bepartaeat^ Yeteracs '
AdBslaistrationj Wasbiiagtoni, So C.
Beneilet lagler^, formerly Veterans' AAmiffiistratios;
(aow I^Tsehburg Training School pisd Hospital^
Solon;y,s Vir^Ma)
Cooperating Units: Follow-up Agency^ latioaml Research Council,
Washingt^il^ B. Co
Yeteresjas ' A&iilnistration^ WashiEtgtoni B^ Go
Maa-Yea;cs: Total - 1/4
Professional - 1/8
Other - 1/8
Project Description:
Retrobulbar neuritis has been reportei to progress to njultiple
sclerosis in 45-50^ of affected iMivi,4uals within 10 to 15 year^o
It hiiiS. been hoped, that corre3.atiOB, of residence with RBK uiight
show x^rhether some eiiiaatte or residential status influenced
pro@iosis w:Ltfe respect to EBJltiple sclerosis c
In the large population of military per r.oaiiel with RBH^ i9i!-0-1945p
only about 8 per cent have devej.oped Mo So to date^, according to
Vo A.' records o Physical esaaainations of patients to vertfj' this
is requiraio If the incidence of Mo So is as lov as the ^h Ao
reports iKiicatej the main objective of the investigation cannot
be acihieveS. but the low incidence of Mo Sc, will be worth reporting =,
The pi-oject to analyze other factors in the Natural History of
Multiple Sclerosis is continuing »
PART Be
lone
CRp^2 NXKDB - Ipiismiology Erancn
PHS-KIH
Individual Project Eeport.
Calendar Year 1959
6. Project Title; Epideoiiologic Investigations of Multiple Sclewsis
and Other Keusological Biseiases in Charleston
Cotmty, South Carolina, and Halifax, Ifova Scotia
Pyincipal Investigators Milton Alter
Other Investigators; R. S. Allison, Heupological Bepartaassnt, "Boy&l
Victosla Hospital, Belfast, Ireland
Rhett Talbert, ProfessosF of Sevu^tslogys Medical
College of Sou-Ua Garolixsa
John GoMaxd, Asst, Professor of PKwaative
Medicine, Salhousie University, Halifax, K» S.
Leonas=a T» Kiirland
Coopei'ating Units; Medical College of South Caroliaa, Cfearlestoc;
Balhousie UnivefBity, Halifax, H« S.
mn Years; Total - 1
Professional - l/2
Otlser - 1/2
Project Description;
The incidence and prevalence of msltiple sclerosis and othm' diseases
of the nervous sys-4em va© det^jrajSned for ths popx^lations of these t-^fo
communities. 3)ata stx-e Ijeing analyzed and reports ere being p^separe'l oa
the frequency of multiple sclerosis, sa^s-^eai© gravis saS. otheif disease.
of the nervous sys's^eja in the coEsmunities and for subgroups of th^l?
respective popxilations .. Clin:>cal repos?ts 'basea on wrastjai ca.s©s dhser'rs'-
in these comtaunities are also lieing prepare » T^se include a st»M ' : ■
CQraistheiiia gravis in twins and an hereditary cere'tseilar ata5a.a vitii
cataract fojRaation.. Multiple scleg^osis pysvalenc« is sXiont 2.5 titaes
grea'ter in Halifsuc than in Charleston^ Tfa® -i^ates f<w ths vMte popu3.s»
tion alone as^ about two tiaes as great. ¥itlxia ©aeh coassomity theTS
is no clear cut sacial se3.ection for ihs diaeass.
PAEP Bo
.Mter, !4irfcon, A:.iison, R., eu, Talbert, 0.. H-^, Kijriand, L. 1\, aci
Godden, Jo 0*; Geo^aphic: Distrilnstion of l^xltiple Selssosis; A
CoErpasdson of Prevalence in Chsas'leeton Co-oaty, South Csjolina, U.B. A
and Halifax Co^mty, Kova Scotia, Canada. To be pabliabed.
Alter, Mil'fcon and Talbert, f!h®ttr. ?-?j=ms-M£enia GxtirlB la Or.e l^leasier
of A Monozygotic TwinsMp., To "be publishsd^
Eurland, Leonard T. and Al'ter, Miltos; Th& Qitffmmt Status of the
■J^pideffliology ard Genetics of My^iBthmxia G/^^viSo S^^WJOSiuia of the
Secoci^ Isterxiational Corigr-ese for I?lj?as taenia Cr3favis„ Ik. pr-sss.
CKP-2 riMJB - Epidemiology Eraisch
PHS^HIH
Badividual Project Eep&rt
Caleadar Year 1959
PART A
7, Project Titles The PremLeffice aad Incidence of Multiple
Sclerosis in Duxbuxy, Massachusetts
Principal lii'Wgstlgator: Howard Do Siedler
OtJier Iai?estigatorss ^felter Deacon, Diix"bury, Massachusetts
Leo Alexander, Bostoa, Massachusetts
Leosiard To Kurlaad
Man Years; Total - 3/B
PS-ofessional « 1/4
Other " 1/3
Pjpoject Description:
The preliialDary investigation of th@ frequency of nmltipla
sclerosis in Duxbury, Massachusetts^ was determined because of
the suspected high frequency of Mo So aioong its realdentso
Although the incidence end prevalence are high, the factor of
chance in selection rather 'than local en-^roBH^irlal situation
esnaot be ruled out., Further studies in the vicinity of
Buacbury aad soEa additional genetic investigation in this
region are indicated.
FMT 3
Publications other than abatrascts from this project:
Deacon, Walter Eo; Ales^adar, Lao; ■ Siedler, lo^-ard Do and
ICurlismd, Leonard T: Multiple Sclerosis In A ^isall lew J&^gl@ad
C(K!sauaity. To he published is The Sew Saglaad Journal of Ifeclieiae.
PES-ffiH
lBdS,vl3,ua3- Brojeet Report
OalmAa.x- Tear 1959
"Bms Ao
8c Fx)ject Title: Multiple Sclerosis in 3M.33S aM Their Relatives
Pzlnc:.pal Investigator: R^ F, Macfe^yj Uaiversity of I3Ji-nois
Other Investigator; 1.. M;jTiantliO|»oulos
pej.-atiag Ageacies: University of I13J.noia
Maa-Yfjars: Total - 8/32
Profess ioxaal. - ^2/3 2
Otl'ier =• 6/3^
Projetjt Bescrtptioa:
To detenfiise whether as^ hereditary factors are involved ia the
caiA3a.-';iOB of Dsiltiple sclerosis by atudylng the oceuiTence of the
diseasje aaiong .'oaoaygotie aiid dlxygcjtlG t^jjs eM their relatives c
The t:a-st phe^o of the stiidy wes coBjpleteS in 19580 The second
phase.. %fh3.cfe will iiavolve the reexasjinatioja of all tarinsy will
begin ia. 1901.
Mackaj/^; Ru ?„ e^ad l^^riaathopoulosj, Bo C* Multiple Sclerosis in
Twins aafl. their Relatives . PreliMtiasy Report on a Genetic and. .
CliEieal Study.. Archo leurol, Psychiat^ 8O: 007 -674^ 1958 <.
Myrisijthopoulosi, M^ Co aM Mackay^ lU P J Multiple Sclerosis in
Tvins aM their Relatives: Geaetic Analysis of Family His-cories.
Accepted for p^^bliGatioa 1^ the Americtm Joura&l of Human Genetics
KIMSiB - Epiaess54oiogj- Branch
PES-KIH
ladividual Project Report
Calendax" Year 1959
PART
9, Psoject Titles Cerel>ral Vascular Diseases; A Stt^'- of TheiJ^
Hatural History in th© Popiilstlon of Rochester^
Minnesota .
Principal Investigaton Anthony Pons
Other Investisator; Clark Millikan
Cooperating Unit; Mayo Clinic, Hochester, Minnesota
imn Years? Total - 1 I/32
Professional - 1
Other - 1/32
Project Description:
The tuaiqtie coBOunity taedical services facility offe?ea "by the Mayo
Clinic and its affiliated hospitals will pyovicte almost con^lete covtja
of diagnosed cerebral vascular disorders in i«itients and at autopsy.
Past medical histories are un^asually detailed and eccusate; follow«irp
facilities s.v& excellent, A descriptive study of variotss clinical aaa
pathological forass of cerebral vasciilar disease aisS: details on selec-
tivity by population characteristics will be carried out firsts
Studies on prognosis of subarachnoid hemors^hage prior to the present
surgical era -vrill be nsa^ to provide baseline data for cossrpsrison with
various surgical procedures new recommezided. The relationship of
cerebral vascular disease with past medical history and pax-tieularly
with other vascular diseases will be determined.
{»P»2
IndividuQl f^Ject Report
Calendar Year 1959
PART A
10» P^ject Title: Paralytic Policsnjrelitis end Aseptic Msnliigitls
Syiidr<ai^ jUa Washiagton, Do Co^ and Sarrouadlng
Counties Durlag 1957
Principal Investigator; Howard Do Siedler
Cooperating Agencies: Do C^ Health Department
Ifen Years: Total » l/2
Professional » 1/4
Other » lA
Project Description:
The report of studies concea:*nlng paralytic poliomyelitis aad asepf^fiic
meningitis syndrome la Washtogton, Do Co and surroundiiisg counties ia
1957 > has "been cjMupleted, The outbreak originated la a small
Southvest quadrant of the city where the population is psrsdondaaatly
negro and of lower socio-eccncHoic staadlngo Paralytic disease mani=
festsd a marked selectivity for preschool age chU-drea frau this
group, the saae pattern obser^ved in the Chicago 195^ epideaiCo
Aseptic meningitis syndrcMe in the Washington group vas belle-rod
to l>e associated ia the majority of patients with polioviroso This
syndrmie in the county ^xjup was associa'feed with polioTdrus to ojaly
1 of U instaaicss where vtral cultures were positive o
P^_B
Siedlar, Ho%'®rd T.; i&dter, Sayiaaur S^ 1!hrupp, Laurie D,; Ut2, Johii E;
Fiaucane, Baaiel L^ and Psrrott, Robert He Outbreak of Type III
Paralytic FolicKsyslitis in Washington, Do Co in 1957« ^or publica-'
tlon in ths Ajasrican Journal of Hygiene o
I»x.K?;'B - yiT^iixernxoxog;/ xsraa.c
PE3»1IH
In'ilTiauall Pr'Oject Report
Calv'Bdar Year 1959
PART Ao
lie Project -Title; gvaluation of Fossibie Teratogeaic Effect of
Asiem InflueD.Esa Virus (Collaborative Project)
Prineipal Ijivestiga.toi': Leonari T„ Surlasd
Other Investigators: H- '"^'d^^teiu,. Biosaetrics Branc-la, K.ISDB
Howarti S. Sit>dler
Sta33ley Ho Fjiro
Cooperating UMts; 7 Cooperatiag Universities and Eospital«
Joims Hopkiris
University (>f Peimsylvania
l&iiversity of Ohio
Baylor Univtirsity
Charity Hospital
Hartford Hospital aad State UniVo of -
Hev York Seljool of M^lcine
IJniversity of MarylaM
Maja-Years: 5?otal - d
Professioiial - k/'id
Other > 1 7/8
Project Biescriptiom:
Certaia vinxs infections during early pregjaaacy sire knowji to bave
an asiverse effect on tlie fe-tiis= Tlie Asian influeaz,a epiciemic
offered ao. uaiisuai opportunity to assess the teratogenic effect,
if aj3y^ of this strain of influenza virus c/ Mstories ha,Ye been
collectet and serological specisieni) have been obtained from about
S^aOCK) wcHnen in 15 centers., For the purposes of this stusly the
M-stories aM sera from mothers of affectet offspring aM controls
will be evaluated; those from 3^500 mothers in ^ m^lcal c eaters
will be utiliaei for the sttidyo
All bloods have been analyzed aM all histories received; coding
shouM be finl,sb«i by Jajauary of 19bO and the report sho^ild be
completed by y^xt Springs
PART Bo
Hone
XISHSB » Spldsffiloiogy Brsach
it Report
Calesatfer Year 1959
gfeM'_A_
12=. Froject Title: Sscess Cosgealtsl McKaalies %n Alesaadris,
¥irgials
F^iscipal Savestigator: Ecfuard D» Siedler
Ofcher investigates-?! ^Iw^as F- McGoiagla
MsK Years: Total - 8/32
I*rofessiOBSl - 2/32
Ofehex" » 6/32
S^jeGt Isescriptioa:
In Felarusry, 1959> there were 12 iafaats reported to h&ire been
borB "irith. coageaitaL ^icEialies ia the Alexsadria, Virginia,
Hospital amossg a to-fcal of 303 deliveries » The source of these
repojris ^as routine birth certif ica^riss o This abrupt increase over
the lujual nsoathly esqjerieace prcgE|»ted sa inirestigatioa 'sdaich
ceatered afcout correlation procedures with other e-^ents of the
prenatal period and probability of this iBcidence of aaasslies
oecurriag by chasiceo
Resent Status; Eie project has been ccsspleted and a report has
been prepared for publieatioQo
TMT B
Sledler, Ho^ar^ D} JfcGough, Thcaas F: Excess Congenital An<»gslies
ia ALeasadria, YirginlSo (Accepted for publicetloa in Public
^slth Reports o )
Individual Project E<gpo5H
Celendsr Year 1959
PABT A
13. Pro.j€rct Title; Experimental Studies of the "MlnaEsata Disease"
Principal Investigator: Ifionard T. Kurland
Other Investigators: Stanley K. Faro
Gert Lacgtier, NIAi«i>
Olaf Mickelsen, BIM^
Howard D. Siedler
Cooperating Units: lational Institute of Arthritis and Metabolic
Occupational Health Ps^gram, Cinci-nnatij OSaio
Cbesepeake Biological Laboratcry, State of
Masylarxd, SoloiKjns, Btoylajid.
Texas Gaass and Pish CoBsnissiQn., AustiHj, Texas
Msn Years: Total - 12/32
Professional - 6/32
. o-ther - 6/32
Project Bsscription:
An unusual neurological illness attacked at l^ist 75 persons in fishing
villages near Minamata Bay in Uyushu Island, Jacpan, between 1953 and 1956»
It was manifested by numbness in exbyeraities and a^ouhd tiae mouth,
slurraS speech, unsteady gait, constricted visual fields, pro^esslve
aaientia mjd psyehoais. Case fatality vas 35 per cent; all affected have
peisnanent neurological or intellectual deficits. As a result of
epideffiiologieal and other studies made by Japanese scien-t'sts, it \fag
concluded that the cause of Minasaata Disease was probably a toxic
chesdcsl cor^ound contained in tb@ effluent which flowed into Minamata
Bay from a nearby factory. Recent Japanese investigations suggest that
an or^aic nsercViry coE^ound used as a catalyst in vinyl chloride produc-
tion may be the cause of Minamata Disease. It is believed tSiat this
coBipound is either formed or concentrated in shellfish aasd other iaar}.ne
life when the usercury compound is ingested by the laarine organisms.
This disease is of interest because it may aid in -^e understanding of
the mechanisms of toxic encephalopathy. We are conducting feeding
eKperiments with shellfish from Minaiaata Bay provided by scientists at
the University of Ktjmamcto, Japan, to help establish the exact cause of
the disease. Studies are also underway to coopare the raJjationsMp of
the seafood poisoning and organic Hg poisonijig in animals.
Project 13=
Ths'^e is reason to ■believe that ia the pjodraction of viayl daloride in
the United States, Asjerl-can industry has taken Qxtrexas precautions tc
pi-evsiit contaaij^tioE of nearby wa-fcesis used foy eosmaarcial fisMng. • If
this is clearly eBtaKliEhe&, knowledge of these risthods of iteiadling toxic
agents -"ifill lae transmitted to auidiorities in Japim concemei with
■previsnthxg say s^cxiryence of the epifismic there.
CXiP-2 NBSB - l^Memiology Br-aaca
fhs-jtih:
Individual Project Report
Caleadar Year 1959
PART A
Ik^ Project Title: Piilyctenulosis in Alaska Hatives
Principal Investigator: Bobert Phillips, AHRC
Other Investigators* Joseph Shelton, AHSC
Leonard T. Kurland
Cooperating Unit: Arctic Heal"^ Research Center
Man Years: Total - 1/32
Professional « I/32
Project Description:
Corneal scars from phlyctenules is are present in aljout ko per cent of
th© Alaska native population. The distriljution writh respect to
geograpi^, diet, incidence of otitis i^dia, the rat© of txibef^culosis
infection and trlTsal cxistoas^ is to "be determined. The incileatsl
effect of prophylactic isoniazide on ih.® incidence rate of acute
phlycteraolosis will "be stvidied in conjianction wilii the ctirrent study
on prcphylasis in tuberculosis. This project was scheduled to go.
into Its full-scale program this year but has been de3^yea h-seause of
difficulty in recruiting aa epidezaiologist with experience la
ophthalmology .
EI1KK3 - Spidesiiology Braach
FHS-NIH
ladiviclual Project Report
Caleadar Yesr 11959
15,. Pro^iect Title: Study of the toeideace and Geograpbic
Distribution of Uveitis
PriBcipaL Investigator j Stanley II» Faro
Ofeh-er Investigators: B&nrj Po Wage-ier, Ms^o Clisiic, sad
Leonard To Ka^laad
Coop8rm.tSas Unit: Ths Vetereas Mm:iDistration;, Washo, D, Co
Btei Yaars: fbtal - 3/32
Professioaal - 2/32
Ofelaer « 1/32
FroJ®'3t I^scriptioa:
Biera have lieeii few stMies reported on the Ineideace, preimlence
and drlstributioa of UT^itiSo The iiicidence for several rsGent
yeaars ia the population of Rochester, Miimesota, vill be determined
thyouf^ the records of the MB,yo Clinic 0 Plsms are being developed
to study the geographic distributioji tram, aetionwide ?A Hospital
disehi^ge data.,
0RP~2 HMDB - Bpidaiaiols^y Braacb
Sadtviduaa l¥oJect Report
Caleadar Year 1959
PART A
160 Project Title: Applications of The Teclmique of Tkm Tissue Culture
to Bfetabollc Problems in Selected Geaetic
Diseases
Priacipal Tjavsstigator: Rofeert So Erootla
Colleboraticg lovestigatora : Dr,. H. Eagle (NIAID)
Dto J, Daroell (HIMS}
Man Years; Total - I/2
Professional - l/k
Other - 1/4
P3P0,ject Description:
In 195^ ^ook and Kbsfes^n first suggested the vsln® of the teehnicjue
of tissue culture In human genetics » based oa tbeir es^rieace
with infantile geisetic agrsaiulocytosiSo ffe© teclaaiqus for sigasipu-
latiag cultures and •ttie ehemieal cc^jgjositioa of the raedia .ha^vs \>®en
developed so that it is feasible to inquire into the ^t^alie
properties of a nusaiber of genetic diseases «
At the present tisae, actively growiag tssrrcm ssjd ©Isia cultures
ere being leaintalned from, patients id.-Sh hereditary aeui-olojical
diseases ^ well as frosi patients with certain E^tabolic disorders .,
Howe'^er, the technical i^rfeetion of skia cell cul.tm*e r»iil req.'xli:--3
considerable ^rorko We hope to detect the ®ccu®iaa.tion in ael3,."
cultures of visible in-feracellular Bje*babolic aseretioaso Wa are
worki)3g ^th Gaucher 's diseases and cartaia othex- M.stoc;ffc;ic aod
lipid storage states 0 As of this writing, howeTCr, <mr ijsaediate
inte3rests continue to be ccmceraed vith psrfectioa of '©eclSKlqusc
PART B
QRP~2 HUB - EpidsEdalogy Brsmch
ras.KiH
Indi¥i<fual PS*oject Report
Calendar Year 1959
PART A
17o Project Title; Possible Association of High Beta«isoai(5l2iobutyr3,c
Acid Bxcretioa With Gout
Principal In-«mstigator: Robert So Ifrooth
O^ier Zafesl^tors : Dr. Jo Eo Seegmiller
Dto Ao Grayzel (HIAMD)
Dto Ho Eldoa Sutton, UniVo of mcho Ifedo School
Maa Yeaj-s: Total - l/k
l^fesslosml - 1/8
Other - 1/3
Project Descriptloa:
Beta-isoaalnobutyric acid occtirs es aa intermediate ^:x>duct in the
physiologic degradation of th:yHlneo It imy also oscur as a metabolite
of vsline though at present this pathway appears l^sss certa:ia and less
ia^rtmit than the fortaer one. The ssaouat excreted appears to de*
p^d in each case upon the blood level, ^ich in turn is a function
of the total miseible poolo m^sthsr one is a high or a low
exsretor is largely independent of Bge sad diet, and appears to
be meinTiy genetically determlnedo ISae fensal geneeics, however,
havesot yet been satisfactorily worked outo
Persons with polycythemia vera, leukemia^ asad ceart-ein other
neoplastic diseases ^id mongoloid idiots (^ho ha-y© a high incidence
of leukemia) put out ^ery Isrge quantities of the asid, ^^j^B^^
irrespective of their genotype <> Probably one reason for tntls is
that ijidlviduals vho tiim over cells rapidly h&-ws a, M.gjQ. ra-;e of
BIA tujrno'VBr, end thus a high rats of thymine degradationo A high
rate of thyiaiae deigradsition sway result in elevated st-eady s'^iate
pools of intenaediate iihyaine iset^olites Includisag. perhaps bet^.'*'
isoaaiinobutyrle acid*
Talbot has resently urged that about 10 percent of all gouty
patienta he sees ev^entuaHy deireiop a neoplastic disease, parfeicularly
neoplBSBis of blood o Presumably tiie jj^ehanisa for 'fchs hypeniricemis
here is tike ssass as that postulated sbo"veo
Project ITo «. 2 - WWB - ^i&mtology Brsmcfe
M effort is now "beiag iE»ds, ia coUaboratioa with the
investigators listed, tot
1} cOT^jsre the frequency of high beta-isoaaaiao'butyric acid
exeretors €unc93g goaty and noB-gouty patients »
2} coegsare the cliBlcal said gesaetic features of the disease in
high sad low excretiiag patients ^th gouto
3) follow high wad low excretors with gout prospeetii'sly to
see if neopl«fetie processes occur vith different frequency
in the two groupSo
If this amino acid is elevated is blood asad body fluic:^ tAen
WA turnover is Increased, then it may eveatuelly prove useful, in
the esrly detection of certain ttuaorso Recent techniesl developc^nts,
notatoly intproveaaents in the Stein-Mose colunm, may boob, mske accurate
detersalnation of the acid la the cerehrospiaal fluid feaail-iao la
this eircuiastsBce;, levels of the acid Eay one dey casplejgexit exist-
ing diagnostic raethods in the detection of scsae ©f the iati^acraaial
tuiBors^ However, such possibilities cmx he approached iJlti:
greater confidence ^^len more is kao^a about the asatabolic figaifi"
essiCQ of the acid in diseases where the tuJiior freely ccassjEdeates
with the peripheral blood .^
Ae of this writing, l8 goaty patients and three psrsor js without
gout have had urine chraaa-feography in S^o Sutton* s laboratory o
CSaly ts?o patients (both gouty) bad an elevate excz^tion of BATBp
Of theg® two, one patient had polycyth^ula imra vith sec^^cjsry
l3Q?;^ruricemia and gout, thas illustrating tJaa associstioa c»f high
BAIB excretiraa with blood aeaplasas» FoUoi^isig the exclusion of
this patient, the ftrequency of high BAXB excretors sacaag p£:.tients
with presuB^d priiaaay gout is one out of seventeen, which is of
the sejne i^sgnitude as the population f^cequeacy in this couiitryo
lo other abnormalities distinguishing the urine ciMfOiKitograffis
of the gout patients frtm th© controls has thus far heen EC;tedo
She chsxrastograJES are still being revie^aedo
PAHT B
Hose
mB'2 wmm - Epidemiology Bs-aach
EBS~ISIH
Infiivlduel fz^oject Report
Calendar Yem- 1959
P.ABT A
l3J4*oj8ct Title: Relatioa of Ability to Tast© Fheayltiiioures sssd
Related Cai^jounds to ^EbigToid Disease
i»rlHcipal Investigator: Robert So KrootJa
Other lavestlgators; Dto' To E^ Rail (KAMD)
Dro Bersiard Witlscip (NIAMD)
Man Tears: !3[?otal. - lA
Professloffi^ « l/8
Other - 1/8
Project Description: •
Twenty-five yeasrs ago Fes discovered that sc»!S persoas are able to
tafflte phenylthiourea CaM esrtalssi related cct^oux^^} while others
ceamoto Shortly thereafter Blskeslee and Sayder sho^^ed thet
inability to ts^te is largely detex-miHiSd by a recessive Msndslisn
gene.. la tfc.© past 15 yesars E^uffierous ia^estigators fea-^a fouM that
isBs^ cci^?ouir.ds in this fsiaily ha*v-e a^raci^le ®at4tl^?roid activity
end soais occur nstuxeliy in f'oodo Eeceatly BsstIb ead KaJjsos (in
19^9) ssd Kitchin, lo«el»SvaKjS, Clarke, eejd ^Cosnel Cia 1S59} have
noted that non-taeters occur with -ondus frequency msisag patients
vith aoB»to:ctc goiter o The latter authors havs noted also that
tasters are escceptlcnally ccKaaoa smoag patients with diffuse toale
goitero Qae possibility is that th<& trait causes-^fferences in
dietary, habits v±f^ respect to aaturaLly occurring goltrogeaso It
seaas sore lik®ly.^ hoiisver, that scsas imii'^.duals (tasters } taste
tl^se coa]S'Oimd0 because the ceHs of their bodyj, including the taste
Tjuids, ffistabolise tMourea-lilcs substsoscss dif f eren-idy ■ ^roaa son-
tasters « Differences in the s^taSjolisai of this class of dietary
goitrogens may esqdaia ^isy n£ai»t®stsrs appear sugeep'fci'hle to aca»'
toKie goiter '^id tasters to tozic thyroid disfeisssc aus (in this
case at least) variation in tasting lability rsfleets isetsSjclic
differences ha^fing significsKice at remote organs - oatsids the
nenrou,a systeanc
Is, eolli^oratioa with l^e T* lo RaU.;^ &a. effort is 'being isade to
associate the clij;d.cal. featux-ss of goitrous patients with their taste
status, "both in the case of to^e aad non-toKic goiter o It is sus-
pected, for exaE!p3.e, that ao!n-t-asters with non-tcKic goites w&j forjc,
a Esore isniform group than tasters ^"ith aoa-»tc5id.c goiter »
In collaboration vith. Bx-o Berpssii ¥i'skop, "k© ^r© iaquSring
fUrfeher into the chesaical nucleus ccBi'erriag this tast-e^aetivity on.
os'gSKiS.c cc^sspoundsv A resoaai-in^ system relating earbsaj sulfur,, aaci
nitrogen appears xmc&BBBX^o "Ehis problem once solved, may hare genes'al,
ismlieatioms In the field of taste pliysioiogy^
'PP'IS 3 Ions
ORP-2 liOmB - EpMeialo.1.
HiS-SIH
Indii'lsiixal Project Report
Calendar Year 3.959
19 o Project Title: The Detection of the C-eaaetis Carrier ia
Peroneal J&iscular Atrop^ by Coaduction
Velocity Studies
Principal Investigator: K« Myriantliopoiilos
Otiier Investigators: Mo Laae^
Maa-Years: Total ~ 4/32
ProfessioBal - 2/32
Other - 2/32
Project DescriptiOTi:
A stuSy t^ Seterniiae father the genetic catrier (wbstlier unaffsctei
cMMrea of affectea parents or iMi visuals sho^ng lack of
penstraace) Ccm be detected by slow paripfeeral nerTe couductioa
velocityo A slo-w-isg of eonaiactioD. velocity la the peroneal-j,
ulsaar aad other aerTss has been repeatedly Aemoiistratefi ia patients
■with peroneal sauscular atrophy o
Soae
CK3'-2 , IKIDB -•■ EpideiEicsiogj Brmich
Indi'^dual Project Report
CaigEdar tear 1959
PA^_A
20o Pi*oJect Title: ^Sis Qusstioa of Penetraace ia Bsrcaeal
Moseiilar Atrophy
J^iacipal la'vestigator's Btinos C Ji^iaathopou3.os
Iteii Years: Itotal » 1/32
P«>fessioael - 1/32
Project Desqriptioa;
A study of fsmiiies wi'^ peroneal imscuiar atrofoJsy to deteimlne
tJhether tbs reducti«m 1e peaetraace ia tMs dlseaoa, as" descrited.
43a the iiteratxare^ casa bs sulistaatiatsd after vigorous a©u2'ologtcai
Presaat Status
With tB® coHectioa of ttm visrxy exteEsi^^e pedigrees tlae study h^ iiotc
Baoved oa to a new p^-ocedtir© for the detection of the gea©tle carrier-
state; tte Beasu2-e2seE.t of ccssductioQ •rolocity of periplaersl . serves
in sasbers of the families c (See Project Ho ^19}
PAHT B
OR?-^ LmOB- Epmeasi.olosy Bs-aacb
iBdivldiial Project Eeport
C&lej^Lar Year 1959
21o Project Title; Genetic and Clinical Investigaticas is
S-t^tOHiic Bjystrepbj
Priacipai Ijavesti gator: IS» M3rri5mtSiopoulos
0-Uier laves tigators : J<, Caogheyj
Mea-Iears: fotal- 6/3ii
Professional- 4/32
Other- 2/32
Project Description:
A study based on history aad exaffidnation to detenssiae if children
of patients •with myotonic dystrophy show congenital aaoiaaUes
jEore frequently than expected; if there exists a sigiaificant
difference in the occurreace of congenital anomalies hetwesn
chiMren of parents vith the ceatplete syMrome exiS. chiMrea of
patients who sbov cmiy cataract; if the sex of the affsetei
parei«t has any effect in the pinsduetioa of congenital anosajl.es
ajBong the cbiMs'ea; and i^at is the reprogtuctive fitness cf
persons affected with HQ^otonic dys tropin „
Individual Ps'O^ect E;;,
Calendar Year 1959
PARS Ar
22.0 ■ Pi'oject Title: Ths D-etection of tlie Heteroaygote in
Cerebroretinal Degeneration (Affijatirotic
Fajsdly Idiocy)
Fdlncipal Investigator: Ho s^iaathopouloa
Otbei- lavestigator: G- Brecher
Cooperating Uait: Cliaical Center, i^IH
IfeE-Years: Total - 2/32
Professioaal - 2/32
Fro^^ict Beserlptioa:
Sjsasinatioa of a large number of peripberal blocsd siaears
fi'oax patients i?itSi tha infantile form of cerebroretinal
'legex-sratioap aa^ siaears from their parents and siblings ^
failed to disclose aay diagaostic changes in t'ae periphes-al
■blo(x5.« ScaHJination of bloc^ smears from ja-tieats vlth tlie
juverlle form of the disease disclosed very striking chartges
lE tt.e IsTJipscytes ia tbe form of large vexjuoles in the
cytoplasjSo The laves tigs.ti on is now eoacentrated oa the
juverlle fonno
PAR!r__Bc
JJoEe
PHS-ICffi
Individual Project Rt-port
CsleMar Year 195<)
?i\m} A,
23 <. pT-oject Title: Sossa Egideialologic Featui'es of Tay-Sacihs
Disease
Principal laves tigator: Mo Myriasitliopoulos . SfllD'B
Man-'fears: Total - ;^/3''^-
Px-ofessional - 2/3Z
Projsct Description;
A st"Jdj to detensine the isjcidence aal prevaleiaea of Tay-Sacas
Disease ^aong i^a ;je'wish asid noa-Javish. popiilatioas of the
lfeit'2d States by laortality 6tatist:ics»
Freseat Status: Mortality statistics tor the years 195^ > 1955
aM 1956 bave already been eolleet«ad and nsDrtiility data for 1957
have aov "beccaae ayailitbieo Bafora'itiosx coaee:>.:mi33g th« etbaic
orig-la. of patients is beisig Irt^lenifsntea, ajad tli® 4ata are beiag
laade xeadQf for analysis.
PAET Bo
limOB - Epi-i . Braacli
PHS-HIfi
IndlvlduaJ. Projefit ll<ir[30rt
CaleMar Year 19l>9.
P:ART A„
^k■o Project Title: Ifeltiple Congexiital i^nomalies in tlxcee
cMlSren of a tssd.lj'
Principal Investigator; 1,. JSyriasithopoiilos
Other Xayes tl gators : R. Hsjaiburger
Co Cheney
Cooperating Uaits: Yale Uaiversity School of Meaicine -
Grace-New Havea Hospital
Maa-Years - Total - cl/3^ . -
Professioaal - d/3''^
Project IDescription:
To titudy genetically^ clinically, anatomically ami pathologically
■wtia--: appears to be a new syrsdroiae of imiltiple congenital
abnormalities in a Hew Sngland fardlyo These vere identical in.
three suci: e^;;i,ve ehilSren, all of -vriiojin died vlthin oae noath
after birth »
Hoae
OEB'-d mmm - SpldeBiiolcgy Branch
FHS-lIE
to4i-vi4uai Project Report
Calendar Year 1959
i5. Project Title: Huntington's CSiiorea is Moaaozygotic I'vins
PrixcipsJL Investigator: Ho ^^rrisEtijopoulos
Other lR-\restigator: Po Rowley^ MHBB
Maa-Years: Total - 2/32
professional - 2/32
Project Bescriptioa:
A comparative study of the onsets course asi clinical fiMlngs
of Buntjjag-ton's cborea xe a pair of feiaale iiK>aozygotic ■ twins
■viltfe esxghs^ls on some pathological findixigs aod eugenic problexas
' in th.e family of the t'winso
Hy3*iaatliopoulos« Up G. aud Rowley^ Po Tc Monovgotie Twins
Concordaat for Huntington's Chorea la a FaB!ll,jr witli Chorea aat
Meatal Illness o Accepted, for pablLcatioe by leurology..
I»a:lvj.€iual Ps-oject Report
Calendar Jeax 195S
<:i6. Project Titls: ParJdJisoiaisja - Ataraxic Brags Study
PrlBcipa3. Investigator: Uc Myrianthopoulos
Otfeei- Investigators: LeoBard To Kurlaiid
A. Kixrland^ Spring Grove State Hospital
Goope rating Uuit: Spring Grove State Hospital
Maa iQ&T&t Total - '^h-/^^
Professional - 8/3^
Other - lb/i2
Project DescriptioB:
A study to determine tiie occurrence of Parkinsonism asBong; the
relatives of two groups of patients: those -ssbo show ParMnsoxiian
sympiosHs on high therapeutic dosages of certaia pheaotMeiSine
deri-vatives, and tSaose who prove to be resistant to the side raff eats
of tbgse drags c The two groups of patients^ actually patients and
controls^ have been selected from the patient population of Spring
Grove State Hospital o The collection of data is almost com^lated;
anal;ysis id.ll follow »
PART B.
Hone
B - i-ipirieiBiologjr Brai:?.cb,
EIS-HE
IsdiTldliaal Project Report
CalffiaSar Year 1959
FART A.
27. Project Title: A Survey of ScMsostoreaics Aj]30Bg the
Relatives of Schizopkrenla Patients
Prijic'.ipal lavestlgator: N» J^jrrianthopoulos
Goopjrating Uait: Spring Grove Ste.te Hospital
Maa-y'ears; Total - 18/32
Profess loaal - 2/32
Otaer - 16/32
Project BeseriptiOE.:
To determiae the occvarrence of schizophrenia eaioag the rejjs-tives
of patiaats 'wfeo have already been selected, for aaaother pixj^ect
(25) aai to detenaine the role of inheritance ia schizophreniac
This project is /j, by-product o? prefect EOo 26 and has the
advasitage of ovexv-iomiiag soiae of the biases iarolved in selecting
an adequate ssaipleo The collection of daiia is alraost completed;
gene-^iic aaaj^sis •aill follow.
PAHT Be
BoBe
AmCJAh ESFORT
CaUtvi&z Year 1959
Biosaafcrics Braach « Collaborative R®seai?sh
Natiomal 2Jssfei£«te of SQur©logi€;al
diseases and Blindaess
Nas:ional Insti«ut«® of Health
^•' SgQPH OF PRCGMg
The interesfes aad ia^smlvsnent of the Bioaetriea Braneh duriag
the calendar year 1959 Toay roughly be divided into three major areaas
1,, Collaborsfciv« Project of Cerebral Palsy and Other
Neurological &nd Sei&sory Disosfders of Infaney aad
Childhoodc
2„ Statist ieal consultation and/ or aarviee given to
iuvflustigators outsida of IMINUS on other projects o
3 Statistical consultation and/or sexvice furnished
to clinical aiid basle research investigators at
lilHDB in thm areas of neurology and bllndaesso
AeeoiQpIishments achieved and probl^as %aieount@r«d during th@
eourse of 1959» as well as proposed future objcetives in eash of the
above thrss as-sasg are reviewad belows
I. CoIIaborati'ge ProjjBct^of Cerebral Palsy aaid Ofchar
Kaurological 3ad Seasory Disorders of lafaney and
In the intensive phase of the Collaborative Projects it is aBtici<='
pated that aoaa 14 participating prosratas will contribute 50^000
pregnancies ov®r five years to account for a ©ininssB of 40^000 live births
available for at l^sast a »ix»y«ar followup^ the purpose of this
prospective approach is to relate factors in the gravida (genetic, family
healthy medical, socio-economic ^ prenatal history^ ®tc,) to outcome of
pregnancyo la 1958 the various institutions had b®en coaapleting pretest
forms of whiieh the purpose was to train local personnel and detexmina
«^ethBr the types of data requested could feasibly and reliably be seeur^t
Cases from a given institution had their unique serial numbers o fhis «»ae
considered the pretest case number «rtiieh identified the patient and the
institution o After pretest forms igere cosapletedg they had been sent by
the iastltutions to the Biometrics Branch for editing and critical revi«»o
For each institution there ttere prepared periodically evaluations of the
2 *
qualil^y of these €oetplig£@d forms and suggestions for improveaent ^ich
^ere t:akea up ^Ith aach inal:i£ufcios3 separately „ There '^an m» attempt
to pretest case collectien or laathodo logical procedures » It became
evldeat: th&t the pretest: f®sis9 would meed consldsrsble esdlflcation
before they were aaltable for full^seal® invesfeigasioiSa As a result,
8«:a£lstieia?8B of the Bsreach ^^orked In close eooperaeio» with pEOject
Services BT&is&h tsesabarcs and 'aith the staff of the Bureau of Social
Scieaee Eesesrcli, Hfeshingtos, Do C, and various coiasultastts, and
devised forms to sec«re tsore meaniagful and reliable data in fche ob-
steericalj pediaeric, ssd aeeie'^«conoiaiC'g!aa«sS:ie areas fchaS: would
also be snore aiasHuable to codiog and t&bulatitss pyocedurea.
In January 1959, ''final" atudy forms, covering the various
aspeees (prenatal, labor, dsiliimrjr, neoaatal, etCo) were distribu&ed
to eaeh of the participating iostitutions^ mmre an institution's
case selestioa procedures, the quality of its data collection pro-
cedures g aad its eosjpleted forais were considared by the institution
to be of sufficiently high eallbre, it was permitfead to stasrt enrolling
so-called "fisal"' study eas«s with a ne& ideatifyiog aerial nuaber
series . lot all institutions !j®li©"^ad that thay qualified iiaraediafcely
for s^eh "fisaal" series uajasbgring . Thsy eoistiaued using the pretest
series m^bering systaa. Ae the y«ar progressed and they ^»ere con-
fident that thmir proeadures asad forma had improved sufficiently, ouch
procesures! and forais ?j<sr® nevi<H9ed by the eeatral offices and,, if
eecaptabl®, the hospital ?jsg psnaitted to ehang® nuinbsring syst®BSc
Baforfcwaatslyj hoi^yever, soias iastitutiosa switched to "final" study
case Eiaabaring even ^hes e-^luatioa of case selec&ion procadures, data
collection procedarsffl or quality of ceaspleted forras indieatsd that
ffiuch iEsprovaramt was still In order . Bs^a received ea preSesfe cases
and ®a "final" sttsdy cases hs-vs be©s tabulated saparataly. As of
Cktober 31, 1959, soaae 5500 gravidas and 4200 babies hsvs besn pro©»
©seed in tha "pretest" series, So the "final" study series as of the
sa^e SBit&^ approximtely 3300 gravidas sad 1800 babies have h&fsa
pro<s:£3seda
Perhaps the largest: single effort of the Bioasetrics Branch
relatiag to the Collsbsrstiv© Project is the processing ©f data
collected ia the course of the studyo The only feasible approach to
ssffisuarigation of the wealth of data beisas collected is to codify the
particent iaforsatiosa ialtially in rslativaly broad and siaiplified
categories, but so as t© perasit identlfieation of abnowaal flnditsgs
and factors for control purposes „ tlor® detailed codes can then be
applied to "abnorsjal" eases and adeqi^ate controls, m required. The
dfisiigs of the iaitial "coarse"' «o<l®3 are twm ±n the procsiss of develop*'
ment. For 10 of the study fortas th® coarse codes a»d their related
editing procedures have been completed „ Full processing of sosas of the
study records for ^hich editing and coding ps-ocedure® have bees developed
is under vfay. Proeessing %JiIl proceed aa rapidly as additional clerical
staff can be hired and trained^
- 3 «
During £he y@sr £onaBl q^eatioias^ires "i^sre a&ot £o eseh in»
sSifeafcion rsqaesfcisag speeified inforBsanieo &s to its case aelectiea
proseduras eoverirag £he follo^ng aspects: (1> fcha segpsent of ehe
heapifeal pspulssioa^ sijch es cliaic or privafee, froo isiiieh study
cases ars dravMj (2) ©£ such ©egsant admiteed or ssaen for preaatal
ear© ©s dell-w^ry^ the eligib£li£y o£ all sm:h pafeieRts for selacfciors
as stud^ maa&si i£ all m>t eligible, She typas of patients routinely
or ascasioaally ©^eluded from possible selscsion ia the study sasple
(basis for eselusios); (3) the {wsias is eiia© ©f case selsefeieo;
(4) eba deseriptioa of the case selec£i©H procedure eepareeely for
casea s^eivissg presai:©! ear® aad f©r those reportiag fo? delivasy
©raly,, iadieatiag Tshssre deae^ by ^hoia, sethoiis used for haadliag
sp&sl&l aitu&tiisna (siocli as refusal Ze psrtieipatie) » snd the aa^li&g
?a£ios aad <5) th& approsiBsafee Eusaber of pati^to per year seleeeed
iat© thm atn^o la gsasralj these deseripfeiojas of case saapliag
pEsca&r«s t5©rs ia aseordaae© with reco^aeadatiens givea by o^sbers
of the Bi®©s£ric3 Brassh cm -visits £© the iaa£i£uei©as <, W'^te sa
In&tltntl&n is s©e registering 100% of ifes ease® iat® th& stody^ a
sysSes^Sie seapiistg procedsE-e has b®©a iaseitufeed fthafe.Mll ftssroish
the aianbes sf ps-egsaat tsssesB assmally £ha£ the iaistltution ess ade-
qmtelf pmces® with tk& faeilitlea, spse®^ aad pessoan®! at its
disp©saio
A ps?©eed5are tjas insSit«|i©d dariag £h® ysar by tiie BioEstrics
Brsaeh ^©reby far all obsteErieal pati©ai:sj aoa jissS ehose beissg
reglEfeersd iat© tk© aStady, a forss (OB-I) is es^jieted aad sent fe©
^a csffife^i dffise by the iastiettgi®a. this fom ^11 f»rai®h is-
i®ms^tl&B f®ff essli iagt:ieuti®si s® obseesrieal pspselatiea ehar®eeer«
is&iesj, psreisslas-ly ^th sespeet te sush is^ss as' age, warisal
sfeee^^Sj rses, g@sta£i©iml sg® at tis© of r®gistrat:iesa iot psreasfcal
ear@» eee« As ® result ®£ fefeis iaf©s®at:i®a, tlis BicKseSrics Braaeh
M.II b© b@fei:sr sbls t© raess^asad special aaspXiag psr^sduws, ^er©
imlT®4.^ B® fehat: it laey b® poasibX© to r©aeh eertaia objastSv®® iot
th® ffitedf as & ^®le «jri|;hs«g icsiag ethers.
It «fss dasls-sd fee arrivs efe s©s® estijaattoa of &he perceatage
®f g«s^@£ pg^gassseiss <ioao, ^Bss^i regi®£e?0d ^r® ^haa ®ae© f©r She
stssdy) t& bs «s|s®e£@d 4a £hs stssdy f nsa sash insti£«s£loa o^f«r eh®
fi^Te^yess p®ri®d dsrisig 'slileh gs.^a'S'idas are tskoa iaeo £h© study o This
©sfe&aetea ^s@ aeeessesy so fehat l£ ssight be psseibla e© defesrsiae
"^uit prs^rtioa ©f s:sp©a£ pragasjseies esuld b© penaiiifeed 0ver«all lafc© ,
the st^dy ^6lu>ut E^&ieiEg the ETisiber ©£ differ^t; gravidas to a Isvel
that -^a^ld bs ias^ffiei^t £© aaee'S'sr ®r dsmsaserat® sSatiseieal
sigaifiesaee for ttue etioiogiesl ssseeiatioz^ o ^Is bscsKase partic««
lariy lssp®rtsat i® eessis^ssioa ^th a stated ebjeetiv® of She sf:ady to
dsfeeraise the s-elaSieiaship of uekstss^a aad ttnsusp^:ted faceors is the
gravida to tm ffiSi®!®!^ of neurological aad seasery disorder® in £h®
BfflSBSS:©. <^2S3ti®aBaisra8 ^©r® dsvised by th© Bi©®a£ries Braisch aad aest
t® &s&h iiisgit^tiosss s^q^esiri^ isforsstisa e@ &o gh® oasploya^t: of a
4 ^-
■sm.it h'lBtotf nmstb&r, a\»ai lability of puaeh cards for aay of ths last
t@n yaars o£ obstetrical adbissiatis^^ baaring infosnsation as to ualt
history auffiber^ year of daii-^ery., age, and rasSo to ghe basis ©f the
retrrarass. dacisiosa coald bst aiad® as to methods by which fehe desisad
ffista C0uid b© secured fr^j eaeh iiasaitutioBo
It is plaaa^d to prepare evmmxy sfeaclstieal reports peri©di<=
eallj d«riag £ha course ef th© 9e«dy» l&ase r€p©r£s Mil include
sux^aary tabulations for esch institution aad for all £he institutions
eoaabinsdo tta& to the eos^les na&ur® of this s^udy^ and the multitude
of vsvt&hl&& t® b© &naljs&ds it ti&ald not be feasible nor praetieable
for feh«ss r®p®r£8 fee b® prepared in great details fhesis staranarj tabo^^-
lafeioas Mil fe« in the io-a& of rislati'^ely simple disfeributioaSg a«eh
as t^o^^Asay &l&8st£le.&tl&os for the Itesis of tm^ox imporsaace and
iateresfto li* is piaaned te set ap du«ay i:abl@s to fea referred t& fehe
eollaberating iastitutioas £er r®viewj suggestieas for additions or
d®lefeieasjj asd for purpsseia ©f indicating priority ia oatm&etien M^h
the p©ri©die faed-feacko It is wst ceat^aplatsd t® prepare detailed^
psriodic analytieal r&p&Tts., describing associations or correlations
of psrinaeal events '^th ths develepsen^ of saeurologieal and other
&9ma®vj disorders uatil da£a oa a auffiei^at a^ssibsr a£ pregnancies
and out:e«me hsv® b@©n eolleceed t© allow for meaningful infeerprafeatiooo
le^sve^j, ©n ©ecaaioaj eabjalatieas and infeerprefeafeions ia eonJaaeSion
M.£h any speeial analyses of ceat:r3l eore dafca eould ba pr®par@do 1&®
sfeports or feabalationss ^ich ar® t© be pr®psrsd pariodieailys will
also bo utilised t® d®t&^min& the general distribution of th@ p-opula--
tions sampled In li:h® di£far«mt institutions ^th nsspeei: to the variables
under coasidigraf;i®a» "Shmf ^11 be ks^A, in addisione ©a a coafeinuing review
basis I;® point up posstibl® siajor diffsrences bet^s)@<sn institutions ^ieh
isay b«t due eiSrhsr to rsn^oss variations:, differ^sees ^ith respoet to
popsilaeion aaapled^ or dli£®T®m.6s s^omg th« iasfeifeutioas in the pro=>
c®dfe»r®8s t-.®e:fesiquesj and laafehods ©£ data e©ll^t:ioa« In thm laterpr®<»
£8&ion of these data, e^nsidere&ioK itRsst be giv®n to I:he3e possible
sf diff«
The continuing examination of dsna will psevide valuable elues
leading tG a review of tha pro«<6daye« g© detessine through ?^a£
sieehffiniesas the observed d@vial:i@®s frmt She general experience are
^^eurring «ithis% a given iaetltution's popula&io&o I^ may ^ell be
that deviations in the procedures e^loyed in £h® solleetion of daea
JBsy aee®un£ for in<gen8ls£^j«i®So
!Mrin§ the course of the year the Braneh ^ief attended meetings
ef «*e Advisory Beard of ehe Gollabera£ive Project and of the Ad a>e
Review Board o He aad ofcher Braneh isesbers attended meetings of £he
Ps^ojeet Direetos'Ss as ^fell as conferences and ^sorkshopa devested to
eoasiderafeion of She ffltu% forass and iata reeei'9'ed dealing «d.feh £ha
foll©5fing aspeets ®f the Pr»jeet: (1) Soeio^eeon^saic^genctie^
(2) prmatals (3) labor and delivery, (4) pediatries » (5) neuro logical^
(6) psyehoiegisals, and (7) pathelogicalo In ©dditios, numerous meetixjgs
» 5
«f nmkll ^rkiiag gifou|»s sn& Bpmi&l isaeeings with ©ufeald® coaaultanfcs
wesre aegended by staff m«ab«2>8 is the v&pmity ©f st&tUtU&l consult"
aa£®<, Every isBfcitation £a &h© ©9llab©ra£lve Projeet wae visifced a£
least oa«e dariBg the ysaar by Branch staff, either as useabers of
Projsee Sita Coiamiefcess, or 83 statiaeiesl eossnltsn^s «n pcocedur@
iB my of the abova jutpeets of th& Collaboraei'e® Project or related
aneillary seudieoo Th© fmrpeae of th@s« visits ^s eo obs^ain infowas"
tism regardissg the charactcristies &£ thu hospital pefntlfitlons^ easA
««leeti<sa psccsdureBj 8«lec£i©n ©f childr«m for staadardlxstlon ©f
the Bayley Payehelogleal Tast^ proeassiag of pafclaate^ eeapletlon aad
editing of sfewdy records, aad 9S:her probieas of a statlsei^al nattsra
with regard to the various aspects of the atu<fy„ Tasee vlslte tsttd^d
mt mlf to "«;&jcata" psrsonziel la the eollaiboratiag instituttons io
th« etaeis&ieal aspects of the «tw<^, hut also go etahaae« the appreeia-
tien of the Braiath staff ©f she difficulti«6s aneosaeared in th®
appliftafeloa of some stisdsr fenas aod of the need ®f posaibly dlffarant
Braach ffiembers work closely with medical aad other professional
aseajbar® of tha Project Sarvieea BraiK^^hs NINDB, in sattlng up study
data fonsss tsfeich are sKitabie for proeessiag and data reductions and
ia devleisg codes and manuals of procedura and laatruetion. Due to
lack of sufficient medical staff in th« Project Serviees Branch, £h«
periodic review of forsis for eosspletenesss conslsteacy, legibility,
and quality has been alusoat completely a responsibility of the
Bloaetrlea Branch . The staff also prepared statistical analyses and
reports for ^sorklng groups and confareneeso For instance, in coanec-
tioB with ® teet-retaat of ths neonatal neurological ©Kaaiaation to
detersis© th® reliability and adequacy of the iteas, techniques, and
the fosB, a Branch ataff a^ber directed the eollection, editing,
eodiag, aad tabulating of the data, prepared the aaalysia, and wrote
a report given at a raeeting of neurologists o Interestingly enough
primarily stimulated by the result of this analysis, two additional
test»retest studies (revised neonatal seurologleal eaKaainations and
the one-year aawrologieal ©aasination) are being plaanedo Additional
examples are ass analysis of the one»miaute Apgar seores* analysis of
data froffl the pedlatrie study fonae dealing with s^y^nosis and jaundie®
ia the ne«»bora, etc. Farther evaluaeiosi of inconing data, auch as
data frora the obstetrical and gyaeeoiogical esaminatioas of the gravidaa
have been accomplished through simple tabulations of various iteas so
that pereeats of given eharaetaristies found ia one institution ajay b®
eooipared with the others c
Braneh ias^bcre have participated in training sessions for inter=
vi^jers by explaining the need for carefully and uniforaly collected
data and its relationship to the role of the Biometrics Branch in the
Project.
- & -
Brauch saemberfi hav® a is© %K>rks.d elogely «ith pr&cedur®
analysts of the Project Servie«s Bra^ehg MIUDBj aatd the Statistical
Pt'oeessiag Brsach, IN^IHj im £he preparation ©f preeedures to be used
iffi the eolleetion of 4&ta eeatraily^ storage of fo£tn«ig aad ©letabliah^
Bserat of w&G&BS&tf eoffitrols sa £hst up-'&o^dat® inforsmtion in mmhmt
&n4 eypes ©f forms received and pati®at8 prcweeesed by iiassitationsi
maf h& avdilabis on a 4Buifr«tt«: basis „
fh® Sranch Chief presented a paper en "Some' Service Bea^fits
to a QomBimity itom a Long^Tena R«searsh Program" at the Health aad
Walfar® Csmacil's Cltisen's Coafsrenee, Philadelphia »,- Peameylvaaia^
in Sspteaber 1959 „ He was also so<^author of £he following publica^^-
tions:
F&llasks E« So? P«r80ti, P^ Ho, Jr=j Kraaiera MpH and
Goldstein, Ho Fatt(&xtsa of Retention, R«lfta8«, and
Dsath of First Adsiissions to State Mantai Hospitals o
Fublie Health Service Publication »o. 672, Public
Health Hojsograpb Ito. 58 » Washington, D. C, U„ S„
Govemiaant Printiog Of flee,, 1959, 53 Pf»
Msn:f statistical problesss r«sain to be solvsdo Aisong thi^e
are:
lo The establishaent of a suitable sasapling procedure
adapted to the situations of eaeh institution and
to the n®eds of th@ Projsetu Sueh p^Niedares laay
be geared to the need for oversai^plii^ on certain
high risk varieblee and for patieats seeking
prenatal care earl^ in pregnaogy; and to the ne^d
for including a certain proportion of repeat
2o The eompletioa &i appropriate e&d®& and smnuals of
procedure for each asp^^t of this study;
3» the further d^^eloipsaent of adequate aethodo logical
tests of reliability and vslidity of th@ data
secured;
4c Inauguration of m^chods for periodic feedback of
tab^la&ed data to th@ institutions;
5o Further planning for data analysis <,
fhe Branch i^ involved In t«o studies, in tihieh it has given
consultation and/or servl^e^ uhieh are indirectly related to the
intensiw phases of the Collaborative Psojfteto In one ©f th«se»
coordinated by the Spidaffliology Braneha NINDB^ a collaborative
prospectiv© seudy of the relationship between Asian Flu during
pragnansey sad the oeeurrenc® and course ®f neurological sequelae in
« 7 »
the offsprlcg at: birfch or withia oo« year of age« the Blootetrles
Brench has been involved a* the eenCral statistieal ageneyo During
the year, scHse 3500 e&BWB from seven inseitutions it>ere edited, coded
and submitted for Esaehine processing. The tabulation and analysis
of these data are the responsibility of the Brai^h. Coasultation re«>
latlng to the sasipling of serological speclaens in the study has also
been given »
la the other study» Branch meeabers have worked with the Director
of Research and Statistics, Baltimore City Health Departnent^ and hie
associates c in planning a study, "Smoking and PrcBaaturlty, " part of
lAlch was financed by contract. The purpose of this study is to deter»
mine the incidence of prematurity among offspring of gravidas who smoke
and oatmg those %Ako do not smoke, and to include within these groups
other eo»varieblesg such as %»ork history, education, blood gtoupingg
and personality characteristics » fo date» so^ 2200 gravidas have been
InterTleived. Of these about 1160 have deliveredo It is escpccted that
an analysis of these dallvered icomen and their offspring will be avails
able sometime in January 1960, The final analysis for the total study
should be ready late in 1960. Prelirainazy data completed on 450 eases »
available to date^ fail to show for the smokers any significant increase
in the incidence of prematurity over noa^^smokers o There is no difference
in the average birth velghte of babies bom to the two groups nor is
there any significant difference between the average Heuro»Ps3^klatrlc
scores of the groupSo The smokers and non-smokers differ with respect
to the percent of primipara (lomer la smokers), eh» perceat with pre«
eclampsia (lo^^r in smokers) « and \iotk history during pregnancy (greater
in smokers) . These faetors will be further investigated with increased
numbers of eases for analysis.
Staff of the Branch have eoasulted with the Dlre«tor, Research
and Statistics, Health Xnsuraace Plan of New York City (HIP) and his
associate^ in pXamniag a s&udy to teat the reliability of certain data
secured on th« past sstedicel and family health history of th« gravidas o
This wmtld be doae by comparing the data secured from the HIP gravidas «
by interviewers using Collaborative Project forms, with data available
from the HI? prenatal records o
Exploratory discussions with officers of Group Health, Incorporated^
Washington, Do €., have taken place to determine the feasibility of
setting up studies^ under g^-ontract^ to test the reliability of certain
data furnished by Group Healthy lucerporatedg obstetrical clients as
compared to data on records available from that Association o
The aceomplishmeats givea above relate to the intensive phase of
the Collaborative Project o In view of the poeaibility that the incidease
of certain neonatal deficits is so low that even 40^,000 live births will
not yield enough cases to demonstrate statistical significance, an
esstensive phase has been postulated o la this phase a number of a{»proachee
are eavisioned hereby the eases available for study in givea categories
may be increased. For iastaaee, it i@ esp^ted thatg la those cownmities
iti ^ieli e©U,abs*r«S;itst isagl Suit iocs &rs l©€«fc<fe4a s«t«apt« will hm
fieilla'foersKi^^ Pr©j#€£» £h« oeewrrsBfi© ®f ti®«sr© logical silia©rd«r t«
^tt&l mt&ti^ti&u ifffie^riSe ate. Althmigh th@ nossib^r ©f ea«®» «#ill. hm
i-««r«ait®d,s e'h* data av«il«bl« will xmt hm as «:arapr®h«a»iv« war m
Sch«>oi. of Pwblie H®«lth, and A)&tti»istr«-£i<r« Mediela® hm^ hmisss. m^i^M'S
£h« tAsk of plasisiai a»fe!s«d©l®gy scd «ppr»®sih«si ©f fth® «a:fc«ii»si'v«
Braseh stsff acmtxrrs pa'ftici|»«iE«d ia fclaat Plajsning Cemfartene^
at Slaaie Feisty ^m York» ia Januasrr 195§s, t» ®«pl©r«i th« wri©«»
Additional sl;tt4i«®s valwafeltf gsi tb® coKdwet of th® essfesMiv*.
pbias®^ aiay b@ axaeetftd by ufeillslag ©«*pits« of pvm^h eards ef ell
iiv® birttiiiis, f®tsl deaths s aad n«oaa««l d*attos paweh»««d by eoo&ra®^
f*«8s co«p«r«tirst Stat® «ad loe«l h««lfch d«psrtess«£i f©r £?s« ©iKi®«
eessssm^d with *b^ issSmusiva phasic S!s«& .s »l;?^# ©f fet«i wksms® i'^
saw forfc City is ewss^cently uiidtet my ob a Jeiae basiis Mtfe tfe® W»
t®rk City H®«ltb »«p®.3ftiB»«»S ,> Ife is ©©nsssrasad sri£]!s tfe« tabulsti^ti .sssi4
•ssalyaia of fflpprj«iB«£ely .380gOOO pmaeh e«^ds f@r feha p««>i©d 1955" 56 .
IS i8 faip«efe«d tfeat a aumbar «f i«lu«bls- Iswsds Mill s&am feo llgbte ss
a result «f this invest ig«ei«K. A e^cijaei' hss b«ea aegc»£i«t«d ^iif.h
t:h® H«^ Yetit SteS,€ Hssalth Dspartsssnt fsfr siaila--f puaeh (e«rdte t&t S&*
Erie C««»«Ey a-fsaa e©'«?«riBg *be po|«siaii«»n .«®rs'e'dl by S;ls® ah.ildr«n's
Hospital J Baffaie,, Muw tark,, ApprexiJaffltmlf 108^000 puiceh sards f*t
thss pssridsd I'J54'-°5? are e©Bg@ni«do N«g®t.iaei^ms er« usadey '«ssy t& son-
«.lu<S« sifflil«r e.a>iil:r«ic£« «giS:h tfea Mia»e»«£s St«Se e««lt.fe Dep«r£^»<a»t
f®r gbe HaiSffi«pin"'Saffis<^ CSmaty arftSg €©veri®g £h« popwl«'i£i®K sisrvtd
by th« UalwraiSy of Miaasasota Hospitals Mi»B«B*|>©li»3 mtmm&tm Mm
feh® Oresen Stafee Board of Health f©r tb.« r^rtlamd City «r<aas, ca-v^riEf;
th® ^|ml«ti©a §®rs»s<ii by t!*® MialfMsei^b C^smty Hospital and Vinlvmmitj ^
©f Or®g«m Hadtesl.SclMKJl Bosptfeal. Rsrtlssd^ Ortgawf, and «ith fehe
Fhilad®lphi«, City Bepastia«nfe ®f PJsblls H««ll;fe f^sr sis* iPhil«d®l|5his
Clity ares, eavmti^ tfee populatisssj smrwm4 by the Pessaifylvaais HespleaL-;
Philadelpfeis^ Pemeylvsaia. Mtmrpts will b® asadft to und^rtsks siaiist
or ffftlated st;udis» dus-iog th« eosiag jsmx is ©efesr «iti«» its «^i(Eh l.bfe.
©©llaborstiag iastitutiaas «sfe i«^st«do
a.
£TS!»^^red Aks-iai; 1959 te miftsid® im'ei»tlg@£!St'8 ©a @tfe«r pftfj®c£S2
(g) fwluati®® ©f stody dMlga ©f « rfeSspesp^eti^^ study
^£ stioI®gy «sf e.«se«brsl p^lsy in ©iie®g©g, »apport«d
by aa ^IK grsatj, asad ««aa«s'i£asi©tt giv^sss on fehe
liRd^atioKs «ad sa®feis©d^. ®f aaaly»i« of data st©cwias=
lat@d las '«®ll as dsts ta hm e©ll®«5ted «m '®'ax'i@u«
9 •■'■
a4squ«it« tAbuJLs^isstSf, pt&e^^vitMXf assd design
and e®iu9tnieti®)& «£ €.£s>d0« f i'^^g^ t& th« medical
wiith a Tmtt&apmti'v®: ai^udy of tfe« etiology of
sftudy of thtt eS:io logy of ees-sbrsl palsy ia
«ev«srsl vturbaa ar^Mts 1% Him««uiotac
(d) Pr«pairatioit of a aatli«s>at.iesl nodal and appiroprl^
attt'feablaa for dstaztaiiaing smi^lm eisa and
isteiroraeing raaults in as is¥«ist:ig£tiOQ o£ %ha
pmportion of Iddtttieal tMos sa^mg ixeim with «
(e) Goaaulfeasioa and sftatisti^al analysis of data
d«aliag ^^tlt honsMmas and mholm^ttfml in <&hivkms,,
(f) Q&mnimtimi on th» mm of "Health \3nit nailj
"MsQtda" and oc thm «ta£ist£eal pKfO€«d!uir«s
aeeaesarf in a study of tha effaets of Influansa
iuoeulatiom ost rsspiretoicy ilMiSsa amoog HZB
<g) Consultation and secvlee in sotting up a study
d@3igis and study fones ftst a proposed g^ollaborati?^.
stu<fy of tha e|;ioIosy of fsv^itiSo
Evaluation of the study daaign and merits of aaverai proJ<^ts
submitted for rasoareh granta fco the Easter Seal R«««areh Foundati«>tt.<^.
United Cerebral Palsy, and tli« Office of ?o«iational Rababilitajeim
kas aliso bean randared at ^he raquast of ir.h@ Mra^&or of the laMtttntm^
■^e»<t applications for ra@@a£ch grants ba.%s h^mn eoneamad with 'Th@
Sola of l^acnatai Jaundiea a@ a Causa of Pr«v@ntabl« Fhyeieal and MimtaS.
Handieapp" "Stu^ of Weatam Region's Naada and Rasourses in &ha Fiald
of Training T«a€h«ir» for Bandie«pp@d Childran^" "A Ctoa^arat iwt Study of
Saleetsd M@ntal Abilities of Carebral Palsied €hildran «fith Varying
Degrees of P%r@®pt«jai Qlaabiliti^iSp^' '"fh^ Res^il^s of Stsraotassie Carabral
Surgazy and E^liabl litation ProeigdiiraiS O'pon Individy^ls ?o«at tonally
Handieapped by Parklaeonism^ Cerabrel Palsy^ and Otfesr E5rsk«wi«sias„"
In addi£ion„ a niBsb^r of proposed projects to bo subnittad fat
rasaareh grsmts in 4goanes:^ion M.th the ao<-ealI^ "esstanaive" piiasa of
the Collsbora&iv® Proja^t %i!er@ revlevad in order to avaloata their stu-Jy
designs 0 Iliess projeeta mnse titled? "C^fflERsnity Ob«t«feric«l Study
Follow-Up^" ''Study of Bfeiologieal Factor® ©f Cesrebral Palsy,"
"Relafeionship of Cigarafet® Susoking. fe© Perinatal toBts^" 'Perinatal
FaeSora of Health and Heusological Seq««la«o'"
He
Review &i & saseascript fflatltle'dx 'A Surrey &t Mind and
Partial ly-Sigheed €hildr«a» In CaliferaiSs Spring l$56" %m& requested
by Pfiblie Health R-eperts prior to a^c®ptas&® i&r p&hll^Mti&nr.
To dmtswBsitne possible stuxdies i4ii€h th$ Bnta^la vdght imdmrt^^
Jointly Mth the. fmtm-mm AStslni^tx&ti&n &a tmtt^vm ^i intmtmt t»
NOTSBe Brm^h m®9ib*r« vmt with th® ca»£#Js Bi(sw«trl€s ajsd Eiral«ugti®tt
M-nsltm, Sispdrts and Statistles Serviette, Ve^tttam Adbiaistx-atioia.
Ideas isere «iiplor«d irelfflei-v* to th« types and in«£!*od« of efcudy ©f
r«s*affefe valeafel® £© HBOTI that esuld b« uisid«s-sak«a wifeh tls« £yp«B,«
of data awiiable to ^h« ?«terans Adaidai©«5e«tion.
A "irking gxtMap^," eomposaid ©f ajsrabar® ©f fehss Bieia«tirie» Btaae*
and th« National 0£fie« o£ Vital Ssatistiea, has vm^ psriodisally t^
ecplore «aysi in wteieh joint projects of benafis to both NlMDB aiad W^
mighfe b« und^ztakdno Initial dtseusslona haw lead &o s pt«pcgai,,
^i@h ia baing mstkad epj ^®reby follosjoba^k and r«e®!fd='aneb©red
stttditts mad surveys eondustttd by NOfS «so««ld be r«la£«d t& th«
Oollaberativig Pr»j««feo
Braneh staff att<mi&d a meeting of th« Sub^eosiBaitt^ia on R%?.£»r<^s
of thm CoEaoittee on Hatamal imd C%iid €&m of a:h« Aatarisan Meditsal
Association^ FItiladelphia, Pannsylvanla, in Augtiae 1959^ £o d«£«miti@
ways io ^ieh feh® Collaborativa Projeet; «igh£ hm of help to the Sub-
eoamittmt in dr<>mins up proposatd prenatal, labor^ mid delivery f^rm^ -
that {night h® r«eoani<snd»d as standard for hospital mm^
Statistical adviee has bean givenj upon requests, by the at»ii
£0 imrious individual investigators in suish mstters as the role of
virus infaefcioas in pr«gnasi^y» methods of determiniag the zygosity of
twins^ and th«i invastigatios of th& prognostic value of ^artain
pathologies! findings in tha placenta »
Meabers ©f th« Braneh staff ptm@Mtly s«rtf« on tha iollmtin^
cosaaittassg thus beings in effect^ chaim«ls of eowEBuuieation v^areby
pzoblecB airees in tha maurologleai field baeooug knoim to the Braneh
end wihareby the Branch's field c^f int«r88t &nd sstivlty be«o«e kmcmk
to other investigators:
(a) Ststistisal Advisory C©sHmitt«e t® 'A Study of Us« of
St«tisti«s3 on Ma£®mi$7 and H«wbom Infant Care in
Hospitals/'
■ (b) Advisory Coatmittes on Epid«aaiology and Bioiaaisy
(HBnDB°Liai3on) „
(e) Coaasitta® on Hoiaenelature and Mmsmttt^m &f tha
Affleriean Aieadaoy of Neurology »
il -
(d) Ad Hoe OsamiCSee on Meatal Retardeeion of NIMHo
(s) NIH Advisory CesaBifctee to mtttcn&l Health Survtty
(NIH9B«L£»ison) »
(f) Panel fox- the Study Grmp on Guide Material f«r
0»fi]Bai?able Studies on Maternal and Perinatel
Sveata Reported on Vital Reeexds,,
fh® Bran&h Chi®f lEas designated by thd Mr^torp NINDB, to
ropraaaat the Institute at tha annual seatiag o£ the National
Rahabilitation Association in Boston, Masatachtseatts^ in Oetobsr 1959.
3» Statiatical aonsttUatloa aad/oy aarvica furnlahad
to elintc,_and
nsmtatloa aad/or aarvica ^urnli
bgaic yaaaarch iav«ge:i^teM.at
gaaa of aaatology aad blindnaaa.
H^gja_th® agaae
Balow ar® iodieated the uoita in KIKDB th&t received statiatieal.
aid froffi the Biosjatrics Braceh in 1959 and tha problona iavolveid:
(a) Laboratory of WsuroanatoEieal Scieaeaa.
Review and criticism of «sauscript of study daaliag «>ith
"A Probabilistie Model of Social Orgaaiastion' in a C8}nkey colony in
Puerto Rico,
(b) Medical Hauralogy Braach.
Consultation and analysis of data on gh@ ^a^ariaoa of force
■^loeity and force ahortaaiag e^r^ea of asasselaa uadar diffarent drtags .
(c) Surgical H®ur<»logy Sraoeh<
AaaistflMBse ia teetiag that aigaifieanea ®f diffaraacaa betvcea
body eesq?9rafturea ©f a greap ©f brain operatad chifflpffiK«®es and a group
of controla.
(d) Ophthalmlesy Braaeho
€oasi2ltatioa asd asaiataaea in eosaimtation of ragreaaioaa and
taate of aigaifieaaee «a the ralatioaahip batweaa aaaaures of venous
pvmasisxe and iaeraes^ula? praasare before asd after the a&ainist ratios
of
G^oattltatioa of the aaalysis aad int©rps-@$ation o£ data on
cesparisoas of the effeetiTaaeas of darapria oa various eatagories
of uveitis patieatSo
Statiatieal aasiataaee im curve sitting^ teats for "goodness
of fit/' aaalysis of variaaee, «m& variance ratios on equirrei eya
» 12 -
(e) Of fie® of MreeS:©?;-, Coilabaratlv® Re«(£aijj'c&.
Statistical amilysia of gt
teao
(f) Epidaiaiiology Braoeho
Joint Btvdf of w©sld-wld® lEsrtality ftosa necrologieal and
related disorders o Sf£or^B to obtain official raorS^ality Bt&tiattca
froB aose 40 eountriee os 26 spceifle dieeass onti^ias is th@
lBt«nuteioaal Classifieatiion of Meeasas h«va resulted ia the eollee^^
tioa of usable data fsrosj raore than 25 of these eetmtries, although
they are not all in the desired detail. For aiost of the countries,
age<»>sdjust@d siortality ret@8 for the various eonditioas ha-ve been
calculated ^ich way shed light on geographic patterns of «eor£allty
from diseases of the ee&tral neri^us syetea.
feehnieal assistanes sad analysis of prevsalsaoce data, by raee^
based on a survey of laultiple sclerosis in a c:otBaiunity»
Consultation and assistance with probl^o of eoti^utlng an over^-
ail ehi»square eeaabining the isfsnoation on a genetits hypothesis in
lauitlplft sclerosis for different age groups o
(S) Publications and teports Seetieno
consultation and technical s^rv^iees provided on statistical
emtsirial relating to perinatal problems in this country sad abroad o
To date, the ^aergles of the Brai^h have been directed to the
aspects of the px^gram atentiened above„ With an im:reaee in staffs
it is escpected that o^her asp^ts of proposed Branch activities ref-
lating to the developffi^t of a pragrasi for statietieal data on
prevaleases incideaeaE and iwrtality due to aeisrologieal and sensory
disorders, vill be eppr^esbed., It is also li@ped that a program to
design and ie^leiaent studies ia order to iavestlgate the relationship
of prevelen@e» iacid@s£ce» and »is»rtality of such disorders to various
biological, genetic^ and eavirmsBsntal factor^f; «»ill be uadertj3k@n
eooperatively with th® Institute's Spidesaiology Branch and o£h®r
interested agencies »
C, RECRUmigHT
Budget for fiscal 1960 includes 34 positions (12 professional-
statistical positions and 22 nonprofessional @lerical»stenogr©phic
positions) „ To dates 10 of the 12 professlon^sl positions and 19 of
the 22 cIerical«8t®aograi^ic positions hav® been filledo The personnel
ceiling of 34 positions is 22 positions (2 professional and 20 noa^
professional) less than the ainieaaa needed to be able (a) to furnish
statistical consultation and guidance required in connection ^^ith the
«' 13
Collaborativ© Project; (fe) to furoish consultagioa end servic® upon
request from elinical sxt& basic reseairch gcteneiofes la neajrology and .
bliadaesa at th® eiimisiel Ceaterj (c) to k«ep up wish editing and
eoars® eodiag of Incoising totem ®f the Collaborativs Project at th«
preeeat levels aad (d) to have stati»tical«^lerieal help available
for the Biaay analyses roqssestsd by the obstetrieal and pediatrics
worfcicg groups » and by aadieal and other profess ional staff aeabcrs
o£ the Collaborative P£@jeeto
One of the serious psoblsos facing the Biosistrl^s Braash is
the heavy load balcg earried by the stati9tisian.e on staff. Although
it has imt been too diffietslt to aeeure ooapsofassional help^ saueh
frostration has resulted frera zh» taany atteapts to reeruit' professional
persons o The great shortage of adequately trained bio»8tati8tlcian»p
plus the inereasad need for auqh personnel resulting from inereased
funds available for madieal researeh^ has made it virttsally iapossible
to racpeet success ia raeruitnent efforts, A eouseientious and continue
ous recruitment effort has been under way for more than a y«sr to hire
additional statiatieiaaSs particularly thoa^a «ieh soaas training in
public health „ Sot only hav® the efforts of the Persona®! BrsBchs KIH«
been enlisted, but also those of th^. eeployment officaa of the Asariceja
Public Health Aaeoelation and of the A!a<ari^@n Statistical. Association.
All of th® school© of public health in th® country were contacted hy
mail and a niasber ^^ere visited personally. It appears that» although
the training programs for such personnel has be«a seossiiiat atitaulated
by th© grants available from NlHg th® aoneoi^eeitive salaries allowed
under Civil Service prove quite unattractive o
Although the nuasber of pTofmalovml atatistieiaas has only
incroased f rc^ 8 to 10 over the past year^ the number of nonpros
fessional employees has increased fro© 5 to 19<. Thie «©uld mean
that ths staff of the. Branch has ssore than doubled during the past
yearo fli@ space allotted to the Bioiaetrlcs Branch is inadequate for
the staff at present on hand^ not to sssntioa the fast th&t £a»t and
eonti'mx>%m espanaion is urg@nt. Tha incoav^il^nce of beissg off the
HIH res«rvstion -^ith respeet to tabulating facilities «ills, no doiabt;,
continue te gro^ as th@ n®$d for auch services iaersasaao
A staff ia@!sber ^^s sent for irainins at the Basic aad' Special
Features 650 PrograsBBing School in order ta secure baeksnouod as to
possible ^ays to establish pro$ra8ss for eoaputer operations in th«
types of ststlatical operations amenable to this systeso Another
staff member attended the Fl^Kwrlter PregraisBiing and Procedure School.,
This traiaiffig^sould perasit th® most effieiens us® of th®. Fle^owriter
machine in preparing prograsisssatic tapes and esploitins the machine's
capabilitias In data origination and copy produtstiouo
X4
It is hoped that it ts&y be pssslbls to send oas or t«D static^
tleisus for sdvanesd tralois^ in bioststistics tbet Mil ba offered
during the smimer of 1960 at the Univarsity of Himiesota School o€
Peblie Hsaltho It vias aol: possible to tak@ ad^ante^& this aussaer e£
tha sassy fise bioststisties courses offered by tb«» Usiversity of
Miebigan School o£ Public Eealtb bseause of th« es&re&te utiderstefflag
of statisticiaas in tb® Eraneho
Ga3.ftEdar Year, 1959
ExtracHjral Frograms Brjsajcb.
Katioaal Institute of Ifeiirologieal
Dieeases and B3^?,ndaess
JSationeJ. Institutes of Health
I E^MKC-H GRAM?S
^- Pgogram developiseats
Duriag the jrear e. continued <g:£p2assioa. has cccxsrred ia the
nimTDsr of research projects end x^ogr-aais seeking to discOv-er tb,e
CBiJse and ei2re of neurologic aad seaxscsry disorders. An increased
sppropi'iaties. ©f 3^ far the various prc^ajEs^ effect iv« Jiily l^
1959, ^s periaittsd the E'.wardisg of. all ists'th^iiiile rssesMpch projecui;
3r«coaHnsiidBd fear approval.. Scsae new and tarpcirtsiit programs have
■been started, aM certain en-goiag pregrsms have "boon strengthened-.
ExtEibers of grants; - As the je&T eMsd (Besaem'ber' 1959) there
were 1,10? aetlTe rese^ch graats. A year ago at this tinffi there
ijers 93-3 active research acd field Irrirestigaticja grants. This
represents a sast gsixi of 21.2^ ixi the year-to-year increase pa.
BiD-iag the year 259 ^J®^* projects Tiere started. The^e were
62 projects -Khieh termineted during the ysar, either bseause c«si-
tiaiiatiorx ■ws.s nci: I'eq.uested, csr due to Isek of success in effligQeti-
tive review*. Tn.& 259 aew projects that treats started this yeav
req.uired a total of 3.96 znillioa dollars to fund^ hence, the eivGrs-ge
n«¥ graat was in the aiaoiint of $15,300. (Eie 259 Ji®^ grants vere
selected from a group of k-S^ eppliesticais that r®q,u2Bted a total
of 9.46 nsilli!^ dollars. Espressfid ia percentages, this laeasis
that 53-0^ of the applic&tiissBS for nevr projects xfere successful,
hut at only ■^2^ of the total funds sought.
Duri33g the year requests to reae\f 125 on-goiiag research
projects w&r® re-tfiewed. Of idaesep IO5 (or 84^) ijsre approved ia
the ajEOuat of 2.00 amillioa dollsrs; hence> the average c^afipeting
eoatinuation grant was in the amount of $19j200. In aidlticm,
95^out of 123 requests for fuMs to sirppleaient ca-goiag sad
active research ps:'oj€iCts -sjsfer© paid.
la.suasaary, the Couacil this yesr reecm^e!ad@d approval foe
459 ccmpetiEg applicaticms in the amount of 7"^ millism dollars.
55i® year-to-ysar laersas® from the previous year is 55 appli-
cations of all types (13.6^ increase) for ea additimxeO. $580,000
ia funds (8.3^ ifiereass in dollars ^proved).
a the r
Studies'' EXic
ti-ixiatitut:.
j(U,stlt tt:
a fiscal ly;
:.ats, tot
■, Stixdy - T grants, , \
'XS; ■^diicii rfr V:
"oliis lEstitu
ws lic-^ i iij.C|i oi il^ ivt^ii, X'ee^:iixcii gyaat funds iiii-lcii
■ ^.16,8S?,000 5*? fiBeal 3.959, Tiie resjalMcg T^''^? of +b.-
xLOids "t indj.vldual projects,
dlsoi^ii' "hijsic neuT-'Oseasoary sciei
of thi'; •:: r^mairdng 50^ of the fuii^ki wii;-
itsed f , rljito aeuii'ologieal disor'^.'°«'s ,, eir^c"
jiissxit, viisrei;©. 25i@se 'budge'tv
- .,td frssj?, the jsr^'^'-io^is y<8ar.
sttxi:. ' ' 3 of chil<3hood :■
-■. e.' .■.; .bis progrfian vises
i'jtu.ii j.fc. a broad ar^a. of resc
'17?;^- si rrid childiiood dis«"d«rs, £
::^ palsy, XDsmsdiSstii, iiycb
'.es and ©tiles' dlserders y, .
ia develcjkment . Without quwai-ltJii »:.«•
..L palsy study h&B stimu.iat<sd iat<sr©st
A r®.pid adviaa©® ia. sudi stijdias may
f;"?t7 years ;, aikd grant suirparfc ii-x thi-f-
■ily.
SiKCirS&rs of Bgiag, :!j2£!AMing p.'5rklassa35,SKi mid othft;.' :
Of chrciGj^- ?;:'roluatery t^v.rsvi^ihxs, use about 7^ ©f tM ,'i:,r:et>t
'Khiie ' ^rfflm is 1 ge^ sxgaasioa dofjs ;.
imlatsR;'. -sat in i.... : _ :>al aad. iiltxascamd 1*-^
cotttrol oi" tia® (Slsisase ijas 3soffc resulted in gem*ral daiin5-eiopHi!gKt .
Jfeltk 'X teva lirag t&ert^y studies "beeai very amailngfull .
tijifc ci-.
is. ;
KS^J' -t-
-' r;-i;^"s'
aad ifc. ^
l®fg£ {
X'l ^:?:: ■ ;
: :- '^a of r«6i8^x*eb.
.:.;L;.d. etw^T th9 n&x\
■XI incrv.
After a rapid increase csn/er a 3 ye^S" pc:ric4^ tJae i».divi<iusl
studies related to the eex^etecr^aseular disorders appssr to have.
arrived at s plsteau. Cxarrsat stipp<xrt is at a level of 3^ of the
graat f-unds. Hows-wer., stijdies related to epilepsy (7^)^ M-Liltipie
sclerosis (6^), scd amzseular d^'-sts-ophj'' (6^) are incraaslng lu
nmibears at a.'bou.t 1^e average ratiss. Vexy little interest is
sppsrent ia nexirotropic viruses, or other aspects of infectious aao.
post-iiifeetioiis neurolegieal disorders. !IMs is an area -that
rssguires activstioa. PoesiMy the sya^osiiaa caa the eneephalitides
held ia Antwerp ia the spriag of tuiis year Ttri.il result in rea«wed
interest.
Brolc'liai'is related to heraiplegia and accidents in general have
ejcpaaded recently. Siis laay Toe &a& t© the speetaeidar, "but as yet
ac83d©fiaitive;, studies oa nm^ve and spinal eord regsnsraticsi.
Ur. Ganrol)®!! eM co-TMrkers at ColxJEbia IMiversity have perfected
tJfee techxiiques that mssy lead, to K^iaisgful advaaces of a pi^aetiGal
aatisre in tiiis field.
Studies on the neur<^iyiosriiie relatiaas, snd on the autt^iomj. :^
aervoiis Byetan use about 65S of the graat funds ^ and are escpaoding
at about- the av<2rage rate. Siis pr^yam is sco^what hampered by
heing very geaersQ. in saatijra euod not i-eadily associated irtth e
singl® disease eBtegery.
Studies ©a disorders of vision use about 17^ of grant funds.
Very active prt^jraais ere vo/d&sru&y into the catise and caa^e of glauccasi
cstarasts, retinopathy and the Hssehsnisms of vi^ual perception.
IT© studies ©a traehcana are sxipposrted although uyeitis is being
actively investigated, learing and eqxiiiibriim studies ^t@ ex-
:^isding very rapidly ^ in numbers. There sre currently 19 grants
fer pocojeets «m the neurologieal aspects of speech disctrders,
suppcorted by $3CX>,000 in grant funds. 13ii8 prograai is increasing
rapidljr.
IS&w g^ogrsms; ~ Several new prc^aias have been started
dtaring th© yasr. in response to el^irly defined needs, aM aimed
Bt solution ©f Important n®ur«2logie and sensory probleins.
ianojQg protocol-type grofOT studies, specif ©ttentioa should
be given to the desisioa of the Couneii to fsvcEP a large ceHabora-
tive eerebrov^^soular project ia Sur<{^e, involving sev^rsl countries
and related pffiaa^ily to neuropathology and epidemiolo^ of strokes.
A grsnt of $100,000 Ims beea rescsai^nded to permit the develo;piBent
of a satisfectcsry prot^ol aad procedure, toother protocol study
is nearly crgenised and r©ady to be launched oa the ®valvsati«m of
Hsethods for detecting uveitis. Brsliainary plans are being worked
up to oarganizfi similar cooperativ© studies on diabetic retinopathy.
■.i<si of work ©n drug therapy fca." asuroiogie discsrdes's
■alii xE^oubteclly cse>xr as a 3?ss-ait C5f a ffiajOK* C'-:»iferenefi csa tJae
subject J fuafis fotr t-jb.ieh will Ije nsde available this year. Si!n;0-£j:-3
pisffls to de^-elop a progrsaa of active grsaat s\sppart in ieMzixig
racilatiosa «ffasts on seir; o',c,3ic axid stm^ory response ifEs laiineh
1^ tiie heldir,;
2* Besearob. cigv;eI<^!S3^tB
A. ^^:g^g^£ggsi ■• Surixig the yeaa? t-uro eonfereaces ^nsre
BpcjRsored Ijy tike MUSB tteoiigii researdi gr-aat f-juads. (l) "Dfeuro-
ajsehanisffis of the Auditoo.'y aad Vestiljular System" iiiss held in
Bathgsda ea Jxme 11-13^ 1959 « A series of 20 p^srs were
prc'seatsd, jxcl^uding 4 fi'cci ISicrc^ean scientists. (2) "Syjiqpbsium
«i the lae'^fesditides" wi-sa helcL ia Mtvesrp on Mi^ 10 - ih, 1959-
In this disevisssioa the p3:'<3'bl=Kn£i of classificatiiKa, deflsiiticsi aacl
dif^osis of x«3st infectious neruritides ^sere vcTVer! nrn-.. Pi iiv -:••■..< ,-
tica is expected in the K.©ar fut?ire.
Ia additiosi a gearat nas niade to the Soeisty fcfs* CK>ippled
Qiildr^^ for partial supfxa't of the lateraaticaial Ceagsfess «a
¥e2i'm'«2! t© Crippled CSaiiciren, to he held ia I96I.
2r Bgilica-tim^is; •- 'Ei.e traasaetiosiB of a eesjferesiee held
ia 195T saA sirpiporbed hy the SJIMSB, -were publisJied this year by
the Hise'bsr-Ifei'per Eress. TaQ title is "The Biology of %elia"
i^Jted hy S. R, Kiorey. Fifty-cae people affi*©- listed aa parbiejlpsiits .
Ia 1959 r^^rints ©f 744 p^^pere that ^^sem^ed ia seientific
iwTnsls v^'C* placed ©n file bji- ini©B grantees. .These wssre
sv^ported t»y 4l2 researd -------,
G^ geatributicms y:xcja '.^aQifie Awards; - ITheysar jeevsaled
no single speetaauiBr de\'elopii!Siit. Rather, aaay ©KceHeat
putlieati^as r«v<^d tb.© s'lovr "btit definite prc^rass toward prc^ram
ohjeetives. Oertaia coatrihatioas hssve tsts&x STSjasBrized ia the
foaicKiag pages, although these do not ascessas-ily r^reseat the
«Kies •iJhich fut.isre resegarch. may shcj to he the ansst iij^ortant .
In a review ai.'tie: r>lf end Cowen of Oolisabia ISai
vcapsity discussed the reXax.iTe ;.rtgK2rfcaace of spilrochi^tffll, ^otozov,:
viral and l:aact.eri^ iafectiisas of the nmr^smB s^fsteai oseurriag.,
in the periffieial period. Thej coaelufe that deispite the great
aiMbsr of iisfectiv^ egents which 2Ksy enter Bxtd demage ths eeatrsl
aiErvcais system ia the perinatal, period, infeeti^aa must still "be
scaisidered to "be oa® of the less common causes of pathologic^
c'^'--^"-- '■• the "bsFGin at '-''*'^ -^-'pss a£ life.
^-.•.:. . Silverman, ;i.=^...>.i^. and Fowlia- hsre reported osj. a
thorough. laTestigatioa of a grcajp of 192 presisitisrely Tiora ixifact-Sj,
eeid fOiUcRv-ea tliis. 'a^ita saurcicjgie aad psyefesss^t^ie exajalBaticms
whsja the tjhiMreas; attaiaad the ag© ef t^o yss^e. It ^as deasoia-
strated. tl>.at approsd-ntately csne qissrtes" of these s-urvivc^a ef pre-
jsatiire "biit^a ®slji"bit©4 sigas of ijsiirologie deficit aisd meatal
ra-fcardaticaj. at tlis age ©f tsi© years, and that laag:us.g© sad spassela
dirsaoility »ss eyident ia about 8o psrseaat of thess ehil&rea.
Taos® f isc-iags stx-caagXy suggest that the prohlsn of ■brsin daassge
amoag pr@iatu!fe irtfaats is ©os imich req.uires at Isjast eq,ual con-
Bicleretion -id-th the prdfcligra of s-sd-uciJus the iamrhaVlty rate sanoiig
these ne-vjliapa iEfaats.
Rjisic sttaiies aj.*© eoeatiiaiiiEg to identify and detsrmine the
ro;i4' of ti.s orgsaie eonstitvtsnts of nerve fi"bea?s aud axoplssm
ia the physiological fuaeticn of sasrv®. A l«sig x'sag« study ®t
M.I.T., UGdssr th© direction of Sr. Fr^aeis 0. Schxaitt, is losing
ma2e to asesrcain the easino ecid conteat of the axqplasai of the
sqsoid, aj3£. ;eee©sitly this group has t^sn able to detest © maabss"
of sjnjRO aeids -Khieh had nort previaisly been deserihed ia this
material. Schgr fundaseatal Imrestigeti^is aare proceeding - csa the
efftgsts ©f IS-irradiatioa ttg^fiaa, the nervous system. Btr. Kgimeth
Brizze^, of the l&iversiby of l?fcs&., is engsgsd ia studies of X-
iTriradiaticaj of the develspiag corehral c^^ex in eats and rats
throisgixorui:, i^r^^iatsl and postaat^ develepmeat, osaturatios ^3d
sgiag. BK". Samuel Hieks, of t-'te H^vard Medical Sehod, uses
ra^iiatioa as a tool ia sti^lyiiig the develt^n^it of the u^aaisRlisa
asrveus ©j-stssu. He has foimd that doses of about SX)r quickly
kill prian.tiire noa-mitotie eufcsyaoal neiaral ceils. The redio-
g«asitive eslls &re the buildlsag hlojks cf the hraia. l^s. Vogei
aoii l^TJiaker, of Ook"b«s11 l&ivcccsity aaad the iknaed Fcsfces Institute
of Bathology, have a®,de scEae v<2s?y interesting ohs«rvati^jB
eas^eraixjg demyeliaizati^Ki end the effects g£ :lrradiati<ai <^
nsyroHis.
Studies of epil^sy and related c^avuLsive disotrders ar®
iasressiag ia Btaabsr, aad sm^vsl sigaif iecaat e-oaatrihutioas have
ap-^eaapsd ia the litesut^s® duriag the past y^c as a result of
vos-k st;3spisr'ted by NIHDB. I^s. Pst^^s, Vcaodsrohe aad ^IsEsa, of
Xscirier ISoiversity siad ths IS:iiversity of CinciaEtati, hssv© iieed
ths teehaiq,ue of localizaticBa ©f biolc^ic fuaetion to proiri(3e
a isleapra? uaderstaading ©f vsa^iems ecemslsive p^^e^-^^^oa* W
aMatioas^ the iafliisaiee ©f 5 aas^or aaliryologic divisi«s3S cf 'fche
esotral i£@r«^us systes^ of the saleii^adsr-telsae^l^iloa; dlencepMlGn;
s^seaeephalaa, rhcssib&omepbslfSi, ssid ^Itml cord - oa iaduced
ssiziires nas test©i. Keisrol^ie testa perfosmed five or tea
:ii, aryi comaa}»s:LcffiiE ware
3 3(?®aeti<ms to Ifetresol of
caa were eomp3r«<3. to tb.o3e c ?
sri^tie seizijras . r"
3 for "b©tt«9r Tiiidsrs-?-;:
" - " '-ej.'si.ty
//rc'jag.Gl-
: O;, ■i?h<xi®s P-'c. I c':i
tsbs-Tita? oo? iiuiivid.'C
. :_
^. iJist afc;
.::3. defaoi
-i.ij.-;Q:su.
*ated, for
lei^©!.
Hmrev«.r,
;pl-.::o'-ia g;ad aca?.a;.«'l uai-^is ox-e quantitative rstliei,' tfeaa quali-
tative. K'g tioiiorajsl -iv-s.-ras in tlte EEG in epilepsy ar® believed
■'CO ';>e tbe :'.es'tl-i- o;ir giiffl-taiicari. cf alaaoraial dexiiritie potentials,
.'^sea.-rcli into tlae causes of Bcl«s:oEiag diaordc:.'-.
:oe.^ '.i^r ;■ z:: ;.;ig for t4i3 isast fSH' ye»rs. Artscent report frcnri
.^is.', u3i:.j;'.3. :>' : end assojiatee at Georgetosra Ifiiivmrsity indieete;?
tlm-'j t?ae dtl- -oa oc? th© eMoiint of esterif^.ed (jholestersO.
in -'.he caret . fluli asay wsU. "be a valu&bJje aid to the
•li..\;- :'-:l3 Cf ia\J.tii,le 3«l:jroEiE. In Ms studist;, aCltltoijgJi lavels
c;.t .';/;-.: ami. ©ste-rified chilesterol irer® r&ised ixt. the cerebro-
spl;jal flitld of patieuts -ti:--^. a -■I'^rieby of neurc^logieal diseases,
oaiy axoltijle 3cle:i'Osis pitieats ver® aharactesrlzed by a propoo^tion
of <(!?■; -:-r whicli ifvas ovsr 6d^ of the total ehol<ss-i;«Ki>I. ^ot'oesr
^ii-Aily "-ppeering 3.«eeeiitly cjoricer-iaed tla® developiaat of cai iKd«x.
tm ■bli* q.ueatii;e.tive assay of eneephalitogenia s^ctivity of oatigens.
35r» EUBW-sffirth. Alvard, of .^Icsr IJjivsc'sity, isijected gvijjij® pigs
'irt.-iia va;ccii-as !*aita;lnl^ /ari-ov-s smounts of brain tss brata
<axs;;.-'®cts iu Frsimd^s s^jtiTaat. By (juaatitatirog the degree of
liptaida, eltocj/jg'il aigas aid blEtoloigie lesions i*ee\i3.tiEg from
th^fiie iajectitKis^ he vas ib.le to establish a axaierieal 3jadex
focr ea'»h of tbts aatigenlo substsneee tested, ffi.s jafjposal of ax
arbitrary unit of ©Gtivitf, in tsirms of which ttue "epaeifie
.:c':>:';' i.^y" cad "'total sabiTity" of eny givea fratitioa e»,a b«
^X;);-c;i^3d, s5irs--lcl f--cll1-'vito i';3'--rch csa's^JLergie ©aeej^aaiomye'- :!■'-/'.:; .
^. gj :; : : itly being perfOTEad, bofcl
and eliaiccfl^ rsa d3.sorder:3 of visicc. 1^'. Ealajis atod IiSiot'eat,
of -'ihis 3r?'-.fii3, :r;:.i; i-ratiao., 3mve rsceatly ptibiisheid extaraively on
the bic : •:-;>ie vlt3;*c:Q\;s body in the derelowiag; eye of
aai;-:!'.:', uaj^s <:mk. PcttS;, of Wester" i:es«rviS l&iivsrsityj
^■' : ,; Trlth boviae '*yos, ^fv«j?e able to dstcfct aad aseaasure
tb. i .u:ivjiiG £nd tifriisiif.pa'-iLar ->ott3.atial3 c>f the l.eiaQ,
7 -
usiag "both wiek ©leetrodss emd efflaventioi^l adcroelsefepodes .
Turaing to clinical iavsstigatS^is, aa interesting teishaiqus for
light eo&gulatiffii utilizing indireet (^th&Lmoseopy has bean
developed by Qrs. B?cskhin:'st; W^^ and Scbapa^ of th@ Hetins^
Foundation. ®i^ hacsre dsvised en lastrun^at for csusing
ehoriGretinri "buens in tise living eye, and ha^e found tJmt it
offers a siiaple ^ad efficient nsstlaod f sar tr^^tiaent of retinal
lesions. Siail^ply, Srs. Csa^'bsll, and BittlsP;, of Colijaibia
ISiivsrsity, lisv® publiabied r@svQ.ts of tlieir investigaticss
indicating tlmt fXicker perisaetsy is a v^usble disgncstic aid
in eases of daroiia sis^le gijssaaam. Ik'. Milton Flosks. of
Staaafcrd Ilaiv®?sity, has found strilsing degeiaerative ehaoges
in the trsibseular meshiicrk of eyes vith pritmry and seeondasry
glauec^i^. H@ si^ggssts that -pei^BoaB destined to hacv« this dissEse
hsye relstivaly yxdnerable t3?©l>€eijlss -s^ieh are injitred "by
Iswels of iasts'Su^stOys^ pz%ssi2?@ idhieh <%?dinarily do not d^mge
the ts^h^iil,^ or optie nerve. Vb.&i the eurtre of intraocular
pr$ssur@ r^iehes the point where enough trabeeizlsr degeneration
las ^eurred to cause insufficiency of th© pressure-regulating
mechanism; progressive glauc@!a is assure unless trestaoent is
ixistitizt^. Toe aim &£ therapy in @az>ly glauecoffit should be to
l<^®r th© intraoeulsr pa?®ssur© sufficiently to prevsat furte®p
trabeeuli^ daas^e, rather tSaasx to le^^r it enough merely to
prevent dam^e to the <^ic n^^ie. SSf. Winstso Heberfcs, «f
'Btmmssi. Gi^y School of fi^dieins; is SkLso actively stxidying
glaucQim, &c^ iias concluded frcm an eight ym3T 8^^rvey of over
SCO ^ti@xts ttot the teehaaigite of tonogE^phy offers criteria
^^lich s^£@ it p^Ksible to diagnose prinssry glauccaua li^f os^
definite visualfield cl^snge oas. be measofed; ev«n vith the most
sensitive methods rifrailal^Ls.
At N^fthvestei^ Uoiv^rsity^ fir. Geoorge ShaTnteugh ccsitinues
his pioneering studies in e^r surgery. In a recent repssH; he
details -t^ie p^misnence of hearing results t<^ to sevent^si y^s^s
after fenestration for ot^cl^'osis. M^en the results of 690
fene6tr&ti<sss i^sere tabulat«i solely vith regisrd to the final
level of h^Bfing at the m<»t recent test, 43^ were considered
successful and JT^ ccgasijiisr&SL fail^Ir@s. Itr. Shi^nbmigh Tmk/^
the int^^stlng point, hoHever, that in csr/sr 4,300 fenestaration
(!p«rati@is perf cs^ti^d by either him or his e^sociates in the le^t
20 y^irs, ®3ly 2 cs£@s of prsired closure of the fen^tira occurred
l&ter thffi2 2 y^trs after c^ex^tiGs.
Up, l^rold Schvtloseeht, at the Henry Foard H^^ital, has
d€a»3nstrated the ^?eeence of acetylcholinesterase el&ig. nsssve
fibers and at the Imses of the hair ceHs in the ec^m of corfci
of tha eat. le has also shotm that tbs presence of aeetyl-
eholinester&se in the cochlea is d^;endent up<m the integrity
«f the olivoeoehlem' bundle. Fib^s of the olivocoehle^ bundle
- 8
■'MKnuirsate isposx ©r w&T^f sloee to the cochlear hMr eslls^ and thsss
flb^s SETS cholinergie. Acety«holi220 li1>eirated at ihe eiidijags of
the c^vocochlsar tract filaera JHSy alter the eKeit®bi3.ity state
«? the hair csells cr ths acoustic nerve eadiijgs. Dr.. Sohutoecht
theoscizes the,t the aH®i2rina cii^lls of the retire, ijhich ^re laaofan
to contain seetyldtxalinastecas®, . may suhserve a fuaetioa similsr
to -!diat ©f Easarossea'e. "bundle in the cochlea. He feels that
Qfbhiar seososry ead-orssas should "be iEre^stigated f0? cholinisrgic
efferent asars-e filers.
During the past y®3ff, s^sppcart has be©a pro/id)Bd for G©vK!?al
nc!^ projects la th© fisld of speech disoexlers, vocal cord axd.
laryngeaJ. fuaation, aphasia, ebc. Of ctsisiderable interest is
the vorls. of Bra. CaE^lsell and Murfcagh, of Dartmouth MedicsQ. School,
on the vosaHzing fuactioaa of the Xarynx. la a recent repcsrt
they give details of tij^a design euad nssults ohtaiaed wl-aa a
sfJEulated leryiis Esds of Gkioeh tulJiag. % iising a hi^ speed
pictuHB <^B3®rffl they ^a?e-r*s aM® to captxsre on film the varioos
jocrrmaemtB of this siniulated las^ynx, Thiay feel that the larynx
should °b@ photographed f^stsn the iaput sid«, as well as £com above,
to detenaine th® €ff (scts of chaoges in the dinKSOsieais sad ecaitotars
ctf the ihf®cicsr storface of the glottis. These may affccrd a
ratioaal Txisis foa? the loacwn coEcplex structure of. the thiyo-
eryteooid muscl®. !I3i« inv^stlgatdrs hypolihesiz® that the actixal
swhglottic shape of -idiis muscle may he the priirory detesfjnloant of
f^&qfieaey of viha?atioa of the vcwsal cords .
lo jimj«3ffii?oT5l€nL ia the deirelcpissg research graats progsram
has t&si €B3ieou3xt@)r«sd. A; miacar' disttjrhanc® in the prc^rsonming and
X'fcview process was created "by trai»fer. of the Field Isvestigatloaa
Ctsaaitt^^ to tdie Mvisicja of Sfisfiorch Graats, as described xaaSbsr
Sectioa 4. This has lad to changes in perscamel adverse to the
best iatea-ests of this Institute, and ^ich are still not resolved.
In genssp&l, staffing is not yet adcqjuate to fuUy eicploit all the
avenues of eocpansion &n& progrmanlng opening up to us. If a
prc^ram ef fc»f@ign grants on a protocol basis heeoni^s effective
additional pressures on resent staff will be felt.
^* Qhanges in the R^gram
Tm> ia^pertant changes In technical administration Jiatters
oceuzred disring the yesar, iSiidli laill have an effect on the
develespgBeat of grant supported programs by this ISistittrbe. Tii&se
changes relate, first, to the merging of the Institute's ed Hoc
Cereteral l^lsy Barietr Cccmittee vith the Evama. ShihryaLogical and
BsvetlessaKnt Study Secticm of the SEKl; and secoEpyd, to the transfer
Ctf the ISeurology Field InvestigatiOQ CcDimittee frcan the Institute
to the Bj[,vi,:; rauts. In libs j . gx'snts
of the g^'"-iVi5 ■i;jji&'. '. -■ otheySj *ifere idmitiii&d "by a special
auvfibsr sv.ies to <!'-Jl .^3 th^a fz^om tbe iMividuaX studies.
This j^'Oijedv -rf oeea discaa-fcinued.
Bslisy ii£ Li.e t'gse of r«s®ardi graat f-uaSB far f oreigii ■;■
hfis a^aln fceei;. ^be-'cg-?!:!. Jfc'.r k. grunte?? sjsy use Ms ftKJ.ds fsrr ■"
trarveS,; fora;;^-; ■ t Is in the -^
his veaucrcb 9;: ; .. ^i3i tli® ti ■
of iii» iKsr*:- iast-iiiu-uitifii- .i bj wisuaeiX is rsot
This, &9 -"'-nv.:' --^tsd ia l*;:, ;?.rTiya3., B.e?^>CGr-tj is t.
favoK"efi ■ ' ristlt.ufc<^
!Kh.« SKiaii greats pi'ogx'aia wss discoatirnssd at the e-
ygar, aftax" e. two j'^ar tri&I. aiis lastittrfe® aaxi its M?/.' ..
Council hsd f << fSrcsa the "bsgSjurilxiQ tbat ther stesII g2?aatB program
fiioixld aot I3© effeetit!TS in attailnlag its o'b5^eotiY€s , ar:a. tl'-s;^. tbia
typs of e,.:a:at. ¥Q«i3,d ba handled Hueh Is^tter thrsm^i
heal.th £-g-a%al-®3 ' gi:aats progjrsws.
5- Bcograa CfbjeetlTes f eg i960
In tb.® next jratsu* it is islamisd to ess^siod the greaats pre:, .
into e&rt^;..iEs SKr-^as that are ujofc now fully trfcilisaa fsr "Shisi attsck
on. 3Sfcm"OiGs5.e aad sigasosfy dlsesi'dSKB- I&^ of th® ehro)a;te dis<nsse
hespitcsIiSr, sc!iCQlsfO!r rebsErdM ehil^r«ai, hanea fcsr agedj, mm tJa®
Ilka asfe fill 4-3 I'Slth patieat loateri&l that sheuJA be utiliassd f oi'
laffeetive eaa &i-'igi2sal resesa-ch jaro"b2jaiss. Every effsart will 1.;
jsed«6 to eBiCCKa^aigC' rese3.5?ch grssrsth in. this nmts^wgd aad f^*til«;
sr^t. It is h-spcsd that ceorliera fw teaia ^-jathois^y' reg;!.atri®e
will "hcj m'^ffilsied ia this ecaaaMsetioa.
he ©rgaaisM. ©s® ef these is the relatism {^ low-l«ve3. ehrox:'
re3i^h:lca?. to elaaajgiBS i2a the C*-'
It is es^Kseted thet e. ,-..-«* ..■.•■,-..-^.-.. ..--..^>.-. . «.. -.^ ...,,-....., ...
Jfexjrolt^ie Research Ixi the 0. S. will he ccs3g>X®tsd this ysm" "by
a Ocamitteie appolsited oy th® tesacil and aicIM. thrcsagh a resesix'eh
graat. Sliia x-sspttst will he .1,mrsliSiaMje i» SB-Mteiaiag th® pr<3p®p
l:^li9!r\-^": 5- ■- •■•" ■ • '•■'•■'-*•-!', mjjjgcKr'G that gees ixit© th© ■vi^lmm pS:?c^;r«ms
■ c ■,. ;!!lcally, progreKcss vill te ss?lgi2»ted m-
■:'.':. .■;Xi^i jk':t-::'-*'' ■■"''■■ '"'••-■-"-.. cerelsriwaseiilM' pTObl'^ns ,
'.:'* - ;■■ retiac, : . ^s ©f isoaisa^g r^wiisfci«i C!;,
■ah 9; 1:
16 iO J:
!^
% g
a p<
CO
VJlOJ
H
M
VD
VO
H
Ui
vn
VD
vo
\o
VO
i^
■€3-
•^
U)
UJ
us
vo
vbvji ovo VQvn in
o\^ O ■• -^ '^ vo '
'f::!
8
Ovji
vo-s
C9
W
StQ
)0\
'vn
fO'
to
^8
Hv;i
VJ1 O
03'«
vn Q «-^<
•^
vo -^
\ap} OJ CO
•^8 ^8
o o
CD
-6S>
I
to
00
^-vVO
Bh ii
vo
WW
ON'*
u> vo
^•^
•?^
VO O G'jS
Vjrj«« ■\o»»
•89-
OS
■®5-
1 ^t
■€9- -^
VI VI
*^H HVi
W
Q ON
VO
CSVf
to (
to
v» (2?
v^ On
p.
»
of tkm
Batioaal laetitute of Heurolcigieal
Bis@ases and Blindness
II. Postjiraduate Training Grants (eon't)
(3» Qphtbalsaology Seetlon
lo Program B@v@lopa®nts
f^o a@w programs in clinical ophttetaology w®r© initiated in
1.959;> bringing the total mmh%r of elinisal programs to 3T. In
contrast to th© small inereas® in numbers of programs during tte
year, th® dollar l@val of support has inereased mrkedly from
1874,928.5 at tto® beginntog of the year to th© current level of
$lii034,178. The inereas® in support 1«t©1 has resulted from th©
approral of larger a^sards for eontinuatlon applieations and the
granting of supplaamtal awards for grants currently in eff®eto
For th© most part, these Inereases are related to au®aentation of
nufflibers of trainees r@e@iving support, as well as to a rise in
the indi'sridual stipend per trainee. Of the total awards made,
$325,541 is (sazsaarked for training stipends, being distributed
325 trainees and I8 student elerkso
There were two grants for training in basie seienees related
to ophthalmology In effest at th® beginning of the yearo One of
these^ for support of didaetle, basi@ g©ien©e teeehing, is due to
temiaat© before th© end of the year. Off interest has b®@n the
establishment of a new grant for postgraduate training in sensory
physiology at th® University of Miehigano Txaining is to be
offered in diseiplines related to hearing, as well as to vis ion o
As of the end of th@ year, total grant support in basie seienees
related to c^hthstaology will amount to $165, 59?..
2= Contributions Besultlng ffoia Particular Awards
It is to be reeogniaed that ©ontributions resiilting frcm
training for researeb, ©ertainly in terms of oitstanding researeh
performed by trainees, may not be diseemible for a number of years
after initiation of a training programo For the present, all the
training programs ean be expected to do is inerease the number of
postgraduate trainees in ophthalmology going into aeadimie medieineo
in reviewing appliaations for continuation of current training
programs, it is apparent that there has been at least a ssaall trend
toward aeadaiie aaa la^estigatlve pursuitg on the part of scam® of
the trainees o
3° Major Problaas Ineountered
One major problau continues to be that of keeping trainees.
sriod of traialK
■ 'ai.8 situation si;.-:
reiativeis/ ■£€%^ txiXl 'iiimfe paid positions a^ysliable in Hjedieal aelK^oie
to absorb the trainees., Moreovei-j the potentiality for ©eonomic r®tinr:.i
in ophtMlMolo^ i8 probably so maeh jgrfestsr in private practiise tte:"
in investigation tliat it tak@s eonaiderabl® dadieation to ras@t4rch
to turn to such as activity.
It thsrsfor® beao!E@s neeessary, and this is also a major probla:i
related to tbi® firat^ to establish training programs with definite
rssaareh outlooks, wlaieb viil inculeert® the trainees with the spirit
of rasaarehj, perSiaps thus lessening for thaa the attraetion of private
praetie©« For the time being, however, the investigative content of
e numbsr of the progrsaas appears to be minimal.
In thg basis 3«2iene€ area, a major j;>robl€m involves loeation
of institutions and of departmaats eaj^bl® of mounting a satisfaetoxy
training pr ograa at the postgraduate level.
h. gbanges and Baprovaaents in Program
&o Dr. Jerome resigned as Executive Secretary of the Ophthalmology
Postgradi;iate Training CcDsmittee, in August.. H® was replaeed by Dr, Isrnard
Sbaeter, in time for the Stiptember mesting of th« Ccsnmittee.
b. The following ni(^b©rs of th@ Ophthalmolo^ Coaaaittee caapl©t®d
their tetass with th@ September, mesting.
(1) Br» F» Brue® Firalick, ChsiKtsan, Department of Ophthalmology,
University of Michigan Medical School.
(2) Dr. S. Rodman Irvine, Clinical Professor of Surgery, School
of Medicine, University of California, Los Ang@l«So
(3) Dr. Fr«d M« Wilson, Professor of Ophthalmology, School of
Medicine, Indiana University.
e. New mmabers who have accepted appointment to the QphthaMology
Postgraduate Training GcaiEittee for four y^ar tenns effective October l^,
1959 az-^s
(1) Dr» M-^rd ¥,Do Norton, Chairman, Bepartaant of Qphthalmolo^-
University of Miami School of Medicine.
(2) Dr« James 0'Eourk@,Dei»r1aBeat of Ophthalmology, Georgetown
School of Medicine.
(3) Dr, Riehasrd C. Troutraan, Professor, Division of Ophthalmology j,
Stat® University of New York, DoTmstate Medical Oenter.
(k) IDr, 3r&dl&j R. Straatsaa^ Assoeiate Professor of Surgery
(^hthaliadbgy) , University of California at Los Angeles.
(5) DTo Fx-ederiek C. Blodi, Associate Clinical Professor
of OpMhalmology, State University of Iowa, -
5" Progrisai Objaetives for i960
m i960 til© otoJeetiv@a will threefolds
a. To bring about a better balance betwtffn basic seienee and
olinieal training programs, Th© developB^nt of knovledge rsgarding
the natura of sensory diseases in humans ^ ami the application of this
knowlfedg® to their alleviation clinically, is largely dependent on
knowledge of the noimal functioning of sensory organs. At present,
th(g o^hEsis in thm program has b@@n primarily directed toward dsvelop"
ment of elinieel investigators « If thes© are not to work largely
ia vacuo^ however, it beeotaes essential that basic knowledge of sensory
meehaaisias be uncovered. To this end, therefore, greater esmphasis will
b© placed on training of investigators for basic research.
bo To plaee further emphasis on investigative pursuits in the
elinieal training programs <, Although there has been .increasing reeogni-
tion on the part of Program Directors that th© primary function of th©
sllnical programs is not clinical instaniction per se, but training for
clinical research, it is apparent that the research content of scaae
programs is still minimal. It is proposed, during the coming year, to
earry out a proselytizing eaaapaign among the heathen to convert them
to th® true religion - research, at least as far as our training programs
are eoneemed. As a corollary to this objectiv©, it woiild be desirable
to look into training approaches and techniques designed to motivate
clinical trainees to beeaae investigators,
e. To continue evaluation of the program needs.. It is r©eognized
that research in ophthalmology, and, indeed in vision in general, con-
stitutes oaly a small segcaent of the overall research needs in biology
and medicine » It is proposed to continue evaluation of the needs in
this area, and to adjust the developBent of programs aesordinglyc
60 Staff A8sisQiE@nt
Bernard Shaeter, Ph.D.
Exeeutive Sesretarjr, Ophthalmology
Postgraduate Training Committee
SlMsfiRi OF CCSKIt ACTIONS
OpM-JisJjBolQgy Applifflaticae
Csleaisr ¥®ar 1959
March
New or Re^iss^l
CoEitiBioatioas
SuppliMients
'So-ia.l
^ Amto Appo
205,150
61.799
$345 3B1
a.
Jun«
He^ or R©vieed
eaatinuations
Suppleaents
Total
^ Ante App»
$127,692
te4,6iia
38,575
$570,915
61
Ncvanber
R®"^ or Bevised
Coat inuat ions
Suppl®m©nt8
Total
' ^ 9,T^^7
178,9^
97*060
|255;739
56
Amto App.
$55T5^~
132,, 519
$ 55,000
260,391
I 0
9^.395
66„3^8.
HOo R@Qr,
k
k
W
i lOo App. 55
2
9
2
IT
^ NOo App. 85
1
I
10*
5& Ko. App, ^
:^o. Appc
3
2
2
T
2
ir
0
3
2
^mpmm
$1,202,034^
^ Agjfc Appo 61
iTla^if
3^
^ Hoo Appo 65
^r
or xtta
National Institute of Neurological
Diseases and Blindness
II TRAINING GRANTS
A. Clinical Neurolo^ aad Pediatric NeTirology
1, Program Develoiaients and Accomplishments
a. Clinical Neurology
The field •whidi receives the largest amount of suppojrb
in the NUSDB training programa is Clinical Neurology. Sixty-
one programs vere in effect during 1959 "with a dollar value
of $2,321,037. Of these seven were activated in calendar
1959- Three grants were teiainated during this period. This
represents an increase of $783,127 over the previous year.
ThlB increase is accounted for almost wholly ty the activation
of new programs, increased nTJunibers of trainees and also a
genesral increase in the level of trainee stipends. The seven
new programs were at a level of $178, Wi-,
In addition to the ahove, two new programs in neuro-
radiology were approved to begin in calendar 196O.
b. Pediatric Neurology
Seven programa wiiii a dollar value of $118,071 arc
currently active. As pointed out in the 1950 annual reiwrt,
sitpends are not a major element in the grants since those
who specialize in this area l:4ave in most caaes completed
three years of advanced training and are therefore eligible
and apply for Special Traineeahipa or similar types of senior
awards.
2o Contributions Resulting from Particular Awards
Tlic training programs supported by the NINDB have been
in effect now for seven years. It is now possible to make
some evaluation of the total, program. Tteo it is evident
that in the field of Clinical Neurology we are ai^roadfeing
an optinaam number of programs. Furthennore, it is now
possible to discern -vdsidi ones are training significant
xsumbers of academically oriented neurologists. Those programs
whicii fall to give ©videace of productivity ore being weeded
out by denial of continuation grants. Review of continuation
reijaests now takes place far enough in advance so that prolonged
terzainal grants are no longer requix-ad.
Indeed it zcay now be said timt In the field of
clinical neurology, there is to be found aajong existiBg
programs a hard core of profijictive onsa which may be
■used for setting Btandsards for new applications. 'Phis
Dffl-y be conrps-rad to a Big League and those vishing to
join it vill have to dejconatrate that they have the Een
end capabilities for first ]ra.te perf onasance .
3. ^jor Probl^ns Encountered
Ths rm^OT problesa still aj^sears to be the provision
of an adequate nuaiber of teacher- investigators in clinical
neaijrology, pediatric neurology and related specialties.
The increasing dsa^ands on the nsedlcal profession as a
•whole broiight on by our explosively e^roending population
has been recently highlighted in the Bane Report (Hiysicians
for a Growing America, Washington, 1959 •)
The present pool of aisdically trained jiiaapower is
Biniaadly adeqviate for present needs, Jxiat to aseintala the
balance for owe growing pomlation will reguir® not Bserely
expansion of present medical teaching and research facilities
bttt the creation of at least 20 new jEedical schools. This
raises the question - Where win we find the j>ersomiel not
only to provide neceasacry msdical care but also to train new
generations of doctors, surgeons and E»dieal reseBrchers?
The question is legitisiate and sn misver is is^erative.
There is no doubt that ve ssist place increased eciphasis
on xhs developjaent of new and inrproved taraining progi:«Das in
neurology (Clinical and ^aic Science areas alike). Every
effort aaast be made to csest the coaipetition for the training
of piractitioaers by encouraging those institutions and seen who
have shown a proven ability to attract and train teacher-
investigators. Furtheriaore, efforts Jiaist be Eiade to siaks
academic careers nsoare attractive through ■fee creation of nsor©
full~time op^rtunities for well-trained aad dedicated teachers
and researchers.
4. Qxaages and iB^rovements Made
A significant step whidi will facilitate grants adminis-
tration is tfee adjustiffiBnt of starting dates of programs to
coincide with tJie acsidamic year, Dujrfjig tSiis 3>est year the
Congress provided funds for this purpose and it is hoped that
by 1961 ail UIHDB training programs will have been converted
to this basis.
Dr. Lawrence Farber resigned as ££@cutive Secretary
of the Sfeurology Postgraduate Traljaiag Coaasittee effective
June 30» 1959' He va& replaced by Mr. Morris C. Leikind who
assumed his duties on July 1, 1959.
^graduate Trainisig CoaHnlttee aad was
auecc-edad "by iilis rol-lowxng persons: Br. Vahe E. AiaasBiaii,
Br. Orville T. Bailey, Dr. Maynai'd Colienj Dr. TJaoBsus W.
Fa3?ia'2S*5 Ite'. t^'tia G. Netsky and Dr. Fred Plum.
5 * l£2^SB 0'''d ^^'•'^ivQg ^o^ i960
Burlag "tJie coming year, emgSaasi® -will "be placed on
iaapjoving tlie quality of existing sarogrsBie in Clinical and
Pediatric NsKrology and 3Pelat«d specialties. Fwrtiiearmore
ths standards for new programs will l>e iinder continued scrutiny
to make BVirs that training for clinical research and teaching
is the primaiy objective.
Since the reseajxh program of the NHJDB in the neurologic
and sensory disease flei'ls is dependent upon a continuing
su^^y of wsJJ,-trained career investigs.tors, it is evident
tliat the grant-in-aid training program ie a vital and funde^
ajentaS. elssaent in this research effort.
6. Ste^y Assigaiaent
Mr- Mcrria C Leikind, Executive Secretary of the
Heorsjlo^' Poetgraduate Training CosHilttee.
Hi
Q
-63- te
o
-€©■
-63-
H
4
ON
b
o
VO
NJ1
3 f3
O
3 9 O
t 6 VO
I » vn
I ON
i »•
\ P2
i H
■qSc p
H « -^ ^
H to
a 0
( 1-1 H
I UJ CO
I V, N.
I fo VO
I O v;'
i U) ON
covo
-^ >•
VO UJ
H ro
cr\-J
■2)3-
tvi
VD .p-H
>» ^ V
C? H H ^
H
fOJM own
cqo ONVO
^ V ^•
VO Son
CDO0VJ1
ro row
ro ro
8 0N-^
ONO
cavo asLti
EO M
" ■ O M )-•
^ >» \«
o rovo
O 0NVJ1
VO-J CD
® VO
I ^'
fit"
si
8P
J5l O
« Q
Pi
1 u
ISO •
is vji
io VO
in
}<B 2
!<;
1959 MMJAL HEPOBT
of -fchie
national Institute of nleurologicsl
Diseases and Blindness
II TRPJ^WG GRAFTS (cont)
B. Basic Sciences
1. Pgograsi DevelogH^nts
In tile field of the basic sciences of neurology,
34 programs were active in 1959 at a level of $95^^ 317 •
One g3?aat vas terminated during the yeaar. There vers
16 new grants yep3?esenting sei increase of $M8-5;,2i30 in
dollar val^e over the previous year.
The basic sciencea represented include Hsuroanatoasy
6 grants. Neuropathology l4 grants, Neuro^ysiology 5
grants, Heuroch^aistry k grants and Nearoifeai'^cology 5
grsatB.
2. Contribationa P.egultiag from Particular Awards
Since, as indicated above, th® basic science
prograsjs are gpite nev it is too ®axlj to have any iadica^
tions of outstaMlng eontribatioas resulting from researdi
psrforaied by trainees. It mi^t be said that in their
preseat state of developssent, the pipeliaes asce beiiag filled
and so we saast wait for a sizable nusiber of trainees to
coais out of t&e pipeline and begin independent woxk befor©
we can evaluate the results. Nevertheless, the increased
XEismbe? of progi^usis is ^leouraging.
3. Major Probleige Baeountered
The eritieal shortage of trained saanpower in the
basic science fields continues to be serious- The laajor
difficulty is priBsrily to find enou^ well qjialified
program directors who can offer, in properly egjaipp©d
dej^iTtB^ntSf l^e kind of post doctoa?al training regjaired.
Secondly cossa the problesi of finding trainees witai an
ade(^ate bacfegre^sad for advanced worfc exiS. iihfs desire for as?.
scadeaic caj^eer. In certain areas, such as neuroj^eiaistry
for ex^sple, considerable basic training in ch^sistry, over
and above that required of medical students appears to be a
s^cessary preireqiaisite for post doctoral training. It is
hoped that the predoctoral training programs of the DGIE
will begin to supply sai increased noBiber of post doctox^l
candidates .
k. Changes and laproveiaents ia Trogscam
Already covered in (a) above.
5. Program Objectivea for I96O
During the coming year the o^bjeetives will "be to
increase the niimber of basic science programs. Never-
theless^ mere niimerical increase is in itself not
sufficient. The quality of the prograais is of the utmost
importance.' The e!B|*iasis mxst he placed on types of
programs designed to produce broad- gaged investigators
competent to carry out independent investigations and
with the qualities of good teachers who ceua attract, inspire
and train new generations of scientists. The acquisition
of technical skills in a narrow field cannot be regarded
as a proper end for a post doctoral program.
Progrananing in this area thus becomes an educational
task in acquainting the scientific conHsanity not only with
the opportunities available but with the objectives to
be attained.
6^ Staff ABsignment
V Mr. Morris C. Leikind, Executive Secretary, Neurology
.Postgraduate Training Committee
-6ft-
i >
• 9
8 »
LI
^ > 1 1
,i^ics o Ci p i
JQ s q <§ rt ! i-3
O 3
of 'fcllS
Ksvtional lastituts of Neurological
Dissa&es aad Bliad22eBS
III. SEiiCIAL TEAimSESHlK
1. 'i?^o^^i. aceoiBpHs3:B2^ts__
fhe substantial grotdili mi/le ia 1959 'W "^^s js-ogram of
5.adi vidua! awards for sdvejiced research training is ■belie-yed to
"ba^ to a great extent, a reflactioa. of tiie success of Iixstituts-
suEpsrted Postgraduate Traiaijog Grant pi'ograjss ia prcsri^xjg a
traiaiHg eiiinate favorable to the dexrelo^s^at of apja^ciatioa
and respect for tfcs impcirtanc-'a of the ressarohor's role in
ffisdical pirogi'esB. In this at^josphera the tradase trlth inv^sti-
gative taleaat is challenged "by the imsolved psroblSES jsreseated
by aeurolog1.cal disorders, aad is aotivated to uadtotaka the
additional yeas^ of specialized study necessary to icaks hira a
eompstent im^estigator.
A total of $1,^09^660 ims avjardsd to IJO traiaaes, ra«
presenting aa increase of a little more than 50^ over 1958*
miPB Spscial Traiiisas are studlying in k-k iaatitutions ia the
United Sta-i:«E, axid 15 foreign institutioss ia AK'geatiua, Canada,
DenmsLrk, Fraacs, Germany, Great Brlt-sin, Japan asod S^edeaj a
tots^l of 95 outstanding laboratory and clinical scientists ars
providing direction and guidance of tl^ training so supported.
Poatdoctoral training and espesrience of the 100 Special
Trainees receiving initial sujyport this year averaged 7 years
and ranged from 3 to 26 years. Although about half of the trainees
■were from 3 to 6 years postdoctoral, seasoned imreatigators also
availed themselves of the opportimilgr for developing new research
techniques or concentrating on highly spscialiaied problem areas.
Mo few3r thaa 17^ having 10 or mora years postdoctoral es^^risnce
cade up this latter gztjup.
Participation of basic scientists in the pz-ogram has expanded
during 1959; 13^ of the traiiiees hold, the Ph.D. as contrasted with
the M.D. degr^, an increase of % over 1953. Newly established
Postgraduate Saraining Grant prograins in basic science areas •yhere
iaanpoi!i®r needs are especially acute have contributed to this incre£ise^
For eaample, a total of 17 a^rards for training in neurochssBistry suxd
2hr in neuro2®.thology arepresents a doubling of the number of Special
trainees in these fields over 1958. Striking increases also occu:a,'e<i
in nsvufophasiaacolosy axid neuroanatojHy> "which had in the past been
repsreseated by only one or two trainees.
Neurological deficits of the young continiis to ps'Siseat a
large and varied muiibsx' of problems acu'tely in need of inYesti-
gatiori;, .for ^aMch. a^jeq.uate3,y ta'^alnad i^esearchers aa:^ jjot available*
ThereTor®, the aiuBibsr of a'tjards for tyaiaiBg in psdia-fcric neurologjr
continued to grov^ reaching 27 tMs year as against 18 in 1958^
2. Contri^utioafi resultia^ from particular awards
An indication of th© success of Specistl Trelneesbips in
lasetiJag program ohjeetiYes is provided by a jreeeat compilation of
information alxjut activities of trainees subseG.uent to training
suT^rto
Since inception of the program in 195 6# 67 trainsss had
con^ileted from 1 to 3 years of ti-ainirig under ^©cieil Traineeship
auspices "by J^xas 30, 19590 Information is available to us from
nearly ^^ of this number, final r<^>oarts from "Kbe trainees them*
selves, -which are submitted a few months after the final training
period has ended, constituting its otain soi^^^«
Of the trainees about whom T?e have infoxaatlon, 77/^ hold
appointiBsaits to essentially fuH-tinse acadeisic posts vith both
research and teaching X'esponsibiliti9s-~50^ obteinad positions
subsequent to Special Traineeship training, aM 27^ i^tumed to
previously teld positions, after leavs spent in adding to their
knowledge and sjfcills in specialized research areas 1 10^ have
academic appointments allowing sos^ tiias for private practice;
35& are serving vi'^ the anaed forces| 105^ indicate private
practice as theix' principal activity, -with research as a udnor
activity at i^pesent.
As additional evidence, of the research participation of
Special Tralness, 32 KMKB Research Grants active at the present
time have 27 Special Trainees named as principal Investigatosre
or co^investi^tors. Although the ei^ct nmaber is not readily
available to us, it is knomi that Research Grants have been
awarded to our Special Trainees by the other Institutes as vello
It is of interest that reprints of 27 ^^blished investigations
resulting from S^ciauL grainfeeship awards have been received,
although a specific research project is not required as a part of
the training program of the Special trainee a
3. Mstjog probleiss eaeountex'^d
Thst only proljlem encountered this year is not a nev one,
and y.-elatss to the revise of applications, -wMch since 1957 has
been an iioportant function of our Postgraduate 5?raixsing Comffiittees.
However, it hss been agparaat tlxat undue delay in acting on applications
seriously inroalrs tbe usefulness of the po^ogram, and vhen consideration
of applications is restricted to the regular meetings of the training
coHonittees^ •Khich occur 3 tiises yearly, action on EjarQr applications
is delayed, to the serious detrinssnt of the prograjn's usefulness.
Accordingly, an ad hoc Interiai Ti^ining CoaMittee is cooveaed 3
times yearly in the intervals bet^j^gen regular cosmnittee nseefeings.
IThe ad hoc conmiittee is cosiBOiaed of jasiabers of ^tch of the Postgraduate
SSfaining CojassLttees, appointed by their respective chairoffin.
Although. coiisultai5,ts from the Ophthalmology and Otolaxyngology
CoBEfiittees have evidenced soae resistance to this procedure, largely
because the nuznber of applications in these areas is snail coisparigd
vlth those fSrom the i^urological sciences, it is believed that aa
numbers becoras more nearly equals this resistance may vanish. In
comparisoa wiidi the gains that have accrued to the program from
application revievr by top-flight teacher-investigators, the
difficulties associated with making procedural adjustmeats from
time to time 83^ odnor iBdeed.
4, Changes astd Iii^goveiaents in program
Aa KIH-vide ehaaage in Keseaarch Fellowship stipends, Pre-
doctoral. Postdoctoral and Special, resulted in the adoption of
a new scale of Special ^raiseeship stipends, aod the jforzaulation
of a new set of guide lisies for deciding tl^ asaount of individual
airards, for vhich the candidate's q,uallfi cations, and an estlssate
of ^lat the training wiH cost provide a basis. Stipends now nsay
range frcm. $6,500 to $17^500, and this ehaage has increased the
average stipend from $7,2^7 to $8,500 psr annum.
An increase in furids eas^o^arked for this program from
$1,500,000 to $1,750,000 was believe necessary in order to ptrovide
for needs arisiiig from general ezpeasion of the Institute 's program
with special an^tosis on hearing and spee(^ fields, azid to provide
for the payment of stipends at the higgler level eidopted this year.
Expa^iSion
of fujida allo't;:
Investigators i
Li be contlr-:. .?.c .
to prov:'-
s.-'miiat
-iiBl and
:.uttEg of s,i^lieatlons
Avei'sgs stipend $8,,^
&1; 9'i
Eli'r-ffl>"^"^i n n^:
ssMp aid Research FsllovsMp
1959 AKIWAL F:
of fhB
:nal Institute of Kgvirolc:
Diseases aa4 Blindness
III. SEECIAi TRAIHESSEIIS
1. Prograra accomplisbEHmts
'She subst-antial gsi'ovth isads ia 1959 "^ this program of
iadiYidiial awards for aavsEced researeli trainlog is t-slieved to
be, to a great ex-fcent, a x'eflsctioa of the success of iBstitute"
supporiied Postgj^aduate Trainiug Graat ps'ograjES la picvidisg a
training ciiraate favorable to ths develo^s^nt of appreciation
ajad i*espect for tha importaace of the resea^pcher's role in
nsdical pceogress^ la this atiaosphsra the trainee with iaviesti-
gati-\ne talent is ehsillcxssad by the unsolved problsffis ps^sentad
by aaSurolog5.Gal disoyders; and is Motivated to imsLsrtaka the -
additional yesrs of specializ-sd study aecsssary to ebTs^ him a
competent investigatoi".
A total of $1,^09^660 ^ms a^raydsd to I70 trainses, re-
presenting an increase of a littls amre than jc^ over I958.
NUnB Special ^frainees are stisSying in kh institutions in the
United States, and I5 foreign institutions in Argentina, Canada,
Denmark, France, Gei^siamy, Great Britain, Jajan and Swedsn; a
total of 95 outstandiaag laboratory and clinical scientists are
providing direction and guidance of the training so supported.
Postdoctoral training and esperiaaice of the 100 Special
Trainees x*eeeiving initial su2?port this year averaged 7 years
and ranged from 3 to 26 years. Al-Wiough about half of the trainees
were from 3 to 6 years postdoctoral, seasoi^d investigators also
availed theaxselves of the opportunity for developing new research
techniq,ues or concentrating on highJ^ spscialized probleia areas.
Mo f e»R5r thasi. XJia having 10 or more years postdoctoral ^jj^rience
laade up -idiis latter group.
Participation of basic scientists in '^he program has es^Davi... .■
during 19591 13^ of the trainees hold the KieD. as contrasted vith
the M,D. degr^, an increase of 5^ over 1958« Kewly established
Postgraduate draining Grant programs in basic science areas where
manpo"Her n^sis are especially acute have contributed to this increase.,
For essmple, a total of 17 awards for training in neurochaaistry ajid
24 in neuropathology represents a doubling of ths number of Special
iTrainees in these fields over I958. Striking increases also occurx^ad
in aeuropharjjiacolosr and neuroanatozsy, ^lich had in the past been
repi^esaated by only one or two tiralnees.
Keurological deficits of ths joung eoBtiaiie to pressxit a
large and. varied aianber of proMeans acutely in need of in-vesti"*
gatioxij for ^jMch a^jequately t3:'ained researebsra are not aTailable*
Therefor©, the numlaer of a^janis for traiaing in paaia-fcric neurology
continued to grot?, reaching 27 tdiis year as againet l8 in 1956 »
2» ContyTbutions resulting ffom pexticulag awards
An indication of the success of Special Txainseships in
jBseting progJ.'QBi objectives is provided by a recent cosijdlstion of
iaformation about activities of trainass subsaquent to tiraining
supports
Since, inception of the program in 1956, 67 trainees had
con^eted from 1 to 3 yeai-s of training under Sjecial TTaineeship
auspices by Jusae 30, 1959=- Irf ormatioa is available to us from
aearly S^ of this number, final reports from the trainese th®a«'
selves, which are submitted a few sjonths after the fix^l training
period has ended, constituting its main source.
Of the traiases about vhom xf® have irrforosation, 77^ hold
appointfijents -to essentially full-tinte acadesiic posts >?ith both
research and teaching responsibilities — 50^ obtainad positions
subsequent to Special ^raijieeshlp training, and 2T3t retumsd to
previously held positions, after leav® intent in adding to their
knowledge sm,d skills in specialized research areasj 10^ have
academic appointsasnts allowing soais time for private practice;
35& are serving vith tb& arazed foarcesj; 10^^ indicate psdvate
practice as tttsi^r principal activity, -Kith research as a minor
activity at pres®at.
As additional evidence of the research participation of
Special 3?ralneeB, 32 NUSX© Research Grants active at tl^ present
time have 27 Special Trainee's named as p2:ln.cipal investigators
or co»inveBtigators= Although the essact number is not readily
avadlabls to us, it is kno'wn that Research Graats have been
atmrded to our Special Trainees by the other Institutes as well=
It is of interest that reprints of 27 published investigations
resulting fvcm Special Trainseship awards have been received,
al-fchough a specific research project is not required as a par-t of
the taraining prograai of the Special Trainee*
foblen^ encoua"te3?ed
The osali-" ■j^dblsss. ^icountered this year is not a new 021s,
and i.°eXates to tlie vevienr of applications, wMch since 1957 has
beea an iBsgortant function of our Postgraduate Training Coannittees.
Hovevez", it has been apparent that undue d®lay in acting on applications
seriously inipairs the usefulness of the progrsau, and when consideration
of applicationa is restric-fced . to the regular laeetings of the training
comnittees, idiich occur 3 tiH®s ji^arly, action on ssany applications
is deiaysd^ to the serious detriffisat of the program *s usefulness.
Accordingly, en ad hoc Interim Tre,ining ConEaittea is convened 3
tiE©5 yearly in the intervals het'SBea regular coinmittee zj^etings,
!i?he ad hoc coEMittes is cosipoaed of E^mbers of each of the Postgraduate
Sraining Conanittees, appointed hy their respective chairs^m.
Although consultants from ths Oj^thalmology and Otolaryngology
.Committees hav© evldaneed sobb& resistance to this ptrocGdure, largely
because the number of apiplicatioEs in these areas is saall conjjiaried
with those from the neurological sciences, it is believed that aa
nuinbers became more nearly equal, this resistance may vaaishc In
conrparison with the gains that have accsnied to the progreaE :Drom
amplication r&vi&v by top-flight teacher-investigators, the
difficiilties associated with joaMng procedural adjustiients from
time to time are usinor in^aed.
h. Changes and laisgovgn^nts in program
An KIH-^de chemge in Research Fellowship stipends, Pre»
doctoral, Ptostdoctoral eaid Special, resulted in the adoption of
a new scale of Special !?rain£eship stlpsiids, aa& the formulation
of a nsrw set of guide lines for deciding the ainount of individual
awards, for which the candidate's qualifications, and an estiimtd
of ^i&at the training will cost pjrovide a l^isis. Stl:^snds now Hsy
ran^ fsxm $6, 500 to $1?, 500, and this change has Increassed the
average stip^id from ^7,2kj to $8,500 p©f asmumo
Aa increase ia funds earmarked for this program from
$1,500, OCXS to $1,750, <K» was believe i»cessary in or-der to provide
for jaeeds arising from gsneral fflcpaasion of the Institute's ps-ogram
with special ai^ihasia cm hearing and 8]^ech fields, Bsui, to provide
for the paya^nt of stipends at the high^ level adopted this year.
of iu::v;
6, Volume of
Aj;>-.
iiaj,w,iv*v v*rn-r,-y Avialysfc in clifis-ge of Specie?
9 awd Research FsilovsMp
1959 MMJAL a^cusf
of tM
Hationsl iBStitiAte of Isurological
Diseases aKd Blinaaess
^jis grogs'ssi of SHrards, desigsasd to si;©;^>rt ths reseas-eh
t^^laSjig of cssSiaatss qualified for iavesti^tivis ca?'®^?3,
coatimKid a-t ai?prasljistely tJ2@ saais fiamjcial I©v©l in I959 as
la 195B-. Eo'^sveg";, th© total ajaai'iat available fog" Predoctoral
asd Fostdocto^Jl Bssaareli FsllcHsMps actualiy has "b^^a iaos^ased
by sea3?2y 50^ as tbg result of tramsfi^f of respcaisiMlity for
Dl\'lsi<Ki of G^ieral Judical Sei^aees^
A total of $535>26J{- -sfEs ®speafi^ for 193 a^^s. A'«raMs
totalling $60,912 -sv^r® aiaae on e^ iastitutioaal basis to stcggosffc .
^ parb-tisas studsats. Tbe Institute taJsss no j^rk In tlis
administs^1;ion of the ^jft^tljs® F@llot?EMp progrsm bsyond lafovidissg
tlos funds for its supports
The asKsmit sj^nt for Predoctojfal aad Bostfioctoral Research
Fel3.oTrsMps in 1959 totalled $^7^^3525 and repres^tsd asx iaoEssas®
of a little 2K>s^ than $200,000 over 1958^ Tas larggjp postion of
this increase tras devoted to Postdoctoral Hesearch F®llo^hi|^e
ThB ^^ssnditure of $337^ 6li!- provided for 56 swards to ®u^tca?t
ressareh training dicing the years i3i!Ke!lia-fc©3^ follo^jljag receipt
of the PheD« or Ms,D. dsgs^ese
Pi'sdoctorai Resear^ FfeHo^sMps^ for trainiag prior to and
dxr^cfcsd to-^ard th© Bi»D. dsgre©, ^jsre asiardsd to 43 iz^i victuals in
a t-otal .amount of $136,7380
2» CoatributioaB resulting trcm particular a^aMs
Detailed info^i^tion about the activities and eontnijutions
of rsseasfch fellotfs subsequent to coBmlstion of si;s^ort i8 unavail-
abl@ -t^ us this year 5, as "Kas truB last year..
3o &iajor jj^oblema @acoun-t:;eged
All th® pirohlsms encountered in adrnMst^ging ths B@s@^^
FteUo'^ship pjragram this y^^f have loe&sa. siajor ones, ssd all ij@s@
coDneeted v±i3a. changes in reviesj sssd ajiard procedures mads Isst
year.
'asse- QhB7iS^3 projec1s@d for 1959j» ^isich tjei?e delissated in -a©
1958 Aaasmal Escort, proved not to !>© aa iHp?ov©asat, l)u.t scatter a
source of Qos^CiBlon leading to vlrteal frustration of ths total
Besearcii FfcHairsMp program's prog3?®3s in aseetiag its pKlssaEy
objective^ 5?iS prlnci^il difficulties vsr® aacoimteafed -whsn Discipline
Panels (cou^/jsei of intz-aaairaL scientists ) giving pg-ellsQinssy revisj?
to agplicatSoas, and ^cse HHEB Staining SoisEBittees (Keiapoiogy,
Ophtl3al33K)lo^ and Otolaafyngolo^)., acting as Institote cojssultaatS;
Slsa@?@@d rn tbs lEJorthinsss of eertain s^plieations for su;gpost« It
Is only y?=5snt3^ tliat this issue lias Ijeea claslfied^ with x®si?aiQSiMlity
for f ina:^ rseass^oSation of FostSoctosfal Bssearch FtgHo^^sMp a^asfds
being -!r«:/y£®& ±s. tb@ Institute's fS-aining Coi^Ealttess, and final Seoieion
oa Brsfi'icto^^ Heee^:^!i FellovsM]^ srsisaiBiag tlie functicm of l^i© HIH
Disei^f'Ja© Pas^ls.
4« Jtonges aasd iKpsfpinsmi^s in :^SQS^ms.
Ae As of October, 19^9» the Institute has "been able to sussus^
./a fact; as ^^11 as naim, loore consist® aSsdnists^tive control aver
i?ostdoctoral Ressarsh Jftellowship ai^Mfds, and, at the earn® tina to
relinc[uish any but nominal control over sherds at tl^ ps^^octc^^al
l®vel. !fhis a;g^a^ to be a logical step, inassnuch as identification
of categorical intez^sts in predoctoral training is esctreEsly difficid.t,
if not iu^ssible, i&ile it is only at the postdoctoral lev«l that
the ©aergence of ^j^cialized research interests is p^'c^tibl©»
Research Fallo^wship Heview Branch continues to receive ^Ll
fello^jship amplications and assign Hhsm. to Ii^titutes and Discipline
Panels, postdoctoral Sessarch Fellowship agglications aaf® turx^d
ov©r to -yie Institute for revieir and a^eeosMSEdatioa f os' action by the
Bostgraduat® gaining Cosssattses, and &V8z& and pajn^nt of those
appcoved, TJilda all ^e attendant ps^Dc<^dur®s.
B. As of January 1, 19^9^ sti^and levels \i&se incr^is@d for
^e» ei^ Postdoctoral FeUoHships, to allow for advances in th® cost
of living -imich nast b© met if individuals er® to continue in training
£ar research e^?e©rs in the D^dLcal eclenceso
Stese ebsn®2S sr© smmsss^sM. In tloe foHoHisg tables
iTevious stipends
$1600 ^ #350 pss? dspsaaaat $lBOO /« $500 per a^sMeiat
IBOO ^ 1350 " " 2000 y« $500 " "
2CKX) ^ $350 " " ^00 /- $500 " "
First jeas" $3800 -/« $350 "
Second ymr ^00 ^ $350 "
TMrd yeas- 1|.&)0 -f #350 "
5« B.X)^g2^ objeet-i-^gs fog 1^0
$l{-500 /» |5» "
5000 /« $50© "
5500 y« 1500 "
It is Ijelievea that in tbs cosdag sf^ap, it ^Xll be possib2®
to stebilis© th® procedures relatiag to edMBist^feioa of FosMoetoral
Pelio^rsMgs^ so tSist tiasse aTa^rds may "be used effectively in rcuoaiEg
out tb© total traiaias program of tlie lastitut®..
B?ogram ea^ssion is not aaticipateS at pj^sseot, since Post»
graduate S^^siHis^ Gssat ftads ar© gs^viSiriS stipends f o? ass iaacr©a®^
Slumber ot ssjstdoctoral felloi«B uatil ^3^ as^ qualified to a|i^ly for
Social fraiaegship Bvs^orto It ia bsOlev^ ^at tb© Beseas^h
Fellowship funds aimllabl@ saow sboiald be s^Ticient to ra&st tb©
research -fcx^Biag nseds of tSios® wbom it H®y l^ hi^sly Sssirabl® to
Bu^ort in dspartsssts wbes^ jao trainisig p^'ograais bave b@@a ©stablisbeal.
6« Voluit® of aggHcatioas
A^QicationB afevieaed:
B?edoctosal FeUowsMj^ kX
Postdoctosral " ^^^__
2ota:i. 105
Ai^ilicaticms a^as^sd:
FSedoctoi^ Fello-KsMps 43 $136,738
(31 s»ev| 12 pgaeirals
previouely eoamltted)
PostSoetorsl FeUoissMps 56 33Tj.6l4
(1{2 asw| lis. yeaemls
p^jviousl^f coasdtted)
part-tiim FelloB3hi|!S 9i» ___60,_^2__
SCSAL 193 $535,261fr
Avigsa^ cost of awards s
S»rsdoctoral $3,200 per amsua
Postdoctoral 6,000 " "
7. Stagf Asslganaeats
Elizabeth C. Eartmsai - Srainiiig AneOyst in cbarse of Social
3?3?alzi3e^iip a^ Research F^Uo^ship
programs «
i©i?©atla AB^iiml l©p@E=t ©f Cllsaieal iJS'Feetigatiosis
At -&© ti^ e»f Go^pietio^ of th@ B®^m%th hssma.1
E@p®i't ®f t^© Cliiiical Inipsstigi^ti^© Hait^ asa increase
iai &1I activities of t^@ Umit »^ i&oteS. A total of -
749 iapati@nt@ v®^® admitted S^i'issg tlii@ ca.l@@dar f@a3>,
ask iaeifeas© of 143 ©^@^ th® past ^ea^o ^© total patient
day® w®?© aajlSS; t^is is as iB@i"©^© of 2s@re &w®w th®
pjemv±€mB fear. Si^ feiMK^s-adj, ©ig&tf-t?/® outpatient®
we?® s@e^9 and Ig275 eossultati©^ wer© r®iicI@^®do fk®
St?sdi@® c@i^t@s*iag ar®imd th®&® patients ^ aad
@tk®2» aeti^iti©® ©f tla® Clinieal fewest igatiw mit^
disfeeted towajsfds fisi't^eg' MBd©^stssdisi® ©f ^©ms'ologief,!
asd op^tlialmological di©©M©s=s ., s^^ssmlted ia tla® s^pe-i?t~
isis of IM projects and @2 publications C@itls@3f pisb-
lisfeed ©f in pa^ss) for tfee cra'^s^t fsai*, W&®^® ^nQh
pafelicatiosss reflect ^emiiltm ©btai^@d from ps^^io^sa
yeasts tli© gl'w®^ iiive^tigatos* ^ae ^©t@d ©sell is &i®
report «
Ha© d@@ig^ p^ohlemm s^i^isg from tM® d©y®lop@®ffit
©f th® a©w ^eisro^tirgisal @?aite hs.'we occ?spi©«l majaf feonffSo
fJa© gs?©«aad for this telMisg^ ^feieh will homm thtm
suit© J h&B mov} hm®n teolsssig aad t&® final pVm^ e©s=.
»itt®« to th® taands of th© a^©iiit©eto This buU® will
coast itut© a n&^ d®psii?t?sr® ia ©p^fati^® ^©r/ign for
aeias'omu'gical ps'oeadMi'eSo ^tk is tke @®%>2>oem?gicaI
operating ro«^ as^d &ib. th® v&sdf, iMii^sive stisclies are
Iseiag yMertate^ ia a eoi^trol ©f air-lior;/© issf @€tiois® ,
and tliese &a^© l$@©a iiaeorporated bf tl£© le^srosisr^ieal
Brai&c!& into th® Eeport w^ich im ^img ©UdieS hf the
Surgical AdsiiBistrati^© Ce^itt©® for th® Matiomal Is-
stitutes of Health.
^sr©® Isat?®®tigat©rs ©f tia© pm^&'fM®mt staff w©r®
lost diariiag tlie year. Br« Glsum m&gep depart®^ ia
Jttlf » to aasn^s th® r®s^Msibiliti©s of Assoc iat® Prof®®-
sor of n@%irologf at Bailor W&lwe^@ttfi Wsm^toUe f^^asa
Dr. CsirtiSj of tia® Section of Memi'oelseMistarjs Isi^ re-
signed to return to teaclii^« Br« Gimter Haa@@ will
be leading in Janusiry^ to accept th® responsiMlit^ of
the creation of a neisrologieal %m±t at the ^iversitf
of Oklahcaaa^ where he will hoM th© rmt of Associate
Professor, ^is vill le&v® ^as^t the position of A@»
sociate Menrologist , until Jiilf% 196®, ^hen Dr. Sing
Sngel returns to take ov®r this position-. In January »
19@©j BTc Bostiag will as*s=iw® te ©stsJslisl^ tIa© S®eti@is
»3~
of Cellular Chemistzr i& the Br&sch of Qpl&tlialffiolosf o
Agaixa„ the Unit has benefited froa the auaer-
ous ^isitiag Scieatlsts amd Guest Wos-kers from abroad.
FroB Si^laad vere two senior investigators: Dr^
TAsmlejs who has Just departed to return to her Insti-
tute ia London e and BTs Williaa Rii^hton^ fr<»i Casibridge,
England, who has Joined the Ophthal@ological Unit, and
who is studying the regeneration of rhodopsin in the
BasKsmlian eye. During the ye&r^ Dr. Frits Buchthal,
fros Copenhagen «, Denaaark^ where he occupies the Chair
of Director of ths Heurophysiological Institute, was
with the Medical Neurolog^r Branch » Dr., John Caughef „
who occupies the Chair of Neurology at Otago Univer-
sity ^ New Zealand J, was with the Medical Heurology
Branch for a period of sis months.
Dr. Wherrett and Dr. Husphrejr^ both fron Tor-
onto j, Canada J, are also with the ISedical Heurology
Branch; Dr. Wherrett is in the Section of Neurochea-
istr^s and Dr. Hu»phref is spending his tiaae in the
pathology and electronics of muscle disease.
In the Branch of l^urosurgerf^ is Dr. Chou^, fron
Minneapolis g who is working with @icroel®ctrodes with
Dr. Choh-luh Li. Dr. Chou will be returning subse-
quently to the professorial staff at the University
of Miimesota. Dr« Strang , from Austral ia^, who was
also with the Neurosurgical Branch/ has stoved on to
Stoc^oln^ Sweden g for a period of sisc sionths^ and
heisce to return to Australia.
In the OphthalsBology Branch, Br. Lale and Br^
Tasaki (the former froa India, the latter from JapaiN)
have now departed g as has Dr. Gerin froa France » w!-^
was ia the Electroencephalographic Branch. At thr
time of this Report there reaains^, in the Branch /£
Electroencephalography, Dr. Morillo,, from Coiual-'^j ^^'^
Dr. Widen » who will fee returni^ ?,'ithis the ner:
week to Sweden.
As always, th© Unit has benefited by --och Visit-
ing Scientists aad Guest ■ Workers ^ and the s.xjcific re-
search undertaken by these investigators aii'i their con-
tributions to the research projects may b© found in the
Branch Reports included herein.
Specifically, the Branch of Medica.1 Neurology
reports as follows:
The Branch of Medical Neurology admitted j during
the period covered by this Report , 26S patient®. This
is an increase of 54 patients over the previous year.
f&e total patieat days ^ss S^SSlj, as iracFeas® of 1,007
patient dSLfm. Tfes average patiemt dafs was 26,0 dayg.
a decrmms® ©f 1»8 d&f© pes' patieat. Two liusdred^ thir-
t«effi outpatient© w@r© sees; an iacipeas© of 57. Tbua
there was a^ ±mcT®sB®d turnoves* ai^d as^ increased auad>er
of patieats botla on th® isapatieat aad outpati^at ser-
vice o
Th® asti^itie© ©f tlae Sectioa of Meuroclaaaiatry
are centered about t^e amisio-^acid ssetabolisa of in
vitro and in vivo st«di®s of norasal sad epil«pt<^nic
cortex p the electrolTt® &nd energy a@taboIis@ of nosttal
and epileptogenic eortez^ and tlae relation of pyridoxine
to certain seisyre almorBaXitieSo This includes studies
of protein etetaboliSM and turnover rates ^ the effects
of certain antieonvals&st drtsgs on the alteration of such
Metabolic processes ^ and the utilization of certain aaino
acids in th@i>ap@utic trials with seisur® pati@ntSo
In Misscle disorders studies are continuing on
the distribution of actin and tropooyosin in noimal
and diseased siyscXe„ Studies of alterations of acto-
aqrosin tensile strength in suscle disorders $ as well
as a cc3»paratlve study of contractile proteins in
saK»oth and ^triatad ^i@cle are being carried on^ and
finally^ attempts to produce miscle lesions in animals
injected with various protein contractile preparations
and adjisvants in hoth animals and tissiaae cultsire are
being done.
Yh® studies ®n new phfsical ssthod® to deterBlp-
Minute quantities of macrc^^lecular constituents Ib
C.SoF. and urine have ^©a terminated with thQ r@^ •'«<'-
nation of the senior investigators Dr„ Ctirtis, ^*s
results are suis^rised below.
Finally the Section has IMicated it© interest
in studying the formation and turnover of F/[A in the
C,H,S. Hiis will be started in ^if » I9@e^ when Drs,
Spom and Hingmaa Join the U^it.
Specifically J s>r. Tsswer hms shown ly tissue
slice technique that there is a very rapid £o£@ation
of glutamic acid and subsequently a slow©;( decline in
rates the latter presumably hf metabolic conversions
to other coi^pounds such as f'-asinobutyrio acid and
glutaaineo When cortical slices were isicubated with
40 bM salonate the glutaaic acid increaf^e rc«m.ined at
higher levels. @lutasine did not subs@i:|uently rise
nor did asaonia decrease in amount. However » the ^«-
asainobutyric acid increased 3X in the above studies o
malonate appeals to block glutssaic acid and is
effective "stabilizer" of th® free glutaimte pool.
Sine® lr-Sj,4-diaffiiiiofeiitfi^ic acid hscB b@ee r©-=
e^ffitlf reported to folocfe »®tabolis® of ^-auKiaotoatfrte
aeid it was also used im. is ¥;itr© slices « Ho @ff@et
OB glm.tsma.te isetafeoliisffia glFCoI^iSg os^ oasfig©® consiiffip-
tioii was noted ii?. ©osic«®ts»atiois® of 4© leMo Wiiea gi¥@®
iB yjyo to mic®j, t&i® coKpoisffid prodmced seizwr^Sg and
fE®~"safe;@qfu<gHat M ¥ltgo studf Bhovimd & r@ductloB of O2
coaswsptioii axRd gffi~SI^at,ioii of tfee ^-aaBiJsolsatfric acid
level o fliis waa s-epeated ±m cats,, injectiieg 8 uMAgs
S3&d m®izweem occufred ia si^ hoiirjii. Here the in ^itro
O2 Gotrnvrnptton decx'@Rse esoixld fe@ e0rF@ct©d hf gT^Tffig '
pfx-idoseal pls.©8pfe8s,t® but got bf givisag r-^Biaobiitfirie
acido ftse latter l©ir@l ^as 2X tfee aorasal aad iscr^ased
during ia©ubatio»o 1liws» B^o Tow©? feels this cob-
fines a block of i^-aniaoMtfric aiCid setabolis® bf
L<»2,;4 disMiaobut^ic acid, ^t he also suggests bM"
ffioffiia iffitosicatioffi of t&© braia cos&sist®Bt witli tiae
h@patot©xlc ©ffects of' this s?iS^taacec. Studies usiisg
aatpas-tic aoid hg the howrj fl^os-iisetric procedures
w@f® imsuccessfulc.
BTo Tow®^ has also imdeytakea a study on ©lee-
trolfte and ©aergf isetabolisis ia aoxmal aad epilepto-
geaie eortes: iss yltyoo Hais p^otsle® cars'ies with it
the p@remiial~IilTI5ult^ of th© qsaaatitatioa of thm
intra- aad ©st2'a-c@llulaa? fluid coiapaz»t^ffit« „ D^o
Tower utilizes the chlorid© spate® aiad concurreatlf
ehseks this ^-ith tli@ spaces calculated hf sucyos®. Bf
thmmm tsehmiq^ms th© chlos-ide umfS smcros® spae®e showed
Glom® csorFespoadeac® ia th® coisaJ. m&d epileptog^aie
eortesSc Missa ia€ufeat@d with gl^at^E'tc acidy glutssis^®
or ©spas>s,giss@ ,, t&.® slice® esghifeit&d a. sharked l&cr®smm
of the i&offi-els.lcrid© spac®., dasma-aaiaobutfirie acid
pi-odue^d lao ekaisge Im. tliifs spa®®,; i^jowevesaro Wtrnm ia-
ciabated uad^r hypmcic eoaditiosEts „ i.^e chloi-id® aad sr'
cK'os® gpace wes"© ^ losg@r similasf,, aad iadicated
s^fi?@lliii^ of . th@ aoa^siacros© space ?jid iaflusE of chl. "
fid® iat© thiss. spaeec 1!his is ©■ss'isisteiat with ree ^at
s'@pos't@ a®d places eafiphssis oe tM profeahle aoa-s" iia-
feilitf ©f thQ eiRlorid® method f©r cleteapsBiaiag ess- -fa-
cellular spa©® iffi d!a®a^ed tiasueo
la ao2S-dajiaged tissue 5 ho-©®¥®rg the Sl'lott-
Hellex- foi-MuIa s^f be used to eistiseat® the crsioa dis-
triMtiois ia th© aoa»©hI©rid@ spac@ C"? iffit:rs^@llular>o
It appsaira tliat aeuroas aecosmt .fog= 7§ percv^t of €©?-
tisal ffioa-shlc-rtde space aad cortical potafsiump biat
oaXf 4i P',- ::f sodisiss. l;gti^si©si of ra aad uptafe©
of K is t;- IG t%s EtSus'QSo Tliis is .presumptive,
aad i&' :cs5Ptical as\d sutjcof ileal
glial IBis tfea?L allows aa
estism,tiom of tk@ O2 coss^ngptiom of eorticai i&@wroMe
in ^iFiss of iio£i"-eSilorid@ mps^m volvms c ' Hi® i£@Mifoiis
@liow@d ali£0@t do^sbl® th@ i^tabolic skctivitf of glifto
It is of ii£t@r@8t tkftt tfe# "extra" ii»@ta^lic acti^itf
of tile aenuron aiasost mx&ctlf mqu&lMd tSi« fraetios
of ii@i&roaal oxidati^® setabolism attributable to
7--a®i®olmtfrie acido
(m^ York Stat® Psfelilatric Institute) » ha¥@ earrl@d
out a 8t«&df OB the iacorporatios of lal>@ll@d a^iao
acids iato protein fractions of c@r@l»ral tissue c tbmf
have »homk tliat L->siuta»iiie-U-C-^^ is incorporated iato
protein-bound giuta^ines tlie specific activitf being
0o5 percent tlie specific acti'iritf of tbe free pool gl^ita-
misso Vlien 40 siM »aolonat@ is added Cblocks glutamic
acid i»etabolissi»°°se@ abo^@| tbere is a decrease of pro-
tein-bound glutamic acido Similar ea^perisieats witli
KOiM KH^Cl Ctbis elevsitem free glutamlne and depresses
free glutaaic acid) showed a striking rise of protein-
bound glutanine. These findings, combined with the
demonstration of sIot? C^^ turnover in protein gluta-
Biates lead Drs„ Wherrett and Tower to conclude that a
portion of cortical proteins ^ in^ol^e^ed in the active
subino group traj^fer^, utilise the carboxi^ and a«id@
groups on protein glutamic acid and glutaieineo fhis
is one approach to Vaelsch's thesis that cerebral
proteins m&f participate in s^ino nitrogen i^tabolis»
and Drso Tower and Waelsch feel possiblf that the
transfer of a»ide from protein gluta9y.n® to free glu-
tasic acid »af b© important to neuronal actiiritfo The
findings with M4CI have :^ obvious bearing on the
chemical basis of hepatic co^ao
DTo Mclhanng since joining the Section of H@uro<~
chemistrfo has also worlied with i^-soiinobutfric acid
and pfridosin@9 and has finished & studf on a patient
with pfrido3Ein@ dependencf . A decrease in cerebral
osfgen consumption was fotmd in vi^o during depletion
which was corrected hf adding pfrldoxine^ Thus this
condition varies froii other tf pes of seizures in i^ich
oxfgen consumption increases » Two tfpes of pi^idoxine
deficiencf have been found bf Dr. Coursin; in one tfpe
there is an abnomallf rapid conversion of pfridoscine
to. 4°»pfridoxic acid, and in the other there is an ab-
nornallf rapid excretion of ingested pf rido%in@ through
the renal app&i'atuSo This patient was shown to be of
the second tfp^o Experimental aElm&l studies in kit-
tens on pprido%is£@«fr@e diet precipitated ataxia and
seizures and death. A studf of the braids <f these
fiiittens showed a decrease of ^-aminobutfric acido This
latter defect could be reversed im ?itro bf addition
of pfTldoK&l phosphate or ^«»£®isiolmt^ic acid, "^is
adds to th® ovidence that pj^ridozal phosphate acts
as a eoenzpae aecessarf fosr th@ eozfma glutamic de-
carboxylase ^ and corx^lates with the study above oa
electrolyte asid energy laetabolism in showi^ the
"extra" sistabolic activity of the neurosi i© dependent
upon the oxidative SMtaboiisas attrilmtable to ^•°aiiino->
butyric acid a
investigators continued their studies on
the quantitative contribution of ^-aninobutyric acid
pathipay to total oxidative aietsboXisa at the
cycle stage, using pyruvate~3->C^^ as a tracer.
studies shouted that 44 percent of the total substrate
aetabolized fross a-ketoglutarate to succinate was via
the r-attiao^^^tyr ate pathway. Since the latter pathway
froa the above to be alaiost exclusively
' it is estiaated that nearly 60 percent of
kl oxidative estetabolisa proceeds via i^aaino-
butyric acid. Since this varies in a sigaoid&l fashion
during 1-hour incubation there iSj, in the »inds of
these investigators, a suggestion of a reciprocal smta-
boliSB via the parallel succinyl-Co A pathway. Mere
studies were done with cortical mitochondria and s^-aiiino->
butyric acid-l-cl'^o comparing the C^^Og evolved to the
total Og consumption. In the presence of arsenite,
which bloclcs a-ketoglutarate to succinyl-Co Af, the in-
hibitory was not seen. Thus^ as levels of the comaon
precursor g a-ketoglutarate^ rises the latter pathway
Csucciayl-€o A) is referred, lu vivo studies using
pyruvate-3-C** show that^ in inXtlaT'studies , the
labelling of glutamic acid and ^-asinobutyric acid is
extreaely rapid. ITeing seizure preparations Cio®. thlo-
senicarbazide and lr»2,4-disainobutyric coavulsants)
these investigators feel the aatabolisa through th^ y
aainobutyric acid pathway rather than the level of the
^-aminobutyric acid itself is the significant factor.
Finally g Dr. Tower and his group have uti.i£;@d
l^ansinobutyric acid to treat ten seisure patients.
Fifty percent of these patients isiproved. The B.B.B.
Cblood-brain-barrier) seeiis to be the chief factor in
the variability of response as the permeability of
the B.B.B. between seizures appears to be limited.
Or. Horvath is continuing his studies on the
BBolecular architecture of sssscle in norieial a».d dis-
eased states s and is now devoting Much of his tiae to
iOBunocheaical aethods. Thus^ in the study of tropo-
nyosin A he has developed tests and standardised
»7-
quaBtitative detoxtais&atioas of iaanuie pirecipitios ,
iacluds am adaptation of the sabat ^tliod ia
•precipitates a?® wastbed asad tl&e aitro~>
contest measured br direct nesslerisation., Sesni-
quaatitative sBeasures aa^ also be obtained by cbro-
nat<^7a|daic technique j, developed by Dr. Miquel^ in
ijhiels antibody and antigen are paper electrophoresed
together. The soluble protein soves bnt the insnine-
precipitate resains at the site of application. This
any thes& be stained vith broaphenol blue, isluted, and
deteraiasd ^Sloetrophoa'^tieailigj ^peefrcpKoiowetr/c ,?//-.
Both of the methods Just listed provide in-
foraation on quantitative bases as to the aoount of
antibody circulating and on the stoichionetry of the
antigen-antibody reaction. Thus, vith clam tropo-
ayosin the systea was found to have an equivalence
point in vhich tvo antibody molecules coebiae vith
one tropcHftyoein A aolecules while in the antibody
ezeees region four or aore antibody nolecules coa-
bine vith one tropt^syosin A aoleculeo Titers rose
as high as 2000 t&g/al. after a second set of injec-
tions tvo Bsonths folloving the first. Circulating
antibodies vere identified by electrophoresis as
^-globulins. These antibodies vere found to fall
vithin one aonth after iaaunisation to about 10 percent
for the maxiaal levels and booster doses raised the
titers in approxiaately ten days. Br. Eorvath carried
out a aH>re rapid extension of this method by using
the passive heaoagglutination test of Torlaender.
This aethod uses tannic acid treated sheep red cells,
laaediately after such treatment the cells bind tropo-
ayosin A and are agglutinated by high dilutions of
anti-claa tropomyosin A. Horaal sera vould not do
this« This test does siot^, hovever, have the accuracy
of the quantitative precipitin reactions, but it is
very auch faster. It is of interest that skin tests
on patients deasonstrate persistence of changed reac-
tivity several aonths after iaaunisation whereas the
epheaeral nature of the circulating antibodies has
disappeared. In addition to this 9 diffusion agar
plates have been used for testing the hoaogeneity of
the antibodies c After the first set of isaunization
injections,, only a single precipitin line appeared on
the agar plate » and it vas ostisaated that is^narities
could not have exceeded three percent. However ^
siailar tests after a second set of injections revesi-ed
nultiple precipitin lines. The causes of this are uov
under study.
Cat auscle ayosia apparently is aore ctmplf^-M.
than that of claa trop«%iyosin Af, and the agar plf.tes
sho^ smvmTAl precipitin lines. Tl!i@ q«3&iititativ@ pre-
cipitia Tmzcttomm fail to show a clsarcut optiisa^
obe@r<r&tio]^ ar@ coosisteat with the concept that
i^osin poss@mmms ssi^eral antigenic groisps asid that th€i
s^bimits of mfosla. possihlf cosisist of a ccmplmx of
twopomfomtn a^d acti^. A study of th@ cross ^@a€tioi%
of cat isfosin and cla® trop<ME^osin ifdveals a 50 percent
crossoir^r, Coasid^riiig the Tmmotm relation between
the two species^ Dr. Horvath belieires this decionsttrates
a close relationship of the two proteinSo
£^0 Hox-vath has also continued his studies on
alterations of actosyosin tensile strength and of
gniscle proteins in neurowiscular diseases „ He is thus
iaeuniziag rabbits with nuscle proteins prepared from
rabbit Kuscle, The initial studies on inoninization
of rabbits with rabbit actin were done probably with
preparations which were 50 percent impure » Under the
ithodSi, which are 99 percent pure bjr the
criteria of polfaserisations, antibodies could also be
developed in rabbits „ Most of the impurities were
presuned to be tropoefosin 3, Vhen tropoa^osin B was
prepared fr<Mi rabbit nuscle it was foimd rabbits could
be isanmiaBed with it, with titers obtained as high as
300 uso antibody N/nlo Sinilarlf rabbits could also
be nade antigenic to troponfosin Ao That this reac«
tion is not due to chemical manipulation naif be in-
dicated bf the fact that fluorescent antimyosin stain-
ing of Kttscle samples confirmed the site of the anti-
bodf reaction 9 and the biological activity of myosin
isolated iTom ssguscle^ in terms of AIT-ase action and
the combination of contraction with mFosinf, is not
altered in the chemical or biological sense » Attempts
to produce muscle lesions in guinea pigs injected with
various muscle preparations and adjuvants have not
been uniformly successful so far^ This has also been
atteiipted in tissue cultures of mmalm in which s<Mfie
effect has been demonstrated f, but ig^re precise studies
are needed to define the conditlonia »
this break-through in imesuj&ochemistry has led
to a temporary stispension^ during the calendar fear
1959 {, of Drc Horvath's collar at ive biochemical study
of smooth and striated muscle « However ^ a dystrophic
mouse colony is being maintained to provide one tfpe
of source material for such studies o
Dr, Bushi&ell Smith, who tm now entering his
year, is in the laboratory with DTc Tower » carry-
ing on a study as to the effects of anticonvulsant drugs
on cerebral electrolyte metaboliigmo He has found a
«9-
slighfe effect la reducing slie. aon^chlorlde space s^s^ivasj
concent ra£io& duriisg iacubstion wifch "BiJSissojE" afe m coij;»
centK-ation of 3xiM/Lo Shia is ^pgossteaeely fehe coa^^-
centras^ion Vtamsa to effectively iohibit hl0t3d e^tsonic
anhydras&o Oehcr concaatx-atiocs of "Diamgrs" are now
under seudyo It is planned to do sisailaic^ studies viifeh
diphenylhydantoia CDilfia^in)o
UTo CuK&is left; €be Branch o£ Msdical Neusology to
return t& teachiaso Bis primary interest during his
stay at the InsfclKuee vas eba£ o£ developing phy8iG«»<»
chemical coethods tor determining snisute aioouats 3£
material in organic fluids, such as spinal fluid aed
urin@o This was directed particularly to the i<krEifei»
flca&ion and characterisation of raacrossslecules^ such
as polype£ld@s» pyrogeos^ ef,Co» which occur In the
urine and other biological fluidso One such etuiy was
directed towards $;be presence of any specific sufe»
stance which might be liberated or pr^^bced i^ as9oci'°^
a&ion with primary or secondary d^Byelinisa&ion in
the central nervous systetoo Qto Curtis, st the time
of his leaving^ was studying this by methods of bubbl»
Ing benzenes under contiirolled conditions of r&te and
drop sises through a column of cerebral spinal fltiiido
With this method apparently c'.oic^lete resaoval of lipids
appears to occuro Subsequent chromatography of such
lipid«'Containlng bensene on silicic acid £apr®gnja^<^
paper detBonel' rated the presence of iecifchins cephslin,
8phingoaiyelia» cholestexoi and cerebsosideso His pre»
liminary studies indicate elevation of sotne eubst^iceSs
particularly the latter threes in cerebral spinal
fluid san^les £r@m multiple sclerosis patientSo ^
quantitative data was possible however by this t^thod,
but the lipid "profile" seesaed consistent with ehe re-
cent report by Sourtellotteo Cosi^liisentary studies
were carried out on a model profeeinj. which was guinea
pig serum asparaginases as xixited in the last Ammal
Report, which yielded considerable iB£ormation« fhis
is a globulin which as reMlly assayabie ^teyme ae*»
tivity,, and can be isolated as & crude fraction ££om
serum by smtssniuia sulfate precipitation and c&t subse»
quently be partially purified with calcium phoephategelo
The crude fraction contains two visible coBtamiaaats by
electrophoresis and at least one liy ultracentrifuge
analyslSo
The previous studies n^orted in 193S indicated
the ensyme activity was associated with the £smte»t
component in the ultracentrlfuge analyslSo However,
-1.©-
purifieatiofi bf tlaes® sieai&s was uiieuc6«@sfulo Is 1938
it mm found that tim cmllulom® rm&im. developed hw
Petesiioift; et al» wotsild complete If absorb this @ffi2f%@c
Studies this fear 02& @li%tioa& of the eiizfne eiearlf
iffidicated thatg under the appropriate pH and ionic
stres^hf, four separate proteie-containing fraetl@^3i
eould be eluted trem these cellulose coluasnSc @ood
separation of the four fractions was obtained ^ but
onlf one contained asparaginase activity o Hiis sug-
gests that c^&plete purification had been achiefed with-
out loss of enKfiBS activity « and represents the first
such isolation of an ensfise protein in this nanner„
the Section of Biophysical Applications has
transferred the eollis^ting scintillation scanner
and its instruaent console to the Departnent of
Radiologf of the Clinical Center „ where it will now
be used as a diagnostic tool for future studies »
to the aaaount of instruteentation technique involved
in this apparatus 9 however^ the technicians from the
Section of Biophysics are working with the Radiological
Oepartssent on each patient scanned c Ihe scans in turn
are read both in the Departi^nt of Radiology and in
the Section of Biophysics; the reason for the latter
being that the Section is attenptlng to obtain 900
confirmed scans before dropping the research interest
in this given technique. At the present tia@ the
Section has 3S9 scans <, We are suggesting to Ore M-
Chiro that methods now be used in the scanning tech-
nique in which the posturing of the patient alight
bring out lesions of the parasellar area and lesions
in addline of the. posterior fossa » such as is being
done in standard radiological techniques. It is
probable that this part of the study will be trans-
ferred to the Section of neuroradiology o
In the S)@anti»)e^ histopathoiogical and chemical
investigations on neuroaa&scular diseases are continu-
Ins 8 asd this is a continuation of a long-tesm study
initiated at the inception of this Institute « Over
the past years the Institute has elucidated the path-
ology of ffiuscle disesuse^ the role of certain cations g
and contractile proteins in miscle diseases and at
the ti^ of the 1958 Report had finished a prolonged
study on the endocrine and a»tabolic aspects of nusc:'^
disease o During the pi^t yesur attention has been p»'-d
largely to regeneration of imscle ±m various neuron-
genie and primary ma&el® disorders c An inclusive
study of the prii^ary pathology of peroneal anisculr-r
atrophy has teen concluded » and the final studier of
the various inter-related factors in cationic pf.«*alysis
have al^o been comcludedo
-11-
To follour th« regeneration of S!uscl@, tritiua
CH^) labelled thymidine has been now used in mom^ 20-
odd c&s^ of different neurological disorders in whieJi
there is sulisequent vasting of nuscles, and autoradio-
logf is noi? undervajr on these sections » Proliferat-
ing cells will Manufacture desoxfribonucleic acid
iJaXA}(, and in doing so incorporate the labelled thf-
fiy.dine. Hie low energy range of tritius allows the
precise localisation of such HHAo
The cationic disorders were studied in rela-
tion to thfroid netabolisn,, to E-42 exchange » and to
aldosterone hj aeans of double isotope derivative
and in relation to certain phamaceutical
such as SC-8109» a steroid-17 lactone » and 2-
neth7l-9-alpha-fluorohfd7ocortiaone» which deliberately
shift i^novalent cations »
Major findings to date are that over 80 percent
of cases of Charcot-Mar ie-Tooth ' s disease denonstrate
aeyoi».thic findings as well as neuropathic findings
on patholc^ical esaaination and on electrosyographf o
!lo such findings were foimd in cases of asyotrophic
lateral sclerosis. Two of these cases which were
clinically classical and demonstrated sensory abnors^-
alities showed only myopathic changes » Eighty per-
cent of the total demonstrated s<m» nyopathic involve-
nentj, whereas 100 percent of cases of asyotrophic
lateral sclerosis showed only neural involvesento
In the cationic diseases g three separate en-
tities have now been separated which way cause sudden
flaccid skeletal paralysis o fhese are fssdlial
periodic paralysis j, paranyotonia congenita ,, and prisary
aldosteronisn. fhe pathophysiology of each is dif-
ferent o In faailial periodic paralysis there is re-
tention of both potassiuB and sodiua^ and there is a
hypokalemia. The potassiua which is lost fro« the
enters the cello Enough water enters the cello
to hold the concentration of potassiua ap-
proxiaately the saaie. This has been confiraed by in-
tracellular electrode recordings » Sodiu» depletion
aids in the recovery of the attack or prevents the
onset of such an attack g and sodium loading precipi^
tates the attack. Sscactly the reverse is true for
paraaiyotonia congenita ,, although in this disease also
d-l aldosterone does not precipitate an attack. Studies
are continuing in the physiology and pharmacology of
ayasthenia gravis, and as stated in last year's Annual
Report «, the objective was that of intracellular re-
cordings of resting potentials in patients with myas-
thenia gravis „ The difficulties of this procedure
poiated out ±m ttee Isugt Asniml Reports ia whieh
descriptions of the pereutaiieous a^ithod of introduc-
ing sderoelectrodes bliadlf inside single o@iIs was
gl'mm. Approiginately 18 such patients were studied
in tfe© current fear» with over 200 penetrations.,
It has b9Gom» apparent g with our pr@sent tech-
nique at leasts we will not be able to suceessfullf
cajrrf out this procedure through th® intact skin.
Such patients would have to have surgical
of the flaascle to earrf on such a studi^c "Ehis
in the program „ hence,, has been tea^porarily abandoned »
', the pr< -
progras itself ,, like nanf others ^ has
now separated into two different components « fhe
availabilitf now of agents which influence th^rroid
for»ation and TSH formation^ as well as aethods of
influencing each independentlr^ has allowe'd the Umit
to wmk.9 an extensive studf of the problen which has
long baffled neurologists, io@o the relation of thy-
roid ffietabolisa to s^asthenia gravis. This facet has
now been worked out hf Dr. Andrew Bngelp and will be
recorded in a separate project .
At the beginning of this reporting |fear» the
Institute was fortunate in having with it Dr. Fritss
Buchthal froa Copenhagen,, and his method of electro-
iphf is now esctensively used within the Branch,
recording instruasentation for the intracellular
work in rafasthenia gravis has been converted ^ there-
fore 9 to this particular project. The nethoda now
used are those of eultiple concentric electrodes so
that Sfuchronization and notor unit areas nay be
napped. The studies at the present tine include a
studf of the internal ocular nuscles in which nirstag-
nus is present in cooperation with the Ophthalaological
Unit, imis studf has Just been initiated. It is of
interest that a characteristic n^asthenic response
has now bean seen in patients with generalised sar-
coid disease, and it ssa^ well be that this technique
nay be of us© in the diagnosis of this disease. The
reason for thiMf, however j ia still not clear and is
being followed at this tieie. fhe duration of the
action potential in varying groups of isuscles at dif-
ferent ages of patients J, which a® yet have not been
charted:, is being undertaken b^ the Fellow assigned
to the project. A direct correlation of the HISS wit&
the Muscle pathology is continua.Ily carried out on
each patient admitted to the mesc1@ projects in this
Institute.
It is of interest that ©lectroBsyograph^f is fal-
len ia disrepute ia a^aa^r i^dtcal e.®at®r® fe th© l^ited
States today, Tfeis iBstitixt® is ©ou- aes.Tiaced ,; af *©'►',,
-13-
aealfzisg soffi@ 110 of our ows. patients using thm Co-
penhagen tfpe of studf 9 that this conclusion was
Tsachsd because such studies were not carried out
with the pathophfsiolosf of the various disorders ±m
sind. It is our belief » after this series of patients,
electrosyogran will be of definite value when cor-
rectlir done and interpreted » and has san^r tises given
us infomation of real importance in the understand-
ing of our patientSo
The clinical pathological correlative studf
of the nervous sf8te» in cases of orthostatic hypo-
tension has now been conpleted, with the serial sec-
tions done on the postnortes case listed in the 1058
Report bf Drso Z>n^er and Shfo In this case Sfs-
Metrical lesions were found bilaterallir on each side
of the brain stea^ in the ventral » intemediolateral
colusn^ and Clark's cell colu^ra of the spinal cord.
Moderate gliosis was also present and most evident in
the dorsal funiculus » In the aiedulla^ degenerative
changes of the inferior olives » the nucleus asbiguus^
the dorsal nucleus of the vagus » the nedian Raphe of
the tmes)&nt%m» and the lateral cuneate
also found o in the cerebellum and ponsp
changes were found in the Purhinje cells and in the
locus caeruleus of the ponSo In the midbrain s, lesions
were found in the substantia nigra » the third nerve
nucleus » the Idinger-Westphal nucleus » and the central
aqueductal gray. Some changes were also found in
the posterior hypothalamus. It is of interest » how-
ever ^ that the cerebral cortex was norauil. Since the
cerebral cortea: is the aeost likely to be affected in
of anoxia 9 and since no thrcHsbotic lesions
in the cerebral blood vessels » it would
appear that this lesion could not be explained
on either of the latter two postulents. A review of
the literature indicates similar neurological find-
ings in the majority of cases reported , and it is
highly suggestive therefore that so-called orthostatic
idiopathic hypotension is^ in fact;, a degenerative
disorder of the central nervous system involving the
above centers » and could be corresponded to the so-
called motor neuron dit^eaise long recogniseed as a
system disease.
Section of Clinical Heuropharmacology con-
tinues its study around the choline esters found
naturally in biological systems s and the study of
muscle cholinesterase and its inhibitors ^ and studi@8
of depolarissing c<^pounds and their effects on myo-
neural Junctions o ffeey ar©., in additioae studying
-14-
ti£9 aisat<»Bl(sal phfm^olcstG&l correlation of tlie moto?
mult im
M disciassed i^ pre^^ious fteaars, ose of the fac-
to3« of aiost ifi2p©s>t&ffic@ ia determiaij^ tise etiology
of Bfsstlaeaia gr&vie would be tb® ideatif isstioa of
a sutetaatce ia diseased aioscle vSaicl& would act siot
unlike c&oliae esters ^ l^ut mot be I&srdTolized hy the
Buscle choliaestefaae as is the acetjrlclioline. Such
a substaace could be preseat in miscle ia abnos^ial
aaounts, and thi;^ pr<mouaeed effects mm susele fuae- .
ticm could occur, ^hwsg for esEaaplet, batfryleholiaec
iaadazoleacrylylcholiae, and dihydro-acrflylcholiae
are all nearly equal to succiaflcholiae ia depolaris-
ias striated ausel®. !n an attes^pt to study the ac-
tion of such choline esters and cheaically related
stttataaees on sumcle aiSBbraae; and to isolate and
identify such choline esters p these investigators
the following
First; a tr&¥elliag fluid electrode is used to
depolarisatioa of the oaiscle aeabraaes. This
las the advaatage of recording the dif-
ferential depolarisation of a large auaber of intact
Boscle fibers. Secondly ^ paper and colusm chroamto-
graphs are used for the isolation and identification
of choline esters and other quaternary coapounds.
Finally^ the heart of the claa venous nerceaaria is
for identification and assay of acetylcholine »
investigators have found that the accur-
ate concentration response relationships could not
be obtained since one depolarization ooopound reduced
the sensitivity of subsequent tests and the test
aDQScles varied considerably in their response. There-
fore g by selecting a narrow range of depolarization
to be produced 9 and the use of <me auscle for each
tests ^ comparison of potency was possible. Their
studies appear to indicate that if choline esters
were not hydrolized by the ousclecbolinssterase, as
is acetylcholine » and tsere hence present in the muscle
in abnoraal asBOunts^ pronounced effects on Buscle
function could occur. The identificatic»i of such sub-»
stances in diseased amscl® ■^onM apparently require
nusele saaples no larger than 1 graa. This study is
of eztreaie ia^jjortance in the disorder ayasthenia
gravis and will be followed throu^ the neast year.
This Section is continuing its studies also of
WBOBGl® cholinesterase and its inhibitors. Thus« they
find that the cholinesterss® content of aiiscl® is low
a^d not uniformly distributed throughout the tissue.
-15-
aad mmcl® h&s aot h^en ad®q«ia.tQly studiod in respect
either to the type of choiinesterase it contains or
as to the substrate and inhibitor specificity. The
approach in the ctwrent S'ear is that of adequately
characterizing this intportant miscle ensyms in rela-
tion to its substrate specificity. Another objective
is to exaaine the activity of the enzyiae in the pre-
sence of ^ell-known inhibitors which are in wide use
clinically J, and to correlate this activity with their
usefulness, ll&ls could then fora a basis for testing
newer coapounds having a potential in the treataent
of nyasthenia gravis. In studying this the standard
Warburg a»n<»setric technique is used for determina-
tion of BBUscle cholineeterase activity. The depolar-
izing properties of cholinesterase inhibitors were
determined by the use of the travelling fluid elec-
trode system. These investigators have found that
Lua had the greatest inhibitory activity on
sle cholinestersMse of any of the conpounds tested.,
had the greater activity in this respect
did pyridostlgain. The @ajor part of this
work has centered around the testing both in vivo and
in vitro of compounds which seea likely toTiave a po-
lenfliiruse in the treatssent of myasthenia gravis.
Galanthaiilne is an alkaloid which has recently
been isolated froa plants of the Aaary— llidaceae
faaily in Russia and Japan „ and in this country by
the Laboratory of Cheaistry of th© National Heart In-
stitute. Another substance of auch proaise is Lycora-
alne^ which is an alkaloid with a cheaical structure
closely related to that of galanthaaine. This labora-
tory investigated both of these coapounds and their
related derivatives as to their auscle potentiating
and acetylcholinesterase inhibiting properties. These
coapounds are both derivatives of phenanthrene and
are of interest because cheaical ly they differ aarkedly
frmi other ccMBpounds currently in use for the treat-
aent of myasthenia gravis. The ce^pounds tested were
galanthaaine hydrobroalde » galanthaaine aethyl iodide,
lycoraalne aeethyl iodide ^ deoxylycoraaine aethyl
iodide » deoseydeas thy 1- lycoraalne aethyl iodide » neopine
and neopine aethyl iodide. In this study the quater-
nary foras of the alkaloids were found to b6 aore ac-
tive in auscle than the tertiary foras. Lycoraalne
aethyl iodide produces about the same amount of inhibi-
tion of cholineeterase as pyridostigain. Galanthaaine,
both the tertiary and quaternajry fom^ produces aore
inhibition than does pyridostigain. Deosydeaethyl-
lycoraalne aethyl iodide was the aost active compound
founds and this compound produces cholineeterase
inhibition @qual to that o£ a@ostig»ifi© or phfsoetig-
»ii8©o Th© ift vivo Kuoel© potent iat lag aetivitf of
th« ccmpo-imWcoTW^l&t^d vmll 'with th@ isUiibitiiig ac-
tivitf o Plasma c red blood cell aad brain choli]i@6~
t«ras« is also inhibited « Tt^ potency of thes« com-
stroeglf au^est that thef will offer advant-
la the traatiBttiit of sf asthenia gravis, Galan»
has already received such trial in the 1ISSR»
and aore recently in Sweden o fhe biological activitf
and use of lycoraadLne has not been previously de-
scribed:, and it would appear that we are about ready
to £ov@ into clinical trials of this coi^pound after
to3iicity studies have been carried outo
To better understand how the depolarising
agents work on suscle ssnbrancts,, a study of the ef»
flux of enzynes fr<» such ausde has also been car-
ried out in this laboratory g in which standard bio-
eh«Bical procedures are used to estimate enzyne ac-
tivity in plasna and ^ascle^ Here again „ the travell-
ing fluid electrode is used to indicate the asount of
depolarization. Ibis laboratory finds that the
Buscle loses aldolase when kept in a solution contain-
ing depolarizing concentrations of potassiuato It has
not been determined » however, if this depolarization
of the cell mm^bseaae is the causative factor or
whether the loss of enzyne is due to activity of po-
tassiuK at another site. In an attempt to find out
whether aldolase leaves the masclQ under the in«
fluence of succinylcholine;, escperiments were done on
pairs of rat suscles reiioved prior to and after the
adninistration of this drug. Changes in the aldolase
content of the escperisental iiuscles were variable
and not pronounced » at the end of brief periods of
depolarization, fhe laboratory has also found that
substances which depolarize nuscle Bienbranes also in-
hibit leuscle cholinesterase , but that such inhibitory
concentrations are such greater than those neces-
sary for depolarization^ and thus esterase inhibition
by these cospounds appear to be unrelated to their
depolarizing activity.
Finally ; in this laboratory » Dr, Irwin and Or,
Korris are doing a microdissection of peripheral nerve
and electrophysiological studies to detemine the
actual extent of the physiological aaat<»iical liotor
unit. 'ih@ two studies on the action of neuroaoiscular
blocking agents on directly stimulated Innervated and
denervated tBusclSe and on blood and tissue choline
esterases in neuroeuscular blockade which were discussed
in full in the 19S8 Annual Eeport, have been cospleted
»17-
aad are now published. Both of these were ©scellexit
studies o The papers published in reference to these
studies were on the contrActual response of directljr
stiJBulated muscle after administration of neurosuscu-
lar blocking agents j, and the effect of certain n®uro«
nascular blocking compounds on directly stisailated
Muscle „ The paper on the effects of selective inhib-
ition of msscle and plasaa cholinesterase on neuro-
nuscular block has been reported at the Second Inter-
national Sfnposium on Ksrasthenia Gravis, and the
sethods and findings naf be found in the 1958 Annual
Report. Ttkeme projects are now terminated .
'^e Section on Keuroradiologf has carried on
studies as to the skeletal changes accoapanyiag Dys-
trophia Ufotonica; the correlation of brain scanning
with standard contrast studies; a study of fractional
encephalography 9 which is anticipated will culminate
la an Atlas; a study of the sella and piuitary in the
horizontal plane ^ which is a conbined X-ray and post-
sortes study; and a study on the encephalographic
changes in the tesporal lobe. In addition studies
are being carried out on a bilateral angiographic
evaluation of the superficial veins and sinuses of
the brain f, and a radiological study of the soft tis-
sues in different suscle diseases is being carried
out to correlate with the overall large prograjK in
;le disordesv.
In coffibination with I^. John Caughey, Associate
Professor at the Rational University of Sew Zealand,
Or. Di Chiro carried out a study of the radiographic
changes of the skull in eighteen cases of dystrophia
syotoniea. Eighty-nine percent of these cases showed
"hyperostotic" changes of the skull vaults which
these authors have grouped into four different cate-
gories. Ihey arrived at the conclusion that the
longer the duration of the disease,, the aore narked
are these changes. They suggest there is also a
possible correlation between the anount of hyperos-
tosis and the proof of hypogonadisffi, and interpret
these findings as due to increased circulating growth
horKones, This project is now terminated and will be
published in the Acta Radiologica.
In correlation with the study in brain tuaior
scanning g Dr. Oi Chiro has picked the confirmed tumors
in which adequate studies » both by means of radioactive
scanning and by means of arteriography and pneumography ,
have been acccmplished. Osie of the chief criticises
of the previous work on the braia scaaaings which is
reported in book form and in the 19 5S ^Innual Report »
is that no definite correlation had been done between
-18-
this and other standard neuroradiological techniques.
Dr. Di Chiro has now over 60 cases which have ade-
quate studies in all three such techniques ^ i. e.
radioactive scanning, arteriography ,, and encephalo-
graphy. It is hoped that this study, upon its cob-
pletionj, will better elucidate the advantages , limita-
tions, and future possibilities of the brain scanning
technique in relation to standard contrast techniques
now available.
The superinposition of different anatonical
structures snakes difficult the interpretation of
■any gas contrast studies. This is particularly
true in the area of the posterior fossa. To obviate
these difficulties g Dr. Di Chiro is undertaking a
c<»ibined laainagraphic study conbined with the or-
dinary encephalograa done by the fractional nethodo
Laninagraphic studies have been done dixrihg the
period of tise that the passage of air through the
different sections of the ventricular systen and
subarachnoidal spaces is occurring. The lajiinagraphic
cuts were taken in different projections and in dif-
ferent planes, \pprozimately thirty patients have so
far been ezanined with this technique . The initial
study is limited to cases without intracranial space-
occupying lesions. This study will be conbined with
routine fractional encephalography in the prepara-
tion of an Atlas devoted to fractional encephalo-
graphic anato^. Combined with this^ brain specimens
are now being studied to establish a correspondence
with the structures seen in the encephalogram. For
this purpose different structures » especially in and
around the brain stemg, are being coated with radiopaque
fluids s and afterwards escamined with laminagraphic
techniques .
fiSany studies of the size and shape of the sella
have been accomplished in the past, and recently a
monograph on this subject has appeared in the British
literature. Hone of these studies, however, indicate
the true volume of the sella in that a reconstruction
in the horizontal plane has not been attempted. Volu-
metric studies of the sella are becoming more neces-
sary with the increasing surgical approach to the
pituitary and sella. ThuSp in recent years hypophy-
sectcmy is being carried out in numerous clinics for
endocrine carcinomas. Zntrasellar implantation of
Yttrium^ seems to be a highly promising technique,
both in pituitary tumors and in other conditions in
which the destruction of the pituitary is indicated.
-19-
^e tranis -sphenoidal route is preferred by s<
authors, and a preoperative knowledge of the lateral
t>orders of the sella and the pituitary is of utmost
inportance for this type of approach. To carry out
this study the base of the skull at postssorteai, with
the dura, pituitary «, and the parasellar vessels still
in situ, is studied with different radiological
techniques s including la^inagraphy . Ketal wire
Barkers and X-ray opaque fluids are used to outline
the different border lines of the sella. These in
turn 9 then,; are coapared with the standard X-ray
files of norsial cases and of cases with intra- and
par a-se liar pathology.
The veuous drainage of the brain „ as else-
where in the body 9 is extremely variable, and no
systematic angiographic study has been done on this
subject. This Institute is perhaps in a unique
position in that we have a comparatively large
amount of bilateral carotid arteriograms, in con-
Junction with the temporal lobe program « in patients
with no intracranial space-occupying lesions » Since
such angiograms are carried out seriegraphicallyj,
the different phases of the superficial venous drain-
age may be demonstrated. Dr, Di Chiro has founds, in
a significant number of cases » that the venous drain-
age takes place through different vascular channels
in the two hemispheres of the same patient; while
the venous drainage on one side may be^ for example ,
through the vein of Trolardg it may^, on the other
sides, ^ in the large vein of Labbe or the super-
ficial Sylvian veinso Dr. Oi Chiro has undertaken a
statistical study of the drainage o f the two hemis-
pheres through the right or left transverse sinuses
as part of this project » It is of interest that
these sinuses also show on the radioactive scans »
and this may be of some value in correlating these
two techniques in this study also.
The last two studies of the Section of Neuro-
radiology are attempts to further elucidate the prob-
lems which are encountered in t^o of the large clinical
areas of the Institute The first of these studies
deals with the encephalographic changes in temporal
lobe epilepsy in which every case of temporal lobe
epilepsy is now studied encephalographically,, in such
a way that a reliable comparison of the two temporal
horns is thus obtained , Each temporal horn is filled
separately s and afterwards e^camlned in two ortogonal
planes. Approximately twenty-soige patients have now
been studied with this encephalographic technique;,
-20^
and it is obvious that aas&y more such studies will
have to be carried out for statistical evaluation.
(Me of th® m^±& probleoffi in rauscle diseases '
of the young infaat is the isiasking of lauscle atrophy
by large amounts of adipose tissue o Im certain cases
of dystrophy this is also true^ in that the muscle is
replaced by such adipose tissue. Soft tissue tech-
niques, determined radiographically, are frequently
of aid to the investigator in determining the site
of spiscle biopsy^ as well &s the extent of the disease,
so that adequate cheaical and other studies may be
carried outo Br. Di Chiro points out the technical
problea^ that are involved in the optimal X-ray vis-
ualization of soft tissues and his present impression
is that in addition to adequate X-ray techniques, some
type of good reproduction apparatus is necessary. Se
has suggested that the Logetron equipment be chosen
for such reproductions. The amount of contrast and
detail obtainable with this equipment is unsurpassed.
It ^ay also be used in other K-ray studies throughout
the Institute s and will be placed in the Photographic
Unit of Clinical Investigations.
Dr. Gunter laase has^ during the past two years,
continued hi© study of the intrasnscular motor and
sensory nerve endings in biopsies froa normal controls ^
and in patients irith n®ur<»iuscular diseases <. The nethod
employed is that of injection of liethylene blue at
the tijaa of biopsy j, as indicated by CoSrs; the acetyl-
cholinesterase stain and silver stains, in particular
the sodifications of Bielschovsky and Winkelaann. The
Biaterials ^@re obtained in the course of routine
biopsies, and only slight variations inposed by the
intravital injection of methylene blue. In all of
these specijoens routine staining methods were also
enployed» and reviewed at the weekly s^opathological
conferences .
XIr. Haase finds the concentration of the aotor
end-plates are in a narrow zone at about the center
of each of th© individual isuscle fibers within a
fascicle. This confiras what has previously been de-
scribed » Changes in the terminal innervation and in
the notor @nd-plat@s of sniscles of patients suffering
from msscular diseases and diseases of the lower motor
neuron, have been found. Thus, marked alterations
of the BK>tor end-plates in myotonic dystrophy have
been found in which there is a marked ramification
of the terminal innervation and multiple end-plates
on single muscle fibers „ 'ftis has also been found
«21~
ie cases of Huntiastosi's Chorea ^ vhieli «eip@ os'isiaallf
biopsied tor eontirol puifposes. Sose eases of Fax>lilJi-
soil's disease showed » ok orthodox stains » evidence of
a mild t^op&thf, this was reflected hf changes
ins d^eaefatio!& of the motow end-plate h^
hliie stains o
In i?efe?ence to the saascle spindle » it is
thought that this nethod does not proKise to bear
fruit „ Spindles „ even in the nor»al ssuscle^ appai>entlf
show great irariationsg and it is ispossible to clearly
state patholf^ical changes in these structures o
DTa Haase will be leaving the Clinical Xnvesti<>
gative Iteit to assune the Chair of Heurology at the
Iftiiversitf^ of Oklahoffiap and this will terminate this
studsr at this Institute » St is hoped that he will be
able to continue along these lines in his new position »
and an ultiisate suimar^ of a larger nusber of patients
be available o
9r„ Andrew Sngel has carried out a thorough
studf of the thirroid function in Bf asthenia gravis o
It is well li^own that 5 to 10 percent of patients
with as^asthenia gravis are also hfperthfroid;; and
idien these two diseases coexist the prognosis appears
to be grave. Sons observers in the past have reported
relation between these two disorders „ and
this view has heett challenged hf others. The studf
undertalsen hj Dr. Bngel to define the interaction
of the two disorders 9 and to evaluate the respective
roles of pituitary TSH and of the thjrroid gland o The
nethods emplofed were utilised on five ns^asthenic
patients. Medication was held at constant levels
during this studf ^ and the clinical evaluation con-
sisted of daily aeasureasents of the pre->deter»ined
group of Buseles. Ttam thyroid status was evaluated
as^follows: Daily BHR^ weekly PBX^, cholesterol and
|131 uptake o In three patients thyroidal secretion
rate was also secured by direct daily counts of
thyroidal radioactivity » corrected for physical decay <.
Steps taken were as follows:
lo Triiodothyronine iTB} was given at a dose
level insufficient to induce hypers^tabolisup but
ade<|uat® to msppsress pituitary TSH is@cretion„
2, T3 was administered at progressively higher
dtm@ levels until hypesnetabolism was induced <,
3o After a labeling dos© of I^^^j, thyroidal
iodine accu^sslation was blocked witli Tapaaole and TSE
«22»
CAraour) was %d^i2iist®if@d in g£>sui|d doses ^ wMile the
fTftctional release of hossoBAl !^^ was sseasured fro^
dajr to daf o
4o Ssme as Step 3^ but with cos&curs-ent ad-
slnistz'ation of sodiiis iodide to offset the th^rroid
hoimoiie srelease-acceleratisig effect of TSEc
5o The prolonged adninistratioas of Tapazole^
until depletion of thyroidal horao£&e stores s. fssult-
iag in hyponetabolism with coneu2°rentlf high pitui-
tary TSH secretiofflo
In the Bfasthenic study g the nyastheaia could
be seen to become worse in all patients who
thyrotoxic. Ho see->8aw relationship could he
although siinor fluctuations occurred until the
reached plus 20 c In one patient who becaaes hypO"
■etabolic on Tapasujle^ the aiyasthenia improved while
the endogenous TSE level was still elevated o Exo-
genous ISS-induced acceleration of horsonal secre-
tion was followed by elevation of the mSL^ and this
by worsening of the ayastheniao ^en this accelera-
tion was blocSied by sodiuM iodide ^ the effect on the
blocked
%.«.«>«»« was also blocked » and only to the extent that
the rise in the BISE was blocked » It is thus apparent
that fS&s P®^ 3®«> b^s no significant extra- thyroidal
effect on si^astheniag, and that there is a direct
relation to the i&etabolic rate and the severity of
the ayastheniao
Siailar studies were carried out in one patient
with f&ffiilial periodic paralysis. In faailial
periodic paral^iS;, as high as 30 percent of patientr
have been reported with esophthalssos and hyperthyro'd-
isKo Induced hypersetaboliss did not worsen the
clinical status of the patient with fanilial periodic
paralysis. Withdrawal of f3 was followed by a s<^^ere
and prolonged worsening 9 and this was relieved ty TSE
administration, TSE withdrawal again resulted in an
exacerbation. Repeated TSH studies could not Km per-
fonrad as th& patient becajse resistant to TSH. VnxxBg
there m&j be a difference between thyrotoxic non-
faailial and familial non-thyrotoxic fora^ rf this
disease 9 naii^iy the response to abnosnsal l€7®ls of
thyroid function„
Dr» Darwin Prockop of the Heart I]^7>titute« and
Dr. Bushnell Saith^ have continued their /studies on
the use of nonoasine oxidase inhibitors (naaely JB 516) »
as an anti-convulsant sgedication for centrencephalic
-23-
seisasrss. Patients were acbftlttod smd sati'-convulsaat
aedicatioi^ yaere reduced to a. ninlBasa, ^heaever pos-
sible to do so vithottt daager to tbe patieat. After
a sh<»rt baseliae period of oteervatioa, tlae patiesits
vere given either a placebo or JB 516 daily for four
to sis veelss, in addition to tbe other Dedications
they had been taking, rshis vos done bjr the double-
blind BDsthod. Slectroencephal<^raaBS were run each
weeks su&d coapared to the baseline ESS. Deteraina-
tioa^ of the aaount of S-hydrosytryptaaine in the
urine were done during the baseline period, and on
the siscth and seventh day of siedication*
In the aajor findings, only two of the pa-
tients receivod JB 516 under this double-blind study.
One developed drowsiness , folloved by generalised
convulsions after reducti<M& of barbiturate. Before
reduction the seizures im»i« fairly well controlled.
One patient becaae hypotensive and had syncopal at-
taehs after four weeks of aadication. During the
fourth weefcp the patient's seisures were fully eon-
trolled. Four patients received placebos - one pa-
tient showed iaproveaeat. At this tine statistical
significance of this series is not such that JB 516
could be shown to give any i^provestent in patients
with this type of disorder o
study of other aonaalne oxidaae inhibitors i»
with more specificity for the central nerv<Ni8 systems
will be undertaken now that a protocol has been de-
sigmid for such patients. Wt, Saith is also continu-
ing his study initiated with Dr. l^rager on the patho-
logical substrata of the Beidenhain fora of <lakob'8
disease. Serial sectioas of the brain were aec<»^-
lished in a patient dying of this disorder p ^ich iP
a relatively rare progressive <teg83^ratlve disease of
the central nervous system^ the etiology of which is
quite otecure and the pathol<^ieal process has net
been well doetnsnted. A cortieal biopsy was obt/^ined
durii^ the third Bonth of this disease cmd the diag-
nosis confiraed at this time, Findings at the present
tiae are those of a widespsread diffuse loss of neurons
in the brain, particularly the occipital lobe, as
aarked by status spcMigiosus and astrocytic pr:»lifera-
tion. The cerebellua shoms a aarked loss of Purkinjs's
cells and granule cells. Ht® lateral colisans showed
degeneratioa. In addition to this, nodules of acute
inflas^tory cells with foci of necrosis were scattered
throughout the brain and spinal cord, and aiay be due to
the terminal infect ioa.
-24-
Finally 9 DTo AXtrocchig In tbo Clinical Inves-
tigative Units and Or. Erooth in the Branch of Bpidem-
iolog^s are Joining in a c<»d>ined study of tissue cul-
ture and chr<MK>soBs counting in huwtn subjects with
various neurological disorders, and froa specific tis-
sues in which local tissue abnormalities are founds
such as in von Recklinghausen's disease. This study
has Just been undertaken and will include tissue cul-
ture of the reaoTOd tissue ^ chronoscne counting of
cafS au lait spots <, local tuaorsj, etc. Studies of
quantitative chroaosoaal abnoraalities in patients
with sental deficiency 9 spinal def oraities «, etc. 9 will
also be doneo
the Methods eaployed will be in the removal of
fresh bone aarrows lAich will be incubated overnight
and treated with colchicine, and then fixed and stained
by the aodifications of the aethods described by Fordi,
Polanijp et al. Squash preparations will be searched
systeaatically for cells in the netaphase of aitosis^
which will be analj^eed both by direct microscopy and
by aicro-iAotography for quantitative and qualitative
almormalitieSo Tissue culture aethods will be used
to grow skiUo auselep marrow^ and neoplastic tissue
in the laboratoryg which will then be treated in a
Banner similar to that above for chroMMB<»al analysis.
The Branch of Electroencephalography s and Clin-
ical neurophysiology e report seven projects. These
projects are centered about the clinical eleetroence-
phali^raphic problems in the field of epilepsy; the
effects of hypothermia and blood pressure on elec-
trical activity as recorded from exposed normal human
cortex; and experimental projects in animals elucidat-
ing thalamo-cortical and cortico-thalaaic conneotios^;
and an analysis of various unitary elements activated
within the visual cortex, following stimulation of
the optic radiations. Other projects relate to as ex-
perimental approach to basic mechanisms underlying
seizures 8 in particular with aicroelectrode investiga-
tions of "self-sustained" activity which is produced
following repeated electrical stimszlation of the cere-
bral cortex.
During the current year^ one Visiting Scientist »
one Guest Worker ^ one Research Associate «, and three
Clinical Associates collaborated with the Branch Chief
in the investigations reported below. In addition to
the investigative work^ the Unit carried out a total
of Is* 579 electroencephalograosg during the period of
eleven months covered by this Repmrt, and twenty-four
iilect^focorticograpiiic studies ;, dux-iiag cortical €xpo-°
sure tn tlie surgical tr@atffi@at of epileptic p«.ti@i%ta
OT OH pati«iffits lift wkoffi operatioos suck as lifpoph|rsec<-'
to»f were beiag doiui as a therapeutic wmasur^ for car-
More specificallf 9 Dr. Cosimo AJssone Marsas
and Dr. Eristof Abrahaai have finished a pictorial aiudv
for an atlas ^ oi 250 epileptic seizures,, obasenred froi^
begiztmiffig to end;, of which 43 haire beea selected » £.ich
seizure 9 in tum^ sakes up to four large plates of th€
atl&Ss aad the different components of the seizure are
sfnchronized with the corresponding ti»@ interval in
the electroencephalogram e This atlas will,; in fact,
he a companion to the book bf Drs. Ajaone Marean and
Ralston^ entitled "fhe Spileptic Seizure" « based upon
gsetrazol> induced seizure patterns. The various pat-
terns described in this monograph are here illustrated
aad coordinated with the electroencephalograaig, and
the varying components of the seizure ^ such as the loss
of consciousness; focal aaovenents Qf bodf^ face or
linbs^, with or without electrographic correlates; auto-
mat isns.^ and seizures produced through chronically im-
planted electrodes 2, are all correlated with the pre-
sence or absence of specific electrographic changes
during each phase of a given seizure c This atlas has
been accepted for publication and will appear as the
Fifteenth Suppleiient of the Journal of Electroencephalo-
graphy and Clinical Heurophysiblogya &»d this wiii^ in
eifects "terminate the research portion of this project,
As an adjunct diagnostic procedure and screening ^ in
cases of patients considered as possible candidates
for surgical treatment of seizures,^ however ^ this typ@
of recording will be continued c
Dr<, AjBone Marsan and Br„ John Van Buren are
continuing their studies in depth electrographf in
epileptic patients o This is a part of an over-all,,
loia^-ter» pr oJ©ct to aap out the functional correlates
and anatoaical substrata of the deeper nuclei of the
brains and particularlf those of the temporal lobe^,
ioS, asitygdala and hippocasBpus o
llectrocorticographlc studies ^ in tesporal lob@
epilepsy 9 and in focal cerebral seizures at time of
exposure during operations.^ has continued o Much of
the original portion of this work has been reported
in :^he book, published hj Thomas, titled "Tesiporal
Lobe Seizures '% edited 'by Baldwin and Bailey o These
findings are considered, in soaie detail, in Dr. Bald-
win's reports on the Branch of N^iurosurgeryj, as ar©
the sttadies or tli@ autos^smie nervous afstmm asid el®e~
ftpliaic^fraphic correlations 9 reported tsf^ £»ro Vam
of the Breach of
9r„ Leaaart Widesi m&d Dr„ AJsK>a@ Marsaa ha^w
ccnipleted a studf on the imitary anai^is of response
elicited in the vissaal cortess of cat. The object of
this studf ^as to detemine the teaporal and special
distribution of individual unit activityp within the
visual cortex and under lyias white aatter, during the
course of the evolied potentials responses elicited
by stiamlation of the optic radiations. The purpose
of this is to understand better the nature of the
various c<M«ponents of the cortical response. This
response is rather artificial and different fron that
elicitable with ph^iological stlwuli; on the other
hand 9 it is a t^ical and characteristic foma of evohed
potential. These investigators find that there is a
correlation to the nualMr of spikes recorded in the
presence of a discharge during the course of a specific
evoked surface response 9 and that such spike dischaz^es
atay be tenporally related to the various components
of such a surface re8s»6nse. Thuss on the basis of the
latency of the recorded spikes and the behavior of
such potentials J, when tested with double shocks and
repetitive stinulatlon, they find that all such spikes
say be divided into two groups » i.eo "presynaptic** and
"postsynaptic" o They find that all spikes tea^porally
related to the first wave of the surface response « and
alaost all spikes firing during the second wave» are
recorded froa the white natter » and all of these have
presynaptic characteristics. Those temporally re-
lated to the third wave have a sore extensive spatial
di8tributi«M&s and are picked up in both the cortex and
the white natter. Sons of these behave as presynaptic »
and others as postsynaptic o The spikes related to
the fourth wave of the surface response 9 and the rare
spikes associated with the fifth wave 9 are all of
postsynaptic type^ and are found only within the cortex<
A positive correlation existed between the pre-
sence of a unitary spike aad the amplification of the
surface response. Thus^, for example « the spikes asso-
ciated with the first or second wave apiNsar yAtmn such
waves have reached a critical size. Such spikes then
rwnain stable, responding to every stimulus . A third
wav« spike g of a presynaptic type,, behaves similarly.
Fost-synaptic spikes « related as ae&& above to waves
89 4 or 5g also may appear iri&en the first wave has
reached a certain sise above this threshold value. They
ares ftt this time however 9 "unstable" aad respond ir-
regularly to stimuli of constant strength. The
-27«
probftbility of their dischftS'giiig is greater „ the
larger the ampiitude of the Xate surfaee wai
These authors conclude that this further con-
f ims soga» of the current concepts of the various con-
of this fiire««ave surface response o The^ also
that this aaf resolve sone of the conflict in
regard to the nature of the third wave» in that thef
find both pre- and post-sfnaptic elements in this wavec
1%is studr, along with those of Dro Li in the
of Keurosurger^s further eaphasizes the atteapts
being aade to understand the slov cortical events in
relation to single cell activit^o These two investi-
gators have also continued this unitary studf in re-
ference to the lateral geniculate nucleus » in an at-
tempt to understand the effects of corticofugal and
corticopetal iapulses upon single elements of this
nucleus o This was an attenpt to see whether either
specific or association cortical areas could exert anf
influence upon incoKing sensorf atssages at a thala»ic
level o The lateral geniculate was presumblf chosen
since it is a pure sensory relay nucleus o The visual
and suprasf Ivian Civhich is an association area| of
the cortex were chosen c These investigators state
that the interest is this project was aroused bf ana-
tcmical work which stated that, in the visual cortex „
about three-quarters of the fibers are corticofugal »
although their actual destination is i»resently
tticroelectrodes were used in this
study, and placed within the lateral geniculate nucleus,
and cortical electrodes were used to nonitor the ar-
rival of the specific visual response o Single pulse
stinulation of the optic tracts and of various points
of the visual and suprasylvian cortex « were carried
out. This project is still being analysed , It ap-
pears « however, that a fairly large percentage of
unitary spikes were activated by both optic tract and
visual cortex stisnlationo In each instance attesipts
were »ade to influence each recorded spike by cortical
as well as by tract stimli. In general these investi-
gators found that cortical stiaulation tends to inhibit
the spikes elicited by the optic tract stlsulations,
but that stimulation of the optic tract tends to facili-
tate the spikes elicited by cortical stiaulationo
However 9 exanples with opposite effects were founds and
these investigators point out that soae of the cortical
effects are likely to be interpreted as the result of
antidroBic stinilation. However ^ the extreawly long
latency of aany spikes 9 elicited by cortical stimula-
tions strongly suggests that these mist be orthodroaic-
ally activated elensnts.
-28-
Or, Paul G^rlQs In his year of tenure in this
laboratory (» carried out nicroelectrode investigations
of the nechacisas of the electrically induced epilepti-
fors seizure 9 i.e« "afterdischarge'^ with Dr^ Ajaone
Marsan. The object of this study was to explore sys-
teaatically« with nicroelectrodeSi, the cellular pheno-
■eaa characterizing the onset, development and end of
the electrical afterdischarge elicited by repetitive
stinulation of the cortical surface, and to atteapt an
interpretation of the mechanisas at the basis of this
self-sustained activity^ This study was perforaed on
catS; and stinulation was applied to the cortex of
the suprasylvian gyrus with various paraaeters, Ci.e.
pulse duration^ frequency g, voltage, etCc). Pick-up
cortical electrodes were silver-silver chloride e, for
the slow surface events » and tungsten aicroelectrodes
for the unit recordings. The aoveaent of the latter
was controlled by a hydraulic aicr<»Banipulator . Dr.
Gerin found that repetitive stiaulatioug capable of
eliciting an afterdischarge, is accoapanied by pro-
gressive and characteristic changes in the spikes
activated by each such pulse > The units tended to
fire repetitively, and the amplitude of each successive
spike decreased until the spikes eventually disap-
peared. In the absence of such changes ^ the develop-
aent of an afterdischarge was improbable. During the
SEG afterdischarge 8 the unitary spikes £, generally ab-
sent at the very beginning, prepress ively appear <, and
their voltage and frequency vary inversely. As the
rate of the firing slows down, the amplitude reaches s,
gradually ; the pre-stiaulation value ^ at which point
the afterdischarge ends . This was interpreted as an
expression of different i^abrane polarization levels ^
the characteristic ones consisting of an excess of
depolarization levels ^ and of long-lasting repolariza-
tion. Since the electrical afterdischarge., elicitable
with repetitive stiaulations is aorphologically siailar
to the spontaneous discharges during epileptic attacks
in huaans^ the understanding of the intiaate mech-
anism at the basis of this particular type of self-
sustained activity is of importance in the understand-
ing of the physiopathology of seizures. Ibis project
has been completed, and the results were presented to
the Atlantic City meeting of the American EEG Socio ty^
and will be reported in the Archives Ital. Biol.^ in 1960.
Dr. Morillo and Dr. AJmone I^rsan are continu-
ing the Eranch*8 long-term study of thalamocortical
mechanisms s and a ccHsparlson between the specific ^ as-
sociation^ and non-specific systems. This continuing
»39-
studies of Snonoto„ RaistoBg a&d otliors associated
vtth Or. AJaoaa H&rsaa ia this ints^st. Th» purpose
oi tS&is study vae that of & uaita^ip an&lfsis in tlii^e
tlialaaiocox^ical 8eotos«o hf stiamlation of diff«»r«»at
thalasiic auelei. T&o cortio&l arsas wev9 the supra-
sflvian (i.e. assoeiatiom areaK &» ^1^ ^ the pri-
■ary visual cortex. Withia the thalaanys the folIo«->
ing nuclei were specificallir stioulated: The lateral
geniculate 9 the nucleus lateralis posterior s and the
nuclei belonging to the non-specific sretems i.e.
centralis lateralis » centre ffiediaau«s the ventralis
anterior 0 SystMuntie survey of depth probing with
the tticroelectrodea was carried out by a hydraulic
aieronanipulatoro Surface cortical electrodes were
also used to asonitor the gross evolied surface
To date this study has been done in over fifty
catSs and observations ;, concerning differences in la-
tency, variability in responses » chances of unit ac-
tivation by different stinuli, and the inter-effects
between different etiamlations upon the ease sensory
unit, are being sade. It will still be several months
before final results are obtained ^ in this study.
Tbm Branch of Surgical neurology » during the
past years has adnitted S31 patients on the ward» and
279 patients were seen in the outpatient area^ in the
operating theater „ 108 najor procedures were completed;
of theses 50 were concerned entirely with the surgical
treatment and investigation of functions of the cerebral
cortes and deep nuclei of the brain in patients suf-
fering froa seissureso Forty-eight operations were per-
formed for space occupying lesions which eaae to opera-
tion through either investigation of seizure patients «>
or patients referred fron other prograas^ in particu-
lar the scanning progran. There were ten miscellaneous
wajor procedures s the majority of which were performed
for the relief of paino Thirty publications were pre-
pared during the period of this Report.
Twelve patients were referred fron the National
Institute 0 and were studied and eventually
treated by hypophysect<»»y or stalk section. The endo-
crine and anatomical studies of this group may be seen
in the Report of Br. Van Buren.
Studies were continued by Or. Deliaban on dis-
orders in the perinatal period » and by Dr. Li on unit-
ary recordings of both central nervous system and peri-
pheral structures 9 both in vivo and tissue culture o
-30-
Ttie Section of Neuropathologf coatiaued its
studies on tissue culture » hypotherffiia^ inBunocheaiistirFE)
and bistochenistry. Sosta studies 1b pirlauEite neurologi"
continued 9 with particuiax* reference to tbe deep nuclei
of the teiaporal lobe;, and studies of effects of radio-
frequencf energy in the sKsgacycle-range upon the cent-
ral nervous system^ Psjrchological studies on patients
with temporal lobe al»&orffialitles are reported below hj
Dr. liansdell and his colleagues ^ and investigations
directed towards a technique bf which the brain can be
selectively cooled thirough shunting inflow blood through
an appropriate type of cooling apparatus are also re-
ported o Specifically, the Branch reports the follow-
ing studies:
O^e hundred and forty-three patients with teap-
oral lobe seizures were studied during the past year^
Of those that casie to operative treatirant^ six deaK>n-
strated a peciiliar bony deformity of the niddle fossa,,
coflusisting of bony spicules protruding into the over-
lying temporal lobe through dural defects., This de-
fomity could not be related to inflasaation or neo-
plasMg or to significant head injury. It was related
to the electrographic abnoraality, Dr„ Baldwin points
out that in extrei^ly local lesions on the lateral
surface of the tenporal lobe, the language abnoraality
observed in Bore generalized teaporal lobe diseases ^^
and described in previous reports » was not present. On
the other hand^, one patient «» with a snail focal lesion
on the nesial surface of the temporal lobc^ exhibited
such langruage characteristics to a narked degree.
These investigators conclude that when the lesion is
nesial or deep within the lobe^, the language difficulty
se«BB more marhed and characteristic, and that it is
unrelated to the duration of the lesion. Such patients
indicate a satisfactory response to standard aphasia
tests, but have great difficulty in describing rela-
tionships between space ^ tiiaej, and action. These in-
vestigators feel that there is no cerebral doainance
in relation to this deficit.
Clinical observations seen to indicate the
chief difficulty in nsnory abnomalitles associated
with temporal lobe disease is not in wemorfg per se,
but in relating given facts to given periods of time.
Perceptual aberrations associated with temporal lobe
disease seem more marked when the lesion is nesial
and when it is bilateral.
The phenomena of automatism associated with a
seizure is being thoroughly Investigated by means of
time photography during a seizure period. During this
»31-
psriod of tiwB th® patieat is given mimes-cms ©timsli
aad his rospoase recorded; his speech also is recorded
during this tins. Dr„ Adaaftievlcz has been studying
this systematically, and correlating the clinical 2ind->
ings with a systeaiatic study of the autononic concoa-
itants carried on by ]>r. Tan Buren. mco LasSeowski and
Br. Otenasete are engaged in the study of the relation-
ship of cerebral dominance to the occurrence of auto-
■atiea.
Dr. 7an Buren f, in his autonomic studies of 22
in 20 patients 8 has found a stereotyped re>>
in which blood pressure was seen to rise. The
change in pulse ^ as it occurred, was towards the tachy-«
cardia. Early changes were cosawnly esophageal per-
istalsis and fall of skis resistance, with the vascular
and respiratory changes occurring later in the
Dr. AJsione Marsanp in correlating the electrographic
phenottena with these autononic changes, finds about
half have a bilateral sysaMtrical aspecific aetrazol
burst associated with the brief autononic response « A
sudden loss of voltage « or a tendency to increase in
frequency of the record, was in all cases associated
with overt-seisure activity.
A study on centrencej^alic seizures was carried
out by Dr„ Tan Buren, and Dr. Mirsky of the Hational
Institute of Mental Health, in which the patient's
level of response was determined by a continuinis per-»
fomaace test, and a sinultaneous auton<»Bic record
was aade in all these seizures c TO date sctee 300
spike-°and-wave attacks have been fully recorded, and
it is hoped to draw correlations between electrographic
features of the attack^ the patient's response „ and
the autononic characteristics. Isolated observations
of interest during this study are that there is an ia-
frequency of autononic changes with the attacks. The
patient nay still be able to carry out rhythnic aono-
Bischanical novenent
during such an attack, while
he is unable to distinguish auditory or visual stiasulus.
Seizure studies in prinates, and in particular
to the frontal cortex of the chiiipanzee , are continu-
ing by neaas of penicillin lesions. It is interest-
ing that the electrographic seizure spreads ia an
alnost concentric pattern acr<^@ the ipsilateral heni-
sphere and then seens to cross the opposite side, spread-
ing fron nesial to lateral. The penicillin lesion was
placed in the interBediate frontal regioa. It was of
interest that bilatexul electrographic abaomalities ,
which began in one frontal cortex, could result in a
unilateral focal notor seizure. These studies on
-32-
seisure saochaaisas resulted In four publicatioius s, as
listed under project MZ£iDB-43Cc) .
In the operating rooBi, per se^ functional re-
presentation in the tenporal lobe of man and higher
prinates has been c<»atinued by Dr. Baldwin and his
colleagues. Twelve unilateral teB^E>oral lobectoaies
were done on patients 9 and the general effects of
unilateral lobectoay in the huaan are still not clear.
Depth electrode studies in the aesial teaiporal region ^
by Dr. NorriSp have reproduced behavior vhich is re-
ainiscent of huaaa autoaatiss. Dr. Baldwin feels in
his patients there is a change in nood and language 9
as listed above, and there aay be ttomm chaise in
libido 9 and there nay be progressive weight gain. In
chiapansseesg during the past year 9 the effect of uni-
lateral ablations and bilateral ablations of the
temporal lobe areas has been studied. The parasylvian
region in the chioypanzee has deaonstrated a aotor re-
presentation of tongue and lips. Bilateral excere-
brat ion of the Broca's area, i.e. the third inferior
frontal convolution (> in the chiApansee does not
materially effect the coonunication pattern. The
chronic effects of bilateral temporal lobe ablation
has continued, and Dr. Eeinrieh Klttver« at the Univer-
sity of Chicago, has cooperated in these studies » and
he was unable to see any stigaata of his "syndrcHse"
in such aaiaals. This Branch now has siz chiapanzees
whose biteHy;K»ral ablations have now been studied for
five years. Their develoineat continues within the
noras established by other investigators.
Dr. Baldwin and Hiss Lewis are continuing their
study of hallucinogenic substances, and psilocin and
various isoaers of lysergic acid are being tested.
There appears to be an apparent siailarity between
peilocin and LSD-25, and it would appear that con-
tinuous adainistration of either drug provides a con-
siderable resistance to further adainistration of
either drug.
Dr. Baldwin, Dr. Bach, Miss Lewis, and Dr.
Klatzo, are co^atinuiE^ a correlative study of the ef-
fects of radio frequency ener^ on priaate brain @ech-
anisas. As of now, 50 Macaca rhesus aonkeys have been
eacposed to radio frequency ranges of 200 to 400 He.
These energies are transaitted to the head by a ground-
to-air transmitter through aeans of an antenna placed
in the roof of a resonating cylindrical cavity. The
antenna in this cavity is adjusted to lie directly above
-33-
the aainal's headj, which was posit i<m®d at the lover
pole of the cavity. Below the base of the skulls the
aniaal was scireeaed fsron radio frequency energies »
nineteen phantoas containing Elliot's solution «, gela-
tin 9 Bilker's saline 9 and other suitable test aedia
were also positioned so as to iaitate the critical
head positions o The aaplitude of the signal received
at the head area was Bonitored by a probe ^ and the
signal was continued long enough to raise the tempera-
ture of the test aediua 50C9 when frequencies of 200
to 400 Me, were used. However, it was only between
380 and 390 He, that clinically discernible effects
were seeus thot^h the teaperature elevation was seen
over 200 Mc. During this 10 HCo range of 380-390 «, the
animal bscaae increasingly drowsy, did not respond to
pain 9 but did respond to light and noise in the usual
Banner. At critical frequency, the aniaal will arouse
trtm anesthesia when the generator is on 9 but returns
to the anesthetic state after the frequency is turned
off o If such a fre<;piency is continued at the critical
levels i.e. 380-390 Mc,s alterations of pupillary re-
sponse 9 paradoxical pupillary responses disorfi^usisa-
tion of eye aov^tsntSs nystagmss grlaaeing, autonoaic
changes s and finally generalized seizures will occur c
If the aniaal is carried to this latter stage $ re-
covery is unlikely and he xssually expires. Soae aniaals
develop focal neurolc^ical signs following long expo-
sures at critical frequeiKies, A long exposure here
is defined as an exposure longer than three ainutes.
Such focal signs consist of facial palsy of the central
type, loss of pain and touch in areas supplied by the
fifth cranial nerve g weakness of one leg or arB„ tran-
sient Babinski responses 9 ataxias and continuing nystag-
aus. Such signs 9 although transient j, could continue
for periods of four to forty-eight hours after esEposure.
The histological and histochoKical imalysis of
thd brain was carried out by Dr. Klatzos in the Labora-
tory of Xeuropathology^ and in this study sodiua
fluorescein was used to study the peraeabllity of the
blood-brain-barrier, and various cellular histoch««ic ^
and histological procedures were €aiployed, Ita*. Klat ''>
finds 9 in the acute experiasnts where the aniaals &n
sacrificed within a few ainutes after the exposurey
that changes in the blood-brain-barrier peraeabil ty
can be found in the pon@s aedulla and extending ''iirough
the white matter into the cerebral heaispheres . Scsse-
tiaes such changes are localized lower and inv^^lve the
dorsal areas of the cervical cord. The histological
changes are confined to a striking tigrolysir in the
of tbe poBSg jBsduIIa and the deatate
nucleus of tho cerebdllusi. Ro aeurof ibrillary chassges
caa be eeesi. In tSm chronic experi»enta onlf a tew
aniaals showed cbaa^^s ia the blood-braia-barrier,
and they were localised in the doarsal portions of the
cervical cord. In a fe^ anis^Is, chaoses in the aiedulla
were such that smll cfstic cavities i^ith i?ell
in the vicinity xseve found.
findings suggest that there vay be a fre-
with ri
quency specific effect with radio frequency energy of
certain characteristics when applied to the priaate
brain « provided @uch a brain is placed in a resonating
chai£»er so that the sinusoidal waves eay actually
algebraically susa^ate at a given focus. 'Shis technique
Bay be useful in the future in that it can affect the
arousal systens and other brain ateia i^chaaisaSe ^n^
yet leave the test animal apparently unharssed otherwise.
Or. Tan Buren is continuing his studies on hy~
pophysectoasyp and during such surgery is asalsing physio-
logical observations in reference to connections of
the huaaa teiqporal lobes the response of the cortex to
hypothermias autonosiic responses « and clinical and endo-
crine effects of hypophyseal stalh section in »an. Bis
is correlating these with the anatomical evidence
found at postaortea. A total of nine pituitary stalh
secticKas were carried out for palliation of setastatic
Ixreast careinoaa. '!Rie clinical experience, however «
has been discouraging, and the patients have shown a
considerable morbidity. A continuation of this series
is not contemplated. Such patients demonstrate marhed
sensitivity to water intoxication » not related to the
intake. £n two such cases routine I.V. fluids were
given {, and the patients becass^ unconscious and had
convulsions apparently due to water intoxication. Fol-
lowing this eaQ»erience, all subsequent pairenteral fluids
were stopped following surgery and patients allowed
to tahe only what they desired by mouth. Although
such disturbances of water metabolism proved reversible 9
the e<miparison between the clinical ccmrse of those sub-
ject to pituitary destruction and stalh section was
striking. In the latter case, the patient's recovery
tvam operation was rapid. %e evaluation of the hor-
monal and tumoral response to hypophyseal stalk section
as opposed to pituitary removal is still being studied.
Or. Van Buren is continuing his collection of
rtem material from hypophy^iectc^y cases , and cal-
culating the total cell populations of the various
hypothalamic nuclei 9 and has noted a 6-3 X
-.35-
in the maaiber of cells la the supira-optlc nucleus
after such procedures <> Patients undergoing such h^-
pophysect<»s^s at the tiae of the operation o were sub-
ject to exploration of the orbital surface of the
frontal lobOg the adjacent temporal lobSg and the
ventral aspect of hypothalasus bf electrical stiaula-
tion. Records were aados, at this tiae, of the respira-
tions blood pressure 9 pulse rate, esophageal and
gastric Botilitf and peripheral circulation with the
plethysnographo Nine of these patients were aaintained
with hypothersia and three with noraothemia. With
one eaEception^ there was no evidence of disease of
the nervous sfsten^ Uhder these conditions ^ the pre-
d<»inaat electrocortlcographic frequencies usually
li^ in the alpha range or faster o Hypothemia ap-
peared to protect the cortex from after-discharge fr<Mi
repeated electrical stimulation while after-discharge
with the same parameters appeared in one garter of
the stimulations at normothermic levels. In nearly all
patients, both normothermic and hypothermic ^ cortical
stimulation was followed by a depression of voltage of
fast activity and an augmentation of voltage of slow
activity,, which was compared with the spreading depres-
sion of Leao. Hypotension under light anesthesia ^ in
both normothermic and hypothermic patientSg induced a
fall in the voltage of both the slow and fast activities.
In two cases the addition of Fluothane resulted in a
greater depression of electrocorticogri4;>hic activity
with progress icNft to intermittent activity^ and in one
case to electrical silence «
]>r. Tan Buren has also continued his studies on
the anatcmical connections of the human tei^oral lobe
in cooperation with Z^. Paul Takovlev at Harvard Uhi-
versity. Two contrasting lesions to the human temporal
lobe were studied by whole brain serial sections and
template reconstruction methods o Lesion in the pcMsterior
porticm of the temporal lobe resulted in a subsequent
degeneration of the posterior portion of the nucleus
lateralis posterior and nucleus madialis dorsaliSg and
ia the medial half of the lateral geniculate body^
while anterior lesions caused degeneration in the
lateral half of the lateral geniculate body. In the
medial geniculate body, the posterior lesion of the
taq>oral lobe resulted in degeneration of the rostro-
lateral portion of this nucleus^ while the anterior
lesion caused degeneration in the caudomedial port ion o
Degeneration in the pulvinar was caused by lesions
both anteriorly and posteriorly ^ althou^ with the
posterior lesion there was greater degeneration in the
medial part of the pulvinar.
—36-
Tsract deg®si@7atiosts were »lso studied la the
tapetuB, a&d Dr. Y&m Buren has outXised these in his
project o DegeneratloB was also found ia the anterior
eoaniesure, the uoeiaate fasciculus ^ the ventral
thalasKic peduncle 9 and the fiistbria-fomii: after anter>
lor temporal lesions. Five other casMi with focal
destructive lesions have been accuaulated hjr OTo Van
Buren^ and are undergoing serial sectioning at this
tine, these anatonical studies ^ after a prolonged
follov-up froB focal lesions,) are of utaost importance
in understanding the anat<aiical ramifications in
Dr. Van Buren is also continuing hie studies
functional anatcnqr aad pathology of the
described
visual afatemg as described in the previous Annual
Beportg and he has now arrived at a satisfactorir
»ethod for two^diasnsional retinal reconstruction.
Br projection of his photographic enlarg«eent » Dr.
Van Buren now has stretched the circunference of the
closed segatent of the retina to over a asters and
tracings of lesions at this aagnification can be
with relatively ssall percentage of error.
Finally, Dr. Van Buren is continuing his studies
on involuntary woveraentSp in which he is still analyz-
ing «, in postaorten aaterial^ the accuracy of Eorsley-
Clark device which he has hiaself constructed. Be
has eonpleted a visit to clinics abroad and in this
country to cottpare the technique he anticipates using
here with those used elsewhere, fhe proposed course
of this project will be to study those diseases in
which stereotaxic intervention is indicated on thera-
peutic grounds. Such patients will be done by photo-
gra^ic records and nultiple flash stroboscopic photo-
graphs, it is hoped that with the use of accelero-
aeters a asans aay be found for sii«ple graphic record-
ing of the involuntary aoveaents, which aay be cor-
related at the sa»e tiae base as other features » such
as ESGf, and autonoaic recording. Ihese acceleroaeters
are now being ccmstructed by the central instruaent
facilities of the National Institutes of lealth.
Dr, Choh-luh Li 9 with the aid of Dr. Shelley N.
Chou and Dr. Jbseidi Miller, is continuing his studies
on cortical intracellular potentials and on cells
grown in tissue culture. In studyis^ after-discharge
produced by continued stiaulations Dr. Li arrived at
what appears to b® the identical cone l«m ions as Dr.
»37"
AjBosis Masfsasi; usissg th@ t^^stea electrode. Ib Dr.
Li*s study aXsOj, d^arliag tS&s so*-caIled epileptic aftef-
discharge « depolarisation occurred and restoratioa
of the resting potential periodically tooSc place. £f
the depolarization continued to growg then the spilEs
acti(»i potential disappeared. There vas also an qjh-
centuation of oscillation of potentials when spike
activity was absent. Tbusj, this appears to be an in-
tracellular confimation of Br. AJoone tfarsan's thesis
from extracellular recordings using the tungsten elec~
trode.
Or. Li also has aade an attoept to deteic^aine
the response in & single cortical neuron fr<MB a closely
approsisiate cortical stisfulus. In this the sosaatooen-
sory aortez of the cat was chosen. The laicropipette
was Introduced into the neuron « and single shocks were
applied to the surface of the cortex not store than
5 BB away froa the recording electrode tip. It has
been stated in the past that the initial 8urface«
negatire potential in response to a weak stisulus was
the result of activation of superficial eleaMKnts,
p:robably dendrites ^ and that the surface-positive po~
tential in response to strong stianilus was produced by
deep neurones in the cortex. Dr. Li*s investigation
shows that this is not necessarily so^, and that the
refractory period of the cells under direct stiSBula-
tion and the synaptic activation of these cells enters
into the response. Or. Iii plans to pursue this further
with conditioned volleys initiated froa other struct
tures of the central nervous systoa.
Brs. hi-B Chou and Orti£ also carried on a study
of the inhibitory intesmeunmes of the cerebral cortex
in the eoBsatossnsory su&d visual areas, ifae wetho<a
eagployed was that of stiaulatlcm of perij^eral nerve,
the lateral geniculate iKtdy or a corresponding point
to the opposite he&isphere, while cells in the soaato-
seitfiory and visual cortex were isfpaled with aicropipette
electrodes, Hyperpolarization of aany cells were re-
corded, aost often froa the visual cortex and the size
and duration were siailar. ^en the lateral geniculate
body was '^poisoned'* with gassBa-aaiaobutyrie acid, and
the re8p<»se8 smeorded fr<m the surface of the visual
cortex, it was found that such responses were «a-
larged, suggesting that this cheaical agent aight have
suppressed the inhibitory int@meuron@@ . 'ShiB particu-
lar work will appear in a book titled "Conference on
Inhibition of Central Hervous Systea and Gaaaa-aaino-
butyric Acid*% published by the U. S. Air Force,
-38-
In a study of the ssraaptic activation of corti-
cal nenpe cells ^ S?8. Li aad Chou introduced aicro-
electrodes into cells of the soaatosensorsr cortesg
vhile a contralateral sensory nerve was stisailated.
They found that about 1 oeec. after the onset of the
initial surface 9 positive potential was recorded fr<»i
the cortical surface, and cortical neurones vould re-
spond with growing depolarisation and spike responses
were initiated frcsa a level of about 10 m7a Sub-
threshold depolari!sati<m was found to be composed of
saall potentials 8 and these snail potentials could
probably be considered to be units of p<M3itsynaptic
potentials., A synchronous discharge of such units
gave rise to a depolarissation of critical siae fron
^ich the spiti^ potential could be generated. Oscil-
lating potentials were found to be rhythaic and graded ^
and probably responsible for the rhythnicity of the
spilse activity, fhe oscillatia^ potentials did not
require a continuovus presynaptic activity, and could
be considered as an intrinsic factor with which the
excitability of the nerve cell is Maintained. Finally ^
they found that tubocurarine does not impede the synap-
tic transnisslon in soao elesmftts of the nervous systeBc
In their work of recording froa single cells of
tissue culture 9 I>rs. Lis Clatzop (3iou and Millers rer
port that the resting DC potential of the cultured
nerve cell was found to t^ coaparable to that obtained
froa nerve cells in vivo, i.e. in the level of 70-80 bYc
The only difference was perhaps the duration of the
action potentials, which were found to be relatively
prolonged. A study of individual glia cells is tissue
culture is now being undertaken in an atteespt to con-
firm and continue boob of the work of Tasakio et al.
Dr. Qekahan is c«»itinuing his investigations
of the etiology, pathology, and clinical manifesta-
tions of cerebral palsy and epilepsy during childhood o
Xn the latter such study, he is doing a combined sur-
vey of the electroencephalograidiic abnormalities and
clinical findi!i^:s in seizures during infancy, in coa-
binatloa with the Mayo Clinic. At the present time
160 patients have been under study. Dr. Dekaban has
Just completed a bookj, The neurology of Infancy, pub-
lished by Williams and Wilkins, which suKsarizes his
basic studies in the estbryology and developmental
neurology of the perinatal period. This is the eighth
book or research mont^raph to be completed by the
Clinical iMit, since its activation.
In cooperation with the National Naval ESsdical
Center and Walter Beed Arm^ Hospital {, Dr. Dekaban is
continuing his studies which now cover 4^1^ ps«g-
aasiciess in x>elation to the coui«e of birth in rela-
tion to neurological abnomalities in infants ^ and
pathol<^ic lesions in products of abortion « '^is
has also been evaluated against the netemal age. Of
these 4 8 156 pregnancies g there vere 312 abortions »
22 still-births, 59 neonatal deaths, and 10 infantile
deaths o Surviving full ter» infants with coa^licated
gmitation and de livery $ or abnoraal clinical state at
birth, were 921 » as against 2,567 noraal infants with
noraal gestation and deliverer. Stsrviving presature
infants with conplications at gestation and/or abnormal
clinical state at birth ^ were 103; surviviiHE prenature
infants with noxmal gestation and delivery, and normal
clinical state $ were 153a It can be seen froM these
figures the coHplications of gestation and delivery j,
or abnomal clinical states ^ exist in one out of three
surviving full tera infants ^ and one out of two pre~
Mature infants <, A cosplete study of this large aaount
of patient material is obviously a long-tem <»e« but
from the preliminary statistics listed by mt. Dekaban,
it should be rewarding o
Qr„ Dekaban has now accumulated 23 brains
children who suffered acute birth injury or who
in chronic phase of cerebral palsy » and a careful
evaluation of the pathology and pathogenesis of acute
birth injury is made on the material consisting of
fifteen of these brains » It appears that correlation
of 9om» of these acute hemorrhagic lesions with
clinical findings of other patients may form a basis
for clarification of certain instances of cortical
blindness and cerebral diplegia^
3>r. Dekaban and DTo Baird are continuing their
long-term study also on the offspring bom to diabetic
mothers s, and now have the outcome of 234 pregnancies
in 48 diabetic womsne and 249 pregnancies in 48 noraal
controls o the percentage of abortions and previable
deaths in the diabetic sample was Si9.9g in the pre-
diabetic sample 20.59 v&ile in the normal controls
12o4„ Stillbirths were similarly high in the diabetic
and prediabetics as compared to the normal controls »
neonatal deaths accounted for 8o3 percent of all preg-
nancies in diabetic women;, as against 3o6 percent in
the sample of nosmal controls « Of the infants surviv-
ing in the sample of 157 diabetic pregnancies, there
were sis atmormal surviving offspring. In the normal
control samples of 249 pregnancies » there was only one
abnormal surviving offspring; a difference of 7„6 per-
cent in the diabetic as contrasted to 0,4 percent in
-40-
the control. Tb^ee of t&ess sis almosaaX sfsrvivlng
cbildrea had severe eoagenital aialto2nBati<»s; tvo had
Mental deficleaesr» aad one epilepsy. Of 41 offspring
vho were stilllsom or died during the neonatal stage,
of diabetic v«»Bettf, 16 had coaprehensive postssorteBt
essisaination. Cerelnral birth injury vas found in t«o;
pulBonarjr hyaline aeabrane disease in eight; congenital
aalfonKations in three o
Three pc&blications ha^e resulted trosk this
study (, as »ay be seen in Project aZB0B»68Cc>,
!^, IDekaban's aeasureaents of estemal end in<-
ters&al orbital distance in males and fesuiles fro®
birth to adulthood are included in the booh listed
aboTe. In his preparation of the horizons of the
aoxmsH developaent of the central nervous systes in
ttice» and in experiaental producti<» of congenital
aalforraations of the central nervous systes in these
aaiaalSj, an atlas has been conpleted vhich is now in
current use in this laboratory. Of the irradiated
BKLee used, 98 litters were obtained « and api^poxi«ately
10 percent of these had eajor ahoorsalitiesp and about
25 percent minor abnormalities.
Or. ZAQSdellf, in the Section on Psychology ^ is
c<«tiauiag his psychological evaluation of t^itporal
lobe diseJ^Ce and he suggests fr^s his studies a c<»fi~
pies verbal facility is i^intained by the Int^rity
of the dcminant tenporal lobe. Ihe nusSwr of cases to
date 9 hoi^ver, in soae coaparisoss is rather saallg
and results s^y be due to chance variations until this
series is enlarged.
Tke Section of neuropathology has carried, as
<me of its aaln interests in the j^ist ysare the in-
vestigation into sons of the basic features of perBe->
ability and aetabolisai of various cell types grown in
tissue culture. For this purpc^e^ the uptahe of non-
toxic neutral red dye and several proteins ^ such as
albumin, globulin and fifaarinogen, labelled with
fluorescein isothiocyaaate according to the Coons*
technique 9 has been studied under various eaqperiaental
conditions. I^ study is utilising both nerve and
aeoscle tissue e, and cultures of living cells are incu-
bated with varying solutions of neutral red or labelled
inroteins. The observations are aade at tiae intervals ^
the cultures beii^ subjected to various espsriBsntal
conditions. The cells are observed in the bright-
field, phase and fluorescence microscope, as well as
photographed by tisi9->lapse cine camera. The uptake of
■»41-
fi®ut£'al red appears to occur oalf in lining cells in
good pl&^iologlcal condition,; and disappears £ro% cells
vbich ar@ dfii&g, and is o!i>viouslf not taken up bf
dead cells » There appears to be a marked difference
In thm ratio of uptake in the various cell tfpeSo
Macrophages thus are filled with granular inclusions
of neutral red in an eictrenelf short axeount of tisec
Astrocytes show conspicuous granules of the dye in
the processes and in the cell hodf after an interval
of tiaso Nerve cells and nuscle fibers » however «, take
up neutral red in a limited waf g, and onlf at the ter-
minal expansicns of such cells which are provided with
undulating nesbri
^e uptake of the various proteins reee^bles in
wafs that of neutral red. Again there is a
sittilarly different ratio of uptake aaong the various
cell types o f&e striking difference is the disappear-
ance of such proteins within one hour f ro» the »acro-
phages^ whereas the astrocytes preserve the proteins
throughout the tiae.of observation, ioe, twenty- four
hours o Th3 ratio of uptake of the varioiis proteins
is correlai.9d generally with the size of solecule;, be-
ing highest for albuain and lowest for fibrinogen.,
The effect cf low tei^perature on this has also been
studied, and under low temperature there is conspicu-
ous reduction in the uptake both of neutral red and
of proteins It is of interest that under hyjK>ther»ic
conditions the macrophages hold the fluorescent pro-
teins and tlufsre are only a few protein inclusions in
the astrocytes 9 after six hours. This picture cor-
responds to the nor»otheraie picture at thirty sinuteSo
It is suggested by these observers the initial uptake
of neutral T9d and proteins takes place by plnocytosiSj,
"drinking by the cells '% and that apparently aacro-
phages can sbetabolise such proteins and extrude them
within a co»paratlvely short asiount of tima.
The project concerning a quantitative study of
the precipitin react ion « by Dr^ Miquelg reported in
last year's Annual Report » and also discussed in the
Branch of Medical Neurology 9 has now been c(»ipletedo
The labile proteins aove rapidly on the electrophoresed
paper 9 but the precipitin stays at the point of ap-
plication , and subsequent eluting allows a seni-quan-
titative analysis. This will be reported in the
Journal of Ia»unology»
Or, Klatso and DTc Laskowski have also finished
a project on the effects of hypothermia on injured and
normal braia tissu®. Th«f find a strikiag dXtte^euQ®
bet«®9s tlie ffiormothoTaic aad l&ypotliesmlc aainal^ as
revealed in tl&e iMhavior of the blood-liraia-barrier o
1%u8, at twenty-four hours 9 when ede»a is naxisiui,l in
the nor»othemic ani»al, the area of altered blood-
brain-barrier in the hfpothemic animal is dlainished.
fhe response of glia cells at coiaparable periods in
the hfpothernic group, as coapared to the noraothemic ,
8hov» a narked diminution. These studies carrjf im-
plications in the use of hypothermia in the treatment
of severe head trauma with brain edema, and have re-
sulted in three publications in the past year, which
b@ seen in project HIHDB-64|c) .
Studies of hypothermia in neuroanesthesiology»
however 9 have been continued by Dr. Pritchard, Or,
Bttchn&ffis and Dr^ ChoUj, in that these investigators
have now successfully worked out a technique for se-
lective brain cooling so that the brain could be
lowered to temperatures of 12 to ISOCs while the eso-
phageal temperature was maintained at 25-30<»C. Since
the cardiac effects of hypothermia are the main limit-
ii% controls on this technique,, it would appear that
an isolated cooling of the cerebral circulation would
obviate this undesired reaction and still allow the
neurosurgeon the benefit of selective hyperthermia
to the head. Similar studies are being carried outp
in CIslo, by Ust. Christiansong and Dr. Baldwin and
STc Christianson are now cooperating on this problem.
Dr. Prltchard, during his tenure of the past
year with Neurosurgery, has continued his studies on
the hypertonic urea solution on intracranial pressure ^
in which the desired effect of reduction of cerebral
edema and intracranial pressure has been uniformly
observed » both in the operating room and on the ward.
No serious side effects have been noted » with the ex-
ception of two cases in which there was a transient
ischemic syndrome in the extremities in which the urea
was administered by vein. The cause of this latter
peculiar syndrome is still not understood, but the
value of urea is now becoming generally accepted in
most neurosurgical clinics. Dr. Pritchard has also
carried out a combined anesthetic study with the
utilisation of succinylcholine in patients wl
cooperate with the siirgeon while under local
thesia.
Dr. Morris 9 Dr. Klaixo^ and Dr. Baldwin are
continuing the studies initiated four to five years ago
by Dr. Charles Wood and Or„ Lawrence Frost on some of
tbm inner connections between the aajpgd&la of the
tvo sides of the brain o Chronically inplanted elec-
trodes in cats and Konkefs were utiliased in this
studf . Such depth electrodes were placed stereotac-
ticallf under »oderate to deep hypothermia » and as
»anf as nineteen electrodes were placed in a single
preparation. Stiaulation of one aai|rgdala resulted
ia a stereotyped behavioral aut<MBatis»g with a charac-
teristic spike-aad-wave af terdischarge » which is re-
corded both ipsilaterally and {after a few msec., de>
lafl contralateral liTo Both the autoiiatis» and after-
discharge were very sensitive to anesthesia » Bi-
lateral sequential or simultaneous anygdala stimu-
lation sonetiaws enhanced or^, in so»e cases » de-
pressed the effect which would have been explained
on the basis of algebraic susnationc this study
gives sons insight to the fact that the anygdaloid
ccMiples nay be one of the sites of autraiatissc Hie
precise nucleus in such a c<»plex renains yet to 1^
discretely localised »
T^iBg theUi, concludes the Reports fro» the
of Surgical neurology c
Branch of OphthalJBiology reports j, during
the current year» the adnission of 177 new inpatients «,
and 75 new outpatients, with a total of 7,491 inpatient
days, Thtm Branch has continued to be the largest
consulting Branch of the Institute, with 838 consul-
tations seen during the past year^ Fifty-nine sur-
gical operations were perforaM»d during the current
year.
Dr. von SallJiann and his associates report the
following specific projects:
DTc van Alphen has continued bis study as to
the basic factors underlying refraction abnormal it ies .
The theory nost often (luoted; and/or defended , is that
of Steiger on the origin of refraction anonalies. This
theory gives no adequate explanati<»i for the neehanisei
of enwtropia or aastropia. Bra van Alphen has ap-
proached this by a factor analysis of the five optical
eleaents based on the data of Steastrda, Or. van
Alphen *s approach was based upon the fact that the
degree of tension in the choroid moat counteract the
intraocular pressure $ and is deterained by Ksasuring
the pressure in the suprachoroidal space » as described
in the past year; seccMtdly^ the relative tension in
the choroid by direct strain g:auge aeasureBent at
-44-
varioias sites before and after sympathetic aad para-
sjrmpathetic stiamlation; aad thirds the effects of
the relationship of intraocular pressure as agaixust
scleral elasticity.
Pertinent to Ttr, van Alphen's theory is his
consideration that the choroid acts in essence as a
sheet auscle„ and the results he has obtained on cor-
relative pressure changes in the subscleral space aad
the anterior chaaber ezaained vith a variety of tech-
niques on the exposed choroid, strongly suggest that
the assumption of this function of the choroid is cor-
rect. The interrelation of these five factors ul-
timately coabine to fora three oblique correlations
between the five optical eleaients in the himan eyoo
Dr. van Alphen proposes to continue this study into
the basic abnomalities of refracti<M& by further iavesti-
gaticos into the tension of the choroid and its ef-
fect on the sclera by strain gauge aeasureasnts on
the eye in situ and isolated o Fron this he hopes to
c<»q;>lete a concept as to the possible aechajiiSBs of
eaoMtropia and its aberrations c
The Ch&it is continuing its basic studies as to
hov light is perceived at a retinal level and subse-
quently transmitted as a nerve inpulse. Such studies
in electrophysiology of the eye are also being applied
in the utilization of the electroretinograa and para-
aetric light sense studies g both in aniaals and aauc
Each year the Clinical Director «, in his report «
aakes aa atteapt to point out what seeas to be out-
standing contributions aade during the past year by
given Sections within the Clinical Utoit, The work pre-
viously described in the Section of Heurocheaistryg by
Dr. Tower aad his associates} aad the work described
now 9 by Dr. FuorteSj, UTo Tasaki, and Dr, Rushton» are
both outstanding in their approach ^ their logic, aad
the probability of iaereased understanding of basic
■echaaisBUs ia their respective fields „ during the citr-
reat year.
Dr. Fuortes is continuing his study of chaages
evoked by light ia the eyes of invertebrates, usiag as
his aodel the Liaulus. Part of this work was done at
Woods Hole, where fresh animals could be obtained daily;
part was coaf iraed at spinal cord level ia cooperation
with Dr. £arl Franks in the laboratory of Heurophysi-
ology^ in order to deteraiae whether certain properties
done ia the Liaeulus are also coasK>a to other struc-
tures. The techaiques involved, again ^ were the utiliza-
tioa of micropipettes ; aad in cases of work done in Br„
Fraak's labos'atos^g two pi^ttes ^©2"® iMrod%ac®d iat©
the sai^ cells Si&'d vaxiovis reepoBS®® stMdi@«l ^ith the
volts^e-clssMp aifithodo
lag t3i€! p&st jresur: 1} th® ©it@ of tJbe ispulis® iisitia-^
tioai; 2} the subliaiaai reeposis®^ to light; S) th®
study of h^perpolarizatioiK potentials elicited hf
ligbt ia tiie fists retina.
Dr„ Fisortes aad bis coll«i&^es t&s.^® founds iia
the past Tear, tliat the resistaaee of the mer^e cell'
saBEltraa^iK the Liimlus efe decreases dmriog illuaiiiia«-
tioso raiffl^ recorded dusrisig ill^^Kiaatioa are smaller
than those recorded ia coisspara^le cosiditioisB ia tl&@
darlaess, tito Fuortes feels that this could lie m^-
plaisedj, assuieiBg that the resietasice of the S€mA fmm-
brai&e does not decrease irerf dr<a@ticallf d%iri^ i!spul@@
acti^itf „ A direct ffiea@ure^@2it of the nsmbrasie r@°»
itistaace of the momsL In the Li»ilias coiaM not b@ ob-
tained«, but reeulte obtalised on spinal siotor neurones
i7ith the voltage s^lsmp do support this agsuiBption, To
eseplain this apparent discrepanei^'^, it m&f he thought
that the i^chanism of inpuloe g&^®r&t±o& in the m^msi
is different from that in the a^on «here ^esahrane re-
sistance decreases bf a factor of SOO or so„ or^ as
an alternative, that this i^puls® activity does not
involve the cell sc«a or in^ol^<9£ only a part of th©
cell
issperii^nts^l finding© obtained so far, in this
Section s, are in agreement with tfe@ secmftd hfpothesieo
lh€' latter hypothesis „ in partic^^isr^ i@ supported in
th® LiMslus hf e^pori^^nts ©ss. ia^-iteitiosso Thusj fol-
lowing ejscitatorf illuMin&tionSs, the frequeiacir of fir-»
ifflg bears a strict relation with .the s^nibrasi© poten-
tial of the soma (siote here ^m^ findings bf Brs»
AjiBone Marias and Li in the cerebral neuron) f, Isut in<=>
hifeitorjp illumination decreases the frei!|U®ncf of fir-
ing without perceptually chmsgiai^ the recorded msmr-
braae potential, fhis is what omm would expect if
both the place of origin of the rhythmical i^puls<3
aad th© site of i^ibitor^ actiois were at a distance
frcm the sojia. Br^ Fuortes fe®ll©if©Si, in fact^ that
tli© iahibitorj^ s^iapsiefs &r© ©st on the g$@aa Imt ©ss thm
siiOSSj at l<II«l-SOO{,i if CM t&a ^mm., Bm coraclmlegSj im
thm ®f® of the LiMiliiis aad wmftonmnrosmm of tk@ ,cat»
that, iapulsee ©rigiaat® ia tlae a^©ia„
A® smy b® recalled fi*©® pj"@vi©u^ Annual Reports,,
^c Fuortee' iffi%^®r.tigati©s&s l©d hiu to tla® cone lu® ion
th&t a chemical subetaacs liberated bf the photore-
ceptor is responsible for evoleiog the nerve cell de-
polarization o Ed has continued this work now on the
study of the properties of transaission free i^oto-
receptive structures to nerve cells in Lioulus by
s»aa8 of an analysis of subliainal responses to dia
lights, and has found thatj, following dark adaptation,
a steady dia illuaination produces an irregular series
of transient depolarizing pulses. He relates this
to Bucb the saae type of inforaation found at the
motor endplate^ and feels it reasonable to think that
transient depolarizations recorded during dark adapta-
tions are, in fact^ due to discrete liberation of
"droplets" of transaitter substance. Ihe possibility
that each "droplet'* is liberated following absorption
of a single quantua of light is now being investigated »
and Or. Williaa Rushtong froa Caabridge, England, has
taken over this eztreaely fascinating facet of visual
physiology o
Dr, Tasakie before leaving ^ completed his work
on the fish retina, and confiraad Svaetichin's find-
ings that hyperpolarizing potentials are elicited by
light in the fish retina ^ and that such potentials
could be obtained in the absence of a negative DC
shift. Electrical currents through the aicroelectrode
do not affect the size and properties of these poten-
tial changes ; and tnm these results he concluded
that the hyperpolarizing potentials originate in a
large space which could be either a large cell or an
enclosed extracellular space.
Dr. Eushton also is carrying on his studies
on regeneration of visual pigiaents, using the technique
he developed in CiBbridge, in which light is received
fros the fundus oculi into an optical arrasgeaent and
analyzed by photoelectric equipaent. This study is
being done on normal human controls .
Using the pure-cone retinae of the Asaerican tree
squirrels Drs» Tans ley ^ Copenhaverg and Gunkel have
studied the spectral sensitivity » the dark adaptation^
and the flicker fusion frequencies of various aerabers
of the squirrel family. They have obtained evidence
that certain species of squirrel have only coses but
not rodSo by demonstrating the absence of a shift in
the peak luminosity of the spectral se^siti'^ity curv®
froa light to dark adapted states „ These high critical
fusion frequencies and the absence of a type of spectral
-47-
sesBitivltf curve would suggest the presence of
rhodopsiiio Two "hiuips" were^ however ^ found and this
was thought to represent at least two idiotosensitive
cone pigments. The «ia»1i«m of these peaks were 490 »§&
and 535 a|te In a further stud^s, after destruction of
the retinal blood vessels so that a retinal degenera-
tion was obtained Cia sone anioals United to the
entire inner retinal layers down to and including part
of the bipolar lairer) there was noted a aarhed reduc-
tion of the electroretinograa vliiche, to these investi-
gators, confiraed the hypothesis that the positive
potentials originate on the bipolar cell layer while
the negative retinal potentials arise on the deeper
retina.
The use of the tree squirrel should be »ost
helpful in providing information on the rMiposses of
the purely photopic nechanisa uncontaainated by any
scotopic aechanisas. Hr. Taasley's previous investi-
gations have already dMmnstrated the reactions of
the retina of the tree squirrel are in aany ways un-
like those of the aore usual aized rod and cone
retina of which the huaan is an example , VnvaUg the tree
squirrel retinal spectral sensitivity curve is such
narrower and appears to reflect the activity of only
one of the three pmaitulated aechanisas for color visions
i,eo the "green" aechaniSBo The ground squirrel » on
the other hand^ apparently has twoj, a "blue" and a
"green". It is believed, froa these studies, that the
photopic and scotopic responses in aan can be sepsirated
by aeans of their reactions to flickering stimuli o
The squirrel respo]»es to flicker have not as yet
been systeaatically studied, but it is hoped that this
will be done in the near future »
In the clinical counterpart of this work« DrSo
Copenhaver, Gunkel^ Goodaan^ and Dodtg have continued
their studies of the physiology of the cone and rod
vision of patients with various foras of retinal de-
generation and color defects j, by aeans of elaborate
psycho-physical testing and spectral sensitivity
curves 9 in addition to the electroretinograao
Daring the past yeaTp for exanple, these in-
vestigators have isolated a cone aonochrcMsiat patient
who eadiibited noraal visual function except for a
complete absence of color discrimination a Scotopic
function^ as tested by the adaptotsetry and periaetric
ligbt seasa studies, appeared nos^sil. Photopic fuac-
tioa^ at least tl&at eediated hf red sensitive cones,
was Bigaificaatly di©iaish€d as deaoostrated bf the
Invest igatioa of the elect^oretinal spectral sensi-
tivity aad peri^tric lig^t sense studies. TSiis in-
foraation suggested to theris invest igatoi^ that part
of tike color loss ^as due to a retinal defect but
did not contritmte to the r/uestion as to the site of
the other abnoraalities wbich nust have been present
to give so severe a color deficiency.
3r. Dodtg i^hile with the group, continued his
studies on pigaentation qH the retina as related to
the spectral sensitivity curve, and chose albinos ^
caucasiasis {, and negroes us his subjects., It was
found that where the retinal pigssnt is v&Tf lights
there is an increase in red sensitivity which re-
flects the absorptiost spectrum of blood. Stisailation
of the retina by scloral illuaination also altered
the spectral sensitivity according to the absorption
spectrusa of blood. These studies indicated that the
pigaent in the coats cf eyes does not itself alter
the electroretinal spestral sesffiiitivity curve, but
the pigaent is nearly absent or reduced the un-
of the choroidal blood vessels results in a
pronounced increase in red sensitivity. "Haus^i the
pigaentation of the retina sust be considered in
future studies utilising the aethod of spectral elec-°
troret iaogr aphy .
Two children wilih infantile aaaurotic faaily
idiocy, and others with late infantile and Juveaile
stages of aasaurotic idl.ocyg completed the clinical
evaluations of this disorder , in that the electro-
retinographic potentials were found to be abaoraal
in the late infantile and Juvenile fora» but noraal
in&e infantile form. This confirms the pathology
described in the retina by the late Dr. J. Godwin
Greenfield, and» together with the previous studies
of Copeahaver and Goodaan^ c(»pletes the clinical
evaluation of this disorder. It appears that in the
late infantile Juvenile form of aaaurotic idiocy, the
electroretinograa could be a sensitive indicator for
the progression of the disorder.
In all of these studies « Dr. dun&el has been
primarily responsible in designing and constructing
devices as needed, in particular during the past year
he has worked on the ssodified adaptoaeter, and the
various optical devices necessary for Dr. Tansley's
worfe listed above » including sector discs and shutters
-49-
for providing pliotopic stimuli of differeat durations
fliclier rates s and on/off ratios » and the apparatus
needed for an intense bleaching light which could be
changed in color and introduced into the pupil with-
out interfering with the entrir of the stiaulating
beasg for Or„ Rushton's studies on the regeneration
of rhodopsin. Dr, Gunkel has also »ade frequent
Its of the spectral eislssion of the high-
laaip and steasureiaents of brightness
of the stiiiulus bea»o
The ^anch lists three projects s correlating
various aspects of knowledge, concerning function of
the cornea both in health and disease o DTo von Sail-
aann reports his studies for deaonstrating possible
injuries to the corneal endotheliums in which it was
neeessarf to develop a technique in which an entire
cell population of this tissue could be studied,
this is of great importance in clinical ophthalmologf ^
and particularly in the so-called Fuchs' dystrophy «
It was of even more importance » however » with the re-
cent demonstration that ch7»otrfpsin« when injected
into the posterior chamber of the efe, has greatlf
facilitated the removal of the lens at operation o
This was found accidentally in other Centers in which
chfmotrirpsin had been injected into the vitrous cham-
ber and subsequent subluiation of the lens was found
to occur. Its use now i&to the posterior chamber of
the eye 8 for the subsequent removal of cataract » pro-
mises to be a possible gnsat advance in the removal of
cataracts c, Accordingly, the Academy of Ophthalmology
and Otolaryngology asked that certain Centers under-
take a study as to the effects of this substance on
other structures of the eye. In this study on corneal
endotheliums chymotrypsin^ was utilized by Dr, von Sall-
mann^ and the report to the Academy may be found in the
Trans o Am. Acad, Ophth, Otolo^, now in press,
OTo von Sallmann has found » by this method » that
in contrast to the generally held opinion that karyo-
kinetic cell division does not occur in the corneal
endothelium of the adult animal, mitosis does take
place c, and the mitotic index of an average of fifteen
dividing cells per population is similar to that de-
termined in the pre-equatorial zone of the lens epi-
thelium» Be found that the injection of 0,9 percent
sodium chloride solution into the anterior chamber
leads to endothelial damage indicated by gaps in the
regular cell mosaic « and by cell degeneration and a
marked increase of cell division in the area of the
lesion. This injury is even more extensive when the
alpha-chsmotrypsia C^bich^ as has been pointed
out above,, has been recoonended for zonulolTsis) i^as
infused for several minutes. The process of wound
healing is initiated bj the fomation of a fine and
dense fibrin net covering the defect in the endothelium
and by an ingrowth of cell elenents from the margin of
the wounds. In his report to the Academes, Dr. von Sall-
maan indicates;, however, that such lesions may be
transitory 8 and do not of necessity contraindicate the
use of chymotrypoin for cataract removals
enzymatic systems of the cornea continued
to occupy Dr. EuhlBian up to the time of his departure „
Dr. Kuhlman has turned to other connective tissue sub-
stances to find if they vary from his previous report
in 1958 on enzymatic studies of the cornea. In this
respect he used the collagen of the developing epiphyseal
plate. He found that the primary spongiosa and cartilage
cells contained more total phosphorous ^ solids » and
acid soluble material than unorganized cartilage cells;
that the activity of both lactic dehydrogenauee and
phosph<^lucolsomera8e was higher in ozganized cartilage
area and lower in unorganized cartilage area^ and that
malic dehydrogenase activity parallels calcification o
Gluco8e-6-phosphate dehydrogenase doubled in activity
as the primary spongiosa developed. Allialine i^osphatase
activity increased with each advancing stage of cal-
cification. There was^ in all, a general increase in
activity with the maturation of the animals o
This is, in essence, in agreement with what was
previously found in the cornea by Dr. Euhlman^, in the
last Annual Report.
Dr. von Sallmann and Dr. Paton also have described
a clinical abnormality^, of a familial type^ of the con-
junctiva and the oral ^icosag which is that of a dys-
keratosis» which occurs in a tri-racial isolated popu-
lation in Halifax County ^ Korth Csrolina, This was
done in combination with Dr. Wltkop, of the Dental In-
stitute, and Dr. Graham of the Department of Pathology
at the University of Morth Carolina. It appears that
the disorder is Inherited as a simple Mendelian dominant »
and the eye changes occupy the perilimbal conjunctiva^
and consist of a firm granular semi-translucent pro-
liferations which is raised above the surface of the
surrounding tissue « Tbe shape of the lesion varied ^
but most frequently it assumed a triangular form or
horse-shoe-like configuration. The surrounding part
of the conjunctiva showed a rather characteristic vascu-
larization. Serious corneal complications were rare^.
-51-
but mfmmtismm dease siee%b7aa@s of prolttmT&tmd tlssu@
cowermd the cornea for periods of timmo There wa@«
on sicroscopic eacaminatioii^ epithelial hyperplasia^
which was accompaaied hf degenerative changes of the
dfskeratotic tfpe and signs of acanthosis » Degenera-
tive changes of the cell nuclei were cosnono and with
the Gieasa stain irregular light blue structures could
be desonstrated near the nucleus or its rennantSa
Tlie tunica propria was usuallf free of najor pathology ^
but was s<^etiffies the site of esctensive round cell in-
filtration o
Such patients 9 also, during physical escasina-
tion^ were noted to have a change in the buccal aucosa,
co-existing with the eye lesions o Ibis was denonstrated
by the Dental Oepartnent to also be a dyskeratosis.
Six projects of the branch » MbSo HIHDB-SOCcK
iriin)B-82Cc) B HINDB-SSCc) s llIKDB-86Cc) « HIHDB-STCcK
HIMDR-dlCc) , and lfIIfD&-94Cch denonstrated either a
basic or clinical investigation relating to intraocular
pressure and the possible raaifications of these ob-
servations in regard to glauconao IRiree such studies
were reported by Oro Hacrig of the Pharsacological
Section 9 one of which was done in combination with Dro
von Sallnanno Such studies were centered on the inter-
relationship of venous and intraocular pressure, and
attempts to nod if y either or both of these by phama-
ceutical agents o Thus^ Dro Hacri made casts by in-
jection into the anterior chanber, showing filling of
the ciliary body of three species: cats, rabbits » and
•onkeys. In all nonkeys il2}„ the material was also
found in the suprachoroidal space o This filling was
found in addition to that of the aqueous veins ^ and
raises the question of whether or not this represents
a second outflow pathway or anat<»Bic da»age due to
perfusion of the cast nateriale This observation^
however 9 together with the knowledge that the outflow
of the eye could be altered in a biphasic pattern in
which the proportionality of outflow to pressure was
lost, Indicated the possibility of a second outflow
systess and Dr^ Hacri now has started preliainary ex-
peri»ents on a^nkey eyes in which fluorescein was in-
jected and again deaonstrated in the suprachoroidal
state after injection into the anterior chaabers, lend-
ing further support to this study. In view of the late
Dr. l-riedenwald's studies, it would appear nore in-
vestigation will be necessary to detemdne how msch
such a secondary outflow system contributes to clinical
disorders «
.52-
Further lav®stigatio& into thiSo so that true
outflow pressures aay be calculated was centered around
the technique of aiaking a ssall incision » 2->3 ara^ in
the sclera and separating the choroid and sclera cir-
cularly for a distance of 5 sdi<, A piece of thin Saran
Wrap is inserted between the two layers of tissues,
and a piece of #10 polyethylene tubing « bent to coin-
cide with the curvature of the eye^, is placed in the
suprachoroidal space, through this incision. This
Saran insert prevents the tearing of the choroid by
the tubing during its placeamnt. Ihe tubing is then
tied in place and the incision tightly closed. Dr,
Maori feels that if the flow to the suprachoroidal
space does exist j, this procedure »ay allow its quanti-
tation, and total flow fr^i the anterior chaiaber will
also be determined so that^, by differences, flow through
the aqueous veins »ay be calculated »
Dr. Cohan is carrying on a sosewhat similar
study with intraocular venograi^y^ in which Hypaque is
placed into the anterior chaaber of the eye. Using
intricate radiological techniques » Dr» Cohan has suc-
ceeded in deaonstrating the venous chsumels of ssall
calibre e He has also shown that introduction of such
Hypaque into the anterior chaabers is well tolerated,
and can be used clinically to establish the presence
of some clinical forss of choroidal detachaento
Or. Maori has utilised the cat eye extensively
to elucidate sechanisaB which affect or control the
intraocular pressure;, and, once again using casts :, in
the cat he found anastomotic vessels connecting the
anterior ciliary vein and the vortex veins, laxle cast
technique also showed filling of the intraocular
veins in the cat. Although the cat has a large
of episcleral veins ^ it has but one large anterior
ciliary vein^, which is prominent Just anterior to the
superior rectus auscle, and this vein Joins the circle
of Hovius by 3-5 branches. At the area of the four
vortex veins, large superficial, intrascleral vessels
lead fr<Hi the Circle baclcwards to the aapulla of the
vortex. Vessels of the iris, ciliary body^ and choroid
also well seen, and their interconnections noted.
Continuing a study of previous years on the
facility o£ aqueous outflow (flow expressed as enn/nin/
aai.B^):, I>r. Hacri recorded venous pressure in different
veins of the eye, elasticity and aqueous inflow, in
addition to measurements of intraocular pressure and
local venous pressures , and the systemic arterial blood
pressures s to determine the correlation between these
various factosre. It was reported last year, by Dr.
Ȥ3-
Macris that two pa.ttei^'s&s of aqueous osatflow cowld he
deecrialaated by such methods; the first pattern he
called "Bsonophasic'% in which the outflow wsub pro-
portioaal to the outflow pressure through the range
of pressures studied o The secoiad pattern he called
"biphasiC'o and was one in which this proportionality
was upset 9 and in which the outflow w^&swc@d as
CBa/ain/ma.Hg decreased progressively as the intra-
ocular pressure was elevated. The values of this
latter outflow and the biphasic outflows were always
greater than those of the a^nophasic at pressures
close to the nor@^l for the anisal studied.
Utilizing these findings. Dr. lacri has at-
tempted to deaonstrate the effects of Diaasos on both
such psressures^ and has arrived at a new concept which
iaplies that the carbonic anhydrase inhibitor « such
as Diamo^s lowers the venous pressure of the intra-
ocular vasculature selectively without interfering
with the general blood pressure. He has also noted
the change between the two types of patterns, i.e.
aeonophasic or biphasic ^ aay occur by utilization of
pharaacological agents such as epinephrine 9 or sec-
tioning of preganglionic syaspathetic fibers. He pre->
Bents g&s a working hypothesis^ that the two outflow
patterns are dependent upon the volume in the vitreous
c(»apartasnt » and that this volume » probably through
vasculature, is under the control of the autonomic
systea.
Studies on the central nervous system control
of the intraocular pressure have continued froa the
anatoBical viewpoints, by Dr. von Sallsana and Miss
Griaes, and frc»i the physiological correlations by
Dr. Lele and Miss Gri^s. In Dr. von Sallauum's
study 9 the orbital contents were reatoved coaipletely^
including the nerve supply as far back as the fifth
neirve ganglion. Sstemal ocular sniseles were carefully
dissected away before fixation. For staining j, the
fixed aaterial was washed in water for one hour, and
then placed in silver nitrate ^ and subsequently to
foraalin and sodiua thiosulfate. In the resulting
preparations the nerves are stained a dark brown, while
the ganglionic tissue reaains white. Other tissues
were unstained. The dissection is acc^aplished under
water ; uaiisg the Zeiss stereoaicroscope .
Dr. voisi Sallaann and Miss Griaes find that the
posterior ciliary branches of the hua^a orbit are
siailar to those observed in the aaonkey. Occasionally
a fifth nerve branch was seen to travel upon the optic
nerve to the posterior pole of the globe «, without
-54-
undergoiag satastoB^ets In the oirblto Such branches
aot fusiag with the postganglionic branches of the
ciliary gaaglioa have been desmnstrated in the cat
but not in aonkey. On the other hand, the human
ciliary ganglion receives a heavy branch froa the
fifth nerve 9 corresponding to the fine branches in
the ganglion in the aonkey . Such understanding is
necessary to select a proper pathnray for studies of
afferent and efferent iapulseS; and to stinsilate the
nerves which could be so classified. Such knowledge
has been used by Hr. Lele and Miss Griaes in their
study on the neural ffiechanissas in the regulation of
intraocular pressure c
These investigators studied the afferent nerve
discharges of the long ciliary nerve in response to
intraocular pressure increases and obtained, in al-
asost all instances s impulses iin contrast to nany
failures when the technique usually used previously
was applied in this laboratory Also^ in contrast
to previous findings » no spontaneous activity signal-
ling resting pressure was observed in such prepara-
tions or in vivo. Dr, von Sallraann does not feel
that the site of origin of the pressure induced after
an activity was conclusive j, but did st^gest that such
nerve structures are contained in the outer coats of
the eyeo Stiisulation of the retrobulbar nerves did
produce changes in the eye pressure^ and these effecti
were aost readily observed in the isolated perfused
eye where the coaplicating factor of siamltaneous
stimilation of extraocular structures is eliminated ,
StiBuiation of the long ciliary nerve produced pupil-
lary dilitation in all c£^es, but there was no prei>-
sure change without circulation of fluid in the
These investigators conclude that a relatively
saall ajBount of afferent activity elicited by iiitraocu-
lar pressure changes j, and the absence of spontaEeous
activity signalling resting pressures » aaakes it doubt-
ful that this sensory path carries enough information
to participate normally in the regulation of intra-
ocular pressure; there are pressure effects resulting
froB third and fifth nerve stiiaulation, although these
do not appear to effect long-teim control of the
intraocular pressure.
•Hie clinical progra^j dealing with intraocular
pressure pathology, i^e. glaucoma p is being carried
out hf Dr. C&un and Br. von Salli^mn^ in which the
particular objectives are to evaluate suspected and
"5i»
Is^^^is $a@@s of gla^c«^a im s® effos-t to f i^S aa? li®r
diagnosis and control; @@eoi%cll7, to fiad the
o£ diiss^al ohaages iai t2i@ iatraosular pres<-
iavestigat©d hf toaogs-aphy; t!ii?d« the asch-
of actios o£ ¥a7io;s@ dsisgs asid operatiird pro"-
eed^iS^eSs as studisd hf t®aog?aphF» assd fom>tli» th@
effect of i2Sstaatai3@o^ss ^Xosd ps^eesus^ chaag@3 on
latest igato^s also i^ish to studf th@ di§~
iatraooular fluid dwrnamlcs i& slsmitm&p the
inflow nechasis^ of which -srill be s-abj@ct to the
greatest stud^. ^^mt s& tocography gi^es aa iadica-
tiosii o£ the ®a@@ ^ith which fluid leaires the e^, the
inflow studies ^ill gi^e asi iadicatioQ of the ease
vtth whi€h fliaid esters the e^e. These investigators
feel, from the limited material @o far studied « though
ther dra^ no eoneliasiGSsSe that there are soi^ extreoelF
provocative cases illustrating the broad spectrum of
glaue<Hia foriss. Tt®f es^eet, also, to undertake
aeas«&re^ent3 to estimate the rate of aqueotius foriaation
in health in patients i^ith borderline glaucosaaj, and
9ith frank glaucoma of vario«as tfpes.
The uveitis ntudf ha£ again accounted for the
greatest aimlser of patients admitted to the ward, i.e.
7Se and thi@ clisiical Bt&df was backed b|r a stud^ of
the thfroid/horsoa© turnover is uveitis hf m*. O'.Eourk^i
a stud^ of <K:ular toxoplasmosis and its therap^^, hf
Br. Eau&saas and a stud^ of the immunological relations
in ocular tissues bj Dr. van Alphen. In the basic
stud^ of Dr. van Alphen, guinea pigs are Inmuaized
to their o^n len©^ their omi corneal epithelitssis and
their own vitreo^iiSg and the tissues are h<%iog®nised
v±th Freund's adjuvant to enh^ce antibody produc-
tion. Dr. van Alphen finds that skin, conjunctiva^
corneal epithelioma s^d corneal stroiia are related ie-
sssnologically. fhe leiss^, eo.?neal epithelium and '
vitreo«as are also related, however ^ no relation ^&b
shoisn betvreen skin ®Md lens. Of the various eye tis-
sue so tested 9 the org£^ specificity was ax^t con-
fined to the lens. Corneal epitheliua appeared to be
a relatively strong antigen as compared to coronal
strosa. Br. van Alphen plans to study the is@une re<~
sponses to the cornea and lens in certain deraat«^e@p
and sight expand his work to the uveal problem in the
future.
The records ©f the large group of patients ^ith
uveitis and toxoplasma dye tests, admitted during the
past five years of the Institute » have noi; been studied
-56-
by Difo Eaufman^ with «aphasis oa certain diagnostic
and therapeutic aspects. D:\ Kaufman appears to feel
that the readily available tu>xoplasaiine skin test
seeas to be reliable in that it was, in the B&ajority
of cases, in agreeoent ^ith the positive results of
the toscoplasBUk dye tests. A false positive skin test
was extreaely rare. It is o\ Interest that 50 percent
of patients with a positive serological skin test and
uveitis reacted satisfactoril; to anti-toxoplasaic
chea»therapy; Darapria and sufa were the main drugs
of choice « llie addition of corticosteroids to the
therapy with Darapria and sul:% iaproved only the oc-
casional patient. Dr. Eaufaan also writes the conclu-
sion that the early onset of t.a uveitis under the age
of 20 with an acute or subacute course «, can be con-
sidered favorable for a therapiutic success,, whereas
in uveitis with a chronic couroa the prognosis was 1
good. Satisfactory results wi\h Darapria and sulfa
therapy were usually not convincing before the tenth
day of treataent. There was no correlation between
the level of the dye test and tie therapeutic re-
in evaluation of hypometaiaolisa as a possible
coexisting accelerator of uveitis ^ Dr, O'Rourke has
tabulated the results of his th3roid horaone turnover
studies in uveitis » He has use thirty patients with
uveitis and ten controls. He f ?und that hyp<»etabolisa
coexisted with eany chronic diseases, including uveitis ,
but that no definite conclusiocs cot;.ld be drawn from
the data at the present tiae. Vho percent of the
iodine pool, utilized daily ^ wa.i^ lo\er in the uveitis
patient than the noraal, and tho percent of iodine
utilized daily in uveitis patients did not vary statis-
tically froa the nora, either calculated per kilogram
or per square meter » but both sst ('O. the low side of
the norao The results of this study did not show any-
thing definite about uveitis' atiology or its respon-
siveness to treataent. It is 3ugc;®sted that as a
follow-up a demonstration of thyroid function ox- dys-
function ^ and its influence o& iasiune response in
patients with uveitis, should lae checked.
Basic studies in the ctiemistry and anatoay of
the noraal lenSg as well as in the cataract » have con-
tinued, and may be found in studies KINDB-88Cc)»
NIHDB-lOlCc) 9 aiad mmSB-lMic) . In the noraal lens.
Dr. Resnik has now deaonstrat^d the great coeiplexity
of the soluble lens proteins ^ of which he has now
separated eight fractions o Fractions A and £ have been
referred in the past reports as beta-crystalling while
F-E have been desi^ated as alpha-crystallin. In
-57"
collaboration with DTo Wasko^ electron ifiicroscopic
observation of electrophoretically isolated saj^ples
of fractions of lens proteins have been carried outo
It was observed that the fraction denoted as alpha-
crystal 1 in contains conpound;; elongated structures o
Saaples from the r^iuiinder of the soluble proteins
contain spheres of different sizes. It is now re-
cognized that the low density elesents^ observed by
the electron aicroscopist in sections of osniusi-
fi^ed leiiSs are the lens proteins »
OTo von Sallmana lists,, in his review , that
his estiaation of the outstanding contribution to
the cataract pro;}ect was the denonstration of the
ultraf ine structures of the epithelium and fibers
is the noneal and cataractous lens^ bf Dr^ Wanko and
Miss Gavin o In this study it was noted» in the
visualization of the X-ray-induced chaises of the
lens 9 that the cytoplasaic ccmponents are seen at
an early stage after irradiation. In the past such
changes were considered as relatively late effects „
These cytological changes were displacesent of the
nucleoli e conical tapering and elongation of mito-
chondria^ and partial disintegration of the nuclei o
The Golgi complex alone remained unchanged during
the time studied. Studies also continued on the
myleran cataracts « and the changes observed were
somewhat similar to those seen in the later phases
after x- irradiation. In the mimosine cataracts, in
addition to the data reported in last year's Annual
Report J, these investigators now have demonstrated
that the initial changes in the fine structure in
these lens epithelia involve the endoplasmic reticulum
and nucleoli. Both structures have a high RNA con-
tent « Later, mitochondria and nuclei also undergo
changes «
These investigators now have under study seven
human lenses with senile cataracts „ In the human
lens one striking difference from the animal catar-
acts is the presence of an opaque conglomerate ^ usually
located near the nuclei^, and of approximately 200 m^
in diameter. This complex bears resemblance to the
cytoplasmic inclusions previously observed in adult
human skeletal muscle fibers, and is tentatively
identified as a lipofuscin-typ© of pigment.
Studies of the similar type body in skeletal
muscle are also continuing in Dr. Wanko's laboratory »
DTo Wanko and DTo Shy are shortly initiating the
electroimicroscopic findings in the mitochondria of
familial periodic paralysis in i^hich there is a high
cationic transports
Of great iiit@r@st is the €osbiffi@4 studf of
DTo v©a SallffiaBHo aad Dr„ R«id of tim Laboratoxr of
Iftitritloii aad EndoeriaologF^ NIA1©» ia autritioaal
eata^actSc Thvm D^o Rsldg diiriiig autrltioaal studies
&m t^e guinea pig^ obs@nred a frequent occurr#Bc# of
catai°act@ wli@ai onlf trfptophane was deficient in thm
dieto fl%@ growth curves of these anisals appeared
nomaig but the cataracts developed regular l|r and
ear If „ It was shown that animals on a soderatelf
supplesented diet showed noraal growth ^ but lemi
changes developed in what were apparently healthf
aniaalSo flie hiiitological features of this cataract
differed t¥om other types of ejcperioental lenticular
opacities as thef did not involve the equatorial
sone where new fibers forced o The clinical si»ilarit|r
of these tryptophane-deficiencf cataracts » and of
various fonsi of paranuclear cataracts in the hunan^
was felt to be striking bf Dr. von Sallsann. fhus^, it
has been shown for the first timep the requirenent of
the lens for one essential a»ino acid^, ice, L- trypto-
phane ^ was greater than that for sajEii&al growth of the
body as a whole c fhis leads to the intriguing pos-
sibility there are^, or say be^ early or congenital
cataracts in the hu»an associated with transient de-
ficiency of essential amino acidSo
The studies of ocular tiaigors by isotope tracer
Methods r/ hy Dr, O'Rourkee has now been concluded^ Dro
0*Rourke found that the total activity detec|ed by th@
posterior counting technique for phosphorus exceeder"
the anterior value by 74 percent in the six patients
studied. He founds in addition, that the highest
anterior quadrant count failed to correspond to th^^
tusor bed in six of eight cases studied, but the high-
est posterior quadrant count was localized correr^ly
in the quadrant containing the tumor in six conracu-
tive studies „ However ^ the point of highest rriio-
activity during posterior counting did not alrays lie
directly over the center of the tumor masso ^'husj,
P^^ uptake has definite limitations for localization
of ocular tumor® » particularly in the anterior quad-
rant ^ as has been anticipated in the utili'^ation of a
pure beta emitter. Future work directed to such
ocular localization will ha^e to await farther examina-
tion of tumor uptake by gamiga-emitting sources . Of
interest in ocular tumors is the report of Dr. Paton
and DTo Thomas on simultaneous occurrence of primary
malignant melanoma of the eye and skin, in which these
investigators feel that the choroidal cumor and the
cutaneous melanoma were considered as independent pri-
mary neoplasms which occurred siMilta&eously in this
patient o It is also of interest that the patient's
-.§9-
brother was subject to eaucleatioa of tb® Figbt eye
for iHiligaaat choroid selaQoaa sine fears previous l:;^.
Dsr. Pato2& asd Ds'. ^o!& Sallaaoa have pointed
out a clinical co?relatio!i of aagioid BtreakSg aad
sickle cell aaemia i@ tMr@@ patieats. Such aagioid
strealES of tbe fuiidus bave previously been correlated
with two other diseases, pseudosasthos^ elasticus,
and Paget '8 disease. Skia biopsies were takea froa
these patieats to rule out pseudozaathoaa elasticua.
The vascular calcif icatioias frequently seen in pa-
tients of angioid streals could not be deaonstrated »
but the presence, now., is these three disorders, in^
dicates that possibly a^e^ia, retinal hemorrhages, or
occlusive vascular disease play a role in the patho-
genesis of such fundus changes. This study may be
coBpared with the study of the previous year, reported
as an addendum herein ^ of the vitreous opacities
diagnostic of f^iilial primary aayloidosis. Here
again thorough opthalaoscopic studies may lead to a
diagnosis of a generalized systemic disorder.
This concludes the report of the Branch of
Ophthalmology .
In closing it c%n be seen that the past year
has been a productive one. After seven years of oper-
ation^ it can be fairly stated that the Clinical In-
vestigative Unit has been flexible and constantly
changing in its approach to various areas of develop-
asnt which may shed further light in our knowledge of
both normal and abnormal functions of muscle, central
nervous system;, nerve, and organs of special senses.
However, one of the main problems an Institute must
constantly face is that of diminishing returns ^ as re->
search projects are continued over the number of years
this Institute has now been is operation. In the
first part of 1960 it is asiticipated that the Clinical
Birector will discuss with each Branch and Section
O&ief this problem^, to make certain that the reward
of such continued research is such ss to Justify the
energy of the investigator.
^&ce again the Clinical Investigative Unit ac-
knowledges its debt to the various other Institutes
which have collaborated in part on much of the research
listed above. In each case^^ a sincere effort has
been made to point out the collaborating unit. Much
interchange has occurred and much knowle<^e gained by
a cloB® coopsration witla the Basic Us^it o£ tl&@ In-'
stitutej) amd ia particular i@ this true iia tlae Lab-
oratory of ^euTophjelologj , ilwch of tt@ data re-
ported hereia would hair® b€@it impossible without
the cooperation of the Clisiical X-r&f Departaent,
Clinical Pathology, smd the Instnsessit Section of
the Central Services. We would once again like to
acknowledge the cooperatiosi oi the national Ha^al
Medical Center, Walter Seed Ax^y Hospital, the
Central Intelligence Agency, and the Atomic £nergy
CoesBission^ with whcM @any o£ these projects were
undertaken. Sach year the cooperation and snooth
relations between the Clinical mit and the S^sreing
Service have been a pleasure to obiservee, and the
last year has not been an essce;>tion to this. Hhe
Clinical Unit once again ackno<?ledges its debt to
Hiss Hulburt, and her three heivd nurses: Miss
SaltoWi, Mrs. Thf^pson^ &^4. MlsiB Maccia.
Mot infrequently 8 probl«ig@ have arisen in
patient care which have necessitated the cooperation
of the staff of the Director ol the Clinical Center »
The cooperation and advice frog) this office has been
indeed eaetresely helpful during the past year^ and
the Clinical Investigative Unil; acknowledges its
debt to I>rSo Hasur, Chapaan„ an^i Farrier.
4kfe^
A3Emual I
Hatio&al Institute of l^eiiro log leal
Diseases a&<i Blindj^ess
Noveatber, 1959
Th@ Bs'asc^ of Medical H®urology admitted ^
during the period covered by tteis Report j 269 pa-
tients. This is an increase of 54 patients over
the previous year. The total patient days was
6 3 981 5, ao increase of l^OO? patient days. The
average patient days was 26 «0 days, a decrease of
1,8 days per patient. Two hundred- thirteen out-
patients were seen; an increase of 57, Thus there
;9as an increased turnover and an increased nuaber
of patients both on the inpatient and outpatient
ser\«^ic© ,
Two senior investigators will have left the
Unit by the end of the calendar year. The first
of these is the Associate Neurologist ^ Or, Gunter
Haase^ who has accepted the Chair in Neurology at
the University of Oklahoma.; here he will have a
chance to build a new neurological unit. Dr. Cur-
tis resigned to go back into teaching^ and his po-
sition as yet is not filled.
Two Visiting Scientists » Dr. Fritz Buchtbal
from Copenhagen s who is the Director of the Neuro-
physiological Institute of that City, and Dr. John
Caughey who heads Neurology at the National Itoiver-
sity in New Zealand, were with the Institute for
periods of tisie during frcm one to seven moaths.
IHeir contributions can b© seen in the projects rs"
ported below o Two Guest Wor&ers were present also
in th© Neurological Branch , One was Br, John
Wherrett fro® the University of Toronto ^ who Joined
Dr. Tower in Neurochessistry; his work may also be
seen outlined below. Recently from the saiae Citys,
Dr„ John Humphrey has Joined the group as a Guest
Worker^ and he has been assigned to the laboratories
of electromyography and siuscle pathology.
The Branch of Medical Heurology reports spe-
cifically on the following projects:
The activities of the Section of Heurocheraistry
are centered about the amino-acid isetabolism of in
vityp and tK\ ¥iiro studios of aormal and «piiepto>
genic cortex',; tbe electrolf te aad enez-gir aetabollsm
of nofwal ani.^ epileptogenic cortex» and tlte relation
of pyridoxins to certain, seizure abnomalitieSc This
includes studtiee of protein setabolise and turnover
rates s the effects of certain anticonvulsant drugs ,
on the alteration of such aetabolic processes ^ and
the utilization of certain asino acids in therapeutic
trials with seizure patients.
In suscle disorders studies are continuing on
the distribution of act in and troposi|rosin in normal
and diseased muscle o Studies of alterations of ac-
tonyosin tensile strength in suscle disorders » as
well as a coeparative study of contractile proteins
in saooth and striated asuscle are being carried on^
and finally a atteapts to produce ouscle lesions in
aninal^ injected with various protein contractile
preps/ations and adjuvants in both aniaals and tis-
sue culture are being done.
The studies on new physical sethods to deter-
stir,3 ninute quantities of macrcmolecular constitu-
«^18 in CS.Fo and urine have been teminated with
th«. resignation of the senior invest igatorj, I^„
Cu^^ is. His results are suaiaarised below.
Finally the Section has indicated its interest
in stilling the foraation and tiirnover of RHA in the
Ceir.So This will be started in J^ly, 1960, when Drs,
Spom aii Dingaan Join the Uaito
Speoif icallys Dr, Tower has shown by tissue
cslice technigie that there is a very rapid foraation
of glutamic r^cid and subsequently a slower decline
in rate 5 th^ latter presuaably by aetabolic conver-
sions to otJisr coapounds such as ^-aainobutyric acid
a£id glutaaiie, When cortical slices were incubated
with 40 wM Ewlonate the glutamic acid increase re-
aalned at°~hi4ljer levels, Glutaaine did not subse-
quently rise lor did aaaonia decrease in asount.
However 9 the r-aainobutyric acid increased 3X in the
abore studies, fhus aalonate appears to block glu-
tamic acid anc is an effective "stabilizer" of the
free glutaaatt pool.
Since L>29 4-diaainobutyric acid has been re-
cently reported to block Metabolism of r-^inol>utyric
acid it was aleo used in in vitro slices. Mo effect
on glutaaate Metabolism^ glycolysis^ or oxygen
-3=-
cosssmsptioa was aoted iia coBcesitratioas of 40 aM.
Wlssn givea ia vivo to ®ice t&is ccmpo'xad produced
seizures 9 aH3 ^®~subseq&i©at in vitgo st^idy showed
a reductioa of Og coasuiiptioa aja3~aa"el©vatioa of
the ^-^aiffiobutyric acid level. This was repeated
in eats 9 iajecting 8 ss^/kg^ aad seiam-es occurred
ia sis hours. E®r® the in vityo O2 coasusption de--
crease could be correcteTlsy giviag pf"2rid©2£al phos-
phate but Eot bf giviag ^~a®isiotoutfric acid. The
latter leviT~was 2X the aosTBal and iac;?©ased during
iflcubatioa. Thus, Br, Tower feels this confirssiE a
block of /■-aBiaofeut^ric asid metabolism by L-2j4
diaainobut:fric acid^, but he also suggests asaionia
intoxication of the foraia consistent with the he-
patotoxic effects of this substaace, Studies using
aspartic acid by the Lo^ry fluoriaetric procedures
were unsuccessful..
Br. Tower has also under ta&esa a study on
electrolyte and energy ©etafeolisa ia normal and
epileptogenic cortex iM vitro. This problem car-
ries with it the pereaniaT^aiff iculty of the quan-
titation of the intra- and extra-cellular fluid
compartments. Dr. Tower utilizes the chloride
space and concurrently checks this with the spaces
calculated by sucrose. By these techniques the
chloride and sucrose spaces showed close correspon-
dence in the normal and epileptogenic cortex. When
incubated ?/ith glutamic acidj glut amine or asparagiae
the slices exhibited a aarked increase of the non-
chloride space. Gaisaa<-aiiinobutyric acid produced
no change ia this space ^ however. When incubated
under hypoxic conditions the chloride and sucrose
space were no losiger similars and indicated swelling
of the ffion-sucros© space and influx of chloride into
this space. This is consistent ^ith recent reports
and places emphasis on the probable aon-reliability
of the chloride laethod for determining extracellular
space in damaged tissue.
In non-daaaged tissue , ho-^e^er, the Slliott-
Eeller formula may be used to estimate the cation
distribution in the noa-chloride space C? intracel-
lular) , It appears that neuroas account for 75^ of
cortical non-chloride space and cortical potassium^
but only 4S^ of sodium. Extrusion of Na and uptake
of K is confined to the neuron. This is presumptive
and is based on the fact that cortical and subcortical
glial elements react similarly. This then allows an
estisaatiosa of th.e ©2 cossimptios of eoirtleal aeiaroias
is t®^£s of nora->chlo?ide space volrais. Hae neurons
showed alsost double the metabolic &cti¥itsr of glia.
It is of iffiterest tfeat the "sstra" ia©talJolic activity
of the aeuros al£^@t esactl;^ eqtaalled ths fraction
of neuronal o3gida.tive setaboliSM attributable to
^-aainotmt^ic acid.
Drs. Wherrettj Tower, aad Heim?icli Waelsch
CHew Yorls State Psfohiatrie I^tit^te^^ h&v® carried
out a 3tudF on the incorporation of labelled aisino
acids into protein fractions of cerebral tissue « They
have sho^m that L-gluts®ine~U-C^'^ is incorporated into
protein-hound glutsmlne, the specific activity being
O.S^ the specific activity of the free pool glutaaine.
When 40 m ^alonate is added Chloc&s glutamic acid
Betabolismi> see aho^e) there is a decrease of protein-
bound glutamic acid. Similar ezper i@8nt@ ^ith
10 BM HE4CI (this elevates free glutasine &&d depresses
free'lglutaatic acid) showed a striking risse of protein-
bound glutaaine. These findings^ co^ined ^ith the
itration of slow C** turnover in protein gluta-
aate^ lead Drs, Wherrett and Toiler to coiselude that a
portion of cortical proteins » involved tn the active
a^ino group transfer » utilize. the carboK^ a^d a@ide
groups on protein glutamic acid and glutasaisae. This
is one approach to Waelsch's thesis that cerebral
proteins may participate in a^ino nitrogen setabolisa
and l>rSo Toirer and Waelsch feel possibly that the
transfer of a^id® froa protein gluta@ine to free glu-
tasiic acid may b© iaportant to neuronal activity.
The findings i;ith WS4.CI have asi obvious bearing on
the chesiical basis of hepatic coma.
Dr. Mclhann^ since Joining the Section of Heuro-
cheraistrys has also worked with ^-asinobutyric acid
and pyridoxin® 2, and has finished a study on a patient
with pyridoxin® dependency „ A decrease in cerebral
oxygen consuBptlon was found i^ vivo during depletion
which was corrected by adding pyrllo^ineo Thvis this
condition varies fross other types of seizures in which
oasygen consumption increases « Two types of pyridoxine
deficiency have been found by Br. Coursin; in one type
there is an afeaorsally rapid conversion of pyridoxine
to 4-pyridosic acid, aad in the other there is an ab-
noraally rapid excretion of ingested pyridoxine through
the renal apparatus. This patient was shown to be of
the second type. Experimental a^iaal studies in kit-
tens on pyridoxine-free diet precipitated ataxia and
seizures and death. A study of the brains of these
kittens showed a decrease of ^-aaiaobutyric acid. This
latter defect could be reversed in vitro by addition
-5-
of p^idoxal plsospte&te or y-zmis^obatfTlc acid« Tteis
adds to tbe dvidenc® tbat pyrldo%al phosphate acts
as a coeszfBe necessary for the eux^me glutamic de-
carboxylase » and correlates with the study above oz&
electrolyte aad energir aetabolisa in showing the
"extra" asetabolic activity of the neuron is dependent
upon the oxidative aetabolisn attributable to ^-aaino-
butyric acid.
These investigators continued their studies on
the quantitative contribution of f'-aninobutyric acid
pathway to total oxidative eetabolisn at the Krebs
cycle stage 9 using pyruvate-3-C^^ as a tracer. Ihese
studies showed that 4^ of the total substrate awtab-
olized froB a-lcetoglutarate to succinate was via the
^-aninobutyrate pathway » Sii&c® the latter pathway
appears frcm the above to be aluost exclusively
neuronal it is estimated that nearly 60^ of neuronal
oxidative B&etabolisn proceeds via ^-aainobutyric acido
Since this varies in a signoidal ioishion during 1-hour
incubation there is, in the Binds of these investiga-
tors, a suggestion of a reciprocal aetabolisn via the
parallel succinyl-Co A pathway. Sere studies were
done with cortical aitochondria and ^-aainobutyric
acid-l-cl^9 coapariag the c**02 evolved to the total
02 consumption. In the presence of arsenit®, which
blocks a-ketoglutarate to succinyl'-Go A,, the inhibitory
effect of higher concentrations of a-ketoglutarate
was not seesio ThuSg as levels of the conmon precursor^
a-ketoglutarate » rises the latter pathway (succinyl-
Co A) is preferred. In vivo studies using pyruvate-3-
C^^ show that, in iniTTar^sludies „ the labelling of
glutamic acid and ^-aainobutyric a^id is extremely
rapid o Using seizure preparations Cioe. thiosenicarba-
zide and L-2j,4 -diaainobutyric convulsamts) these in-
vestigators feel the aetabolisa through the ^-aminobu-
tyric acid pathway rather than the level of the ^-amino-
Imtyric acid itself is the significant factor.
Finally^ Qr. Tower and his group have utilized
^-aainobutyric acid to treat ten seizure patients.
Fifty percent of these patients improved^ The B.B3.
Cblood-brain-barrier) seeas to be 'he chief factor in
the variability of response as the permeability of
the BoBoB, between seizures appears to be limited.
Dr, Horvath is continuing h^s studies on the
aolecular architecture of auscle in noraal and dis-
eased states, and is now devoting mich of his tins to
iOBunocheaical aethods. Tlius,; in the study of tropo-
ayosin A he has developed tests asid standardized
Qwajatitativ© detesmissatioias of iaami© pr©cipitias.
These includ© as adapt at io£i of tite Kabat iiethod ±n
wh.±Qh iEgai2is®-precipitat@e are ^ash@d! asad the siitro-
gesfi content saeasisred by direct He^slerizatioa. S^ml--
quaxfttltativ® m@asu£^s@ maj also b@ obt&iaed b^ chTo-
atatograpkio teolmiqus^ developed b^ Br, Miquel, ia
which antibody as&d antigen ar@ paper electrophosresed
together. Thm moluhle proteis^ mo-^es but the ismnme-
precipitate rcsaias at the sit® of application Ttk±e
maLf then be stained with bromphes^ol blue» eluted, and
detemiaed eloctrophoreticallj .
Both of the s^thods Just listed p3t0vi.de ±n-
fonaatios^ 022 quasititatlv® bases as to the amount of
antibody circulating and on th@ @toichio@etry of the
antigen-antibody reaction* Tfeus, with cl&m tropo-
myosin the sjmt&m was found to have an equivalence
point in which ti^o antibody molecules combine with
one troposyosisi A Esol@cule„ while in the antibody
excess region /'.'our or siore antibody i&olecules com-
bine tii'ith one tropomyosin A molecule. Titers rose
as high as 200(1 iig,/ml, after a second set of injec-
tions two months following th@ first. Circulating
antibodies wer@ identified by electrophoresis as
^-globulins, 'fhese antibodies were fo%md to fall
within one s&onth after imEsuni^ation to aboaat 10^
for the raassisksil le^el^ and booster doses raised the
titers in appj.-oisiKately ten d&fs. Dr. Horvath car-
ried out a sHore rapid e:ss.tenm±on of this iiiethod by
using the passive heBoagglu^tination tesst of Yorlaender,
This BKethod ubos tannic acid treated sheep red cells.
Immediately aft®r such treatiient the cells bind tropo-
siyosin A and ar^^ agglutinated by high dilutions of
anti-clam tropomyosin A. Hormal sera would not do
this. This test does aotj howm'^ets have the accuracy
of the quantitative precipitin reaotiosss, but it is
very auch faster » It is of interest that skin tests
on patients demos^trate persistence of changed reac-
tivity several months after iffiauniaation whereas the
epheseral nature of the circulating antibodies has
disappeared. In addition to thlm^ diffusion agar
plates have heeu used for testing the homogeneity of
the antibodies. After the first set of ismmizatlon
injections j; only a single precipitin line appeared on
the agar plate » and it was estimated that iaipurities
could not have e:%ceeded 3^. However ^ similar tests
after a second set of injections revealed multiple
precipitin lines. Th® catises of this are now under
study.
Cat muscle myosin apparently is more complex
than that of clae tropomyosin A^ and the agar plates
-7-
show several precipitin lisses. The quaatitati^e pre-
cipitin reactions j'ail to sliow a clearcut optina.
These ot^ervatioim a^e cossslsteiat with the concept
that layosin pc^sesves several az^tigenic groups and
that the suhunits ct myoBtn possibly consist of a
coaiples: of tropoaircisln a^d actia., A studf of the
cross reactiois of cjX @fo@iQ a^d clasi tropc^i^osizK
reveals a &H crosEDver, Coaasideriag the r©®ote re-
lation between the i^o species ^ Dr. Horvath believes
this deiioaetrates a a lose relationship of the two
proteins.
Br* Horvath hai also continued his studies on
alterations of actemfi^si^ tensile strength and of
ouscle proteins in n@\'.roMiscula<T diseases. Me is
thus iaeaunising rahbits ^ith auscle proteins prepared
froB rabbit nuscle. Tbe initial studies on iassuniza-
tioB of rabbits with ri\bbit act in were done probably
with preparations which were 5C?,^ iapure, 'Onder the
present methods, which i-xre 99<^ pure hf the criteria of
polyaterisation.j antibodies could also to® developed
in rabbits. Most of the isapurities were presuised to
be tropois^osin B. When tropostjosin B ^as prepared
fr<»B rabbit ra^cle it was fow^d rabbits could be ia-
auniseed with it, with titers ;^Mained as high as
300 gig„ aatibody E/ml. Siailarly rabbits could also
be Bade antigenic to trop<^^(tsin A. That this reac-
tion is not due to chemical sianipulation aay be in-
dicated bf the fact that fluorescent antiayosin stain-
ing of mssGl® samples coafirr^d the site of the anti.-
body reactiDi%^ and the biolcgical activity of ayosm
isolated f^om. mxmcles in tersis of ATP-ase action r.ad
the cossbiffiatioa of costractioa with mourning is &f-t
altered in bhe cheaical or biological sense. At^^eapts
to produce tpiscle lesions in guinea pigs inject-od with
varioi^ smscle preparatior^ and adjuvants h&v® not
been unifortalf successful so far.. This has bIso been
attempted in tissue cultures of auscle in wh2.ch soae
effect has b^en deaonstrated „ but aore precise studies
are needed to define the conditions.
This M^eak-through in i^mnocheaistry has led
to a t^ftporarf suspension^ during the calendar year
1959, of Dr. Horvath 's comparative biocheaical study
of saooth and striated auscle. However^ a dystrophic
Bouse colony is being maintained to provide one type
of source material for such studies.
Dr. Bushnell Smith., who is now entering his
second year, is in the laboratory with B^. Tower j, car-
rying on a study as to the effects of anticonvulsant
drugs on cerebral electrolyte setabolis®. He has
space sodioB G!i»ceataiati£«i d-oring tuciil)8.tlc«j wlti:
"Blaaox" at a concsntya'Slcja of JisM/L.. 'IM« i-& 6^==
pr£Oa£iajai&®I^ tij® coo.c<tntsation Kaovm to ©ffg:cttv©ly
inhibit blood carbonic afil3ycifs.ss@o Other cfme«Rt.ra-
tioas of "Biafflox" ar»e ao»* under study » It is
Tito Cartis left tJi® Brancis of Msdlcai Seurologj'-
to z^tum. to t^acteiaigo His priisary interest dia'irig, his
staj at tixe Institute was tjx&t of (i«v©l©p,iEg, pbyelco^
chsBSicfiul saethods for d®t#yBJiiiicg iaiR«.ite amo*axits of
material ia organic fliiXdSs sucii as apioal- fliild a,zsd
uriaeo SMs wes di.i?®ct@<i partlc-^lariy tc tji® i-iecitl'--
.fication aad ch«..-r».ct®rli>at,loii of iBacr?3mol^cu.lt*, e-jLCik
as poljfpgptidas,^ gj'rogeasj, etcoj tfiaicii oo^-uy ic tft#
lirlais aad oiher fciological fluids-. Ca® sucb st-a«ly was
dlrssctM tOfim,T&& the prseexie® of asjy &p»e»;tfic aul3 =
staac© wbich aaigtit Isis lllssyatigd or producgd in associ*
ation witti prlasary or s<scoadar>' iiea^liaiiAtioj'? SLa
tlj® o©ffitr&l sasrvous syst.«Bia I*™ t'urtis.^ at fehs tisis
of fels leav.tagj, was stud^riag toy ffl^thc?dg of bubbl*
iag benaeio^j, yadey controlled '."•onditicas of rstt^. as.d
drop ei2.es thrismgbi a colisBa of cerebral spinal fiaidc
Witfc. tiiis vrnthod s.ppar©)&t;i;f caapj^t*® rsac/'al of lipids
app^asi's to orc-wp^ SubSisqtjsn'i chtcsaa.t.og^yby cf gaci.
lipid =ctmtaiBing, benzene on silicic acid iwpr^^iated
papsr dae'on^trated th@ ppsseac© of lecithin j, -cmgin&Xtxis
Ephiagoa!3r«glla J cholest@fOl. and cey^sbj^sitiss o Sis pre =
Itmis^ry studies indicate ©levatiOB of soebs fi'ub®%ajs.e@6 ,5
particularly tlis^ latter 1ib,r®'#j is cs-mbtul spicfil
fluid saatp3Las f^'Ofe ffiiiltiple solsrC'Sis patiitntso !*g
q;uas,titatiye date ^ia.s possible however "by this sssthsfd^
■but the lipid 'profile" s®@Bs®d coaslstsct *it.a tiiis r@=
c^ttt report by Tourt@liott® =. Ccsapiiassntarj^ studies
v@r@ earrii^d oat oa a r&Qdj&l proteia^ i^hieh was gi^a®)k
pig sertm asp8.i?a,ginas@,j, ae noted. Ixi tfee last Arai-ual
Bepcrt^ which yieldsd considafabl® iaforsaattono Thl&
is a giobiilia '«fhich ha,B r^adil^jf asssyable enzyim se=
tivity^ aad cas. be iaolated as a cr^de frfectlcu frt®
s©r;sii "by g«amC8).ia?r. s-»,ilfe.te p*'8ctpitstia» aad- ca& su,bs«i=
^Bx% crud® fiactioR eo^taias t^o "/isi&l® coataisisaritft
b^r electr-cpiicresls and at least one by 'jltr9icei:trl.fuga
lli® pre^rioue ot.uaie» reportsu U), a.-^^. i.jui _.;.., -«*e.*
'feh@ @nsyiB6 actlvitv waa assodat®*! with the fastest
<!!affipcss4ieat ia ttet ult.rs.cej?triruge anal jets •. H-TweYery
»9-»
imyificatiOE hj t&ws® ^easis -ssras sssssuaccessfwl, la
1958 it was f©m&^ i.&at t&e c©Il«aIos© r®si& developed.
by Petersoiiji €*t al^ wo^sld eompletQlf atessoicto this
eazjfsss, Studies this f®&^ an ©l^tioB of th® «Qssyae
clearly iadieated t.hat^ umd©? tfe® appropriat© pH aad
ioisic stSfSBgth; foi\r separate ps>ot@l2&-coatai!iisig
fractiojis couM b® @lut@d tram th^ee cellulose col-
mms. Good separat-losa of tS&@ t<mr fractious waa ob-
tainecli, but only o»e eoataii^ecl asparagisiiiB® activity,
l&is suggests that complete purification h&d been
acbieved without li>s& of eisusysi© activity » and re-
PT@SQ:&t& the first ®ucl& isolations of a@ emiyms psroteiu
in this wmM@r.
The Seetioa i>f Biophysical Applicatioas has
mo^ traissferred the collimatimg sciaitillatioQ scanner
aad it4S i!gst£'UB!i@at console to the Department of
Radiology of the Clinical Center, where it will now
be viB&d as a diagaost-ic tool for future studies. Xhie
to the amount of instru^s^ntation techniqise involved
in this apparatus s ho.iwever, the technicians frost the
Section of Biophysicsa are working with the Eadiological
Bepartssent on each p'i.tient scanned, H&e scans in turn
are read both in the Departssent of Badiolc^y and in
the Section of Biophysics? the reason for the latter
being that the Secti-.m is attesptiJEig to obtain 500
confirmed scans befoA'e droppis^ the research interest
in this given techniL|ue. At the present tim® the
Section has 35S scassB, We are suggest in®; to Dr. M-
Chiro that siethods mdw be used in the scanning tech-
nique in which the posturing of the patient asight
bring out lesions of the paraBeilar area and lesions
in SBidline of the p^iterior fossa^* such as is being
done in rtandard radiological teclmiquesa It is
probable that thiB paivt of the study will be trans-
ferred to the Sectioai of Neuroradiology,
In the !aeantiB@; histopathological and chenical
investigations on aeuroaaaascular diseases are continu-
ing» and this is a coatinuatioas of a long-teE-m study
initiated at the inception of this Institute, Over
the past years the Znstitute has elucidated the path-
ology of amscle disease, the role of certain cations,
and contractile proteins in aroscie diseases and at
the tiKe of the 1958 Report had finished a prolonged
study on the endocrine and issetabolic aspects of jsuscle
disease. Durii^ the past year attention has been paid
largely to regeaeratioa of lauscl© in various neuro-
genic and primary muscle disorders. An inclusive
study of the prisaary pathology of peroneal auscular
atrophy has been concluded j and the final studies of
the various inter-related factors in cationic paralysis
have also been cosisluded.
-10-
To follow the regeaeratioa of m^m^le^ tritium
(H^) lafeeiled thFaidiae laas teeesa a©w lase'tl In some 20-
odd cases of different ii@%srological disorders In which
there is muh&®qu®nt wastisag of mwsci®sr aad autoradio-
logy is mow tmd©nraf on tites© mictions. Prolifsrat-
ifflg cells will ©asa^afactuar© desoxfriSKJSHucleie acid
CDNA); a££d iit& doisg so incorporate the latselled thy-
aidiss®. The low eaergy rassg© of tritissra allows the
pr®ci@® localization of shicIj DM»
Th® catioaic disordei-s were st'Mied ira rela-
tion to thyroid asetabolis^^ to 1-42 e^ch&i&g®^ aad to
aldosterone hf aseasas of doulsI@ isotope derivative
aethods, and in relation to certain phariiaaceutical
agents swch as SC-810@g, a st@roid-17 lactone » and 2-
fflethyl-S-alpha-fliiorohydrocortisosaeg, which deliberately
shift fflonoval@mt cati<
Major fijadlag-s to date are that over 80^ of
ca«jes of Charcot-Marie-Tooth ' s disease deMoastrate
sayopathic fissdings as well &@ sieuropathic findings
on pathological ®3samiB,atioa and on electrosayography.
No such findings were fotmd ira cases of a^ayotrophic
lateral sclerosis. Two of these cases i;hich were
clinically classical as^d deaos^strated sensory abnors^-
alities showed only myopathic chaises. Eighty per-
cent of the total demonstrated so®© myopathic involve-
aient, whereas 100 percent of cases of aaayotrophic
lateral sclerosis showed only neural in'^olveaient .
In the catioffiic diseases, three separate en-
tities have now been separated which m&j cause sudden
flaccid skeletal paralysis. These are familial
periodic paralyBis^ paramyotonia congenita, and prisE&ary
aides teronissi. The pathophysiology of each is dif-
ferent. In familial periodic paralysis there is re-
tention of both potassiuffi a^d sodiui^;, and there is a
hypokalemia. The potassiim which is lost frois the
serus enters the cell. Enough ^ater enters the cell,
however, to hold the concentration of potassium ap-
proximately the BQSUS. This has been confirmed by in-
tracellular electrode recordings. Sodium depletion
aids in the recovery of the attack or prevents the
onset of such an attack, and sodium loading precipi-
tates the attack. Exactly the reverse is true for
paramyotonia congenita, although in this disease also
d-1 aldosterone does not precipitate an attack. Studies
are contisiuing in the physiology and pharmacology of
layasthenia gravis, and as stated, in last year's Annual
Report 5 the objective was that of intracellular re-
cordings of resting potentials in patients with myas-
thenia gravis. The difficulties of this procedure
■=-11"
vrer@ polluted out lu the last Asaual Report, in '^hick
descriptiosss of th® perctstasaeous method of iatroduc-
i^ mics'oelectrodes blls^dl^^ issside single cells was
given. Appro3s:i^t@l^ 18 such patients were studied
is the current yeaxj witla over 200 penetratie
It h&s hsQoms apparent tlaat^ witla o«r present
technique at least, we will not be able to success-
fullf carry out this procedure t&rough the intact
skin. Such patients would have to have surgical ex-
posure of the musQl® to carrf on such a study. This
phase in the program g, hence, has been teiBporarily
abandoned. However, the progr^i itself, like @any
others, has notv separated into two different compo-
nents. The availability now of agents which influ-
ence thyroid fos'aatioa and TBE forsation;, as well as
ssethods of influencing each independently, has allowed
the Unit to ^ake an esstensi'^'® study of the problems
which has long baffled neurologists j, i.e. the rela-
tion of thyroid metabolism to myasthenia gravis.
This facet has now been worked out by Br. Andrew
Engslg, and will be recorded in a separate project.
At the beginning of this reporting year^ the
Institute was fortunate in having with it Dr. Frits
Buchthal froa Copenhagen , and his ^thod of electro-
myography is now extensively used within the Branch.
The recording instrumentation for the intracellular
work in myasthenia gravis has been converted, there-
fore ^ to this particular project. The laethods now
used are those of ■ multiple concentric electrodes so
that synchronization and @otor unit areas nay be
mapped. The studies at the present ti^e include a
study of th© internal ocular muscles in which nystag-
was is present in cooperation with the Ophthalsaological
Unito This study has Just been initiated. It is of
interest that a characteristic layasthenic respoiase
has now been seen in patients with generalized sar-
coid disease, ai^d it ©ay well be that this technique
nay be of use in the diagnosis of this disease, l^e
reason for thiSj however (, is still not clear and is
being followed at this time. The duration of the
action potential in varying groups of miscles at dif-
ferent ages of patients f^which as yet have not been
charted, is being undertaken by the Fellow assigned
to the project. A direct correlation of the EUS with
the sfuscle pathology is continually carried out on
each patient adsiitted to the msscle projects in this
Institute.
It is of interest that electrosayography is fal-
len in disrepute in raany medical centers in the United
States today. This Institute is now convinced, after
"12-
B&Siljzlng SOBS 11© of our o^^ patieats usiag the Co-
pesahagea tjpe of stud^r, that this co&clusioa was
s>eached because such studies %ere not carried out
with the pathophysiology of the various disorders in
igiBd. It is our belief , after this series of patieats,
electrosa^ogra© will be of defis^ite value when cor-
rectly dose aad interpreted, aad has ms&f tiises given
us inforaatiosi of real i@portai»ce iii the understand-
ing of our patieiits.
The clinical pathological correlative study
of the nervous system in cases of orthostatic hypo-
tension has now been completed, with the* serial sec-
tions done on the postmortem case listed in the 195S
Report by 23rs. ISr&g®^ ^^d Shy. In this case s^-
^trical lesions were found bilaterally &n each sid@
of the brain stea, in the ventral « intensiediolateral
colussn, and Claris 's cell colusm of the sp;\nal cord.
Moderate gliosis was also present and most evident in
the dorsal funiculus. In the raedulla^ degenerative
changes of the inferior olives » the nucleus a»biguu@p
the dorsal nucleus of the vagus » the sedian Raphe of
the tegaentuskg and the lateral cuneate nucleus were
also found. In the cerebelltim and ponSj, neuronal
changes were found in the Purkinje cells and 3.n the
locus caeruleus of the pons. In the saidbrain, lesions
were found in the substantia nigra, the third i^erve
nucleus, the Edinger-Westphal nucleus « and the central
aquedttctal gray. Soss changes were also found in
the posterior hypothalamus. It is of interest j, how-
ever, that the cerebral cortex was norsial. Since the
cerebral cortex is the stost likely to be affected in
cases of anoxia 2> and since no thrombotic lesions
were seen in th@ cerebral blood vessels ^ it would
thus appear that this lesion could not be explained
on either of the latter two postulents. A review of
the literature indicates similar neurological find-
ings in the majority of cases reported , and it is
highly st^gestive therefore that so-called orthostatic
idiopathic hypotension is^, in fact, a degenerative
disorder of the central nervous system involving the
above centers,, and could be corresponded to the so-
called laotor neuron disease long reco^ised as a
systeai disease o
The Section of Clinical Meurophari^acology con-
tinues its study around the choline esters found
naturally in biological systems ^ and the study of
muscle cho lines terase and its inhibitors, and studies
of depolarizing compounds and their effects on nyo-
neural junctions. They are^ in addition^ studying
As disctise.
tors of most iJipo-i'taaee i::* deisifiaiffiiag t»fe eiioiu-g,}."
®f gj^ast&esia gratis wo?Jil-i &® the icl<3©tif icatioa of
a s^lsstaffis© in dis€-sas©fl ©oscl® ^/feieh wo^ld ;act tmt
■oalilie ckolia© estc^rs, hut not b® !if.sSr®lise-J. tof the
aiiscl® sbolia@st@iF5i@@ am is t&@ ac@tf icholisae.. Siscfa
f.imDv.miB ^ aiftd tii^is pronotmcBd effects ©a aiascle fiwc-
tioXc. could ©ecuL?. "^'^iSp for ^Kample^ teiatyr^'AchoIiivs ,
EX'® S.I1 iieas'Ij-' ecfjuil to s?aeel.is^lcfeoliE® ia d©p©iaj.*is:.-
l©.g striated gaiscle, la a®. att@®pt to st!ti4|' tfe© ac-
tioi'i of swcfe cfeoiiij® ejst©rs asad cfeeaica-llp- related
tautest aisces oz> suse.l© s^ssafcraae ^ aad to isolat® asci
idC'iitify sucia o&olrlsa® esters ,, tfees® ini^esitigatorgj
ijseci the f©llo'a?iiRg ^@tlit©ds:
Firsts a travelliag fluid elestxod® is iis©d fee
fea-feffitial elepolsxJ.satica of a large B?ssfe®r ©f list act
graphs are lased for the- isolatioa asd i«l®2&tifisafi;:lo:a
of clicsiiis© esters and otMes* quaterssarf c©®p©imds
Fiaallf J, tJie hesirt of t&e clam veaeuigg ^rceasria ;,i
"jsed for idsatificatioB a.Bd assaj ©¥~saS¥f f leloTfsae ^
Thss® ia'??©stigat©iPS feaire foimd tisat the acoTi?,;;?-
at@ ©oaceatratioa 'fespoas® relatiosas&ips could saot
l»@ obtaiis©<S siSace aa^ depolaspiaation c®aipouiad reduce:
tMe s@s.sitivitf ©f ^'ssfeseq^est tests aad tla® test
MiBiil^B varied eoasiderafel^ In t&eis? r®apo3as©o Tfeera;"-
fore,, toj selectisg a laari'©^' raage ©f depolariziatioa
,to Ij@ produe®4g and tlse use of oe® fflsssl© for @ac.M
tes'.:, a cosparisoBi of pot^^cj ^as peiBsl^l©, Th@i:r
studies app^ajf to inaieate tlsat if eUaolin© esterts
^©jfcs sBot hfdJToIi^ed hj tlsi® a?a.sel© choliEiest^rasej, as
in al3ffio3»al aso^iSitSg, prosiO'j®c©d effects ©a msBcle
f^mctios GOs2ld ©cemr. Tfe© Mentif tcatioa of siieSs sub-
staases ia disseassed ^sscl© ^ouM appareatl^ require
®ys<5l® samples nc las-ger tliaa 1 grai®« This! study is
of 'a^trejaje importaiac© is t£i© disorder mjastfeenia
gra-fis aEd will fee folloi/ed ths'o^li tlie m.®2it fear.
Tfeis Section is contltming its studi©® also c::"
asisele cfeoiisaesteTas© aiEd it® ligkiMtoi"®, 'BmMg. th®;-
fisad tiaat the claoliB®§teras@ coateat of swsele is lew
aa4 Slot •oBifox'sly distsfife^ted tlaroug&OMt tie ti^siaej
aac - .1 in respect
eitfees to tie X'^rs oz ciaoliEeiii: erase ic coataias or
as to the substrate aad inhibitos' specificity. The
approach ±& th& cuirrest ^eas* is that of adequately
character ising this important imsscle eo^iiae ia reXa-
tioffl to its substrate specificity. Astother objective
is to exaaiae the activity of the essysie in the pre-
sence of well-kiffio^a iathibitors which are in wide use
clinically 9 aad to correlate this activity with their
usefulness. This could thea fo7» a basis for testing
newer coapounds having a potential in the tre&t»ent
of ayasthenia gravis. In studying this the standard
Warburg aa&osetric technique is used for determina-
tion of ffiuscle cholinesterase activity. The depolar-
ising- properties of cholinesterase inhibitors were
determined by the use of the trat^elliE^ fluid elec-
trode systesc These investigators have found that
AiDbenoniuai had the greatest inhibitory activity on
aniscle cholinesterase of any of the cos£s tested.
Heostigaine had the gre:ater activity in this respect
than did pyridostip^n lacks. The major part of this
work has centered around the testing both in vivo
and in vitro of coapounds which seean likely to have
a polenlliial use in the treatment of myasthenia gravis.
Galanthamine is an alkaloid which has recently
been isolated froai plants of the Aaary— llidaceae
family in Russia and Japan » and in this country by
the Laboratory of Chemistry of the National Heart In-
stitute. Another substance of much prosise is Lycora-
mine^ which is an alkaloid with a chemical structure
closely related to that of galanthai^ine <> This labora-
tory investigated both of these coispoisnds and their
related derivatives as to their smscle potentiating
and acetylcholinesterase inhibiting properties.
These coaipounds are both derivatives of phenanthrene
and are of interest because chemically they differ
markedly from other coigpounds currently in use for the
treatment of ayasthenia gravis o The coispounds tested
were galanthassine hydrobromide ^ galasitka^iae iiethyl
iodide 0 lycoraiaine Methyl iodide ^ deoisylycor^Kine
methyl iodide , deosydemethyl-lycoramine methyl iodide,
neopine and neopine methyl iodide. In this study the
quaternary fo^wa of the alkaloids were found to be
more active in isuscle than the tertiary forms. Lycora-
mlne methyl iodide produces about the same amount of
inhibition of cholissesterase as pyridostigmin. Galan-
thaminee both the tertiary and quaternary forSp pro-
duces more inhibition than does pyridostigmin. Deoxy-
demsthyl-lycorasiine aaethyl iodide was the most active
compound founds and this -compouiid produces cholinesterase
lohitoltioil equal to tlaat of sssostigi^izse or ph^sostig^^
aiae. Th® la vivo stuscle pot@i3tiatlag activity of
the co^pom&T^correlated well with tlie iMaibitiog ac-
tivity. PlasBias r®d blood ceil aad l»raia daoliaes-
terase is also ii^ibited. Th® potency of these com"
pouiads strosgly suggest that th#f will offer advaast-
ag@s in the treat^eat of ayastheisia gravis. Galaa-
thasiae has already sreoeived siieh trial in the USSE,
and iBos*® rsceiatl^ ia S^edea. The biological activity
aad use o£ lyco?a@ine has not h®en previo^ssly de-
scribed» aad it would appear that we ar© about ready
to stove iato cliaical trials of this coapotmd after
toxicity studies have h@®n carried out.
To better imderstaad how the depolarisii^
ageats work on amscle ^eajbraaes, a study of the ef-
f luz of easyses froa such snsscle has also beea car-
ried out ia this laboratory j, In which staadard bio-
chemical procedures are used to estimate easysie ac-
tivity ia plassa aad muscle. Here agaia, the travell-
iag fluid electrode is used to iadicate the aaotmt of
depolarisatioa. This laboratory fiads that the
ouscle loses aldolase whea kept ia a solutioa coataia-
ing depolarisiag coaceatratioas of pot^siiaa. !t has
not been determined; however, if this depolarization
of the cell ise&ibraae is the causative factor or
whether the loss of eazya® is due to activity of po-
tassium at another site. In au attempt to find out
whether aldolase leaves the ausel© under the in-
fluence of succiaylcholiaej, experimeats were done on
pairs of rat muscles removed prior to and after the
adBinistratioa of this drug. Changes ia the aldolase
coateat of the esperi^eatal muscles were variable
and not proaotmcedj, at the end of brief periods of
depolariasatioa. The laboratory has also found that
sul^tances which depolarise muscle isesibraaes also in-
hibit Buscle choliaesterase, but that such inhibitory
conceatratioffiss are much greater than those aeces-
sary for depolarisatioa^ aad thus esterase isahibitioa
by these compounds appear to be unrelated to their
depolarizing activity.
Finally, ia this laboratory ^ Dr. Irwia and Dr.
Norris are doing a aicrodissectioa of i^ripheral aerve
aad electrophysiological studies to determiae the
actual extent of the physiological aaatomical aiotor
unit. The two studies oa the actio© of aeuromiscular
blocking agents oa directly stimulated innervated and
denervated giuscle, aad on blood aad tissue choline
esterases ia neuromuscular blockade which were discussed
ia full ia the 1958 Ansual Report, have beea completed
aad are a©^ publisiied. Botfe of tliese were ©steel Isat
studies o The pap@2:>@ published in referesuce to these
studies vier® on the coatractual reispoas© of directly
stiiiulated isuscle after administration of asuroisuscu-
lar talockiag ageats^ aad the effect of certain neuro-
nmscular blocking coi^pounds on direct l|r stimulated
nuscle. The paper on the effects of selective inhib-
ition of jm@cXe and plassa cholinesterase on neuro«-
smscular Islock has been reported at the Second Inter-
national Ssn»posiuBi on Msrasthenia Gravis , and the
methods sand findings may be foimd in the 1958 Annual
Report. Ttaese projects are now teraiaated.,
The Section on Neuroradiology has carried on
studies as to the sSeeletal chaaiges accompanying Dys-
trophia Myotonica; th® correlation of brain scanning
with standard contrast studies; a study of fractional
encephalography;, ^hich is anticipated will culminate
in an Atlas; a study of the giella and pituitary in
the horizontal plane « which is a combined X-ray and
posti»ortem study; and a study on tke encephalographic
changes in the tessporal lobe. In addition studies
are being carried out on a bilateral angiographic
evaluation of the superficial ^sins and sinuses of
the brain p and a radiological stuay of the soft tis-
sues in different ssuscle disease® is being carried
out to correlate with the overall large program in
Buscle disorders «
In cosBbiaation with I5r. Joha C-iUgheye Associate
Professor at ths Ifational Uni'^ersity ©f Mew Zealand »
Dr. Di Chiro carried out a study of the radiographic
changes of the skull in eighteen cases dystrophia
isyotoffiica. Eighty-nine percent of these cases showed
"hyperostotic" changes of the sliull vaults which
these authors have grouped into four different cate-
gories „ They arrived at tlie conclusion that the
longer the duration of the disease « the »ore marked
are these changes o They suggest there is also a
possible correlation between the amount of hyperos-
tosis and the proof of hypogonadism p and interpret
these findings as due to increased circulating growth
hormones » This project is now terminated and will be
published in the Acta Eadiologica.
In correlation with the study in brain tumor
scannings Dr. Di Chiro has picked the confirsied tumors
in which adequate studies ^both by i»eans of radioactive
scanning and by means of arteriography and pneumography g,
have been accois&pXished, One of the chief critic isiis
of the previous work on the brain scanning j, which is
reported in book form and in the 1958 Annual Report j,
is that no definite correlation had been done between
-17-
this aad other standard raeuror&diological techniques „
Dr, Bi Chiro has no^ over 60 cases -which have ade-
quate studies ia all three such techniques « i,e<,
radioactive scaimiQgf, arteriography ^ and efficephaIo->
graphjr. It is hoped that this studf » upoa its coii-
pletion^, will better elucidate the advaataices^ liaita-
tionSg and future possibilities of the brain scanning
technique in relation to standard contrast techniques
now available 0
The super is^pos it ion of different anatomical
structures i^s&es difficult the interpretation of
nan^ gas contrast studies. This is partisulsirlf
true in the area of the posterior fossa o To obviate
these difficulties, DTs Di Chiro is undertaking a
ccmbined laainagraphic study cossbined vi^t the or-
dinari^ encephalogram done bsr the fractional aethod.
Laainagraphic studies have been done during the
period of tiase that the passage of air through the
different sections of the ventricular sfs-tem and
subarachnoidal spaces is occurring. The laiainagraphic
cuts were taken in different projections and in dif-
ferent planes, Approxisatelf thirty patients have so
far been examined with this technique. The initial
study is lii&ited to cases without intracranial space-
occupying lesions. This study will be cossbined with
routine fractional encephalography in the prepara-
tion of an Atlas devoted to fractional encephalo-
graphic smatomy, Cc^bined with this, brain speciffiexas
are now being studied to establish a correspondence
with the structures seen in the encephalogra»o For
this purpose different structursB, especially in and
around the brain stera^ are bsis^g coated with radiopaque
fluids 9 and afterwards examined with Ia£sinagrai^ic
techniques .
Many studies of the sise asd shape of the sella
have been accoisplished in the pastg and recently a
monograph on this subject has appeared in the ^itish
literature c Hone of these studies ;, however ;, indicate
the true volume of the sella in that a reconstruction
in the horizontal plane has not been attestpted, Volu-
eetric studies of the sella are becoming store neces-
sary with the increasing surgical approach to the
pituitary and sella. ThuSs, in recent years hypophy-
sectoisy is being carried out in s^umerous clinics for
endocrine carcinosias , Intrasellar implantation of
Yttrium®^ seeiss to be a highly prosiising technique ^
both in pituitary triors and in other conditions in
which the destruction of the pituitary is indicated.
-IS-
Til© traas-spheacidal route is ps'®f erred hf sosse
atatho2«9 sad a preopsrativ® lyao^ledg® of the lateral
iKorders of the sella aad t&@ pituit&r? Is of tit^ost
:^portai&ce for tkis tj^pe of approach, To carry out
t^his study the base of tl&e skull at poetsiortesi^ with
%-t\e dura; pituitary j, and the paraiBellar vessels still
i£i situ, is studied with different radiological
t.^chai<|ue8 , includis&g l^iatagraphi^. Metal wire
ffitarkers a^d X~ra|r opaque fii&ids B^e used to -outline
the differest border Hues of the sella „ l^ese ia
Ituriia the&£, are coiapared with the stasidard X-rar
f ila^ of sftormal cases aad of case® with iatra- ai£d
para->eellar pathologic
The ^esious drainage of the br alia ^ as else-
where ia the bodfi, is eztre^el^ variable j, aad so
s^tenatic angiographic stud^ has beea done on this
subject o This Sastitute is perhaps ia a uaique
pc>3itl&a ia that we have a cc«iparativel^ large
asKsvu&t of bilateral carotid arteriograms,, ia coa-
Juactioa with the temporal lobe progra^^^ i^ patieats
WLlth ao iatracraaial space^occupyiag lesioas, Siace
8U3h aagiograj^s are carried out ser iographicallf »
thsi differeat phases of the superficial ^eaoua draia-
ac^ nay be deaoastrated, Dr, Bi Chiro has fouads ia
a Digaificaat au&ber of c&s®Ss that the venous draia-
&k,^ takes place through differeat vascular chaaaels
tsk the two hemispheres of the saae patieat; while
thA veaous draiaage oa oae side say be^, for example «
through the veia of Trolard^ it iBayg oa the other
si-\3 0 be ia the large veiss of Labbe or the superficial
iSylviaa veias. !^o Di Chiro has uadertakea a statis-
tical study of the draiaage of the two heaispheres
thrcugh the right or left traasverse siauses as part
of t.is project. It is of interest that these siauses
also tho^ oa the radioactive scans 9 and this say be
of soiB value ia correlating these two techniques ia
this ESudy alsoo
The last two studies of the Section of Heuro-
radiolc^y are attempts to further elucidate the prob-
1«ESB wh'.ch are encountered in two of the large clinical
areas o£ the Institute. The first of these studies
deals with the eacephalographic chaages ia temporal
lobe epilepsy ia which every case of tesjporal lobe
epilepsy .s now studied eacephalographically«> ia such
a way that a reliable coElparison of the two temporal
horns is fans obtained. Bach teisporal horn is filled
separately, and afterwards e^asiaed ia two ortogoaal
planes « Ap.^roxiaately twenty-B<me patients have now
studied with this encephalographic technique ^
and it is obvio%£S that m^skf xiore such st«£«lies will
ha've to be carried out for statistical evaluation <,
C^e of the maiB probleais la isuscle diseases
of the srouag iafaat is the aaskistg of iBuscle atrop^j
by large asaounts of adipose tissue « In certain crses
of djrs trophy this is also true^, in that the miscli is
replaced by such adipose tissue c Soft tissue tech-
niques ^ determined radiographically, are frequency
of aid to the investigator in determining the s'te
of suecle bioiHsy^ £U3 well as the esstent of the iisease^
so that adequate chesical and other studies na; be
carried out. Dr. Di Chiro points out the tec/izic&l
problesss that are involired in the optisal X-r&y vis-
ualization of soft tissues and his present impression
is that in addition to adequate X-ray techniques ^ soae
type of good reproduction apparatus is necr.ssary» He
has suggested that the logetron equipiaent J® chosen
for such reproductions o Ths aaount of cQvtr&st and
detail obtainable with this equipment is .^isurpassed .
It say also be used in other X-ray studi -i throughout
the Institute, and will be placed in the Photographic
Unit of Clinical Investigations o
!^« Gunter Haase hasg, durii^ th) past two years^
continued his study of the intramuscular motor and
sensory nerve ending in biopsies frci normal controls ^
and in patients with neuroamscisiar diseases. The method
employed is that of injection of ssett.'/lene blue at
the tijue of biopsy, as indicated by '.o«r»; the acetyl-
cholinesterase stain a&d silver Bts.:.nes i^ particular
the modifications of Bielschowsly w-M Winkelmanno The
isaterials were obtained in the co%i'-s@ of routine
biopsies,, and only slight variatic^is iaposed by the
intravital injection of aiethylene dluca In all of
these specimens routine staining £^thods were also
employed 9 and reviewed at the weekly isyopathological
conferences o
DTo Haase finds the conce\'>tration of the motor
end-plates are in a narrow zone s.t about the center
of each of the individual muscle fibers within a
fascicle. This confirms what haci previously been de-
scribed o Changes in the tesiainal innervation and in
the motor end-plates of muscles of patients suffering
from asssctlar diseases and diseas^es of the lower motor
neturon^ have been founds ^t^^ narked alterations
of the motor end-plates in myotonic dystrophy have
been found In which there is a marked ramification
of the terminal innervation and multiple end-plates
on single muscle fibers. H^is has also been found
iE cases of HuEtiiagtoa's Ctios-ea, which were origiaally
biopsied for coistyol purposes « Some cases of Par&itt-
son's disease showed s ©a ortlnedox staias, evidence of
a Biild safopatljf ; this was reflected bf cSiaagee suggest-
ing degeneratioss of the asstor esad-plate hj msithflene
blue stains.
In reference to the »wscl@ spindle ^^ it is
thought that this method does mot promise to bear
fruit. Spindles 9 e^ren in the norsial ssuscle^ apparentl|r
show great variations » and it is iaspossifele to clearly
state pathological changes in ttiese structures.
Drc Eaase will be leaving the Clinical Investi-
gative Unit to assuas the Chair of neurology at the
University of Oklahoma ^ and this v^ill terminate this
study at this Institute, it is hoped that he will be
able to continue along these lines in his new position,
and an ultissat© sissaaary of a laxger number of patients
be available o
Dr> Andrew Sngel has carried out a thorough
study of the thyroid function in aiyasthenia gravis „
It is well known that 5 to 10 percent of patients
with myasthenia gravis are also hyper thyroid » and
when these two diseases coesslst the prognosis appears
to be grave, Soae observers in the past have reported
an inverse relation between these two disorders » and
this view has been challenged by others,, The study
was undertaken by Dr, Engel to define the interaction
of the two disorders 9 and to evaluate the respective
roles of pituitary TSH and of the thyroid gl&nd. The
methods employed were utilised on five myasthenic
patients. Medication was held at constant levels
during this study » and the clinical evaluation con-
sisted of daily measureseats of the pre-determined
group of sBuscles, The thyroid status was evaluated
as follows: Daily BMR^ weekly PBI, cholesterol and
ll31 uptake. In three patients thyroidal secretion
rate was also measured by direct daily counts of
thyroidal radioactivity » corrected for physical decay o
Steps taken were as follows:
1, Triiodothyronine CT3} was given at a dose
level insufficient to induce hyperaetabolisais but
adequate to suppress pituitary TSH secretion.
2o T3 was administered at progressively higher
dose levels until hypersa&etabolis® was induced »
3. After a labeling dose of 1^^^, thyroidal
iodine accuaulation was blocked with Tapasole and TSH
-21-
CArsBour) ^as &dm±mtBt®red lu graded doses ^ while the
fractional release of horaonal l'^^^ was measured from
dajr to daf .
4, Same as Step 3^ but with coiscurreat ad-
ministration of sodium iodide to offset the thyroid
horaione release^acceleratiEsg effect of TSE.
5. The prolonged administration of Tapazoleg .
until depletion of thyroidal horaone stores, result-
ing in hypoaetabolisra with concurrently high pitui-
tary TSH secretion.
In the asyasthenic study » the myasthenia could
be seen to beco^s worse in all patients who becanse
thyrotoxic o No see-saw relationship could be seen^
although minor fluctuations occurred until the BHR
reached plus 20, In one patient who becaae hypo-
ffietabolic on Tapazole^ the myasthenia improved while
the endogenous TSH level was still elevated. Exo-
genous TSH- induced acceleration of horsonal secre-
tion was followed by elevation of the Bl^^, and this
by worsening of the myasthenia. When this accelera-
tion was blocked by sodiua iodide » the effect on the
disease wajs also blocked, and only to the extent
that the rise in the miR was blocked. It is thus
apparent that TSH^, per se^ has no significant extra-
thyroidal effect on asyasthenia^ and that there is a
direct relation to the metabolic rate and the
severity of the myasthenia.
Similar studies were carried out in one patient
with familial periodic paralysis „ In familial
periodic paralysis^ as high as SO percent of patients
have been reported with exophthalEK>s and hyperthyroid-
is»c Induced hyperaetabolisa did not worsen the
clinical status of the patient with familial periodic
paralysis. Withdrawal of T3 was followed by a severe
and prolonged worsening ^ and this was relieved by TSH
adainistration. TSH withdrawal £^ain resulted in an
exacerbation. Repeated TSH studies could not be per-
forB»d as the patient becaae resistant to TSH» Thus^
there ®ay be a difference between thyrotoxic non-
faailial and faailial non-thyrotoxic for^ of this
disease, naasely the response to abnoraial levels of
thyroid function.
Dr. Darwin Prockop of the Heart Institute :, and
Dr. Bushnell Smithy have continued their studies on
the use of isonoastine oxidase inhibitors (nasiely JB 516) ,
as an anti-convulsant medication for centreacephalic
89t3M3t®s. Patieists were adeiitted aad aati-costvulisaiit
sedicati3ias weire reduced to a jEi»iis8«HB» 'Bfeeaever pos-
sible to do so without daager to tfee patient o After
a short fcaselia® period of observation ^ tbe patieats
were giwa either a placebo or JB 516 daily for four
to 8i3s weeks, ia addition to the other aedications
they had °3een taking. This was. doae hj the double-
bllQd aetliodc Slectroeacephalograiis ^rare rua each
week^, aad corapared to the baseliae ESG. Detesaiaa-
tioos of the »B»}unt of 5-~hirdro3s;Ftr7Ptaaia@ ia the
uriae weru doae duriag the baseliae period^ aad oa
the sixth aad seveath day of aiedicatioB.
la the fflsajor fiadiBgs» oaly two of the pa-
tieats r®c;©ived JB 616 uader this double-bliad fitudjo
Oa® dev©lo|>ed drowsiBess^ followed by geaeralized
coavulsious after reductioa of barbiturate o J^fore
reductioa the seizures were fairly well coatrolledo
Oae patieist became hypoteasi^e aad had syacopal at-
tachs aftBr four weeks of isedicatioa, Duriag the
fourth wc'^kg the patieat's seisures were fully coa-
trolled. Four patieats received placebos •- oae pa-
tieat shcvTed improveieeat , At this tins statistical
sigaificajstce of this series is aot such that JB 516
could be saowa to give aay inprovemeat ia patieats
with this type of disorder o
the study of other ffioaa:®ia© o»:idase iahibitors,
with ®ore specificity for the ceatral aervous systeai,
will be uadertakea bow that a protocol has beea de~
sigaed for mwih patieats. Dr. Smith is also coatiau-
iag his study iaitiated with Dr, Drager oa the patho-
logical substrata of the Heideahaia form of Jakob's
disease o Serial sectioas of the braia were accomp-
lished ia a patieat dyiag of this disorder » which ift
a relatively rire progressive degeaerative disease of
the ceatral asrvous systea^ the etiology of which is
quite obscure aad the pathological process has aot
beea well docurseatedo A cortical biopsy was obtaiaed
duriag the tliird %oath of this disease aad the diag-
Bosis coaf irs^d at this tl&s. Fiadiags at the preseat
tise are those of a widespread diffuse loss of aeuroas
ia the brai.%9 particularly the occipital lobe^ as
aarked by status spoagiosus aad astrocytic prolifera-
tioBo The cerebellum shows a marked loss of Purkiaje's
cells aad graaule cells » The lateral colunas showed
degeaeratioB. Ia additioa to thiS;, nodules of acute
iaflaMiatory cells with foci of aacrosis were scattered
throughout the braia aad spinal cord^ aad may be due
to the terminal infection „
Finally,, Dr. Altrocchip in the Cllaical lavesti-
gative Unit, aad Dr, Srooth ia the Bx-aacfe of Spidesaiolog,'? ;
-23-
are joiaiag is a coBlsiia©d study of tissue culture aad
chroa©sc^© misatiag la h«masi subjects with various
neurological disorders ^ aad froia specific tissues
in which locsl tissue alinormalities are founds, such
as in von Rec'i^liEghausen's disease. This studf has
just been usdsrtaken and will include tissue culture
of the reaove^l tissue ^ chromososae counting of cafe
au lait spot@> local tuaiors^ etc. Studies of quan-
titative chrc»oso®al. ahnorssalities in patients with
Btental deficl':acys spinal def oraiities j etc.^ will
also be doneo
The setfflods eaplojred 'will be the removal of
fresh bone mavrow^ which will be incubated overnight
and treated with colchicine ^ and then fixed and stained
by the sstodificxtions of the sssthods described by Ford,
Polaai^ et al. Squash preparations will be searched
systematically for cell^ in the aietaphase of mitosis »
which will be naalyssed both toy direct aicroscopy and
by aicro-photouraphy for quantitative and qualitative
abnoraalities. Tissue culture methods will be used
to grow sSEin, muscle, oarrow^ and neoplastic tissue
in the laboratory, which will then be treated in a
similar io that above for chrososcoi&l analysis c
ISiis cosrludes the Siajor findings of the Brajftch
of Medical Meur<'Iogy.
PHS - NIH
Indi'ffidaal Project Report
Calendar Y©ar 1959
Serial NOo NIPDBwi(e)
ic Medieal Neuxoiogy
2o Cliaieal Neuroehecistr
3, Bethesdaj Md„
4„ Saae as 58»NIf®B-27
£§r.L4°
project Titles Amino Acid Metabolism in Normal and
Epileptogenie Cerebral Cortex ixj VltEjOo
Pri<:eipal Investigators? Dr^ Donald B„ Tower and
Ita Sinund Lo Peters
Other Investigators: Dr„ Gyy McKlianne Dro John Vftierrett
Cooperating Dnits; Dr„ Bo Wo Albers, NINDB Lab» of
Neuroanatoioical Sciences«
Kian Years r Patient Days: 0
Total: 0„8
Professional: Oo5
Othisr:. 0o3
Project Descriptions
OlA3JgtiEe§,' To study the i^ yitro metabolism of amino
aeids and related compounds in brain tissue samples f'oi!
exi>erifflentai animals and frora huraan patients oporstec
on for focal epilepsy o
=^^M!i?,* See previoas reports on this projeeto
Pgiie.nt Mi^MriaM From ^^'^ -r^tients admitted .f:'"-
purposeso
.Efejoy HgjdLngs,;
(1) The changes of free amino acids in sliees c'
cerebral cortex during in^ubatioa Iji^ MSSQ, were
investigated in detail with respecT to time of iu
The following table suasitariaes the findings;
Slice Total (Glutamie
Acid + Glutaraine)
Sliee Glutamic Acid
Slice Glutamine
Medium Glatamate
(^ Glutamine)
Slice Ansnonia
Slice Y°Aminobutyrie
Aeid
Initial
Changes from Initial Le^el at
c e> />
15,
llo4 +lo65 44<.35 +5^0 "«4o85
7o75
3o6
5ol
2ol
-ihlo35
•K)o3
«0a3
«0o8
+4ol
•K)o75
«li2
-80„4,
+3o2
*lo75
=0<,15
42o4
4-2o45
"2o25
c=0.35
These results Indicate a very rapid initial formation of
glutamic acid^ and a subsequent decline presumably by
metabolie conversion to other ccwapounds Ceo go 'yt='aminobutyrir
acids glutamine)o Mostg if not allg of the glutamine
increase during incubation appears to be accounted for by
uptake from the mediiua (initial content there is leakage
from slice during preparation )» Only isotope studies can
settle this questiono The source cf sunino groups to support
the pronounced synthesis of glutamic acid from its known
precursorj a^ketoglutarate^ is the chief probl«5m posed
by these datao
C2) Companion studies wSiere slices were incubated with
40 n^ malonate in the medium denoastrated s.triking
differences: glutamic acid increased by30 to 6o5 \M
over initial values and remained at this high level
subsequently^ glutamine rose little if at alls medium
glutamate also changed little? slice amaonia did not decrea
but rose slightly; and sliee y^^jinobutyric acid rose by
nearly 3 times as much as in control studies tabulated
aboveo The mechanisms of malonate inhibition here are
not yet clear beyond an evident block of glutamic acid
metabolism, but this e}q)@rim@ntal situation is proving
valuable as a means of "stabiliasing** the free glutamate
pool in incubated slices from its normalp rapid and active
changing facetSo
C3) A number of additional experiments were carried out
with L=2o4«diaminobutyric acidg recently reported by
Kessel to block farther metabolism of y^arainobutyrie acido
No effect of this compound when incubated ja, ^itro with
normal eat cortex slices was observed (examining glutamate
raetabolismp glycolysis and oxygen consumption) in concentre:
aip to 40 n|^ EoWiSver adajiiiistsred Ij, ,vlyQ. to miceo
seizures oecsirred i2 or more hours later^ Brains of animals
with seiaures exhibited la jri tg£ a reduction in slice
pj^gen consiffiipticn (7^ of eoatrols aad of injected mice
?githout seisures) and a proaoaaeed elevation of Y^sraino"
butyric acid levels C9o0 iM/g^ compared to 5o6 in controls
and 5o3 in injected raice without seiaiares)o 2«dimensionai
papet chroEatograsis confirmed the latter and suggested increase
of glutamine and decrease of glutasaic acid in brains of mice
with seisureso These studies were repeated on eats injecting
3 Ej/kg of diassinobutyric scido Seizures occurred in about
6 hours and brain slices from these animals incubated
in yitra revealed the following: oxygen consumption 87%
of expected v^alues„ corrected to the latter by added
pyridoxal phosphate but not by added Y^s^i^obutyric acids
levels of Y'^aisinobutyrie a©id over twice normal with marked
increase during incubation; very low initial glutaraic acid
(about 605S of controls) and very high initial glutaraia©
(about 3 times controls) with scase decline in glutamine
and stase rise in glutasaic acid during incubatiouc The
findings confirmed a distinct block of -y^arainobistyrie acid
metabolism^ but also suggested asmonia intoxication of the
Brain Cglutamine elevation)^ consistent with the known
hepatotoxic acid of diasBinobutyric acido Further studies
of this aspect have not yet been carried outp but are
coQtemplatedo
C4) Attoapts to adapt an unptibiished fluorimetric procedure
for aspartic acid developed by Dro Oo Ho Lowry proved
coB5>letely unsuccessfulp despite veiry extensive effortSo
!nius no data oh aspartic acid atetabolism under normal or
other conditions have yet been obtainedo Utilisation of
various other ensyaatic assays is now under investigatiour
Significance of Project: Hi© prosecution of this project
is of fundamental importaace to an understanding of the
roles of the glutamic acid»aspartic acid group in neuronal
metabolism and ih' the seizure processo
Proposed C^utsgt To continue the above and related studies
with special emphasis on the effects of various other
metabolic inhibitors and on obtaining data on aspartic acid
metabolism,, ,
Part B Incli|d|^: Yes
Serial No. NINDB-^Kc)
PHS « NIH
Individual Project Report
Calendar Year 1959
£aits«
PHblieatlonsi
Xo Tower« D„ Bo
The Effects of 2«4)eoj^'=0«Glucose on metabolism
of slices of cerebral cortex incubated _in vitjcpo
Jo Neurochein. 3: 185 Cl958)o
2o Tower, Do Bo
Glutaraie acid metabolism in masmalian central
nervous systeso
Po 213 in Bruckeo Fo CEdo) Biochei^istry
^ tht, Central Nervoas. gysteai (IV Internato BioeheHio
CongroB Vo 3)(, London^ Pergamon,, 1959„
3o Peters 5 Eo L. and Tower „ Do B,
Glutajtiie Acid and glutamine metabolism in cerebral
cortex after seizures induced by methionine sulfoximinec
£o NearocheBo 5: in press (1959)o
4p Tower, Do B„
r^euroehesaistry og a>ilepsv: Seizure Bteehanisias
and Managgaenta Springfieldj, Thoasas, 1959o
McKhannp Go Mo„ Albors, R, Wc, Sokoloff, Loo Mickelsen, 0,
and Tower 0 Do Bo
The quantitative significance of the gaiMa-araiHobuty?
acid pathway in cerebral oxidative metabolism^
In SobeAtSfl Eo (Sdo) X,nfjilbition in ^j^
Nervous Sys^tan and Y^aminobutyri^ Acido Londonj,
Pergamon, in presSo
Honors and A^gds^; Noneo
Serial NOo NIM)B^2(c)
lo Medical Neurology
2o Clinieal Neuroeheraistry
3o Bethesda^ Mdo
4o Same as 53«NIP®B-25Ce)
PHS « NIH
Ind:i¥idiial Project Report
Calendar Year 1958
PaglA;
iProject Title? Electrolyte and Energy Metabolism in Normal
and Spileptogeni© Cerebral Cortex in Vitx^c
Principjl Investigators s Dr^ Donald Bo Tower; MTo Eo Lo Peters
Other I.iv'estigatorss Dro Bushnell Smith
Cooperotiag Units; None
Man Years; Patient Dayss 0
Totals loi
Professionals loO
Oti.ers Ool
Projecf Description;
Ob'a<?.tlves^s To study In ¥itro^ metabolism of eleetrolytess
Tpotassium^ sodiian,, ehlorideSo etCo) and of en«rgy-=
producing cycles and coi!^)onents thereof in incubated slices
of cerebral cortex from experimental animals and from htanan
patients operated on for focal epilepsyo
Methods g See previous reports on this projeeto
.Pg.Ll.g.nt _lfa_t eri a I , s Obtained from NINDB patients admitted
for other purposes o
Ifeloir Findings; During calendar 1959 attention was demoted
to problems of fluid spaces in the tissue slices and of
effects of various In, M^^°> conditions thereono It was
considered essential to gain more insight into these
problems before proceeding with studies oa human epilepto^
gfeni© material or with the use of radioactive ion tracerso
CI) Fluid spaces calculated from chloride as the iadieator
were cc»^ared with spaces calculated from sucrose as the
indicator on the same sampleso Normal cortex and cortex
from animals i^ith experimentally induced seizures Cmethionine
sulfoximineo Megiraide) exhibited close correspondence or
identity of fluid spaces determined by ea^ method and sliee
swelling was limited to the chloride and sucrose spaces^
in ©oafo^ttity with various previous reports by others,.
C2) Similar studi«s on slices incubated with added gl^taffli
aeidj glutamine or asparagine in incubation mediwD exhibited
a mark@d increase of the non«ebloride (or Bon»sueros@)
space during incabationp but addition of Y^^oinobutyric
acid produced no change in this space from normal controls.
Sliees ineubated undBt hypoxie conditioni Cl(^ oj^gen)
exhibited a ssarked diserepancy between ehlorid© and siserose
spaces,, indieating swelling of the noB«si8erose C? intraeeli'
spaee and influx of chloride into that spaeeo This latter
finding is consistent ?iith several recent reports on intra«
cellular shift of chlorid© during spreading depression and
anoxia of cortex 4s, vi^o The iaqjortanee of carefully
defining these changes before attempting to estimate
'"intraeellular"' cation eoncentrations is obviouso
C3) 1^ conq)aring fluid spaees and electrolytes in ineisbate
slices of subeortieal ^ite matter with those in ineiibated
slices of cerebral eortex (same animal) it has bees possibl
to estimate by the EHiott'=^©ller formula the relative
distribution of son«ehloride space and of potassium and
sodium therein between neurons and non^neuronal cells in
normal eat cerebral eortexo These data may be sunmari^ed
as fol loins s
Cortex
White
Neurons
"'GUa'°
'"Glia"'
Non«Chloride Spaee
i% of total volo)
CI)
CF)
22
30
10
12
17
19
Sodium
CI)
90
42
42
Cp-Eqo/mlo non=Clo
Spo)
CF)
14
43
43
Potassium
CI)
112
161
164
C^fiqo/mlo non=€lo
Spo)
CF)
180
163
174
[l = initial! F = Sample incubated
60 mino]
Two general eonelusions may be deritred from these data?
first cortical neurons account for about 7S^ of cortical
non«chlorid@ space Cor 3^ of total cortical volume) and
of cortical potassitaa in non^^ehloride spaces,, but only
45!% of cortical sodium in these spaees (final incubation
values)," and ^gcondo the extrusion of sodium and uptake
of potassium normally observed during incubation of these
cortical slices (see previous reports on this project)
are limited to the neurons^ The latter conclusion has
important implications for cation turnover in cortex and
for the observation made previously in this project that
epileptogenic slices are unable to effect this cation shift
during jn :gitrjo ineubationo [it should be pointed out
that the foregoing calculations have assumed astrocytes
to comprise part of the chloride space on the basis of
rscent electron microscope studies of incubated slices
reported by de Robertis and by Luse],
(4) From the foregoing plus other data previously ob
in this project, it has been possible for the first time
to estimate oxygen consumption (as a measure of energy
taetabolisra) by cortical neurons and non=neuronal cells
in terms of non^chloride space volume ■= a more satisfact:
parameter than previous values based per unit weijht or
per cello The values for cat cortex in terras of substia
metabolized (oxygen consumption/3) are as follows:
Cortex White
Neurons "Glia" "^Glia'*
/.iM/hr/mlc non-Cl. Spc 75 41 40
The higher metabolic rate of neurons is consistent ??iUi
a Huraber of previous studies^ but in the present terms
is highly suggestive of a direct relationship with thf
cation shifts illustrated above ■= a relationship
already su'jgested in other contexts by Keynes, Furth:
the "extra" metabolism by neurons almost exactly eqaa
the fraction of neuronal oxidative metabolism (33/ :?J/h.
non=Cl Space) attributable to the y^Q'^ino^jutyric acid
pathway [See project 5*^«NIM)B= 3 (c)], suggesting thai,
the latter pathway, unique to neurons, may account for U
higher metabolic rate of neurons compared to ^lia (whici
lack this pathway) and may be closely coupled with
electrolyte metabolisto
Significance, of Proiect: Energy metabolism is the basic
factor in neuronal function and activity, and electrolyte
metabolism, which is clearly dependent upon ite, provides
an important bridge between cellular chemistry and the
functional activity of impulse conduction^ "Die unders'-^
of the factors involved is essential both for normal
neuronal tissue as well as in hyperactivity status like
seizures „
Propgsed Course; To continue studies along lines indicated!
by 1953 and 1959 findings on both the electrolyte and
energy aspects of the problera„
Fart B Includgd: YeSc
Serial No„ 59°NIM)Bc^2(e)
PHS " NIH
Individual Project Report
Calendar Year 1959
Part Bs
nPublieations:
lo Tower,, Do Bo
The effects of 2'=Oeo3{3r=D=^liieose on metabolism of
slices of cerebral ©ortex ineubated jn vitrop
I- MsmM^o 3: 135 (l958)o
2o Tower 0 Do B„
Glutamic aeid metabolism in masmalian central
Nervous systemp
Po 213 in Brueke,, F, CEdo) Bioehemistry
M JM Pgnti^al N®rvou£ System. (IV Internat„ Congro
Bioeheffloo Vo S)^ London^ Pergamon,, 1959,
3„ Towerr Do B„
N^iiroch^istrv o| Epi letssy i Seizure Mechanisms
and Management o Springfieldo IhomaSp 1959o
4o Totserp Do Bo
Seme neurochemical aspects of cortical neurobiologyo
In Schad^p Jo Po and Tower „ Do Bo CEdSo) S;^,rueture
and Function of ^e Cerebral Cortex (2nd Internato
Meeto Neurobiolo), Ansterdamo Elsevier„ in presso
Honors and Amrds ; Noneo
Serial No„ rar®B-3(c)
1„ Hedicai Neurology
2, Clinical Neurochemistry
3, Bethesda, Mdo
4, Sane as 58=>NINDB=.30(c)
PHS " NIH
Individual Project Report
Calendar Year IQS*)
Project Title: The Metabolic Significance of Y=°Aminobutyric
Acid in Neural TissuCo
Principal Investigator; Dr. Guy Ho McKhann
ether Investigators; Dr„ Donald B„ Tower, Mr» Edmund L„ Peters
Cooperating Units: Dr« R. Wo Albers, NINDB Lab of
Neuroanatoraical Sciences.
Man Years; Patient Days: 0
Total; 0.<?
Professional: 0.7
Other; 0,2
Project Description:
pblQCtives; To study the metabolism of Y°°arainobutyrlc
acid in neural tissues, to study factors affecting such
metabolism, and to deduce therefrom the significance of
this compound in neural metabolism and function.
Methods ; See previous project report and under Mafor Findings.
Patient Material; None.
fteior Findings^
(1) The experimental studies reported in 1<)58, demonstrating
that Y-^aniinobutyric acid can act as an effective substrate
for cortical oxidative metabolism, have been extended by
determining the quantitative contribution of the yaminobutyri
acid pathway to total oxidative metabolism at the Krebs cycle
stage. With pyrttvate'='3"C as tracer, the labelling of
glutamic acid and Y'^aninobutyric acid in incubated cat cortex
slices was followed with duration of incubation and specific
activities of the two compounds determined. Calculations from
these data showed that 44% of the total substrate metabolized
from a-^ketoglutarate to succinate was metabolized via the
Y^aminobatyrate pathway during 1 hr. incubation. Since the
latter pathway is exclusively a neuronal pathway, it can be
estimated that nearly 60% of neuronal oxidative metabolism
proceeds via y^arainohutyTic acid.
«2-
C2) Data from the above study indicated that the propor,;.. ., ,
of oxidative metabolism directed via Y^arainobutyrie aeid
varied in a sigmoid fashion dsiriag 1 hro incwbation;,
suggesting a reciproeal relationship with metabolissB via tiP-
parallel succinyl^-o A pathwayo Extensive studies have bseu
carried owt on the factors infiueneing the amount of sabstx;'
metaboiissed via Y^a^^i^'^butyrlc aeidc utilizing cortical
mitochoudria and Y"araiitiobutyric acid»l«C^^ and caaparing
C O2 evolved to total oxygen consumptiono Some a=ketoglut=
arate must be present for transamination with y^aroinobutyf if.^
acid if th@ latter is to be further metabolizedo As the
concentration of a^ketoglutarate is raised to 1 BiM„
metabolisia via "YfeatBinobutyrate inereaseso llcsfevero as the
coneentration is further inereasedo a marked inhibitory
effect is observedo In the presence of arsenite («*idi
blocks a=^etoglMtarate to sttccinyl<=Co A metabolism) the
inhibitory effect of higher concentrations of oi^ketoglutarstc
is not presents Thus^ it appears that there is a reciprocal
relationship between metabolism via Y'='a>ai»obutyrate and via
the parallel suecinyl^Co A pathwayo and that as levels of
the common precursor,, a<=ketoglutarate ris©« the latter
pathway is preferentially favoredo
C3) The metabolie significanee of the Y=a°inobutyric acid
pathway Jn vij^o in mouse brain has been investigated with
Dr^ Alberso Following parenteral injection of pyruvate=3=
C^^ the specific activities of brain glutamic acid and
Y^aminobutyric acid have b&en serially determinedo Preliminae v
results indicate labelling of glutamic acid and Y^a^inobutyric
acid from pyruvate=3«C*^ is extremely rapido
90 seconds after parenteral injection^ the SoAo of
Y^^Jsiaobutyric acid in brain is 50% that of glutamic acid,;
By 10 minutes after injection;, th® maximal 3oAo of brain
Y==arainobutyric acid is attained and is then some 20% higher
than the maximal S^A^ of brain glutamic acidc These findiRns
strongly suggest that aeompartmentation factor is involved,,
sueh that the labelled glutamic acid formed from labelled
pyruvate has not during the time intervals studied
equilibrated with all the cellular glutamie acid, and hence
the labelled fraction has a much higher S^Ao than that found
for total glutaraate and it is from this fraction that labelled
Y^aminobutyrie acid is formedo These interpretations are
consistent with analogous data and interpretations repoi'ted
by Waeisch for brain glutamine labelling from injected glutamic;
acid«C^^o
In view of thecompartmentation factor,, the metabolic?
rate of the Y^a^^inobutyric acid path?jay in brain iq jivo
cannot be accurately calculated from present data,, but the
findings clearly indicate that the pathway is,, if anything,,
more acstive Jn vivo than ig, jitrg^o .
-3=--
(4) Studies on *rarious seiz«e preparations^ notably with
thiosemiearbazlde and L-2v4«diainiinobutyric acid as con-
vulsantSo strongly suggest that metabolism through the
Y»aminobatyric aeid pathway rather than the letrel of
Y-aminobatyrie aeid itself is the signifieant factor^ Thus
in both thiosenicarbazide and diarainobutyric aeid seisures,,
cortical oxygen constitution was significantly reduced„
consistent with blodcs respectively of the glutamic
decarboxylase and y-^smimbvityTlc transaminase steps of the
pathiray by these ageutSo Howe¥er„ yan^i^o'^'^^y^i® ®^^^ levels
were half normal with thiosemicarbazidQ and more than double
normal with diarainobutyric acido When seisares failed to
occur after administration of either agent Cpresmaably due
to insufficieat dose)« none of these abnormalities oecurred,
indicating the close relationship of seizures to dysfunction
of metabolism via the y'^minobVLtyrie acid pathwayo
(5) The analytical problem of Y='amiKo^«*y^i'2 acid levels in
brain [Cfo 5a=NINDB»30CG)] has been resolved satisfactorily
Studies by both Roberts and us have clearly sh<»fn that
Y«aininobutyric acid levels continue to increase linearly
with time after excision of brain samples^ due to continued
operation of glutamic decarboxylase anaerobically but
failure of subsequent aerobically=>dependent pathways for
disposal of accumulating Y^aciinobatyric aeido Comparable
levels of Y^aminobutyric acid by fluoriroetric and mi©ro«
biological CJakoby enaymes) assays have been obtainedc
Sianifieanee of Prsiec^s The findings emphasize that the
Y«affiinobutyriG aoid pathway plays a major role in neuronal
oxidative raetabolisra^ and that its derangsdient is intimately
- associated with development of seizureSo Study of the factoi
which regulate metabolism through this pathway may elucidate
some of the regulatory factors in neuronal functioning.
In addition the concept of compartmentation of metabolic
activity among different types of cells and among different
intracellular loci has far«reaching implieationSg providing
potential links between raetabolie activity and specific
functiono
P,yopose,d ^our^es. To continue above studies in progresso
Serial NooNI^TO»3(c)
PHS « UK
Individual Pnjtct Report
Calendar Y^ar 1959
P?yt B;
McKhann G„ Mo and Towers Do Bp
GsMia«arainobutyric acid: a substrate for
oxidatrfe nsetabolism of cerebral eortexo
Mfi^ Phvsiol. J^fe's 36 C1959),
McKh'.nn, Go Hk, AlberSo B„ Woo Sokoloff, L=,
Mickvlseiie Oo and Toiler^ Do Bo
The qssantitative significance of the
gara!a«aminobtttyri© acid pathway in cerebral
oxidative metabolisiSo
la Roberts 0 E. (Ed. ) Inhibition In the
N^iryqus System aM Y-AninobutYgic Acido
London^, Pergamoao In presSo
Towerc Do B^
Seme neuroehefflieal aspects of cortical
neurobiologyo
In Schad€„ <lo Pc and Tower, Do B. CEds.)
Structure jM ^^"®ti9n ^ ^ Cerebral £9.y^3X
(2nd Ia?jivnvv.j "siieto Neurobiolo) Amsterd*aai,
Elsevier^ In presso
Honors and Amsitdg.; Nonso
Serial No. NIM)B^(c)
lo Medieal Neurology
2o Clinical NeuroehOEistry
3o Bethesda,, Mdo
4o Same as 58-NI^DB°23Cc)
PHS « NIH
Individual Project Report
Calendar Year 1959
Part, As
Project Title; Clinieal Evaluation of Various Amino Acids
and Related Compounds in Control of Seizures^ including
Studies of their ffetabolism iti -yiy,Q,P
Principal Investigator; Dr^ Donald Bo Tower
Other Investigators: Dro Guy McKhanng Dro Bushne?-! Smithy
Dro John Wherretto DTo Co Ajraone-Marsanp HTo Eo Lo Peters,
Dro Go J4 Shy
Coopsrating Units; Co Co Pharmasyo
Man Years ; Patient Days : 125
Total: loO
Professional ; 0o5
Other: 0o5
Project Description:
■^>i€otiy.eg.; To assess the effectiveness of various amino
acids and related compounds of the glutamate»aspartate
group for control of clinieal seizures and to complement
these studies with investigations of the in yiyo metabolism
of the various compounds in use^
j^th_ofes See previous reports on this projecto
Patign't -Ma^Q^^ai • Admissions to NINDB wards specifically
for this project, plus follow-up studies,, and use of patients
admitted to NINDB for other parposeso
(1) All patients previously carried on oral L^asparagine
therapy have been discontinued or switched to y^aminobutyrie
acido The asparagine phase of the project is ©wupietedo
Reports from cooperating clinics [See 57=NiNDB«5Cc)] have
finally befea received as of 1 Sept^s^er 1959 so that this
study can be written up in the near futureo
(2) Limited trials with oral y«aminobutyrie acid have
continued, utilizing a total of 10 patientSo Overall results
are similar to those reported in I^^, about half improved
(two essentially seiaure^^free) and the rest not benefittedc
EEG studies on one of th© seizure-free patients indicated
a very dramatic improvement of the EBG abnormalities while
on Y^ai^ifio^JUtyri© acidp but other patients have failed to
exhibit similar responseso From the bloody urine„ and
cerebrospinal fluid levels of Y^aminobwtyric acid obtained
during 1953 and 1959 it sems evident that one factor in
variability of clinical response is blood=brain barrier
permeability to Y'^a^^no^K^y^ic acido Animal studies recently
reported by Van Gelder and Elliott indicate that normally
penetsfebility is miniraalo but other studies on seizure
subjects (Cfo Lending, Slobody and Mestern; Purpura ji^ ^<. )
indicate modification of barrier permeability during
seizures or concomitant with chronic seizure stateso
Variability in such modification undoubtedly occurs,,
clinically and is in part reflected by CSF levels of Y^araino"
butyric acid and clinical responses of our patientSo
C3) One patient with '"essential'* hypertension was
specifically studied for effects of Y'a'ninobutyrie acid
on the hypertension^, following the recent report from Japan
by Tsukada ^ jlo A significant,- reasonably sustained
reduction of systolic and to lesser extent of diastolic
pressure was observed during oral Y="a«ninobutyrie aeid^
CSuch a response was not obtained with various other agents
tried during a previous NINDB adraission)o No sustained
effect on seizure frequency was obtained during the same
therapeutic trials a result consistent with but not proof
of peripheralo systemic action of Y^^aM^nobutyric acido
Data recently reported by Elliott and Hobbiger for e^eriraental
animals definitely support such actions for this compound,
Signiliegpfig ^ Pygtect ; This project is part of a long term
study of the bioch@ai@al basis of seizureSo Clinical
applications of promising leads developed in the experimental
phases of the study are important both as potential ew^li^
raentary clinical validation of e:q)erimental findings and
also as potential net? and more rationally based therapies^
Proposg^ Cpugi^t t Present results indicate that little
further infoxmation is to be expected from patient trials
now in progresso It is cont^nplated that this project will
be suspended sometime in calendar 1960^ unless appropriate
new developments warrant otherwise^,
Part B Included; YeSc
Serial No. NINDB-^/lfc)
pas = NIH
Individual Project Report
Calendar Year 1959
P?yt B;
Piijblicgtions;
lo TosTOr, D« Bo
Neurocheaistrv of Epilepsy; .Seizure Mechanisas
and Managemento Springfield,, ThomaSo 1959o
2, Tower f, Do Bo
The administration of gaiMa«aminobutyrie aaid to
man: systmie effects and anticonvulsant actiono
In Roberts^ E^ (Edo) Inhibition in the Nervous
Svstaa and Y°AminQbni,1;Yric.,Acidy London ^ Pergamon, In press «
Honors i^nd Atyards: Noneo
^
Srsrial NOoJSI©^-
1« Medical Neurology
2o Clinical Neurocliemistry
3o Bethesda,, liW.
4o New
PIIS " NIH
Individual Project Report
Calendar Year l959o
P^rt A:
"project Title: Anticonvulsant Drugs and Cerd)ral Electrolyte
Metabolism^
Principal Investigator r, Dro Bashnell Smith
Other Investigators: Dro Donald B<, Tower^ Mr^ Edmund U Peters
Cooperating Units: NonSo
Man Years : Patient Days j 0
Total: Oo6
Professional: 0o6
ether: 0
Project Description:
O^iffctiye?: To study by detailed ia Mtsa. methods effects
of ant i eo n vu 1 s a nt drugSp reported to affect cerebral
electrolytes^ on the electrolyte metabolism of normal and
epileptogerdc brain sarapleSo
Mgtjiogg: Standard procedures of experimental animal
preparatioHv brain sampling^ slice incubation and
analyses for tissue and incubation medium potassiuWp
sodium and chloride will be used^ based on procedures
already developed and in use in this laboratoryo Initial
studies will utilize soluble preparation of acetazoleamide
(Diajaox) and diphenylhydantoin (Dilantin) „ In the former
case^ additional studies on the effect of this drug on
the carbonic anhydrase activity of ineubated slices will
be carried out by standard proeedures already established
in the literatureo
P^tiftnt M^,^erial: Noneo
l^uLgS. fia^iaggx This project has been activated only 4
months during calendar 1959o Base line studies on normal
cat cortex slices have been carried out and a preliminary
survey of Diamox concentrations added to the incubation
medium of such slieest; A slight effect in reducing the
non-chloride space sodium concentration during incubation
with a Diaraox concentration of ^ilVt.o (approximately
the concentration known to effectively inhibit blood
carbonic anhydrase)» Other concentrations of Diamox are
now under studyo In addition sotae effect of these loiar
Diamox cancentrstions in expanding the non<=cIiloride space
of tissue slices is so far apparent^
^i_cfai_|ieatKie of Pro,|ect ; Various types of evidence
suggest that narcotics t-nd anticonvulsants raay act
physico-^hcsnicaily at the excitable msjubranes of conducting
cells 5 presumably by altering ion fluxes across snah
atrabraneso For two antioonvulsants more detailed
meehanisras have been suggestedo It has been proposeti
Diamox acts via its inhibition of carbonix aRlIydrase^
resulting in intracellular accianulation of carbon dioxiuo
Cand bicarbonate ioRS derived from iE)^, nomsally removed
I'rora the call by ?jarboni?, aiiliydreseo Acciuaulsited intra^
cellular bicarbonate is generally thought to exclufle
;30diu!n entry and henee radiace ©xcitabilityo Conversely
:lt has been proposed thai Dilantin increases sodimn efflux
from the intracellular spaee by laechanisms &s yet unknown
and hance also reduces Kccitabilityo The itj viiiro,
demonstration of these effects would help establish the
validity of these concepts and peraiit more detailed studies;
of th© ffiijchanisms involvedt. Furthermore avs liability
of means for saanipulation of slice electrolyte metabolisffl
■&ould immtisuvshly increase possibilities for eluei dating
many of the ntetaboll© faeets and mechanisms related
directly or indirectly to the electrolyte transport
systems th«5raselvesc Tliese studies bear on three in?)ortaiit
aspects of neural function j seizures^ anticonvulsant drii^j.
actiono and the neuraahtsali;:;)! mechanisms subserving
sxcitation and condr
Prcipo.s.ed £ou££gj T: ;? the typss of stndi •-■
Initi'itad at i5lar;.-5p',
£Mt B -la^Madg Noc
2n CliHiaal Neurochajjistr,'
3„ Bethesda, Mdo
4o Same as 53-NINDB°26Cc)
PHS = NIH
Individual Project Report
Calendar Year 1959
Part A:
Project Title: Comparative Bioehemistry of Smooth Muscle
and Striated Muscleo
Principal Investigator; Dr^ Beni Horvath
Other Investigators : B&'d Joseph B, Proetor
Cooperating Units: Dro Ko Lakio LPB„ NIAIS©
Man Years: Patient Days: 0
Total: Oo2
Professional: 0
Other: Go 2
Project Description:
Object igg§.g To characterize the actwayosin of smooth
(uterine) and striated muscle in physico«ch«aical terras
preliminary to study of actomyosin synthesis in muscle.
!,: See previous reports on this project >
P^ti^nt ^teyigl' Nones
Ma\pr ^iSJjngs;: Work on this project was tecjporarily
suspended during calendar 1959 nhile immunochaaieal
procedures and findings for other projects in this
laboratory [see 59='NIMB« 7 (c)] could be evaluated
for application to the basic problems of this project
The finding [project 59-NHDB=7 (c)] that antibodies
to clam tropomyosin A cross react with cat myosin with
a 50% crossover indicates as relationship of the two
proteins despite the very remote relationship of the two
specieso Such data have an obvious bearing on the problem
of comparative biochemistry of muscl©,^ but more
investigation is required before full scale applications
can be made here^ rvfeamrfiile the "dystrophic^" mous©
colony is being maintained to provide one type of source
material for such studies* The application of insnuao°
chemical techniques to these source matoxials may be
expected to assist greatly in the analytical problems
inherent therein:,
jQJi Proj ec|; : Studies on formation of actoniyosin
may have an important bearing on the locus of disease in
muscular dystrophy and other myopathieso Development of
suitable raicromethods and animal preparations is a
necessary prelude to extension of experimsntal animal data
to human specimens.
Propose Cogpis To extend these and related studies
to include miee in various stages of their disease in
order to obtain information on the dynamics of muscle
degeneratiouo Such information will subsequently be
applicable to projeeted studies of muscle protein
formation (synthesis) in uterine muscle under hormonal
stimulatioUo
Part B Include^; NOo
:;',<?jrial No
I;, Sitedica.
3o Bethesda^ Ido
4o Same as 53«NINDB=35Cc)
PHS - NIH
Individual Project Beport
Calendar Year^ 1959
Part As
Project Title: Distribution of Actin and Tropomyosin in
Normal and Diseased Muscleo
Principal Investigators DraBeni Horvath
Other Investigators s Dro Igor Klatzo; ffro Joseph Bo Proctor;
DTo Jr. Miquelo
Cooperating Units: Dro K, Laki^ LPBo NIARD
Man Years: Patient Days: 0
Total: lo4
Professional: Oo3
Other: Oo6
Project Description:
(jBjjieeti^ves: To obtain additional information on th©
molecular architecture of musc:.e<, to study the distribati
of functionally important proteins in normal and diseased
muscle» and to establish immunological properties of
funetionally important muscle pr:>teinSo
S^thpd^ : See previous reports on this project and
under teajor findingso
Patient Material ; Nonco
M^joy FjLndinos: Previous studies ha?e indicated that
structural muscle proteins may have un'jsual imraunologieal
properties and that immunocheDiical meth-^ds may be used
to advantage in combination with other n^thods for
elucidation of the structural interrelationships of these
proteinso The following represent progress in these
approaches: using primarily clam tropomyosin Ao
(1) Tests were developed and standardized for quantitative
determination of inraune precipitins:
Ca) an adaptation of the Kabat method vhere ism^une^
precipitates were washed with saline and aitroye^
content determined by direct Nessletization;
(b) a chromatographic method developed by Dr^
Micpel in which antibody and antigen solutions
are applied together on a paper strip ^nd
developed with buffer „ which removes soluble
muscle proteins while the imraune-precipiiate
remains at site of applieationo The latttv
can then be stained with broraphenol blue,,
eluted and determined spectrophotanetrically,
On a variety of systems results by the two
methods gave close correspondence^
C2) Both above methods provided information on quantity
of circulating antibody and on stoichioraetry of the
antigen-antibody reaetionso With the clam tropomyosin
A system it was found that at the equivalenc® point two
antibody molecules combine with one tropoayosin A molecul©,
»Aile in the antibody excess region^ four or more anti*
body molecules combine with one tropomyosin A moleculeo
Titers between 200 and 500 l-'^o antibody N/ralo ivere found
after the first series of iEmtinizing injections and rose
as high as 2000 i-'^o/alo after a second set of injections
two months latero Circulating antibodies were identified
by paper electrophoresis Y=°9lo^"li*^So The antibody
titers fell within about a month after imsaiinization
to about l(^ of maximal levels,, and booster shots given
at this time indicated that 3-10 days are required to
reach maximal titer and that drop in titer begins
almost inffltediately thereaftero
(3) For extension of these studies a more rapid test
was neededo It was found that the passive hemogglutination
test of Vorlaender (using tanni© acid Jryated sheep
red cells) ©ould be adaptedo Inaaediateiy after tannic
acid treatmentp the cells bind tropomyosin A and are
agglutinated by high dilations of anti==clam tropomyosin A
sera^ while remaining intaet with normal sera or in
absence of tropcmjyosin A., This test does not have the
accuracy of quantitative precipitin reactions „ but it
is very much faster^, Within an hour of bleedings an
estimate of the amount of circulating antibodies may be
obtained,, idiereas the precipitin reaction requires a week
to reach ecKopletiono The hemagglutination test is being
further developed in terras of specificity and
standardization at this timoo
C4) In contrast to the ephaneral nature of circulating
antibodiesc skin tests demonstrate persistence of changecl
reactivity several months after immuni2ation„
C5) Diffusion agar plates have been used for testinr the
homogeneity of the antibodieso After the first set of
immunizing injectionSj, only single precipitin linef_
appearedo From tests with various dilutions of antigen^
it could be estimated that impurities in test preparations
could not have exceeded ^»o Similar tests after a second
set of immunizing injections revealed multiple preeipitin
lineSo The causes of this are currently under studyo
C6) Experiments with eat muscle myosin indicate that
this antigen is eonsiderably more complex tlian clam
tropomyosin Ao Agar plates show several precipitin lines
and the quantitative precipitin reactions fail to give
clearcut optimao Both observations are consistent with
the concept that myosin possesses several determinant
antigenic groups and that the subwnit structure of myosin
aay consist <-? a coroplex of tropomyosin and actino i
study of the coss reactira of cat myosin and clam
tropomyosin revc-^^led a 50/o crossoFer^ ioeoo S^a^f tte
antibodies to cltn tropomyosin was raaoved from the
immune serum by cat mjosino This is a very respectable
figure in ccajparison o those in the literature, andt,
considering the remotf relation between the two spocieri,
indicates a close relationship of the two proteins,
Significance pf Pjfojert.; The inBaunological findings are
consistent with pres nt concepts of the Myosin molecyie
as consisting of sub riits = Tropomyosin A^ Tropomyos n B,
and Actino The latter can be prepared in a hifjher s^ate
of purity than myosii. itself^ so that they are more
suitable for investig. tional purposeso Since thes*^ proteins
are iso«antigenie„ imajnologieal responses of the jrganisra
may be in^jortant in coiditions where destruction f muscle
could permit these protuns to escape frcsn the u &-.1
confines of the muscle aid enter the general boy
circulatioHo
Prppos^,^ (^ffly,^,e,. To extend and coifirra thee findings
by quantitative immunocheaiaal methfdSo An. to evaluate
the significance of immune reactions in pa'ients with
neuromuscular diseases by skin tests and ^y quantitative
precipitin reactions of their sera,
£art B Included; YeSo
Mo NI?f)R-7(c)
Part Bo
Pu|)licatio\is:
U Ilorvatho Bo„ Miquel^ Jo^ KlataOj lo and Proctor« JoBc
Iranunoehesnieal Studies on Muscle ProteinSo
NeijirolpgY.: in presSo
2t, Miquelo J^o Horvath(, B^ and KlatzOo 1°
A Chroraatographie Technique for the Quantitative
Study of the Precipitin Reaciiono
Jo i^aaalo ° in press o
Hot^org gnd Ayardg; None^
ic. Medical Neurology
2c Clinical Neurochen-
4o Same as 53«Nir®B-j
Iidividuai Project Sepost
Pjfcject Title; Alterations of Actorayosin Teijsile Strength
and of Muscle ''roteias in N@uronmsou-Var Diseases.
Principal Investigator: Dso Beni Horvath
Other Investigators: Dr. Go M. Shy;; Dr. Igor vlatzo;
Dr. Wc K„ Englts; K^p Jc^sepli Bo Procter,
Ccc3>0rating Dnits: Koie,,
BHan Years: P8tii.32it Days: 0
Total: Co 4
?iOfess2onal: ObS
c. ascription:
jyjMMIi- To ccaapaye noimal and diseased Iianian muic
biopsy spaciciens for aotomyosin content,, tensilv; str-
of actcfflyosin t.iireads prepared from sunk biopsies^ s '
pbysiec^choimica ' •■■■•' ..-.-...;»., ,:,,..„.,.-„; .,.4..- „
pfotejc threads
'^±1 --:ai appffoacfees 3:jfe:;.!iii:! •
pi' ^ b©en applied in prelicd.:-
;stu....j.'; 'aiisoiEusCiSlar diiseases as
iollomi
CD iDiiaKnisatioJi of rabbits with ausdie p.:'oteins pr:
from ifabbit ausele was restadiedo Old rap-r;-? v>;dif
that rebbits could be iciaittiaed xdtii rab'
ncvi appears thcLt snsih ^:n-3«iria-J2^& -^-'t' i, _ ,,i. , ,,....
5C% h-im?:., In the ■.; aistin pre;
by ilc- . :..; - - ; V ; ■ , ,, ,.ure by t!ie ci',
of aut.ibodi«5?,- in rabbi
of .:-.. _-.-,. - --Ai )-^ i-.^■V;-^•:/^^':"•;• 7^
Vjhen tropomyosin B sKii f
Serial No.,, i--^-^^^^- -ic)
PHS - MIH
Individual Project Report
Calendar Year i95<?
Part B:
1, Horvtitli, B< aad Proctor, J, Bo
Quantitative Studies on the Composition of
Dystrophic Muscle
Proc,, AssctCo Res,, ^^r^c |^nX-» Digo : in press.
2., Klataso, I,, Horvath, 8. and Engle, W<. K„
Observations on Myosiii in the Abnormal Muscle,
using Fluorescent Antibody Technique,
ri2£° iSigc, K^„ ^^„ Jlfenl. DiSc in press.
Serial NOo NINDB^Q(c)
lo Medical Neurology
2o Clinical Neuroehemistry
3o Bethesda,, Mdo
4o Same as 58°Nir©B"33Cc)
> pes = NIE
/; Individual Project E,port
' ; Calendar Year 195^
Part A;
Projeet Title: The Surfiee-Ch^aieal Behavior of Urine in
Relation to iu Surfaee-Aetive Macromolecular
ConstituentSc
Principal Investigator? Dro William Cc Curtis
J.- Other Investigators? Mvo U Kenerson
"^' Cooperating Units? Nona
;' Man Years- Patient Days? 0
C Total? 0
l Professionals 0
I Other; 0
'^ Project Description?
Obieetivess To develop suitable physico<=cheraical methods
for isolation, identification and characterization and of
macrfflBoleculeSo sucli as polypeptides^ pyrogens and the
likep vrfiich occur ir urine and other biological fluids
but whose chemical individuality^ physiological significance^
and laechanisms of uction remain obscureo>
Methods t See previous reports on this project o
Patient Material? Obtarined from NIIDB patients admitted
for other purposes i
Mgi or Finding^ t Ncueo Owing to resignation of the
principal investigator during calendar year 1959, no
significant advances in this project were madCo
Significance og Project; iifeny of the coi^lex polypeptide
iaaercmolecules which normally are excreted in the urine
are considered to be by'^roducts of i^ yivq degradation
of proteinso In pathological states,, notably neurological
and neuromuscular diseases^ urinary output of these
materials increases markedly^ The increase may be due to
substances characteristically associated with a particular
disease state. The lack of any successful atten^t to
characterise these substances makes this project of
in5)ortanee in this regards
Proposed C<?urse; Since this project was conceived and
conducted in its entirety by the principal investigator^
his resignation necessitates tesmination of the project;
£aEt B Included; Noo
Serial No. WINDB^lO(c)
1^ Medical Neurology
2» Clinical Neurocheinistry
3o Betbesda« M^
4c Same as 58°-NINDB«32(e)
PHS » NIH
Individual Project Report
Calendar Year 1959
Part A;
Project Title: Physico-chemical Studies of Human Cerebrospinal
Fluido
Principal Investigator; Dr., William Co Curtis
Other Investigators: MTo t^mar Kenerson
Cooperating Units: None
Man Years : Patient Days : 0
Total : loO
Professional: 0o5
Other: 0o5
Project Description:
jSU.g!!l^.ives : To determine whether specific substances
liberated or produced in association with primairy or
secondary demyelinating processes in the central nervous
systeta give rise to alterations in cerebrospinal fluid
composition and characteristics which can be demonstrated
by physico-chemical techniques^
J^$hqjgg; See Major FindingSo
Patient t^terigl; Obtained from NINI® patients admitted
for other purposes^
Majgy Findings; CD Prior to the resignation of the
principal investigator in fflid«1959p saoe progress in
fractionation of cerebrospinal fluid by physieo<=>chemical
procedures had been effectedo 1^ bubbling benzeneo under
controlled conditions of rate and drop siseg, up through
a coltann of CSF coo^lete removal of lipids appeared to
occur and subsequent chromatography of the lipid containing
benzene on silicic acid impregnated paper demonstrated the
presence of lecithin^ cephalinSo inositideSp sphingomyelin,,
cholesterol and cerebrosideso Preliminary studies indicated
elevation of someo especially the latter threoo in CSF
sanQ)les from multiple sclerosis patients^ No quantitative
data wre possible by this method,, bat the lipid "profile"
appeared consistent with the recent report by Tourtellotte?
The benzenie^bubbie lipid extraction procedure and the
previously developed carbon=di oxide foam extraction procedure
for proteiHs and peptides [58»NIM)B'=32Cc)] would appear to
be promising approaches to isolation of these fractions when
present in minimal concentrations in CSF and sitnila;
biological fluidSo
C2) Complementary studies on the model protein,, guinea
pig serum asparaginase^ yielded considerable information.
This globulin with readily assayable enzyme activity can
be isolated as a crude fraction from serum by ammoniuffl
sulfate pcecipitation and partial purification with calcium
phosphategelo As such the specific activity is much enhanced
(enzyme activity per unit protein nitrogen)^ but the crude
fraction contains two visible contaminants by electrophoresis
and at least one by ultracentrifuge analysis. Previous
studies indicated that the enzyme activity was associated
with the fastest component in the electrophoretic analysis
and with the slower component in the ultracentrifuge analysis,^
However^ purification by these means was unsuccessful. In
1953 it was found that the modified cellulose resin developed
by ':>@terson and Sober would con^letely adsorb the enzyne»
Studies this year on elution of the enzyme clearly showed
that under appropriate pH and ionic strength conditions, four
separate protein°containing fractions could be eluted from
these cellulose columns to which the crude asparaginase
preparation had been adsorbed. Good separation of the fraction
was obtained and only one contained asparaginase activity
(of much higher specific activity than any previous
preparation). This suggests that coiiq)lete purification had
befin achieved without loss of enzyiae activity, and represents,,
as far as we are aware^ the first such isolation of an
enzyme protein in this manner. Insufficient material was
available from these preliminary runs to permit full
physieO"=cheraical characterization of the pure fractione and
the resignation of the principal investigator has delayed
further studies in this regard,
SicmifiCj^np^ of Prgigct ; This project represents a long
range effort to solve the analytical problems presented by
small samples available from patients with d^i^elinating
diseases. Traditional approaches and methods fail« so that
the development of new, sensitive and specific procedures
would not only be of great practical value but «fould also
permit fresh attacks on promising leads in the pathological
chemistry of derayeXinating diseases in maiic
Prpposed Cgursei The CSF studies conceived and carried out
entirely by the principal investigator are terminated owing
to his resignation^ The protein studies will b© incorporated
with suitable modifications into project «59=NIM»=» 13 (c)„
iMX I JMMii* No,
2o Ciinieal Neurochonistry
3o Beth@sda« Mdc
4o Sme as 58<=NIM)B"29Ce)
PHS - NIH
Individual Pffoject Report
Calendar Year 1959
Ai
Project Title: The Selation of Pyrldoxine (Vitamin B, ) to
Certain Seizure StateSo ^
Prieeipal Investigator: Drc, Gay Mo MeKhana
Other Investigators s Dr^ Donald S. Tower, too Edmund L. Peters
Cooperat ng Units i Dr, Olaf Mick@lsen„ NIAMD Ub„ of Nutrition-
i>ro David B. Coursin^ Sta Joseph "s Hospital„
Uncasterp Pa,
Kin Years Patient Days: 0
Total: l„6
Profess iona': Oo6
Othe.-: loO
Project )escription:
JliiSli^^: To elaborate the role of pyridoxine (Vitaaiu
%) in certain seizure states by both in vivo and in vitro
studies. "^ "^"^ '^ -5t=&=.
^^^^^^.•^ jMerial; Patients admitted to NINDB specifically
for this projects
JSIA^: Pyridoxin© deficiency can be produced in man and
e;q)erimenta.t animals by dietary means and by the use of
pyrxdoxine antagonistSo There also exists in man an inborn
error of pyridoxine metabolism manifested as >;yridoxine
dependenjyo" A similar condition may be present in the
I=straiii of mi ceo
Eegardless of the cause or method of induction of
pyridoxine deficiency, the clinical end=point is generalized
seizureso Ig jijro the deficiency can be evaluated by
determinations of levels of cerebral amino acids Caotably
glutamic and Y=aminobutyric) and by evaluation of cerebral
oxygen consumption in deficient and control subjectSo
Location of the bloek of cerebral metabolism under
these conditions ean be determined by addition of the com=
pound which is metabolized one step beyond the site of the
bloek, specifically,, Y^aniinobutyrie acid, and comparison
or the effect of its addition with those after addition of
the coenzyme form of the missing vitamin itself„ pyridoxal
phosphate,, " ^' '^w^^
CI) Studies of the original case of "pyridoxine dependency'"
were completed in 1953 Lsee 50^NIM)B=29Cc)3 and have now
been published Lsee Part B]. The essential finding was
decreased cerebral oxygen consumption in yivo during
pyridoxine depletion with very rapid restoration to noma!
following intravenous pyrldoxine, changes closely
paralleling changes in clinical state and in the EBGc Dr„
Coursin^ cooperatin with this projecte has subsequently
conducted preliminary investigations of pyridoxine
metabolism by this patient and other human and animal
SfflbjectSc His findings indicate that two defects of
pyridoxine metabolism may occur: CI) an abnormally rapid
conversion of ingested pyridoxine to 4=pyridoxic acid^
the normal urinary excretion products yielding elevated
blood and urine levels of the lattery or C2) an abnormally
rapid and excessive excretion of Ingested pyridoxine
directly into the urinOo resulting in low blood levelSo
normal output of 4=pyridoxic acidg and very high levels of
B6 con?)Ounds themselves in the urineo The pyridoxin©"
dependent patient studied here exhibits the second type
of abnormalityo and thus represents a deficiency state
secondary to ma ive urinary loss of ingested vitamino
C2) Experimental animal studies have been carried out
on weanling kittens placed on a pyridoxine«free diet
(devised by Dr^ Mickelsen) together with appropriate
litter=«i|^^ dietary controlSo Within 6 to 0 weeks deficient
kittens/progressive weight loss^ coarseness and thinning
of hair, ataxia and ultimately seizures o followed rapidly
by deatho None of these effects occur in litter=mates
fed the same diet suppleaented only by pyridoxine, and
the iseight gain curves of these controls are identical
to kittens on regular dietSo Studies of brains from both
sets of animals have shown the following;
(a) Litter=mate brain weights are identical for
deficient and diet'^control aniraalSc
Cb) Incubated cortex slices from deficient animals
show a significant decrease of Y='aJ»inoI»«tyric acid
c<aaipared to the rise observed in diet control and
normal animalSo The decrease can be reversed to
control values by j^ :gi.tro, addition of pyridoxal
phosphateo
Cc) Incubated cortej: slices from deficient animals
consume oxygen at a rate only 7^ of the rate for
control slicesp but can be corrected to control, normal
values by jjg, vityo addition of either pyridoxal
phosphate or Y^aminobutyric acido
These findings are consistent with previous studies tdiich
all indicate that in pyridoxine deficiency the production
of Y°a®inol>utyric acid in brain is rev^rsibly impaired by
deficiency of the coenayme^ pyridoxal phosphate^ necessary
-3«
for functioning of the syntfeesiaiog engyaeo glutamic
deearboxylaseo In additioa the present findings clearly
showe for the first timej that thie metabolie bloek is
associated mth reduced oxidative metabolisi&o due to
reduced substrate metabolism via the Y^aoinobotyrie acid
patlmayv in braiQo It is significant that in seizure states
due to pyridoxin© deficiencies b cerebral oxygen consisaption
is reduced (even during seizures) in contrast to the usual
finding of elevate*,^ oxygen coasiaaption during seizures
and normal consumption iuter°ietallyo
Si^gi^cgagg, M, ?.K9l^%' The ro|.e of the 'yfc'aainobutyrie
acid shunt pathtmy in cerebral oxidative isetabolism is
discussed in a ecsapanion project [see 59<«OTI®B"3 (c)3
This pathimy accounts for some 40^ of total cerebral
oxidative metabolism and an even higher proportion of
neuronal oxidative oetabolisma Studies on pyridoxine
metabolists and function ^^hasise that the maintenance of
this metabolic pathway is essential for nonaal neuronal
functioning i^ ^;mM, ^^^ ^^^t its derangeaent results in
neuronal hyperactivity and seizureso
PropQsecf !^ow,^P°' "^^ dietary study on kittens is coa^jlete
and in process of preparation for publicationo Further
studies on pyridoxine dependency states will be conducted
utilizing additional patientSg as available, and the I<»strain
of mice.
Pagl s iflgindM; Yesc
Serial Noo!E^5rliil>
PHS - NIH
Individual Project Report
Calendar Year 1959
Payt B;
Pub^i^3,tipns:
lo Sokoloffo Loj Lassen^ Nc Ao, McKhannj Go IL^ Tower„ Do Dc,„
and Albers« l-'o
Effects of pyridoxine mthdratral on cerebral
circulation and metabolism in a pyridoxine^def^endent
childo Nature ,173; 751 (1959)o
2o ?4cKhann, Go Uo, AlberSo So Wo, Sokoloff^ U,
Mickelsenj Oo and Towero Do Be
The quantitative significance of the ganma«'
aminobutyric acid pathway in cerebral oxidative
metabolisfflo
In RobertSo Eo CEd<,) Inl^ibition in the I'^enyqus
System and ,Y°Aminobutvric Acido London , Pergamon, In press
3o Towers 0° Bo
Ne^rochemistrv of Epilepsy: Seizure Mechanisms
and 61anaqeiiient.o Springfield,, Thomas „ 1959o
Honors ^nd Awards s None^.
NINDB°l2(c)
Serial N0o<=»==«==»=««=>==~=*=~='
lo ffedical Neurology
2o Clinical Neuroehanistry
3o Bethesda„ Md„
4o New
PHS « NIH
Individual Project Report
Calendar Year 1959
Pj5^ A:
"project Title: Isolation^ Fraetionation„ characterisation
and Metabolism (Synthesis^ Turnover, etc,) of
Ribonucleic Acids in BraiOo
Principal Investigators: Dro Michael Sporn and DTo VJesley
Dingman
Other Investigators: MTo Edmund L„ Peters
Cooperating Units: None
Man Years: Patient Days: 0
Total s 0
Professional: 0
Other : 0
Project Descriptions
Oblectiygg: To carry out detailed studies of the
characteristics and metabolic activity of cerebral
ribonucleic acids (RNA)c
%tho,d^ ; Isolatioa„ fraetionationj and characterization
of brain BM will be carried out by tissue ultra«
centrifugation using density gradient methods,, chemical
and chromatographic dissoeiation and fractionation
procedures will then be applied to ultracentrifuge crude
fractions o Behavior of brain RNA fractions under various
of these procedures will be compared with similarly
isolated liver SNA as an initial approach to characterization.
Metabolic aspects will be studied utilizing carbon«14
labelled precursors and components of BM to yield
information on RNA synthesis and turnovero Rtach of the
foregoing has been applied to RNA of a variety of biological
materials by a number of investigators with success but
little has been done on brain RNA to dateo
Peitignt, Material ; None^
Mai or Findin^^; This project i« to be activated in July
1960 when the principal investigators come on duty in this
laboratoryp .
Siqai,fiQ,a?ce of Project: Numerous studies mostly by
cytological techniques have established (1) that brain
RNA is very actively turning over^ C2) that neuronal
activity oan markedly alter amounts and characteristip^
-2-
of brain RKA, (3) tbat & '<^arietf of toxic agests
affect RNA in brsiin priraiiril^, and (4) that a
ataaaiber of vital processep in celular aetabolism
Cnotably protein s^i&tfees'.Ls) depend on brain
RNA. Tb® strdie^i propos4^d here represent a
beginning in a sic ire detained approach to the
understanding of these facets of brain RNA.
Course: T© i®p3.®3eeK.t the proposed
Part B Vncluded: !!>.
Serial NooiEI^SliliiL
lo Medical Neurology
2o Clinieal Neurochemistry
3o Bethesda„ Md„
4o 58-NIM3B=34(c)
PHS « NIH
Individual Project Report
Calendar Year 1959
P^yt Ag
Project Titles Cerebral Protein Metabolism and Turnover in
Tissue Slices incubated Jn j^i|£go
Principal Investigator: Dro John L„ Wherrett (Guest Worker)
Other Investigators; DTo Donald Bo Towers MTp So L. Peters
Cooperating Units: Dro Heinrleh Waelsch^ New York State
Psyehiatrie Institute
Man Years s Patient Days: 0
Total: io5
Professional" lo3
Other J 0o2
Project Description:
Objectives,: To determine whether slices of cerebral tissue
will incorporate labelled amino acids into the protein
fractions of these tissues during incubation ^ yitro
andj if so^ to study rates of incorporation^ turnover and
factors affecting them in san^Xes of noxiaal manmalian
cerebral tissues o
Jiil2d£' See previous report and Efeijor FindingSo
Patiep^ ji^l^erial; NonSo
Jlijcty Findinag.:
(1) The hog pancreas enzyme of Barry was found unsuitable
for enssyraatie hydrolysis of th© isolated protein fraction
and the use of mixtures of pure enzywes (trypsin,, etCo)
«»as equally snsatisfactoryo Howevero pancreatin PJF CViokase)
was fownd to give very satisfactory and reproducible results^
C2) After cat cortex slice incubation,, free amino acids
isolated in the TCA^soloble fraction gave quantitative yields
comparable to previously established free pool levelSo The
pure protein fraction obtained averaged 3% of the wet weight
of the sac^ileSo in accord with numerous previous analyses
by otherso Acid hydrolysis of the proteins yielded total
glutamate (glutamic acid 4- glutamine) of 73 ijWIOO rage
proteins and total smide analysis yielded 55 /-Wl(X) mgo
proteinso Analysis of the ensyme hydrolysate of the slice
protein fraction yielded regularly 55=6^ of the total
rflMtaraate v^liins obtained by complete acid hydrolysiSo
a yield consistent with a niasber of previous reports by
otherso Correcting these yields to the total content, the
following normal values for protein bound amino acids in
incubated cat cortex slices were found: glutamic aeid 43,
glutamine 30, and asparagine 25 iM/lOO mg, proteino
(3) Incubation of slices with !>glutaraine-D=C and
isolation of free and protein°bound amino acids for
quantitative assav and C^'^=<5ounting^ demonstrated in«
corporation of C into protein=bound glutaBine^ the
3A being about Oo5% the SA of free pool glutamine„ This
finding is of the same order of magnitude reported by
Lajtha^jio for ineorporation of various C^'^^araino acids
into eerebral proteins ^ vjjgOo
(4) Slices incubated with 40 raj raalonate (which markedly
elevates free glutaisie acid [Cfo 59=NINDB= 1 tc)]>
exhibited a significant decrease of protein~bound glutamine
with a coB5)arabie rise in protein=bo«nd glutamic acido
Similar experiments with 10 ag NH4C1 C?*ieh markedly
elevates free glutamine and depresses free glutamic acid)
exhibited a very striking rise of protein bound glutamine
with a coi^arable decrease of protein^bound glutamic acid^
Slices from animals with methionine sulfoximine induced
seizures (where free glutamine synthesis is almost totally
inhibited) exhibited normal protein=bound glutamic acid
and glutamine levels,, These data^ together with the
apoarently slow turnover rate of protein glutamate shown in
C^^ studie^t suggest that a portion of cortical proteins
is involved in an active amino group transfer process with
amino acids of the free pool, utiliasing primarily carboxyl and
amide groups on protein glutamic acid and glutamine
respectivelyo Hie raetaboli© and functional implications of t
these findings may have great fundamental ic^ortaneep
Significance of. Project; The experiments to date indicate
the feasibility of studying a number of aspects of cerebral
protein metabolism by the use of incubated slices in yi^rp..
Several invest! gators,, notably V^aelseh„ have proposed that
cerebral proteins may participate in amino nitrogen
metabolism, and liaelsch and vje have jointly evolved a^
concept that the transfer of amide from protein glutamine
to free glutamic acid may be important to neuronal activity
as well as metabolismo The integration of oxidative
metabolism Tin Y=aainobutyric acid with these aspects may
provide the missing link between -v^amlnobutyrate^glutaraate
dysfunction and seizures^ And the findings with PH^Cl
have very obvious bearing on both the seizures and hepatic
coma aspects of cerebral ammonia toxicityo Here the
connections betwesn structure and metabolism and between
'jjstabolisK and functional acti^fity are finally beginning to
emerge^ so that evantual integration of these various facets
of ^cellular biochemistry may b© possibl@c
Proposed Course; To cont nue the above studies and tc
extend them to"°aspartic acid,, with the use of other C*
labelled amino agidSc and vdth the use of N^^^labelled
gliitaraine and N^<=aRanonia,
£Mt.Si§SMM» Yeso
Serial No»?™B»l3(c)
PHS - NIH
Individual Project Sepoft
Calendar Yaar 195<?
Part B;
Publications;
1, Totwr, Do B,
Scote neurochemical aspects of cortical
neurobiologyo
In SehadI, Ja Po and Tower, Do Bo CEdSo)
^tryeture _a_n,d FHSfijioa of JJ?e Cgrebggl £ot^^
(2nd Internato Meeto NeurobioLo)„ Amsterdam,
Elsevier„ In press o
Serial Mo, NINDB-MCc)
1» M®«lical HQurology Bs-aach
2, Sectioa oa Neurological
Disorders Service
3. Bethesda, Marylaad
4o CoffitiBuatioa of IflHM-lSCc)^
1958
PHS-MIH
Individual Project Report
Calea^ar Year 1959
Part k.
Project Title: Tli® Histopatfeological aad Chemical
Investigations of Neurosiuscular
Disorders o
Principal Investigators: G, Milton Sh^
Thcodor Wanko
GuiLter Haase
Man Years:
Total: 4,4 Patient Days: 3,768
Professional: 2c8
Other :■ 1 = 6
Project Description:
OBJECTIVES:
This is a continuation of the long-tera study
initiated at th® inception of this Institute, Over
the past years these studies have elucidated th®
pathology of nuscle disease 3 the role of certain
cations and contractile proteins in muscle disease,
and at th© ti®e of the 1958 report we had finished
a prolonged study on the endocrine and Kstaholic
aspects of Muscle disease « During the past year at-
tention has been paid largely to regeneration of
ffiuscl© in the various neurogenic and priaary muscle
disorders ,
An inclusive study of the prinary pathology
of peroneal auscular atrophy has just been concluded
and th© final studies of the various interrelated
factors in cat ionic paralysis have been concluded,
-2- Serial WOo HINDB-MCc)
METHODS BMPLOYED:
To follow regoneratioffi of aaasclsj, tritiua
labelled thymidine has been used in sone 20-odd
casses of different neurological disorders ^ and auto-
radiologf is now underway on these sections. Pro-
liferating cells will manufacture mtAg and in doing
so incorporate the labelled thiwidine. The low
energi^ range of tritiua allows precise localisation
of such DHAo The cat ionic disorders were studied
in relation to thyroid seetabolisSg to K-42 exchange ^
to aldosterone by means of double isotope deri'^a-
ti^^e @@thod3f, and to the relation of pharmaceutical
agents such as SC^^SlOSj, a steroid-17 lactones and
2-ffiethyl-9-alpha-.fluorhydro cortisone j, which de-
liberately shift monovalent cations. Sodium and
potassiua were studied by flaai* photo®etry» and
chloride by the Cat love technique,
Eighteen cases of Charcot-Marie-Tooth disease
were studied after the pathology had revealed an
initial impression that a primary disorder of auscl®
in addition to a disorder of nerve was present in
this dis@ase. This was controlled by a series of
15 cases of assyotrophic lateral sclerosis ,
MA JOE FIEBIEGB:
Q^®T SO percent of cases of Char cot-Marie-
Tooth disease demonstrate myopathic findings on
pathological examination o Mo such findings were
found in cases of amyotrophic lateral sclerosis ^
Two of this series are clinically classical ^ but
demonstrated only myogenic changes. Eighty perc«it
demonstrated sos^ myopathic involvement „ whereas 100
percent of the cases of amyotrophic lateral sclet-'osis
showed only neural involvei^nt <.
In the cationic diseases 9 three separate en-
tities have now been segregated which may cau?« sud-
den flaccid skeletal paralysis. These are: il}
familial periodic paralysis; (2) paramyotonia con-
genita; and C3) primary aldosteronism . "Hi® patho-
physiology and treatment of each is different. In
familial periodic paralysis there is a retention of
potassium and sodium. There is a hypokalcs&ia. Such
-3- serial NO. NIMDB-MCO
pot&s&±%m lost fro@ tM® ses-ii^ mnt®T& th® c@ll.
iKo^lb water ds&ters the c®!!^ liowe^srs, to hold
the coi&c@&tS'atioiti of potassi%isi appro%iaat®ly the
asms. Sodium depletioia aidi» im th9 recor®?^ of
the attach c or prevents the ossset of esseh aa at-
tack. Sodlim loading precipitates the attack.
The adasiaistratioa of d->l aldost@ro§i$ does not
initiate a& attack. Carbohi'drat© iisitiates the
attack 0 as has b®ei% long kaowno Exactly the re- -
verse is true for paran^otos&ia cosgsnita^ al-
though also in this disorder d-X aldosterone does
Qot precipitate an attack. As noted In the 1958
reports catio£&ic K coaceiitratio&is withi3& the cell
were coaf irgsed &y reatiag poteatials ohtaiaed by
intracellular microelectrodes o
The stiidies on regeneration of 'muscles bf
use of tritium labelled thfmidi]g@ siust await a
three-months' film escposur® l^fore the autoradio-
graphs w^f he read. A study o-l the mitachoadria
isi familial periodic paral^is will he uadertakea
ora appropriate sectioiss by Br. Wai&ko with the
electron ssicroscope.
PROPOSED COURSE OF TIB PKOJICT:
Muscle disorders ^ill coatinue to occupy
®uch of the time of the Medical Neurology Branch
in that so Bsaaj different paraasters of investi-
gation Kay be brought to beas' on this readily
accessible material.
smmFicmcE to IEIIROLOGICAL EBSEASCH;
O^er the past seven yea^s this Institute
h'm clarified sany of th© probl^is associated with
disease of striated mascle which constitutes 80
percent of the body eiase. Su^h initial promise
Justifies continual research In these fields.
Part B included: yes
Serial Mo. mEQB^lMc}
PHS'MSE
Iffidividwal Project E®port
Cal@K&<lar Tea? 1959
PajptB: Hoaors^ Awards ^ aad Publicatiosss
Publications other than attracts from this Project:
Haas® J, G.« amd Shy^ Q^ M, The Pathological Basis of
Peroaeal Atrophy o £ia preparation.
EowleiTp Po To, asid llimasip B. The Sffect of Sodiiin
Loadiog and Depletioi^ oq Musculas: Strength and Aldo-
sterone Excretiois in Faailial Periodic ParalfBis.
An. Jnle of Med., In Press.
Shy, do Mo SoBie Metabolic and Sudocrinologic Aspects
of Disorders of Striated Muscleo Proceedings of the
Assoc c for Research in Heriroiis azid Mental Diseases j.
December » 1053. In Press „
1, Medical l^rblbgy ' Irazich
2, S®ctioi& ou Heurological
4o Coffitinuatioffi of MIHDB-lSCc)
PHS-HIH
Individual Project aapofft
Calendar Yea? 1959
Part A.
Pro-ject Title: Th© Physiologi' and Pharaacolog^
In Mf aetteonia Gravis
Priacipal lavestigator: Go Milton SSay
Other Investigators: Andrew Ssgel
Mark Lane ■
Williim Matthew
Man Years: Patient Days: ^^l
Total: 4o4
Professional: 2o8
Other: i„6
Project Description:
OBJgCTI^S:
As stated in last i^ear's Aimual Report,
the aain objective was that of intracellular
recording of resting potentials ia patients
with siyaetheaia gravis. The difficulties of
this procedure were pointed out i^ the last
Annual Report » in which a description of .the
percutaneous method of introducing micros lec-
trodes blindly inside single cells wa® given.
Approximatelf 18 such patiecits were studied
in the current fearj, with over 200 penetrations.
It ha® becoae apparent that^ with our present
technique at leasts we will £iot h® able to suc-
cessfully carry out this procedure through the
intact skins and that such patients say have
to have surgical exposure of the muscle to
carry on such a study. This phase in the pro-
grajs^ hence ; has been tei^porarily abandoned.
It is of interest that this progras^^ like many
others J has now separated into two different
-2- Serial Ho, MIMBB-lSCc)
coaiponesits . First, the availabiliti" of agents
which iKfiuence thyroid format ioza and TSH for-
siatioffi, as Well as stethods of intln®nc±ng iQde-
pendentlf, has allowed the Uait to aake aa ex-
tensive stud^ of the profeles uhich has ioag
baffled neurologists, i.e. the relation of thy-
roid laetafeolisB to myastheaia gravis. This
facet has been well worked out by Dr. \Edrew
£ngel; and will now be recorded ±& a separate
project.
At tb® begimii&g of this reporting year,
the Institute was fortunate in having with it
for & period of one sooth 5 I>r. Fritz Buchthalj,
and the Copenhagen aiethod of electrosgyography
is now beizig extensively used within the Branch <
The recording ix^trusentation for the intracel-
lular work in ayasthenia gravis has been con-
verted therefor® to this particular projects
which will be referred to in succeeding Annual
Reports as the electrophysiological abnormaliti^
of muscle disease.
MEfHODS BMPLOYSD;
Multiple concentric electrodes were
utilized in these studies so that synchroaiaa-
tion and motor unit areas i^ay be snapped 0 Studies
at the present time include a study of the in-
ternal ocular Euscles ia a^tagaus in coopera-
tion with the Ophthalsologicai Unit^ which is
just now teeing initiatfe-d. Of interest is the
fact that the characteristic response of eyas-
thenia gravis has sow been seen in over 60 per-
cent of patients with generalized sarcoid dis-
ease. The reason for this is still not clear »
but is being followed at this ti^e. The duration
of the action potential in varying groups of
muscles at different ages of patients which as
yet are not charted is being undertaken by the
Fellow assigned to this project. A direct cor-
relation of the mSQ with the miscle pathology is
continually carried out on each patient adad.tted
to a auscle project in this Institute.
-3- Serial Ho,. 11
COUESE OF THE PROJECT:
This will l>e a long-term project ^ co&tiQU-
ing probablj^ for tk@ duratiosi of admissions of
patients with aeuromiscular disorders »
SIGHIFICAHCETQ THE PECXjRAM:
Electrosi$rography has fallen in disrepute
in aiost aedical centers in the Uiaited States to-
day. This Institute is convinced , after analyz-
ing moms 110 of our own patients and the Copen-
hagen study^ that this conclusion was s'eached be-
cause such studies were not carried out with the
pathophysiology of the various disorders in i&ind„
It is our belief 9 after this series of patients »
that the EMG is of definite value when correctly
done and interpreted^ and has ^sany tines given
us information of real iaiportance in the understand-
ing of our patients.
Part B Included Ho
Serial NOo MIHUa-ieCc)
1. Meislical Heurologf Braach
2. S@ctioEa on Biophysical
Applications
3. Bethesda^ Maryland
4. Saae as !ilNI>B"12Cc) , 1958
Individual Project Report
Calendar Year 1959
Part A„
Project Title: Clinieal Patliological Correlative
Study of the Hervous Systen in
Orthostatic Hypotension.
Principal Investigators: Glenn A, Brager
G. Milton Shy
Man Tears
Total: 2.2 Patient Bays: 37
Professional : 1.4
Other: 0.8
Project Description:
OBJECTIVES:
To study a series of patiesi^ts ^ith uncom-
plicated orthostatic hypotension in which no gen-
eral asedical disorder such as dial»etes, syphilis j,
or other systesiic diseaise is to be found. In
such cases the nervous system is always involved.
Controversy's at the present j, escists as to whether
the nervous systea pathology is primary or secon-
dary to the neurological findings. The presence
of a given reproducible syndr<»i^ of the nervous
systea associated with hypotension would be an
arguaent in favor of the nervous gystea disorder
as the etiological agent; provided the areas of
involvement were not synonyaous to those induced
by hypoxia, or^ upon postaortea esaaination, re-
veal multiple vascular lesions.
-2- Serial NOo HlMPB-°I6Ce}
PATIEirr SATEEIAL:
Four patients ^ith sui identical sjmdroise
have now been ac^itted to tfeis study 9 and ccaaplet©
serial sections have now been obtained and studied,
on the case reported in the 1958 Annual Report.
METHODS EMPLOYES:
Fixation was as descrilied is the previous
Report o Bepresentative serial sections of the
central and peripheral systea were prepared in
the usual nanner and stained or impregnated with
heaatosf^lin and eosin^, cresfl violet » and by the
methods of Eolzerg Holies ^ Cajal's gold subliis-
at©5 Sasith-Quigleyj Sudan lY^ Bielscfeowsky,, and
Penfieldo Pathological reports fro® patients
dying subsequent to hypoxia and chronic ischemia
were reviewed and ccmpared, la addition the
prisat® work of the Laboratory of Anatoaical
Sciences on fetal hypoxia were reviewed and coa-
pared.
MAJOE FimimS:
Abnoraal neuronal changes were found in the
v#ntralj intemediolateral ^ and Clark's cell co-
luians of the spinal cordo Moderate gliosis was
also present and most evident in the dorsal funicu-
lus o
In the Esedulla degenerative changes of the
inferior olives ^ nucleus aabiguuso the doxisal
nucleus of the vagus ^ the sadiun Raphe of the teg-
mentum!, ^1^^ the lateral cuneate nucleus were found.
In the cerebellusi and pons« neuronal changes
were found in the Purkinje cells and locus caeruleus
of the ponso
In the midbrain., lesions were found in the
Bul^tantia nigra ^ the third nerve nucleus ^ the
Edinger-Westphal nucleus j, and the central aqueduc-
tal gray.
Serial Ko, KIlBB-16Cc)
la the dieacephaloB sosa changes were
jfouad la the posterior hypothalamiit ^ and ia the
intercalated nucleus of the saanilary body.
Changes vere also found in the caudate nucleus;
the cerebral corte:^ was aomal.
It would thus appear that the lesion in-
volves almost exclusively autononiCg, basal
ganglionic s and spinal notor cells g, and that
this lesion is synMtrical and does not corres-
pond to ischesfiia or anoxia ia the adult c
SIGWIFSCAHCB TO HEUROLOGICAL RESEARCH;
It is highly suggestive ia these studies
that so-called orthostatic idiopathic hypoteasion
is in fact a degeaerative disorder of the central
aervous systesp involving the above centers « and
could be corresponded to the so-called ootor
disease long recognised as a system dis-
PROPC^EP CODRSE;
These findings are to be published.
Part B Included Yes
Serial lo, JIM^MlSl
PK - Mil
iBdividual Project Report
Pagt B; lo©02?Sg Awards j, aad Pulalicatlon©
Publication® otli©^ tliaia absticactis froB t&is
Project:
1. Bragerj ©« A. » amd EhYs ®. M. A B©-
sociated witii Orthostatic Hfp&t®B3ioi&.
To to© FuWisfeed
Serial NOo NIHDB-17Cc)
1 o Medi cal Neurology
Clinically Applied
Pharmacology
Bethesda, Mdo
Continuation ol NINDB-23Cc)
PHS-NIH
Individual Project Reports
Calendar Year 1959
Part A,
Project Title: A study of naturally occurring
choline esters.
Principal Investigator:
Other Investigators:
Cooperating Units:
Bichard Lo Irwin
Jay Bo Wells and
Andrew G. Engel
None
Man Years
Total
Professional
Other
(calendar year 1959)
lo2
0o6
0o6
Patient Days: 0
(calendar year 1959)
Project Description:
OBJECTIVES: An increasing number of choline esters
are being identified as natural constituents of
biological systems o The physiological significance
of choline esters other than acetylcholine is
largely unknown,, Pharmacological data is not
prevalent o The objectives of the present study are;
(a) ?o study the action of choline esters and
chemically related substance on muscle membraneSo
(b) To isolate and identify choline esters or other
quaternary compounds which may be present in bio-
logical systi
- 2 -
METHODS EMPLOYED; A traveling I'luid electrode
technique is used to measure depolarization of
muscle membraneso The techniq^/e has the advant;<j;e
of recording the differential cepolariawition of
a large number of intact muscle fibers ^ and
provides a convenient means to determine whet'*er
chemical substances depolarise post-synaptic auscle
membranes. Although the metnod is not enti^'ely
quantitative, it does allow s^miquantitat?*^® com-
parisons of the depalarizifig potency of vArious
drugs to be made. The method also perm:?cs the
observation of the time course of depolarization
of an intact whole muscle; thuw havino advantages
in this respect over a microelectrodc' techniqueo
Paper and colurai^ chrirmatogrAphyare used for
isolation and identificaticA of caoline esters
and other quaternary compoiids.
The heart of the cUm venous mercenaria
is used for identificatiop and assay of acetylcholineo
This method is being adapted to the search for
other active compounds «
MAJOH FINDINGS; Comparisons of the natural occurring
choline esters and othe; depolarising compounds have
been made using frog muscle and the fluid electrode
technique o It was fou'^d that accurate concentra-
tion-response relatlor.shipg could not be obtained
sincv^ one depolarization reduced the sensitivity of
subseviuent tests ard test muscles varied considerably
in their response. By selection of a narrow range
of depolarizatiof. to be produced and the use of on©
muscle far each test a comparison of the potency was
possible, Butyrylcholiasj imadazoieacrylylcholine
and dihydro-acrylylcholine are nera-ly equal to
succinylcholines, (a neuromuscular blocking compound)
in depolarizing strength o This .'Appears to indicate
that if choline esters which are not hydrolysed by
muscle choliaesterase, as is acetylcholine, were
present in muscle in abnormal amounts pronounced
effects on muscle function could occur,, The identi-
fication of @uch a substance ±u diseased muscle
would require the use of small muscle samples*
Recent expera.ments indicate that acetylcholine can
be assayed from muscle samples as small as one gram.
.. 3 -
Ssperiiients ±n which excess acetylcholine was
added aiiowed recovery of the excess o It thus
may be possible to identify other less labile
choline @st@r@ from miiscle if they were present
providi)tj adeciuate tests can be developed.
Present experiments appear to indicate that low
concentxs.tioB3 of active choline esters affect the
response of (the venous mercenaria heart to acetyl-
choline o This may offer a new approach to the
identification of choline esters in physiological
syst<
SIGNIFICANCE TO THE PRO^M OF THE INSTITUTE:
Information ccticerning the biological activity of
substances whf.^h occur in animal tissue greatly
enhances our l^:iowledge of normal and pathological
physio logy o
PROPOSED COPRgj; OF PROJECT; To continue to study the
biological ef:'@cts of choline esters and to attempt
to isolate ani identify these compounds from tissue »
Part B included: NOc
Serial Noo NINDB-18Cc)
1 o Medical Neurolojgy
2„ Clinically Applied
Pharmacology
3o Bethesda, Md.
4o Continuation of NINDB~22Cc}
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A,
Project Title: Study of muscle cholinesterase and
its inhibitors o
Principal Investigator: Richard Lo Irwin
Other Investigators: Henry Jo Smithy III
Cooperating Units: Laboratory of Chemistry of
Natural Products s National
Heart Instituteo
Man Years: (calendar year 1959} Patient Days: 0
Total : lo2 (calendar year 1959]
Professional : 0 o 6
Other : 0,6
Project Description:
OBJECTIVES; The cholinesterase content of muscle
is low and not uniformly distributed throughout the
tissue. Muscle has therefore not been adequately
studied in respect to either the type of cholin-
esterase it contains or as to substrate and inhibitor
specificity. As August insson has recently pointed
out (Method in Biochwnical Analysis > 1957^ , the
results obtained with inhibitors and substrates
are dependent upon the enzyme preparation used,
both species and organ specificity being of Im-
portance » In view of these considerations, one of
the objectives of this project is to adequately
characterize this important muscle enzyme as to
substrate specificity. Another objective is to
examine the activity of the enzyme in the pi
of the well-known inhibitors which are in wide
.- 2 -
clinically and to correlate this activity with
their usefulneuso This would form a basis for
testing newer compounds having a potential in
the treatment jf myasthenia gravis o A further
objective is to determine the inhibitory and
depolarizing activity of compounds either used
or proposed as \iseful agents in the treatment of
myasthenia o
METHODS E^LOYED. The Standard Warburg mano~
metric technique is used for determination of
muscle cholinesterase activity. The depolari-
zing properties ol cholinesterase inhibitors
are determined by vse of the traveling fluid
electrode system us3d by Fatt , J<, of Physiol^ 9
111: 408 „
MAJOR FINDINGS; In the course of this project
the clinically useful therapeutic agents used
in the treatment of myasthenia gravis ha.ve been
studied to determine whether a correlation exist
between clinical efficacy, inhibition of muscle
cholinesterase and depolarization oi muscle mem-
branes o Ambenoniiua was found to hfive the great-
est inhibitory activity on muscle cholinesterase
of any of the compounds testedo Neostigmin has
greater activity in this respect than pyridostig-
min and also has musscle membranes depolarizing
effects which pyridostigmin lao^s. Thus, since
pyridostigmin does not depolarize muscle membranes
appreciably and has a lower ir;hibitory potency
than other useful coAapounds, ao direct correla-
tion exist between clinical use^ muscle cholines-
terase inhibition and depolarization of muscle
membranes 0
A major part oi' the work this project has
centered around the tasting, both in yiyo and
in vitro ^ of compounc's which seemedTikely to
Have a potential use in the treatment of myas-
thenia gravis and poosibly other neurological
disorders. Galanthamine is an alkaloid that has
recently been isolatsd from the bulbs of Amary —
llidaceae plants in laussia, Japan and in this
country by the Laboratory of Chemistry of Natural
- 3 -
Products vif th© Neeionai Heart Institute..
Lycoramiae is aa *ilkaloid with a chemical
structure closely related to that of galanthaminep
We have investigated these compounds and several
related derivatives ajs to their muscle potentia-
ting and acetylchc inesterase inhibiting propertieso
These compounds ari derivatives of phenanthrene
and are of interest because chemically they differ
markedly from the other compounds currently in use
for tha treatment o.- myasthenia gravis., The com-
pounds tested were galanthamine hydrobromide,
galanthamine methyl Iodide 9 lycoramiiie methyl iodide,
deoxylyooramine methyl iodide j deo^.-demethyl-
lycoramLn© methyl iocidej neopine and neopine
methyl ;lodideo
The quaternary forms of the alkaloids were
found to be more activs in muscle than the tertiary
forms o Lycoramine methyl iodide produces about the
same amount of inhibition of cholines; terase. as
pyridostigmino Galanthamine , both the tertiax*y and
quaternary form, produces more inhibition than does
pyridostigmin or edrophoniumo Deox^-demethyl-
lycoramino methyl iodide was the most active com-
pound foundo This coiapound produces cho lines terase
inhibition equal to that of neostigmin or pbysostigmine,
The in vivo muscle potentiating activity of the com-
pounds li'well correlated with tlia in vitro muscle
cholinestexas© inhibiting activity.. Plasma, red
blood cell and brain cholinesterase is also inhibited.
The potency of these compounds suggest the possibili-
ty that they may be cf value in the treatment of
myasthenia gravis. Whether tliese compounds will
offer advantages over the therapeutic agents now in
use for the treatment of myasthenia will depend on
toicicity studies and clinical trials Galanthaalne
hydrobromide has received such trial in the USSR
and more recently in Sweden o The biological activity
and use of lycoramine and deoxy-demethyl lycoramine
has not been previously described,, A recent mono-
graph from Russia ciescribes the use of galanthaalne
hydrobromide in a neurological disorder, "Cerebral
Paresis in Children and Its Treatment", IS, Bo Bydinovfi
and E, Nc Pravdina, Publisher: Academy of Pedagoglcsl
Society of the RSFSR , Institute of Defectology,
MOSCOW;, 1959,
- 4 -
SIGNIFIGA??CB TO THE PROGRAM OF THE INSTITUTE;
This project relates to the development and testing
of clinically useful drugs for the treatment of
myasthenia gravis o
PROPOSED CQgRSE OF PROJECT: To perform toxicity
studies on the most active compounds of the group
of alkaloids mentioned above to determine whether
clinical testing is feasible or desirable. Other
active compounds are being considered for pharma-
cological testing.
A rapid j sensitive and graphic method is
being developed for determination of muscle chol-
inesterase in order to facilitate the study of
Its inhibition. A more purified muscle esterase
preparation will be studied as to substrate speci-
ficity and compared to a purified acetylcholinesterase
ob:ained from other tissues.
Part Bo Included; Yes
Serial NOo NIHDB-18Cc:
PHS-NIH
Individual Project Report
tgtlendar Year 1959
Part B; Honors, ..wards, and Publl -^^ions
Publications other ts.an abstrac <3 from this project:
In press: "Cholinester.se Ic^ibition by Galanthaa&ine and
Lycoramine''o Richard L, iTvin and Henry J. Staithg IIIo
Biochemical Pharmacology,
Honors and Awards relating t this project: \ None
Serial No„ NIHI3B-19Cc)
1 » Medi cai Neurology
2o Clinically Applied
Phasrmacology
3. Bethesda, Mdo
4, Cosstinuation of NZNDB-24Cc)
PES-NIH
Individual Project Report
Calejidar Year 1959
Part A»
Project Title: A istudy to determine the effects
of depolarizing drugs on muscle
enzymes.
Principal lEvestigator: Richard Lo Irwin
Other Investigators: Henry Jo Siaithj III
Cooperating Units: None
Man Years: (caiendar year 1959) Patient Days: 0
(calendar year 1959)
Total :
Oo8
Professional :
0»4
Other :
0o4
Project Description:
OBJECTiysS; To determine whether depolarization
of muscle "Sembranes effect the eff Iiuc of enzymes
froja muscle c
MBTKODS EtiPLQYEp: Standard biochemical procedures
are used to estimate enzyme activity in plasma and
muscle.
Mammalian in vivo escperiments using pairs
of muscles are utTlizeS~'in both experimental and
control procedures.
A traveling fluid electrode procediire is
used in isolated muscle experiments to determine
that muscle maabranes are intact during experi-
mentation o
- 2 -
MAJOR FINDINGS; Muscle loses aldolase when kept
in a solution containing depolarizing concentra-
tions of potassium. It has not been determined
whether the depolarization of cell membrane is
the causative factor ^ or whether the loss of
enzyme is due to the activity of potassium at
another site. Even less is l&nami about the
effluK of other enzymes from muscle, although
it has been observed that certain of themj,
phosphohexoisomerase^ transaminase and lactic acid
dehydrogenase, are present in the plasma in increased
concentration in muscle dystrophies o Plasma con-
centrations of these enzymes, and aldolase, are not
increased in muscle atrophy of neural origiUo
Laboratory, and particularly in vivo experiments
in this area 9 are notably few.,
To date we have attempted to determine
whether aldolase leaves the muscle under the in-
fluence of succinylcholine , a compound which de-
polarizes frog muscle membranes rapidly at a
concentration of 3x10-%., Experiment® were done
on pairs of rat muscles removed prior to and after
the administration of the drugo Changes in the
aldolase content of the experimental muscles were
variable and not pronounced at the end of brief
periods of depolarization. Additional experiments
are needed to determine if significant changes in
the aldolase content of muscle occurs during drug
depolarizationg
We have found that substances which depolar-
ize muscle membranes also inhibit muscle cholinesteras
Inhibitory concentrations are much greater than those
necessary for depolarization, and thus esterase in-
hibition by these compounds appear to be unrelated
to their depolarizing activityo
SIGNIFICANCE TO TEE PROGRAM OF THE INSTITUTB; The
efflux of enzymes from muscle due to the action
of a drug would be a new finding in drug action
which may aid in understanding abnormal states in
muscle,
PROPC^ED COURSE OF i^pJECT; To continue to invest i-
gate the conditions which Influence the movement of
enzymes out of muscle.
Part Bo included s Ho
Serial NOo NIN!B--20Cc)
1, Medical Neurology
2c Cliaically Applied
Fhannacology
3o Bethesda, Mdo
4. New
Individual Project Eeport
Calendar Year 1959
Part Ao
Project Titlei The localisation of muscle fibers
in a single motor unit.
Principal Investigator: Richard L. Irwin
Other Investigators: Forbes H. Norris, Jr.
Cooperating Units: None
Man Years; (calendar year 1959) Patient Days: 0
Total : 0.8 (calendar year 1959)
Professional: 0o4
Other : 0o4
Project Description:
OBJECTIVES: The interpretation of muscle actlor
potentials obtained by electromyographic recording
is handicapped by a lack of knowledge as to ■f-ae
exact anatomical distribution of fibers of t single
motor unite The objective of this project is to
develop suitable methods and to study the anatomical
distribution of the fibers of a single mrtor unit
and its electrical activity.
ISETHOps mmjyma The project is in an early stage
and changes in the experimental procedure may be
necessary. Bat preparations are in ure; the study
will be extended to cat. Single motor unit pre-
parations have been achieved in acutci experiments
by many workers; chronic single imit procedures
should also be possible o The work cf Eccles 8t
Sherrington in 1930 establishes the anatomical basis
-, 2 -
for this study. Anterior rami of fused roots
are isolated for se¥@ral lumbar segments o By
microdissections the middle ramus is pregressively
divided vmtil only one^ or a very few fibers reioaino
The rami above and below are resected. Histolo-
gical studies of roots, nerve and muscle will be
undertaken in order to chart the extent of sub-
sequent degeneration o Evoked electrical activity
will be recorded by conventional methods to de-
termine anatomical electrical relationships a
ilAJCai FIHDINGS; None
gIGNIFICAKCE TO THE PROGRAM OF THE IHSTITOTB;
This study, admittedly facing a difficult technical
problem, if aiccessful will provide a direct
correlation between anatomical and electrophysio-
logical areas of the motor unit. It might thus
have some bearing on clinical electromyographic
studies 0
PROPOSED COmi??E OF PROJECT: See Methods
Part B included: Ho
S@rial Noo N£NDB~3lCc)
'u Medical Neuro
i;„ Clinically Applied
Pharmacology
i>o Bethesda^ Md.
<u Continuation of NINDB~2lCc>
PHS-NIH
T^dividual Pjpoject Report
Calendar leux 1959
Part Ac
Projec\ Title; TMe action of neuromi&@cular blocking
di'ugs on directly stimulated
issiiervated and denervated muscle «
Principal Investigator; Richard L<, Irwin
Other Invi^atigators: Jay Bo Wells and
Henry Jo Smith, III
Cooperating Units; Hone
Han Years? (cal®m?.ar year 1959) Patient Days; 0
Total I 0 (calendar year 1959)
Professional: 0
Other ; 0
Project Description:
QBJSCTIVES; Co study the decrease in contractile
response of ^.lirectly stimulated skeletal muscle
which follows th® aaainistration of certain quater-
nary ionso
METHODS EMPLOYED: Stated in Annual Beport« NINIB-
irCcTTI^BC" — "
MAJOR FIKDIMQS; Details of the major findings of
this project are stated in the Annual Report of
19586 In general, this project has shown that
the clinical if.y useful neuromuscular blocking agents
decrease muscle function by additional processes
as well as by interruption of transmission of im-
pulses between n©rv© and muscle,.
- 2 -
S£GNIFICAHCE TO THB PROGBitM OF THE INSTITUTE;
The drugs investigatad in "the course of thi»
project are in c(»niiion clialcal us©o They also
serve as valuable research tools in clarifylog
physiological processes related to transmissioi
of impulses between nerve and muscle o
This project contributes to an increr-ied
understanding of the physiological processes
related to myasthenia gravis »
PROPOSED COURSE OF PROJECT'o Terminated^
Part B included: Yes
Serial No„ NII!IDB~21 Cc)
PES-NIH
Individual Project Eeport
Calendar Year 1959
Part B; Honors , Awards ^ and Publications:
Publications other tlmn abstracts from this projects
Published in 1959: "The Contractile Response of Directly
Stimulated Muscle after Administration of Neuromi^cular
Blocking Compounds". The Journal of Pharmacology and
Experimental Therapeutics 9 125: C2I Page 159b February,
"The Effect of Certain Neuromuscular Blocking Coaipounds
on Directly Stimulated Muscle", Commimication in Curare
and Curare-Like Agents » Slsevier Publishing Company,
Amsterdam, 1959a Page 395,
Honors and Awards relating to this project:
Uo So Government Special Service Award, Jay B<. Wells,
Serial NOo NINDB-22Cc)
la Medical Sfeurology
2o Clinically Applied
Pharmacology
3o Bethesda^ Mdo
4o Coat inuat ion of NINDB-20Cc)
PHS~NIH
Individual Project Report
Calendar Year 1959
Part Ac
Project Title: Blood and tissue cholinesterases
in neuromuscular blockades
Principal Investigator: Richard Lo Irwin
Other Investigators: Jay Bo Wells and
Henry Jo Smith, III
Cooperating Units: None
Man Years: (calendar year 1959) Patient Days: 0
Total : 0 (calendar year 1959)
Professional: 0
Other : 0
Project Description:
OBJECTIYES: To determine the function of specific
and non-specific cholinesterase in relation to the
blocking of transmission between nerve and muscle^
HETHODS EMPLOYED; Stated in Annual Report » NINIB-
m^cTn^sB: — -
MAJOR FINDINGS: Stated in Annual Report, NINDB- 20(c)
Tsiss: ~ —
SIGNIFICANCE TO THE PROGRAM OF THE INSTITUTE: Thi»
proje©i has provided information on tEe metabolism
of chemically useful cholinesterase inhibitor*
and neuromuscular blocking compounds » In addition,
it has increased the understanding of the physio-
logical processes related to myasthenia gravis and
its treatment by cholinesterase inhibitors a
PROPOSED COURSE OF PROJECT; Terminated,
Part B included: Yes
Serial NOo NINDB-22Cc}
RHS-NXH
Individual Project Report
Calendar Year 1959
Part Bt Honors 9 Awards , and Publications
Publications other than abatracts from this project:
"The Effects of Selective Inhibition of Muscle and
Plasma Cholinesterase on Heuromuscular Block" o
Proceeding of the Second (1959) International
Symposium on Myasthenia Gravis o
Accepted for publication and in press by the Arthur
Ho Thomas Publishing Company ^ Richard L<, Irwin^
Jay Bo Wells 9 and Henry Jo Smith j II I »
Honors and Awards relating to this project: None
• I'ciri
Iduai Pxoj&ct R(i':'.
Lendar Year 1959
■ikuU C;
oveaai ,.
p. Si
.rjjtivcss Few authors have reported on
ftletflcds Ejnp xoved » Tha skiaj.i X-rev
„^^,^ ..„^jJlndi|^E :, ^ ■ .:; ..;^,
cases showed "hypei-ostotic-' changes of t;
h&v£ been grouped in fcux •i;V5reicnt typs:-
of the skuli changes is he Xonojr
disesss the more nr;sx^€c ; hvDsros-'io"
eight oesas with
-- •-,■ --■ -.^ V-- - -rf,^ - ^^i^.,-.:^ -,--.., i§JL=5sSfe'=
skulls of petienta with dystrophis myotos
"]>!© changes fosind may be psthcgeosticsll--
inci/Siisec iir::;ulating growth hormone ..
PHS = NIH
Individual Project Report
Calendar Year 1959
Part 3g Honors s Awards and Publications
Publications other than ebstracts from this projects
Di Chiro9 Giovanni and Csughey, John Egertons Skull Changes
in Eighteen Cases of Dystrophia Myotonics o (Accepted for
publication in Acta Radiologicaj to be published in the near
future)*
Honors and Awards Relating to this Projects
None
L-oradio:
PMS " HIH
Individual F-Toject Report
Calendar Year 1959
At
Project • ,;ISA (radio-iodinated serum albumin)
Encephalogxaphy and Conventions!
?\leuroradiolog:lC£l Methods
Principe ; :-''&r,ni Di Chircj Uu, D.
Other In'. a
Uan Years? (calendar year 1959) Pstient Dey
Totals Qo2
Prof ess ion ei-; Ool
Other? Ool
Project Desc
.QMS£M^££i" " •^'•5 "ifesejJE the reiiabiiity of a coffipHrstiveJ
!\wj method as the "brain scanning" in coapsrison to the neuro-
i'.-jdiclogical methods <> Smphcsis has been laid on the intrscrsnj
s 53ce"Occupying lesions » To establish the advantages and the
pitfclis of the? two respective techniques^ To estabiiish the
rfslative value oi tha "brain scenning" tschnique and of the
nsuroradiological nathods in the diffe;
differently locatod lesionSf
i^eJhods^^Egiijl^^:, - verified cases oi J.
a;3oC(s-C!CCi2pyir.0 lasions which hav© b©en diagnootically scrked
Uy both with "breiri, scanning" snd different neurorsdio.logical
rosthoda have been compaxeG.-
MJi>XJLIirj^iriSi° "^^-^ ^inal screening of the col;;:
- is being done at pr®sent<»
tTiis present contribution i?
ths lirritationSf and tha <
Serial Koa,^..
i. Medical K. ■„,.„„-,,
2o Neuroradiology
3« Bethesda, Maryland
4« New
PHS - HIH
Individual Project Report
Calendar Year 1959
P^rt^s
Project Title a Combined Laminsgraphy and Fractional
Encephalography
Principal Investigators* Giovanni Di Chiro, M. D.
Other Investigators s Mone
Cooperating UnitSJ Diagnostic X~Rey Department, CO
Men Years* (calendar year 1959) Patient Dsysj r-nua
Total! 0.2
Professionals 0.1
Other t 0.1
Project Description:
Gb,-iectives8 The superiinposition of different enotoirdcsi
strictures often makes the interpr^ tstion of eneephelogrephic
findings difficult. This 5s especially true in the posterior
fos&a. L^ainagrapby may foe* a i?:etJod lor tetter visualizatior
of the different structures b<3rurring th@ patiiwsys of the
cerebrospinal fluid. Coimperativeiv sraell structures not
desjcnstarated before siey be visualized with this new technique r.
gtetbods ,Empl.ov.e.di Laminagxaphic 'cuts" of the different
sections of the air filled cerebrospinal fluid pathways have
been taken. The laminagraphic study has generally been done
"dynamicaiiy" that is during the passage of air through the
different sections of the ventricular system and subarachnoid; I
spaces according to the fractional encephalographic technique
ad modum Lindgren. Laaainagrephic cuts in different pi*ojections
and in the two ortogonel planes have been taken, vdth the
patient examined in the sitting position different technics!
problems concerning the associated lan-dnegraphic ana encephalo-
graphic techniques have been solved. The number of lajninegrephic
cuts carried out has varied. Up to now about thirty patients
have been examined with this technique. Our experience is
limted to cases without intracranial space- occupying lesions.
M5ior,,,F;^n4,ifiq^s The visualization of the different
structures demonstrated by fractional encephalography has
been markadly ijnproved.
- 2 -
3lBnMi£^^§.,S9^.^SliS£lSRl5^l:u.f>P:^,fr.s^^)}^ Fractional
encephalography con'jbined with isfflinegrsphy is a technically
difficult procedure. The improvement of the visualizstion
of the different structures will however pay its rewards.
Individual Project Report
Calendar Year 1959
Project Title? The sella and the Pituitary in the
Coronal Plane
Principal Investigators s Giovanni Di Cliirot ;
Joseph iV.orel, R. T,,
Other Investigai. ._•.,
Cooperating Unitss Diagnostic X°Ray Deosrtme;..,
Pathological Departnit-
f-^sn Y£srS5 (cEiendc. : 959) Patient D;;;
Total: 0.2
Professional! QA
Others 0.1
Projection D^:.:xv.=,i^».^.. = - ,
;i-i y
Cfo^eptly^5% Surgery of the pit^.i.
problem of neurology. Hypophysectomy is carried out in differs
conditions. Pituitary edenomss have been lately radically
removed in ten cases by I^orlsn» Intrasellar implantation ,
Yttrium 90 seems to be a highly promising technique to be o»e..
a wide variety of conditions (British,, Italienj and American
authors). To approach the intrasellar region for thes^ .!•;-■:-.
purposes the trans^sphenoidal route is preferred by Si--
authors. The preoperative knowledge of the lateral bC/,;.:,:-.:rib
of -the sella and of the pituitary is of. utaiost importance for
trahs-sphenoidal surgery. Furthermore the assessment of the
exact three-dimensional size of the sella is a probieffi which
has not yet been solved. "' " ":"r~-^ ■.- '—:■- -nly the ^'"^ '""'''
of measuring ths length t '^'lia? nc
y xs T.O .
B^it£Q^.J~b:9:cii:L!i}:i - i;^-^ss of sk;' ' '] the di
pituitary J and th© paras&llar vessels -cAtu i
Serial No, NIND&-27(c:
- 2 -
with different roentgenographic techniques including laminegraphy.
ftetallic wires and X-ray opaque fluids are used to outline the
different border lines of the sella end of the pituitary and the
adjacent structures. The obtained results are compered with
standard X-ray films of normal cases and of cases with intra-
and perasellsr pathology. Volumetric measurements are being
made both in the specimens and in the X-ray films. Due account is
of course given to the roentgenographic magnification which is
tested in comparable conditions.
Significance to Keurological Refearch; It is hoped that
this study will increase our knowledge of -^he anatomical substratum
of the pathology of the sellar region.
Part B included s
Yes
No E
Serial Noo , ivH\iDB-2b
io Medical Neurology
2. Neuroradiology
3. Bethesda, Marylend
4. New
PUS » NIH
Individual Project Report
Calendar Year 1959
Part /\s
Project Titles A Bilateral Angiographic Evaluation of the
Superficial Veins and Sinuses of the Brain
Principal Investigators* Giovanni Di Chiro, U» D.
Other Investigators* None
Cooperating Units? None
Man Years s (calendar year 1959) Patient Days* None
Total* 0.2
Professional* 0.1
Other* 0=1
Project Descriptions
Object Ives 8 The venous "drainage" of the brain through
the superficial veins and the major sinuses of the convexity has
previously been studied with different techniques (anatomical »
with radioactive isotopes). No systematic angiographic study
has been done on this subject. In particular no bilatersl
angiographic comparison of the problem of the superficial
venous drainage of the brain has ever been done« Such s study is
considered by the present author important especially in regard
to possible anatomical fundaments for the predominancy of one
of the hemispheres.
Methods Emplpyeci* At the NINDB we have a comparatively
large material of bilateral carotid angiographies in patients wit
no intracranial space-occupying lesions and with no gross
sbnormaiity., This represents an ideal material to study the
problem of superficial venous "drainage" of the brain. In addition
every angiography is carried out by us seriographically with a
minimum of six films on each planeo In this way the different
phases of th© superficial venous drainage may be angiographically
demonstrated. The seriographic "rhythm" has been in different
occasions changed to arrive to an "optimum" for studying the
venous discharge. In a certain number of patients who have
received bilateral carotid angiography? tests are done (in the
neurosurgical department) to assess which hemisphere is the
- 2 -
predominant (Wsda-test)* This will of course make
possible a comparison of the bilateral angiographic findings
with reliable determination of the functional predominancy
of one of the hemispheres «
Major Findings s In s significant number of cases the
venous drainage takes place through different vascular channels i
the two sides of the same patient. I'v'hiie the main drainage
venous trunk on one side may for instance be the Trolard vein,
on the opposite side the Labbe's or the superficial Sylvian veir^,
may be the main discharge pathways. A statistical study of the
drainage of the two hemispheres through the right or left
transverse sinuses is part of the project.
Sionificfflpe ,;tp, Keuroloaical Research: It is hoped that
the present study will be e contribution to establish whether an
anatomical vascular fundament exists in relation to the pre-
dominancy of one of the hemispheres.
Part B included*
Yes
No W
io P.iedicai Neurology
2« Neuroradiology
3. Bethesda» Maryland
4o New
PKS « NIH
Individual Project Report
Cal&ndar Year 1959
Project Titles Encephaiographic Changes in Cases of
Temporal Lobe Epilepsy
Principal Investigators s Giovanni Di Chiro, Ko D<,
Other Investigators? None
Cooperating Unites lione
f/an Years s (calendar year 1959) Patient Days: Kone
Totals 0.2
Professionals Ool
Others Od
Project Descriptions
Cfoiective.s? To assess the frequency), the type, and the
entity of encephaiographic changes in cases of temporal lobe
epilepsy (tolo©.) using a standard and reliable encephaiographic
Methods. EsjBployeds Khile reviewing the available
encephaiographic material of t.loe* (in particular cases with
associated angiomatous malformations and cases with bitemporal
foci) the present author arrived to the conclusion that a
standardized encephaiographic technique to give a demonstration
of the real anatomical conditions of the temporal horns and the
surrounding structures is necessary. For this reason every case
of t»l.e» is now studied ©ncephalographically in such a way that
reliable comparison of the two temporal horns is obtained in
every esse. Each temporal horn is filled separately and after
examined in the two ortogonal planes. Tine technique of filling
the temporal horns has been simplified and standardized so that
the X-ray technician will be able to carry out the necessary
maneuvers.
Major Findings s About twenty patients with temporal
lobe epilepsy have up to now been studied with this encephaio-
graphic technique. Further experience will be accumulated in
the future.
„ 2 °
Significance to l^e\»r.o,j.p,c;i,cal, R.e,se^i;phs The value of
encephalography in establishing the anetomical changes in the
temporal regions in cases of t.l.So will be definitely assessed <
Part B included!
Yes
No Uj
Serial Ko. MINpB- ■
].. Medical NeuroiOi
2o Neuroradiology
3« Bethesda, P/arylt
4. New
PHS - NIH
Individual Project Report
Calendar Year 1959
Project Title! A Radiographic Study of the Soft Tissues in
the Different Muscle Diseases
Principal Investigators? Giovanni Di Chiro, M» Do
Other Investigators! None
Cooperating Units » Diagnostic X-P.ay Department, CC
Man Yearss (calendar year 1959) Patient Days* None
Totals 0,2
Professional! 0«1
Others 0.1
Project Descriptions
Objectives? This project is a long term study of the
roentgenographic changes of the soft tissues in cases of
pathological muscle conditions. No large and systematic study
of this type has been carried out before.
F/.ethods Employed s Several technical problems are
involved in the "optimal" ro®ntgenographic visualization of
the soft tissueso Different methods and techniques have been
suggested and usedo Long exposures with scarcely penetrating
X-rays, particular type of screens, injection of X°ray opaque
fluids, injection of gas, and color radiography have been some
of the technical methods suggested to obtain a good demonstration
of the soft tissueso It is our opinion, however, that at
present the best available method is a combination of a good
X°ray technique, particularly suitable for soft tissues, and
a good reproduction technique. Th© "Logetron" equipment has
been chosen for th© reproductions. Th© amount of contrast and
detail obtainable with this equipment is unsurpassed. Control
studies of normal cases end possibly of autopsy specimens will
be carried out.
None yet.
Serial KOo NIivDB-30(ci
^ 2 -
^ionifipance, to , Ne,urolpqic,aI. Researchg The different
muscle diseases may possibly show different patterns of
roentgenographic soft tissues changes^
Part B included?
Yes
No Xl
Serial No» NIMDB~31Cc)
1. Medical Neurology ^rancS*
2o Section off Neurological
Disorders Service
3. Bethesda, Mdo
4o New
PHS-KIH
Xndividual Project Report
Calendar Year 1959
Part Ao
Project Title: Thyroid function and neuromuscular
disease
Principal Investigator: Andrew Go Engel
Other Investigators:
Cooperating Units:
Man Years: (calendar year 1959) Patient Days: 570
Total :1.0
Professional : 1 . 0
Other :0.0
Project Description:
OBJECTIVES; (a) 5% to 10% of patients with myasthenia
gravis are also hyperthyroido Where the two diseases
coexist the prognosis appears grave,, Some observers
reported an inverse relation between the two disorders ;
this view has been challenged by others » The present
study was designed to define the interaction of the
two disorders and to evaluate the respective roles of
pituitary TSH and of the thyroid gland in whatever
this interaction might be,
Cb) 10% to 30% of patients with periodic
paralysis are also thyrotosico Such cases are
usually ma- familial ; they are precipitated by the
thyrotoasic sti^e~and abate when the latter is treated.
In 1926 Shinoshaki reported worsening of the periodic
paralysis by thyroid extract in 7 non-familial cases,
4 of whom had goiterso In 1943 Wolf reported ameliora-
tion of the familial and non-toxic form by the a^lmin-
istration of*^ thyroid extract o In the present study
- 2 ~
the effects of thyroid si^bstasace and TSH in a
euthyroid patient with t'^® familial form of the
disease were observed o
METHODS EMPLOYED; Five m^asth^-fiic patients were
studied^ Antiinyasthenif; jaedic«.tioas were held constant
during the study. Th® cliaickl ©valuation consisted
of daily measurements of; H^cd grip, ana elevation
timej^ Bianual muscle testings cliplopia measurement
in prism diopters by the Lancaster red and green test^
or measurement of the limits of uniocular ductions to
the nearest degree on a projection perimeter with a
target that required macul .s' perception. The thyroid
status was evaluated as fallows: Daily BMR; weekly
FBI; cholesterol and I~13/ uptak@o In three patients
thyroidal secretion rat© was also measured foy direct
daily counts of thyroid..! radio-activity ^ corrected
for physical decay, as described by Goldsmith , Greer j,
Solomon and Benuac
lo Triiodothyror/iae CT3) was given at a dose
level insufficient to Saduce hypermetabolism ^ but
adequate to supprisss pituitary TSH secretiouo
2o T3 w<^ ad2r.inister@d at progressively higher
dose levels until hypermetabolism was induced*
3n After a labeling dose of 1-131, thyroidal
iodine accumulation vas blocked with Tapazole and TSH
(Armour) waa administered in graded doses while the
fractional release cf hormonal 1-131 was measured
from day to d&yo
4, Same as Step 3;, but with th® concurrent
administration of Mai to offset the thyroid hormone
release acce)l©ratiag effect of TSHo
5. Fitfolonged administration of Tapazole until
depletion of thyroidal hormone stores resulted in
hyporaetabolism with concxirrently high pituitary TSH
secretiono
The patient with familial periodic paralysis
was carried on a constant Na, K and carbohydrate diet.
Daily Na» K balances, and fre^aent senm E determina-
tions were obtainedo Clinical evaluations were
carried out at 3 aom« and 8 ao^o Thyroid function
- 3 -
©valtiatioas were axi above » Steps 1 &Bd 2 were as for
tlxe myasthenic pati©jate<, Stfep 3 consisted o:' tbe
administratioB of graded doses of TSH uatil tae
patient became hypermetaboliCa
laAJQR gIMDIHGS;
were noted:
in tfee myastfeenic study t&e followii'.g
Tfefeyapy
T3,<i00 meg
rS,>10G meg
TSHjTapaKol©
TSifjTaparjiole, Nal
TSH Thyroid Mo„ of if feet on
Secretion Secretion BMF Studies Myasthenia
C+)
<}
3
IDne
++
3
Tors©
++
2
'ors©
C+)
3
illghtly
worse or
no change
„
1
Better *
Tfipa20le * ++
*Ii8layed effect '
In all patients %'too became thyrotoxic, the
myusthenia becsym^^ worse. No see-saw relatioiuship could
be Been, although minor fluctuations occurreci until the
BUR reached plus 20%* In one patient who became hypo~
metabolic on Tap&aole, the myasthenia imprcred while the
eadovsnous TSH level was elevatedo Sxogenf'as TSH-induced
acceleration of hormonal secretion was foliowed by elevation
of thu BSSRj and this by worsening of the r//astheniao When
this acceleration was blocked with Hal tfcy effect on the
disease was -also blocked, but only to thti extent that the
rise in the BME was blockedo It thus ap >@ared that TSH
per se Liid no significant ©xtrathyroidal effect on the
myasthea.lao
Influced hypermetabolism did not wrsen the clini-
cal status of the patient with familia* periodic para-
lysis 5 Withdrawal of T3 was followed nf a severe and
prolonged worsening i this was relieve/ by TSH administra-
tiono TSH wivhdrawal again resulted in an exacerbationc
Repeat TSH stuCy could not be performed as the patient
became resistanv to TSHo ThuSp these may be a further,
difference betwecin the thyrotosEic nonfamilial aadthe
familial aoathyrotoxic forms of th© disease,; namely the
response to abnormal levels of thyr-oid functiono
» 4 -
S2GWIFICANCE TO THE PROGRAM OF THE INSTITUTE;
The thyroid function study ob myasthenia gravis
has therapeutic implications for thyrotoxic myasthenics
anda possibly g for euthyroid patients as wello It
may also offer cues for further studies on the
biochemical lesion in myasthenia gravis o The study
on periodic paralysis may contribute to further
differentiation of the familial from the non-
faiailial- thyrotoxic form of the disease.
PROPOSED COroSE (M PROJECT:
Part B included: Ho<,
Serial ^, KIKBB- 32(c)
1, Medical Heurolegy Braach
2, Sectimi ©a lfe«r©l®glcal
0l8®r<Sere Services
3, Be£hesda» Iferflsad •
4o New Project
PHS-HIfi
Issdividmil Project Report
Csleadar Year 1959
Part A„
Project Title; Studies ®£ the Chr^sesi^aal Constitution ©ft
1> Hmum subjects ^th vari@«ss disorder^o
I) Local tissise al^sonmlities.
Prlneipai iBveatigators: Paul H. Altroccbi, MoD.
Robert Kreoth, M»D.
Other lawstigater: G. Milt@a S^, M.B0
C@©peratiffig Units:
J^a Years (caleadar year 1959) : Fatieat B^s (caleadar
Tetal: 0 year 1959); 0
Professieasl : 0
Otfeer: 0
Project Ifescriptioa:
0BJlCfI¥ES;
T® further d®c«®eat the rep@rSe«l chr^fflscaaal aberrati®iES
iE fatieats ^th Klinefelter 's sjnadrms. Tamer's syndrCTse, md
T® explore ths possibility ®f qtamstitati-^e chr^seseaEsl
aba®riS8allties ia patients with awntal deficiency, spisz&l defor-
mities, asssltiple c®agealtal anoBaalisg, &&d various neur®l®gicsl
disorders.
•£& investigate the saicre-genetics ef l®cal tissue aba@r°
maiities -—e.g., cafe au lait sp®tB, ^itiligiaeus areas, n&'^i.
X® 8tu«Sy quaatitstively the chrsaeoscsBsl eoaatitution ©f
neoplasias ®f the nerveus ^stea, bsth- benign and malignaato
If the teehffiiquess becesse sstsffieieatly refiasd, t© analyse
individual shrasos^s ss©re aiautely. f®r qualitative changes ia
reiatiaa t® the ab®ve diserdera.
- 2 -
fresh b©ae saarrow aspirae©s will be incubated ©veraigfet,
treated with colchiciae, aad thea flsed sad staieed by ®>difi-
caticms ©f t:fe® methods described by Ford et al., Folaui, Tjio
et fil. , sad Fargusoa-Ssaith. Sqtsssh praparaaioas will be searcljed
syssematieeily f@r eells is efee saeeaphase of Esieosis ^ich ^11
fefeen fee SEslysed both by direct saicrascopy aEd by aicre-pbeSography
for i^a^&titatX-we and qtaaiits«;ive absorsalities.
Tissue cul£«are i^eb®ds will be ased to grow ekia, isascle,
assrrs^p and aeeplffifieie fiissue ia the laboratory, which %-ill thea
be treated in a. mamisr similar to thst stationed above, for ch?o~
fiaslysis.
W& ssajer fiadissgs hs^e beea reported as yeto
It ia b©ped that fflicre-gesatic studies loay help clarify
the nature of csrtsia disorders ©f the aery®«s systesa. Siace
ssjsay ffl@m'©l©gical dissaees are hereditary, swch studies form
©sae aspect of ss evcrst^isl naSBy-proaged attack an the precis©
gea@°e®syass-bi©eheffiieal defects im^i^sd^
M0K?S1^ CQgESE 0F TM PIOJECT;
B®ae asarrm? gpeciasaas and @£her tissue sMspieB will be
obtained frsm patients on the wards ®f the Clinical Center.,
They Mil thsa be caltared ssd suitably prepared far chr®B®sssial
maslyai®.
Part B included
S.. i^lzTc'olcgical Disorders
3o Bftliesda, Maryland
4. CG«t±EU«.tioa of WIIDB-]
Individual Project Esport
Cal«3Bdar Year 1959
^^ect^TitleJ Pathological Jitudy of letraaaisc^lar
Motor asd Saasory Nerve Endings is
tiie Normal. ^^--.^ -'e, BJeiarojauscular
Diseases.
Principal lave.stigator; G. E. Haase, M.D.
Other Iisvestigator: Koae
Coopgrat lag Ilnltg ; None
Man Years Patient Dajs- 0
~~Totan ~ 3.0 ^ ^ - ~-
Prof essioaai i 1.0
Other; 2.0
Pro,-5.,-ct Description:
Of2^|ectiv«; The study is cosaeeraea with an xavesti~
f^atlonTato the histological structure of the laotor
and senmorj nswe endings ia sorssal auscle asd with
changes occurring ia tltes® sts'isetures iis various
diseases affectiag the aeuraatJg;?ylar system. Mor-
phological chasges hava beea dssc-'lbsd, in particu-
lar, by Coers CCoers aad Wolff: The laaervatioa of
Muscle - Thoffias 1059) tn a variety of diseases af-
fecting the lower aiotor jseuroE aad iacludiag priiaary
saem:'Opatfei3S as well as myopat'Aies. The objectives
of the pressat study are to dstermiais whether such
chaages eaa be observed ia th© i-ich biopsy isaterial
available at this institution. It was further hoped
to obtaia iiaforaatioa about morr^oiogical changes of
the muscle spindle. in a variety of diseases.
saethylene blue at the tirae of biopsy
by Cfeers.
AcstT aesterase stain as siodifisd by Goers.
2. Serial Ho. MSDB-SSCc)
3. Silver stains, ia particular, the modifications
of Bielschowsky and Winkeliaanii.
Patient Material; The material is usually obtained
in tlie course of routine biopsies, and only slight
variations are imposed by the intravital injection
of methylene blue. In all these specimens, routine
staining methods are also employed by the Section
of Neuropathology o
A total of fifty-five biopsies have been
obtained in the ioanner described. The patient
material includes predominantly patients with a
neur(»iuscular disorder o Several patients with in-
voluntary aaovements were also biopsied o In addi-
tion, material has been obtained at the time of
autopsy from patients dying of diseases other than
disorders of the neuromuscular system. Finally,
various muscles frcm various laboratory animals
have been obtained.
Major gjadiagsi The concentration of the motor end-
plates in a narrow zone at about the center of each
Individiial mus<cie fiber has been, in general, con-'
firmed, at least in the rat. Recently, several
muscles such as the sternooleidcNaastoids and the
biceps have been stained with the acetyl cholines-
terase stain in muscles obtained from rabbits and
catSo Here, there appears to be either distribution
in several bands or in a fairly random manner. Since
the slides provide only a two-dimensional aspect, it
will be necessary to reconstruct the position of the
motor end-plates in all three dimensions of the
muscle.
Changes in the terminal Innervation and in the
motor end-plate of paties^ts suffering from muscular
diseases and diseases of the lower motor neuron have
been found, such as bulbous enlargement of the axons,
rich axonal sproutii^ and enlargement of the motor
end-plate in the case of neuropathies. Marked alter-
ations of the motor end-plates in myotonic dystrophy
have been found in two patients. Since the inception
of the study, this has also been reported by Coers
and Wolff. These same authors report changes in the
motor end -plate in cases of myasthenia gravis. So
far, only two patients with this disorder have been
studied in the manner described and these changes
have not been found. Marked ramification of the terra"
inal innervation and multiple end-plates on single
fibers have been found Ib two cases of Huntington's
3, Serial No. Him)B-33(c)
Chorea, who originally were biopsied for control
purposes. Some cases of Parkirasos's disease showed,
on orthodox stains, evidence of mild myopathy, and
these were reflected by changes suggesting degenera-
tion of the motor end-plate hy methylene blue stains.
With regard to the morphological changes in
muscle spindles, it is thought that this method does
not proffiise to bear fruit. The muscl© spindles even
in the noxTiiai apparently show great variation and it
is believed impossible to clearly state pathological
changes in these structures.
Recently, the estracKSUlar smscles of a patient
dying of non-neurological disease were obtained and
it is intended to study the ©ye axuscle® in a number
of cases. During: the last month, small specimens of
Miscle from the zone of innervation have been for-
warded to Dr. T. Wanko for eiectrosuicroscopie inves-
tigation. Results of these exaasinatioas are not yet
available.
Proposed Course of Pro^ject: Because of the antici-
pated d^arlfure "oi the investigator from K. I.E. , the
study will be closed at this institution but is in-
tended to continue similar investigations in the
future ,
Significance to Meurological Research; These studies
contribute towards understanding of the normal inner-
vation patterns in atuscle and the changes produced
by various pathol<^ical conditions.
Part 1 included /ZZZI/ ^es /T^^J ^o
Serial Bte, »IMDB-34(c)
lo Hedi<sai Neur®l@gy Branch
2. Sectien @n Neur®l<ssical
Disorders Services
3a Beshesda, Maryland
4, C®n£imi«ti®a ®£ WIKDR-ilCc)
PHS-HIH
Indivldtsal Pr@Jecl: Report
CAieodar Year 1959
PABT A;
Project Title: The Use @£ a tteo^tamine Oxidase Iadiibi&&r (JB>516)
m &n ARti"C@mnil8&nt Msdicaeioci £&t CttnereQc<sphaIic
Seizures
Principal Im^astigaeors : Darvin Pr@c!atp» MoDo
Busho®!! Saith, Mo Do
Oeher lavestigaeers: Aodre^ ingal, H.D„
Mark Lane, )LD»
Ceoperseiag IJnits: Kri8t@£ AbraiUBs, Eleeer@etiicephal®grapli^
Branch
J©ha Oaces, National Heart IasCieut«
Man Years (calendar year 1939) : Patient D^a (calendar f^stt
Total: Oo5 19S9>: 250
Professional : 0, 5
Other: 0
Pr®Jec£ 0&8cripti«»a:
^JECTIVSS:
The ebjecti^^ df the present stud^ is t@ evaluate the
effeetiwness ®f JB-516 ( (phenyl i83pr@pyl) - tg^drasine) as an
anti-c@nvulsant in pere^nfi with centrancephalic seizureso
JgTHOPS EMPIX?!gEI);
Patients were admitted ax^A snti>e«n¥ulsant i&edlcatl<sns ^fsre
reduced to a minisaaa %ih®ndver possible to do so witl^ut danger te
the patient. After a eh&rt baseline period of observati^nj patients
«ere given a placebo @r JB>516 daily £@r four to six weeks in addition
to other medications the? had been taking o This v&a given in a i@xm
to the investigator o Eleetr^aaesphalograms were run each
Serial m. mmE-^mjc)
- 2 -
waek and cmipaxed ee> th® baseline BB6» Oegereiaa£i®ns of eh«
aia@uiie @f S-b^&s&s^ttfptamiim la £he orine «?ere d@ne durlag t:he
biBsellae period and @a the 6th and 7th d^ ®£ @edlc££isao
Ttf@ patients reeeiired JB»SlSc One <lev®l@ped drowsineiis
f®ll®H9d by generalised €@isnmlsi®ns after reduction &i barl»i-»
turate medicati^eiSa Be£®re reduction the eeisures were fully
c®ntr@lled„ One patient becJKie l^p^teoslve and had syncopal
attacks after fear «feeke @f sedlcatioac Doring the 4th week
the patient ^e seistsres «ere fully e®ntrolled, Feur patients
received placebos » cme patient sh®wed iaq^roventento
JB-S16 Bh&fss slight signs ®f e®ntr®l ®£ centrencephalic
seizures.
PRQgQSBP COURSE OF PROJBCT:
The 8tu% ®f ©ther tsoi^oains oxidase l^ibitors with ti@r@
specificity for the central eysten will be uadsrtakene The pre-
project is disc®nein;^ed.
PM7 B incltsdsd m
Serial m. mm^-35ic}
2, Seeti@a em Beurolc^ical
Dism-ders Services
3. Beehasda, Hsrylaad
4o ^nfclnuati&a of HIsaB-16Ce)
PBS-HIH
ladlvidual Project Sepmrt:
Caleada? Year 1959
PAitT A;
Project Title: A Sttsdy ©£ Progressive Psreaehj^iaaeoias Degeoerfflti®®
®£ the Central Nerv@u@ S^stas
Principal lovestlgaters : Bushaell Smith, MoO.
Glenn Brsger, MoO.
Other Isvsisfeigafeors:
Ce^fieratiag IMits: Surgical Etetar^legy Breach
Clialeal !feuropath»logy Braoch
EJaa ?ears (caleadax: year 1959): Patient Hays (calendar fssr
Total: 1.0 1959): 2
Fro£essldaal : 1.0
Other: 0»0
Project Descriptiew:
OBJECTXVgS ;
Microscopic stndf of the hral@ and spinal c@rd of a deceased
51 yaer«old vhite fecsale vith a cliaical diagmaiu of progressive
pareach^isAt@ttft degesM8rati@a ®f the ceatral s^ervous sy&tesa. 0p@a
cesaspletlon of this studf , ce>r7elati@)B @£ the fiadiags will he mads
with the cliaical data, pertiaeat literature @ad fiadiags ®£ braia
biopsy soade dtsri^ the third n^ath of the illaess, (See MM!%->l6-c)
HSTBOBS SMPLOgEDi
The spiaal cord, br&ia stem, cerebelltOT, aad cerebnga
ssetiofied and etaiasd with the routias teehaiqvBs £®r desHmstratias
morphological chaages ia the nervous eysteiao Special staias «ere
used f®r the dem@astrati@a of irooi, iaclusiea bodies, and lipids o
S^3rial m>. KIM>B"35Cc)
- 2 -
T?V!»?sv.i..~.'rFi.",^S!Tl'.S '
fher© is widaspread diffuse l®ss «f neurons ia gh« feraiso
•Ri® «jccipi£al cortex is marked by statws spcmglosus sad asfcrecycie
prellfarafcica. The eerebellufii shews l©sa ©f Purkinje's calle and
graaule cells <> The laeoral colvmm ipyTm±6&l ersc£s> show
degsti3rati®no
The te®dules ef «cute inflfflsjatory cells with foci ©f o®c?<»ei5
Bcattered thraaghocit the brain and spinal c©rd are probably d«e te
the teraainal tnfectiefn. (See H1SDB-I6«c)
This is « relatively rare, pr^grecsive, degenerative disfs«s£.^
©f the central nar^jimas systeaio ^e aei@l®gsr is quite ®bac«re ©ad
th@ pistk@l@gicai prGC9Sa freaa begltmiss t» and has been »all
daewEEented, A cg»rtical bi®p$y «!as (!?>btaiaad disrlng the third mnth
®? the dlseasao The path©l©gical mt^sf laaterial obtained sis:
asnths after the ©nset ©£ the e®»di£i®s should reveal infensssti^
cenesraiag the pr®g?e8s of the di«3®rder. Spacial histolegical
jstttdies ffisy b® helpful in establishisg the eti@lo©'. It is ale^ ®t
lap®reacice t@ cerrelate the clinical pictare with the path©l@gieal
flndiags,
S^MULje^giL^-^CJBCT:
The pr^mied c®wr®e af the pr©ject is t® ces^late the
ffiicr©sc®pic etu<^ utidartakea and ©©rraslat® with the clinieai
fiadiiigs=
PART B iaeliaded
SUIg^ABY
Tha activity of the Braneh is <iaLvid.#d beti^8«n -mutim dia.gaostie
seiTcie© for thig eutir® Cliniieal Center «M resea^dio In a l^rge p^rtioj;
of t?i® paUeiit. population of HIMIB* as mril m of otbar Ir«'U.tttt®3S.5, ih&
In the ©l©v«n won^te incliad®d betwss®n the last j,'©p-£5rt. (pr®pnr©d
lio¥fimb®y 30» 1958) and th® psreansnt om (prepared NcvsAer 1^ l'^55?,} s tet.&i
of 157? ©leetTOQtiagphalogs^MQfflessftimtlmis hm^ hmn ««!,Yl«!d 0ut -^siVh
th® fQllowlisg dlstjlbutioK arao'ng patieKto of the irai^'ious Instituiss*
JCIo o o
0
291
MCEo . o
a
liS
samis. o
o
53
°
73
lOii
^M)Bo 0
o
1100>
Total 1579
It s®@ifi» worth @mph*s3iiing that this total rspres^nte th# hightst
n'ssabsr ©f soEfflainfttlons esnl©d o^t diiring the last sJje jmr<Bc This® ■^3i®
monthly srerag® muaber of sxaratriattiorra has ris«R frosa ^o^ in 1951?^, atsd
12$ ia 1958 t© lii3o5 in l???9o Althou# th® laajoril^ of r^fei^ds rvtill
jsosaa from ®ur Institutes it is iRt@j?i8sting to note that *J2ing' tb® last
four years *b©ut on#=thir-d, of imtient® h&re b9®n referred froas oihgr
Imli'Ujt®®^ mang i«hidi ^® NCI sssmimts for over 60?K=> A ©onsid®r*bl(^
nussbgy of E2XI ^eaBniiJstioris •»!©?»& p«r.fo2ia®d. not a® a simple diagnostlffi
px-oee^r® btit a@ parfe of y®@®«rcsh projeeti oa-lgijiating o-ut®ide of ®'ur
, .Diirtfjg th» sme period of timej is »llaboration wits th® Branel?^
of^ life'urolegieal Surgsay^ 21^ el©ctTO@@rtic®gmphie ntudi^s -,»» p#rfo»i-sd
©K'ith,* ■occasion of eort±«sl Kiepastii^ diiring surgieal treatsasat of @pi-
l«pti*^!' jxiatient© or during opei'atioas carried out for hjpop\^M®@ta-s!^ in
'mm^ of ekt^'ftOTm;.: .,.E3ct®raiT® SBQ studiss ia resting- «goKdltioM and during
isijcttsi!® aBd ela«strisal atisaulatioB ii«©r« also eairied ant on a certaiw mm---
\mr of fs-pilepti,© yabj®©tg tin which elest^^jdpg had hmn dh.TOiBle«aiy isipls.ntM'd
withiB imbsort-ieiil str«aetu2'*.® for dlagnoatie IwsaliaiBg purposes an 5*S!ll
as for imr«stlgatiofflo
Seri«l EEQ examinatioas with qualitatlv® end quantitative analysis
of epileptifoxiB abnormalities tis3*e also carried out to help in a project
of the Branch of Clinical Neurology^) designed for the purpose of assess^
ing the -value of new n^dioal trealanents of seisureso
From the Branch of Electroencephalography and Clinical Neurophyaiology
a total of 9 research projects are in prog^'ess or l»ye been ooropleted
within 1959 o Of these p k are confeLnoations of projects ppsviously outlined
in other reports (36Cs 370,, 380^ 39C) and 5 tre naw (liOCj laCj 120^ k3Q>
li6C)o Three of these projects are carried out in strict collaboration with
the Branch of Neurological Surgezy and the deified dsscriptLon of two of
them will be found in the report of that Braneho
Projects 36Qf> 3?C|, 38C and li3C are ralate*^ to ^ix)ioo=electroen(^phA»
logrqphie problasns ia the field of epileps^yo Project Ut'S deals with tiie
effects of hypothenoia and blood pressure on thg electrical activi^ as
reeordable from exposed rx}»sal human corteiCo Projects 39C, itlC ani k2C
deal with experimental investigation of thalamo°=>i^rtical and cortico°
thalamic relatioi»hipj) while project UOC rspresen^:>s an experJinental approa^
to the problm of seissureso
Project 36c (continuation of ICj 1958) has been corapletedo It deals
with the study of close relationship between clinical events and tleetr©<=
graphic pa**«"is taking plac® during the course of epileptic seizui-^So The
results have been collected in a monograph in the foa'm of an Atlas wi^i^
has bem accepted for publication and will soon ap^er as a supplemenc to
the Journal of Electe-oaneephslography and Clinical Neurophfysiologyo Ttm Atlam
includes a wealth of photo ^aphie docimentation correlated with EEG tracings
of ii3 diffenint seizures select©d out of «wer 250 ictal episodes o Althov^
its investigative part may b@ considered acccffliplished^s, this stutjy is conti-aad
for practical purposes as an important adjunct in the routine screening of
possible candidates for surgical management among the epileptic patients
admitted by the Branch of Ifeurological Surgeryo
Data pertaining to project 370 (continuation of 20$, 1958) end
project 38C (continuation of 3Gj, 19^) ar® still in i*ie process of being
elaborated and analysedo Both invBstigations are part of a long range re^
search dealing with diagnostic and plqrsiopathagemitie aspects of focal
epilepsy and,, in particular^, of temporal lobe epilepsyo Cases suitable for
chronioal electrode iisplantation must be selected with great care} they ar®
of necessi^ rather rare^ and additioiul cases are needed before attempting
My reliable evsluaticoi and int®a?pretation of the monerous interesting
findings provided by each single casoo Also the number of patients in which
a complete and satisfactory electrecorticographie examination may be carried
out traa the exposed cortex on the occasion of surgical interventions is
•till inadequate to allow my dafinite conclusiono In addition^ a long
genstic aspsats
study deals w^.t?i
elici table on tii
radiatloiio '^- -: U'te furi-
©leaentis aativsT : th-? rli
and by tiielr t«;v
postsynaptic ete::^.,!-;^ tt^i
ftmstions'i substs" '^ cf '
aee®pt<?i for pub
Br«.r.^o It is .;
piiy:.lffiulaT^ it .
sv'j&®rn.ng th© ■
:jf.-!p«tiM,v.* slec'. .
'.es^'ifetd in del
ciuring reiaetiti-*-
tae e®lltaiaif ineBiK ^^s.n^ oiites plum aanif eating itself with repetitive
firing and pro^^i assiva dee^^s&se in -olltude of th© ynita-^' spiJceso mm
^i® d®pola2lsa.:lan OTeg^ads a eri lae, the spUce fiilag stops and
shen this sUg® U reaahadg salf^^.: :, actimty will io>lle^, fh©
lfttt«r wcaiid e&ormwpimd to a prc-gs'sssiv® snK^ol&slastion pr®c«ss aixd is
^araet®K.s®dJ.y high fr^ouaney low voltage spikes whidi prog res si^^l:^
inereas® irx their amplitude and deareass in their rat« of firing o fhU^
?l^««f .^ ^^^■'.°^ T^^'rf % I^ ^°^3.d appear fr«m thess eacperimnte
« L??!.?i Itf '^^^^^•^^f'isi^A^ featu.fBg of the "epileptic" ntuJonal pool
3^ aet««12y this slc^-, longlasMng pj«eess of rapolarizationo Thi^ steidr
haa baen caaplersd aM a paper has bser. suTanittad and aeg®pted £or pvAlZ
"jid etiot)ai
•as besn ecrapletedo This
-i' the evoked pot«nti.&l
:'Clo^ring sMsmilation of the optde
s'levlor of the Tarious wsita^y
-ic and UJO.dsrlying white Matter
ci different eoinpensnta of th#
>.;1q to differsntiat© pr@-= trom
if Aug s^dencean th« aiiatm©-
5 >;:Ks\«l r®sp©n0©o The resfult®
b^^n subiaittad and
. by a guest worice-i.- ,.^. .,^:
a epilgptic ssisure end ia
i/'Y®8tigatibn of the saeehanlci::*
!i is produced folloidng
- :-r-8l eortaxo The results arw
>}3,on5 tiles® •Bould suggest that
progressiTO dep^larixatioa of
T+ ^«!T^®fL^" ' ? '' '^^^'^ .related to ?m^B®% 39Co
inS? f ^l'!f '"'^ fit«>..ha«igi«. in this Btu^ an attSpt wa^ m^d^ te '^
a2>3a or a .aaarby es.yti«jal essoeia- sa may eontrol t*e ar<H.val ®f
S^ t^fhlt I J ^ ^*!f'^''i g®^'^^^^^^^ tmamB, upon txnit&ry spited elicit.
StSf T^r^L'LfS" J'^aot^8t.i^ulatio« a. .-all as bn/^rtical ^jSi '
in SVa Sa^S-' " '^^ v^^mted and the vart<ms results Bm now
Another purely expsjiaentsl sta<^ o£ Project U2C « This also
deals with thalamocortical inschanisiiB o It Involves a syst^aatie oortle&l
niezoeleotrode sttidjr of the three main sjstesss (specific^ associatios and
diffuse or nozt=>speolflo)» and has the purpose of analysing and esMphaeisizig
the toain ftuKstional differences ezisti!^ antong theao The large noaber of
data collected out of more than $0 cats ©wplqyed for this project ar@
presently being in the process of elaboration and though it ia not yet
possible to outline hes^ any (iaflnite conelusionsp the ani^ysjls of th®
results should be ready before the end of the yearo
A SBsall project (RCj, 195fi) i« aot mentioned among those undex-takaa
in 19^9 o Htis concerns the preparation of a coaplete bibliographirafl. list
of pap«Kre dealing with electroencephalography and Clinical Neuropl^siology
for the last ten yeajrs (l9U9»a558)o This project waSj houeverj, eaoMstmd
in oooperatimi with Baco Co Hsnry of the Institute of Liviiig (Hartfordj, Goraac
in spar© tiro®? it progresses slowly but should be conpleted during the
ittxt yearo
The Qiief of the Branch took part in the colloquiun on "Teaohio^
methods in Electroexusephalography" organized by the CSaramittes on Edttcation
and Training of tla American EEQ Society in Atlantic City^ ,^n® ,1959o A
paper was presented on the "Method of interpretation of the EEQ of adulta^s
as wen as a second brief paper (inrlted discussion on "EEQ InatnaentatloB
and Technique" )o Following an official invitation, a lecture was alao
given at th© Montreal Neurological Institute in October 1909 on Ihe subject
"In Neurology this interest© me roost" o
The following papers related to research projects outlined and ooa-
sidared completed in previous annual reports have appeared in their final
form in this calendar years
lo EnoHotOj To Fo and Ajmone Marsan^ CoS Epileptic Activatioa of Sit^l^
Cortical Neuroxis and their Relationship with Eleetroensephalographic
Dlschargeso ESS Clino Neuropl^siolo 1959^ 11« 199»218o
2o Enonotog To Fo» Unilateral activation of ttie non=»specific thalamic
system and bilateral cortical responseso EEQ CliOo Neurophysiolo 1959o
nj a9'=232o
3o Longg Ro OoS Modification of sensoxy mechanisms by 8id>cortical
structures o Jo Keurophysiolo 1959» 22s la2=>l|27o
As indicated by the names of the investigators in the various research
projeetSs a COTsiderable contribation to the activity and research of the
Brandi has been provided by scientists temporarily affiliated with the
Brandi for training purposes or for active cooperation or original investi<=
gationo During 1909 one visiting scientist, one guest workers owe research
a^sociat* and ths?g® cliiiieai asisociatss w©nit ths appreciated call.?j't :; ■-
ator® In #lther routine cila^cstio serrle® of th<s ^aaeh or it®
y©e@areh aetivl%-o Tha:lr aithttslastis partielpation and tJie oxitit,^
contilbution of som® of thiis» inveartlga'tors des@r«(«s mors th^n aisii: ;,.,
aekao^9dg6ia®Ht,. It is through these as well as ttirough tha anojsyssoits,
but <|aite efficient daily halp o,f th® feeehid.ea2 and ^eat-^tvarial steff
that the functioning of tha Braiish wag rnsd® posslM.to
A« ift the preTiisu® jBa-m Urn Qllxdo^l Dire©t®r has prcwidgd eoa-
tiaaoue construetivs . eooperationj, Tjs«ful suggestiom and inv&lu^bl© hsi;:
iHh«y«v®y r®qu©st«dj for thij, th® Chitf of th® Braneh wishes to expt^m
his most slne®ir« appreciatioao
0RP=2 Serial Noo MiaDEk36(Q)
lo Elsct^^cephalography
and CliUo Neurophysiology
2o SEQ
3o Bethesdaj Maryland
Uo Contiimation of gOGp 19565
7BC, 1957 and IC^ 195^
PHS-NIH
Indi-^ldual Project Repcvs-t
Calendar Tear 1959
Part Ao
Project Titles A SQiaure /tlae (Cn.inical«Electroeneephalographie
Gorr«lation3)o
Mj^ipal Invast^^atort Gosiaw Ajmone Marsan
Oth^ In^stlgatorst Kristof Absshaa
CtogpgggMg^^^^^dtss Nous
Man lears (calsndss' yeas* 1959) s
^oUST" 2oO
Psrofessionalg O^U
Ot^rg I06
F^gjggt__ Inscription g
Ob jeetjyes s Outlinsd in the titla and d^seribed in preirloas
reports (78Ge 1957) »
Methoda^ ^yloyedt Deseribed in previous reports (iCp 1958) o
Major flndingss Chit of over 250 epilapt-*". seizures of different i^ipes
obserred firom beginning to end and recorcL^d photographicsally and by
continuous dietatlon on t&pe^ h3 h&ra been ssleeted and laounted in an
Atlas formo Eaeb seizure consists of frera one up to four larg© plates
and ths Atlas contains a total of 91 plat@So In each plat® EEQ tra@°
ings and synchronized corresponding photographies a^jpear^ oorrelatsd
by a detailed deseription aM eoMaenta of both clinical and electro^
encephalographic featurasp All the vari^.:s clinical signs wex^
analysed in detail and separated into different groups o A nuaOser of
interesting observations are discussedo Thes® include coesisteJMe and
synt^roHgr of Ixjth clinical and eleetrogx^phic chaises | presence of
clinical changes in the absence ©f EEQ m4.3>Iificationss definite ESQ
activation in the absence of visible clixiical featureai various possible
EEQ pattexas aeeoaspai^ring loss of «x5nseiousn@ss| focal roovgrnents of
Part B iacludsd les /^ ^ /y
body^ fao« axid I'Mbs wii ^graphic ,
various types o-T aiitoKati, «^ c .s^-^-., c:.,. vv^.v.:..-.a- ©leafcrographie chaiigg®j
sevaral ssizurfs obser^sd in the same subjeeti eleetrographic eor=
relates ■Wlien i^ing eha.'onica*i } j implanted eleetrodsSs etso
Signif icanc';^^to _gie p:. >ggr. of th @_ Igg ti fate, ? The projeet is related
"ic J "and" ^^m~^^^BX^j pert "^""'£tie' genSral'^sti;*);^ of diagnosti@p
pathogen© I'd. c and therapeuiieal aspeets of epilepsy-;, and in particular
of teapc-al lobs seisriires.. It falfillSj, in additiorig the need for a
clear i jonogmphic demonstration of the various clinical patterns
which lihe diffsr®nt s| lleptic attael^ra oslginating in different cortical
x^gt.iis viss assume o It is^ fiJiallys an attaiapt to correlate the
mod'-i^icationfi of the eleebilcal activity of the brain with the nuraex^
ov-is t!\\iltifo.m motor i5'?pe«yfes of clinical behsTfior and a complement t@
ifie inonograpli published iii 19^7 by one of the auttiors on the localizing
significance of the va^loafi dinleaS, maMfastations in the different
types of ep3.1epsy (see project TSC, 19$7)o
Proposed cQurg§ of '^'t®,,^^!;!?®'''* '^^ px^sjeet in itaelf is.overo Th®
TOnograpTHaffi 'Bi^^ec®pt®(i""Wr pubjlcation and will appear shortly
as Suppleiaent #l5 of the Joiimal of Seetroencephalography and Clinical
Neurophsrsiolegyo Ths Ntuc^ Is^ howaver^ carried on for practical pu3^=
poses (in cooperation i^ttth tha Branch of J^tirolsgical Surgery) as an
adjunct of vr© various ssreeaing and diagnostic procedures in cases of
patients eoasidered as p&ssible rsanriidatea for surgical treateaent of
seizures o
Serial itoo iiJIM)B^36(C)
PHS^MIH
Icdivldual Pyojest Report
Part, 38 Honors^ AwerdSij, and Publications
Publications other ^ari abstiracts from this projects
Ajmone Marsanj Go and AamhaiBs KoS A Seissure Atlas (Clinical=
Electroencsphalographio Correlations V. Supplamsnt il$i EEG
Clino Neurophysiolo in pffssso
Honors and Aisards rslai^ing to tJiis project'
Nos'a
0RP=2 Serial NOo ^i\iIf^DB=37(G) ^ ^
lo EleeilroeneispHjS.oglpftp^
and Clino Neurophysiolog;
2o EEQ
3o B9thesda» Maxyland
Uo OontirmaUon of QIC, 19Si
79C, 1957 and 20* 1958
PIS=MIH
Iriditldual Project R®pos-fe
Calandar Tear 1959
Part Ao
Project Title? Itepth slsetrogr^hy in ^ileptic patients o
Principal Investigators CtosiKO A^Eone Marsan
Other Investigatoggg John Van Bursa
Coopsrating Units; Branch of Neurological Stjrgesy
Man Yeara (calendar year 1959)8
"""fSteTT lc8
Professionals Oo2
Others 1«6
Project Description?
Objeeti^est S®© preirious reports a
Major findings and proposed co^rae of the projects New data collected
sine© the liast report arb still in the process of analysis and elabor=
ationo In the nseantia© collection of farther cases is oont^aplated
in view of the fact that patients siii table for this ^|» of study are
rather rare^
Part B included Yes H^ No /^
1,0 ]^8Q'tZ08n00p^83.0g]!VpiQr
3o Bsthesdaj, Maayland
Ito CJoatimation of 79G, 19^s
SliCa 1957^ 30, 1958
PHS^MIH
Galesdte? J®& 1953>
Parte Ao
Project Titles El@et£-oco7tieogsapMe stuies in t©aper^ lob®
epile^^ and la fossl cer/oral s@i8m°@So
Priasipal Znvsstigatoyg CosIm© A^aaon© Mai'san
Otheg Jn-m8Ugs.%OT&i Madtland Bal<teia
Co<^<9gating IMtsi Braneh of Neurological. Surgsz'y
Man gears (caleadRi- year 1959) s
Professional? 0
OthsTJ 0
Prp^^eet Besegiptiaag
Objectives g S©@ previous reporfe (f^.Oi, 19^7 ) =
Ma jog ^findings and, proposed govts® of th@ projseti Ifew data collected
sfcce' W® las't report mm sttlTTS^Wisialyssdo " 1j® project oontinstss
with addition of tbw cases o
Part B included ^®s £7 ^ ^
0RP=2 Sexlal Hoo m.mB-?9(0)
and C3.1no Ifeforopl^siolor
2o EEQ
3o Bethesctej, Maryland
ko ContinuaUon of ^Gj, l9$f
PKS-NIH
IndLvidsial Projeet Rsport
Calenday Tear 19$9
P/irt Ao
Pro j9et^^_ Titles Uhitaiy enal^s of the response elicited in Ifc©
Tlsual (^rtex of eato
PrlBeiffal Investigators g Lenmrt Widsn and Cosiao A>Jona Marsan
Otbgy InyQS tigatorg: Nom
Cocparatiag Unites None
Man Years ( calendar year 19S9h
Totalt lo7
Professional « Od
Othsrg IcC
Project Deseriptiong
Objoetiyipa? To study tesporal and spatial distribution of unit aetiviigr
■S^xHSOfie ¥isiial cortes and undsrlying ^ite aiatter duing th® coarse
of the eiroked surfac® TBspons® aSLicited by a^jnulation of the optic
radiationSs and to analyze the function^ characteristics of the
unitasy elements in rala-^on to th® varioxis phases of the surface
reaponsep Th® purpose is to understand better the nalair© of l^e various
eoB^onents of the response o This response is rather artificial and
different from that eliciiabl® with physiological stiimilij on th® other
haMj) it is a typical and charact©riati© farm of evoked potexitial &M
it is a usefua. tool lending itself to the analysis of basic properties
of the specific projection sys terns o
Part B included Yes ^ ^ £J
-2 Serial M. i!gMDB-39(C)
Methods etspla^dt Itescilbsd in pnjjaet 5C, 19^f^.
Major findJBgss
lo The majority of spikes racorded, discharge during the com*se of
the specific e-^oked surface response arA may be temporally related
to its various eoinpoRentSo
2o On the basis of latency and of their behavior when tested wiih
double shocks and repetitive stiimilations all spilkes a^ be divided
into two groups? "presysaptie" aal "postsysiaptic" o
3o All spikes teit^soxally related to the first wav^^ and alaost a.11
spikes firing during wave 2 are recorded frcan udiit® matter and all
have presynaptic characteristieso Those teiaporally related to wave 3
have the most extensive spatial distribution being pi^ed up in both
cortex avd ishite jnatters s<sae behave as presynaptic^ others as post^
synaptic events o The spikes related to wave k and the rare oiws
relal^d to lijave $ and all of the postsynaptic type and mat of than
are only f o\2nd within the cortexo
Uo A ^sitive ^rrelation «$ists between presence of spikv? and
ansplitude of the surface respomso Thi^ can be espresssd ae follow®/
first or second wave spikes appear ^em waves 1 or 2 have retched a
critical sizso The spikes then rasaain stable responding to e%>©ry
stiHuluSo A third wave spike of a presynaptic type behaves siatMarl;
Spikes of postsynaptic -type related to waves 3» it or 5 also raay np^:
when the first wave has reached a certain sizej above this threshold
values howsvers they are "unstable" responding irregularly to stiai^lii
of constant streng^o Their probabililgr of discharge is greater th'g
larger the aisplitude of the late surface wav«o
$o These finding provide further confirmation of some of the sutk
concepts of the nature of the various ccaaponents of the •^sual"
responseo They also offer an fiocplanatlon of the difference of opim
still exLstisg in regard to the nature of wave 3^ which is considers
as presynaptic by sosaep and pcsitsynaptie by other investigatorso On
tte basis of otir results, both pre^^ and postsynaptic eleiaents are
present in wave 3o
-3 S®xlal fee fflfflg^39CG)
Sl^aifiaiBs® t© t^ ^^TOgiga^_^tl2®^^togtite|e§ fhis ps-ajeet ^aphasias©©
aetl^ijjo In partleml&ffp it deals wittj tb© speeifie pr@J®©tioa sj@t=s®
betM©®n fMA$mxs aM eort^s vihl^h asr® of iznquestiosiabi® iutsrestp and
in Ti©i? of th© faet that far-rsaoliing oonelus-l.OHs c©B«i:iiisig ^^±t
QTg&r&.B&i'A&si. has bsaa 'Ir^iilt upojo. th® firaetioml substx'ats of th© ©voked
3rospom®9 th® sboTO^clossribsd inTOstigstica appears mors than ;1ta8tifi©d.c.
Propoeed aoxirf® of t.h© pgoj®ets Sis prsjeet has b©®n tsraimteda
prsliiBimfy '^^^/'tos^ pr?©s@stsd at tiki Jfeiroh Meeting of tis® Esstss®
Assoslation of 13.®';fero©ne@phal©grap!i8rao a© final p^jor has been essst
sad aessiJted for yablisati ouo
s^^^s^i ^'^<' .MmMMSd,
Iridividual Pro,ieet Repcrt
Calendar Jem 1959
Part jBj Honors g Awards^ and Publlca-y.ons
Publi,8atlosM other thasm abstjmetffl from tiis projeets
Widenj, Lc and A jmone Harsaaj,. Go t Unitairy analysis of the respona®
elicited in the visual eorteat of eato Archives Ita3.o ffi.olo 1960o
In prasiio
ORPog - S®rial NOo i^Il^EB4tO(C)
lo ElecTro© nbepmlog sraph;-
and CliHo Heurophyslo.
2o EEO
3<. Bathesdag Maryland
lie
PHS-nilE
Individual Projeet Haport
Calendar Tear 1959
Part Ao
Project Titles Microeleetrodi inyestigations of the laeehanieasi of
the electrieally induced spileptif oysa aei»ir®
("afterdischarge*' ) o
Principal Investigator g Paul CJerin
Other Inyestigatora g None
Ck?operatini^ Unitsai Kon©
Man Years (eeaendsr y»ar 1959) «
" Totair loO
Professional? loO
Others 0
Project itea@ri,ptioM8
Objegtiyea^ To esplore systemati(»lly by means of laicrseleetrocigSj
"ihe cilKTar phenoiaena eharacterizing the onsets de-^loproent and end
of 1*18 electrical afterdis charge elicitable by rspetitiv® stiumlatiox-
of the oorti@al surface and to attenpt an inte»pretation of th®
iBechanisms at the basis of this type of self=sustained aetivityo
Methods aiqployedg Aeute escperimente ware p erf or jaed on catso Eiee=
^^ai ' stinulation was applied on ©i® cortaae of the supmsylTian
ggrrus vi-tti variabl© parameters <> Piek=up cortieal eieetrodes wer®
silver=>silver ehlori.de for the slow siirfa@e e^rents and tungsten
raieroeleetrodeSs the movement of the latter being eonfcroHed by a
l^draulic joieroraanipulatoro Recording was carried out dsiring th«
stimulation and feUosdng ito A total of 2^00 afterdis diarges wer®:
elicited and of thea« 600 were reeordad on film ^th a detailed
analysis of 80 diffei^nt units aetivated during their derelopnseMo
Part, B included les ^ N© £7
Serial NOo li4lM)B<=>l0(C)
Ma^pr fiiKiinga?
lo Hspetitive stijiiulationj, c&ps&le of eliciting afterdischargep la
accdsapsnied by ss-ogresslve ds^eloping and cha raster is tic changes in
the spikes aetivatsd by each elQetric p«ls®o Units tend to fire
repetitively and ^b© as^jlituds of each successive spike decreases
until th^ e-s-entts/iBy EJight disapj^aro
go In the absence of such chsngeSj the develojaaent of an afterdis chaste
is hi^ly iurprobibleo
3o During the E^ afterdisohargeg \anit sjxLkes generally absent at th®
very bagiradngj; 3K)gressiTe3y appears their voltage is at first low
and their tr&qa'm^ highp than th® rate of firing slotis dowi and their
araplitucte reash^ia tb@ pre'=8tisssilafcion valtai at ^ich point the after-
discharge endSo The spike ehatig®® have been interpreted as -Oie ex-
pression of dri/i'erent wsmhr&xm polarisation levels » the charaeteristk?
ones consistl3ij of an excess of depolarization and of longlasting pe='
polairi^atioii t recess o
Sigrlfit^nee to the prograa of th® Inatituty? This is &a flKpari»ental
ar^S'oech to'^SFproSlS of epilepi^o I'^'eleetrieal afterdi8<*arg«
<7iicitabl9 T ?.th repetitive stisaalation is morphologically indii8tiB=
^ishable tvm a spontaneous eleotrographie attack occurring in huaansi
affected bv epilepsy and recorded froa their exposed cortical tuxfacso
The unders'i&ndJ.ng of the intimate Msehanisra at the basis of this par^
tioular ty.e of self^sustained activi-^ is an issportant step for tl«
understaiKfii^ of the pi^raiopat^iclosr ©f epilep^o
Proposed faura® of the projeeti This project has been eoiapletedo
Results wTr© presented in June at the Atlantic City iaeeting of the
Americaa ;SQ Societyc The final paper has been sent and accepted for
p^&licatl>ao
Serial Noo MBtDB«4tO(C)
Individual Pandect Report
Calendar Wa? 1959
gagt^g Ecmapss Awards, end Publi.eatlons
Ptafeliiy tioKs other than abstracts f:.>Ga this project*
Qmi-is Paols Microel©ctrods ?.^^stigs^iosls on the mcbanisias of
tis© ©leetxleally iadaoed ©pi^sptlfom stSsup© ("aft©rdis(Siar^")o
itr'ilslres Italo Blolo 196O9 tn presso
rosoi^ aiKl Aisards islatir^ to ■Oils projecto
0RP»2 Serlsa Ifoo MIliDB4tl(C)
lo Elcciroeneaphalographjr
I:
and Clino Neurophysiology
EEQ
Bethesda, Maxyland
PHS=NIH
Individual i¥o>0t R@p©rfe
Cal«nday Tear 1959
Pax^ Ao
Pro^aot Titlai Effects of cortieofVjgal and cortieopet&l iiapuloas
upon single ©lamants of the lateral genieulat©
nucler/3 o
Principal Invaatlgatosin Lannarfc Widen and Gosimo AJmone MarBaa
Othgir iHvestigatorg 8 Eon9
Coojperatinjg „!J|^,1^,^ Koj»
Man leara (calendar yjax* 1959)8
Prof asaiomCL St Oo'^,
Other? IcJ
Pgo;3get Deaeriiptlrru
Cfejectiveag TMs fetudsr was undertaken in an atteaspt to im-estigate
wMtbBpl^cifte c: asaooiation cortical areas may exert any effect
upon the incowing lansojy messages at a tilmlandc level and spec-
ifically Tjpon unit' activsitisd within a sensory relay nucleus <,
Visual and ouprasj LTdan (association) cortex and lateral gaaaiculate
nucleus were the i gions respectively selected for this investiga-
tiono The inter®£' in "Miis project was aroused by anatcmical
work, stating that ^Ji the visual cortes about 3Aths of ttie fibers
are eorticofugal, although their actual destination is presently
Methods employeds j he escperisaBnts were performed on unanesthetized
IT^rveau '"Isblpn?'^ paraMon) catSo Tungsten aicroelectrodea vmre
Part B included Tes £7 ^° S
=2 Serial i*o^ M0B-Ms.-
placed within th@ l®t®ml geni!Si3.at® nucleus and cortl.eal ^aetrod^g
wers used to monitor the arriml of the specific visual resp«n»@o
SLngl® psalse stimilatiea of th@ ipstlat®ral ©ptic tract and of v.srlua:«
pointa of the vts-ual and isups^sylfisn cortsx was carried outo Hi ©tie
stlHulatioB was also used (s;lBgl@ flaah®s of light of progressiTely
inssHeaslng intensity) o
Major fladiirigsg these ar® still in the procsss of being analyzed in
dfitafl^ Tt^rly larg® percentage of about 200 unitary spJIJces TB&yrmv.
from the r«gion of the lateral gani©ilate nucleus war® activated by
both optic tract and visual cortex stimulationo In eAdti instaae®
atterapts were n»d® to inauene® each reeorded spike by cortioal as mil
as by tract stimuli c It wag found that diffeysnt types of effect ©culd
be obtalnedo In generalj, cortiaal MtdjisulaUon t«nd8 to inhibit th«
spites elicited by optls tract stijnwilatlon and stiinulation of the optis
tra©t t»nd8 to facilitat* tb® spikes ©licitable by cortical etii!mlatJ.c...-,.
EsEanples with oi^ait® effects (faeilitatoiy action of cortex and isi-
hibltosry action of aptie tracts) were founds as well" aa rm:'® iMit^nw©
in «4jieh botli stiisiall woi^ld havig a raeipr-ocal facilitatoj^- or iJilPiibitox-
©ffecto ScHae of th® oortieal ©ffacts are- very likely int©rprett,bl® as
the remilt of antidstattie stimulation^ howsverj, the extMsaely long
laten<^ of majagr spiks® elicitud by cortical stiimilation strongly sug-
gests that ■Bhest be ortodroitiically activated eleraentso
Significance to the program of fee__In8titutfiS This projeot dsals Mi\h
ih® ImmW^iMMroi '^ffi®HwHiHiiS~uioiHy£ng sensory pareeptioao
Ree«nt.ly there haa been a las'ge munber of experimental results indi=
eating 't^e ®xistsnc® of in^iortant eo2?ticofugal influenceg upon th©
non='Sp®@ifl.c rstieular fomiattc© and ajaphasizing th® role of the fon'-.er
tn exerting a control on the different affes^nt messages at th&% level,
therefor© providing some indir«et inforjnation to our understanding of
problems related t® arousal and consalousness in genea^o It is^
hoMgver^ in the neuropJiysiologieal ata.^ of ttie reeiprocal relatiofn-
ehipi betiween corteac and spaedfic -chalamie nuclei i*iich one tmst look
for the integrating aie<ghani»m® of ttm psreeptual data whidi foj^a tH
uni^ of the actual vigilant consciousnesso
Proposed eourse of the proie<gts The e:iEperlmental j®rt haa been com-
p^^TaiS°''^'n5iinii^~dr"&nprocses of amiyaing th© various d&ta
and preparing the presentation of results in a publishsble formo
0RP»2 Serial Noo litIM)B°li2(C)
lo Eleclroe nlcaphai ograpl5^
and Clino Neurqphgrsiol
2o £EQ
3o Beth©3d«p Mayyland
Uo Nev
PHS^illH
Individual Project Report
Calendar Tear 1959
Part Ac
Frojegt Titles Thal«Biocortic«a jaatthanisiaso A eoisparison bet«e®a
spe<d.fiCg association and non-specific systesoso
Principal lavegtigatori Arfeuro MoriUo
Other Inveati gators 8 Cosimo Ajmone Masraan
Gooperatirtg Unites None
Man Yeara (calendar year 19 $9) 8
*otair loO
Professional? loO
Others 0
Project Deaeriptiong
Objectives s Sons of the neuropJ^ysiological characteristics of these
iihT9'3 functionally different systems are relatively well knowio The
purpose of this project is to ex:iti@nd the knowledge ws already possess
and gather new infonaation about fim differential behavior in the
three thalaiaocortical sectors, by means of unitary analysis within the
cerebral eortaat upon stimulation of different thalasaie nucleic
Possible functional inteirelationEihip between these three systsrss wars
also investigatedo
Methods employed* Escpsriiaente wers parforrasd on cats partly under ba5P=
Wburaie anssthesia and partly uranssthetized (cerr»au isole" prepara^'
ti,on) o The studies were carried out on the suprasylvian (association)
cortex^ as wsH as on the prLnsar^f visual cortecSo uli^in the thalamus
the following nuclei were specifically stimulated: lateral geniculate
inucleusp nucleus lateralis posteriori, and nuclei belonging to the non=
specific 3yst«!s (centralis latexaliso centre medianumj, ventrali®
Part B included Yes 77 ^o ]^
Serial llOo ^^-^^u-
antexdors et«;c,)o SyBteraatic suw©?- thro^tgh ft© cortical depth of
the two aboveraentionsd areas was carried out »5.th tungsten micx^^
eldctrodee eontrolled by a hydrauliLc micronsanip ilatoro Surface
cortical rejsording was also employt'd to monitor *ihe gross mirfae®
(evoked) responaco
Ma te fir
fiBdisgm The variouffl flt»d3;3gs obtained in ^-^er $i eat® ®r@
IjP^ proc«8S of being anal-'-sed in detailo 01 nervations eon=--
ceming diffarenees in latency ^ vfriabtlilgr in latency and chainees of
anit a©tivaiion by different at-lmrlig inter^^ffects b«tvj®en the dlf-
f6r«mt stdMilations upon the s'me uni,tajy elesGentp etCo .. w«re made sM
ftrom & preliiulriajy analysis t'jie results appear rather iit^sres tinge,
JPyopoaed ooura®, o^ the projr^t? Completing the analjoi® -nd carryixig
«mt7'"^''nSsSy7'''^ii°tt^ before draning flm; oonclusiom-.
Si^flcanc® t-o -yy program '>f the Institute? 15: is typ« o.t -imrestiga"
llm "oi3wlS"'1b@" 'useful not' oH f for' ^ucida€Sg ths' intiraat« ieeha?slsm@
of th;.'ilaiaocortieal reli^ «yi tema and ps»blemi9 r«'.',ated to pe: «eptl©»
and csontrol of cortical aet/.vityg as irell as for general prtiemg
eonneetsd with arousal^ at^'antion and sensoay eliiborations bi ,• could
also provid® seme clue for the understanding of ©@rt«in type'i ^'.f "focaj"
epil©ptog®nic lesions whic'. may actually Invol?® t^ectorss ircluc-qg bolii
cortasE and "fchailaitaus ('«*ree"Aalaraic" cone«pt of Gteiataut)o
itonual Repo;£ ' Novesnber, 1959
Suirgical Neurology Branch >
Na£lonAl Isistieute of NeuroCLogical
Diseases and Blindness
SUMMARY
During the period of this repor&» 231 pati ti were studied on
the wards, while in the Outpatient i)epart]nent, 2}' patients were
examined in a total of 394 scheduled visits. In fh& neusrosurgical
operating room, 108 major procedures were completed. Of these, 50
were concerned entirely with the surgical treats « tt asid Investigation
of epileptic mechanisms, 48 were performed for pace-occupying lesions
which came to operation through investigation '■" 'S-iileptic patients
or patients referred from other programs » Thr jt^ 10 miscellaneous
major procedures. These were performed for tl sf of pain. This
report is based on information drawn from the investigations in ward
and clinic, as well as relevant Isboretory work. Thirty reports were
prepared for publication during this year.
The majority of the patients studied suffered from tei^oral lobe
epilepsy. Some cases of focal epilepsy originating elsewhere in the
brain were studied, and a emstll group of centrencephslic seizures were
also investigateJ, Twelve patients referred from the National Cancer
Institute were studied and eventually treated by either hypophysectooy
or stalk section. This small group of patients provided a source of
considerable information on relevant endocrine problems, as well as
physiology of the orbital frontal cortex.
The etiology of tenq>oral lobe epilepsy has been further studied.
In this year, several patients with ten^oral lobe epilepsy came to
operative treatment without clear evidence for the precipitating
cause of the epileptogenic lesions . In these cases, a bony deformity
of the middle fossa was discovered. This was not apparent on pre-
operative or retrospective postoperative examination of the plain films <
The deforntity consisted essentially of a stalactite formation of bone.
Several spicules protruded «:hrough the dura into the brain. The
peculiar c^nbination of bony mass, dural defect, m,d cortical lesion
was related to electrographic abnom^lity, as well as pathological
changes in the underlying brain. The cause of the bony deformity is
not clear. In some cases, there was a history of injury to the head,
but this did not appear significant . In others, there was i^ reliable
clue as to cause-effect relationships. The bony spicules are not
metastatic and do not constitute evidence of osteosGa. Nor was there
evidence of scute or chronic inflammatory change. In these cases no
other etiological factor was evident. These cases may be compared to
those mentioned in the previous Annual Report, in each of which a
vascular malformation was discovered at operation, being undisclosed
by pre-operative investigations which included arteriographic contrast
studies »
On the ward, the ictal, interictal, and postictal behavior of the
epileptic patients fonned the basis for the majority of observstionB .
2.
1© addifeisu, several psobleaas @f iu&raetable paix& were iEvesfeigafeed
aad Khe application ©f urea fee abaermal iagracranial pressure was
ceafcissuedo Several cases ®f cerageraifeal defects ©f She brain were
studied^ arad all the patients concerned forss the bmsis ©f social and
psyah©l©gical studies within the frasssswork ©f the ward envirooisent „
Autoasati^E was once assre a principal target ®f investigation o
fhe seizure observation program developed by Miss Pimie and carried
®a by Mrs« fhooepson, has provided sease 2,000 photograph© ©£ patients
as they appeared during this peculiar fractionatloa of consciousnes® o
Each patient is being subjected t© a series of stlisuli during the
period @f his autotaatisiB, while it is photographed and notedo His
response to pain, pressures heat, cold, touch, noise, and light was
cataloged,, The relationship of his saovements t© the spstial charac-
teristics of the environment and to these stianili Is also notedc
These patients do respond to pain by withdrawal or by cosabination of
withdrawal and semi-purposeful njoveasento Pain will interrupt the
repetitive pattern of rooveffients which seems to charscterlse the outward
expression of this peculiar state o That interruption is short-lived,
however, and the state cannot be Interrupted by touch, ordinary pres-
sure, heat, ©r soldo The patient will turn his he^ad towards a sharp
noise and his pupils dilate at the gound. His pupils do respond to
light individually and consensually^ Insofar as exasiination is pos-
sible, the reflexes have been tested occasionally during these auto-
asatic states o Apparently, no abnors&al reflexes have been elicited
and the deep tendon reflexes are not markedly different in response
during this state » Since it has been known for seise tinte that automa-
tism and speech occasionally coincide, sas^les of such speech have
beess recorded and the patient, in turn, has been subjected to stereo-
typed language stiiBullo The response to this complex stiisulus pattern
is variable and apparently irrelevant » Dto Adarakiewicz has begun a
systematic study of this fascinating condition o H^Ls study begins with
a photographic comparison between the actual clinical state as recorded
froas a patient, and the imitation of this state as portrayed photo-
graphically by one of the mfsdical staff quite faniliar with Its
characteristics. All observers agree that they can tell the occurrence
of such a state by 'looking at' the subject's face, but no observer has
been able to say what facial characteristics indicate either the begin-
ning or the continuation. Conversely, all observers agree that they
can tell when the condition is over by observing the patient's face,
and yet there is no agreesnent as to the relevant facial changes. These
changes are the object of a search continuing in the presents In
addition. Dr. Admkievtcz is studying changes in vital signs and skin
resistance, the observation of which may support or otherwise relate
to the systematic study of the autonoialc concomitants of automatism
conducted by Dr, John V'an Buren, Dr, Lsskowski is engaged in the
study ef the relationship of handedness to the occurrence of automatism
and its particular characteristics in the individual case. He' is
studying lateralization of speech and relevant cerebral dominance in
these pati@nts by means of the Wsda test, Dr, Otenasek is assisting
him with this study. In addition, Dr, Adamkiewlcz is studying the
problem of unusual bleeding in patients aociing to craniotcsssy, while
Dr, Maccubbin has begun an intensive review of the results ©f treatment
of tess^oss.1 lobg epilepsy durireg she past 5 years c. la addifciojs 60
ehe 8&a£lstlcsl a&d systensaeic S8p@ctis of this study, he is studying
Che £ela£ioisship between ares of ablation and subsequent clinical
findings, as well as between ar@a of ablation and subsequent electro-
graphic characteristics „ He will, in turn, relate wherever possible
the pafthol®gical lesion as Identified in the laboratory t© the clinical
characteristics of the case^ In addition, his study will incorporate
Inforssatioo derived frous the routine investigations of physical descrip-
tion, language characteristics, and studies of social interaction^
Mrso Thempson has continued the observation of physical characteristics,
including photographs, the language sanapling, and the basis for social
studies begun by Niss Pimie,
In the neurosurgical operating room, the studies @f airborne
infection continue., Miss Lewis is conducting these, in cooperation
with Dr, Herman and other nsesabers of Mr» Snow's staff „ Various aseptic
techniques are being tested and are under study at present. The use
of special clothing, ssasks, and development of traffic patterns more
suitable for reduction of airborne infection are being developed and
testedo New and msre effective sasthods of cleaning are als® under
study o Many of these ideas have been incorporated by Dr, Laskowski
into a report which is being studied by the Surgical Administrative
Committee of NIHo Miss Lewis has c@cspleted her Procedure Manual for
Neurosurgical Nurses » This embodies descriptions of £hs various special
and general techniques, as well as instrumentation and its particular
usageo Dro Van Buren has coespleted the developsaeiKt ©f a stereotaxic
instrument and is now preparing it for use on patients in the operating
rooffic I» cooperation with Dr, Clarence Hebert and staff, the use of
urea In conjunction with hypofeheHaia has been developed and is now a
useful and successful tool in the treatment of increase of intracranial
pressure during operation, as well as in the protection ©f the bratin
which must be handled during surgery <,
The design problems arising frmi the development of the new
Neurosurgical Suite have occupied many hours <> The ground for the
building which will house this suite has been broken and before this
the final plans ccoKBitted to the hands of the architects o The suite
will constitute a new departure in operative design for neurosurgical
procedures o
There was some progress in the laboratory ^ as well, A study which
effectively bridged the artificial gap between laboratory and clinic
was Dro Van Buren 's analysis of autonomic concomitants of automatism.
This study, based on the wsrd, was conducted in part in the Laboratory
of Electroencephalography in cooperation with Dr, Harsan, In addition:,
and with touch the same approach, these investigators and Dro Allen
Mlrsky studied the effect of centrencephalic discharge on the patient's
response to the standard test situations as well as the sutommic
changes which occurred during the discharge.
In Neurosurgical Anatosg^, Drc V@n Buren has studied th^connectlori"^
of the human tes^oral lobe with Dr. Paul Yakovlev, as well asS the
\
4.
pa£hol@gicaI anatoa^ subsequeae £o & twmt in the pari@£al region, a.
suprasellar ateningiosia, snd £emp®ral destruction doe to an extra-
cerebral neoplasmo These studies wer© controlled by cootparison with
5 "nomeal" brains subjected to similar processes of intbedding and
sectioning. His studies have provided physiological » as well as
anatoisical inforraatlonr He has studied the electrographlc activity
of the cooled hxjo^n frontal lobe snd its response to hypotension, a^
well as the autoncssic responses subsequent to electrical stiasulatior
of the orbital frontal cortex. These observations were made during
the course of hypophysectoio^ or stalk section for metastatic cancer.
These operations provided anatomical material which permits a qua;.tl-
tative evaluation of hypothalamic and hypophysial tissue o They also
provided opportunity for stud^ of the endocrine effects of stalk sec-
tion and hypophysectcaay which were carried out in conjunction with the
Cancer Institute » In addition, Dr. Van Buren has continued his study
of the human visual system and has developed a satisfactory method for
two-dimensional retinal reconstruction. Similarly, he has continuer
his anatomical studies which form the background for the future clii&al
investigation of involuntary
In Neurosurgical Physiology, Dr. Li has studied the cortical intra-
cellular potentials in epileptic cortex, as well as the response ef
similar potentials to a single cortical stimulus. In a further inves-
tigation of cerebral cortex^ he studied inhibitory neurons and syiaptic
activation o£ nerve cells in the primary visual area. Also, in e/njunc-
tion with Dr. Igor Klstao, he is also investigating electrical a tivity
of various cellular elements which can be studied in Dr. Klatzo s
tissue culture apparatus »
In the Laboratory of Neuropath© logy j, Dr. Klatso has begui a study
of morphological chsmges due to radio frequency energy. He s also
studying the pinocytosis and uptak@ of proteins and neutral red dye in
vitro. In conjunction with Dr. Engel, he has studied the Mstocheoical
and electrophysiological characteristics of muscle fibers irown in
vitro. In collaboration with Dr. Jaime Miquel, he has un>@rtaken the
quantitative study of precipitin reaction. Along with Dr. Laskowskl,
he has studied the effects of hypothemla on injured muf normal brain
tissue. He has also investigated the pathology of Kun- Disease and
localization of myosin in human striated mitscle with various
investigators.
In Developaaental Anaton^, Dr. Deksban continues the study of
etiology, pathology, and clinical o^nifestations of cerebral palsy.
He has also begun a systematic study of epilepsy Ir childhood. The
latter is, in. fact, a collaborative project in whiih his Section and
the Sections bt Neurology and Electiroencephalografhy of the Mayo Clinic
are participating. He is continuing his production of congenital mal-
formations of the central nervous system using ri.ce as escperimental
animals. In the clinic, he is studying the incidence and type of
central nervots ©ystea abnormalities in of f8pr:,ng bom to diabetic
mothers. Similarly, he is studying the produc'^s of abortion and their
relationship to maternal condition during pregnancy and the course of
birth. ':
5.
The Laboratory of Clinical Psychology under the direction of
m, Herbert Lausdell has added ^s. Sylvia Jones (^judiologist) to
the staff. Under the direction of Dro Lansdell, the laboratory
continues to samljze all test results obtained from patients suffering
froaik epilepsy snd various other neurological diseases <> DTo I^^snsdell
has worked with Drc Laskowskl in & study of cerebral dominance and is
also studying the verbal efficiency o£ patients with tes^ral lobe
epilepsy o
The Laborsitory of N@uromiesth@8iol@gy has been osaintained through
the efforts of DrSo WilliaB Pritehards Charles Bustoasaj and Shelly Chou,
These investigators have continued the dewelopasant of m technique by
which the brain stay be selectively cooled through shunting inflow blood
through an appropriate ^paratus. The outflow blood is siiailarly
shunted to a warsdng apparatus « It is hoped that this method will be
soon applicable to clinical trials and that it will provide an efficient
e:»qperiiEtental tool in the study of the effects of low tesoperature on
prlniate brains in laboratory investigation. In thi§ laboratory,
Dr, Bucknara is also studying the effects of selective cooling of the
cerebral spinal fluid on brain ten^erature and is beginning preparation
for a study of selective cooling and/or heating of the hypothalaaaus »
In conjunction with msaibers of the frlmate Neurology Laboratory « he
has studied the effects of fluothaae on chin^anaees with polygraphlc
recording devices „
In the Laboratory of Primate Keurologys Dr, Forbes Korris has
been investigating the effects of nucleuts sss^gdallformis stinsulationo
He has Iffiiplsmted depth electrodes in the liiiiblc system mxA superior
brain static In each preparation^ he averages 19 electrode placements »
Action potentials were recorded from other electrodes during and after
stimulationi, while he made movies of the total effects, when present o
The animals were awake and free of narcotic effects during this stima-
latlon« He succeeded in evoking reactions sitailar to those seen in
human autoffiatiasj. These j^tereotypsd reactions were concomitant with
a spike-^and-ws^e discharge recorded from the mesial temporal region o
In addition^ Dro Horris has been investigating ais^gdalo-aioygdala
connections by conventional physiological techniques »
Dro Bachs Miss Lewis, and Dr„ Baldwin investigated the effects
of radio frequency energy on the awake, unanesthetiaed rhesus monkey.
Such energy developed from standard ground-to-air transmitter was
conveyed to the monkey's head^ which could be fixed in certain posi-
tions by a specially designed head-holder. The head and head-holder
were contained in a reson&ating cavity of copper mesh, so designed as
to permit both observation and photographic recording of the monkey's
reactions o Electrographie studies were also carried out after standard
placement of cerebral electrodes „ Som@ animals were subjected to radio
frequency m.d sacrificed ioBaediately thereafter, or actually killed
during exposure to radio frequency energy o Their brains were studied
under ultlri^iolet light for iainediate changes in blood brain barrier o
The majority of sraimals were autopsiede ®fter which brain and spinal
ccrd were subjected &o conventional his&ological sad hlstochemicAl
techniques o Exposure to radio frequency energy within the range
2C0 to 400 Mc» at s standard output o£ 100 watts was undertaken o
Tliere were ns* clinicsdly observable effects save at frequencies
b«itw@en 385 and 390 Mc« Siore effect was observed at 388 than at any
o^her frequency. The clinical effects consist of drowsing, arousal,
(upillaxy dilatation, disorganization of lisob {Qov@a@nt8, vertical
rystagiBus, horizontal nystagmis, unilateral grisiace, salivation,
tachycardia, increased ventilatlono In seme anixasls there was a
teaqperature rise as saeasured by rectunso This was trivial and
onpredictsble, Electrographic effects consist of developoent of a
"sleep" record during radiation and return to a norasal "waking"
xecord thereaftero Application of critical frequencies will arouse
mi animal from deep surgical anesthesia during periods of escposure to
radiation. Likewise, e:^osure to radiation will forestall the effects
ol! heavy barbiturate sedation „ fhe physical characteristics of the
resonating cavity and the antennae of the target area within the cavity
h<3ve been intensively studied o M esqperiinental design consisting of
a plastic phantom of knmm voluase equating that of the monkey's head,
and an an^litude signal recorder form the basis for these physical
observations. Nineteen phantoms of different shapes and in various
positions corresponding to the shapes ss&A positions? of the monkey's
heads have been tested. There is a clear correlation between ampli-
tude o! signal, temperature rise of 5^0 o» and frequency of carrier
wave. Carrier wave patterns from 200 to 400 MCc tested under these
conditions produce equal rises in tea^erature in the phantom system^
Yet the clinical effects are only apparent in the narrow frequency
range of 385 to 390c These results have recently been reported by
Baldwin, Bach, and Lewis, and by Bach, Baldwin, and Lewis at the
American .Psychiatric Association meeting and the Trl- Service Microwave
Conference 0 These reports were based on the stud^ of 50 animals <, Such
reports f&^^ the basis for continuing studies based on a new (kilowatt)
transmitter, physical capability for peak pulsing the energies and
developmettt of a si^&al generator system permitting application of
radio frecuency energy to single cell systems in tissue culture.
The effect of ablation on the coomunlcation pattern of the chinqpan-
see has beem studied^ Three animals have been subjected to unilateral
and then bilateral ablation of the area usually described as Broca's
area in the feumaao Such ablations were preceded by electrocortlcogri^hy
and a sequential stimulation of the precentral and postcentral and
other relevant cortical areas. The ablations did not significantly
alter the coommication pattern of the subjects. In other ehiiqpansees,
the entire cortical convexity ha® been exposed at a single operation.
Sequential electrical stimulation ®f the exposure has been undertaken
and the effects recorded. Then the area was surveyed with recording
electrodes,, and finally a frontal parasagittal penicillin focus was
establiehedo The effects of this focus on the electroencepha}.ogram
and a@ recorded by color photography have been noted. It lasy be that
there is some relationship between & change in blood vessel color and
the electrical spread of the seizure.
In further studies on the effects of hallucinogenic dru$s, it
seeass that feh®re is a wbstieutiv® telersRce befew®@n lysergic.acid
\
and psllocitio Tfee effects of lysergic acid on fche ehiiapaasee
decrease if the drug is administered each dsy for oae week. The
aniisal becocies resistant to it in the second week. If psilocin is
substituted for lysergic scid in the first week, the animal is
resistant to lysergic acid in the second week.
Miss Lewis hss continued her observations of social hierarchy
and cotE^unication in the chia^ansee colony. Dr. Bucknsm and
Hiss Lewis have draitm blood which has been tested systematically by
Dr. A. S. Wiener of the New York D^edical EK«iners Office. Dr. Wiener
is now in the course of a study of sub-groups in these blood sao^les.
It is hoped that these heaaatological investigations will lead to a
further imderstimding of circulating blood in the chimpanzee,
including clarification of their extreasely efficient clotting
mechanism.
2. KisiBropseheiisgical Seeeiaa
3. Be£lesda, Msyylaad
4. N][Na\»61(c) 1958
PHS-SJIH
Iffldi^idssal Frojeee Eepost
Galetid«r Year 1959
P«rt_A.
Project Title; Spil@p£@seaic Heehaalsaw in the Br&ln of Mas and
©the? Prisiates. -
PrlBeipal lavestigstor; Maitlaad Baldwi®, M, S.
Other Is^@sZtmtot@i J, M. V«sa Borea, M, D,, C. Ajesaae MseseA,, Mo B.
I, Klfitso, M. D., S. Ao LewiKg R, SI. m4
S, A. B«ch, M. D.
Em Years (Caleadar Yeas 1959) ; V&timit Days
Total: 7.0 (Caleadeg Ye^r 1959)
Professional: 2.5
Othar: 4.5 4043
Preject Descglption:
Ohjeetiwe;
a. To sttsdy eousal aEsehaaisBS of epileptie seizvtTeB is%
mam assd other priaatss.
b. To stud^ the eleetrograpMe chorsctes-istiea of
epileptogenic activity in the brain of mast xaA other priraates.
Co To stuidy the approved nethods of surgieal therapy
for these lesions and develop new therapeutic methods.
d. To stud^ brain function as it is exposed in f-z
extravagant experiseents devised by these lesions.
Methods EBployed;
a. Clinical neurological exanination.
b. Special radiographic exaaination.
e. Eleetrographie exaaination.
d. Eleetrocortigraphic exaaination..
e. Eleetricsl stismlation of the lesion exposed at
operation.
f . Selective isolation of the lesion at operation.
g. Photographic and sound recording.
h. Histological and chealeal exaaination.
2, Serial No. NINaB 43(e)
HaiQg giadingai One himdred foircy-three pa£iea£s with tea^v&l loba
itres were studied
seisures were studied during the pase year. B& those Chat cans to
operative treattoent, a new etiological factor was tmcovered, aad a pecu>
liar relatioBshlp between language difficulty and location of objective
lesion in the affected lobe wais noted « In 6 eases in which the etiology
of the seizures was not clear before operation, a severe b<my defoxmity
of the siddle f^sea was uncovered during surgical exploration. This
consisted essentially of bony spicules protruding into the overlying
temporal lobe throu^ relevant dural defects. There was a aieningocortical
cicatrix. This deforsiity could not be related to inflSBsaation or neo-
plasa, although it n^ have been related to otherwise insignificant head
injury in 2 casas. It was related to electrographic abnomality, and
objective pathological changes in the relevant temporal lobe. In previous
reports, the language difficulties of t«aporal lobe patients have been
outlined and enphasisedc During the past year, several cases did not
exhibit such lan^sage difficulty, although it was quits clear that they
suffered fron tesu^ral lobe epilepsy which was localized to one or the
other teoipdral lobe. At operation, it was noted that in each ease thare
was a sa»ll, well eircuaseribed objective lesion in or on the lateral
tes^oral cortex. ?or exaatple, in one such case, & tiny neningioaa lay
iobedded in the lateral temporal cortex. In this esse, the nan's language
was direct, einple, end devoid of the characteristics associated with
tea^ral lobe disease. On the other hand, a patient with a awill congeni-
tal vascular nalfonution of the lassial toaporal structures esdiibited
these language characteristics to a auurked degree. He typifies an
apparent relationship between location! of lesion within the lobe and
language diffieultsi. When the lesion is aesial and deep within the lobe,
the language difficulty seeas marked and characteristic. If the lesion
ii lateral and superficial in relationship to the affected lobe, the
language difficulty is tainiatal or absent. In the case of the patient
with the mall nenlegieasa, the seizures had begun 10 years before opera-
tion and eontitemed until treatnent without significant alterati«m in
pattern or frequency. Likewise, the total duration of seizures in the
patient with a ttsslal vascular Balfesawtion was appro^iatately 10 to 12
years. Thus, in tltis ssaall group, the duration of the lesion does not
to signifiemtly alter the occurrence of language difficulty.
The language; of all patients with teo^ral lobe and other epilepsy
is being studied. These studies are in addition to the formal psycho-
logical testing. Each patient aust provide a l,000-^»3>rd sasple of con-
versational speech %^ich is recorded surreptitiously. He also provides
a 1,000-word written account of hisself and his hone. It is hoped that
these language s^^les, sose of which are recorded on tape, can be
subjected to further linguistic analysis by oians of a panoraaic analyzer.
At present, each patient is also tested by the cosBson semantic method of
object, word and action relationship. It is very difficult for a patient
with tea^oral lobe disease to provide a rapid word association between
3. Segial Ho. HITO 43(g)
Mttior giadiaajg (cont'd): awcfe single objfiictis as etsaiy off eaible. Ho em
aphAsia Seses ^t^ta £se£li£y, but t^ma ha eatst use. his l£»gHas« to dese^ibe
ffelatioaships be£«eea space, tisie, a&d ac&ios, ha usually hecorass ia-
craaaiffigly eoe^lieated in raspmasfi8« aad i£ pireased sueeussiba either to
Irritability and even rage, or uaiatelligible deaeriptioBs. tb>
difficulties are ao «ore coaxBon ist left handed thaa in right handed
individuals, nor are they particularly relevant to aisbide^erity. 1
cerebral doasinaaee of these patiente Ib being cheeked by use of the
test.
As has been previously SBentioned, G»st patients with
disease eoeaplala of difficulty in sesKeibering or are labeled aa having
poor asessories. In the past year, it has beeose increasingly clear
these patients h^e, in the ssost literal sense of the tesm» good
They do record and can recollect recent events. HOvever, there ia^ of
course, soae difficulty in doing this, m the past, this has been described
to a difficulty in recollection and nothing further has been said t^out It.
Mtually, it m^ be a difficulty in recollection, but on closer exasiaation,
it is also a difficulty in tiae relationships. For ezai^le, if a patient
with mesial t^^oral lobe lesion is asked what he did yesterd^ at 9:00
O'clock in the aosaing, he finds it eztresely difficult to answer with
any degree of accuracy. He goes through nosa^l asffioeiation atteapts aad
tries to "think backwards" in tesss of the routine of the ward day, or
in relationship to a special event of that ds^, such as a paeuiBoenceph-°
alograa or other dia^ostie exaesination. Despite considerable effort
and sincere leotivatioa, he is usually unsuccessful in his answer. Hsfw@ver,
if he is asked eSb&at brushing his teeth or about any other routine series
of actions which w^ have t^en place around tbe tints at question, he esa
build up 8 relatively accurate description of the iBoming's activities i
Likewise, if he is asked about a particular object, such as a chair or
table which he has seen during the pest tgoming, he can build up a
reasonably accurate account of his spatial e^^rience during that tijm
period. That is to s^, he can daseribe his room as it appeared during
those hours. Now, if he is asked specifically wSsat the chair looked like
during a certain tise period, or if he is asked whether he brushed hia
teeth, ate hie breakfast, etc. during this certain tit^ interval, he does
not answer accurately or he eas^ot answer at all.
The study of perceptual aberration la tes^ral lobe patients is
continuing. fJhen the lesion is «Ksial in the affected lobe, and pa^tiei!s>
larly if its effects are bilateral, the patient has very considerable
difficulty in deaeribing the space in t^hich he liv®9. He csmot relate
objects within that space with may ee©?sr«sy, ?sosr can h© describe ±z&
shape with any clarity. She pstieat ssho fees lived ia the wa^d rcs^; :■•-:-
30 days end tiffe© h&s &®sa ^le to asadertsks e©^liea£@a>sy©tKslQgieG;:.
iik2®^§k©st th&t psri©ds iinds it difftole t@ 4ifss? s sisspl© floos* plim
:.f. Ms se^ or £© ■sel&te ©bjas^s witMs ':l'-. "'' -"-sd t& re" "-■ '' - ~-
MaiQg Fiadlngs (ceat'd); objects la
do this,
ittm tss^ral Uihe epilepsy (£or
ia pa«ietAl cesien <nr the so-ealled
As nstsd fsevijauuly, patients
al>«rr«tioB8 can be iRfltscnced by diseussioa of these auras, fhust,
patiest is asked to describe every detail of hie aurae to the h&st
reeelleetion mA the& is cross-ezaained on each detail, be will £.i
begin an ietal pattern. Such perceptual auras are occasionally f&
conceptual change, as for exai^le in the ease of the patient who h&^m'
thinking about a phrase or sentence which occurred in rmdtim eonvers r
or casual reading, and th«& perseversted on this thought, at th{» ^
wondering what it sMsnt, and then while aware of its passage thro:^^„
Bind lost the sense of its laeaning. As he experienced this pmmxssm t^i^
aental Aberration, he was also aware that his surroundings aeeaied. diM%':
and nore sharply outlined, and then he was al»}st totally unaware &f. si
save for one objeet>~the book containing the phrase or. the prntam %"-.
the sentence. Th» book or the perstm was ea^hasised in his nlsd ^
alaming clarity and then he progressed into the pattern of his huL^...--.
ictus 9 Such a eo3tbi.r\ation of perceptual sad eenceptual factors in thm
anrae usually indicate progression to or priaary invol'^eaent of ^h'^ '■''-^■^
in the doffiinant teoperAl lobe.
Dtering the past year. Miss Piraie, and eore recently UrSo them-pstm,
been sta«fylng the photographs of aute^mtiaat settneneeSc tbrnttt sm^r.
to be sees relationship between the B»sor phenossena of these 9eqiNffi<£®«(
fhis is being studied in detail by ISrs.
STo John Vmi Bur^s has studied a series of 22 seizures in 20 pseicr.
»Jeet to seizure activity characterised by aut^matisn and prede^'^ — -
epileptogenic activity en EES for possible correlations I.
f% §g^ electrogr^hie functie^o The seizures 9tme»& a rtmt^i. ^f^.^i^-
paUent to patient Ia that a given response t«aided ta'
in a stereotyped, fashion^ thus, if a change in blood press^^e
the blood pressure was sesn to rise; if a change in pulse, occ^
was toward tachycardia with practically no exception c fhǤ
two individual variations that could appear consisted in the inclusion.
or oMission of an s^ifeonsaie responee or a change of se(|u«fiee of a^^mtiv:-'.
In general, the rssults of the present exanination agreed with timt 6f :
mm^ (see bibliography) in that early chani^s were tmmsemly
peristalsis and fells of «kin resistance^ with vascular chsn-j
of response had been preceded by sews aatonoaie change o
In corx^lating eleetrographic pheaenaaa with these vegetative ehan,
half the bilaterally s^piastrieai "aapeeific SEStrasol burst©" 'mm.
with brief autoneaic changes^ usnally tachycardia and i&ll &£
but «rore unaeccsqpanied by msy ®bservabl@ change is ntm--
loss of voltage with a tendency to increase in tfes
of the record (appearing over 1/S sec„ or less) was in all case:
5. S*inal HO, _lM^-.431cl__^_^
Major gtffidiaRa (ceae'd)? associated with overt seizttre activity.
ustsally ia tis® £oxa of an atttoRatista or a t^m ■■
elosie seizure^ Garadoally, progressive increaae in the nrea involved
by epileptifom activity with increaae in voltage posed a particeslar
problea in that relationships to suddenly appearing autonsBtie changes ox
loss of responsiveness in laost eases could not he made. Several instances
were obtained of focal spike activity of sudden appearance or progres^ii^e
augmentation without any detuonstrable vegetative or clinical
A further stu% carried out with I^r, Allen Hirsky of NIMH was
in patients subject to three per second splke-and-wave attacks, either
spontaneous or precipitated by photic stiaaalation or hyperventilation..
The patients' level of response was detesained by a continuous perfosatance
test (a motor response to certain letters presented either visually or by
loud speaker) . A siasultaneous autonead-c record was aada of all these
seizures c To date, s<me 300 spike-vid-wawe attacks have been fully
recorded o The oaaterial is at present under analysis and it is hop@d te
draw correlati<ms between electrographie features of the attack, the
patient's response^ and the autonoaiic characteristics o Isolated obser^'a*
tions of interest include the infrequeney of autonoBBie changes with the
attacks and the ability of the patient to carry out a rhythaie ssnotonous
nechanieal tu^emmt during an attack vAnasn he is unable to distinguish
auditory or visual ayabols. The lack of relationship between autongotie
features has been apparent on nuaierous occasions c The aut«tuM»ic response
of these attacks is a«ch siaq^ler than that of attacks of teaqporal lobe
epilepsy. The nature of the change, however, is quite sinilar, affecting
predoninantly respiration (inhibition) and falls of skin resistance ,
In the laboratory, the relationship of frontal cortex to spread of
seizure discharge has been noted and further studied. A penicillin
lesion has been produced on the frontal cortex of the ehlrapansee m&d its
subsequent spread recorded electrographicallyo Interestingly enough^ the
seizure spreads in an aloest eoncaktrle pattern across the ipsilateral
hemisphere and then seesu to cross to the opposite side, spreading fron
aesial to lateral, finally, electrodes record seizure activity freei
frontal, parietal, and occipital cortices, Bowever, as sdght be expected,
the discharge is greater in ae^litude around the area of the lesion.
Paradoxically, the aaiseal suffered a contralateral focal notor seisswre
despite the bllaterallty of the electrographie abnomality. (The^
penicillin lesion was in the interaadlate frontal region and anterior to
preeentral cortexs which had been carefully narked out by electrical
stlMttlation.) The snisBal suffered eleetrographleally and clinically
evident status epilepticus. The focal ssotor seizures contlniscd "■-, a
Jaeksonian oareh on the side opposite the lesion, while all electrodes
to record seizure disttjrbanee for 2 hours. Subsequently, when
were closed and the eraniotcnaQp revised, th«. aninal was eoi^-
seious, but continued to have focal ssotor selzur@8. It was then
necessary to give an anesthetic to control the seizure process. It is
interesting that bilateral electrogre^hic abnonaality which began In one
frontal cortex should result in a unilateral focal notor seizure pattemc
Slgatfieanee to Meurological Researchg These observations aisy
6. Sesriffil Ito,, ^HM^lli^L
Sigatfteaffiee to K^Mg^lcgieal Reseageli (c®n<i:'d)g asaeieibute fe©was?ds
of epilepeie aseebaaiims as they ^ceur ia tss^i^al lobes o£ higbes' ^tss^i^.
ggepoaed Cdarae @f fctoe Fgeiecftg The ^I'arious elinie&l and espegi-
il studies will b« eostiffiued.
?as£ B ifficitadodi Y®«
serial N®. J&mm 43(e)
PHS-NIH
Individual Vv&ject Reports
Cal«id«7 Year 1959
Part B? Headrs, ^^ds and Pttblieati^ias
Pttblicatioas ®thBz ehsa abstracts f?®a this project:
Baldvin, K„z Surgery of epileps3fo In Jackson, I. J. and
qpsoa, R. K, (ed.); Pediatric Kearosttraary, Springfield,
K Co Thonaa, 1959, Chap, XXI, ppo 512-529,
Edgar, R. and Baldtrtn, M,: Vascular Balfoneations associated
with temporal lobe epilepsy, J, Neurosurg, In press.
Pimle, F, A, and Bal&dA, M,: Observing cerebral seizures,
m. J, Htirsing, 59; 366-369, 1959,
Van Buren, J, M,: Some autonaalc eoneeaitants of ictal
tiaa. Brain, Sis 505-528, 1958,
Honors and ^gwards relating to this project:
Obj«cfcive«; To ^-.^....-^. „...^.. , .-.-,., ,..„.,.--„,^ ....-
iSbia the feessspoeffil lobe of mm& aad bighej:
i. EU...-...-. u... .....................................
chisgpaaEea arad ®»akey fee^orel lobs®: (a) directly, s
ejcposuKe; (b) ladirecfily by depth elcetredes «sd sc®!;-
2. Ablation of all off paicfcs of tha teu.;;
3. AiEfitosBical "'-"--s— ■ -- "-s.-.^,?,^ '...«.3„ ;■
lobe ejMsisloos,
2o Serial No, MINPB 44(c)
Major Fladlngg (coat'd); obtAined fooa postcentral, as well ma
pzece&tral. As noted last year, the areas
eoaparsble to the repsresentation described by Broca have been excised.
In last year's report, the effects of unilateral excision have been
deseribede Now it is possible to note that bilateral excision of these
areas does not materially affect eooBunication pattern, fhe chronic
studies of effects of bilateral teaaporal lobe ablation are continuing.
DTo Heinrich Rluver has cooperated in these during the past year, and
it is interesting that Im was unable to see any of the stigma of his
"syndroeie" fs these ^nii^als. There are now 6 chia^anzees whose bi-
to^toral ablations bsve been studied for 5 yearSo All of these anisals
have continued to co^ete in hierarchy and tribal structure, and their
developoaent appears within the nones established by Yerkes, Nissen,
and Kohler. There seeass to have been soae wei^t gain in the past year
in 2 of these aninals. This weight gain is out of proportion to that
of their peers who have not been subjected to such operations.
12 unilateral tenporal lobectoeoies have been perforated on patients.
The general effects of such unilateral lobectoogr in the husum are still
not clear. There is sosse change In stood and Isiguage. There aay be
in libido and a progressive weight gsino
As noted elsewhere, Or. Norris is studying the effects of stesial
tea^oral depth electrodes. He has succeeded in reproducing behavior
which is r^alniseent of huE^a autOlaatiSB^ alw&g with or besides a
of other responses.
Miss Lewis and Dr. Baldwin are continuing th@ study of hallucioo-
genie subst^^ces. Psilocin and variotis isomers of lysergic acid are
being tested. In addition, these drugs are being tested, one against
the other. Such adeainietrstion has revealed a& apparent similarity
botween psilocin md LSD- 25. Adsdnietration of LSD-2S daily for one
week provides a considerable resistance to further administration.
Likewise, daily adninistsation of psilocin for 7 de^rs provides a
considerable resistance to further adsdnistration of lysergic acid.
Significance to aeurologieal Reaeareh; This project provides
opportunity for study of the functional representations of the tes^ral
lobe, as well as its structural relationship.
Proposed Ceurae of the grejectg This project is developing
because of inforastien derived fron eleetsieal, surgical, anatoaieal
and bioehesical studies. It will continua devslopnent £ro« this wide
Past B included; Yes
Serial N©» MINBB 44(e)
PHS-NIH
Individual Fr@jec£ Report
C«Iend«7 Year 1959
Part B; Honors, At^ards mad Publications
Publications other than abstracts frosi this project:
Baldwin, M., Lewis, S. A., and Bach, S. A.: The effects of
lysergic acid after cerebral ablation. Neurology, 9, No. 7:
469-474, 1959.
Honors mtd Awards relating to this project:
Serial No. NIKDB 45(c)
1. Surgicfil Neurology Branch
2. Priaaste Neurolog]^ Section
3. Bethesda, Maryland
4. New
PHS-NIH
Individual Project Report
Calendar Year 19S9
Part^
Project Title; Effect of Radio Frequency Energy on Primate Brain
Mechanisos.
Principal Investigator; Maitiand B®ldarin» M. D,
Other Inveetigatorg; Sven A. Bach, M. D., Shirley A„ Lewis, R. N,,
Igor Klatzo, M. D.
Han Years (Calendar Year 1959) Patient Days
Total; 7.0 (Calendar Year 1959)
Profeeeional: 2.5
Other: 4.5 0
Project Description;
Objectives; To study the effects of radio frequency energy
as applied to the heads of living nnnkeys and ehisDipanzees .
Methods Eaployed;
1. Electronic
a. Development of transaitter aeries of physical
capabilities for applying the energy to the target areas.
b. Further research and developosent of electronic
devices §o s@ to produce pulsing and oodulatlng which will pereait rapid
application ®f peak power free of carrier wave dependence.
c. Developssent of panoraraic analyssers sufficient for
frequency analysis and record of other wave characteristics.
d. Developsaent of signal generator and connections
capable of introducing critical frequencies without QDlnisml thesnaal
energies into tissue culture atedium.
e. Development of rsssote recording devices capable of
telessetering electrogr^phic outputs activated in £» e^eriisasntal snisial
by photic driving.
2. serial No. HIMIffi 45(e)
Met).^0ds SteplayedXcoat'd):
£. Orehodss eleetrographic recordiag of the effects Gf
radio frequency,
2o Flu>togr^hic recordigxg of clinical effects.
3. Histological aad chemical exaainatioB techniques.
Major yiffidiBsa; 50 Macaca rhesus otonkeys have beea exposed
to radio frequeacy energies in the range of 200 to 400 fiiCo These
energies were trrnxmexLtted to th£ head from a standard gromnd-to-air
tranirasitter through the aeona of an antenna placed in the roof of a
cylindrical copper sassh resonating cavity. The antenna was adjusted
so as to lie directly above the ahissal ' s head, which was positioned at
thB lower pole of the cavity. Below the base of the skull, the snlasal
'^as screened fros radio frequency energies. The physical characteris-
tics of this arra^ have been Bsmitered directly and studied indirectly »
Nineteen phantoous containing Elliot's solution, gelatin. Ringer's saliae
and other suitable' test media were positioned so as to imitate critical
head positions. The n^litude of the siipa^l received at the head eres
was iisonitored by a probe, and the signal at a given frequency was
continued long ez^mgh to raise the tes^ersture of the test astediua II^C.
Frequiencies from 200 to 400 Mc. were used. The results indicate that
there is a unif om thensal response in this test w&ditsa which occurs
sosae i:i»ie ffiftes the signal has beg«aa. Hm7sver, only those frequencies
betwet^n 330 «s%d 390 He. produce cliiiicaliy discernible effects „ These
isffeets consist of. sinusoidal alteration in. SKrareness in which periods
of seftialng alertness alternate with periods^ of dro«7sines@. ^ring this
tisae, the ffininal does not respond to peiin, but will respond to light
and noise in the usual manner. Hone of these aniisals were SBS&thetiz&d
or nare«itised in aay way in the bsslc esperiasents. However, soae were
anesthetized with pentobarbital to surgical levels so as to test the
effects «.f radio frequency on this depressed state. At the critical
frequenci^38, the smimsii arouses fr«» the anesthesia while the radio
frequency is on and then returns to the anesthetic coea when the radio
frequency ;ls turned off. This appears as an "on-off" relationship.
If the radio frequency is continued at critical frequencies (380-390 Mc„)
the period .sf sinusoidal awarenesSe which is brief, is followed by
alteratitm in pupillary, response^ psradoxicsl pupillary response,
disorganization of eye eaovesssents, horizontal and vertical nystag^sis,
griaacinga autonomic changes, and finally a generalized seizure which
usually begins with eye blinking as^d head nodding. If the animal is
carried to. this stage of reaction, recovery is unlikely and he usually
dies. However, if the animal is exposed to radio frequency energies so
as to produce any of the preceding signs or all of them, recovery is
precept and us«sal Sons animals develop focal neurological signs
following long eisposures at critical frequencies. A l®B.«r -asp^si^jws is
3. Serial Ho. NINDB 45(c)
Major Findings (cont'd); here defined as an es^sosure longer than 3
ainutes. The focal signs consisted of a
facial paralysis of the eeiatral type» loss of pain and touch in the
areas supplied by the first and second divisions of the right fifth
nerve, weakness of one leg or of one asm, unilateral or bilateral
plantar extension, trunkal atasda sonetistes accoepaniad by a c<m-
tinaation of previously developed nystagsus. These focal signs vere
transient and the anistals recovered in periods varying frool 4 hours
to 48 hours aftar esq>osure.
It is possible to introduce radio frequency energy into a
tissue culture bath by msesaa of & signal generator and appropriate
connections. The protot]7pe for such a desi^ has been developed and
will be applied in the laboratory of Neuropathology. It will be used
in order to test frequeiicies and specific frequency effects on uni-
cellular eles^nts as they are maintained in the now standard techniques
available for this pur^^se. These elements will be photographed and
subjected to various corollary tests. There is proe&ise that radio
frequency energies in these ranges has effects on the chroaatin patterns.
Sooe such effects have already been observed by Heller in the paraaecia.
The histological and histocheaical analysis of brains derived
at postmortea esaoiinatiim is being conducted in the Neuropathology
Laboratory tsad has been described in armther portion of this Annual
Report .
It la worth asentloning that the orthodox electrographic
response to radio frequency energies in what we have called the
critical frequencies is eh« production of a "sleep" record. When the
radio frequency energy is turned off, the record reverts to a norassl
"alerted" tracing. There £ire autonoaie ehasages, such as tachycardia^
hyperpnea, and probably hypertension. No attes^t has been aaade to
record these on the polygraph in a aysteaatic ssanner. Soae of thea
have been recorded at raadoa.
In emsmsy, th@ aaajor findings in this project are that
frequencies within the rsmge of 380 to 390 Mc, when applied to the head
of a living, waking monkey, asesi. to cause alterations in awareness and
other changes which oi^ be related to stiaulatlon or activation of
brain stea aechani^is. Th@ effects of this reaote stiaslation are
transient when it is properly controlled. It has a paradoisieal effect
upon surgical anesthesia in that it umtmB to arouse the anesthetized
Sisnificanee to Neurological Research; These findings suggest
that there aay b« a frequency-specific effect when radio frequency
energy of certain characteristics is applied to the priisate brain.
It is thought that radio frequency energies in this narrow band of
the spectrua aay alter neuroaoleeular structures within the individual
•euaran or glia so as to produce transient changes in the living
tuttbn application of this new esperiesntal tool tgnay Indicate its
4, -^^ .=^:.-
Siffntfiemce t® Newr®l®^leal Reaearch (e.cafc'_41;
uaefBslHiess in the study ©f waicellwlw pirepasratioa* , The results
obtslmed indicate tlwBt it cm ffl££®ct the arousal systeaw aad other
brain stea saechaniaos and yet leave the test animal apparently
Proposed Cougse of the Frolect? The electronic capabilities will
be enlarged, k kilo«/att transsdtter with capability for pulsing and
oodulation has been ©btained and is being s»dified. The output of
this transiaitter will be calibrated in tesa» of the physiological test
HE»dels previously used and then its output will be applied t® the heads
of Monkeys and finally eMsapanzees. If the effects observed and noted
above are not species- linked and can b© transferred to another species,
it awy be that the ^plication of these frequencies will be s»re
uaivere.^! md effective. They will be applied to unicellular cl«
in the tissue culture systea as noted abotfe. The effects will be
■saitor^d wherever possible by orthodox recording techniques and «
new telemetering and recording technique is now under developaent,
a
Part B included; Yes
Serial No, NIMPB 45(c)
FSH-NIH
ladividual Project Report
Celendar Year 1959
Part B; Honors, i^ards aad Publieatlona
Pttbliestioas other tha& abstracts froa this project:
Bach, So A., BalduTin, M. and Lewis, So A.: Soae effects of ultra-
high frequency energy on prieate cerebral activity. Proeeedings
of Third Tri> Service Conference on Biological Effects of Microvave
Energy. In press.
Baldwin, M., Bach, S. A., and Levis, S. A.: The effects of certain
radio frequency energy on priaate cerebral activity. Neurology.
In press.
BoBOTA and Avsrds relatieg to this project:
Serial No. NIHDB i|6(c)
lo Surgical Neurology Branch"
2o
3. Bsthesdas Maryland
lie NINDB 63 (c) 1958
PHS-NIM
Individual Project Keport
Calendar Year 19S9
Part A.
Frojeet title; Effect of Destructive Lesions upon the Function
and Structisre of the Human Central Nervous Systssn
Principal Investigators J. M. Van Bursn, Mo Do
Other Investigators s None
Cooper atii^ Units;
Man Years (Calendar Year 1^59) s Patient Days (Calendar Year
19S9)i
Totals 1„2
Professionals OoU 351
Others 0.8
Project Description;
Objective; This study has a dual aims (l) to carry out
physiologic aT~'anatoinical correlations in manj, (2) to evaluate
the effects of new methods of treafeaent of timors of the central
ner-^us system „ In the present program attempt will be made to
utilise the intmsion of disease upon the central nervous system
of man as an "experimental" lesiono ■
Method Bmployed:
Specifically, the material is used in three major ways;
(l) physiological observations can be made during surgery, (2) the
effects of surgery itself can be evaltiated., (3) post mortem material
may, in certain cases, prov® valuable for anatomical studies <>
Major Findings;
A« Ablative pituitary surgery in man.
lo Clinical effects of hypophyseal stalk section in man.
The program of ablative pituitary surgery in conjunction
with the Branch of Endocrinolo^, NCI, has been continuedo A
Serial IJOo NINDB ii6(c)
total of eight pituitary stalk sections were carried out for
palliation of metastatic breast carcinoma c Clinical experience
with this operation has been discoiiragingo The patients have
shown a considerable morbidity and at the present time^ contintia-
tion of this series is not contanplatedo Specifically, the
patients demonstrated marked sensitivity to water intoxication
with irregular and sporadic water outputs not well related to
intake o In the first two cases where routine intravenous fluids
were given (1500 to 2000 cco daily) the patients became unconscious
and both had convulsions apparently due to water intoxicationo
Following this experience, all parenteral fluids were stopped
following the surgery and the patients allowed to take only what
they desired by moutho Despite this precaution, several patients
between the fourth and seventh day became increasingly drowsy,
poorly oriented and several hallucinated^ Although this disturbance
of water metabolism proved eventually reversible in all cases ^
the comparison of clinical course between these patients and those
subjected to pituitary curettage as well as stalk section was a
striking featurec In the latter case, the patient's recovery from
operation was rapido The eval\iation of hormonal and timoral
response to hypopt^seal stalk section as opposed to pituitary
removal is still pending o
2o Quantitative evaluation of hypothalamic changes
following hypophyseal stalk section in mano
Collection of post mortem material from the hypophysectomy
cases continues and work has been undertaken to devise a suitable
means for quantitative anatomical evaluation^ Total cell estimations
(cell counts) of the supraoptic nucleus may be easily carried out
(in one esse of hypophysectomy the left supraoptic nucleus contained
11,500 cells, the right 10,500 cells with a normal between 60,000
and 90,000 cells, according to Rasmussen), Quantitative estimations
of cell pop'ilation in the para ventricular nucleus, however, has
to date not been satisfactory due to the confusion caused by a
mixture of Large cells from both the perifomical magnocellular
nucleus and the adjacent large cells in the lateral hypothalamic
areao Likewise, the characteristic cell form of the nexjrons seen
in the supraoptic nucleus seems to be less vxell marked than the
para ventricular nucleus o Further reconstruction work must be
done in this direction and it is possible that a delimitation of
this nucleus adequate for counting may be achieved by combined
cytologic al and topographic relationships » Similarly, difficulty
has been encountered in evaluating neurosecretion in the human
post mortem hypothalamus and further experience is necessary to
determine whether reliable results can be obtained by histochemical
raathodso
3o Serial NOo NINDB U6(c)
Bo Physiologieal studies of the human fronto-orbital
avBctacBo
la Autonomic responses o
In the past year, eight cases subjected to pituitary
avTgery were subjected to exploration of the orbital surface,
adjacent temporal lobe and ventral aspect of the hypothalamus
by electrical stiitiulatlonc Kecords were made at this time of
respiration, blood pressure, pulse rate, esophogeal and gastric
motility and plethysmogranio Since all patients were carried
under general anesthesia, the influence of this v^on the changes
in the above functions were investigatedo Fluothane anesthesia,
even though apparently light, seemed to be attended by a large
number of negative stimulations o I'lore responses were obtained
with light barbiturate, (thiopental anesthesia) and the majorilgr
of the examinations were carried out with thiso The anesthetic
appeared to abolish all gastric contractions and plethysmogr^hic
recordings have been unsatiafactoryo The effect of stijuulation
at a given perimeter was most maricad on the mesial tonporal region
when the stimulator was inserted backward along the medial aspect
of the temporal lobe, so that it lay near the uncuso The charac=
teristic response in this position was prolonged expiratory apnea
which might last a total of two minutes o Bradycardia was also
a common feature o Blood pressure changes were usually of slight
degree, though frequently a fall was seen with bradycardiao In
a few instances, an apparent motor response was seen with esopho<=
geal peristalsis and in one case, the onset of a few gastric
contractions. Curiously enough, no autonomic response has yet
been seen from direct stimulation of the floor of the hypothalamus
either anterior to or lateral to the hypophyseal stalk »
2o The electrographic activity of the cooled human
frontal lobe and its response to tiypotension^
In a study carried out with the aid of Doctors F, Norris,
K. Hall, and G. Ajmone-Harsan, in twelve patients undergoing
hypophysectomy with light anesthesia and artificial ventilation
producing hypocapnia, the resting and post=atlBiulation electro-
corticograms were recorded before and after reduction of the blood
pressure with Arfonad (R)o Nine of the patients were maintained
with hypothermia and three with normothermiao With one exception,
there was no evidence of disease of the nervous system «
Under these conditions, the predominant electrocorticogr«phlc
frequencies usually lay in the alpha range or fastero Hypothermia
appeared to protect the cortex from after-discharge from electrical
stimulation while after°-discharge with the 6ame parameters appeared
in one quarter of the stimulations at normothermic levels o In nearly
ko /Serial No. NINDB lt6(c)
all patients, both hypothermic and normotheimic , cortical
stimulation was followed tj a depression of voltage of fast
activity and an augmentation of voltage of slow activity which
was compared with the spreading depression of L^Oo In one case
with miliary cortical cercinomatosis, spontaneoiis epileptiform
activity was recorded which was potentiated by stimtilation des-
pite the presence of hypothermiao With li^t anesthesia, t^po-
toision in both the normothermic and hypothermic cases induced
a fall in the voltage of both the slow and fast activities, although
the effect was of relatively minor degree even with systolic
blood presstires in the range of 30 mm. tig, in two cases the
addition of Fluothane (E) resulted in greater depression of
electrocorticographic activity with progression to 'interroittent
activity and in one case, to electrical silence o In the latter
case, recoveiy was uneventfulo The depressant effect of hypo»
taision upon cortical activity appeared separable from that
induced by cortical stimxilation and potentiated by deeper anes°>
thesido
C. Anatomical studies o
lo The connections of the human tenporal lobe.
Two contrasting lesions of tiie human temporal lobe were
studied by the use of whole brain serial sections and the template
reconstruction method with Professor I'aul Takovlev at Harvard
University.,
The first case was a posterior lesion, an infarction
resulting in destruction of the cortex of the posterior, superior
temporal region and the area about the tQHporo=>parieto=oceipital
junction which extended in depth to the mid=superior portion of
the internal sagittal stratiORo The second case was an anterior
lesion resulting from a surgical amputation of the anterior temporal
lobe o
The posterior lesion resulted in degeneration of the
posterior portion of nucleus lateralis posterior and the nucleus
medialis dorsaliSo In the lateral geniculate body, the posterior
lesion caused degeneration in the lateral halfo In the medial
geniculate body, the posterior lesion resulted in degeneration of
the roptro-lateral portion of the nucleus while the anterior lesion
caused degeneration in the caudomedial portiono Degeneration in
the pulvinar from both lesions appeared to overlap in the medial
and lateral subdivisions in the nucleus. With the anterior temporal
lesion, degeneration was more pronounced in inferior parts of the
lateral and the medial portions of the pulvinar and there was nearly
complete destruction of the inferior portion of the pulvinaTo V/ith
5o Serial No, NIM)B 146(c)
the posterior lesion, there was greater degeneration in the medial
nucleus of the pulvinar which extended farther superiorly than in
the lateral portiono In this case, the inferior subdivisions of
the pulvinar vas sparado
Contrasting tract degeneration was seen in the tapetuiUo
The anterior lesion causing degeneration in fibers passing anteriorly
on the ventricular aspect of the splenium of the corpus callosura
while the posterior lesion caused degeneration in the posterior
portion of the splenium o Degeneration in the temporo=parieto=
pontine tract was erideht in both cases, although the myelin loss
was more distinct in the case of the posterior lesiono The ventro=
gaiiculate component in both eases but the tectal component passing
to the brachium of the inferior colliculus was degenerated only in
the anterior tsnporal legionc As astpacted, the anterior temporal
lesion caused degeneration of the inferior portion of the geniculo=
calcarine radiation while the posterior lesion caused degeneration
in the superior portion^
Tract degeneration peculiar to the anterior lesion
included degeneration in the anterior commissure, \mcinate fasc=
iculus, ventral thalamic pediancle, and fimbria«=fomiXo The re-
taition of eortico-medisl portion of the amygdala was associated
preservation of the stria tanainalis despite ne®* complete destruc-
tion of the baso-lateral portion of the amygdalae
2o Material collected for anatomical purposaso
Useful anatomical material for other studies has been
obtained from a surgical excision of a metastatic tumor in the
high parietal region with postoperative suarvival of six months,
a suprasellar meningioiria, and a local tanporal destruction from
an extracerebral tumoro In this conjunction, five "normal" human
brains have been obtained and are in the process of embedding and
sectioning in various plsnes for use as reference o
Significance to Meurological Hesearchs
The present study with patients undergoing pituitary ablative
surgery has provided further insight into the effects of derangements
and deficiencies in this system^
The nearly unique oppoxiiunity afforded by hypophysectorny in
exposing a normal human brain for physiological study is pointed out©
The importance of this project in providing valxiable anatomical
material for further hurasn neuroanatomical study should be emphasizedo
6o Serial Noc _NIND_3 U6(c)
Proposed Course of Project?
Kaking use of experience gained to date^ regarding quantitative
estimation of damage in the hypothalamus following pituitary ablatlvt
surgery, quantitative correlations between function and structure «re
planned with the cooperation of Dr, Mortimer Lipsett of the Branch
of Endocrinology, NCIo
The orbital surface stimulation st'tidy will continue to attain
a wider case experience a In addition, the "activating" effect upor:
the EG (Kaada) of stimxilatlng the autonoinically active areas on
the basal surface of the brain will be studied (only two cases up
to present report} c
Work will be continued in the hypothalamiC"=anatondcal studies
to develop better technique for quantitative estiwationo
Serial No„ NINDB it6(c)
Fart B, Honors, Awards and Publicationfj
Publications other than abstracts from this project:
Van Buren, Jo M. and lakovlev, P. I» Connections of the
Temporal Lobe in Man, In press (Acta Anatonica).
Van Buren, Jo Mo and Bergenstal, D., Me An Evaluation of
Graded Hypophysectomy in Man = A Quantitative Anatomical
and Functional Study* In press (Acta Anatomica)o
Van Buren, Jo Mo, Norris, h'o Ho, Hall, Ko D, and Ajmone=>Mar3an,
Co The Elactrographic Activity of Cooled Human Frontal
Lobe and its Response to Hypotensiono In press (Jo Neuro=
surgery) ■>
Serial No, MINDB kljc)
lo Surgical Neurologr Branch
2.
3o Bethesda, Mary 3a nd
Ito WINDB 6ii (c) 19^8
PHS«NIH
Individual Project Keport
Calendar Year 19S9
Part A.
Project titles A Study of the Functional Anaton^ and Pathology
of the Human Visual System
Principal Investigators Jo M. Van Buren, Mo Do
Other Investigator 8 s None
Cooperating Unites
Man Years (Calendar Year 19$9)' Patient Days (Calendar Year
— — ------ ------~-~" 2.9S9)i
Totals Oo6
Professionals Oo2
Others Ooi^
Objectives This study is directed tcward a better under«'
standing of the correlation of form and f\inction -sdthin the human
visual systemo It is intended to carry out these studiss correla-
ting clinical physiology with anatomy using the best quantitative
methods available o At the present time, the study has been divided
into three parts s
(a) Retina
(1) Study of the normal human and primate retina using
the Golgi and chromatic method So
(2) Study of the effects of the lesions of the optic
pathways upon the retina »
(b) Study of the effects of lesions of the optic pathways
upon the lateral geniculate bodyo
(c) Study of the visual field defects following teiiiporal
lobectoir^o
2o Serial Noo NII^B U7Cc)
Method Employed;
The methods employid have bean given in detail in report
for Calendar Tear 1957o
or Findings!
The preliminaiy findings given in the report for the Calendar
Year 1957 had indicated t e practicality of undertaking these
studieso Due to a still iiadequate quantity of material, effort
has been directed only toK.ird collecting human material suitable
for this researcho
After considerable trial and error, a satisfactory raetiiod for
two dimensional retinal reccnstruction has finally been devised
whici is both simple and peiiits quantitative study* This entails
the ir.itial 1$X. photographic ailargsmsnt of the specimaio Un this
enlarged photograph, arisas o ° degeneration can be maxiced in detail
from microscopic examination Following this, the original specimen
can ther. be projected at itO aiameter magnification and although •ttae
cellular areas cannot b-a seei in detail at this power, the precise
areas of. degeneration could oe marked from a noted photogr^h by
comparison of general landmaicso Since the circximference of the
closed segitjffnt of retina nov (at )^0X) measures something over a
meter, tracings of this can :>e measured \d.th a relatively small
percentage erroro
Significance to I^ejirological R^tsearehf.
The general aims have been previously given in the 1957
calendar report o In brief, it is considered desirable to re-
examine the visual system in man by anatomical reconstruction
studies i vrfiich may be correlated with the clinical exanination
of the visual fields
Proposed Course of Project;
Ttie primary aim continues to be that of collsctj-on of raaterialo
,rart Bo incliaied les /"T' ^^
Serial Noo ICTNDB li8(c)
lo Surgicall^'eurology Brsn^
2.
3o Bethesda, Maryland
kc NINDB 65(c) 1958
PHS-NIH
Individual Project Report
Calendar Tear 1959
Part A.
Project title; Studies of Involuntary Movements
Principal Investigators Jo M,, Van Biaren, M<, Do
Other Investigators; None
Cooperating Units; '
Man Years (Calendar Ysar 1959): Patient Days (Calendar Tear
1959) ;
Total; l„2
Professional; Ook
Other; 0,8
Project Description;
Ubjective; At the present time, there is no adequate
explanHioiTo? tha cause of mechanism of production of involuntary
movements = It is hoped ty careful correlation of clinical findings,
recording of the electrical activity of deeper structures at operation
and study of the anatomical material may provide new information on
this subject.
In order that recordings can be made from the basal ganglia and
coagulation carried out here if indicated, a stereotaxic instrument Is
needed to guide the electrode o Since the available designs seemed
inadequate in saae respects, development of a new instrument has been
under t£^ en o
Method Employed;
lo Clinical observationo
II. Photographic techniques o
III. Analysis by illustration of movement phases o
The possible use of accelerimeters for the graphic dmonstration
of the directional phases of involuntary movements is boing investiga=
tedo VJhether this will prove to be a practical recx>rding techaLque
ramaim m be detemiinedo
2c Serial Noo HINDB lt8(e}
Major Findings!;
Over the past two jusrs^ it has been possible to obtain "fche
brains of twelve cadaver;jo Studies in these oases have indicated
that the changes made in the tilting mechanism for alignment of
the horizontal axis of ths apparatias vith the anterior posterior
lins is effective and presented the errors prsviouaJ^ introduced o
After the previous year's experience (see report for Calendar
lear 1958) all brains were fixed in 1$% forsTialin i-rithout perfusicno
S'sidies on weight and displacement changes over a two week period
failed to show any snarked' ■variations o This was encouraging in tfcat
it indicated we war© dealing with a brain little changed frosu its
size in vivoo Subsequent discovery of other work on" this matter
has confirmsd our opinion in this regardo All brains have been
sectioned after agar ©mbedding and photographed under a grid
aligred with the anterior-posterior cornmissure lineo Thus, 2k
hemispheres are now available for comparison aivi form in each
iiBtmce material froin whicli precise measurements may be taken.,
Inquiry regarding individtial variations in the relationship be^
tween surgically important fjtructures and the anterior coramissare
has lik8^d.se been encouraging in these twelve speciroens, since
these variations have pro-iffd small when viewed in comparison to
the magnitude of the tliera]:©utic lesion,, Two of the 21; hemispheres
have been embedded for serial section in the sagittal plane in
celloidin after marking cf the transverse anterior and posterior
coimnissural axis (as is dcme in the specimens embedded for section
at 2 mme intervals in agai')" This material will permit better
identification of tract £.nd nuclear areas and' will be available for
comparison with the opposite hemisphes'e sectioned in agar (no shrink-
age x-iith latter embedding) »
Design and construction in the past yeai* has centered principally
upon apparatus for depth Btimuletion §jid production of lesions o The
difficultj?" of finding a thermostable insulating substance capable of
withstanding sterilisation has occasioned considerable loss of tisa©
and effort and as yet a satisfactory substance has not been founds
Work in this regard will continue o
Visits have been made to clinics both in this country and
abroad to obssrve both the therapeutic indications and operative
techniques o
Significance to Neurological Research?
The present ■woiAz has servisd simply to acquaint the principal
XH^estigator Trf-th the ivischanical prafieiencj' of his g1i.Teotajd.c
:xst:?-a5Kirrt, and thus has dealt sii;jpl;^' ;^lth teciaulaai datailso The
riltiJTJate eourae of the prcjeet ±3 to study those diseases in vbich
3o Serial No. NIMDB U8(o.)
stereotaxic intervention is indicated on therapeutic groundso This
material would fall largely in the group of involuntary moveraentso
Proposed Course of I'roject;
Photographic records both by moving picture and by multiple
flash stroboscopic photo grsphs, although providing a record, the
patient's movements are bulky to handle and are difficult to
analyze o It is hoped that with the use of accelerimeters a means
may be found for simple graphic recording of the raoveraent which
could be correlated on the sane time base as other features (£EQ,
autonomic, motor, etCo)« During the course of therapy, studies
will be made of the areas to be destroyed by depth electrode re-
cording and stimulation.
Part B iBcltided Yes /XT No /^7
Uo Serial Noc NIMDB i^8(e)
Part B, Honors. Awards and Publications
Publications othar than abstracts from this projects
Van Buren, J. M,. , A Projection Apparatus for Human
Neuroanatomical Keconstructiono In press (Anatomical
Hecord)o
PMS-SIH
C^mtO&s tmt 19S9
4. Hmt
tfatt Taara ^c«l«»«teg y^r 1959^ s PafelMt Days
T®tftl§ Oo5 CCalaadag Y— r inn
Pr® f «Msl@eal g 0 o 5
PitigC|_^SC.glptt@ttg
Ctejgctlvsas T® ®£tt%, S>y e®«iv<eetiAl «l«cer«s|»hysl®l«8ical
«vf.4@(ie@ i®r ^leh wss pre««a£i»d 'by a saceait argids fotsa
ehls la&®irae®iry CFr««£ at al lf5$>, as vail as in
^BlS[^^ Awaka cats a&d aeaiieays with chr<S8iisally
subcortical &apth «lacte®^as w«f« stadi@do Oa®
alect«s4la was stiaatlatad, «bll@ @th«rs wasa reear^d, watil
ail p<t«sij»la cisdbi&atisos had ba«» st»«liad, im:lu4i««
tintltaneswis ®t ae^aatial etiaalati^a «f t»s aiaet?®da6<,
IM additi®a t® f@utitsa stu<^ <si lataaci^s^ fatigtiability^
and thras&^lfSa^ cha affacts ®i aitasthesla aad gaaaffaliaad
hyfethaeaia CS4 t® t6^o> wsra studied.
Major ?tndiagag Analysis ®f th@ data freei cat has net
b^mt ce^^latado Tha us® <$f ass&ays began aoly raeentlyo
Sijaiftcaffica t® aangalajical ,Eaeeagchg Ihis study att«pts
t® l®calis@ anygdala^anygdals prapartias ta specific sub«
divisions ®i nucloms anysdali£<^mis. It als® attempts ta
alucidata t^athar tli«^« caamactiaas mx^ diractg ■eno°, ar
ssulti^syn^tic and t® p^*@vide an (glactraphysialagical
Page 2 Serial No 0. NINDB-.l|.9(c)
confirmation of a finding in a parallel project, that
facilitation and inhibition exist in this systenio
Such information might be of use in the problem of
human temporal lobe epilepsy „
Proposed Course of the Project; Initial study of the
data obtained in cat seems to support the assumptions
made in originating this projecto Analysis of this
data will be completed, while actual experimentation
continues with monkeys o
Part B included: Yes [J No ^
Serial Noc NINDB=5o(c)
lo Surgical Neurology Branch
2o Primate Neurology
3o Bethesda, Maryland
iio New
PHS-NIH
Individual Project Report
Calendar Year 19$9
Part A;
Project Title; Effects of Nucleus Amygdalifomis Stimulation
Principal Investigator: Forbes Ho Norrisj Jr*, Mo Do
Other Investigators; Maitland Baldwin, Ko Doj Harold Lanauze, MpSo,
Igor Klatzooj Mo Do
Cooperating Unit; None
Man Years (calendar year 19$9)i Patient days
Total: Oo5 "~~~" (Calendar Year 19S9)
Professionals Oo5 0
Others 0^0
Pixiject Descrix>tion;
Objective; ■ The first objective was to develop a technique
in this laboratory for subcortical depth electix)de
irgslantationp Such implantation had to be adaptable for use
in chimpanzee^ thus presenting an engineering problenio
Secondj it seemed wise to re-examine previous reports of the
effect of amygdala stimulationo Third, since an earlier
article from this laboratory (Frost g t al 1958) had described
bilateral amygdala activity after unilateral stimulation^
the effects of simultaneous, bilateral stimulation, or
bilateral sequential stimulation, were studied <,
Methods Employed; Subcortical depth electrodes were
implanted stereotactically under moderate to deep hypothermia
in the limbic system and superior brain stemo As many as 19
placements vseve made per preparationo Inexpensive, commer-
cially'-available materials x-jere usedo Cats were studied at
firstj recently^ monkeys have been pr-eparedj, Action
potentials were recorded from other electrodes during and
after stimulation, while somaitic effects were studied from
cinematographic records a
Major Findings Stimxilation of several amygdala sites
resulted in a stereotyped behavioral automatismo
Page 2 Serial Noo NINDB-SoCc)
Concomitant with the automatism there was a characteristic
spike-and^wave after^discharge^ recorded both ipsilaterally
and (after only a few mseCo or less delay) contralaterallyo
An early cat preparationj whJLch incurred a temporal lobe
lesion during implantation^ had such automatisms spontane-
ouslyo These automatisms and after-discharges were very
sensitive to anesthesiac,
It seemed clear that bilateral sequential or
simultaneous an^i'gdala stimulation sometimes enlianced or
(in some cases) depressed the effect which vrould have been
expected on the basis of algebraic sumrnationo The interval
between stimuli which gave the greatest change was five to
six mseCo, which is the interval found by Sherrington for
optimal facilitation of spinal reflexes o The anatomical
localization of such points is presently incorapleteo
Significance to Neurological Research? This study has
provided evidence that nucleus araygdaliformis may be an
exciting locus for automatisms c Thus, it bears on the
problem of human temporal lobe epilepsyo From the bilateral
stimulation studies^ it might be concluded that both these
nuclei drive the same (? mesencephalic) areaj howeverg this
evidence is not yet substantial e
Proposed Co\irse of the Projects The results in cat are
^ing analyssed'tt Actual experimentation vrill continue in
monkey and chimpanzee o
Part B included; Yes £7 No fU
1.. Surgical Neurology Brand
2. Primate Neurology
3. Bethesda, Maryland
4» Refer to kJINDB 67(c}-73^
PHS-NIH
Individual Project Report
Calendar Year 1959
Project Titiei The Recruiting Responses
Principal I?ivestiqator? Choh-Iuh Li
Other Invest iqatorss Shelley N. Chou and Joseph Miller
' Cooperating Units; None
Man Years Patient Days
(calendar year 1959) * (calendar year 1959) »
Total 0,4
Professional 0«1 None
Other 0.3
Objective? To investigate the intracellular potentials of the
cerebral cortex in response to stimulation of the "intralaaainar system"
*rfiich is supposed to be directly related to the underlying activity
of the cortex o
Wa.1or Findings i Depolarization with repetitive discharges and
hyperpolarization with cessation of spike discharge in response to
thalamic stintulation were found.
Significances This is the first attempt to record recruiting
responses with intracellular electrodes* The effect of recruiting
responses on sensory responses wis studied with extracellular micro-
eslectrodes in this laboratory in 1956. The information of the
present invest igut ion will direct our interest into an inquiry of
the effect on the cell membranes .
Proposed Course: Further study of the effect of the thalamic
Intralaroinar influence upon cortical cell responses.
Part B included Yes U No ^
Serial No. , NINDB, 52(c)
Ic Surgical Neurdlogv' Branch
2. Primate Neurology
3. Bethesda» Maryland
4. Refer to NINDB 67(c)-73(c},1958
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A.
Pro.lect, Title? Cortical Intracellular Potentials in Epileptic
Cortex .
Principal^ Investigators Choh-luh Li
Other. Invest iqatprsi Shelley N« Chou and Joseph Miller
Cooperating Unit s No ne
Man Years
(calendar year 1959) s
Totals 0,8
Professionals 0,2
Other* 0.&
Patient Days
(calendar ,,Year,,„1959|s
None
Ob,1ect5.ve; To study the ffischanisffi of epileptic discharge in
single cortical cells.
Method Employed 8 An epileptic focus in the cortsK was produced
by repeated stimulation and the epileptic after-discharges were
recorded with intracellular electrodes and surface electrodes,
Mjajor Fir^dincisj! In the pre-ictsl period #ien the surface
electrode recorded electrical inactivity s microeiectrodes detected
asynchronous discharges of cortical units in high frequency » Wien
the so-called "epileptic after-discharges" occurs depolarization
and restoration of resting potential periodically take place. And
if depolarization continued to grow spike action potentials disappears
There is also an accentuation of oscillation of potentials when spike
activity is absent.
Serial No.
Significance of program to Institutat The mechanisis of
©pileptic discharge has baen studied with intracellular electrode's
under th® effect of strychnine* This study further confirris the
previous observations* In addition it is suggested that ths> surf-jice
electrical record, at timiis,, providt'S no iififoimation as to hm tha
nerve cells und^meeth scto
Proposed Course, of Project 8 Further study in connection wiMi
thelanic stimulation is to be mad@.
Part B included Yes ^^ Ho /^
S«yial No. NINDB - 52(c)
PHS-NIH
Individual Project Report
Calendar Year 1959
Part B? Honors* Awards «nd Publications
Publications Li, Choh-luh. Cgilij^l^aSji^celiular Potential
and their responses to strychnin® , Jc Neurophysioi,
1959, 228 436-450,
S»riai No, NIMDB --^ 5gJ£_|
ic, Surgical Neurology Branch
2. Priraat© Neurology
3. Bethesda, Maryland
4. Refer to NINDB 67(c}-7t(c) ,1958
PHS-NIH
Individual Project Report
Calendar Yaar 1959
fart A.
Project Title; Cortical intracellular potentials in response
to s siiDfle cortical stliauius.
Principal. Investiqatora Shelley N, Chou
Other; Investigators 8 Joseph Miller and Choh-luh Li
Coopeyatirag Unitst None
Man Years Patient Days
(calendar year 1959)) » (calendar year 1959) »
Total* 2.0
Professional J 2.0 None
Others 0.0
Project Description!
Object! vet To re-evaluate the early observations of E. Do
Adrian with intracellular recordings from cortical cells.
Methods employed 8 The somatosensory cortex of the cat was
chosen. With the micropipette in the interior of the cells? singl®
shocks were applied to the surface of the cortex not more than 5 mm
away from the recording ©lectrode tip. Simultaneous recording of
the surface responses were also made.
Major Findings t It was said that the initial surface-negative
potential in response to weak stimulus was the result of activation
of superficial elements, probably dendrites? and the surface-positive
potential in response to strong stimulus was produced by deep neurones
in the cort©3?. The pres®nt investigation shows that this is not
necessarily so. The refractory period of the cells und@r direct
stimulation and synaptic activation was slso determined in this study c
Serial NOe HZWIB 53(el.
SionificancQ of prograsa to Institute; Th® observation of Adrian
has been duplicated by many psysiologists and his interpretation
accepted sine® his study 24 years ago. His concept has been also
used as a basis for rasny hypoth®sis concerning the elactricaX activity
recorded fros the surface of the cerebral cortex. The result of the
present study is not a challenge to Dr. Adrian's theory bvt provides
evidences that sisy b@ useful in the interpretation of cortical surface
records.
Proposed Course of Projects Further study of direct cortical
stisaulation with conditioned vollays initiated from other structuros
of the central nervous systess is to b« madSo
Part B included? Yes ^ No ^
Serial Noo J^IWDB 53(el
PHS-NIH
Individual Project Report
Calendar Year 1959
p^rt Bi Honors* Awards and Publications
Publication* Li, Choh-luhe Sja^hronlrftlon of Unit ActlvitY
in the Cerebral Gorteae. Science, 1959,
129» 783-784,
2. Priaat© Neurology
3. Bethesds, Maryland
4. Ref&r to NIND8 67|c}-73(e),19S5S
PHS«NIH
liftdlvidusl Project Raport
Calendar Year 1959
Part Ao
Project Titles Study of iRfeibitory lat»rneuroR«s of th©
Cerebral Cortes
Princ^Pit Impeitiq^toyt Choh-luh Li
Other Invest iaators 8 Shelley N. Chou and Anaendo Oitiz
Coopeyst^g^ Unitfi None
Man Years Ptti@nt Days
(ciy^fndgr ytgy ^95?^ jc^lwd^r yefr 1959) i
Total* 0.4
Professional: 0,1 None
Other? 0.3
Projeet Description 8
Objectives To igsvestigste the intracellular responses with
hyperpolarization recorded froas different cortical areas of th®
cerebral cort®?? and evoksd by volleys initiated froM different
sources,,
Methods Baploved^ Th© sells in th© sosnatosensory and visual
cortex were iapaled with micropipette electrodes as^d a peripheral
nerve, lateral geniculate body or a corresponding point in the
opposite hmisF^ere wss stitiulated.
Major Findings ii Hyperpolsrization of many c©ll# were recorded?
aost often froa the visual cortex o Th© size and duration were siMJsr,
In a series of essperiiisnts the lateral geniculate body was poison@d
witfe gasans-^sino bityrie acid and th® responses recorded froa the
surface of th® visual cortess were found t© fee enhanced, suggesting
that this ch@»ic8l ag©nt might have suppressed the inhibitory
interneurones.
.J, rocii-^^,jo i..yif ^.nn'.xx.yXei llsis study is csa-
beginning of «n i?jv«»tigation of the action of gaMia-^iino butyj-i.
acid on th* central n^fvans aystSB. Th® preiiaif.'sary ofettrvation
9©fffiis to indie ®te th.tt und&r certain eircu^sttsacss this chemiesJ.
iigdnt does not inhibii +h" --<: '" nuurones but inhibit the
inhibitory neurones c
ProposecS course e-f prpj®^;,, tudy of th© action oi-
ggflBma-ifflino butyric aci6. aifiid aij.i'ija ciRigs la to b9 isiad'e.
Part B included Ye-; ,^ No /[7
lixNDS c>4(c:
PHS-NIH
IndividiisI Projfsct Rigport
Calandgr Y«sir 19S9
Iffi^t Bs Honors, Awards and Public at iojig
Lit Ghc•^s-'lu■h Stnd Chous Shelley No Jj^MMJi^i^-C
.&i^J2?f.y.l!S^IL=il„l5l2ILii;l£Si,2£j^» '^*5 appear in
book tit.l(ad •*CoEif©r®nctg on Inhibition of Centra]
Nss-^t'ous -Systs® and qmsm-^fSiino bfjtyric acids''
sponsored by th© Air Fore® Office of Sci@sitif:.f.
Ressessrehj U„ S„ ALr Force, Washingtoay Do C.
Sarlal No, N2NDB 55(
!• Surgical Nsurolo^ Branch
2o Primat« Neurology
3. 3fith6sde» Maryland
4. Refer to NINDB 67(c)-73(c),1958
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A.
jproject Title? Synaptic activation of nerve cells in the
priffiary visual cortex.
Principal,, Iny^^1;i<^^tor8 Choh-luh Li
Other Invffftiq^tprg Shelley N. Chou
Cooperating Unitst None
Man Years
(calendar
Totals
Professional!
Others
0.4
0.1
0.3
Patient Days
(Calendar year 1959)8
None
Object ivy » To study the intracellular responses of visual
cortical nerve cells.
Methods eaplovedg The cells in the visual cortes of cats were
impaled with aicropipette electrodes and the lateral geniculate body
was stinulated.
Major findings 8 The outstanding feature of the responses is
hyperpolarization. In most instances hyperpolarization follows an
initial excitation. The initial excitation may be ev@n suppressed
by the arrival of ir^ibitory iEspulses.
Significance of prooraa to Institute; The above observation
is in contrast of the responses obtained from the somatosensory cortex
and suggests that inhibitory process is very important in visual
function.
Serial Mo= J^HOB 55 (e)
Pj^postd t;>^oi,yotg This study is to b® ext«nd«d to t«st the
influence of th» thalai^ic activity on the visual cortical c®lls in
ttrflis of intrttcollular responses.
Part B included Yes O ^o JS7
le Surgical Neurology Branch
2. Primate Neurology
3. Bethesda, Maryland
4. Refer to NINDB 67(c)-73(c)a9~>^;'
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A«
pro.;!e>et Titles Synaptic activation of cortical nerve cells o
Prircipal Invest iqet org Choh-luh Li
Other Investigator? Shelley N. Chou
Cooperating Units s None
Man Years
(calendar
Totals
Profess ioniil J
Other
Patient Days
(calendar year 1959)8
None
ives Synaptic ©^citation of nerve cells in the cerebral
cortea has been made and thoroughly investigated with intracellular
electrodes o This study is an attempt to investigate the responscjs
recorded from the interior of the individual nerve cells in the
cerebral cortex.
Methods employed s The study was carried out in cats. The
cells in the somatosensory cortex were impaled with micropipette
electrodes while a contralateral sensory nerv© was stimulated.
Ma.ior findinc
as followss
The results of this study may be sunsaarizec!
(l) In about 1 msec, after th© onset of the initial surface
positive potential recorded froia the cortical surface? cortici
neurones would respond with growing depolarization and spike
responses were initiated froa a level of 10 mV.
Serial
(2) Subthreshold depolarization was found to b@ cusposed of
smsii potentials. The ssall potentisle can be cont.idered to
be units of postsynaptic potentials; a synchronous Oischarge
of thes@ units giv^ rise to a depolarization of erit.cal size»
from which spiks potential is generated.
(3) Oscillating potentials are rhythmic and graded^ prs.bably
responsible for the rhythmicity of spik® activity. Ths
oscillating potentials do not require a continuous presyuptic
activity and may b© considered as an intrinsic factor with
wtdch the ©jscitability of the nerve cells is msintainedo
(4) Tubo-»curarine does not impede synaptic transmission in
som© elements of the nervous system.
Significance of program to Institutei The above observations
have not been reported in the literature and may be of some impor-
tance in th® understanding of the function of the cerebral cortex.
Proposed course of projsctt The study is to be extended
concerning Integration function of the cortejc. Thus the interaction
of the thalamic and sensory volleys can bo studied in terms of
intracellular responses ^
Fart B included Yes [^ No f^
Serial NOo mw>B - 58 (c^
PHS-NIH
Individual Project Report
Calendar Year 1959
Part B» Honors* Awards and Publications
Li, Choh-luh, Some Properties of PyriBaidal
Neurones in Motor Cortex with Particular
Reference to Sensory Stimulation.
Jo Neurophysiolc, 1959, 22? 385'-394.
- 57(el
io Surgical Neurology Branch
2e Primat© Neurology
3. Beth«sdav Maryland
4. R«f«r to NINDB 67(c)-73(c)a958
PHS-NIH
Individual Projoct Report
Calendar Year 1959
Project Titles Electrical activity of individual flia cells
in tissue culture material •
PrincJD^^ Inve^1;ie^t0y$t Choh'-luh Li and Igor Klatzo
Other Invest iflp^orsg Dr» Shelley N. Chou and Joseph Miller
Cooperpt^nff Un^tse None
Man Years
Patient Days
(f y^ffndy, yesiL
mBi^
icilA.f.n^.Sg,Xg.iML.m2l»
Totals
0.4
Professionals
oa
None
Others
0.3
Pyo^ec^ De^Cyiptio"*
Objt^tivea To study the nsn^rane properties in response to
convulsive and anti-convulsive agents.
Methods Egploveds Similar to the project study «dth spinal
dorsal 9an9lion cells in tissue culture.
Major Findings » Preliralnsry and not conclusive.
Siqnif icjance of program to Institutes The glia elements hove
recently been considered to he extrwely important in central nervous
function. Thus it has been said that glia cells also participate in
"ffiteaory nechanisffl*". It is our belief that before a fair understanding
of the physiological properties of these cells is obtained the validity
S©?iel No» Wm>B » 57(c;|,
of any hypothftsis eoncerning th« roI« those eleeente plsy i:^ <^«8-
tionabl»» Th« significance of this study is* t}i«r«fore> obv^oust
and this study oay provide Avid^ncs fro* which a n«w concopt ^f
nsrvous function may be derived.
proposed course of projep.tt The obstacles of this research
is again the nethod of culturing these cells in a proper i^edium si.
as to facilitate the entry of the nieropipette into the interior oi
these cells. Further effort is to be made along this line.
Part B included Yes £7 No ^
Serial No, NINDB 58(c)
1« Surgical Neurology Branch
2. Primate Neurology
3. Betheedd) Maryland
4. Refer to NINDB 67(c}"73(c
PHS-NIH
Individual Project Report
Calendar Year 1959
Pairt A.
Project Tit;iet Electrical activity of individual neuronal
el«n©nts in tissue culture.
Principal livcstiqatorss Choh-luh Li and Igor Klatzo
Other Inves iqatorst Shelley N. Chou and Joseph Miller
Cooperating Units » Neuropathology Section
Man Years Pstient Days
(calendar year 1959) s (c^alendar year 1959) i
Totals 0.8
Professional! 0,2 None
Othert 0.6
Project Description!
Objective! To investigate the individual nerve cells in tissue
culture in response to epileptic drugs, such as metrozol* strychnine;
acetylcholine, etc« aad in response to anti-convulsive agents.
Methods Employed! The spinal dorsal ganglion cells from chick
embryos were used. These cells were explanted in either collagen or
plasma clot media on Meximow's glass cover slips. The cells multi-
plied and on the 7th day the cells were subjected to investigation
with micropipette electrodes in a chamber under s binocular micro-
scope. The membrane resting and action potentials of the individual
ganglion cells were recorded. Into the bath of the cultured chamber
was added various chemical agents of appropriate concentration.
Electrical measurements of the cells were made again. The excitability
of the cells was then studied.
Serial No„ NINDB 5b (c)
Major Findings 5 The resting electrical activity of *-.he cultured
nerve cells was found to be comparable to that obtained from nerve
cells in vivo. For exaffipls: The resting potentials of the ganglion
cells in tissue culture measured 70-80 mV and action potentials as
large as ^ mV, The only difference was, perhaps? the duration of
the action potentials which was found to be relatively prolonced.
The responses of the isolated cultured cells are under study aid
the observation can only be considered preliminary .. Conclusive
statements can, therefore, be made at a later date.
Significance of the Prooram to the Institute? This study may
throw some light on the mechanism of epilepsy and of the drug action
on this disease. On theoretical grounds this study m«y also provide
an understanding of the effect of an active nerve cell upon a
neighboring resting neurone in the absence of synaptic contracts.
Proposed course of project t This investigation depends largely
on the techniqije of culturing the nerve cells in a special cultured
medium which will facilitate the impalement of the cells with micro-
electrodes, A great deal of time has been spent on the improvement
of the method and at the present no satisfactory solution has been
mads. It is hoped that when the technique is perfected valuable
data can be obtained in a minimum length of time concerning not
only the problem of epileptic activity but electrical activity
of brain tumor cells removed from human patients.
Part B included Yes /x7 No /^
Serial
FHS-NIH
Individual Project Report
Calendar Year 1959
Part B» Honors* Awards and Publications.
Publications Li,, Choh-luhj Engei, K. and Klatzo, Igor^
Some Properties of Cultured Chick Skeletal
Muscle with Particular Reference to Fibril'
lation Potential. J. Ccanp. Cell Wjysiole,
1959f 558 000-000 (June issue).
Serial No. NINDB 59 (C)
1. Surgical Neurology
Branch
2. Clinical Neuropathology
Section
3. Bethesda, Maryland
4. New
PHS-NIH
Individual Project Report
Calendar Year 1959
P|'o;{^ct X.i'<^^9» Sl^udx 9T^_ Morphological Changes due to
EMposuge to Radio- frequency Energy.
Principal Investic^atort Igor Klatzo, M, D.
Other Investigators s M. Baldwin, M. D., E. J. Laskowski,
M. 0., S. A. Bach, M. D. and S. A»
Lewis, R. N.
Man Years (salendar year 1959) % Patient Days (calendar
Total: 4o0 ygax 1959) 0
Professional* 1.5
Other* 2.5
Project Descriptions
Objectlyg.g This project is designed to provide the daca
on the morphological changes produced by exposure of pritrates
to certain radio-frequency energy. It constitutes one of the
aspects of the research Project # N- 1-527 conducted in The
Surgical Neurology Branch which is concerned vdth vari:»us
problems connected with the effects of this type of eriergy.
M^-^hods Employed! Primates are exposed to yario'js ultra-
high frequencies within micro-wave ranges as descrited in
Project # N- 1-527. Sodium fluorescein is used for study of
the permeability of the blood-braln-barrler (BBB). Various
histochemical and histological procedures are employed to
assess the changes in the central nervous system of the
primates which are sacrificed at various time intervals after
exposures.
Major Findings; Pffeliminary findings indicate the following!
in acute experiments, where the animals are sacrificed within a
few minutes after exposure in the "low position" the changes in
the permeability of the BBB can be found in the pons, medulla
and extending through the white matter into the cerebellar hemi-
spheres. Sometimes, the BBB changes are localized lower and
Serial No. NINDB 59 (C)
Major Fj-ndinqs (cpnt 'dj s
involve the dorsal areas of the cervical spinal cord. The
histological changes in the acute experiments are confined
to the striking tygrolysis in the large tegmental neurons
of the pons, aedulla and the dentate nucleus of the cere-
belluBic No neurofibrillary changes can be observed in
these neurons.
In the chronic experiments only a few animals showed
changes in the BBB and they were localized in the dorsal
portions of the cervical cord. The morphological changes
were found in the majority of the animals and were seen
mainly in th© dorsal areas of the cervical spinal cord*
They consisted in severe tissue destruction, mainly in the
posterior coluims. In these areas small cystic cavities
could be seen transversed by greatly proliferated blood
vessels with abundant reticulin<> Changes in the medulla
and pons found in a few animals showed similar cystic
cavities with well preserved neurons in the vicinity.
Proposed, course of the project; It is proposed to
correlate precisely the morphological changes observed
with the dose and frequencies of the exposures as well
as with the head positions of the animals. Similarly,
correlations will be attempted between the morphological
changes observed and the clinical effects of exposure.
It Is intended to study the biological effects of this
radiation on the cells of the central nervous system
grown in tissue culture.
Part B included? Yes CD ^^o f^Z7
Serial No. NINDB 60 (C)
1. Surgical Neurology
Branch
2. Clinical Neuropathology
Section
3. Bethesda, Maryland
4. Continuation of
NINDB 74 (C) - 1958
PHS-NIH
Individual Project Report
Calendar Year 1959
Patt A.
Pyo.^ect Titles Study on Plnofiytosis and Uptake of Proteins
and Neutjjil Red Dye in Vitro.
Principal Investiqatogi Igor Klatzo, M. D.
Other Inv^si^iqatorsi J. Mlquel, Ph. D.
Man Years (yalendar year 1959) s Patient Days (calendar
Totals 4.0 year 1959) :0
Professional* 1.5
Others 2.5
Pro.ject Description g
Objeci;ivei The main purpose off this project is to get an
insight into some basic features of permeability and metabolism
of various cell types grown in tissue culutra. For this purpose,
uptake of non-toxic neutral red (NR) dye and several proteins
(albumin, globulin and fibrinogen) labelled with fluorescein iso-
thlocyanate according to Coons' technique is being studied on
various experimental conditions.
Methods Employed t Ner/ous and aiuscle tissue is grown in
vitro. Cultures of living cells are incubated with various
solutions of NR or labelled proteins. Observations are made
at time intervals; the cultures being subjected to various ex-
perimental conditions. Cells are observed in bright-field,
phase and fluorescence microscope as well as photographed in
the time- lapse cine camera.
Major Findings 8 The uptake of NR takes place only in living
cells in good physiological condition. HR disappears from the
dying cells and is not taken up by the dead cells. There are
marked differences in the ratio of uptake between various cell
types» Macrophages are filled with granular inclusions of NR
in a short time. Astrocytes show conspicuous granules of the
dye in the processes and perikaryon after an inteir\'al of time.
Serial No. NIMDB 60 (C^
Mji jor Find inq s ( cont ' d ) ;
Nerve cells and muscle fibers take up NR in a limited way and
only at the terminal expansions which aire provided with un-
dulating membranes.
The uptake of various proteins resembles in many ways that
of NR. There is a similarly different ratio of uptake among
the various cell types.. The striking difference is the dis-
appearance of proteins within one hour from the macrophages,
whereas the astrocytes preserve the proteins throughout the
time of observation (24 hours). The ratio of uptake between
various proteins is correlated generally with the size of
molecule and is lowest for fibrinogen and highest for albumin.
The effect of low temperature (4 °C) has been studied on the
uptake of NR and lafc^lled proteins. There is a conspicuous
reduction of the uptake of TJR. With regard to the proteins it
is interesting to note that 6 hours after feeding the hypo-
thermic (4 °C) cultures show macrophages filled with fluorescent
proteins whereas there are only very few proteins inclusions in
the astrocytes. This picture corresponds to the appearance of
the normo thermic (37 "C) cultures 30 minutes after feeding with
protein. It is attemptsd to correlate these observations on
the uptake of NR and proteins with the phenomenon of "pino-
cytosls". The plnocytosis ("drinking by the cells") has been
observed as a formation and disappearance of clear vacuoles
in the undulating taembranes of various cell types, particularly
macrophages and astrocytes; it is suggestive that initial up-
take of NR and proteins takes place by plnocytosis with con-
sequent concentration of the substances under study.
Pyopo^ed course of t^e projeet^.s It is proposed to continue
this investigation in order to investigate further the various
aspects of this basic physiological mechanism of uptake of
various substances in the cells grown in vitro. Especially,
attempts will be made to correlate the ratio of uptake and
metabolism with that of plnocytosis and influence this ratio
by various chemical and physiological conditions.
Part B included? Yes CJ No ^
Serial No. NINDB 61 (C)
1. Surgical Neurology
Branch
2o Clinical Neuropathology
Section
3o Bethesda, Maryland
4. Continuation of
NINDB 77 (C) - 1958
PHS-NIH'
Individual Project Report
Calendar Year 1959
Part A.
Project Titl^i Study of Regeneration in the Cen1;rjil
Nervous System,
Prtncioal Investigators Armando Ortiz-Galvan, M. D.
(Now at the National University o
Mexico General Hospital, Mexico
City, Mexico) o
Other Investigators t Edward Jc Laskowski, M. D. and
Igor Kiatxo, M. D.
Man Years (calendar year 1959), s Patient Days (calendar
Totaii 0 year 1959): 0
Professionals 0
Others 0
Pgoleci; Description i
Oblective ; Saae as NINDB 77 (C) - 1958
Methods Employed s Same as NINDB 77 (C) - 1958
Ma^or Findings 3
Proposed course of the project; The project has been
discontinued since the Principal Investigator has returned
to Mexico.
Part B included? Yes CZ/ ^'o HJ
Serial No. MINDB -62 (C).
Ic Su5fgical Neuffology
Branch
2« Clinical Neuropathology
Section
3o Bethesda, Mairyland
4, Continuation of
NINDB 78 (C) - 1958
PHS-NIH
Individual Project Report
Calendar Year 1959
Pfiii-A
iA
Ps-oiect Tit let H|s'^o^heBl«'.aJ__anri E ^e^lrophyslolOQieal
Obsegyatjions on the Muscle F^iieeys Grown
la yityo»
Principal Inyestiqatori W. K. Engel, M. D. (Now at Queen's
Square, London, England) o
Other Invest|.qatogsi Choh Lu Li, M, Do and Igor Klatzo, M.D.
Man Years (calendar yea^^ ^959) » Patient Days (calendar
Totals 0 ^§31. 19.59.1 « 0
Professional? 0
Otheff! 0
Pro,1ect Description t
Oye£l|vei Same as NINDB 78 (C) - 1958
Metho(^s EmiJlovedt Same as NINDB 78 (C) - 1958
Ma lor Findings g Same as NINDB 78 (C) - 1958
Proposed course of thig project t The part of the project
concerned with the electrical acti^^ity has been completed.
The remaining studies will be resun i upon the return of the
Principal Investigator from abroad.
Part B included? Yes ^SZ? ^'^
Serial No» .^NINaQg (g)
PHS-NIH
Individual Project Report
Calendar Year 1959
Part B, Honors, Awards and Publication
Publication other than abstracts from this project:
Engel} W. Ko : Cytological Localization in Cultured
Skeletal Muscle.
In Preparation.
Honors and Awards relating to this project t
Serial No. NINDB 63 (C)
1. Surgical Neurology
Branch
2. Clinical Neuropathology
Section
3. Bethesda, Maryland
4. Continuation of
NINDB 79 (C) - 1958
PHS-NIH
Individual Project Report
Calendar Year 1959
?3T%. A-'
Project Titles A New Methoci,,fpr Qu^ntj-^a^ive Study of
Precipitin Reaction.
Principal Investigators Jaime Miquel, Ph. D.
Other Investigators % B. Horvath, M. D. and Igor
Klatzo, Mo D,
Man Years (falgndar year 1959) s Patient Days (calendar
Total J 0 year 1959) 0
Professionals 0
Others 0
Proje^-^ Descriptions
Objectives Same as NINDB 79 (C) - 1958
Methods Employed s Same as NINDB 79 (C) - 1958
Ma^or Findings: Same as NINDB 79 (C) - 1958
Ps-oposed course of the project 8 This project is completed.
Part B incl'ideds Yes 2Z7 No £Z7
Serial No. NINDB 63
PHS-NIH
Individual Project Report
Calendar Year 1959
Part B. Honors, Awards and Publicat on
Publication other than abstracts fror. this project:
Mlquel, J., Horvath, Bo, and Kla'f.zo, I. ;
" A Chromatographic Technic for che Quantitative
Study of the Precipitin Reaction".
Accepted for Publication in The Journal of
Itwnunology.
Honors and Awards relating to this project:
Serial No. NINDB 64 (C)
1. Surgical Neurology
Branch
2. Clinical Neuropathology
Section
3. Bethesda» Maryland
4o Continuation off
NINDB 81 (C) -1958
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A.
Pro.lfiPt JlUeJ Sjuj^of the Ef f,ec1;8 of, HffioJ^h,ermi,s on
In.lured and Norwal Bra^n Tjtsu^.
Principal lay.esl^j.ga'^orj Edward J« Laskowski, M. D.
O^her Investigators ; Igor Klatzo, M, D.
Man Years Ccaler>dar yeaf^^_19-5_9lj Pa;j:,j.ent Pays fj?;^lf ndag'
Totals 1.0 year 1959) > 0
Professional: 1.0
Others 0.0
Prc>1ect pescriptions
Qblectlyes The continued use of hypothermia as an adjunct
in neurosurgery has prompted this investigation to further assess
the effects of lowered body temperatures on the various aspects
of brain injury. The responses of the various elements of brain
edema and the blood-brain-barrier were too be established and
then correlated with responses of the same tissue elements under
varied conditions of hypothermia.
Methods Employed? The assessment of the effects of hypo-
thermia is based on a study of our standardized cold lesion as
described in Project NINDB 57 (C) - 1956 in normothermic animals.
A comparative study of normothermic and hypothermic animals In
response to this cold lesion Is further described In Project
NINDB 31 Cc| - 1957. Brain lesic^s were made in groups of cats
under normothermic conditions. Six hours later the temperatures
were lowered to 26 "C and maintained there for the remainder of
48 hours at which time they were sacrificed. Minor variations
of this same general procedure were introduced.
Serial No. NINDB 64 (C)
Ma Joy, Fj.nd^nqsi A most striking difference between the
normothermic and hypothermic animals has been revealed in the
behavior of the blood-brain-barrier. At 24 hours, when edema
is maximla in the normothermic group, the area of altered blood-
brain-barrier is diminished in those treated by hypothermia. The
astroglial reactions are diminished at comparable periods in the
hypothermic groups as compared with the normothermic. The
degree of involvement increases however, and is maximal at 48
hours after which time both groups follow a comparable course.
In the current group the degree of change in all elements is
markedly less than in the noitnothermic group at that time and
is similar to the picture seen at 6 hours in the normothermic
group. This suggests the measure of benefit which may be
derived from the use of hypothermia in the treatment of severe
head trauma with brain edema.
Proposed course of the pro.iepts This phase of the project
is complete. Further evaluation of the responses of brain
edema to hypothermia applied at various time intervals is
indicated however^and studies will be continued.
Part B included*. Yes iSI7 No CJ
Serial No. NINDB 64 (C)
PHS-NIH
Individual Project Report
Calendar Year 1959
Partf B. Honors, Awards and Publication
Publication other than abstracts from this project!
Laskowski, E« J«s Observations on the Effect of
Hypothermia on Experimental Brain Lesions. The
American College of Surgeons, "Surgical Forum".
Vol. IX. » 714-717, 1959,
Laskowski, E. J. , Klatzo, I., and Baldwin, M.:
Experimental Study of the Effects of Hypothermia
on Local Brain Injury.
Accepted for Publication in Neurology.
Honors and Awards relating to this project;
Addendum to NINDB 75 (C) -1958
Ic Surgical Neurology
Branch
2. Clinical Neuropathology
Section
3. Bethesda, Maryland
4.
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A.
Project Title; The Localization of Myosin i,n Human
Striated Musple by Fluorescent Anti-
Principal InvfstiQator: Igor Klatzo, M, D.
Other Investigators t B. Horvath, M. D. and W. K.
Engel, M. D.
Part Bs Honors, Awards and Publication
Publication other than abstracts from this projects
Klatzo, Igor, Horvath, Beni, and Engel, W, Ko
"Observations on Myosin in the Alwtiormal Muscle
using Fluorescent Antibody Technic".
Accepted foi- Publication in the 1958 issue of the
Volume of The Association for Research in Nervous
and Mental Diseases »
Honors and Awards relating to this project i
Addendum to NINDB 76 (C) - 1958
1» Surgical Neurology
Branch
2. Clinical Neuropathology
Section
3. Bethesda, Maryland
4.
PHS-NIH
Individual Pffoject Report
Calendar Year 1959
Pait.,A.
Projg^l, Title,? S^udy of_ Pathology of Kuyp Disease o
Pr^ncipajt_ Inv^.stiqator « Igor Klatzo, M. D.
O^her ][nveftiqatorsi D. C. Gajdusek, Mo D. and
V. Zigas, M. 0.
Part Bj Honors, Awards and Publication
Publication other than abstraets from this projects
Klatzo, lo, Gajdusek, 0. C, and Zigas, V. :
"Evaluation of Pathological Findings in Twelve
Cases of Kuru"o
Accepted for Publication in the Volume of the
International S^^wposium of Actual Encep^alitides,
Antwerp, Belgium.
Honors and Awards relating to this projects
Addendum (Publicatioa on which
there is no current project).
1« Surgical Neurology
Branch
2» Clinical Neuropathology
Section
3. Bethesda, Maryland
PHS-NIH
Individual Project Report
Calendar Year 1959
Pay^,„B. Honors, Awards and Publication
Publication other than abstracts froao this project;
Engei, W. Ko, Kurland, L, T«, and Klatzo, I.s
An Inherited Disease Similar to Amyotrophic
Lateral Selerosis with a Pattern of Posterior
Column Invol^^ement. An Intermediate Form?
Brain. 82? Part II, 203-220, 1959.
Honors and Awards relating to this projects
2. liiev©lopEieatal Neurology
4a Bmm as NXMJB^SS (c)
Ijsdividuffil Projece Report
Cal®a4«s: Y®&t 1959
i^L^
Ft >1ect nsia; Investigs&ion of the E«:ioiogy, Psthologjr md
*^' Cliaiaal MaaifesSffiftions of Cera&rel Palcy and
Allied Cosadlelons; Also of th« Bpilttpsy During
Shlldtood,
Principal lw,^sttf^tot% Aastole S, ©eksbsn, MoS,
Other I«v««tlgffitog»^ Sona
Coopega&itiK Uaiea; Hone
^n ¥aar« ^calandar year 19S9>s ^tlcnt Daya (calaadar year 19|9|
frofeseionals 0»2 399
OShar: 0.4
Projaefc Dascripfcions
Oblactivaas Comprehacsiv® clinleal, laboratory and g«na£icel
invastigeSion of a aalacted group of children suffaring
frora organic brain syndronas and epilapsy and corralation
of thua obtaiaad data with tha findings in pnaumo«ncaphaio°°
gr^n. Tha main objectivas ara: 1 « Corral^tlon of th@
clinical features of cerebral dysfunction with the eite^
eis@ and character of the cerebral lesion. 2 • Clas8ifiea<=>
tion of a larger group of children suffering froa organic
brain condition according to the etiological factors
triienever these were established. 3 ° Preparation of
publications based on eiaaller group® of patients presen%°
ing particularly important aspects in relation to pathology^
pathogenesis or response to a new typ® of treatment o
Methods Baployeds
lo Genetic investigation,
2o detailed neurologic&l eitaadnation^ including de^elop°
Rental testing and electroencephalogram.
3. pBeuraoeneephalogratn.
4. Other special tests as indicated.
PatlenE Mateglala
AvOT.Stay in Day«
Admissions s Children mie 17 21
Children Femal« 18 29
CllnlcAl Project
M«1or Findtng»g
Cusrlng 19S9 3S pstisnts wertt studied in great d«eail as
in«pffitie»ts and 35 on the out°patlaat bAsiSo In Add!"
tion^ out of 160 petients under speelel study on epilepsy
during ixiisaey (in cooperation with Hayo Clinic), 65
were re-exfnined clinleelly and with special laboratory
tmta.
Material from a considerable proportion of the in°patients
fomted the basis of couBBunieations already published as
listed below and the part of the Biaterlal is currently
evaluated. Our s^in purpose is to document hitherto un°
known factors responsible for congenital raalformations
or brain dssage « as it was done in our studies on of£°
spring of diabetic eaothers ■> or to contribute to clar°
ification of clinical and pathological aspects of cerebral
palsy, epilepsy end stental deficiency.
Out of 35 iQ°patlent8 s, in 16 we were able to establish
etiological diagnosis. Of tSse rsiaaining 18g in ^ots
only descriptive diagnosis was possible, the site of
pathological lesion was determined in 10 patients. The
latter finding is of importance because it narrows th®
possibilities in differential diagnosis; also in the
future 3o<a@ of these patients osay becoae subjects for
revealing elinico^pathological correlations.
Rssults of studies on a number of patients studied are
reported in the publications listed below. Final
analysis of the «^teri«l has to await aceuomlation of
Bore patients.
Significance to Weurological Research; In a majority of cases
the etiology of cerebral palsy and allied conditions is
poorly understood. Better knowledge of hereditary factors »
clinical oisnifestations g as well &a the location and ssctsnt
of the lesion may further our insight into the diverse
etiology of these conditions. Full understanding of
pathology and etiology in larger groups of children with
brain daiaage will suggest eventually better directed
preventive and therapeutic laessures.
Proposed Course of the Project:; accussulation of taore data
is needed and the organisation of this project reamins
unchanged.
Part B iaelud®d Yes / x / No / /
Iscividuai Froject Eapo?t
Gelesider te«r 1939
Part Bs Honors, Avsrda and Publications
D«k«bsn, i^atole and Drager, Olenn: HeCastases of the
retlnoblestoi&a to the central nervous system.
Advisability of a e<»Bblned intraorbital and Intra^
cranial rsooval of th« affected optic nervSo MtiA
Archives of Ophth„ 66s 239=245, 1959,
Dakabcng Anatolas looks Neurology of Infaacy, 1959,
Wllllans & Wllklns, laltlatore. pp. 16 -f 388 » 404,
Honors and Awards lalatlng to thjs Project;
lo Assistant Professor of Neurology at George Washington
University Medical Schr ol.
2. Consultant District oi Coluabla Children's Hospital o
PHS-aiH
Individual Project Ettpor£
C«lend«7 Yeer 1959
3. Bethasda, Maryland
4. Ssme as NINDB->83 (c)
^•^^ ^'
Projact Titles Materasl Gondision During Pregnaacy snd the
Course o£ Birth in delation to Neurological
Abnrireaalitics in the InfftQts and Pathologic
Lesfons in Products of Abortion.
Principal Investijpgiors Ar.atole S, Bakaban, MoD„
Other lPvcstiRator;n Dr„ T.So Cone and Dr„ H„Ho Hill 9
• R«tioi?*al Naval Uedieal Center; Dr,
LoJo Geppert snd Dr, H,Lo Rivfis
Walter Reed Aray Hospital
Cooperating Uaitti: National Hawal Medical Center and Walter
Reed As&y Hospital.
Han Yeera Ccalenfiar year 1959);
Totals 0.3
Professional I 0,1
Other: 0,2
Project Description;
Oblectivess Analysis of various ebnorsial factors occurring
in pregnan): aothers or complicotions of birth which tmy
cause or contribute to neurolc.'.ieal abnonsalities in
infants .
Methods Employed?
1. Prenatal care of tsothers und r research end their
individual final assessment.
2. Recording and evaluating of t m course of birth
and pertinent abnortaalitles.
3. Sszaiaination of the net»bom inf^its during initial
hospital stay.
4. Follow°up ttxssilnation of infanti,.
5. Gross and microscopic examinatic\ of the products
of abortion.
JLmsi^pt {ct
Pattaata M«f rial;
1. All pregnant vommi wlio were receiving prenatal care
at the National Naval. Madical Center and Walter
Seed Axisy Hospital and subsequently were delivered
in these hospitals b4\'n«een March !„ 1956 and March
1, 1957,
Clinical Project
Malor Findings g "Rie total of 4,156 pregnancies and products
of these gestations '^ere ttudied in great detsil regard^"
ing pressature car^, confinsment^ infant's state at birth
and his subsegueni course up to one year of age At the
present tiase the j^itsalysis nf the de&iographic data on this
oateriel is eo^lQted and rsady for publication. The
folloMng tm> cables give s>:ae insight into the demo-
graphic asp '^Q oS this study,
TABLE I
Classigjcatld of the outcome of gestation in _4^156 pregnancies.
Abortions. «» o .,.,,,...„ o„„.. o ,'. . .312
Pir«vi«bl« .».«,<...«...,,.. o ., o o . . 9
StillbitCuB. .,.. o .,«.«..,....,.,., 22
Heonst''i Deaths, ,,...,,.. 59
Infa»-^J^o Dei'.ths ...,....,. , . , . 10 -
g.j^ iving full term infants with
aoiaplicated gestation, delivery
or abnormal clinical stete at
birth. .....,.,....„»„,.„,..,, ,921
Surviving full term infants with
normal gestation, delivery and
normal clinical state at birth o . . . . . , . . . o 2,567
Surviving premature infants with
complications of gestations g
delivery or abnormal clinical
state at birth , .,.,.,.,..,. o.<,.. . .,103
Surviving premature infants with
normal gestation, delivery and
clinical state at birth c . o ........ .153
Total. , , , o o . o o . o , . , o , o » o , .4,156
ng^lLesalM®a,JE£^£X-,L^i£i5SSi.
^^ALM;
Mt^&m ..8 & 28 y®fflx»
8«.tw®es» i9 S> ^ years
Ove£ 3S fmmt»
GROUP A
g^2L.l,
^.,
54
2&
12
820
5U
155
368
175
122
35
1?
■■J a
Th® avalustion of th« ri»al?»d«r of feh® »«t-«^.i.--
follow «d It is likaly fco fehro** swr® light: on fe!s^^
tloias %^ich »r% Imsludfti la eh@ &roup of »«RKjil
defl^si'mey^ «pil«p^y mad cmt^ht^l palsypo
^^^iiUmmm to MeuroloRlca4 R«i8^gcUs S£ Is p^?tulafc<^t.
that varioug riwirorifliMmf,®! f setoff® acting duris^g pre-
nsfesXj, intranatal sni «airly pastnsfeffll lif® ®ay be
responsibl® for br«in dassaga isnd ea« assosiste^ elln.u
»equ«la« in infants o This «Sudy q>ay r«veal th« relstivs
lta:x>?£siae« oi eertMn iitctors smd slso £U«ir !««:: id«ne^> .,
Sin&% ensraful s«d utiifosia sjssteslnaeionai ae« being «5o?»o
ted d-asiag «ll sfcages of |>y«»»fc®l «««S pas^mtrnJ /it*,
£i«»^i anai:y«t» i*f th®. tlMivg» should b® i'tf,ta^is>»«-
fx'o^sm C;oujfj6,g_jgf_jag_.Fy^^j£i, Gompl^tloiS of tb ■■
«n4 3ir«^rafcion of she «iii«eKi®l ioT puhliom-'
f&tt B tnciudsd
t"^
Serial Ho. HlWDB"66 (c>
PHS>HIH
Xncivldual Project £ ^porc
Calandsr 7ettr 1(^:9
Perl: B,s Honcrss Awards anri 3?ublica£io«MJ
Dekabane AnaCole, oto alcS Corralatlon of £he ia®d£cal condi°
tlca of the oiSspsrlnj and of Ch« outcoea of 4,156
pragnsnclas %;i.th aatamal ecata during gastation^ typa
of d£>livery aid eotulitlon of tha infants during first
4 days of lifiu Pa/.'t Z; Dastosraphic charaetaristies
and £U£S!ssarlzed raavlts of the investigation. In press.
Honors and Awardu iielating to chis Project; Hone
serial Ho, SIHDg°67 jc) __
i. Surgleal Neurology
2. Dav«lopnitnt«l Neurology
3. BcthMdA, Koryland
4o Same m NINDB-84 (c)
PHS=H1H
Individual Project Steporfe
Q^lmdatr Year 1959
^•^^ ^°
Prolect Tifcleg P«thologic®l Lesions in the Central Kervoua
System Occurring During PrenAtal, Intran«tal
and Eerly Postnatal Ufa.
Principal Invegtti^torg Aaetola So D^kaban^ M»D.
Othar Inveetlgatores Martha Soring
Cooperating gaits g None
Man Years ^calendar year 1959) s
Totals 0.6
Professionals Oc2
Others 0.4
Projject Dtfcglption^
Objectiveag The causation and pathology of the aajorlty of
patients with mental d«licieney and cerebral palsy are
largely unknown c Detailed esEanination of the brains of
ehlldrsn viho suffered frota such disorders and eorrela*
tion of these findings with the clinical data is expect'^
ad to prcvide valuable information for ;tlucldatlon of
etiology of such conditions and eventually they may
suggest possible preventive
Methods Eaployedg 0@tailed sxffieination of brains and spinal
eords f rora patients ^o suffered £rca cerebral palsy or
allied conditions by laeans of g
lo Gross eiswaination and disseetionao
2o Microscopical study of sections whltsh were treated
with chroraatie silver » csyelin and imt stains as
well £8 hj various hlstochttslcal procedures «
Material s Twenty^three brains froa children viho suffered
acute birth injury or who were in chronle phas© of
cerebral palsy vere studied o
Neurepathologle&l project
serial Mo, W£NDB^67 (c)
Major Findings SlghC brelns ivtm patisnes 8uf£«rlng £tam
c«r«bral palsy end allied Civttditlons w«r« afeudled in
detail and p&st oS. fch« Infox nation obtained was publish^
ado Cafrently^ careful sval istlon of pathology and
pathogenesis of acute birth Injusy Is made on material
consisting of 15 brains with such lesions. It appears
that correlation of soaie of these acut« heaM>rrhaglc
lesions with clinical flndlnL^s of other patients nay
form a basis for clarification of certain instances
sf cortical blindness and cerebral diplegiSo
Significance to Kaurologieal Reaearchg Such studies are of
great importance as the nu0jib«r of brains exaialBed in
detail in the instances of cerebral palsy and allied
conditions is rathar small. Studies relating to this
project resulted in 2 publications during l9S9o
Proposed Course of the Proieet, I^rgher accuffiulation of
data is needed.
Serial Ho. HirmB-67 Cc)
PHS-KIH
Individual Project l«port
Calendar Year 19S9
Part B. Honors g Awards a»d Publications
R'.ce, E.Co end Dskaban^ Anatole: Congenital hwaiplegia
resulting from cerebral laalf orsaation . AHA Areh.
Pathology ^s 348-351, 1959,
Dekaban;, Anatoleg Arhinencephaly in aa infant bom to a
diabetic mother. Jo Neuropath o and Exper. Heurol.
18 s 620-626 B 1959 «
Honors and Awards Relating to this Projects Rone
serial Ko, mHDBo68 jc)
lo Surgical Neurology
2o Dcvdopoiental Neurology
3o BethesdAg Maryland
4o Seme ae NINDB«8S (c)
PHS-NIH
Individual Project Eeport
Calendar Tear 1939
MELA,
groject Titles The Ineidenc® and £he Type of £he Central
Nervous System Abnormalities Encountered
in Offspring Bom to Diabetic Hothers.
principal Investli^atorag Anatole So Dekabanj M.l}„
Robert L„ Balrd, MoD,
pther InvMtigatorsj.
Cooperating Units ^ None
Man Years {calendar year 1959h
Totals 0.6
Professionals 0.2
Other; OA
Project Deacrlptlong
Obiectivesg Our cllTileal and neuropathoiogleal studies In-
dicated that severe abnor«iaIitles atuat occur not in-
frequently In Infants bom to diabetic laotherso COekaban,
A. and Mageeg KcS Occurrence of neurological abnonaalities
in infants bom from diabetic laotherso Neurology 8i 193°
200^ 1958K It became important to evaluate statlsti-
eally the incidence of these abnormalities in larger series
of offspring bom to diabetic mothers and to analyse the
findings in light of findings in series of normal controls o
^hods Bmployedg
1. Critical assessment of maternal diabetes and her
toS^ffil pregnancies o
2o Examination of all her offspring.
Material; The outcome of 234 pregnancies in 48 diabetic
vomen and in 249 pregnancies In 48 normal controls were
analysed, Tb'® iffiofeh®r8 w®r« g>«r8onslly interviewed and
the offspring 9XsmLa9do
serial Ho. mHDB°68 (e)
Mftlor Ftndtngsg The outcome of 235 prsgnaneiss in dlAbetlc
and predlftbetic women w&se Investigated and th» results
obtained were cotapared with the corresponding data in
the 249 pregnancies of loatched normal controls, the
percentage of abortions and previable deaths in the
ilabetic sample was 29 o9, in the predlabetic sample
2^,5 and in the normal controls 12o4o Stillbirths
o curred with the following frequency: 11. S per cent
ill the sample of diabetic caothers, 5.1 per cent in the
pndlabetlcs and lc2 pe^ cent in the normal controls o
Th& neonatal deaths amounted to 3.3 per cent of all
pr^ipancies in the diabetic womeae lo3 per cent in the
pr( diabetics ^oid 3.6 per cent in the sample of normal
eoi trols <, 'These values demonstrate clearly that the
i&iil wastage in the diabetic women is significantly
greater than in the normal controls. The fetal loss
during the predlabetic stage falls about midway between
tixiit in diabetic and normal control mothers c
Th\^ main purpose of our study was to test the hypothesis
th:;;t the morbidity dating since birth in the offspring
of diabetic mothers is also increased as cooqMired with
the sample of normal controls. There were six abnormal
8ur\jiving offspring in the saaple of 157 diabetic
pragiancies which mounts to a total of 3.8 per cent
(or .'o6 per cent of the surviving children). In the
normal control sample of 249 pregnancies there was only
one alnormal surviving offspring which constitutes the
incidence of 0.4 per cent. The difference in percflatages
in thmm two groups was significant at P less than 0.01
indicating that our hypothesis is very likely correct.
The abnoiiaalities in these children include mental
deficleQc:% congenital malformations $ birth Injury and
epilepsy.
Three of the sis abnormal surviving children bom to
diabetic mothers had severe congenital malformations s
two had mental doficiwicy and one sequiala® of birth
injury and epile>>8y. Of the £orty»one offspring of
diabetic woisen who were stillborn or died during the
neonatal stage sixteen had comprehensive postmortem
escamlnation and ahe major findings are as follows;
pulmonary hyaline membrane disease was found in eight
patients e congenital omlfoiaAtions in three$ cerebral
birth injury in two and no gross, demonstrable lesion
in the remaining three. Factors, possibly pertaining
to th@ increased fetal loss and to the higher rate of
morbidity among the offspring of diabetic mothers ar®
discussed in publications listed beK^w.
Slgniflcmge to Hau^oLoglcal ^mmxchi Yl. ,
tlons ^ich Are tha :r«sult of ou? studifts @st&biigh@4
for th« first eiiac th«t aatarnal <ii«bc£«s should also
be Included to the known causes of aan^al deficiency
and cerebral palsy in a proportion of offspring c
Proposed Course of the Projects fha question of extension
of this project to include e:\periBi@ntal approach to th€!
fltetabolie derangmsnt during olabetic Acidosis in
pregnant fefflales is currently mder discussiono
Part ® Included Yes / k / Ko /_;,/
serial Wo. NINDB»68 jc)
Indlvldvi«l Fs iject Reporf
Calandar Year 1959
Pwft Bg Honors 9 AwacUs and F.ibllctttions
Dekab«n, Anai£ol<i and BaJrd, Roberts Th« ouCcoom of pregnancy
in diabat.s women. Part lo fetal wastage g, laortallty
and oorblclty in the offspring of diabetic and noraal
control otcthars. J. Padlat, SSs S63<576, 1959.
Dekabsn, Anatol€t fh« outcome of pragaancy In diabetic
woia«no fa?t lie analysis of clinical abnontalltlas
and pathological le^iions in offspring of diabetic
mothers. J. fodlAt, In press ^
Honors and Awards Relatl.ig Co tl)is Projects Hone
PHS^NIH
Individual Project Rsport
Calesidar Tear 1939
Serial K»). tJI!iDB°69 Cc)
1. SmglTIl Neurology
2. Developmental Neurology
3. Beehe ia, Maryland
4o Saae is NINDB°86 (c)
^•'•^ ^'
Project Titles Heasureasents o£ External and Internal Orbital
Distav^ce in Kales and Finales froia Sirth to
Adulthood.
Principal Inveetlftatorg Anatole S, Desban, MoDo
Other Inveetigatorss None
Cooperating Onitas Rone
Han Years (calendar year 1959k
Totals 063
Professional: 0.1
Other; G.2
froject Deseription^
Oblectiyess It has been found thst the neasurement o£ the
Interpupillsry distance in hus&tns for the purpose of
estioation of hypertelorisia anl abnoraality of the
sphenoid bone is unsatisf actor:'. It is thought that
either external or internal orl>ital distance or index
thereof should take place of t^« Beaeurosents of the
interpupillary distance o
Methods Eoployed^
I. Measurements of the above^^eiasd distances in huiaaa
a&lm em4 fcsiales at progressive ages beginning froa
sero to 20 years of age.
2. Correlation of physical sseaeurenents of a sstall group
of children with aeasureaents nade on cephalonetric
x»ray8.
3o Statistical analysis in various age horisons.
Matertals^ Heaeureaents of all horisons have been taken.
'~~" This°auou»t8 to the total o£ 600 hesd sieasur^aents ,
rAi.ni.si.iSil Pvai^t&t.
S«£ial Ho.
Major Findtngas fast of the da£a de: Ived from ehls study
waa analysed aad published In the book "Heurology of
Infancy" g pages 3S°37. Entirely mv aro data pertain*
ing to the norm In various ages oc the interorbital
distance and also to the volume oi: the skull as
measured in live subjects.
Significance to neurological Rese«rc^ i To make the e8tima°>
tion of conditions such as hyper elorism more scientific,
the measuroaents of stable bony itruetures rather than
movable organ as eyeball, shoul*: be performed. As an
example a coneommitant divergaru strabismus can be givci;
in this instance measurement oi the interpupillary
distance for the estimation of the abnormality of the
sphenoid bone would obviously give false results.
Proposed Course of the Projectg rhe remainder of the otatarial
will be evaluated and tshen suitable patients tflth sp< df Ic
clinical entitles will become available reports for ^jublica*
tions will be prepared o
Part a included Yes / x / Mo /
Individ ml Project Report
Cel.ttdar Year 1,959
Part Bs Honors, Awards and Publisstions
Dckftban, it$itot^% Fagos 3S->37 in Books Neurology of
Infmcy. 19S9, Willi^sas & Wilkins, Baltiiaoroo
Honors and Award Relating to this Project; None
^■LAt,
£i®84E of fete mSo
Principal Zay^sfety^ateg?^ Anatol® S„ DskafefiKn^ M„0,
Other » 0o6
Ob^ecfcivan; fha guspoe® oM ehis projsee is Khe produc-
tion fiisd asualysis ©f eoRg^ital, ffito©Eu,ells;l®s of tha
CSS and tha p»cvisi®sa of notsas for feb.e -^^jf^eloimasst oi!
thti) GKS in i!d;e«.
1. DJLS»«i6£l<5n of £h® ClfS of siee of 16 progs \:
2. PreparaeloEi and sfcjBining of eas-lal sec.
3. Xdentlfisafeion as'.d oufeltnisng ©f ffi®ls>. «£rweturer.
on th® low power raic^ophaotcgiTiaphi r
4. X=rsy radlt.fcioa cf pra^,aii«;; asic© £rs® « strata
whieh do®® not eb.ow imy aignificasst-. iaeidetsc® c:g
5. X^ray radiation og pr«,gsMsnt Slask G 57 ude® iu
s®var«l sfesges of pregsiaaaey td-Sfe sltallsr para^
iaa«fee£® 2:o these for eiles ir-. ST'd.ss Albino; th®
Seri.1 Ko. MHDB-70 (c>
strain u88d h«rfi show An sbsiortaally high Incidence
of sponteneous laalfoxss&tions oi the CNSo
60 Gross, skeletal, find oicroscoplcfil »x«seinBtlon of
th« obtalnad speciaen.
ttetariel % Mice strsin: ^IH s&ock "gfinersi purposs Swiss
Albino" find Blfick C 57.
HBjor Findings; An fiClas of noifs^l raouse brain has been
prfiparcd cad bound. It is In currant us 9 In our
Ifiborstory.
Carsful dissfiction of br«ln and brainstaa of fatue and
young tsd.ce in elsven age horisons Kara parformedo Tha
spaclBtans ara eactlonad serially and stained. It needs
to be stressed that to obtain one perfect set of aerial
sections for one horizon it is usually necessary to
process and sectioii sis to tt««lve brains. Only those
sets vhlch are ii» ideal conditions can be utilised for
description.
Production of taalforoiations by means of s-radiation.
We are considerably liraited in space for isaintanance
of mice. Since only certain age mice can be used^ we
have to harbour th-aa until they attain it. Than, only
about 20 percent of those kept bscoae pregnant as a re-
sult of restricted duration of mating time. In strain
"gwieral purpose Swiss Albino" 98 litters were obtained
froa irradiated fcothers. Approxiiaately 10 percent of
these had cgajor almort&aiitiass about 25 percent minor
abnormalities and the remaining are free of detectable
pathology. Similar parameters of irradiation and
technique were applied to strain Black C 57 and so
far 45 litters w«^e obtainad.
Significance to Heuroloslcal Researchs An
approach to congenital malformationa of the CSS is
necessary to help us understand certain obscure aal«>
formations oceursring in humans. The provision of
norms of the central nervous system has to precede
the experimeiital production of congenital malforma-
tions, as there does not esist saj proper guidiln
the form of an atlas or of a satisfactory reference
during cotisesutlvs stages of the development of the
mouse . Majority of the stages in this strain are
not yet completed and flnAl analysis of data and
coiuparison with the findings learned from irradiation
will be don® during the coming year.
SeirUl Ho. mmn-70 M
FgQPoaed Co-irse o£ th« ProUcts for fcschniesi rsasons w«
h«d to I! Cop further IrradlAtioB of csiee for tha time
being o It is plenned to resume this experimental work
beginning n^st yeer.
;:ical Keui-ology Brancr
c. ..oGtion on Clinical Psycho
3o Sethesdas Maryland
4. Same as MINL3 - S3 (c)
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A.
Pro^iect Titles Effect of "fear-provoking" stimuli o;\ visual
discrimination in primates.
Principal Invest iqatorg He Lansdell
Other Investigators g None
Cooperating Units s None
^'an Years
(calendar year 1959) s
Totals 0,0
Professionals 0,0
Others 0,0
Patient Days
(calendar year 1959)
None
Objectives To investigate the disruptive effects of certaii.
stimuli on performance in a visual discrimination task in an atte;nt
to quantify and systematize the nature of such "fear-provoking"
stimuli, and to use such data to evaluate changes that may be
specific to temporal lobe removal,
Ma-)or Findings? This project was discontinued as no laboratoiN
space was made available.
Part B included
Yes
Z7 No zS7
ic Surgical Neurology Branch
2. Section on Clinical Psychol'
3. Bethesdas Maryland
4. ^me as NIND3 - 3,9 (c)
PnS-WIH
Individual Project Report
Calendar Ysar 1959
Part A.
Project Titles Psychological Evaluation of Temporal Lobe
Disease.
Principal Investigator; H» Lansdell ■
Other Investigators s M, Baldwin, A. Mirsky? Jo Caldveil and
Uc Kannarino
Cooperating Unit si NB.'H Section oa Animal Behavior
Man Years"
(calendar year 1959) s
Totals 3.0
Professionals 1,0
Others 2.0
Patient Days
(calendar year 19^9} t
None
Project Descriptions
Objectives To study patients vnth temporal lobe disorders w.th
emphasis in the areas of intellectual ability, visual and audit'r',
perception, linguistic functions and other more general "person;! ity'
features.
^^ethods Employed; Intelligence and personality tests? aphsjis
audiometries and other specialized verbal testsf tests of visual per-
ception. Tachistoscopic recognition. Continuous performance tert.
Auditory testing during neurosurgery on conscious patients.
ft'ajor findings 5 A few of the new tests used in the past yex:
appear to hold promise for measuring the effects of temporal lole
surgery?
Serial No„ NIMDB - 72 (c)
1) The MP/PI, a personality questionnaire originally designed
for "psychopathological" patients, has shown a consistent picture
of improvement after surgery in five temporal lobe cases. Four
"exploratory" cases without surgery did not. Three nontemporal
and five pituitary operations did not show similar effects in the
retest scores,
2) Gorham's Proverbs Test has shown considerable consistency
in improved scores upon retest in 12 cases of neurosurgery (including
5 right temporal) but not in 2 cases of left temporal lobectomy.
Six follow-up cases who had some time ago undergone left temporal
surgery. did not score as well as any of six follow-up cases with
surgery on the right. This test would seem to be likely to dis-
tinguish the laterality of the surgery better than any other test,
3) Bass" Famous Sayings has a scale termed "Social Acquiescence"
which appears to, drop after temporal lobe surgery (4 out of 6) but not
usually after nontemporal (l out of 5),
4) An unpublished "Estimation Questionnaire" by Bruner and
Pettigrew purports to measure "breadth of category" in thinking by
requiring multiple-choice estimates of the dimensions of various
things or events. Four right temporal cases reduced their estimates |
six of seven other neurosurgical cases increased their estimates,
5) Schlosberg has published a set of 48 pictures of an actress
posing in various emotional "states," Using his unpublished norms;,
it was found that in the second half of the test three right temporal
cases made more errors of judgment postoperatively and five other
neurosurgical cases did better.
There is some danger that the above results could be misleading?
l) The number of cases in some of the comparisons is rather small and
the results may be chance variations, 2) The control groups are not
perfectly appropriate at present? e.g., high IQ's in the case of
pituitary operations, tumor pathology and smaller removals in the
cases of nontemporal surgery. The present data suggest there is a
rather complex verbal facility maintained by the integrity of the
dominant temporal lobe, and a socially- important kind of interpretive
function seems to suffer in some respects after the operations? but
they respond (in the post-operative period at least) with a happier
outlook to a questionnaire.
Significance of ;the program to the Institutes Several of the
new tests appear to offer good possibilities for distinguishing the
psychological effects of temporal lobe surgery from other forms of
surgery, and even the side of the temporal lobe surgery. If the
present indications prove to be reliable in future cases? they
will provide important implications about the contributioiii of the
temporiil lobes to nprroal intellectual or ecootionai activity.
Propos^KJ course of the pro.iecti The next year's cases should
provide adequate nuabers and better control data to check the above
Implications* And sufficient data on a variety of additional
questionnaires, perceptual and Intellectual tasks nsore recently
adopted, will help us describe better some of the important
functions of the temporal lobe in ntn.
Part B included Yes [J No /^
Serial NOo NIMDB 73(c)
1. Surgical Neurology Branch
2. Section on Clinical Psychology
3. Bethesdas Maryland
4o Sanie as NIND3 - 90 (c)
PHS-MIK
Individual Project Report
Calendar Year 1959
Part Ao
Pro^iect Titles Body Temperature in Chimpanzees with Bilateral
Temporal Lobe Damage.
Principal Investigators Iv'ildred L. Blevins
Other Investigators 8 None
Cooperating Un^.tss None
Man Years Patient ."Jays
(calendar ysar 1959) g (calendar year 1959);
Totals ' 0.0
Professionals 0.0 Mono
Others 0.0
Pro.lect Description;
Object iveg To record the rectal temperature of noimal chimpanzees
and chimpanzees with damage to both temporal lobes.
Mafpr., Findings ; This project was discontinued as tho principal
investigator has left the Institute,
Part B included Yes CJ No 13
Serial No. NINDB-7li(c)
lo Surgical Neurology Branch
2o Section on Pain
3o Bethesda^ Maryland
Uo NIlffiB»9l(c)s 1958
PHS=NIH
Individual Project Report
Calendar Year 1959
Part Aq
Project Titles Fluothane Studies o
Principal Investigators Kenneth De Hall, Mo Do
Other Investigators s Philip Geisler^ Mo Do, Forbes H,
Norris, Jro, MoDo, Wiiio Lo Pritchard, M»Do
Cooperating Units s None
l%xi Years (calendar year 1959); Patient days
Totals OoO (Calendar Year 1959)
Professionals OoO 0
Others 0^0
Project Descriptions
Objectives s Same as NINDB=9l(c), 1958 o
Methods Employed; Sane as NII®B»9l(c)s 1958
Major Findings; Same as NINDB-9l(c), 1958c.
Proposed Course of the Projects This project was
discontinued upon resignation of the principal investigatoro
Serial Noo NINDB-75(c)
lo Surgical Neurology Branch
2o Section on Pain
3o Bethesda, Maryland
Uo NINDB^92(c), 1958
PBS"NIIt
Individual Project Report
Calendar Year 1959
Part _Ao
Project Titles I-i^otherniia in Neuroanesthesiolos''
Principal Investigators V/illiam I^e Pritchardj Mo Do
Other Investigators s Charles Ao Bucknam, Mo Do
Shelley Chouj Mo Do
Cooperating Units; None
Man Years (calendar year 1959) s Patient days
Total: lo3 (Calendar Year 1959)
Professional; Oo8 0
Other: Oo5
Project Description;
Objectives; I^othermia has been well accepted as a useful
adjunct to certain neurosurgical procedures c Further eval-
uation of established techniques on patients and development
of more ef fpctive techniques in the animal laboratory ar>e
the objectives of this projecto
Methods Employed; ^ypotheima by immersion in ice water
bath is -being employed on all patients id-th space-occupying
lesions and vascular lesions o Observations on "brain fall'^
away'% retractability, and amount of bleeding are made at
operation o Various physiological parameters are monitored
during the procedureo Post«<iperativeIy, the patient is
watched carefully for signs of cerebral edema or hemorrhage o
In the animal laboratory a technique has been developed
by which the brain may be selectively cooled by the shunting
of inflow blood to the brain through a cooling apparatus o
The outflow blood from the brain is then shunted through a
warning apparatus « A sigmamotor pump is used to pump the
blood from each heat exchanger to the brain and back to the
hearty respectivelyo
Page 2 Serial Noo NINDB»75(c]
Another technique is currently being studied in which
profound hypothermia of the total body is produced to levels
where cardiac standstill resultse This is effected by the
employment of an extracorporeal pump-oxygenator with partial
cardio-pulinonary bypass j circulating the %'enous blood from
the animal through an oxygenator 5 a heat exchanger, and then
back into the animal's arterial systeme
Major Findings; Further experience with ice water immersion
hypothermia to levels of 30°Co in patients has substantiated
the previous impression that this technique is beneficial in
neurosurgical procedures « Bleeding has been less of a
problem^, brain retraction is facilitated by an increased
extracerebral space ^ and post<=operative edema and hemorrhage
have been less frequently seen^ Cardiac arrhythmias have
not been observed at these temperature levels and there
have not been any other serious complications of hypothermiao
The laboratory investigation on dogs has been rewarding
in that it was possible to work out the technique of selective
brain cooling so that the brain coiild be lowered to a tempera^
ture of 12"l^Co while the esophageal temperature was main=>
tained at 25'=30°Co The majority of the animals survived, but
a few of them succumbed to ventricular fibrillationo However^
it would seem that the multiple cannulations and vasculax
surgery in the neck might be somewhat cumbersome for clinical
application.
With this in mindj total body hypothermia by blood stream
cooling is now being evaluatedo- Insufficient work has as yet
been done to allow conclusions o
Significance to Neurological Research 1 The clinical applica=
tions of hypothermia would indicate that low temperatures^
even in the moderate range which has been usedg are of valu©
in neurosurgical procedures «
Experimentally^ it has been shown that much lower brain
temperatures may be reached by selective blood stream cooling 9
This procedure may be too cumbersome to allow clinical
applicationo However^ if the total body cooling procedure
can be sufficiently refined^ very deep levels of hypothezmia
could be attained and unusual advantages would be afforded
the neurosurgeon in having a practically bloodless field and
considerably more space to work ino
Page 3 Serial Noo NINDE-?5(c}
Proposed Course of the Project; It is intended to continue
the use of moderate levels of hypothermia on patients^ and
to perfect the laboratoiy procedures utilizing deep hj-po^
thermia in the hope that clinical application may be
feasible in the near future
Part B included; Yes [J No ^
Serial Noo NIJJE'B=76(c)
lo Surgical Neurology Branch
2 6 Section on Fain
3^ Bethesda, Maiyland
k. NIIIDB-93(c)5 19^5
PHS=NIH
individual Project Report
Calendar Year 19^9
Part Ac
Project Title: Succinyl Choline in Av;ake Craniotomy
Principal Investigator; V/illiam Lee Pritchard^ K^ Do
Other Investigators s Maitland Baldwin, Mo Do
Charles Ao Eucknam, Mo Do
Cooperating Units; None
Man Years (calendar year 1959) i Patient days
• Totals loU (Calendar Year 1959)
Professional: Oo9 0
Other: Oo5
Project Descriptions
Objectives j To produce a state of anesthesia in which the
subjectj patient or animal, is awakei, able to cooperatej
and suffering no discomfort.o Such a state is particularly
valuable when electroencephalographic and cortical stimu-
lation studies are required^ such as in the sui-gery of
epilepsy and in studying the electrical activity of the
chinpanzee brain o
Ilethods Employed; The subject is induced by conventional
anesthetic technique and is then paralysed by intravenous
administration of succinyl choline » He is then allowed
to awaken and is mechanically respirated^ while in a
paralysed states The drip of succinyl choline is then
carefully titrated to the point ^■jhere the subject can
coramunicate by sign language and motor activity resulting
from cortical stimulation may be observedo Thus sensory
phenomena and motor responces may be noted by observers »
Major Findings; This technique has' been further refined
to the point at present so that it is being well tolerated
by seizure patients and the desired i^esults are being
obtainedo Improvements have resulted largely from trials
with chimpanzees o
Page 2 ^ Serial No<= NIiroB-76(c)
Significance to lieurological Research; This method has
developed to become a valuable addition to the anesthetic
management of patients undergoing epilepsy surgejyo
Proposed Course of the Projects Attempts to further
refine this technique will be made by increased use on
seizure patients „
Part B included s Yes ^ Wo ^
Serial NOo NINDB-?7(c)
lo Surgical Neurology Branch
2o Sectrion on Pain
3o Bethesda, Maryland
ko NINDD=9U(c)<, 1958
PHS-NIH
Individual Project Report
Calendar Year 1959
Part Ac
Projact Title; The Effect of Hypertonic Urea Solution on
Intracranial Pressure o
Principal Investigator; William Lee Pritchard^ lU Da
Other Investigators; None
Cooperating Units ; None
Patient days
Man Years (calendar year_19gg); (Calendar Year 1959)
Total; Oo3 ' 0
Professionals Oo3
Other; OcO
Project Description;
Objectives; Evaluation of the use of hypertonic urea
solution for the reduction of cerebral edeinao
Methods Employed s Patients with intracranial mass lesions
undergoing surgery are observed for relief of edema or
reduction of brain volume following the administration of
intravenous urea solutions Patients on the ward having
clinical evidence of increased intx-acranial pressure are
given ureag following which clinical signs are carefully
observed© Blood studies and urine volumes are followedp
Major Findings; The desired effect of reduction of
cerebral edema and intracranial pressure has been uniformly
observed^ both in the operating room and on the wards o No
serious side effects have been noted^ with the exception of
two cases in which there were transient ischemic syndromes
in the extremities in which the urea was administered by
veino
Significance to Neurological Research; These findings
support those from other institutions regarding the out-
standing value of this new clinical toolo
Page 2
Serial Noo NIIffiB-77(c)
Proposed Course of the Project; The project will
continue in the manner outlined above o
Part B included; Yes [J No ^
MomL BEPORS Galeoder Y«£r 1959
Ibm fic£lvi£y o>£ th« Branch in 1959 ben(s£i£ed grsatly
froo eh® appointmsa^ of thr«tt invest igfitors on the Visiting
Scientist progrem. Th®y wers Dr. Ko Tansley^ Br, Fo I&1@ sad
Or. Eo Tfiflaki. Is loy opinion ehsir coQtrilm$:iO]as^ which ere
not AS y«t puMlsbstd^ will be oi ccmaidersble valu@ ia thtt
various £i«ld8. Mi<sr(» new t«chBiq«^e sra d<&velo|»ad «sd eau^t^,
Chfilr 8£udie8 s^rve as & platfona for fiuTgh^r isvestlgations
hy peraasteae nsBibArs of £h« si:s££. Tha sppoiataieat o£ ches«
scidn&lats «xpir«d ia August. Ml v^o had th« opporttsaity to
viprk :4i&h Chest ars grateful for v^at thsy could l@^m^ aad
feel the loss of th«3(S most Gimpet&Rt worMra,
Xh« arrival of thm ssiineat BTo W. Rushtoa^ uorkiag with
i>r. Fuortos as a Vlsitiag Scisatist 6inc« July of this y&&x^
«pp«ars to M of ths ^iestsst isi^act on th« resssrch efforts
of this Sr«tBch si^c® its inception <, "Shi la^ahcrs of this
Branehj, &ad mey I say of the InstitutSj, will consider them*
valvds fortuoaiie to witness tha invest iga&lv® approaches of
^ ^fe a brilliant asm.
Bro O^V^urte^ who assisted moat «ffectivaly ia adainis-
trativ.. ms&ttm$ ssad as a teacher in the past y«ar trntil July^
was for-:;>^4 t© -.^Sfflijaate his assigmaent as a coas«ltaa£ because
of h545 ohx^T&tUm to Csorgatown University. Eis talent of
orgsssl^stica j>^d, psrof««8ion«l coajpeteaaa are painfully missed.
The two-ya^r stay of all four Clinical Associates and
one 8®nasrca Assoc. ^.t® ended or is ending this yearj and new
young ophtfeA-lsaoiegiSN.^ will be joining the clinical' staff .
Such roe«tiott of th® yoiag investigators unavoidably causes
difficult sitviatioas ts. /isw of Its adverse effect oa the con-
tiauation of projects ho\h of cliaicsl and laboratory nature.
But the fee's rssasins grei^sfully acknowledged that these
talented yoimg vmn have B\.bee«neiffllly contributed to various
project are4is during th®i;'. tw years and that they have been
sttmulated to further wssrfc in the line of their interest in
new positions.
Ia vi«w of the number of individual projects^ £he
results can only be feri®fly g-tamsrissdo AgaJjaj> ia ths lisas-
ii^t of basic research isstarast© ara the se«di©s on elsmsentary
•» 2 «
processes o£ vision, condmitfid 3sy Dr, fwatt@& sm co^wsrkersc
Thfii sxparlsiea&a on the Lteuiue «ye sho^ved th&£ physiologic
ll^t etissull d^cr^ase %he. r«sist:a&c« ofi ehs zufet-v® cttlls,
bu£ £o only & !&i»ds)?££^ d®- ;?«« itnd specifically^ chst r«siee»
sncft of KhA call maBsa&ranft Is no6 graaCly chansaiil during
ia^uls® aceiviey. Thsr® # v®riou£ ttx^leoaCions for ehis
phsnoiaeno&o Sr. Fuor&«s j@ls th«& She ftxperia»n£«l r«8uls:g
on isihibieloa of this Ittsm :a» «y« support: the theory of £ioa<»
involveme&t of cell somata by iis^ulss activity md that
iiBpulses origiaat'S ie ths axon, fropsrtiea of tranamiesion
froen photorttc«ptor etractur«s to the x&«rva ceil of th« Lismlus
hava beea studi«d by aaalysie of subliminal respona«s to dim
ii^t. Dr. Fuort«!!t proposes the coocept that discrete libara-
tion of «i'uaKtitiae of a ttimsmitter subataacs ia retaporaaibla
for tha traaaisat depolarr? slag is^sulsaa ^tihich he had raportad
to occur nmder ateady dim Illusaiaatlouo Dr„ Fuortee and
Dro Eushton plan to atisdy zM fascinating poasibility that
aach .quantity of tha trant titter substance is libarat«d by a
eingla. quant »a of li|^t.
Dr. R. Tasaki in DTo Fuortas* laboratory worlsad on
hyparpolarislng potentials elicited by li^t in the fish retina
and thou^t that these potentials originated either in lar@8
cells or in e^r^seellular costpartn^ss^tis.
' Hesulta of S«. Tans^-'iey's co°>worker's SK@ studies on
pure'^cone laeiasitalian tmtine.'i (S'i^lsrrels) iera not aa yet avail-
able^ but evidesscii ^a&B obi -iijmd that certain squirrels have
only cones as dmaentmtTat®: by th<3 abssnce of a dhlft in the
peak luminosity of the apv...:tral sensitivity curve from the
light- to the dark«adapte« state. Th# inv«s@tigators hope
that th®®>.^ studies on tree ssad ground squirrels will contrib^
ute to our knowledge of the fustdMnental raach^missBS of color
visiono
la the cilBicisl eovsaterpart of this work^j Dr®,, CopeB'i-i/isrj,
6unkel|» as&d Good^usn »Kmtixmd tS^-physlolo^ of catm and x^\
vieioa of patients with va^rious fonos of retinsl degeners? .'m
and color defects in u^lcl-^ in addition to their elaborate >
methods of psychophysical •eattngj spectral a^iasitivity -txrvts
vera obtained^ The \mi&in\ Msa o£ ths sMthods tm-nd in tAi@
laboratory for clinical pif.posss i«@r@ «hown ia& t'te reraits
obtained on pat teats with various types of juvenile rMurotic
family idiocy^ as fel^y allowed for distinct iois mxtonr thm infan*
tile^ late infantile and Juvenile fon&«
Sro Gunkel played &a. is^ortant role in th>&<s stisdles^ r^
a factor of effecting coatiaulty in the ever-cte.siasg list of
InvestigBfeors la this laberetory {Bomssheia^ Xr/jXj, ©&©*Kea..j
• $ -
profile studies ®r@ his rsspooslblllty aloa®^ sad his vnusuel
talent for isodlfyiag or constructing new ln3tr«m@nts^ optical
devices find seost cooi^les spparatus Is appreciated by everyone^
Aa^ng the studies on ev^wsotaa dynamics end releted prob*
lems of physiology end pathology of the intraocular pressure^
the invest iget ions of X^le end Qrlsads on the neural raschanism
involved in regulating these functions deserve ei^hasis. The
elaborate technique of Dr^ L@le in securing Intact and func-
tioning aye nerve preparations allowed clarification of obscure
conditions which iould not be explained in previous experimental
work;, aa for instance^ the poor reproducibility of pressure*
induced afferent is^ulses in vlvoo The investigators attacked
the problem in a cctaprehensive and syst«aaatic w^ by studying
afferent nerve discharges of long ciliary nerves in response
to intraocvilar pressure increases and obtained in almost all
instances iia|(ulses in contrast to the laany failures with the
techniqtie used previously in this laboratory » Again$ in
contrast to previous findings^ no spontaneous ec£ivity signal-
ing resting pressures was observed in such preparations or in
vivoo The search for the site of origin of pressure- induced
afferent activities did not render conclusive results^, I
believe^ but sorely suggested that such nerve structures are
contained in the outer coats of the eye. The aaenyfold escperi-
aients of stiiBuiating long asod short ciliary nerves or the
cilia37 ganglion under various conditions are of great inter-
est not only becatsse of the effects on intraocular pressure
and outflow but also because of the applicability of Dr« Lele's
technique for related studies in this field.
For a systasaatic approach to studies of afferent and
efferent 2iiipulsa activity in the posterior ciliary nerves^ a
thorough knowlsd^ of the ccmpleK anatoioy of these nerves is
necessary, Sia^le dissection does not permit the desaonetra-
tion of fine branches j, but they can be asade visible under the
dissecting microscope by the use of a modified silver technique
(Grimas). With this aethod^ differences in a given species and
between species iee&g, tsenkey^ his&sn) can be dssionstrated.
Dro Macri's Iss^ortant work on the intraocular pressure
problem centered around the correlation of the venous pressure
and the eye pressure^ and atte!n|»ts to d^nonstrate with his
ingenious technique the effect of Dismos on both pressures.
Dro Macri's new concept 1:^1 ies that the carbonic asahydrase
inhibitor lowers the venoua pressure of the Intraocular vascu-
lature selectively without interfering with the ganaral blood
pressure. Els distinction between a snonophasic and biphasic
outflow pattern^ as reported last year^ was th© s-'^ibjsct of
further eKperiiaentetion. The chan^ frcsQ one pattern to another
- 4 -
by phannacologlcAl agsa&s C^piaspS^^isc) o^ ^ sec^ioalng pre*
gaagiioalc sysapsthaeic fibers poses intriguing problesis which
need further clarificAtiOQo In view of his interest in vsscu*
Isr effects connected with the in&raoculfir pressure^ Dr, Macri
elaborated and studied for the first tis.-&g naiag e cast tech-
nique^ the est mud monkey venous oculer circuletory system
fdiich is closely connected with the ^.^ueous outflow system. As
a species variation of the cat 4siasecaiioeing vessels connect the
anterior ciliary vein and the vortex veins. The cast techni<j »
also shoued beautifully the filling of intraocular aqueous veins
in the cat and the &s yet unexplained connection between anterior
chamber and the svprachoroidal space in the monkey.
A similar are% Intraocular venography j, was further per-
fected l>y DTo Cohan. Ssing an intricate radiological techniv^ue^
he succeeded in demonstrating venous channels of very smell
calibero ^ also shovwd that introductions of Hypa^^ue in the
anterior chaml^r is visll tolerated and can be used clinically
to establish ths presence of subclinical forms of choroidal
Xhe clinical program dealing with intraocular pressure
pathology (glaucossia) is developing more and more into & «%ll<-
rouuded and planned study ;, dua to the stimulating interest and
esiperience of Dr. Okun and the increase of personnel <> His
specific plans for study are well taken and promising^ as the
diurnal changes of outflow patterns^ the effect of various
sympathtsaiffletic and anticholinesterase drugs on the a-^ueous
outflow and meaeureasnts to estimate the rate of aqueous forma*
tion in health in patients with Wrd^rlin® glauc«»nfi and those
with frank glaucoma of various types »
The outstanding contribution to the cataract project is
related to the doaonstration of the ultref ine structures of the
epitheliuB and the fibers in the normal and cataractous lens by
Dro Hanko end Miss Gavin, As far as ccsa^arieoas with light
microscopic studies are concerned^ a fair parallel of findings
obtained with th@ two techniques was d^oorastrated in some
respects^ but our knowled]^ of fine changes in the cytoplasm
and nucleoplasm was vastly enriched by electron microscopy .
This new information was particularly exciting in the visual i«>
sat ion of X»ray induced chants in cytoplasmic cot^onents at
an early stage after irradiation^ ^aereas In the past^ such
changes were considered as relatively late effected Theccooper*
at ion of the electron microscopists and the biochemist (BTo Resnik)
proved fruitful^ since it was possible to show that the fine
filamentous elements described by Dto iJanko as possibly charac-
teristic for the lene are products of all interactions of soluble
proteins sad th® fiacative^ Dro Wanko and Miss Oavin are studying
« 5 •
&t prdSi»ffi& th® fia@ storphoio^ of 1@bs msSerisl from patients
wieh sdmiie caear&cc v^lcfe should si low in&eres&i^g essBparisons
with eho r@sul&3 rspor^ed by ehese invest igetors osa verlotss
DTo Bfts&lk has assda grsae progress im his physlochemical
sttidias of lens p70&@ins« gs has dea^ns&ratsd the groat c^a^
pi«xiey of Che soluble Isas protsias of v^ich @ fractions hav«
b««a sep«ra£«d« Treasfo^astion of these fractioBS iadw:^ by
freezing or by the use of solvents lndic«te the difficulties
in arriving @t an tmderstemding of this protein system. DTo Besnik
collaborated in various enzyme studies with Dr. KuhlsBSSi which
will be taken vp later as tl^se studies do not deal to any great
sQsasure with th@ 1@g3»
the cooperative study of the histological laboratory of
this Sranch with the laboratory of nutrition a^ Endocrinology
of NSSM) resulted in a piece of work which sai^t have practical
interest. Dr. If. Hsid of MIMID h^ carrisd out nutritiotaal
studies on the guinea pig for tsmsy yesre and has observed the
frei^usnt occurrence of cataracts when only tryptophane was
deficient in the diet. The growth curves of thes® enieaals
approached the noratsl^ but cataract developed regularly
early 0 It was shown that snivels on a laoderately sv^pl
diet strived at a norsal scale aM that lens changes developed
in other apparently healthy aaisiale. The histologic features
of this cataract differed f ran other types of expsrisental
lenticular opacities as they did not involve the equatorial
area where new fibers form, fhe clinical similarity of trypto-
phane deficiency cataract and that of various forms of peri-
nuclear cataract in t^ hissB& wss striking.
The greatest si^aiber of patients adsoitted to the wsrd are
those with uveitis » Althou^ they are studied thorou^ly with
all avaUable laeans little has been eccos^lished |ja this as in
other ophthalmology depsrta^nts in establishing the etiology^
pathogenesis and rational® of tbsrapy of this disease. An
approach based on the underetandisg of issmmologicsl s^chanisias
mi^t £i!^rove the precarious situation of ovx ignorance. £t
was for this reason that Sir. van Alphen's iBt@r@st in the
iBs&unological relations of ocular tissuss is so t^^eely. It
provides hope that the responses of eye tissues to disease will
be better coaiprehended. For the ttoe being Dr. van Alphen plane
to study the latasune responses of the cornea and lens in certain
denaatoseso m might espand his w^rk to the uveal problem in
the future.
Records of & Isrgs group of pstisats with t^rveltis and
positive toxoplassaa dye E©sts sdiaitee^l la tfeis p^Bt 5 years to
the Institute^ have ^en styloid ^ Btc EmnSms^ with et^hasie
- 6 »
on certala diagnostic aad eharapsuCic aspects.. Sosae o£ the
concluslone are of interest o Th® readily available toxoplasmine
skin test seeoed to be rsl labia &3 £n the gr@at oaejority of
patiants with positive raaction vas in agracsDsnt with tha posi-
tive restjlt of the toxoplasma dye teste A false positive skin
test was extreaisly rare^ Patients with a positive serological
skin test and uveitis reacted satisfactorily to antitoxoplasma
chemotherapy in about 30%o The addition of corticosteroids to
the ther^y with Daraprjja and sulfa in patients who did not
respond to the chesaotheropy alone^ lotproved the condition but
infrequentlyo Early onset of the uveitis under the age of 20
years azid an acute or subacute course can be considered favor*
able for a therapeutic success^ whereas in a chronic course
the prognosis Is less goodo
Dro O'Bourke has tabulated the results of his thyroid
honsone turnover studies in uveitis (30 patients with uveitis
and 10 controls). Be states that hypooetabolism co«exists with
many chronic diseases including uveitis aitd that no definite
conclusions can to drawn fr<»i the data available at the present
tiiae.
The following investigations cannot be grouped under one
of the main projects. They ®re partly clinical and partly labora«
tory studies^
9ro van Alphen has casspleted his fundamental study on
basic factors in refraction an(»>alie8o The {oanuscript is not
available as yet but the statistical analysis it contains would
not lend Itself to a short abstract <> Dr. van Alphsn arrives at
the conclusion that the of ten»def ended and o£t^s«<iuestioned
theory of Stelgsr on th@ origin of refraction ancmalles is tmten-
able, S^rtinent to Sr^ van Alphen's theory which ^e considers
tentative is the behavior of the choroid sb a sheet muscle a His
examinations on correlated pressure changes in the subscleral
space and the anterior chamber examined with a variety of tech-
niques and strain gauge measurements on the ^|»9sed choroid
strongly suggest that the aasimiption of this function of the
choroid is correct.
In the clinical study on detection of ocular tuiors by
i30t<q^ tracer msthodSj, Br. O'Bourke collected the results fr«n
8 patients with malignant Gselanomas in the choroid vdilch were
studied with respect to the rediophosphorous uptake in the
diseased tissue. Comts of beta-emissions obtained by the
routine anterior counting procedure were unreliabl<» and some-
times misleading.. Posterior counting provided informstion for
a correct localisation of ths t^saor although the highest radio-
activity did not aiw;^s lie directly ovmz the centcsr of the ttmor.
This discrepancy was d^oonets^ated Isy coj^ering the count sheets
with the pisthologlc sect lens 0
- 7 -
A oew project on fi cytological level orlginaeed frotn a
comparative 6£udy eugges&ed by th<& ^sd&ssy o£ Ophthalmolo^ and
Otolcsryngology in which the use of slphaochyseotrypsin in cataract
aiurgery and the side effects of using this enzyaae for zonulolysis
were investigated o ?or d«&9Qstrating possible injurious effects
on the corneal endothelium it was tasceseary to develop a tech*
nique in which the ©stlre cell population of this tissue could
be examined o With this mthod it was shown that irrigation of
the anterior chamber with 0o9 solution of NaCl and with the
enzyme produced damage to the endothelitiSj) but the lesions were
wider spread when alpha^chymotrypsin was used, ^e of the
significant restilts of this study is the desaonstration of karyo-^
kinetic cell division in the normal endothelium of young adult
animals o It was generally asstaosd in the past that the corneal
endotheliuB multiplies by eaitosiSc It is planned to extend
studies on the endothelium as this cell l^er plays an isipor-
tent role in maintaining the normal transparency of the cornea
and its healthy condition influencing the stsaos of corneal
transplantation with penetrating grafts. Little is known about
the physiology and pathology of this tissue^ suggesting that
tl^ studies should be aactended to tissue culture and electron
microscopic technisitses.
Dr. Wanko and Miss Gmviu have collected more material
from muscle blopsise for electron microscopic examinations.
They describe^i in normal muscle fibers heterogenotis accumulation
of packed granules i^ich^ on the basis of histochemical react ionsp
might ^ considered to be a lipofuscin<
A clinical as&d histological study carried out by 9r. Baton
ax^ me <»a a tri-^rsaial isolate popislation in Halifax county which
was shown to have a fesnilial disorder involving the eyes (Dr. Graham
of Duke University and Dr. Witkop of the mi) revealed that the
eye lesions consisted of plaques of hyperplastic spitheliias with
signs of dyskeratosis and acanthosis located in the perilimbal
sone. The middle Isyer of epithelium was the site of dyskeratotic
changes^ whereas the sv^rficial epitheliiss under^oent parakera-
totic changes. Later it was discovered that the evaluated members
of this population had also buccal mucosa lesions which ware inter-
preted 1^ the dentist as 'Hohite sponge nevxis," It appears then
that a new type of familial dyskeratosis involves outstandingly
the conjunctiva bulbi @nd is accos^anied ^ similar changes in
Che buccal mucosa.
The following stisdiee by Brs. faton and Copenhaver are
essentially case rsports^ but represent new ami interesting obser-
vations. Or. Fstsn described the occurrence of a primary sialig-
nant splenoma of the choroid in a patient ^i^o had a similar lesion
in the lids and the adjacent skin of the same site. Such co-exist-
ence of mali^sant melanooas at these two sites have not been
. 8 -
reported in the past» Based oa & previous report from this
Brench^ the fimdus picture of sagiold streaks wss described
in deteil by Dr. Patoa in three patients with sickle cell
anemia. It appeared unlikely that these two diseases co-existed
by chanceo The patients did not exhibit signs of pseudoxanthoma
elasticua and Paget *s disease^, the usual systemic diseases con-
nected with angloid streaks. The new observations might necessi>
tate a change in the concept of the pathogenesis o£ angiold
streaks o
Or^ Cope haver gave a dramatic account of tl^ detection
of the self-inflicted nature of a lesion viilch has been labeled
with a vdiole battery of diagnostic possibilities., The patient
had lost the right eye by self«mutllAtiou and presented a large
ulcer of the bulbar conjunctiva and the adjacent tissues of the
other eye when she was admitted to the hospital as a diagnostic
problem. She was observed to induce injury to her only eye by
placing tablets of aspirin into the conjunctival sec. After
discharge a psychiatrist obtained a confession fr<m the patient
as to her sel£'>i&tit Hating tendency.
Not grouped with other reports are the findings of two
new studies by Dr. Kuhlaaan v&o spiled Lurie's technique of
microch^oical enzyme determinations to the priasery and secondary
aqueous humor of rabbits. Malic and lactic dehydrogenase
present in small asaounts in the normal aqueous hiaaor appeared
increased three^* to four- fold in sauries of the secondary aqueous.
The enzyme contained in old animals was lower than in young
rabbits.— Following the investigations on the enzyioe systems in
the cornea as reported last year^ Dr. Kuhlman subjected another
collagenous tissue-othe collagen of the developing epiphyseal
plate^-to microch^Blcal procedures similar to those employed
previoxisly in examinations of the normal and irradiated corneal
epithelium. The following enzyme activitijss were assayed: lactic^
malic^ and glucoee-6«>phosphate dehydrogenase; phoaphoglucoisomerase;
aldolase; alkaline phosphatase c frimery epongiosa and cartilage
cells contained mors total phosphorous solids and acld*8oluble
material than tmorganized cartilage cells. The activity of both
lactic dehydrogenase and phosphoglucolscmerase was higher in
the organized cartilage area and lowsr in the unorganized cartilage
area. Malic dehydrogsnase activity paralleled calcification^ but
was more imlformly distributed. Mdolase activity was not detect*
able by the assay^ method used. Gluc@ss«6->phosphate dehydrogenase
doubled in activity as the primary spongioea developed. Alkaline
phosphatase activity Increased with each advancing stage of
calcification. There was^ in general^ an overall increase in
enzyme activity with the maturation of animals ? The interpreta-
tion of the accumulated data ssust await further studies.
„ 9 -
In concluding this awmexy it itight be juetifled eo
point to the participation of the meiabers of this steff at
various meetings and to the considerable niaaber of scientific
papers completed in the report period as listed in the two
enclosures 0 It speaks for the unlimited energy and devotion
of the investigators to their work^, for the outstanding techni-
cal assistance^ for the dedication of the nursing staff and the
secretarial staff j, that the program could be continvied and
expanded o All lasmbers of this Branch are grateful for advice
and help they received by tb& Directors whenever such help was
sought e
Ludwig von Sallman&j> H.D,
Chiefs Ophthalmology Branch
Hatlosal Institute ol^ Netirological
Diseases and Blindness
FOBLICATIOHS *
Ophthalmology Irsacfe
1959
1. CohaQj BoS.: EKperiinental isitraocular venography j, A.M.Ao Arch.
Ophth. (in press).
2. Copenhaver^ R.M. and Guakel^ S=BoS fhe spectral seasltiviSy of
coior-dsfsctiv® subjects detersaiaed by el®c£rore£inography^ A.MoA.
Archo Opfeth. 82:33-68^ 1959 »
3. CopenfeaveSj, R,M. aad Goodman^ G. : Tisa electroretinograHi in infaa=
tile, lets infantile aad juvenile amsuroeic femily idiocy^ A.M. A.
Archo Ophth. <in press).
4. GopsEshsv®?^ R.H. ; A report of sa uausual salf° inflicted ey®
injury^ A.M.A» Arch. Ophth. (in press).
5. fuortes, H.G.F.: Discontinuous potentials evoked fey sustaioed
illumination in the eye of Limuius. Arch, ital. Biol. 92s 2*3-250^
1959.
6. fuortes^ M.C.F.: Integrative isschsnissis in the nervous system^
Ansar. I3at. £3; 213-224, 1959.
7. Fraakj K,^ Fuortes^ M^G.F.^ and Nelson^ P.G*; Voltsge-claa^ of
motoneurone stma^ Science^ l^;38»39^ 1959,
8. Gavi% H.A, and Lloyd^ B.J.^ Jr.: Knives of high silica content
glass for thin» sectioning, J, Biophys. Biochem. Gytol.. 5:50?^, 1959,
9 a Kau&t£n^ H.l. and Csldwell^ L.A. : Pharmacological stisdies of
pyrimethsmine (Baraprim) in assn^, A.M.A. Arch. Ophth, 6l:883»890^ 1959.
10, Kaufsnan^ E.S.^ Remington^ J.^ Melton^ M.L.j, and Jacobs^ L,: Relative
resistance of slow-growing strains of tosoplassEa gondii to pyriac^-'
thamin® (Barapriaa)^ A,M.A, Arch, Ophth, 62;61l°615^ 1959,
11, Kaufamn^ H,E, and Thoasasy L.B.s She vitreous opacities diagnostic
of fsmilial primary saayloldosis, Hew Eng« J, SSsd, (in press),
12. Katifamn; H,£.: Primary fssailial anyloidosis^ Annals of Intern,
md, <in press).
13. Eeiaingto% J,S,; Jacobs^ La mid KsMmaug H.E,: Adult toxoplssioosis!^
New Sng, J. Med, (in press),
* Fublicetions listed ss "ia pr®as" in the report of 1958 are not
included here.
- 2 -
14. Kutolssa^ RoS. and Resnik^ RoAo : Snsymic studies oi X-irrsdiatad
comsa and leag wieh spscial refersnce to glutahion® reductase^
Biochemo J. 72:261-2655, 1959.
15. Kuhlsaaa^ R.S.: Species varia£ioa in the anzyms coateat of £he
corneal epiehelitasj. J= C®lic aad Coap. Fhysiol. 53;314-»326^ 1959.
16. Kiihlman^ E.E.: A mlcrochsmsical study o£ the developing epiphyseal
plete^ J. o£ lone and Joint Surgery^ (iu press),
17. Kuhliaanj, S.E. end KaufmaSj, HoS. : A t&icroch^sical study of th@
aqueous htistor enzymeoprotein interrelationsj, A.M. A. Arch. Ophth.
(in prsas).
18. Kuhlman^ R.!. and itesnik^ E.A. ; Ths oxidation of G^^»labeled
glucosd and lactate by the rabbit cornea^ Arch. Siochsia. Biophys.
(in press).
19. L«la^ Fo?, aad Grimssj, P.A. ; Th® role of neural aaschanisms in
the regulation of intraocular pressor® in the cat^, lxp©r. Heuro.
(in press).
20. Pato% Do and Thomas^ L.B.: Siiaultaneous occurrsnca of th@ primary
ajslignent aelanomas of the eye and tha skin^ A.M. A. Arch. Ophth ,
62;645»652. 1959.
21. Fato% D„: Augloid straak® ©ad sickle ceil saeaia^ (A report
of two casss)^ A.M.A, Arch. Ophth. <ia pr®ss).
22. Resnik^ R.A. and K®nto% E.B.s Lens Frotaias; II, The effect
_ _. of pH on alpha crystalling Asa. J. Ophth. ^j52«'55^ 1939.
23. Resnik^ R.A,^ Wanko^ T. and Gsvin^ M.A.: Observations on th®
lens proteins alpha md beta crystalling Am. J. Ophth. (in presa).
24. Sesnik, E.A.^ Wanko^ S, and Gavi% M.A. : Observations on a
cytoplasmic component in lens fibers^ J. Biophys, Biochem. Cytol.
(in press).
25. Tasaki^ K. : Sosae observations on the retinal potentials of th®
fish^ Arch. ital. Biol, (in press),
26. von Sallmsnn^ hog Collins^ S.M. and Gris^s^ f.A. : Miiaosine
cataract^ Am. J, Ophth, ^zWl-lUg 1959.
27. Reid^ M.S. end von Sallsaann^ L. s Nutritional studies with the
guinea pig. ?T. Tryptophan (with asple dietary niacin), J. of
KutritiQUc, Cisa prsss).
» 3 -
28. voss Sallmarm^ L.^ R®idg M.E,^ Grlssss^ f.A. and Golltos^ E,M. :
Tryptophen-deflciency cataract in guinea pigs, A.M.A. Archo Ophth.
62: 66 2-67 2j 1959,
29. voB SalliBSim; L.: Esq^erimsB^al studies of sqsb2 oculAr effects
of alpha chya>otr3rpaii%^ Trsas. M. Acad. Ophth. Otolg (in press).
30. von Sallmaan^ L.: Familial dyskeratosis of the perilimbal
conjunctiva^ Trans. Am. Opheh. Soc.^ (in prass),
31. von SalliBfiaai, L. and Pa£on, D. : Heraditary dysksratosis of the
bulbar conjimetiva and oral mucosa. I. Ocular Manifsstsfeions^
A.M.A, Arch. Ophth. (in press).
32. WankOj, T. and Gavin^ M.A. : Elactron microscope study of lens
fibers^ J. Biophys, Biochem. GytoX. 6:97-102^ 1959..
33 o Waako^ T.^ voa SallHasan^ L, and Gavin^ H.A.: Berly changes in
the lens epithslium &f£er Roentgen irradiation^ A.M.A. Arch.
Ophth. (in press).
1939 Pr«s«ntations
Ophthalmology Brascb
Fourth Conference on Ophthalmic Biochemistry^, Cambridge^ Massschueetts,
February .<:l-Z^i, 1959:
KiihlEa% a.EoS The Oxidation of C^'^-labgled Glucosii aad
Lactate by the Rabbit CorB^a.
60th Annual £ieetlng of the American Roentgen Ray Society j, Cincinnati.
Ohio^ September 22-25^ 1959s
Cohan^ B»Ec: Experimental Intraocular Fenography (exhibit)
Midwinter National Meeting of the Association for Research in
Ophthalmology^ Edge^ater Park^ Mississippi^ February 19° 21^ 1959s
Resnikj, R.Ac s Observations on the Lens ProteiOj, Alpha and
Beta Crystallin.
WankOj, To; Structural Changes in the L®ns Epltheliiaa after
Roentgen Irradiation^ An Electron Microscope
Study,
American Medical Association Meetings Atlantic City^, Kew Jersey^
June 8-12^ 1959 s
Wanko^ T^s The Crystallia Lens C®xiiibiS)
American Society for fharmscology and Experimental Therapeutics^
Coral Gables^ Florida^ August 31 » September 3^ 1959:
Macri^ foJoS Acetasolefimide and the Venous Pressure of
the Cat Syec
American Society of Parasitologigts^, fena Sfeate Colleggj, PeartaylvsaiiSj
August 30-S®ptember 1^ 1959s
Kaufman^, H.SoS The Relationship of Toxoplasma Dye Test
and neutralisation Antibodies.
Conference on Inhibition in the £C@rvous System and f'^Aminobutyric
Acidp Duarta^ California^ May 22° 24^ 1959 s
FuorteSj, H.GoF.: Ixihibition in Llmiilus Eye.
95th Annual Meeting of the Amisricsn Ophthalmology Society^ Hot
SpriagSs VtrginiSj, May 28-30^ 1959;
van SallsEsnn^o Lo ; . Familial Byatersfcosis of th® Perilimfeal
G®nji4Sicti'/ao
» 2 -
American Acadmay o£ Ophthalmology and OColsryngologyj, Chicago^
Illinois^ October ll-U^ 1939;
VOQ Sallman% L. : Sense Ocul&r Bffects of Alpha
Ghymotrypsln.
Symposivea "Long Term Sfgects of Chronic Radiation Exposure"
Bethesdap Maryland^ October 29-30. 1959;
von Sallmasn^ L<. : Delayed B£f®ct8 of Chronic RadiatloUo
(Discussion)
Combined Clinical Staff Mseting^ Mational In£titut<gs of Healthy
B@the8da^ Maryland^ March 26^ 1939:
von Sallmannj L.,: frimary Ai&yloidosis
(iBoderator)
ADDgKDUM
1958 Presentations
Ophtheissiology Branch
SysaposiuDa "lategrafcive Mechanisms ia Biology" Msefcing of the
Aaerican Society of Naturalists^ Washington^ D«C,^ December 29^ 1958;
Puortes^ MoGoF.s Integrated Jfechanisme in the Nervous
System o
Washington Society for Electron Microscopy i, Fifth l4eQtin& Bethesda^
Maryland^ Becaaber 12^ 1958?
Wanko^ To: The Fine Structure of Leas Epitheliusio
Addendum to Serial No, NIMDB LL (c) ;19^8
1„ Ophthalmology Branch
2o Microbiology Section
3., BetheadEg I'teryland
PHS « NIH
Individual Project Report
Calendar lear 1959
P^rt Bx. Honors K Awards and Ptablications
Ptiblications other than abstracts from this projec*-.!
Kaufmanp HoEo asd Thonasg L„Bc,s The vitreoas opacitlv\?
diagnostic of familial primary amyloidosiSg New Engo J.
Medo (in press) o
Honors and Awards relating to this project; None
Addenditm to Serial No<
1» Ophthalmology Branch
2o Physiology Section
3o Bethesdag Maryland
PHS - NIH
IndiYidnaal Project Report
Calendar Tear 1959
fe^ytBj, Honors g Awards and Publications
Publications other than abstracts from this pj*oject:
Copeishavers Ro Mo„ and Gunkelo R, DoS The spectral
saasitivity of color-defective subjects determined by
electroretinograpbyj, A„M„A, Arch, Ophth.j, t^i55-6Bg 1959.
Honors and awards relating to this project: None
Add&nd^m to Serial Mo. £m€SB-'85 (c)
1. Qphthalsaologsr Branch
2. ClaeEisefy SacSlora
3. Bethesdfi; dryland
PES - EIH
Individual ProjacS Report
Calendar Year 1959
Pars , Bo Honors^ Awards and Fufelicatioxis
Fubllca£ioB@ o&her th&a abstracts ST'om this project:
Kufelman^ EoEo and Hssaik^ R,A. 5 Enayase s£«di«s of X"irratiiaced
cortiea and leas with special r@f®r«nc@ to glu£ahiou@ reductase <-
Biochsffi. Jo 72:621-265^ 1959 »
Kuhlmsug SoS. and Besnik^ R.A. : Xh® oxidation of C^'^-Iabeled
glucose and lactate by th® rabbit cornea^ Archo Biocheni,
BlophySo (in press).,
Honors and Awards relating to this projs.ots None
Serial Ho. NINDB°?8 (c)
I. Ophthalmolo^ Branch
2o
3» gefchesda^ Maryland
4= Same as S3IKDB-4'' (c)
PBS - HIH
IndividiiaX Project Report
Calendar Year 1959
Project Title: Basic Factors in aefraction Anomalies
Principal Investigator; Gerard van Alphen^. M=Do
Other Investigators;; None
Cooperating Units: Hone
Man Year® (calendar yesr 1959): Patient Days: Hone
Xotal; Oo5
Prof es s ionai : 0 » 5
Other: 0
Project Description:
OI),jeetlv@as Ssbs© as last year end essentially aimed
at completing a theory on the origin of refraction sa«Haali©s.
1) Statistical: factor analysis with rotation of the
correlation raatrlx of the five optical elei&snts feaaed on the
data of stenetromo
2) Physiological: the degree that the tension in the
choroid counteracts the intraocular pressure is determined by
oeasuring the (a) pressure in the suprachoroldal space as
described last year., (b) relative tension in the choroid fey
direct strain gaug® aseasureassnt at various sitas^ before and
after gytepathetlc aad parasympathetic s«;i«s«la«:ion« (e) the
effect of (li) on th@ resist ioaship of intraocular pressure
versus scleral ©lasticltyo
«> 2 -
Major Ftndlagss fhres obliqtjc factors mi^ esqplAln the
correlations betus^n th@ fiv@ optical ®lsiesats in thm hvasaxi
®y@o The load o£ thmu^ factors Indicates existing llaks
betf}e@n th@ various opitical @l^iaan&s ssd th@s« lioks can M
e«ntativ@iy explained ^ A Eiajor assis^tion In this ccoicept is
that th® choroid essentially behavas as a sk@et imscis and
therefore counteracts part of th® intraocular pressure o For
this assuBption additional avid^nc® is obtained £roi& strain
gau^ saassursmaats on both in situ fiti^erimftnts and ssperi«
:s.on isolated «y»@^ in loonkmp and cats.
Sifipificance to Fro^^ of Inst^tutas As 8t®im^'B
thaory on the origin of ralraction anon^liss^ althoo^ wld<sly
adh@r@d to^ is obviously untanabl«^ no adequate «3^1anation
exists for th@ iaechanism o£ «(BB»gtropla or ametropia. The
leads of the 3 basic factos^s Involved rev«al links hstween
th@ various optical alasusnts and a t^ntativa interpretation
of thase links maj form a basis for a theory on rafraction
Proposed Coursa of pEo^ects To pursu® the effect of
ths tension in the choroid on tlite elasticity of the sclera
by strain gauge saeasureiDents on ^es in situ and isolate
eyeso To coraplete a concept as to the possible aieclianisn
of ^la>ropia or its aberrations o
Part B included; Yes /°T Ho £TJ
Serial Mo.N2MDBo79 (c)
lo Ophthalisology Branch
3. Betkesds, Haryland
4. Sesse m NIHDB»43 <c}
FRS • HIH
Indivld«£sl Project' Seport
Caleader Year 1959
Part Ao
Project title: Xsa^nologieal Relations in Ocular Tiss
Principal Investigator; Serard W» van Alphen, Mc D^
Other Investigator; Sarah Kobinette, Be Sa
Go^eratins tPsiits; ^&sm
Man fears (calendar Ya©r 1959) s Patient Dayss Sons
Total: 1«5
Professicmal; 0»5
Other: loO
Project Descriptions
3. skin.
gives g fo esa»lne possible iiaaxmologieal relations
between skin s eemjssnctiva, comsa snd lena; to determine tahether
last yearns flndis^s of is^mnological Interrelatiooshlps
between variosss eye tisessea is confined to the species or
whether organ epecificlty een be deisonstrated; to test the po8'°
sibility of ai&tos@nsitisation against varioiss eye tissues; to
investigat@ the reaction of the lens after passive cellular
transfer of hypersensitivity to the anterior ch^nberof the
eye; to find iasiainologieal cities for oc%slar involvement in
patients wiljs, various allergic dsreiatoses^
Methods Eaaployedg After emscleation of one eye, gislnea
pigs are IcaBunised to their, own lens, mm corneal epithelitm
and ocm vitreous o The tissues are homogenized with Freund's
adjuvant to enhance antibody prod«setionc their blood is tested
.for antibodies by the Owchterlony a^thodo . Anti-calf eye tlaatBe
sera are obtaisied by iutessigiisg gmlaea pigs ^if.fe ealf less®,
vitr«o»ss, corneal epithelis?®, comsal strosm, conj^asaetiva, and
=, 2 -
skino The sera are tested for tasttsal eross rei^ttlena and for
eross reset lo&s.vlth various eye tissues of soiEsg jBmtsoala ^nd
som& other saaj or. representatives of the vertebrates by maans
of ^ar diffusion ffiethode. Rabbits &rs iaaasanized «lth re°
peated injections, on honsologous lens in t&'S n@ck and the foot
padso Lyn^hocytes are collected frota the regional lya^h
glands and transferred to the anterior chaster of the eye^
Ijsjqr Piadicgss Skin, eonjssnctivSs corneal epitheli^am,
and corneal strom are related InsBtmolosieally, as well as
lens, corneal epitheliuiB and vitreous; h(K?ever, skin and lens
are raoto Of the variosss eye tissues tested, organ specificity
is alsaost esclusively e<»ifined to the lens; and aati»ealf lens
seruss not only cross reacts with the lens, best also ^tth the
vitreous of the different vertebrates. Corneal epithelitam
appears to be a relatively strong antigen as eoi^^ared to
corneal strona. Antibodies against cwn eye tissiaes could not
be demonstrated by present DSthode. The restslta of -passive
cellular transfer of hypersensitivity to. the anterior chasaber
of the eye snd its effect on cornea and lens is as yet con^
jcctural.
Slgaifiemce to Prograis of Inst i tastes A kn«»$ledge of
iKsaainological relations between various tissuies is theoretie
ally intriguing and necessary for an understanding of the
response of the eye to disease. It supplies a theoretical
basis for certain e^qperisstental and clinical observations 's^'hisls
Lssmmolbgical relations between skin, cosijunctiva snd
but it'bbvipiusly doas not support al legend iaesmologieal
in densatdses associated t^ith cataraets^ The
relatively high antigenicity of corneal epitheliiim as coo^ared
to corneal strb^a strtmgly supports recent stk^estions that
the reooval of epitheli«Bsa of a corneal transplant isay decrease
an issBBsne response <,
gr<^OBed Course ^of Project; To repeat the ®sp®riffients
on autosensitisati®n in inbred guinea pigs (strain 13) and to
coB^lete current esperiasntSo To study- pat ients^ith certain
dematoses »h«»?iag ocular Eaaif ©stations of cbmea and lenso
F«rt B included; Y®s £y Bo ^
4o B^sa as H2HDB'^3 <c)
PBS - HSH
2ndividysl Projset EteporC
Calendar Yesr 1959
Past Ao
Ftfojeeft Title; Clinical Glsissoas Stady
Riebajfd Oglesby, M<,®o
Coopcrsting Paiess NGne
Man ¥e^?s (e^lffissday yeasf 1959) g P^feiaat ©ays; 1,453
Total; Sp6
Profsssiossal; hA
OS&asrs 1«5
Ol>jee£lve3;
I) the sasin object!'^® is fc® ®val«sat® ssspecSed sasd
kaam cssss of glssscosis ia an effort £® find easlisr rasaas
of diagssosis -ssid bettesr fm&iis of eoi%t£'0lc fh@ principal tool
of investigation is repeated toraogrep&ys with md without
provocative testings
s) fh® sssehsnisaa of diisiTBsl cliaages in intra"'
ewalar presssa^® are investigated by mesas of toaogyaphyo
b> ffee laschanisBi of aetion of varimis d7«sgs end
opeirative p£'oc@d«ss>es is st^ied by tonogs'aphyo
- 2 -
e) The e££ec£ o£ instantsaeous blood pressure
changas on the ineraoeular eession is eo be investigated by
eonographic ssans, in association «ith the Heart Institute.
2) To £«£Sther investigate the disturbed intraoetalar
fluid djsamsLcs in gljausotaa, the iofle^ aschasaistss &re
studied. Just as tonography giv@s mt indie&tl<m of the ease
with ^ish fl^id leaves the eye, the i&fl<^ studies give an
indication o£ the ease «rith ^ich fluid esters the eye.
Methods Baployeds Bach patient acceptable for the
st^y £@ adsaitted to the hospital for a mini^ura of several
days in order that an extensive gls^soma laosissp can be per*-
formed. In addition to the history md general physical
examination, specific tests iacluds tonoo^try vfith day curve,
applanation tonoi^try, biomieroseopy, gonioscc^y, repeated
tonography t?ith and ^eithosst provocative tests, and studies
of recovery from tonography as detersained with the applanation
tonoESgterc In addition, visual field sttodies are carefully
perfortsed «ssing the ^Ida^mi periiseter and Sfsnkel tangent
screen, flhen the patient ^s intraocular fitsid dynasaies have
been observed over a tis@ interval, the response to indicated
therapy is subsequent ly evaluated. . Patients are fol loaded at
four to six Bxmth intervals after discharge, at ^ieh tina
they are re>evaluated.
Major Findings 8 At the present tiajs, the mseber of
patients in this study is too ssall, and their period of
follow too short to dr^? many conslusiozis itsm this longatena
project. On an individual basis, ^e feel that ^e have
encountered setae .extris^ly provocative cases illustrative of
a broad spectrum of glaycos^ forms. In one or t«ro cases of
secondary glaucossa the diagnosis ^as suspected on the tasis
of tonography alone, and ssbseqtaently validated when episodes
of increased tensie»i occurred. Is other cases, repeated pro-
vocative tests and tonography have failed to ineriiainate
glauG<»» during an Initial adsission and the diagnosis made
in subsequent nonths. At the present ti^, the cases of
borderline gleuccHaa have not been follo&ed for a sofflcieat
tisea to judge the value of the data obtainedc
gr^osed Course of Frojects It is hoped that the siee
of this project vill continue to increase. A reservoir of
t?@ll°3tudled patients ^o reside in the Washington area is
being b«silt up and it is hopsd that by continuing studies oa
this increasing population a m&ssts of earlier disgoosis can
be established, fhe nest logical step will be t>
of various aaans to delay the onset of ssanlfest gli
gjgisif icaae® to Pg©graia &S SasSimt;®: Tls© d^sscribed
pr©jese£ is of tiss^ly is^®ir£a;a©@°''t5'"'Se""^brie Health Sesnyice
&@ t® tise gr^is^ ^as'esess of doct&ts ^b& Isys^a alike esa-
ceraiBg ta@ sigaificaas® of eesrly gla^iics^ss diagnosis. f&sgJtsgfe
are ferths? iaspir^ii. It is e^&asised th&t tais Ias£lta£<2
©ffers a UBiqsi® fispportasity for siseh detailsd obser^atioas ©£
glSBceaa patisnts, f©r Tontlv^ lah&'f&t&tj st^J^iss can bs
repeatedly p®rf©sms4 ^sadeg' a eoasides^iablj? Issager p©?l®^ of
f&n /T
./vT
Serial Ho. KBJDB^l Cc)
1„ OpbtfialiQology Brmch
2,
3o Betheada, Maryland
4. Hear Project
PHS •=■ SIH
Individual Project Eaport
Calesdar tear 1959
Part Ao
Project Titles SisRsltaneous ^corranee of Prisary Malignant
of the Eys find Skin
Principal Investigators: David Faton, M, D.
Lotsis B„ Ittomas, M. Bo
Other Investigators: Koi£@
Cooperating ©nits; Departraent of Pathologic Aaatoasy
llAtional Ceneer Institute
Years (calsmdar year 1959>5 Patient Dayss 35
Totals 0.5
Professional: 0.5
Other: •
Project Description:
<»>jeettves: To contribute to the question, first, of
coexistesi^e eH primary maligoant jaalanoms of the eye and
raelanostas at other sites; second, of the familial oeeisrrenee
of this uveal
Methods Bg|>loyed» Bostine clinical and histological
exasinations vere performed.
Major Findings; ffee case reported had a pigoented skin
lesion for sisi years covering the lids and adjacent tissue of
the right eye, ts»hich was repeatedly treated with electrocautery
during this span. Biopsies of a skin nodule indicated that the
lesion was a salignint s^lanosa., The patient was admitted to
the Mia. A pigsented area near the raaeula of the right eye was
detected, and wide escislea.of the skia lesion and orbital
e%«nteratiOQ was pcrfonasd in th® MGIo Th® hi8tologi@al
exasainatioa o£ tta® skiB sfeo^d jusetional aevns end a aodtsle
vith ehe chavact«7i8t:ies of superficial is&lignfint anlaxioni&o
In the cesijtsnetiva, signs o£ pre^eancerous melanosis were
observed and the choroid txtsa&v vas diagnosed as an early
msligndnt ntelanoiBa with spindle eells of t3n?« A aitd 5.
Clinically, however, the appearasciee of the choroidal
was ecn^fctible with the benign lesion, the choroidal
and the ctstansosss nelanoma were considered as
prisory neoplasias which occurred siiaiiltaneattsly in this
patient, the patient's brother was subjected to emsclestion
of the rig^t eye for taalignant choroid nelanoma nine years
Sigaificaafce to Prcgraa of Institute s this is a new
observation of the sinultaneo^s occurrence of priaary otalig'
nant ssftlancmae in the skin and the choroid. A familial
of such eye tmaora is esctrenely
Proposed Course of Prpjeets this project has been
temdnated.
Part B includeds Yes /fT" ^o £J
Serial HOo NIMDB»8l Ce]
PBS - NXH
jadividwal Project Report
G&lendar Year 1959
Part B. Ifonbrs, Awards, axtd i^blleatlons
Publications oti.sr thsn abstracts frota thl« project i
Paton, Do exui Tdoass>s, LoB,; Sitratltsneous oectjirreQee of
prisksry asHigaaT.t mel^gnooisa of the e7e and th& sklno A„H,Ao
Arch. Ophth. 6? j 645-652, 1959.
Honors end Avucda relstiog to this project: None
serial Hoo KINDB»82 (c)
lo Ophtbalaolosgr Braach
2.
3 a B#clui0dft« iterylaad
4o S«M «8 HIMDB»50 (c)
PHS » NXH
iQdi-vldaal Frojsct Report
CAleaidar Ya&r 1959
Projcee Tiel«: Iatraoe«alar Astgisigr^i^
Principal Imwstigator: Bruc« E. Oohaa^ Mo Do
Other IsrssseigAtors:
Coop#rAtlng Units!
Has 7«&rs (ealeadar jraar 1959): Paeiemt Days: None
Total: loO
Professional: IcO
Other: 0
Project Description:
(M»jectiveeg Iscent studies pre^ousljr reported have
rated the i
initial pathmys of aqueouB hmoz ontflow la
the rabbit by means of radiographs of the eye taken after
replaeeoaent of aqueous haoor by «mter soluble radiopaque
soltttionso It is thou^t that by modifying these teehnlqves
and devising nev ones^ further isforiB&tloa msy be obtained
queotts outflow chasiiiels and intraocular vessels la
Eially Intact eyco
Methods aqployed:
1) Has aqueous iaamt is replaced by the san
of sodiua diatrizote (Hlypacpie) in a control rabbit eye ead In
an eye iaaaedlately folloviag cyelodialysiSo Radlographgr of
these eyes Is then carried onto
2) Through a sa»ll conjunctival incision the anterior
ciliary win of the cat's eye is isolated^ divided betveen
ligatures and both cut ends cannulatedo Radiographs are
taken daring injection of sodium diatrizote (I^paque) by
with a ser«v°>type electrical Infusion pisop. Clinical aa^
- 2 -
histologic seudiss o£ ehs «y«8 fire ntsde ae ^aryijig iae«rv«la
aftar Cha x^raya ar« obteisuidc A lambar of radiographic
teclmiques are an^loyed to dbtais ttm intraocular <s<eQOtta
pattama is& varioua projeceioaao
Major Findiaga; The t;echBlqu«a nsatioaed above
Lted in the suecaj
reanlted in the sueceaafisl ^ssasmetSAtioa of (1) the
anatoagy at the acute cyelodialyaia la the rabbit eye^ and
(2) tbM roentgea^aaatooy of the intraocular venoua ayateaia in
the eaaentiaily intact cat eye, including the iatraseleral
venous plexua, the veins of the ciliary body, the choroidal
venous ayst«n and venous plexus of the optic nerve. Clinical
and histologic studies of the cat eyes aaade at varying intervals
after the procedure revealed essentially n
Sisnif icaace to Proyam of Insfeitufces It is hoped th^
loeationed above may lead to better understanding of:
It is hoped that
studies
1) The dynaiBic anatoay of the intraaeleral venc
plexus which is intimtely related to the leechanism of
outflow andg therefore^ glaucoaao
2) Xhe djfUBiaic anatomic pattern of the veins of the
ciliary body and choroid which are of inportance in the
ptqfaiology and pathology of intraocular pressure and in diaaase
of a&e oE^eal tract, i»eo6 uveitiso
3) Tbi possibilities for future possibile investigation
of the intrsoeular veins in man by angiographic methods »
Proposed Course of Projects It is proposed to conplete
the initial sutdies utilising these ne^ techniqueso
Part B included Yes ^ No n
Serlel Ko. HIKDB«82 £c)
Pt€ Bo Honors^ AwurdSg ced Pt^lleaticnis
Publications oeter thsiK abstracts frosa tfois prejvct:
Oohan« Bsue« SoS Experisaental intrsoeulsr ^maogrsphyo
AoHoAo Asch, (^hthc (In Prdss)^
Honors and Avards relating to this projset:
Scientific Ssshlbit "Exp«risteBtal Intraocular VanDgrepby**
«BS asardad th« Bronze Hcdal o£ the Aatrican Roentgen
Ray Society at its iO^li Asnasal Meeting in Cincimtatis OhiO{,
Smptmibes 22»2S» 1959o
serial NOo NIMgB-83 (c)
I. Oplaehfilaology Sranch
2,
3. Bechesda, Msryland
4« Sams as HIin»<>46 (c>
PHS - HIH
IniiivldiBal Project S«port
CalftttdAc Year 1959
Project TiUs: fS^old Kozssontt 7«rB»ver in Ih^ltit
Priaeipal laveseigator: Jai^s Fo O'Boisrkag M. Do
Other lorastigatora:
Goop«ra£iag IJeiSs:
Kaa Yaara (ealeadar yaar 1959) Pa&leaS Days:
rotali 0.5
Professional : 0« 5
Otber: 0 OaSpaei^at Vialfts:
Project Deseription:
Ob4aet,iwe; Sadiothyroxins turiKraer stales la
uveitis: a masore o£ peripheral utilisatioa of fe^roid
honaose in patieats vith taf^al lnfi«raastioa»
Msthoda B^jployed; Patieats ffith uveitis
for evifteace of tfe^^roid dys^'ss^^tioae T^sosi
astabolism bat euthyroid status, are selected for the tarn-
over 6tu<fya Fifty aierocurie injeetioas of 1^^^ thyroxine
are laade iatrstveamssly sad the plaesa radioaeti'vity is
daily iev 15 days thereafter «
From the data provided^ the halfotias turnover of
tl^roxiae is calculated liaeraly as iwll as derived from
formnla, Additioaal factors studied are the measure of the
extrathyroldal t^rosias pool« percentage of iodini pool
utilised daUy per kilogram of body weight aa.A p&s
of body ^srfac@o
Ten control patisnts ha«e al»> been studied,
ia age from 18 to 68 ysarso
- 2 «
Thi?ey unrsltie
patients aad 10 cosktrols
Konaal
Value
Coatrol
Patients
C105
Uveitis
Patients
C30)
Value
Control
Patients
CIO)
Uveitis
Patients
(301
T 1/2
5o6-9<,5
5o6«8&8
7o3«;l4o2
6371
7o53
10.21
% of Iodine
pool Wti"
lis«d daily
9o0-l2»2
7.87-l2o37
4„9l-l0oS0
10„52
9,25
6.81
lodisM uti«
liaad daUy
(laiero^
m/70 ki^o)
43^a
45»63
23«72
52
54
47
Iodine uti«
lisad daily
(saiero,
im/lo73 Sa.MJ
4l«71
41^63
21-71
51
S3
44
The results of the &tmdy so tas da not tell eaythins
about ijiveitis'.'eilology &x its r^sponsl^^soess £0 treatiaento
A report oa the aeasiareiBents taksa to «i©te is being prepared
for pablicetion„ It is liissiy tiiBt hyipemmioUm wexists
^ith mmy cbronia diseases^ laeltading isveitiSg best the
sigaif ieaj^e of tlm assoeiation eould only be shown by:
(a) deaonstratlng that thyroid fmetion or dysfunction ean
inf Itaence the iwame response in patients »ith uveitis
(Dr. Bergenstal has good i^ie&e «I»on« ti^ ^^ •^^^ *^*'> «nd»
(b) desBynstrating in %poa»tabolie patients that the kinetics
of thyroxine turnover and the oatiarel history of uveitis
are each influenced by therapy with thyroid bonsanes. ,
(Thsr^^oxine or Triiodothyronine) <>
Significance to Propyaia of Institutes laboratory
findings conneGted vith the most threatsaing ma&l'wA
problem in clinical ophthalmology » that is» uveitis^ ere
of paramount interest, fiowevar, at present no definite
conclusions can be dra^ from the available data of the
present study.
« 2 »
gyopoacd CMsrse e£ ggo^ftct; Dr. 0'S«ak« haa MxbHk
ASsigiBBftnC as constslScsC So t;fap (teatii&lasolosy Braoch as
his
of joly 1959o Ths project eaaoos ba eoB£isaaad in Kb*
fttture. le is hoea^ thae 16 cast h» reacCi^ead at a later
Part B iacissdad: Yes £y No /^
Serial Mo» HISDB-84 Cc)
I, Opbth&lntology Branch
3o Bethesda, Maryland
4. Sasffi as KXNDB<-47 <c)
PHS - HIH
Individual Project Iteport
Calendar Year 1959
Part Ao
Project title; Detection o£ Ocular Twnor by Isotope
fracer Methods
Principal Investigators James Fo 0*Rourke, MoDc
Other Investigators: Hone
Cooperating E!nits:
Han Years (calendar year 1959): Patient Days; 332
Total; 0c5
Professional: 0^5
Other;
Project Description;
Objectives; Sadiophosphorous uptake of loalignant
mot' t£e posterior choroid; comparison of trans >
conjunctival and trans-sclersl counting laethodso
BSethods BBgloyed; Five hundred stierocuries of sodium
radiophosp^te is given intravenously to patients shoving
solid detKshment of the retina. Both anterior (trans*
conjunctival} and posterior (trans -scleral) counting is done
after 24 hours under general anesthesia in the operating
room as part of the procedure of planned enucleation. In
each case four quadrants are counted for one aiinute each,
the first quadrant being the area shcfsm to have highest
radioactivity during a preliiainary scan. Anterior counts
are made at the equator vith the globe rotated maximally,
using a forceps o Posterior counts are im.4& on bare sclera
follc^iag surgic&l exposure and detschssent of one rectus
sleo
- 2 "
Ibe eoiqiarlsoas w&dtt betaie&si the e^o cotmting teeh^
niques are the follovtng: (a) difference la total radio<°
activity (anterior versus posterior) as expressed by counts
per minute recorded for four quadrants, (b) difference in
radioactivity recorded over the highest siogle i^adrant in
each area, expressed as percent increase above the four
quadrant laean, (c) accuracy of local isat long, that is, eor~
respondeace of the hi^est single qusdrsnt vith the kncwa
site of the tumor bed 6
Major Findings^
1) Total radioactivity detected by the posterior
counting technique exceeds the anterior value by 74X in six
patients studied (rasnge 53% to I20X><,
2} (a) The highest anterior quadrant count exceeded
the mean value by 25o3% in 8 cases counted (range 5.2X to
48.8%). (b) The highest posterior quadrsnt count exceeded
the masn veliae by 74.3% (range 47% to 100,3% in 6 cases) <
3) (a) The highest anterior quadrant count failed to
correspond to the tuoor bed location in six or eight eases
studied i (b> The highest posterior quadrant ootmt v&b
localised correctly in the quadrant containing the tumor
in six consecutive studies made 6
4> The point of highest radloaetivlty during posterior
counting i&s marked on the sclera during operation) did not
always lie directly over the center of the tuimr vmaa as
demonstrated on pathologic section.
Sfignificaaee to Program of Institutes The study as
conducted to date Ws failed to develop any really nc» know-
ledge; it merely demonstrstes s(»i®thins that is already well
known by twrkers in this field. A report on the above find^
ings is being prepared. Further clinicsl studies are needed
to extend the series but suitable cases for this purpose are
rare. Basic studies are possible usit^ the C^^c^ma S-91
melanoma; these might be used to examine the tumor t^take
of gaB8Ba»emitting sources or to devise an sudorediographie
method of ocular counting.
Proposed Course of Project ; It is planned to continue
the project when patients vith uveal malignant mslsnomas or
with other intraocular tui^rs can be admitted o
Part E inelffidsd; ¥©s [J , Ito /X/
Serial Noo NINDB«85 (c)
lo Ophthalmology Branch
2. Fhanaacology Section
3o Bethesda<, Harylsnd
4o New Project
PHS • Mm
Individual Project Report
Calendar Year 1959
Part Ao
Project Title; Study fsa a Possible Second Av^ueoxia Outflow
Pathway in the Bye
Principal Investigator: Frank Jo Macri^ PhoD.
Other Investigators: None
Cooperating Units: None
Man Ye^rs (calendar year 1939): Patient Days: Hon*
Total: 0o8
Professional: 0,4
Other: 0,4
Project Description:
Objectives; Casts made by injection into the anterior
chamber showed filling of the ciliary body of three species:
cats^ rabbits and monkeys. In vsonkscys^ the material was also
found^ having a sheet-'like appearance^ in the suprachoroldal
spAQe (twelve of twelve monkeys). This filling was found in
addition to that of the aqueous veinSj, etc, Whether or not
this r^resents a second outflow pathway or anattsaic damage
due to perfusion of cast materiel is not known. This obser-
vation together with the knowledge that outflow of the aye
could be altered to a "blphaslc" pattern in v4iich the propoz*
tionallty of cmtflow to pressure was lost^ Indicated the
possibility of & second outflow system. Preliminary expert*
ments on monkey eyes showed the presence of fluorescein In
the suprachoroldal space after the material was Injected Into
£h® anterior eh-aaber^' -lending further S'jpport for this study.
Methods toployed; In Chese initial experimental
snucl®ated^ arterially perfused ayes ere used. The intraocular
and venous pressures are raessured so that true outflow pressure
may be calculated « A small incision (2-3 sm,.) is made in Che
sclera end the choroid and sclera separated circularly for «
distance of about 3 tm.o A piece of fchin Saran Wrap is inserted
betvieeu the two layers of tissue o A piece of #10 polyethylene
tubing^ bent: to coincide with the curvature of the eye^ is
then placed in the suprachoroidal space^ through the incision
and above the Saran Wrap insert. The insert prevents the
tearing of the choroid by the tubing during its placement o
^y means of a preplaced matress suture^ the tubing is tied
in place and the incision tightly closed. It is felt that if
flow to the suprachoroidal space does oscist^ this procedure
may allow for its quantitation. Total flow from the anterior
ch^miber will also be determined so that^ by difference^ flow
through the a^ueoiis veins may be calculated.
Major Findings; There are no major findings as yet
because the project has only recently been initiated o
Significance to Program of Institute; Should this
study show that a second aqueoxis outflow mechanism functions
under physiologic conditions^ this finding would be new and
of great interest for all studies on aqueous dynamics «
Proposed Course of Pro.lect; Continuation of this
project with modified techniques is planned.
Part B included:
Y«s£ir
Ho IE7
serial mo. OTSiBB^S6 (c>
1. Ophthalsology Brasich
2. Piiars^cology See t ion
3. Betiaesda, Marylsrad
4« S?e^ Fsojece
Pert A,
Ff©j©s£ f itleg Masesay of th® Vsnmts Ciyeelaeioa of th® Cat
ly@ gsKil the Aq«S80ttS Oueflcw Cbeimels in the
Sat, Ssbbife aad Monkey «
Maa fears; (e^^^sE"-^®^ r*^s? 1959)
To£sls 0o4
Projact BescripSiaaj
Objaefeives; fh® ca£ eye is b®iag raekes- esstsasively
latraoe^ala; psessusre. Before thi# sSsidy was isaidereakan £fesr@
was 3S® d«taile<l asaa^osaie descripsiea ©f eleheff' £&« ^®i3«ms
cls-sai®ft®3ry sysee® or of £fe© ai^ueoeas o®ftfl<^ syseem in this
specials., flsis faee together with She obsesvatim ^&t iatrs^
©oslss- psiKss'i^r® msd '5?@ncssje pressisr® are iaeississely selefced
s^de i£ ©f gs-^cf. ia^orisKe® to determine s&a
Bgaehods E^>loy@ds .Cases a&a sad® by isij action of
Tygon paiStT^sdeniag for 24 ho^ss's ia 70X alcohol and then
digestion with HeOH,
^|^_Fi®di|^£» ^e asQJor differeae© in th® veaosas
asasttswsf of the cat as coj^as-sd t© tfe«8 Immn or sBoakey was
th© large anssfeoaiffitic cosmsction feats^asn th© anterior ciliary
= '' <o
vein and tfe© aa^svdla of ttie vortices » Altliossgh the cat has
a lafge nisssber of epis^Iersl veins, it h>m b^t one large
anterior ciliary vein, vhieh is proadnen^ j^ist micerior to
the stsperior reetus iraiscls^ fhls vein joins the eirsle of
HoviuB by 3°S brat^shes. At the ares of the four vortex
veins, large 8«sper!ielal intraseleral vessels lead froa the
Circle baek^srds to the as^ulla of the vorteso Vessels of
the iris, ciliary >»ody, and ehoroid were well seen and
their intereonnest.cms noted o
Casts made b/ anterior ehmiber injection shewed
filling of the ciliary body as wll as the eaqjeeted filling
of aq^ieous veins, litc. In the loonksy the smterial went
beyond the ciliary body and was fosnd in the suprachoroidal
spaee as a broad, :hin sheet o In no ease ^as the cast
noted to cossmmiear.e with the vasculature of the ciliary
body areao
Sigttifieancti to Program of Institgtes The el«iei°>
dation of the venoms network allowed an esplanation for the
similarity of venous pressure recorded fron the vortex and
anterior ciliary visin in the eat. It was of fandaa^ntal
interest that filling of the ciliary body was obtained;
this being s»re e^suansive in the laonkey in which cast
material was seen In the s^praehoroidal space c Hils is
suggestive of a oet^ond outflow pathway wisieh is at present
being Investigated.
Proposed Coiiirse of Project; this project will be
terminated .
Psirr TJ 4 »>««>? t!H?s»^° "^ma ft JSSn iTt
serial No. MIMDB>87 (c)
1, Ophthalnology Breach
2o PbazB^eology Section
3, B«£ii08da» msylmd
4o Sanse &s BWSf&^Z (e)
BIS » MIH
ladivl^saaX Projact: Bepoirt
Cfilesidar Year 1939
Part A.
F?oJ«c£ Tiele: Stis^ oa th@ Flmrmacods^sj^dcs of Various
Ag^ixta A££®stlQg Ia&S£oeulfir PsttSsurA
Principal rovsseig&tor: frassk J. Mseri, PhoDo
Other I)m^aatigator: £^d«ls '^a SalltBaon, M<, D,
Coopsra£i!3g Ualts:
Years (caleadar jresr 1939): Patient Says; None
Total: 0,8
Pro£®88iorsal : QA
Other: 0o4 Outpatient Vielta: None
Project Dascrlption:
Objectivsa; To teat ^ario^ss drugs for their abili^
to alter intraoeulas preseura and to dstenoine their
of actioSo
Methods Esiployyd;
mce in the malate
Various factors ksiowu to be of
ixsportance in the maiateaance of lOP are loeasured and
recorded. These are t^ "facility of aqueoos outflow" <flow
expressed as c^t/sai£s/isa.Hg) g v-esoi^s pressure in different
veins of the eye, elasticity and squeous inflow. In
addition to the msasur^ients of XOP snd the local venous
pressures » the systeoie arterial blood pressures are also
recorded to detensine the correlation between these functions.
Gats and monkeys are us^do
Ma^lor, Findings; It was reported last year that two
patterns of aqciaous outfloir could be discriaaisated by the
methods ea^loyed, Hie first pattern ^ich ^e called 'teoao-*
phasic" wis one isi «fhich outflow (esi^ressed as "C", aaa/sLn/aOpRg}
vae proportl^uO. to outflos? pressure throuf^sout the range of
pressisres studiedo fb@ sseond pattern called '%ipiMMie" was one
ia i^ieh this proportional isy ^las ups@t and in which "G"
=. 2 -
4&Gte&a«d pTOBS®sslvmly as tb& iMtra&euLez pressure vas
•l«vaead» Th« mlis*a o£ "C" isi £be biptuutie (ngtElows
fwre alwiQrs greater ehan those of fcbe B»no[^gAsie ae prtt<=^
asures close Co the noraal for eiM aaisasl. sttsAimdo
Diannxg aa agent fouiut effeefiive ia loweriag i&tra«>
ocular pressure of glaueciofieous patli^ts^ was studied rather
l&tttBsivelsro 1!hs ooly activity aseri&ed to Biasox ia the
literature is its abait:r to lahibit earboaic aahgrdrase a&A
through this aiction a deeraase of aqi^ous ioflov is postulatcdo
At this tiaae, «s take ao eseeptioa that this i8«, ia part at
least, a meelueaisa ehereby tl^ iatraoeular pressure is
It WBS reported last year tlmt Dismox was capable of
redueisag the veaous pressure of the eat and
also cosverted a s^nophasic outflow to
:iag the current y^sa has
T&o questions then arises
lo Does t&e fall of venous pressure e«i^ee the fall of
intraocular pressure induced by SiamoxB or vice -^rsa?
2» Vtiat is the laechsaieffi of the biphasic outflow?
1° Piaaox lowering of veaoua pressureo
&o It was first ascertained that Diaaox acted
directly on the eye to lower the venous pressure of this
organo This was done by perfusing eaecleated cat eye through
the ophthalaic artery with Sagle*s Basal Medim coatainii^
10% plaasao Perfusioe with fluid coatainiag Oiasssgy ia
coaceatratioas siailar to those used "to :£^%
fells of both the intraocular
Bo Ihe intraocular pressures of 15 cat eyes (in v^^
were msistaiaed ctmstaat at different pressure l«veli
coaneetis^ the anterior chaa&ers of these ^es with
bottles « la 12 of these eyes tbe vmoue pressure was found
to fall after the adisinistration of OiaaaoXo ISo significaat
chaage of systemic blood pressure was notedo la another
series of animal Sg the blood pressure was raised and
lowered by various raesmse so that an iAflueace on the
venous pressure of the eye would be exerted, m every cases
the intraocular pressure was found to chsnge ia the snae
direction and to die avse degree as the venous prsssureo
Eaising or lowering the intraocular pressure from
levels only produced falls of veaous psessureo It
be said that the intraocular pressure is directly
on vewjtts pressure and that Diaias^ lowers intraocular pressures
ia part at leasts tisrough this
= 3 <=
S° Meehaalan of blp!ga«te otsfefloWp
A bipfeutle ffistfiofi eoold be Isdsesd by s^etlon of
tbe pssgoaglionie fibers of ehe Beptxias emrwiieel jsaoglloso
Stlsaeletion of ehic tmrm psod«£C«4 « rise of both intsa«
r» as vmll as ire^rsing «kd oaeflow b«ek eo t!w Bosopli&sie
psetemo Bssmfrmil o£ ehe bipiiasle pae£«rs eould «l8o be
effected by topieal applicatiois of a 10% emffilsioiii of phenyl^
i^eefeios of epls^pbritse or
Offtes tixBUSa Afi«r the atisulatios of ths eillery
gffiiglioe (effceti'^s^estess es aoted by miosis asc^ s
fall of botb iatrae«tslar pres^sse aad <^$esioi8s pressure) the
oistf I09 pattern f^ould cog»Mirt to tb^B blpbasle
this represents suppressimi of tlae syopatbetie
is m>t eleas-o It mg^maxs then tbat tbe
of tiee sssnopbesle <mtf Io» to tbe bipbasie om
eaffi be regulated by ttes
In tbese stedles it ^s £&mi tl»t redss^lsg ^itreosgs
'^oliaae by t&m^ffix^ aliciuots of vitreous eotsld eois«ert a
aonopbasle oistflo» to tbe bipbssle; or if tbe biplmsie
form escisted fxmijaml^ tbls would be fortber exaggerated
by tlbs proeedisreo The reverse pbenaeaino& vm» observed by
laereasiag <9dtr®otss isolmsm^ As a working t^pot^siSe* it
is eosieltsded tbat tbg* two outflow piitteraa el^d ari
on thm 'mlwm ia tbe ^treosEs @o!^art3aei2t ^d that tbis.
foltssHi . (probably tbrough the wf'Stglati&rs) is usader the
€oatro^ of the atsitonoaii€ . s^r^o^ss systeiBo
i j^poaaies might eostribyte to tbs uasderstasdii^ of
the patfeology of iatraoeieler pressisre la relation to tlig
glaiseosa probl^&o
."^iZ SSSLt^'"'-'
________,,_^^^,,.__,.___,_^__^^,^^ All stttd-ie«; on this,
project
Fart B iaelssded Ym, /^J - M© ^_
Serial Ho.^MTOB-SS (c)^ .
i« Ophthalmology Biraneh
2c Chesdsfery Ssctioa
3o Bcthesda, m^rylsoA
4g Sema as NINBB'»54 (c)
pas » KIE
Xndivldnal Project Repea-t
Calendar Year 1959
Part Ao
ProJeeS Titles A Stwiy of the Proteins of the Lens
pTineipal Investigator: Robert A„ Resaik, PhoD„
Other Investigators! John Papaconstsntinew, I^.D,
fheodor Wmko, McOo
CooperatiBg Paitst Departoeat of Zsfcryology
Carnegie Institute of W^shix^ton
an Years (calendar year 1959) s Patient Days; None
Totals 2oO
Professional: loO
Other:
Projeet Deseription:
Objectives? To obtain physical and cheaical data on
the lens protein.
Methods Ensployed; Methods and techniques eosaaenly
used in the physical -ekomsical characterisation of polysaars
and polyelectrolytes, are used. In addition, tecfeaicisaes used
for the studies cf proteins are eaployed.
Major Findings: the fractionation of the soluble lens
protein from the lens cortex by colunst ehroiostogr^hy has
indicated the coB!|>lexi£y of this system. A total of eight
fractions, A-H, has been obtained. Of these only G and B are
h(»ne%eneoas v^mn subjected to boundary electrophoresis.
Fractions A, B, C, D, E, and P ®a«jh contain two to three
ponentSo Sosse of the proteins in these fraetions are capable
- 2 -
of isndergoing various eraneformfttiooso Fos- example^ the
amosint of protein in fraction F increases at £be expense of
that in fraction Go H&is transformation may be indueed by
freesing estd thsi7ins & nsixture of the l@ns proteins o In
Edition, similar treatment of fraction 6 altme results in
the appear&nee of fraction Fo The trmasformation is due to
the effect of solvent, pH 7, 0»(K>5 H phosphate buffer.
Fractiosus A^S have been referred to in the past as beta°
erystallin while F-H have been denoted as alplim>=crystallin<,
fhis «ork has been done vith BTo John P^aeonstantinou,
. In collaboration «?ith DTo f , Wanko, electron miero"
seopic observation of electrophoretically isolated sauries
of three fractions of the lexts proteins has been carried out.
!t has been observed that the fraction denoted as alpha<»
crystallin contains coogpound, elongated structtsres. Ihs
8aiq>le8 obtained from the remainder of tha soluble proteins
contain spheres of different sizes.
fhe electron microscopy of the lens protein has been
discontinued at this time because of the eoqplescity of the
lens protein system^
Significance to Program of Institutes Tfe® identic
fieation of those proteins in the lens ^ich are particularly
susceptible to alteration or interaction brings us one step
closer to a basis for correlating chemical changes in the
lens i9ith its transparency »
2t is naa recognized that the l0^ density elastents
observed by the electron microseopist in sections of osmium^
fixed lens are the lens proteins.
Proposed Course of Project? fh® cheasiesl basis for
the trsasforioation of~soae of the lens proteins will be
studied o Xt is possible that this may be correlated «irith
the gelation of alpha-erystaliin belos? its isoelectric
point o
Part B included? Yes Qf ^^ CJ
3 -
Serial Hoo HBiiBB^^S (c>
PBS » HIR
Xndlvldnal Projece Bepore
Calendar Year 1959
Part Bo Honors, iaiBrdB^ snd Pobliea^lons
Pisblicsfciona other Chan abstracts from this projeet:
Resnik, EaA„ snd Sfentoa» EoB„; Lens protein; Ho The
effect of pS on alpha^eryst^llin, im, J, Ophth. 48:52«55»
1959 »
Eesnik, RoA,, Wanko, T. and G£nrin» KJkoi Observations on
the lens proteins alpha* and beta°<erystalllno Asbo J.
Ophtho (In Press)
Honors and k^axda relating to this projects None
S«riel Mo. MIMDB-89 CO
1. Ophthalmology Branch
2. Chemistry Section
3o Bsthesda^ Maryland
4, New Project
Individual Project Report
Calendar Year 1959
mLA-
Project Titl®: An Investigation of the Enayae Syst
Present in Cornea and Other Collagenous
Tissues
Principal Invsstigatort Hobert E. Kuhlnian
Other Investigators: Mone
Cooperating Units; Kona
Man Years (calendar year 1959); Patient Days: Hone
Total: 1.0
Professional: loO
Other: 0
Project ©©script ion:
Objectives; To study the calcification of the
collagen of the developing epiphyseal plate.
SSethods Employed; total solids, lipids, phosphorouSj,
and acid soluble laaterial were determined. In addition^ the
following mzym& activities were assayed: lactic^ snaltc, «itil
glucose-6-phosphate dehydrogenase, phospfeoglucoisomerasei
aldolase i alkaline phosphatase.
Ma;^or Findinas: The total phosphorous^ solids^ and
acid soluble laateriel were ell found to ba higher in the
primary spoagiosa and cart 11 aga calls as opposed to th«
unorganized cartilage cslls
» 2 -
The Activity of both lactic dahydrogenass and phospho"
gXucoisoioerasa is higher in the organized cartilaga area and
lower in the unorganized cartilage area..
Malic dehydrogenase activity parallels calcification^
but i6 BK>re unifonsly distributed o
Aldolase activity was not detectable by the assay
method used»
61ucose»6»phosphate dehydrogenase doubles in activity
as the prijaary spongiosa develops =
Alkaline phosphatase activity increases with each
advancing stage of calcification. There Is^ in general^ an
overall increase in eosyiae activity with the maturation of
Siffliificance to Proj^aa of Institute; Fast studies
in this laboratory have indicated that the activity of
the enzyise of the cornea vary both with age and the specific
layer of cornea studied o It was therefore decided to study
the develo;«tent of other collagenous tissue »
Froposed Course of Project; This project is terminated.
Part S included; Yes JTJ Ho CD
« 3 -
Serial Ho. M^B-89 (c)
FHS - HIH
Individual Project: Report
Calendar Year 1959
Part ^ Bo Honorsi, Awards and Publications
fuS^lic&tions other than abstracts iraa this project:
Kuhlsaan^ E.S. : A microchsmical study of the developing
epiphyseal plate> J. of Bone and Joint Surgery^ (In Press).
Honors and Awards rslating to this project? Hone
Serial NOo NINDB"90 (c)
1^ Ophthalmolo^ Branch
2o Chemistry Section
3, Bethasda, Maryland
4. N«w Project
PES - NIH
Individual Project Report
Calendar Year 1959
iMLA'
Project lifele: Aa Investigation of she Snzymatic Sysfe*
Present in the Aqueous Hxsmor
Principal Investigators Robert E» Kuhliuan^ MoDc
Other Investigators; Herbert !» Kaufisan^ M<,Do
Cooperating Units? None
Man Years (calendar year 1959 )s Patient Days; Hone
Totals Oo5
Professional; Or. 5
Others 0
Project Descriptions
Objectives; Microchemical procedures for the assay of
enzytffies and metabolites in micro saxcples of aqueous humor are
developed avid analyses performed.,
Methods Employed; Lactic^ Bsalic and glucose-6-phosphat®
dehydrogenase^ together i^ith protein concent rat lon^, vvere d«ter*
mined in the aqueous hunor and blood of rabbits ^^
Major Findin^a: Giucose-6*pho8phate dehydrogexiase was
not detectable In the aqueous of rabbits » Halic and lactic
dehydrogenase were present in the S'-i^ueous of normal rabbits
in relatively small amounts.. The activity of these enzymes
increased three to four fold In samplas of aqueous humor sub"
sequently removed. The protein concentration in these samples
of av^u^ous was about 40 tii&es gre&ter than the first samples
drawnc Because of the cos^Xlcatlons of increased protein
':onc»s?trEt-»«>T?- it if. difficult to interpret th^ rssylts obt.ain«»«^
. 2 "
The aozyms levels in aqueous ob£aiaed from old animals
was lo^er thaa that found in yoting animals.
Significance £o Prp^raga of Institute; The results
implicates age as a factor related to the activity of enz3mies
in the aqueous humors The traumatic effects of removing
small amounts of anueous eiqihasised that dx^e consideration
be given to this when Interpreting such datao It is possible
that acute uveitis caused by allergy or endotoxin may cause
a relatively low ensyme to protein ratio in the a^^ueous
similar to that observed in secondary anueous^
Proposed Course of Project; This project is terminated
with these results o
Yms nn
Serial No.. NiaDB--90 (c>.
?HS - HIH
Individual Project Report:
Calendar Year 1939
Part B. Honors^ Awards and Publications
Publications othar than abstracts from this project:
Kuhlata% R.So and Kaufman^ HoSo: A microchemical study
of the aqueous humor enzyme^protein interrelations^, AoMoAc
Arch. Ophtho (In Press)
Honors and awards relating to this project: None
Serial HOoljraPB^9l j^
2c Physiology Seefeion
3o Bethesda, Marylaad
4= Sane as NlHDB-39 (g)
PHS - NIH
Individia&l Project Report
Calendar Tear 1959
Part Ac
Project fitle; Studies on Central Nervous Systea Control o£
lntr@oc«slar Pressure. (An&toagr of Posterior
Ciliary Nervesl)
Principal Investigators; Lsdwig von Ssllta^nn, Mo Dc
Patriela Grliaes, B„ Ac
Other Investigators: None
Cooperating Itoitss lone
5fen Years (calendar year 1959)° Patient Days: Soce
Total; loO
Professional: 0.5
Other: 0.5
Project Description:
Objectlvegi Studies on the anatongr of the posterior
ciliary nerves, as eistlined in last year'^s report, h@ve be^n
extended first to determine the vsriations of this nerve s^ippH
to the eye in one species (c@t| and, second, to establish
interspeoial differences c Sismsn material v&a subjected is
i£8lng the sasie teehnieal procedures &s issed in the est a>4
Bonkey prepsratlonSc IThis technique sad dissection hss i>een
elaborated by Miss Griowso An Is^rovcd photographic technlq<s6
slla«»ed cle&r deoonstration of psrtinent observadonsa
Methods Staploy^d; the orbital contents are reo^ved
coepleteiy Inelading t&e nerve supply as far back ss the fi£t^
nerve ganglion,, the estr®oc«lar ?&«.8@1©8 are Ger«€oliy ^Is^"
wsshed la water for B.t lesst one hsmt, and is then pl@e«d in
an Oc5% sol«ition of silver nltrste for ts^o liOKis-So At the end
of this time, tik& eye is trsnsfefred to 10% formalin for 10
ffiinistes, stnd, finsilly, to & 5X 8ol%ition of sodimo thloetiglfate
for sppx-oximsitely 30 minutes. Treatment, with silver nitrate
and ths 8«(bsequent steps are carried o«st in d^rkotess. In the
resulting prepsratlon nerves are stained & dmrk bro»m wfeile
gsnglionie tissue resgiins «ltitfta Other £iss<tees sre ynstslnedo
Dissection is s^eos^lished «mder water using the Zeiss stsr«
somleroseope , snd photographs are taken &s warranted.
In soiae insts^nses fresh ntsterial is- dissected, &nd the
relationship of certain branches to the ciliary and posterior
ganglion is determined^ Utese branches sre then removed,
fixed in VL osmium tetrosside, ^isbedded, snd gross °seetlonftd.
Data on fiber -size distrlbsation in the varlotas nenti'es thus
may be obtained <>
Mfejor Findings; fhe exmainatlons of the hwmsL orlital
nerves sitowed a distributtlon of posterior eiliary branc*is
similar to those observed in the monksyo Oecsslonally f^ V
nerve braneh vas seen to travel along the optle nerve to the
posterior pole of the globe without undergoing anastr^sis
in the orbit. 6. Siadt braa@hes not fiissing with postgarglioni^
branches of the eiliary ganglion have been deaamstrsted in tM
cat btit not in the monkey o On the other band, th(p hmsm mil-
iary ganglion received a heavy branch from the V aerve eorre8°>
ponding to the fine branches to the ganglion in ch^ monksya
Stsch eonnections between the V nerve and the gii^i^llon eoold
not be demonstrated In the cat,
Slgffiificginee to Frogram of lastitate; fhe «snderstsnding
of the <ec«erse,' ramilicatlon8"'snd fusion of j osterlor eillary
nerves a^kes it possible to select the prop'ar pathways for
studies of afferent and efferent is^^lses mA to stitmlate
nerves which co«ild be classified „ fhe ad vantage of the knoW'^
ledge of the t^ography of these nerves attd their distribution
%& shown in the stswix by L«lc and Grimes..
Proposed Ccasrse of Pgoj@ctg fhe Invesiigsfeion has been
cooapletedo It is planned ^i^^. resent ^e resiilts at the
meeting of the Assoelatloo t^t Research In Ophthalmology in
1960,
10 ty
Serial Noo NINI!B--92 (c)
lo Ophthalmology Branch
2„ Physiology Section
3o Bethesdaj, Maryland
4o. New Project
PHS - NIH
Individual Project Report
Calendar Year 1959
Project Title: An Unusual Self-inflicted Elys Injiary
Principal Investigator; Richard Mo Coponhaverg M„D„
Other Investigators
Cooperating Units: None
>lan lears (Calendar Year 1959): Patient Days: 121
Total: 0,2
Prcfeesionals 0=2
Other: 0
Project Inscription:
0^jj|gji4£g§: To provide a ibasis for the differential
diagnosis of ulcerations in the coajunctiTa or other parts
of the diseased eye and self-ijaflicted lesions,,
IkJ^oM-JiaKlgzifiis Clinical observations} hlst<-
logical ©xaminatiofis of biopsies froia the conjttactiva<.
Ma.lor Fi^djLfigss A thirty-four-year-old ^ite female
had lost the ri^t eye because of a relapsing wdcerative
process of the coraea and conjmactiva of unknown etiologyo
The eye was eraacleated because of paia at the request of
the patients The bulbar conjunctiva of the left ©ye
developed a large ulcer j, th© nature of vhich could not Tbe
diagnosed^ Lethal midline granuloma $, actinomycosiSg tuber-
culosis o syphilis s collagen disease ^ lymphogranuloma
venereuBij, granuloma inguinale j, histoplasmosis ^ sporotrichosis
- 2 -
and cryptococcosis were mentioned as diagnostic possibilities c
The location of the extensive conjunctival lesion suggested
self-anitilationp and the biopsy^ which showed necrotic
tissues surrounded by a wall of healthy epitheliuaij,
supported this suspicion „ MaderosiSg broken lashes and
small corneal abrasions provided evidence that the patient
had inflicted injury to her only ©ye^ Later it was dis-
covered that she introduced parts of aspirin tabloid into
the conjunctival saco The patient's arms were placed in
casts c Following thisg the conjunctival ulcerations and
other signs of irritation improved rapidlyo The psychiatric
consultant suggested that the manipulations on her eye
jaiFht be a coi^mlsive symptom of this inhibited^ isolated
woaafio Psychiatric examination carried out after the
patient was discharged accomplished a confession of the
patient as to the self~BSutilation of the eye which had
led to the loss of one eye and extensive damage to the
other o
Siffpificanee to Program of Ijaatitute; See Objectives o
£E2]j2iaL£SJM:ifi-SO£2iSSStJ The study has 1been
terminated o
Part B included! lea ^ No /7
3 -
Serial Mo, NINIB~92 (c)
PHS - NIH
Individual Pre ject Keport
Caleadar Year 1959
Part B^ HoftorSi Avards and Publications
Publications other than abstracts from thia project:
Copanhaverg RoM<,s A report of an unusual self-inflicted
eye injuryo A.JLAo Arch,, Ophtho (in press).
Honors and Awards relating to this projects None
Serial Hoo NIHDB''93 (c)
lo Ophthaliiiology Bsraneh
2a Fitysiology Seetioa
So Bethesd^, mxylsaa.d
4„ New Projeet
PHS - NIK
Xndlvid^sl Frojeet Report
Calendar tear 1959
Part Ao
Project Titles Anglold Streaks and Stekle Cell Anemia
Principal Investigator; David Paton, H^Do
Other Investigators; Laidwig von Sallto^nn^ MoSo
Cooperating lyinits: Hone
Man Years (calendar year 1959) s Patient Days; 93
Totals 0„5
Professional: 0o5
Oth3r;
Project Descriptions
Objectivasg "Angioid streaks" on the fuadiss hsve been
correlated with pseudoxanthoma elasticuta or Paget "s disease„
The observation of this is rare^ l^t characteristic Hindus
pictures in two patients with sickle cell disease suggests
that pathogenic factors, other than those considered now,
might be responsible for the developasnt of the lesiouo
Methods Ea^loyedg Funduseopy, biomicroscopy, fundus
photography, and histological examination of skin biopsy, in
addition to the usual hematological, radiological axid physical
examinations o
Major Fiadingsg The fundus picture observed in two
young Hegro males with sickle cell anemia were typical for
angioid streaks; the s^culae were not involved and the vision
not impaired o Vascular calcifications seen frequently in
patients with angioid streaks could not be deaonstratedo Skin
biopsies taken from the neck and axilla showed no evidence of
- 2 »
ps«»sdoxanehoQ3 elastie%isic ftie observation of a third yomig
Negro with siekle cell disesse ȣas tmd& available for stmdy
from the Wilsaer Instit^stec Again, ehe fisndus shoved typieal
angioid streaks. Histological eKSmlnatioa of eyes of patients
with siekle cell disease and sngioid streaks are not avsil^-
able as yeto The sbsense of signs of pseudojcanfchoce elasti'^
cma @nd Paget °8 disease or giassificstion o£ vaseular ealei^
filiations indicate that either the ^esds, retinal heinor°
rh^es or the osclusive vaseular disease plsys a role in the
pathogenesis of the ^mdiss changes o
Signifieanee to Frograa of Institute; The eoneept
that angioid streaks sre eselusively eonneeted vith pse«ido°
xanthoma elastieum and P^et^s disease has to be eorreeted
and other pathogenie faetors stseh as o^eltssive vassular
disease have to be eonsidered as possibly correlated with the
typical f^mdus pictttreo
Proposed Coarse of Projects Studies on this rsre eye
condition will be continued when patients are available o
Part B included; Yes /gT No fj
,. 3 -
Serial Hoo HIMDB-93 (e)
PHS - NIH
Individual Projeet Report
Calendar' Year 1959
Pagfc Bo Honors, A^srds and Piublieafeions
Publie^tions other than abserasts frost this projects
Paton, Do^ Aagioid streaks snd sickltt cell anemlSo (A report
of two cases) AoM^Ao Ardaic Ophtho (In Press)
Honors mid Awards relating to this project: Hone
Serial Ko,^!IIM>B»»94 (c)
1. Ophthalmology Branch
2. Fhysiology Section
3o Beehesdfi; Maryland
4. Sane as NIHDB-40 (c)
PHS - NIH
Individual Project Report
Calendar Tear 1939
FartjLo
Project Title: The Study o£ Neural Mechanisms in the
Regulation of Intraocular Pressure in the
Cat
Principal Investigator: P.P. Xdele^ M.D.
Other Investigators: Patricia Grimes^ B.A.
Cooperating Ihilts: Hone
Man Tears (calendar year 1939): Patient Days: None
Total: 2.0
Prof ess lonal : I . 0
Other: 1.0
Project Description:
Objectives; In an effort to evaluate the role of
the central nervous system in the regulation of intraocular
pressurej, eKperizaents in this laboratory have been directed
toward definition of the afferent and efferent limbs of a
possible reflex mechanism. Previous studies using the
isolated cat eye confirmed the observations of von Sallmaim
et al (1938) who described afferent impulses in the long
ciliary nerves evoked by increased intraocular pressure.
Although use of the isolated preparation simplified the
experiiaents and allowed for accurate determination of anatomic
structures^ study of the pattern of afferent activity indicated
probably fatigue of the nerve endings during prolonged
increases in pressure. It was^ therefore^ planned to compare
the results of ©xperi^ats using tfe® Isolated eye with those
in situ.
" 2 -
There have been nusisroiis statements In the literature
concerning pressure changes following stimulation of various
efferent nerves supplying the eye^ von Sdllmann and Lowenstein
(1953)^ and Gloster and Greaves (1957) described lOP changes
in cats produced by stimulation of certain points in the dorsal
hypothalaius , In addition to these observations^, Perkins (1934)
reported that antidromic mechanical stimulation of the fifth
nerve in rabbits produced a marked increase of the IOF<,
Investigations have be@n carried ®ut^ therefore^, to determine
the effect on the IGF of electrical stimulation of the third
and fifth cranial nerve using both in vitro and ia situ pre-
parations o
Methods Bmployad: Isolated Eye. The animal under
light pentobarbital anesthesia is killed by air embolismo
The eye with intact nerve supply is dissected out as rapidly
as possible and placed in a bath of warm o^genated Krebs*
Ringer '°61ticose solution. The extraocular muscles are
carefully removed. In an effort to maintain the eye in the
best possible condition the ophthalmic artery is cannulated
and perfused vlth warm osygenated KB<G solution at such
pressures as to maintain the 10? at approximately 20 am<> Hg°
The third and fifth nerves are then dissected and prepared
either for recording afferent activity or for stimulationo
Two 22 gauge needles are inserted into the anterior chamber
for recording IGS and for increasing the pressure by infualono
Xtt situ preparations » The animal is anesthetized
with pentobarbital and the femoral artery and vein are
cannulated for blood pressure recording and injection respec-
tively. The skull is then opened and the frontal lobe of
one cerebral hemisphere Is removed to expose the roof of the
orbit and the ophthalmic division of the fifth nerve in Its
intra-cranial course. The orbit is unroofed and the superior
rectus muscle is removed to expose the nasociliary nerve and
the proxijual portions of the long ciliary nerves. The long
ciliary nerves are then freed and prepared for recording of
activity or stimulation at either the central or peripheral
endso
The ciliary ganglio% alsO|, may be exposed by retrac-
tion of the lateral recti.
Major Findings; M afferent nerve discharge is evoked
in the long ciliary aerves of both the isolated and in situ
preparations \^en the 10? is raised by infusion into the
anterior chamber. In the isolated eye the response consists
of a transient phase^ characterized by rapid firing which
lasts as long as the presstire is rising^, and a sustained phase
of slow firing^ th® frequency of which declines slowly for 2-3
minutes. The total response includes the activity of not more
- 3 -
than 6 units o Esq^erimsnCs in situ yielded rssponsfis which
were similar to those of the Isolated eye except that the
transient phase was less pronounced j, probably due to adapt a*
tion of the globe to the higher testing pressures j, and the
sustained response continued for the length of the stioiuluSo
The relationship between the amount of evoked activity and
the pressure level was non^lineari. and there was no evidence
of different units coming into activity at different levels
of lOPo Ko spontaneous activity was seen in 907. of 50 nerves
tested o
Szperisients designed to find the site of origin of
the pressureoinduced activity indicate strongly that it
arisea frost nerves lying in the outer coats of the eye «diich
respond to stretch-
Continuous "spontaneous" efferent activity was recorded
iT<m the central ends of the cut short ciliary nerves. Rais-
ing the pressure in the ips Hater al or contralateral eye
failed to produce any detectable changes in the level of
recorded activity o Efferent activity In the long ciliary
nerves was also found to be unaffected by changes in the
ipsilateral or contralateral eye pressure <>
Stimulation of the retrobulbar nerveSj, however j, did
produce changes in the eye pressure. These effects were most
readily observed in the isolated perfused eye vdxere the c<si>
pllcating factor of simultaneous stimulation of extraocular
structtures is eliminated . Stimulation of the ciliary ganglion
<or its motor root) in the Isolated perfused eye produced a
syraaetrical constriction of the pupil with a fall in intre*
ocular pressure which is mslnteined for the length of the
stimulus. The pressure change is reversed when the flow o£
fluid through the vessels is discontinued. Under these condl*
tione there is « rise in pressure during stlaulfition. These
same effects are observed in situ with and without circula-
tion. Stiamlation of the long ciliary nerves produced
pupillary dilitatlon in all cases but there was no pressure
change without circulation of fluid in the vessels. In the
isolated perfused eye a fall of lOP occurred during stimula-
tion. The msgnittide of this fall was approximately 1/3 of
that resulting from parasyo^athetic stijnulation. No pressure
changes were observed when the eyes of animals previously
subjected to cervical sys^>athetlc neurectooty were used (antik-
dromic stimulation oS efferent fifth nerve fibers).
Despite the observed pressure effects due to stisoula*
tion of the syB^athfttic and parasympathetic supply |> retro-
bulbar nerve block did not effect the resting intraocular
pressure in the anesthetized c&t^ nor did it affect the rate
- 4 -
of recovery o£ the lOF ixaea ssiall ia^osed changes. This is
&n interesting observstlos in view of the fact that lOP In
man falls following nerve block (de Roetth).
In view of the relatively small amount of afferent
activity elicited by 10? changes and the absence of "spontaneous"
activity signalling resting pressures^ it is doubtful that this
sensory path carries enough information to participate normally
in the regulation of £0P<, However^ the techniques es^loyed
do not permit recording the activity of very small fibers vhleh
may be involved in such regulatiouo Although there are pressure
effects resulting from third aad fifth nerve stimulation these
do not appear to effect long-term control of the lOP.
This evidence indicates that in the cat the pathways
investigated do not contribute to the normal maintenance of
pressure in the eye.
Significance to Program of Institute; The results of
these experiments have is^lications for any experis^ntal
studies of the intraocular pressure. The isolated eye prepare*
tion of fimctionally viable neuromuscular apparatus proved Co
be very suited for the problems under study and supplooeat
essentially the results obtained in the living eye. niis
technique is also adaptable for studies on the ciliary body
and presstires in various parts of the eye as indicated in Che
project of Uxo van Alphen^ listed vinder basic factors In
refraction an<»aalies<.
Proposed Course of Project; Thig project will be
carried on by Dr. von Sallstann due to the departure of
Dr. Lele. Since there are so many reported differences between
the rabbit eye and the cat eye with regard to neural effects
in the ZOP^ it is suspected that species differences may be
of considerable importance in the investigation of this problea>
It is planned^ theraforej, to continue this work using the
monkey eyej, which is closer in structure to the human eye than
is the rabbit or cat and should yield data more applicable
to the situation in man.
Part 1 included; Taa/ITT" So /°~7
. 5 -
Serial No. NINDB«94 ^c)
PHS » NIH
Individual Projsct: Report
Calendar tear 1959
Part B. Hoziors^ Awards and FublicatlouB
Publications other than abstracts from this project:
Lele^ P >Po and Grimes^ FoA. : The role of neural mechanisns
in the regxiiution of intraocular pressure in the cat; Sxp.
Neurology^ (In Press),
Serial Mo. HIMDB«95 (c)
Ic Ophthalmology Braach
2. Physiology Section
3. Bttthesda^ Maryland
4. Sem ae NIIlDB°-60 (c)
FHS - HIH
Individual Project Report
Calendar fear 1959
iSEUL-
Project Title: Design and Construction of Ophthalmic
Instrvonents
Principal Investi^tor; Ralph Do Gunkel^ OoD^
Other Investigators: Mone
Cooperating Units s Hone
Han Years CcAlen^AX- year 1959): fatient Days: None
Total: 0,5
Professional: Do5
Other: 0
Project Description:
Objectives: To inske iiaprovesnents of instruments used
in clinical and laboratory ophthaliooiogical work. Specifically^
to desi^ end/or construct such devices as are suggested or
required by current projects <>
Methods ^ployed; The trend of this project has been
to involve the investigator more and more deeply in work with
visiting scientists. Since the clinical associates usually are
here for two years only^ it has been helpful to have Dr., Gunkel
provide a measure of continuity in the €ildctror@tinography and
psychophysical testing programs <> Techniques end instruments
must fzsxially be modified for each new study j, and continued
collaboration appears So be th® most productive method <>
- 2 -
Work wlch the loodified ad£p£ODi»ter continues^ In that
periioatrlc light sense studies are routinely made on clinical
patients having certain types of retinal degeneration^ but the
potential usefulness of this type of s^asureoient appears to be
much greater than tixas has permitted us to realize,
Htosierous optical devices were constructed or adapted
for the work with Dto Tan^leyo These included sector discs
and shutters for providing photic stimuli of different
d\uratio% flicker rates^ or on/off ratios o Also required
was an intense bleaching light which could be changed in
color and introduced into the pupil VTithout interfering with
entry of the stiiaulating hesaio
Frequent sffiasurezoents of the spectral emission of our
higlh-'pressure Xenon lamp were required and occasional measure^
ments of the absolute brightness of the stimulus beamo
Contact lenses and other devices were constructed as
needs arose in the use and handling of laboratory animals.
Major gjndinga; The light sense studies have demons
strated characteristic types of photopic profiles in four
different kinds of color blindness deflciencyo They also
have shown macular impairment in numerous cases triers it was
suspected but not demonstrated by visual field testing.
The obvious result of the development of the various
laboratory aids and devices has been to facilitate the work
of the project involved. These findings are discussed more
specifically under the projects of Dr, Xansley and Or. Copenhaver<
Siga^^,^g«nc« ^o groSg«a of ^nsUgute: It is expected
that this work will b^ useful for the purpose of distinguishing
photopic and scotopic mechanisms (work with Dr. fansley) and
that continuation of the psychophysical testing of patients
with color sense disturbances and various forms of retinal
degeneration will provide important information for the ^iag*
nosis of such diseases <>
Proposed Course, , of ,„ Fro-lfct ; Dr, Rushton's study of
retinal pigaients and their relation to vision and color per-
ception C^th normal and almorraal) will require the construc-
tion and/or modification of a number of instruments <> Part of
DTo Rushton's work can add validity (or discredit) to the
study of retinal profiles^ and the two phases of investigation
are certainly very intimately related. For this reason^ colle°>
boration with Dr. Rushton appears to be the most promising
possibility for the coming year.
Fart B included; Yes /~°7 No ^T?
Serial NOo NIHDB-96 (c)
lo Ophthalmology Branch
2o Physiology Section
3o Bethesdag Maryland
U, Same as NINDB-58 (c)
PHS •» NIH
IndividiJal Project Report
Calendar Year 1959
Project Titlas Fmactioaal Studies in Retinal Anomaliea
and Diseases (Electroreticographyj,
Adaptometry^ aad Perimetric Light Sense
Studies) .
Principal Investigators? Richard Mo Copenhavers, M^Do
Ralph D„ Gmxkelg 0<,D„
George Goodmafij, M^Do
Eberhard Dodt/M„Do
Other Investigators s Noae
Cooperating Unites None
Man Years (Calendar year 1959)! Patient Days: 100
Total: lo3
Professionals lo3 Ovit|iatient Visits: 23
Other! 0
Project Description:
Ob.^eet^yps: Ihia study >^ich is a continuation of a
previous project is concerned vd.th the investigation of
visual function in patients with retinal abaosrsualities
utilising new adaptometrics perimetric and electroretino-
graphic testsj, in addition to clinical examination^
Special emphasis is placed upon those conditions where
there is a selective affection of the scotopic or pho topic
retinal processes. When possible j other affected menfeers
of the family are studied.
The objectives of this -dy are as follows?
1) To aid in the difffe- -ati^i diagnoslSg prc.rjaosls
and genetic counselling of patiL-it^j with retinal abnormalities „
2) To investigate the cli.rlcal usefulness cf adaptometry 5
perimetric light sense studies and electro retinogrjphyo
3) To study the physlolofj] of rod and cone visioc. in
these patieats fey means of perisielric and electrorsttinograj^ic
techniques -which permit a separatt evaluatloa of tlia photopic
and SCO topic response «
fe.JiifcH?^^..! Epaployecl ; After ;liiQ.ical ophthalmologic
exajoinatioii the following specie L tests were performed s
i) Adaptometry: The coa"3e of dark adaptation if.
deteradnsd for a pai'amacular retliaal area on the Goldmaii.a
aiaptometer,
2) g^yim^Mffi. AJ^gil'it sfms testlag; The a'bsolut^j
light threshold is determi^'.e'i for red a&d btoe stimuli .from
CO 4jO degrees over one or 'jiore marldiaaa in the 'yisujil
field o The thresholds for blTO .light afford a "rod profile"
cf the:- retinas, a®d the thresholds for red light reprerent
the Bicdified "cofie profile" of the retinao Special attach-
aefits li'iive been added to tho Goldasa.nfi adaptometer to make these
studi R .s ^-ossiMe <>
.3) aieetroretinoffl'atiiy ; The ERG "a are obtained by
means of e^at^aci lens electrcdes and recorded on ar. SEG
machine c Th-'? aS'* of an intecse light source supplied by a
xenon lamp in rcxjjriuction with doubls interference and neutral
density flit'; a makes possibla not only the separation of
sci. topic axtd photopic functioa but allows the stuciy of various
photopic mechanisHis associate^', with color vision^
Ij^jor Finding^; In addition to the majox- findings
described in last year's reporb the following can be added;
A con© monochromat vas discovered vho 'aAiblted normal
visual function except for a complete absence of ec-lor
discrimination o This anomaly .i5 extremely rare and was
thou^t to he of interest to color theory <, Scotopic function
as tested by adaptometry and perimetric light sense studies
appeared noiiaalo Photopic functioaj at least that mediated
by red sensitive cones g was sigfiiflcaBtly diminished as
-3-
demoastrated by the iavestigation of the electroretinal
spectral sensitivity and perimetric light sense studies,
Ihis informatioa suggested that part of the color loss ie
due to a retinal defect but did not contrlbuts to the
question of the site of the other abnormalities T«hich nnist
hare been present to give ao severe a color deficiencyo
The spectral sensitivity curves (Dodtj Gopenhaver
and Gunkel) detex'mined by ©lectroretinography were also
studied in albinos j, Caucasians an.d Negroes ^^ere the degree
of retinal pigmentation is quite different^ It was found
that vdiar© the retinal pigmentation is very light there is
an increase in red sensitivity >}hlch reflects the absorption
spectztua of bloods Stinsilation of the retina by scleral
illumination also altered the spectral sensitivity according
to the absorptioB spectnam of bl^od. These studies indicated
that the pigmant in the coats of eyes does not itself alter
the electroretinal spectral sensitivity curve ^ Mt vhea the
pigment is nearly alssect or reduced the unHaskliJ.g of the
choroidal 'fedood vessels results in a pronounced iacrease in
red sensitivity dependent on the absorption spectrum of
Mood Itself c ThiiSj, in ftiture clinical studies utilising
the aathod of spectral electroretiiiography this factor must
be taken into conaidor'ationo
Two children each with infantile amaurotic family
idiocy and the late infantile and juvenile stages of amaurotic
family idiocy had coa^slete clinical evaluations including
electroretinographyg (Gopenhaver and Goodman) „ The electro-
retinographic potentials were found to be novel in the type
of disease occmring earliest and nearly absent in late
infantile and juvenile amaurotic family idiocyo These
findings correlate closely with ^at is known of the retinal
histopatholo^ in these diseases and our concepts of the
site of origin of the electroretinogram„ This study was not
only of theoretical interest^ but indicated the electroretino«
gram might be a useful tool in the early diagnosis of juvenile
amaurotic family idiocy and a great help in clarifying the
diagnosis between such conditions as Tay^Sach's disease and
metachromatic leukoeneephalopathyo This is a val^iable
technique becase it supplies the clinician with an objective
test in individuals who are infantile and demontedo
■Sigaificance to, Progyam of Ip;st^tT;^t9S The functional
study of. retinal diseases tbaj lead to a further clarification
of basic problems in retinal physiology which will result in
a better understanding of numerous clijctical diagnostic problems «
- i^-
Proy ;sed Coffirsa of Pyo,j^et; Dr, Ottiwell Jones
has taken t.,8 place of Dr, Copenhaver„ With the advice
of Dr. Rushton and the help of Dr^ Qunkel he is going to
continue and to extend studies on the outlined perimeters.
Patients are continuously referred from various medical
centers for psychophysical testing aadg thusj. subjects
for such studies are a'railable„
Part a included Xes /j? No /~7
PHS "" NIH
Iftdividual Project Report
Calendar Ysar 1959
Part B; Honors s, Awards and Ptfslieatioas
Publications othsr than a'bstracts from this project:
Copenhaver^ RoMo and Goodmans S.j The olectroretiaogram
in earlj infaatilej late infantile and ju'^enile ainatsrbtic
family idiocy, A„MoA, Archo Cphth, (in prQss) .
Honors and awards relating to this projects None
Serial No, NINIB°»97 (9)
1„ OphthaliBologjr Braixch
2^ Physiology Section
3» Bethssdaj l-iajylaad
4o Saffi© aa NINDB-57 (c)
■ PHS - NIII
ladiYidtial Project Report
Calendar Tear 1959
Part A,
Project Title X 'JJBG Reactions of Pure-Coae Mammalian Retinae
Principal Inve?jtigatorss Katharixje Tanaiey,, D,SCa
Richard M,, Copenhaver^ Mo-D^.
Other levQstigatorJ Ralph D, Gunkelj, 0„D,
Cooperatisig Units: None
Mae l9a--s (Caleisdar Year 1959) °
Totel; 1,0 Patieat Days: None
Prcfeasionals 1,0
Ot'.iers 0
Prrject Description:
Ob jl motives: To study the spectral aeasitivityj,
'i^rk adaptation;, and flicker fusion frequencies of Trariouf?
ffloiabers of the squirrel f amilyc 'Siese havii^g the only purs'"
cone retiiiae kisown aioongst jnasmials,
%,t',^PJ?,s, ^P^07Q,4' The apparatus .5, coaaistiag of a
Xenon high pressure lamp and a set of double interference
filters to prodiice nearly moaoehroaaatie light stimuli $,
already in use here^ will be employed to measure the spectral
sensitivity curves of various squirrel species c Both
flickering and single j^lash stimuli will toe used to study
flicker responses aad dark adaptation curves,
Ma,1 or.,, Fiqding^g : Adequate data have been obtained
for reliable seasitivity curyes on sevesral different species
aqairrel.. This vrill fee analyzed and presented for
cation early ifi I96O0
Some new observatiofts regardiBg the flicker ER0
and the depressed off-effect at high stinsalus iatenaity
will be presented c Evidence that certain species of
squirrel have only coaies aad not rods was accToxnalated
by demoastrating the absence of a shift ia the peak
Itanlnosity of the spectral sensitivity cmrve from the
light to dark adapted states » these high critical fttsiojs
frequencies and the alssence of the type of spectral
sensitivity curve usually found in the presence of
rhodopsino Two "humps" were found in the sensitivity
curves of these squirrels and were thought to bo
representative of at least two photosensitive cone
pigments o The maximum of these peaks were about A90 mp.
and 535 nf^o It appears probable that the green sensitive
pigment identified by other workers in vivo bleaching
experiments is responsible for the green "hump" found
in the electro-spectral sensitivity curves o The blue
"hump" was less predictable and thought to represent a
highly labile blue sensitive photopigmsnt,,
Acquisition of a Zeiss photocoagulator has
facilitated a study of the effect on the ERS of deli^jsrate
daxaage to the retinal circulation » A discussion of these
findings will probably comprise a third publication =, It
caii be saidj, howeverj that the destruction of the retinal
vessels produced a retinal degeneration in some of the
animals limited to the entire inner retinal layers down
to and including part of the bipolar cell layer 0 The
marked reductioio, of the electroretinogram following this
degenarat5.on was taken to confirm the hypothesis that the
positive potentials originate on the bipolar cell layer
while the negative retisal potentials arise on the deeper
retiaao
Significance to Program of It^stjlt^ate ; One of the
great difficulties encountered in studying the human ERG
is the separation of the pho topic (cone) response from the
scotopic (rod) response o Most members of the squirrel
family possess pure-cone retinae so that a good knowledge
of the reactions which can be obtaiEed from such animals
should be most helpful in providing information on the
responses of a purely photopic mechanism uncontaminated
by those of the scotopic mechanismo Investigations
already carried out in Europe have shown that the
reactions of the retina of two species-— a tree squirrel
and a ground squirrel-~->are in soma waya quite unlike
those of the more usual mixed rod and cone retina of
which the hujoan is an example o The tree sqiiirrel spectral
sensitivity curve is much narrower and appears to reflect
the activity of one only of the three postulated mechanisms
for color vision—the "green" mechanismo The ground
squirrel apparently has twoj, the "blue" and th© "green",,
It is hoped therefore that a more complete study on
several species of "both tree and growid squirrels will
provide information a'tjout the fundamental mechanisms for
color vision o Dark adaptation hasg so far., only been
studied on a tree squirrel which gives a curve similar
to that found by psychophysical methods for the human
fovea o
It is believed that the photopic and scotopic
responses in man can be separated by means of their
reactions to flickeriog stimuli. The squirrel responses
to flicker have cot yet been systeiaatically studied o We
intend to repair this omission and hope to discover \diether
in this respect also the reactions of the squirrel" retina
resemble those of the human photopic mechanism.
Proposed Course of Pro.iect; The escperlmental
part of the project has been con^jletedj, and data are
being analyzed for presentation in three publications o
Completion of these reports will terminate this projecto
Fait B included Yes £J No ^
&ui)
Serial No„ NINDB-98 (c)
lo OphthaliQology Branch
2„ Physiology Section
3o Bethesdap Maiyland
4o Same as MINDB-56 (o)
PHS - NIH
Individual Project Reports
Caleadar lear 1959
Project Title; Eleetrophysiology of the Ejye
Principal Investigators M„6oFo Fuortesj KoDc
Other Investigators: Kyoji Tasaki^ M„D„
W.AoHo Rashton„ F<,R„S„
Cooperating Units J Laboratory of Nevirophysiology^ NINDB
Marine Biological Laboratory^ Woods
Holes, Massachusetts
Man Years (Calendar Year 1959) Patient Days'. None
Total: 4o0
Professional; 2cO
Other: 2.0
Project Description!
0^i§cjti3[gg: Study of the changes evoked by light
ia the eyes of invertebrates (Limulus) and vertebrates
(fi^) has been continued o Part of the esperimants on the
Limulus eye have been performed in Woods Holej, Massachusetts j
Ti&ere fresh aniiaals could be obtained daily » Takiag
advantage of DTc ^<. Frank's kind hospitality^, additional
experiments on nerve cells of vertebrates have been p©r=>
formed in the Spinal Cord Section of the Laboratory of
Neurophysiology (NINDB) in order to determine whether
certain properties found In Limulus are also common to
other structures,
Jfethods Ekaployed; Glass micropipettes filled with
3 molar KCl were introduced in the ceils to be studied and
were used both for recording potentials and for passing
2 -
CTirrentSo In DTo Frank "a laboratory two pipettes were
introduced iato the same cell and various responses were
studied with voltage-clanrp method o
JT^joj F^qt^lr^jgys ; In accordance with the plans and
problems outlined in the preceding reportj, three major
questions have been investigated:
1) Site of xBipulse initiation j
2) Subliminal responses to lights
1) It was found during the past year that resistance of
aerre cells in the Llmulus eye decreases moderately during
illumination. Spikes recorded during illumination are
smaller than those recorded (in con^arable conditions) in
darkness. This can be explained asBUiaing that the resistance
of the soma membrane does not decrease Tery drastically
during ijsgnslse activity o Direct measuremeat of manterane
resistance during an Impulse could jsot be performed on
Limulus but the results obtained on spinal motoneurcnes with
vol tage-^c lamp support the assumption,,
In order to explain this result it may be thoughts
a) that the mechanism of impulse generation in somata is
different from that of axons {vhere men&raae resistance
decreases by a factor of 5CX) or so) i b) that impulse
activity does not involve ceil somata or that it only
involves part of cell somata »
All experimental findings obtained so far are in
agreement with the second hyjjothesisa which in particular
is strikingly mipported in Limulus by ejqjeriments on
inhibition. Whereas following excitatory illuminations
frequency of firing bears a strict relation with the membrane
potential of the soma^ ijahibitory illumination decreases
frequency of firing without perceptibly changing the recorded
membrane potential. This is what one would expect if both
the place of origin of the rhythmical impulses and the site
of inhibitory action were at a distance from the aomao It
is found, in fact^ that inhibitory synapses are on the axonSj
at 100 ^ - 200 u from th© sona.
The conclusion of this work is that both in the ey©
of Limulus and in the motoneurones of cats impulses originate
in the axonc
- 3 -
2) The study of the properties of transmlssiofi from
photoreceptive structures to nerve cells in Limulus has
been continued by nieans of an analysis of subliminal
responses to dim lights „ It has beea found that (follow-
ing dcrk adaptation) steady dim i,lJ.umination produces aa
irregular series of transient depolarizing pulses o Since
previous work from this laTsoratory had led to the conclusion
that a chemical stibstance liberated by the photoreceptor
is responsible for evoking nerve ceLl depolarization » it ia
reasonable to think that the transient depolarizations
recorded during dark adaptation are due to discrete
liberation of "droplets" of traasmitter substance o
The possibility that each "droplet" is liberated
following absorption of a single quaat«m of li^t is now
■beiflg iavestigatedo Dto William EushtoKj, Visiting Scientist
from Cambridge^ Englandj, will sow ig ia charge of this
probleffio
DTo Kyoji Tasaki has conqjletgd his work on fish
retiaa as plamted and left the Sectloa in September c He
has confirmed Svaetichia^s fielding thi-t hyperpolariziBg
poteatials are elicited by light ia the fish retiaa » He
foffind that 1) hyperpolarizing potentials* E^y be obtaiiied iss
the absence of a aegative DC shift j 2) e?.9ctric curres^ts
through the microelectrode do not affect b'.zq and properties
of the hyperpolariziag poteatial chaagQo Fi-)m these results
he ccncltaded that the hyperpolariziag potenti>.ls originate
in a large space which could be either a large -^ell or an
enclosed extracellular space.
Significance to Program of Institutes It is hoped
that the work described may be useful for a better ut-ier-
standing l) of the nature of such elementary processes of
vision as: a) mode of excitation of photoi^ceptors and
b) trfbnsmission of excitation to nerve cells j 2) mechanj.^ja
of generation of impulses in aerve cells j 3) elementary
interaction between nerv© cells ia the eyeo
Pyppoqed Cotarse of Project; Next year's work will
coaceatrate on the properties of subliminal responses with
particular reference to an. analysis of the «timber of light
quanta required to elicit a response in different conditioas.
The chaages indtaced by light adaptation will also be studied c
It is hoped that some ftsndameatal properties of the process
of vision will he revealed "by the plaaaed experimeats„
Part B included Yes ^ No £2
Serial No. NINDB~98 (e)
PHS - NIH
Individual Project Report
Calendar Year 1959
Part B. Honors g Awards and Publications
Fuortes, M.GoFo? Integrative mechanisms in the nervous
systems Amer. Nat.^ 215213-22^^, 1959 o
Franks, K.j, Fuortesj, MXoF^s, and Nelsons P„G.: Voltage-
clamp of iBotonetiroae somaj, Science p jJS53S~39j, 1959.
FuorteSj, M<,GoF, s Diacontinijaous potentials evoked fey
sustained illumination in the sye of ^^^M.b Arch, ital,
Biolos, 2Zs243-250, 1959«
Tasaklj Kyojis Some observations on the retinal potentials
of the f ishg Arch, ital, Biolo (in press) o
Honors aud Awards relating to this project; None
Serial Hoo NINDB-99 (c)
lo Ophthalmolog/ Branch
2o Cytology and Hlsto-
pathology Section
3. Bethesda^ Maryland
4. New Project
PHS - NIE
Individual Project Report
Calendar Year 1939
Part k<,
Project Title: Studies on the Corneal Endotheliim
Principal Investigator: Ludwig von Sallatan% MoD.
Leo Caravaggio^ MoS.
Other Investigators: Eleanor Collins
Cooperating Units: Hone
Man Years (calendar year 1959): Patient Days: Nona
Total: 4=0
Professional: 2.3
Other; lo5
Project Description:
Objectives; ]Hiysiology and pathology o£ the corneal
endothelium is not well understood although its iiaportance in
certain disease entitissi, particularly Fuchs' dystrophy jr has
been appreciated following advances of bioraicroscopic techniques.
The prominent role of the condition and preservation of the
endothelivm for successful penetrating corneal grafts has been
repeatedly eiiq>hasized in recent work. The limitations of our
knowledge of this cell layer in health and disease rests In
the difficulties to evaluate morphological changes on routine
sections. Atteinpts to use flat mount techniques In the past
have been mads on portions of the sndothelivmi, but eKamlnatlon
on v^ole flat mounts of this cell layer have not been reported
or carried outo The present study deals with two aspects of
. 2 -
the problem; £lrst$ to datensine the regeneration o£ the
endothellusn under physiological conditions and second^ to
examine the process of healing o£ chemically or mechanically
induced wounds.
Methods Employed; The flat mount technique devised
for the lens epithelium \4hich have been subjected to the
Feulgen reaction^ was successfully modified for the corneal
endothelium o Mr. Caravagglo succeeded in separating the
endothelium attached to the Descemet's menbrane from the
remaining layers of the cornea and In mounting such prepara-
tion of young adult rabbits in their entirety. The number
of cells in the whole endothelium was calculated and the
mitotic index determined. Injury to the endothelium was
Induced by irrigation of the anterior chamber with 0.97.
solution of sodium chloride^ by similar treatment with chy-
motrypsln and by removing clrciimscribed strips of the endo-
thelium with a blunt instrument. Other eyes were subjected
to routine histological examination.
Major Findings; In contrast to the generally held
opinion that karyokinetlc cell division does not occur in
the cornea of the adult snlsial under physiologic conditionj,
it was established that mitosis takes place and that the
mitotic index of an average of 13 dividing cells per popu-
lation is similar to that determin&i in the pre^equatorial
zone of the lens epithelium. It seems superfluous j, thereforej.
to resort to the assuoq>tlon that exidothelial cells multiply
by amitosis in efforts to replace dead cells.
The infusion of 0.3% sodivm chloride solution into the
anterior chambsr leads to endothelial damage Indicated by
gaps in the regular cell mosaiCj, by cell degeneration and a
remarkable Increase of cell division in the area of the
lesion. This injury is more extensive v^en the enzyme alpha-
chymotrypsin^ reconsmended for zonulolysls^ was infused for
several minutes. The process of wound healing is initiated
by the formation of a fine and dense fibrin net covering the
defect In the endotheliust and by the ingrowth of cell elements
from the margin of the wound. Eere again a great nuaber of
dividing cells are observed in the surrounding zone.
Significance to Program, of Institutes Knowledge of
the behavior of the undisturbed endothelium and of the endo-
theliisa subjected to various injuries is of importance for
the understanding of endothelial disease of priioary nature as
wall as that accompanying other diseases of the eye. It ml^t
opon ways for attempts to Influence such disease states thera-
peutically or to prevent Injuries of ths cell layer by routine
surgical procedures^ by storage and keratoplastic techniques.
- 3 -
Proposed Course of Project; It is plaimed to study
fige-lnduced morphologic changes of the endotheliuBi end at a
later date to approach more basic aspects hy tissue culture
techniques and electron microscopy <>
Part 3 included; Yes ,^7 So '/"^
- 4 -
Serial Noo KIin)B«99 (c)
?HS - SIH
Individual Project Eeport
Calendar Year 1959
gart B. Bonors. Awards and Publications
Publications other than abstracts from this project:
von Salliaaim^ Lo: Experimental studies of soiBe ocular
effects o£ alpha chymotrypsin; Trans. Am. Acad. Ophth.
Otol.^ (In Press).
Honors and Awards relating ta-thls project: Hone
Serial No„ NINDB->IOO (c>
lo Ophth&liDoIosy Branch
2.. Cytology mstd Hl8t:o<»
pathology Section
3p Betheeds, Maryland
4o New Project
PHS - KIH
Individual Project Report
Calendar tear 1959
Pare A«
Project Title; Eye Changes in a Familial Type o£ Dy8ker&«
tosia of the Conjunctiva &ad the Oral Moeos&c
Principal Investigator: Ludwig von Sallmsnn, Mo 0^
David Fston, M„ Do
Other Investigators: None
Cooperating l^nits: None
Man fears (calendar year 1959): Patient Days: 34
total: 0.2
Professional: CI
Other: Od
Project Description:
Objectives; To study clinically and histologically
the eye lesions in a faaiillal disease which involves predost^
Inantly the perilinbal conjunctiva and the oral nucosao It
occurs in a large tri •racial isolated population in Balifax
County, North Carol inao
Methods Buyloyed; 128 of 390 persons in the ey@ diS'-
ease lineage «;ere repeatedly esmmined biocsicroscopicsllya
Scrapings from the conjunctiva vere obtained from 21 patients
and biopsies from the periliBsbal area in 7. fhese 7 patients
and 3 isnlnvolved meiaibers of the family were adsiltted to the
Ophthalmology Branch for detailed study^ the biopsy material
Wis sssbjected t© rewnsttss histolcsglc ssgnaiastioa wieli a battery
of staining procedures sad phase contrast oderoscopyo
Major Findings; Other Investigators (I>ro 6rsi]i@in mad
Go Wiekop, SVu, DoDc) hecve studied the socio "egonoioic and
genetic: aspects of the disease <> It appesrs that the letter
is inherited as s, sl^le Mendelian dominant, fl&e eye ehsnges
o€«spy the perlllasbal conjunctiva @nd consist of firm gr^n^
ular .smiotrensliaeent proliferations raised above the surface
of the surrounding tisstse, fhe shape of the lesion vsried
biiat most frequently It sss&naed a triangular forts of horse-
8hoe»like conflgusrationo %he surrounding portions of the
conjunctiva shotr & rather characteristic vaseulsrisation
vhich explains the term "the red eye" used by the patients »
Serious corneal cooplleations were rare b«s£ somtiiDas dense
membranes of proliferated tissue covered the cornea for per^
iods of tiffiSb the histologic exasainatlon shoved that the
epithelium in the involved part of the conj«snctiya v&a
thickened to various degrees and that the epithelial faypo°
plasia was aceoispanied by degenerative changes of the dyskera--
totie type and the signs of acanthosis, fhe epithelial calls
of the niddle. layers were often swollen and rounded and the
cytoplasia was acidophilic ,> Degenerative changes of the cell
nasclei were cotaBon., With the Gleosa stain irregular light
blue structures cotsld be deoonstrated hear the maeletss or its
remnants c fhe nat«ire of these blueostaining coiii>onents is
not clearo Spotty keratinisatlon and cytonecrotic signs
becaaae widespread towards the epithelial surface, fhe tunica
propria was usually free of n^jor pathology* but was sosaso
tiiaes the site of extensive round cell inflltratlono
Curing the physical exanlnation it was noted that a
change in the buccal outcosa coexisted with the eye litaionso
It was diagnosed by Dr^ Witkop as "wblte sponge nev^s of the
oral aaacosa" and was described as histologically similar to
the conjunctival change „ Xn view of this new finding th«i
original inpresslon that the lesion could be considered as an
atypical lln&al vernal conjunctivitis had to be discarded mid
the diagnosis of familial conjunctival dyskeratosis of the
eonjuaetiva and the oral mucosa accepted »
Sj^nifiganee to grograa of Institiates Although this
disease Has not Wen reported in other Isolated populations
where intensarriage is fre<iuent. It cannot be excluded that
the entity exists but has not been discovered o
Progosed Course of Projects This project has been
terminated o
Part B -included s Yes ^ Ho £7
Serial NOo HZNPB-IOO <e)
PBS - HIH
ladividwal Project R«p©rt
Cal«n<Sar Yesr 1959
Part B. Boaors, A»&tdB, and Publications
Publieatioiu other than abatrs^ets from this project;
von Sallicann, I^td^ig and Pston, David: Rsredltary dyskara-
tosia of the btilbar conjunctiva and oral miseoss. I. Ocular
seanifestetionso Aisar. Med, Assoc. Archives of Ophthalmology
(In Press).
Honors and lAsrards relating to this project: Itone
Serial Koo Nim>B»l01 (c)
I. Ophehalffiology Bre&eh
2„ Cytology and Histo-^
pathology Section
3o Bethesd^p M^Tyland
4» Saote as !iIHDB->37 (c>
PBS - NIH
Individual Project Report
Calendar tear 1959
Part A.
Projeet titles Kiatritional Cataract « fryptopl^ne
Deflcieney Cataract ia Colnca Pigs.
Principal Investigator: U&^tg von Salltaami, M,D.,
Mary E„ Reid, Pbi„D„
Other Investigators: Patricia Grisees, BoAs
Eleanor H„ Collins
Cooperating ^its: Laboratory of Nutrition and
Endocrinology, NXAIS
Man ^ears (calendar year 1959) » Patient Dayai Hone
fotsl: Oo2
Professional: Ool
Other: 0,1
Project Dessriptioni
Objectives; In the past, eisperisae&tal cataract induced
by deficiency of essential asalno scids have been studied pre°
doaainahtly in the rat. When lens opacities develop in this
species, the ani^l appears to be in an esstresisly poor state
of health. Secondary effects dee to the near starvation con->
dition of the rat caimot be distlnsuished readily from the
priaary effect of the amino acid deficiency, ffie vise of
guinea pigs as the ejqterimental anis^l obviates this eoB^li"
eating factor^ therefore, ^speriments are conducted on the
guinea pigs to determine the tryptophane requirements for
maintaining clear lens where the diet contained eo|>le dietary
niacin and all essential amino acids but tryptophane.
" 2 -
"Mmth&is EBjaloyad.s Male guis5@a pigs 3-5 years old
^@7@ pla£@d oa th@ esperiiosntal dle£ x^ioh cemt&tn^sd 0.1%
of th& smLno ae£d rangii^ f7«H& G<,02 &o 0„l%. thsB® gsinaa
pigs sod eootarol animals ^e^e reg^lss-ly eheckad for ehelr
^®£g&t gain, s^aMaed at w@@kly intervstls ^it& the slit Imp,
eM killed as va?l@«£s iatsrvals.- Both eyes of 135 gitioiea
pigs w&z® €m2€:l@&t@d asd s^bjseted to histologic exasiinAtiiono
To ao^lify p^eviossly g'sportsd obseyvafei^is on the rat lens
epiela®lii5sja, several litters of t&ta {52 ealBals) were fed
t3ryptop!sss®-4afieisa£ diets of "^a^ioes types » Nine weeks
aftee feasting began the right eyss wesre prepared for cytologic
essfissismti&fi of ^e leas epithelisis in ^ole ce^snts sad the
left @y©s ^@?@ ^seS for histologic: sttsdi^s to alio;; coeapsro
isem of zh® i-essslts %?i^ those t^taisied in guinea pigs.
Ilsj@g Fladigsgat Guiaea pigs oa a diet coataiaisBg Q^l%
tsrypt:0ph^S"di9el©is3 iocipieat cata?aet«^8 chas^es as early
as l°2 ^%®ks after the feeding ves started, the gro^ of
these anisals ^as only ©lightly retarded „ Most of the aniar^s
transiffiot alopecia &M for a s^sort ti!Q@ had mffollet?
astd excreted soft, mtio^tsmd i®c®So Saiall stsppl""
of the esiino aeid added to the bae^l diet delayer? o^et
of lentie«3lar chss^ea and prevented esteasive lens depffS®*
Mexissal gres^h w&b obtain^ by the addition of 0.03% ^'^
tryptophane^ a lewl i^ieh is not sufficient for ce^>l®t®
lens protestism. Tffis ©"isossr had fross 1/4 to I/:" ih® gr4^th«»
proswting aetiwity of the L foz^a. fh® presene® >5 the B fora
did not appear t© s?3ppr@S8 the preteetiv-® acUtr-.' «f the 1"
isea^r m. th® l@ss„ 2a faetp at th© higher sapplitsasntal
l©^lsj it atght esert slight additional ©Cf sets,.
the initial histologie lesions we-zs characterised by
fiber hydrops prad^jsinantly aroand the esstMres. Later the.
deep eortes ^as the site of fiber drnfcmstloa. From there,
the lesions spread tcf!$ards the s^r^e^e. fhe Xens epitheliiUGi
md all cos^onents ©f the lens eqtsiiaor pras@2«r84 their a»rph«.
©logical integrity in contrast to ^y of ths histologically
studied- foraffi ©f escperissatal satftr®©t„ S^ts sasffered loss
©f weight instead of gaining weight. Cataracts developed
fewr weeks after the diet vsaa star^.ed, fhe hlstopa^ology of
the rat ©atsrsct was similar to that oistlined for the gwines
pig.
Sig^ifieyee to grogrgg pSlmtltut®'. It was sham
for the first tis^.that the rs^ir^sent of the lens for one
essential eisino acid (L^tryptophane.) ^as greater than that
for iBSsiseal gro^h of the b«Mly as & ishole. fhere ia the
distinct' possibility that early ©r congenital estarssts in
Zh® h^n ares s^saec£®d with ts-ssisient d©fi®i©asj ®f ©sssn«
tial a@ino acids a
of ©tiles' pirojeete ©a
S3 „
Fast B iaeli^ei;
„ 4 -
Serial Noo iSIKOB-lOl (e)
Calendar fear 1959
Part B. Honors^ Asmrds, And Publications
FisblieatiGns other than abstracts from this project:
voa Salliaajm, LsKfcjigj Said, KarySoj Griiaes, FoA„; and -
Collins, EleeaiOS" M» : f ryptophaae-DeficisBey cataract in
gisiaaa pigs. &„M<,A<. Arch., .Opfeth.», 62s662»672, 1959c
voa Sallmam&, L&ad^ig astd Reid, Hary £.: Isatrltionsl
studies with the gisiaea pig ¥i„ fryptopheae (with aa^le
dietary niaeia}. (!n Press)
Hoaors aad ^srds relatiiiig to this projeet; ^osae
Serial do , £l^shJsS^SiLki^Ji.22^
lo Ophthalmology Braneh
So Cytology and Histo-
pathology Section
3<. BetheadSp Maryland
4.0 Same as NINDB-45 (c)
PHS - NIH
Individual Project Report
Calendar lear 1959
£&£kA'
Project Titles Study of Ocular Toxoplasiaoais and Its
Therapy
Principal Investigators Herbert Eo Kaufinans M.Do
Other Investigator: Richard G„ 0»Connorg MoD,
David Patony M.D<,
Richard Copenhaverj. MoDo
Bruce Cohan„ MoDa
James CRourkes McD„
Ludwig von Sallmann;, MoDc
Cooperating Units: Laboratory of Tropical Diseasesg
NIAID (Toxoplasma Dye tests were
carried out in this labo)
Man Years (Calendar Tear 1959) Patient Days: 3180
Total: Oo5
Professional : 0 » 5
Other: 0
Project Inscription:
01?jectivea: Evaluation of clinical observations
made on patients vith uveitis of possible toxoplasmic
nature o
Method? Employed; The etiologic workup on patients
with uveitis consisted of a routine hemogram» urinalyaiSj
sedimentation rate 5 X-ray of the chest and skull and often
the handSp antistreptolysin 0 titerj, brucella and tularemia
agglutination test^ serological tests for syphilis, measure-
ments of the total protein and albumin and globulin fractionsj
blood sugar^ blood urea nitrogen and serum calciumo Skin
tests vith toxoplasmin and toxoplasmin controlp hlstoplasmin^
coccidiodins, heterologous staphylococcal antigen^ Dick test
streptococcal antigen^ and lymphogranuloma venerum^ as veil
as the first and second strength purified protein derivative
of tuberculin were also done. On many patients j, samples of
aqueous and serum were tested for precipitating antibodies »
Major Findlmi^s: Of the great number of patients
admitted to the Ophthalmology Branch with uveitis^ IO6 were
found to have a positive toocoplasma dye test titer in the
absence of other obvious etiology^, and were treated vith
Dasraprim and sulfonamides » As a rule^ the course lasts
six weeks » Only patients with active lesions were suitable
for evaluation of therapyo Ninety-nine of the IO6 patients
with positive dye tests of different levels had also a
positive toxoplasmin skin testo A survey of an additional
100 patients with negative toxoplasma dye tests revealed
only one person with a positive akin testo This person
with •'false positive" skin test was the only one in more
than 200 subjects on vixon. the toxoplasmin control was
positive o The results indicate that the skin test is a
very reliable procedure » Forty- three of the patients
with marked activity at the onset of treatment were free
of signs of inflammation following the course of chemo-
therapy^ and more than half of this group underwent complete
remission o Corticosteroids were added to the treatment with
toxoplaamacidal drugs when oases did not respond satisfactorily
to the chemotherapy^ In only 7 of 35 patients of this group
did the signs of inflammation disappear.
The therapeutic response to Daraprim and sulfona-
mides seemed to be more favorable vhea the onset of the
disease dated back to an age under 20 years. The
chronicity of the disease appeared prognostlcally unfavorable o
Satisfactory results with Daraprim and sulfa therapy were
usually not convincing before the 10th day of treatment,,
There was no correlation between the level of the dye test
and the therapeutic responses o
Significafice to Program of Inatit^tp; Evaluation
of the skin test as compared to the toxoplasma dye test
is of practical importance because of the unavailability of
dye tests in many states. The results with the use of toxo-
plaamacidal drugs are encouraging when they can be administered
- ;) -
in. a relatively acute stage of the disease vhich had its
onset at an early ageo Thus^ the results are a valuable
contributioc to the meager kaovledge of the diagnosis and
therapy of one type of uveitis „
ProT?osed Course of Fro.lect; Results will be
reported by Dr^ Kauflnan in the near future and studies
on the disease continued.
Part B included! Tes J^ No fj
Serial No„ NINIS-102 (c)
PHS - NIH
Individual Project Report
Calendar Year 1959
Part B, Honors g Awards and Publications
Publications other than abstracts frcm this projects
Kauflaans HoE.g and Caldwells Lee A,s Phamiacologieal
studies of pyrimethamine (Daraprim) in maag A.M. A. Archo
Ophth.p 61j885-890s 1959.
Kauflnanj, H„E,s Rendungtonj J.^ Meltonp M.L.j, and Jacobsj, L«
Relative resistance of slow-growing strains of toxoplasma
gondii to pyrimethamine (Daraprim)^ A.M.A. Arch„ Ophtho
|2 8611-615 p 1959c
Remington^ J,S,g JacobSj, L.j, and Kaufmanj.H.E.s Adult
toxoplasmosis^ How Eng„ J. Med. (in press).
Honors and Awards relating to this project: None
Sa^i&l so, i03 (c)
Ij Ophthalnologsr Branch
2, Cytology and Bist:0'»
p&tl£E>log}r Section
3^ B«th«ad«9 Maryland
4, SasM «a HINDB 52 (c)
PES » HIH
Indi^dnai l^rojccfe Bftport
Calead&x- Yeax 1959
Part Ac
Project Title: Electron Ifc'^roacope Sto^iies on Blopaias
o£ liusaen Muscl« Diaeaaeu
Principal InfestigaSors* Itseodor Wan'^e Ho So
G« Hilton tbsys Ho D
Other Imeetigatora:; Mary Ann ^•a'via» Mo So
Cooperating UJlts: None
Man Tears (ca.andar year 1959): Patient D^oras
Total: loO
Profeasiona:.! 0.5 1400
Otter Oo5
Project Oeacripticb:
Objectives: To detensiJEie hy HHaaa of the electron
siicroBcope detectable change in boaan muscle affected with
various dystrophic dieeaaea as coD^>ared »ith noroel tiasoeo
MethodB Bcsployedg libtsrisl obtained froa xauscle bix^sies
on human stsbjWts Wit&' Wacle dyssrophise of varioue fcinde ere
ixoBttraed iantetl&iately after ixcislon in 1% osffiiun tetroxlde for
fixation» Thia Is followed by debydration and^ in some ceseSt
by additional im\<regaBtion ^ith 1% phosptotnngatic acids
«nbedding in nethiiGrylate and araldite and sectioning on
a Servall oltremicrotOTieo
An RCA electron taicroacopee Model EMU«'3C» is used in
these studies o Control and coc^arative essaminetions are
carried out 9ith the aid of phase contrast and light aicroscopyo
o 2 *
Major Findlosa; Durlog She last; year more spftcinmis
of irarloaa diseases were colleetedo The ts&in atteaeioae
however, was directed toeard the taorptology of s CTtoplssmic
inclusion, tdilch occurs aomally in the auscle fibers,, vascular
endothelia and pericyte«o It is an agglooerate frt&ieh consists
of globules of various densities together with opaque granuleaa
and shovs no discernible b<Msndary fr<xB the surrouoding cyto*
plasoo This ccsBplex usually is found in the iricioity of nuclei
and soBsstiaees in close association with mitochfMidria. Escaa-
iaatimk of autop^ speciiasna from aged htsBsn heart auscle
revealed the presence of a large gstad>er of conglomerates of
e£inii«!X cog%»ositioao Coacoaitant light laicroscopie oh«>
serrations on froeen sections indicate the presence of lipid
stained structures <> In one instance in the literature such
an agglomerate is shown in an electron micrograph and is
termed "lipofuecinD" A similar structure has also been shown
to exist in the interstitial cells of the testiso
In order to obtain ssore inf oroation on the cooposition
of this structure, sections of skeletal muscle have been
subjected to ch^ilcal extraction with chlorofona-iKthsnolo
Tine and temperature of this extraction wnre systematically
variedo As a result, the indivi^sal conpomnts of the
agglcNBerate usually di^layed loss of thsir o^Mr»all opacity
end frequently there was a dissolution of the granular
portions^ Ho»s^er» this fittding was not yuff iclently coosistentt,
and at the eas^ tisis« other cellular conponents sotBetiiaBS also
showed a reduced opacity <> The enisedding medium was dissolved
to varying degrees by the sol'vents as well , Therefore, these
experiments did tiot se»H to provide conclusive results aqd the
following procedure has been Initlatede Boaan heart muscle
obtained at autopsies of aged individuals was choeea &» the
test material because of its abuodszKe of the described
agglomerates p Very esmll tissue blocks are subjected to
extraction with lipid solvents such as ehlorofona^methanol,.'
acetone, ether and pyridine prior to and after fixation ia
the usual mannerc Ti^y are then eiBbeddedi, sectioned end
examined in the electron microscope and c«q>ared to tmtreated
control specimens of the same series » So results on these
e^ierii^nte are available at presfloita
Siaanif ieence to^ Program of Institutes It is possible
that significant £»rphological differences between normal and
dystrophic muscles might yield eocs insight into the cjrtopaChoo
logy involved in these diseaseso
The investigation on the heterogeneous agglcnaerate
might yield i&£ot?^tiai& as to its chemical composition and^
at the same time^ might lead to a z^thod of characterizing
lipid structures of other cellular constituents by means of
the electron microscope »
« 3 -
Propoagd Cwssm of ?goj*ct;
■mssle «U1 b« eoaeiisiised vith ^^IaI attaation baiog gUea
to stmcturcl derails &t the Z disc le^l; eo ths e^ oaospho-
logieAlIy distinct t^rpes of isgpof iiffioeata fisd to idaotif Icatlon
of the deaamg hetaroi^«aeous £ggl<H2]er«te in ffluscla fibers and
blood vessel ^allso
Obaervfitioae cu ogrotonic dystrophy vill be coatlxaiedo
Furtber studiea of HesiJnig-HoffEeaim's diaaaaa* of faailial
periodic paralyeiS; o£ progree&i<»« rasacolar dyatropfay and
other neurooisHiiscular d .eaaaea Bill be ptir«8«do
Part B included; Y@& O" So ^J
Serial No„ HHJDB-'104 Ce)
la Ophthaltoology Branch
2„ Cytology and Histo-°
pathology Section
3, Bethesda, Merylsnd
4o Saise as HlKDB^Sl (c)
PHS - «IH
Individual Project R^ort
Calendar Year 1959
Part Ao
Project Title: Electron HieroBCopie Studies on tissues of
the Sye, such as Splthellum, Fibers and
Capsule of the Lens, Epithelium of the Ciliary
Body, the Optic Herve and the Conjunctiva.
Principal Investigator: Theodor Wanko, MoD,
Other Investigators: Hary Ann Gavin, MoSo and
Ludvlg von SalltBann, MoO,
Cooperating Inits; Hone
Man Tears (calendar year 1959);
total: IcO
Professional: Oo5
Other: Oc5
Project Description:
Objectives: I) fo investigate the nonoal characteris-
tics of lens tissue eleeaents as seen in the electron inicroo
scope, 2) to investigate the ultrastructure of the lens
epithelium and the lens fibers after cataractogenlc agents had
been adninistered , 3) to esc^aine human cstaraetous lenses,
obtained imnediately after operation, in order to gain insight
into the submlcroseoplc cellular pathology, 4) to study the
morphology of the ciliary epithelium vith the electron oiero"
scope. Information on the ultrastructure of the epithelium
may lead to an understandixig of its ^metioa, and particularly,
its role in the formation of aiqueous humoro S) ¥o study the
normal characteristics of human conjtmetlval ultrastructure
vhieh should serve as a control in examination of pathological
tissasfic
Methods Evaployedt An BiCA eleetron mlcroseoptt* Model
EMi°3C, is used in these studies o Control and coa^arative
eKaoinations are carried out with the aid of phase eontrast
and light mieroscopyo Ihe tissues are obtained either from
the anesthetised snltoal and iisEBedistely ioaaersed in the
fixation msdium, or fixation is started in sitUo Biopsy
specintens of eon June tiva are imoersed in the fixative isaned*
lately folloi^lng exeisiono All tissues are then dehydrated
in alcohol, dissected and eoibedded in Methaerylate« For the
past several isonths araldite, an epoxy resin, has been used
as an esdjedding stedlunt parallel to Hethasrylateo A satis >
factory procedure was developed only after a long period o£
eaperinentat lotto Prellolnary results indicate better preser-
vation of the tissues as coaopared with Hethacrylate. Sections
are cut on a Servall ultrsaiicrotome and transferred to col-
lodion filmed grids covered with @ fine carbon layer.
Major Findings;
lo Korii^l Lens
fhe electron microscope study on the general cytoardhi-
tecture and on the pattern of distribution of fine structural
eleaaents in lens epitheliua and cortical lens fibers of the
normal mature experimental animal (rat, rabbit, guinea pig,
calf, Shesus monkey) hss been concluded o These results are
contained in last yearns report »
A Joint investigation with !>r„ Ro A^ Resnik (Section
on Bioeheiaistry) dealt with the fractionation of the cellular
coisponents of the leas and the isolation of cytoplasmic stmc"
tures, which from their appearance under the electron bean have
been termed "low density elements." fhese structures vera con°
tained exclusively in a supernatant obtained after centri-
fugation for 16 hours at 105, OOOxg in 0o8^ sucrose^ Accord-
ing to &r» Resnik' s results, they repre8ent~the product of
interaction between the soluble lens proteins {alpha-, beta-
mtd gaasma~crystallin) and the fixative osmium tetroxldeo They
appear as spherical and f ilamantous structures of 100 to 120 A
diameter. They have been observed both in sections of intact
lens tissue as well as in sections of & pellet obtained after
fixing and sedimenting the supernatant c A farther s^aratlon
and morphological investigation of the individual crystallins
was attea^ted. The results at the present time remain iaeon<»
elusive, since alpha °>, beta- and gamma-erystallin are in
reality generic tenos for con^onents which conprise several
not yet separated and characterised proteins,: Therefore, tbta
study on the soluble lens proteins has been diseontinned for
the time being.
AC present, & study of the lens sutures is beliag
esrrled oist« They represent an intricate system of Intar-
eellular relationship, snd serial seetione may provide in£or«>
nation on their three dimensional arrangement o No major
results are yet available u
2, Experimental Cataract
X^ray cataraet; In addition to the groups of lenses eaEaoined
4, 10 and 14 days after eKpoststre of the eye to 1500 R, as
deseribed in last yearns report, a series of lens epithelia
was studied 24 hours after the same amount of irradiation.
This experiment Indicates that the first morphological changes
include displ^ces^nt of nucleoli, conical ts^ering and
elongation of mitochondria aad partial disintegration of
nuclelo The present observations were Integrated with light
microscopic studies. Gradual changes in fine stxuetores in
the lens involve the following structures in the following
sequence; nucleoli, mitochondria, nuclei, endoplasmic
reticulum, l<m density elements, cell membranes. The Golgl
complex alone remained unchanged during the time intervals
studiedo This project on early changes of lens epithelium
after Roentgen irradiation has been discontinued ,
Kyleraa cataracts <2f4^6 weeks) ; . Further studies of the
initial phases of myieran»induced cataracts added no new data
to those obtained last yearo The changes observed are 8ome>
what similar to those seen in later phases after x -irradiation.
At the earliest phase, however, morphological changes are too
advanced to provide information as to which structures in the
epithelium are first affected »
Mimpsine cataracts (5~7«14 days)g Zn addition to last year's
data it can be reported that initial changes in the fine struc-
ture in these lens epithelia involve the endoplasmic reticulum
and nucleoli, both structures of a high ribonucleic acid
content <, Later, mitochondria and nuclei also undergo severe
changes c
3o Boman Cataracts
At present 7 human lenses with senile cataracts have
been obtained <, A fe^ specimens fr<m two of these lenses have
been examined. It is noted that human lens epithelial cells
contain the usual cytoplasmic constituents in an arrangement
similar to that obsenj'ed In the mature experimental animal.
Zn human lenses one striking difference is the presence of on
opaique conglomerate, usually located near the nuclei, idterein
at least two different eoa^onents can be differentiated. One
is represented as a round, dense homogenous particle of
ca. 200^ in diameter » The other is a dense granular
formation of sisal ler sisso Several of the Isrger particles
are closely surrounded by a quantity of the gr@msles„ No
distinct boundary between this eoxigloiaerate snd the sur«
rounding cytoplasm man be diseemedo This eoii^>lex bears a
reseoiblanee to eytoplasmic inclusions previously observed in
adult huiQsn skeletal lassele fibers, capillary endothelitsm
and heart imtscle of aged hunmns «^ere it is otost abundant o
The structure, at present, is tentatively identified as a
lipo&ascin-type of pigsoent; a more detailed escplanation of
it is contained in the report oh the nsisgle biopsy project <>
The parts of the project on the lens eon^emiog
myleran, siiaaosine and husian cataracts will be continued.
4. Ciliary Body and i^tie Nerve
Both projects have not been continued during the
last yearo
So Conjunctiva
One normal and five pathological (Sjogren's syndrome)
biopsy speciisens have been collected so far. Their pro*
cessing has been started c No foajor results can be
reported as yeto
Significjance to Program of Institute; Based on the
previous study of nonal fine structure of lens, a consider-
able amount of inforomtion on esperiiaental cataract and
some information on human cataracts has been collected o The
investigations revealed that the reactions in the tissue
seem to be specific to the type of catsrsctogenic agent
eiq>loyedo After further collection of data cossparisons with
changes in human cataracts will be possible c
The study of normal human conjunctiva should serve as
a basis for investigations on pathological processes in that
part of the eye^
Prtyosed Course of Project; Observations on human and
experimentally induced cataracts will be pursued. The study
on human conjunctival tissue has been initiated. More mater-
ial on both projects will be collected.
Part B included: Yes /x7 No /"T
Serial NOo WIMDB-104 (c)
PHS -o NIH
Individual Projeet Report
Calendar Ye&r 1939
Part Bo Honors, Awsrds, and Publications
Publications other than abstracts from this project:
Wanko, T. and Gavin, HoAoS Electron microscope study of
leas fibers. Jo Biophyso Bioehemo Cytolo, 16s 97 -102, 1959.
Wanko, To, von Sallmsnn, L., and Gavin, MoA.: Early changes
in the lens epithelium after Roentgen irradiatioUo A eor«
related light @nd electrcm microscopic study. AoMoAo Arch.
Ophtho (In Press)
Resnik, R„Ao> Wanko, f. and Savin, HoAoS Observations on a
cytoplasmic coiiponent in lens fibers. Jo BiophySo Bioehemo
Cytolo (In Press)
Resnik, RoA», Wanko, 7. and Gavin, MoAc: Observations on
the lens protein alpba« and beta«crystallino Am. J. Ophtho
(In Press)
Wanko, ¥o: fhe crystsllin lenso Electron microscopic
investigation of the nonaal fine structure mtd of «xperi>
mentally induced cataracts. Esdiibit at the AoMoA^ Meeting,
Atlantic City, Ne» Jersey, 1959.
Honors and Asrards
H<morable Mention " by A„MoAo for e^ibit on "Ute Crystallin
Lens," June 1959, Atlantic City, Ne%r Jersey,
Related Publication
Gavin, HoAo and Lloyd, Bo Jo, Jr.: Sbiives of high silica
content glass for thin->8ectioningo Jo Biophys, Biochem.
Cytol, 5; 507, 1959 o
I, 1959
CLIRICM.
Oi Chlr®8 Go sad C«agh<S7, Jo So s Skutll eh«at«0 in «i«he««i cas^
of dyserisphi® Bjr^e^alAo Acta SA4i<»l^ic»e la pr«s«<,
Dr«s«?s 6, Ao sod Shy» So MoS 4 ripr^diaeifel® a^ursl^ical
H^rvatbs Bo, Mi(qu®le, Jog Klats®^ lo asd Frece(sr, Jo BoS Ihuim
chsnical 9t«£di«« ®Oi snsscltt p?@£«inso Heurology, in prttSSo
B^rvaehs Bo and Pr^e@r, Jo SoS Qu«8ii£l£a£iv« studies oo eh«
»itl<9a e>f %etr®phic suscleo Prsco Msoco E«So Harvo
:o Mso, in pr^isso
Iirwia, Eo I.O md iaith, H» J.s Ch@ll»e9t«rA9« iiibibltl««a by
g«lffis£baaBiti@ m%d lyc®tSBd.ai»o Bi®ch«io Phaffiios in prcaso
Ix^a^ Ro &,o, WdllSg Jo Bo and Smithy Bo JoS lb« <x9tter«cell@
tms^<mm ®f directly ctiewlseed auscl« «fe«r 8^4mlsiimttmti<m
&f nsu?«aHiscuiAr blocking csa^miaAao Jo Phacao «ad Saparo
fh@r«i»@u£ic@ USs lS9e l939o
Xxvlae &o Lo» HftllSe, Jo Bo <aad SsBleb^ H, Jog Th« «ff«c£ ®f carsaln
BsaMHoacttlar blacklo^ ceEgp«iimds on dlr^c^ly aeinulAtad Musclao
^ Cwragg and Cug«ga°Llka Aggn€eo .^naCerdsB, Slsaviar
Publishing C®oB po 395, l959o
Is«la» Ko Lo, »sllas •'o Bo aad SasitK So Jog Tli® affacKs @f
saloscfciva ii^iblel@« ®f nuscla «ad plasna ch®lln@$e<3r«sa <m
aaursmacular block o ?r@Co Sad Intarsaeo Sya^. ®a Bfyaa£h#n£a
Grsviao il^rthtsr Bo th<sam Publlahliqi C®oo 1b pseaao
Go Mo 8 Mbera, Ko Wo» S«^@l@£f, Log Hlckalaaa, Oo and
, Do Bog fba q»aael£a£lv« slgalflc«iea af tha gaau^
aalm^bueyrle acid paehway lo carabral axidatlva awfcaballsBo
la Ssbartsa «> Cldo^s loblbltlott la tha Manwwia Svmtm aad
^a^a-aadaabtttyylc Acido l^dsop P«rs«<>»a» la pr«»»o
Go Ho and Towar, 0, BoS GaaaM-aninebutyrle <»cldg a
subfltrat® f@r ®Kidatlv« wmt^b&liem @i ems^tsl c@rtaxo Mo
Jo Physiol o His 36, l959o
= 2 -
Pat«r«8 So Lo md twme. Do BoS Olu^aiie «eld aad git
■•e«lM»liMi in c«srfll>ral core«s aft«r Miisuras Induced by
■eehieaiBc Anlfosiadaao Jo Hcus»ch«Mo ^s» 1959, im pr«ssc
Sswidy, Po To mA JLlima, BoS ¥h« ttffece of •sditsa l9«dli« «ffi^
£«adli«l p«ri«dic pKalyais, iteo Jo Itedo^ lo |»r«seo
Shy, Go MoS S«a^ ssEj^bollc and 9aa&critusl<a^ie «8p«cts ®f dl«@7d«rs
•f striAtftd nasclso Prsco Aa«<9Co R«So Hervo Iiisaeo DlCoc
in pr«s»o
S(9k@l®ff8 Lo» Lass«n, Ho Aog tIcKhasa, 60 Mog f<9Wiy, Do Bo and
Alb«7S, Hog Effects of pyffidmtine iriehdrawal «n c«cdbcal
drcttlatlsa and eataboliea in a pygidogina° dapandant childo
I73g 7111, l959o
Tiswsr, Do BoS It^a af facts ®f 2°daoay«d°gluc®«# oa aatabolisa of
©lic«s ®f e^rabral cortex ineub«t@d ^ SlSSS" ^^ Baurochanc
^3 l8Se 19580
Towsffg Do BoS Gitstsaaic acid natabolisM in ■«— laltan central
systeBo Po 213 In Brttek«« Po (ldo})3 Biochgtiafegy ®£
Vo 3>, Laatdon, PargWKSo, 1959
■veua Svatan <IV Istasnato BlochWo CsngCos
ParsAMso. IS
, Do BoS Sana neureehaBical aapaeta of cortical n««r<gbi®iogyc
In Schad«» J„ ?o and Tfl«ar» Do Bo CBdSo^s Sfenictura and
Functi<ai of Jh£ CarAral Cortas C^nd Intamato
bioloK i
EiS3ivl®r9 in prassc
TowsTp Do BoS Iha adainistration of gaaaMi«>aninabtttyric acid t®
nans Systaaic affacts and aaticoavulaant actioab In
BebartSs £0 iMo}% IiAitettion in tha Barvwta 8yat«a sad
=^l^HSXS^ isM. l-3odsn, Per8«Mn» in prasso
Surgical, Bang@logy Bjanehs
Bach, So, Baldwin^ Mo and L«wi»a SoS S&a» affaeta of isltrahigh
fraquaney ®B@rsy on priaftt@ car^rsl activityo Pr®Co 3rd
7ri<=-S«r^ic« Csiaf 0 on Biological Sffacta of tSicroifava Saar@ys>
in prase o
Baldwin^, MoS Surgary @£ epilc^syo In JacksoQe lo J. and
Eo Ko <Ed«o>8 Pediatric Manroeurgaryo Springfiald, Charlas
Co Th«naa, 1959, CSiapo SSLl^ ppo Sit- 529 o
- 3
BAldwlB, Mo.Bachg, So ssid Lsfwls, SoS thm <s£feec« of ctsrtala iradl®
fr«quMicy «n«xiy <sa priamf cmtsbtstl •c£ivi£yo Hcunsl^syp
la pi
Baldvia» M., loswise So aad BAcfag SoS mia Affects sf lyssrgie «cl<l
«feer c«r«l»ral oblA^i^Oc Keux^®l«sy 9g 469, 19S9o
, Ao SoS C®7?«l«ti«!e ®f eb« a»4ic«l cssdlcim «>f £h« off'
•priBg and @f th« <mt c«m» @f 4a56 prsgoBaelM wl^ Mt^nMl
»tAtm «3urie3 gcsfcatltsat, typm ®i dsliv^itry aad eooditi^e &t th»
iafaafcs dariai fi^At fdur dAy® @£ li£«„ Pai^t £§ Ocaographlc
duuTActsrlselcs and •uHMurisad result* si th« ln9«fleig«ei@ao
la pr«sso
» Ao SoS ArhiaasftcsphAly la aa iafaae b@m £« a diab«tlc
B@£h<sro Jo H»sr^atho & Expa^o Hau^oloe, la pircaso
Ao SoS lh« ^ec«as @f pregoaac^ la dlabaelc tnsaaao
fart IIo Aaalysls ®f cl laical abn^saalltlaa aad paeh<el««lcal
l«sl@QS la @ff8pris% &i dlab«eic s&eharao Jo Padlato, la ptm»^
Ao S, aad Balsrd, SoS the mitossm of p?<2saaacy la diabaelc
waaeao Wse% lo Fatal ttrnta^m^ aoreallt.y aad a»>rbldl£7 la tha
sffsprls® ®f dlabaelc aad'iK>nMl ceatcel aecharso Jo P@dlatoe
la prasso
9«kaMsi, Ao So aad Drasar« Go AoS (tefeaaeaaaa af ch« ratlnoblaateiM
t® eha ceaeral aarwMss ayatwto AdvlMblllty ®f a c(saiblaad
iB^raeisbltai aad lacraeraalal reaoval of eha affactad optic
msv«o AHA Arcfito CphChp 661 239o 19S9o
l^ar^ Ro £0 aad Baldvlas Mp s Vaacular Mlfomatiloffis ^as^clatad
»lei> £«»i^£'®l li^l»a epllt^ayo Jo Maurosux^r^e la prsaso
« Ho Sos Kurlaads La To aad Klats®, ZoS Aa laharltad dlaaaaa
siailfis' to aaifettofhiQ lacaral scl®T(mi® la a pateara of
poaeafflor coIuhb Itsvelvaaanto Aa. iiseessasidiaca £oxb7 Brala
||8 203, 1959o
Slaeso^ Xo, €ajdu®«k. Dp Co .aad Sisas, ¥oS Svalaa«io& of paeholesleal
fladli^a la tf»alva easaa of Kuruo laCo Sy^o of Actual
BacaphallCidaa, Aaewacpo Balslua^ la ptm»o
lo» Horvath, Bo aad i^el, Wo KoS €fb^@mtvmtt&et» oa syoaln
la tit® ^sist^.'m^ mapG.1% vi&ittg iln^s^^cmt aatlbody taehalco
Assoc o Saso BafVo Mirafco DlSo, la pr@@So
» 4
So JoS Oi»e«rvatiotta on th« «f f«c«s of h7po£h«E«dA
brain lcsi<»ao /m<, Coll, of 8ttrs<>» Sueslcal
V®lvam IS.
i, go Jo, Klae«@o lo and Baldvia» MoS EsperiseaMl study
of th« «f£«c£s @f h'^othemiA oa local l>x>ala iigaryo
in press o
Li, CuS S<onc praparfclca of pyrttsidal
particular rafarancft to aaaaory
Us 385, 1959 o
Li, CoS Coreical ineracallular potaneials and ehair
•erychniaso Jo Siaurephyaiel . Ut 436, 19S9o
Li, C,s Synchronisation of unit activity in the c«r«bral cortdXo
Scianca IMs 783, l959o
Li» Co and Chou, SoS Iid&ibitory intaraaurooaa in tha
In Cenfar«ac« ®a Inhibition of Caatral Ver^raua Syat«a and
Cana-^Aain^Butyric Acids spcnaorcd by tha Mr Force Of fica
of Sciantiflc &aa«arch, U&AF, Haahis^toa, So Co
Li, Co, Snsal, Ho Ko aad Slatzog loS S«a».pr<sp«rti#fl of culturad
chick akalatal saatcia uith particular tafaraeca to fibrillatien
potential o Jo Om^o Call Physiol. SSs 19S9o
Mi^ual, Jo, Horvath, Bo and Klatso^, loS A> ehroMtographic tachnic
for tha quaatitativa study of the prseipitin raactiouo
Jo laauaolo, in prasSo
Pimia, Fo Ao and Baldcfia, MoS (ftearvins ear^ral saisurea,
ABo Jo Nursleg i9g 366, 1959 o
Rice, Eo Co and E^ekiiban, Ao SoS Coogsnital haBiplagia rasultiog
fr<» cerebral aalfesaatioao Mk Archo Pathology Mg 348, 1959 c
Van Buran, Jo M,s S«aa autoasaic coac«aitaata of ietal autsMtisno
Brain 8ls SOS, l958o
Van Buren, Jo MoS A projection apparatua f®r hunaa nettroanat<snical
reconatructiisno Anato Record, in praseo
Van Buren, Jo Mo and Bargaaetal, Do MoS An avaluation of graded
hypaphysectea^ in eun » a quantitative anatsaical and functieoal
atudyo Acta Aiwteaica, in preaso
- 5 -
Vsa Buffcos Ja Hof, 9®Tst», Wo Hoe Hall, Ko and ASaaa* ttersca, CoS
thm «l«ct?<9gri^ic £ceivi£y of C9®l®<i huana frea^ttl leb«
«ad its r«Sip«iBe« £e h^«t«aa£i«Qo Jo K«isr®avt7So » in prseso
¥Aa Bur«o» Jo Mo Aiad T«kflivl«v, P. ICoS Cseiasctices of eh« to^oral
1^« in sano AeC« ^oAtoaien, in p7«s9o
Ophfchalaelegy Bgaachg
G«shane> Bo goS g^esioantal intraecula? vwtsgrapbyo iBM. Archo
6i»&eho» in psttSSo
0 Eo MoS A r«p®;e of «n ususti£l fl«lf°inflice«4 «ye
injury <x iSSA Aseho Op&tho^ in pr«sSo
, So Ho cad Gosdnang CoS fb« €ilac£7«e«£iae3raB in
infaa«il«« la£« infaatila mad Jttv«nil« aEUturoeic faaily
idiocyo iffil^ Arsho G^htko » in praseo
, Eo Mo sa^ Confeai, So OoS fb« ap«c»«l saasieivicy of
colo^daf«cti^?« safejieeea doeostsinsd by oloctrorotioographyo
AHA Aseho Opla£bo 6|s SS, 19S9o
Fsaoks Koe Fuecees,, MoQ.f.^ and l^ssOp ?<> CoS ¥®leas«»claBp of
@aao Sci^sc® l^s 38» 1939o
?u®st;«a, SfoGof oS latagYaeivtt G»disai«BM in tha narvsua ayetaBo
SsssSo Sa£o Us 213, t939o-
Fu®s£esg, MoSoFoS M8s«aei»ae«ss pofeaaeiala «wek«d by suatainad
illv9Biaa£iaa ia tha ^a of Lii»al<8»o Areho i^alo Biol, 97i
243« 1959 o
Gs^in« SloAo ead U<sy^„ Bo JoS Saigas @f ailies &&&t«&t glaos for
^in^scetieoij^o Jo Bi^hySo Bioehaso Cytolo Is 507, 1999o
Ho SoS Prleaasry fasiilisl assyloldoaiao Aoao Intmrn^ Hado,
laps
Ho So mS QalSmllo Lo AoS Phama£olosic«^ atudiaa of
pyriBaehanina C^asra^7l«> in autao AHA Asrcho ppheh. Us 885,
1959 o
Ho So, E^a£^eo»* Jo, liaison, l^o Lo and Jac@ba, LoS
Salativa ?aeiaci»ee of slo»»er«9lQi aeraiss of gosbsplaaBta
g@esdii t^o pyri»8%I»aina (BarapriaK AHA Areho C^heho 6|s
Mi 9 l®S9o
. 6 =
41«sssMelc «f find.li«l psimry ssiyl^itdteAieo Mo^ Sq^o Jo
Medos in press »
Eo Eo3 Sp«cl«» vairiAgi«« ilk thtt «wyiM ceoeeae o£ th«
cdTo^i «|>i£haliuBo Jo Cttll and &mpo Physiol o J3s 314« 19S9o
Ko log A aBicr@«hflsical study @£ the dsrvAlq^iag ^iphyscal
plaeso Jo ®£ bcoe & J@iae But^mtjo io pi
Ro So aad &au&B«a, Ho loS A edcr^chaeiical sEudy of eh«
iwaor oosysBft-preecia iffi£a?rftl«ci€iaSo AMA Archo Ophfehos
in pr«8So
SUihlafiSs Ro Eo «sid R«sz&ik„ Ro AoS Sae^ie «eudi«9 of 2»ircadi«tsd
c®tn»A sad l^ss vtth sp«cifil fsfsrsecc £® glutahi9ta« r«duetfts«o
Bl®chaao Jo 72% 261 « 1959 o
Kuhlasa, Ro So and Rssaik^ Ro AoS m« @xi<k»ei@Q ®i C^^-labslsd
glucssa aad lactate by ^« ssSb^it c«?@aao Archo Bioeh«ao
Bi@phySo, in presCo
Lels» P. ?o aed Gtiasm^ Po AoS thm t&lm @t asural aechaaisas in
tha r^u&a£i««R of inera®cular ptm&saTm la £ha ca£o Sicparo
Hausoog in p7«sso
Pat@Oe OoS Angioid aeraaka and aickla call anoBia, (A rapoct of
ttm eaaas.) AMA Archo Ophtbo, in prasao
Pat^n, Do and Th<ssMa» La BoS 3iaultaae®u« occurraaea of eh« prinary
aalignaae aalaaoBsa of «he «ya and eba akiUo AMA Ardto Cpheho
6|s 64S, 19S9o
Raid, Mo Eo agtd vae Sallmeaao LoS iSutiritioctal atudlaa ^eh eha
guinea pigo ¥Io Trypesphaa <«i£!i ^^la diatary niacin) o
Jo of Hutritian^ in praaa.
, Jo So, Jacabfifi ho and Efiu&ume He loS Malt eoa@»
plasBoaiSo liaif Sago Jo Medo, in pr^So
Raseikg Ro Ao and KanesSe So BoS hms ps©t»iu»s IIo Iha afface
of pH oa alpha csyseallino ^o Jo C^httXo M° ^^e 195^°
Eesnike Ro Ao„ ffaokOp Xo and Gavin, Mo AoS Obearvaeions (sn eba
l«»a p£o£«ins alpha and ba£a crys^sllino Aso Jo Ophthof,
in pirasso
R^ike Ro Ao, Wai&Os To and Gavins ^<> AoS Ol»sairv«ti@aa on a cyeo°
plaseiic c@a|»6nant in lans fihafSo Jo BiophySo Biochoso Gytolo,
in prasso
» 7
«l^a ehyme>tsyp»i.wio Tr«e«o isu, 4ca4o Ophtho Otdio, la prasso
JuaceivAo Traoso ^o Ophtho Soc,, la p;««Sa
voa SalloAaae lL„s Ocular nfiaifeseagisaas ei ttmili&l ^saign
v®s Sallnaaae Lo, C«111em, Sx> Mo sad GrlsM, Po Apg MiaeAiiM
cAt«r«c£o Mo Jo Oplaeho 47g 107, 1959 „
^rsa Sallaaaa., ho, &ttid« Mo Eo» Griess, ?» Ao aad G«lliBS, So MoS
Trype(3ph«i^d«flci«&cy caear«c£ la su^ma pigSo AMA Archo
Qphtho Ms 6di, 19S9«
¥«Mkl, KoS Sea» db»9T9Atl€tQS oo eiie rsgiaal pet«agi«ls @i the
fisho Arcbo iCftlo Bielo, la pr«sSo
HAokOe ^o aad Gawiag Ho AoS El«ctr@a aie?@««^« s£u4fy of l«as
fib«;8o Jo Bi«phySo Bl^hSBo CyC«l„ 6o° 97, 1999^
To, ^F«a Ssllsaaoa, ho oad Govia^ Mo AoS Early ehai««s ia
eh* l^ms «pi£h«li«n &itmx So«aegea i7?A«liaei«Ni6 AMA Archo
Oph£ho« ia ps®A»o
El»ctg«>aaca{»halcBraphy Bgaachg
« To FoS IMilae«sral aceivati«a ®f th« nsMk^epecific thal4
•yse«a aad bilaeeral eoreical re«poa8«eo SIS Clia»
physsi®lo Us 219, 1959 »
e To Po «ad AjBeB« Marssa, CoS ^il^tlc ccei^ael^m of
slagls c®7feicAl osuroas Aad feh«i? r«l£ei@ct9hlp ^eh «l<8ctre»
aocephalegrsphic diaehsrgeso E^ Gliao K«u?^hysi®l'o llg
199« 1959o
^ria^ PoS Micr€»«l«c£r®d« iav®@eie@eieas ea th^ aechsslsas @f t'»3
•l«cfe£ieally iaducad «pil«ptif®ffB SAlsurea i'"*tt»tdisch»ss(f}o
Archo itAlo Bi@lo« ia pr««So
hse^i, Ro GoS SfediflGAtlsQ ®f saasefy aschaaiflns hy 0ul»c®rticdl
•tfuceu?«go Ja HAurophysiolo 22g 412« 19S9o
Hidaae ho sad AJmsba Mars«a, €oS Umitsry eaalyslA ®f £hc rsspoosA
«licit«d ia th« visiMl cmrtss. ®f c&to Ascho italo Bi@lo,
la p;«seo-
AjBOM Itarsfla, Co aad i8>xaiksm» HoS A S<i«ug« Atlaa CClioical^
Sl«ctns«tc«phal3ssfiphle Go^rslaeioas) o Suf»pl«aaafe Ho, IS,
iB6 C&iBo li«ura^yelel o » la prMSo
, Ao SoS Hffug^l^y of Zafascto Balfelao^e» HilU«» «ad
Ulikiose 19S9o
Shy« G, Mo «SMl iUlegas, Ro Do <14s,)g Dl»8r4»ga o^ ^«
Hotor B<Mroa (Vol. XXlDriXIe MSH®}, SAl£iiB07«, Mill
aod Wilkiase la pr«sSo
¥«v«r» Do BoS KwrochaaifttFif of Bpilgggys Sfigarf
Springfield. ai«?lee Co ThoBas, 19S9o
AHASPS, RlCQggniOHS, AHD JggI¥ffIM
Staff Ao9<sinmmt» t& galv«y«l£tgag
Dffo Caslne iyaeaa HasrsttB, Ssat^cter £a Cllalcsl Ileuc®l«i8y» €«©rga
Dr, Msifelaad Bsl^»iE»» Asodciata Clittlcal Profe^aer of
University
Dro Aa«e«t« So D«kab«a, (^•i»£«ae Pr«fM»s9r ®i: il«tt;®l®sy, G(^£$e
lJashiaee«» Uttiv«r9iey
Dfo Co Mile®a Shy^ A«s®ci«t« Clinical Fr#f«£<i«r ®€ li«B?«le$3rp
G®@ffs«e®«m Univarsisy
Dro Sisnald Bo tmrnz^ Msociata Clinical Professor ®€ Hsnrelsgy
Aa«eciae« Prefeas ®r of Bi®clieBl«ery
Univarciey
Dro Mai£laa&d B«ld>$ia, UoSc Haval Itedicsl C/^tar^ Baebas^^ ^o
Dro Aaaeola So D«ka!»«n« Gbil4r«&'a B@@?ita'l., Haslaiat£««3« Do Co
Dro Go Miltm Shy^ tloSo Maval Hedical Ca&ter^ B«^aada» Hd. aa^
Do Co 6i»«ral fieapleal, W^abing^tms Do Co
DTo C9«i»s> ^B^ »sr@ans 9smi4eate Sastanx 1^ 8@eiaey» i9$9c
Dro Bruca Eo C@ba&, Br@nsa Msdal far aidtibi£ &% ^esetiesaa Baaaegen Bay
Saciaey, 8«pe«i*arB 19Si»o
Dro Lttdnrig ven Sall»asn, iMCim Heva B^dal f@r 1939 "in ras^ssi^iis* of
hi® dia^iE^ishad mmv^im t» ^h^uAmtesy" o
Dro Dsnald Bo t^mr^ Chairaaa, Sactian on
^ad«^y of Nauralisty^ 19S?°1$S9§ Bditarlal B«ard»
Hauraiagys aod £i@€lb«saie®l
MTo Jay Bo Walls, Superior H^csm^llsimmt ^ms4^ I3IH» 19S9
Jaia^agf I to Bm@^^®r 31 e IB^
M®&lm pas® iffit© gs^at Motos^i© io^e®s
ei^ili^@d ^a@ as*® Isitl^atalF «l©p®@^iit upon idoals tisat hav®
l2a©c^ e^ls©€li.©cl iss iimtitiatl®^©. Parlia^sMaiy ngl®^ trial
©f Bsaatfes Idsacatiosg s^ W©ifar©a a^«3 t^ Ilatioaal Iiistlt?st©e
of i^als.
B^ha^iQr i© t&© outward ®:^r@@si@si o2 iatsraai ^aii
Ideal® eoBts^itete to tia© im^rovs^snt of iateraal valises, ^@
ii:it@r'mlisatioa ot as& i^al i^ tr^e^s^O'^sI^ acG@l®s>at@S %'
''ts'aditiosif, '* or an id^ai ^a^ tec^® a social crosKF^atioag aa
"iastltntios" isi its <mn wl^t. I^als ©ay !3®cq3s@ "?saeritt©a
Ia®«" la t^ie f®s® tSi^F as^ ®W52f© p€!^erf«ai tliaa aa^ ©tatutor^
regi&XatiOB, Most sosiai fes&avt®^ is g«5%'©rii©cl 1^ t&e fore®
of ©osial €©avi@ssti©S®e ^puiar id©al@o Mtfeoiat t^@d t©s 3.©gal
ist©2'v®2itioa, Idaal,® ©aa 1^ to© Idly ta&es or^ oss t^ ©tla©^
l^a^^^ fall isto la^srop^t®. T^i® l©ad@ to a d3t@rioratiosg of
asiteriiai ¥al.«i©s ^hlch In tii,rm ts r©f l©st®4 ^ a <^t©rloratioa
tn feslia%-io2*. Ii^al® te^ to "risis d®s?^il.I'* aM on tMs aseoimt
!Si©d to te ©ontiPiioii®!.? ©tri^^s for.
Ideal® asr© m^t oai^ i^ortasst liistoric for^s h^t th®f
®^&lv® hietorieall^, Hard~woE M^a® iraliis© ar© saf©g®ardf®d
asd ®Ht©^@d saaiislf thw&v^ tl^ ©if©Iisti©JB of disproved i^alSi
T© aoe^^pii^ls tlii©a ii^aie is@®d t© ©^©i^© at a rat© tfeat will
proirl^d e^ipr®te^iir©' ©tato^este of r®@©arelj progjr©s© ttermsgiS"
05st tls® ^ar, ■ I hawm att^apt©d ^i^ t® eoatl,!!^ a® ia tSi© t^o
pr-mvlmm /.aaRSal a^p©rta aa ©^loratiom ©f ®or® gesaral @©i©ati-
Tbm&® t^ad to b© aiF©rl@o^©d tn th® i^mdl&jQ^ a^
3®eMiig isrg©BS|^ ©f ©?ar daii^ ^ssj^rta^iKgd » ¥©t I lisii®^?^
tli®f .ai=© tsvil^ ^rtii^Bt to ©or tiltimat© te®t acSii©^'^i®at o
- a -
BiatG^ the GhBi^tng torc®& of cl^eis&st&ao©. C^S£^ i@ a ^riod
v^B ic^als do not a&aas^ ahle to Isdep pac^ '&itb social^, ©cosis^^Cs
political ai2d @ci@atific dianges «Mc& appear ls@yoad o«ir isisder->
etaB^^ or cost3>@i. 1% sa^ Iw tStat every period of historf
hsB this ais^ctj, F®t ours is SortimateXy the oqIst oq® tve ha^?®
to face.
.Altliotsg^ ws as^ inclined to deprecate altruii^Bo faith
ai£d mstual tri^t as ^ifig "umr^al" or 'ispractical^ '* we actually
liv@ b^ t^3@@ i^als. Maj^^s&d co^ld i^t lia^e ©vea lasted to
tM© rl@!E^ moiseiit witlio^t Sia¥izig ^v&lop®d steadfast biological
foiss&datioi^ for altr^^^e, faitis assd siutual truest. I'^ae fusictioos
ar© Imilt ioto oi&r cliaseiSs @o to speaM. These vital laechaiiiesKi
have eari^d for laa oisr biological ass well am social freedoB.
Coupled ^itb SLfa&smv^mQo such ideal® caa iiapel achievements that
will 0tili furtt^r enlarge hi^aia -digi^ty asd fx^edt^o It seoss
^>€®@@ar^ ualy to eocoura^ a greater awaresiaes of the oppor-
tiiMty J^fore u®. The rest irould Bema to follow. Isprov^s^iH;
ifill 1^ mea^red In "little pieces of the strivixag/* is asy
siogle act iptes&^d toi?ard the realisatiosa of aa issproved ideal,
TbiQ purpose of this esisay is to diiscisse certain i<^al@
relating to the pisreuit of ©cieoceg relating to the is&terface
esieti^ betimes scisQ^^ aad society^ a&d to the coatritmtioos
^ic^ @cieac© shoiald be ®aMag toward the es^oisragesieat of
irortli&er social p^rpo^s aad maosm. It ie say intentioa to
show tlat:
I. ^e selection of worthier vali^s In a c^ssocratic
eoGtetf deipends lapoa i^als conceived by individuals ^
especially ^ individuals i^ssessing training and
esperienc© in the dispassionate essrcie© of evaluative
eMlI@. Im. r^c^sit y@ar@ this process ^ich is essential
to de£socra€^ hae }^^n Qso^d a^id given a^ayo
2, Zn science there has been aa unfortunate rejection
of the iaportan^ of evaluative JudpaentSs and of the
^^irability of scientists contributing in a professionally
broad and respon^bl® vb^ to the detenaination of social
purposes and sieans, C^ly through an effective and di^
interested asfastption of this responsibility can science
escai^ fr<^ teiag a toy of technology ^ pitted against all
saQEier of ccBS^tltive special-interest see^rs throui^-
out society,
3, Science is revealing a ne^ ethic i@hich is based
upon scientific ratMr than religious or i^ilosopSiical^
grounds, ^ron^ these findings ^ science aay be enabled
to provi^ an increasing pon^r and guidance for'^life^,
lit^rty^, and the pursuit of h^piness.'^
~ 3 -
huB wm^ to offer sooietsr^ botli apas>t aad l2®|roEid
utility.
@. Wl&at ^©uld s®€!B to tm stoat Qi?g@ntly ?eQui3r@di in
all thim is Slrstg a more @i2c<oe@s£ul iaterfao® bet^eea
@cl©m^ and society ^ a^d sscoad^ a gzea-tor sosn^ o£
pro^essiosml, r®@p^B@iMIitf- a^d probity smoiig scieatlstSc
l^is lattar ^tll call fc»£> tSte rosiSBptioa of ©os^tJaias
aMs to th@ idealistic ssplrlt of cs>aft^!aiis^ip(, akin
^shup^g to th@ professional ssotio@ o£ & gudia.
All tiais wiXl r9Q«ir© individijsal iatsra&l acti<
w^IX as ac^isistrativ© cihaisg®® s^.lati&g to tlie co&ditioos of
@ci@sitiflo ent©7ps>ia©. Heitli®? ^® iadi^id^al iateraaX actioos
sior tiss a(g^Bistrativ€» chsangs)® will suffice uloiss. Buit they
ara ac^ie-^afel©,, to^et^ra as a aatural otatgrowtli of tii© ^ider
z^^cogEitloa ajBd ©s©rci^ of aaa*© capacity Sos- altarui^tj, faith
asjcl EUtual triasto
la a denocsratic c<^^m£ityo isSi^re caa srespoasiMlity l}@
pla^^d fox' fosfsiitlati^ asbd litproviog "^be ideals aad purpoees
of society aad its ii^titutioas; Doss tb© responeiMlity lie
isi tli@ ^^hit@ Hoisse? la tliee CaMoat:' la. tiae Gos^^ress? Iq the
S^sps*^^® Coiu*t? Si:^ tli3 eoi^i^iiicatioiis iiKhastry? la t&e ^a^^t^
plae©;' A^oag tli© citisEeas^ at large?
Improved t^ay@ o£ laa^dling society's p^dbl&StB iieed to
1^ eoae^ivod aad nad© a-??ailal3l© broadly t^roiagSiout society »
'Skwm^.gh tfe® actiois of political aad social a^ade^s^ e-volvi^
id@als will iffi£lf^@jG© tlm det^elos^ssat &mid improvement o£
society *'@ purpoi^s as^ ^aiBBo ^lo&g Vac most import aat jm&as
available as« iastit«2tioii@ vhleh th^sss®lv@a prepress tbrottgii
b@coiaiiiis more closely alpprosimatsd to tli® soble i<!^al@ for
wMc^ tli^y r$pr@ee3t am ©sbodiiaeBt, It is cM@£ly by tbi@
loaveisis^ of id@al@ tlia;^ society cai% be i^proired^ ai^ chiefly
b^ s^^asiss of iastit^ioES that i^als can h&cwm '*great historic
farces o" Each oi i^ ^ores reapossibility £or the choic© of
hoth ti&e eitda ami th)@ 3&©ai^ of oisr society » Desirably $ this
r©^poasibil4ty is bos'jss -^rc^s^ th© e^rcis© of iadividjaai
is%t©rps^tatioiiSo fo5r®?ilat0d a© co^scieatio«©ly aad ratioaally
as possible. Th±^ i@ e^seatial^ "bf diefiaitiosis iss a de^aocratic
cc^gsiTHity. Sadi'^id^aal deSaialt of cassci^nssc® ia tiiis pisblic
r^®|K5asiMlity Im «latrij^atal aad morally repr^lass^ible.
la additios^ to mwdh broad-baned iadi^idisal respoasibility
th®r© is also prof@s@ioaal r^spois^iMlity. boraa varioualy 1^
la-©yor©j> ^lysiciaaSp teacfefsT^cIeaflsfSo civil serv^mtSg aad
- 4 -
ot&ore; pro£e@@io£ml 3r@s]sos!siMIity wMcli i.m far kea^rler than
that borssQ 1^ ths citls©as-»at~l&rge/ Thlfs additional smepoii"
siMlltjr grows oat of tis® profe@sioii&I ^ills asd escperieace
o£ the i&divi^ai. Tlau^s! ^3 sciezitist® «e l^ar a pvotQ@Bi.Qn&l
respooeibllity bsca^s® of o»r first-kas^ kno^ledg® of the-
s&atur® assd i^taatialltie© o^ scies^ce. T3il@ £iaB^@ ns rs-sponr^ili^lc!
not osil^ for tS&e esicelleace o£ i£3-9^@;tigativo work for ^-liicls m^
ara sore or lom& ^iireetly ^H^spoQSibl®^ but ^l@o for contrilsti-
tloos oi pvotQB&lon&l i@@i^t aad effort toward aoMovii^ a
wor^lQr d0S!tisi|r tor oisir social aaiS isastitt^tios^l. ©sivircogi^iismts :
Cfer r@0pos©ifeillt^ ia tMs ^©r® iEclosivo pro-
i®B®i.Q&&l ®©Bi^ d©ri^'es qssit© Baturallsr fr<M tij© faets:
i> tSiat oi£r o9a protoButos&l destis^ i@ Isitimat®!^
SKK3a£<i u|» Mtis t^ acM®¥@s&9ats of our is^ediata
professional csa^moit^s 11) t^at tMgs gro»p ia tizrn
bas til® ca|»&oit:r ^<^ cos3:tril»uto mor® @ffecti?«I? to
t&io acMev®3ie£tt@ ot omr ©ocietiT^ az3i<S lii) tl^^'^ otss*
r©@pO!i@ibility for a sbasi*© in msSsists tM@ go ^eli
ia its ©atiret^ is iisgl©ct©d at oar owa ^ril^
iBdivi dually 5 ii^titatioaally asKi as a society i
Btmahow orgaiaissatiooal aad societal tbigise@s Ita@ isiduesd
a p^^oliological d^arfiag of tlto cosceptiosi of tl&e ooly proper
role of th@ i^di^idssai ia a di3aiocrac3r» The totra @e@tis^ id^al
ha© l^®£i lout to ©os^ dagr©®^ and individual respoi^iMlitjTg
e3p®cialiy iadi'^ldiial professioaal respoc^iMlitF^ h&B h&mn
QvodQ<^ asd giv<&s£ a'^ay. ^is idsal hzB b@©E @rodod i^ofar &^
individuals and i^titutiojm reject iiKlividtsai seBpomi.htM.tf
or fail to allo^ for it. E^^Jdction is of c<mrse encouraged
hf those ^os@ ^sstMtioE favors tl^ir o«a li2iit@d interests «
Failure to allow for it has two principal ovtslmn oasg a
lack of faith ia the williisg^sa or capacity of individuals
for beariag @ttch r^spoasiMlity; th© oth©re an ua^illiisgsess
to copQ With the cos^usioss that aris^ out of the i^idesprcac!
e303rci®© of individual rsepoi^ihility, Th^ ideal has Ise^a
givea away insofar as those to wh<^ it should heloag hav© Etot
coQceived th® sseed for or es@rcis®d suich respojisifeilitFt, or
heca«s© th©y eajoy respo^ibility that is strictly Halted
to th^ir owB iiKsediat© work^ or feecssss© thQf accopt a vi®^
of th^3ss©lv©s as helpless cogs^ too ineffectual or too
iaad©q«aat©ly ioforEied to fe© al?l© to essert aa ©fleet ob t&e
aaaaiv® asid ©lappc^^dly iaflealfele iastita^tioa or sociotF*
To th© ©xtsat tliat individual respsasifeilit^ and
©specially individual ps-ofessioaal re@poa®ilsility i© pr©©i5acki<^...
or avoidodg casr iastitrntioss asd society ar© mad© to d©pead
«p<^ ^adefflosratic procedssres. Hiis is perhaps aot disadvaa-
te^oiss ia ite@lf ia the e^ort viewg and ^mdsr a broadly
re@po£@ihls a^i ol^Jective leadiSrshiPs but it i^evita^ly
eatails two fiartli®r ©a^taatial ioss©©.9 both of which l^ar
». s »
iaportaatlsr upon <mr nitiJStat© iastitistioaai &^ social accesR-
plisl^oento Firsts tiiQwe i@ a Ig-^^ of W^ iJiao^ cos^ci^ntioi^
and vesposmlhl® i!it@lI®ctuaX contriSMtioaa wMc^ ot^r^i^©
coald laav© S2®©s ma«^ toward a ®or© d^©4s?al>l® ilsstis^, SegeosKl^
ficstioa acd Sioti^atioa ^ieh otherwise® d®s>i«^s from tte siaas-iss;
ot social reaiposisiMlitsr.
It Xm o$t@i2 mppsm^d that &Qt®ntX&tB d@al ra^^sr
©zcltisivelsr vrith fucts^ assd that tke^ eliMmte frc^i -g^is-
dalit^r&tioiis aisy eoieslc^ratioiis o£ ^'aims. It i@ s^pp^g^d
that facts ax^ a@@^£&ied Isj^ sciesitists asid @i3r8^eaatl@9«i im
^8 tl^QS
r®l&t&oa to ot3&@? facts^ ti^eii^stii^sa o»t of t^ esa^ssiEtio^
oS 8aci& r^latioias &mrg!& g^assraX ''la's® of £iatc3r@<,'* Msms^iSF-
©tiuadliise axriffiifsg fsroii tM.s suppo^ltiosi ^aj 1^ d^vast&tiag^
Scientists liafT® l»e& Mocked oi* di^y.si^d frost s^sj^sssibX®
positiomio in part at X©a«t <m tb^ BB&mptiQn t&at tlzsir
resu^Miag casa sad eS^ouXd @^at tu isoXation trc^ co^ssid^ratiosi^
o2 vaXua. Tkim pri^tiir® suppissition that scientists ^o^^ld
b® professionally obXigated to r@j©ct vaXt£& diaesrimlaatioeiiSe,
or tfeat t&ey ajf© iXi-fitted ls;r tb^tr ©eieatific ®^p®iPi®Eic^
to mafe® vaiii@ discs'isinations., r@ps^@9@t3 a oompXetoX^ inade-
quate coi^captiosi of both the eco^ asid s^-^od of sclenc®.
1» Ivalia&tions in science. It is tnsB titat in
til© factual mt&^ ot isgnisy scieatists ts^ to charactsiri^e
their ofesenratioa® la a fozm as free a© possible frc^ parsoiml
Mas and o^iaioa; thtm is aa ideal towas^. ^hich all scientists
stride o ]^5t faetSj, evea "^©ss idealXj?' ©stalsliehedo as^ ojsl^'
bricks frost ^hic^ the st^i£ctis£>@. of seieaee 1@ ds-^^lopa^, Ei;
thea^X^^So fact® tend to ^ uMnteresting^ ThB really @igm^~
ieant features of ©oience as^a eeta&XisSiM^d frc^ facte 'i^i^ &i^®
given aeaningg ^i^.^ ^ali^i, through eonoeptisal thisi^^.
2>'roa start to finish of ssky scientific problems
©cieatiste are essgaged i^ valtse discriminatios^j, in
co^sittissg ths^seX^s to choicee which se^ereXi^ deXitUt
whateirer may he the ultimate val^i© of t&eia^ ecientifis
a€»::QiipllslKBient« 'St^ '.ectiOB of a prol^Xe^ to stmdiTf^
choice o| ^thods^^ da- .o^s@nt of conc^ptisal and tecSiMcal
operational definitica^ att@Egpt© to isolate fact@ fr<^
a^tifs^cts and fro^ msdg L^^issg a@s«^ptio2is<, eelectio^ of
the©© facts pspesis^d t '^ ofeiJecti'^eiF seaaii^fisle i^.t©r-
protatioa of the factt data C^hicla asre isieiritahX^ cs©-
poanded of tJieoreticaJ 'sterpretatias© aad g©s^» pere^ptici*©! ,
» s «
As&d tlie ve{»a«^at&t4oa of t&eae cS&ta liad &siterpifeta%ios!@ to?
t&jQ i^iarposes af ssaaaingSial CGSBassoleatiLoa -» eacii step iia
scientific aj&aom^tkt^teBiswt roqiBiaroe valtse discslai&atiOBS of
a Iii8& or^r. ^ diSfeveaitlal eapaci%|r for baodU&s th^m
difficult diseriBisiatioias is tto pjrlmi.p».X distiactioss ^t^m^
truly great aad less®? scientists.
TitiQ pr6f@@sioa of @ci©@«^ t^r»fore g^aaade aa ©^srci^
of value dicca-iaaaatioagt and groyideg; a oontiBttiBS disi^plf^
ia giafeii^ oai^ ®¥aiuat&oss®. it eas readily fe© <«>f5^
tlsat oali? g©i©®ti©ts as*© profeseiosaily qualified to make
Judsnenta coQCorniag values tbat are latri&sic to sci&zK^.
3. Bvaiuatioas of seientista, ^11 of sci®^^ and
tecSmolosy Spends upon a oaall %ut indispensable population,
of creative scientists « B&sh m»m bs@ professionally discipli^^
to deal vith peeuliar ii^tnsaental d®vices« with el»stra@t tk^^s^t
at tlie liaita of conception, and Mt^ certain @eae?al prii^ipl©@
«liicb eiiX4o tSieir intellectual progression, ffbat a scientist
sees vAth his inetruBM»ats and ^at lie interprets free t^^
revelation® is l»y no &&sam o&vious. ^ Z bave written else-
where e> "^ @ore adequate t^derstas&di!^ of nature cao^t ^
achieved 1^ th@ B^tz^t; it mmt h& Itrou^t aibout t!^roug^
tise consideration of aat^^rials wit& «Mc!i t!ie scientist i@
already familiar « Iven tli@ ^^ost gifted and ei^rgetie p^reon
esist have acbieved a certain aaetery in t^ field of Me
pretsEi^d ©cc<»^li^»sents, @e ^ast bave a Iseen se^^ of
^at n@ed@ to l»e done to solve a given pro^l^s and a mSil-
cient s&iil to do t^at,<,,. S^twtaat scientific acii&evsa^nts
t&us see® to depend upon tlie fruitful cosbinatioa of a
of esmatially positive factor@| &mm of tiiese rela^ to
coopeteace^ eelf-discipli^ and niS8l»le iaagiaativeness of tiae
scientist Mssself and o^bers concern liis surrouadii^Sc
in laboratories of tbe Bsderal <^v@r^sent ^ill fl^isely
ia thm sense of advaaciisg t^ frontier o Am tlie rate of
advanoaaent a&y lie speeded up 3«^i&^at ^ si^^iiaistrative
hustUag or hf providiag additional @omy or perao^i^I in
a given field. But saltatory advanoeaent of
t^ IdLttds of change ia point--of-view tbat say alter
entire ^aracter and direction of scientific pursuit
of advaaosawnt t£iat say cut sbort years of
are not libely to <s^cur en^pt iriaere circ«aMStaacss are
especially favora&le for cs^ativity. In ^ Ions runs tia©
reputation and credit of any laboratory will de^ad upon a
few advaaeee of this sort far acre tSaaa upon tbe easti^on of
stu<aieg that w&u &smt entirely takHISr:
^le oreati^ of worthier new c(»acept3 in scies^ iis
is«>oseil>le with«mt intellectual non-eoefes^ity, ^at &m
' to he "l<^cal reasoais^'* evolves as a delayed
of scientific a^iievasi^nt; thi^ the ste^ in
- t. »
t^ f@?^aigi«m ©f a ^m? oc»»€^|»t s^t «mir £!!®@^ &li@&
qmutl^ mm "iUogieal,'* It
p3foos^s&B ysM.dk &S0 aot vmS&r s£^ ©ss-tlef astoiry <legE«f» &S
xfolwsit^xv e<m^^€»l, ^b&%w&Qt id©a@ iai9c»l««d ia tiM es^&tioa
&s ts"^® &B ^sii^i® frosi pdTS^QU^ ap^&Ie ccseTCioa^ or
o? ^rsntteiosg ajad ia sot ^isg <i@©ts>os»«d ^Flsoa
iBte?aall^ iacoseeistfial;; pa^adosioallFe eoieai
asd so:^ eolieroBt as ito liaitsd viosa ay»
f&» ^aaneti fo7 & itoi«atific Truth i^^ldk ean
li» realised) bec<^63 @VBr mor& pooorfiil aa oraror ia
.^mt^^^^s is oo^^est 9iti& ma^ otter oaXUa^s
^satesmlly es«at«»ff a imaX for lategrity; a lie ia
for it ^11 te foaad out throtigei t&e
of seiaaes, Sciaatiate are oro-
t®d to tlfte practiG® of 9r«^>ily«
tida r«g&rd oaly iasof er m tls@7 ara
to a^&Bdoa t&eir profa^ioeal rola ia soeietFc St
aloea are adeo^talsr ^ualifiad to evaluate a follow aciaatiat
smd bie aelsatifie parfoss&siacao Siaee acieatifio at
piiiteasts of i^lsli <i«&Ut|r ara the aiaie Qua aoa for ^
asaataaca of & aeiaatifie aataSilisS^iSf ."fSa^'Soda for
salaetioa wsA ^rosotfoa of seiaatieta naat b» baaad a^..
aoiostlf i<i o€^i<toratioa9 appUad by aeiaatiata keowMs^aSHm
.__ ^^ ^^ iadividaal aad hia fiald of l0araia«.
profaaaioM of seiastiata ia aaiqaaly firaovladseabla
the crita^ria aadarl^rioe tboea diaeriadaatioos
^t^ aill f Qatar S9mls» acieatifio excelleisoa. tbmw etloaa
cea prs^wat t&a frea<S€®, tribi<^ craativity raqairaae ««»
haixm WBod as a aiaaltar for iaaffieiaaosr? aaparficiality or
aacritieal partiaaagOdpo Seieatiata ara aall avara «iat
^' ?*if ^'^ profoaaiott doaa aot provido tbaaa diacriaiaativa
aTalttati<^Be tboy aili aa^rtbalaaa ba aada by
- @ «
^&f lack the mtcesaar^ qu&li£icatioas. It tMs amssB about
Ctli70«2g2i c&@uai£i®®{5 os> default of; the ©cieatists coatcevoeds^
or b^ direct iosi oi persoEis uaf ami liar <srith th& values aad
conditiosKS ®@ee@ti&I to pvof^mslo&Bl ®^c&llmjs^@} p th© r@sisXtisig
action® are certeda to br©®d @«iispicion aad controversy tJiat
Mil t3s@ deeply iii|juricm@ to the iateraal order a&d to thd
exteraial stasidii^g of ti^ l,2^titutioa<.
3. ^valuatiosss of scieac® ia relatioia to goci®ty»
Science coasisli~of a coriectiosTof iaSofaaiiong a~l>o^ of
tlieory aad a a^tbodolo^. All of tb@ disciplines of science
ebare in tlseir dedication to certain geiaeral principles of
is^uiry and evidence: this for^s tSie only basis for tbe
«snlty of science o Science is one of the fe^ creatii?®
intellectiaal activities t^at is truly progressive. Theo-
retical siotio3ss tested and fcmnd valid are of use in tbe
^^g^^t of furtl^r ynderstas&ding. It is this progressive-
wsms wlaic^ gives science mucSa of its po^er, i^ further
so^arce of power derives frc^ tS&e scientist®' internal
disciplii^ alws^s to ®ee^ sisipler and isore general
es^ressions to accoiant for the vast scliea&es of nature.
Since World War l^ science has bec«%se do^iinaat in
generating and directing the developaeat of technology.
In earlier yearsi, the relatione l^tween science aad
eapiric&l di8CO¥ery W&-&S sporadic^ ifith practice influencing
theory sor® cftss than the revearseo Since World War II o
science and technology have been move and more limped to->
gether, Iliere is aom developing a widespread concern
within the Saecutive aad Legislative Branches of the
GoversK^nt regarding the eistent of tolerance to be allowed
for the "tyrani^** of ^ich science and technology seen to
be capable, ^e question of ho^^ i.e^g hy vh<m and by what
criteria science is to fee ©Talisatedj, is acute a® well as
Important.
Several serious problens need to be addressed:
How does science need to be distinguished froan tech-
nology in terp^ of both its plaiming ;'and realization;'
How can th® i intellectual content and poi^r of the
educational aad research activities cf science be
strengthei^d ^ CHow can the mutual is^terdepeadence
of scietice and the huBsanities be aore fully recognized
and laade effectual ) 9hat branches of sciea«^ need
emsourag^ient for the isa^diate and a^re distant
scientific and technological advantages of society?
(How ca^ scientists best participate in the social
value detsermiaatione this requires > How can progrsuu
developg^nts in science be generated and encouraged
aojre in accordance with professiCMial scientific rather
than slHply political and econoeiic conceptions of need
« ® »
aisrti o£ research pot@fftti&iv £^ a ©ei^Qco n^xt ot
limited r®aow^G@mo h<m csm th® t®M0mQ^ for ec!gap®titlve
ovesr~jT58ti2icatiosio fos? "tf ramisi^g with facts" fey
scientists be dl@co32ras:®dv CEow can si^gI^ fortJarig^t
sad natural traits as professioi&ai coogruity asd
csmdidsi^ss te giv@£» ^s^@i&t@s> es£com'ag^se]at?)
F@w of th& afflsvers s«caisssesac!®ci for th®^ prdb.
hB-r® lm®n piat to aj^ test. Thie pro^l©ms th^aselvse aye
aot di^stiB&isg; tli©y as^ g^ttiisg wor@® as public
a^ n^eds ar© 0:Kp>a5idiiis aad as comi^titiom Iseyood the
cositrol of cMsr scciQty is ezaertiog && avalaocbe of pree^iur®®
OQ o%s7 t@cS^sioiog^o "^e^ p£^!»l.essi3 Itiav® !^®s& addressed %n
different ^a^© aad with p^rl^a^i^ gr@at®r deg?ee@ o£ ©t£cc@&s
ia @as^ other democratic co^usiitieso The Waited States
cloarl^ hSLB oo raonopoX^ o£i cifeativity in stcieace aad m>
siiiecux^ on ^ays for tli© l^st utiliEatiiOQ of such tsil©at
£or iMpyovls^o 8afegtsas'di£ig and realisi^ a better d@@ti8^
foT aaakiad.
We used @p®edil.F to brissg the®© ieisuiss to mox®
©hjectiv© aaaiysi® a^d to mj^k o^t waj® for improviag th®
ifiit@s>dap@ndeiat worisi^ s^iatiosss h@ti^e®a @ciesto® as^d society.
To this ®ad„ there is a^ ia|>erati7e sseed to stop erodiag
and giving away the heart o£ professional responsibility
^ich belongs to scientists.
Fo^s^r and "stealth are actively sought; technology
yields poser and li^alth; technology is dependent upon
science o ?et becaui^ of vast discrepancies in their
relati^?© coste^ ther® is a danger that science p
lUEsped tog@t^r -^ith tedb^^logyg will be conceived a£
ridii^ on th© co&ttails of techs^logy instead of the
other way armmd.
to mak© a fre^ analysis of the role of
Oovera^ental Institmtioss^ bearing directly or indirectly
a
for democratic Qove'rss^nt i^ th© lat® ISth and 19th centuries^
^h@n science was a'isBgligiM® factor in th@ healthy 's^lfare
and defense of society o @ay r@q^re revision no^ when
science has becoese ^o prcmis^nt ami indisj^nsibl®. It is
mandatory that any institutiCHsal revisions be performed
with conscious delil^ration and wisdo® instead of si@ply
by improvisation. Our Clov©rss3©at will es^oy wisdosj in
its councils to the c^gree that it can understand and
foster islsdom and can distinguish this trosk the caco^o^
of liM.ted->iBterest appeals. Decision a^ng« in areas
relating sciesaoe to society^ iS^aId^^_as earefuliy ogjec^
HWied as'"ar®_lh© i^isioES and interpretations of the
SupreBse' "Court iffi~th© ""field" of "la^.
It iB @^id@3t t&at scioetist® are i§@@di@{| m»t osily
fos' tia© ©valuations of eeiesseg of ®cle»tl.@tis aisd of
@ci«gBtific pertoim&ssi^o hut also^ as part&cipuJStB isi tt^
difficult J^d^^&t&l ©valtsatioi^ r@Zati3ig seiesc® to
society c "Ha© J sue® i3©@d&d a© ftili and r@@po^til9lo partic-
ipaj^ts througlioat t^ daeisioB g^E^iag process©® i3i7olvod
la th@ coaceptioa &&d re^alisatiosi of society's goal®.
Aitboisgh all ^f thte se&aB p&tmtSitlf tr»@2, w^@^ it cas^&
to practice tli^sre ar@ obstacles « Sos^ of tii@^ &xl&&
out of t&o tendency to deprecate t^ scieatists* trainiog
and capacity for aakii^ evalnativ® Judgments. A ^eccmd
ol^tacle results frt^ the eaqptectatioa that @&i©Bti:^ic
vali^s are to he measored according to @ar^®tpiac® iraltses;
that what is scientificalisr ''good" or "bad" is deten&ined»
as are so msu^ other social v&l^msi, hf Bcsm Mnd of seal®
of popularity;; throu^ personal suasionjj coorciong or appeal
to esstsmal a«£thorit^o Sose scientists ma^ b® persuaded
into a degree of confoxmit^ to this expectation^ especially
when it is held rath@r imifoxnlf laty those controlling the
snpports of science « Bespondia^ to such an sspectations
scientists aa^ esepx^ss the goals of their scientific
endeavors entirely in texmB of tochnological &nd ®arhet>
place considerations. Thia in itself i@ a principal
ohstacle to the oaltivatioii-' of high qv^'ilt^ science. It
is a barrier to understanding of the aatnre and scope of
science hf a ^der pisblic.
Tb& ^^r®e to ^ich scientists »ak® vim® of "a
tyranny? of facts" or other liaited-isterest techniqt^s
"^ich ar® forelgsi to a profesaic^ial scientific code., is
a B^asure of their failure to Qualify properl;^ for hearing
their ^alid professional responsibilities. It is not so
m(Kh that the facts and concepts of science ^i®d~trai^lating
for the p«gri® as that jfee pngposes and sy®teiB of yaltaea of
science ^ed trai^latingo
WE moufitos OF mmm ^alobs
Ivolutionp ae ^pularly understood^
conflict as tk® priiscipal fulonsn around ifhich o^trolutionar^
progress ta&©@ pla&^„ It de-«i!&asis®s altzuLsss and co>
operation as contrifi^ting importantly to evolution, l^m
popular derivations fr^ the teachings of Darwin and^ inc^eed^
of Mars and I^ecd am wells gi<re ^tm only half of oi&r nature.
Conflict caxmot ^ piAt aside altogether g b^t as an instmaient
for evolution^ conflict tal£©n alo^ is lilse the odd half of
a pair of scissors. M ^gikomt^ on conflict &@ the bg^ls for
individual or collective evolution reveals onljr half of oui-
opportunity^ half of our capabilitsi, and half of our
responsibi li ty .
Bow tMs motion o£ th® significasios of cos&flict caa
ha.^ beetle ©o wid©!^ accepted In tli® face of c<si@e»>22plaGe
evidesK^ to tS&@ costs'ar^g ^ow it c£m Isa^e aags&ified tl^
acc®ptas£ce of cosiflict aa a wajr to t&0 soliatioa o£ prohl^im^
aad hot? it can liave sectsred tis© social acceptance o$ coQflict
to th© degree th&t it l&ai^ is Is®fo3^ W imderataadisigo It is
aot tliat Dea^lwto Mrs or Freud accos^lished tble f@at direct 1^^
becatase the popular cosc@ptioa @iil»rac©0 osil^ fra^ssstary parts
of tlidir contrilmtiosis. It ha@ J^n^ aABplerp aad lieoce^&M>r®
laTg to bgliey®
or
that e^olutiCTtt_ prooeiSi" pria^iosaiaantly
_ _ 'afiure ip coisflict gjtttatioasfl aad taat
Lvidual "^cceeds or fails accordistg to bis aatural
la vhich Ms poteailalities for cosfiict are of
sociaFTorces
aad* Tsealtli are
prTncipal det@:^aaata? taat tiae individaal is merely a
aoyiag atCT^" of coaflictsa ©a^ Ssiag" tSJa vicij^ of iaetiact-
ttal dri'Feap chiefly of a gg^^s® "a^^^i®a^g®®a5Ie aatureT
A more valid thesis^ I l3©li©¥e^ is that altruisiaf,
t&Xths aad ^istisal trust are 1»uilt iato our behavior Just
a© ®U£>®ly a@ @x© tlio ^chaaissas for aggression aad coaflicto
Sach of these ^^^t^os represeate a vital force xyiiicli has
develo^d prc^ressivelj throoghosat ^bylogeo^. Each has
plas^d a ceatral role ia the detesmiaatioa of the freedom
as well as of the survival aad creative evoliatioa of hiol<^ical
orgaialsatiosm °
FiaatSj, which mast x^maia relatively fixed
ia relatioa to their eaviroisseatSf, are capable of
livix^ off fairly hoeac^eaeously distributed raw
chesiical^o Biolot^ical systaas of discrisiiaatioa
upoa ^ich plants depend are coaceraied «ith rela-
tively eie^eatary ch^aical aad physical factors*
Aaiaalgg oa the other haadg deg^ad u^a partly
orgaaised cheiiical sii^^taac^s «rhich are hetero-
geaeottsly distributed aad ^i^iich they ^ust actively
seek outo Aaimals isust be able to discrimiaate
obsjects ia their eaviroasaeat ^14^ may provide
secure thera
suitable eaerj^y sources,, aad secure thera for
their o<i^i^ aad their progeay^s use. Aaijnals are
characteristically atofoilec l^ilt for ^ctioa, Ihe
evolviag aerviP^m system has S^ea fro@ the I^giaaiag
a system that Ib both selective aad directive «
EL^er aiaimali^ have more cc^ples syet^es for
discrimimatiosk aad actioa^ and a greater capacity
to leara ae^ discr^iiaatioi^ aad i^w actioa©«
me ability to discrisiaat® is iatiaiately
related to ^hat ^@ call appetite^ feeliag aad
>tioa and also with ^chaai^ys coaceraed ia tis©
" 12 ~
direction of actios. B^avior Is g@£S@rat@ci }siy
moti'^atioi^ ^Mcli ar® In tarn ehapsd ^ Mologioal
Byet&m ot v&lvu&s Aether tlteea are co^cta&Bls^
B&adfest or oot. Built is&to sudi differentiatiag-
actioQ-geEbsratistig syst^as air^ ss^chassiiass for valts@
disc^iBiQatioiss a2fecti&g t£id psr<@©@?iFatioa of t^
individual a^ the preservation of tbo species.
Both of tkese ^nds of discriaisatioas astd actions
aro vitallF essential, Sarylval anU ovoiiitioa cowld
not have goae very t&s in tha creation of complex
foras of life witaoat haviog a ^[ological^ouSaafioa
lor cootseratioa and altrtti^ as ^11 aa tor ccMabat.
Cooperation and faith in scsae degree are al>solutely
essential for tise reproduction and survival of most
offsprings and are vo^ f ar-reachis^ in yielding
internal Mological satisfactions. Heitiier aggres~
sion nor altnii^B reqMres deliberate coi»ciott0
participation!, even in those organissas capal>le of
cojmcXmsasms& .
We acts ax£d llveg by faith: faith in ourtselves;
faith in the coi^detency of natm^; faith in each other.
Svery perception aaid every overt act 1& based on faith.
Action follows the state of the nervous Bf&tem whether
it be iso-called "spontasieous'* action., refles action or
action of the "will," 1!he state of the nervous systea
Cthe braiZH&ind) is variously called an iaagee an idea^
a feelijsig^ an ei&otionf, or a 3t£<^@ent ^hi«^ in turn is based
upon ct^parative evaluations of various iaasea^ ideas
feeiisgSg ©tCe fesilt up and stored during previous experi-
ences of the ©pedes and of the individual. Knowledge
of the outeid© world Caasd of ourselve®) largely evolves
out of a cis^ulative experience ^ic^ begin® with our o^n
"spontaneous" actions. Deliberated decieions— -even
decisions based ©a strong feelings of "^ili '• — are
largely founded on ^stesas of experiential consistency
&Bd the projected faith derived froa that.
To be ^tesained by oas*s o^a aatus^ is to^ be free*
An edu©a^ed"Saa"is saSCd to "be~oi»s ' able tb'lprestee ihe
cosfieqisences of his actions in the ^^^st ^ssibXe totBMty
of their relationships (Senait Eby^ 1051) , A wise aan is
eost fully self-aware. He is sei^itively ^spathic regarding
the possible consequences of his actions consi^^red in the
widest contesKt and in the loi^est view, A ^ise and
resolute person has a store of stable and worthy eiaA&s
patiences and a style for engags^sat in action. Gon«
seiousness Cs^d the contributions of educaticm and wisdoa
to a conscious and resolute person) provides the fullest
opportunity for the developaent and exercise of capacit^-e®
- 13 -=.
for altnaie^ f ^th smsid mxtual tr-^mts ^hldt ^Qs^tholema
r&k^n Ju@t a@ madk fsaturai as^d vital ©ec&ax&isas as are
tSae most priMkttve acts o£ coo^ratios^ observed in lower
asiiiaals.
Freedcm to act imrpoaef^IiS' w&t& iatelllgeat fore-"
si^t of tti® probaSils cos2S5@qu@ac®8 of actios stands as
aoral tveedtm whBn tlie social cos^eqisesices of tbi& action
are taMea into accot^t. Tbsi&et actions are aieo both
natural and vital. Tbe^ r®lat© importantly to @yr7ival
and ®abody tii® realization of vital satisf actios^.
"IIaa*s capacity for intelligently directed self-develop-
laent coalers «pott liiai tae ability to detezmine the pattern
of fais caltnre and" so to 8faape~"^l® ccmrgie of tounan evolttilc
in direclions of bin own c&oice. T&ie aftilitye jg&ica no
olher aniaale faavep its man's laoat dietiactive character-
iatiCo and it is p®rh&g@ the aoat significant g?act feno^n
^gonBdence^n[g"^«dson"^rri^»~TgBgr:
flie brain-Mnd is an evolutionary tool like
teeth and claw®^ Isot '^e can espect fron it a Biuch
sore creative perfoxmaace. fhe brain-nind of saan
is highly develc^ed with respect to its capacity
for discriiaiaation aioong objects of the envixt>i8Bent
in favor of suitable energy sources. The present
uneven distri^tion of wealth and power throughout
the world is largely due to the purposeful use
of the brain-aiind according to the cuBBulative
oethodolo^ of science « ?et garnering and
exploiting energy sources is not tl^ greatest^
and certainly not the loftiest £> purpose of aai&ind,
With all that the brain-mind has acetaaplished^ it is
still a very incoiapletely exploited Instnsaent for
contribmtiisg to the e2Stei»ioa of freedoia and to
the further encouragesaeat of aan*8 natural
capacities for altruisa^ faith and sutual trust.
Within the last few yearS;, discipline basic to
>logy and psychiatry have contributed directly to a
systetQ of biolc^cal. ethics that is based eijstire^ on
scientific grounds. The work of Dr. Paul Maclean is
particularly signif leant in this regard K^tct^oase of his
delineation of sepazat® brain saechanis^s which relate to
preservation of the self and to preservation of the species*
Work such as this prca^ses to provide the first systeai of
ethics to be developed without dogg&a. Scientific contri-
bsatioas relating to coasciousaeese appetite ^ emotions
leaamiags asenory, sotivatioBs value discrieinations
ditcision aalsings and will are pertisaent to any consider-
ation of what we have to deal with in huasan nature. I&ey
» 14 -
also @how th&t hxm&n nat^is^ m&f Is® cos2@id@rsd tnm a positive
as w© 11 as ^T^^ tlia Bor© traditioaally asgative poiat o« vi©fr.
Such contri^tioQ@£ ^&sstg ciain&latives will p^o^ide a ocmtiQi£->
potoatlalltie© o£ ul^ lsif!aaa l»&havios><, f3i@@® fields o£ sciesic®^
although late to aattsi^e^ portetnA to cositribate mor@ inport&atl;)^
thaa assy otbBv intellectual eaters^rio® o£ aan to his ultisate
£ul£illa>eat la "life^ Uhert^ aad t2ae inxrsuit o£ happiaess.''
SCISUCE AS A HCHAM VALflB
Science itself ha;s ©^ol^wd as a valued huaaa enter-
prise o The eapbasie has hsen greatest ^ in this country^
aad especially in recent tiassc upon science as valuable
£nm a predcffiinaatly utilitarian point of view. Science
has proven so useful in finding and exploiting suitable
en»rgy sources » that its contributions throui^ technology
to the stamiard of living is taken ^ m&ay to be science ^s
chief social valu@o Yet those vho ha^ heard the 'beep"
of an earth^ satellite or have seen one crossing the ekyi,
have experienced an inevitable cultural thrill through
their ovn perceptual confismatioa that @an can do such
a thing. This response carries ^ith it the further
recognition that the world will never be the eaoe.
Science in this way fulfills a part of man^s innate
curiosity « Almomt all of astronosy and astroidiysicS{>
most of the earth sciencess asd bic^iedical sciences in
particular^ coMribut© to fulfilling the innate desire
of man to ^no^g to ui^derstand,, to cosuprehend^, the universe
and himself. Scientific discovery ultiaately has a
cultural impact upon the ^ilosophy of thou^t and upon
the vitality ©f ideas. Science stresses that the
individual^ th© cosHssunity,, and the universe itself^ is
always in the process of becoaiaga and that none of this
transacildh gm& be asde to stand still. There is a
certain aati-inertial force i^ovided society through
scientific ent@rprie&c Science detrasOEs authority; it
eai^asisee the intrinsically creatine aspect of aan*s
own life and his capacity to create increasing freedon
within the total dostaia of orgai^c and inorganic
evolution. In ms^ ways^ science provides useful impl^aents
for cultural develo]|aient .
Scicac© is a<^t a body of do^sa: It %s a way of life.
The requii^^s^nts of tS^ creative process i@pose self-
discipline and intellectual integrity. £n the pursuit of
science only that <s&ich can be cof^smaicated and sustained
by others is retained and dignified as part of the orgaai;^d
knowledge of science. T3se process of creating new concepts
- Ig ~
T^qMrfis asjeiiaaaa fre®d<^. Progressively leaa Sreedc^ list
seeded for t^ e:spXoitatioi3 of airailable cosoepts^ h&mii^B
for i^vQlope^sit; &i£d tod^solog^. I%e need for fTeodom^
freedon in t!iixslci»0:> f reodosi ia diaciaseioa^ freedom to
6saBOostr&t9 thia tsru® nature of saa& as»d bis aocletfs freadoa
of piOilicatloiSp ail 7@<3uired Iqr sciences i® a fiarlt&er coiottri-
tnition to the etrsszgtli of freedcs throt^out society « Accept*
saca of the spirit aod ssethodoiogy of science h^ society's
leaders assists society ia adapting to aev situations vithoiat
the kinds of fear ii^ich have attended drastic changes ia th@
C»ltt2r@ is affected hy the ehallesge of the adventure
of sciences of the f rentiers to be sorpassedg of the t^dcoaing
effect of th® uiticno»n« Science provides concepts of enoxraosts
intellectual satisfaction^ enrich&ent and eatesrtainoftent .
Science contrilR&tes to the discipline of a cultivated society
and to the ii^pi ration of its youth. Kaorsteia Teblen ^rrote
ia 190@ '*!n ^jth-sahinge, foUElore^ and occult sysaholiera
many of the lower barbarians have achieved things beyond
vih&t the lattesr-day priests and poets know how to propose.
2a political finesse «, as is^ell m in uareasoningo brute
loyalty {, laore than oise of the ai^ient peoples gives evidence
of a capacity to ^ich no modern civilised nation &&ay ^tpir®.
To mo6evf& civilised tsBsnp especially in their intervals of
sober reflection^ all these things that distinguish the
barbarian civiUsations seem of dubious value futile in
ccaparison with tibte atdiievoaeats of sciences They diedndle
ia Bcn*s esteea as tiae passes, TblB is the one secure
holdis^-ground of latter-day convictions^ that 'the isMsrease
ftd diffu®i<
and diffusion of leaovledge asosg aen* is indefeasibly right
and good, ishea seen ia such perspective as will clear it
of the trivial perplexities of wos^ day life^ this propo-
sition is not questioned isithin the horiaon of Western
culture 9 and ao other cultural ideal holds a siailar
unqv^stiosed place in the convictions of civilisoed aaHhind.'*
TQWABD m imm* m^im
1. Cultural differences affecting science in
relation to society. iPresearch eater^ise'tSia^ depends
upon the patronage of a donsocratic society depends upon a
relatively broad understanding throughout the society of
the values of science and of the conditions under ^ich
science can flourish or ^11 languish. An obstacle to
such uaderstaadiag is that society is made up of aany
different cultural groups ^ each of vhich has its <ysn set
of values and coiaception of the conditions i^ceseary to
its o@n kind of eni^rprise; e.g.^ schoolboysj, preacherS{>
- 10 -
a?tl@ta<, eal^^asn^ t®&^seT&g thleveag BStXlor&s playm-^'igSits^
piaysidasee poiic€»©3i<, pilots^ liusisiesssua&c factor? "^ox^orn^
tel&vtBion iss^cmsorsp isis^rsg ?®@a&rcli sciei^tistSj) baalierso
soldier® 9 etCo £ii gsasral^ tl%@r® ®sl®t only limited cross-
group familiarities 9 altlK^S^ schoollH^s^ &a a grouP{> stttdy
teadsierso asd vie® i^raa; thidvos study policGsaeSo etc. As&
indivioUsal In os& group is Xitoly to Judge th® actios^ of
masaSbBre of iy^ otiisr group aceoj^^disag to iiie <»?52 codes tn<S^®dg
b» aa^ ksKSfw no otSior. Hie siapiest traaslatioas aro between
grou)^ "^^oae ?a2.uoSt> actions^ and cooditioios of work are
ISJSKnm to $acli ot&ar tliroin^ a coati^^sisi^ iateractlosia 7et
difficult traaslatioi!@ ma^ Is® required betweeai groups wlif^a
superficial faailiaritF with each other may bliad tiien to
fuadaiaeatal usiderlyii^ differences »
Ti^ predc@3tiaai&t @y@tesi of v&lvms and cooceptioa
of iporM!^ coadltlOQS in our society (at tMe titsae)
relate to tlse saarkotplace « Sy aad large;, the leaders
of GH»r society understand the valutas and conditiosm
relating to mscceseful business ai^ political
enterprise 0 1^1@ in the code 5i^sidi& is also laoat
often publicly interpreted by the cooanunications
industry. This code is therefore the cogi»onplac@
and priiaary cultural reference by "s^ich actions are
interpretedo For this reason it is quite under-
standably although regrettable s that a rei^arch
enterprise is likely to be evaluated according to
standards of the ^arl^tplaoe.
P> further general feature of the action inter-
face a@ong different cultural grou]^ is that ths
predominant group i^t only evaluates tlas actioait of
oihe'r' ggoupa in the light of ita own systesa of
value'Sa'laiaf 'iha^ if" actively egerts "presCTares to
c^pel cottfoiBS"ty o'f action in ac<«3raiince "wTtS~lhat
sifflaesys^^iu 3^thing 'el&e would e^ea 'alien" aiKi
■"nXop^aTp' if not "ispropero '* according to the
code of the predcsainant group, This te^ency is
entirely nat-oral^ and it is equally .onreasooado As
an esaiaple: pressures are eseerted,, directly and
indirectly^ ^y the pred<%Binant group of ri^t-
handed persops to disguise or eliminate left-
handedness,' at the very leasts to require left-
handed perso^sB to adapt theaselves H^o the way in
^ehidi hands ar© to be shaken., tablei^ set^ doors
opened s faucets tunaedj. ^riti^ desks arros^ed^ @tc>
These two gesaaral facts of cultural interaction^
ccstpelling JudgB»»nt and conforaity to a foreign code^ have
a powerful influence upon the action interface e:sistii!@
betf^een scientists es^a^d in re^ardb and the patroi^
- 17 -
ot sel'aace. Bi^isieos sind poIi.tic@ ar© cGSxsfQtltl-wr fields^
as is scioiicea Tet^ tl^ basis fo? tb© CGetsnetitioa Is fimda-'
m@ix^&llf diffes^at. Bassiiaess aisd politics are saisdy for
tbe purposes of social service^^ social po^^r and social
control 0 To a large degree the aarketplao® and public
opinion d®t@rsilne@ vshat. is correct ^ «?&at ffisa^mrea success o
and what standards of conduct mtmt !3e seto Most trtsstees
of universities assd managers o£ business as well a© »oet
seabers o£ tb® Congress and D&derai Eaeecuti'^eSj, are ssen
vitb esrtensive experience in tbe professions of business ^
lav and politics^ Imt little or none in tbe direct pursuit
of science, K^iey aire^ therefore^ in general^ well fitted
to predict tb® social usefulness of a products to estimate
tbe popularity of a public policy? and to evaluate tbe risks
and costs of an econc^ic venture. Tboy are culturally
bounds l^rforce of tbeir own code and previous eacperienoe^
to evaluate a scientific enterprise in accordance «itb
sucb terms. Only very rarely are sucb individuals
experienced in Judging creative scientific endeavor ^
scientific conseptSe or tbe conditions essential to
professional esscellence in science. Moreover^ because
tecbnology requires conditions that are easier %o appre-
ciate according to «arlsetplace standards^ and because
acienoe and tecbnology are often lumped togetbers aistalten
Judgaentg arising out of a contusion of these two activities
are unfortunately often reinforced in an individual's
essgerienceo to the obvious detriaent of science,
2, Attractiii^ the ablest scientists to an orsaniaation.
There is no 8u£$sti'tute for iet^ns thehi^est standards, and
for providing the greatest attraction possibles for hey scien-
tific personnei« A relatively few top>quality individual
scientists can provide bm aura of excellence for the entire
organization that ^arill conclusively es^nsre future recruitsient
and retention. Such individuals ^ill illustrate th& creative
process^ the internal s@lf<«discipline9 the professional
competence^, and the intellectual devotion r^qui3E*ed by
science. Tl^y will live out the satisfactions which derive
from intellectual pursuits and B&t the intellectual and
eseperiiaental pace Sc"r the scientific community o according
to their own lights. They will ensure the astablisfai^nt
of traditiosmi most suitable for individual professional
development and achievement a Other scientietSo whether
beginners or established inveatigators» will draw pride txtm
association with these individuals and theiB> professional
accomplishments »
It is clear that without substantial evidence of
es»:ouraging creative accomplislia^nt and of providing
creative individuals positions whex« they can accomplish
«. 2.S -
scientific ii^tltutioa« Without stibstasitlai pgofQe^ioaml
Itloa Isotb wltMn aod o^tsids of tli@ orgaoissitiose
recogait&osi is measiiigfialo It s^gStt lie urg^d tbat
sisace only a s«lativ@l^ £@w iadividtaaXs ^^Itl^iB aa organisa-
tion aro likeXy to lie MgS&I^ cve&tlw®^, it ia not necdstsaxy
to indulge in developis^ a truly creative anvirossaeat:
thie ia a ruinone siscoeoesition. It an institution is
uaal»lee for whatever reasonsp to attract a^ to lee? the
2?reciou@ Ce?®n tboiigis ts^sall) fraction o£ highly creative
scientists u^n ^^um its professional repntation dependa,
it can loee m>t&ing not already lost.
Tflien even a ^ew l^igbly creative scientist© find
that a given institution is best froa the point of vie«
of their individual professional develops^nt and acccsa-
pli^saents then there are fei? obstacles to the a«^iinistr ac-
tion of that organisation:
i) RecmitBent and retention of top- level
scientists is made easy.
ii) A scientist «ho enst leave the organisation
I position can so lon^r 1^ made available to
hixss leaves with a sense of pride in hia professional
eapsrienc® ^od association ^erith the organisation; on
the oistsid3o he is a knoi?l@dgable advocate for its
scientific program smd its professional support.
iii) Internal profe^lo^al ideals to
greater freedcsi^ dignity and responsibility for the
individual scientist 9 tend in a self-coatrolfe d^
group^correctiag way to elevate the standards of
esc©li@n€© of scientific perfox^aac® entirely in
the shmu€& of administrative intervention.
lv> me s^atnre and licence of the
istration ae representative of this respected
GGimtmltW of ©cholars becosjss a«to®atically '
, v) Mvocacy for the support of the organi-
sation program ^ctmss more objectively scientific
end less poMtical in character; thiSe in tnra« has
a strong sa«ji favorable effect bacte «poa t^ profeasioaai
reputation <pS the organisation.
vi) l^e ^"aln© eystesa of individ»ml scientists
becoses more closely identified with the professional
esscell^nc© of the organissation and less concerned
with ^solisjesits; y^t at the &m& tisie improved
esoitments i^c<^ie even more evidently deserved and
easier to Justify and to acquire.
- m -
limitation! to ttmtw aoe«mpli€M.s^ i®p©rtai&t iat©ll©©tual
work T^ill li© ®<^tly iist®gsal.g ^Ims-® f®^ limit atioa© caa
1^ BBSilgsmd to th.& ©a¥iros®©Eit<, Tljfcssr ^©©k a ssettiag wte2?e
tltoF cam lia-^© tis© g:?®at©s!t ®©opa and freedom for Smtfe tis©
pg-s-iogicai aisd tli© logical @fep® of tfe^is- scieatific mss-k.
T^ iBmmB at state ©©^ i®taiigibl©s, ti&t %h^ IsipXicatio®®
y©ac& Into ®v©p^ a©p®ct of dail^ l±f®i do©E5 tte orgsMaa-
tiosi ^^ tHe sei®atist*© tiro aed tla©a gitr© it feae& to him
to ©saplojp aesordiag to his ©im csssicsptioE o^ tlj^*© mo&t
tisnltt^ utilisation? W^at are t^© tias-dessasicl® ^Mcfa
dists"aet frc^ tfe@ laaia goals? I© tltosr© a teadessey to
s^©3?t-»c«it sigalfica?at z^^-earcsls ia favor of laKSs?© taagibl®
or "practical" s^sialts.^ Ar© ^ala3*i©S5 prs®otioffi®8 assd
both tlie tassgibl® a^ is^tasi^ibl® @ispport@ of re^arcli
pro^i«3©d aceas-cSisi® to tit© M^^sst pff©f©s®iosi®S. staiKiardSa
Rssd sjo ot&®s>^-. Doss legitisssat® px*of®«®&©siai a;ctlvity
I3@0d to lS!3 Ji%©tifi@d oa t^ ^o^is of @Dst~^ci@Qtific
crltei'ia.
It tm ®X®ar Isejpoad peradvoat^r® of dis^afot tfeat
iES®'^©® s^^d to te settled Isy scientists siooor^l^ to
©ta^das*^ of psrofeseioaal emptrsitlom' aad pai^fessioaal
discipUa© wMcli tMf tak© y^spoasiMlitF «or settiag:
sio oi£S «als:@ 1© s^tal^I^ qisalifieS; i^o osm ©Im® hem a
M^@r ©ta&® ia tfe@ ®oatii!3Kitisag ©^©reis® cf ti^oa® practi«^3
'B^idSi will Fi©M t&® Ii4gli©st staasdsrd® of py©f©ssioaal
wli©tSi@K' t^ss orgeMsatiora is laad^jc tSs® aagl© of a vissXv&vB&tj ^
aB i^sdustsrial cosk^S'^.^ or the llov@s*^i©s£t . fli@ Qs^gcsibtiai
vali^ J^d^ei^t® ia J©la ®©l©ctiois ars laad© oa tli© feasls of
tla« prof®®g?S,e'iiial id®Btificsitio®iS aad tte Mstor^ of pro-
^©ssiofflaX acecsapli^lj^ffits witSaia tl&ei ©rgasi^atioa, ^i?
orgasjisatioBS are Judged os tin© fea®i© of t.^eir iaitial
prograaa leadersp aad os evid@n«^ that iadi^idwal ©ci®ati0ts
cust coatriMt© im a je®spo^m±hM "^b-w towss^d aa Idfaal d®stii^
^o3p ,asa^ Isstitutioa t^at ^as^siot_,f®t £^js fooimd dowtt_^l^ -s^kssOfL.
traditioBSj, or % :tli© @^@2a Si©avi§r f©^® «^» ea^diocrlty, ^^v^;.^^^
Tk® ultim&i^ l©y@i of accg^plisisa^at imd port
ia any acieRtlllg-^i^^aatloa d©]^ad@ ^t oaly i^oa tae
itialK
and if 5 ia tia© a®gs^-gat©9 tli®y are mss± @b to load to
coatlswsiag isteriaal ' ips=o^i'©^@at iis tise p2?of©si®ioaal
etaiidard^ of tte© on ^jisatioss tfeat orgasiaiatioa caa
witlistm&d m® isipact of raida on it@ ^eiositigtt©^, hone©
•=. « -
OS its iif® blood.g h^ cs3iiip®tisg estorps-iissefg; it will es&jof
Ees^asifoilitir tor h.±0i prot^s^tosml staisdards smst b©
dori^ bjr tke profe®j3i©iBfi hori^ vtth steadfast asd d©-
p@r@<Maalia@d oSj^^sti-yit^j, atolsig alwsy® toward tli©
liig&eat 2?<@aii.'sa!lii® l@v@Xs of @ci©s£tific acMievf^^at »
Sixac® l?o»rM War IT^ t&® "impact "of ®Gi@i^^a» y©al2.Eed
throu^ t@Glmolcigy) has o^tstrig»p@d ^i^}>®t of tli® other
forces iau?I^©E£CiE^ l3«isis^B®5 law aad politics =. la p»®®©at
cirdsaseta^e^esp tlsa leaders af ^ocMtf Bsd patroa© o£
®cl©stific ©iat«r|?ri£i© ar® l^cmad to fe® d©p®iad©atj, la all
of t£i@ cosipl®^ a.sis& co^f^^iasg di@ciisloa^ relating to science^
affairs ^,l<sl£ is contrllfatod Ijy sc;i©ati®t©9 cosjesuitaats
lind a3s^iiitt©@e of BGi®nti.@tBo So m^eh d@^f©Iog^at&l
to isocialj political smd MXitaa?^ j^teds iksw ©3pr©s©®d aad
lor MiicJSi tec&aoiogs' caa mxgplf partial b^^qtb' provided
th® ^oessajf^ <l©"^lops$©atal ®assi©s cais fe© p^t fos^ardo
that til® cosa&ii®(tl f^^aarai asi<d sjoa-I'sidsrai S?"^clg©ts are
is@isf^icl®2&t to ^tLgpport th^m alio
E&s c^n tlft@@@ c<:^p@tii3g interests for
t®cliaoIogy fe© reesoli^ed? Eow caa ffefflowr^^® 1^
eaf®fpaard3d to ©issmx-e a feroad rassg® of ©cieatifie
activiti©ssg u^^ ^ich tise fut^tgra of techs^log^
d©3poad[fi? St is ispoQ t2ils Joasti^-groasid of
t^clusical mad sei®s&tl£ic diecrisKlaatioiis that so^®
■v®xy i^irg© ©ocial 3?=3@pos3isiMiities are beissg traos-
pQ&^d %Q ^^t&ntlf.i.e as^d techsalcal Goam<stSktB asȣ
c<;fflsiltt@@0 tnm thotr traditioaai lacatioa isi t&e
haadst 6^ |j%i@i^@s@ as3d political leaders « Tlsia isajp
b@ isavitalsl©; f^tg it easa fee da^©rma® iasoSar
as w& ^^ajr ^ssssro^i'?® tim ©sstaia^t o£ tlis traas-
poattlcn of respoasibiXity^ or Islia^ ourselves
to th& t&ct 'mB.t u>££@£^v@r me re^-^mihtllty be
traaspoised it mmt contimm to }s® re'spox^ibl^
SsorjMfo SfeysTj, it is t&e sci®atist «^© tiads MKS®2.f
Is lem faM^iar terraia. If &@ act|3 wit&emt
r^Sard to mwdt respo&ysiMIitids^ or ^aie&
ac^ptis^ gemral social respousiMlitiee for
tb& @€i®atif;ile ajad techfdeal decision Ite is
forwordis^g te tsscoiies gisiltF of a f^iti litre to
aamm& ht® f«jiXI osid proj^r progeasioisal reapo^i-
bility, Mf -filial of bis l^&riog tbo iiill "
iaplicsitioiss of .inic^ £^®pQj^(iMlity Im as pale ae
the stat^BieM of as ad^srtisii^ s^asi tbat h@ bears
no r^Bs^asibilitsf for tl^® tides of piablic taste
nor for tbe creation of is®w marketplace denaodSo
." 31 .-
r@&pQm^lh±li.tw ia afgaim r^iatiag to ®ci©Kc5© asjsd
tediaiolog^ i@ talsiag piss,©© mor© and sor© x-apidly.
Tfeer© i® EO goJlisg ^adsward, St Kay b® tfeat
l3issiffi©®©£> i®gai ami ^iitioal leader® cam Xsaa-n
to dif.f©r©sstie.t© ®©i®ae© «rc® t®cto©iogFa a^<^
fffosB tosii^es ©mterprises ©ad to trassiat©
olJijectiv^ly £r<m oss© co?^ to aisotSser. To t^
to cofSttiKH^ to S»@Er isi full tte ssocial sand pol.lt:icai
res^ssttoilities aad opportaMties j'i^XcSod fejr ©cissscs®
cmd t@€luioiog|r, Om thio oth®? hein<lo it m&f ho th&.t
mG±®ntlstB cai£ learn to accept axid 1^ accepted tor
a fuller gslaar© of social ami politicsal s^sESHJESi-
Miities relating to @ei@QC^ aod t@clmolog^'o IMs
will y©qttisr© tis© scieatists to l^ar a aaore difficult
aad foaf^liijg s®t of r©spo3^ilsl,IitJL®® thaa th©y Slav©
imwall^ feoris© fesretofor®. To ssosae d«gi?$® both
hat as :^t t.S&'sy Saav® taSessi plao® to only a m&aor
<2egr«»a l£& e<mpariso2Q. witl& 1^® ftiill scop© o£ tte
protelasso 'Ha® g^ESsa^al s^attera i® osfes of over-
®lj5iplificatias& .sad of artful dodgissg o^ sr®ffliJoasi~
Mil ties oo l»ot& sid©So A solmtios li®a gjgst Aa
recogi^sBlag taae ^actg of %"]^ "coiiy©yp;bao® of"
se^ral ^Afferent galtayal" patteriss Into aa
bftXAg&toyy wbrfeiag reTaflJM^asly reqi&Ared to
solve iagortaat aocl.al'" pyotelaaSfl aad fisecoaga a
caa lio issost flttioglF ll^oriieo S% att«cipt to
©HSIai^ tfe© •c«I^?ar"Wgl®y®ac®s ia ©itSs©3f
(lix^sction oialf destroy© liatwral ijatra-cialtural
safe^ards asad int®2*f©ses ^itii tla© d©v»lojpsaeat
of full professional Ant^m^t^ «^ffl«5 jtsd^issiMlitr-.
Ctoa areajMas. whj @€l®ao& ma:f ap^ay to fe© bo otMctlv®
la t^Q soviet gpiott i& tJtat tb® Roaiaiaag coasldey thimmlvem
fo1iave~a scieatitic society. *l3>8yegore tte®y «acoant©r oo
•coa^lict bet^ea social^ pontical aiad aaa^elplaoe criteria
'aaa~fSe"gy®te^'"o2f yals^s a»d conditioas esseatial to acieace.
l&vS tead® to af fecs'F'geffiss'al Seatwaf©© of tiseir ®«S®eatioaal
system as well as ©siesstific asd tecfaaologtcal.eaterpriseo
Sn otliQs* co«atrl®s oiss ©aa ideatify fwrtteer diffareac®® la
r©isp©©t to Cialtua?al iatafractioiMS affeetlag scieae©^ a©
ca3SI»ar®di wit& @itlier tt^ So^i^t B^et^s or t/vir owao lis®
obaervcs&le differeajces asre sot s^ta&I® to advocate
worthy f o
fact ^hat
for ^s© ^ o^3? ®oci©typ tast tfe®y do retaforc© tfe®
ja eyolifed
». 22 -
4. 1^ Ideal of njtof®B@iomll^^ Owe prijaary
coacer® as eoi®ffit'i®t0 ffeTatsJS ib tfee growtfe is iat©!-
lectual ai£d croati^w pt^wsr of omre®Xv@s aad our col»
iQiagueSs to til® HM^rovsmetu^ of our ^eiital garfusp aM
coraprelsteQsi^'Q tbaor±®m ol Bct®mG&o Oux* Msiisoss is
Th& BOTtQum ^fmrmslt o£ siew Isamirledse pro'tridt^s a special
from th&t of ais:^ ottLos: iiat^^Ilect^al calling o What
sci®att®ts s®®k i® ta® devolopaesiit of iasw.'O'e'ed cosscapt©
tJa&t will poia®©ss ^ra®aiatic lateIS,®ct«sal 'rali^ assd will
ettmd tsstissg agaissst ali Talid esa^ ©^spsffioac©©, lli©
iat^alloctual value coj&cesms ^ia®tb©y th® co«ic@|>t provides
a greater g@m»?alis;is>tioe or siMpIi£lcatloss ot ideas^ or
vrib®tli@r it acco«mi® saor© essplicitly for tSi® Sacts it
relates o iMtho^^ i.n bicssiOdical 3«;i©i30© tisi^ con poiM
to taagifel© ©vidtesicss of progree@ iss tOEm® of a»w
O£i@^^!0B8 £S&^ gesmSi, axstd wbv therapeutic agent®;, tites®
ar® l»|r~px>oduist® yielded t^ron^^ t&@ pisrisait of l®@@
tangible goals. /^. a@i? le-^@I of «as&d@retasKiiiiig can ba
l»roissslit al$o%£t eitl^r 1^ beginMsag witb t&e isv^stigatloa
of explicit prohlmm i& partleular disdas® ©atity^ or a
give© sslck p®r©<m) or tlaroii^ tli© iav©stigation of
S®3a©rai j^g'ofelssyg CtSae rasMi® ot ^5*sical-c&®3®ical actio©
of ®sm^fm!i&g or how Intosna.tlon may to g^io^ticallji'
trjmi@E3itt.4@^|! 0 la either ca^e, as important en® to
t2s® ©cop® of tfe€> i^ltiaat© sei®atific accasspl40feM>at
is ttmmx m the a^feJoMtioa; '*1Sfe©r© i@ ia«? haxm la
@tra<Jl^i!ig a S'p®cial msfeiject: -^m hwm i® ia doie^ a!^
kisitd of worl; with a- laariro^ aisa aad a sxarrow adad"
CJ» Hssg&lissgiS Jacte83ioi&e 187?) j
T&er© iss SKO sudi tJaisig as a Ic^c <jf creativity:
tfe® creatit?® pro^^s® iss yoaily p*-©- logical,, 1S»© eacpositosi?
order of @^lam&tios£ a^ to wl&at w® &a<?t@ accc^plislied iis
eei@nc@^ ai%d Si^w i«f^ j^a^e t®@ted omr id@a@9 cosscaals the
actual ord©r of <il%®co«^ry, logical :f@ats!a.vp©@ of sci©aoo
ar@ 3s>@@mtial £or th® lo@ic-tig£ait tsstiaig o£ xsasw cosice:pt&
agaiisst Bei^^ ©sipa^irieaoesc ¥©t t&® logical f©at«ar®e of
Qew coisceptsB caiii&^t te cleared @p ^^til t^® solution to
this probli^ is e?l^€»sit. Slot oiil^ 1^ it 3^c@38^x^s ^^
orde? to b@ creatiir<3j; to M rid of iater£@ri]iag precai!iBitt«»d
opifiioas aisd prior a£^smsiptioss@^ h&t thB &'sperl9jxc@ of
creative work aa&®s it iiacresusia^ly diffiosalt t^r®afteff
to i&old pr©i?lQCial ^ews. Seieatific fcao^lod^g asEd wil^a
it tSi® tn.il|r pro:ig<ssBiosial sciesitist, cwsi ^»atber tlm
-" 2S -
^atterlfi® of Its o^u fictio©®* Its sw^sa* i@ mssfe t&at
it will d®f©at «3|fSt€Sj^ of tMo^g&t t&at ^os&t upa& m^s^loUf,
eoereioiB or the enssalumlon of ©:iK|j@ri@M5©<. '»© ^isrsuit of
oev too^led^ S^as tls®?efos^ a literati^ ae w^ll as a
ateral^ discipMisisass i]s£li2®m^ o@ the iffidiTi.«l3s.aX aisd oa
M® a^ss^midtf^ W&m^SMXsm ami i^i©®ci2rit^9 aad a lac^ of
coi^ldem;® i£i b&±m ^^® to do 3c^®tMi3g trortlft^il® In
V&e aratol© fi©id of eciLeace ^@cs^s© of ©stsyaall^ imposed
iiaitatioais bri^s witii .it a «tecas^ of 4ia'fe®il©ct«iai asswS
p3irs!Ei% o^ ssci®3%tifi€ UmovMdgm Im^asohlt^ sml Xil^ratissg
a® w©ll a@ dliS4SipIi3>%« It is also e'l.ierlaetiss;. C£ia^«»3
lit the cbaracter of tl&0 ©cieatiflc ^roastier^ tiliasf^s ia
til® scs€io-e«Q2t«^Ac sL&d socdo-political con^jgt ia wMc&i
t^© &nt®vpTi.EB iB CQmSxs,Gt&d^ cSuaBges in the p®r&omi&l of
sci©ati®ts<, ai^atiai^trators ajad spogtsorsg all ocmtrilmt®
to & dgmfiMe traissactioa ia ^icfe failisre to ^ re^lectiv®
ajad g^If-cffitlcare Tsstfiiriiasaally aad collecti'^olyj cast l®ad
ifefa^.t> tisaft aff0 liScslSP to h&v® devostatiag cosss!»q\s®2ic©s
for l»ot!i t§^ imM^idiml a3%cl te^ orgaMis^^tioiK,
Wfeat s©®^© t© te ffequiiped is a r©stityttAoa
idoal qS ps^fesieioiiall^ ae practieedp for
»!©» i:^ fli© guild®, i^ thlm is 2a©aiat as iacreasod
of ^reoaal d^dieatioiSj, gr«at«r ®®B®a ot imii-
vid^al ffsspoasibiliti? to o^*© o^ss xs'orli: aad to t2ae woirk
of oista^£s colieagtsefiii, sn ©lilasr^d ss^sis® o£ jlc^^ti^icatloa
tlbis^ou^ l£idli;ldtial £md group ac^tDmplisSmeats a Mggor
tlinaait of ps'id© i» tSi© ssastery amd ©sEarcis© o^ |?rof©©©io®al
S&ill "^ji© attitiscJe 1® olsarl^ to fe© di^tiapsi^aed fr<3^
©OBteaporaspy dtr^e of oe^'s Ijois^ aa "orgaaisatioaal maa,"
^^ de§p?@® to vlalcls a s€i®tiiti@%<'@ prof@ss®ioaial ood® o£
obstriicted or diverted liy Me ^tirro^mdis^c aiad tlm
to wfeicSs a :®ei®at3.®t persaits tbis to tals© plac©j,
GQwtaln ii^vitabl© los®@s of pyo^©ig^ioaal poros*
sy caag aiad oft©sa aroj, how®v©ra ©s-cxied; aad gi-?«ea away*
2t i® aot tl^ hasajpd o^'tlse avalaacSs© t^at nsd-tm ®ci@iatific
Qut^vpriBQi it iB tfe© ©lew Mt IsF Mt losss of professional
ideals, 2d©ai@i> fey ©abodsriisg tlismselipes ia iastitiitiosSe
h&a3m& Qssdisrifflg historic fores©®. "Aa i«S®al i© a pictiir® of
~ 24 «
tSt© place yoii will m^-mT qsaite^ Irat alwa^ stsd^r© to
^©acliiB Its attaliKs®ist lasppesus ±u littl© pi©G@© of •&©
@t?iviisg..,iz£ ass^ oi&s email K^iac© of &©Ks©g?t i!at©il©ct«al
Ijeginula® toiffayd tfa<& msattaiBabl® is fo3r©¥©ff rigtit at
Biological SBd social ©irolKtioa ls.im gi?®d«aallsr
aeMiSVQd g3r©at@r d®g.w?!®0i of o&l^gat® coopiaratioift and
^@@a at th® &'zp&^m® ot c@rts>J.si arMtrarj modest oi s&X^i&h
^havior oa tli© part of tls© iadiifi^tsale j£aia3.if ^ orgaciisatlosii
ami society £, this psttiy eoss^tsfictiosi has l^esi ca;tmt02^ala3ic!@d
©a*:^ of t&®s© l©-^®!©. T^ prog2P®©(si'B'e gai^» cass. 1^ ajuj^jre-
ciated sHsadiS.f t4x2tQf«Slii aa ©lu^iaaatioa of ctaaparati'^^
paaysiolog^ !md b®h&viors aiod throngli slb ©siamlsBatioa of
tile faet@ o£ hlstorf ov©^ a tiaae ocalo of c@atm'i®Sa
"m® r@0$sXtimt a^iev@fis@satis &ave seosit sulssttaatilall^
great^x' de@:g^!>s& of £r®edc»a asd seXS^^dotdsmLmitiosa wi-^ira
a wi<leelsig fr^as^Ho:!:^ of cooperatio^a £^t3t ajtd Mstu^l
isftter<l@pend®ac®. "l^i® £iiad@ its espx&Bmtoa, ia ais^
lapoa £o<lQrat<3r<i suctiviti^s aiKd ii^cr®a®ia@ amtmal iat@7«
ds-^©Iogia©ffit© ar© m>t al'^afs asid umiforsilj isa th® dS.r®ctioi»
oS ©alargissg ®p^«ir®© of i2st©rd®^ad®ac«jj ia the f±®ld of
isteyssaticwaal travel asd ©ascfeas^c tSaesres Sia® &®®a a fealf
ce^tuiy o£ deterioration iifi £o2^aliti@s i?^lcla is not
entirely of feet 'l^ pv&&tl&& hf techssoXogif^al iispr0¥€»ss@sst@»
■ ''■
It i®- pat@8itX^ tnm^ tu tlis© aggr^g^tae tSaat imr&v
hBtov® Isi th® M@tb£iP of ma^ ks.'ire tl^x^ te^is so ®a^
liaiivi^a^BlSj f«a®il.'te®3 ©I'gJMisatioia® amd tioei^ti.©© .
so iissstrlcaMy iij::£©3Ma©p®iad©:at» 'ik& gesss^'aliaatloa i©
illiistirated ©^ei-^jls^re oz© lo^sss tool maansfacturiaga
t7syEi8pos>t%tio$as i^^^isatrie^t) tk© imt@rd®^iid@sic© oM
«i®^©Bd©at K^IatiomsSg ^Ij^ttos- cosstracted hj ty^dlvtdu&l&o
m^^jtB of a .faMX^e ojtgaaisatioiaSg a giwssn <®o«l©tFo ©s'
aasstrafeliee of ^atios^ isaa of-^a tees i^^d sad SsDe^a
i<3es5itlfi©d om tte l^a©i@ of nass^^ motiY®^ aad si® a fel-
filM©Kit of im^row sad proffiocial IffiteR-^stSo W<b ©xt®ffi.t
» a®.-
part M iOm tsiMvi.^m.1^ SssallWs oxgAais&tioa^ society
of more «st®a@ive vespoaslMliliies at ©a^ Xevelc
to li«» ratioai^ about fflors eos^les ^qisatiosms ^&
ed&pch fos'o £md o&doavoff to &g^i.®v®s a M^b®3? l<9^»>oi of
tioa. ^tsur £s-$m tJiie h®lm e'lmtwas^ to iaat«s%^9 it is ia fact
sm «3Et«i^Bi^^ Eoi a^T© i&ddqisato s«i;er®8&sitatio@ of vital prinr-
eipl@@ ^at a£^ mstkv® mi^tm^QSkt all «»f lifoo
eiS»l«(» Op97PB.tm to aliCf» iffiffii£»l^iEllg tS^gr^Sffi of
«9lf»dat«3^^atic^« fStes® priaeiplAe a?@ svweeptlMe to a
}t afficeliPS'atiQa of tSmi? effect tli^msgls
i o»f tlSE^s ii^ tltojf a^pl^ to isocial
fift^r all tMs is> ottl; t&9 C9&t«i{saial of
lag a «ogU.j:%® eoka£i®pti«m of. Molc^oal ovolatioac
.jDoss im&sft hav® f JE^®od«B& to raaMpiiat® tSae
M@ l.$:l®al@ smd M@ actim^T Cmm ha cisooese ld»
}? BmwmBis^ in ^^ aeittal a:Q£^ |]^m^oiog;ieal fields
mm im^p^s^'^ tiaft sas«st ©ric^s3j&@ la tM® iKi^ard tbat Iras
,_. ,_^ ,. . , -__ .- . - , „^ _ , - ?!wmSLw
of tiMs iodi^doal^ xsisilfs soeiety
ij%23^a0i^ mmv tlie 09&tax>ie«> aad
si^aiitei^® of iww ie^l.iltt©9 ^i$l£ iac«ati^os abarpesiml by
£imfaiitep»® o&' iww ie^l.i]^t©(, i^im iiic«ai&^wsi aBaz-pess&a i
nm pso&^^&im of tragic; asadl ^%^aiaig alt^jraative®^ tMe
fr«B<loiB caa M} s^^&tlff @st®a^d Isy tls^ ie^li^ttaal, tb»
OK^aaiBatioac, 'tfc® «p®i@tSF aad tlse speati^s, ; f^s M<tuiif®ii
oaly a ^4»9 i?«sco@iiiitioa aad awlaase of a t^ital Mologieal
~ sm «M«^ baa l^oogbt us to IOm psfstmrn^t Im "
^ritag® viM<^ baa 1»s?oagbt us to lOao ^s^ofsest l«v9l of
®voiiati09i aad mwissnitaaiSli^, St aaede oaly tfae ^doy
g»co8n&ti03i @5^ g®I>Ba8® of taatagal t«w8«nciog toward
So ^ f:ar«® i^ to IJ© d»t®mis®4 Is^ ostas owa natisr®.
1^0 s«fi8»si0 ®qmU^ to nm iodividifiai, fffiaii,ly9 orgaa^aatioa,
isooi€ity, 07 !E8^ja^ a® a «S»ol«. A wits6 and iweol^te
eus^ i^ff^am» i£!i ssiM's ir^edeia tlm3(agl& t&is awani is
dizr^fzt v^ to lil3@ratd oturselirais fsran tSM t]»id88i£-ab3
of oiAT o^na bra^r teadaneieso Siteii aa effort eaa etfoot
in am Uv^B t&at will iasmstmw&hlf to^ayd u© is "lif®^ liberty o
ttM tm ptijcsmlt of &&pp&a®@s.«* Ase wi> too hloM to ts^sa
ssricMMi:^ t^ Mgisi»^surte<ll iaapsai^a) sad e&iali^atiQss of csa
ti>selsaax»? Ef «@ ts^kis a«M& ^&lm tsorieKasii^e do «e
that tto&s9 i® soa^ ®e0&«7 or S(£»jr@ diir^st va^ :?03r
uxm E^ttj^ s^RitMSSEM. Fg^^RAss mmummmB
mat tbBv® ii^sld be e;^ kimi 'oi~*f&mlt7" orgAHls&tioa at
14a& for tfiitd @®tsl»l&ffil^BQ&t of tto Sa£stit«st®@.
ixamm&'Si&ttom macmm tfe® s«i«i8iti®t@9 as a s»tma Sox-
Std23^&tio& as^ oaspreseioa o£ opisiloa fti^ tb® se^eatiistSs
ami ^ a @@«fiiaaiflBSi fosr Toaderias a<Svi08 aed tf^&sg actiosa
os^aalsat&oa tsciald pirovi<2o tbe aetoatisto eo a «iiole vitb
of ©£^33^6^ titat hsm &ls9@^f l€ms teos affort^d iaadividbaAle.
&i!3d sreispomiMiity tritHi^ tgs® prcifefflsioa of stclGStifltiB at
tim mM l^ ni0^ mmi ^a^ tS&at tMs baa iim^ etsltivatCMl 1^
tis® g:r®at laaii^'^fsiti^^o
Ism^rlc^lf i^msx^ b^ <s^tls tlbe m»rtMEeg»ffi@ of it(S i@oi®»tistSi;
c@&S.f iKmaid ^ %dtli tin© ^pat&tioa o£ tS&@ IisstitiBt®®. ?07
- - r Oi&efi ------
tfi» l^aboratofff OULefs o£ tlw Basic aesaarcSi 9vosr
mmm^ d®^t@d ^slr twlce-iioatblL? suietiais to a dis-
ammkon of tte s«lati'^ val«»B ©f ®«scla a "faculty"
sati@® aasS o« ifsy® ia sM«fe tit® 14s&& laigbt Is© deaaoeffatically
p«8t lato ®««®€t. ite-iag tMs pariod Dr. E©ty prowided a
*KrtSi®r ootaS^l© e©®t??ife3itio® fey s^ecanoadiasr tfe» «as»aBlaati<
iiAr^/tinii^f ^s*i&»^russ2ss isr5is.
3a tM 3^jetm. of i&@@s foiimriag tfeormsg^ dl@cm@ioa
with tlw Braas^ CM«.f@ of t^ Ci4al«ai Kav«g8tig&ti«»oa Pvogrs
o£ SIISI aad MSlsee a.^ ^t^ie die«»is8&oa in B^SEeesitiw Staff
!Seetias0 ^tlsi^ t^ l^o lastitist^s, tho aattor ir^^ brmsiiitt
h®t&w® tt^ Se&@atifi« Di»»ct<^s for coasid03>^'ati&a) w ais all-
BIB "fasmlt^" oicgaMk^tioa. mf» SG&®atlfic Diffsetos*®
Sfi6^st9d tSiat a ts>iai of tSie idea ebowld Ito aaiSd sspoag
tt& mQtetkttmtm of tto tpo iaitiatits® Saatittst^; if^ aft®?
a psrlod of ®s;p®ri®ft£i®9 ^Sa® s^aalt® emmd to 1^ mrtli-
ivM^^B t^ ^la^i eo^Id M @c$@@l«l®^©d fo2? Mdes- adopt &oa
^ Zi ■-
aaso^ysex' tiai ^eajr^ mtii mm Spir&i^ of I&S^s toSor® m&
l^mmSblTf vffi® fisi&Xiy i&smss&fOdo h% a iseccMid open ^siet&ns of
£U»simM a& Oia&saa^ as^ D7» Sari Fru^ eus liei«far3r» «e««
tlio £I<oos'. T^s« wa0 @ oaftatsKMss os^yoeslaa of &s«<@s^3to
is s»?iQ«$i^i®s> :^si9i tliM» o@tal»UGs&^i&t of an Asssiably o£
3@l@£itls>ts. ^^9 CSi&lssisuiii pgo-teat «aai iastr^iGte^ to appoint
a C<2^itto® ta draft & Coa^tiiatioQ cM^li wmiltf tfeoa ^
pw^ms&ti9^ to tte s«si«z£ti@t®. la d«3® c<mr@«> a S^fo^iaioziaS.
CQffisstitiaticm ^m <&doptoSs asMi i@ msi Fall of 1039 a s^vi^ed
Coastittstios i^aa fasn&l.^^ s^do^t®4 ^ a @»ail iM>t® of S^
a«»iB!«s>a of tl»@ 8»ci®ati@t staff of t&m two Ssastitttt^e. 'm&f
also 4»xps@oe»3d tlieir ^l®b wlusitariir to partieip&t® ia
fataife s«»tt9<^M@a of t^ /^ss^l^.
M f^ us is !sao^i&0 eudb & "faeaitF"^ offSstaimsttioa
vi^ia tto SoTO^ae^at i@ uritiwmt pr®«e<ieat; s^ot tbis is
aot (SKurpyisi^ ia ^i€>«r of t&s f aot tbat tSt© Mattioaetl
I^titistft® of EsaJl'^ aro tli@m<tiwfi witli^mt 9«rftlle£ ia
or i^r&t of oTgaMa&tioa wit&ia t^ ^toverae^at.
j^teatial ^'s<aa of tM» i^aaan&ly to ti&® tsslti^at®
stator® of t^ Sastit^tess aad to tise lov®l of p^ofessioaal
resa?^ ia wMeSi t^ s^i^atists t&e«salv«e vi&l Ss® li®i<Ji:> ia
Miftitad oaly ^ t^ ^i^ica^ ddtaniiaatioa aad «ilUaga®ss®
of wm^wz ot i^M® Mmm^^l^ to mas&m iafSiiridaal ffiBst
eoXiaotiva s®^p&^tM'll%f of a ooastraeti^F^ aatiss«. "Sk^mm^
nm&f h&v& a midqti& opportaaitr to oreat® «m
for £sci®ati®t^ @l$m^i^^ff® &t tim Ism mtd
ssciaffltf ia'^^S-So^Qs^si^ii^Cis itceordcKi eii9lo9«es ia all
eatsiporiea aftes> oal^ ^^^ ¥®^ ^^ on^ioirsaBt^ oae f<9®3p ia
m l>xl®f a pQ^lod m ^iMcsh ad^qaately to (M' ~
too l>xl®f a pQ^tod ik ^iMcsh a<l®<iaately to d^'valop or
a^altmt® tisa wttlM <i»f Jaaior aei^atista. If temsaem
to follow m&tc^.%tiea|.l^ ia aacfe iaataaeo of 'a
ii^s^iisi^ for a f^ll $^@r at tbo BUB, thraa disagraeabla
alt®?a&ti¥®@ TO^ld £»$ forefiHi: i$ e&t&ar tS&e Eastitatas
voal^ Itave to is® ®wrm^^ iac^fiMt^lsr,, o:f 11> tliare voald
^ imts3®<iuat0 @pa®® Jo? @3M®&tial r®s®areli G^ratioas after
oml|r two or tlms® ^:;3^^ of aaeli practice ^ os' iiil tUtsra
wmM h& no op^rtrnjitf to pronci® reisaarcls er^aisag for
asspis'EBt mi$.0f&ti&^n&u'' Masa tto su»8t affaotiw aciast^ta
aim oftaa aateil to fill attractive ras®ar«l^ m^ ~
poata alaaslaerao ttor® i(gi a eoatiauiag ri^ of loaia^
&®at raeaaraSi talaat f^c^ tlw laetitat^s^ tl£@ ^sf
-» m -
S3iejst&s%® to pss^^s® £Oae&s«& &tf®cttvel'^s &^ £o' JttM.02^
taraia&as^ t&at all oS tSw ecieuftiato participate is a
PFOv&<led trai&das and esperiesioe iia xemordk for dofiaite
tmt lisited psrioclfi of tia®^ o«@. for frcn t«o to throe
Faars. Altiio«s^ tHis period aigbt bo estesdsd for aa
additioaaa yaar is oseoptioaal caseso that f?oiald ordiaarilir
bo tlta fiaal iiait« 'ns& oaiip poosiblo 9xe»pttom traold
oocwr oa tbo occassio^ of ^aoaaeios rossultiag f ?cm tbo
rotireseat or clopartiaro of seaior scieatiatSc
is tborefo^ to b@ of feotod b^ oatabli^^ag a fim
ataadiaSff prior to tSs@ ^BspHo^Rsat of a e@^ Jaaior
of t&o tias-Iimitod mttsxse of Ma a^^iataiiat
f^ praotio© of a poii$^ of "t@aa$r@'* l& so ataadard
ac!£«ted.c ^rid t^t it tm ist^lf
^ eo&eatieta. Stteb pra^viaioi
ariso aooag tsciaatist^^ ®a^ oS ^Sufm is ^voting Ms
oaergios to r^^aarcbg aad for ^si^osso iBSvitablj^a
bid oal^ limited looal ?a^ard^
9. lfe@ grjlacipto of ^*Sal^atical" lu@@ve» Creative
soieatif ic e&dfsa^or <&fliwi^e a etaaterF of~l^^[ect laatter aad
tSie eaeroisse of is^tiatlve^ iBeif-disGipliae aad personal
devotioa at a le^i t^at csanot be siistaiaod iadefiaitelF
vitboat iatell®oti%al s^fresbac^at aad reviiifificatioa.
» bigiilF creative scieatific tTorSSe vitb the iaw
tioss msk iffiteraal iavolves^at that this eatails^
to '*go stale" i?i^out periodic reUef ia the forsa of
o|^iort^iaiti®s to roam? tSK»ir »aatery of the fields
to leara ae^ t©ehaical a@d coa^»ptaal ahilis aad to <^l>taia a
i^r^ persi^cti¥@ o^ ®@i@atifio valaes reiatiag to their ik»s&.
ISO asm degree this Mad of "<^aag0 ia pace'* is effeeted b?
iSia iadividml iave^tigator vithia his aor»ai wsMas pattera;
~ ~ a of Tsarso he is liSeel^ to beeoat
less a9are of the cl!;»as9eptiaal strietaree ^i«h ma isipoveri^
his ace(»pii^iiag eb^^t® effeoti^?® aad ereati^ ^^avors.
t^ai^ersities of hi^ staadia® hssm loag re«ogaifled as
latial re<sair«wats for stastaiasd
hij^ (piality oreatiw s^ioian^ap the need for their seaior
f aealts^ sm^rs to "^ givea eisteaded periot^a of t&ate avajr
froa ret^iar dutieep ^sssali^ at ee^ea-spear iatervals.
Liiliorator^ CS^efts of the Basic Bfeseax'Ch Progrssp
iaitiated dii^m^eioi^ oa ^M,& es^^e&t aad were eaooar^eed
hf th® Bireolsor of m^s ^> B:^sert S« Steiis^ to draft plaas
for St. '^Sab^i^i^ai'* Imme £>rosr8ao ^toder the (^aimaaship of
Dr. David m^^^ am Mtm G«Bsaittee estabUiS&ed the easeatial
«. ^ ».
tettoritF for mim p^mttm i© f^sim^i ie ©^sitis^ TOgalstiss^
S^?c^d@ t^ mel02' ®©toatist Ii®l©ag4t^ t® ^® pesssansait
otteeiMs t© neqet^© ist®lLl®ctia£l assd t©<5^sic®i skills aM
to &a^ es]^£>i©s^^ i^ t^ &Mmmto& ot m&m aMll@ %o
sfftsfeiag iswi^s ©imHas- ^ital 4at©ia©ct^Bl
fsiastioa intrinsic to ths life oS aa issvastigator.
Svsal^ tle@2® waas a® ©sspsv^sios ®f ss@@d for ^©y© formal aEd
3s»sif@@ ^wU nm m&ti^^ eisHsm&S&aa into £ie:
, _._ SJS'®vS.®4o® of «3o«ss'®© ^mwU a®^ ss^sa^rs «^®liag into tk^\0B
J?©©? ra^^®r© of t&5 WI^ Seieatifis M-wtm^ Cc&^t^m ©s^afe-
m^t&t ©f BdE^atidia is t^® 8Qi&mm» I^.s i^ids ^il f@ei3.itat®
8. gerttoip ©st^jKSioii @f @<!l?i^at4o®ai op^z-t^ssiati©® at t^ Ml,
Ds". Dmi©a. Bt^$.^m i«5 ^Sd2f®^ ®f tto Soa58?€l of M2»etOlf8 of
til© ^f& WmM^ttQ^, fto Eo©2p«i ais© ii^iia^^a ©^§Sa®2' ^p?®®®g&t-
ta^s® OTO^e will ^ i^^Xy g5©it~ssEStaiaiag Si?<si tisitioa.
eas p£^¥l«i^ will ^mii&^f^dl^ ^ow® ^^mttet&l t© t^
»» «.
wbia ^Plvm ieml^t a@d j^at&sfacticm trcm p&Jctletp&'^^W i®
Shaam&cologs!' h&'^® €>sinr«0so<i tlieir ao#4 fos* a f ^cilit^f fas'
direct invontigat&osK of al&s&Ioid fipy&tl&@®i® in pIJ3At««
Duriog tlM» jr^ar a ntsat Ilttl® sreead^oiape veue coioatiractoii
smA ps&t isito opjratioffi is]»d@r tto direction of Dr« aanmf
grcmpts of traaQ)»ill48»r@o iHE^dAOtoffiisotie drogSs Btarcotict
figi«!i»tSo «to^tnMisii!<ie8 aa^a 4C«vft&ral stlBUlasstiS caa noo h®
BttsOXed ia relation to thBts sietaMllc pswcmsnsijsis a^
tlw vs^ itt lOftieli tlK9iP as^ liafidlQd and isaetiiratiiKi ^
plants. It %7ill al@c hsi poe&$hlei to lai^i c<^;»l<9.%
I^ST See<ti.»g plmtm ^tH radioficti^ Smildisig; Mo<^l&8e ^ tMe
s^osi&Q ill ffiasiiF ^B&eus &&v3Li^ di££laslt lal2or&ktox>7 e$i»t2b«tie
!S%^ £ir@t picocedwres tmd^s^aJtoait 1^ Dx>. ^«M ^ffid
bis Gallsi9W*i»& iS2%v® «»tal»Iiffilii®d ceartaiss oowsosi £«iatur<fi«
of ^otaS»ol£o pat^»a^« ^Mis^ ara coeiaa^m to Mi^r MaanalSei
0iss;le G@llod orgam&saeiis and M{siM»r plmit&, mis m^v^latio^
coafi:^asi
that it tr&.Il l»@ practicsi&l® to ©ssadis® a
^rsmth aad Sftaxreatia® o€ largo qumitittoii o£ partleelar
aatalsoUo @te|ss ^11 i?s»6illtat® tise eolation o£ a maOmr
of iJBportimt g»r«^^lcis^, ^Xth m^ti&lsk imf atmm ostabUislMd
la s»lafi%» m^ ^"^ issc^lodgo of tl^ easo»tial muSsstrateSi,
oauf^SfidSs ^^iOi&QtcfOif- #i(»a<, ii wiXl I2® pommSjal® to <30isflx«
fiisd «xtaad tMm flMls^^ eaci& si6»r@ qisicielj t& hisl»»r
s&»imal@o ^«d^r@ of t^ IstStoratorf wtXX &sm b& a3»l® to
@i£d to io^ for tariaBt® ass^ i30MSl@t@ac&«>e ov@>r a v®x^
h^oBi& Molog^oal field of ©aid^avaro
mmmL ommmmi
misi F®ar l&s« ^lt^i^@®d a ooiattiasi&sg l^^nn^ciat of
o^tstasdiiag rseaar€i9$. |)api£s^ frtci® tli® aasi« ainKWarc^ FsfOigrasK.
Hie ent&r® ent«3i^ris« ' @aa !st@i 3i^acU.l3P Jiastifi^ o^ tto bral«B
of a tms of i^ie ^^allj' C3f@atl«« id#aa broisigSit forS;&. ¥Ss«s
©tatft® of ^h» f^ifOgr^B i® also js®Mi8!ir«d fegr tlae las-g® aum&or
of iwltatioaai w^icfc fr.<aa^ to 4t® ®ei®siti©t8 t<s p?«Jirid© pai^ea"®
for aatioml tmd iatarmatloaal jaa^tlsagej, «md to l«ct«jre to»for«
or to ioim tH® fec«ilti®m of <mt&tmm.m midmrmlU®m> ^«sdgl2Si;
i^ tte ImiTomtm fmg^Ulcatl&m of »ci@atifstS3 aoegsiJ^ pomitU
tor^o It iis ®Ti^nt tSsat -y&e Pro^'sa is ^alsdiig In mm^^tlom
m m IntolUjefetmal sm^ msm&viwBv^al v^mmxc® for ^IMotlv®
- 31 »
ecieati£&c training tanA @S9srtesee &t ail ie^ols. Ss&rXjr er^vf
^laivoTsities Six& »®pvesmnt»d Isgr on® or isore scientist®
ia t]ii9 program this ye&r.
Dr. lortitter MlsMsia ^m eoat to wor& £or tluree
«».».«, at the S^adei lastitut® ia Warsaw, folaado aad Dr.
Stafaa Brutboeiilgi of that Xastitute has boea seat h^ th®
Polish Acadenr of Seieaoe to yorh with Dr. llishhia aad Dr.
Bal Bosvold for about a jrear as a Gueet Worlsor. Altogether
sixteen of our scieatists were seat abroad for periods of
trork aad iatollectual eacchaagpa dariog the year, there v^r&
aias scieatiets is the ^ogrsM «ho attended iateraatioaal
Boetiags outside this cotsatrf , Dietii^^shed scieatists
froai sore than tveaty differeat eouatrie® ^ieited the Basic
iopch ffrogrsaa this jpear.
of the traditioaal «a|rs of iapro'Pia^ the creative
of aa orgaaiaatioa '-— > thi^igh the use of eacj^rt
•— has beea activsljr esploited this ipaar as
ia the pasto 'm^ t«el^ MStfbere of Boards of Scientific
Conacelors of the two ZastituteSo ItllB aad JSlSOBg have con-
tioued to give eacouragsaents iatellectual etiaulatioa aad
to provide prograaiaatic as eel! as scientific advice. S€ssm
thirty seven other eaEpert ctMMUltaats participated and advised
ia xelatioa to si^ciaX aspects of the Trograsa. ^ofeeeor
Terstea Veorell of the Ihidversity of ^ppealao S«edea and
Professor llXrich Fsraach of tte Bez Plaaek Institute in
OaxBHStadte We@t Gszaaaor ceem to woxft for a period of tiae
with Drs. Zchiji Tasahi aad Coastaatiae Spyropoulos at the
Woods Sole Sariae Siologieal Laboratory this
Siailarlyp Drs. Sydney Breaaer aad Traacis 2« C« Crich
CaEBbri
froB €aEBbridgei> Sne^laiidQ paid worhiag visits to Or«
aerahard's Section oa l%ysical Chestistry. Altogether absut
a dosea foreign scieatists speat worhii^ periods in tto
Progrsai« fhrossgh a chance encouater with Dr. Eaamsel P&ore{>
Zkirector of B^^earch' for t^ International Busiasas Itachiaes
Corporations bm eosce^ionally escitiag resesgrch collaboratioa
has been arrai^ed. %« Sidney Bora&ard iatroduced a grov^ of
eagiaeers aad saathesaticiaas of the zea Beeeorch Divisions
violting Bethesda at mto Piore*8 sD^sgsstio^ to the conceptual
of '*br@^i^ the eo^'* f$ir
«f taitae ptsi^ in m^miXe trasMnissiono aad saore ^nerally ia
all protein syethesicB, Dr. Berahard aad Dr» Daa Bradley had
of a way l,^ which the bulk of the preeeatly tedious
Leal identifications of oae after another of the aaiao
acids ia serial order could be short-cut by utiUsii^ advaaced
electronic oo^^mters in elaborate logical aaalysesp Dr, WilUt
Ouda of lEas has since then been devotiag f^l tiae to the
difficult aatheaatical end of this isvsstigatioa. m has beea
able to pat to worli the best ZBH coaputer prograaners aad to
Lt the ffiost aodes^ esm^ter e^suioaeat for this purpoas.
- ^ ^
tsciftoiar aotod for his ^^ Im t^@ fi^M^ ^o died
stop tkmB f a^ ^ss ps'oc^sciQd f a'^orolil^
&B to ^s^^tSias^ t^ ^n&oe^ptB a^
mm^^l&ms ha>tk t^ m& ttB BaMe ^«^^^ .
of iEi^®®tigatiois 9ili to «<orta2«MI®, m®r@as it
ir@a?® of cosspiosoe^ly eoEsacieati
@os*le to 4»ti&v^ms t&@ ^qoseoQ of lea&so aeids ia
V^^S/Sim tM® tim to & g|Rtt®7 of St f®v ii«s&s« S£
o^t Savos-al^a^ it ^11 vsatly cioe@X@?&t« t2» aaaj-^isia of
di££®2^^iKBft ia '^^ aljQGNSt oQisatIi@8s protoisffl of iagportaaoo
to Mologsr es^ ^^Oi^iosgo ©^ it will me^ p^&stles^lA tiM
i^'Stific&tioa of ^ @it®s of «l@f@ct of gea^tieall? '
<l@if®i®^@^a.l g»d @@t&l^l.ic <^»3fo^m>
Diirii^ tl^ f^as* Parofessor Iso Sssilard snil»lis^d t^
t^isos^ of agisig -wM.^ h^ ^wXo^d isMIe fi^rvias as a
C^^g^alteBt to ^e i^'ogs'i^. ^ sioi? I.e^ ^propsratiom t^o
E^fw ami ©Q^aii^ cli&ilei^i^ pap^r^ oe tli© t&®os7 of aati-
i^<£^^ for^&tias^. Mtar lo^ deii^ratio^o Dr. Sisilard
€l^®li£i&d a&plo^^m^t is tM® Progrssia ia f a^or of ose^pttm
a io^-t^m MIE ©sts-a-^yis-ai groat nisic^ irili allow &ia to
retain M® i^at at tBt@ las^ieo S^x@i Ia@tit«st® ia t&e H^ves^it^
of Oiicsg© mkd ©till eoliste^a-te 'sltfe o^is" mtmSt f ©y «i^t®®«^«S
^ric^ @@ a Qmst Wo£^£>, ^fortsmat®!^^ tli@ sa@@ ^@®gE t&at
Br« ^S^l^rd ^om iafox^@d of favosrs^le aetioa <m t^ MM graato
to also i©a?@@d that ^ ^a@ a feig^li^ ®ali@aaat t^^r ^sliic^ is
A f!iM4Miy[. ^^m
Prior to ap^iss'^ggmt s® Dir^ctos* of Basic Se^arcb for
til© t'&o IsstiMt^Ss I' dis€s^a©<i with ©^^s^offi© cos«ai2'S©d
^iilf©2ra-ti© li^tstio^ ©ja t^ l@£^tls of ti^'l f@it it
70^^saal»l@ to ®o^mit to msf^ h&mf a^aiaist^ati'P^
Mliti@@. ^i® ^ar, ^^^ti? te@fore tli® ecstplstioa of
F©ar@ is of fie© 9 t as^d tte t^© Iss@tittst«i Dii?©€stoy©* ^arsissioa
- sa "
to Ir^ mU^m^l fs«@ ^lis ^&qs^ '*i» tM ^a? im^mm
^l.i0W it is- S^nlwetM- for a scientific progrm to Isave a
£iMta«i«Mi@ i^y.^ gam U^l^ t& ^assm s^ &mssms^tm
%m ^b& m^t^vm m Mm ti^m tn oMtm &® sti?®tclK»S
fiFw«e Its "^» pGse@a@&e^ oS tli@ pa^@®r to ®s^
Ilia® ilMt (£«sl^es fri^ a ^^97 P$ir0o@a3. c^^s® to oo&ttm^
- 34 -
2^>;^l^sla©d Pai^gs
W@ pp, la; J. Hist. ^d»e 195@s ISs 111-112.
2. M-risapstosj RoB. Ceatyal eoatrol of afferent
actiiritfo Oispt©r 7 CpP-. ITi^lSB} sad Di©e3S©0ios
Co6t@llO0 H.T. ©ds* EaticaXar fogaaatioa Qg ttie
bga&a. B<^toa3"IIttl©s Bro^a & (io.s i9f^
siv ?< f6@ pp.
3, Livlsj®stoSi> B.B. Csatral coatrol of receptors aad
s®E©orj trasjg^lasioia ©ysteisB, €&apt®r 31- (pp, f41-
[ 7^) Imi Wields i?.9'Magomi, B.W.^ aad Hallo ¥.£.»
eds. laiidl»oo& og gfaysAologys SQCtiOia 1; Ifettro-
loloCTg vol, 1, WasMsgtoSa D.gr7"^Aiasrica£^
Lolciileal Soeiet^s 1958 9 alii ^^ 779 pp.
^^iu
Vesti^lar Intlfsi^wx^m oa spiaal @@chaM8ms« Sgper,
^wrol.a l^i^o 1: 248-273,
S. Livlsigsto@i|, R.B. StSBSiation^ pp. 417^423 la: Brasier^
H.¥,, M,Tr: OTosiaSi Maoy, ^r, fdiia3aiioa„ 1&SS>, 4S0 pp.
s^m&Bi OF imt!ML upoafs iiBmy
©rgaala^d In tl-90 seetioiiSj ©a® ^isg a field ®tati©© ia
s^!28is^F ot th@ s©©tios's s'essars^ astivltlQis ^iss-iiBg !§§©.
Ill® sr®sea3pe& of @a©la seetioa is e^sffiel^Btly a©iq«© te
safe® an overall ©las^a^y of asti'^iti®© 1©8S ®©aaiagfial t&as
Ih^iag IBm^ U^®, Eidaard Si^aa, Srsa© Miai©
&ud Med W@d®^ ,l@ft tk® s©ctloa f©S" pe©iti©as ©isewia®^©^
SK-Si Sidamn sffl4 F©«l©s? goiag t© las?'rsz*sl Haiversity, I^o Misl©
to Cairo J Igypt* S^® x-esearsla associat®, ©?» I<®aa®t& Wolf j,
«©spXst®4 bis toisi? ©^ duty aad traasfeffred to ^asssefeiasetts
!l?2&@ tissue cultur® ^ssilt husi bees ts'a^^ferred td
t^@ S©©ti©K ©a M@m^ocjtologf aad reorganised iia<l©2? Dr, So L,
Eeseas-eli acti*#itie© of thm ^eti©a oa B©¥©lopi3®at
aad Keg©si®ratl©s fall iat© tli© eatagog"!©© @f C^) s®®:?©-
aiteratiGSi© is t^© ©aatea.! sa©r??®^^ sy®t®^o
ta'iti?m~lafe©l@d tlsi^midia© iato d®©^ril3©ia?2el®i© acid iMA)
of ^jy?ki®g SMsh c©Ils la tla® sf^slatively iimecessibl©
sai^Eliasa ©^^^©. P^©gaa.at sic© wer® 4iy©©t@«i iats'©¥®a©usly
^itk t^yaiaiii©-^® aad &ill©€l at various i®t®g'¥al©. Auto-
radiogrsi^ w®r® pi?©|»ai?ed of ©©ctiosia tlsroiagfe tfe© sa^ry^il©
teaiia©, li©¥©a~daf s^ryos fised ©a© toisr aft©r ®a^iJ<ss«H'© t©
tli^i«lia@-=E® ©&©^©d li®avy lafe®Iiag of m^&t c@li aiicl®i ia
~ g -
Asmioial Eei;>ort@ (I95@)
wail of til® cerebral v®3icl@^ si,ud almost no Ialb>@ll&@ tn the
iamer h<o Thus the exteroaX l&a.lf of the prisaitlva
ependym^l layer is the sit® of I^A synthesis, 31k hours
aftsr &z.posms'® to thysaidiae-H'^; th« labeled aucl^i occupied
the Izmeic (veiitriculsx) half &t the primitive ep@iadysml
layer J, and sost mitotic figures at the ventricular surface
contained labeled chroasMBosses » Forty -eight houre after
injection^ labeled nuclei had migrated ls.t^ra.lly; aoms had
entered the d@v@lopi!ag £aantle layer ^ but wnny retained in
the primitive ependyiaa and had repeated t.he cycle o£ MA
synthesis J, siigration^ and division ^ Bevolopment &£ the
primitive ependyaa was similar throughout the esibryonic
nervous syetea, the data show that the cells of the
primitive ependyeasl layer behave synchrocously^ ai^ that
the site® a£ IMA synthesis and nitoais ai-e different.. The
vt&etB ot Schapsr and gauer are conflrtsed: the primitive
ependymal layer im & p@eudo@tratif ied coluustiar epithelium
within ^ich nuclei of undifferentiated t^ells laigrate to
and fro in relation to the mitotic cycle o
Using this saas material,, in additional experinenta
employing tritiuis-labeled thyaidia® in Edce^, it was found
that the pris^rdium of the cerebellua mid® its appearance at
11 days of geatationo At thie tiioe 3 a^^nes c<M^rising the
pri@ordiu£i are recognisable, Cell^ of the ependyseal region
migrate into the intex^mediate ^on@ to participate in forma -
tiosa of intracerebellar nuclei o I>ev@lc.psi@fflt of th© varloue
c©j®p©si®ats of th® cerebellum were trac€>d on different day®
of g®stati©n of ®iceo Th® ceils destined to become Pur kin je
neurons isigrat® froaa th® primitive epeiidysal region to their
definitive poaitlonis in the future ceri^bellar cortea: and
rapidly differentiate there <>
These banic studies on histogeneisis of the nervous
system by th® tritium-labeled thyaidin'S technique and radio-
autography have been discontinued reluctantly^ those
participating in theei having left the laboratory. It is
hoped that other studies will be undertaken by thia method
i^en personnel are recruitedo
Cb) DrSo Lo Guth and C. J. galley have carried out
studies to evaluate the relative role© of th® syapathetic and
parasyaipathetic pupillary nerve fibers luad to detemine
whether autonomic neuros^ can maintain the function of auto-
aoaic effector organs other than those that they noraally
Annual Reports (19S9)
iaaervateo They have observed tliat th® atropiaised pupil
dilates significaatly ia darki^^Bs ai&d that a slgaif leant
portioB of tkis dllatioa is abolisi&ed by sympathectoayo
Contrary to ct2rr@nt opl&loa t^® sympathetic :&®rvous eyetera
playa am active rolej.ratber than laerely a tomic o&e« in
n&intainins pupillary dil&tioia in darkness, Furtberaora«
tb@y found that pupillary sis® was partially restored under
the influence of "foreign" nerre roots ;, altbou^h tlMse
roots did not mediate a "darimess reflex" c Ibis vas
accsoi^llshed by transecting tbe 8yaq;>atlietic raai of T 1 to
T 3 to alloMif collateral sprouts froa rcuai of T 4 to T 7 to
innervate tbe pupillary ganglion cells of the superior
cervical syiapatbetic ganglion in cats. Tbe nerve fibers
apparently retain their original specificity j, inasamch as
tbe heterogenously reinnervated pupil dilated in response
to decreased environmental teaperatujceso Although Dr .Bailey
has left the sect ion ^ Dr. Guth is continuing these studies o
Dro Guthp collaborating with Dr, James Caapt^ll
of Columbia University aad Dr, X^aatar Soutter of Boston
University 9 is trying to determine tdðer or not diai^irag-
aiatio function can be aaintained by the recurrent laryngeal
nerve in aonkeys. "She proxiaal recxirrent laryngeal and
distal phrenic nerve segaenta have been anastonosed in large
CynoBolgus aonlceySo Eegeneration has been in progress for
nearly one year. Dr« Earl Franlc of the Laboratory of
neurophysiology will cooperate vlth Br., Guth early in
Koveaber to deteraine el€M3trophysiologically the state of
the diaphragaatic relnnervation in these aniaals. Dr. Guth
previously conducted a sijailar study in rats and demonstrated
that vagophreaic az&astoaosis did indeed restore function to
tk@ denervated heaidiaphraga. If the eicperiaent in the
monkey succeeds j, it irill be possible to ccmsider application
of t&e operative procedure to those haaan disorders
characterized by pathology of the phrenic nerve, for exai^lep
"bulbar" policmyelitis, to try to enable patients to survive
without the assistance of an artificial respirator.
Chief of the Section and S>r. S. a. Feringa^
collaborating vith Dr@. J. 3. Caapbell, A. Bassett and
Co Thulm® of the Departaent of Meuroeurgery^ Coluabia
University; have continued to study regeneration in the
s^^^aliaa spinal cord. A study of transected spinal <ord
of 16 aoakeys with ^pm of several ailliaeters vas car/:led
outo In a report of this ^orls. presented at the April ae^tlng
of the Aaerican Acadeay of Neurology , postulates for
4 -
Amaual Reporta (1959)
d«tarsAialng ©fficacy o£ regeaeratioa ia the ceatral norvous
®y®t«a w«r9 laid domno Titss© ar®: TlieK'© laast to© proof that
tl&e spinal cord was B@vered, tl&aro Bm®t b® clini;ialiy
obsorvable sigiis of restitution of isotor aad/or sensory
functions; th®ro must be proof of physiological conduction
across the healed lesion® a including electrical recordings
from the spinal cord following stimtlation above and/or
below; transynaptic potentials mast b® d<s^onstrat®d ,■ finally^,
tl&er® mi&t be unquestionable irerification of re-e@tablislia®nt
of histological continuity » All of tkese are needed in one
and the &sm& anis^l. To date., no single esperiaent in tbi£>
or any otaier laboratory l&ae fulfilled all these postulates
ia tBaaaalSo Current studies in cats and laon^eys are in
progress coBdslning the techniques of surrounding the lesion
with Hillipore to prevent encroachaent of connective tissue^
and treatjaent of the anistals with Piroiaen. Multiple short
segments of frosen dry peripheral nerve hcmograftSp have
been isplanted in some, A preliminary operation to fuse the
skeletal elements of the spine prior to spinal cord transec-
tion has led to improved histological and physiological
results in catSo By conbiaing several procedures p each of
which has soaae d®33onstrated oeritp it Is hoped to achieve
fulfillnent of our postulates o
Dr. Feringa^ collaborating with Drs, Canpbellp
Eassett and H&uline^ h&v® explored oethods of grafting seg-
aeats of large peripheral nerves ^ using the goat aa the
principal laboratory aniB&lo Eoiaoiogous nerve segssents^
banS^ed by freezing; freezing and irradiation 9 and freezing
and drying; were i^lanted in gaps produced surgically ia
the sciatic nerve of these animals o Preliminary studies in
cat© J, with saailer nerve© « deigns trat®d siE?ift functiimal
and anatomical regeneration across gaps of I c®<,e bridged
with freshen -dry segnent@ of nerve wrapped in Millipore
sheaths o It i® hoped that the studies in goats will provide
inforsuition adequate to permit the method to b@ extended
to human subjects for the repair of large peripheral nerve
gaps.
<c) Studies on alteration of th@ structure of the
central nervouss systesi resulting froa asplzyssiation neonatorum
and nitrogen asphyxiation of newborn and young asonkeys have
been carried out in collaboration with aumbers of the field
station Section on Perinatal Physiology in San Juan., Puerto
Rico 9 and with Dr^ J» CanBerueyer as consultant o
<, S ".
Asmuai Esport© Cl®^®)
AspMysia a@onatoruii ^m@ isiduced la saoaksys ,^@ar
terra by detaching the placeata at hysterotcmy uoder local
am®@tli0sia£ keeping the fetal a®stbsranas intact » Eleven
to 16 minvit®B later the fetuses were delivered froa their
sembrasses aM resuscitated by pulfisoaary iosuf flat ion with
oKyg®n. The infant monkeys shoved neurologic detlQlt®
during lifeo Five were killed by perfusion-fisation at
2 to 9 days of age^ Brains of these and of 2 vhich were
not asphyxiated were studied c A coiaaon pattern of structural
alteration was encouiatered in the nervous systea of the
asphyxiated aonkeyso Muclei vere syiametrically affected;
those most consistently and severely dasiaged were the nuclvMs
of the inferior colilcultiSf gracile and saedial cuneate
nuclei], roof nuclei of cerebelluia^ ventral posterior group
of «l»halaatic nuclei ^ globus palliduSf putasnenj, and vestibular
nucleic The cerebral cortex w&u severely danaged in only
on@ i@onkeya Lesions began irith primary nerve cell and» less
frequently 0 neuroglia cell lyeis and losso Secondary daoage
of myelin sheatha,, and reactions of astrocytes ^ endothelial
c®lISs» vascular adventitial cellSj, and phagocytes vere notedo
A relation of lesions to vascular distribution was not
apparent o Heisorrhages were seldoa encountered o
Asphyxia neonatoxrua vas Induced near tersi by remov-
ing fetus in aenbranes and peraitting its respiratory
aoveaents to stop before resuscitating with pul8K>nary 0^
insufflationo Six Infants were killed 3 to 10 daySp one 10
Boaths later; by foraalin perfusions Oix newborn and
4 juveniles were asphyxiated in 9^9 resuscitated sinilarly
(cardiac arrest in one)p and killed 10 days later.
Appropriate controls were provided » Brains of experiaental
and control aniaals were sectioned serially for Missl and
other staisaso A consistent bilaterally syaaetrical patters^
of brain damage always followed asphyxia aeonatoruSi^
conforming to nuclear boundaries „ Ho hei^orrhages were seeno
Reuroas amd neuroglia vere destroyed focally in 3 or 4 dayso
Beactiona of macrophages and astrocytes began before 9 daySo
The aicroglial reaction had cleared at 10 aaonths^ lesions
being aarked by asphyxia. Least daaiage occurred in an
asphyxiated newborn requiring no resuscitation; w&mt daaage^
after 11 minutes ai^phyxiatlon, Muclei of es-uditory,
vestibular^ and stKuatic afferent pathways ^rer® prone to
injury, with aaxiatil effects in inferior collicuiio Cortic&l
lesions occurred in two; a central cerebellar lesion in one»
Hitrogen asphyxiat; on failed to produce this pattern of
destruction; no foijial changes were observed 10 days after
cardiac arrest » Aitphyxia neonatorua and Mjs asphyxiation have
quite different effects on the central nervous system of
Kacaca ssulattao
Asmual E®po£>ts Cl95@)
CKalsea pig f@tue®@ w@r® asp^ysiatad at t9s% by
clasping the i&teri»© blood 7@es©l@ durusig laparot<xB^ aad
r@suscxtat®d by xnButtl&.tlom of their Itmgs. Ol^ex-vatioxts
o£ d@gx-#8 of aapliyKia m&d d«gr@@ of rasultieg aeurologlcal
deficit ^®TQ B&de. Tl^er© w®r® indications tliat asphyxia
9Vdn in aaali degree produced aeurological deficits at least
trm&siantlyo Asp&ysiBt®d aaiaals asad th^ir control iitter-
aates ^®r® t@3t®d in an alternation ^so during t&Q first
we®k o£ lif@ or dtsrin^E tis@ t^elftla ^®®k. Som@ of tlaes® ^®r®
tested also isk a v&t®r sasi® at alK>ut IS aontlas of &p)o
Asphyxiated ani@al@ ^ad® ^»r@ errors tSian tbe ctHSitrols m
learning tliese tasfes^ althoo^ releaming test* did not obov
t&at tlisy forgot aaore rapidly tlian controls. Tbe learning
deficit seoaed to becGsae less ssarlced am the aaiieals grew
older. Tl&er@ va@ no correlation of learni^ perforsaance and
degree of a@pl^y:siap Th® l&istological examination of t^e
brains of tl&®@e aspMysiat^d pigs repealed ds^age sisailar to^
t^u^ less s®v®re t^asj^ tMt reported previously.
w@r® a&mt only in acute stage®, dsrosaatoly t ic
in sieoro^s^ loss of n®taron®« aad neuroglial reactions
appsared^ notably in the bral& stea and thalamus » Circuta-*
scribed bilaterally syB^strical loci of daa»s^^ ^mr®
e©co%3ater@d i^ t^e tkala^i of loag-ter® aniaals. fhm ©ign@
ef dsM&g® w®r@ l®se ^rkmd in anij^ls living for a year or
s^re t^aa im th&se dying during the first few days or weeSss,
tt.® neuroglia cell cbanges &ubstid@d wit& tis^. Long-tera
survival animal© exliibit@d lainiisal brain dasmge;' ti^e cerebral
cortes and cerebellum app®ar®d to be unaf fectedo Tbis
GEperi^nt yielded fm.'-tber evidence tl^t aspiiyxial episodes
at birtt^ produce neisrological deficits ^ learning defects^ and
brain damag©. It cststs do^bt ®n tlt@ tresis that tbe skort
&©p&yxial episodes @©@n clisiicaily do not cause bows
usidesirabl® s®q«@la@^
Section on M®urocytology
So L, Paiay^^ d&ief
As tbe Section has dev@lop@dj» its interests and
pi?®bi©ais ia-B'@stigated fall into two categories: )^>rpbological
aisd cli«mical.
la tij© first group oiar in^^estigstioa© tfeis year have
h®®n directed to\?&rd learaing m^r® abo«it tke relationship
h®tw@esk the B^uron ai^d itss support xng structures j, the glia in
th® central nervous syst^ aad the capsular cells in the
sesasory ganglia „ By isprovisig the preservation of the central
- 7 -
AsmwaX E©|rarts iimw)
©©sp^oiss syst^a ssid fef careful ^tisdj^ of tfe© 2aoa-B®ural
«i9a»ats we havo obtained a t©^tati?@ pict%ax>® of tb® two
Bost aisiaerous glial £©1I®» "^©s® two calls huv® ba>@a
variously described by otl&er is^sstigators ^Ith thct result
t&at a heated discussitm bas arises ©v@r tb®ir distiagssisb-
iog cbaracteristicSo Hii® controversy i© i>as€'d upon tb®
faets tliat aeltber @id@ in t^© argus^at b&s aobie^ed
s®tisXact©ry fisatios ©2 tl&® tissts© a©d tbat ii®itb®i:- sid©
baa !^de ol^@rvatl®s@ pa^'allel to th® @tb®r, A@ Hii^bt Is®
©3?p®©t®d o\sr ol^er^atioijs iadicat© tliat h&th sides Im-^©
sea© dsgs*®© of ©rrog", TIa© Sijrat ©©11$ idei^-^ifled mi tli©
oligodeadroglioeyt®^ occurs &s a satellite ^f n©iir«%^ aad
i^ rows iB tbe fa@cic>ali of tbe ^it© s^tteifo This «ell
aucl@ii@ aad a t?ell»d@£ia@df irregular border ^
a cytopla^i de^zsely paotced vitb rlboauclCNdproteia
i;^ €@d0pla@isic retic«ilim is spei^e^ but;,
sip&ificaatly^ it bii© a teadeBcy to swell iDider lesiB tban
optical ®oEditloii@ o£ fisatios. Because of its tesdeiaey
to swells tSsis cell bas beeo oaly poorly praserv^M by other
iii¥esti^tor@ ftiad h&& beea desigsate^ ^© tlia astrocyte by
eiiie group aad tb® oligodeadrGgliocyte by th® other group,
•^e- secoad e@ll type bss beea seea by ©say oa© of tbes©
groups of i^"ffe®tigBtors, ^i® celli? identified by vxas as
tfe@ ast^ocyS;© im agreossat ^itfe Lusa* i® ^i^e I'oluBltoua,
ba@ asa igad®jat©d or irregular isucl®u©» and r. kigbly folded
boundary, M section it is s^i^rouiaded by cluster® of ^sall,
rousfeded or ©¥al profil®©^ ^©^^ats of th® iiu^@rcms sleadsr
prososses protrudis^ fro^ its surf Be®. ^4 J cytoplasa is
l@i@ d®si£3© t^^ tbat of tb@ oligodesidroglii^cyte a@d tb®
eiadoplasiaie 2?®tieul?i® i® proaiaeat ratb©r vJaaa tb© riboaucleo-.
p^'otein @raaul®s. ^Iso loag, tbia fila^eats occur ia
fe^mdle® ia tbts ©ell aad is tb© procss®©©, Tbis study is
©till ia progress o Furtber ^orfe mmt h® doa© t© ©ubistaatiat©
th®m dsfiaitioE© of tb© t^@ c©ll tfpmm.
In ttm p®ripb®ral gSBglia ©lacb aeuroa i® eaclemed
witbia a cap8ui@ cossiiietiag of icb^s^a cells « la tbe dorsal
root gaaglias tt^ capsui® ofearact®ri®tically is closely
apposed to tk© aurfac® of tb® s©iaroa ^Ee@pt ia certaia spots
wbere tbe two surfaces diverg®, foriiiag bays or lakes iato
^icb tb@ capsular ©@11 ©ead© protnadiag ridges aad aicro-
¥illi. fb©s© spot© ar© associated witb intracellular
¥@©iel®s ia tb© capsul©. It is possible tbat tbes® forms,-
tioa© ar© r©Iat©d t® ioaio m:tv^smmts duriag tb® actiiimties
of tb© c©ll ©urfac® ^icb is part of i^uls© propagatioBo
la tb® gasgiia ©f tb® eigbtb ^©r¥©^ mfBllu coat© maay of tb©
anurous. W@ lm.vm @tudi@d tb<s©@ ia tb© goldfisb. ?b® ^y©Iia
occurs ^itb ^ario^i© d©gr@©3 of coaipactaass o Modes of
~ s =,
Asmual Eeport© Ca.@@@)
I5ajsvi®r are abseisto TM® pr®s@ae@ of jeyeiia oospletely
surrouQdisg % s&e^iroia rai@e@ tl^@ qu@®ti<m of transport
o£ siatrl@!it@ a&d ©sschaa^e of ^@taboilt@& b@tv®®B tb®
aeisroB aed tl&@ ®strac@Ilular spac@o Stueh cells are
9&s'h&pm miT& B&en&hlm to pliysiologlo studies t&an those
o£ th9 Qf^&tffsa a®rvou@ systsa w&er® dxtracollular space
is also limltod^ by t^ clos® pactei^g of all eleaents.
I»ro Brigiitaasi and DTo Allseifs have cos^leted a
^istocbaaical study of species diffes'e&ces ia the distri-
Imtioa of c^liaestera©© activity ia th® ceatral aervo«s
syst^sio P@eudoc^.elia®iitera8e occ%t?s ia tt&e vascular
®adotla®liuB ia tha rat^ goldfisslip aad toad^, tout ia t!i®
glia of t^e cat aad roaster c The sigaificaac® of this
dietrlMtioa i® aot cle&r at pyeseato
1!&@ clK^Ei&al studies of tliis sectioo have
c&r£>ied out imder the directioa of DTo Altosre. His
iavestigatioa® have Iseea coaceraed with the role of
7-si^siiaobutyi-ic acid ia the metabolic areactioas of t^®
toi?aiii« thiB study is based upoa the obsesrvatioa that
V-assiaobutyri© acid aad ita direct precursor ^ glutamic
acidp occur i® large quaatities ia the braiao The easya©
^icli catalyses the coaversioa of glutasate iato GABA is
localised ia gray aatter^ possibly ia the aeuroas^ aad is
aot fouad ia other tissue® of the bodyo The setabolie^ of
Omk by the ceatral aerrous system is liaked with cerebral
pyridoasiffi® isetabolisiB a^ i?ith osidativ© systesao by ^ay of
®p©cif ic ©asyseso It i^ postulated- that s2.utasat® aad
OmSL are iatermediatets ia the osidatiosa ©f ©-ketoglutarat®
by braia smd that the®® iateraediates ®ay be of siajor
quaatitativ® ia^ortaace ia cerebral oxidative aetabolie»o
Eoweverg the rat© of coaversioa fro® glutasaate to 6&BA ae
^asured ia isotope e^perimeat^ would lead to aa extraordi-
aarily high rat® of essidative metabolissa^ evea if oae
assumed that all cerebral oseygea ooasus^ti<m was obligatorily
liaised to mm ssetabolism. Thus the hypothesis must be
tested further 5 hy esplaratiem of the ©ise of the pool of
active glutamic acid ia tfea braia aad by critical aaalysis
of the itethod^ fc»r aeastsri^ tk© coBversioa rate to Q&Bh<,
TIk© section h&B fesea host thi© year to BTc Joha
HillSs MWim traia@®p aad ISTo ^iry Srilio^ research S®lloWg
both of liacm will h@ studyiag certaia &©peetffl of the
peripheral aervou® syst®®, Br, Lo Issbre® hass joiaed with
BTc Altoer® as a Research Aa®©ciateo
,&si.aus.i l@p©i?t© ilBQB}
CoiI®g® i® E®ir©rf®2"dg Psaas^I'SfaiaiEi, aiad also l@etw£'ed
at tia© E0©k©f©ll®3* Institute^ Maw Yos-tei, tk® Uaiversity
©i?®pipg 4tiaatiG Citj's ®j£d th© Lima®®© S©ci©typ lioadoE,
a 5ksarsfe®E' ®f t=ls® III ^tp,dv S©©tioa ©s C©2.i Biology «
Was^lssgv :i,ety for lJL©et2'®sa Mieroseopy aiad '©ill ®iicc@®d
a m5.ti@)Baa QfMtm'®m.G® ps> "Ishibiti©a is th.® Central W@tv&^&
ilsetioss of lsp©E»iis©ataI Majiropattology
pg.s?t, of a .l®sg ra®g® ^laa to ustafeli^ @st3Pa- aadl iistra-
s^ia-sl faetora iisiralved is tk© aos-^S. ^aistensii©® of ©piaal
stm% Qf tli# ^asisislas' ©f£?t€© r@¥©al@d t&® widespread dietri--
as^ls^l sp©si@e„ Tt& presesis© ©f ®u©^ fils@s?s lass g-as?®!;^
&©©a eos-s'^ctlF i^t©s?pr©t©«l. ami tli© igipslficaac© <©i ©stab-'
twofold s sa^®ly Ca) t© ai?©id tlist thmBQ f iteillary .eosajaeetiosss
su?© cllais©.!3®cl eapillarf f ifes?©®i®^ im4 (Is) sot to ®v©rl©©fe
t^© p&fsieal proper ti€!S of tli®s© eonsieetioiss ^icsa la
cerebral ®mmk m&j b® ®tr©te^©sS BMd i?®©i3lt iia di®t«rt@d
vascular Iimssisi wit^ abaos'^al fl®w sf fele^od, Tli©ir la^fg®
miMjSir ia tl4© mplmB.1 cofd should fe^ ©©ssidos'Sd i^ ©valH&tiag
Aa©ta©y ijtody we® aij^^d at th® ®ligoii©adrosytes
alaag til® v®sm®lUo Is all aai^als t^^s© cell® m®®msd t© hm
&rs?fesg©sl, in ©I'tietes's^ 3f©t5?© ©i? ©Mali gr®Mp@ aeas- pert¥a®<sisias*af
arraEgad 11,'araroffi© @r p®io,ts ©f ar'^oris-atioa of v@BS©l©a
Mum® wa© a^^aii^^cl iM ^aaE?i®r t® eiappos't old©r cosasapt® tMt
tjli®s© cell© ^7ouI® h® cosie©ra@d wlt^ tli© fiaastiosa ®f ismaroaal
aE-raagaMiist ®f tSa©@® cslls ®sagg©st9d thut ta®y sip® c©siG©^a®cl
- 10 -
Am&ual R@poTtB <1@39)
witk iuityiimic coatroJL of tolocwA fi©^ t& nourone. TMs
hypothesis^ pr®@®i%t®d at th® Coi&£eir®iao@ oa Mieroclrcula-
tiosi ia Physiology aad Pathology W&y 4,g 1959 at th© KoIoE
hsM op®ffi®d i^ev &v@S(u<@a for asm toxical p histocht^icalp
physiological and pathological iffiv®stigati<Ki@c Th®se
ohservatioa® Im¥@ initiated further research to dsterslao
t.^® osact lists' Ibut ion la a tridla^i^ioaal m^®l of
esBtr&l a®rvou@ tifissus and to assess th® reactloB of these
cisllss uad^r abnormal conditiooSo ?ho coii^lex arransosents
of oligodendrocytes and vessels ims isore striking in the
spinal cord; this observation Bay point to the no®d for a
store intricate control Biechaniee in this organ th&n th@
brain to p®rait outiaost econoaioal distribution of blood
betveen acti'^rat^d a@uroniSo
A& part o£ an investigation on the rospon@e of
the ti@@u@ to ^vbnorssial capillary blood flow a dog; ssat^rial
iaject®d with oil vas studied and reportsd Jointly with
Dr» Eoy Lo @wani&<, University of Oregon^ Medical School ^
Portland;;, 0ro8oa» "Sk^ tissue changosp isihich varied greatly
ia sia®s^®r@ always the result of capillary obstructiono
'th® tendency of perivascular conversion of fibrinogen to
fibrin tvas 1@S8 stripling in dog than in £sano Tsio oth®r
Gbservatiosm vere: (a) a striking diffusion of iron B.m
indicative of disturbed iron @©taboli@sa in fat esbolissii
and (b) the aggregation of oligodendrocyte nuclei in eaall
foci of necrosis ^ith di@app®ara£%c@ of neurons as indicative
of relatively greater resistance of oligodendrocytes to
ischemia than neuroa^o
An extensive review of histological material and
of published studies by others formed the basis of a report
at the Annual Meeting of Aia@r lean Association of Sfeuro-
pathologists^ Jviu®s ISS®^ and a review article will be
p%!tblished in Srgebnisse der Anatomle» Conclusive evidence
of the artef actual nature of dark neurons is glvesa., As a
consequence^ a revision sust be made of conteaporary views
on the role of So-called dark aemrons during nonaal cell
activity and reaction to diseases o Only siaterial fr@® of
darte n^uroi^ should be used for cytological and neuropatho-^
logical studio®. It tm gratifying that it ha® been possible
to ©©tabliisla th® priacipl® of fissatioa and autopsy for
pr®v@nting moraal neurons from art if actual changes «
"^ith the aid of IsaryoBetrlc methods it has
possible to d«^»>astrate that the sise of neuroglial nuclei
is greatly influenced by fissatlveso The shape and staining
of nuclei j, ia particsular of astrocyte nuclei ^ varied greatly
with the t®chni«|ue u®©do With the best procedure available
- il -
Amsiml Beport® (ISSS)
tSi® astyocyt® nuclei ®slaifoit©^ aa ©xtr®®® dsgr©® of pleo--
sso7pliii@si is &&mt r«gios@ amd asaimal @p@«si<8@ ®^c®pt @@v9ral
of tl&® @^11 ro4esitSa Fo? ixiv®atlgatloi&® cofflc@ra®d '^itla
ideatificBtloB of Be«iroglial c®ll typ© oaly sp©eies vitk
®a©iiy l«l@attfiafel® astroeyt© aad olig©d©adr©cyt© auclel
A® & cosi0@qts®Qc@ o£ tSii®s9 studies all Isistological
arterial fised by po^fueioa 1@ prepared according to a
it3cJ&«s® la whicte oacli step has beea developed ia this sectioQ:
(a) Slodificatioa ©f Heidenlmia'® Susa aolistioa as p®rfusat®
for fisatioa; ib) Autopsy delayed 4 feowrs after th.® perfu-
elojs followed by imasdiate traas>f®r o£ blocks to alcotiol and
®&Ot»®ddii&s l£E p^v&ttin; a&d (e) microscopical seotioos
sstaiaed by t&® periodic acid gdsiff procedure ooiabiaed "s^itlK
gallocyaBia-cSiroES aloiao
Tf?® ©©i'i®s of aiaiisal© were studied by DTo Helen
E^i^ey to establish th& di^tribiatioa of estradiaral fat; one
coaoersed th& coaditlos© ia ttoe cat f?02a aevborxa to adult
aad tke other a cosiparativ® etudy ±u the rabbit and atoakeyo
She reported for th® first tijm iu a systematic study th®
i»ti?lc&ta m&a&&£ ii& «>iki<sk fat i& ^«posit«d; this p02<»ita th&
coapl@s so^®s®Bt of the vertebral coiwaa without tearing the
epioal cord asid rootlet© »
Th® @@ctio& has beea host to I>ro SSigcosi Mais
CUBi^OTsity of StockholiSj, Swedea) duriag 1@8@„ DTo Selea
Do Eaassy left the Sectioa duriag th® curreat yearo
Secti«m oa Fiiactiossal leus-oaoatomy
Grsmt Lo W&^mmaQ&s Chief
Frofeeisiosial persosael of the Section of Fuactioa&l
H®urogiaatosgy are: Eichard Gacek aad Grant L. Easatusseai, Chief „
■Bui® ©ectioR coacera® Itself primarily le^ith nervous pathways
and co!sm@ctio^@ o£ th® brain and ^spinal cordo
la order to better understand the neural saechanissi
of hearing^ studies of the auditory afferent syBtea so long
aeglectedp hav© received particular atteatioso Point to
point iffitor neuronal relatioaships exist ins bet-^een the organ
of Corti and tl^e cochlear nucleus end the ijatsnaer of projec-
tion froa th® latter to higher auditory nuclear groups has
been restudied in saor® detail than heretofore by the experi-
aeatal anatomical approach, th® study dealiag ^ith the
- 12 -
Ammal E®ports (1959)
inrojoctioGi of coc&le&r nerve fibers oq the cochlear i^ucleus
luus been camplmtsd for botla the cat and chinchilla <> THh®
special arrangenant of the nerve torainals and aanner of
distribution to the different subnucloar groups of the
cochlear nucleus has been determxned and correlated with
the sites of lesions o This inforaatlon has been brought
together in the forsa of a plastic aodel of the cochlear
nucleus it^ich permxts one to gain a three dimensional view
of the course and distribution of cochlear nerve fibers
that transmit nerve lapulses froia the different tono topic
regions of the organ of Cortio
The efferent or recurrent connections of the
cochlear nucleus have been studied extensively in the cat.
The wmt important finding is the discovery of two
nusisrically important bundles of efferent fibers originat-
ing from higher auditory levels c One has its colls of
origin in the nuclei of the lateral lemniscus p its fibers
descend in th® stria acoustic dorsal is to the dorsal
cochlear nucleus of the opposite side. The other arises
from the superior olivary nucleus and terminates about cells
of the ventral cochlear nucleus of the same side. These
efferent® plus th® on@ previously described (1958) together
constitute a rich feed back innervation from higher
auditory centers c The fact that recent {^ysiologlcal
experiments of several workers have shown that neural
activity of the cochlear nucleus can be suppressed by stimu-
lation of higher auditory regions leads one to assume that
this phenomenon is effected through the descending nervous
connection described abov®. Dr. Gacek has played an
iaQx>rt&nt pMart in these investigations particularly in
perfort^nc® of the operative procedures involving placessent
of the lesion© vii^ually.
study of efferent and afferent connection of
higher auditory levels is being continued.
Eobert ^oord$ a student of the University of
Maryland ^forking here mider a MS Predoctoral Fellowshipj,
coB^leted hi© study concerning th® question of possible
presence of an efferent cochlear bundle in submamnalian
animals possessing a poorly differentiated hearing apparatus.
The experimental results d<»Qonstrate for the first time an
efferent coapoi^ent of th® cochlear nerve in the pigeon and
alligator which 1© hc^^logous to that found in maEaaals. The
efferent^ have been traced as far as the receptor epithelium
- 13 "
Aaaual Exports (195®)
of til© primitive orgaa of Coffti aad ©f tk® lag^mas
stx«acture o£ unknown fuactiom aad sot pr®t&&nt in
Ssio^iedg® of tte pr©®®acffl of tia© ©ffesreat© in aa.t®als
hmlm »i^pl@s.<- orgaxi <»£ Corti tliasi o£ sisi^raale ie important
relativs to tia© detesTaiaatioa of th® quest ioa of wfct®t^®r
or not tism r®c®ptor c®ll@ h&v^ & dual iimarv&tioiio It
ahould; t>9 sucl& oasier to eettl® the question of ultiaat®
tersinatloa of tl&e efforonts !» aa aaliml iaavis^ a aiaplT
cosistructed r®c®ptox* orgaa^ Tfeis work is b©iog U8®d as a
tfeQsle for tlm d^gjp®® o£ doctorat® of phllasophyo
UTo Gac®k faA& purau®d furtfii©!!" th® problem ©obc©s"»'-
log tls^® ultiaat® tersaismt loa of t&® af£®s>®iat vestibular
fite®3r®o Att<rapt® t© ®olv© tlais qu«»@tioa wtiliziag various
w@Ii kmcma @£p®riffl«&tal a®uroa»&toaical t@ci»nlqu(&a Ikave
prQv®d fruitless. E® hi^ traced th® sff@r@ats up to but
aot b@yo3d tk^t basesisat asabraa® of the receptor opit^llim,
DTc Go Dofeljsmaj, iatoroatiozuilly isnowii tor fvuada-
siontal contributions on th.@ anatoay aod pliyalology of tho
vestibular receptors ;> Joiaed tli® ©ectio» ia May aad pursued
bistocSieiaical studies ou thBS® orgaaSo He plaos to r@tura
iron Surope aear the begloai&s of next year to resuoe
studies ^hich coiscera deteraiiiation of efferent inner vat ion
of tl&@ receptor® by bistocS&eiiical aetf&od (cbolineoteratse
activity) o
MTo K®skt loreetf a senior medical student of ¥al®
r® Joined the J^ctiosa under tb© COSTBP progyaa for ti¥o isontfe®
and G©i^l®t®d tk@ study begun last year on fiber connect ion®
of tbe ar®a post!
Section on Perinatal Pbysiology
Co fiSo CoaibSp Chief
During th® past y@&r tk© activity has been ©speri-
ttal invest igatioB and extensive data collecting on
adver®® factors ia •» m perinatal period of rbesu® saoafeeys
resulting ir aeurolo ticai aad psyclboiogical deficit® ia tfiie
off©pri».go th® f±T &dv@TB® factor tested lia® been asphyxia
aeoaatorumc
l)ata ou -®kJiStruatioia of rk@@us sionkeys under standax'd
" 14 -r
Aaaui&i E@p©i?^s (IS^SS)
coaditioos coffitiau® to b« colloctedo 2h*o Mcobeon cgM"
8ist@iitly tiAB found thm m»nBtsu&l cycles of iadlvldual
raonksys to be subject to vide variation whlcSi spreads
tiuroughout th® y^Si-To Ther® i&as b®&a no &y&%mmtic
relation b«tw««B regularity of cycles aad fertilit^^,
B^tisi|;0 sbov tbat co&c^^.tioa occurs tbrougtout the y®ar,
A cosiparisoa is aov b^iag ssad® by Dt<, Yollm^n
b«tw«ea tb« reproductlT® p^rforis&ncse of tb« laoaic&y
colonics la o%ar E«>th®&da laboratorioB a»di la t&® 3aa Jaait
laboratory „ QTo Volltsa^Ug 1^0 Joia@d our staff in August
Is also b®gisiB&i£ig ovulatory toista otx all of our Ktotii<my»
usix&g dally vaginal snearSf, crystalliasatioa of the c«rvicv.l
miGu&a body t«»p®raturej, a&d fluetuatloss la total aad
dliferesatial whit® c«ii count,.
Data coatijQUi® to b« collected on susituratlosi la
infant rhosus 'eaoniseys and on tho car® required for s'^&ri.n^
thm&o A nursery j, patterned in laany vays after thooe in
hospital us®j, is maintained for the care of infant aiO£tkey».-.
Records are kept of daily weights « food intake p teaperatur^t,
and respiratory rate<, Heart rate is recorded electrically „
Gra@p r9tl®x la routinely aeasuredo The maturation of the
ability to @elf-feed is asaessedo Moraal ranges for all of
the above have been established o Special aethods of
feeding and regulation of body temperature have been
developed o This Imowledge has been applied to the care oi
Infants daaaged by either fetal or nei?bom asphyxiation o
Meurological deficits of experiffleatally induced
asphyxia have bees investigated by all aeiabers of the
Sect ion o Monkeys of known mating dates were delivered by
uaesareaa section near full termo fetuses were asphyxiated
by removing the uterine contents intact and waiting until
intra-amniotic respiratory efforts ceased or were about to
cease befor® freeing the infant frcM» the fetal ncgstbraneso
Asphyxiation times were varied; eos^ infants were able to
breathe spontaneously j, while others had to be resuscitated^
Resuscittitlon was accojaplished by intermittently inflating
the lungs with pure o:sygen through an endotracheal tube
from a rubber bago Activity^ respiratory effort and heart
rat® were recorded,.
newborn sionkeys were asphyxiated by placl»K
them in a glass jar through which nitrogen was flowingo
Other laoalceys were delivered at once by caesarean section
AiJmual l®p©rts <I9S9)
to 6®rv® a@ coiitroltio Aepkyieiated &&d oontrol inisiutm
raised ia tto lalKsratory aiad r®quir«d t^® aafs^^
itaat utu'siisg car® as h@aXt^y &nd sick aaewborn k:4]a&a
iafaatfio Motioa pictures w©r® tafeeia duriag t!&© ©speri-
Bsats aod at iiatervals ther®aft@r; a<»urologic&l
93C8u&io&tloii8 ver® perforaod regulasfly ; @I®ctro-
encapliftlosraf&ic t3?&cing@ w®re tafe®a at intervaiet;, and
a great varlsty of pky&iologicai data vara recorded lor
later stwiyf review aad coiaf»ari§^i&o Infants which
seeasd uall^eXy to aur^iv«j, as well sus some healthy one®«
were killed ^y per£u@ion-f ixatioii for histological
studies o
Techaically satisfactory a©physiatlOH-r©»U!seltatioa
was accoapiished in fetuse® aad aewtKsras. fbe differeace®
in the responses of fetal and newborn oonkeys to
asphyxiation observed dm^ing these studies fell into
three groups: (a) th@ fetuses were quiescent except ior
respiratory effortSp whereas the nevhorns struggled^
defecated and salivated; <b) the heart rate fell slovly
in the fetuses p while in the newborns the heart rate fell
abruptly and then rose slowly; (c) th@ fetuses could be
resuscitated 5-1/?. minutes after their last gasps^ wh@?®as
the newborns could not be resuscitated if asphyxiated
for 1-1/2 mlEiuteg) past their last gasps » These findings
cootplesaent tSiose of Dr» Dawes and his associateis^ working
in this laboratory s who have shown l& acute experiissnts
differenco® in blood pressure ^ cardiac glycogen reserve
and blood sugar between fetuses and newbori^ asphyxiated
pauBt their last gaspso
Urs, Marisa Xo Bsmires de Arellano^, Max Eanlres de
Arellano and Do ho McCroskey have contiiiued to attempt to
establish exact criteria for neurological ©lamination in
the infant ^jakey., St Is hopod that their work^ added to
that previously done is this laboratory^ will result ia
& cos^lete publishable protocol whic^ can be siade available
to other investigators,.
Standardised neurological examinations have been
perfonaed periodically from the time of birth oQo Motion
picture records of the examinations are made at established
perios^o Blectro@nc@phalographic recording are also
periodically taken. Photic stimuli are used to activate
the EBOo The neurological and electroencephalograph ic
studies are carried out on both the asphyxiated and control
anissals, neurological deficits of considerable degree and
Aujdual Exports <1@S9)
p®rmxmt®nt smture kav® h®m& ohB@vv®d is @om® of th&
a@phyjslat@a aos&teoys^ Wltbin these j, t&sre has b®®n
littX® t®ad6incy for lateral i2@di sotor deficit®, 1%®
geaeral pattora S&as h®9u on® of d^reo-athetoid aov@»
rasBts and a smrked lag ia tli® developasat of isolated
ffloveaessitj, s»cli aa pawingj, 7«mc&issgj> and picking up saalX
objects o The SSG'@ of laost of the asphyxiated aaiaals
did not differ grsatly frora the oorml. ths s&oet Eiarkod
fiadiiig has beeigt a depression of the electrical activity
durir^g the first five or six post-asphyzial daySo
Miss Sasoa has heea stvidyii&g the psychological effect®
produced hy asphyxia aeoaatonmo Usiag both asphyxiates
uml Q^r^als In a test battery she ha@ fouod ao sigaif leant
dif fer@i&c@i» ia learning ability between the groups so far
t@@t@d CS asphyxiates; 5 nomals). Also^ no significant
eorrelatiom «a® found to exist between the length of
^^physslatidn and object diecriaination leamingo Bo«r®verj,
morraal controls have been found to be significantly isor®
ssiotional than the asphyxiated subjects <> iSon&eys with
severe neurological defects could not be subjected to these
psychological testes <>
A y@ar ago plans were initiated for a collaborative
study between messbers of the field station Section on
Perinatal Physiology and a group froa The Muff ield Insti-
tute for Medical Eesearch, Oxford^ England, Pro Geoffrey
Bawes and 3 m@mh&ffs of his staff from Oxford received a
grant from United Cerebral Palsy Eesearch and Educational
Foundation to pemit travel to Puerto Eico for this work.
They arrived in early August and conducted experiments on
fetal physiology of th^ prisaate during August p Septeiaber
and early October. Twenty sionkeys were raated for this
projects Eight infants were born spontaneously and 12 by
cesarean section, Hine of the 12 mothers that were
subjected to section survived, Several other newborn and
young aonkeys were m&de available for the study, A great
deal of physiological and biochemical data were collected
in this ^hort period of tiisso This is being readied for
publication^ and plans are being aade to continue the
research in Puerto Eico in another 9 laonths. It i& hoped
that the @®^@ group of investigators will participate. The
^ost substantial findings are suamarized in the following
paragraj*®:
Aim-&B,l Ecipog-tsi CS.S59)
Ofeser^y&tiasaii te^o b©©si imd© om. 12 to®tal laos^^ys
geoiaFiSii age froa 115-X3© day© Ctes-a is al3®y;t 16® ds^)o
a ©at^0t@2? ims is®©;?t®d inters th® f ©©©ral arsea'y for
2a i fo@tal g^*3iak©y©j, aa a2?a wa© also dslivofod tte@is^
a ©©^ag-ata lacisi©a asica tia® brachial af t©2?^ wa© catfeet©!*-
is©cl s® tliat si^api®© ©o^ild '©© wit&'d?a^sa frc^ tJpibBta,f i©s
la th® 3 ^©lasgest ®oafe©y® C-12@ day© gesltntiQa ssr 1®®@) a
®t®a;iE© iissisiij® ifs® m^«l® o^©2r t^m a<tGk of tia® foetus aM
1^ per s^jat fei!^©r; valia©® as &i^ a© 77 aad 7® p©a» c®ait
ws)r® ©tjF©©r'«'@d„ fk® blsod Is&ctat® eoac^ssts-atio-a wa© of
tto SEa© ©r^-sr ^® ttet ©e©a isi ©i2s ^sakeys S-i2- (tey© aft©r
bis-tfe i7-17 ms/l^Q mJ.)o la 3 foetal ^iuk^jB^ fasm-al
as'ts^ial M©©el samples witMs^-awa at tli@ p@afe &£ a ist®riu.©
©i' ^.p t© 35 Ma Eg) &©£st£.ia®4 I@©s Og Clc& - S pQff c®Bt
SEtm'atio^) tiaaa did ®i^ipi#^ witfed^aina dwriEg a qui®©c©sat
period te@t^€S4i& eostraetioas , Oa d©liv©3?j' of tfe© f€»eta©
tiosi f@II t© 1©^ 9'^lu®iJ£. «soMpas?abl© with thoB® ®&mm>mlf
@te®^¥®d te fcrn^am c&Td blood ©®®pl@®^ @v€® tfeoagis tto
^lac@jata ^^ib ii©t f®t @®parat©do It i© tk©g'©f©r® sagi@®t©4
that ©ord Mo©d si-i^i<isi;, tal£@a after dalivaryp smy gi¥© a
I'll® ia tlj® p'isnt^o A®.^ it is lBt©^@®tiEig tlsat tia® ©a^@
a®e®iisli]sg and tk© d©^ccjMi^ a©rta ©ssist^ as to® b©®a si&©w®-
s^ppl? ®f fl&@ ter^iiml E©s^©s iia tit® @iaao®®triit»o l'ia@s©
a©s='«?®^ pas© fs*©® tSsi® «st©.^ia^ ^aseulaipis Into t&@ @iido-»
feo Csals^s ®2'» B#sa@2'y ®ad Miss S^^ssa &air® b©®ffi
casp^j-fissg out Cflactx'oaisatGaical atiadi©® ©s comaectios®
- i@ -
Amual Exports iim9)
Tises© es;p®ri®aat© hav« ail b®€ss carriad out iaitially ia
catfip but ^isailar @tiidl@@ will be w&dis on aspS&y./.iat^d asd
control moBkBys in ord®r to a®®k sieuropkjrsiologicial
®vid@Btce of d£^ag@ tkrougla asphyxia tioa to thlm ..i^portaat
ootor pathway o WitU ®l®ctrieal sstisniilatioa of tfe®
c«r«b®ilaffis cortical reapoa®®® way® readily obtaiii®d
froB th® contralateral a»t®rior aigsaoid (iMSitor) g^mSo
Sssftller potential® war® obtais&sid from th® coiaitral&--.@raI
posterior sigflBoid gyruffi, lpsilat®ral r®spo^se&S;» ^.^m
pr«»3®s&tp wer® tsMall^ l]&c<a£&@ist«mt{, and only found li- tka
anterior gyrus o t%® activ® c«r«%»«llsir ^on® formed &
longitudinal strip conoii^tias of t&@ lateral ojti®-^h&li of
culat^np til® is«dial two-tteirdst of Gsn&& I» tin© BS®di&l oim-h^lt
of cru@ Up and the parasasdian lobulOo Ti&@ larg^at r&Bp«msd
r^ultod from sttiasulating of tbe anterior t%%>tkird@ o:^'
thio »»dial Kme-tl&ird of crus I. tfe« r®s%slt® lar^re as r«idlly
obtained in S®ffiibutali3;®d ae ia ciirari»ed pr@par&tion®o
In a related (study j, si@t&odic stiissulation tl&rou^oi't
tbe dioncop^lon ^hil® recording £r(«B tbe i^ilateral
•ignoid gyri iia® s2]lio<^n timt tSsi® active di«»nc«ptealic aroas
include eoaantially th« sonsory patliway ^ad tto coiurs® of
tb« bracliiuisi conjm&ctivurac
In 17 aniiaals ^itS& prior wi0B®nG®phB.lXc d@etruction
of tb«» isddial l^miscus and the bracfeiu@ conJuzEctivuB&a tHe
active ar«a9 w®r® tho saa^ «itk th® @Kc®ptioB of th®
anterior part of tk@ red nuoleusp tb@ fields of Forel;, th®
sona incortaj, and ta&® Bsas^acept&alic tegsaentumo It h&®
also b®@n ®@tablielM»d that single shock etimulation of th®
cerebellar h^ais^eres will induce in Se^but&lized cats a
bilateral multiple alpliia-rhythm r®@poj»iie in the cerebral
cortexo This is mmt pronounced 1^ the contralateral
ectoeyl'^ian (auditory) c^rtesSo
An observational ©tudy of behavior and «sociaI orgai^i-
xation of rhesus SKonkeys in the free range colony on Cayo
B&atlsk^o (now auatf^ring 300) was begun in Jusne^ 193®^, by
MTc Aitmamso I^To Ejoford froa the University of California
i® Qontinulag these iavestigatimaso When the laboratory
assumed control of the Santiago colony $ it Qosmimt&d of
about 150 mmtoye^ Since th««i they have isicreaised to nearly
twice that nuMter; there are now about 2S0„ The rate of
ilmual Eepoi-ts (iSSg)
mortality is I©Wp about 5 p®jc- c©sit par yewo Fiv®
f®Hs.i®s feav© Hired saor® tMaa SO y@ar® oa tl^ islainSo
Ha® ratio of a^tur® sal®® (5 off aor® year© of &g©) to
laatur® f^ssal®© <4 or aaor© y®as*® of ag©> i® oa® to fiv®«
MatiBg activity coffiBsac<SKS> lat© iia July, H®arly ail
youns i&r@ bor£i diiuflag th@ period o£ 4 sicmtias corassnciag
iu f©bs"uaxy= Appiposiis^tely @5 p®r c@Bt of th« m&ture
fe^iai®0 liav© iafamts bora tlai© y©aro At least Biac©
^id-105@# th® ffloaie«y popuXatio© !aa© l2®®s ditrided iato two
soeial grottj^j, osa® approxiaately twie® a© itu-g® &® tSa®
0tla@ro Kscept fosf as occasjloii&l eulmdult la&l^^^ msmb®r@
do SMC»t shift £roi£ oim group to t&® ot&®ro T£id groups
s^rstally occupy 6®parat® parts of t^ islasid; though th&y
sfcmr® much coissaoa ground o ^®%r t&® cssst^r of ®acS& group
ar@ 2 or 3 o£ tl&@ largest stal^fij^ which a.r® cl®&rly
£iig|g@st in d^miimssc® r&xkko M®&rhj &t® f®aitl®& with tli®ir
youjags up to 3 year® oldo Suteadult aaal®®^ low ia doiaiiisac®,,
ar© usually at tfe® .p©ripla®ry of t&e group® «
^o Citaadler^ ui&d^r the direct icm of iDr<> G&vai& at
til® l@diical Coll@e;« of Soutb C&roliaap is carry lag out
aatl&ropo@@trlc studies oi^ tSi@ Cayo Saatiago coloayo Th®f
are costtSuctlsii a lmigitudias.1 gro^li study with fsaia
<9fflpS&a@i@ OS& sor^i^lp developaaeatal isorptiologyo They hop®
to identify th® nora&l rat®; duratlosi and course of groi»th
and to isolate soMm of th® factor® rMioh aay siodif y this
pattern » So farp blood c®ll cousLts smd hesioglobia
detetrmiimtioi^ h^v® b@e2i done la 1S2 as&inalSo K®w studies
will b® added stortlyo
Oth®r Ac?tiviti@©if Laboratory of
l@iiroami.toaical Scla^c©®
'fh® ®ci<mti@t@ of tias) LaS»oratory of Mf®uroaQatoiaic&l
Sci@mca@ ba^® hom^ c@.ll®d upoa to participate in activities
BOt directly f®l&t@d to coaductiag @:sp®riM®ntSo Sev«»r&I
3®rve on cow^ttt&®B ai^ advisc^y paB®l@c
BTo Falay trasssf ®rr®d fr^a th® Matoaty aad Physiology
gteiimv^ip Paa^l to th@ Cell Biology Study S^ctiOB^, PMo
M® is also Secretary of th® Aes®^ly of ^ci®2iti@t@ of Mile
Pre Lloyd Guth is a ']Bt«mb®r of th« Anatomy aad
Physiology g®il©i^hip Paa®lp fum. DTo Miltoa Brightmis i®
- 20 -
AiMSUftJ H®poyt8 Ci'^SS)
?iC€k-Pr€»@ideK&t of tlm WasbiagtOQ Society o£ £XectrG4si
Uicroecopyc Dvo Co Jo B&ii«»y recently l9ft this
laboratory to S9rv® a@ Executive Secretary o£ tb® 28eat&X
B«altlt Study SectioQ^ I>WS.
OTo Easffiusson is % ja«flfi»@r of tho Traimeoship
B«vio« Boards MUTOBo He serves on ttee Coanalttee on
KearJiag and BioacousticSj, national Acad^iy o£ Sci
Rational Besearch Coimcilc
Or. Co Mo Cosebs bolds & courtesy appoiBtn^nt aia
Aanociat® Pro£«»aaor of Anatoffiy^, and OTo Ho Ho ilacobsoisij,
aj Associate la OtototricSs at tbe Uaiv«»3:sity of Puerto
Rico ^School of Medicia«c Heitber on® of tiiese appoint -
Bents carries teaching duties but both provide valuable
contacts ivith other scientists o
The Chief of the Laboratory serves on tho following
conalttees: Foreign Fellowship Cossaittee^ PEG; Anatoa&ical
Sciences Training Cotmitt^&^ mm; Cosuittee on Prijaatesij,
National Ac&desy of Science® -national Research Council;
Executive Cona^ttee^ Aaerican Association of Anatomists;
Henbership Coaraittee^ American Academy o£ Heturology;
Coiaseitte^ on International Col labors t ion ^ Anerican Acadeay
of Sfeurology; Research Advisory aoardp United Cerebral
Palsy Edsearch and Educ£»tioaal Foundationo
Editor i&l tasks have engaged scote of the investi-
gators' £i»e dtiring the yearo The Chief of the Laboratory
is editor of ' Kxperiaental Seurology" ; Dr^ Palay is on
the editorial board of the saxie, Dro Easmissen is editor
of a sK>nograph entitled ''leural Mechanls@@ of th<& Auditory
and Vestibular Systeii^' «hich is th® @i?£th In a series of
"Syii^josia in th® M^uiroftnatoaical Sciences" g ©dited by tk®
Chief of the Laboratory « Dr» Cluth is translator and editor
of lUu^n y Cajal's boott on neurogenesis » «rhich will be
published in 19S9o
- 21 -
PttblSfflhad Pa.p&V9
lo Albersi^ RoW« J, «iidi Mo Wo Bsrig&tma&o A saajoir eompooeat c£
neorohypoplsiysial tiseuo associated with antidiuretic activity..
Jo Wewochem. » 3: 2&9-276; l959o
2o Bailey J, Co J» ^ aad TK'.Fo Wiadieo Neurological j> pcychdlogieal
aad aeurohietological defects f<^owiag asphyxia neonatorum
in the guinea pig, Eap<, NeuTo l^i 467»432p !959>
3« Ba&ey^ C. J, and Lo Gutho Role of the sympathetic nervous
system in the pupillary response to darhnesso Exp, Neuro «
U 166-1708 1959o
4c Bradley^ D, Fo and M, Ko Wolf^ Aggregation of dyes bound to
polyanionso Proco Nato Acado Sc, ^ 45; 944-952j» l959o
5o Brightman^ KSoV/, Early effects of intensive 3:« ray irradiation
of the diencephal<m in the rato Expo Wenr, ^ J : 97-1 i6« 1959«
6o Erightman^ MoV'e and £t>W, Alberse Species differences in
the distribution of extra-neuronal cht^inesteraees vrithia the
vsartebrate central nervwzs systenae Jo Neurochemo g 4:
244-250^ l959o
7o Cammermeyer^ Jo and Ro Lo Swa^ko Acute cerebral changes in
experimental canine fat emboliamo Exj^o Neure g 1: 214*232p
l959o
8« Combs ^ Co Mo Coarse of fibers of braehium conjunctivum
revealed by evoked potential naethodo Expo Weuro ^ J[: 13<>>27^
l959o
9e Guthp Lo and K» T^ssako Restoration td dia^ragmatic function
following vagophrenic anastomosis in the rato Expe Neuro ^
1^: l-12p 1959«
10, Palay^ S, L« and Lc Jo Karlino An electron microecc^ic study
of the intestinal villus <> L . The fasted animalo Jo BtophysiCo
Biochemo Cytalo p S: 363-372^, 19S9o
ilo Palay^ SoLo and Lo Jo KarliOo An electron microecc^ic study
of the intestinal villus. !L The pathway of fat abeorptioso
J, BiophysiCo Bioehemo Cyt<^ 9_5: 373»384p 1959o
-22-
IM a^mcks Jc Bo Jro ^ asad ^o F.-, V-'iuwIleo Brain damage la the mosik®/,,
l3o »Lol>«rte9 Eos 1° ^= Low«s U GuSlb^ aad B„ lellockc DietfibuSioa
of g&mms.-<bmlnobu£yi'ic acid 9:^4 other Amino &cidc in nmrvi^xB
ti»eue &£ various •pecS««o Jo Ea^ 2ooL , 138s 3l.S"}<S;8j>
1958 Cas^>e%r®ct isa I959)»
14. SidmajS;, Ro U 3 LLo Miale aad K. F«de?. C«il prollfera^Saa aa<^
aaigraiioK. in the primitivas «)p<mdymal aoaes aa Autoradiographic
study of M«t©g«ne»i« in the aervousa syetamo Expo Nettgo is
322-333-, 19590
15o Wl»dl®j, Wo To s "Slapben Walt«r E«ia«<mp 1880"^1942," £.Kyo Newfo^
j^s Ui, 1959,
Ifec Windl«s ^'^ ^° R®g«Bor»8i€m in relatioa to the process td agiag
Is th« nervous ftyetemc Jn "Th« Procees of Aging is th«
N«rvow9 Syetem'% J. E. Birrett^ Ho A. Im^a, W, Fo V.'iadiei,
iede.Jp Sprifigfiftldp aio ;, Cluirles C Tfe©m»aj pp^ 40»475, 1959^
lo All»«rsj, Ro Wo Tfee metabolism ©f -y ^amfcobu^fTaS^o fe *'A.«ma®
Acids aisd !sl«jicI®©tid®!S m tla.© C«®lral N®J?'wa« Sf®t®m.c/"
Ro Oc. Brady aad Do Bo T©w@fj, f©ds<,|p Jiciisia Wil*?^ ^ pwtec
^o Aifeersp Ro Wo TIs® aisls'ifewtim €if y »amiffi«lMst|rrat® aa>a s©£&««d
y "-AmteelmtfyJc Aeidp" Eo Robeits aiad Ao Viaa Ha3rr«v®M,,
C®dSo ) 9 P©f games, f i^ pre»»|o
3o Alb©r»^ Ro Wc ^ iM-id W. Bo l^ebf. TrassaasaimMems aaid «fe®
i!»el:@pte lab@ii@g ef gliyi:^akm%t@ i^ thm br&i»^ Sbido
4o Alte^!^*,, Re. Wc ,; a»d W,., B. Jatefef. Ejsefe^^g® reaclicsas catalf®.^
5c, A3ielf©dp So g R.. Wo Albors asd Co Cl«m«ffit®., Ttee diatribe i€®
60 Bradlefg Do Fo asad M. Ko W@lfo N^urocteesmistffy @f
p©l'^tHiel«o«ide»o M "',N®«tr©eb©8aielffif «i' Amis© Acids aasd
Nuclee^id«»<," Jefea Wiiay,, |>abo (M pwmsnh
7a Byigfetes^^ M. W. Tte.e vascttlar s«^ply eC lb© spiaaal eord ©I
80 Byig&tassssp Mo W. Tl»e e^aiitabmsy ©f eM©fal lsfdyal« a» ife®
a,a««5tte@fie l©8? «fe© ralo Py©Co Soco E3ep<gra Bi@lo aad M^d,.
9o C».s»m©ffm@y@s-5 lo A c©s8q»ayativ® st^dy ©I She isafcervasessiaff
eisgsK^ctiv®. tiiffsufs- fibes's el «b@ central ©ervous syatemo
iOo CamsTOyKsscyeg'p Jo A eompafative atmAf ©I tb« iatervaseMS.*!-
c©ffi!s®ctive li®Si»s«s fibes?© of tb@ Cisastyai i3i#rv«u© »ymtmtgio
ffi^eJtei mtfes ©pteal €©xd a^x@ t@ i»Sividiml,y regieasal a^
tectoieal v®.^ia.tSG®»o Acta AaAS®mte«. Ci»> pT«s>®«|.:,
"24-
S2o Cammoffmey©?^ Jo Is t&e |s@yivasc«sla3r oiigod®Bdrocy£e a.ae«h««r
el&m^nt c<mtitiMi&g thm Mood s^^^y to stsurond? l%h Cond^dtenaa
cm Microciffcalat©yy Phtyoi^ogy jmd Pat&oiftgyo Traaso
Micx-dclrGo CoMo (ia pr«es|o
13, CampbaU^ So Bo ©ad ^^ Fo Wisidieo a«8iati«® of ^iUiipor©^^^ to
hsaliag &a<2 T^g^&ev&titm in trftssected apis&al cords of
monksyso Neurology fia pv^eaU
by So R%SE»^ y Caj&io Spriagfitdd^ Ei> j;. Charles C TlidmAs
Do Bo Mickel«@^c TKe quantitative significaac 6 of the
y '>'amtaol»tal:y7ic acid pathway isi c«£'®bral oxidative met&bdlism«
Ibido |in press |o
16, Ramirsede AreliazitO; MoLKo., Do McCroskey^; So Dmn«iry A^d
Wo Fc "V^'iadloc N«ttrolfi»gic«ii deficits oC aspSjyxta aoosmtorum
iffl WMMikeySa Trftsso Aodo HeaspeL AssoCo 1 959 lia pr«»s)o
ITo Ramsey^ H@i<ssi vio Wmt in the spidus-al ep&ce in yoims and adult
catBc Aaoo Jo AoMo Ci» p3P®s®Jo
I So Ramsey^ H«l«a Jo Comp&ratSv® m®ppl»el«gy of fat ia th«
epidural spa«®o Azmo .I's^ Aaato lis ps-eae)*,
19= Wiadlsp Wo Fo Foreword to "Atlas ol ths Dog Brain„^" by
Lim^ JLiu aad Mo^stt^ Spriaga$ld^ Bliffloiej, Charles C Thoim&Sp
20o "Wolfp Mo Ko amd D. Fo Bradleyo QuaMiSative dy« ®p«ctr©|^otom©try
with tfe® aid of a ssmi-miero-magaetic ©tirs-isg bas-o _Staia T®etor,
( i» presa}o
Pgelimiiiagy papeg^g Abstracts aad Discaasioas
I. CsxmsswBy&ffg So Discussioa la **Tlie Pyocoes of Agiag la
th» l@gyott@ SysteiB" «!©; J^. So birres., "^
Mo' Ac Sisus^ Wo ^c WlndlCp Sprlagfleid;, 111 op
s> So A cs-itlque of ae^sroaal hypesrelas'CMa&tosls »
J. Ho^ssropatb. SsEpo Ifsiaro 2.@5'9o
So Coel^j, Go Mo aad Su® Sasono C®r®b®llo~corobrai 7®l&tloa~
aship bet^eea crus X and aetsmory ^eotor cortex »
Asiato B9o»« 1959^ 133:2«3o
4o C^il»@;7 Co Mos 3o @o Firoaterap Ho Ho JacotooQ; Po l«o
lfleCrosle®y» M.IoB.SaaireE <te ArollaoOp So 7o »»«^«p
Wo 3ti9&l« Vo Fo Vindl«« A ooadltlon r®e«aifi>liag
•<cer9fe>?al palsy" la youag Baoaca aulatta survl^iag
asp&ysla aaoaatoruaV Aaat, RaOo 1959 « 133:4®2.
S, Ba^©s, Go Bo£ So M. JaeobsoQa Jo Co Hott aad Ho Jo Sk®ll®y^
Observatioas osi tl^e rb«su8 mismk9f la ut®£Oo
Jo Physiol „s Loadoj, 1939 o
@o Falajp So Lo» Ao Balratl^ So Mo MgG@® Sussoll^ TS&@ fla®
stsnsctm^e of asoplasmo Aaato B®Cop 133:313^ 195^0
7o Baaek^ J, Bo Jx>o« aail Wo Fo Wladl®, Behavioral d©flcit@
correlated «ltl& neuropatS&ology of a8phys:ia
aeonatortiie ia SSacaca nalattao Aaat, Beco 19509
lS3:3S5o '
a. Sidmap Eo Lo aad Xreae Lo Mlal®o Histogenesis of the
@@isse cerebellys studied by aut<»radlograi&y with
trltiated tliymldia®o Aaato Eeco^ 1959^ 133 i2)i
429 o
9o Blikmsks Ec Lop !?eae male aad Ked Fader » Cell algratloas
iB the limiature neuroeplthellua of aouso embryos
studied by autoradlogra^y with trltlated thynldlse,
Aaatc mc.s imBg 133: 430 »
IGo gidssasp Eo Lo aad Iresi® L. male. Pattern of hlstogeaesi©
la the apous© cerebellua studied by abator adiogr aphy o
Jo Heuropath, Eicpo Heurol.
- 2® ~
PrelimlB&sfy papers j,
Abstracte and Discussions (coQtdo)
11^ Wis&dio^ Wo Fo DlscisBSioa of: S:^®rias©atal b&sl?3 of
r®duc@d lipogeQ®©l3 in i^it@ Jiattes* of (.^eiitral
nervous systeai, Sawl Eo Sorejo IraaSo A?io
Neur. Ass. 1959 c
12 o Wolf 9 Mo K. and g^^eiel Bo Aron^ono Gro^ttii ilnoit®&z®&cQ
and B®tachro3sa@y of colls cultured in thm
proeonce o£ acridia© orang®, Anatc Eecop lSi}9j,
133: Ml.
13, Wolf; Mo So Fluorescence and laetadlKrcwasy of living
ti@®u® culture cells stained witli acrldin® orange «
Ssc^rpta Medicao
ISeriai Ho. MMMzMM^Mz.-
1 . MsTijr'oasia toxica 1 Sc. .: ^, .
2. Section on Qevelopsseal
and lageaerRtA--^
ladivi^luEl Project Eepo:rt
Calesidar Year i95S'
Ps'ojsct f itle : Aspects of esperimental ststiroemb^yc:: :^
Principal .Investigators L. Gutfe-
Other Invest igato's-s I lose
Cooperating Uaits; lloae
l^a Years Ccaieads-r year 1950) :
Total c 5
Prof ess iomil ; ^3
Other 2 o 2
Project Descriptions
Qb.iectivess To test aad evaluate t:is Bsisrogenetlc
concepts of aetirotropisa and of layotypic spec if i cation of
neurons »
Methods employed; 1, Implantation of varioua ejffil>5.''y ..
tissues into tfee feraia. 2, Cross-aE-Sstoaosis of tifeisl c
peroneal nerves in th.e I'at aad salaE'Saiero
Ba.^or flndingga; Cross-snastosKsis of the titoial biic
peroneal nerves in the rat h.&& beeB g'.©r fos^sied , Jfo cr:' •'?,>?-
of restoratiosi of function ^es fowad. This; res'ttl
those re|)orted previousli? by cips2.'£'y •■■ .
Sip;,al£icai5c©', 1» Tke espejE-iiaeiitg.! evideE.: .,^,
the doctrine of aeurotropisia fcjha all toeen deprived ir^;-;
e^pei'lmeats on regeaeratiKg nerves <. These ca0c7i,'aai6iii
Mve been conceptwaily s.-K"ieaded to oatogenj; without tid^?.!-
tionai esperlsieatationc Such additionssl expsriBaeatatios^
meems ^&rrnnt@d In vie-?? of the great, disaiiraila'j'itles
l3©t^0©a ontogeny and nerve regeneratioa^
I's theos-y of myo-g-^pic speexxic... ..
has long been pusEllsig. Fiartaer iaventiiiatio
Page 2 Serial Mo. NIHDB-»MA-DR-1
Part A Project Description (coat'd)
phenomenon i9ili probably shed light lx>th on the hosiiologoiis
response and on chemotropissi.
Proposed course of project; To be coatiauedo
Part B included; Yes
Serial BTo, HINDB-M-DE-l
PHS~S?IE
ladividuai Project Eeport
Caleadar Year 1950
gagt„3: BonoTS, Aisards, aad PablicatioES
PublicatioBS other thsn abstracts from this project:
Gath, L, : Transiation; "Studies on Tertebrate lfeuroge■fi^^;
("Etudes S'ur la Keurogeads© de Quelques Vert^for^s'')
by 3. Eaadn y Cajal; Springfield, Illinois, Claarles
C Tho@as (in press) c
Honors and Av/ards relating to this project: Hone
PHS=NIH
I&dividusa Pr©J«!et Report
Past Ao
Priseipai Mv«stigatd2-8 ? Xrea« Mial« »»d Richard L. Sidmao
Oihj»t Mv9g%ig«t®r8 1 Noti&«
Mfeffi Years |cai®3£dasp y^ak 1959!?
Totals 1,3
PFef«ft8ias«l; <,9
Olfe©r? o4
Pr eject De«cj?iptl^t;
Object! v€i» g To ai^Iys« the bebavi^r @l cells i%. ih® immature
mamiaa£ia£ &-@;vous sfst«m i& srder to cXarlly m«chasisms &i
n&WTCsiBi: as.d pathotogieai d^velepmssto
Mi^hoda em:pl#yed^ Auteradieg^aS^y osiffig tritium lab«l«d
^&f midjte® ^tbyjaidiffi©°H^| was ®mpi@y«d i® pr^gsaist mic®o This
labeled ©ucl«@tide i@ ifficer|»©rated isl© deescffibesjueicie %.^ii iDHA*
©I calSs abosst t@ «Et«r €@il division a®d lfe«f>®alter ?©fsa*i3ss a« a
pex'maseM aoafkss' m thc^-se e«ll6c JLab«2®d «mbi°ys¥^ic tissues w^r^'
ll%@d i& B«miei''8 fl^id^ «isnb€dd«d ls% wax^ $<»€ti9%«dj, asid ^iFepar««3
f@r aat@i>adiog?aphi€ study by Lsbla^d^e <^i]^«<i liquid @m«lel«@
t®efe«4queo
Majey fiadia^s; Pr^gsaist smcg «;@?® give®. tfitium»lafe®l#d
tfeyj^idiae 4 5 l*e/gm ©I mett«®l^ i®t.r*v€8j©uely at vari^is atagas ©f
gmmt^im^ Smsm mmm killed at latfip tttages e£ g«atati<^ ^rhiie e«&©r«
w®f® »il©w@d i© dellv«r HBsir offepriigg^ whicte w®ye killed at g-sgtti&r
la!l@a?vai» up t© e@e mcsills p@«tffiatally<, A aimlSay d®fB® «(f Ifeyasaidtet-M^
"i^ii giv«a subcufaa@9U»if l& y^usag mie« at ««i@€t@d p@et®alal slagsfi^ '
affid t&ey w€J?® km«d at regiday imiervai* Ikare*!!®?, Wb^e emfery©©
•tt'r teiP(&iia» wer« i8@ctle@®d ffi^si&lly At 5 ©f SO f* *&d ®t4sdi®<J ■s.ial©-
it w%s p@e@iM@ t® traes e®12s aaigrati&g'fi'em tig® a€liir@lf
stak§®s t© tk@ir d@stJb&ftt£@£ is lh@ ssaiufe cfirsb^lltsisso Titmt ^#
Q®l§i II nmus^s ».s@B® twQtn IMs 8®us'€@o Th@ ®jct@c%jy, g.raa.iuils^s'
e:@2''efeeU«im la tim mmhrfoig 4icapp@&r®d b«tw@ssi IS etssd i,Q dm.fs
p@etig«,tsllyo . Fr&m this eeusc«» eext&M ^®m©Ms of ^e c@£'«b«»ilas>
€®?-lfi%;^ i!»el%dii&g grft^ul® emUe amd cells of tlb@ moieewlax' i&fer;;
w^s*® (i«3riy«d^ Pr«»iilerfttiv® a,etivity i% the @xt@s^al gra^^af
i£>f «r r®a^€l%®d its i»«ak im. thm first we®k afta? biiPtfej, &t wfeiek tim^ r,
llyi^ m ^@ primitive @p@sdp»al r^gioet had subsidedo IhAs d%Msl
t:h« bfaMo
Siyaificfefecti; Asst^yadiegrapliy with tlfeymidi©®=H^ i« a p®w#sff'al
iS^w l@@l ii^ h®«@t@f®r@ usmd los> tis^ at%idf i^ ®mbvy<ei@gi€^
p^&&^sseSo U aM®w« ii^bslmg td eslls &t a w@ll'-d@fls^^d pmsied c^
t&eir life eyd«^ auad »ll@ws &«s@ e«lls t@ be £ell@«if@d thx&ikgh th@£r
eisbs^^tgcffit migs'atieeis %i&d diffs^ssHatits^ B 8k@uld ail®w a,
d@lj&il#d aseaiysis of mhmu aasid b«s^ the vfts>ie(ee p9.st» ^ ^m bf %M
l®£m isa «nabx'yoisd€! Ill^o This is @f iMriffisie -^al^e^ «sid alse wiM
s@rv« as a basis i®v analysis «f d@v«lepm«£lal delsets tsf &« '£\<&rv^<»is%^
eyslsisno A fair assalogy €a@ be ds'awsi with eesg«sitai h&&wt di@«%3a,;
^*feicfe fe&« fe®«a clasilied »@ w®ll by r®latisg tfe® detailed embx-yesiic
d®^«l©pm®El ef tte® fe«art t© Ites tim® during piP®g®a®ey wl^^i t&e
ms^tK^r was ill @r ls^%si>®do Th® us« @l tM« m«lfeod hsk& m»d&
p®is»ifei® a ci@ay®r piclur® @f tfe« s®qu®®e« e€ d@v.€l©pmeffit @£ fefe®
«l®TO«B®t« (8i thm c#r®b€llum tfe&si with thm @Id@s' sje®i«g«pef im®ssft«l
Prci^@«»d ceaggfe ^ Ik© pgejfeet^ Tsmj^iPaFil-y di«c@©^tM»@d
b®c&m8« feotfe Di-o Miai® amd Dfo Sidsssais bav@ J,«ft tb® iate®r«t@rfo
A manuiiesipl is isi pr@e®©s ©f b©isg readied l@r fwaMicalieiEo Ttee
fiti* iss "A Dyss*mie app3Fe>a€fe t© c®y«b€llAr Metsge®®©!© Im tte«
m@«®® uMsiag triliutm labeled thymidS^^o "
Part B iactodgd? tm
Pa£f_B_s H@gs@r®5 AwartSf, asd PmMlca.ti<e®s
Sidm»ms Ro Lc c Ir@a© Lo Mls»l©j; asad No WmdrnWr, Cell
M©®©f® a®4 Awards rel&tlag t«> this pso^meti M^s-m
Serial m. HIIfD&-m-I
Section OB Developajeat
and B,egen®s&tion
3,
4o
PHS-NIH
Individual Project. Report
Calendar fear 1S59
Part Ao
Project Title „' Regesieratioa in the spinal cord.
Principal Isivestigators; J. Bo Campbell (consultant).
Earl R, Feringa and W. F, Wiadle
Other Investigators s A. Bassett (consultant), C- 'fhulirvj
Cooperating Units: Department oi Neurosurgery, Coluabiis
University, College of Pfeysiciaasi &
U^n Years (calendar year 195S) :
Totals 1.4
Professional r 1^0
Others o4
Project Descriptions
Ob.lectiveag To attempt to obtain anatomical, ©lectsro-
physio logical J and functional evidence of regeneration of
the spinal cord in cats and monkeys.
Methods employed; In cats and Esonkeys the spinal cord
«as transected and repaired by the Milllpore technique.
Additional variables studied ^eres treatment with Piromen,
filling the gap in the cord i^lth multiple short segments oi
peripheral nerve, and fusion of the spine prior to cord
transection. Standard electrophysiological tests v?ere done
to attempt to detaonstrate electrical conduction across the
transected area after 3 to S months.
Ma.fpr findings g In the cats o»ly one animal out of 15
showed evidence of coordinated talking Biove3a0at3 after cord
tii'ansection and repair by the Millipore technique. This
^ge 2 Serial NOo HIJPB~M=m:d
Part A Project Description (cont'd)
aairaal also received Firoaieac Several other cats with siaple
transections of the cord showed electrical conduction fro®
several centimeters above the gap to several centiiaeters
beio^ the gap and xls© versa - Microscopical studies
demonstrated axons crossing the gap in these animals <>
In the csts with large spinal gaps filled ^ith segaents
of peripheral nerves, vfe have seen a^cons groining i^to the
graft area, and have electrophysiological evidence of
conduction into, but not across, the graft area.
The ne^ series of studies in the monkeys are incomplete c
Significance ; Importance of studying the phenomenon of
regeneration in the central nervous system is self evident o
Results of this study may be applicable to almost any traxmati-
injury of the brain or spinal cord and amy thro^ light on aixy
one of a number of degenerative diseases.
Proposed course of project; Spinal fusions t?ill be dose
in cats and monkeys. Experiments ^ill be designed to
©splore further the value of the Milllpor© technique plus
Piromen in fused animals as a means to obtain anatomical,
electrophysiological, and "clinical' evidence of rsgeneratios
of the cordo
Efforts will continue to bridge gaps in the spinal cord
with segments of fresh or banked peripheral nerves <>
Part B included s Yes
Serial Mo. ^^^mB-m-DR- 4
PHS-NIH
Individual Project Be port
Calendar Year 19S9
Part B; Hoaors, Awards, and Publications
Publications other than abstracts from this project;
Ompbell, Jo B. and Wo F, Windles Relation of Millipore"-
to healing and regeneration in transected spinsil
cords of monkeySo Heurology (in press) »
Honors and Awards relating to this project; Hone
serial MOo NI^i^M^l^f
1. Heuroaaatomical Science;
2c Section oe DevelopsieRt
and E©g©aeratioii
3= Bethesda, ^rylaad
4.
PHS-KIH
Individual Project Eeport
Calendar Year 1959
iMXA'
Project Title. Tfee fimctioaal role and specificity of the
sympathetic nervous system in tiae regulation
of pupillary function.
Principal Investigator; Lloyd Quth
Otfeer Investigators; Co J. Bailey
Cooperating Units § Hone
Hs&a Years Ccalendar year 1058) t
Total? 1.3
Professionals loO
Other i c 3
Project Descriptions
Objectives g To evaluate the relative roles of the aya-
pathetic and par® sympathetic pupillsry fibers, and to deter-
mine whether autonomic nerve fibers can saaintain the functioc.
of autonomic effector organs other than those ^hich they
aorieaiiy innervate.
Methods employed i 1» Study of the size of the atropiaisa
pupil before and after sympathectomy <.
2. Tsansectiosi of sympathetic rami Ti„3 to silow collatera
sprouts frosa rami ^4^7 to innervate the pupillary ganglioa
cells of the superior cervical sympathetic gangiiocio
3« Preganglionic vagosympathetic nerve anastosjosiSo
4, Stimulation of sympathetic rami Tx„7 ^ith physiologies 'i
recording of the effects of this stiMulationo
Page 2 Serial Ho. HIKDB--HA-DR-6
Part A Project Descriptloa C*^oat'd)
H&jor findinaa; 1. Tiae atropinized pupil dilates
significantly in darkness, and a significant portion of
this dilation is abolislied by syHipathectomyo It smy b©
concluded that^ contrary to current opinions, the sym-
pathetic nervous systeia plays an active role (not iserely
a tonic one) in maintaining pupillary dilation in darkness.
2o Pupillary size "isas partially restored under the
influence of the 'foreign' nerve roots « Efowever these
roots did not mediate a "darkness reflex". These fibsrs
apparently retained their original specificity inasmuch
as the heterogeneousiy reinnervated pupil dilated in
response to decreased environmental temperature.
3. None as yeto
4o Hone as yet.
Significance % 1, These results correct the erroneous
opinion that the sympathetic nervous system is not ref lexly
activated by darkness «
2» We have foxmd no evidence of central nervous
system reorganization; however the experiment 'hss contaminated
apparently by regeneration fromi Ti„3, and so it is not
possible to draw reliable conclusions from our observations^
Proposed course of pro.iect i 1. Completed ^
2, To be continued during the coming year and extended
by studying the effect of unilateral sympathectomy on the
contralateral normal pupil.
3<, To be initiated during the coming year,
4o To be initiated during th© coming year.
Part B included s Yes
,'iyi .s-w i. J7<j , ji^jAK-i^A;-"- j»r.~i».a— V
PBS~.Hm
Individual Project Report
Calendar Year 1959
gart Bg HoQors^ Awards, aad Publications
Publicatione other than abstracts frora this project i
Bailey, C J= aad L. Guth; Eole of the syaipsthetic
nervous sfstesa in the pupillarj response to
darkness. Expo HeuTo 1? 166^170, 1959 o
Honors and Awards relating to this project s None
Serial Noo HIlDB-MA~DE-»7
1= Neuroaaatoaical Scieaee
2. Sectioi> on Developsjeat
and RegeaeratioB
4,
Indi-^idual Project Eeport
Caleadar Year 1950
Part Ao
Project Title: Eeterogeneows reiaaervation of the diaphragsi
Priacipal Investigator: Lloyd (Suth
Other Invest igatorss Karl Fraak^ Laiaar Soutter, aad
James Bo Campbell
Cooperating Units s Laboratory of Heurophysiology;, KiHDB,
Massachusetts Mesaorial Hospital, Boston,
College of Physicians & Surgeons, Coiujai>J
University
mn Years (calendar year 1959) ;
Totals «6
Prof essiosia Is c 4
Otfeer : o 2
Project description:
Qb.iectives; To determine whether diaphrsgaaatic fvmctloB
can be issalntained by the recxirreat laryngeal nerve in rats and
aS9thod@ eaploved: Aaastoasosis of proximal recurrent
laryngeal and distal phrenic nerve segaeats.
jgB.iog findii^gss The recurrent laryngeal nerve can restor
function to the denervated hemidiaphragm of the rate The
wojokeys i^ve not yet been subjected to careful physiological
evaluation,
JiSliJi;S^£§ * 2^ the experiaeat succeeds ia the iaonkey
x»e say then consider application of this operative procedure
to those hussan diseases characterised by pathology of the
page 2
Part A Project Descrip-:
phrenic nerve Ce»g»j "fotiibsK'" polioayelitisj
such patieats to siirvive Tsy.thout the £sgistsii-..-ti ^^i -i-.r.
artificial respirator.
groposed course of pro.lectg Tlae expei-iJueB
may be repeated, oe a larger group of subjQcts to ia:(.ui;
observatioas Biore suitable for publication-, 'iilus Eionlse:
«ill soon be teatecl here= Tfeist phase of tfee essiperiiaeiii-
then be discontinued her©, as it is an applied clinics.:
investigation. It -will probably he cent:'" ' ' ■" :
clinical investigators.,
Part B included; Tes
Individusl ai'ojQct Eeport
Calendar Year 1959
Fart B; Eoaors, Awards, aad PuMicatioas
PaMicatioia-3 otfee^ tfeaa abstracts froiK this p^v^jeetj
®ith, L» acd K. Frank; Rsstomtlos of diaphragajatic
function following vagoph.T®n±c anastomosis Ib t&fe
rato Ixp. Neui-,. 1:1-12, 1959.
Hoaors and Awards relatisag to this project ; Hoae
Seff'ial Mo. MIlDB-MA-Da-9
1. Meuroaisatojssicai Scieaces
2„ Section on Development
and Begeaeratioji
3. Bethesda, S^ryland
PES-HIH
l0dividual Project Report
Calea<5ar Year 1959
iMl^^,
Project Title? Histological studies of the aervous system
of lacaca imlatta after asphyxia neoaatorvm.
Principal Investigaton Wc Fo ?Pindie
Other Invest igs tors: J, Cajmaersieyer
Cooperative Uaits; University of Puerto Hico School of
Mediciae and USPHS Clinic, Saa Jmian
Maa les.jt's (calsadar year 1959):
Total;: 1,3
Prof eesioBal ? <.4
Otfesr s o 9
£*foject Descriptiosas
Ofe J^deJ-,Z§s '» "^-'^ deterualne the pattern of structural
changes Ik. tha laosikey brsia after asphysiiatiois at birth.
X^:iJlS^JL^§12iiS5I^ ' Fetuses of kaoisin gestatiosaai age
were oMaiaed froBa Ejosikeys b3ped under controlled coaditions
by cesiBxe&n sectioj?, close to term. Half the fetuses were
ssphy3fiated by reisK?val of the uteriae contents without
openiag the chorionic ssc. Other fetuses ■were delivered
ms controls o At varyiag tiases after delivery the infants
■©ere killed by the perfusion-f ixation techaique.
Serial sections of the experiffiental brains and brain
stesas aad otfeer section.^ of represeatative levels of the
spii:ial cord vmre prepared . Every tenth slide 'was stained
by -the buffered thiosiia Missi stain and alternate tenths
by the ?/oelcke ssyelia stain. Selected sections were staiaed
by Holtzer. .PTAH &nd Bodiasi methods and by other techaiq-ue®
for iron Siad fat .
feperimeBtsii aaiMals were . compared isith control animals
of comp&rafol® age for gross and microscopical differences »
CineBaitogi'Ssphic »ud other records of essperiaients were used
for revie-ffliag ftmctioaal observationso Studies ha-^-e been
carried out on six aBimsils living 2 to 10 days and on©
iivlEg 10 noRtfes*. , one preirisaturely horn, a«d three controla-
Page 2 Serial Mo. lypPB-ifA-D^-J
Part A Project Descriptioa (cont'd)
Mt Joy „f iadingg ; Experliaeatal aniraals^ which showed
extensive neurological deficits during life were paired
with controls of siiaiiar age. The brain daajage was alaost
perfectly syaimetricai in the eicperimental anisials and
principally in the gray matter o There were changes ia
white matter and destruction of myelin (at birth the
nyelination is quite incoaplete), but these were probably
secondary to neuronal damage » There was a striking local-
ization by cytoarchitectaraiiy defined nuclei, with damage
usually conforming closely to the anatomical boundaries,
some nuclei being spared even though surroxinded by damage o
The pattern of changes was the same in all experiments,
but the destruction varied in Intensity with duration of
asphyxiation.
The cerebral isocortex showed diffuse subtle changes
of the neturons with le@s complete staining than in the control;
yet with no clearly abnorsaai neurons nor neuroglial changes
at early agesc la a few folia of the vermis of the eerebelluia
there was loss of Purkinje cells and a slight neuroglial
react ion o At 10 months, there was atrophy arouued the
central sulcus of the cerebrum; a large central lesion occurred
In the vermis of the cerebellum.
Other areas of the bra in ^ brain stem, &nd spinal cord
had 20 to iOO per cent of the neurons damaged, usialiy to
the stage of ghost ceilSo There was a reaction of early
macrophages and an astrocytic hyperplasia in most damaged
areas. Mo hemorrhages, nor thrombosis were seen. At 10
months the microglial reaction had cleared and lesions
were marked by gliosis «
The inferior colliculus showed the jaost severe damage..
Other areas of extensive damage were most of the thalamic
nuclei, the subthalamic nucleus^ interstitial nucleus of
Cajal, globus palliduS;^ the whole reticular formation, the
superior colliculus, oculomotor, trochlear, and abducens
nuclei, most of the trigeminal nuclei, superior and medial
vestibular nuclei, cochlear nuclei, superior olive, nucleus
gracilis and cuneatus, most of the gray matter of the cord
(except in thoracic segsaents) and the roof nuclei of the
cerebellumc
Paga 3 Serial Mo, Mmm=MkzS^:i^
Part A Project Descriptiou (coat'd)
Slgaif icaace ; This is the first experimental study
of the effects of neonatal asph^p^xia in an infrahuman
neonatal pris^te.. Histopmthology of the infant monkey
torain is significantly different from that of adult m&n
after asphyxiation and is different froim that reported im
human infants^ where hemorrhages, cortical atrophy,
hydrocephalus and vascular infarcts have been emphasized.
Proposed courae of projects To continue as quickly as
time and preparation of aiaterial periaito
Part B included s Yes
Serisi Ho. KimS-m-DR-^
PHS-KIH
Ittdividual Project Report
Calendar Year 1959
Part B; Honors, Awards, sad Publications
Publications other than abstracts from this project:
Ranck, J, Be, Jrc and W, Fc Windle; Brain damage lu
th© monkey, J^fiafii, mulatta . by asphyxia neonatorusi.,
Expo Meur. 1:130-154 Ci95&) «
Honors and Av&Tds relating to this projects None
aerial Ko, NI]sn)B-MA-DS-2l
i, Heitroanatomicai Science;-.:
2. Section on. Developaeat
and Begeneratioa
3o Bethesda^ Md. a.nd 3Bn
Juan, P. E.
4o
FHS-NIE
Individual Project Report
Caleadar Year 1959
Part A,
Project Titles Psychological and feistopathological deficits
of asphyxia aeooatoruiB in guinea pigs.
Principal lavestlgatorss C J, Bailey and "W. F. Windle
Other Investigators; "Hone
- Caoperating Units ^ University of Puerto Rico School of
Medicine and USFHS Clinic, San Juaa
Ifen Years (calendar year 1959) ;
Total: o7
Professionals ,5
Other: o2
Project Description:
Objectives; To deterniiae the ability of guinea pigs to
learn and reisieraber simple maze problems at various ages after
asphyxiation at birth. To extend earlier experiments of Becker
and Wiffldie to older ages and different test situations c Tc
correlate physiological and psychological studies with hisfo-
pathological observation® on the bra ins o
Methods eau^loved; As previously described? (a) aspayxiat
by intrauterine ischemia at full term, (b) resuscitstiori by
intratracheal insufflation ^Ith 03, Cc) study of neuromuscular
and neurosensory deficits, (d) testing learning ability in mass
and Ce) histopathological correlations. Litterstate controls
vere used.
-._: - Serial No, MimmzM&::m::Sl
.v-M :■ -: Project Description (cont'd)
m;jor tlndin^jBt Qulaea pig fetuses ^ere asphyxiated at
tersa \3f ciampiag the uterine biood vessels diiring "iaparotoay
tad resuscitated by insufflation of tfeeir iuBgs= 0"oa©x-vatioBs
of degree of asphyxia and degree of result iag aeuroiogicii
deficit is@re isadeo Tfeere rsere iadications that asplayxlis.
©vea in saisli degree produced neurologies l deficits at least
tyaasiesitiyc
Asphyxiated auinssls aad their control littermates ^ere
tested ia an alternation saaze during the first iseek of life
or duris&g the t-^eifth ^eek» Some of these -were tested siso
in a ifafcer aiaze at about 18 months o£ age» Asphyxiated
aniaals joade more errors than the controls in learning
these tasks, although relearning tests did not sho« that
they forgot snore rapidly than controls « The learning deficit
seeased to become leas Barked as the aniiaals gre>» older.
There was no correlation of learning performance and degre®
of asphyxia ^
The histological examination of the brains of these
asphyxiated pigs revealed dassage similar to, though less
severe tbmn, that reported previously. Hemorrhages sser©
seen only in acute stages o Chroaatolytic changes in neuroas,
io3® of neurons, B&d neuroglial reactions appeared, notably
in the brain steia and thaiaiauSo Circuiascribed biiat@rally
sysswetrical loci of damage "were encoimtered in the thaiaal
of long-tarffi animals. The sign® of damage were less inarked
in aniaials living for a year or Bsor® than in those dying
during the first fe^ days or ^seebSo The neuroglia cell
changes subsided with tiae. Loag^terui survival aninals
exhibited miniaai brain damage; the cerebral cortex &ixd
cerebellum appeared to fee unaffected o
Significance g This experiment yielded further evideace^
that aaphyxial episodes at birth produce neurological
deficits, learning defects, and brain damage. It casts
doubt on the thesis th&t the ahort asphyxia! episodes seen
clinically do not cause some undesirable sequelae.
Proposed course of project; Experiments terminated.
Part E included; Yea
Serial MOo HII3DB-MA-DR-~2i
Individual Project Report
Calendar Year 1959
Part B; Honors, Awards ^ and Publications
Publications other than abstracts from this project;
Bailey ;, Co J„ and W. Fo Windles Neurological,
psychological, and neurohistological defects
following asphyxia neonatorum ia the gtiisea
pig. Sxperiaiental Mcurology (in press) «
Honors and Awards relating to this projects Hone
Serial MOo NIMDB~M-DR-23
1» Meuroanatomical Sciences
So Section on Developsent &md
Regeneration
3o Bethesda^ Maryland
PHS-HIH
Individual Project Report
Calendar Year 1959
P^rt A.
Project Title : Begeneration of peripheral nerves over
long gaps.
Principal Investigator; J. B. Campbell (consultant) and
Earl R. Furijoga
Other Investigators; Ao Bassett (consultant) and Co
Thuline
Cooperating Iteits; Department of Neurosurgery, Columbia
University, College of Physicians &
Surgeons
Ifan Years (calendar year 1959) :
Total; lo4
Prof essiosa Is o 9
other ; o 5
Project Descriptions
Objectives s To ez^plore methods of nerve grafting across
large gaps in peripheral nerves.
Methods employed; Hoawiogous serve segments, banked by
various methods C^rossen, frozen irradiated, and fro sen-dried }) ^
are implanted in gaps in the peripheral nerves of cats and
goats o Subsequently, anatomical and functional regenex'ation
are studied.
Ste.lor findings; In the cat good functional and anatoiaical
regeneration Tsae obtained across ga^a one centimeter long
which had been bridged vsith frozen nerve segments and \?rapped
in Millipore sheathSo The temporal history of the regeneration
through the graft is being studied. Banked frozen irradiated
nerve implants in cats have provided a superior method for
Page 2 Serial MOo NIKDB«-M'-DR-23
Part A Project Description (cont'd)
bridging large defects »
Studies in goats are ia progress,
Si^Bif icance ; These escperiiaeats are designed to
explore a metiaod of bridging laajor defects in peripheral
nerves and .«re expected to be directly applicable to htiiaan
subjects. Other methods of bridging long nerve gaps in aian
have been disappointing.
Proposed course of the project; Experiments ^ith
frozen nerve grafts \»ill be continued to study the time
coijrse of the process of regeneration.
Part B included? Uo
Serial. No. NINDB-MA-Da--24
i NeuroaiaatoiBiaal Bcietxce
'^. Sectioas on Devexopaieni
and Regeneration
3. Betheada, Iferylaad
4. Hew
PHS-NIH
Individual Project Report
Caleadar Year 1959
Part A.
Project Titles HistoJ^oglcal study of the nervous aystesa
of the Macaca mulatta after asphyxiatioZK
i»ith nitrogen gaSo
Principal Investigator: W» Wo Ifindle
Other Investigators; Howard N, Jacobson
Cooperating Units s USPHS Clinic, Saa Juan, PoRo
Man fears (calendar year 1959) ;
Total; 1.2
Professional; .4
Other; .8
Project Descriptions
Ob.iectjLves; To deterisine whether or not the pattern
of structural changes in the monkey's brain after asphyxiation
with nitrogen gas (anoxia) is similar to that after asphyxia
neonatorum o
Methods e^gloyed; Monkeys delivered naturally by
vaginal route or delivered by cesarean sections were placed
in an atmosphere of nitrogen gas in an enclosed chamber
until respiration had ceased » The a&iaials were then resus-
citated by iasufflatiou of their lungs with oxygen < Experi-
ments «ere performed between days 1 and 10 after birth » Four
young adult aonkeys were asphyxiated with nitrogen similarly;,
In one of these the asphyxiation v&s continued until cardiac
arrest. The chest was quickly opened and massage of the
heart restored circulation.
Serial sections of the brains of the monkeys were
prepared and representative levels stained \sith buffered
thionin Nlssl stain; alternate sections stained by other
methods.
Page i- Serial Hoo MM!^^:M::MtM
Part A Project Description (cont'd)
Major findings; The pattern of structural ciiaage in
the brain after asphyxia neonatorum of th'9 atonkey did not
occur after asphyxiation with nitrogen gas and resuscitation.
Even iii the one aniaial with cardiac arrest and subsequent
cardiac massage to restore circulatioa, a comparable pattera
of structural change via.3 not encountered »
Signlfieanceg These observations throw doubt on the
assuEiption that the effects of asphyxia neonatorxm are
essentially due to anoxia.
Proposed course of pro.lectg The study is continuing
and the results ^ill be correlated ^ith physiological ob-
servations and biochemical studies of changes occurring during
birth o
Part B included; ISo
Serial Ko, KIKDB-NA-HC-1
lo Keuroanatoajical Scieace®
2o Section on Neurocytoiogy
3, Bethesda, USaryland
4o
PHS-MIH
Individual Project Report
Calendar Year 1959
Part Ao
Project Title; Ultra structiire of nervous system..
Principal investigator; 3aaford L^ Palay
Other Investigators: Spencer Gordon, Jack Rosenbluth,
Milton W, Erightmsin
Cooperating Units; None
Han Tears (calendar year 1959) :
Total: 3ol
Professional: 2,5
Other: »6
Project Description:
Objectives: To study the organization of nervous tissue
at the level of fine struct"are, particularly the relations
l)et\<ieen nerve cells and between the several cell types of
supporting cells and the nerve cells.
Itethods employed: The principal instrument employed is
the electron microscope. Tissues are prepared for examination
by fixation in osmium tetroxide, embedding in methacryiate or
araldite, and sectioning. The sections are motmted on carbon^
coated grids, stained i9ith lead salts, and examined in the
electron microscope. Thicker sections are mounted in glycerine
and examined in the phase contrast microscope.
Major findings g Study of the glial cells in the central
nervous system in collaboration with Dr* Gordon has revealed
some distinguishing characteristics that will help to identify
glia and vill help to resolve the rather bitter diaagreeaents
which have marred the development of this subject. Two general
types of glial cells have been identifiedo The first is a cell
nith a rounded nucleus and a \»ell-defined irregular boundary
enclosing cytoplasm that consiats almost entirely of ribonucleo-
protein granules and a sparse endoplasmic reticulum. The
Page 2 Serial No, NIIJDB-NA-KC-l
Part A Project Description
reticuliua is susceptible to 3-weliiag if the conditions of
fixation aare less than optimal. Because these cells sre found
as satellites around neurons and in ro^s in the ^hite m&ttew,
they have been identified as the oiigodendrogliocytes., The
second cell is Hiore voluminous, hag aa indented or irregularly
elongated nucleus and a less easily defined boundary. Usually
it is surrounded by clusters of small rounded or oval profiles
vhich represent segments of the nuzaerous slender processes
protruding from its surface « The cytoplasm is less dease
than that of the first ceil and membraae-bouad structures are
prominent rather than the ribonucieoproteia granules. Fre-
quently the cytoplasm of this cell type contains bundles of
long thin filaments, about 80 1 in diameter, ^hich also appear
in the processes. This cell appears both in -white and in gray
matter and is often associated isith blood vessels and the
submeningeal and subependymal tissue. Its characteristics are
consistent with the usual description of the astrocyte. In
addition there are cells which do not fit exclusively either
category and must be considered as intermediate types.
All cellular elements in the central nervous system fit
closely together like the parts of a jigsaw puzzle. The slim
crevices between them allo^ for about 100-200 A of extracellular
space in the one measurable dimension <> It is probable that
edema represents an increased intracellular fluid compartment «
but our studies on this important point have not advanced
sufficiently to render an opinion. As the descriptive analysis
of the glia is a basic precursor of any satisfactory "sork on
the extracellular space in the brain it ^ill have to be completed
first «
With all the interest expressed concerning the small
extracellular space in the central nervous system, little
attention has been paid to the fact that in almost all parts
of the peripheral nervous system^ neurons, their processes ^
and supporting elements are in the same close contact. With
Dro Rosenbluth i»e have been examining the interface between
the capsular ceils and the neuron in sensory ganglia. In the
dorsal root ganglion, the plasmalemma of the ca£^ular cell
usually follows closely the contour of th© neuron, separated
by 100-200 1. In certain areas, however^ this distance
increases to 0,1-0,3 jx. These bays are filled by ridges and
microvilli projecting from the capsular Y»all. Eo^s of vesicles
and tubules, 200-600 A across, appear predominantly in the
perineuronal zone of the capsular cytoplasm, apparently rising
from invaginations of the piasmalemsm. The surface of the
Page 3 Serial He
Part A Project Description (cont'd)
capsulsr cell facing the pericapillary interstitial space is
coated by a basement meiabraae aad exhibits broad, flat,
overlapping cytoplasaic expansions. The cytoplasm of capsular
ceils contains granular endoplasmic reticulum, Goigi laeiatoraaes,
siitochondria ^ and assorted inclusions. Devious channels,
100-30U 1 ^ide, bounded by membranes continuous vtiith the
plasmaleimaae, cross the entire thickness. Single or multiple
aesaxona also lead from either surface of the capsule cell
to small axonal ttvigs enfolded into the cytoplasm.
The neuron does not display the surface irregularities
of the capsular cell. Desmosomes or other specialisations
of adherent cell surfaces are absent. However, short, stubby
neuronal processes frequently thrust into the inner 2;one^of
the capsule. In the neuron chains of vesicles, 200-600 A In
diameter, extend from the surface obliquely into the cytoplasm.
Frequently^ elongated flattened cisternae appear parallel to,
and Just beneath the surface, sometimes studded on their deep
surface by ribonucleoprotein granules.
In the ganglia of the eighth nerve many of the neurons
are surroiinded by capsular cells that develop myelin. Some
perikarya are coated by typical compact myelin, at least
0.1-0.5 |x thick, showing a periodicity of about 100 A. The
innermost lamella of the myelin sheath is separated from the
neuronal plasmaleiama by 100-200 1. The outermost lamella is
covered by a thin layer of capsular cell cytoplasm. The
sheath completely encloses the perikaryon and is continuous
with the myelin sheaths of the t^o processes issuring from
its poles. Modes of Ranvier do not appear in the parikaryal
myelin sheath.
The capsules of unisyelinated eighth nerve ganglion cells
resemble those of ordinary dorsal root ganglion cells. Inter-
mediate forms exhibit incompletely compacted myelin consisting
of multiple, closely apposed sheets of capsular cell cytopiassi
100-3,000 1 thick. This cytoplasm often contains endoplasmic
reticulum, mitochondria, and rows of vesicles. In places the
cytoplasm is absent and the t^o limiting surface membranes
merge for short distances to for© the cajor dense line of myeli
The bipolar ganglion cells contain peripherally located
Hisal bodies, prominent Golgi complexes, mitochondria, gran-
ular inclusions, and neurofilaments. In some of the heavily
myelinated cells the ribonucleoprotein granules are sparse.
The observations raise questions concerning the role of
the perikaryal myelin sheath in impulse propagation and in
transfer of metabolites and nutrients across the neuronal
surface.
Page 4 Serial Noc HINDB-HA-MC-l
part A Project Description
Sigpif icance ; These studies provide the basis for a
detailed understanding of the interrelations between neurons
and their supporting structures. The close contact among ail
these elements suggests that mechanissts for free transport o£
nutrients and ions isust be very efficient and must have
intrinsic vectorial coaponeats. The mfelln sheath around sojeq
periksrya suggests that certain generalisations for the
mechanisms of impulse generation are either not applicable here
or that a supposedly unrestricted extracellular space is not
essential.
Proposed course of pro.-ject; The results presented above
are incomplete o The study must be extended, particularly the
morphological isork on glial cells. Some attempts at functions!
correlations \9ill be made with the dorsal root ganglion cell
in order to ascertain the significance of the bays and vesicles
in the capsular cells. An additional study on the epeadymal
lining \»iii be carried otit in collaboration T?ith Dr. Brighti^aa,
Further work ^iil also be undertalsien on synapses and dendrites
in the cerebral cortex on the ^uthner cell in the teieost
fishes «
Part B included: Ko
Serial Mo» WINDB-NA~HC-6
i. Neuroftnatomical Sciences
2„ Section on SJeurocytoiogy
3c Bethesda^ Maryland
4.
PHS""IIIE
Individual Project Report
Calendar Year 1959
Part A,
Project Title c Relationship bet^eeen neurosecretion and milk
eject ion V,
Principal Investigators Milton W. Brightsaan
Other Investigators: None
Cooperating Units; None
Sbn Tears (calendar year 1959) ;
Total; .5
Professional; ,3
Other ; o 2
Project Description:
Ob.iectives; To determine ishether a depletion of neuro-
secretory oateriai occurs concojaitantiy with release of oxytocin
froa the hypothalamus and neurohypophysis in response to various
stimuli .
►loyed: About 175 feaale mice were divided into
several groups; Ca) virgin diestrous, (b) pregnant ^ Cc) partur-
ient;, (d) females permitted to nurse their litters for periods
ranging from 5 to 120 minutes, (e) nursing feajales presented
with litters rendered incapable of suckling.
The brains and pituitary glands were stained vsith chrome-
alum hematoKylin, coded and graded according to the amount of
stainable material present.
^,1or findings; There was no demonstrable change in
content of neurosecretory granules la the cells of the paraven-
tricular and supraoptic nuclei, median eminence or pituitary
stalk in any of the groups. The affijority of the ceils were
only sparsely granuiar.
Page 2 Serial Ho, NiNDB-»A-HC-6
PsLXt A Project Description:
The stiMull of suckling and of behavior associated yslth
suckling (group e) resulted in a statistically significant
depletion of neurosecretory meter ial from the infundibular
process .
gipnif icance : In addition to osmotic stimuli, the act of
suckling results in a release of hormone and of stainabie
material f froia the infundibular process »
course of jro.lect; This project has been suspended
Part B included? No
Serial Ko, UINDB-KA-NC-T
1. Neuroamatomical Sciences
2. Section on Neurocyto3.ogy
So Bethesds, dryland
4,
PHS-NIH
Individual Project Report
Calendar Tear 1959
i^rt A
Project Title; Species differences in choiinest erase activity
of the central nervous systea.
Principal Investigator: Milton W, Brightman
Other Investigators; R. Yf. Axbers
Cooperating Units i None
Man Years (calendar year 1959) :
Totals o8
Professional; ,6
Other: =2
Project Description:
Objectives; To investigate the sites of ' pseudocholin-
esterase" (PChE) activity in different species .
Methods employed s The Koeiie histocheaicai method for
cholinesterases »
te.ior findings; There is a remarkable species variation
in the site of extraneuronai cholinesterase activity. Such
activity occurs either in the endothelium, e.go, rat, goldfish,
and toad or in the glia, e.g., cat and rooster. There is no
obvious phyletic pattern of distribution.
3i,<pnif icance : The close spatial relationship between
neurons and giia, and the occurrence of pseudocholinesteraseg
in glia or endothelium, suggest a modulating influence of such
enzymes en nervous activity.
Proposed cottrse of project; The project has been completed
and published o
Part B Included; Yes
aerial Mo., MI«DB~M-MC-7
PHS-NIH
IndivlduAl Project Report
Calendar Year 1959
J^SXJi' Honors, Awards, and Publicationa
Publications other than abstracts from this project:
Brightiaan, Mo Wo and R. W, Albers^' Species differences
in the distribution of extranetaronal cholinesterasea
within the vertebrate central nervous system.
JL' Meurochei^. . 4:^44-250, i959.
Honors and Aisards relating to this project: Kone
Serial Mo, MINDB-MA-HC-S
1. MeuroanatoBjiC;®! Science:
2 c Section on J?eurocyto log-
So Betfeesda, Maryland
4.
PHS-KIH
Individual Project Report
Calendar Year 1959
part A
Project Title; Metabolisja of the nervous system: quantitative
aad cytocheiaical studies.
Principal Investigator: R. W, Albers
Other Investigators: L, Embree
Cooperating Units: Section on Clinical HeurccheEiistry, HIHDB;
Section on Enzyaes aad Ceiluxar Biocheiaistr
Man Years (calendar year 1359) :
Total: lo4
Professional: Id
Other : » 3
Project Description:
Qb.lectivea; To assess the functional significance of
special aspects of biochemical pathways as th@y occtir in the
nervous systess.
Methods employed; Quantitative histochemical techniques;
isotopic studies; chromatography; cytoiogicai fractionation,
Ma.lor findings: Methods have been developed for the
study of the rate of conversion of C^'^-giutamate into
Ci4_«y-.arainobutyrate in vivo. This has included a^thoda for
processing tissues^ separating the isotopically labelled
metabolites and determining their specific activities.
Studies have been carried out on aiice, measuring the rate
of this conversion in brain. Both amino acids become labelled
very rapidly. The specific activity of "Y-aminobutyrate attains
50 per cent of the specific activity of the giutamate in less
than 90 seconds. Calculations based on this type of experiment
lead to a rate of metabolism that ^ould require an imps-obable
Page 2 aerial Mo, NIK'DB-M-HC-S
Part A Project DeBcriptioa
rate of cerebral oxygen coasumption for th® mouse even if ail
of the cerebral oxygen coasumption iiere linked to f-^mlno-^
butyrate metabolism Because of this fisdiag several esperi-
nents are being carried out to investigate possible sources
of error in this type of saeasurement <>
Dro Lo Embree has been associated ^ith the sectloii as a
Research Associate since July 1. He la currently conduct lag
acme e:)cperiiaents in the area of succinic semialdehyde
nrataboliara/
An investigation of the types of traasaaiaases occurring
in brain was carried out with Dr, Wm, Jakoby of HIAMJo This
study has helped to explain the unusually rapid incorporation of
C^^ froffl glucose into brain glutamic acid. A study '®as also
carried out with Dr,, Jakoby i^hich elucidates the struct\sral
requirements of substrates for the enzysae, glutaHiic-Y~sisjiaofe^*y^
transaminase o
A review of the literature concerning the distribution
of Y'~^^ii^<^^^'^y^3^@ &n<i related enzyme systems was prepared
and presented before a conference on "Inhibition in the
Central Nervous Systesa and 7- Amino butyric Acido'
Signif icaoce t The basic problem amy be formulated as
follows:
(1) Relatively large quantities of Y-^JS^iiHobutyric acid
iy-KB) exist in the central nervous system = This is a unique
situation not found in other matamalian t issues ..
(2) The only known direct biochemical precursor of j-ABf
glutfifflic acid, is also found in uniquely high concentration
in the central nervous system.
(3) The enzyme which catalyzes the formation of v-AB froaj
giutassate appears to be localized to the gray matter of the
central nervous system^ probably to neuronal elements ^ and is
not found in other saisiaalian tissues «
C4) The metabolism of y-KB by the central nervous system
is intimately linked to pyridosine aietabolisia by virtue of
the two enzymes, glutamic decarboxylase and glutaiBic~«|^aaino-
butyrate transaminase ^
Page 3 Serial No. lIKDB~M~HC-8
Part A Project Descriptioa
(5) The metabolism of Y"AB by the ce»tr®i nervous system
is closely liBked to cerebral oi^idative metabolism toy virtue
of the enzym&g succinic segsialdehyde dehydrogenase (see
NIKDB-MA-MC-2 {1958}) „
(6) Evidence has been obtained relating cerebral pyri-
doxine metabolism to cerebral oxidative laetabolism.
(7) C\iaiitative observations have been published by
other investigators indicating tMt y-AB is metabolised
rapidly.
(8) The.- SUM of the known reactions occurring in brain
tissue asetafoolizing y-AB is
a-ketogiutarate -s- DPN — -^ succinic acid + DKSH + CQj,
From the foregoing, ^e have hypothesized that glutasEt®
and Y"AB might function as intermediates in the oKidstion
of G~ketoglutarat9 by brain and that thi® might -be a pathisay
of major quantitative importsnce in cerebral oxidative
laatabolism.
The high concentrations of both Y""'^-® ^^^ glutaijate In
the central nervous system have led other investigators to
propose a more direct influence of these aiaino acids upon
the excitability of certain neurons, either as a cheasical
mediator of synaptic transmission or as 'modulator' substances,
Pharmacological activities have been found for both saolecules
in various neural perparations.
It should be noted that the two hypotheses are not
mutually exclusive « However, some of the evidence ^hich
has been adduced in favor of the •■neurohurooral'' hypotkesis
might also be considered as secondary to effects on cerebral
oxidative metabolismo
Measureaieffit of the quantitative contribution of ^-^8
oxidation to total cerebral oxygen coasusaption is a direct
test of the hypothesis, ^hich would have major significance
both to our concept of cerebral energy Metabolism and ss a
stimulus to research which might relate defects in these
unique cerebral eaayme reactions to neurological disease
processes =
Page 4 Serial IVo. HIIDB-M-Mll-S
Part A Project Description
Proposed courae of project ; Data cfotained ia the preseat
experiments \?iil foe extended and coiapared ^itfe that obtained
by other teclssaiques to estabiisfe its validity ot to deteriaiae
the sources of inconsistency. SKperisaents to study the possibj
existence of a relatively sisall pool of rapidly astaboiialsg
glutamic acid a?e plaaoed.
Further studies oa succinic semaldehyde defeydrogeaase.
i&cludlBg fui'ther purification and characterisation, are
contemplated.,
l^rt B included § Yes
ladividual Project Li,c^.:^^ ^^
Calendar Year 1950
Pagt S; Honors, Awards, aad Futelicatiosss
Publicatioas other than abstracts from tliis px-ojeet:
Sokoloff, Lo, Lasssa, M. A., MclMian;, 0. M. ^ Tot,.
Albers, E. W. : Effects of pyridoxiae vilthd^i.-:.
cevehTQ,! circulation asad metabolism in a pyri.ilc
depeadeat cbild. .Hat_-are . 17S:75i-753 {1959:
S&lv&dor, E, A. and iilfoers^ E. Wo : The clistrl'out.-.w-i o;
glutgrnic-Y^^^S-aotJiityric trsBSSEUKase la the aervou,'
s^steia of the rhesus mat^ey. J. Mol_. Claerr: - ''?[-
AlberSj, E« Wo aad Bi'ady-, E. 0-, •, Tke distrifetitio;
glutamic decarboxylase ia the iiar'??ous system ok x,i.'.\
shQ&UB ^.ohkej, J,o 3±q1, (^m. , 234:926-923 (1950).
Hosiors and Awards ^elatiag to this project; Mone
Serial Noo NINDB^-HA-BJ^-l
1. Meuroanatomical Sciences
^o Section on Sxperistentftl
Neuropathology
3. Bethesda^ Maryland
PHS-NIH
Individual Project Report
Calendar Year 1959
Part A,
Project Title: Pathogenetical factors in the develupssent
of myelopathies.
Principal Investigator: Jan Cammermeyer
Other Investigators: None
Cooperating Units; None
Man Years (calendar year 1959) :
Totals 2c4
Professionals ,8
Other : 1 o 6
Project Description;
Objectives: (a) To obtain detailed inforioation about norma i
histological and physical characteristics of the spinal cord to
disclose factors involved in i^intenance of tissue tension and
blood circulation, (b) To assess histological characteristics of
varied functional conditions of neurons and neuroglia., (c) To
correlate cytoiogical characteristics of the spinal cord with
different degrees of functional abnormalities, (d) To clarify
the mechanisai of cell damage and progressive nature of tissue
changes is i thin the spinal cord.
Methods employed; Standard conditions of fi;catlon and
histological preparation of the brain and spinal cord.
Major findings: As part of a long-term project to study
factors concerned vith preservation of spinal cord function,
the following observations iwere made:
(a) The vessels of the central nervous system are surrounded
with numerous connective tissue fibers and these fibers pass
from oae vessel to another thus forming an anchorage for the
vessels. These intervascular connections are noted in most
animal species^ moat strikingly in the pigeon but not in the
opossum^ They are most numerous in the spinal cord.
Page 2 Serial No. NIHOB-M-gP-l
PsLTt A Project Description
(b) Aa analysis of the entire histological asaterial made
it possible to establish the principles for proper fixation,
autopsy and histological stainiag in order to obtain even
appearance of neurons ;, neuroglia, vessels and fibers. The
Bost important fact fias the revelation that the autopsy nnst
start after a delay of several hours after the perfusion.
The necessary delay varies ^ith the fixative used, for &
rapid fixative as the Heidenhain's Susa solution four hours is
enough, but for a slon fixative as 10 per cent forssalin even
after a lapse of 24 hours the autopsy should be prepared with
greatest care.
(c) Study of the neuroglial nuclei in noraal aniirail
laaterial revealed:
Astrocyte nuclei vary in shape and size isith region and
aniaal species. The largest cats have the largest nuclei as
neasured in longitudin&l sections of the spinal cord.
Oligodendrocyte nuclei very in size but their average
size is constant through the spinal cord and in cats of
different size. Their appearance is the a&me in Bost animals
with the exception of the guinea pig, haaster, squirrel and
pigeon. In these species no distinction could be made between
oligodendrocyte and astrocyte nuclei.
Cd) Microeabolizatioa obtained by intravenous injection
of oil in the dog resulted in a series of focal daissage, one
of 9hich consisted of a minute pericapillary condensation of
tissue and another of an aggregation of surviving oligoden-
drocyte nuclei after the neurons had disappeared.
(e) The oligodendrocyte nuclei foraisd clusters along
vessels near neurons and points of vascular arborization in all
13 norosal enimal species studied. Hone appeared perineuroaally
or interfascicularly arranged.
Significance; (a) The demonstration of numerous inter-
vascular strands of connective tissue fibers in different
aniiaal species is significant for interpretation of experi-
mental results to avoid an erroneous diagnosis of vascular
fibrosis. That such a system of fibers under pathological
conditions stay influence the blood flo^ in the small vessels
is formulated as a hypothesis to be verified in future
experiment So
Page 3 Serial BJo. HIM?8~MA~EP~l
Part A Project Description (coat'd)
Cb) The dcffioxastratlott that dark aeiuross are avoided by
proper autopsy procedure is of significance for settling
the discussion about the artifactual nature of these cells.
As a consequence the entire concept about the role of dark
neurons in cell physiology and cell pathology has to be
revised.
<c) The demonstration that astrocyte and oligodendrocyte
nuclei are not readily distinguished in all species is of
importance for those concerned with these cells' function.
Only such species should be used ^here an e:sact cell classi-
fication can be made.
(d) Fat emboli elicit cerebral changes of similar nature
in dog and man. This is true for the size and shape of
lesions and the speed of reactive changes. Of considerable
interest is a striking mobilization of iron. The intensity
of fibrin reaction «as less in dog than i»an. Another fact
was the high frequency of hydrocephalus. The latter is
typical of norisai dog material too.
(e) The study on the distribution of oligodendrocytes
in noratal asaterial has shed light on a poorly understood
profolesi; naiaely v^hat are the factors regulating the intrinsic
blood flow of the brain. For the first time the role of
Oligodendrocytes has been invoked.
Proposed course of prelect; To continue the study on
the distribution of neuroglia cells by means of a model o
The chinchil a is used because of the conspicuous difference
between nuclear types.
To analyse the appearance of neurons and neuroglia la
nornai amterial after the aniasals have been forced to perform
a certain asK>unt of «ork. Mice^ cats and laonkeys are used
because of the significance of using anli&als ^ith varied rate
of metabolism. A-^vaiting histological preparation.
To study the reaction of giia vascular complex in
eKperiajents \^ith antisaetabolites, nutritional deficiency,
, anemia j isicroeisboli, etc. Material of this nature has
already been asseicbled and histological preparation is under
^ay.
Part B included: ¥es
Serial Mo, MJ®B-M~lg=l
PHS-NIH
Individiial Project Report
Calendar Year 1959
Part B: Honors, Awards, and Publications
Publications other than abstracts from this project:
Cammermeyer , J. : A comparative study of the intervascular
connective tissue fibers of the central nervous
Jo Comp. Neurol . (In press).
Casusermeyer , J. : An evaluation of the significance of the
'dark" neurons. Ergeb. Anatoaie (In press),
Cssimermeyer, J, : Differences in shape and size of neuroglia:
nuclei in the spinal cord due to individual, regioaal
and technical variations. Acta Aaatomica (In press).
Casffliermeyer , J., and R, L. Stpank: Acute cerebral changes
in experimental canine fat eisboiism. Sxg. Heur. . i:
214-232 (1969).
Caismermeyer , J.: !s the perivascular oligodendrocyte
another elenent controlling the blood supply to
neiirons? 7th Conference on Microcirculatory
Physiology and Pathology. Trans . Mi croc ire. Conf .
(In press) .
Jori«i No. NINBB-MA-£_P-'
i » Neuroana tomi cb 1 Sc 1 1? i « u-:
:io Section oa ExperimejRta
Neuro pa t lao 1 ogy
3. Bethesda^ dryland
4 o Uet!
PHS-NIH
[ndiiriduai Project Report
Calendar Year i959
Part A.
Project Title I Introduction of a new chemical fixative for
tissues c
Principal Investigator: Mignon ^lia
Other Investigators^ None
Cooperating Units; None
Man Years (calendar year 1959):
Totals lo4
Professional:: leO
Other: .4
Project Description;
Objectives? To find a suitable fixative for preparing
autoradiograms from the central nervous system after S35-
methionine injection and perfusion fixation. To introduce as
a fixative a compound whose properties jsay be assumed to be
suitable for this purpose. To investigate the effectiveness
of the compound as a tissue fixative in general and a fixative
for nerve tissue in particular.
Methods emgloved: Animals were anesthetized by chloroform
and fixed by intravascular perfusion preceded by isasihing out
of blood viith Travenol. Brain^ spinel cord and a number of
other organs were removed and processed for embedding in
paraffin » Blocks ^ere sectioned and slides prepared c Approx-
imately a dozen different microtechnics for demonstrating
structures inside cell bodies as «ell as relations between cells
and their processes vtere tried ^
jor findings; Tissues from mainly lats, about 10 weeks
old; and from a few guinea pigs^ 2 days old^ have been examined
Page 2 Serial Ho, NISSDB-M-Sg~4
Part A Project Description
The compound acts as a primary fixative. No addition of
indifferent salts has been m&de. A standard concentration for
the fixative has been worked out. The time required fox-
rendering complete fixation of the brain was established by
removal of brains at different times after perfusion. Washing
of tissues after fixation is not necessary. Tissues can be
transferred directly into 95 per cent ethanol.
The reaction of the fixative with proteins, lipids and
carbohydrates Jjj vitro has been studied.
The histological picture seen ia paraffin sections shoiys tl
following: No artificial spaces occur around ceils or vessels.
The cytoplasm is homogeneously fixed. The shape of nuclei is
well preserved, the nuclear awmbrane is clearly shown. The
nucleolus is very distinct. Chromosomes are well fixed.
Sifgnif icance; A new chemical primary fixative has beea
introduced with very good fixation properties. Especial iy
conspicuous are the good results obtained with silver- technics
on nerve tissue. The fixative is not volatile and thus
agreeable to work withj the compound is inexpensive.
Proposed course of project; A manuscript on the new
fixative will be submitted to an anatomical jourjaal.
Part B included: No
Serial No. H|JSm=MrM=a
1 o HeuroeBatomical Scieaices
2o Section OB F-anctioaal
Individual Project Repoict
Cfelendar Year 1959
Part A.
Project Titles A study of the auditory afferent and
efferent systems..
Principal Investigator: Grant L. Easaussen
Other Investigators: Eichard Qacek
Cooperating Units: None
Bian Tears (calendar ^ear 1959) :
Total: lo4
Professions X : » 6
Other: >8
Project Description:
pb.iectivea: To continue to eaeplore and reveal unknown
anatomical neuronal connections of the afferent and efferent
auditory system; to learn something about the anatoiBicst.1 and
functional interrelationships of the^^e t^o systems.
(1) The Question of tone or frequency conduction ;iocal-
ized i9lthln the ascending path^say is poorly understood,, One
of the imjor objectives is to determiae the point to point
Interneuronal hook-up that evidently exists between the organ
of Corti and the cochlear nucleus and the projections frosi the
latter to the superior olivary comples and to the higher
auditory nuclei. C2) Also to learn @or@ about the intrinsic
and extrinsic recurrent or feed~back connections of the
cochlear nucleus and higher nuclear levels.
Methods eaoloved; The ne^?er and saore effective tech-
niques are chiefly depended upon for demonstration of aKonal^
preterminal (Mauta-Gygax laethod) and tariEiaal or
synaptic degeneration (lasnussen -method)^ as ^ell as C3olgi
preparationso The employment of the experiicental techniques
Page 2 Serial Mo, MMm=M=mzl
Part A Project Descriptioa (cont'd)
on subjects la which am^ll isolated lesions are properly
placed lastkea it possible to rsveal important complesly
arranged aeuronsl connections = The Oolgi metfeod isill he
used as supplement to the ot&er techniques.
Ma.^or findineis; The study of the (1) afferent and
(2) efferent nervous connections of the cochlear nucleus haa
disclosed the following informatioao The spatial arrange-
ment and tersQination of the cochlear sfferents related to the
different turns of the cochlea (cat and chinchilla) has
been completed » The inforaatioa obtained from the study of
the experimental smterial has been transferred to a three
dimensional model of the nucleus constructed of plexiglass =
This permits one to visualize isore clearly the "unrolling"
arrangement of the cochlear nerve fibers within the nucleus
in respect to the coils of the cochlea , The apical neurons
transmitting the louest frequencies terminate most lateral
and ventral; the middle and basal progressively more medial
and dorsal in posit ion « The efferent conasctioas eater the
nucleus via (1) the dorsal acoustic stria, (2) intermediate
acoustic stria and (3) the caudal trapezoid body. The first
originates from the nuclei of the lateral leasaiscus and
terminates la the dorsal nucleus of the lateral lemniscus;
the second one connects the S-shap@ olivary segment \gith the
ventral cochlear nucleus and the third collects fibers from
the inferior coilicuius and dorsal nucleus of the lateral
lemniscus and terminates predominantly in the dorsal cochlear
nucleus of the same side as described in 1858, The first t^'o
mentioned efferent conaectioaa are of recent discovery.
An uncrossed component of the efferent cochlear bimdle
has come to light. It arises from the principal olivary
nucleus ; unites «ith th© crossed limb of the olivocochlear
bundle before leaving the brain and proceeds together to the
cochlea. The termination of the homolateral component is
related more to the apical cochlear turns than is the crossed
component .
The new observations dealing ^Ith the efferent fibers of
the cochlear nerve and cochlear nucleus have been prepared
for publication and will appear as a chapter in a monograph
"Heiiral Mechaaiams of the Auditory and Vestibular Systems",
publisher ; Charles C Thomas.
Paga
Part
SigRif ic: ,„^^ . ; -;:.-, ^::^..- , ....... :.^i. .. .- ■„ .. ,..
relatiosiships existing at the synaptic i@¥ei bet'iseesi t&e
affex'eat aad elf.&Tent siiclitorj? system is basic to aa
underatassdiag of tfo© aeuromschajsiissi of laea:?lQgo Mel
inforiaatioa is esseatisl for a foimdat-ioa upon '^aic'-^
physiological ©sperlsae^'fes for tesvirsig the ;hmcl:ioE=
parfclcalarly of ths descending conviuctioa syratur.:-
Proposed cota''3f_^f jagoject ; To sstsad .. .....^.,y .....
affe.reat and efferent auditory sfstam to the s-apeskox
olivary coasplex and higher auditory i^^'-^-.-
Part B iiseiudedj Mo
serial Mo., lU^feilzprS
i -r NeuroaaatoiBicaiSciences
^« Section on Fwaeticaai
Heuroanatoiay
3. Bethesda, BSiryiand
4.
PH3-NIH
Individual Project Ri^port
Calendar Year 1959
Part A.
Project Titles The comparative anatomy of the efferent
cochlear bundle in selected submaBssallan
vertebrates; an escperimental study.
Principal Investigator: Robert L. Bo^rd
Other Investigators: Grant L. Basnmssen
Cooperating Units: This project was initiated July 1, 1S53
under the auspices of Public Health Ser-
vice Research Fellowship #9003 under the
sponsorship and guidance of Or» Gordon M.
Ramm, Departaient of Zoology, University of
Maryland, and Ds . Grant Lo Rasmussen, this
laboratory.
Man Tears (calendar year 1359) t
Total I 13
Professionals l^^l
Other ; <, k,
Project DesciPiptions
Ob.lectives; (1) To establish the presence of an efferent
cochlear btmdle in subasaraEsalian vertebrates. C^) To study its
central and peripheral anatomic relationships to the acoustic
nerve complex.
Methods employed r The surgical aidlioe incisions in the
medulla from the dorsal approach, at the level of the facial
genua, where fibers uf the efferent cochlear biudle have been
definitely established to cross in masimals. Folloiwing the
placement of favorable lesions, serial sections of the brain
stem and inner ears are prepared by degeneration methods o The
Nauta-Gygax technique for degenerating axons is applied to
intramedullary material and the Sudan black and Marchi methods
Page A Serial Noo MIM)B-NA-FN~5
Part A Project Description Ccont'd}
are employed on the peripheral portion of the acoustic nerve »
Baa.ior findings; An efferent coaponeat of the avian
and reptilian cochlear nerve has been discovered by experisiental
degeneration Methods. This efferent bundle is similar in
topographic relationships to the olivocochlear bundle previously
described In leaisiBais, These cochlear efferent^ decussate dorsal
to the medial longitudinal fasciculi, traverse the facial genu
on either side of the brain stem and join the vestibular root.
Peripherally the efferent fascicles traverse the vestibular
ganglion and gain access to the cochlear nerve via the
vestibulocochlear anastomosis. In the pigeon efferent fibers
are traceable as far as the cochlear sensory epithelium and
the sensory epithelium of the lagena. Although observations
are less complete for the caiman at this tlme^ it is presumed
that the distribution of the efferents to the organ of Corti
is similar to that of the pigeon.
Significance i The disclosure of an efferent cochlear
bundle in the bird and reptile adds support to the contention
that the efferent innervation of the cochlea plays an
important role in audition and suggests that the efferent
cochlear bundle is a part of the necessary neural equipaieat
involved in the nori^l hearing process. Furthermore, the less
highly differentiated cochlea of these submammallan forms is
more favorable for determining the ultimate termination of
these efferents J i.e., whether or not they terminate on the
receptor cells along with afferent fibers «
proposed course of the pro.lects This project, iinder
the present fellowship, will be terminated December 31, 1959
and the results used in the preparation of a dissertation for
the degree of Doctor of Philosophy. It is expected that work
will continue in submaisaaalian forms along lines designed;
CD to determine the origin and termination of efferent fibers,
and (2) to study afferent and efferent connection® of the
auditory system.
Pmrt B iiaclud@ds Ho
Serial Mo= MIM)B-MA-FM-6
1. Neuroaniatoffiical Sciences
2. Section oa Fuactiouai
Neuroanatomy
3. Bethesda, SSarj^laBd
4.
PHS-HIH
Individual Project Report
Calendar Year 1959
jpart A
Project Title I Further studies on th© efferent component
of the vestibular nerve.
Principal Investigator: R. E, Gacek
Other Investigators s Go L, Rasamssen
Cooperating Units: Hone
Man fears (calendar year 1959) ;
Total i 1.7
Prof essiona 1 : 1,5
Other : o 2
Project Description:
Ob.iectivee; CD To deterraine the laanner in which the
efferent vestibular fibers terisinate^ i.e., whether or not
they end on the vestibular hair cells as the afferent vestibular
supply does. C^) To locate the exact cells of origin of the
efferent vestibular fibers »
Methods employed? The Sudan Black technique previously
described by Rasmussen (1953) for study of Waileriaa degeneration
of nerves of the petrous bones is employed subsequent to
production of lesions in the vestibular nuclei and other regioi^s
of the hlndbrain. Serial sections of the vestibular ?oot and
all Its peripheral branches including the receptor epitheliuia
are studied in a large series of experimental aniiaais (cats
and chinchillas). Pifotargol silver. Glees' ajamonlacal silver,
and Nauta-Gygax axonal degeneration methods are employed to
demonstrate the ultimate termination of the efferents.
The laethod of Brodal, ^hich is based on the phenomenon
of retrograde cell changes, is used to demonstrate the cell
bodies of the efferent fibers.
*'art .?: '
W^.ioT, X^^6.±nk.3'. Kc jag. j or fiadlags coBcerniag th© t&rssiix;^-:.
or exact ce^is of origia vi-f the efferent vestibwiar fibers
can he reported at this tiiaao Origiaal observatloas dealing
i9ith the us-igia of tiie vestibt2la.r efferent fibers and tbeir
course sad distributioe In the labyriath have been prepared
for p-abiicatioa assd will appear as ^ chapter ia & asoEogySiSt?,,
■ Ifeurai MecMaissES of the Auditory aad Vestibular Systems' =
Signlf icsnce ; ExperisieBtaj. neuroanatomies 1 description
of the tersaiaatioffl of the efferent vestibular ajatetsa i®
needed to verify the fact that eadiags possessing character 1»
of centrifugal fibers have beea described ia the vestlbuigr
neuroepithelium bf electron, roicroscopic and histochealcal
sieftns. Slucldatiosk c£ the ultimate terisiastion of these
effereats ^ill be of particular use in physiological study vi.
this effereat isystem which ssay regulate sensory inputs as ths
cochisar efferest bundle does ia the cochlea,
Proposed course o| pro.iect; Study of the ultimte
tenaisatioEi of 'the effereats ia the vestibular ejad-orgaas
will be coatiaised usiag «ipjiropriate experissentai aeuroas^.* '
i*®rt B inc]
Serial No- NINPB~NA-FH-7
1. Neuroanatomical Sciences
2. Section on Functional
Neuroanatomy
3. Bethesda, Maryland
PHS-NIH
Individual Project Report
Calendar Year 1^59
Part A.
Project Title: An experimental study of the ascending and
descending fiber connections bet^seen
corpus geniculatum media le and auditory
cortex .
Principal Investigator: G^ant L. Basmussen
Other Investigators: Jost B. Walther
Cooperating Units: The National Academy of Sciences by
aTsarding an appointment under its
Visiting Research Scientists Program
to Jost Bernhard Walther o
IfEin Years (calendar year 1959):
Total: 2,0
Professional: <>2
Other: .8
Project Description:
Objectives! An attempt (a) to improve the kaovf ledge
about the auditory connections ascending from the thalamus;
(b) to explore descending connections from cortex areas
knoisn or suggested to be auditory in function; Cc) to learn
the pattern of innervation of 'sustaining" auditory cortical
projection areas.
Methods employed; Lesions are placed at various locations
in (a) the medial geniculate body and (b) the classical
auditory and other cortex areas of the cat. The resulting
axonal degeneration after 6 days' survival tisie is stained in
serial sections i»ith Kautas technique.
Ma.-jor findings; Histological sections of 17 experi-
mental anls^ls have been processed and studied thus far but
the observations and series of experimsnts are too incomplete
to offer any significant observations at this timeo
Serial Mo. MMM&zSAdUrl
Ic Heuroanatomicai Scieace.
Section on Perina.tsl
Physiology
3. 3sE Jtsaa^. Puesfto
Saiae as NIMDB-NA-DE~
19§@
PHS-NIH
Individual Project Report
Calendar Year 1959
Par-^ A,
Project Title? Ecological study of rhesus monJseys on Cayo
Puerto Rico
Principal Investigator?; C. B. Koford
Other Investigators : None
Cooperating Units s University of Puerto Rico School of
Medicine ; San Juan
Man Years (calendar year 1959) ;
Tota It ^ c 1
Professional: i^O
Other 5 1 o 1
Project Descriptions
Ql?,iectives; To study monkeys in natural social groupings
and their relations to a aemlnatural environment o Tv> estab-
lish whether a supply of experimental aniisals can be produced
mori& economically in a free-ranging colony than in a iaborstory
colony.
MlhQ^SL^SM&liijMi The principal laethod of study is
systematic year around observationo Periodically several sioakey:
are trapped for examination, measurement and laarkingo Approx-
in^tely 85 per cent of the animals are distinctively tattooed
As far as possible, the reproductive history^ group sssoci@tio»,
and other important facts in the life of each anijaai are
recorded for analysis.
Major findigga; In 1956, ^hea. the Laboratory assumed
control of the Santiago colony, it consisted of about 150
moaJfeeySo Since then they have increased to nearly t\»lce that
nuiaber. There ar@ now about ^80 « The r®t@ of mortality Is
lovi , about 5 per cent per year» Five feissies have lived asose
Serial Sc. NIlDB-Mil-PP
1.
Hsiiroana tomica 1 3c ->.•-:.
ki.
SeotioQ oa Periaata.;
Phys-J'^logy
3.
Smn JuaKij Puerto
HiGo
4.
Same as l?imiB-M-S(a~16
1958
PHS-MXH
Individual Project Report
Calendar Year 1959
Part A,
Project Title? Hormal reproductive fuactioR in the rhesus
Priacipai Investigators r. Howard No Jacobson and K. F»
Voilmain
Other Investigators I Mone
Cooperating Units; University of Puerto Eico Medical
School and U8PB3 Clinic, San Juan,
Man Years (calendar year 1959) :
Total: 1,8
Professional: 1,0
Other,- oS
Project Description:
Objectives J To obtain data on menstruation in monkeya
under standard conditions. To observe whether or not
seasonal variations occur.. To study spontaneous fluctua-
tions of the iseastrual cycle. To obtain data on conceptions
in the monkey and detes-mine tiiihether or not seasonal changes
la conception rate occur in a climats of essentially oae
season.
Methods eaoloyed: (a) The animals are fed a standard
superior diet and are inspected daily for evidence of
menstrual bleeding. Matings are presently confined to
«hat is considered the laost optimal portion of the menstrual
cycle. Care is exercised in choosing couples for mating
and ii&compatibiiitiea are matched for and avoided ishen
known = Miniausj gentle handling of monkeys is routine.
(b) Statistical analysis of menstrual records; calculation
of parameters for the length Sknd variability of the jaenstrual
Page 2 Serial lo. NII<K>B-MA~PF^2
Part A Project Description (coat'd)
cycles observed ia Bethesda and Ssa Jtianj testiag for
sigaificaace of possible differences; analysis of a possible
correlation between the degree of isregularity of the
menstvu&l cycles as found ia Betfeesds and Saa Juaa;
analysis for aa aanual fluctuatioB is the variability of
the meassryal cycles, (c) Statistical analysis of mating
records; tfa© distributioa of fertile aad sterile matings
to the days of the menstrual cycle Tsiil be stusniarized.
The hypothesis will be tested according to ^hich the fesrtile
days vary ia a positive and liaear correiatioa ^ith the
length of the laenstrual cycle.
a^.lor fiadinga; The a^nstriial cycle of individual
monkeys is subject to ¥fide variationso These variations
are spread throughout the year. There is no systessatic
relation between regularity of cycles and fertility »
lutings in this same colony sho^ that conception occurs
throughout the year. This is in contrast to most published
reports. The colony as a ^hole is remarkably fertile, part
of ^hich is tentatively attributed to the care isith ^hich
the aatiags are per foriasd. In a recent threes-month period
during a season when relative infertility had previously
been observed in this colony 17 out of 43 moskeys conceived.
Of these 17 monkeys 9 conceived foilo"wing the first mating
^hich was performed on the 11th day of the menstrual cycle «
gignif icaace : The results bear on the futiare develop-
stent of the colony for optiEsal reproductive perforisaaoe and
for rearing of a healthy stock of monkeys. I^st of the
hypotheses concerning reproduction in the human have their
origin in observations on prissates. Our data indicate that
seasonal variation in fertility is not a major factor in
the rate of conception. Further , ^ith careful supervision
of a iBonkey colony forty per cent of selected feaiales asay be
expected to conceive.
Proposed course of project; To continue to study factors
influencing reproduction in the ^>nkey.
Fart B included: Ho
i. M^uroana toxical Scissces
2. SectloBi on Perioatsl
Physiology
3. S©ia .Jyaiis Puerto
4. .3aiae as NI2®B-NA~DR-17
1958
PHS-MIH
Individual Project Report
Calendar Tear 1959
Project Titl®§ MBtiuration in infant rfaesiss isoakeys and car©
required for rearing theffi»
Principal Investigator c^ Howard M, Jacobson
Other Investigators '^ None
Cooperating Units s University of Puerto Sico Medical
School and USPHS Clinic^ 3aa Juan, P E.
Man Years Ccalsndsir year 1959) s
Total; lol
Professionals o2
Oth@r? c9
Project Description;
Ob^][ect,iyes g To collect data on noraal cage reared infant
rhesus aionkeys in order to describe growth and development and
the kinds of variations encountered c To establish the standards
of care required for th© rearing of infants daiaaged at fetal or
newborn asphyxia t ions c
ifethoda employed g A nursery patterned in laany details
after those in hospital use is maintained for the csre of
Infant monkeys <> Records are kept o£ daily ^sieights^ jailk
intake, temperature ^ aad respiration ratCo Heart rate is
recorded electrically . (^asp reflex is measured routinely.
The maturation of the ability of self- feed is assessed,
i&.ior findings s MorEial ranges have been established for
birth weights of infants delivered both vaglnieilly ftnd by
cesarean section. Ranges have also been established for 'weight®;
heart rat©^ teraperatiire^ respiration rate and dentition
throughout the first tt?o months of life. Food requirements
and methods of feeding «ere established and also methods were
developed for the regulation of body temperature o
Page 2 Serial NOo M^Q^zMk::i^3-^
Part A, Project Description Ccont'd])
This k%oT9l@dge hft@ been applied to the cai^e of infants
damaged by either fetal or newborn aspiijsciation. In a
series of 10 technically successful asphyxiatio!i-»r6suscita-
tion experlMeats 9 babies ^ere jsaicttaiiied in good hesaltho 0&®
of these tables required hand care for nearly 10 months! c
Ifony of these infants required prolonged assistance In
leArning to self-feed.
Slt^nif Icance % These normal values should prove useful
to others establishing primate colonies. They are also
essential in assessing the standards of care of this nursery
in comparison to others- Furthers these studies shon that
it is possible to raise severely handicapped infant monkeys
in a state of good health o
Proposed course of pro.lect; To continue collection of
data and improve standards of nursery caret,
Part B included g No
Serial Ho. MIM§=M^I,^^A^
^Jeuroanatoiaicai 3cie».«
Section, oa Perinatal
Physiology
3 c Sail' Jxsaa., Pu€»Kt.o
Eicb
4 c saiae as l§im>B-?W~9E~>ii
1958
PHS-NIH
lEdividuai Project Report
Calendar Year 1959
^eX^'
Project Title i Th© intrinsic nerve supply to the ©ndoi»€tri«K
in cat and isonkeyo
Principal Investigator? Howard No Jacobsoa
Other Investigators^ Hone
Cooperating \M%t@i University of Puerto Ricoj Medical
School and USPH3 Clinic ^ San Juau
Ifiin Tears Cc^^e^^^ year 1959]) t
Total; IcO
Professional i c 2
Others c8
Project Descriptions
Object lyes g To determine whether the priiaate has an
Intrinsic nerve supply in the endoaetriuaa siaiiar to that
found in the cato It such is found then to deteriaine the
course and distribution o£ these nerves,,
Itfethoda employed g The endosietriuis of adult cats and
rhesus inonkeys «as stained by the laethods of Dastur and of
leddel using methylene blue dye. The dye was injected both
iatra-arterially and locally into the uterus of lightly
anesthetized animalSo Whole mous&ts of tissues «ere prepared.
:^i.-|or findings s The endoraetriu® of the monkey is
densely supplied «ith fine terminal nerves. This verifies
the earlier «ork reported in cats. These nerves pass from
the muscularis of the uterus into the endometrium and are
found approaching the surface endometrium. In suitable
sections the nerves i^y be seen arborizing around secretory
glands and there is some evidence that they pass to individual
cells 0 The nerves may also be seen penetrating into the
vicinity of the arterioles of the endometrium c
Psge c. Serial Mo. lUffi-fclk;^^^..
Part A ftc'oject Oescriptioa (cont'd])
^SaMAMSSfis This ia an unequivocal example of the
psirticipatioa of tfe® nervous 3fst@ju ia aa area which is
usually considered to be exclusively controlled by hormouesc
The iilaysio logical sigaif icanee of tli@s© nerves sm^f help
elucidate me'ctesissss of uterin© bleedisag,, aad may pearfeaps
be involved is sittch tlsiugs us nidatioao
g:yj>jBo_sad yoi^si^ of , pro.lept s To coatiaus t!3« histological
studies to determiae islsetfeer tlae huflsau uterus is' aiiailarly
supplied with i««rve®j to devise laeans of studying the functional
sigfflif icastc® of these raerveso
Part B included 5 Sfo
Serial ^o. 1?ZMDB-1A-Fg^5
1. Nstjroajiatoiaical Sciences
2. Section oa 'Feriaatal
Flays ioiog^- . .,
3. l^a.Juaas Puerto "" '
Eico
4. Same as MIIBB-M-BE-IS,. 1
DS-=19, 1958
Individual Praject Report
Caleadas:' Year 1959
Part A.
Project Title: Neuroiogicai evaluation aad electro-
eacephalogs'apfeic studies iB the moakey
(Vesica satlatta) at
Friacipal lavsstigator : Maria I. E. Eamirss de Arellaao
(consul taat)
Otfaer Investigator 3: C. 1. Combs aad M^ Eamii'Sis de
Arellano
Cooperatiag Units: University of Puerto Eico Medical
School aad USPHS Cliaic, Saa Juaa
^li Years {caleadar year 1959) :
Total: .9
Professional: .5
Ot&er : . 4
Project Descriptioa:
?.1@ctiyes.: To determiae the aeisrological deficit
resultisag froia aspSiysia neonatorum ia MOEkeys by laeaas of
neurological esamiaatioa aad eleetroeaceplialographic studies*
i^tlioda e:^^o.Yed; Standardised aeiarological esamiaatiom
are perforaed periodically from the time of birth oii>. A
laotioQ picture record of the esaaiaatioa is Esade at estab-
lished periods. Electroeaceplaalograpliic recordings are also
doae periodically frosa tia© time of birth oa. Staiaiess
steel aeedles applied to the scslp ar© used. Both moEopolar,
using ©srs as refereace^ -aad bipolar recording® are made.
Photic stimialatioEi is used as ssa activation procedwre. Both
neurological aad electroeacephalogrsphic studies are carried
out on moakeys asphyxiated mt birth (tectoaiqu© used ia this
laboratory) aad oa control aaiiaais.
Page 2 Serial Ho. MXNBB~NA-PP-5
Part A Project Description (cont'd)
^■ior fiadiags; Ifeuroiogical deficit of consider®bi©
degree aad persistesit ]iiature has he&n observed in the
asphyxiated Bsonkeys. There has been little teadeacy for
lateralized Ktotor deficits. The general pattern has been
one of choreo-athetold moveiseats and a saarked lag on the
developiseat of isolated jaovemeats such as pa^ing^ reschiag,
and picking up Bm^il objects o The electroencephalogram
of jcaost asphyxiated monkeys did not differ greatly from tlra
normal c Most laarked finding is depression of the electrical
activity during the first five or ,si35 days.
3isrnif icaace ; A prospective type of study ia privates
(liscaca aulatta) has enabled us to study the neurological
deficits due to brain damage as a result of asphy^^ia in the
nev»born .
Proposed course of projects To complete. the study.
Part B included ° No
srial 2^0, ;HOIBB-l?A-PP-.S
1 * He^roasatomical Scisac©s
2, SsctioE oa. .P8ri5sata3.
Physiology
3» 3aB Jiaia, Fues"to
Eico
4. Saae as MB3BB-.MA-DB-20
3.@§3
2Bdividuai :teoject
Calendar Yeas* 1959
Fart A.
Project Titles Psychological ©ffeets of aspliyssia sieoaatos'iiM
ia rhesus w£>n'k®fG.
Prifficipal Investig&to:^ i Buq ¥. Saj^oa
Other Isi¥©stigators : Hosiq
CoopQyatiag Units 5 USFHS Clinic, San Juaa
Man Yaa*'© (caleadsa:' year 1959) 1
Tota.l: l.S
Proftssioaal: .7
©the.:: ,9
i'roject Bescriptioa;
C{3.iectives; To evaluate the feeM^vior o^ rjaesu© ajoafeeys
4)'teir Rspfe;p'xia ssoaatorma as cospsred ^itJsi tlae betiavios" of
cQsjparaM© aojrmal conts'ols. Primary esjpMsis feas bees placed
on leax'aiag abilities.
Bge.^hodgi eipgloycgd; A t©st featte^'y lias hQen developed for
bot^ asphyKiatesd aad sorEsai auis^ls. Testing starts at 60 da^s
of age &\\d oonti.nne& thro-^gbout the fis-st tvio y®as?s of life;,
Tfe© batte:?!^ isclndss laeasisi'es of leas-jaiag ability j, both i® sisipl©
aad diffic^jlt Isaraiisg aitiiatioas, tests of atteiatioa, psr-sev-
eratioBj activity, eaotioaality, and geaai^ai reactivity to
surroMudiags , StaEdsrd ps^'cfeological testing ©qwipsent is
used as f?ell as strictly obssr^atiosal tecliaiquas.
la.lQg .jl'iM-lags; ^o sigaificaat fiiffsreaces in Issrsiag
abiliti* l!^ foses foisad fest^eaa groups (5 aorj?ials; 5 asphyxiates).
Also ao sifsif icaat correlatioa ©sists festifeea leagth of
asphysiatioa snd object disjcrimisiatioa learning. Ho^evaj?,
Goraal cojstrols Ita^a bsos fo-aad to be significantly m>Te
emotioj^l ttsasa asplsFSiatsd siatejects.
Page 2 Serial No. HIHDB>lA-P5^-6
Part A Project Descriptioa (cont'd)
ai^nif icaace ; The majority of the tests are still in
progress ; so group coaparisoas can not be discussed thoroughly
as yet.
Proposed course of the prelect; The ps-eseat test tosttery
T»ill be continued uatil all ania^ls have completed ito Additiorml
tests planned for the sear futiar© isill be conditioaiag proce-
dures to evaluate soase of the seasory abilities of the animals «
AlsOj aore sensitive measures of attention or responsiveness
to environiaent ?»ill be initiated o
Part B included; Ho
Serial Ho. MIEI^EzikzEirl
Neuroaaiiofflicil Sci«"n
2. Section oa Perinatrf :
Physiology
3o Sass Juaja. j^uex'to
4o New
PHS-HIH
Individual Project Report
CaleadajF Year 1959
Part A
Project Title? Evoked potential evidence for connections
from the cerebellar liemispheres to the
sigmoid gyric
Principal Investigators: C Mo Combs and S. Y. Saxoa
Other Investigators s None
CooperatiBg Units: Mone
Ifan Years (calendar year 1959) ;
Totakl; 1.3
Professionals .5
Other ; „ 8
Project Description:
Qt^jectiveSc To find whether using the evoked potential
method a connection could be proven to exist bet"5»een the
cerebellar hemispheres and the gigmoid gyrl as ^as clearly
implied by physiological studies o
Methods employed; Data -were obtained from 40 cats either
anesthetized with Nembutal or s^intained on curare-like drjugs
Single shock electric stimuli were given to the exposed
surface of crus Ij crus II, paramedian lobule, tuber versa!®,
or culiaen of the cerebellar cortexc Evoked activity was
recorded with cathode-ray oscillograph from the exposed
surfaces of the ipsilateral and contra lateral anterior and
posterior sigmoid gyric
^ioi,-»=£ia!di JLMS ° T^® largest cortical responses were
found In the intermediate one third of the eomcraiateral
anterior sigssoid gyrus o Smaller potejefcials were consistently
obtained from the imteral part of the contralateral posterior
Part A Project Description (cont ' a,«
sigmoid gyrus.. I:p®llaterai responses c «hen present, were
SBMftll, incojisisteot , and only fouad in the aaterior gyrus,
TJa© active cerebellar zone foraaed a longitudlzml strip
consisting of t&e lateral one half of culBuen^ tbe aiediitl
two thirds of cms I, the aediai one half of crus II, and
the paraaiediaa lotoul©. Within this region, the largest
responses resulted from stimulation of the anterior two
thirds of the Medial one third of crus I. Mo potentials
could be evoked with stirauiation of the lateral parts of
crus I and 11, tuber verrais or the laedial one half of culffiea^.
The results \9ere as readily obtained in the Membutalized
a@ in the curarlzed preparationso
Significance g Although evidence has existed for many
years that repetitive or phariaacologic stimulation of the
cerebellar hemispheres could ex«rt a distinct effect on the
contralateral motor cortex (i^nterior sigiaoid gyrus), previovss
to this study ao investigators had been able to find any
indication of this ^ith the evoked- potential method.
£S^tJBSiMSA.S^£mmLS^. P^QJSS^ ; The project is finished on
the cat^ but it is felt that these findings should be tested
in the monkey,.
Part B inciudied? tes
serial MOo gr?.HDB-M"FP~7
FES»WSH
IadiT?id^6l Project Eepo^t
Calendar ^ear 1959
Pagt B; Hoaors, A'sards, asd PtJDXieations
Publications other thSE abstsract® froia tijis project:
Coabs, C. Mo aad S. ¥. Sason: Ivoked potential QvidesiGS
for Goaaectioas froja tbe cerebellar Sieiaispheres to
the sigmoid gyri. Esperimestal Heyrology (ia prssa)
Honors ©ad Awards relating to this project: Moae
aerial Moo KIHDB-HA-PP-S
i o Keuroftnatomical Sciences
2.. Section un Perinatal
Physiology
3 c. Saia Juas,- Puerto
Rico
4= Mew
PHS-NIH
ladividiial Project Seport
Calendar Year 1959
SMi.^A'
Project Title; Multiple alpha-rfaytha cortical responses
resultiug from single shock cerebellar
stimulation.
Principal Investigators: C= Mc Cossbs and J- Mo Deanery
Other Investigators; Hone
Cooperating Units s None
Man Years s
Totals i"3
Professional? =6
Other ? « 7
Project Descriptions
Ob.lectivess To determine i*hich cerebellar areas will
produce a aailtiple aipM-rhythiE cortical response when stiaiu-
lated; to detertslae the cortical areas whare these responses
Bsay be obtained; to .eetsbiish whether these responses use
the saroe pathways as those ^hich have been described as
resulting from stiiaulation of various other neural structures.
jg^thods eaaployedg A variety of experimental preparations
have been tested in csk s in order to find the one aost suitable
to the carrying out of this project » After much experiinenta-
tlon it has been found that cats deeply anesthetized with
Nembutiil are raost satisfactory. In these aalnals single
shock electrical stimuli are given to the exposed surfaces
of crus If culsaea^ or tuber vermis of the cerebelluiBo
Simultaneous electrcencephalographlc recordings are made
from various areas of the bilaterally exposed corebrsl cortex.
Mtt,ior ^iytdings; The preliminary findings in this study
indicate that single shock stliaulation of cerebellar crus I
will induce in the Nembutalized preparation a bilateral
multiple alpha-rhytSm response in the cerebral cortex. It is
most prvtACMicea i& tfee cojutrsistersi ectosyivi®», iauditof y }
cortex » iS^uf is&t@restlng details which have 'be^.n s^^axk aumst
be ojfflifirffl.ed with subsequent expeyimeBtatioffi-
,.4iMJ=ii£ia£l " 'y^® signilica.ace of this stuclj -wlli
probably ceater about the mecfaajsiSEfi aa>d pttfe^ways whereby tfe©
cerebellar hezsispfeeres caa i.tid«ce tfeia multiple cerebral.
respoi3>a« .
-J^9.-K?.^Jil..,fe^J^I'#-f ^jf-,. MgJ.!tg.1^- ^' To tt.'Mtimif. as dssscrib^d
;altjn»ve is order tu folio® up these prieliaiiaary liadiags
krt B icciuded.^ Mo
serial Mo, HI^B-,m-Pg-^
1. Neuroanatomical Scieaces
2c Sectioa on Perinatal
Physiology
3. San Juaa» Puerto ■
Eico
4. Ne^s
FH3-HIE
Individual Project Report
Calendar Year 1959
Par-^ A.
Project Title; An evoked potential study of coanections
between the diencephalon &nd the sig^aoid
Principal Investigators; Jo M, Deanery and C. M, Coiabs
Other Investigators: N-ne
Cooperating Units s None
mn Years (calendar year 1959) :
Total; loS
Px'of essional s IcO
Other; «8
Project Description:
^bjecjivggs To find those areas of the diencephalon
^nhieh ^hen stimulated 'would evoke a potential change in the
ipsilateral anterior and posterior siipaoid gyri= This should
give an indication of the diencephalic regions -which can
serve to relay impulses to the nso tor- sensory cortex, (sigEoid
gyri)o
Methods employed; Data have been obtained fr-m 77 cats
either anesthetized with Jfembutal or jasintained on curare-like
drugs. In 17 of these aniaals electrolytic lesions had beeis
placed in the red nucleus and medial lemaiscus at least one
laonth prior to the eKperimeats described. Single shock
electric stiBiuli ^ere given through juxtaposed bipolar elec-
trodes which ^ere aoved stereotactically millimeter by
millimeter throughout the diencephalon. Consequent electrical
activity was recorded with surface electrodes on the exposed
ipsilateral anterior 'and posterior sigiaoid gyri and visualized^
after amplification, on a cathode ray-oscillograph ■>
Page 2 Serial Ho, NlgiDB-HA-Pg-S
Part A Project Description (coEt'd)
t^jor fisdiags; Tliere ^ere ao qualitative differences
bet'ween the diencephalic areas Tshicla ^hen stiiauiated evoked
& response ia the anterior sigmoid gyrus and those -which
evoked responses in the posterior sigmoid gyrus « In the
animals ^hich had had no previous lesions the active dieia-
cephalic areas were; a, reticularis; ventroposterolatsral
nucleus; ventroposteromedial nucleus; no vei2tralis pars
medialis; n. centralis pars lateralis; fields of forel;
zona incerta; red nucleus; mesencephalic reticular sub@taace;
These structures essentially include the seasory pathway
and the course of the brachium conjunct ivuja through the
diencephalon.
In the 17 cats ^hich had had previous mesencephalic
destruction of the brachium conjunct ivuja and the medial
leamiscus, the same structures responded «ith the exception
of the anterior part of the red nucleus^ the fields of
forel; the zona incerta^ and the mesencephalic tegnentu^o
Significance; The results of this BSipping procedure
will aid in designing further experiments to establish the
precise diencephalic structures involved in the cerebellar
influence on the niotor cortex o
Proposed course of pro.lect ; To fill in a few hiatuses
that are in the data and prepare for publication.
Part B Included:
Seriax Ho. !HMI>B~»A~Pr ^ ( j
1. MeuroABatoBlcai 3cleac€rs
2. Stctioa oa Perlaatai
Physiology
3. San Juan^ Puerto . j
4 . New
Pfi3-tfIR
ladlTldttal Project Report
Celeadar fear i95d
Part A.
Project Title I Physiological studies o£ fetal aad nevbora
Principal lavestigs^tor ; Geoffrey 3. Dawes (consul taot)
Other Investigators.; Howmird li. Jacobsoa^ Joan C. Mutt
and Hea^ber Sheiley-Ec ton
Cooperating Units ;^ Ruffiel<ll Institute for Hedical Research,
Oxford, Sngland, mad USPHS Clinic San
Juan> P. R.
Man Years (calendar year 1959> :
Total: lo6
Professional s o8
Other : „8
Project Dx^'ScriptiOBc-
Qbiectiyeet; ^e primary object of this work «aa to
a»ke physiological observations upon the cardiovascular and
respiratory systetmsi of fetal and newborn priirates, and, in
particular, to ex^lor® the feasibility of undertaking
experisaeate upoo the monkey Ijj M,i££"
Methods, esgloyeds Various physiological Methods were
eaployed. Observations were mAde on 12 fetal rhesus atonkeys,
6 newborn, 2 ^ged i to 2 years and on a few adult feiaales,
^.lor fiadingg; 1. The fetal environasent , In fetuses
the 0^ saturation of blood fros th© descending aorta
(obtained by casnulating a ieieor&I artery from a leg with-
drawn fros the uterus) averaged 58 per centn The O^ saturation
of blood froa » brachial artery (obtained by withdrawing an
ars fro» the uteru6 through % separate incision) was consis-
tently higher by about 3 per cent; values as high as 79
Page 2 Seyial No. WIMPS- MA-PP-ip
Part A Project Descriptloa (coat'd)
per cent have bees observed. The blood lactate la fetuses
«As of the s&Bie order as that in siewborn aonkeys <7«17 asg/lOO m.
the blood glucose (aeaie 29 ag/lOO bU.) was less then in isoakeys
8 to 12 days old (49 sg/lOO al). These observations
suggest that the private fetus norsiailj has an adequate
oxygen supply under pentobarbitone anesthesia; the oxygen
content of the blood fell profoundly on delivery^ as the
uterus contracted, even though the placenta «iaa not
separated.
2. O2 consuaption after birth. In unaneathetlzed
oonkeys, within e few hours of natural delivery exposure to
a culd environment (33** C or less) caused shivering and a
rise in O^ consumption. This effect was reduced or abolished
when the O2 content of the inspired air was decreased to 15
per cent or less.
The rate of O^ consuaption at an environaientai teaperature
of 35** C C JL£« , within the neutral sone) rose progressively
during the 8 to la days following birth froa about 10 to
nearly 20 alAg/minute; these 6 sonkdys had been reared in
an incubator at 30** C.
The oean 0^ consuaption of 8 anesthetized pregnant
teaale aoakeys (4 o 7-8.6 kg) was 6<.2 alAg/alnute, and that
of 8 anesthetized aonkeys 8 to 12 days old (0,4-0.56 kg)
was 14.8 al/kg/ainute. The greater rate of 0<2 consuaptioQ
of the newborn monkeys was attributed to their relatively
greater surface area/imit body weight Cmean 1123 sq ca/kg as
coapared with 488 in adults) , and this is probably the ultiaate
physical reason for the increase in O2 consuaption at 35^ C whi.
takes place after birth.
3. Cardiovascular and respiratory reflexes in newborn
Bonkeys. In monkeys 8 to 12 days old the Herlng-Breuer
inflation and deflation respiratory reflexes were present;
they were abolished by cutting the vagio Stiaulation of the
peripheral vagus caused a profound fall in heart rate and
blood pressure. Occlusion of the carotid arteries caused
a rise of blood pressure; denervation of the carotid sinuses
caused a rise of pressure, and abolished the response to
carotid occlusion. Thus the cardiovascular and respiratory
reflexes investigated were all active »
Page 3 Serial Ho. NIJ-jDB-MA-PP-lO
Part A Project Description (cont'd)
4o Anatojaical chaages ia the circulation after birth.
In 6 laojskeys 8 to 12 days old the ductus arteriosus ^as
closed and ^ould not admit a probe postmortemo The ductus
venosus ^as also shut, and indeed very hard to find as
compared with fetal specimetis. The foramen oirale was,
ho'wever anatomically patent; there viere no macroscopic
js in the free edge of its valve.
5. Other physiological and biochemical changes.
During gestation the blood pressure rose from about 33 mm Eg
at 115 days to over SO asa Hg in monkeys 8 to 12 days old.
The ability to survive asphyxia (as measured by the time to
the last gasp) fell from 25-30 minutes at 115 to 120 days
gestation, to less than 10 Minutes at birth. The, carbohydrate
content of the heart fell pari passu from about 20 mg/g to under
S mg/g after birth. The carbohydrate content of the lungs
fell from 115 days gestation onwards, that of the skeletal
muscles fell after birth. There ^ere ample glycogen reserves
in the liver, in both fetuses and newborn monkeys. These
observations are "^ery like those recorded in fetal and newborn
iambs. However, unlike iambs the O2 capacity of the blood
showed no significant fall after birth.
6. Asphyxia or anoKia. There was a striking difference
in the behavior of fetai laonkeys whose umbilical cords were
tied^ as compared with newborn monkeys given nitrogen to
breathe. In the fetus there was a rise of blood pressure
lasting up to 10 minutes, no struggling, a steady fall of
heart rate and a great increase in blcod glucose . In the
newborn there was a rapid and profound fail of blood pressure,
followed by a short period of recovery during which the
heart rate increased somewhat from a low leveii there was
struggling and the blood glucose fell. These differences
require further study.
Sig:nif icance ; It is evident that there is much useful
basic inforamtion to be obtained on the physiology of the
primate fetus. The difference between the behavior of the
uterus under esperiiaent, as compared with that of the sheep,
is particularly interesting; the primate uterus is thick
and soon begins to contract vigorously. The facilities at
3an Juan, not only for producing mated monkeys of known
gestation age, but also for rearing newborn monkeys (with
24 hour supervision and 2-3 hourly feeding schedules) are
exceptionally good.
Page 4 Serial Mo, NIHSB-HA~PP~10
Part A Project Descriptioa (cout d)
There are also a number of specific conclusioBS ifhich
may be dra^n fro® this work; thus, firstly it is e^ideat
that sampling cord blood after delivery is ualikeiy to give
a realistic indication of the conditions of intrauterine
life so far as respiratory metabolisia is concerned. More-
over the results suggest that the priaate fetus has a far
better supply of O2 than might be inferred from Barcrof t ' s
evocative phrase "Mount Everest ia utero". Secondly, the
O2 consumption of newborn monkeys changes in the same ^ay
as does that of newborn laaibs after births but the time
relations of this change are quite different. They are
similar to the few observations recorded in huiaan infants
and it is clear that this problem needs further investigation
Thirdly, it is evident that some of the principal respiratory
and cardiovascular reflexes are active and we are therefor©
in a better position to interpret the anatomical and physioi: _
changes vvhich occur in the priiaate aft^is' birth. Fourthly^ it :
particularly interesting that there are a progressive series
of changes in the carbohydrate reserves of many animals as
gestation proceeds, and that siuiiiar changes occur in the
aonlsey. The relevance of these changes to the ability to
\fithstand anoxia or asphyxia at birth needs no eaiphasis.
Finally, the discovery that the behavior of the fetus and
the newborn differ during O2 lack has already started a
further series of investigations which are now being piarsued
in San Juan and in Oxford o
Proposed course of project; Studies are expected to be
continued ia August 1960, ishen the research team can again
assemble ,
Part B included: No
Serial HOo HIMPB-M-PP-ll
1. Neuroanatomical Sciences
2. Section on Perinatal
Pisysiology
3» Saia Juaap Puerto
Rico
4 c New
PHS-NIH
Individual Project aepos*t
Calendar Year 1959
Part Ao
Project Title,' Tests of ovulation in the monlcey
Principal Invesstigator : E. Fo Vollman
Other Investigators; None
Cooperating Units s Kose
Man Years (calendar year 1959) :
Total; 1.2
Professional: o5
Other ; .7
Project Description:
Objectives; One of the important factors in breeding
monkeys is the precision ^ith t?hick the time of ovulation ssiay
be estimstedc So far, only daily palpation of the ovaries
(Eartraan) has be@n us@d systematically for this purpose.
Methods approved in human sterility %vork should be tried in
the monkey. The suitability and the degree of precision of
clinical tests for ovulation should be ascertained in the
monkey and tested by timed letatingSo
fefeithods employed;
1« Daily vaginal amfSStvB (Papanicolaou-Shorr)
2c Crystallization of the cervical nmcus (Zondek)
3c Course of body temperature
4. Fluctuations in total and differential white cell count.
Ifajor findina^^g Project started in August 1959, no
results yet available.
Significance; It may be expected that through a EKjre
precise estis^t© of the time of ovulation the conception rate
in the colony is to increase considerably c It might help to
eliminate sterile fessales.. as ^ell as subfertile male monkeys^
thus saving space ^ food and labor for fertile aniaialSc
Serial HOc,
fA~PP-ll
Part A Project Descriptiost (cont'd)
course of project ; To adjust tecSmical details
of th© tests sierationed ateDve for routljae perforffisace under
tlse preseat conditions of the colossf , To parfora trial
matlngs over a period of at least twelve moBths and to evaluate
the results.
Part B included? Ho
lo KeijroaiiatoiaicEl Scieacss
2„ Section on Periaatal
X%ysiology
Rico
4 . Ner^
PHS~Nia
ladividuai Project Eeport
Calendar Year 1959
Part A
Project Titles Besponses of fetal aad ne^vborn monkey
to asphyxiation sad resuscitation-
Principal Investigator; William F. Windle and Staff
Other iGvestigators? None
Cooperating Units: University of Puerto Rico Medical
Sc&ooi sad USPH3 Cliaic^ San Jnan
I^n Years (calendar year 1959) :
Totals 2.0
Professionals .6
Other : 1 . 4
Project Description:
Object iyesg To determine the physiological responses
of both fetal and newborn monkeys to asphysia. To establish
criteria for determining when a given aspliyKiatioa should
be terminated in order to successfully resuscitate and
maintain an infant laonkey.
Methods employed: Fetal luonkeys ^ere asphyxiated by
leaving them within the aianiotic saco They ^ere resuscitated
by iateriBittentiy inflating the iwngs with oxygen froa a
rubber bag through an endotracheal tube. Activity^ respira-
tory effort, and heart rate •©ere recorded o
Newborn monkeys tsere asphyxiated by placing them in
a glass jar through ^hich nitrogen ^as flowing. The same
method of resuscitation described above ^sas used. Similarly,
activity, respiratory effort and heart rate were recorded »
i^.lor f indiaigs : Technically satisfactory asphyxiation-
resuscitation isere accomplished in 3 fetuses and 3 newborns c
Page 2 Serial No, NIHDB-KA->gpc^l2
Part A Project Description (cont'di)
The dilfereaces ia the responses of fetal and neisjborn
monkeys to ssphyjjiation observed during these studies fell
into three groups » (a) The fetus vfSiS quiescent, except
for respiratory efforts, ^shereas the newborn struggled ,„
defecated and salivated. (h) The heart rate fell slowly
in the fetus » In the ne'wbora, ia contrast, the heart
rate fell abruptly sad then rose sloisly. (c) A fetus
could be resuscitated 5 and one half alnutes after its
last gasp J whereas the newborn could sot be resuscitated
if asphyxiated for one minute after its last gaspo
Significance ; The general term 'asphyxia neonatorusi"
has been used to include both fetal and newborn asphyxia-
tionSo These findings, however, show that the responses
of the fetus to asphyxia ia different from that of the
ae^born. This inforaiation complements t,hat of. Daises and
liis colleagues in acute experiments in that thsy have
sho^n differences in blood pressure response, glycogen
reserve in the heart, blood sugar bet'i^sen fetuses and
nei^borns asphyxiated past the last gaspo
gyo posed course of project : To atteiopt to combine
the chronic experiment with survival with soxae of the
techniques performed by DaT<es and his colleagues in acute
experiments.
Part B included s Ho
Si3smaary Report o£ Laboratory of Biophysics
Calendar Year 1950
Ketssð S. Cole« Chief
Tlie cesstral objective of the Laboratory of Bicjpliysics
is to uaderstasid the snatus'e asid the issplications of the ion
ssovcBisBts ftmdsinesital to the initiation ond propagation of
a nerve i^^ulse. The staff, John \U Koore, Eichard Fits-
Htigh, Eobsrt E. Taylor, William J, Adelmaa, ^se KnoK Chandler,
John E, Gebhart, and Ernest E« l^hitcogab, have continued to
progress toivards this objective, in part with the collaijora-
tioa of the Haval Medical Eesoarch Institute, and the
CoBiputation Lal^oratory, Slational Bureau of Standards.
The characteristics of individual ionic movements
as first determined frosa saoaeureaents of the squid as:on
mezsibrane current and potential under controlled electri-
cal, gecsaetrieal and ionic conditions have led to far
reaching conclusions a But subnequeat Tiforls has made it
necessary to undortal^ an es:Qi!iination of the e:stent to
vjhich the Measured saesabraae currents depend upon the
adequacy of these controls. The records asid analyses
generally confirm the 1958 prelisiinary conclusions that
the fisesibrane potential of strong ai^ons could and had
usually been reasonably vrcll controlled and that the
qualitative characteristics of these asjons were similar
to those of less difficult assonso The conditions for an
adequate control have been found to be more stringent and
the understanding of failures to be saore difficult than
had been anticipated. The confusing effects of instability
can be reduced by restricting the aiessforane current measure-
Bont to the region of best potential control but aa estisiate
for the accuracy of control smst av/ait further investigations
of the resistance between the control electrodes and the
capacity of the mesibraneo
The sodiusi potential of Ho^lsia and Hu5?ley laeasured
by voltage clamp may be agsus^d to b© as good a Kieam&re
for sodiufii ion concentration changes inside the ason as
it has been found to be for those outside. Thus isieasured,
the net sodiism tntlmi of the surviving mson at rest and
the increase by stismlatioa are in general agreement ^ith
isotope BeasuremeatSo The net flow of sodium is reversed
by voltage pulses above the sodium potential as predicted
by the sodiuaa theory. By the saiae procedure, it was
found that ten percent of normal e:8:temal divalent ion
concentration increased the resting net sodium inflow to
about three tiines the norsial value o
SuEBaary Repoii't of Laboratory of Diophysics (eout'd)
The phenccjGMO. of finito arsd iiif laite traias of
lupnlaca, tmodal broal: excitatioa, i'GfS'aetoz'iaoss, aad
accoEomodation dopesd tipon certaia Liatheaatical pfopertics
shared by a large class of cysteEis^ electronic aad chess-
ical as v/ell as physiolc^'icaXtt The well l^aiovva vmx der
Pol relajsatioa oscillator' equations havG been gesaeralir.od
to include these pheoosaeaa acd the Eodglsin-^Iiuxlcy o^mid
oasoB equations have been reduced to a qualitatively
sisailor tortAo The geasoralisod ociuations caa bo repreoonted
on a plmio with rcgioas eorrospoiading to the phyoiological
states doscrit'Cd l>y classical xiew^ophysiologyo Thus a
basis for deeper aad more useful undsrotanding of vfoll
Ima^m pheaosseaa is eEsergingo
Digital coiapatatiojae for a Kjod'a.llated axon ^ith a
modified nodgkim-Hussley meiabraBe at the aodea give aa
iB^ulso velocity of llo9 a/sec for various super thres-
hold stimuli l^ut th© loag latency at threshold requires
ioauch more esrpensive coasputer ruas thaa have yet boca
u»dertalsea, Aual(^ coii:^utatioBs have £]ho?m that v;ith
reasoajiblG saodificatloBS^ the IIodglsia-Eussley B^uid axon
o.'iuations produce action potentials agrcoiBg closely with
those obtained by Dro John Daltoa fron a lobster osion in
nox^al and osccess potassiuas lacdiao
Iii a joint project^ ^vith Dto Seyisour L« Friessj,
MRS, oa the action of oyatliotie aeotylcholiaesterase '
inhibitors^ pure optical aad gecaaetrical iscssiers In the
ethyleaodiaaine series and ia the 1^ 2 ~ soaiaocycloheKaase
faifflily have been cosHpasxsd by In vitro Cwsysao inhibition
and nerve blocl^adeo AlthoughnsoWTLTaecs of investigation
are interesting and prsaaisiag the rogBlts are oo increas-
ingly divergent as to further decrease the probability
of a causal relatioaahip betv/eon the tvic processes o A
shift of eaphasis froH desheathod v/hole nerve to single
node preparations is giving the results a clarity not
possible t;hen the «35rtJ.gs dif;2use to siaay sites of actiono
Si32®jary Sleport of Laboratory of Eiopliysics
Calendar Year 1959
Keaaeth S. Cols, Chief
TIae central objective of the Laboratory of Bipphysics
is to wm«l©rsta3Jd the mature smM the iBplicatiosas of the ion
movosiessto fimdax^ental to tho iiiiti&tiosE aad prc^s^ation o£
a aenre iss^ulse* The staff, Joto We Moore, Eichard Fits-
Hugh, Hobert S. Taylor, Willism J, Adelmaa, V.» Kaoss Chandler,
John !1, Gebhart, and Ernest B» VJhitccjs^j, have coiatinued to
progress towards this objective, in part with the collajbora-
tioa of the Naval Medical Eesoarch Institute, aad the
CoEjpiatatioa Laboratory, Natioaal Dureaii of Standards.
The characteristics of individual ionic moveiaeats
as first detenained frc^ laoas^ireiiieiits of the sqnid assoa
meiabraa© ciarreist aad potential under coBtrolled electri-
cal, geoiaetrical aad ioaic conditions have led to far
reaching conclusions. But subaei-iueat vork has made it
necejasary to midertalse an essamiaatioa of the ©stent to
vfhich the measured meiabrane currents depend upon the
adequacy of these controls. The records aad analyses
generally confina the 1958 prelisiinary conclusions that
the sieiabrane potential of strong oszons could and had
usually been reasonably \?oll controlled aad that the
qualitative characteristics of these asjons were sisailar
to those of less difficult aKons. The conditions for an
adequate control have been found to be mora stringent and
the understanding of failures to be saore difficult than
had been anticipated. The confusing effects ©f instability
can be reduced by restricting the sseasbrane current measure-
saent to the region ©f best potential control but sn estimate
for the accuracy of control laust av/ait further investigations
of the resistance bet'WQen the control electrodes and the
capacity of the aiesibrane.
The sodiua potential ©f Hodg^^in and Husrley Beasured
toy voltage clasip aay ho assusssd to be as good a Eieasure
for sodiusi ion concentration changes inside the ason as
it has feeen found to be for those outside. Thus s^asured,
the net sodium inflow of the surviving asoa at rest aad
the increase by stiiMlatioa are in general agreeesent with
isotope sKsasua^aentSe Th© net flo© of sodium is reversed
by volt^e pulses above the sodiuss potential as predicted
by the sodiusa theoryo By the sm^ procec2ur©, it was
found that ten percent of normal ©internal divalent ion
concentration increased the resting net sodium inflow to
about three tinies the nonaal value.
S43irdaas?y Eoport of Labos-atory of Biophysics (cont'd)
The phenoEiGxaa of finite and iiifinite trains of
in^ulsoG, ticodal broali cjscitation, rofs-actojciaess, and
accoiataodatioii dopead upoa cortaisi jiatlienatical properties
shared by a large classs of Bystems^ eloctronic and. chcn-
ical as well as pliysiol«^ical» Tlie yell kssowa vmi der
Pol relaasatioa oscillator cciuatioas Iia^'o been Q-eacralined
to include th©so ghemoiaeaa aad tlio nodgliia-HuHley Gviuid
txis^oa equations have beesi reduced to a qualitatively
sixailax forsio The geaieralisGd OiiuatioBG caa bo repreoontGd
on a plane v;ith regions eoscrospondisg to the yliyaiological
atatos described by classical neu-^ophy^iologyo Thus a
basis for cioojoor s.ni{ moTo useful underDtaadiag of woll
knovm pheaoxacBa is esserging.
Digital coajnatatiosiQ fos? a xaodisllated axon with a
iaodificd Kodgkia-HiiSiley membrane at the nodes give aa
ifiipulse velocity of 11 o 9 sa/soc for various supea,' thres-
hold stimsli but tke loag latency at threahold rou^ires
much more ©2speiisive cosg^uter ruas thasj laave yet boos
imdertalseao Aaalog eosaputationa hav© sihowsa that with
reaso3aal>lo modifications^ the ISodsItiis«"nu2£lGy c^itiid a^sosa
o.-iuationD prodae© action potontials agrGcing closely with
those obtained by Dr^ Johsj Dal ton fffom a lobster osaon in
nosnaal and OKcess potassium sscdiao
In a joint project, with Dr« Seysour L* Friessp
KMRI, oa the actiosi of sysathotic acetylcholinesterase
inhibitors, pure optical and gecaaetricai isoiaers in the
ethylcnediamine so2.*iss and in the 1, S- - asainocyciohoxa^e
fasttily have hecn co-apar-ed by in vits^o Cwiaysae inhibition
and nerve bloelsadCo Althcmgh'^UoWTTaaG of investigation
are interesting and xsroiaising the rosiulta are no increase
ingly divergent as to fisrther decrease the probability
of a cauoal rolatioaohip between the tv<?o processes „ A
shift of cEipfeasis fre®i desheathod whole aorvo to single
node preparations is giving the voBaltB a clarity not
possible when the <f3n.igs diffuse to saaay sites of aetiono
L^BOMTOSY aw wmrnwrnBiQumY
Wad© H. ^ffs^^llc Oiief
Tfe® Spiral tog^ §®©ti©@g is^^r tte l®a^rs&i# ®f
Stafts of t&® £i@«s^is^ pro^mi® tk® ^ ^^ B ©pikes aindt ^Jo&Xy-sie
€of tls@ ffol® of til® 4®©^itie ^2?©e©^®g©„ Claapis^ t@€3i^iss
Ih&v® &@@& ap^ii®^ aM til® s^s^t^ m^® @®si@i3t@^t iritis the
pr^viovm hfpom®siXm tliat t^ k @pil£© os>lgi§&^t@^ in tH®
asosa maul tiat tSie B @pik® oirigi@£t®@ fs^^ 4»^ly & p^s't of
t^ ^aaa. ir@?& is goi^ foTf^s&M tQ plot thi» fi®M arousiS
& sisgl® cell £i€ti^at®<S Issr ai^ti^r^^e stimulation. Tkim
ps-ojecst is ^p®ii^at oia a^pii®&tio^ @f ai^^is ^t&oS of
ii^Tovisg tb@ @igiml to @®i@@ r^tlo.
FFactiQs.1 @@tte^ f@s- iigfor^ati©^ r@ts>i@vi2ag i&s>@
Ssvelops^nt i§& joiait s»s^j@€t@ @f t^i® I&bosmtory 'smS tli®
iMbo^&tory of €Xiiii@al ^i®i&s©@« 4 @oSifi«SAtioffl of a
^tlio4 d®¥is«S l»F €@% will to ^1^^ hf Ihf. Fs^ak is t&$
first piB&s® of t^is ps^i«ct« %i3 is aa iEiporta^t a^
p@rtisiSEit as^a« ^si^ eeesst b@ fo^^ to r&is® sigaal t@
©oiis® ff&tio !©§■ igl©?fo@l.®©tst3^ ®®s»& ^ ^®I1 ®@ otia©^
Work is ^c»irisi^ isi t^ <li£<@»3tioia of a^@if©i@ of i^t®»
It is g©i&sr^lf @^©«^^ tfeat cm ^sfei'a®® p@t®^tial®
ati'S'® t® ©sosia^ a^ ® i>®^^t p^i4e®.t4am p®s'p®g't@^
to pao^s t&at sa®i;^tis>@ %gsi% i^t^^s^ill^as' i?®€@^^^
t®cJiaie®» la a ^^fi^a ©f @s€®ll®®tl^ ^®®ig®®^ ®^is®ffi^©ffit®e
l®lsoffig frank ®^ ©©©&©§• hm® mowm. tfet t^4^ i^ m&t tff«s®o
f^ stsbiiitsr ©f t^® ^^fes-msi® itt ^^possia al@© Imm iss|S®rt®at
i2®ps®s®io®o ^^i^io^m if©g^ M®^ ®feoiB tliatc witia ®a©g^~
Gl«ct7od@s i^ t^ spiigal g^@^e Ml'po^a ps^4i3@@@ a ^uick
negative @€dsig, 1^@ ps^asat tos'^ i^ii^ta@ tliis ^i^sli
^gati73 @wtm^^ i® ©s^ntlallF ^ -airtlf^el. It' is p^^&My
diss to abooirimi @@^iti¥it|r to ^^^^a ©f t^ s^iss'oi^
Tim §«stio@ o@ Si^oisl. .i®i^®®s i;^i®.r tb^ l®^d»:sfsMip of
D^% T^isakie Sis® ^ail® ©s'^^r&l <£l®i7@l@p^mt^. ^I'lsp® tSa» @9St
i33ig^s>taat 013® i@ sss-ioiss application @f a^^imt® t^®@ff®tic&l
twB&t^&t to tsm©©? ^t^di®@, 1&i@ mig'^ ®iiii 4o^ i@ eoilalio?3\<
tio» witli Pif@o ^^os^il t^&^ l^p^ala^ Fs'sssM f3^ss D^s^tadt^
@@in@&s»y asd Hi!^ f^o^ Bs'ookSia.^®ia» It lias l^^n f^sogiais®^
fo? ©oisa ti@g tM^t tr@,^s> ^t^ ott®^ m^mt&iwsm^ h^4®wmt®
*>nii %i;> tw <,- .
to ff^: .... cm. ton 5ao¥
Fisjrth:.-. Isa® ^^^^n 4--y^9 f^*". the g^asral propoisitlois
of th® tM?o &t&b]i.® St- ' ssgiffij &iK«S® of r®sctiv®
pol3r*Kirn': reapv^issiis , 'Ah'H . ^:^3 ©f tlals to itestosa©-
syx-.
FwrtfKer worle oa UM s?xd '^^^F^. Sp^ctroscQpF is al®«» plasm/Sf-i
leaderfjfes.p of IH'«, Ms-: -d witfe «>. broad progi'sua
iB tise g;©K©ral .mr©a ",c.r s-.?^-^'; 1±55 I:',ts.'b!>:5.e
©ssjp'loyBSE-.t of fer;.
An iiitoa'Siv© ^ork .' :
laatlon of tSie geail af th® iss^irrai ss^'aiiLey .-
AKot&ier specific pre 9';1 ''s-'? l5r^-!,„ ;"as'.f'5ja swad
highly @:Kcit;afele klp^: .■ ,: :.. of 1^:^
csjsp&l sfEtem asad §4®®oci , ..._... _ ^In® m&clmni.Bmi ..
iutensXvB study 1® baing WKsd© ©a tto® saltiliE® bug lei of th&
tio» study OS a ©m&li group o-f s^ia"K'®i mom= rJs. is
reassirkafeX® fcji* th® ip-^'-^f-ia'^taoa alrsMy c-Mai.a...... ....... also as
aa iliustratioffl of h'- fee d®as ^'Xtt & small greup of
i"oductioa of t&® ilais Imo&i-s.tor^ hr.B
■sii, ia lt0®lf, « ': - .. - _., ......-,„.. 1® -©jgs also itt"
■i,?a®.st3,l ill lm,l -..!i :lh® i^q^lTTml immM'^j to tJbe lAS.il.
tMs VKKTk <i^als wit& tim tw&^m^tsa e^<^tlou pm'mmm^
oi thm fsmmfo^, A great d^al of si@^ i^'csfm»ti®i& 3&a@ i^»®issi
ol»taiffi$S<, Siiailaaritiess s^^ MM®rmmssmm wl^ ^ta iw^ tM
eells is p^artieulsffly isigs&ifieasil; isn vi«« <j£ t^ aj^i&t^-??©!^
high 02seitS4bilitjr of tSs^^ laippocsas^iaSo It i© is!it®a^stiaig
to aot« tlmt th@ el®ctffosiBd«afoscopi» pist^s^@ @l&o%; & sm&.llm^
tlaasi usual #%t^»c«lli3l;^ 8pa<3« for tise bippoc&apai aisias^s^aaSo
n&ls »up|>li®s i&S@r®ati&l stupport fov tits hf^tb&stB t^t
aect»ulati«2^ o£ S ioa la estsfa^^Iliaiup spacd is tto eaiiiSd
of tlae ^pol&spXziBiSi a2ti97«£K»t<9atial0o "Slis?® as« also
ia^oartasat i^®v<@msoa i» this agrissseBt £os> &»ck&stl&m at
to gais 2ios^ I^d«?l®dg9 of ^cit^sal ii&tegs^ti-?®
^&ic2a t^ :^:i3^i^ of til© ^11 ^isoa i@ t^ @a^ j;»oist.
& v^^^l® p:?oJ®@t ^^@ §s^-im %mkas tr&&@^s to
K ioffi s«i®s^£^ fs^ssi t^ €oS't@i£ '^y 9ss>iotae «si»i»£Bieal
Dr. E@^.tm i® ^ieo€m&&i.m ^itl^ aa it^ti^s^sti^ mtito^ &t
cos4i2@ti^ -s^l^sis of ig^iisog'^'' ^is^riaisatioEi at <8o^tica3.
aaalyeis i% tl^ Sipog CSiSo ^g&is ^s^ is sAsmd @t 3t«MF of
ths ji^iasksmmm oi att®e&tio§&« Iss^itimtioao «llscri@ii^tias,;
•stiffifitioffig stQo Saei^l^atal to tht^ ^a»?al psx^^as^j, a
vsry ias«£^ jmthod of oastrajs^ll^ai!' stimalatioii xim i^m^l^m^
umA & eigi^ficsi&t stvuly ^a^ of stissEltas parMsitter©, %is
B»tliod is particuXas'ls^ us^fial £o? locatlssg. th@ c@2.is i^t
reactiag is th» i^ar *7ici8iitf of t&s ®I®ctrod»o Dr. @tr^^^asiis@s
is procesdlsg @ith a projsct ^ssissg tSae dorsal iroot e®i3.s of
tias £rog spinal cord in ^fei£l& cssXIs asd sisotrodss eau S3®
directly ^isyalissd. ^&iii project is ®3q^ectsa to aid i»
Gl0&stm W s^ ^i^ GO&trav®rs^ alxD^at tb® ''gaia&t" @3etrae®XIi2lar
positive spils®s first ssrioiisly aiaalysed hy 3?r®ygaag„ Qsm
grovsp Iio2.ds tSiat timm^ positive @pils®@ i^icate timt a large
part o£ t&e is^^rafi® of stas:^^ €@il typ®s is !^t 9l@cti:>ic&lly
escitabl®. Affiot!i@r gr®^ coasi^g'S ttot t&i® for® of potential
is recorded 021X7 fro@ i3^i2ra4 s4»IlSo "S^ ®I®ots^dl^ is m> «»los@
to tSi® si^sbrais® timt iisjisr^ ®a^m$t b® @s3li^®^ ^lo tte ai°g%!t^i&t
1^^ dssfiffiit® mimms^^ It ia to ^ ^ot@il. t^t mmm'&l
Serial MOo NINDB»NP-SS~5
lo Labo of Neurophysiology
2o Special Senses Section
. 3o Marine .Biological Lab,.^
1?bod@ Hole, Mas@„ and
BethesdEj, kdo,
4o Combiaatioa of la^ 3 and
4^ 1958
PHS-NIH
Individual Project Report
Calendar Year idd9
Part Aq
Project Title: The meciianism of nerve excitationo'
Principal Investigators: lo Tasaki^ T^ Teorell^ '
Uo-^ranck and Co Spyropoulos
Other Investigators: L. Nims'^ Ao Bakj, M^ Eazy and
D. McK.en£i@
Cooperating Units: Departments of Biophjsics and
Physiology^n Uppsala^ Sweden;
Depto of Electrochemistry^
Eduard-Zintl-Institutei, Darmstadt^,
Germany; Brookhaven National
Laboratory^ Upton^ Long Island^ Mo Y„
Man Years (calendar year 1959) :
Total: 5
Professional: 2„0
Other: 3„0
Project Description:
Objectives; For a number of years^ the primary
objective of the Section on Special Senses has been
the elucidation of the mechanism of excitation. This
process constitutes the primary activity of the
cellular elements of the nervous systemo In addition^
it is involved in many other well known biological
processes such as receptor activity^, muscle contraction^
cell division and amoeboid movement „ Experimental
attempts during the last year at solution of this
.problem were spurred by collaboration of members of
this section with outstanding scientists from other
institutions^, both in the United States and abroad.
These collaborative scientists were Torsten Teprell
of the University of Uppsala^ Uirich Fraaek tvom the
PHS-NIK
ladiiJ'idual Project Report
Calendar Year 1959
Part Ao Projo Dssc. Ccont^) Serial Ho, NINDB-NP-SS-5
Page 2
Eduard-Ziatl-Institut© in Darmstadt ^ Germany and
Leslie Wtwy> txom the Brookhairea National Laboratory,
Methods Baployed: _ The method of intracellular
multiple wkre electrodes^ the method o£ intracellular
injection and ths method of perfusion of the intra-
cellular compartHiQnt were employed with the squid giar
axono Standard microelectrode techniques were employe.
in conjunction with the isolated dorsal root ganglion
of the frog to- steady tbe effects of Ba"^, Standard
radioactive tracer techniques and the method of Obric-':;
and Ulfendahl (for simultaneous Bseasurement of radio-
active Na and K) were employed in conjunction with
electrophysiological techniques to study tracer
movements in the squid giant axon^ The Obrink-yifeadas
method w&s introduced into our laboratory by
Prof, Teorell„ These same radioactive tracer techniqti
in conjunction with a cation exchange meBibrane from
Ionics^ Inc^ «?ere employed to study tracer movements
in artificial membran®®„ A rotating fractionator wns
employed for measuring tracer movements during the
action potential,
Major' Figdings;_
( 1} Mo¥@iaents of txa.^. -.-;., o-. across membrane in gen;
The prXncIpIes^govirniag fhe~moviment© oS" tracer's
aca'oss animate and inanimate laembranes and their rela ;
to the movement of the untagged species were defined
by application of the modern theory of thermodynamics
of irreversible processes, Esjperimental verification
of the proposed principles underlying movements of
tracers across membranes and their relation to the
movement of untagged parent elements were obtained by
the study of movements of tracers across cation
eschange resinous membranes^ It is found that^
e Incept in th© case where the ratio of the concent-:
of the tagged species to that of the untagged species
of the same elem©at is the same on the two sides of fc:..
membrane^ th© moveiaent of the tagged species dr ■
give any information as to the laovemeat of the
untagged upecies., -The physical information obtain.
bf the tracer technique was clarified.
Individual project Report
Calejidar fear 1959
Part A, Projo Base, Ccont,,) Serial Ho. IIINDB«NP-SS-5
Page 3-
C2} Movement of tracers across the aerve membrane
The tracers employed include K*^, Msi^, Ca^^, P^^, cr^
BT, etCo It was fotind that Na asid K had a time
constant of outward movement of the order ol 50 hours^
24 42
Na being somewhat faster than K at room temperature.
45
The time constant of Ca is far more rapid^ of the
order of 6 - 8 minutes,, Evidence was obtainedj that
45
an appreciable amount of Ca Introduced into cell was
bound. The movement of negative ions (chloride^
phosphate and sulfate) was far slou'er than- that of the
positive ioas« This provides the first biological "
experimental evidence that the nerve membrane has a
fidsed charge behaving like a cation exchange membrane.
That biological laeEibraaes have such properties was
proposed more thas twenty years ago by Professor Teox^e';'
The tsacer T?hos© mov®rae»t was found to be fastest wa^e
tritiated water with a time constant of less than
30 seconds. The effect of a variety of. agents t^s '
studied upon the movement of these tracers „ These
agents included repetitive suprathreshold &nd subthreshc'
stimulation^ t@aip®rature^ sero calcitun in outside medivi,
sero sodiuDSjo high potassium^ de- arsS byperpolarlaatior
by applied currents^ pH and narcotics^ Stimulation
increased the out flux of both Ha^'* and K^^y Ha^^ belsg
favor©do Low' temperature increased the outflusc of K '
24 '^''■'
Low calcium increased the outflu??. of both Ha and K" ,
the latter being favored^ Stimulation did aot
appreciably affect the movement of the negative tracer
ionSo PotassiTJKi depolarization increased the outfliTr^
of tooth Ha and S » Currsst 'depolarissation incx
24 42
the out flux of ?39th Na and K ^ favoring the latter
By the use of a rotating fractionator^ it '^•aa
possible to collact samples of sea v<^ater flowing by thr
giant a^son at different intervals diiring the action
poteatialo Breliminary reeult® indicate that both
K • and Ma flow out of the &ko-q. both at the beginnii -r
and at the end of the action potsntialc At neither
PHS-HIH
Individual Project Report
Calendar Year 1959
Peiyt A.. Pro.}, Desc„ (f cont . 1 Serial ?'«
time did sphere appear to be any profound preference of
one ion over the others,
C3) A mathematical formulation of the proee;;!-
e asci-gatibn in apAjg^!^..^^^lIIJ^^^^^Q eKcitabte syi^'miT"
In the past few"yeiuFs"¥fiire Eas"T>e©n develo^¥"ln~thTs
laboratory the two-stable state concept of nerve
issscitatioa, Dxiring approximately the same interval
time, it has been becoming more apparent that excitrr
in living cells shows many of the same characteristic?
as certain inanimate systems,. Two such well known
systems are a redox system comprised of a metal in
contact with an oxidijsing rigeat^ and a system comprise.
of a membrane separating tvfo solutions at different
hydrostatic pressures. Today's outstanding authorit-::'
on this system is one of otir collaboratort3„
Professor Ulrich Franck and the discov&rer. of the sfs
system is Professor Torsten Teorell^ our other co"""
Discussions during the past summer have led to a
agreement on a mathematical formulation of the e^mi':-:
process applicable to all these systems, animate and
inanimate^
Cfcber reia-fcgg G.evelopments^
a) It was found that dorsal root 'ganglion cells,, ii;.
the absence of Na"*' and in the presence of Ba+"''' give '^" -
to action potentials which may b© of the oormal p "
but of an appreciably incrcjased duration or of a
reversed polarity. In the latter instance^, the c.-:
displays a resting potential of reversed polarity
■■mil.. Such behavior was aiiticipated from the two
concept of excitation and provides the most strik
illustration obtained to date of the "flip-flop"
property of the membrane prescribed by tlse two-st.
state coEC©pt„
h} A method %■■■&&■ developed whereby a iarg© portiOi
'■he cytopla.gira could be contimicveJy perfuEr^ed w±t.ti
'.onic KCl for 20 - 30- mig?'- of 0,0
Calendar Year 1959
Ao Pro J,, ItesCc, (coat,)
Serial Ko. HIHDB-MP-SS'>5
c) It was found that when tia© Eormal squid aasoa i
subjected to stroBg isyperpolarisBlaig curreats a
"fajperpolarisimg respous®" ai3p®ar© wfetch shows s
of " refractor iii©s@"j, a depeadeace upoB tbe presesac©
of Ca*+but sot iipoia !&'„
d) UpoE super cool lag a squid giaat assoa (with the
outsid© mediuin ia the frosen state) ^ it was torn.
the m©3Htoraa® potential fell rapidly to a very low valu©\
At tiiis pointy respoases of the hyporpolarisisig varie
e) At the sc-oustical meeting held at MIH last suaem^
tiiaory of. Eiechasioi'sceptiosi ^iaich w&m based apoa the
stafol© concept of esjcltatioE was pres-aated.
In anticipation of coatiauiag previous work os.
aad IFR Spectroscopy^ one of us attended a wor,
at ¥ariaa Corpo tn Palo Alto^ Califoraia d©sigsjed
provide ©sp©riesic@ with th@©is t©clmiq.u©s =
g) Diirtfflg the laast year^, tbg chapter oa "Esscitatic
aiad Syaaptic Transmission" of the Asaual Review of
Physiology vj&m comple^tsd fey -aembers of our sectioEe
Sigaificance to Meurology Research: This iavestigatio-sr.
is 'i^©cled°l;o"^oiatribute to tfe@°Tmd@rstaEdiKg ©f the
Eor35.al fuB,ctioffi of th© n©r¥ous system,
Propogeg Course of Project; It is our opiffiioB that
© sp loi t at iosT^ ol ' ¥h® purely' electrophysiological
approach to th© problem of escitatiom is searly cc
At this tiaiej w© feel that the more prosiisiai
research ar® thosa utilisimg chemical,^, .spectroscopic
aad aechaaical or thermal traasducer techsxiqueg. To
this ®ad^ w© isitead to study., ia th© sieset £@w years^
the process ol 'SxaitatioB with such tools as int©r'f©r®iiice
Microscopy J, IfMR spectroscopy .^ EPR spectroscopy .^
ultraviolet aad visible light spectroscopy^ Fur them
w© plaa to nak© aa attempt to measure MechaEsieai ai
PHS-NIH
lodividual Project Report
Calendar Year 1959
Part A» Projo Desc„ (contj Serial Ho„ KINDB-HP-SS-5
Page 6
thermal changes during the action potential „ Professor
Teorell from Sweden and Drs, Arvanitsdsi and Chalasonitis
from France have had experience with some of these
techniques in the past^ We are contemplating inviting
these scientists to collaborate with us on this general
problemo Two years ago, w® collaborated with
Dr„ Richard Sands at the University of Michigan on EPR
spectroscopy „ We plan in the nest year to resume this
study o
PES-NIE
Individual Project Report
Calendar Year 1959
Part B; Honors, Awards and Serial HOo HIHDB-MP-SS-5
Publications Page 7
Publications other than abstracts from this project:
Tasaki^ I, Physiological properties of the myelin
sheath and of the node of Ranviero Chapter VI in:
The Biology of Myelin^ Vol» IV^ Progress in
Neurobiology^ Korey^ 3. Roj Ed^ New Yorkj Hoeber-
Harper^ 1959^ xxii, 405 pp,
Tasakij, I„ and Spyropoulos^ C, S, Stria vascularis
as soiirce of endocochlear potential^ J, Heurophysiol, ^
1959, 22: 149-155, "
~° I
Tasakij, I„ and Bak^s, A, F„ Voltage clamp beh vior of
iron°nitric acid system as compared with that of
nerve membrane. J, Gen. Physiol,^ 1959, 42^ 899-915„
Tasaki, lo Conduction of the nerve impulse.
Chapter III in: Handbook of Physiology/ Section I;
Meuropfaysiology^ Vol. I,, Field» J,^ Magoun^ H„ W.
and Halla V„ E^l ®<^^°j "Washington^ D, C.^ American
Physiological SocTefy, 1959, xiii., 779 pp,
Spyropoulos, Co S, Miniature responses under
"voltage-clamp'\ Am, Jp Physiol.^ 1959^ 196: 783-790.
Spyropouios, C, S« and Brady, R, O^ Prolongation of
response of node of Ranvier hy metal ions„ Sciences
19 59 5 129: 1366-1367, =====._=_
Tasakij, I, Demonstration of two stable states of
the nerve membrane in potassium-rich media,
J, Physiolo (London), in press,
Spyropoulos^ C, S, and Ezzy, M, E„ Nerve fiber
activity in heavy water^ Am, J, Physiol,, 1959^ 197;
808-812,
Tasaki, I, Afferent impulses in auditory nerve
fibers and the mechanism of impulse initiation in
the cochlea, (Presented at the Conf , on I3:eural
Mechanisms of the Auditory and Vestibulary Systems^
Bethesda, Md,, June^, 1959) To be published as a
monograph by Charles C, Thomas, Springfield,
PHS-KIH
Individual Project Report
Calendar Year 1959
Part B: Honors^ Awards aad Serial Ho, HINDB-HP-SS-5
Publications (cooto) Page 8
Tasaklj, I, Resting and action potentials of
reversed polarity in frog nerve cello Mature (in press)
Spyropoulos^ C S„ Cytoplasmic pHo J^ Neurochem,
(in press)
Spyropoulos^ Co S„ and Tasaki, I„ Conduction and
traneaission in the nervous system^ Chapter in:
Anno EeVo Physiol . (in press)
Honors and Awards relating to this project:
Dr, Tasaki was invited to participate in the
Conference on Meviral Mechanims of the Auditory and
Vestibulary Systems, Bethesda, Mdo^ June, 1959„
DTo Spyropoulos was made a member of the
American Physiological Society,
Serial Ho. MSIfD&-IIP»SC-.i
1. lAh of ll®t&jraph^£ioiogy
2. Spl^l Cord S«retio£
4. CoffitiauAtJ
Isd&vidual Project St&port
P&rt A.
Project Title I G«B«rfttloi& of iaptilses la serve eells.
Prii&cipAl laveetigfttors; E.^ Fr«]^ «j^ ». G. F. Fuortes
Other la^Yestigfttors^ F. irel8<^<, W. I^Ii as4 M. Beelcer
Cooperatlae Usits: Or. M. S. r. Fuortee of tbe OpbttMiIiioIosf
Bmnoti of XXKDB tifts clevotedi considerable tine to tble
project. Dr. !7o Rftll of tSse Office of MftttaeMAticftX Eeiseiircb
of VIAIS) is' providing imporlAmt theoretioftl eesiBtftSce.
HftB Teftrss Psitie»t Sttyss Moae
TotAlg 8.7
Professionals S.§
Other; a. 3
Project Sescriptiosis
Objectives £ To deterssiifie %^hic^ pe,rt£ of tbe
fri
Lbtite tbe various eoopos&esits of tl^ recorded poteatials.
tbe tiae e^^exAce of their ^ctivfttios). aad %im ^i3ftiiti««tive
aspects of the ehaoiges ea^b p«rt
Meihode Eaagloireds Cl| Toltmg® c2@%p t<#«stoiq'iji^. A tecbai^<^'<..
bas bees* developed for tb@ ii&troduct^ioii of co^c«iffitiric iiicro<-
pipettes ifisid^ a cat*'s spis^l &>t€^mseom. Wmimm^@m»mt of
the cisrreat throegb tkm <mtmT pip^^tte r<@(iat3.ir@4 to J^-st aaiffi>'
taia tbe potea'Cial ot tb# i.W!;m¥ pip#tf« m^ mmf deeir@d level
persits tbe Hii£.Mp«£laiio% of tbe pote^ti^i ui this p^ss^tm*M4
portion of the cell im the face of activity %& v^rioii&s ptuetm
of tbe cell. This tecbsiqiie has jre^isired a det&ile^ mtm^f of
tbe costrol of 8i.se asid shape of glass »sicropip<^tt^^' hf
fibre. Xars^ SecJser. A device for tmetlm, 's^^ advasisiag t8s@
coaceatric sicropipettes has beea developed aad a coatract
let for its eauiafa^^ture. C3!) Sisgle cell estersal fields.
A secoad esperiaental approacb is oeder ^^f to deteradne tim
e:stracelliilar potentials produced ie tbe volLiire cc^dyictcr of
ladiiri^jial Px>oJ««st Seaport
Bftfft A. lii)tbo4s &apl@f#d C^i&t.)) Serial ROe RIin»»M^SC«3
the spiftfti cord hy metivitf km ft siagltf mdtamweom. Tbis
r«4uii«c stlnulAtic»fii i® th« v«atr«l root of tbo ftxos frooi
tte BlBsl^ eoll to IM stttdiod. A f«« TOBtrAl root fibors
At » tins aro 4rA«» up into a eoftra* nieropipotto ttad»r
llias«r's stoliatioft. It is tboA pos«ibl«, nelag » bridgo
oircQit^ to stiaulAt* Aad r«cor4 BimatAMOualy tb«
Ml«et*d Moa vbilo Bapplsg tta# potostlal f &•!« i® tie
•plsal cord vitb « aicroelectroste. Varloai* typots of el®e-
trod»s Affid «I«otro<te mvrmje will b« uoftd for wmppttsg tbs
*«A** ftad «*A-B" type fields surrotMdiag tb« Motossuroa. It
is &fttieipAt«d thAt it jrill be Moosssry to uso t^cbuiqttes
d»volop«d ia ProJ«ct Ro. KIHDd<.RP-9C--S for iBer«ASi8«
sisnAl to aoisA ratio ia tbis study. C3> Iferkii« teebai
Correlation of aioroeleotrode positioa vitb tbe chmmiotmv
of pot«atiAl8 recorded would provide ▼aiisAble iaforsAtioa
oa tbe roles of differ9At aeuroa pA;ft8. Dr. P. Melsoa bas
beea prinarily respoasible for tbe developaeet of a aerbiei
tecbai<|»eo ^ bas also set up aa isolated frog cord
pr(gipArAtioa for testiiig tb# carfelag te^ebal^fise.
Major Fiadiagss
CD «ae of tbe voltage claap teobaiqae applied to
spiaal notoaetirofts bas led to tbe coaclusioAp
certaia asswBptioas^ tbat tbe resistaaee
iaside aad outside the cell decreases by a factor of ^ily
S to 3 duriig activity. Wbea tbe clasped region separates
oms part o£ tbe eeuroa froa aaotbers voltage cbaages ia one
part cAaaot Affect tbe other. Tbas tbe claa^Eied sroA caaaot
lie betweea "A«* ead "B** regioase siaee A activity elicits B
firiag evea ia tbe preseace of tbe elaap. These results
are eoasisteat vitb tbe earlier hypothesis tbat tbe "A**
spike origi^t^s ia the axom« but suggest thst tbe "B** spike
does »ot iavade sore ttaaa a part of tbe eoBA»deadritic
W Ixperiaeats to detemine tbe poteatial field
grouisd ^ sisgle notosieuroa have beea reported by fatt. lis
coaolusiosi tbat ttm ^11 sooa is tbe source of tbe **A«* spike
aad tbat tbe "B" splt# represeats ccAdaotioa out tbe dea-
drites is ia disag? ^e»tat vitb tbe results of tbe voltage
cla«p teeb^que tm. freygaag°s iaterpretatioa of giaat extra-
cellular respoases. It is therefore aeoessary to repeat
Pattys aaasureiseate with laore elaborate tecbaiques for
recordiag the fiel«^ potentials m&d for ii^su^iag that tbey
are froa oaly one cell.
Ii&divicl^i^l l*©i®ct import
■•'^rt h. la-toff Ftaidiiigs Ccmst.]) Serial Ko. HIMBB-lfP-SC»S
5£ch of tte ««cb0^qu«8 o» vbieb this •xperiaent
<^i>^^«l6 bfts now b«6A worktfd out a»d ««st9d a«|»ArAt«l7.
It 7«v-t&s to bm «•«& «httth»£- tboy cab b« aate to wortc
sisal tea- .^uel* for % l9ws •aoueh tin® to co«|»l«t9 a
of tho fifi^is.
CSD i^-^ . ]f«l80i&' e BMurkiffiff t6ehAi«a« «Bs»loys 6oac«atirie
plpett98 for ^otb lAtn«- and •stf«oellttla7 s«cor4iffig8.
Aft«7 rscordift^ -^.^ii v.ctivity$ f93rroefani<te in tbe ies#r
pip«tt« ASMl f«rri4; «itr*t« i% tb» outer ar« •zi>«l>l«d bjr
ioatopboresis^ pwo&m^iag m Prisssiftft Bluci reftetiOK at tbe
•i«ctro«ifi tip. Blvti^ i|»otf$ 10-^30 Bicroas is diftaeter bfev@
t»««i& obtftiufsd ia or KK>skr eotosauroa sooAta is about five
cftsea. Tbese are Ei%rk;^d by li^ai^ger **8ig»posts** o» tbe
oord rburfAoe. Aggl'itiie&tioei oi «sord substaae® deereases
tb* eertaiaty of el^^ctrock?) pot^itios as tbe spot aaf Koire
ofi witbdrawal of tbe pipette » Tbe agetbod appear* to b@
practical for idestivicatioie of tbe eell pesetrated but
probably not for deteirsifiing . f roa irbicb part of tbe cell
tbe recording was mmtk>..
Sigttifica»ce to aeeear-febs Tbir^ is tbe eajor psoj^ct of
llie 3pi!tAl Cord 'S^^MmT Sesults of tbeee 3tttd4®s add to
fttffidaaestal Itaovi^dge of basic aecbs^Eisae &t
pbyeiologf , Specif i&aiy,, tber say lead to a better
uffi^rat&Bdieg of tbe irole of t.»ie deiidritee
of iiitegratioa of pr^st^a&ptic iBifluei&ce@. A goal of liajor
eigBifioaace to muxs'^logj is tbe elucidiitioB of ameb&mimm
of repetitive lapuls^^ ges»»ratioB iia
Prppoaed Course of P?/oj®ciig l^oitsge ©laa^iag studies %r@
temporarily discobtiPM^ii^iafig results Iron lield tmmam
neAts arouBd cells and tbe results, of Project Kfo. mmm^nP-^C-B
If tbese a&d otber stis'lies isupport tbe as^uaptions aecessarf
to success vitb tbe vo.tag^ claap technique, it vill be eoi&»
ti:@ued to explore tbe .natusfe of eysaptic potentials.
Field mmtivaf«nm&%B are Just ^gis@i^ a@d will be
coBtiaued until cosdnctioB is^ d^iadrites bas beesi tested
or tbe laethod proved iitpractical .
A ®»m esperinesst h&» beea proposed hf Br. Hall for
^tensiaing tbe relative ieportasoe of a&m. versus dendrite®
im eoatributiisg to tbe Ei(»%6ured aw^&rase ?esi stance. Tbiu'
iEi.v«Kl¥€5© wm9,em^m&9Kit of tfee cwrremt vol tag* pbiiais® sfeiftfc
M.€t will probAtoljr b« £tt@sept«ii h}' 'tSi« Spii^I Co^d 3@ctiigii
fraaliEs Z. , P»aori:»aj M. G. F., am^ 2l®.l@oag P. S. Voltage
Activity isi tfe® c®^ts*al i^rvsKs /jyatess. E-sad&oaik of
Physiology - MSH2f^i^'2i®SI ^ C:ii3iJ9]i • CbaffiFirr' ^I-i;;
igafcibltieR ia tla@ lo^ms saeiral f^ji^il cord. gsep. M©b»@1.
ilBm} 1% ^-4S.
t&e e®istrfe3. :*»©i"?©«as gs^^st^a. IM.\! Tims>sa©ti©Bs cjss li®41osi.
?i«.<jtTOaics imm} m^i si^ss.
te'. Fir^ffik Wk& im.r±t94> to b@ a ig£^ia£i)®? '^f tins l.tdica.1
Ite". Fraiik ^fas a©l5®d to li® a^ i\.'3g:oci&t® iSditoi' f<»!r tli®
thm Aimml _^vifw of l^tSiSiMil'-
.M&l^jl^.- ■ ** - " °*
Society 4;® l^>k|ftSs t&« Joliiii Oms'tiii S«b©c,. . .im ■a"
Serial Ko. HINDB-MP-SC-S
1. Lab o£ HmuTophfstologf
i. Sptsal Coi'd Ssctios
S. Betheeda, Harflasd
4o M««
ludltriduai Project Sftport
Calendar T^ar 19ft9
Part A.
FrojACt Titla: Augnefttatios of signal to aois« iratlo.
Prlft^ipal Iav9Stlgato7 ; K. Frat&
Otb«r l!sv«etigator: P. Holsoii
CoopAiratiss ^Aits; lSz>e R. Cox of tbd LalMS-atorj of ClisieaJL
Seiftsca, mMH, and Dr. R. FitsHugh of tha Laboratory of
Biophyeics, HZNSBs, ara coatribttting to tbis proJ«ot.
mm Taars; Patiast Oajra: Moss®
Total: .5
Prof asslonal s ,4
Otbar: .1
Projaet BasQrlptioiss
ObJ.#ctlvae i fo fiad praetleal sAtkods for s«aaBi«g racisrraat
sigsfels i£ ordar to igi£r#asa tba ratio of signal to aoiea.
If tb« eigaal rapdata at tba aaaa tia® during aacb trial it
will add lieaarljr witb tba atiab^r of trials C«pocbs| is'bila
aoii8«g baieg x^ffidon, tsuda to cancel a»d iacraaaaa offily as
tba a^uara root of tba »uabar of trials.
Mathods Eapleyads Tba aetbods listed are sot original witb
iha Spinal Cord Sactioa, but are beiag coasiderad for tbeir
applicabilitf to saurophysiologioal raeaarcb. CD Tbe
racurreffit sigsal-plua aoisa is traaelatad ii^to digits&l for®
•itbar ia real tiae or froai a sloped tape racordisg. Saeb
epocb is divided into tine slices aed tba digital signal
plus noise in correspondii^ slices is auatted for
of epocbs. Tbis digital cootpttter teobnit
successfully at M.S.T. and is practical for neuropbysiologi^
cal applications, ifiodifieatioe of a cosatercially available
digital pulse beigbt analyaser vould provide an adequate
solution at a cost of about $30^000. laezpen&ive coai^ters
Aadi¥i-iiJMi Project a®|K{S-t
.;, iksikiQdai l^Iof®«l icomt.} S®risal llo. 2llllll©-lfP^SC~8
tow p®rf®g%ids!g f^is s|}®eialls5@d fagjctios^ ar® i^-t liii®l.|^
to turn d$>v<gl®p«S isi tis© ^@e^ future. iS,} <%gmlog st3issd.s>g
of @ig^«>i-p.l«ia-gi©4s@ ^f 'stor«g« ia & SMtrias of eosd^ffis^rs,
soliitiom «s&i%s &u opm^&tlosi&X saplif i@r mm^ sosim form of
bigh sp««dl ss'ite^li. 1^. Fit^Eug^ b&e &S7«#iS to h@lp vitis
py#liffii»^K'f tfi®,i» ©f tfeis ®ps>roaefe. C^l^ 1^. Cox. is
«;splori£S ft 8BAsaS»€»ir of i^tho^s i&eludiag the mm^ of l>«i^
sto?6^@ t^^s. i4} A s^r® e«3sa>3s^sos» S^yit iis^xp^igsiv®
a»at^o4 laas ';t»^& d®vi3«€ by Mk>. C^ affid sgodifl®^ for UiS«)
fef tSi® SsiiaaS. C©M S®etioa. Tfeis ,aa®tho4 traaslatiBa aigaal-
plus^mois® isito ^^iristioms i.m i»l@a@it|p of «% f.f. no^^Iat^ti
to m»'lim jfffeti® fef A faetor of 10 m^pms'^ ps^etieaij, Imt th®
nstlaod BiiM^Bita fef ^>t p^'O^iSii^ % oo^ti.«&&£oys ifsftdont of th®
««i£;st#!i,t®d iii^ii^I ss it (^!7@;io|»@< TSais is t-^ a^tliod plasj»«>d
for UB^ is ;s'®yoFdiau ®iffigi# c®ll p©t@mti!ii f4®148 is Pff©J'=' ■ -
Mo. MM23®=»1P»SC»S.
gi^gifleaffic# to g®s<»&refei T^g^ as^ sifiis^ applir^tioas of
^m ps?llSl^ir°©in^lfmr"t© aiois© r^tl© ffisig^satati®® »©t o®.l^
in @«i-Si'opfef®i©l0gf laet Im Mo®®di«iiI y#®<@^r©lj iM g®®®«=®,l.
Alomi^ "ssitli s,€l^ai;©@fi5 4ii totn ^roesnsi^ t«H3tei#i©© ia gs^sg-al
"febi® ^fU'tie.'®!!^ t®elssii(§iii® '©ill be of gs-sat isipO'ftase® &s
tte ®i^giJ,®rftti©i& of @l#etrl€al siga® ©f s^srott® aeti^ity
^m
^_^j^s«^. C^g^KE'®^ of ^^jf€$?- A ffi^f^^jr ef ^ssiSl® solmtiom&
fo'^i^'pfoHi!® e»f"®5g»£lEsi©ffi of signal to ^©is® wmmim t&
asist 1*® giHT'tim t© tfe@ ^#t^^ far ^f#lopi^ a practical issts'!!:™
ais&t of ^id® 4^p|jlte«%^i]lity ®itli@:.f witfei® %tm IIH or fejr sib
1. LAt» Of M«iiropIay8iolog7
2. Spisal Cord S@etlosi
3. BetliosdA, MAryl&Ad
4.
ladiTidttAl P)7oj«ct
Fart A.
nroj^et ¥itl«: lib* «ff««% o£ anosia oq
Mobrftso potdstial.
Oth«r Xav«Btigaitorss S. ?t(uBlc ftsd Ho m^^vsw
Toarss 5tit&«nt Sftys; Noeie
VotAls 1.0
Pxof ••siosfti s .3
Otb9?s .f
^tivess To tmat ?«pori;a t»f SoJLaodlla aimI Skogltaad ttet
potoatial oS sB0to»$ti7Ofts ds@7«ft8«s Ik two 8t«pa
ttathoOm ^loyod; Itvsxm-vmOiTttm 90te&ti#l o£
asphfx£a bf
SoBUlts of EOlaodift e&d Skoglyad
&m ft«tri!»yt#d to
by blood pressuTs f>9Bp<xB8e>e to sapbsrxiA'
tts blocted t
bf b«sas»«boiiiua isiftteioa^ 09ll
potostiftl «a8 abowa to bo r«aftrl»&blsr usftf footod
by lo&s povjiodfi '9f
SAgaificftaeo to acaoftgcbg Tb» ponsibility of a oeeaitivo
doSttdoaco of acrvo coil »
90t«@tiftl oi^
oftoa booft e«egoat«d. Kt ia ttuss^foro
to 8bo« tfeftt At l@A8t ift apla^l »0tois@ta7oi&e tissder tbo
ditioaa of tbo^ «xpfrin®»t3 this popular ^i®^ is fhlm
P8S-HZM
mdividtaal Project B^port
P»rt A. C^oBt.) Serial Ho. NIKD&-KI^SC-7
Pgopoiw4 Coygse of Pfojgeti Ii^ Is poseibl® thAt th« «£foet
of oxyson lack aight b« <lcaoastrat«d If tbo blood eircala-
tioa could te iatftrmptod so tliAt n@taboIit«s
potassiuBg If r«IeA0ed tram tbo eollj, would lot
dlstolf wmmpt ft««y. Hovevor^ eto prActioftl dsporinsat for
tostiiig tilis e»i;g««tto£ feAs f9t booa d#iris«d.
Part B iffioXttded Tes Mo S
Seriftl No. MINI]&-MP^SC-8
1. Lftb of Nourophjraiolosy
2. SplffiAl Cord S«etioa
4. %•«
PHS-MZfl
' 191
XadiTidual Projoct Beport
fftrt Ac
Project Titles 6«»»i««lo& of iBiMlms la tb« Mftttthser
C«ll of the goldfish.
Prinelpftl Xs^estlgfitor s ¥. Oikaim C^iaitiag 8el«a«l8t>
Coop«r»tifig 0g£it8£
Totals .ft
Prof essioffiAl s , S
Olh«ri 0
Project Descriptiomi
Objectivee ; To uise the large Hftuthaer cell of the gold-
fish M A notel for testing idsas om aeeheAisMS of iapuise
tiOA iffi Spiffiftl
•< aiployedg latra- k&A extracellwlajp recording of
Aotiom poteatleie duriag eati- and orthodreaie stinulatic
asd dlreet eseitatioe «bro«igb the aieropipette will be
is volti
If possible » voltage damp techai^^s will
also be used. Markiag teehaiqwes and histological studies
will be an is^ortant aspect of the atttdy.
Major fiffidiagas Or. T. Olhavw is a viaitiiig scientist witi
the Spiftftl Cord Section for five noiths. Work ea this
project is jttst
lierve ceil provide iVspbrtaat guides for saaller cells Just
as studies on the gia^t axoa of the 8<|tfid have contributed
so Mich to urn usderstaadiftg of coadiietiom aad exeitatioa
ia all fibers.
Proposed Course of Project; Coatiiiuatioffi of this project
after Br. Oiitawa reiuras ^feo JapaA
the usefttlsess
of the resulta obtaiaed.
Part B i^luded -Tee m 1
Serial !©» lIia-SIF-BS-i
lo .Isaboratory of fe^roplsysiologj
4. Coffitiraati®^ of liHDB»MC»I3
Iiadi^idssal Project S©po?t
Cal®ffidar fear W^
Psuft A.
Otiaer Savestigatorsj . M®gd©l!?ia Irasfi^ M,D<,g Sid Gilaasis
M.Dog- a^d S®ls®rt B.. LiviiigstoiSB 'l.D.
Coop@ratiS8g IFskitsi Mobs
Mass fears _ „
T©tal; ^°^
Frojeet D@©®ripti@sis
O^J®etiy®g; C^r r^eogsiiti©® of tia© spatial world
la wlii^ w@ liW aisd ®f cmr ©^^ >©di@s dispo^d wittsin
t^at mp&e® is dsri^ed frc^ @©^@r&I €l&a^^Is of @e^3ory
iriec®ral.» f^#®® mw@t&sm ar® is^©i¥®d in aost of «mr
troliisg poster® a®d loe^^oti®^; str®BmB of aff*r@st.
iat®raet 4s' ©iipra^piaal a^ epical iser^oii® ©triseter©®
and ©offiverg® t© isiflnseiae® tk@ aeti^it^ ©f t&© fisa®,! soaaois
patlij, til® ffi©tor is^its, ^Tk^ s©ffis@rf ©rgasi ®f parti@tiiar
important® to tis® maifflt©is©js«i® @f «^a?4iliferi^sm sad orient a-
tioai is tfe® as®ffia»adit©rf p ^f icsg®®©ties,llf ©Id®st portisu
of til© iffiE^r ©ar^ t^® labfriistl @r ^©stilmlar appar&tti® „
tls® eQ®pl©2 actual interactions sm©^ aeti¥iti©s ^©diatssd
t^roiigls t&® v®stilisila.?j> s®^@iatal nnd iat@rs@^s©atal pro-
pricspisials and pyramidal ©I'st®^®^ as rmfl^ctrnd hf altera*''-::
Im spiaal ^otor osstfiow„
eats is mm^lMf@d^ l®isp©^®.s ar@ 2=®sor4®d frsss a "rari@t^
of aipiiaal ss©s'¥®i!,; 'S'^Mtral ^eot® r:;^?' :~i :\a.i filam@at» ®f
applied t® tte® e®r#tealI?Mp C0i?@fe;.x..... -k^ .ft^^-^-^^jr; aad
Serial WOo KIM-HP^BS-Ig page
Major Flndlaggss Itouroiihysiologic evidence suggests
that fibers witiiiQ tbe vestibular nerve cross Ji£st below
tbe obex a&d pass directly to vestral born cells of tbe
contralateral cervical cord tritbout synaptic relay „ This
finding is supported by unpublisbed anatosic studies of
Grant Raasrassen. Tbere are significant differences in
the configuration of responses obtained bilaterally froe
Botor nerves of cervical and luntbosacral segments of the
spinal cord„ This implies important changes in orgaiii°-
zation along the nsiuraziSj, vith the vestibulospinal tract
beconing less iaportant at lover levels than reticulospinal
C and/or relaying propriospinall neurons. Activity in these
tracts is reflected in individual components of tl2@
recorded ivtm cervical levels. Hiese conposients can be
selectively influenced by particular techniques of stinu-
latioup anesthesia^ and asphyxia. Descending fibers of
the nsdial longitudinal fasciculus aahe no important
contributions to descending vestibulofugal activity.
Vestibular responses ^ particularly those recorded
fron cervical levels 9 are influenced by neck anascle pro-
prioceptor stittulation^ Tentroflexion of the head throu^
300 is sufficient to markedly diainish ipsilaterally
recorded responses and to coapXetely abolish the contra-
lateral onesc Gradually increasing ventroflezion of the
head selectively inhibits conponents attributed to retic-
ulospinal iapulses before there is any chai^^ in the
coaponent supposed to be due to vestibulospinal activity.
This effect persists but is significantly reduced following
complete cerebellectony. A tonic inhibitory control of
the cerebellum on the vestibular systeR is demonstrated
by a ffiar&ed ausnentation of the vestibular respom^s
following acute cerebelleetosayo 'Sho resposwes undergo
a further growth following ressoval of a large portion
of the aedial reti^^lar fomationj, deaotystrating that
the reticular foraation exercises inhibitory influences
upon the vestibular afst&n irtiich are independent of the
cerebelliSBo
vestibular influences affect segnental
spinal reflexes by an initial enhanceaent followed by a
sharp depression and a subsequent period of re-enhancMtento
Ihe re-enhaneeaent disappears after cerebellectoay. The
early facilitatory influences appear to be bilaterally
reciprocally organised; the inhibitory inf Itu^nces appear
to be bilaterally syaaetricalo Both cervical and lumbo-
sacral outflows yield two successive wave responses to
vestibular stiaulation. These are isifluenced bilaterally
syaasetrically in parallel fashion i^ both cervical and
l?;abosacral outflow® o Projectioiss res^n^il^l® for a large
spileelihe wave in the radial nerve response are more direct
Serial Ho o KiaK*-!gF~B8-I^, pag® 3
and latperious aiad ssot so extensively distributed as are
those for the two wave responses. Yentral root responses
to single shock vestibular stisstslation reveal the firiBg
of snail motor units; more rapid vestibular stijiulation
recruits large motor units o Descending vestibular
influences induce activity in lumbosacral laotor units
earlier (even though the deseemding path is longer) » and
have a nore prolonged effect om. segnental activity^ than
do propriospinal influences studied hy Lloyd in the spinal
cat by aeans of brachial plexus stinmlationo
importance of tonic and phasic suprasegaental
control of spinal reflex activity is investigated. In
decerebrate preparations ^ singX^f^ shock activation of the
descending vestibular or propriospinal Siediating systems
evokes a pattern of facilitator^ and inhibitory excita-
bility changes of lumbosacral ventral horn cells. Tte
prominent inhibitory influence of intersepsental proprio-
spinal activity can be eliminat£)d by high spinal tran^
section. Ttm protracted inhibition of local and long
spinal reflex activities following hi|^ frequency
vestibular or brachial plexus stimnslation is abolished
by a small localised incision tfi the midline at the
caudal limit of the med^slla^ int^drrupting coatlnolty
between medial reticular fomation and spinal segments.
Significance to Science; The mechanisms underlying
muscle tone,, posture and locotaotion are basic neurophysio-
logical problems. Any isicreased knowledge of mechanisms
of circuitry in the central nervous system and especially
of integration between the classical and the diffusely
projecting syst«ffis is of esi^cial value.
Proposed Course of Project; It is proposed to
pursue a continuing stepwise analysis of the i&echani«Bs
of vestibular integration.
Part B included; t®B
MS - HIH
Individual Project Report
Calendar 7@ar 1339
Part 6; Ps£bXi cations
Gdrnandt^ BoEop Xranyi^ Uo^ susd Livingston^, R.Bo
¥e8titnilar inflmtnees on epinal nschaniflsas. Sacpero
Ifearolog 19m, li24A^^3.
Gernandtj, B»S. and Gilmanj, So Descending vestibular
activity and its modulation fay propriocseptiv®» cereSjellarj,
and retieiilar influences, Hxper, ISbutoI.^ 19S0a l:^4^m4.
Honors and Awards s Presentation of tbis naterial at an inter-
national Symposium on Stoural Mealianisisas of the Auditory
and Vestibular .SysteiBiS at the national Institutes of
Health fay invitationo
FisLic m<B mmt€^ - ush
tte bi<»7Btls»sis of Itsf&s «g^iii» Smttw i
bar t«» Ot&MT gS«»3pS ®2 iSf«S@tig&«@ig^«
t^ ^9p&^^tttm of si^«e&f i<5Al&7i->laSMilo4
iwm rat il9«$ff tiees* Baft® fe®®a misa to is«
£off fattr €^®i^ sfstfe^sia. i%«8 tli» «p9ro|>vift«o lat^?*
_ for fattf &«id fois&tloei i® & »«wmpc© of
atoffiB. ^Is&®s^l8«?-'r7:!li-" ^32el«otl4» CfPMB) is tte
'#fSPidliao s»el«otid» is
as ®ff®©ti 1.
of ae^stfi ^i^si^^^ 4 to
ii^ tMs ®®eti^ ia I@S8»
oarli' tSii@
ia Ia^@^to7ioa la t&o O.ft. aa
Thava la aa
fear
vitmaia Motia. m» psmssaea of divalaat a
la ttseaaas^^v aai t&a f^^p9@tiv9 affioao7 ^ HiB^ * tti'^ *" ^^o
A «9taii«« attt^ of tl^ sao&aaieiB of t&is earteosylatioa
la Iwiag essntl^ ^t vitft a perif ioti
« m» im^Uo® of- «»is^l«s fl^lliaaolipite
iB' ^ta ^i^si^^s^ 'tMt epl^^&o tii^aaa obtaiaa*
patioata witfe QsmSsm's 4SLemm ^ta&fs®a t&ta fosaatioa of
tha aeoiaRaat®^ off®ii^i^ ^s^^am&k^^ is e&ta. Vitb
of Tarioua ps?9@issi§«^p© of t^ o®s®^@<o@i^ soiooalo* it
mt tMt t^ mtis% i5s@l@®^l@ mf h» aya-"
»@® o&^irmtio^ toiiS t© s^adloff ualitely tbi
it t&a otiol^:r ®£ ^^lo&^'s ^^ftse is aa oseasi
'p<Miaaulatioa of o^ta^iis ai&tos'ials t^o^ ft^A l»lood ooXl'
^leaFtxf^tioii mC i® ®(i^i@i®t^t ^m m& faiiaopo of
j-rv-'f-^- r ai Ba®i© E®©©®f>©fe «,l@/3@/St
jj€'g^f@©t@^ 1® ©©©^j'^ti®® with Ds^o C&fefi®® Sw©@lc<?f ©f tfe@
pesmdm mm f@s®©ii"lff~l"i© ©iifmfie r©m©tt©® fe©t^ipe@® ptospfentidrc
i»ti@ac I® tfe© ©®®f!S© ©f timm& mt^X<&m,c. t&® aai^sg^ of "■■■ -
- 3 »
HivmetoT of Basic tlmseaxeh - 10/30/39
Hate As^satolt ep«&t th® past f^ar workiog at tlis
Has Plaack iBsstitut fttr Zsllcb««i« la Mualch vlisrs Ho particle
pats4 in stu41S0 vbicli ^alt ivith ssvsral laportant stsps is
tbe pathway of tbs bioeynttoeis of t«rp®B®ao 3p«cifically« h«
doaonstratsd t&» ensfaatic isonss'lsatioa of tBts »->«arboA itttsr-
Mdlat® ieopsnts&sri pfropbosphats to disMtbyiallyl pyrophosphate.
Ths lattsr coi«»ouBd is r^quirstf for ths coadsesation of t«o
3-carbon frasae&ts to font ths 10«>ca7hon gsranyl pyrophosphats
and stahssqusatly ths 15<-earboa farassol pyrophosphats. Ha
participatsd ia sxpsriasats vfaich dsaK>Bstffat«d ths coavsrsloa
of thsss lasrgsr aolsetsiss to squalsast, ths iaesdiats prseurso?
of cholsstsrol aad othsr tsrpsaoid vatsri&ls such as ths
stsToid honaoass aad vitanias &b Dp K^ aad X.
Oo Bradye M.lDc
LIBRARY
N|H
'1^ Amazing Res€
Amazing Help.
http://nihlibrary.nih.gov
Library, Ace,..
National Ins........ of Health
Building 10
Bethesda, H/laiyiand 20014
1 0 Center Drive
Bethesda, MD 20892-11
301-496-1080
50
ATE DUE
• ■>«
1/ Pnr^
SAVUOnD
rRlNTEOmU.t A
U75
Live Music Archive
Librivox Free Audio
Metropolitan Museum
Cleveland Museum of Art
Internet Arcade
Console Living Room
Books to Borrow
Open Library
TV News
Understanding 9/11