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COMMISSION ON EPIDEMIOLOGICAL SURVEY

ARNMD FORCES EPIDEMIOLOGICAL BOARD

SUMIMARY OF THE ANNUAL REPORT

OF THE COMMISSION

FISCAL YEAR 1966

The findings in this report are not to be construed as anofficial Department of the Army position unless so designatedby other authorized documents.

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MARCH 1967

t

THE DRIRCTOR'S SUWEARY REPORT

The Commission on Epidemiological Survey held its annual meeting atthe Walter Reed Army Institute of Research on 9 September 1966. Seniorrepresentatives of 'he Department of Army, Navy and Air Force and theU. S. Army Medical unit and other personnel at Fort Detrick who attendedwere:

U. S. Army Medical Unit

Colonel W. R. Beisel, MCCaptain M. K. Ward, USPHSLt Colonel K. R. Dirks, MCLt Colonel R. W. McKinney, MSCMajor H. I. Rapoport, MCMajor G. E. Shambaugh, III, MCCaptain A. C. Alevizatos, MCCaptain C. P. Craig, MCCaptain, R. D. Feigin, MCCaptain Z. V. Staab, MCDr. G. LustDr. V. G. McGann

U. S. Army

Colonel J. W. Cooch, MC, Walter Reed Army Institute of ResearchColonel L. P. Frick, MSC, Medical Research & Development CommandColonel C. W. Johnston, NSC, Medical Research & Development CommandColonel R. M. Nims, VC, Fort DetrickLt Colonel R. T. Cutting, MC, Medical Research & Development CouuiandLt Colonel J. linarson, MC, Office of The Surgeon GeneralLt Colonel J. C. Fitzpatrick, MC, Medical Research & Development

Command

U. S. Navy

Captain J. W. Millar, Bureau Medicine and SurgeryCommander L. W. Miller, Bureau Medicine and Surgery

U. S, Air Force

Colonel S. Lutz, Jr., MC, HQ, USAF, Office of The Surgeon General

Guests

Dr. Frank A. Carozza, Jr., Union Memorial Hospital, Baltimore, MarylandDr. Harold N. Glassman, Fort DetrickDr. Riley D. Housewright, Fort Detrick

i,

ii

Dr. Gustave Dammin , President of the Armed Forces Epidemiological Board,attended and made many helpful suggestions in connection with our mission,The Director expressed grateful appreciation to Captain Sidney A. Britten, USN,Execitive Secretary of the Board, and to Miss Betty Gilbert, AdministrativeAssistant, for their continued assistance in conducting the Commission'sactivities.

The agenda of the one day's meeting was devoted to reviewing work com-pleted or in progress by investigators of the U. S. Army Medical Unit andone of its contractors.

VENEZUELAN EQUINE ENCEPHALM ILITIS VACCINE

Clinical studies of 40 persons given attenuated Venezuelan equineencephalomyelitis (VER) vaccine revealed demonstrable viremia in 13 subjectsand clinical symptomatology in 15 subjects. The clinical findings did notcorrelate with the presence of viremia. Transient electrocardiographic

abnormalities were noted in 47.5% and transient leukopenia in 407 of thevaccinees. Eight individuals followed with daily electroencephalogramsdemonstrated no significant change subsequent to vaccination. There wasno statistically significant correlation between any of these responsesor combination of responses. The virologic studies demonstrated the presenceof low grade viremia up to day 12 postinoculation. In view of the low levelof viremia it appeared unlikely that vaccinees would infect Aedes aegyptimosquitoes. Members of the Commission on Viral Infections kindly studiedthe data and reached the same conclusion. Further studies are in progress.

METABOLIC CHANGES IN INFECTIOUS DISEASES

Intensive studies of metabolic and biochemical changes occurring inman during the incubation period and clinical course of various infectiousdiseases have been conducted. The objective of such appraisals has beento develop a better understanding of the fundamental nature of infectiousprocesses and to search for objective clues which might lead to earlydiagnosis. In tularemic infection caused by aerosolization of virulentPasteurella tularensis (SCHU-S strain) levels of certain blood amino acidsare decreased from 12-36 hr before the onset of fever. The changes aregreater in those persons with more severe illness. The loss does notresult from excess urinary loss but perhaps from excess utilization bythe liver and spleen. Amino acids are used for new protein synthesis.

There is a diurnal change in the concentration of blood amino acidsin normal individuals. Following VER vaccine administration at 0800 hr,there occurred an obliteration of the normal diurnal amino acid rhythmthat began within 1 day and persisted for 4 days. When the same vaccinewas administered to 20 other volunteers at 2000 hr, there was an earlyrise in blood amino acids of 2 days duration followed in turn by a fallto below normal concentrations for a total of 6 additional days. Thechanges in this latter group also included a loss of the diurnal rhythm,

iii

but in addition several patients showed up to an 80-fold increase in proline,a marked increase in glutamic acid, and a depression in glutamine. Thus,the exposure at 2000 hr was accompanied by a distinct pattern of metabolicchanges, some of which might involve an inhibition of the enzyme glutaminesynthethase.

Changes in another enzyme, tryptophan pyrrolase were studied in thelivers of mice infected with a small number of pneumococci. This infectionwas associated with a stimulation in the activity of this enzyme within 2 hr,but late in the infection the enzyme activity showed depression as it doesduring endotoxemia. The early induction of tryptophan pyrrolase was dependentupon the presence of an intact adrenal gland, an observation compatible withthe known ability of cortisol to induce this enzyme. Late in infection,however, when plasma steroid levels were high, the enzyme activity fell andcould not be stimulated by additional cortisol, an observation compatiblewith toxic inhibition of enzyme synthesis in a dying animal. Incidental tothis study was the first description of a circadian change in this enzyme.

The infection-related stimulation of synthesis of new protein moleculeswithin host cells is initiated by early sequential changes in deoxyribo-nucleic acid and ribonucleic acid (RINA) function within the cell. Thesewere studied in several tissues of the intact mouse after infection witheither Diplococcus pneumoniae or the Trinidad strain of VIE; similar studieswith VII were conducted in cultured tissue cells. It was possible to showdifferences in the direction of change in RNA and protein metabolism due toeither the bacterial or viral infection. In addition, VIE infection ofcultured cells was shown for the first time to be associated with inductionof a new viral RINA synthetase; present techniques have not permitted identi-fication of this enzyme in the intact animal host.

Studies of staphylococcal enterotoxin reveal that it is highly anti-genic although the rate of antibody formation is slow. There appears tobe a relationship between the level of circulating antibody and degree ofresistance to enterotoxin in primates. Staphylococcal enterotoxin differsfrom bacterial endotoxins since pyrogenic tolerance as measured by reticulo-endothelial system reactivity is transient. When animals are pyrogenicallyrefractory they react much less to intradermal injection of enterotoxin.These studies have broad implications and suggest that antibody inhibitsskin reactivity.

The Comnission, through the University of Maryland contract, hasextended the studies relating to the protective efficacy of typhoid vaccineand pathogenesis of the disease. Typhoid vaccine K (acetone preserved) andL (phenol inactivated) protected voluntoers asainst a low infectious chal-lenge of 100,000 bacilli (expected to produce illness in 25% - ID2 5 ).Aerosol exposure to an ID2 5 of Salmonella typhosa filed to induce illness.This suggests that the respiratory tract is not a site of invasion. Pene-tration through pharyngeel or tonsillar tissue appears to be an unlikelymode of entry. Typhoid bacilli survive for 45 min or more in the stomach.

iv

Organisms apparently multiply in the intestinal lumen and penetrate themucosa. The lamina propria of the small intestine shows mild inflammatorychanges during the incubation period after large oral inocula. Minimalchanges occur after an ID2 5 dose. Bacterial interference as a human hostdefense mechanism has been shown by studies with antibiotics given beforeinfectious challenge. Nonabsorbable antibi6tics reduce the numbers ofintestinal bacteria altering the pH. Under these circumstances smallernumbers of ,acilli cause clinical illness. Further interference studiesare in progress.

The extensive studies of the effect of bacterial endotoxin in animalsand human subjects show that during active infection with S. typhosa manacquires increasing hypersensitivity to the endotoxic component of themicrobe. Intradermal testing with purified S. typhosa during illnessreveals intensified 24-hr inflammatory lesions when compared to controlpreinfection responses and intravenous injection of the endotoxin elicitsmarkedly hyperreactive pyrogenic responses and subjective toxic responses.The endotoxin tolerance mechanisms possessed by normal man remain intact.The repeated administration of endotoxin intermittently or by continuousintravenous infusion causes tolerance to develop rapidly within the frame-work of the hyperreactive state. In spite of marked activation of thesetolerance mechanisms, the febrile and toxic course of the disease remainsunchanged indicating that en#otoxemia does not account for the sustainedillness. Although endotoxemia may not account for sustained illness, therelease of a relatively small bolus of endotoxin into the circulationduring typhoid fever (or upon institution of appropriate antibiotic therapy),could readily induce an abrupt intensification of the febrile and toxicstate in the hypersensitive host.

The vaccine trials indicate that the conventional typhoid vaccinesare effective in protecting man against low infecting doses which mightbe expected in a water-borne exposure but would provide no protectionfrom an exposure resulting from the consumption of heavily contaminatedfood containing more than 10,000,000 viable typhoid bacilli. Apparentlythe Vi antigen r se is not responsible for stimulating the protectiveantibody. Mechanisms involved in vaccine-induced resistance are notunderstood.

In conducting the research described in this report, the investigatorsadhered to the "Guide for Laboratory Animal Facilities and Care," as promul-gated by the Committee on the Guide for Laboratory Resources, NationalAcademy of Sciences-National Research Council.

In these studies the strictest standards which apply to human subjectsas volunteers were adhered to.

v

The Executive Meeting was devoted to hearing of the progress in thestaphylococcal enterotoxin B program and the need for evaluating severalvaccine@; VIE, EV plague, and Rocky Mountain spotted fever. The spottedfever vaccine studies vill be conducted in collaboration with theCommission on Rickettsial Diseases.

Colonel Dan Crosier presented a paper describing the program of thisCommission to the Association of Military Surgeons on 9 November 1966. The1967 meeting of the Commission, scheduled for 7 and 8 September, will focuson a discussion of metabolic changes in infectious diseases.

Theodore E. Woodward, M.D.DirectorCommission on Epidemiological Survey

vii

TABLE OF CONTENTS

The Director's Summary Report i

Clinical Studies of Venezuelan Equine Encephalomyelitis VaccineStudies in ManAristides C. Alevizatos, Captain, MC 1

Venezuelan Equine Encephalomyelitis Vaccine Viremia Studies in ManRobert W. McKinney, Lt Colonel, MSC 3

Changes in Whole Blood Amino Acids during InfectionRalph D. Feigin, Captain, HC 5

Serological Studies on Staphylococcal Enterotoxin BVirginia G. McGann, Ph.D. 7

Mechanisms of Pyrogenicity of Staphylococcal Enterotoxin BFrank A. Carozza, Jr., Captain, MC 9

Recent Studies on Anthrax ToxinMartha K. Ward, Captain, USPHS, Mary H. Wilkie, M.S., andAnne Buzzell, Ph.D. 11

Influence of Pneumococcal Infection on a Host Enzyme SystemMorton I. Rapoport, Major, MC 13

Alterations of Host Cellular Ribonucleic Acid Metabolism duringInfectionGeorge Lust, Ph.D. 15

Mechanisms of Endotoxin ToleranceSheldon E. Greisman, M.D., Edward J. Young, M.D. andWilliam E. Woodward, M.D. 17

Typhoid Fever: Pathogenesis and PreventionRichard B. Hornick, M.D. 19

Studies on Rocky Mountain Spotted Fever: Serologic Response in Man toVaccination with Combined Epidemic Typhus, Rocky Mountain SpottedFever and Q Fever VaccineCharles L. Wisseman, Jr., M.D., and Theodore E. Woodward, M.D. 21

Influence of Tularemia on Insulin SecretionGeorge E. Shaabaugh, III, Major, MC 23

DD Form 1473 25

UJNCLASSIFIED

DOC WENT CONTROL DATA.- R & Dfetel~SGGUitej. 1U~e .'. b~. andeae someaId. Nas~t be entfered. Wheata SMASHl 5S"! to e1.idlbEJ

GIS90A1411 AC TIVITY Gj.ge G.S*.r a. TSCUROITYCLASUIFICATIOR

U.S. Army Medical Unit U;CLASIFIEDort Detrick, Frederick, Maryland 21701 s uu

CLINICAL STUDIES OF VENEZUELAN EQUINE ENCEPHALOMYELITIS VACCINE STUDIES IN MAN

4. DESCfttPTIVE "OTC$ (7Y"sepow ot nhl"dts

S. AUTMORIS) (PlIED 7ein.#

A LEV IZATOS, ARISTIDES C.

a. REPORIT DATE MG TOTAL NO. or PAGES 7 No. aPRPSeptember 1966 4 + 2 Illustrations 07 Pmp

5G. CONTRACT OR GRIANT W, 5G& ORIGINATORPS REPORT HUMISERIS)

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10. DISTMISUTION STATEMECNT

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Forty volunteers were immunized with live attenuated Venezuelan equineencephalomyelitis virus vaccine and evaluated closely from clinical, laboratory, viro-logic and serologic standpoints. Some degree of reaction was noted in 37.57. of theseindividuals with 101 of them having 3+ reaction. Viremia was demonstrable in 32.57.;

47.57. had transient electrocardiogram abnormalities; 407. had transient leukopenia.There was no consistent positive or negative correlation between any of theseresponses or combination of responses.

14. KEYWORDS

Venezuelan equine encephalomyelitisVaccine, attenuatedImmunization

DD =" 1 4 7 3 'mauus.UNCLASSIFIED

UNCLASSIFIED3

flautiy lasifcaton DOCUMENT CONTROL DATA. - RS 0

U. OS.ON N ArmyTIVIV(Cqp. m._) As m~ONT SECUNITY CLASSIFICATION

*Fort Detrick, Frederick, Maryland 21701 UNCLASSIFIED

F-. GROUP

a. SISPORT TITLEG

VENEZUELANI EQUINE ZNCEPHALOMYLITIS VACCINE VIUEMIA STUDIES IN MAN

A. O9SC%-vmTO woC~ NO11(l's tgpW# Sad inhpo.ve Saeso)

S,. AU THORISI (P1Mg nimS. &OWoInik~tial, face GISA)

* McKINNEY, ROBERT W.

S. REPORT OAT9 75& TOTAL NO. OF PAOSS or. NO ma Es'

September 1966 7 5SM C0OWYRACT 0R GRANT NO. S&. O*IGINAT8WS 64EPORT NMUW8RISI

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10. OISTRIUUTION STATEMESNT

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$I- SJPOLCMIENTANT NOTES1 12. SPONSORING MILITARY ACTIVITY

Coossission. on Epidemiological SurveyArmed Forces Epidemiological Board

IS. AUISTRACT

An attenuated Venezuelan equine encephalomyelitis vaccine was studied in 40 mento determine viremia levels.in order to determine the potential for mosquito trans-mission. It was concluded that the results of this study and prior artificial anddirect feeding investigations indicated little or no such potential. It was proposedthat the restriction against use of this vaccine strain be lifted.

14. KEYWORDS

* Venezuelan equine encephalomyelitisVaccine, attenuatedIummnization

* Mosquito transmission

DDoo .O1473 us6Pl,"aeSpR gave- 1 "AN' a E I""S UCASFE

U.edt C.lAssifeicalioni

Fort Detrick, Frederick, Maryland 21701 a.otu

CHANGES IN WHOLE BLOOD AMINO ACIDS DURING INFECTION

6. 0ESCRIPTIVE 000O8TES (ltpS SI ,p a"~ 11iuhot" dales)

.AUITHOMIS) (Pont I me. Mkh. lAnitl, Ifeil Naem

FRIGIN, RALPH D.

6. REPORT DATE 746 TOTAL NO. OF PAGES 7. 0O. OP waEps

September 1966 7 + 10 illustrations I11S& CONTRACT OR GRANT NO. Is. ORISINATOWS REPORT NUMUERSIN

6. PROJECT NO. IB622401AO96

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I0. DISTRIDUTION STATEMENT

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11. SUAPPLEMENTARY NOTES 1t2. SPDOMSOING MILITARY ACTIVITY

ICommission on Epidemiological Survey1Armed Forces Epidemiological Board

tZ. ABSTRACT

Blood amino acids appear to follow a circadian periodicity in a number of species.Respiratory acquired tularemia in man caused significant decreases in these acids priorto the onset of signs or symptoms. Live attenuated Venezuelan equine encephalomyelitisvirus vaccine caused a reversal of normal duirnal rhythm of the acids regardless oftime of inoculation, 0800 or 2000 hr. Staphylococcal enterotoxin B given to micecaused a rise in tryptophan, attributable to inhibition of tryptophan pyrrolasa. Thechanges can be detected by a practical method using small amounts of blood.

14. IKEYWORDS

Venezuelan equine encephalomyelitisTL laremiaStaphylococcal enterotoxin BVaccineMetabolismAmino acidsCircadian rhythmicity

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SIROLOOICAL STUDIES ON STAPIIYLOCOCCAL INTZROTOXIN B

6- DESCRPTIVE NOTEII (TAMp 01#01001 mad bIftal,. SWISS)

ii. AU THOHIII (Fine Som. .5mwe trjuje.lost "mae)

McGARN, VIRGINIA G.

4. REPORT DATE To. TOY AL N.O. OF PAGES 10. Por marsEF

September 1966 7 plus 2 illustrationF IIS. CONTRACT OR GRNAT. MO. M. 000101NATOPPS REPORT NU004EHI1SI

6. PmejacY PO. IB6224O1A096

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'ommission on Epidemiological SurveyArmed Forces Epidemiological Board

18. AUSIOTACT

Data on the serology of staphylococcal enterotoxin B (SEE) indicate thathemagglutination and toxin-combining activity were more sensitive than precipitationas indices of antibody, and that there was a relationship between circulating antibodyand resistance to overt effects of SIB. Studies on antibody response suggest that

1519 my be highly antigenic but that antibody development may be slow. Some factorsthat enter into the time of appearance and magnitude of response are challenge dose,previous experience or prechallenge antibody, and antitoxin treatment. These resultswere derived from studies in which monkeys received a single dose or several widelyspaced doses of unaltered toxin. At the present time it would be unwise to predictthe effect of multiple, closely spaced exposures to unaltered toxin or to toxoidpreparations, or the response of another susceptible species, such as man.

14. KEYWORDS

Staphylococcal enterotoxin BSerologyImmunology

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*U. S. Army Medical Unit UNCLASSIFIEDFort Detrick, Frederick, Maryland 21701

8. RpoRTl TITLE

MECHAMISMS Of PYROGENICITY OF STAPHYLOCOCCAL ENTEROTOXIN B

4. OselCRPTIYE NoTEs t1mss. uepfsf and In.shImov date@)

S. &U "GoalS ("ve OS* ad*& WNW46. his# name)

CAROZZA, JR., FRAN A.

S. REPORIT OATS 74. TOTAL NO. OF PASES lb. No. maRps

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10. DISTRIOUTIONd STATEM6ENT

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Conmmission on Epidemiological Survey

Armed Forces Epidemiological Board

Rabbits became pyrogenically refractory to staphylococcal enterotoxin B (SEB) aftezdaily intravenous injections. This state was transitory and disappeared completelyithin 9 days if animals are not repeatedly rechallenged. The state appears specificfor SID since-refractory animals react normally to endotoxin and endogenius pyrogen.

The refractory state is not mediated by a demonstrable circulating humoral protec-tive factor nor generalized hyperactivity of the reticuloendothelial system. Theoccurrence of the state can be correlated with a significant diminution in skin sensi-tivity to enterotoxin.

These data are compatible with the thesis that the fever produced in rabbits by SRI

is mediated by a hypersensitivity reaction possibly of the delayed type.

14. KEYWORDS

Staphylococcal enterotoxin BPyrogensDose responseIndotoxins

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I s. REPORT TITLA

RECENT STUDIES ON ANTHIRAX TOXIN

4. DESCRIPTgVE NOTES (2J.p. of *aO - ad teehujV0 SONIA)

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SeTember 96 6 + 2 illustrations 8

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If- JOPLELMENTARY NOTES [la. SPONSORING MILITARY1 ACTIVITY

Comiso Fone Epidemiological SoardeIArmed Fone Epidemiological Suarve

"IS.AUSXMu lure filtrates of anthrax toxin have been concentrated by ultracentrifugation,I producing ultrafiltrate residue (UFR). Electrophoresis on paper, cellulose and gel

discs has been carried out onl UFR. Immunodiffusion and chromatography studies havealso been conducted. Some fractions have not yet been identified, although some arerelated to previously known fractions, protective antigen, edema factor and lethalIfactor.

1 14. KZYWORDS

AnthraxToxinElectrophoresisChromatographyUltracentrifugation

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INFLUENCE OF PNZUMOCOCCAL INFECTION ON A MOST ENZYME SYSTEM

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RAPOPORT, H. I.

0. IMPORT ,ATE T.& TOTAL HO. Op tA s l,.. MO. or Rare

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11. EIEPPLIWENETAftV "OTUS 12- SPONSORINGO MILITARY ACTIVITY

Commission on Epidemniological SurveyArmed Forces Epidemiological Board

Up. ASTTRACT

Both stimulatory and inhibitory influences have been observed to be at work onthe tryptophan pyrrolase induction system. Adrenal steroids play a major role in thestimulatory aspects which we have noted. Data are not available as yet to statecategorically whether changes in tryptophan pyrrolase activity In pneumococcus infec-tion actually represent changes in enzyme synthesis or indirect changes in cofactoror substrate concentrations. It is apparent that additional studies will be requiredto define better the nature of the factors that mediate early host adaptive changesin infection.

14. KEYWORDS

TryptophanPneumococcal infectionEnzymesMetabolism

142 UNCAUSSIFI• D

* I1NtLA gIulkmlD 15i

DOCUIMEET CONTROL DATA- R & D@RIIqNSlllllN~ ACTIVSTVIC.pg515O h ]G RNpOT SaCURIT? CLAMIICATION

S U. S. Army Medical Unit UNCLASSIFIEDFort Detrick, Frederick, Maryland 21701 26..GouP

2 . REPORT TiTLE

ALTEIATIOIS OF HOST CELLULAR RIBONUCLEIC ACID METABOLISM DURING INFECTION

4. OUENSIPTveV NOTaE (po of-"Iotu A-n heine)n.. date@)

S. AU THOR40) (MMso me. okW@ hgtftl, Sent gG~m)

LUST, GEORGE

4. naPO *T DaTr 5.L TOTAL NO. OF PAGes 15. ea. op auraSeptember 1966 7 + 8 illustrations 1 8

44, CONTRACT ON GRANT NO. S&. OR14INATOW5S REPORT NUMlERII)

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11. SUPPLENENITART NOTag 12. SPGCCSORINS MILITARY ACTIVITYIoCommission on Epidemiological SurveyArmed Forces Epidemiological Board

10. ADSST'" ectrophoresis on agarose gels separates ribonucleic acid (RNA) species dis-

cretely with good resolution. The method provides a rapid, sensitive way of screeningRNA preparations for complexity of individual samples or in comparison of them fromdifferent sources or experimental conditions. The 6S MA and the other minor componentiare apparently associated with ribosomes. The observation that the 6S MA is associate4with the ribosomes may be of value in elucidating its function. It may well be thatthis band is where messenger RA is found.

Although this method must still be refined In several ways, it is already veryuseful. An emphasis on alterations of specific MA molecules as well as other metabo-lites, should provide significant contributions in order to define the host metabolic

response to infections more precisely.

14. KIEYODUS

MetabolismRibonucleic acidDeoxyribonucleic acidRibonucleic acid, viralElectrophoresis

00 =0"0147 me Um1N S JAN 1O. is ISLASS

. 6*6 9* NIAS11

UNCLASSIFIED 17

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V.@~w~~ CTIVITY &&.mu PA.REPeT SECk#6,?y CLAIONFICATI@Uo University of Marylnd School of Medicine UNCLASSIFIED1 29 South Greene Street 6. eRoup

Baltimore, Maryland 21201

I*- REPO*T TITLE

MICHANISMS OF INDOTOXIN TOLERANCE

4- OESCRIPtIVE NOT6%S (Tae *efpl and bM.Nft. dktoa)

S. AUT"O6iS16 (Fe l ahike WHO. RlsIe)

GREISMAN, SHELDON E., YOUNG, EDWARD J., WOODWARD, WILLIAM E.

6. REPORt DATE 7A. TOTAL No. Ow PAGES 'IF NO. P REs"September 1966 3 2

We. cmRAcr ow sCRAI no. DA-49-193-MD-2867 W ooIGINATOR.S REPORT NUM.SERI)

SMo.,cT .o. 1622401AO96

a. Task No. lB62240lA096 01 .. otER RPoRT eoS ( mmy A" q be

tWork Unit IB622401A096 01 901.5. mNSmuT,@UT STATUMUT

Each transmittal of this document outside the Department of Defense must have priorapproval of Commanding General, U. S. Army Medical Research end Development Command,Washington, D. C. 20315

lb 12, SPONSORING MILITARY ACTIVITYA ver`aton6 Whv een published in Journal of U. S. Army Medical UnitExperimental Medicine 124:983, 1966. Fort Detrick, Frederick, Maryland 21701

ReA present observations, considered together with those of other investigators,

support the hypothesis that pyrogenic unresponsiveness to endotoxin involves two dis-tinct immunologic mechanisms. In terms of this hypothesis, the rapid reduction infebrile responsiveness to endotoxin is mediated by desensitization at the cellularlevel. With small doses of endotoxin, such as those employed in the present studies,this desensitization is primarily specific; with larger doses, nonspecific mechanismsare superimposed. So long as the subsequent doses of endotoxin are closely spaced orcontinuously infused, optimal conditions are provided for cellular desensitization andpyrogenic unresponsiveness to a given quantity of endotoxin can be induced rapidly andmaintained without the requirement for antibody. However, as the interval between endtoxin challenge is lengthened, cellular desensitization wanes and tolerance becomesincreasingly dependent upon those antibodies directed against the common toxophoregroups responsible for endotoxin pyrogenicity which assist the reticuloendothelialsystem in the clearance and destruction of this molecule.

14. KEYWORDS

EndotoxinPyrogensStaphylococcal enterotoxin B

lscherichia coli endotoxin

.'147 = 4m mewIUL&SII now as4

C~3LASSIFIED 19

(5~~~i ~ ~ * H*.iet. atde. body *I bStnoct ea s OFXnd .deMj watdm, Rt be .pt.,eE tow. on -Hef I*~t elessnII

University of Maryland School of Medicine UCASFE29 South Greene Street

UCASFE

3, 049pp TNO IT)(PLE. d~ edI .

HORNICK, RICHARD B.

41. REPORT DATE 1711 TOTAL NO- Op PIGS, Job. No. OP Revs

September 19bb 58-. CONTRACT 0R GRANT MO DA-49-193-MD-2867 194. ORISIMATOfrS REP-OatNUERS

6. PROJECT no. lB622401A09b

e.Task No. IB6224OIA096 01 .aON& .m 1100117MONoae(Ajv~Wuoo .oetmewaa~ee

os Work Unit lB622401.A096 01 901to. DISTPIGUTIOW STATEMENTEach transmit tal of this document Outside the DepartmeAt of Defense must have prior

approval of Commanding General, U. S. Army Medical Research and Development Command,Washington, D1. C. 20315

I I- SUPPLEa~MENTRY NoTEs 12. SPONSORING MILOITARYV ACTIVITY

U. S. Army Medical UnitFort Detrick, Frederick, Maryland 21701

*'MAS~otugh the volunteer studies have shown typhoid vaccines to be effective against

low dose challenge, the exact mechanism or mechanisms of this action are not apparent.Vi antigen did not appear to be necessary for the virulence of typhoid bacilli in manas in mice and probably was not important for the immunization of man. Hybrid strainsof Salmonella typhosa have been isolated from the stools of volunteers.

14. KEYWORDS

Typhoid feverPathogenesisVaccineslImmlunity

DD .12""147 - hEM? UNCIASSIFIED

UNCLASSIFIED 21sacuritt Clota"sification nI e ~ IDOCUMENT CONTROL DATA- R & D

(Secutr €).440fMgc4fim of tile, be* of "afmOct .,,d Indexingj a of,.10. mutm# a. tesmd hn. he *-ol -por to I la-elflodIO~kGINATING ACTIVITY (C a..ator acmrvctAsi.)rimUniversity of Maryran~cnool of Medicine N CLASSIFII29 South Greene Street 2 C. LSIOUPBaltimore, Maryland 21201

3. OEPONT TITLE

STUDIES ON ROCKY MOUNTAIN SPOTTED FEVER: SEROLOGIC RESPONSE IN MAN TO VACINATION WITHCOMBINED EPIDEMIC TYPHUS, ROCKY MOUNTAIN SPOTTED FEVER AND Q FEVER VACCINE

4. DE[SCRIPTIVE NOTES (2 f" .1 -"a# a.d kWfmwi. dfte..)

S. AUTUO•NISI (lm flt nal. majdo•S initiaU l.sal nammr)

WISSEMAN, JR., CHARLES L., WOODWARD, THEODORE E.

6 .EPORT DAVsE •. TOTAL NO. OF PAGES lb. NO. OF NEFS

S*.C €TROCT ORNT Ne.A-49-193-D- 2867 I. OSGINATOW • REPORT NUUUENISI

b. p-t.CCT"NO 1B622401A09b

Task N,. lBb22401A09b 01 Owe .m•oo 0n) NOwSI, (Aar. * et mP so "W

Work Un)t 1Bb22401AO9b 01 901

tO. D1t8'TN"3UTION SrAT A EmNTEach transmittal of this document outside the Department of Defense must have priorapproval of Conmanding General, U. S. Army Medical Research and Development Comand,Washington, D. C. 20315

1 1 . 5U;-L9%4Nt%' NOTES 1I. SONSONI0NG MILITANT ACTIVITY

U. S. Army Medical UnitFort Detrick, Frederick, Maryland 21701

A total of 17 men have now been given a combined epidemic typhus, Rocky Mountainspotted fever and Q fever vaccine without untoward local or systemic effects. Prelimi-nary serologic testing has revealed little if any difference in response to the com-ponents of this vaccine as compared with response to monovalent vaccine after a singleinoculation. Additional studies are in progress to extend these observations and tomeasure the immunogenic effect of multiple dose vaccination.

14. KEYWORDS

Rocky Mountain spotted feverEpidemic typhusQ feverVaccinesSerology

o14.S wo •R9=Y, edLI IUNCIASSIFIIDlmewI aSMmaem1

UNCLASSIFIED 23security aasmaAlcation

DOCUMENT CONTROL DATA - R & D(S,"wtI .. aaajU161Ms, ofd. e.b a .o abesiect a, ind kexi asnsbhi@U maust b enterd whoa From" 16"t to £Ja&Wan4

I. O*lOINATING ACTIVISTY (CV8.ess a1eg) Si& NEPONT ECURITY CLASIFICATION

-US. Army Medical Unit I UNCLASSIFIEDFort Detrick, Frederick, Maryland 21701 A6. G.ou.

a-. m9PORT TITLm

INFLUENCE OF TULARIEMIA ON HUMAN INSULIN SECRETION

4. OESCRIPTIYEC NOTUS (1bPs 1ustdkih.i.di

S. AU T"O"40N1 (pFint Si, milah Idl. Seat seamo)

SHAMBAUGH, III, GEORGE H.

0. REPORT OATE 7&. TOTAL NO. OF PAGES 17. NO* OF REP"

September 1966 5 + 4 illustrations 9C*. CONTRACT OR GRANT NO. ft. ORIGINATOlS RIUPORT NUNlaRISIeg

a. PtcOJcT No. 1B622401A096

L Task No. 1B622401A096 01 55. OTHER REPORT NOIS) (Apy area, &atm•m e, my besaisd

SWork Unit 1B622401A096 01 00410. 09TRIu MTION STATEMENT

Each transmittal of this document outside the Department of Defense must have priorapproval of Commanding General, U. S. Army Medical Research and Development Command,Washington, D. C. 20315I1. SUPPLEMEN9TARY NOTES 1. SPONSORING MILITARY ACTIVITY

A version has been cleared for publication Commission on Epidemiological Surveyin Diabetes. Armed Forces Epidemiological Board

'-6s-h6.#5

m insulin concentrations were measured serially in 7 nondiabetic subjectsfollowing a rapid intravenous (IV) glucose load during a preinfection control period,early clinical respiratory tularemia, and again in convalescence following therapy.Within 24 hr of onset of clinical illness the rate of glucose disappearance from theblood had diminished significantly. In contrast, there was a brisk onset of insulinresponse which reached higher peak concentrations and fell more slowly then the responsobserved during preinfectLon control period. The pattern during clinical illness wasdifferent from that described after IV glucose loading in maturity onset diabetes orobesity, and may have been influenced by glucocorticoid excess. The magnitude of insuliresponse during clinical illness was significantly increased and was directly related tiheight of fever. In contrast, the rate of glucose disappearance was inversely related t4fever. The inverse relationship of the magnitude of insulin output to the rate of glu-cose disappearance suggested a peripheral inhibition of insulin action during infectionAlthough fever may have played a role during acute illness, the persistence of an ab-normal insulin response in 1 patient during convalence suggested that this change wasnot dependent upon fever alone.

14. KEYWORDS

TularemiaMetabolismDiabetesin*l1 in4A

ADM10 WPM= UNCLASSIFIED

msa sUbm

S... JL. :

UNCLASSIFIED 25

bcugty classjflc.Iti"

DOCUMEN4T CONTROL DATA. -£ 0(sewfoty esweenwoeS of tolte, of *&~140 A00040 &"Wms .l am"l be .Utamd whn 0aww" B5s el Is 0lm00

I. OUI*IWATING ACTIVITY (08000100 0 ~0 REPORT SeCwIIRIT CLASIPICA i.Comission on Epidemiological Survey of the Armed UNCLASSIFIEDForces Epidemiological Board and U. S. Army Medical &A nPUnit, Fort Detrick, Frederick, Maryland 21701 NA

a. RUPORT TITLE

COMMISS ION ON EPIDEMIOLOGI[CAL SURVEY, ARMED FORCES SPIDEID4OLOGICAL BOARD, SLWARY OfTHE ANNUAL REPORT OF THE COMMISSION, FISCAL YEAR 1966

4-D6SCRIPTIV9 NOTES (27nS of ep951A and AnlmolW, daft*Sumary of the Annual Report, Fiacai Year 1966

kAUTNORM (IPW a.lunSald~oh~ldgi&* AS.) C. ALEVIZATOS, R. W. McKINNEY, R. 0. FEIGIN,V. G. NcGANN, F. A. CAROZZA, JR., M. K. WARD, M. H. WILKIE, A. BUZZELL, G. LUST,M. 1. RAPOPORT, S. E. GREISM&N, Z. J. YOUNG, W. E. WOODWARD, C. L. WISSEMALN, JR.,gR. a_ MOICK, T. E. WOODWARD, G. K. SWEAG II

o. REOC STE TOTAL NO. 0F PAGES 176. NO. or RaeS

March 1967 25 010SCONTRACTYONGRANTMNO. 9L016MTW EOTHNO06

DA-49-193-MD-2867 .OlGlAOSRERTUIEII

6. Pwaajcy No. IB622401A096

4. Sb. OTHE RPORtT NOW~ ~V41'eame WJSIS *51 *5 plaed

Each transmittal of this document outside the Department of Defense muat have prior* approval of Coirnnding General, U. S. Army Medical Research and Development Commnd,

Washington, 0. C. 2031511. SUPPaieiETARYv MOTES 2tS 900100144ORS MILITARY ACTIVITY11

.S. Army Medical Research and Development~ommand, Office of The Surgeon General,epartment of the Army, Washington, D. C.

19. AUSTRACYProgress is reported in selected areas of research in medical defense aspects of

biological agents by the U. S. Army Medical Unit and one contractor.

14. KEYWORDS

Venezuelan equine encephalomyelitisRocky Mountain spotted feverQ feverEpidemic typhusTularemia

* Typhoid feverAnthrax toxinMosquitoes

* MetabolismStaphylococcal enterotoxin BEndotoxinVaccines

- .=414 7J3.~JMU. WC