DOCUSEIT REM!

U 104 070 EC 071 899

TITLE The National Eye Institute Annual Report; FY 1974.INSTITUTION National Eye Inst. (DHEN/PHS), Bethesda, Md.PUB DATE 74NOTE 97p.

EARS PPICE RF-S0.76 HC-$4.43 PLUS POSTAGEDESCRIPTORS *Disease Control; Exceptional Child Research;

*Interagency Cooperation; Laboratories; *MedicalResearch; *Preventive Medicine; Public Health;Research Projects; *Visually Handicapped

IDENTIFIERS *National Eye Institute

ABS 'PACTPresented is an annual report of research and

supported by the National Eye Institute (NEI) during the 1974 fiscalyear. It is explained that the purpose of NEI research programs is todevelop scientific knowledge which can be applied to the improvedprevention, diagnosis, and treatment of visual disorders. The sectionon extramural and collaborative programs focuses on research relatingto retinal and choroidal diseases, corneal diseases, cataract,glaucoma, and sensory-motor disorders and rehabilitation. Describedin the section on intramural research are programs of the ClinicalBranch (such as laboratory study of ocular disease in patient);projects of the Laboratory of Vision Research related tobiochemistry, experimental embryology, experimental pathology, andneuropnysiology; activities of the Office of Biometry andEpidemiology related to diagnostic methods, incidence of disease,identification of risk factors, and comparison of alternativetreatments; and public information and program planning efforts. Alsoincluded are lists of references or publications (given at the end ofeach subsection) and a list of intramural research projects. (LH)

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TraininPjouams

AIt),,uh the Admintrati,-4 inn tn the current trai-inx laant prueram is t,einr 1114,:entt7te,t.

qty

L974 appropriation, togetht!wits, the release cf rY !?73 f-mr::s, has enabled the Iost!tutv t)

auar a total of 49 at s level of S1,857,000,inclAthc S454,0W of ir:Nounce- 4 f7,r 6 competing applicattons.

Fel!..vsLip support 1-t aztnt $362,000 for commItr..-cr 12 awards made pri,;r t 4 t.t :f traLning programs. plu:is;1,30,0000 for the bupport of ts ;:l!';t.tg

. Re,earth Contracts

!Alring IN 1974, 19 t;ntrattt. ..ere f.:1,:ed, at a total cost of $2,20,0-:.',eventeen of these were exrIv!,:ive:v f:r :nstitute's collahnrative .4t-dvol evaluate treatment mr./alIt;eb fzr :Ialetit retinopathy. The remainiorcntracts were awarded fc.r :A..7e::;me=t ...::-: a I..arge-Scale Method for

tne Preparation of 1.:od ''4ter Segments -1-he Bicstatistical AnalAniis:lata btained from the rla -:on. .11 ::::a::ratIve Study."

B. ,)r7ahization and Staffini:

1 -q-ei.r4n Structure

giver the past year, the Ex:ram-:a: 7..r:)zram have been restructured toref!e..t more accurately :he trczram 1:tiortties. The new ma!or--rc,eram areas, with esti:rates :f :;-- s.r.s.t.nrt levels for research erant

are fol:ows:

Prozram

Rk:tinal and Cheroidal Diseases:orneal 7)iseases

'atara,7:

t:laucoma

S. Senorv-Motor and keh

:74 Research Grant Funds

$9,687,0005,148,0002,718,0003,348,0006,604,000

To achieve this programra:c f_.!...e7ta::n at the operating level, pro-.iirectort, have been ass:Ygnef.: 'ts,asls cf the revised structure,

11.11 be responsible for cbordiratIng t;dt r. contract and grant supportedin their designate ;irc,grama. the responsibilities

7an.lzenent personnel in the ::.-ntrnts a '1-ants Branch have beenrt to reflect the same 7r.S'77E7 7..a7a7enent framework.

2. National AdvisorxKmlimull

In order to establish a sound basis for Institute program planningActivities in each program area, a subcommittee of the National AdvisoryEve Council has been established to review current research support and,with the advice of scientific and technical experts in specific programareas, tormulate recommendations regarding program balance to be trans-

mitred to the full Council. Review of all programs is expected to be:omplered by November 1974.

3. Vision Research Program Committee

All part of the recent review of Federal advisory committees, theInstitute proposed to eliminate training grant and fellowship review fromthe functions of the Vision Research and Training Committee, and broadenIts sphere of activity to include not only the review of special project

grant applications, but also participation in the analysis of extramuralprograms and in advising the Institute in its support of specific research

areas. It was also proposed that the k:ammittee be renamed the VisionResearch Program Committee, and a revised charter reflecting these changeswas approved by the Secretary, HEW.

4. Establishment of Data and Analysis Unit

In response to increased data requirements for analysis, reporting,and management of Institute programs, a data and analysis unit has beenestablished in the Office of the Associate Director. Initial efforts have

begun to develop a comprehensive information system which will serve as aresource for extramural operations as well as provide analytical data for

program planning, budget formulation, and reports.

5. Staff Changes

The following personnel have been appointed to key positions in theExtramural and Collaborative Programs during the past year:

Dr. Wilford L. Nusser

Dr. Luigi Giacometti

Dr. Israel A. Goldberg

Dr. John B. Mathis

Chief, Scientific Programs Branchand Acting Program Director,Glaucoma ProgramProgram Director for Cataract andCorneal Disease ProgramAssistant to Acting Program Director,Glaucoma ProgramProgram Director for Sensory-Motorand Rehabilitation Program

3

P 4, 4

RETINAL AND CHOROIDAL DISEASES

The NEE Retinal and Choroidal Diseases Program is divided into six dis-order areas: Circulatory Abnormalities, Vitreous Degeneration and RetinalrIttachment, Developmental and Degenerative Abnormalities, Maculopathies,inAors, and Pveltis.

CIRITtATORY ABNORMALITIES

These disorders, which may be due to environmental influences or heredity,include development, obliteration, tortuosity, occlusion of blood. vessels, andtwmorrhage. They may include such clinical diseases as retrolental fibroplasia,diabetic retinopathy, and macular degeneration.

Preretinal vitreous monitoring of oxygen has been proposed as a usefulmethod of studying a variety of conditions of retinal toxicity and degenera-tion in wh4c4 ketinal blood flow is an important factor. Dr. Noble David andassociates"'" at the University of Miami have continued to use fluoresceindensitometry for studying the relationship of blood oxygenation to retinalblood flow. The rhesus monkey has served as the animal model in which con-striction of major retinal arteries and veins during hyperoxia and dilationduring hypoxia were demonstrated. Retinal blood flow increased considerablyin hypoxia and showed a moderate decrease in hyperoxia. These findings indi-cate that the retinal circulation parallels that of the brain in adjusting tochanges in the arterial oxygen partial pressure (p02) with compensatory changesin blood flow. These investigators continue to apply techniques for quantita-tive measurement of relative retinal blood flow compared to such variables asblood pressure, blood volume, hemorrhagic shock, and optic nerve atrophy.

The pathogenesis factors which determine the evolution of different vas-cular patterns and techniques of altering hemodynamics to prevent retinalcomplications in patients with branch retinal vein obstruction are being studiedby Dr. Frank W. Newell and his colleagues4'5 at the University of Chicago.The retinal vasculature of patients in these studies have been followed forperiods of up to five years utilizing fundus photography, fluorescein angio-graphy, and measurement of arterial perfusion pressure. The lung -term

fluorescein angiographic assessment and vascular dynamics of these patients indi-cate that they can be classified into four major groups: Group I includespatients in whom arterial perfusion pressure, retinal circulation time, andvisual functions remain normal; Group II includes patients in whom arterial per-fusion pressure is normal, but there is some delay in the retinal circulationtime; Group III includes patients who demonstrate an impaired arterial perfusionand retinal circulation time demonstrating marked venous stasis; and Group IVincludes patients in whom arterial perfusion is grossly impaired and retinalcirculation time shows gross venous stagnation.

careful quantitation of an experimental model of retinal eschemia andvascular proliferation may assist in the identification of factors associatedwith retinal vascularization and proliferation. Dr. Arnall Patz and associates'at Johns Hopkins Medical School are conducting a study to determine the optimalpot levels associated with production of retinal capillary and small vessel

.)e. The 're .4pene vela t ly a i rear up to a pol

..;)t, Hv. .,usl.lino0 non level, in this tant, produced chary s; with 'ht..

tftv t canillary non-perfusion, a determined b.! flu 111)4 ;:tpliYr rt' t i'.ret 01 rot i whenia produced.

.n the et,-,ire of ,ztadv of retinal hlood flow in choroidal and fetio....1

v&-c4;at'eTV'', hr. Atnall Pat...7'11 asmwiates, in collaboration wit 1/4.

Laherltery at John:, h,pidns Pniverstty, have (1,.monntr,tte.! that

ereen dve ...ill permit iwcared absorption angiographv of ti-e,

offal t l i tni,. The li-Iltations of iluorescein dye are eliminated iv, in-

,leen. The application of infrared absorption angiograph)' to the,it-uitineons study of choroldal, :and retinal circulation is in progres and willptt in trvelieation of the eontrihution of the choroidal and retlhal cIrcu-

latien to retinal oxygenation. Roattre choroial circulation can ho ,..hervedthrouch sirnItaueous photography of choroidal and retinal circulat;or,-:.

the optic eup. called papilledema, has been proiured in e..norimentalmodt'ls by the use of intr.tcranial surgery. Dr. Mark O. Tso and associat at

the Ar-!e! Forces Institute of Pathology have been using experimental moeelscreated by trrelsing intracranial pressure nonsurgicaily or by loweril ; intrA-

0:Llat pres:ur. The mechanism of breakdown of the optic nerve-blood birrier

In the oi)t:c dis.c is currently being studied. The leakage of fluid from thevasculature of the optic disc and possible from the peripapillary ehoroldalpitls t panilledema is being investigated by use of histochemical techniques

horseradish peroxidase as a tracer substance. Intravascular

io!ection of this enzyme as a tracer will show areas of localized disruption

tat nerve harrier.

-he anima model for papilledema has been produced by x-irradiation of

the o,ipital lobes of rhesus monkeys. Of thirteen monkeys irradiated,four develoned full papilledema, three showed mold edema of the optic die,.

while t!e remaining six developed atrophy of the optic disc. Those animals with

papilleda also showed an increase in intracranial pressure. Electr6n micro-

scor- stud of the Optic disc of animals with papilledema demonstrated swelling

as As f!uid accumulation in the intercellular space. Extension of this

worK it' of animal models will be of assistance in understanding the patho-

eene:4:1 papilledema. The relationship between the peripapillary choroidal

and rho :'entral retinal circulations with increases in intracranial pressure or

decr.a,e.: intraocular tension may be defined.

Dr. David J. Applel° and associates at the University of Illinois havedesigned a study to analyze the efficiency of argon laser burns of blood vessel

elosur,. or obliteration and to analyze factors relating the movement of fluid

herwoon various retinal and choroidal components. Monkeys have been subjected

to photocoagulation treatment with subsequent histopathological and electron

microscopic analyses. The results show that specificity of vascular effects

ascribed to the arson laser is unfounded. The investigators have never found

a destroyed or oezluded vessel in the absence of significantly destroyed nerve

fiber parenchyma. In addition, choriocapillaris closure has been a

rot,:tint

6

YllhEors PE CENeRATION AND RETINAL DETACHMENT

Iht,4e disorders include rhegmatogenous and other retinal dettichmel.ts due) vitt-vow.. tiber formation and shrinkage, and vitreous liquification and opa-

ci:Icasi-ln,

tier ion

.\n increased understanding of the biological role of hyaluronic acid int',, vttreous may' lead to the possible use of this biopolymer to control inflammation and regenerative processes. Further characterization of the struct'ire,r IsiAloroni acid in solution and as a solid could be important in the possibleterapeutic use of hvaluronic acid. In addition, the vitreous is useful inthe ,ztudv of hiosvnthesis of biopolymers. It may be viewed as a simple connec-t:N/0 tissue. Dr. Endre A. Balazsll and associates at the Boston Biomedicalizosearch institute have been studying enzymes involved in the synthesis ofvi,real components. They have also been investigating the role of salts sucha. A; dtum chloride on the swelling properties of vitreous gel. It has been..uggeso.d that the biopolvmers may serve as volume regulators for gels suchas N;itreous.

naluntRasimien t

investigation of vitreous membrane formation development as a consequenceof 1.etirrhage and intraocular inflammation is in progress under Dr. David A.',..ant11- and associates at the Retina Foundation in Boston. They find thatv ;rreou :3 membranes may develop because of plasma clotting or aggregation ofTO4telets. This group of investigators has conducted studies which document

effeots of injecting platelets with or without plasma tnto the vitreousTt now appears that when blood components are released into the

vitreotJs cavity, intact platelets play a role in the instantaneous formatione: ILembranes. The vitreous membranes can be formed in the absence of plasmaproteins provided the platelets are physiologically functional. In some re-spects, platelet membranes resemble vitreous floaters which are seen clinically.Platelet- induced membranes are,not accompanied by a proliferation of fibroblastsand fibroblastic membranes which may lead to retinal detachment.

1:nucleated human eyes are being examined by Dr. Robert Y. Foos13 and.1.1:.ociates at UCLA. He has observed a prevalence of proliferative vitreo-retinopathies which resulted from complications of ocular disease or surgery.This high incidence indicates the need for a better understanding of the under-lying events and the relationship of these events to more complex lesions whichload to blindness. The proliferative lesions at the juncture of the vitreousand retina range from simple epiretinal membranes to processes in which bothfibrous and vascular components lead to retinal detachment. Epiretinal membranesare delicate strands on the surface of the retina. Their cause is poorly under-stood and has been the subject of study by Dr. Foos. They are found inas,:ocisrion with developmental, inflammatory, vascular,and mechanically producedlesions. The experience in Dr. Foos' laboratory indicates that the membranes;r:):inate in the glial cells which become mitotic through a variety of stimuli.

7

Dr. Miguel P. Refojo" and associates at the Retina Foundation, Boston,point out that in cases of severe vitreous traction these is need for a materialwhich will tamponade the retina against the choroid during formation of choroi-retinal adhesion and will not pass through a retinal break. Dr. Refojo hasbeen developing synthetic polymers similar to the natural vitreous body of theeve. The gel must be injectable and must not hinder vision by scattering light.

DEVEL0PMENTAL AND DEGENERATIVE ABNORMALITIES

Piement E ithelium

This is a single layer of cells in the retina which contain varyingamounts of pigment. These cells are firmly bound to Bruch's membrane whichis bound to the choriocapillaris. The intimate relationship between the photo-receptors and their blood supply suggests that the pigment epithelium has acritical role in the maintenance of the photoreceptors. The pigment epitheliumhas been implicated in clinical problems of maculopathies, retinal detachment,visual pigment synthesis, removal of rod outer segment debris, and informationprocessing as implied by its contribution to the electroretinogram. Due to anawareness of the implications and critical role of the pigment epithelium,new concepts ,df the pigment epithelium involvement in retinal degenerativedisorders are developing.

It is unclear whether the pigment epithelium follows the general biologicalphenomenon of phagocytosis or whether this structure had additional speciali-zations which are characteristic of these cells. Dr. Joe G. Hollyfield" andassociates at Columbia University have shown that phagocytic activity beginsearly in the amphibian embryo and is responsible for the removal of egg pigmentwhich is eliminated from cells of retinal neuroepithelium. These investigatorshave explored the question of whether the phagocytic activity of the pigmentepithelium is specific or an indiscriminate scavenging. The study has shownthat pigment epithelial cells will phagocytize polystyrene spheres which havebeen injected into the space between the retina and pigment epithelium in thefrog embryo, tadpole, and adult; and, therefore, the phagocytic activity is notrestricted to rod outer segment discs.

The interphotoreceptor matrix appears to be synthesized by the neuralretina and the }figment epithelium with possible 2onvibutions from the photo-receptors and Muller cells. Dr. Lynette Feeney1'011 and associates at theUniversity of Oregon Medical School have used radioactive precursors of proteinglycoproteins and glycosaminoglycans, which are components of the interphoto-receptor matrix, to produce autoradiographs in an attempt to v rify the site

of matrix macromolecules. Autoradiographs of 10-day old and adult mice wereprepared for light and electron microscopy. Pulse label techniques show that

although the apical microvilli and their cell coats in the 10-day old mice are

proliferating maximally, the adult microvilli show a more intense labellingwhich probably relates to increased phagocytic activity.

Most of the studies of pigment epithelium have involved embryonic eyes asa source of explants or in situ observations of phagocytosis, proliferation,

or cell movement. Conclusions with regard to potential activities of these

8 11

cells have been based upon. hitopathologic observations. Dr. Mark 0. Tso18and as:iociatea at the Armes: Forces Institute of Pathology collaborated withDr. tlanil Albert and associates at Yale University and developed a method oforgan ,:altele of human pigment epithelium and choroid in an effort to study

recrtions of this tissue to various stimuli. These investigators haveAl,own that preparations of human tissue obtained postmortem and during surgicalproceaarea MAV be maintained in culture fcr at least two weeks. The tissuedoes not proliferrre or degenerate and appears to remain active and suitabletor molphological studies. The culture system employed produced pigment epi-theliam which resembled the in situ tissue In that there was a persistence ofapioal v ill1. terminal bars, infoldings of basal plasma membranes, intact base-ment %embranes, and lielanin and lipofuscin granules. The techniques may beutieful, in studying the cytological behavior of pigment epithelium in vitroduring various stages of retinal diseases.

pr. Kenneth Brown19

'

20and associates at the University of California

have concentrated their efforts upon the functional relations of photoreceptorsto the pigment epithelium. They have described the anatomic relationshipbetween the pigment epithelial cell and photoreceptors in frog retina. Thepigment epithelium forms apical processes which, in the cat, ensheath the coneouter segment. Although the functional significance of this sheath is notunderstood, it is evident that the pigment epithelial cell relates to the coneas well as the rod. These investigators point to the similarities of the choroidplexuaes of the brain and the retinal pigmen epithelium and choroid. A seriesof intracellular microelectrode experiments indicate differences and similari-ties in ion permeability and flux at apical and basal membranes of the pigmentepithelial cell. Ouabain placed 04 the epithelial side of the tissue was foundto depolarize the apical membrane but was ineffective when places on the choroi-dal side. These observations indicate that the apical membrane, but not thebasal membrane, contains a sodium-potassium pump. The physical condition ofthe pigment epithelium used in transport studies is examined by scanning electronmicroscopy. These in estigators have developed a technique for verticallycracking the epithelial layer at cell junctions so that latel-al surfaces ofindividual cells can be visualized.

Membranes

The production of an electrical response to the absorption of light byphotoreceptors is related to a system of light-induced membrane reorganization.Investigation of intact membranes and relevant membrane models may further ourknowledge of the mechanism of energy-transduction and transfer in photoreceptormembranes. The structure of photoreceptor membranes and visual pigment proper-ties are the subjects of current investigations.

Dr. Kent Blasie11 and associates at the University of Pennsylvania haveapproached the description of membrane structure and light-induced membranephenomena at the submolecular level. These investigators have determined byx-ray diffraction the location, of rhodopsin within the profile of photoreceptordisc membranes, the forces responsible for this location, and tho localarrangement of rhodopsin over the surface of the disc membranes. It is anti-cipated that analysis of diffraction data from the disc membrane profilo will

9 Jo

permit A sletailec! evaluation of in. th- twinbr:Ine sttqcture

at the :um,s:lecular level. T. date, ',v., 11 1z 3r t- tit a model tf ..1

photoplkment molecules which nrotru, t:1 -c,ious layer and into ti 'POe.

cores causes the 1,11,-.to;,:s- , --se dei-ssi,r iflt0 the lipi2

and in a transmembrane direction.

ln.ne L. Hubbell-- .2!:d he Pniversitv of C.4Iifer, bave

been inrerested in the location r :; Clo disc membrane. Thei; 3Vcsown thdt the surface of the r:,0:0:,,;!o le tole is in direct contac.. with the

hydrocarhsql chains of the phospoli..,,I,! et tt,, Tin:: membranes whiel it rei:et:ates.

The distribution of rhodopsin noleQuIc! tt,.. plane of the membranes has seenstudies! by techniques whio', reypal :Ins surfaces. It has been fcu:i

the rhodopsin behaves as a solute wt.iL:1 is regulated in its solution by

Ca-eful studies by this group indicilte thAt rhodopsin completely viomets:s t*ethickness of the membranes. Th:1, proces:: by which the light energy it; traLsducedto produce the electrical response may relate tn a permeability change in the

disc membrane. The model systems of ,Ilodcpr!in in a phospholipid pertits

the investigation of light-activated ion wvement in membranes. Resulrl of

model membranes appear to be consistent with current interpretations of !7-r:aystu.iies of intact photoreceptcr membranes.

7r. Richard A. Cone23

and associates at the Johns Hopkins University arcst4.iyin2 the effect of rhodopsin molecule on tne general disc membrane charac-teristicg. The rapid lateral diffusion of rhodopsin within the disc membranehas been observed by microspectrophotometric techniques. Their results ineiicatethat the effective viscosity of th(, membrane permits rhodopsin to float freelyin the lipid phase. These investigators find that rod outer segments offer thebeet nodel for the study of rapid latral diffusion of proteins in membranes.by observing diffusion constants or rhodopsin, it n4111 be possible to determinethe effective radius of the molecule within the lipid phase of the membrane.This work implies that in the plan,. of the membrane, the rhodopsin moleculeMu4t be slightly elliptical or nearly circular in shape. Rhodopsin may be

thought of as a neuronal protein, in a neural membrane, and knowledge of itsstruct;re and function will reveal. factors which influence transport of drugs,

nutritional components,and the spread of electrical energy in photoreceptlon.

The question of rod outer segment disc organization and thT7 localizationcf rhodopsin have also been investigated by Dr. Edward A. Dratz24 and associates

at the University 4 California. Preparations of intact discs and rod outer

segment fractions were exposed to membrane-permeable and membrane-impermeable

reagents which label amine acids. They found that half of the rhodopsin amino

groups were labelled by the membrane impermeable reagent. These data indicate

that rhodopsin must protrude into the aqueous medium between discs. It seems

clear that rhodopsin exposes a hydrophilic surface on the outside of the disc.It is still unclear whether a single rhodopsin molecule transverses the discmembrane or wli.zther rhodopsin molecules are situated on both sides of themembrane. Factors which influence membrane structure and function will be moreeasily understood as more information about membrane proteins and ion transportis obtained.

Visual P gments

The question posed is how changes in molecular structure of visual pigmentrwle:ues relate with nervous excitation of thf. photoreceptor. Since structuralchange,; in the photopigments are the first events in the transduction process,compreh,n:.ion of visual pigment photochemistry will help to understand visualyx,-itatiun. Correlations between ionization and hydrogen-ion concentrationchanges of rhodopsin and the late receptor potential have been investigated byDr. Santc,rd E. ostroy-5 and associates at Purdue University. They have isolated

thermal intermediates of visual pigment bleaching. Their experiments showproton uptake during illumination and proton release during later processes.These reversAble effects implicate hydrogen ion changes in visual adaptation.Furthermore, ionization changes may be a controlling factor for the existenceof photopigment intermediates.

Dr. Bruce E. Goldstein26

and associates at the University of Pit:sburghemphasize that in addition to morphological differences between rods and cones,rod and cone pigment regeneration in isolated retinas are different. Perhaps

the observed effects are due to chemical differences between rod and conephotosegments. They have used the early receptor potential to show that thefrog's green-rod and cone photopigments regenerate in the isolated retinawhereas rhodopsin does not. It appears that photoproducts of cone pigmentbleaching may decay faster than rod photoproducts. Microspectrophotometricmethods will detect rod photoproducts, but in the absence of cone photoproducts,they may have decayed to a non-visible portion of the spectrum. Differencesbetween rod and cone photoproduct chemistry may be important in understandingwhy some degenerative diseases, such as retinitis pigmentosa, appear to beinitiallv'selective for rods.

MACULOPATHIES

Dr. Edward Norton27 and associates at the University of Miami continue

to study macular diseases in selected groups of patients with special emphasison diagnosis, classification, natural history, and hereditary and familial as-pects. Wherever possible, histological correlations are made with the clinicalobservations. These investigators have contributed to the understanding of thepathophysiology of macular diseases. Among the specific diseases studied arecystoid macular edema, idiopathic central serous choroidopathy, and seniledisciform macular degeneration.

Dr. John D. M. Gass28

, Bascom Palmer Eye Institute has reviewed 200 pa-tients with macular drusen and disciform degenerative changes. He has concludedthat all of these patients have familial diseases which affect the choriocapil-Idris and pigment epithelium. The involvement of the overlying retina issecondary. It is important to continue the study to detPrmine whether there isevidence that any form of medical treatment alters its natural course.

Some clinicians have advocated a therapeutic approach to the problem ofcentral serous choroidopathy and have employed photocoagulators. Dr. EphraimFriedman ~9 and associates at Boston University Medical Center are among thosewho have emphasized the need for controlled studies of "nontreatment". These

1114

investigators have presented clinical data from 27 patients with documentedcentral serous choroidopathy who were not photocoagulated and whose conditionwas followed by fluorescein angiography. These investigators believe that inmost cases the disease is benign and self-limiting, and therefore, may requireno treatment by photocoagulation. They do recognize that in some cases photo-coagulation may shorten the duration of a given episode of central serouschoroidopathv; however, there are potential hazards in the treatment.

Jr, Samuel V. Vainisi30

and associates at the University of Illinoishave been concerned with the establishment of a breeding colony of baboonswith heredomacular degeneration. They have been interested in the inbred colonyof sixty baboons at the Brookfield Zoo. These animals are being examined, andbehavioral, photographic, electroretinographic and fluorescein studies will beconducted in order to describe progressive lesions which might be detected inthe macular region. These investigators observed behavioral abnormalities ina baboon which led them to suspect that the animal had visual acuity deficien-cies. Clinical tests indicated that the animal had juvenile macular degenera-tion. It was planned that the animal would be useful in establishment of abreeding colony, however, she died of unknown causes. Histopathologic analysisconfirmed the clinical diagnosis. It is assumed that the lesion may be inher-ited and indicates that the baboon may provide a nonhuman primate model forinvestigation of macular degeneration.

Further studies which involve the creation of experimental models inrhesus monkey in order to study various pathogenic mechanisms of macular degen-eration are being conducted by Dr. Mark 0. M. Tso31 and associates at the ArmedForces Institute of Pathology. These investigators believe that one of thepossible pathogenic factors of macular degeneration is chronic exposure to anexcessive amount of light. They produced an experimental model in severalstages of development by exposure of the macular region to the light of anindirect ophthalmoscope. The light provides a mild photic insult. Fluoresceinangiography showed that leakage of fluorescein is the first clinical sign ofdamage to the macula. The leakage started 24 to 48 hours after exposure and isprobably caused by a mechanism other than photocoagulation. These experimentsdemonstrate that a good experimental model can be produced.

TUMORS

Biochemical Developments

Retinoblastoma resembles other tumors such as lymphoma for which thereis evidence which suggests a viral cause. Althovgh direct evidence for therole of a virus is lacking, Dr. Daniel M. Albert 4 and associates at YaleUniversity School of Medicine argue for a viral etiology in retinoblastoma.Electron microscopic examination and immunologic methods have yielded littleevidence of viral infection. Based on biochemical methods, these investigatorshave been studying the RNA-directed DNA-polymerase activity in human oculartumors. This enzyme is important because of its presence in animal RNA onco-genic viruses which have been analyzed. This enzyme activity has not been de-minstrated in normal, rapidly dividing tissues but has been found to be presentin ten specimens of retinoblastoma.

115

Ultrasonic Developments

At Case Western Reserve Univers. , en untie eme : ' ta' se

have been combined under the direction of ..at' and :r. Edward W.

Purnell. These investigators have develepec a hama ntilt 1-ecam eltrascnicpulse-echo apparatus for the two-dimeeeiona: visealtet:e:e :t eceIar tissee.The scan mechanism and display unit are eeffieteet:e eee:acIe sc that they canbe rolled to the patient's bedside or intr tee opezetene :ecru. :he se of thisportable unit in the operating roam is tnt first apeelt:aeeee of S-scanaingtechniques in surgery. The B-scan ultrasonograpte: 11A-7.*:4 i.. eseecia:ly help-ful in explorations of tissues behind the eve gleot_ c ete examinationis made possible because the flexible hanc fLVT!..:* re-airs the capability

of larger scanners to differentiate finer tissue tetaile

Further work on improving capabilities et c =agnestic systemsto ensure a more reliable diagnosis of ocular aa t. rr:t.ea: tumors is being con-

ducted through the collaborative efforts of 4:%-r. 1. .7aciesec aed

Dr. Frederick L. Lizzi at Columbia Universite Ent lavers:el Research resstitutein New York City. A large number of patients tare teen exameeed ulerascnically,and clinical studies have demonstrated the valet ultrasceic methods

for patient evaluation. These investigators terve eeeireee a teal be scanning

system. The equipment being developed by this greet.- we.:: enhance tissue ref lec-

tance levels and separate tissue planes, both of are .;.34.t.4: in demonstra-

ting variations in ocular rumor patterns star rieeeesee eemerrtage. he ultra-sonic measurement of tissue characteristics Us tee :4 sruaee en erect- to improvethe diagnostic usefulness of these methods.

UVElTIS

Studies in progress in experimental animals ende:a:e :ha= erestaglaedinsare important in the development of teflammetive eee t.'nt :Jelman eee. AS aresponse to mechanical trauma or induced eveieie, e---e-eg'andim-leke substancesare released into the aqueous humor. Sebstermee sreeC ereeeagIar4in-like activ-

ity are not detected in uninflamed eyes. 7.!:". Lennete E. Eaker.s.:- an associatesat Columbia University have been exploring the r:le :f eetszaelar.dens in thephysiology and pathology of the anterior uvea. 74 ets4 iireeseleaecrs have used

the rabbit to demonstrate that fluorescein-iris =gene:ranker. :echreieees are use-ful for recording alterations in the diameter aed ptemeaeelety et he uvealblood vessels. Topical application of preeteelenteres ereeree:es eascOilacionand an increase in permeability of blood vessels a: :Ce tase cet the ins whichare more sensitive to the actions of the eree.teglame::s. vascular altera-

tions produced by prostaglandins in the anterior eeea ma7 Cemenished by

prostaglandin antagonists. The action of eresteellestie-':::ckene agents may

be of value in the control of the clinice: tend:tee:: :f ac-_:e en:eriee eveitis.

Dr. Laszlo Z. Bit°36

and associates at :clencie :neeeret:y have been

investigating the mechanism and character:et:es t!,* :zee:lg.:are:en transport

system. It appears that a single episote :f ese:::e is :aeale :t eamagengan absorptive prostaglandin transport and ..t= eteanelece:c it :-e anterior

chamber. The evidence suggests that tert se:f.teet:el rereecral :f pr:sta-

glandins from the aqueous humor in tne '17:fteT :emcee :-e :diary

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33. Holasek, E. andscanner. Proc.

Reid, T.-: 0A-dtrecte4 DNA-polymerase activity inReport of tts r.resence and possible significance.Ophthal. Oto. 77: 630, 1973.

Sokollu, A.: A direct eontaiet, hand-held diagnostic B-of the 1972 Symposium of :E' E, Boston, Mass.

34. Coleman, D.J., Jack, ILL., and ?renttrauma. Am. J. Ophthal., in press

L.A.: Ultrasonography in ocular

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1973.

36, Bito, L.2fluids to

37. Smith, R.barrier.Ophthal.

.: Absorptive transport of prostaglandin' fromblood: A review of recent findings. Exp. Eye

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76: 937, 1973.

if

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the blood aqueousprimates. Am. J.

CORSFAL i-)TEASES

The cornea is composed of three main layers. The outermost consists oftypical stratified epithelium; the middle, central portion or stroma, consistsof a connective tissue, consisting of collagen fibers embedded in mucopoly-sacenarides. The third or inner membrane, called the endothelium, consists ofone laver of flat cells bathed by the aqueous humor. Accumulation of water0,curs in the stroma, while the outer epithelium or the inner endotheliumprovides the metabolic activities necessary to maintain the dehydrated cornea.The site of the transport process, as well as the mechanism by which water isremoved normally from the stroma, are of critical importance for the under-standing of corneal physiology. It is now established that a fluid pump whichis concerned with the maintenance of the hydration of the stroma is located inthe cornea endothelium. The mechanism driving this pump and how this pumpoperates are not understood. Dr. Jorge Fischbarg, Columbia Universityihas,however, recently discovered that the endothelium layer generates a smallelectric potential. Electrical potential across biological membranes areusually associated with active transport ions. This could form the basis forthe water pump which is present in the endothelium. In support of this idea,Dr. Fischbarg has noted that several drugs which inhibit the fluid pump of thecornea also depress electrical potential. The electrical potential developedby the endothelium of the cornea has also been measured by Dr. David M. Maurice,Stanford University2. The magnitude and size of the pump according toDr. Maurice suggests that it could be related to the active transport of ions.

The cornea is the only tissue with high collagen content that is trans-parent. The collagenous material of the stroma is made up of small fibrilswhich occupy about 1/10 of the total thickness of the cornea. The trans-parency of the stroma of the cornea was first explained as an interferenceeffect based on the perfect regularity of the collagen fibrils--the latticetheory. According to this theory, the cornea is transparent because there isa "destructive"interference of the light scattered by the individual fibers.

Recent work by Dr, George B. Benedek has discounted the need for perfectregularity in the collagen fibers in order for the interference mechanism tosucceed and has indicated that the cornea is transparent because the size ofthe fibrils and the spaces between them are of such values that the incidentvisible light is not scattered. The findings of electron microscopy substan-tiate this view, but the effects of fixation and embedment on the regularityof the fibrils are uncertain. Clouding of the cornea was ascribed to a dis-organization of the fibril lattice and Benedek considered it a result of theformation of open spaces in the structure, the so-called lakes.

This question was partially solved by measurement of the angular andspectral distribution of the scattered light by Dr. Frederick A. Bettel eheiat Adelphi University. Dr. Bettelheim found that the light scattered in nor-mal bovine and human cornea is largely due to the birefringence . Theintrinsic birefringence is the result of non-random distribution of collagenfibrils at different loci. However, in the visual path most species haveminimal birefringence areas. The distribution of equal birefringent areas ofthe cornea in different species account largely for the adaptive processesthat the species evolves within its environment. According to Dr. Bertelheim,*Double refraction

19

there is a strong Interplay between the two tasks of the cornea: mechanicalprotection and transparency. Molecular superstructures are built to accomplishboth of these tasks and therefore, the molecular organization of the peripheryand center of the cornea may be different.

Herpes simplex infection of the cornea is one of the most importantocular virus disease. Its importance stems not only from the frequency ofinitial attacks, but also from the likelihood of its recurrence with pro-gressive scarring and morbidity, and also from the fact that this is one ofthe few virus diseases that may in some cases be successfully treated withchemotherapeutic agents. In 1961, Dr. Herbert E. Kaufman at the University ofFlorida showed that 5-iodo-2'-deoxyuridine (IDU) was a therapeutically effectiveantiviral agent in the management of herpetic keratitis. Since then, severalother promising antiviral nucleotides have been synthesized and evaluated forefficacy in control of herpes virus. Among these are: (1) cytosine arabinoside(Ara-C), (2) adenine arabinoside (Ara-A) and (3) trifluorcthymidine.

In 1973, Dr. Kaufman4 reported that trifluorothymidin4 appeared to be themost useful of currently available antivirals for topical treatment. Trifluoro-thymidine is virtually non-allergic, is approximately ten times as potent asIDU and is much more soluble. Most importantly, the rapidity and regularityof ulcer healing with trifluorothymidine is far superior to that of IDU.

Recurrent herpes simplex is one of the major problems in ophthalmologyboth in terms of morbidity, and in terms of visual disability. Present evi-dence indicates that once someone has an initial attack of herpes simplex theodds are approximately 25% of having another attack within two years. If therehas been more than one attack of corneal herpes the odds are approximately43% of having another attack within two years. The pathogenic mechanism of therecurrence so characteristic of herpes simplex infection is unknown. Manyhypotheses have been proposed to explain what appears to be latent herpessimplex virus infection in many experimental animals.

Recently, Dr. Anthony Nesburn, Estelle Doheny Eye Foundation Laboratory",has found that latent herpes simplex virus can be isolated from rabbit tri-geminal ganglia between episodes of recurrent ocular disease, whereas noevidence of herpes simplex virus infection was found in any other tissuetested. The concept that virus might not be latent within the cornea epi-thelium but might come to the cornea from exogenous sources has raised newhope that such recurrence might be preventable by drugs. Dr. Kaufman reportedthat the prevention of recurrent herpes simplex might be possible through theuse of interferon. Interferon inducers such as Poly-IC were studied byDr. Kaufman extensively and found to be very effective in rabbits and otherrodents. In monkeys and in man, however, these interferon inducers seem tohave only a minimal effect which disappears rapidly. Human interferon on theother hand, according to Dr. Kaufman, effectively prevents herpes infectionin monkeys even when given as drops as seldom as twice a day. The findingthat human interferon administered to monkeys protects against herpes isencouraging, and certainly justifies further attempts to define the thera-peutic dose required, and the practicality of administration to man for theprevention of the herpes simplex keratitis.

20

:0 t,:1 s aprlied clinical research, clearly one of the most excitingpmvws it' corneal research Is the therapeutic soft contact lens.

the leA ,v ,,,vering the cornea and protecting it is not new, but the abilityt pr,tect t' t' c.,rnea with an optically clear dressing which. is well toleratedha-; n.t h,k-1 po,i1A0 until the advent of the soft lens. Dr. Kaufmanb devel-oped 10.1 !ir:..t reported the use of the soft contact lens for the treatment ofcorn, 1

Rek'entiv, soft contth't lenses made of hydrophilic gel have proven safeand effective for tlie treatment of bullous keratopathy. Bullous keratopathyis a :ondition in which the inside layer of the cornea, the endothelium, isdama%ted as a result of cataract extraction or because of degeneration causedby aging. It is estimated that of the five hundred thousand cataract extrac-tions done a year, approximately five percent result in bullous keratopathywith swelling and clouding of the cornea, blisters on the surface which canbe excruciatingly painful, and reduce vision. Soft contact lenses create asmooth optical surfilte, improving vision in a significant proportion of thesepatients. In addition, in the vast majority of such patients these lenses,by preventing the blisters from breaking in a painful way, restore comfortto patients who might otherwise be in agony. They will be helpful to patientswho develop bullous keratopathy after cataract extraction, but also to thosewho develop this condition from degenerations due to aging and other causes.

In addition to their general availability for the treatment of bullouskeratopathy, these moist, optically clear, protective lenses have proven use-ful in many other kinds of corneal disease. In some patients with arthritis,and in otherswho are merely aged, normal tear production becomes deficientand the eve dries and becomes scarred. Soft lenses have provided a moistprotective blanket for such eyes. By protecting the surface of the corneaaffected by a wide variety of other conditions, they have permitted cornealulcers to heal. By creating a smooth surface, without rubbing off the surfacetissue after injuries and other conditions which create irregularities in thecorneal surface, they have prevented tissue damage while providing good vision.Good vision is present since their smooth spherical surface becomes theeffective front surface of the eye.

Another exciting development stemming from basic research is the findingthat the collagen fibrils of the cornea can be altered by heat so that thefront of the eye changes its shape without the cornea becoming scarred. Aprocedure called chermokeratoplasty, developed by Dr. Antonio Gassett andassociates at the University of Florida6, has been used on dozens of patientswith keratoconus, a bulging forward of the front of the eye which grosslydistorts vision and can even ultimately rupture. This special heat probeirons the cornea back to its normal shape and permits these patients to func-tion again without the risks and enormous expense of corneal transplantation.This procedure has shown a high degree of effectiveness.

it has been demonstrated that the corneal shape can be changed with heat,and this offers the possibility that, with further research, nearsightednessmay be effectively treated, and other kinds of optical corrections may beperformed in a relatively simple manner.

21

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t.t.s ,si't,r row:. r ;.sat re they are most needed.

,sily Rix tracht.ma laboratories in the world today,rt o o tla, United States; The University of Washington, tne

C.I!'! ,!11.3 tft SAn rrancisco, Harvard. Recently a large tra.-(.:t1A soar. 1.n.t ,!t the Lister Institute in London ceased operations after

tjl,rtuant research in the field.

tr.v!.om.. :s important public health problem for industrial-irtd natis, only :otintTii,s lise the United States have the resources to

rest.ar7h Lia:A1,13o on a sufficient scale. Research aimed at con-:1--11in.s. blinds-is .1s t s tra.lioma can be justified on humanitarian grounds

bet there !s ass.) a long-term economic benefit since developingean elf-sufficient sooner and will need less economic aid

if t'le burden o: caring for those who are economically blind is decreased whilethe nimbvr of rrodective .adults is increased.

A -uballttal numh r of trachoma cases in American Iwians have beenrepnrted. :;ince 1q6r, Dr. Chandler Dawson and associates")", at the University

(7.1:f(4-: can rrancisce have been conducting controlled chemotherapy trialso: trachoma amoag American Indians. The goals of Dr. Dawson are to evaluate

nAe or long acting tetracyclines in the therapy of trachoma, the role oftspe-,,:.,,:f ic-chlamydial antibodies in tears and serum of infected persons andto detn-ilise the effect of lysozyme on extracellular chlamydia. The resultsof tr1Lbo .,tadieb provide guidance for the Indian Health Service (USPHS) andNivat,s :'r' al C,suneil in it of trachoma control programs.

ophthalmelogtsrs are accustomed to identifying signs of fully expresseditihorted d':,ea.2b in the eye, for example, the macular cherry-red spot ofTav-:;aehs cii.esse and cornea verticillata of Fabry's disease. Physical signscYf the carrier state of inborn errors of metabolism are much less frequentlyobserved, and have never been described in some disorders. Accurate, safe,expsditim,,, and inexpensive tests that will identify heterozygous carriersate indfhpensable for genetic counseling.

:leentls., such tests have been developed for Tay-Sachs disease and Fabry'sdisease. !1*. dsard Cotlier, University of Illinois Eye and Ear Infirmary',has sh,wil that the specific enzyme deficiency that characterizes Tay-Sachsdis,ast can he detecLild in human tears. Affected homozygous children showa virtual ahlince of the normal enzyme hexosaminidase-A, whereas asymptomaticceirrie: heteroz7p,w1), individuals have an enzyme level that is intermediateber4oere tat ,f :iisvar;4., and normal Individuals. Similar results have recently!:fn dete:ted tcr ti,ta enzyme deficiency of Fabry's disease by Dr. Cotlier andhis .p4s1, lates-D. Tirtually no activity of the responsible enzyme, alpha-gala,Aosidase-A W34 detected in the tears of affected male patients, whereasirier femAc patleets have intermediate reduction in activity as comparedwith nomal .ndIvids41s.

p.

f t.A)23

REFERENCESCORNEAL DISEASES

Fischbarg, J.: Active and passive properties of the rabbit corneal endo-thelium. Proc. of the International Sumposium of "Transport Processes ofthe Eye", J.A. Zadunaisk, ed. Exp. Eye Res. 15: 615-638, 1973.

Maurice, D.: The potential across the corneal endothelium and its signifi-cance. 19.291n1E1111E2PIOA1. P in Press.

Bettelheim, F.A. and Kaplan, D.: Small angle light scattering of bovinecornea as affected by birefringence. Biochem. Biophys. Acta 313: 268-276, 1973,

4. Kaufman, H.E.: Nular virus disease. Annals of Clinical Res. 5: 189-196, 1973.

5. Nesburn, A.B., Cook, M.B., and Stevens, J.G.: Isolation of herpes simplexvirus from rabbit trigeminal ganglia between episodes of recurrent ocularinfection. Arch. Ophthal., in press.

6. Gasset, A.R., Shaw, E.L., Kaufman, H.E., et al.: Thermokeratoplasty (TKP).2.1...:hatA'S24421A1114 77; 441, 1973.

7. Chandler, J.W., Gebhardt, B.M., and Kaufman, H.E.: Immunologic protectionof rabbit corneal allografts: Preparation and in vitro testing of hetero-logous "blocking" antibody. Invest. Ophthal. 12: 646-653, 1973.

8. Weimar, V.L., and Haraguchi, K.H.: Quantitative analyses of morphologicalchanges in cell growth by graphics computer techniques. A methodologicstudy. Analytical Biochemistry, in press.

9. Hook, R.M., Hook, C.W., and Brown, S.I.: Fibroblast collagenase partialpurification and characterization. Invest. Ophthal. 12: 771-776, 1973.

10. Sugar, A. and WaltmAn, S.R.: Corneal toxicity of collagenase inhibitors.Invest. Ophthal. 12: 770-782, 1973.

11, Berman, Michael B., Barber, J.C., Talamo, R.C., and Langley, C.E.: Cornealulceration and the serum antiproteases. I. arantitrypsin. Invest.

12: 759-770, 1973.

12. Hanna, L., Jawetz, E., Briones, 0., Keshishyan, H., Hoshiwara, 1., Ostler,H.B., and Dawson, C.R.: Antibodies to TRIC agents in tears and serum ofnaturally infected humans. J. Inf. Dis. 127: 95-98, 1973.

13. Hanna, L., Jawetz, E., Briones, 0., Ostler, H.B., Keshishyan, H., Dawson,C.: Antibodies to TRIC agents in matched human tears and sera. J. Immunol.110: 1464-1469, 1973.

14. Singer, J.D., Cotlier, E., and Kammer, R.: Hexosaminidase-A in tearsand saliva for rapid identification of Tay-Sachs' disease and its carriers.Lancet 2: 1116, 1973.

15. Del Monte, M.A., Johnson, D.C., Cotlier, E., et al: Diagnosis of Fabry'sdisease by tear alpha- galactoaidase -A. New England J. Med. 290: 57, 1974.

CATARACT

01 -, Ieu tv!.!var(b. to olueldate the mt=4chanism which rs:Wt in1,:s, tranipiren...v. A prerequisite for this, however, I-- an un-Cer-.t4toin.! :or the quite remarkable transparency of tho normallen . This tr,..1runc... depeds upon the maintenance of a hich dei.roo of order

:.;ie 04 t'he lens, tntil recently, no clear ovidei;,.o:o :osponsible for this order14

At i 4;:. .

. '.

to on t

.7101ecul,r

41,04 t

Mviphi University , has developed ,p,cial4.!.e thods that are useful for providlny. tItnr-

!,.;. And sonea research: transparency and. Actually, the two facets are COMI'lt.:-

r )%s;..t:e.:; provide information from which one cl: !nf,n1,+ 4.; changes that cause cataracts.

D.. , h.14 ft the bovine lens (and later in LL1,) 1, q- only at low angles and was due totu.:4: experiments during which the len:,

v. ...Ale;icies, he found that the structur..,1 -hangesth, guLte different in the cortical and nuclear

one may infer that cortical cataract; .3re of ao' lakes and separation of fiber cells) than thosei,Iclude senile cataracts characterized 1- increasing

;.:-rd, oleeclos in the fiber cell.

: .11,a-rrystallin protein in the lens and the mechanismit Ivczt,d to aPluminoid and subsequently to the opago,-, 71:)tcrial

in zatAr,;,:t. been or interest to many investigators.

Betten0i,-'s- work on the existence and function of phosphopeptidesin the ilzgrc-(lat-i.,r. alpha-crystallin appears to provide a breakthrough inC., ,:.it.Lra:.t the first to prepare an alpha- crystallin which

ev.i,le,we of cryst:illnity by X-ray diffraction. This was lost: by theor,,teln d ring dialysis, although the two phosphopeptides retained an altered

di:4ractioz. pattern. The amorphous protein could then be recombinedwit t ph0,4nhpentide!) to yield the original crystallin complex. The impor-ta of this work derive, from the revelation of a new and unexpected factor

coltrol of organization on the macromolecular level.ntil pvcr x.Ipc'ared, it was tacitly assumed that the alpha-rv!ta!lin car,rivd within it the machinery needed to control its

,o:YiAhration. :,ithough recont 'work by others has indicated a possible roler Alco!,01,, ,:uc;or, and calcium ions in alpha-crystallin aggrgation,

or.' 07 phe-::'honeptidos ./i0W3 the problem from a fresh viewpoint.

!ere are mally ppssiblv mechanisms of lens opacification, including thosechare.; co;,a't], tho Ac.ittering or absorption of light, The theory

-cdtoriri; indicate that aggrvgation of the crystalline protelns inier, can nrcAuce ar the case of cataract.

Rig COrl AVAILABLE27

11r. ludith ledziniak and associates of the Massachusetts Institute of

Technologyl , have provided evidence which implicates calcium in the aggregationof alpha-crvstallin of human lenses. The process is irreversible and producesmolecules of a size which can affect light transmission. The authors equatedcalcium ion and total calcium in their discussions of cataractous and agingtense; and were able to demonstrate an effect of calcium which may have somepertinence to human cataract formation. They also found important evidence ofcompositional changes in the higher molecular weight alpha-crystallin aggregates.During aggregation there is an increase in leucine, which would depresssolubility by making the molecule more hydrophobic, and a decrease in tyrosine,possibly because tyrosine is tied up in covalent linages peculiar to theaggregation process.

Dr. Abraham Spector, Columbia University4

, has continued his studies ofthe effect of aging on protein synthesis and protein structure of the lens andhas attempted to correlate his findings with the development of geriatriccataract. He has demonstrated that the alpha-crystallin macromolecule of thelens increases in size as a function of aging. The only chemical differencenoted between the large macromolecule and normal sized alpha-crystallin isthe presence of 2-31: sugar and a decrease in solubility. This finding sug-gests that the insolubility of the alpha-crystaliin as a function of agingmay be associated with the development of geriatric cataracts.

Disordered carbohydrate metabolism has been long considered a potentialcause of cataract formation. In 1957 it was found that an enzyme,hexokinase,has a key role in lens glycolysis. Since the action of hexokinase on glucoseis the major controlling step in lens energy metabolism, the characterizationof this enzyme is of great importance. A failure of the enzyme activity, forinstance, can produce a significant metabolic stress on the lens. Dr. LeoChvlack, Massachusetts Eye and Ear Infirmary5 , has studied the hexokinaie andfound that it consists of two forms, only one of which is prominent in thehuman lens. The two forms of the enzyme (or isozymes) have a different dis-tribution in the lens and different sensitivity to the glucose concentration.The potential significance of Dr. Chylack's finding is that for the firsttime there appears to be a chance of correlating changes in a major enzymeduring the pre-cataractous stage with the subsequent development of cataract.

The lens contains the highest concentration of protein and glutathioneof any tissue of the body. This unusual characteristic imposes a need forthe continuous supply of amino acid for the synthesis of these compounds.Because of its avascularity the lens must derive most of the constituentsrequired for metabolic energy and synthetic reactions from the surroundingintraocular fluids. Although the mechanism for synthesis of amino acidsappears to be present in the lens, studies from Dr. Venkat Reddy, Oakland

Universitvb , have revealed that transport mechanisms rather than syntheticprocesses play a major role in supplying amino acids to the lens.

Another aspect of lens enzymes and metabolism has been studied in thepast year by Drs. William Rathbun and Katheryn Wicker, University of MinnesotaMedical .4chooli. Dr. Rathbun has successfully demonstrated the activity of the

enzyme '- glutamv1 trahspeptidase :r the ..ens. a re, end-rme it ilatathttne

metabolism. The function of giutathione :n tt,e :eta and the cetails of ttsmetabolism have long been mysterious processes :e:r-se :f extremely highconcentration of glutathione in a:: normal letste 17. MeSt cataracts

without leaving a trace o catabolic protaoti. 7-e tarti:alar mcde of gluta-rhione metabolism is of timely interest in eitN, :f faa.1 taat tt has beenfound recently to be involved in amino a::: trans:r: it th.;. 'tiapay. :f it SO

furwtions in the lens, !)r. Rathbun's finolnLs 77.-=.7.7tInen. since

amino acids are so important In lens metab:::st.

Dr. Kenshi Satoh and associates from tte :ante-ndo Ttkyo,Japan8, have restudied the fluorescence of :he :lama: :e.t.a and :Otatned defini-

tive results. There are two fluorescence tams : tte cm) band isexcited at 290 nit (in the long wave ultraviolet toe :Lae ;:m) band ts

excited at 340 nm. The purple fluorescence is tne ma: :r one in al: prtteinfractions and its intensity is relatively constant vitt aze. The blue fluor-escence increases with age especially it ,tie inscl-:le dr:teia fraction.Although the application of this research t: cetarot:zemesis is net yet appar-ent, there is much earlier work concerned wit:. lens flacrez:ence as a diagnosticor predictive tool. More recent research is to:nctoPed with _tinges in certainamino acids which are correlated. with the format_.- :clear cataractand changes in state of these amino acids (most ..amortaatt:7 rTrpeine and trTpto-phan). An important finding is that both :nest .:1-arescence are also

found in the rabbit lens which is far removed frnm tte ta.maa: lens in manyparameters. Thus it will be possible to carry oa: some experimental studiesin an animal model.

The idea that exposure to sunlight may p:al. r::e i: the fcrmaticn of atype of cataract called brunescent catarec: E.: and tased t'niefly

on clinical evidence concerning the geograpnita: tistriatitn :f :ataracts.Experimental evidence for this concept has been laoei4 am::: the recen: workof Drs. Seymour Zigman, Joanne Schultz, ant 'Tereia :he 7ni7ersity of

Rochester9 who were able to demonstrate tiocnemita: ttaraies in :he lenses ofmice exposed chronically to long wave ealtraviolet Liztd, tae kind tfultraviolet which reaches the lens in vivo. .;-..f:t7 :f ligt: exposure,the mouse lenses began to show alterations it '-action profileincluding particularly an increase in insolutle :".:ar.ges in permea-

bility to amino acids and in their rate of inoortdrati:: int: tr:tein werelikewise shown for dogfish lenses exposet in vitr: wa-re -1.tra7iclet

light for 24 hours.

A search for early changes in the alzents Has been

pursued by Dr. John Kuck, Emory University. "e::ri :n:qrass tt explorein experimental animals the combined effe:: :f ai,..ents such as

trimethylpsoralen and ultraviolet light an :acaratttgenicagents like certain drugs and toxicants ia foot. :rne :f the principal aims of

Dr. Kuck's investigation is to determine if 7."--4,-J-4; are

accompanied by permeability changes wt.:ion :an moo: tracer uptaaebefore visible lesions become evident.

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aqueous humor flow and resistance ti: its estal-lishesintraocular preRgure at a certain :eve: -f th. intra- andextra-ocular vessels. VI supporte,! rnitedStates and in Sweden have been examinzrr t*e thltS

Aq.ueous Production

Dr. Richard Brubaker and Ie., at t. .:-.Indztioni have

examines the filtration coefficient ef tntra-zulir 7Asc..;lature in monkeys.They conclude from their findings t.s.at iffere-es in intraocular pressurebetween individuals, the therareutic :f >..s...-.ti .. agents, and thediagnostically recognized effects :f water crinelaz on intraocular pressureare all mediated by physic - chemical events at the intraocular blood-vesselwall. The role of neural factors it ;rocess has also been demonstratOby Dr. Bernard Becker and associates at was'int:.:-n University in St. Louis"when they found that the instillaticn of -.y-,:,.)-osrotic agents into the third

ventricle of the rabbit brain (near the hvp:::nalame:41 resulted in an eleva-tion of intraocular pressure. This eat-eat:oh :f tntracdular pressure was notobserved in single eyes which underwent :::it nerve traasection but remainedin the contralateral nontransected eve.

Dr. Keith Green and associates at :c.r.ns H:pkins 7.7niversitv,4 have devel-oped a mathematical model which describes aa~ measures the various factorsinvolved in the production of aqueous h-am:r a: the ciliary body: facility,pseudofacility, capillary pressure, active secretion, and the mean pressure indexfor filtration. The model has been employed- in examining the long-held viewthat active secretory processes are primary in ague: .us humor fcrmation and thatpassive, pressure-dependent factors (ultrafiltrati:n. play only a minor role.Their analysis of perfusion data frog the isc:ated rabbit ciliary body, fromrabbits in vivo, and from man indicatec t'-..et the reverse obtains: thatultrafiltration accounts for ap;)roximately of aeuedes production. However,the situation is still not clear, because researchers a4 Uppsala Universityhave presented data to the contrary. Dr. Am4ets Bill' demonstrated thatincreasing the blood flow in the anterior -zvea and ciliary process in monkeysdoes not yield automatic increases in the rate of aquecus humor formation.He concluded that in the monkey, at least, ultrafiltration does not play animportant role in aqueous humor formation.

In many instances, the treatment of glaucoma involves the use of pharma-cological agents which reduce aqueous production. primary among these areadrenergic substances, for example, epinep'trine and carbonic anhydraseinhibitors, for example, acetazolamide (Diamox. klthough the clinical valueof these agents has been recognized for many years, the biochemical mechanismsby which they lower intraocular pressure are ±ust being determined. In manytissues adrenergic agents activate adeny: cvc:ast tc procuce adenosine 3', 5'-monophosphate (cyclic-AMP). It is this -messenger- which actually mediatesthe physiological events which catecholamites initiate. Evidence has beenreported in the past, by Dr. Marvin Sears a: TaIe '_"niversitv, chat cyclic-AMPmay play a central role in mediating the action of catechclamines on aqueoushumor dynamics. specifically, adrenergic :tents, ,./-t:ch decrease intraocularpressure when administered topically to the rabtit e7e, also increase theconcentration of cic-AMP in the aqueous h r. In addition, intracameral

ye-"10!, of towta, t;14 thtraolar pre!ssure. Ferther researehalong the..1_, !Ito's %writ's.: !.anpham and hts assooiatee at Johns Hopkins

epicar. to (.!e;nollstrato this tht, relsitionhips betwoen epinephrine,cvdti-.VT, pre',-;are are predominantly dependent on the alpha-agonietie of epiaophrinehm.

It has been A'mnlsfr..fed by Dr. Monte Holland and associates at Tulanel'nv...rsItv that at.cous pfoduvtion is decreased and outflow facility isircreased foll.wing chemical :Iympathecfomy with h-hydroxydopamine (6-HD)applied topice!ly to the eve of animals. Most importantly, they found thatthe henefi:_fal pressure-lowering effects of epinephrine can be enhancedfollowing ttis ehemical eympathcctomy. It has more recently been demonstratedby Dr. Albert Zeller at Northwestern University9 that monoamine oxidaseinhibitors have smiler potentlatlag effects on the action of eainephrine onthe rate of aqueous production and on intraocular pressure in rabbits.Thee, findings suggested that patients with glaucoma might be aided by combin-ing 6-H:1 with topical epinephrine therapy. Dr. Monte Holland and hisaseocia:es conducted a series of clinical studies using this pharmacologicalprocedure on patients suffering from glaucomas that did not respond well tostendard pharmaeologieal treatment. In one study10 they examined epinephrinedoee-reeponee relationships and demonstrated that the chemical sympathectomywas effective in lowering intraocular pressure over a 5-decade range ofepinephrine concentrations. The results of a second studyll showed that thesupersensitizine effects of 6-HD obtain with a number of alpha- and beta-adrenergle amines without systemic side effects. However, epinephrine wasfound to be the most desirable agent because it was effective for a longerduration. In reviewing their experiences over two years with 92 patients(128 eyee), Holland and his asseclates12 concluded that 6-HD chemical sympa-tbectomy is an adjunct for therapy which can provide a patient who hasuncontrollably glaucoma a medical alternative to surgery.

Researchers at the University of Alabama, Washington University, andUppsala University have been examining the role of steroids in glaucoma. It

has recently been reconfirmed by Dr. Ralph Levene and his associates13 thatsteroid glaucoma :an be consistently produced in rabbits by topical treatmentwith a 17 dexamethasone solution over a period of a few weeks. Examinationof steroid of in humans provided even more exciting results14 when itwas found that 85 patients with primary open-angle glaucoma had significantlyhigher plasma cortisol levels following orally administered dexamethasonethan did 77 normals, in nddition, the data on plasma cortisol level indicateda possible trend with age for the glaucoma patients but not for the normals.It has also been demonstrated by Dr. Bernard Becker and his associates atWashington University that patients with primary open-angle Oaucoma are moresensitive to steroids in both ocular and non-ocular systems 1,5,16. Clearly asystemic endocrine marker provides the potential for differentiating indivi-duals with glaucoma.

Differential responding to steroids might also provide a methodology forioentifying in,iividuals who tl,av be predisposed to elevated intraocular pressureand glaucomel"".1. Ur. Becker and hie associates have defined three groupsof normal individuals in terns of their response to adreno-cortical steroids--igh, moderate. and low responders. This response can be blocked to

)

different degrees in each of the three groups by pre-treatment with acortisol antagonist. It was found that "blocking" occurs earlier in glaucomapatients and in high-cortisol responders than in subjects who are low ormoderate responders. These data are interpreted as providing further evidencefor the theory that genetic factors relate the response to steroids andK laucoma.

Research at Johns Hopkins University, Washington University, and theMedical College of Georgia has demonstrated that intraocular pressure canalso be affected by the administration of a number of autacoids (hormones)including prostaglandins (PG). The prostaglandins are a group of fatty acidswhich are known to antagonize the lypolysis induced by adrenergic agents.Their biochemical effects are exerted on adenyl. cyclase (the target of epine-phrine and a number of hormones) and on an enzyme involved in the productionof cyclic-AMP.

Dr. Keith Green at Johns Hopkins19, employing the isolated rabbitciliary-body preparation, presented data to indicate that PG enhances thepermeability of the ciliary membrane which in turn results in elevatedintraocular pressure. The primary site of action appears to be on thefiltrative channels of the ciliary body. Dr. Tzu Chiang at the MedicalCollege of Georgia2° also demonstrated an increase in intraocular pressurewith PG's in anesthetized rabbits and, in addition, showed that other auta-coids, in contrast, caused a lowering of pressure. He also reported thatplasma PG-El levels in patients with open-angle or narrow-angle glaucoma werefound to be higher than in non-glaucoma patients.

The ocular hypertension responses to some PG's, can be antagonized by anumber of agents. Dr. Chiang demonstrated this to be the case in rabbitsthat were pretreated with either epinephrine or prop ,23sterone21, --. Dr.

Becker and his associates at Washington University24 25, 26, 27 have demonstrated

22

that imidazole (a histaminic substance which enhances the reduction of cyclic-AMP) and indomethacin (an analgesic) were also effective in reducing theocular pressure induced by PG's.

Dr. Keith Green28 has also examined the effects of A-tetrahydrocannibinol(THC, a marihuana derivative) on aqueous humor production. THC was found todecrease the secretion and increase the filtration rate in the isolatedrabbit ciliary body preparation. When live rabbits were injected with THC,intraocular pressure was found to decrease and both total outflow facility andaqueous protein level were found to increase. Dr. Green reports that the dataavailable to date suggest that the response to THC involves vasoconstrictionin the ocular blood vessels yielding a decrease in blood pressure, and thus adecrease in formation of aqueous at the ciliary body. The vasoconstrictioncaused by THC may also reduce intraocular pressure by increasing aqueous

outflow.

Asueous Outflow

Mechanisms involving the structures in the angle of the anterior chamber- -

the trabecular meshwork and Schlemm's canal--are involved in the coatrol ofaqueous humor outflow from the eye to the venous circulation. Research with

t4if;36

monkeys by Dr. Anders hill 4nd associates at Uppsala has recently show thatan initial ellect 01 constant artificial intraocular pressure elevation is aprogressive int-Tease in out facility-9. However, this enhancement ofoutflow is only short-lived; outflow facility decreases after about two hoursof maintained pressure elevation. Scanning and transmission electron micro-scopy indicate that the initial facility of outflow is due to damage ("punch-ing hole-t") in the endothelial walls of the meshwork and of Schlemm's canal.By .4 hours, the defects area occluded by endothelial cells, blocking outflow.Along similar l inen, Dr. Morton Grant and associates 34U at the MassachusettsEye and Ear infirmary have demonstrated that the rate of aqueous humor outflowthrough the trabecular meshwork and Schlemm's canal can be increased in

enucleated monkey eyes by mechanically pressing the lens posteriorly. Thiseffect was graded, reversible, and repeatable as long as the tissues in theangle of the anterior chamber were not damaged.

Employing the technique of suction gonioscopy, Dr. Bernard Becker andhis associates at Washington University have examined the phenomenon of bloodreflux into Schlemm's canal31. They found that the frequency of occurrenceof blood reflux in patients is correlated with intraocular pressure level,facility of outflow, and corticosteriod responsiveness. An additional prelimi-nary finding requiring further investigation was that the frequency of bloodreflux in high cortiscosteriod responders was similar to that in glaucomapatients.

Efforts to improve the adequacy of the outflow channels make use of drugsor surgical procedures. The latter are usually reserved until all attemptsat pharmacological maintenance of intraocular pressure have failed. Para-sympathetic (cholinergic) agents, such as pilocarpine and anticholinesterases,are the medications primarily employed. However, employing a techniquedeveloped for the determination of small amounts of epinephrine in thepresence of a large excess of other catecholamines32, Dr. Ernst Barany andhis associates at Uppsala presented evidence to indicate that epinephrine(an adrenergic) also increases outflow facility.

Advances in therapy with pilocarpine have been made using appliancesthat ere easily placed directly on the eye. Dr. Bernard Becker and hisassociates have employed soft contact lenses, presoaked in pilocarpine. In

a study with monkeys33 they measured the amount of tritium-labelled pilocar-pine entering the aqueous humor. It was found that there were higher andmoreprolongeri concentrations of pilocarpine in the aqueous with this systemthan with pilocarpine eye drops. In a second study34 soft-contact lensdelivery of pilocarpine was examined with primary open-angle glaucoma patientswho were otherwise uncontrolled on maximum medicinal therapy. It was reportedthat approximately half of these patients benefited from this new therapeutictechnique.

The soft-contact lens technique is not without caveats. Apparently,

larger doses of medication are pulsed into the eye in a relatively shorterperiod of time than with conventional eye-drop therapy. This raises thepossibility for the occurrence of toxic effects. Another device which appearsto be enjoying more stable effects employs a thin plastic wafer placed underthe lower eyelid which allows a constant release of the appropriate dosage.

`.31

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t.11 inete.!sing detailed itiew:vAL:e o: t. mor;,aoligy arz: an.:Jomy oi the

drainage system, investigators are conce,ned deve:nrtient )1 new

surgical tochniquos An example .1.1 .1 a pr,ocLoul H' fowuj at theMassa%Ithsetts 7:0 inAl Eat Dr. N1)rt-1 Ciant hiA associ-ates have attempted to devise a method pit luantit.tive peyttp,iou of excisedsegments of the atvle cat the thee experimentsprovide evidence thar. through chi, ,,trecure is -ery sensitive to slightphysical distorionr.3. By perfusion of entieleated,eyes, this research grouphas discovered e..veral taetors in mforoslirgery of Schlemmr' %anal that havenot previously i'ven reconized3i. Specifically: (1) in the current surgicalprocedure of probe trahe,:ulotumy 3b extet7po there is a strong iendency for

ehannel opened by the surgery to close again, apparently as tho disruptedtrabecular meshwork tissues go hack into place; and (2) passing the probeinside Schlemm's canal damages the outer wall of the canal, causing changeswhich tend to hinder aqueous outflow through ' :he collector channels. In

addition, in comparing a number of traheeulotomy techniques in enucleatedeyes, these investigators find that internal traheculotom, yields a greaterincrease in aqueous outflow than does trabeculotomy ab externo and suggest,therefore, that it is more promising for clinical uw.

Dr. 1:rant has also. examined the feasibility of cyciocryotherapy intreating a number ut typos or advanced, inadequately controlled glaucoma38.At the end or f,,llow-op periods of approximately one year, the procedure wasfound to have maintained a reduction in intraocOar pressure in more than onehalf of the ewes. Complications did occur In 16 percent of the cases, withsignificant decreases in vision in 5 percent of the patientn.

Considerable research is being conducted in a number of centers to examinevarious types of laser sergery in the treatment of glaucoma. It is hoped thatlaser energy, and the conromitant benefits of laser surgery in general, can beemployed in effectively decreasing intraocular pressure.

NEURE 11.0G I CAI. AND VAS CI'LAR EFFECTS

One of the most puzzling anpects of glaucoma is how elevated pressurewithin the eye causes the destruction of the optic nerve. For any given levelof pressure, some patients have mare resistant optic nerves than others.There is considerable evidence that optic nerve destruction and the visual-field loss of glaucoma may be caused by changes in the blood circulation of

the eye. Thus, it is important ro evaluate tne eye's circulatory system aswell as the intrao(ular pressure in studying glaucoma.

Evidence for reeitice4 vascul.irity in glaucoma ce)mns from research at

Uppsala University and at Geotge Washington University. Dr. Anders Bill andhis associaten have shown tO4t blood tlow Otroug'4 the optic nerve head can be

improved by reduoing Intt'aocular pressure and roseAbly also by raising blood

pressure 19. In addit ion, they have alie shown4441 that topical administra-tion of pilooarpine and twos t igmine in monkeys results in an increase in

blood flow through the anterior uvca. Dr. Mansour Armaly42 employed heatonductanee as a measure of blood-flow rate in cats and monkeys. lie reports

that remarkable changes occur in both the choroid and optic-nerve circulation

*s intraocular pressure is manipulated.

Recent studies by Dr. Douglas Anderson at the Bascom Palmer Institute at

the University of Miami have been concerned with the acute effects of intra-

ocular pressure on the optic nerve. intraocular pressure was elevated by

means of a manometric system through a small needle inserted into the anterior

chamber in the eyes of monkeys. Various parameters of optic disc function

were studied. In one experiment", it was determined that the resultant

isehemia produced graded effects on the optic disc which were correlated with

the induced intra-ocular-pressure level. However, these were also accompanied

by graded effects on the outer retina. Even though the disc and the outer

retina are served by the same blood supply, the latter effect is not a common

observation in glaucomatous damage. Thus, these data suggest that non-ischemicpressure-induced effects may be involved in the neuropathology associated with

glaucoma. in a second experiment44, ischemic changes in the optic nerve were

studied by recording optic tract responses to flashes of light directed into

the eye. It was found that elevation of intraocular pressure did not diminish

nerve fiber conduction until the intraocular pressure was elevated to diastolic

blood pressure. These data suggest that when intraocular pressure is elevated,

the nutrition to the disc can be adequate for normal metabolic functions, and

that the disc is not starved until intraocular pressure is considerably eleva-

ted.

Dr. J. Terry Ernest at the University of Chicago45 describes a double-

cannula technique for measuring, in cats, the tension of the optic disc while

manipulating the perfusion pressure. His studies indicate" that the bloodcirculation at C'e optic disc autoregulates; that is, it can adapt to short-

term decreases i perfusion pressure. This finding is supported by a study

involving fluorescein angiography of the disc47. Dr. Ernest suggests the

possibility that high intraocular pressure may contribute to the breakdown in

the autoregulatory mechanism of the optic disc circulation.

A group of studies by Dr. Bernard Becker and his associates in St. Louis,

48-49 has been directed at examining drugs which may protect the retina and

optic nerve from damage despite the presence of anoxia due to reduced blood

circulation. These studies stem from the suggestive results of an earlier

pilot study with humans in which diphenylhydantoin (DPH, an anticonvulsive)

appeared to protect 1/3 of the glaucoma patients treated from field loss.

Basically, employing an in vitro rabbit retina preparation, it was found that

one effect of hypoxia was a reduction in the amplitude of the electroretino-

gram. With the administration of DPH, this reduction in amplitude was inhibi-

ted. Further studies are being conducted to examine the possible therapeutic

role :of DPH in greater detail.

Dr. Morton Grant at the Massachusetts Eye and Ear Infirmary50 reports an

interesting condition in which obstruction of retinal blood flow results in

ti`!39

elevation of intraocular pressure. He has identified and documented, in sevenpatients, a new clinical entity which involves a reversible unilateral shallow-ing of the anterior chamber, with angle closure, resulting from occlusion ofthe central retinal vein.

IMPROVING DIAGNOSIS

The basic tools employed in the diagnosis and measurement of glaucomatouspathology are gonioscopy, tonometry and tonography, perimetry, ophthalmoscopy,

and angiography. Much current research is being directed at improving thesemethodologies.

Schiotz tonometry is employed to ascertain intraocular pressure bymeasuring the depth of indentation of the cornea when a standard weight isapplied. In contrast, Goldman applanation tonometry measures intraocularpressure as the force required to flatten a standard area of cornea. Schiotztonometry is usually performed with the patient lying down, and applanationtonometry with patient sitting. Dr. Douglas Anderson and Dr. Morton Grant51have compared the two techniques in 906 patients and report the following:(1) Pressure measurements with both techniques are affected by the position ofthe patient; (2) pressure changes with position were greater for patients undermedication than for those not under treatment; and most importantly, (3)Schiotz measurements are not as accurate as applanation measurements and canbe relied on for only rough estimates. In this regard, Dr. W.K. McEwen52 hasdescribed an information-processing methodology that can be employed to improvesignificantly currently used data reduction techniques for Schiotz tonography.However, there are other problems with Schiotz tonometry and most currentefforts (for example those by Dr. Richard Brubaker at the Mayo Foundation andDr. Irvin Pollack at Johns Hopkins University) are being directed at improvingapplanation techniques53-54.

Because one of the first signs of neural damage is excavation and cuppingof the optic disc, evaluation of the disc is most important in the diagnosisand treatment of glaucoma. For example, Dr. Bernard Becker and his associates

at Washington University55 have recently measured the vertical-horizontal ratioof the optic cup in glaucomatous and normal eyes. Vertical elongation was

observed in 33 percent of the glaucoma patients, but in only 4 percent of the

normals. Investigations directed at improving the evaluation of the optic

disc are being conducted with NEI support at a number of research centers.

Among these are studies involving mathematical analyses, computer mapping,

and laser and contour angiography of the optic nerve head.

41)

REFERENCESGLAUCOMA

1. Brubaker, R.F., and Worthen, D.M.: The filtration coefficient of theintraocular vasculature as measured by low-pressure profusion in a primateeve. Invest. Qphthal. 12: 321, 1973.

2. Krupin, T., Pidos, S.M., and Becker, B.: Alteration of intraocular pressureafter third ventricle injection of osmotic agents. Amer. J. Ophthal.in press.

3, Green, K., and Pederson, J.E.: Aqueous humor formation. Exp. Eye Res.16: 273-286, 1973.

4. Pederson, J.E., and Green, K.: Aqueous humor dynamics; A mathematicalapproach to measurement of facility, pseudofacility, capillary pressureactive secretion and Xc. Exp. Eye Res. 15: 265-276, 1973.

5. Pederson, J.E., and Green, K.: Aqueous humor dynamics: Experimentalstudies. Exp. Eve Res. 15: 277-297, 1973.

6. Bill, A.: The role of ciliary blood flow and ultrafiltration IL aqueoushumor formation. Exp. Eye Res. 16: 287, 1973.

7. Langham, M.E., Simjee, A., and Josephs, S.: The alpha and beta adrenergicresponses to epinephrine in the rabbit eye. Exp. Eye Res. 15: 1, 1973.

. Radius, R., and Langham, M.E.: Cyclic AMP and the ocular responses tonorepinephrine. Exp. Eye Res. 17: 219-229, 1973.

9. Zeller, E.A. and Hsu, M.: On the mechanism of inhibition of monoamineoxidase. Life Sciences, in press.

10. Holland, M.G. and Wei, C.: Epinephrine dose-response characteristics ofglaucomatous human eyes following chemical sympathectomy with 6-hydroxydopamine. Annals Ophthal., 1973.

11. Holland, M.G. an Wei, C.: Chemical sympathectomy in glaucoma therapy.An investigation cf alpha and beta adrenergic supersensitivity. AnnalsOphthal., 1973.

12. Holland, M.G., Wei, C., and Gupta, S.: Review and evaluations of 6-hydroxydopamine (6-HD) chemical sympathectomy for the treatment of glaucoma.Annals Ophthal., 1973.

13. Levene, R., Rothberger, M., and Rosenberg, S.: Steroid glaucoma in therabbit. Presented at Atlantic Section, ARVO, November 1973.

14. Rosenberg, S., and Levene, R.: Suppression of plasma cortisol in normaland glaucomatous patients. Presented at ARVO Meeting, May 1973, Sarasota,Florida.

15. Zink, H.A., Palmberg, P.F., and Bigger, J.F.: Inc.reose sensitivity totheophylline associated with primary open-angle glaucoma. Invest. ahthal.12: 603, 1973.

16. Bigger, J.F., Zink, H.A., Palmberg, P.F., and necker, B.: An in vitroevaluation of tetrahydrotriamcinolone. Invest. 0.2thal., in press,

17. Becker, B., Podos, S.M., Asseff, C., and Cooper, D.C.: Plasma cortisolsuppression and glaucoma. Amer. J. Ophthal., in press.

18. Phelps, C.D., and Podos, S.M.: Genetics of glaucoma genetic aspectsof ophthalmology, in International Ophthalmology Clinics, M.F. Goldberg,ed., Little Brown, in press.

19. Green, K.: Permeability properties of the ciliary epithelium in responseto prostaglandins. Invest. Ophthal. 12; 752-758, 1973.

20. Chiang, T.S.: Effects of intravenous infusions of histamine, 5-hydro-xytryptamine, bradykinin and prostaglandins on intraocular pressure.Arch. Int. Pharmacodvn. 207: 201-208, 1974.

. Chiang, T.S.: Effects of intravenous infusion of autacoids on intraocularpressure and aqueous humor protein concentration. Pharmacologist 15:209, 1973.

22. Chiang, T.S.: Effects of epinephrine and progesterone on the ocularhypertensive response to intravenous infusion of prostaglandin A2.Prostaglandins 4: 415-419, 1973.

23. Chiang, T.S., and Thomas, R.P.: Effects of progesterone on the ocularhypertensive response to prostaglandin. Europ. J. Pharmacol. 22; 304-310,1973.

:14. Zink, H.A., Podos, S.M., and Becker, B.: Inhibition by imidazole of theincrease in intraocular pressure induced by topical prostaglandin E.Nature New Biology 245: 21, 1973.

25. Podos, S.M., Becker, B., and Kass, M.A.: Indomethacin blocks arachidonicacid-induced elevation of intraocular pressure. Prostaglandins 3; 7, 1973.

26. Podos, S.M., Becker, B., and Kass, M.A.: Prostaglandin synthesisand intraocular pressure. Invest. Ophthal. 12: 426, 1973.

27. Jaffe, B.M., Podos, S.M., and Becker, B.: Indomethacin blocks arachadonicacid-associated elevation of aqueous humor prostaglandin. Invest. Ophthal.12: 621, 1973.

. Green, K., and Pederson, J.E.: Effect of A-cetrahydrocannabinol onaqueous dynamics and ciliary body permeability in the rabbit. Exp. EveRes. 15: 499-507, 1 73.

29. 'vedberg, B.! Effects f artifiial fntraocular pressure elevation onchamber anvie stc,:ctures. Abstract. Ex2. Eye Res., in press.

30. VanBuskirk, E.X. and :rant, W.M.: Lens depression and aqueous outflow inenocleated primate eyes. Arnez:1101., in press.

31. Phelps, C.L. , Asseff, C.F., Weisman, R.L., Podos, S.M., and Becker, B.:nood ref lux into Schlemm's canal. Arch. Ophthal., in press.

32. Rentzhog, L.: Double isotope dilution derivative technique for measurementof catecholamines. Acta Physiol. Scan., Suppi. 377, 1972.

33. Asseff, C.F., t:eisman, R.L., Podos, S.M., and Becker, B.: Ocular penetra-tion of pilocarpine in primates. Amer. J. Ophthal. 75: 212, 1973.

34. Podos, S.M., Becker, B., and Hartstein, J.: Pilocarpine delivery withsoft contact lenses, Soft Contact Lens Symp., Ch, 28, 1972.

35. Armaly, M.F., and Rao, K.R.: The effect of pilocarpine Ocusert withdifferent release rates on ocular pressure. Invest. Ophthal. 12: 491-496,1973.

36. Johnstone, M.A. and Grant, W.M.: Pressure dependent changes in structuresof the aqueous outflow system of human and monkey eyes. Amer. J. Ophthal.75(3): 365-383, 1973.

37. Johnstone, M.A. and. Grant, W.M.: Effects of microsurgery of Schlemm'scanal on the human aqueous outflow system. Amer. J. Ophthal., in press.

38. Bellows, A.R., and Grant, W.M.: Cyclocryotherapy in advanced inadequatelycontrolled glaucoma. Amer. J. Ophthal. 75(4): 679-684, 1973.

39. Alm, A., and Bill, A.: Ocular and optic nerve blood flow at normal andincreased intraocular pressures in monkeys (Macaca irus); a study withradioactively labelled microspheres including flow determinations inbrain and some other tissues. Exp. Eve Res. 15: 31, 1973.

40. Alm, A., Bill, A., and Young, F.A.: The effects of pilocarpine and neo-stigmine on the blood flow through the anterior uvea in monkeys. A studywith radioactively labelled microspheres. Exp. Eye Res. 15: 15, 1973.

41. Alm, A., and Bill, A.: The effect of stimulation of the sympathetic chainon retinal oxygen tension and uveal, retinal and cerebral blood flowin cats. Acta Physiol. Scand. 88: 84, 1973.

42. Armaly, M.F.: The effect of ocular pressure on blood flow rate in thechoroid and optic nerve of the cat and monkey. Paper presented at ARVOMay 1973, Sarasota, Florida.

43

43. Anderson, D.R. and Davis, E.B.: Sensitiviti es. cipressure-induced ischemia. Arch. 0phnha1., in

44. Gerstle, Ca., Anderson, D.R., and Harrasaki, 17.1.;ERG and optic nerve conduction of visual imp,.;lce. 911::

121-124, 1973,

45. Ernest, J.T.: in vivo measurement of optic dist.20111th, in press.

46. Ernest. J.T.: Autoregulation of the optic disk nrrienOphthal., in press.

47. Ernest, J.T., and Archer, D.: Fluorescein anti:17-ra.tt: T :f

Am. J. Ophthal. 75: 973, 1973.

48. Honda, Y., Podos, S.M., and Becker, B. The effg-::on the electroretinogram of rabbits. Effect.' :f

Ophthal. 12: 567, 1973.

49. Honda, Y., Podos, S.M., and Becker, B.: Tne effent :fon the electroretinogram of rabbits. Il. Effe:ns :f t77:,:x=a ancInvest. Ophthal. 12: 573, 1973.

50. Grant, W.M.: Shallowing of the anterior cot: cfthe central retinal vein. Amer. J. Ophnhal. :4-3.

51. Anderson, D.R. and Grant, W.M.: The influence :f i7.t.7accu:ar

pressure. Invest. Ophthal.. 12(3): 204-2:2.

52. McEwen, W.K.: An advanced method of infcrmaticmSchiotz tonograms. Invest. Ophthal., in :7,res.

53. Dunn, J.S., and Brubaker, R.F.: Perkins applunstim t:I:A=ener.and laboratory evaluation. Arch. Ophtha.l. F9:

54. Viernstein, L.J., and Pollack, 1.P.: Cc-nsta.n: ?..-:-::4=ation tom-

graphy. Paper read at ARVO, March 1973, Saras:na,

55. Weisman, R.I.., Asseff, C.F., Phelps, C.D., .F0f. E. . Secker. 3.:Vertical elongation of the optic cup in glu::ma.. 77L-ma. )L.;n7. as.Ophthal. Oto., in press.

44

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and nonspecific changes occer in sebtellelar ereteizatien. These observationsin the mouse are expected to tell is meth ,ebeet tee eathtlogy of human extra -ocular muscle dystrophy.

Since all oculomotor neurons participate stmply produce a requiredmuscle tension without regard to the type tef move one, the sepranuclear organi-zation must be arranged to produce the observe: water neuron behavior. Severallines of research have shown that each of types .of eye movement (saccadic,pursuit, convergence) are governed by separate nterolegical substrates at highercentral nervous system levels. Severa :a.ttratorles have reported data indi-cating that inputs from these separate systems are integrated into a commonneural output at or before the level of cceleactor neurons. The question iswhether this Integration takes place at the neter neuron itself or at somesupranuclear interneuronal level. Dr. Ecwart Keller at the University ofCalifornia, Berkeley, has studied the behavior of both the abducens and oculo-motor nucleus motor neurons during accomnocateve ccevergeeee eye movements inthe alert monkey7. The observed behavior was eeneered teeth that of the sameneurons during versional (parallel or cc: agate; eye ecvemeets. The behaviorwas found to be identical, indicating that ceeleecter eatt dishcarge is deter-mined by fixation angle without regard to the tee* of movement used to reachthat angle. An analysis of the unit firing rate alsc suggested that the sepa-rate inputs controlling vergence (anttparallt: or disuective) and version eyemovements are probably combined at some sepraneclear level before the motorneuron. The present study of motor neuree respcese during vergence adds quan-titative detail to our understanding cf the final level cf the cculomotor system.The results, showing that inputs from vergeeee aed version systems are integratedat some neural level before the motor neeroe, were net entirely anticipatedsince various studies have demonstrated the tedependeece of disjunctive andconjugate eye movement. The vergence and version teetrel signals seemed likelycandidates for summation at the oculomctcr neerees.

Dr. Alexander Skavenski and Dr. David Rebteace en studies conducted atthe Johns Hopkins University and School of Mediciree have investigated the roleof the abducens neurons in the vestibelo-eeelar reflexe. The eye position inspace is the mechanical difference between the head pcsitien in space and theeye position in the head. Head motion could disturb visioe if compensatoryeye movements were not generated by the bran. dead rctations produced as ananimal moves in its environment lead tc cempensatcre eye movements which pre-vent images from sweeping across the retina toe gete'ely. To insure that eyeposition in the head is just equal and opposite to the head pcsition in space,the brain must be able to sense head position. The reseIting response is knownas the vestibulo-ocular reflex. These itvestigaters studied the motion of theeye of an experimental monkey in the light and in the dark when the head of theanimal was rotated in a measurable fashion. Semeltaeeoesly, they measured thedischarge rate of the abducens motor neuron. The relationship between dischargerate and eye position did not change when eye pcsitice was determined by eithervisual or vestibular stimulation. Further, no difference was found in therelationship between discharge rate modelatioe and eye velocity when the latterwas induced by eiaual or vestibular stemulatiee. These results suggest thatmotor neuron behavior is determined only by eye pesitton and velocity and isnot determined by the type (saccade, pursuit, vergence, or vestibular) of eyemovement that created the position or velocity. r=anges of eye position in the

head were found to eeual and opposite to changes of the head position inspace over the ranee cf about .01 or 1.5 Hz during sinusoidal rotations of thehead without vision. The investigators have suggested that there exists in thebrain stet a neural integrator between the vestibular and oculomotor nucleiwhich converts head velocity signals to eye position signals. The phase shiftobserved in these experiments between the head velocity and the dischargepatterns of motrneurons can be anticipated only if such a neural integrator is

postulated in the path of the vestibulo-ocular reflex.

Drs. Albert Fuchs and U. Buttner of the University of Washington have beeninterested in the modulation of visual information processing by eye movements.During eve movements the perceived visual world seems to be stationary, whereasa moving object presented to a stationary eye causes the perception of movement.in both cases, a movement of retinal image occurs. Previous physiologicalstudies in other laboratories have suggested that the dorsal nucleus of thelateral geniculate is the earliest station along the visual pathway where visualand eve movement interaction occurs. The investigators at the University ofWashington have now studied the discharge patterns of single cells in thelateral geniculate nucleus and the pregeniculate nucleus of the alert monkey9.These discharge patterns were analyzed during spontaneous saccadic eye movementsand unit activity was recorded either with the monkey in the dark or subjectedto short flashes of light. Eye movements were carefully recorded and comparedto the discharge patterns of the recorded cells. Nearly all of the unitsisolated in the lateral geniculate nucleus exhibited no change in activity witha saccadic eye movement in the dark or during light flash stimulation, and the

investigi7.:ors have concluded that no visual and oculomotor interaction occursat the lateral geniculate nucleus. Of the 55 neurons isolated dorsal to thelateral geniculate nucleus and believed to lie largely in pregeniculate, 39exhibited a clear change of activity with all saccades in the dark. These unitseither were usually silent and exhibited a burst of activity with a saccade ordischarged at spontaneous rates and exhibited a pronounced inhibition withsaccades. However, the activation or suppression of activity began an averageof 80 milliseconds after the saccade. Of the 39 units, 26 also responded insome manner to the flash stimulus. These results indicate that the pregenicu-late nucleus receives both an oculomotor and a visual input. However, thesaccade-related unit discharges appear to occur too long after the movementeither to participate in saccadic suppression or to aid in differentiating thosemovements of retinal image due to eye movement from those due to movement of the

visual world, per se.

Drs. Samuel Ron and David Robinson of Johns Hopkins University have con-ducted a quantitative investigation of the direction and type of eye movementsevoked by stimklation of each subdivision of the entire cerebellum in the alertintact monkevu. Each subdivision was systematically explored and eye movementand stimulus current were accurately measured and recorded. Three regions ofthe cerebellum were found to participate in oculomotor control. Within each

region the type of eye movement was the same but the direction varied withstimulus location so that all eye movement directions were represented in each

region. Saccadic movement was found to be evoked from the vermis, lobes V-VII.

The directions of the saccades varied with electrode placement. Saccade ampli-

tude was independent of pulse frequency, pulse width or pulse length, but,

above threshold, increased with increasing stimulus current. Another regica

49

involved wos tl., ru an..! 1`N rm .oich

14Au...74tiOS tn those Hi vo!. IV! ).,* I I ' :;mt.oth noverents ')di' fit. vel-ott 4, n ,scn nn in

Smooth MOVVIEc 4: '411. t *% *-t 1 MCA tl'-7;11 \same dtreLti.,n. hi third regton , !..he ilnenlnn,

nodulus, ind nvn.o. %vstonmus nvoheufror this reglnn. AII th r stinn.,111 ;no i:Lirehe! 4,nn. w, (orsichredunreare:' -0 r1-.e nculomotor w...stnp, nnit: 4, V kl k. 011 b 4,4

a stimnlns ;:nrrnt yt 1 nilliamn. nvknLia a ioirlvcoherent pin7ure rhe types ovc r rilAt Ary tt,6 with thevarious cerebella,: divisions. 'Ow ..n..,-,tnntnrs hope L'iar rf!SLCItS will

clear true way !or 1.1r L.omplex Innt will pronide a net,: understand-ing of thn role c. cer0,ellum in thc ..nn,troi et eye movomonts.

In studs Lnriductei at the. ':niver,itv of Califoinia, Berkt-loy, Drs.Gerald Wesrneixer and Sidney Nnir invi.,sti,:niten: the role, of the brain stem andcerebellum in the control rf monnli4nt. Tney found"- ti at s!_imulation ofcertain rogiuns c' the brain stem of a: rt. ,,,Ionkeys r.sused nn inhibition of

sa.:.cadie eye mnvements. For the dnrat1:n of the stimulatinn. Nacnadle MOVO-ments were carried. out, rogardlens of !_ne v: Such. stimulus. Hnwevcr, 1".0 Inter-

fereni'e with smooth pursuit eve mvvenent ot :onvergettce eye mnvoments wasevident, nor did acoommodatton or vestibular movements appear to be affeLted.The6e reults, as hAve others, suggest that saccadic eve movements are differ-ent from ther .lasses of eye movoment. 'ale function of the cerebellum in thecontrol :It eye movement was studied by Drs. Wertheimer and Blair in cerebellec-tomized nonkeys. These animals showed an inability to maintain an eccentricgaze. A sacade into the peripheral NE:J.,: was always followed by h drift backtoward ontin: Two other abnormalities of eye movement control wereappnren:! t*.e a,,ie,le of 411 smooth pursuit movements and, during the firstweek after ,,:rehellectomy, absemle of convergence mvements. This latterdefect ws portion.. nvercome at longer postoperative tines. However, thesemonkeys nevnr fu.ly recovered the ability to maintain a converged position ofthe eves. Otiler types of eve movement did not appe4r to be afiected: saccadicmovetner, t, 1s perfectly normal, and no abnormality in nnv phase of the vestibulo-ocular response was observed. These investigators have suggented that thereis something special about straight ahead gaze in oculomotor function sinceafter ':.erelsollectomy this is maintained when gaze in no other direction can be.The motor nenrons from oculomotor nuclei recorded in alert cerebellectomizedmonkeys fired at their usual, quite rapid rites when the monkey was lookingstraight ahead, and their discharge rates were found to he modulated in theexpected way during sa,:endes and drifts. Thus, it appears that gaze-holdingfailure is no: due to an inability of the motor neurnn itself to continuefiring. Furthermore, the results of this study ar.ni that the mechanism formaintainine, a steady impulse rate in oculomoter nein7ons during straight aheadgaze loos nnt res :th in the cerebellum.

in wiPh Dr. Suzanne McKee12, Dr. Westheimer has shown that smoothpursuit ,ke movements Involve an element in their neural control that is not

describabe as the oquivnlent of a steadv state evi: position or a simple func-tion cf its r-te ,t -hang,e. These findings are in -onflict with Denders' Lawwhich states that the orientation aroun.1 a fixoticn axis in alwav,: the same nomatter what mo.:ement pro,:eeled the arri-11 nr the ovi_, in a nnven fixation

posttioo. dut.1 !)-or tle w, I r o! Wostheimer and McKee show that Donders'

Joes 1,=',i f6r the plirstilt hyntem. Not only may the observed torsion

asso:Aatd wit! a ^t, ti 0,7e di rfer from the torsion found during :steady fixa-

ties, ht* thP the lIze of the torsion also varies with the directionet he tr,tion. ruu 4nvttgators do not as yet have sufficient data to form -al .a; +> ri;vs roparding the direction and extent of this additional tor-sie en....ondere eve mcvemenf, Those studies, electrophysiological

rl!Allre, dad ,1-.11r.ct.ve ob!ervations suggest that smooth eye movements, unlike

satads, ar... not 7.1mpenhatod ior in space perception. Apparently, significant

dt!:erences !n !h.-. neural substrates of smooth tracking and saccadic eyesosemeets.

Ur. Barara Gordon of the University of Oregon has studied the responsesof rourcns in tne super:nr eolliculus in unanestherized cats13. The receptiveit' id properties esit; in the superfieial layers were found to be similar

ts thov.%. descrlhed l'or anesthetized animals. The least sensitiveporti,n-; of t", totint:vv field, however, disappeared under anesthesia. Thus,

anes*llesia hs,; t(ect 'f decreasing the size of the activating region of

the rts.tptive tield. Vlsual receptive fields were found in these studies toSe %ties !arger in the deep collicular layers than in the superficial layers.

de;, Inver rtptIve fielcs included the entire contralateral visual field.!lye' rpond;:!,2 to a wide range of stimulus sizes and shapes,

were 1:re!,o1 1;:v ee1eetive (responding only to movement with a horizontalv.mporwtlt !,ward tho perIphcry of the contralateral visual field), andresaondee maxlInall to rapid stimulus movement. Many deep layer units, espe-ia!Is those In :he lateral portion of the colliculus responded to auditoryr som.ttle scirsli. A mber of units responded to both auditory and visual

and a few rcsponded to both somatic and visual stimuli. These recap-pt,,,ort,ts ar consistent with the notion that the colliculus may

Se in of head and Nye movements made in response to moving!:7-.t.'!. The oe11!, dc.,11Thed in Dr. Gordon's studies may provide information

Oese: 1.. able to track a stimulus visually regardless of whetherCs :It ! Initi .;lv Impinges on its visual, auditory, or somatic sensory

conduLted by Dr. Westheimer and Blair -4 suggest that the motetpatswa (o accommodatlor (the alteration of lens shape) does not have asynapee In the ofliary ganglion while that for pupil constriction does. This

conclun :r.im investigations which indicate that the sphincter irldaeand the Lilinry musci1; of the alert monkey differ in their frequency responseto intracranial e:Ltrical etimulation of the third nerve. Furthermore, local

application o nic.ttne to the ciliary ganglion abolishes pupil constriction,but not acccmmodati,m, upon electrical stimulation of the third cranial nerve

preximal t, thu aselion. These results are very suggestive that thereexist,: an un.ntertupte neuronal path to the ciliary muscle. This conflicts

wtth noralls aei.pted thPoriim. of the pattern of innervation of the intra-

ocular muscles.

V1SVA!. !:FRVCS SYSTEM

studies of neuronal activity In the visual nortical area of

monkey vie1ded consi4erable information on the functional organization

of .pest' aroa5t. stuay of area 17 has shown that at least two systems

-tpi

of neurons occur, arranged in a series of columns extending from pia to whitematter. One system has common receptive field properties within each columnwhereas the other system is aggregated according to eye dominance. A bort-,zontal organization is also evident which corresponds to cortical layering,separating simple monocular responses in lamina IV of the cortex from complexbinocular responses in several laminae. Dr. Jennifer Lund of the Universityof Washington School of Medicine has conducted anatomical studies designed toestablish morphological correlates for these physiological findings15.

She has attempted to determine if there is some simple basic plan of neu-ronal organization in the visual cortex which might correlate with and betestable by physiological studies. The monkey was chosen as the experimentalanimal because the primary visual cortex (area 17) of the primate is moresharply divided into a series of clearly limited laminae than is that of thecat or rat, and these divisions provide a useful set of morphological landmarks.

Dr. Lund has found three basic cell groups in area 17: pyramidal neurons,stellate neurons with spiny dendrites, and stellate neurons with spine-freeor sparsely spined dendrites. These three neuron groups show different distri-butions in depth from pia to white matter and differ in their relationship tothe zone of concentrated termination of geniculocortical axons. The neurontype most closely related to the laminae receiving a heavy geniculocorticalprojection is the spiny stellate cell. This cell type is restricted to laminaIV. Pyramidal neuron cell bodies .;17e almost totally excluded from lamina IVCwhich contains the broadest band of geniculocortical axon projections. Theapical dendrites of lower pyramidal neurons bear many fewer spines in laminaIVC than in lamina V and VI. The basal dendrites of upper pyramidal cellsspread superficially and deep into lamina IVA. The area of thalamocorticalfiber termination, rather than within it. Spine-free stellate neurons occurat all cortical levels and the sparsely spined varieties have not been foundin lamina IV but occur in other laminae. These and subsequent anatomicalstudies are expected to provide us with a road map of this portion of the brain.A clear understanding of the neuronal interconnections should help to explainmany of the findings of visual neurophysiologists and point the way towardfurther productive physiological studies of the visual process in the cortex.

The longest fibers of the optic tract reach to the upper layers of thesuperior colliculus of the midbrain. Dr. Gerald Schneider of the MassachusettsInstitute of Technology has studied the effect of lesions of the superior col-liculus in newborn hamsters on the formation of abnormal retinal projections16.The normal terminal area for optic tract fibers was destroyed in newborn hamsters.The animals were allowed to grow to maturity, and the distribution of the optictract fibers was studied at that time. Considerable evidence of terminationwas found in areas normally devoid of such optic tract terminations: the remain-

ing tissue of the colliculus and the thalamic nucleus. An abnormally highdensity of terminations was found in part of the ventral nucleus of the lateral

geniculate body. These thalamic regions received connections from the superior

colliculus in the normal animal. If the superficial layers of the superiorcolliculus were destroyed unilaterally at birth, axons from the eye contra-lateral to the lesion not only reached the area of early damage, but formed anabnormal decussation, crossing the tectal midline to terminate in the medialzone in the undamaged colliculus. Axons from the two eyes appeared to compete

sfi2

for terminal space in this intact colliculus, because they terminated in anonoverlapping manner. If the axons from the eye contralateral to the remain-ing colliculus were eliminated at birth, the anomalously recrossing axonsincreased in quantity and spread across the entire superior colliculus on the"wrong" side of the brain. Hamsters with such an anomaly showed wrong-directionturning in response to visual stimuli in a large part of the visual field.These studies provide new information on the factors which control the routingof afferent retinal fibers during the development of mammalian visual system.Lesions studies such as these can give important insights into the factorswhich control development in the normal system.

Dr. Frank Walsh of the Johns Hopkins School of Medicine and Dr. RichardLindenberg of the Baltimore City Morgue have completed the first volume ofNeuropathology of Vision: An Atlasli. This two volume set is intended to sup-

,

plement major clinical texts by providing visual assistance to students andall physicians interested and engaged in the diagnosis of lesions involvingthe visual pathways: the optic nerve head, orbital optic nerve, intracranialoptic nerve, chiasm, optic tract, lateral geniculate body, optic radiation,and calcarine cortex. In each case, the pathology of the structure is dis-cussed and illustrated extensively. The authors of this atlas hope that theirpublication will serve to integrate basic information regarding neuroophthal-mological diagnosis now found in scattered publications throughout theliterature.

The retinal ganglion cell serves to integrate the responses of severalretinal photoreceptors and is thus the first locus of visual image processing.Current theory holds that the output of a given ganglion cell is controlled byto spatially overlapping mechanisms: a "center" mechanism and a "surround"mechanism. For an on-center, off-surround ganglion cell, the center mechanismwould cause excitation during the period when the light is on and inhibitionafter the stimulus is terminated. The surround mechanism would cause inhibi-tion when the light is on and excitation after stimulus termination. Theresponse intensity curves, which are used to describe the fields for bothmechanisms, have their maximum strength in the center of the receptive field.The curve fin. the center mechanism has a higher mean and lower standard devia-tion than that for the surround mechanism.

Given these spatial and temporal characteristics of the center and sur-round mechanisms, it would be expected that the response pattern to a stationarystimulus would be dependent upon the stimulus location in the receptive field.According to the model, three basic response patterns should be observed for anon-center, off-surround ganglion cell: (1) in the center of the receptivefield, a stationary target should produce an on-response; (2) in the distantregions of the receptive field periphery, an off-response should be observed;(3) in the region closer to the receptive field center, a double, on and off,response should 1).? elicited.

Drs. Ray Winters, Terry Hickey, and J. Pollack, at the University of Miami,have examined the effect of variations of stimulus distance (from the receptivefield center) and target intensity upon peripheral response patterns of singleon-center retinal ganglion cells16. Their results revealed two types of on-

center units. one group responded to annuli of light flashed outside the

53 53

receptive: field contet region with bu!st-, .1,_t;v1t,,. it *.he -nget and

termination of rho, stimulus. These (-ells were, the,, oe--;enter, on-off sur-

round evils. A so:,,nd group of cells pave re:tp,nses t'nat Art. ';ithililr t.) those

predicted by the spotlall',--overlapping, dual me:han.i.sm t%corN: tht.v were nn_

center, off- surround i'el!%.

In related studios, Dr. Winters, together with Terry hiel:ey and D.has examined. the effect of varying the size of the stimulating flash of lighton the responses. to these two typos retinal ganglion eellsP4. The stimu-lating flashes -wore annell of constaet inside diameter but varying outsidediameters. The two groups of cells ceuld be distinguished k-n tl'e basis of theirresponses to rhanges in annulus size. Regardle:'s of the location of the stimu-lus in the receptive field periphery, the first group of cells showed spatialsummation of both the on-excitation and ott'-excitation responses. The effectof stimulus si7e on the responses of the second group of cells was more complex,appearing to be dependent on the location of the stimulus in the receptivefield periphery. If the inside portion of the annulus was near the receptivefield center, in the on-off zone, then small increases in stimulus size pro-duced an increase in the strength of the excitation whereas large changes instimulus size led to a decrease in the strength of the on-excitation. Off-excitation, on the other hand, was a function of spatial summation across theentire receptive field periphery. Thus, the center and surround mechanismsappear to be spatially coextensive for the first group of cells but not forthe second, at least in the receptive field periphery. These results add anew element of complexity to the picture of the retinal ganglion cell integra-tive function.

Dr. Duco itamasaki and associates at the Bascom Palmer Eye Institute inMiami have embarked on a study of the neurophysiological impact of visual depri-vation on each of the %'sual centers from the retina to the cortex. In a recentstudy2° they have detailed the response pattern of two types of ganglion cellsin the normal (non4eprived) eat retina. One type of ganglion cell exhibitedthe so-called sustained response: when a small stimulating target was movedto the peripheral, inhibitory, portion of the receptive field of the ganglioncell, a reduction in the firing rate of the cell was noted. Then, as thetarget moved from the surround to the center of the receptive field, the firingrate Increased to a maximum and remained at an elevated level for the durationof the time that the target was in the center of the receptive field. Thesecond type of ganglion cell, the transient response cell, showed no evidenceof entry inhibition. However, as the stimulus reached the center of the recep-tive field, the firing rate increased suddenly and then dropped back to thespontaneous level almost as rapidly. The investigators have determined furtherthat with increasing stimulus intensity, there is a linear increase in themaximum firing rate but no significant change in the size of the receptive fieldcenter. This observation indicates that the response properties of the centerand surround components of the receptive field must be changing proportionately.These studies serve as the controls against which these investigators willcompare data from their studies on ganglion cells from visually deprived animals.

The superior colliculus of the cat receives visual inputs from both reti-nae and from ipsilateral visual cortical areas -7'13'19 and the Clare-Bishop

area. The cells in the most superficial collicular areas respond best to may-

s! A:1! t pr art selectieelv responsive to stimulil" , 1 wttnio r,o;tivc Heide. Further-

-,!re1nted tieille we. by the two eyes despite the pre-e:e .tAlattr ee-ini' :onnt 1 ' .`3C1 of the collicelus. Two

t t .17' There ei e:an Reeenquist, weeeing the the laheratory.ieetette of P,.:nt.svi\an!a have identified those

s ir t.,A 0, dt.i which are responsible for the corticalst 1""t1.17 t re. ,e;-e.: r eelliollusel 13v stimulating these cells electric;

t:hat is, npplving electrical stimulation tocolliculus and determining those cells in the

stz, '1",x tneth investigators were able t- plot the recep-tte t'te An=! stusi y;onovl! ehv,iclegical properties of these cortico-te.-!A to 1-e In layer 7 and were what are commonly

'zsmp:vx" ,eege receptive fields and responded maxi-ma:lv te a slit stirulus :--oving slowly across their receptive field.Mcsz were direerion and orientation selective. However,zsa e : the ,\Ils eid net ',new improved response summation with,tie:es leeetn t,en slits parallel to the receptive field axis were sub-eriteted for ,pet, is sti-teli. This is in contrast to the behavior of mostereee in to, str:site ,,,rtex. Also, most of these units responded very1.eil to mal moving spot as stimuli. The data from these experiments are

wit:1 the obtzlined *'rom ablation studies in that the propertiesof te .'.'ttire'te.tal cells identified are precisely those which are lost in the

fe!l.wiee removil of cortical area 17. Apparently direction selec-tivity in,.! t e effectiveness of the ipsilateral eye in driving collicular unitsare de,,ndent en binocular, dlrection-selective inputs from the striate cortex.

A stuey et the develpment of visual information processing capabilitiesIn .r.e per. z c,'lliCulu3 of the neonatal kitten during maturation has beenc,ei:t.ed v Drs. Kim, Stein, 1,eler Lobos, and Lawrence Kruger of the Univer-sit,; ef Aezeles-- . These investigators found that informationrrc-ess. in thP sueerinr colliculus advances with age, and a distinct matura-ttonal secuence can he demonstrated for some neuronal response characteristics.Sire r,,ns of :he -,uper:ot colliculus were studied from late fetal sagesue ueeeks ef agt. During the first few days of life, few active neuronswere found, and these which were encountered had significantly lower rates ofspontaneous activity than those found in the adult. Prior to seven days ofage, stir.ult 1:11ved inPifective although somatic and acoustic stimuliwere capable of exciting some neurons in the deeper laminae. Between 7 and 9days of age, visually responsive neurons were monocularly activated by thecentralateral eye and ,t.tst excited by stationary visual stimuli. Those neuronsrespensi to moving stimuli at this developmental stage were most effectivelyexcittd by slowly mcving iargets. Neurons responsive to movement only wereabsent. From 10 to 13 days until 7 to 8 weeks of age, the proportion of neu-rons binocularly a,tivated, sele,tivelv responsive to the various parametersof mevement an: responsive to movement but unresponsive to stationary light,all tn.:reased progressively. Statienary light became a relatively less effec-tIve 5 c lmt. T,s r.!%an movc,nent in neurons responsive to both stimuli, and a ten-den:y for neuronal fatigue with repetitive stimulation decreased. Althougheac'n property did not become apparent simultaneously, in each neuron, matura-tional changes in neuronal specialization paralleled the sequence of events inthe :evelepment et visual'v euided behavior and may reflect the maturation of

the corticotectal pathway in the kitten.

The difference between the responsiveness of superior colliculus neuronsto stationary light in the immature and adult cat is striking and has prompteda detailed examination of "static" properties in young kittens in order toquantify the stimulus parameters affecting response latency during criticalstages of development. Drs. Stein, Labos, and Kruger23 have now shown that theminimum as well as the range of latencies of on- and off- responses to largestationary stimuli gradually diminishes in the period from 1 to 8 weeks. By

the end of this period, the latency values are comparable to those of matureanimals. In these studies the off-latency displayed a wide range of changerelated to manipulation of stimulus variables and could be eliminated inde-pendent of the on-response by reducing stimulus intensity and duration. Theinvestigators found that the minimum stimulus duration and intensity requiredto elicit a response gradually diminished during the developmental period.

In studies conducted at Harvard University, D. Van Essen and J. Kelly,working in the laboratories of Drs. David Hubei and Torsten Wiesel have pro-vided evidence that the shapes of cells in the visual cortex of cats maycorrelate with their response properties to various types of visual stimuli24.The experimental procedure involved extracellular recording with microelectrodesfrom a number of cortical cells. Each time a cell was reached, its receptive

0field was mapped by a procedure involving the recording of its responses tospots and slits of light projected onto a screen within view of the experimentalanimal. After the receptive field characteristics had been determined, themicroelectrode was advanced slightly to penetrate the cell. The impaled cellwas then stained with Procion yellow injected through the hollow electrode.After sacrificing the animal and sectioning its brain, the investigators wereable to identify the stained cells and determine their shar.,1. Although thetechnical complexity of the experiment limited the number of cells mapped andstained, the results of the experiment suggest that, in the Hubel and Wieselterminology, "simple" cells are probably stellate in shape and "complex" cellsare likely to be pyramidal. "Hypercomplex" cells were identified in only twocases, and one was stellate and the other pyramidal. These studies, whichprovide a correlation between a functional property and the appearance of acell, are likely to prove of fundamental importance for future studies in manyparts of the nervous system.

Because of their relative simplicity and the accessibility of their neuralelements, the visual systems of several crustacea have been extensively studiedas models for various elements of visual information processing in mammals andman. In studies conducted in the laboratory of Dr. C.A.G. Wiersma at theCalifornia Institute of Technology, Drs. Hugo Arechiga and Keiji Yanagisawahave investigated the response to light of the visual interneunms of the cray-fish25. These investigators have found that illumination of areas of they eyeoutside of the receptive field of a given interneuron results in an inhibitionof the light-stimulated response of the interneuron. Regardless of the distancebetween the inhibitory light and the receptive field, no decrement of inhibi-tion was found. Neither was there a tendency for inhibition to decrease with

time. The threshold for eliciting inhibition from a given area upon another

was much higher than the threshold for excitation of the impacted area. Dark

adaptation of the eye caused a widening of receptive fields with a correspond-

511

ing reductish r tne in area, This effect of dark adaptation on lateralinnititin is remar',ablv similar t that described some years ago by HoraceBar low and cowz,rKers for the cat. In the crayfish, every field but the receptiveone acts as an -.'ff" inhibitory surround. Therefore, the change in responsive-ness found H: Arehiga and Yanagisawa can be attributed primarily to an expansionof the ex,:itats-ry field rather than to a reduction in the inhibitory strengthof the surround. This change in field organization might be neural in nature,as postulated by Barlow for the cat, or more likely, the results of a peripheralmechanin, such pigmunt migration in the photoreceptive units.

Be.Lause the ground squirrel has an all cone retina, it is the experimentalanimal of choice when one wishes to study vision without the confusing influ-ence of the a:hromatio rods. Dr. Charles Michael of Yale University School ofMedicine has studied the response properties and receptive fields of opponent-olor and opponvt-contrast cells in the lateral geniculate nucleus of the

ground squirrel-t% The majority of the color-sensitive neurons found had thecommon concentric center-surround receptive fields consisting of one blue-greenopponent-color system in the center and the opposite type in the periphery.That is, a given cell might respond when the center of its receptive field wasstimulated by a green light but be inhibited when the same photoreceptors werestimulated with blue light; stimulation of cells in the surround elicited anexactly opposite spectral response. Because of their double opponent fields,these geniculate cells were optimally influenced by the simultaneous presenta-tion of two different colors: one covering the field center, the other illumi-nating the surround. Dr. Michael also found opponent-contrast turons withreceptive fields of the same center-concentric surround arrangement. Thesecells had very strong antagonistic surrounds and consequently were insensitiveto diffuse light. The opponent-color and opponent-contrast cells seem to besegregated into clusters in the geniculate. This investigation has speculatedthat the double opponent-color cells probably receive excitatory inputs fromtwo sets of optic tract fibers with simple circular fields and with oppositetypes of blue-green, opponent-color properties. A single afferent fiber hasa receptive field which coincides with the cell's field center. The fields ofa second set of fibers are distributed in an annular fashion around the cell'scenter, they collectively form the surround of the cell's receptive field. Anadditional two groups of optic tract fibers with the opposite types of opponent-color organization and with the appropriate field positions in the center or thesurround may make inhibitory synapses on the geniculate cell. The opponent-contrast cells probably receive inputs from two sets of optic tract fibers withcenter-surround receptive fields. A single excitatory afferent has a receptivefield center which coincides with the cell's field center. The surround fibersencircle the cell's field center and collectively form the surround. They areinhibitory and probably make presynaptic contacts on the terminal of the centralfiber. These studies have further shown that two general types of fibersefferent from the retina are sharply segregated. The directionally selectiveaxons travel only to the superior colliculus while the contrast-sensitive andopponent-color sensitive units go only to the lateral geniculate nucleus.These studies have enlarged our understanding of the mechanism of chromaticstimulus integration in the visual nervous system. Dr. Michael has provideda mociel "wiring diagram" which may represent the general pattern in otherspecies with color vision, including man.

57

I)

Drs. Russell. aeValoia azai Ptrnaa

Berkeley, taaether with Dr. MAX SneCae:_\ a,Technolagy, 'ae., been atudv:ng ta.camparina their results with raae, a:taaa,1

payahaphaai:.al cxperiaents. ra i eaa:a

experimental anima: WiLl,on which electrophYsioloaical staieavous svarem an he performed, 1-

monkey subecta was tested w;0-: aaataqualities, Me human lnd maalea.in form ani quite similar in aas-let, _Drs. DeValois and :'largan, togetate »;t: aa-aHull, tested the spectral aenaiti,Ita

y,_,11711' -%

scotopic and plerople aonditiana. Tat ,t...e.ta

between tht species. The relatiea lae -a. -:

the spectrim were virtually identiaal. a-a t'ac. ahr;:att a: .aaaremarkably eloee. thew rem 1t aeeaea+ t. at eata teethe phutorekepive pigments in taa cwt.- apeale a-a --a aaa _-receptor reeponees are cembined neurally art auite 5-aaala.DeValois and Richard MarroLca-!' have reaeracd 77*7:

lateral geniculate nucleus of the macaque monaee. F.: ea-a ce___ :-,a aaaaaeaeato stimuli varying in wavelength and purity (:ape:.. eaa aat--aed..The type of raapenae of any given cell was i2C-17t77.: t- .aaa-length, some ae7ls were stimulated hv :alue an:others gave the reverse response. Still others tetaeaen:a:system. The reaponse magnitude of anv given cell, writ t%'E7 -exaitaf.t:e :7 tani:i-tion, was determined by the purity of the stime:as. 7at 71S7S 7.77 c-aese

taken togttuer, are entirely consistent wits, the epezarl :s:aaaedfor this sare monkey species in the psvceenve:aa. crtsaaankaats. aaaa wcrkcontribaces to uur understanding of tht rile ef t-eaein monkey, and perhaps human, perceptian ef

Dr. Gunter Von Noorden of the Baylor Colleae biaaitlaa aaa temcna atr:ed-a-that unilateral lid closure of visually immaturi,

amblyopla in all animals so treated :f

age. Ti the treatment is delayed until twelve weeaa .7! aaa. --aa sama:7iaappears. During the age of susceptibility, Dr. vat. 'aoaerate: taa: aertadsof occlusior as brief as 2-4 weeks were effective ia taastaa: ae-aE-at amh:aaaia.Amblyopia also appeared in those monkeys which were ma:, attaamatt aaaaal_ag thefirst week of life. Correlation of these data with tnaae attaa:tteat r m '-::ratan

patients indicates that the human visual system remaa,ea aenaa::aaa eaaa:a:araI

lid closure (induced for therapeutic purpcses'; to a tleaa:c :f tame tnanthe menkev's. These results with the monkey are 7fa.71t7,..:1:7:T "-eean.ae

of the similarity of the visual system in this animal T: 114=.. :1 ::herstudies31, this investigator has examined the hLate:aaat ata-aeaas La tee aaseal.

nervous system resulting from unilateral lid F.:1:.;;7.17i: .7 araff:ifLa: sarabiansius,again in the immature rhesus monkey. Sections fram tea :a:aaa: jaeLaa,-

late nuclei, and areas 17 and 18 of the visual .stet :tan maaaaa,a aa:a :eta-.tar-ally demonstrated amblyopia were compared with siara=ar ttsaues frpai .seas.monkeys. The only histologic change observed :n :nee taetaa.::eee mom k4-rs vans a

significant reduction of cell section area in all :f :_'era: ianiae-late nucleus that received input from the deprive: aa eae_ -aea

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Thts is the well Known deserts:, .tirati-n effa_tt, desoribcd byW..stneimer. Stabilization -t t an ii

tin.- baeKivr,un,' or tha

retina greatly reduced the dep..--ent._ I: upd:, area.Dr. Kee..ev has speculated that ret-. media-eo by both the"s:Istained" and "transient- s.ste..t. .-n -r:marilv t4e-,ustAideJ" system wh.n -,tag es are .t .o. «..i _o tn t'n.1 retina.

Whet. :!Ifferent images are :.resent tt-e retinas f humantbt SVster strives to pr. duct at7le te7ieiei image. 7-is fusionalresponse is believed to be made of twt .._stint: tt-..ritl.trnents: 1) i centralfissional response whose magnitutie is limited :: 7.:*.e extent of the so-called

Pandm's fusional arcs and a m7tor res;--nEc t.7 tne form of compensatory eyemovenents. D. Andr.A. Kerte:t7 iZtrtter' 7:-,:-ersity nes reported thatetinal .:';ages which differ ty a rptati.:-.al are fused by a nurely

central mechanism with,:ut any evidence tf :-stensattrY eye movements°. Thus,cvolofuional stimulation appears tc cffer -alua'le aPproath to the study^,f the ,tent :'.3A. t,t the fus:t--1:. in,a.mio aspects of

Panum's fusicaal areas. The cohtnal resp:ae iry:Ives dt:ection or assessmentof C r .tiSparltv 671 the proLessrg. ir the interest of bi-n-ulnt vision. Dr. Kertesz nas ccndutted experiments designed toexplore- the processing ofdisparate images _rte central fusionlamechanism. Tn one e haF dot:: st.zest that the primestrategy of the central -te:chanism is t: :ring t:-.e largest oessible portion ofthe tw,., retinal images into c:rrespendente. _..is portion, the visualsyster, Anpears tc disoard the rest of tte ;a:tern as aoise which isa.t a alld tart stimulus. When the .f.;_sit-". 7ttechanism is sperating,

th.s is not percei:.-ed by the subett. !'erteso s,iggests that two,entral could to posttulat {: is ext::af.n t`e visual system's approach

the retina: image disparity: a net ism that is Lut e; to oriea-tAtion,:.1 dit.parities, -TronP that SC'7'.%-$: p;v.,:t.,nal. disparities.

Ft has :.ow producod dat..i4 to :4.--uppt,rt t-at it is the disparity(Introeu_e.i bv the stim%:%.,, et each pair f-f retital s.tats :n Cle two eyes)whitn te ;)1.:marf:v of displacementbetween the two images does not appear L: :E ilt:riant a stimulus to the

The.ic results :-Tse -f ttte-r investigat:rsnav "ier.-r.rated .:eteotlrs in the vi,zual

c.21-lex t-e -shd

PsychrhYsi.al studio nn the mechanist of stereopsis conducted by Drs.:,111tmsin Riohirds and David Regan at the Massachusetts Institute of Technologyha-e raised the possthiliry that two,separate mechanisms function for the pro-cessine binocular rues for depth".J. The experimental subjects were askedto fi-xate on a gr,!en point in space and were presented with stimuli consisting,-3f parallel bars. The viewing system was arranged so that each eye could viewonly one of :4 pair of bars, and the two eyes were required either to converger -J.verge in Or,ler to product a single perceived image. The MIT group has

t:und a numher of subjects who are capable of processing one type of stimulus,exampit. convergent disparities, but not the other. When the ability to

process both convergent and divergent disparities is present in the individual,the eXiStrnce of two separate mechanisms can still be demonstrated by plottingfield maps for stereopsis for each type of disparity. Extensive measurementson one observer have shown that the zone of the visual field over which con-vergent disparities are processed may differ quite distinctly from the zoneover which divergent disparities can be integrated. Furthermore, Dr. Richardshas found that for those individuals who possess one or the other of the stereo-processing mechanisms, a contrast reversal of the stimuli and backgrounds maylead to a reversal in apparent processing mechanisms44. Thus, those who areable to process convergent disparities presented as light bars on a dark back-ground, when presented with dark bars on a light background, may lose the formerinability to process divergent stimuli but now lack the ability to process con-convergent stimuli. Dr. Richards has suggested that such reversals in depthwith contrast ma. he the result of interactions between the center and surroundcomponents of the disparity mechanism.

Dr. Patricia Ondercin, with Drs. Nathen Perry, Jr. and Donald Childers ofthe University of Florida have studied the phenomenon of ocular dominance45.They have found that dominance appears to be a continuous function which isnormally distributed in the general population. By placing lenses of variousdicptie powers in front of one or the other eye of the test subjects, theinvestigators were able to establish, enhance, or decrease ocular dominance bymodifying the image clarity in one eye. These results indicate that dominance,as measured by dichcptic stimulation, is not a static characteristic even inadults. In these experiments dominance was shifted to the nondominant eye evenin subjects showing strong ocular dominance under normal viewing conditions.

In a joint experiment conducted by Drs. Joseph Sturr and Davida Teller atSyracuse University and the University of Washington, respectively, the inter-action of the two eyes was evaluated when a test stimulus was presented to oneand an inhibitory stimulus to the other". These studies were conceived as afurther test of the physiological site of the Westheimer effect. Dr. Westheimerhas shown that the threshold of perception for a small test spot located in thecenter of an illuminated disc varies with the diameter of that disc. Thethreshold for the test spot rises with increasing disc diameters, reaches a

maximum for an intermediate disc diameter, and then falls again. This desensi-ti7ation effect has been attributed to the existence of an antagonistic surroundin the receptive fields of neural units within the retina. Concentric receptivefields are known to occur in various vertebrate species at the bipolar, ganglion,and lateral geniculate levels as well. The studies of Sturr and Teller weredesigned to expose the possible interactions of stimuli to the eyes of thehigher centers of the visual nervous system. In their studies, the test flash

3

63

was presented to one eye and the sensitizing disc or annulus was presented tothe other. With steady presentation levels, dichoptic interactions were foundto be small or nonexistent. However, under transient conditions, dichopticand monoptic effects were remarkably alike. These results are consistent withthe conclusion that steady state disc annulus interactions and transient discannulus interactions probably occur at more peripheral and more central locationsin the visual nervous system, respectively.

Fr: -1k Bagrash, a student of Dr. James Thomas of the University ofCalifornia, Los Angeles, has conducted a series of experiments which suggestthat the human visual system contains tunable channels which can affect thetransformation of the photic stimulus into a perceived image47, The experi-mental procedure involved measurement of threshold intensity for light discsof varying diameters. When the subject briefly observed an adapting disc ofgiven diameter at suprathreshold level, his subsequent threshold of perceptionfor a test stimulus was markedly increased when the test stimulus was of thesame size as the adapting stimulus. However, when the test stimulus differedmarkedly in size from the adapting stimulus, no significant difference inthreshold intensity was observed between control and adapted trials. In otherexperiments, annuli were substituted for the adapting disc. The data of theseexperiments suggest that adapting area is not the sole determinent of theobserved effect. The spatial distribution of the adapting area and its inter-action with intensity both appear to play a role. Dr. Bagrash argues that theeffect of size tuning en threshold intensity can best be accounted for by somemultiple, as opposed to single, channel tuning mechanism interpretation. Theseinvestigators, together with those in several other laboratories around theworld, are exploring the implications of psychophysical studies which suggestthat the visual nervous system "tunes in" those portions of a stimulus whichare of interest and "tunes out" much of the additional visual informationpresented simultaneously.

64

REFERENCESSENS0RY-MOT0R DISORDERS AND REHABILITATION

. Steinman, R.M. Haddad, n.m., and Skavenski, A.A. Miniature eye movement.

Science 181: 810. 1973.

2. Wyman, I), and Steinman, R.M.: Small step tracking: Implications for theoculomotor "dead zone". Vision Research 13: 2165, 1973.

3. Sansbury, R.V., Skavenski, A.A,, Haddad, G.M., and Steinman, R.M.: Normalfixation of eccentric targets. Oft. sop,. of Amer._ 63: 612, 1973.

4. Scott, A.B., Rosenbaum, A., and Collins, C.C.: Pharmacologic weakening ofextraocular muscles. Invest. Ophth. 12: 924, 1973.

5. Pachter, B.R., Davidowitz, J., and Breinin, G.M.: Morphological changesassociated with myoneural junction in extraocular muscle of the dystrophicmouse. Acta Neuropath. 24: 214, 1973.

6. Pachter, B,R., Davidowitz, J., and Breinin, G.M.: A light and electronmicroscopic study in serial sections of dystrophic extraocular musclefibers. Invest. Ophth. 12: 917, 1973.

7, Keller, E.L.: Accommodative vergence in the alert monkey. Vision Res. 13:1565, 1973.

8. Skavenski, A.A. and Robinson, D.A.: Role of abducens neurons in vestibulo-ocular reflex. J. Neurophysiol. 36: 724, 1973.

9. Buttner, J. and Fuchs, A.F.: Influence of saccadic eye movements on unitactivity in simian lateral geniculate and pregeniculate nuclei. J.Neurophvsiol. 36: 127, 1972.

10. Ron, S. and Robinson, D.A.: Eye movements evoked by cerebellar stimulationin the alert monkey. J. Neurophysiol. 36: 1004, 1973.

11. Westheimer, G. and Blair, S.M.: Saccadic inhibition induced by brain stemstimulation in the alert monkey. Invest. Ophth. 12: 77, 1973.

12. Westheimer, G. and McKee, S.: Failure of Donders' Law during smooth pur-suit eye movements. Vision Res. 13: 2145, 1973.

13. Gordon, B.: Receptive fields in deep layers of cat superior colliculus.J. Neurophysiol. 36: 157, 1973.

14. Westheimer, G. and Blair, S.M.: The parasympathetic pathways to internaleye muscles. Invest. Ophth. 12: 193, 1973.

15. Lund, J.: Organization of neurons in the visual cortex, area 17, of themonkey. J. Comp. Neurol. 147: 455, 1973.

65

16. Schneider, G.E.: Early lesions of superior colliculus: Fit. tars affectingf rma t ion of abnormal rot I a1 proles t ions Praia, aoh . reol. 8: 73,

1973.

17. Lindenberg, R., Walsh, F., and Sacks, .1.: Neuropathology of vision: Anatlas. Lea 4 Fehiger, Pub. 1973. (Philadelphia)

Winters, R., Hickey, T., and Pollack, 1.: Effect of variations of tarrotlocation upon the peripheral responses of on-center retinal ganglion cellsin the cat. Vision Res. 11: 1487, 1973.

19. Winters, R., Hickey, T., and Skaer, D.: Spatial summation in the receptivefield neliphery of two types of on-center neurons in cat retina. VisionRes. 13: 1499, 1973.

20. Hamasaki, D., Campbell, R., Zengel, J., and Haxelton, L.: Response of catretinal ganglion cell to moving stimuli. Vision Res. 13: 1421, 1973.

21. PaLmer. L. and Rosenquist, A.: Visual receptive fields of single striate`cortical units projecting to the superior colliculus in the cat. BrainRes. 67: 27, 1974.

22. Stein, B., Lobos, E., and Kruger, L.: Sequence of changes in properties ofneurons of superior colliculus of the kitten during maturation. J.Neurophysiol. 36: b67, 1973.

23. Stein, B., Lobos, E., and Kruger, L.: Determinants of responses latency inneurons of superior colliculus in kittens. J. Neuroph 36: 680, 1973.

24. Van Essen, D. and Kelly, J.: Correlation of cell shape and function in thevisual cortex of the cat. Nature 241: 403, 1973.

25. Arechiga, H. and Yanagisawa, K.: Inhibition of visual units in the cray-fish. Vision Res. 13: 731, 1973.

26. Michael, C.R.: Opponent-color and opponent-contrast cells in lateralgeniculate nucleus of the ground squirrel. J. Neurophysiol. 36: 536, 1973.

27. DeValois, R., Morgan, H., and Sodderly, D.: Psychophysical studies of mon-key Vision Res. 14: 75, 1974.

28. DeValois, R., Morgan, H., and Poison, M.: Psychophysical studies of monkeyvision -- -I. Vision Res. 14: 53, 1974.

29. De Valois, R. and Marrocco, R.: Single cell analysis of saturation discrimi-nation in the macaque. Vision Res. 13: 701, 1973.

30. Von Noorden, G.: Experimental amblyopia in monkeys. Invest. Ophth. 12:721, 1973.

11. Von Noorden, G.' Histological studies of the visual system in monkeys withtxperimental o.nnlvopia. Invest. Ophth. 12: 727, 1973.

32. Grobstein, P., Chow, L., Spear, P., and Mothers, L.: Development of rabbitvisual cortex: Late appearance of a class of receptive fields. Science180: 1185, 1973.

33. Ralston, H. and Chow, K.: Synaptic reorganization in the degeneratinglateral geniculate nucleus of the rabbit. J. Comp. Neur. 147: 321, 1973.

34. Chow, K., *lathers, L., and Spear, P.: Spreading of uncrossed retinal pro-jection in superior colliculus of neonatally enucleated rabbits. J. Comp.Neur. 151: 307, 1973.

35. Pettigrew, J. and Barlow, H.: Kitten visual cortex: Short-term, stimulus-induced changes in connectivity. Science 180: 1202, 1973.

36. Lund, R., Cunningham, T., and Lund, J.: Modified optic projections afterunilateral eye removal in young rats. Brain Behave Evol. 8: 51, 1973.

37. Baker, F., Grigg, P., and Von Noorden, G.: Effects of visual deprivationand strabismus on the response of neurons in the visual cortex of themonkey, including studies on the striate and prestriate cortex in thenormal animal. Brain Res. 55: 185, 1973.

38. Tulunay-Keesey, U.: Stabilized target visibility as a function of contrastand flicker frequency. Vision Res. 13: 1367, 1973.

39. Tulunav- Keesey, J. and Vassilev, A.: Foveal spatial sensitization withstabilized vision. Vision Res. 14: 101, 1974.

40. Kertesz, A.: The effect of stimulus complexity on the human cyclofusionalresponse. Vision Res. 12: 699, 1972.

41. Kertesz, A.: Central component of fusional response: The effect of stimulusparameters. Vision Res. 13: 495, 1973.

42. Kertesz, A.: Disparity detection within Panum's fusional areas. VisionRes. 13: 1537, 1973.

43. Richards, W. and Regan, D.: A stereo field map with implications fordisparity processing. Invest. Pphth. 12: 904, 1973.

44. Richards, W.: Reversal in stereo discrimination by contrast reversal.A:Amer.J.opto.Arctner.Acad.to. 50: 853, 1973.

45. Ondercin, P., Perry, N., and Childers, D.: Distribution of ocular dominanceand effect of image clarity. Perception and Psychophysics 13: 5, 1973.

46, Sturr, J., and Teller, D.: Sensitization by annular surrounds: Dichopticproperties. Vision Res. 13: 909, 1973.

47. Bagrash, F.: Size-selective adaptation: Psychophysical evidence for size-tuning and effects of stimulus contour 6 adapting flux. Vision Res. 13:575, 1973.

67

ANNUAL REPORTNATIONAL EYE INSTITUTE

July 1, 1973 - June 30, 1974

REPORT OF THE DIRECTOR OF INTRAMURAL RESEARCHCarl Kupfer, M.D.

Although the National Eye Institute's Intramural Program will always

constitute only a modest portion of the nation's total vision research effort,its continued development is crucial, not only for direct research activ-

ities, but for the evolution of NEI's total program. The expertise centeredin the Clinical Branch and Laboratory of Vision Research, as well as the

Office of Biometry and Epidemiology, serve as an invaluable resource for allInstitute programs, providing guidance to extramural program management,program planning and analysis, and the Office of the Director. In general,

the scientific direction of the Institute is greatly dependent upon thishighly-regarded corps of professionals, many of whom are internationallyknown for their research contributions.

In a time of decreased Federal emphasis on research training, theintramural research facilities of the NEI can also serve the young investi-gator who desires experience in a stimulating intellectual atmosphere, aswell as the senior vision research scientist who wishes to take advantage ofthe unique resources and opportunities for collaboration at the NationalInstitutes of Health.

The Eye Institute has the only eye clinic in the United States wherebeds are allocated solely for the purpose of ?ision research and where thereis such close and consistent collaboration between clinical and laboratory

scientists. Its progress during the short time of Dr. Bailintine's adminis-tration has been noteworthy; yet, its needs remain critical. Because of

limited staff there are no studies underway in two of the Institute's five

major programs: Cataract and Corneal Diseases. Otner programs are only

minimally represented. In the coming year, major emphasis will continue tobe placed on strengthening this vital program to further its development asa national resource and model for clinical vision research.

69

6s

ANNUAL REPORTCLINICAL BRANCH

July 1, 1973 - June 30, 1974

REPORT OF THE CLINICAL DIRECTORElmer J. Ballintine, M.D.

The Clinical Branch has continued to develop its program of studyingocular disease in patients by laboratory methods. Patients are admitted tothe Clinical Branch only if they are appropriate for enrollment under one ofthe research plans. These research plans must meet the same standards ofscientific valiiity that are imposed on non-human experiments and, at thesame time, must be ethically acceptable and incorporate appropriate safeguardsfor the patient's rights and welfare.

During the year a six member Protocol Review Committee, three of whosemembers were not physicians and three not part of the staff of the ClinicalBranch, began a detailed reivew of all research protocols in the ClinicalBranch for scientific merit and ethical acceptability. Each investigator hasrevised his research plans to meet the requirements of the Committee. It isexpected that additional review by Clinical Center agencies will be requiredin the near future.

The renovation of the outpatient service area was largely completed andwe moved from our temporary quarters. The renovation of laboratories fortissue culture and for the study of retinal and choroidal biochemistry wascompleted. A completely renovated operating room, equipped for ocular micro-surgery, vitreous surgery, and electroretinography was completed. Apparatusfor performing B-scan ultrasonography of the eye and orbit was placed inoperation. Equipping a laboratory for neuro-ophthalmology was also begun.

The staff of the Clinical Branch consists of four senior staff physicians,three physicians who are clinical associates, and one who is a staff associate.Two senior staff members are not physicians. Eight biologists and technicansand four secretaries support the staff. The commitment of the staff to inves-tigate the important categories of disabling and blinding eye diseases isapparent in the individual research project reports.

In addition to conducting research on its research protocols, theClinical Branch in collaboration with the Experimental Pathology Section ofthe National. Eye Institute Laboratory of Vision Research, examines histopatho-logically approximately 100 eyes per year, most of which come from theautopsy service of the Clinical Center. Consultations were furnished foL 850patients being cared for by other Institutes in the Clinical Center. Therewere 2,550 outpatient visits during the year, 150 admissions to the inpatientdivision, and 75 operations were performed.

The Clinical Branch conducts several investigations in the field ofglaucoma. One of these is the prolonged observation of a series of patientswith ocular hypertension. These observations are expected to help determinewhich signs have value in predicting which patients will eventually require

(A-0

treatment, and to determine if early treatment of ocular hypertension has anyvalue in preventing visual field loss.

The study protocol has been completed and registration of patients iscontinuing. Closely related to this project is the continuing study of thefactors affecting intraocular pressure and their alteration by pharmacologicagents in young and old normal subjects and patients with ocular hypertensionand glaucoma. A study of the mechanisms responsible for the patterns ofintraocular pressure variation allows a clear understanding of the actionsand suitability of pharmacologic agents used to treat glaucoma.

The aim of a related study which is on the enucleated, arterially per-fused cat eye is to determine the pharmacodynamics of agents able to alterintraocular pressure and to further the understanding of mechanisms whichmaintain the intraocular pressure. A schema to explain some mechanisms bywhich aqueous humor is formed has been developed and the mechanisms of druginhibition of aqueous humor formation has been clarified.

Glaucoma-related studies are underway to determine the rates at whichsodium and chloride ions enter the aqueous humor and the effect of unilateralcommon carotid artery ligation upon the flow of blood to the ciliary body andupon the formation of aqueous. Findings have shown that there is a reductionof ciliary body plasma flow which is associated with decreased aqueous humorformation. This is consistent with the view that aqueous humor is producedby ultrafiltration. The relationship between blood flow in the ciliary bodyand aqueous humor formation had not previously been demonstrated in vivo.The definition of this relationship allows a better understanding of themechanism of aqueous humor production and may be important in the managementof glaucoma patients.

NEI scientists have developed an animal model suitable for studying theeffects of chronic elevation of intra-ocular pressure. The researchersinduced an experimental glaucoma in the eyes of normal rhesus monkeys byrepeated circumferential photocoagulation of the recess of the anteriorchamber angle. This technique produces a reduction in the coefficient ofoutflow and a chronically sustained moderate elevation of intraocular pressuresimilar to that seen in human chronic open angle glaucoma. Cupping of theoptic nerve head, bowing of the lamina cribrosa and loss of retinal ganglioncells in the perifoveal region similar to the changes seen in human simpleglaucoma accompany the elevation of intraocular pressure.. This model willprovide a tool for studying why and how glaucoma causes visual loss. It willall investigations that cannot be performed in man but are necessary if weare to understand the effects of glaucoma in patients and it will permitcomparisons of retinal optic nerve function in the glaucoma eyes to those inthe control eyes. The effects of chronic elevation of intraocular pressureupon the rate of formation of aqueous humor will be investigated.

Other investigators have shown that blastic transformation of a patient'slymphocytes induced by phytohemagglutinin can be inhibited by gluco-corticoids.The sensitivity of this inhibition may be related to whether the patient hasglaucoma or not. This effect is being systematically investigated in fami-

lies of normal subjects and in glaucoma patients and their families.

72 t.

Eye institute scientists are looking for methods to demonstrate andassay a possible vasoproliferative factor in the vitreous humor of patientswith such vasoproliferative diseases as diabetes mellitus, sickle celldisease, Eales' disease, and central retinal vein occlusion.

NEI scientists are also carrying out a trial of argon laser photocoagu-lation for patients with several diseases of the retinal and choroidalvasculature and of the macula. All patients undergo an exhaustive evaluationbefore treatment and during the follow-up period. It is hoped to gainconsiderable more clinical information about treated and untreated individualswith these diseases. Approximately 50 patients have been treated of whom 35have diabetic retinopathy but were ineligible for the nationwide, NEI supported,Diabetic Retinopathy Collaborative Study. Two other projects are attempts tosearch for, properly classify, and clinically define new techniques which willelucidate the cause, prevention, or treatment of selected choroidal-retinaldegenerative diseases (such as retinitis pigmentosa and familial maculardege.leration), and of a broader range of genetic and familial diseases.

NEI scientists are also attempting to characterize the biochemicalproperties and functions of the visual pigment in vertebrate retinal receptorouter segments. Of particular interest has been the finding that rhodopsinin vitro is phosphorylated by the terminal phosphate group of ATP and thatthis reaction is stimulated approximately two -fold in the light. Studies areunderway to determine if this reaction occurs in vivo, and if so, to quantifyits extent and reversibility under various conditions of dark- and light-adaptation, and most importantly, to determine its role in the physiology ofvision.

Clinical Branch scientists are studying the usefulness of radioiodinatedchloroquine analog for the diagnosis and detection of intraocular melanoma.The patients included in this study are those referred to the Institute forevaluation of pigmented lesions of the eye, resembling malignant melanomaand those patients in whom the ocular media is opaque. The value of using1-125 labelled chloroquine analog for the detection of intraocular melanomais being studied. Based upon the patients studied to date it appears thatthe 1-125 chloroquine analog offers some aid in the differentiation of patientswith intraocular melanoma from other patients with benign lesions or withmetastatic disease. To date there have been no verified false positive tests,but the use of this test is not the final word in the differential diagnosisof malignant melanoma inasmuch as there have been three false negative teststo date. Another project has the broad objective of applying current proce-dures for psychophysical tests, improving their form and scope, and enhancingthe usefulness of ophthalmic instruments for clinical work. The datagenerated by these instruments and methods for visual examination contributeto the other research projects within the Clinical Branch.

The results of a study designed to determine whether the Bausch and Lomb"Soflens" and the American Optical "Bandage Lens" are effective in the treat-ment of bullous keratopathy are being prepared for publication. Finally,

there is a study designed to evaluate the efficacy and safety of n-acety1-1-cysteine, a mucolytic agent in the treatment of the signs and symptoms ofkeratoconjunctivitis sicca. This investigation will provide needed information

73

70

on thk. ttratmont of patients ..0, ry rtet 1V4 4k,hlet cclls wiil alloN.",o,;'.1;As,M8 ii1VOIVed in keratneontunctivitis

ine clinical Branch hah continued to ::oopers.re :alstit:zteh; La

vzr-it, 0I unique rseartm is7-rt.:-Ities. A

centivued in diabetic retinopathv as part ol tbx $tlArT :f amcngPlma by the Epdemiology and Field Studi,ls Brara;1 ;t ill:tonalInt;.ttlte i Arthriti, Mtt ibi 1tt nd stti-

"qic.roangiopathy was undertaken among the 0..c,Lp wt:hit the Clinical Center by NIAMDD. Other cooprt.tivt the

ot immunologic aspects of ocular malignant me,amoua:t. :0.:peratik*zn

wItt, the CcIlular and Tumor Immunology Sez:tion. a.tc1-v,Diviz;i.,n of Cancer Biology and Diagnosis of the Na.iorka: :=:_xtitute;i.d .ituay of Sjogren's syndrome among pat e: es..atilmen by

the NtLional Institute of Dental Research.

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The major finding of this stud).* so far !'a., been the continuing evi-dence supporting the concept that the enzyme aldose reductase is involved ininitiating sugar cataracts. This enzymt see' us t: Le t"-.e zommon mechanism by

which the sequence of events ieadin t*e e.e."..ent of di.lbetic,

gaIactosemic, and xylosemic cataratl- 1:-Itlate,d. kr. active inhibitor of

aldose reductase (A.R.) has recentiv t-eer. tc :.revent cataractous

changes in cultured lense ,. expo,et: tc ---:entrattons of galactose.However, improved methods ' deliver' -f t-e =.?. inhibitor by topicalapplication must be achieved before this prtted...re of controlling cataractformation can be considered effective.

NEI investigators hope that this type of study on sugar cataractsmay serve as a model by which other mechanisms of cataract development canbe uncovered, and may also provide alternate neans of preventing cataracts.Even though the initial phase of cataract devel.vment may be different inthe other forms of cataract, it appears that the terminal stages are quitesimilar.

The aim of a third project within the Laboratory of Vision ResearchSection on Biochemistry is the study cf factcrs which letermine the normaldevelopment and function of the retina ;.e. pigmented epithelium. TheInfluence of hormones on normal and abnormal development and the uptake andbinding of vitamin A in the retina have been investigated during embryonicdevelopment. Biochemical analyses of enrrme activities were performed toassess the effects of hormones on the retina after in vivo application orincubation with retinas in organ culture.

Mdior findinp,s of this pro'ect 'tare :teen: that the hormone cortisolaffects normal enzyme development in the em'oryonic retina while progesteroneappears to retard normal biochemical clevelcqment; that a specific, highaffinity receptor that binds vitamin A has been found in the embryonic retina;that pigmented epithelium cells respond in culture to hormones such asthyroxine and cyclic AMP with marked ohanzes in pigmentation, morphology,and enzyme activity. This work attempts to pinpoint early signals, such ashormones and vitamin A uptake, that are critical to normal retinal developmentand contrast them with those found in the diseased state. It is hoped thatsuch studies will ultimately uncover compounds which can correct retinaldevelopment in the embryo.

The LVR, in cooperation with the Laboratory of Chemical Pharmacologyof the National Heart and Lung Institute, is investigating the concentrationsof cyclic nucleotides in retinal photoreceptors. Mese have been found tofall dramatically when a dark-adapted retina is exposed to light. These

intracellular hormones may act as intermediates in translating the initialphotic stimulus on the retina into the neural response which is transmittedto the brain. This project is designed to study the enzymes of -cyclicnucleotide synthesis and degradation to determine the critical point at which

light exerts its influence.

78-

The findin of this pro .0t wa-:, that extremely high concentrationsof t-clit ':!!' were found in retinal photoreceptors, The levels of both

and eveIir AMP were founil to he dependent on the percentage oflight-bleach of the retina. Phosphodiesterase, the enzyme of cyclic nucle-otide metabolism, was found to he activated by light and thus control cyclicnueleotide concentrations in the photoreceptor. This is the only well-defined enzymic activity known to be regulated by photic energy. It is hopedthat this study will lead to a }letter underqtandinp, of the biochemical basisof the process in normal vision and lay the groundwork for an understandingof the underlying problems of retinal degeneration and blindness.

In cooperation with the Laboratory of Pathology it the National CancerInstitute, the LVR is attempting to isolate specified membrane proteins onghosts of rabbit corneal cells derived from tissue culture and primary cul-ture of cells from normal tissue.

Herpes simplex virus (HSV-I) - induced antigens have been demonstratedon membranes of infected rabbit corneal cells (SIRC line) by specific immuno-labeling. The use of the hybrid antibody method for localization of antigenicchanges on viral-infected corneal cells represents, as far as can be deter-mined, the first application of this method of immunolabeling to experimentalstudies directed at control of herpes simplex keratit...s.

Arother project is the study of structural and functional aspects ofthe bovine rhodopsin molecule.

It has been postulated that hydrophobic bonding between rhodopsin andthe lipids of the rod outer segment memarane is of major importance for themaintenar:e of the structure of the membrane and for the functional role ofrhodopsin in that membrane. The thermodynamic values which have beenobtained here support at least the first of these concepts, and we now havea clearer concept of the magnitude of the forces which are involved inrhodopsin-lipid interactions in the membrane. Additionally, NEI investigatorsnow have the ability to predict molecular dimensions for various models ofthe structure of rhodopsin and to consider these for consistency with otherevidence concerning the behavior of rhodopsin during the visual process. Infurnishing information concerning the structural and functional role ofrhodopsin in the rod outer segment, these studies are intended to contributeto an understanding of the basic biochemical mechanisms which are involved inboth the normal and pathological aspects of scotopic vision.

Studies on calcium-dependent macromolecular association or dissociationoffer the possibility of yielding information which may be significant ininterpreting the role of calcium in the changes which occur in the rod outersegment membrane following exposure to light. Another important finding byNEI scientists within the Section on Biochemistry is that calcium plays avery dramatic and central role in the excitatory process in vision. Thissuggests that abnormalities in calcium metabolism by ocular tissues may leadto impairment of vision. Furthermore, it may be highly significant if anypathology of vision could be understood on this basis. Also, the flourescent

79

probes discovered as a result of this project report the nature of the iso-lated visual receptor plasma membrane. This may be of use to others studyingmembranes, particularly those investigating the biochemistry of isolated rod

outer segments. They will contribute to an understanding of the basic bio-chemical mechanisms which are involved in both the normal and pathologicalaspects of scotopic vision.

LVR investigators are studying the renewal of photoreceptor cell outersegments, a continuous process which is impaired in some pathological condi-tions such as progressive degeneration or developmental anomalies of theretina. The purpose of this project is the elucidation of the biochemicalevents involved in renewal, especially the distinction between transport ofopsin to the outer segment and any further modifications of opsin necessaryto produce light-sensitive disc membranes.

The indication is that opsin is transported to the rod outer segmentbefore the vitaminAchromophore is attached to produce a light-sensitivevisual pigment. The presence of pigmented-epithelium does not appear toinfluence the rate at which the chromophore is added to newly-synthesizedbovine opsin which accumulates in the outer segment.

Isolated frog retinas, on the other hand, show little accumulation ofopsin and seem to add chromophore shortly after opsin is transported to theouter segment. It appears that the final steps in the outer segment renewalare regulated largely by the photoreceptors, not by the pigment epithelium.This fact has an important bearing on the identification of the cell typesresponsible for the defects in any of the various retinal dystrophies.Attempts will be made to demonstrate the location of rhodopsin precursors inthe rod outer segments and to correlate the amount of precursor seen in frogor cow rods with specific differences in the structure of the rods.

NEI scientists have previously found that there are two types ofphospholipid which are required for the structure and function of the visual

pigment rhodopsin. In this project the distinct roles of these phospho-lipids were separately investigated.

The finding that phosphotidylethanolomine (PE) is directly involved inisomerization of all trans retinal to 11 cis retinal is probably the firstinstance in which a "pseudo-enzymic" function of membrane phospholipid hasbeen demonstrated. This could provide a model reaction for phospholipidfunctions in other membrane systems. Another important finding of this pro-

ject is that abnormal rod functions observed under certain pathologicalconditions, such as retinal dystrophy, may be related to degeneration ofphospholipids associated with rod disc membranes. For example, phospholipidperoxidation by light has been suggested to be responsible for Turkey Blind-ness Syndrome, a veterinary disorder characterized by a degenerativeendophthalmitis with detachment of the retina.

In the visual receptor cell, the movement of ions across its membrane

and the control of this ion flow by light-released intracellular excitatorytransmitter have been shown by NEI scientists to be basic in the initiation

of the light detection process of the visual system. The nature of thisexcitatory transmitter, how light and the visual cell control its passage

across membranes, and how this transmitter in turn regulates movement of ions

across the visual cell membrane are the focal points of these investigations.

The understanding of how membrane-bound proteins control the passageof materials through membranes is of foremost importance whether thesematerials he ions in the photoexcitatory process or ions and substrates ofvarious sorts in the processes of development and maintenance of ocular and

nervous tissue. Revelations of how visual pigments, probably the beat char-acterized membrane protein, control movement of materials across membranes

are a major contribution to biomedical research. The successful adaptationof the electron microprobe for the quantitative study of biological cellswill have impact in many areas of biomedical science because it will fulfullthe demand for a rapid and sensitive method for determining the ioniccompositions of cells as small as one micron in diameter.

The Section on Experimental Embryology in cooperation with the Clinical

Branch of NEI, the National Institute of Child Health and Human Development,and the School of Medicine at UCLA has contributed in the past year to three

of the five NEI program areas: Retinal and Choroidal Diseases, Cataract, and

Corneal Diseases. First, it demonstrated that the PE cells of the embryonic

retina can synthesize fibrillar collagen. This gives substance to the sus-picion that these cells may produce the abnormal deposits of collagen seen insuch disorders as senile maculopathy and Drusen formation. Second, NEIscientists working on this project have discovered that collagen-bearinglavers produced by retinal PE can induce the sclera. This focuses attentionon the possible involvement of this epithelium in conditions such as blue

sclerae and some colobomata.

In the past year emphasis was placed on in vitro studies extending thelist of previously identified factors governing the early steps in themetaplastic regeneration of lens from the dorsal iris of newts, animals witha natural ability to regenerate a normal lens. These findings define morevigorously the in vitro conditions that opti,aize early steps in Wolffian lens

regeneration. This project will continue to focus on the tissue interactionsinvolved in ocular embryogenesis with emphasis on the roles played in morpho-genetic foldings and induction by epithelially produced matrices.

The Section on Experimental Pathology has studied normal and pathologiceyes by light microscopy, histochemistry, transmission electron microscopy,

and scanning electron microscopy. Several animal experiments are pursuedfor the control study of the corresponding pathologic materials.

Through the use of the electron microscope this study has revealed thatmicrocvstic dystrophy of the cornea epithelium begins with formation of an

abberant basement membrane within the epithelium. The epithelial cells which

are trapped beneath the abnormal basement membrane appear to undergo degen-

erative change and form the cyst. The epithelial layer over the basement is

free from the cystic change.

81

It 1,00n fouud thit the maturation of the coneenitallv cataractous!,!ou,;,, !el,: -011 appe.11- to occur slow,r fhln that of the normal cell and thatthr tmtlit.st de:ii,rnerative change, sweiline, of lens fibers, is i ound in thepott.rior zove.

th:s pro 1 t?c t has rev(-:iled that it is almost impossible toseparate the retina from the pigment enitholium without breaking the fines!;,icrvvilli of the latter cells. The attachment of the retina to the pigmentepitholium appears to be firmer than nerally thought. This information isimaot!ant for understanding the pathophvsiology of retinal detachment.

%,ratled study ,A pathoLvie niarorials is one of the most basic andNrt Int task:; in biomedical research. This laboratory is one of a few

which are capable of pursuing this type of research on pathologic eye

Also within the Section, retinas of normal rhesus monkeys have beenhhotocoa.4ulated by a ruby laser following the technique identical to that ofthe clincal application. The animals were sacrificed at several timeinterya;s and. the retinas studied histologically, electron microscopically,and by tvpsin digestion technique for retinal blood vessels.

Mtho,1711 necrotic changes in the photoreceptor cells and the pigmentepithelium in each burn lesion are extensive, the retinal tissue appears totolerate the treatment rather well. Each lesion is sharply circumscribedand the repair process seems to take place within the damaged area. Thestructure of the retinal tissue between the burns is not disturbed at all.'No aporceialAe swelling or cell infiltration has been seen in this normalarea. This treatment appears to remove a great number of photoreceptorcelk from the retina. The simplification of the tissue may be the reasonfor the olinieallv beneficial effect of this treatment. Small numbers ofstirvi.:1:w retinal cells seem to be sufficient to maintain the normal functionsu' the retina. The findings of the present study favorably support the useof photoco.vulation therapy. The multiple laser burn appears to be safe tothe rvtinal tissue.

Among several important contributions in the recent retinal studies,kflonstrations of the morphologic changes of the outer. segment membranes byliv,ht and of the renewal mechanism of the photoreceptor cells appear to bem:)st ..ignifteant. Retinas of the rhesus monkeys were exposed to continuousflahel of light (ten per second) by an electronic strobe light installed inthe lamp house of an ophthalmoscope. The animals were divided into two

flre group was exposed for one hour and the other for three daily 30-minote exposures. Animals were examined by electron microscope at varioustime intervals after the exposure.

All exposed retinas began to show pathologic changes in the outer seg-ment -t.Irting on the second day. Two days after the one hour exposure thepla,4rta membrane of the outer segment was fragmented and vesiculated and thestac;: OT the disc membranes became irregular. After the three 30-minuteexpoLrs the outer segments formed knots a few microns away from the ciliary

junction. The outer sements closest to the inner segment, which are believedto h newly formed portions, were found to be larger than the distal halves.This suggests that mild repeated stimulation resulted in hypertrophy of theouter segments.

These cimiges hcom been found to stay in the retina for a long periodof time. Irregular arrangement of the outer segments was found one yearafter the exposure. Also, a small number of photoreceptor cells in theexposed area hey.an to degenerate in the later period.

It is eomplon to find pathologic changes which are identical to thoseof the plesent experirent in the outer segments of "normal" human retinas,particularly at the macular zone. These findings indicate that the humanretina may accumulate photic changes with time and that along with certainother factors, photic damage may induce macular degeneration.

The mechanism and site of aqueous formation remain major questions ineve physiology and are important to understanding the pathogenesis. Thefunction of each layer of the ciliary epithelium, which has not been clearlyshown, is to he demonstrated. by another LVR project using rhesus monkeys.Fine structure of the riliary epithelium has been studied after alteration ofthe intraocular pressure in various conditions and durations. The mostextensively performed experiment during the past year has been the perfusionof the internal carotid artery with hypertonic solution. The accumulatinginformation from this study is significantly approaching a newer understandingof the function of the ciliary epithelium. The future course of the projectwill attempt to pinpoint the function. of the non-pigmented epithelial cell,

Drugs which destroy cell microtubules reversibly are among those whichare used commonly in cancer chemotherapy. It is essential for us to under-stand the precise funcricns of microtubules in ocular cells if we are todetermine accurately the dosage levels of anti-cancer drugs which are safefor the maintenance of normal vision. Microtubules are conspicuous componentsof developing lens cells, inner segments, filament regions of photoreceptorcells, and nerve axons. It is conceivable that drug overdose could lead tocataract formation if it destroys the microtubules in an elongating lens cellduring a critical period. Likewise, vision may be impaired by disruption ofmicrotubules in photoreceptors and axons. This study should help determineif any of these ocular cells, which depend on microtubules and microfilamentsfor their normal function, may be sensitive to chemotherapy and other environ-mental or hereditary insults.

The Section on Experimental Pathology studied the ultrastructure andfunction of the pigment cells of the eye, the purpose of which has been toinvestigate and define more precisely the intimate physical and chemicalinterrelationships that exist between the pigmented cells and the visualcells of the eye. LVR scientists have utilized an hereditary pathologicalcondition as an experimental tool to investigate how the membrane discs ofthe rod outer segments are digested by the pigment epithelium. Analyses ofnormal and mutant cells have been carried out by light microscopy and moderntechniques of high resolution electron microscopy as well as cytochemistry at

83

both levels.

Cytochemistry at the electron microscope level has enabled the investi-gators to localize within the pigment epithelial cells and choroid cells theenzymes that are involved (acid phosphatoses and catalases). Differences inthe packaging or these enzymes by normal and mutant pigments epithelial cellspermit a greater definition of the steps involved in the formation of cryso-somes and melanosomes. NEI scientists have shown that there is more relationbetween these processes than previously known. Such studies on pigmentedcells of the eye contribute directly to our understanding and managing ofmany retinal and choroidal diseases.

Studies on the physiology of the primate visual system were conductedwithin the Section on Neurophysiology during FY 1974. Experiments were com-pleted on the analysis of graded, visually evoked extracellular and intraocularresponse from the foveal region of the striate cortex of anesthetized,paralyzed rhesus monkeys. The findings show that the earliest electricalresponses detectable in the foveal striate cortex, following light stimulation,is a graded extracellular potential which is positive at the cortical surfaceand negative in the gray matter and has a peak latency of about 60 msec. Theresponse is similar at both on-and-off-phases of a light stimulus. Thereare indications that all three cone mechanisms participate in this response.Each cone mechanism contributes a similar potential to the response butantagonisms between cone mechanisms is apparent. The proportion in which acone mechanism contributes to the response varies from one area to another.This Implies topographical differences in the representation of cone mech-anisms in the striate cortex.

Such studies of retinal function at the cellular level should provevaluable for understanding vision and the pathophysiology of retinal diseases.

At least three independent information-processing systems have beendistinguished in the primary visual 7rtex of the rhesus monkey. Themajority of color sensitivity cells respond without regard to stimulusshape or direction of movement. Cells in a second group respond only to veryslowly moving, precisely oriented light bars without regard to color ordirection. Cells in a third group respond preferentially to stimulus move-ments in one direction, without regard to color or line orientation. Mostcells in this area of the visual cortex (area 17) are thus specialized forthe detectioa of a single stimulus feature at the expense of other features.

The color cells tend to be located in two distinct regions (layers 3Band 419 near the termination sites of lateral geniculate axons. Directionalcells are usually found in layer 4A, which contains axon terminals fromadjacent cortical regions. Orientation-specific cells tend to occur in theupper and lower most layers (2, 3A, 5, and 6).

It is essential that scientists understand the normal mechanisms ofinformation-processing in the visual cortex before they attempt to definethe nature of the visual defect in such conditions as congenital cataract,strabismus, astigmatism, some types of color deficiency, the aphasias, and

disorders of reading (for example dyslexia) in children.

In cooperation with the University of Vienna in Austria, the Section.an Biochemistry of LVR, and the Laboratory of Biochemical Genetics at theNational Heart" and Lung Institute, scientists from the Section on Neuro-physiology have devised a preparation of the cat retina which has allowedthem to make intracellular recordings from most of the neuronal types thereinand to stain the neurons with procion yellow dye. This marks the first timethat such techniques have been successfully applied to any mammalian retina.The responses of "A" and "B" type horizontal cells, horizontal cell axonterminals, both rod and cone lipolar cells, two distinct types of amacrinecells, and several classes of ganglJon cells have been identified.

Horizontal cells have been sh)wn to have unusual properties which mayprove to he broadly significant to understanding of the central nervoussystem One such astonishing finding was that the axon terminal of the "B"type horizontal cell has responses which are unrelated to those found in itscell body. herees only 40% of the amplitude of the cell body response isgenerated by rods, 80% of the amplitude of the axon terminal response isgenerated v rods. Furthermore, the rod signal of the axon terminal has beenshown to be over one log unit more sensitive than that of the cell body. Thusthe "B" type cell body and its axon terminal system appear to be functionallyindependent units. other neuronal types are currently under intensive studyand it seems possible that an exhaustive description of neuronal propertiesin the cat retinal may emerge in the next few years.

85

LAHORAToRY OF VISION RESEARCHPUBLICATIONS

Hess, H.h., and Pope, A.: Microchemical studies of alteredeell mmhranes in Creutzfeldt-Jakob disease. Arch. Neurol. 30, (in press)

Ben.;ineer, R.E., 'Fletcher, R.T., and Chader, G.J.. Guanylate cyclasesinnIbition by light in retinal photoreceptors. Science 183: 86-87, 1974.

1,rnsinger, R.F., Fletcher, R.T., and Chader, G.J.: "Piggyback",chrondtorabhv: Assay for guanylate cyclase in retina and other neural tissue.J. Neuroo.hem. (in press).

Chader, G.J.: Some factors affecting the uptake, binding, and retentionof ( H) cortisol by the chick embryo retina as related to enzyme induction.J. Nouroihem. 21: 1525-1532, 1973.

Chader, G.J., Bensinger, R.E., Johnson, M., and Fletcher, R.T.: Fhos-phodiesterase: An important role in cyclic nucleotide regulation in the

Exp. Eye Res. 17: 483-486, 1973.

Chader, c.J., Fletcher, R.T., Johnson, M., and Bensinger, R.E.: Rodouter segment phosphodiesterase: Factors affecting the hydrolysis of cyclicGMP. ExT. Eye Res. (in press).

Chader, G.J., Herz, L.R., and Fletcher, R.T.: Cyclic nucleotide hydrol-ysis: Some possible natural regulators of phosphodiesterase activity inretia and rod outer segments. 3. Neurochem. (in press).

Chader, G.J., Herz, L.R., and Fletcher, R.T.: Light activation ofphosphodiesterase activity in retinal rod outer segments. Biochim. Biophys.Acta. (in press).

Chader, C.J., Johnson, M., Fletcher, R.T., and Bensinger, R.E.: Cyclicnucleotide phosphodiesterase of the bovine retina: Activity, subcellulardistribution and kinetic parameters. J. Neurochem. 22: 93-99, 1974.

`;oo Il, Lewis, Marc S., and Folk, J.E.: Relationships of thecatai;t:,: properties of human plasma and platelet transglutaminases (activatedblood :04zulation factor X111) to their subunit structures. J: Biol. Chem.249: 940-950, 1974.

00,ilembre, A. and Coulombre, J.: Morphogenesis of the eye. In Zinn, K.Ed.): 7nternational Ophthalmolagy Clinics, Boston, Little, Brown & Co. (in

press).

Cculombre, A. and Coulombre, J.: The skeleton of the eye. II. Overlapof thc gcleral ossicles of the domestic fowl. Dev. Biol. 33: 257-267, 1973.

86 173

Coulombre. A. Johnston, M., and Weston, J.: Conference on neural crestin nornal and abnormal embryogenesis. Dev. Biol. 36: f1-15, 1974.

Dow, B.M.: Funotional classes of cells and their laminar distributionin monkey visual cortex. 2. Neurophysiol. (in press).

nvornik, D., SlmardDuquesne, N., Kraml, M., Sestanj, K., Gabbay, K.,Kinoshita.., J.H. , Varna, S.D., and Merola, L.O.: inhibition of aldose reductasein vivo. Scionce 182: 1146-1147, 1973.

Embree, L.J., Hess, R.H., and Shein, H.M.: Microchemical studies oflipids, proteins and nucleic acids in polyoma virus-transformed hamsterastroglia. J. Neuronath. Exp. Neurol. 32: 542-551, 1973.

Cabbav, K.H., and Kinoshita, J.H.: Aldose reductase from mammaliantissues. In Wood, W.A. (Ed.): Enzymes of Carbohydrate Metabolism, New York,Academic Press.

C'oldber; S.: Studies on the mechanics of development of the visualpathways in the chick embryo. Dev. Biol. 36: 24-43, 1974.

Gouras, P.: Opponent-colour cells indifferent layers of foveal striatecortex. J. Physiol. (Lond.) (in press) 1974.

Gouras, P. and Chader, C.: Retinitis pigmentosa and retinol bindingprotein (Editorial). Tnvest. Ophthalmol. (in press) 1974.

Gouras, P. and Chader, Retinitis pigmentosa and retinol-bindingprotein. Invest. Ophthalmol. (in press).

Gouras, P. and Padmos, P.: Identification of cone mechanisms in gradedresponses of foveal striate cortex. J. Physiol. (Lond.) (in press) 1974.

Hamai, Y., Fukui, H.N., and Kuwabara, T.; Morphology of HereditaryMouse Cataract. Exp. Eye Res. Vol. 18, 1974.

Harris, W.F. and Robison, W.G., Jr.: Dislocations in microtubularbundles within spermatozoa of the coccid insect Neosteinplia Texana andevidence for slip. Nature (London) 246: 513-515, 1973.

Henson, D., Helmsen, R., Becker, K.E., Strano, A.J., Sullivan, M., andHarris, D.: L'ltrastructural localization of herpes simplex virus neoantigenson infected corneal cells using sheep anti-human IgG anti-ferritin hybridantibodies. Lab. invest. 30: 376, 1974, (Abst.).

Hoff, M. and Gouras, P.: Tolerance of mammalian retina to circulatoryarrest. Doc. Ophthalmologica, 10th ISCERG Symposium, Junk Publishers (Hague)1973, pp. 57-63.

Holt, W.S. and Kinoshita, J.H.: The soluble proteins of bovine cornea.Invest. Ophthalmol. 12: 114-126, 1973.

87

Jedziniak, J., Yates, C., and Kinoshita,Exp. Eye Res. 16: 95-104, 1973.

os,..41a4e

Kabasawa, I. and Kinoshita, J.H.: Carbohydrate aast-tiated zemmacrystallin of the calf lens. Exp. Eve Res. :6:

Kabasawa, I, , Lou, M.F., Merola, L.O., ant Unoshits1-phosphatase in the lens. Ophthal. Res. (it press).

01-

Kenyon, K.: Ocular ultrastructure of in diseaaes.In Goldberg, M. (Ed.): Genetic and Metabolic Eve Disease. Ice:cc. :ittie,Brown & Co., 1974, pp. 139-185.

Kenyon, K., Sensenbrenner, A., and Wyllie, =;.eatin -dIareetructureand histochemistry in mucolipidosis II disease). 'L=e,:ltatr. R;4'4. 7:

560-568, 1973.

Kinoshita, J.H.: Cataractogenic effects of lactose and ;a..La.:I:dee.Sipple, (Ed.): Sugars in Nutrition, New York, Acadenir Pre se,

Kinoshita, J.H. and Merola, L.O.: Cyanate effects, DM theInvest. Ophthalmol. 12: 544-547, 1973.

fltro.

Kinoshita, J.H., and Merola, L.O.: Oxidation of :hit: irrld7re -4 tnehuman lens, In Ciba Foundation Sumposium 19: The man Lena in IeLatton toCataract. Amsterdam ASP, 1973, pp. 173-184.

Kolb, H. and Gouras, P.: Electronmicroscopic onserrations 7: nidmanretinitis pigmentosa. Invest. Ophthalmol. (in press)

Leighton, S.B. and Dow, B.M.: Servo-controlled ni:rrina ienerarorfer single unit studies in vision. Vision Res. 13: 2195-1:;'1,

Lewis, Marc S., Krieg, Laura C., and Kirk, Willian nclec4Iarweight and detergent binding of bovine rhodopsin. Exn. Pre 1es. :1: 2S-40,1974.

Newsome, D.A., Fletcher, R.T., Robison, W.G., :r., Eemrvn, andChader, G.J.: Effects of cyclic AMP and Sephade: fraction on cIrmed i-ertmAIpigmented epithelium in tissue culture. J. Cell Biol. (it r:res-To.

Newsome, D.A., Fletcher, R.T., Robison, W.G., re7.11-7a, andChader, G.J.: Effects of Cyclic AMP and sephadex fractions df d-.7.ink embryoextract on cloned retinal pigmented epithelium in tissue :::Z.re. 2. CellBiol. 61: 369-382, 1974.

Newsome, D. and Kenyon, K.: Collagen produced in ritzt rT the retinalpigmented epithel_ium of the chick embryo. Dev. Biol. 32: L973.

Newsome, D., Takasugi, M., Kenyon, K., Stark, W., and 7pelen,corneal cells in vitro: morphology, and histocompatibilitT _n yens ofpure cell populations. Inyttcnol. 13: 25-32. :;7a-

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genetic constitution for the treated twin and his co-twin control. This studywill provide a careful appraisal of the effectiveness of a clinically acceptab'emethod of controlling accomodation.

Other OBE studies relating to twins include: a thorough description ofbiases and other methodologic problems which might adversely influence theaccuracy and validity of twin heritability studies, an attempt to assess therole of genetic factors in determining normal levels of intraocular pressureand in determining the size of the physiologic cup of the optic nerve headas measured by a horizontal cup/hisc ratio, and to assess the role of geneticfactors in determining the intraocular pressure response caused by topicalapplication of corticosteriod eye drops.

The Association of University Professors of Ophthalmology (AUPO) Work-shop on Clinical Trials was conducted by OBE to familiarize clinicalinvestigators with methods of good clinical trials. A panel discussion andsix presentations: ethics, control group and randomization, objectivemeasures and double-masking, reproducibility of measurements, writing aprotocol, and practical applications were held at the AUPO meeting in Novem-ber, 1973. The presentation .pre discussions were tape recorded and submittedto the authors for editing. All materials have been edited, and the manuscriptis being submitted to the American Journal of Ophthalmology for publication.

In addition to these activities, OBE prepared a booklet containing infor-mation supplied by sixteen states which nade up the Model Reporting Area forBlindness Statistics (MBA). Over a period of eight years each state voluntarilymaintained a registry of its blind. In the booklet OBE classified personsadded to each state's blind registry according to their age, color, sex, visualacuity, age when blinded, causes of blindness, and other factors. Althoughthe data is uniform from state to state and has been very useful to NEI, thereare no immediate plans to continue the 14:RA since little additional knowledgewill e gained from its continuance. Efforts are under way, however, to makeuse of MRA data for designing studies directed toward better understandingthose factors which are associated with the major causes of blindness in theUnited States.

93 ii,f2t

OFFICE OF BIOMETRY 6 EPIDFMIOLOCYpuBLIcArIoNs

iello, L.M., Berrocal, 3., Davis, M.D., Ederer, F., Goldberg, M.F.,HArrl.;, '.D., Mint, D.R., Knatterud, Margherio, R.R., McLean, E.N.,!--lcMeei, MYers, F.L., Norton, E.W.D., Patz, A., Prout, T., Riekhof, F.T.,.-Itraats-7a, B.R., Tasman, W., vanHeuven, W.A.J., Watzke, R.C.: Diabetic,..etinpltv Study. (Letter to the Editor) Am. J. Ophthalmol. 76: 403-405,1473.

L.M., Berrocal, J., Davis, M.D., Ederer, F., Goldberg, M.F.,J.D., Klimt, D.R., Knatterud, G.L., Margherio, R.R., McLean, E.N.,

McMeel, j.W., Myers, F.L. Norton, E.W.D., Patz, A. Prout, T., Rlekhof, F.T.Straats,,,a, B.R., Taman, W., vanHeuven, W.A.F., Watzke, R.C.: The DiabeticRetinDathv Study. (Editorial) Arch. Ophthalmol. 90: 347-348, 1973.

Ederer, F.: Patient bias, investigator bias, and the double-maskedprocedure in clinical trials. Am. J. Med. (in press).

Ederer, F., Mantel, N.: Confidence limits on the ratio of two Poissonvariables. Am. J. Epidemiol. (in press).

Kahn, H.A.: Comparison of localized treatments for bilateral disease.Invest. ophthalmol. (in press).

Schwartz, J.T.: The Twin Heritability Study. Part I. Perspective,Problems and Approach. In Goldberg, M.F. (ed.): Genetic and MetabolicEye Disease. Boston, Little, Brown, 1974.

,chwartz, J.T., Reuling, F.H., Feinleib, M., Garrison, R.J., and Collie,D.J.: Twin study on ocular pressure following topical dexamethasone. PartI: Frequency distribution of pressure response. Am. J. Ophthalmol. 76:126-116, 1973.

(lchwartz, J.T., Reuling, F.H., Feinleib, M., Garrison, R.J., and Collie,D.J.: Twin study on ocular pressure following topical dexamethasone. PartII: Inheritance of variation in pressure response. Arch. Ophthalmol. 90:281-286, 1973.

ANNUAL REPORTOFFICE OF SCIENTIFIC REPORTS AND PROGRAM PLANNING COORDINATION

July 1, 1973 - June 30, 1974

The NEI Office of Information was redesignated as the Office of Szien-tific Reports and Program Planning Coordination during the year, reflectingboth the reorganization of public affairs activities within HEW and theInstitute's own decision to centralize program planning activities within theOffice of the Director.

PUBLIC AFFAIRS CUTS AND REORGANIZATION

On July 19, HEW Secretary Weinberger issued e memorandum calling for thereduction in the amount of "self-serving, promotionally oriented material inGovernment." Each agency was allowed to present its case on which of itsinformation activities could be considered "public affairs" (defined by HEWto include such public relations functions as publicity, press relations,films, exhibits, and other agency-initiated promotional projects) and whichwere not. The Eye Institute supported NIH's argument, which HEW eventuallyaccepted, that its information program is largely concerned with answeringpublic inquiries, scientific and technical reports, and consumer healtheducation. Recognizing this, the Eye Institute, as well as other Institutesat NIH, were asked to identify staff members whose functions were associatedwith public affairs activities. One public affairs staff member from thisOffice was identified who, according to HEW guidelines, was transferred toanother high-priority area (Extramural) within the Institute. The remainingstaff were identified by the Institute as having non-public affairs informa-tion responsibilities, a classification which was accepted by NIH and theDepartment.

The above reclassification and transfer resulted in a centralization ofall Institute/Division public affairs activities in the Office of the Director,NIH. Because public affairs was never a major NEI activity, the informationactivities of the Office have continued generally as before.

A second part of the public affairs reorganization was the reduction inthe number of HEW publications. As a result of the Departmental request, NEIidentified three of its twelve publications to be eliminated, but retainedtemporary authority to publish its experimental newsletter, 20/20.

Aside from corsuming a considerable amount of staff time in respondingto numerable memoranda from NIH and HEW, the impact of the public affairsreorganization..on the National Eye Institute has been minimal: no highpriority pubfications were eliminated, and we have been allowed to continueour information activities as in the past with a few minor exceptions.

95

PUBLIC INFORMATION

Publications

Partly as a result of uncertainty concerning the fate of publicationsduring the public affairs reorganization, no new fact sheets or health edu-cation booklets on eye disorders were published during the ye&r. An HEW-initiated project to produce a booklet on eye care (as reported in last year's'Annual Report) was temporarily shelved due to uncertainties within the Officeof Consumer Affairs, HEW, over the future of its consumer publications seriesof which the booklet was to be part. An attempt will be made duringthe coming year to publish the completed manuscript for this booklet as anNEI publication.

In cooperation with NEI Extramural and Collaborative Programs, two newfolders on extramural support programs (Special Visual Science!' ResearchAward Program and Specialized Clinical Research Center Grants) were prepared.Two issues of 20/20 were mailed to the vision research community. Whether Ornot the Institute is permitted to continue this publication depends on theresult of a readership survey which will have to be undertaken in the nextissue prior to obtaining formal OMB approval.

year:

The following number of NEI publications were distributed during the

Cataract (booklet andfact sheet)

Dieletic RetinopathyRetinitis PigmentosaMacular DegenerationStatistics on Blindness

.1969 -1970

Retinal Detachment--- 2,8813,926 Refractive Errors---- 2,8353,126 Glaucoma 3,3012,841 Corneal Disease 2,6732,849

in the'Model Reporting Area,

Corneal Disease Task Force ReprintU. S. News and World Report Interview with Dr. KupferBlindness and Services to the Blind in the

United States (OSTI Report)Security is an Eye Patch

367

21200

267

48,120

Requests for the latter publication, supplies of which were inheritedfrom the former PHS Neurological and Sensory Diseases Control Program, werestimulated by an announcement of its . 'ailability mailed to the nation'sophthalmologists by the American Association of Ophthalmology. Over 450 re-quests from practicing ophthalmologists for multiple copies were received,resulting in the near depletion of supplies of this very popular booklet.Over the past three years, the Institute has distributed over 240,000 copiesof Security is an Eye Patch.

Public Inquiries

Approximately 800 written inquiries received by the Office required anindividually written response, whereas the number of telephone inquiries

96

9/ fr

increased by approximately 33 percent: over 2,400 telephone calls were

handled during thk: year. The majority of inquiries concerned cataract, both

research and treatment. In particular, there was great public interest inpharoemulsifi,:ation and the role of nutrition in cataractogenesis and pre-

vention. Other areas of interest concerned laser treatment of glaucoma anddiabetic retinopathy and the possibility of individuals coming to the NationalEye Institute for treatment. Replies to approximately 160 letters from thepublic expressing concern with the institute's support of diabetes-relatedresearch were prepared.

The Office responded to 35 controlled, written Congressional inquiries,and 96 telephone calls from Congressional offices.

Press Relations

Five press releases were prepared (new members of the National AdvisoryEye Council, a warning of the possible damage to the eye when observing theComet Kohoutek's approach to the sun, announcements of the appointments ofDr. Nusser and Mr. McManus, and Dr. Kinoshita's receipt of the ARVO ProctorMedal.) Eight stories were prepared for the NIH News and Features service,mailed to science writers in the professional and general press. Ten storieswere prepared for the NIH Record. Announcements were mailed to the visionresearch journals concerning new NEI grants and awards, the availability toinvestigators of breeding pairs of rats with inherited retinal degenerations(produced under an NEI contract), and other items of immediate interest to

the vision research community.

The Office assisted press representatives from the Associated Press,U. S. News and World Report, Readers Digest, the Blue Sheet, Woman's Day,Medical World News, National Enquirer, U. S. Medicine, and Medical Tribune.

Miscellaneous

In cooperation with the Office of Biometry and Epidemiology, the Office

helped coordinate arrangements for presentation of a workshop on clinicaltrials, in conjunction with the winter meeting of Association of UniversityProfessors of Ophthalmology. The Office also coordinated arrangements withthe Laboratory of Vision Research and Clinical Branch for a tour of theInstitute by AUPO members.

A public relations proposal concerning the Framingham Eye Study was pre-

pared. Its primary objective is to help enhance patient recruitment effortsfor the study and to provide means for informing the professional and lay publics

of the importance of this investigation. Thus far, a radio spot announcement

was prepared and distributed in the Framingham and Boston areas, encouragingthose who had participated in the Framingham Heart Study to take part in the

Eye Study as well. Letters encouraging participation in the study have alsobeen drafted and will be mailed to prospective participants. Finally, a

supplement to the NIH science writers service, News and Features, was being

prepared for distribution to the press and to members of the Study. This

activity will be pursued further in FY 1975.

Four Search for Health columns were prenarod t-or the NIH Office ofInformation eancerning terminology relating to the eye, eye diseabee, eyedisease diaenosis, and methods of treatment which were mailed to weeklynewspApers across the Pnitod States.

Arrangements were made in cooperation with the NIH Office of Informationfor Kupfer's appearance on a Tampa, Florida, television talk show ineoniunction with the Spring ARV() meeting in Sarosota. The Office coordinatedarrangeNents for interview' with Dr. Kupfer by the Readers_ .hest, U. S, Newsand World Report, S. Medicine, and the American Ontometric Association News.

The Annual Save Your Vision Week Presidential Proclamation was prepared.NEI's contributions to the NIB Almanac and NIH Annual Report were prepared.The Office coordinated Institute submissions to the NTH Scientific Directoryand tibliography as well as this Annual Report.

Ali,iistance was provided to the Director in the preparation of presenta-tions before the Association of University Professors of Ophthalmology andthe 'ssociatlon for Research in Vision and Ophthalmology.

PROGRAM PLANNING COORDINATION

Following recommendations of the NEI management conference held lastSeptember, the then Office of information was designated as the coordinatingpoint within the Institute for program planning and development activities.The Information Officer, Julian Morris, was designated as the Planning.Coordinator. Although.the Information Office had been actively engaged inplanning activities, this designation reflected the Institute's desire toformalize its planning activities and provide better organization andfollowup.

The Office has thus had major. responsibility for preparation of the NEIForward (Long Range) Plan as well as special planning documents required byNIH and HEW. It has also: worked with the Executive Officer and budgetOfficer in the drafting of narrative materials related to AppropriationsHearings, developed materials for various preserv:ations to NIH staff regardingprogram plans, in cooperation with other segments of the Institute documentedspecific needs for additional funds and positions, coordinated arrangements forthe Cataract Workshop, and assisted in the arrangements for the NationalAdvisory Eye Council Program Planning Committee's review of the Retinal andChoroidal Diseases, Cataract, and Corneal Disease programs.

For the coming fiscal year, the Office has major responsibility for coor-dinating the Committee's review of the Glaucoma and Sensory Motor Disordersprogram and in following through on the Committee's activities to the draftingand publication of its final report.

INTRAMURAL RESEARCH PROJECTS

Clinical Branch

Ballintine, Elmer J., M.D.Ocular Hypertension StudyAqueous Humor Formation in Monkeys

Bergsma, Donald R., M.D.Studies of Choroidal-Retinal Degenerative DiseasesStudies of Ophthalmic Familial and Genetic Diseases

Charles, Steve, M.D.Development of Improved Instrumentation for Vitreous

Surgery

Eichenbaum, Daniel M., M.D.Combined Clinical and Experimental Animal Study of

the Pathogenesis of Abnormal Proliferations inthe Vitreous Cavity

Foon, Kenneth, M.D.Inheritance of Susceptibility to LymphocyteTransformation Inhibition

Frank, Robert N., M.D.Argon Laser Photocoagulation of Retinal and

Choroidal DiseasesBiochemistry of Vertebrate Retinal Receptor Outer

Segments

Gaasterland, Douglas E., M.D.Study of the Use of Radioiodinated (1-125) ChloroquineAnalog for the Differential Diagnosis and Detectionof Intraocular Melanoma

Experimental Glaucoma in the Rhesus Monkey

Cunkel, Ralph D., O.D.Design and Construction of Ophthalmic Instruments;Research in Methods of Evaluating Visual Processes

Kolb, Helga, Ph.D.Anatomy and Pathology of

Kupfer, Carl, M.D.Studies of Parameters of

the Mammalian Retina

Intraocular Pressure

Macri, Frank J., Ph.D.Study on the Pharmacodynamics of Various AgentsAffecting the Intraocular Pressure

Clinical Branch (cont.)

Ross, KarynCiliary Body Blood Flow and Aqueous Humor Formation

in the Rhesus Monkey

Sullivan, William R., M.D.Comparative Treatment of Bullous Keratopathy with the

Bausch and Lomb "Soflens" and the American Optical"Bandage" Soft Contact Lenses

Studies of the Effect of Histocompatibility (HL-A)Testing and Corneal Transplantation

Treatment of Keratoconjunctivitis Sicca with N-acetyl -1-cysteine

Laboratory of Vision Research

Section on Biochemistry

Kinoshita, Jin H., Ph.D.Chemistry and Metabolism of the LensCataracts

Chader, Gerald J., Ph.D.Biochemical Development and Function of Retinaand Pigmented Epithelium

Cyclic Nucleotides and Vision

Helmsen, Ralph J., Ph.D.Induction of Buphthalmos in Chicks by Feedinga High Level of Glycine

Chemistry of the CorneaMechanism of Herpes Simplex Virus Infection of

Corneal Cells

Hess, Helen H., M.D.Biochemical Composition of Photoreceptor, Neuronal

and Glial Cells of Normal and Pathological Retinaand Brain

Lewis, Marc S., Ph.D.Chemistry of RhodopsinPhysical Chemistry of Model Gel Systems

O'Brien, Paul, J., Ph.D.Synthesis of Sugar-Containing Polymers in RetinaProtein Synthesis in the Retina

Shichi, Hitoshi, Ph.D.Biochemistry of Visual Pigments

(44 100

Laboratory of Vision Rose r h (cont.

Section on Experimental EnibrYo.L.

Coulombre, A.J., Ph.D.Ocular Morphogenesis

Section on Experimental tatho ogy

Kuwabara, Toichiro, M.D.Anatomic and Pathologic Studies of CinularEffect of ,.aser on the RetinaLight Effect on the Retina

Okisaka, Shigekuni, M.D.Effect of Intraocular Pressure on the ':iszN

Epithelium

Robison, W. Gerald, Jr., Ph.D.The Functions of Cell Microtubules and Mt--t':_lamten=s

in Ocular TissuesUltrastructure and Function of the Pigmema Zel:s n'

the Eye

Section on Neurophvsiology

Gouras, Peter, M.D.Physiology of the Primate Visual. System

Dow, Bruce M., M.D.Information Processing in the Visua: :.ores nne

Rhesus Monkey

Nelson, Ralph, Ph.D.Electrophysiological Studies of Mammalian Retins

Office of Biometry and Epidemiololy

Office of the Chief

Kahn, Harold A.The Model Reporting Area for Blindness StatistinsNational Health and Nutrition SurveyFramingham Eye StudyComparison of Localized Treatments f.7.7 B

Disease

Ganley, James P., M.D., Dr.P.E.Systemic and Ocular OnchocerciasisLymphocyte Transformation Response ir. T-rsutw.r.

Ocular Histoplasmosis

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