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N The New England . Journal o e iclne FORMERLY THE BOSTON MEDICAL AND SURGICAL JOURNAL-Ettablished 1828 VOLUME 264 JUNE 15, 1961 NUMBER 24 Original Articles The Nephrotic Syndrome as a Complication of Perchlorate Treatment of Thyrotoxicosis . 1221 R. E. Lee, R. L. Vernier and R. _ A. Ulstrom The Emerging Pattern of Urban Histoplasmosis: Studies on an Epidemic in Mexico, Missouri 1226 M. L. Furcolow, F. E. Tosh, H. W. Larsh, H. J. Lynch, Jr., and G. Shaw Constrictive Pericarditis Due to Histoplasma Capsulatum . . . . . . . . . . . Charles F. Wooley and Don M. Hosier Partial Anomalous Pulmonary Venous Connection 1230 with Unusual Variations . . . . . . . 1233 Robert B. Kalmansohn, James V. Maloney, Jr., and Richard W. Kalmansohn Special Articles An Appraisal of the Smoking-Lung-Cancer Issue 1235 Ernest L. Wynder Some Phases of the Problem of Smoking and Lung Cancer . . . . . . . . . . . . . Clarence C. Little 1241 Medical Progress Intestinal Absorption - Aspects of Structure, Function and Disease of the Small-Intestine Mucosa ( Concluded ) . . . . . . . . 1246 Leonard Laster and Franz J. Ingelfinger Medical Intelligence Anuria as a Presenting Symptom in Unsuspected Leukemia . . . . . . . . . . . . 1253 Jerrold Post Hazards to Health: Effectiveness of Seat Belts in Preventing Motor-Vehicle Injuries . . . 1254 Robert G. Frazier Case Records of the Massachusetts General Hospital . . . . 1256 Editorials The Great Debate . . . . . . . . . . 1266 U rban Histoplasmosis . . . . . . . . . . 1267 Cost of Medical Care . . . . . . . 1267 Regarding Gamma Globulin . . . . . . . 1267 Massachusetts Department of Public Health . 1268 Book Review Correspondence . . . . . 1268 Books Received Notices . . . . . 1270 Second-Class postage paid at Boston, Mass. Published weekly at 8 Fenway, Boston 15. Domestic, $8.00 per year. New (3rd) Edition! Sodeman's Pathologic Physiology Gain greater accuracy in daily diagnostic and treatment measures with the help of this lucidly written text. 28 outstanding contributors bring you the results of their most recent investigations into the mechanisms of disease. They show you how agents bring about dis- ease - what causes a particular symptom - what changes take place in the body during disease - how one disordered system affects another. This New (3rd) Edition represents a thorough revision - skillfully holding normal physiology to the minimum needed to satisfactorily understand and interpret the abnormal. Completely rewritten sections include : Genetics; Water and Electrolyte Balance; Protective Mechanisms of the Lungs; Disorders of the Gallbladder and Pancreas; and Diseases of the Nervous System. 1270 1270 You will find answers to hundreds of such basic ques- tions as: How does cardiac hypertrophy lead to con- gestive heart failure? How can you evaluate pulmonary function in disease of the lung? What is the basis for modern liver function tests? How do endocrine dis- turbances affect blood formation? When is splenectomy contraindicated in purpura? How does kidney disease produce edema and how does it affect therapy? The.physician who understands HOW and WHY dis- ease symptoms occur will find himself on firmer ground for making more accurate diagnoses and for instituting effective treatment. This book offers doctors in every field of medicine a vast store of usable information on mechanisms of disease. By 28 AMERICAN AUTHORITIES. Edited by WILLIAM A. SODEMAN, M.D., Sc.D., F.A.C.P., Dean and Professor of Medicine, Jefferson Medical College. 1182 pages, 6%2" x 94", with 194 illustrations. About $14.00. New (3rd) Edition - Ready in July! To Order See Saunders Ad and Coupon on Page xvii Inside ~ r

With ".rorer anedical management and adequate control of s,.izUres, rpiieptic persons may lead pro- ductive, ;anctioning lives." To implement this goal, many ciinicians rely on DILaNTiN for outstanding control of grand mal and psychomotor attacks. "ln most Cases DILANTIN is the drug of choice.:.. Toxic symptoms are uncommon and when they do appear they are usually readily controlled; the drug is and s.Ijidely available."' DILANTIN vv~i; :;n ~dantoin sodium, ''nrae-Davis) is 2,; ,i;: uo3 in saverai iorms, inciariing Xapseais, 0.C3 ';i. ;nd 0.11 Om., bottles op 100 and 1,000. I FA ;:ii`',' ;FIF .,J T;3 0 ;l'JU L13 A I I TS for }h, rjSvcna- HELPSKEEPNIM motor r:!*.,r'~: =yELANTSNJ IN THE :~.~.~ apsauis ;~,l~,ni ;,n , ~~ mg., phenoi,,z:; '-ji.n! A ;-n,., d es- MIDSTOFTHINGS oxye,~~: ~wri:; ~.° :°urocnloride 2.5 mg.), bottles of 3 00. for "AILONTIN` Xaps2als (phen- suxir;,i Dm., ~ottles of 100 and mnT. ,er 4 cc., 1o-ounca bottl (mathsuximi;le, Parke-C<.;. i :-'_, aoNTIN= Capsu;_n s i.25 G rn bottles ;r aataiis of

! a breathing sperl*fr Quadrina mom a rapid way to clear the airway • stops wheezing • increases cough effectiveness • relieves spasm In chronic disorders associated with obstructed respiration, t'ne dependable antispasmodic and expectorant actian of Quadrinal rapidly clears the bronchial tree. Patients breathe more easily and acute episadeo~ of bronchaspasm are often eliminated• Quadrinal is well toferated, even on'prolonged a1~miru7tratiarr"'~ ~ REM potassium iodide in Quadrinal provides an expectorant of time-tested effectiveness and sclfety; - tndications: Bronchialasthma, chronic hro ~ch :i;, pulmonary fibrosis, pulmonary emphysema. tfvadrinak iAblets, containing ephedrine HCl (24 mg.) , fl phenobarbltat t24 mg),`Phyllicin" ;theoptr,Jirne ralr um salicylate) tt3p mg.},andpotassi>#m iodids..0.3 Gm.k+ . ~ - ~ "-~'' I Alsa availahle- a new Quadrina[ dosage form with#aste-appeaf for all dge R: ~~ ~~ ' fruit-flavored QUADRINAC SUSPENSI€1N (1 teaspoonful '.)uadrfr:ai Tabi2t1' t KNOLL PHARMACEUTICAL COMPANY, ORANGE, NEW aERSEvi rR 'Quadrinal. Phyllicin" :.5 Ft ~w ^8k%Alr.rWX irK `R# N< e i: a a•

nearly identical to mother's milk' in nutritional breadth and balance A new infant formula Enfamilm Infant formula Five years of research and 41,000 patient days of clinical trials demonstrate the excellent per- formance of Enfamil. This new infant formula satisfies babies and they thrive on it. Digestive upsets are few and stool patterns are normal. Enfamil produces good weight gains. In a well-controlled institutional study2 covering the crucial first 8 weeks of life, Enfamil pro- duced average weight gains of 11.3 ounces every 2 weeks during the course of the study. Enfamil is nearly identical to mother's milk' • in caloric distribution of protein, fat and car- bohydrate• in vitamin content (vitamin D added in accordance with NRC recommendations) • in osmolar load • in ratio of unsaturated to saturated fatty acids • in absence of measura- ble curd tension for enhanced digestibility Babies started on Enfalnil stay on Enfamil 1. The Composition of Milks, Publication 254, National Academy of Scienees and tiational Research Council. Revised 1953. 2. Brown, G.W.; Tuholski, J.M.; Sauer, L.W.: :4finsk, L.D.. and Ro.enstern.l.: J. Pediat. 56:391 (\lar.) 1960. fl Mead Johnson Laboratories Synobol of service in medicine

in severe drug and food sensitivity... rapid relief and control of symptoms on short-term therapy with Decadron® Brief treatment with DECADRON-orally or parenterally-can provide rapid and effective control of allergic emergencies and acute allergic disorders such as reactions to foods, drugs, plants, weeds, and animals. In 40 patients given Injection DECADRON Phosphate, "subjective improvement was often noticed within one hour and objective improvement recorded within four hours."t Therapeutic doses of steroids may help prevent recurrences of severe allergic states, without interfering with desensitization or other immunity procedures.2 Before prescribinQ or administering DecADeON, the physician should consult the detailed information oa use accompanying the package or available on request References: 1. 6rater, W. C.: Southern M. 1. 53:1144, 1960. 2. Feinberg, S. M.: Med. Sci. 6:(No. 3)181, 1959. Su plied: As 0.75 mt;. and 0.5 mg. scnred, pentagoo•shaped tablets in bottles of 100 and 1000. As fnJectien DECADRON Phosphate in 5 ce. vials, each cc. cantaininQ 4 mg. of dexamethasone 21-phosphate as the disodium salt: inactive Ingredients: 8 mg. creatinine, 10 mg. sodium citrate; sodium hydroxide to pH 7.8, and water for injection q.s. I cc.; preservatives: 0.32 per cent sodium bisuifite and 0.5 per cent phenol. DECADRON Is a trademark of Merck & Co., Inc. S MERCK SHARP L DOHME 411) Division of Merck & Co., INC., West Point, Pa. ffs uecadio Decadron_ TREATS MORE PATIENTS MORE EFFECTIVELY DECADa00: Recommended dosage schedule in the treatment of drug and food sensitivity reactions time amount administration .. O t;:n [C. , t•7 3 rls'.i rcilon .~a;iW Phnspnate ..trdntuscLl3r ^.it0d 3S n7c,',s57r; i .. ...-. ° ljolet UterJCy, +(iie tne fvst c-al r.ase lonr or fe7`.z:rs rore ttt: finat parenterat dose.) " 2nd day two0.75mg.TabletsDECa0R0N b.i.d. 3rd day two 0.75 mg.Tablets DECa0e0N b.i.d. 4th day one 0.75 mg.Tabtet DECAOROe b.i.d. 5th day one 0.75 mg.Tablet DECADRON per day 6th day one 0.75 mg.Tablet DECADRON per day 7th day RETURN VISIT t !

contain an ootimai ratio ef inetn-jn~onetamine and enobarbit~l to suporess acpetite and ease emotional symptoms of tooo wi"tnnravrai. ;.- ,r- proved Mental ; pro:iuced b_ Amb r _ ;i s , ,e ~xtra nncour- =ern~nt i:te a 7aluncod rr.er-_II ,vei~ht ;>ian. Am`..::r resr,onse .~..;i ^~ StJpp led. .lmbar 7- ' Ytentab coflt-. InS: "' -tn3,i1• eti-rne HGi 1~ e.. I ^P p rr,ii .I 54 c rn ;. '.' ;,r.). =.=1c'1 .'.znbar I .-'XteRtab c'7`."71r etnamnnet3m •~e Extentab" before breakfast pro:,;aes nppetite and mood control for 10 to 12 hours, in 3 sm ;le,cor;troi'~.ed-release, extended action tabfet- ;;iso available are regular AMBAR TABLETS. Each contains rnetnamphetamine HCI 3.33 m-,.. phenobarbital 21.6 m,., ('. 3r.). For uso in convent!oro: dosade schedules (one or t,vo t.i.d.). or for intermittent or suoplemental theraov. Precautions: .',dnn;nister A.rnhsr .'nth caution to patients ::ith car_i,ovascular dis, ~se or h~~~perthvroidism. Con;r~- ,;i;c,atad in . ., e „it:1 ,. :ncr:sies to,vard .:ar'r.i,u• :tas or sy mr. t~emi^ietics. sc.asional side erfects scc`1 ::s nervnusness or excitement fiave been moted , e usua;ly intre~~uent and sli;nt when Ambar's reccr~i- . ,ondeci dosa-c, _.re folio:red. ,~' '- ~N .. Fi ROBINS r.o., i 7(.. •~ Fi~.1r)rlu Vn- a~ .:+ __.. ..~_, , .. .,~., . ..,, .. .. . ~ T~

THE NEW ENGLAND JOURNAL OF MEDICINE Bendectin r- at bedtime prevents morning sickness here For,nuta: Each white, specially coated tablet contains: Bentyl (dicyclomine) Hydrochloride .......... 10 mg. Decapryn (doxylamine) Succinate .............. 10 mg. Pyridoxine Hydrochloride .............................. 10 mg. 1. Middleton, T. F.: Postgrad. Med. 24:699. 1958. 2. Nulsen, R. 0.: Ohio State M. J. 51:665, 1959. 3. Personal communications, 1956-57. 4. Towne, J. E.: Internat. Rec. Med. l; t:583, 1958. Geiger, C. J., et al.: Obst. & Gynec. :;:688, 1959. June 15, 1961 "...I have gained the best results with f Bendectin]. .. Because these tablets have a protective coating ... the dose taken at night be- comes effective in the morning."1 BENDECTIN Measure your present therapy against these demonstrated advantages:  proved relief in more than 9 out of 10 patients2-5  no phenothiazine-like side effects n daily therapy costs less than a quart of milk DOSAGE : Two tablets at bedtime. suPPLY : Bottles of 100 and 500. ra..ocnnans: eeHOCC•IH®, eEN.vi®, occ.Pnrn® U Merrell ® THE WM, S. MERRELL COMPANY Division of Richardson-Merrell Inc. Cincinnati, Ohio • Weston, Ontario ,

~.. 's Vol. 264 No. 24 ADVERTISING SECTION in edema or hypertenslon 1 , more doctors are prescribing- more patients are receiuing the benefits of more clinical evidence exists for- See "Dr.B"on NBC-TV : TUESDAY NIGHT,IUNE 27,1961 A P=rtrait ot !ne larnJr oirsioan anj - meoal ; _:ntt~Oulicn5 ;o 11. neal!r, cl !tle CHLOROTHIAZIDE than for any other diuretic-antihypertensive DIURIL is unique. There is no other brand of chlorothiazide. Dosage: • Edema-One or two 500-mg. tablets DIURIL once or twice a day. Hypertension- One 250-mg. tablet DIURIL or one 500-mg. tablet DIURIL two to three times a day. Supplied: 250-mg. and 500-mg. scored tab- lets DIURIL chlorothiazide in bottles of 100 and 1000. DIURIL is a trademark of Merck & Co., INC. Additional information is available to the physician on request. MERCK SHARP & DOHME QS~ Division of Merck & Co., INC., West Point, Pa. • HYNrRrENSiON CONGESTIVE FAILURE t`RLraLNSTRUAL ttNSiON EDEMAOF PREGNANCY CiitHtioSiS:^:iTH A~sciiLS RENAL EDEMA L i

x TI-IE NEW ENGLAND JOURNAL OF MEDICINE Protects the angina patient better than vasodilators alone Unless the coronary patient's ever-present anxiety about his condition can be controlled, it can easily induce an anginal attack or, in cases of myocardial infarction, can delay recovery. This is why Miltrate gives better protection for the heart than vasodilators alone in coronary insufficiency, angina pectoris and postmyocardial infarction. Miltrate contains PETN (pentaerythritol tetranitrate), acknowledged as basic therapy for long-acting vasodilation.. . . REFERENCES: 1. Ellis. L.. B. el nf.: Circulatiun 17:9+5, Mav 1958. 2. Friedlander, H. S.: Am. J. Cardiol. 1:395, Mar. 1958. 3. Rlseman, J.E.F.: Kew England J. \1cd. 261:1017. Nov. 12, 195!1. 4. Russck. H. 1. et a[.: Circulation 1?:169, Ang. 1955. 65. Russek, FI. 1.: Am. J. Cardiol. 3:547, April 1959. S.Tortora, A. R.: Ucl:Yware \I. J. 70:298, Oct. 1!1!iR. 7. 1Valdman, S. and Pehier, L.: Am. Pract. & Dige.t Treat. 8:1075, Jtdy 1957. Supplied: Bnttles of 50 tablets. Each tablet contains 200 mg. Miltown and 10 mg. pentacrythritol tetranitrate. Dosags: I or 2 tablets q.i.d. before rnrnfr and at bedtime, according to indiridual reyuirenrents. - asts June 15, 1961 What is more important-Miltrate provides Miltown, a tranquilizer which, unlike phenobarbital, relieves tension in the apprehensive angina patient without inducing daytime fogginess. Thus, your patient's cardiac reserve is protected against his fear and concern about his condition; his operative arteries are dilated to enhance myocardial blood supply-and he can carry on normal activities more effectively since his mental acuity is unimpaired by barbiturates. Miltownm (meGrobamate)+PETN , j WALLACE LABORATORIES / CrrtnbNrp, N. J, U

Vol. 264 No. 24 ADVERTISING SECTION when an antihistamine alone is not enough... 'ACTIYS ANTIHISTAMINIC•DECONGESTANT i relieves the sneeze, wheeze, and other symptoms of HAY FEVER and ALLERGIES • effective in low dosage • safe even for the youngest children Combining 'Actidil' (an antihistamine of unusually high potency) with 'Sudafed' (an orally effective nasal decongestant), 'ACTIFED' is "effective in a significant percentage of cases of seasonal and nonseasonal allergic rhinitis failing to respond to antihistamines alone."' good to excellent results in rhinitis previously resistant to antihistamines : Seasonal Adults Hay Fever, 137 Patients* _Childreti„ Nonseasonal Adults Rhinitis; 150 Patients* Chlfdren ~ 70°o relieved ? _ _ . . ~t7°le__relkv 33°io relieved ~~ ~44% relieved Prescribe safe 'ACTIFED' in tablet form or as a pteasant•tasting syrup: Each scored tablet contains - 'Actidil'® brand Triprolldlne Hydroohloride. ...,. 2.5 mg. 'Sudafed'O brand Pseudoephedrine Hydrochloride. . 60 mg. Each 5 cc. teaspoonful of the syrup contains - 'Actidil' brand TriDrolidine Hydrochloride ....... 1.25 mg. 'Sudafed' brand Pseudoephedrine Hydrrochioride. 30 mg. DOSAGE: (may be given 3 times daily, or, be- cause 'Actifed' F(as such a wide margin of safety, may be adjusted to provide optimal therapeutic effect in stubborn cases) Tablets Syrup Adults and children over 6 years 1 2 tsp. Children 4 months to 6 years. .. 1/2 1 tsp. Infants up to 4 months ....... - 1/2 tsp. (While pseudoephedrine causes virtually no pressor effect in normotensive patients, it should be used with caution in hypertensives; and although triprolidine hydrochloride has an unusually low incidence of antihistaminic drow- siness, appropriate precautions should be observed.) 1. Feinberg, S. M., Feinberg, A. R., and Fisherman, E. W.: J. Indiana M. A. 52:2137 (Dec.) 1959. °Adapted from authors' table. ~ BURROUGHS WELLCOME & CO. (U.S.A.) INC., Tuckahoe, New York xi

xii THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 AN AMES CLINIQUICK® CLINICAL BRIEFS FOR MODERN PRACTICE Quality of diabetic control & Quantitation of urine-sugar In the diagnosis of diabetes, the urine-sugar test may be little more than a screening adju- vant. But in the everyday management of diabetes, the urine-sugar test is the most prac- tical guide we have.' Routine testing, however, should not only detect, but also determine the quantity of urine-sugar. Quantitative testing is essential for satisfactory adjustment of diet, ex- ercise and medication. Furthermore, day-to-day control of diabetes is in the patient's hands. Quality of control is thus best assured by the urine-sugar test which permits the most accu- rate quantitation practicable by the patient. CuNITEST® permits a high degree of practical accuracy and is very convenient.' Its clinically stand- ardized sensitivity avoids trace reactions, 'and a standardized color chart minimizes error or indecision in reading results. CuNITEST distinguishes clearly the critical 1/4%, 1/2%, ~/4%, 1% and 2% urine-sugars. It is the only simple test that can show if the urine-sugar is over 2°a.' Your nurse or technician will appreciate these advantages; your patient on oral hypoglycemic therapy will find them helpful. Furthermore, CLINITEST may be a vital adjunct in the management of the diabetic child or the adult with severe diabetes. (1) Danowski, T. S.: Diabetes Mellitus, Baltimore, Williams & Wilkins, 1957, p. 239. (2) McCune, W. G.: M. Clin. North America 44:1479, 1960. (3) Ackerman, R. F., et al.: Diabetes 7:398, 1958. FOR PRACTICAL ACCURACY OF URINE-SUGAR QUANTITATION Standardized urine-sugar test...with CQLOR-CALIBRATED GRAPHIC ANALYSIS RECORD A line connecting successive urine-sugar read- . Ings reveals at a glance how wel I diabetics are CLINITEST® cooperating. Each CLINITEST Set and tablet.re- ; re- BRAND Reagent Tablets fill contains this physician-patient aid. 01561 h_. ._._:...w-.....-.~-.--s-.,~.._.~....-...-..._~.- _.._.~___._-__..._ .. (w)

Vol. 264 No. 24 ADVERTISING SECTION How to help your patient stick to a . bland diet The secret ingredient in a successful diet is acceptance. How much easier it is for the patient to stay with a bland diet if it includes dishes like these that please the eye as well as the palate. Pictured: tender broiled meat patties made with crushed corn flakes and water, flavored with salt and a touch of thyme, tender peas and carrots mixed, and buttered baked potato. For color there's molded gelatin salad and a pretty-as-a-picture dessert: lime gelatin whipped with applesauce and topped with custard sauce. N` 4Diet patients welcome appetizing dishes like these. '.~ CJ United States Brewers Association, Inc. For reprints of this and 11 other oiet menus, write us at 535 Fifth Avenue, N.Y. 17, N.Y. xui

® Cl JW , Q -a: !. . ?rM ~ 7kt~ _ a. a k 41 ~6 ~~~'`~ , D 0 ® Y t w r ® Mt 4 , tia 1 , ~.1+ M r ® , sxcg~;to ~ ~ m m .~_.._...~:~: ~ 4

0 . < , B UM 0 + 1) «- A V T, i • K r? When fluid "backs up" in the body, as it does in ede- matous states, Naturetin, an ". .. extraordinarily effec- tive diuretic...,"1 serves to remove fluid excess. The diuretic effect on the patient is dramatic. Usually, the blood pressure of normotensive patients remains unaffected. Naturetin has no apparent influence of clinical importance on serum electrolytesa and it causes a relatively small increase in the urinary pH.3 For the next patient you see with evidence of fluid retFjion, prescribe Naturetin and observe how the ates open and release the excess fluid. The aver- ., • reti _ C Squibb BendroHumethiazide Squibb Bendroflutnethiazide with Potassium Chloride SQUI88 age dose is a single 5 mg. tablet daily; to initiate therapy, doses up to 20 mg. may be given once daily or in divided doses. Supply: Naturetin Tablets, 5 mg., scored, and 2.5 mg. Naturetin c K (5 c 500) Tablets, capsule-shaped, containing 5 mg. bendro- flumethiazide and 500 mg. potassium chloride. Naturetin c K (2.5 c 500) Tablets, capsule-shaped, containing 2.5 mg. bendro- flumethiazide and 500 mg. potassium chloride. References: 1. David, N. A-; Porter, G. A.; and Gray, For fun intorm.Gon,R. H.: Monographs on Therapy 5:60 (Feb.) 1960. , eee your Squibb 2. Fuchs, M.; Moyer, J. H.; and Newman, B. E.: Op. Product Referenee cit. 5:55 (Feb.) 1960. 3. Ford, R. V.: Current Therap. Or PIOdUC Res. 2:92 (Mar.) 1960. 'NATURRIMI ® li A EOUIR~ TRAYEMARK. Squibb Quality- the Priceless Ingredient

xvi rn A / in otitis and pyelonephritis or other infections . THE NEW ENGLAND JOURNAL OF MEDICINE t. ;.Z a © A EN ~01 N June 15, 1961 antibiotic therapy with an added measure of protection ~T ® •'~ T IAL ~l IL;®~L/ ~ DEMETHYLCHLORTETRACYCLINE LEDERLE against relapse-up to 6 days' activity on 4 days' dosage against secondary infection-sustained high activity levels against "problem" pathogens-positive broad-spectrum antibiosis CAPSULES, 150 mg., 75 mg. - PEDIATRIC DROPS, 60 mg./cc. - SYRUP, 75 mg./5 cc. Request complete information on indications, dosage, precautions and contraindications Q froul }onr Lederle representati%e or write to Medical Advisory I)epartment. ~ ~ ~ LEDERLE LABORATORIES, A Division of AMERICAN CYANAMID COMPANY, Pearl River, New York ® (Z ~ ~ ~ Is %M ac, .

Vol. 264 No. 24 ADVERTISING SECTION Xvii I -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -I ~ ~ 4 Valuable Additions to Your Pro fessional Library ~ I The Annual Mayo Clinic Volume New!-Important Mayo Advances in Diagnosis and Treatment r E] Easy Payment Plan ($5.00 per month) 0 Mayo Clinic Diet Manual, about $5.50 0 Sodeman's Pathology Physiology, about $1-t.00 LA Name .................................................................................................... .............................................................................................. Address ................. .................................................................................................... ............................................ NEJ\t-6-15-61 . This latest addition to the famous Mayo Clinic Volumes is packed full of new diagnostic methods, new treatments, new surgical techniques - all described so that you can put them to work immediately in your practice. Now in its 52nd year of publication, this volume presents the Clinic's investigation of practically the entire body - Head, trunk and extremi- ties - Genitourinary diseases - Blood and circulatory organs - Radiology - Anesthesia, gas and intravenous therapy - etc. You'll benefit from important advances made in 1960 on such problems as: Care of lacerations of the face - Emergency treatment of severe head injury - Medical Management of Pancreatitis - The Place of Diuretics in Hypertension - Re- lationship of Dermatology to Systemic Medicine - Neuro- ophthalmology for the Busy Practitioner - Bacterial Infec- tions of the Spinal Column - Diagnosis and Treatment of Bone Tumors in Children - Sciatic nerve palsy following delivery. Collected Papers of the Mayo Clinic and Mayo Foundation. Volume 52. By the Staff of the Mayo Clinic, Rochester, Minnesota; and the Mayo Foundation, Universitv of Minnesota. About 8Cr} pages, 6" x 9". with 277 illustrations. $15.00. Nev - just Published! Mayo Clinic Diet Manual New (3rd) Edition!-Gives You Today's Standard Diets in Easy-to-Use Form The Mayo Clinic Dietetic Committee has spared no effort to make this revision as complete and accurate as possible. It clearly reflects the advances in food, vitamin and current dietary practice that have been incorporated into Mayo Clinic procedure. Once you have established that your patient needs a special diet, turn to this manual for all the information you'll need to prescribe it. Each diet can bc easily adjusted to the requirements of individual patients. There is a gen- eral description of each diet, showing types of food to be included or excluded in each program. Wolff - Anatomy of the Eye and Orbit New (5th) Edition! A classic work giving full, beautifully illustrated coverage to the structure, development and com- parative anatomy of the eye and orbit. Widely popular with physicians through four previous editions, the book has been carefully brought up-to-date for this revision. Contents cover: Orbit and paranasal sinuses - Eyeball - Appendages of the eye - Slit-lamp appearances - Extrinsic muscles - Nerves - Visual pathway - Vessels - Development - Compara- ttve anatomy. Revised by R. J. LAST, M.B., B.S. (Adelaide), F.R.C.S. (Eng.), Professor of Applied Anatomy and Warden, Royal College of Surgeons of England. 508 pages, 7" x 10", with 438 illustrations, 54 in color. About $18.00. New (5th) Edition - Just Ready! Among the important changes for the New (3rd) Edition you'll find: New information on the low cholesterol diet for atherosclerotic disease - New diets low in fat content in- tended for both reduction and maintenance of weight - A new sodium restricted diet for children - A new low sodium diet for use in hepatic coma - Changes in the low calorie diet for use in pregnancy, with reduction of the caloric value to 1500. By the COMMITTEE ON DIETETICS OF TtIE MAYO CLINIC. 222 pages. 6" x 9%t", spiral binding. About $5.50. New (3rd) Edition - Just Ready! Blechschmidt - Stages of Development Before Birth New! Here is a beautifully illustrated atlas, graphically de- picting all the facets and refinements of prenatal growth and development - from the unicellular level until the moment of birth. The text is run bilingually in two columns - one German and one English. Chapters cover: Fertilized ova in the oviduct - Blastocysts in the uterus - 2-30 mm. embryos - Newborn infants - Body regions in human embryos (with organs in these regions): Head, Neck, Dorsum, Ventral Trunk IVall, etc. By E. BLECHSCHMIDT, M.D., Professor of Anatomy and Director of the Institute of Anatomy, University of Gottingen, Germany. About 680 pages, 7%z" x 10%2", with 600 illustrations. About $23.00. New - Juft Ready! - - - Use Handy Form to Order These Volumes and Book Advertised on ~W ~ 0 B. SAUNDERS COMPANY - West Cover - - - -i d Washington Square, Philadelphia 5 I~ Ptease send me and charge my account: 'Z Mayo Clinic Volume, $15.00 tZ Wolff's Anatomy of the Eye & Orbit, about $18.00 :.ril Blechschmidt's Stages of Development before Birth, about $23.00

0kc ~1 "PLE GINEm' BRANO OF PHENOIMETRAZINE BITARTRAfE ; new, potent appetate-suppressan "Plegine"provides strong appetite suppression, yet does not penalize the patient with disturbing side effects. An average weight loss of more than a pound per week has been shown clinically-even without di- etary restriction. Weight loss has been obtained with virtual absence of cNS and cardiovascular compli- cations. No significant effect on heart rate, blood pres- sure, and respiration has been reported. Episodes of nervousness and insomnia have been rare and usu- ally minor. "Plegine" truly offers: FIRM APPETITE DISCIPLINE WITH A "VELVET TOUCH"

"PLE GINE" provides unique benefits in the management of obesity • suppression of appetite readily and easily achieved • significant weekly weight loss recorded clinically • virtually no effects on blood pressure, pulse, and respiration • low incidence of nervousness and insomnia • no tolerance reported to date • high degree of patient acceptability DOSAGE AND ADMINISTRATION: The usual suggested dosage is 1 tablet b.i.d. or t.i.d., one hour before meals. Dosage, however, should be adjusted to the needs of the patient. In some cases, / tablet per dose will sufiice; in others, 2 tablets b.i.d. or t.i.d. may be required. A dietary regimen is advisable in conjunction with appetite-suppressant therapy. AVAILABILITY: No. 755-Each "Plegine" Tablet contains 35 mg. of Phendimetra- zinc bitartrate (scored), bottles of 100 and 1,000. CAUTION AND CONTRAINDICATIONS: No adverse effects on blood pressure, heart rate and respiration have been reported with "Plcgine." However, as is true for all medication of this type, "Plegine" is not recommended for patients with cor- onary disease, severe hypertension, or thyrotoxicosis, and should be used with caution in highly nervous or agitated individuals. t1YERST LdBORdTORIES New York 16, N. Y. • 111ontreal, Canada 6113

~~ =~- .~ • . . . versus semi-synthetic penicillin Potassium Penicillin V Recent clinical evidence sheds new light on some important questions ... Q. Which of the two oral penicillins provides greater antibacterial activity? In a follow-up studyl of oral penicillins, McCarthy and Finland compared the antibacterial activity of potassium penicillin V and semi-synthetic peni- cillin. They said: "Penicillin V provided greater activity than phenethicillin [semi-synthetic penicillin] against the streptococcus and pneumococcus, at least equivalent activity against the staphylococcus and sarcina in the serum and the same or greater activity in the urine ..." In another study2, Griffith found that penicillin V not only produced peak levels of serum antibacterial activity faster, but produced values almost half again as high as those obtained with semi-synthetic penicillin. A direct laboratory comparison3 by Abbott scientists revealed a measur- able difference in activity, milligram for milligram, between the two peni- cillins in vitro. Against four pathogenic strains (staphylococcus, strepto- coccus, pneumococcus, and corynebacterium species), potassium penicillin V exhibited from two to eight times the antibacterial activity of semi-syn- thetic penicillin. Q. How valid are blood levels as a basis for comparison? In comment on the two penicillins, McCarthy and Finland state' :"Thus, although the claim of better absorption and excretion and higher serum level of phenethicillin may be partly correct, strictly speaking, this is true in a very restricted sense and is therapeutically meaningless. Indeed the claim is misleading since it clearly implies greater antibacterial and presumably curative activity; which, in fact, the drug does not possess ..." Q. Are there useful differences in resistance to penicillinase? In another recent reporta, Geronimus commented :"Very large concentra- tions [of semi-synthetic penicillin] ... were required to inhibit even so-called

moderately penicillin-resistant staphylococci when populations were em- ployed that approached those found in vivo. Inferences regarding the pos- sible effectiveness of phenethicillin in infections by penicillinase-producing staphylococci drawn by others from experiments with relatively minute in- ocula were found to be unwarranted." McCarthy et al.5 reached a similar conclusion :"Both of these penicillins [potassium penicillin V and phenethicillin] are qualitatively similar to peni- cillin G in their susceptibility to penicillinase produced by Staphylococcus aureus." At Abbott, investigators studying the same subject3 found that the rate of destruction of all three penicillins was so great that any differences were of no therapeutic significance. Q. How does the safety of oral penicillins compare? While surveyss have established that oral penicillin produces fewer and less severe reactions than does injectable penicillin, to date no clinical studies have produced any evidence that one oral form is less allergenic than another. Q. What about recent editorials on oral penicillin? Recently, New England Journal of Medicine editorialized': "It thus appears that the major claims of phenethicillin over penicillin V are not well founded. More data are needed to permit a complete comparison of these and other penicillins, particularly in their effects on infections caused by penicillinase- producing staphylococci, but it is fair to say that the new, so-called syn- thetic penicillin possesses no demonstrated virtue of importance that should impel one to choose over other available forms." ' And in England, where semi-synthetic penicillin was first discovered and marketed, British Medical Journal editorializedg: "There is no evidence of any activity superior to that of other penicillins against Gram-negative species, and what differences there are against sensitive species are in favour of penicillin G or V or both; this applies to all varieties of streptococci tested." Q. What are the benefits of Compocillin-VK? Compocillin-VK is Abbott's potassium penicillin V. It offers early, high con- centrations of serum antibacterial activity against penicillin-sensitive organ- isms. Following appropriate doses, initial activity levels are higher than those obtained with intramuscular penicillin G. Available in easy-to-take forms for any age : tiny Filmtab' tablets, 125 mg. ; and 250 mg. ; or as granules for tasty cherry-flavored Oral Solution. COMPOCILLIN=VK ABBOTT (POTASSIUM PENICILLIN V) 1. McCarthy, C. G., and Finland, M., New England J. Med., 263:315, Aug. 18, 1960. 2. Griffith, R. S., Antibiot. Med. & Clin. Therapy, 7:129, Feb., 1960. 3. Laboratory Records, Microbiology Dept.. Abbott. 4. Geronimus, L. H., New England J. Med., 263:315, Aug. 18, 1960. 5. McCarthy, C. G., Hirsch, H. A., and Finland, M., Proc. Soc. Exper. Biol. Med., 103:177, Jan., 1960. 6. Welch, H., Lewis, C. N., Weinstein, H. I., Boeckman, B. B., Antibiotics Annual, 1957-58, p. 296. 7. Editorial: New England J. Med., 263:361, Aug. 18, 1960. 8. Editorial: Brit. M. J., 2:940, Nov. 7, 1959. F,Lw1.0-FiLn 5[.LED TABEETS, 1esOti

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The New England Journal of Medicine Volume 264 Copyright, 1961, by the Massachusetts Medical Society JUNE 15, 1961 Number 24 THE NEPHROTIC SYNDROME AS A COMPLICATION OF PERCHLORATE TREATMENT OF THYROTOXICOSIS* R. E. LEE, M.D.,j R. L. VERNIER, M.D.,j AND R. A. ULSTROM, M.D.§ MINNEAPOLIS, MINNESOTA PERCHLORATE is an inorganic monovalent anion that, like thiocyanate, is capable of inhibiting col- lection and interfering with retention of the iodide ion within the thyroid gland. Wyngaarden et al.,1•' in 1952 and 1953, were the first to compare, in animals, the effects of perchlorate and other mono- valent anions, and they found perchlorate to be ten times as potent as thiocyanate in discharging iodide previously collected by the thyroid gland. Perchlorate has been used widely in England and Europe gener- ally in the treatment of hyperthyroidism, and has distinct advantages in that it is effective, inexpensive and relatively nontoxic.3-7 Godley and Stanburys re- ported the results of treatment of 24 patients in 1954, among whom they listed the following complications: gastrointestinal symptoms in 2; pyuria in 2; and mini- mal proteinuria on occasional specimens in 2. One of the patients with pyuria had a previous history of pyelonephritis, but neither of those with proteinuria had a history of prior renal disease. After this initial report, we found no mention in the medical literature of renal complications that had followed the use of perchlorate, although skin rash," gastrointestinal syTrlptoms,°•s leukopenia6 and loss of hair' have all been described. The purpose of this paper is to describe a patient with hyperthyroidism who was treated with per- chlorate and in whom a nephrotic syndrome subse- quently developed. CASE REPORT A 6%s-year-old girl was first admitted to the University of Minnesota Hospitals on September 29, 1959, with a his- tory of polyuria, polydipsia and decreased attention span. Fullness of the neck, increasing "nervousness," voracious ap- petite without weight gain and prominent eyes had been noted during the previous 6 months. The past medical his- "''From the Department of Pediatrics, University of Minnesota Medi- cal•;School. • dided by grants from the Graduate School, University of Minnesota, Licthed States Public Health Service (H-2085, H-5662 and E-2618), Viirytesota Heart Association and American Heart Association. -Vresent address: Lowrey Air Force Base, Denver, Colorado. ,4-Established investigator, American Heart Association. ~.associate professor of pediatrics, University of Minnesota Medical Sc}t6ol. tory was noncontributory except for a laceration of the left side of the face at the age of 3 years that had resulted in a long scar. The family history revealed that the patient's mother, paternal grandmother, maternal grandmother, a paternal aunt and 3 maternal great-aunts had had thyroid goiters that had required treatment (Fig. 1). Physical examination revealed a hyperactive girl who was quite labile emotionally. She was above the 84th percentile for both height and weight (Fig. 2). Examination of the eyes showed bilateral exophthalmos, inability to converge, lid lag and a constant stare. She had a long diagonal scar across the left side of the face, and there was loss of the motor component of the left 7th cranial nerve. The thyroid gland was diffusely enlarged to 2 or 3 times the normal size, but no nodules were palpable. A minimal, soft, blowing, systolic cardiac murmur was noted at the 4th left intercostal space. The pulse was bounding and full at a rate of 140 per minute while she was resting, and the blood pressure was 130/68. The skin was moist and warm, and a slight, fine tremor of the hands was evident. Neurologic examination revealed increased deep tendon reflexes. The results of pertinent laboratory studies performed soon after admission included a radioactive-I"' uptake, counted over the gland, of 71 per cent in 24 hours, with 82.8 per cent of the I"' bound to protein in the plasma, a basal metabolic rate of +16 per cent and urinary creatine- creatinine ratio of 50 per cent. The protein-bound iodine was 14.7 microgm., and the blood cholesterol 141 mg. per 100 ml. Scintillation counting over the thyroid gland after I"' administration revealed no hyperactive nodules. X-rays of the chest were normal, but fluoroscopy revealed a bulky heart, without evidence of distinct chamber enlargement. X-ray examination of the hands and wrists indicated a bone age compatible with the standards for 7 years and 10 months. A diagnosis of hyperthyroidism with diffuse goiter was made. Selected details of the clinical course and labo- ratory values are presented in Figure 3. Therapy with potassium perchlorate, 125 mg. orally every 6 hours, was begun on October 17, but because of dyspepsia and vomiting, which developed after 3 days, sodium perchlorate, 250 mg. every 6 hours, was substituted for the potassium derivative. The gastrointestinal symptoms were relieved, and there was laboratory and clinical evi- dence that the hyperthyroidism had improved. Twelve days after perchlorate treatment was begun a maculopapular, nonpruritic rash was first noted on the cheeks and later over the arms and trunk. The white-cell count, which on admission had been 7500, with 3 per cent eosinophils, was 3550, with 8 per cent eosinophils. The perchlorate was dis- continued, and diphenhydramine was given. Beta-hemolytic streptococci were grown from a throat culture at this time, and cervical lymphadenopathy, with an elevation in tempera- ture, developed. The rash disappeared gradually over a period of 8 days. Two days later (and 10 days after the perchlorate had been discontinued) the rash again was noted, and the patient complained of pruritus. The white- cell count was normal. It was believed that the rash was probably not due to drug toxicity, and sodium perchlorate

THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 1222 therapy was renewed. A mild skin rash over the cheeks and elbows continued intermittently during the next 3 weeks, and then disappeared. During this time there was evident clinical improvement of the hyperthyroidism, with a decrease of the protein-bound iodine and a decline of the I"` uptake to 12.8 per cent over the gland in 22 hours. On November 16, 10 days after the 2d course of treatment was begun, the I"' uptake was 2.5 per cent at 24 hours, and the blood cholesterol had risen to 239 mg. per 100 ml. 0 0 D O O FIGURE 1. Diagram, Showing the Incidence of Thyroid Goiter in the Patient's Family. The patient was followed in the endocrinology clinic, and on January 15, 1960, was considered to be mildly hypothyroid on the basis of recent values of the basal metabolic rate of -3 to -15 per cent, a low protein- bound iodine and a blood cholesterol value of 293 mg. per 100 ml. The patient's mother commented that the child was still quite active, with a good appetite, and a decision was made to observe her at frequent intervals. Evaluation on February 19 revealed no clinical change, except for a slight weight gain. Her parents thought that she was doing well and elected to skip the next appointment. She did not return to the clinic, even though the parents observed that her "hair was falling out" (March 11 ) and that she appeared pale and her face was swollen (March 19). Her family physician was notified, and on the basis of his finding generalized edema and a+-L + 4- test for protein in the urine, he made the diagnosis of nephrotic syndrome. She was then returned to the University of Minnesota Hospitals, where examination revealed a lethargic, edem- atous, pale girl in acute distress (Fig. 4). There were no signs of hyperthyroidism. The thyroid gland was diffusely enlarged (neck circumference, 31.5 cm.). The deep tendon reflexes were not compatible with myxedema. The results of laboratory studies at this time included a blood urea nitrogen of 70 mg. per 100 ml., hypoalbuminemia, pro- teinuria (16 gm. per liter), an erythrocyte sedimentation rate of 65 mm. per hour and total serum lipids of 1560 mg. and blood cholesterol of 500 mg. per 100 ml. A 12- hour specimen of urine contained 21.6 x 10° red blood cells, 24.7 x 10° white blood cells and 14.9 X 10' casts; several cultures were negative. A Mantoux skin test was negative. A percutaneous kidney biopsy was done on April 5. A low-sodium diet and cortisone in a dose of 320 mg. daily, by mouth, in divided doses (Fig. 3), were started. Perchlorate was discontinued. No clinical improvement was seen, and the laboratory values were not improved: the cholesterol was 848 mg. per 100 ml., and the basal meta- bolic rate -36 per cent (corrected to nonedematous weight). I"' uptake by the thyroid gland was 72.5 per cent at 24 hours; 35 per cent of the I"' counts in plasma were pro- tein bound. On April 25 characteristic myxedema reflexes were first observed, and the neck size had decreased to 29.5 cm. Because of extreme lethargy and the suspicion of clinical hypothyroidism tri-iodothyronine (25 microgm. per day) was given from April 27 to May 9, with improvement in activity and sense of well-being. During treatment with tri-iodothyronine and cortisone hypertension developed, and all medications were discontinued. When the drugs were discontinued, a massive diuresis ensued, resulting in a loss of 10.4 kg. (23 pounds) of body weight. At that time the blood urea nitrogen was 14 mg., and the serum cholesterol 428 mg. per 100 ml., and the erythrocyte sedimentation rate 92 mm. per hour. One week after medications were stopped, the quantitative urinary protein loss was 4.2 .gm. per liter. A 2d renal biopsy was done on June 9. A repeat Addis count of a 12-hour specimen of urine showed 150,000 red blood cells, 2,760,000 white blood cells and no casts. Since May 14, 1960, there has been increasing evidence of eye signs of hyperthyroidism (lid lag, inability to con- verge, staring and increasing exophthalmos) and increasing size of the thyroid gland. The patient's mother believed that the child's activity slowly returned to the hyperactive state. The vital signs, including the blood pressure, re- mained normal. Minimal proteinuria and an elevated eryth- rocyte sedimentation rate were still present 1 year after the 1st treatment was initiated. The hyperthyroidism is now controlled by the administration of propylthiouracil. No toxic effects of this form of therapy have yet been observed in this patient. Morphology of the Renal-Biopsy Specimens The 1st renal-biopsy specimen, which was obtained early in the course of the nephrotic syndrome on April 5, 1960, contained approximately 20 glomeruli and associated renal tubules. Approximately half the glomeruli showed minimal to moderate endothelial hypercellularity, with occasional FIGURE 2. Photograph of the Patient Taken Shortly the Onset of Clinical Thyrotoxicosis. Exophthalmos is apparent. after adhesions to Bowman's capsule. The remaining glomeruli in the specimen were normal. There was little evidence of thickening of the capillary membranes by routine histologic methods; however, periodic acid-Schiff (PAS) stains of thin ( 1-micron ) sections revealed irregular nodular thicken- ing of the basement membranes of occasional capillary loops (Fig. 5). An additional finding of great interest was the presence of basophilic masses of a crystalline precipitate ad- jacent to and within an occasional tubular lumen. This material could not be identified, but special stains indicated

Vol. 264 No. 24 NEPHROTIC SYNDROME - LEE ET AL. that it was not amyloid and that it was PAS negative. Frequently, the material was noted to protrude into the tubular lumen through breaks in the tubular epithelium (Fi¢. 6). The 2d renal-biopsy specimen, obtained on June 9, after treatment and partial remission of the nephrotic syndrome, rontained only 6 glomeruli and numerous tubules. The glomeruli were entirely normal, and no deposits of the precipitate described above were observed in the renal tubules of this specimen. 20 0 D~scnprgea DIN 0 16 ,la 7 N wE 12 2 . m 0 A 8 U m 2. 4 a 0 .. 0 . • O o • A ______________________ 0 _ ____ __-_ _J------------------------- --------_-_-__a----_S-- -'•--___------- ~ 120 A A . - • n ,~ p 80 . ... . ••• •A• • • • • • •• •• *• • ••e , ~ cn_ a 4 0 `-------------------- ------------------ ------------------------------------------- v a,70 ~ I m~ ---------------- ~e 50 -----------------------------------------------------------------ILL: E 4 F q {~j~ ~° y , 2 a O j~ ~_~ ` C ° ia 0 L ------------------------------------------------------- _ ___ _ __ ________ --- >~ + ++ + +++ in the second renal-biopsy specimen also suggests that smaller amounts of this presumably toxic agent were present during the partial remission associated with treatment of the nephrotic syndrome with corti- sone. Although the renal disease was preceded by a known infection with a beta-hemolytic streptococcus five months earlier, neither the clinical course nor the 1223 r_____0 _______, _~Q____0 K CI°a 0 SEPT a!- OCT NOV. I T DEC. °-Ia,geo NaCf04 JAN. +++++++ + ++~+t ++ + ++ ++++++++ + ++++f ++ ++ ++ b +++ ++ ++ ++ +Q ++++++i9.+-+ - • ----------------------- +-+- + -------- T3 Cortisone ° zs „9 iaor szo mWaar aose_.__ FEB. MAR. a a APR. MAY JUNE FIGURE 3. Diagram, Showing Selected Clinical Data and Therapy. Electron microscopy of both specimens was performed. The renal glomeruli showed minimal endothelial prolifera- tion, nodular thickening of the lamina densa (basement membrane) and fusion of the foot processes of the epithelial cells (Fig. 7). These findings are typical of the ultramicro- scopical changes observed in various forms of the nephrotic syndrome.° The changes in the epithelial cells and the endothelial proliferation were somewhat less pronounced in the 2d specimen. It was not possible, by electron micros- copy, to identify the tubular precipitate described above. DISCUSSION The progressive appearance of the toxic symptoms of nausea, skin rash, leukopenia, loss of hair and the nephrotic syndrome in this patient, in the absence of a previous history of renal disease, suggests that the renal complications were on a toxic basis. The observation of an unusual basophilic crystalline de- posit in peritubular loci in the first renal biopsy may be additional evidence of a toxic renal injury in this patient. The nature of this material is not known; however, it may represent either a breakdown product of perchlorate or some by-product of the toxic cellular effect of perchlorate. We have not encountered a similar histolo.gic lesion in other renal-biopsy speci- mens from more than 50 patients with the nephrotic syndrome in childhood.9 The absence of this material renal histology suggested acute nephritis. Other authors° have noted that larger doses of perchlorate were associated with a higher incidence of the severe type of toxic reaction than when lower dosage levels were used. In retrospect, the dose of perchlorate used in this patient was the maximum dose recommended by previous authors°,10 for adults or large children. Smellie11 treated 6 hyperthyroid girls, six and a half to thirteen years of age, with doses of 150 to 300 mg. of perchlorate daily, and found no toxic effects. The incidence of toxic reac- tions for perchlorate in 484 reported cases3-s,11,12 was approximately 5 per cent; however, no patient in these series received over 2 gm. per day, and the majority received only half to three fourths of that dose. Other compounds, such as trimethadione13 and mercury,l..1' have been implicated in the etiology of the nephrotic syndrome in humans. The aminonucleo- side1G of puromycin and trimethadione" have been shown to produce a nephrotic syndrome in rats. The current data from the studies of aminonucleoside nephrotic rats suggest that the mode of action of the aminonucleoside is at an enzymatic locus.37 The exact site of action of the perchlorate ion in

1224 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 the production of nephrosis is unknown. Direct renal pharmacy and at the pharmaceutical manufacturer. toxicity, blockade of certain enzymatic reactions and There was no evidence that the stock was contami- degradation products of perchlorate are among the nated by any other compound, or that an improperly possibilities that need consideration. The finding of labeled substance had been dispensed. a crystalline basophilic substance in tubular and peri- tubular sites in the first renal biopsy might suggest that the renal injury was at the level of the tubule: however, the chemical nature of the substance could not be ascertained. Guttmann and Lewitus,'s using radioactive potas- sium perchlorate (KC1O,, C1" and 073), have shown that the molecule is excreted in the urine relatively unchanged and that free chlorate ions, which arc FIGURE 4. Photograph of the Patient Taken during the Course of the Nephrotic Syndrome. known to he nephrotoxic, are present in insignificant quantities. They also showed that perchlorate ions do not under7o any isotopic oxygen exchange, and con- sidered the action of perchlorate on the thyroid gland to be due to a glandular factor, involving trapping, which is selective to inorganic ions fulfilling certain requiretnents of charge and size. This observation is evidence against the theory that the molecule has a mode of action at an enzymatic locus in the thyroid gland. We investigated another possible explanation of the toxicity observed in our patient by carefully checking the source and the chemical contents of the stock of perchlorate that she received at our FIGURE 5. High-Magnification Light Micrograph of a Section of a Portion of a Clomerulus, 1 Micron in Thickness, Stained with the Periodic Acid-SchibF Method (X800). Note the irregular, nodular thickening of some of the cap- illary loops. Several excellent studies previously reported suggest that thyroid function in patients with the nephrotic syndrome is normal,1D--- even though low protein- bound iodine, low basal metabolic rate and high cho- lesterol are regularly found in association with the FIGURE 6. Light Micrograph of a Section from the First Kidney-Biopsy Specimen (Hematoxylin and Eosin Stain X258). Two tubules containing granular organized material are shown. On the upper left, the less intensely stained material bulges into the tubular lumen through a defect in the epithelium. Centrally, the material is more intensely baso- philic and lies in a peritubular location. A segment of a glomerulus is seen in the lower right corner. syndrome. It is of interest that the clinical "rebound" phenomenon of increased thyroid activity that usuallN • occurs after discontinuation of perchlorate was not seen in our patient, despite the high uptake of radio-

Vol. 264 No. 24 active 1131, increasing gland size and increasing ex- ophthalmos observed. It is possible that the low- sodium diet, which is also low in iodine, together with an increased excretion of protein-bound iodine NEPHROTIC SYNDROME - LEE ET AL. 1225 are patients who recover only partially9,13 and others in whom the outcome is quite unfavorable. Mild but definite evidence of renal disease continues to be evident in this patient, although the presumably toxic A B FIGURE 7. Electron Micrographs of a Representative Glomerulus from the Second Renal-Biopsy Specimen (A X7200 and B X20,000). The number of endothelial cells (END) is increased, and there is excess basemnt-membrane material (BM) resulting in nodular thickening of the lamina densa (as top center) and appearing as strands of material extending across the lumen of some capillaries (center), ef]ectirvely reducing the luminal area of the capillary. The epithelial-cell (Ep) foot processes ('fp) are fused, forming an almost uninterrupted layer of cytoplasm about the exterior of the basement membrane. in the urine, as well as fecal iodide excretion, acted as a protective mechanism.2'- One might have ex- pected the clinical hyperthyroid state to return in this circumstance when urinary iodine loss became minimum and the dietary intake of iodine became normal. This was, in fact, the sequence of events observed. Recently, the nephrotic syndrome was reported to have developed in a patient with hypothyroidism of three years' duration.=3 This observation is of interest, since the signs of the nephrotic syndrome appeared as the present patient became mildly hypothyroid. The relation of hypothyroidism to the nephrotic syndrome in the 2 cases is not known; however, further studies of the relation appear to be indicated. The prognosis of the nephrotic syndrome that has been reported to result from contact with various toxic substances is generally good"•"; however, there agent was removed more than six months ago. A definite assignment of the role of perchlorate in its etiology will probably never be possible. Neverthe- less, the temporal relation, the previous suggestive dermal reaction and the finding of a crystalline pre- cipitate in the kidney biopsy strongly suggest an etio- logic role for the perchlorate. SuMMARY A study of a six-and-a-half-year-old girl in whom the nephrotic syndrome developed during perchlorate therapy for thyrotoxicosis is reported. Renal morphol- ogy studied in biopsy specimens by light and elec- tron microscopy demonstrated glomeruli with en- dothelial hypercellularity, irregular thickening of capillary-loop basement membranes and fusion of epithelial foot processes. Basophilic crystalline pre- cipitates in the tubular epithelium were noted. Later,

1226 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 a renal biopsy was normal. The possible association of the renal lesions to perchlorate therapy is discussed. REFERENCES 1. Wyngaarden, J. B., Wright, B. M., and Ways, P. Effect of certain anions upon accumulation and retention of iodide by thyroid gland. Endocrinology 50:537-549, 1952. 2. Wyngaarden, J. B., Stanbury, J. B., and Rapp, B. Effects of iodide, perchlorate, thiocyanate, and nitrate administration upon iodide concentrating mechanism of rat thyroid. Endocrinology 52:568-574, 1953. 3. Kleinsorg, H., and Kruskemper, H. L. Erfahrungen mit der Perchlorat-Therapie der Hyperthyreosen. Deutsche med. Wchnschr. 82:1491-1495, 1957. 4. Buttaro, C. A., and Brunori, C. A. Caso fatale di "crisi tiroidea" in corso di trattamento di tireotossicosi con perclorato di potassio: peculiari aspetti clinici e patogenetici. Riforma med. 69:145-148, 1955. 5. Morgans, M. E., and Trotter, W. R. Treatment of thyrotoxicosis with potassium perchlorate. Lancet 1:749-751, 1954. 6. Crooks, J., and Wayne, E. J. Comparison of potassium perchlorate, methylthtouracil, and earbimazole in treatment of thyrotoxicosis. Lancet 1:401-404, 1960. 7. Mosbech, J. Treatment of thyrotoxicosis with potassium perchlorate. Ugeskr. f. laeger 121:1166, 1959. 8. Godley, A. F., and Stanbury, J. B. Preliminary experience in treatment of hyperthyroidism with potassium perchlorate. J. Clin. Endocrinol. 14:70-78, 1954. 9. Vernier, R. L., Worthen, H. G., and Good, R. A. Pathology of nephrotic syndrome. J. Pediat. (in press). 10. Wilkins, L. The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Second edition. 556 pp. Springfield, Illinois: Thomas. 1957. P. 140. lI. Smellie, J. M. Treatment of juvenile thyrotoxicosis with potassium perchlorate. Lancet 2:1035. 1957. 12. Southwell, N., and Randall, K. Potassium perchlorate in thyro- toxicosis. Lancet 1:653, 1960. 13. Heymann, W., Hackel. D. B., and Hunter. J. L. P. Trimethadione (Tridione) nephrosis in rats. Pediatrics 25:112-118, 1960. 14. Wootton, I. D. P., and Giddins, A. G. Acute mercury poisoning in infancy. Laneet 2:1038. 1957. 15. Fanconi, G., Kousmine, C., and Frischknecht, W. Die konstitu- tionelle Bereitschaft zum Nephrosesyndrom. Heloet. paediat. acta 6:199-218, 1951. 16. Wilson, S. G. F., Hackel. D. B., Horwood, S., Nash, G., and Heymann, W. Aminonucleoside nephrosis in rats. Pediatrics 21: 963-973, 1958. 17. Wilson, S. G. F., Heymann, W., and Goldthwait, D. A. Studies on mechanism of production of nephrotic syndrome in rats by Atcleoside. Pediatrics 25:228•241. 1960. 18. Guttmann, M. A. S., and Lewitus, Z. Mode of action of perchlorate ions on iodine uptake of thyroid gland. Intcrnat. J. Appl. Radia- tion 7:87-96, 1959. 19. Kalant, N., McIntyre, W. C.. and Wilansky, D. L. Thyroid func- tion in experimental nephrotic syndrome. Endocrinology 64:333- 343, 1959. 20. Recant, L., and Riggs, D. S. Thyroid function in nephrosis. J. Clin. Investigation 31:789-797, 1952. 21. Robbins, J., Rall, J. E., and Petermann, 114. L. Thyroxine-binding by serum and urine proteins in nephrosis: qualitative aspects. J. Clin. Investigation 36:1333-1342, 1957. 22. Rasmussen, H. Thyroxine metabolism in nephrotic syndrome. J. Clin. Investigation 35:792-799, 1956. 23. Etzwiler, D. D. Hypothyroidism and nephrosis. J. Dis. Child. 100: 587, 1960. 24. Williams, N. E., and Bridge, H. G. T. Nephrotic syndrome after application of mercury ointment. Lancet 2:602, 1958. THE EMERGING PATTERN OF URBAN HISTOPLASMOSIS* Studies on an Epidemic in Mexico, Missouri M. L. FURCOLOW, M.D.,t F. E. TosH, M.D.,$ H. W. LARSH, PH.D.,§ H. J. LYNCH, JR., M.D.,$ AND G. SHAw, M.D.¶ KANSAS CITY, KANSAS, AND MEXICO, MISSOURI U RBAN children, because of their more localized environment and less frequent exposure, appear to be more suitable subjects than rural children for studies of the acquisition of infection with Histo- plasma capsulatum.1,2 In these papers two sources of infection among urban children were reported: visits to farms or prior rural residence and exposure in urban structures contaminated with bird droppings. Kier et al.g have reported a third. source - importa- tion of contaminated farm soil or manure as fertilizer. In the present paper we wish to call attention to a fourth source of infection among urban children - namely, infection in wooded, open park areas con- taminated by bird droppings. This mode of infection is illustrated by the report of an epidemic. TIiE EPIDEMIc Mexico, a city of 15,000 people, is located in east •From the Communicable Disease Center, Public Health Service, United States Department of Health, Education, and Welfare, University of Kansas School of Medicine, and the Pathology Department, Audrain County Hospital. Presented at a meeting of the American Public Health Association, San Francisco, California, November 3, 1960. tMedical director, Kansas City Field Station, Communicable Disease Center. 3Surgcon, Kansas City Field Station, Communicable Disease Center. §Consultant mycologist, Kansas City Field Station, Communicable Disease Center. ¶Pathologist, Audrain County Hospital. central Missouri. Its chief industry is the manu- facture of fire-clay bricks. During the second week in April, 1959, similar illnesses characterized by chills, high fever and cough developed in 4 boys in Mex- ico. All 4 had x-ray films of the chest taken at the local hospital, and 2 were admitted there. The clinical features and x-ray findings in these 4 cases led the hospital radiologist to suspect histoplasmosis. Positive skin and serologic tests later confirmed the diagnosis. An interview with these boys revealed that they were all boy scouts and members of the same troop (No. 36). Furthermore, their only close association was related to scouting activities. All 4 had onsets of illness within twelve to fourteen days after March 28, 1959. On that day a group of 64 scouts from the 4 Mexico troops had worked together clearing a large city park. The main activity had been raking leaves and debris into piles, which were then burned. MATERIAL AND METHODS Since it was probable that a large proportion of the scouts in Mexico had been exposed to the in- fection arrangements were made through the organi- zation for further investigations. An epidemiologic questionnaire was completed by 113 boys, but not all were willing to have the diagnostic tests recom-

Vol. 264 No. 24 URBAN HISTOPLASMOSIS-FURCOLOW ET AL. 1227 I mended, which included skin and serologic tests and x-ray examination. The histoplasmin used in skin testing was lot HKC-5 diluted 2:1000; this potency is equivalent to that of standard histoplasmin. The tests were all given intradermally in the right forearm, and read- ings were made at forty-eight hours. An indurated area of 5 mm. or more was considered a positive reac- tion. FIGURE 1. Mexico, Missouri, and Surrounding Areas. At the time of the skin testing, blood was obtained for serologic testing, which was performed by Dr. Joseph Schubert, of the Communicable Disease Center, Public Health Service, Chamblee, Georgia. Two complement-fixation tests were performed on each serum, histoplasmin being used as antigen in Description of Source The site of the epidemic was called the Historical Society Park because of its interesting history and the sponsoring by the Historical Society of its pur- chase. This park consists of an 11-acre plot on which a large, plantation-type home, which was built before the Civil War by a prominent judge, is located. It was the show place of the area, and to add to its historical importance, this home was at one time oc- cupied by General U. S. Grant when he commanded troops in this area. Later, the house fell into dis- repair, and the grounds were converted into pasture for livestock. For the past fifteen to twenty years the grounds had been completely untended and had become heavily overgrown with brush and trees. During this time, the city of Mexico had grown around the property so that it now lies near the center of the city (Fig. 1). The city began clearing the property in December, 1958. At that time it was described as a jungle, with dense underbrush and vines scattered among very large trees. Leaves and debris were at least several inches deep upon the ground. The park property had been a favorite roosting place for starlings begin- ning about 1950. By the summer and fall of 1955 this park was inhabited by thousands of these birds, and their droppings almost completely covered the ground. Because of the noise of the birds and the disagreeable odor created by their droppings, the local residents had undertaken eradication measures, which had resulted in a marked decrease in the population of birds since 1955. However, at the time of the epidemic there was still evidence of consider- able bird droppings, especially in the southeastern quarter of the park. RESULTS Table 1 compares the skin test and serologic and x-ray findings on boys who did and did not work TABLE 1. Results of Skin Tests and Serologic and X-Ray Findings. GROUP SKIN TEST SEROL0010 TEST X-RAY EEAMINATION TOTAL TESTED NO. POSITIVE PERCENTAGE POSITIVE TOTAL TESTED NO. POSITIVE PERCENTAGE POSITIVE TOTAL TESTED NO. POSITIVE PERCENTAGE POSITIVE Worked in park 64 62 97 60 36 60 60 28 47 Did not work in park 46 19 41 32 8 25 36 9 25 one test and whole-yeast phase organisms as antigen in the other test. A titer of 1:8 or greater by either test was considered positive. X-ray films, 14 by 17 inches, were evaluated by physicians experienced in the interpretation of x-ray study of the chest. Pulmonary calcifications were not considered abnormal findings in this study. Soil samples were collected on several occasions from the park suspected as the source and cultured for H. capsulatum by a modified flotation method° fol- lowed by mouse inoculation. in the park on March 28, 1959. It can be seen that of the boys who worked in the park, 97 per cent had positive histoplasmin skin tests, 60 per cent had positive complement-fixation tests for histoplasmosis, and 47 per cent had active lesions on x-ray examina- tion of the chest. In the group of boys who did not work on the property only 41 per cent had positive skin tests, 25 per cent had positive complement- fixation tests, and 25 per cent had active lesions on the x-ray films. From these data it appears that practically all the exposed susceptible boys became

1228 THE NEW ENGLAND JOURNAL OF MEDICINE infected. It is not surprising to find a number with evidence of H. capsulatum infection even though they did not work on this property because Mexico lies within a highly endemic area. Fifty-five per cent of Junior High School students in Mexico, excluding boy scouts, are positive to the histoplasmin skin test.4 Furthermore, though only a few scouts ad- mitted having visited the park before the epidemic, its central location favored casual visits and ex- posures. TABLE 2. Soil Collections in Historical Society Park, Mex- ico, Missouri. DATE No. OF SAMPLES No. POSITIVE PERCENTAGE CoLts.crEa CoL* orTM ON CULTURE PosrrrvE 5/6/59 6 5 83 7/14/59 26 15 58 9/16/59 26 16 62 Totab 58 36 Average 62 Only 10 of the boys who worked in the park gave a history of a clinical illness. Nine of these had positive histoplasmin skin tests and serologic and x-ray findings, and in the other only the skin test was performed, which was positive. In 5 of the 10 boys a moderately severe illness developed, lasting from one to six weeks, with symptoms of chills, fever, cough, malaise and chest discomfort. The other 5 reported symptoms of a mild upper-respiratory-tract infection lasting a few days. Table 2 and Figure 2 show the sites and results of cultures of soil samples taken from the park. On May 6, 1959, 6 soil samples were collected on the southeastern sector (marked Troop 36 on Figure 2), which was the area where the 4 most severely ill boys had worked. H. capsulatum was isolated from 5 of the 6 samples. At the time of this collection the ground was relatively dry and almost completely clear of leaves and debris. About ten days previously a city employee had run a disk-type cultivator over most of the property to loosen the topsoil and prevent the overgrowth of weeds. The underbrush was com- pletely cleared, and many of the smaller trees had been removed. In spite of this, enough trees were present for the grounds to be almost entirely shaded. Approximately two months later, on July 14, an additional 26 soil samples were collected from the entire area of the property. Fifteen of these samples were positive for H. capsulatum. On September 16, 16 of 26 more soil samples collected were found to be positive. The majority of the positive samples were from the southeast quarter of the park although 3 isolations were obtained from the southwest, and 4 from the northeast section. Sixty-two per cent of all soil samples collected from this property were positive for H. capsulatum by cul- ture, an unusually high yield. With this many re- peated and widely distributed isolations there is June 15, 1961 little doubt that the fungus was flourishing abun- dantly throughout a large portion of the park site. When the high percentage of soil isolations in this large, open area became evident, a question of considerable interest arose. Did the frequency of isolations from the park represent an unusual preva- lence of the fungus there or merely reflect a high prevalence throughout the entire area? For this reason soil samples were collected from 68 selected sites within a radius of 3 miles from the city of Mexic'o and in the city itself. The sites selected were all open areas that were both shaded and along creek beds, assuming that these would be the most Missouri Street Cleared Area !rZBoseball + Diamond I ~ ~ ~ ~ ~ ~ ~ ~ 0 ~ ~ Troop 40 01 0 I 0 I ~ 0 ~ I 0= Negative + = Positive o + x V 0 a r-_.. I \ , , ( + Troop 39 0 0 \\V~,~ ~ + + ~ + ° ~\ I_~--1 +°0 I + Troop 36 ~ °} I ~ + L f }~++ 0 0 --- -i + ( Troop 38 ~ + +° I ~ + + +I I+ + Western Street ~HQuse + 0 I rainaqe Ditch 0 Troop 36 I I FI6URE 2. Sites of Soil Samples in Historical Society Park, Mexico, Missouri. favorable environments for growth of fungi. How- ever, there was no evidence of excessive bird roosting at any of these sites. As shown in Figure 1, only 1 of the 68 soil specimens studied with the procedure used on the park soils was positive for H. capsulatum. It is quite clear, therefore, that the frequency of isolations from the park was unique and not in any way typical of similar sites in the same area. DISCUSSION As mentioned previously it is now clear that there are at least four distinct sources of infection for urban persons. Visits to Farms or Prior Rural Residence Studies published in 1957 and 19581,2 gave clear evidence of the relation between farm contact and .

e Vol. 264 No. 24 URBAN HISTOPLASMOSIS-FURCOLOW ET AL. the incidence of histoplasmin sensitivity. Among city children who had visited on farms the estimated annual conversion rates were twice as high as those of children who denied such visits. If the child had lived on a farm the annual conversion rate was over five times as high. Exposure to Imported Farm Soils or Manures The first report of H. capsulatum infection due to the importation and use of infected soil was presented by Kier et a1.3 in 1954 from Memphis, Tennessee. Similar epidemics were reported from Rockford, Illinois, in 1955,5 Mountain Home, Arkansas, in 1956,° Dallas County, Alabama, in 1958,° and Sturgis, Mississippi, in 1959.$ In these urban epidemics it appeared quite clear that the importation of infected material contaminated by droppings of birds, usually chickens, was the cause. Exposure in Urban Structures Still another group of epidemics have been as- sociated with the demolition of buildings in cities, particularly belfries, old schoolhouses and various other old buildings, all of which were contaminated with bird droppings, usually from pigeons. The first reported epidemic of this type occurred in Plattsburg, New York, in 1938,° with subsequent epidemics in Mandan, North Dakota,10 Warrenton, North Carolina,ll and Cincinnati, Ohio.12 In the Fort Leavenworth, Kansas, study2 conversion rates were especially high during the first year of the study among the top-floor residents of a large apartment house, where a sprinkler system was being installed. The remodeling for this equipment scat- tered pigeon dung deposited in the attic and created considerable dust. The rate of infection was markedly lower in the following year after the re- modeling had been completed. Exposure in Open Urban Areas Finally, and most recently, infection occurring in open areas in cities has come into prominence. This form of exposure appears to be both endemic and epidemic. Perhaps the first epidemic that came to attention occurred in Madison, Wisconsin,13 in an open area on the edge of the city in June, 1948. Ten persons became infected while digging fishing worms in a shaded, marshy area on the edge of Madison. H. capsulatum was recovered from the site. Recent inquiry'i has revealed that the area was known to be a resting place of large numbers ( thousands ) of blackbirds and starlings. The next reported epi- demic, which ocaurred at Walworth, Wisconsin,15 also an area known to be of low (4 per cent) histo- plasmin sensitivity, involved 19 persons and was asso- ciated with excavation for a basement on a large, shaded lot. In Walworth itself the prevalence of 1229 sensitivity to histoplasmin was shown to be directly correlated with the distance of residence from the site of the epidemic. H. capsulatum was repeatedly recovered from soil taken from the site. Ten years previously, starlings had roosted in the trees around this lot, and considerable droppings were reported to have accumulated. Neither birds nor droppings were evident at the time of the epidemic. In Columbus, Wisconsin, also an area of low histo- plasmin sensitivity, another urban epidemic occurred in an open area around a church.1° Digging around shrubbery in the church yard in an area contaminated by pigeon droppings resulted in the infection of some 23 persons. H. capsulatum was isolated from the contaminated soil. This report represents the fourth epidemic of this type. Unlike the Wisconsin epidemics, the Mexico epidemic occurred in an area of generally high histo- plasmin sensitivity. Nevertheless, the epidemic was clearly defined, and more than 20 persons were in- fected. Here, again, there was a history of starling infestation and heavy accumulation of their drop- pings. Two urban endemic areas of high prevalence of histoplasmin sensitivity surrounded by rural areas of low prevalence have been reported. In Dalton, Georgia,'' where children in the city of Dalton had a sensitivity rate of about 60 per cent to histoplasmin, those in the surrounding rural area showed a preva- lence of only 20 per cent. It appeared that the infection was centered in this city, particularly in the wealthier, more shaded areas. Inquiry revealed that from the early 1930's until about 1950 large flocks of birds, principally starlings, wintered in the area from late October through March. At times, over 10,000 birds roosting in the large trees lining the streets of the wealthier residential area were counted, and accumulations of droppings were defi- nitely noted.l$ More recently a high prevalence of histoplasmin sensitivity has been reported in the city of Milan, Michigan, in the center of an area where the preva- lence of sensitivity ranges between 2 and 11 per cent among school children.19 In this small city the prevalence was found to be 61 per cent among school children. In Milan, also, there was definite evidence of excessive starling harborage, particularly near the schools. The droppings were reported to have made the ground white and walking hazardous.'0 The association of soil contaminated with chicken and pigeon droppings and infection with histoplasma has frequently been observed. Contamination by bat droppings l and on one occasion oilbird droppingsZ" has been reported. Most of these sites of infection have been rural or in caves or other rather remote locations. The present paper points up the impor- tance of contamination of soil in urban locations by I m

1230 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 a new type of bird - namely, the European starling (Sturnus vulgaris linnaeus). Further investigations of the part played by these birds in infection with H. capsulatum is being undertaken. SUMMARY AND CONCLUSIONS Further evidence has now accumulated that city dwellers contract histoplasmosis by contact with point sources of growth of the organism and not by the casual inhalation of wind-borne spores dis- seminated throughout the city. A pattern of urban histoplasmosis that includes at least four distinct sources of infection has emerged: visits to farms or prior rural residence; exposure to imported farm soils or manures; exposure in urban structures frequented by birds; and exposure in open urban areas. In each of these forms of exposure, urban infection can be related directly to exposure to sources contaminated with bird excreta. An urban epidemic of histoplasmosis in Mexico, Missouri, illustrating the fourth source of infection listed above, is described. Frequent isolations from this source indicate a high degree of contamination with Histoplasma capsulatum. It is postulated that starlings and perhaps other gregarious birds that frequent cities may be impor- tant in creating sites of florid fungus growth within communities in areas of both high and low prevalence. REFERENCES 1. Furcolow, M. L., and Ney P. E. Epidemiologic aspects of histo- plasmosis. Am. J. Hyg. 65:264-270, 1957. 2. Anderson, N. W., Doto, I. L., and Furcolow, M. L. Clinical, x-ray and serologic changes with Histoplasma infection. 1'ub. Health Rey 73:73-82, 1958. 3. Kier, J. H., Campbell, C. C., Ajello, L., and Sutliff, W. D. Acute bronchopneumonic histoplasmosis following exposure to in- fected garden soil. J.A.M.A. 155:1230-1232, 1954. 4. Furcolow, M. L. Unpublished data. 5. Loosli, C. G. Symposium on clinical advances in medicine: his- to~lasmosis: some clinical, epidemiological and laboratory aspects. M. Clin. Nortk America 39:171-199, 1955. 6. Chin, T. D. Y., et al. Epidemic of histoplasmosis among school children in Arkansas. South. M. J. 49:785-792, 1956. 7. Hosty, T. S., Ajello, L., Wallace, G. D., Howell, J., and Moore, J. Small outbreak of histoplasmosis. Am. Rev. Tuberc. 78:576-582, 1958. 4 8. Hagstrom, R. M. Epidemiologic studies by county health depart- ments. Mississippi Doctor 37:141-145, 1959. 9. Nauen, R., and Korns, R. F. Localized epidemic of acute miliary pneumonitis associated with handling of pigeon manure. Presented at annual meeting, American Public Health Association, New York City, New York, October 3-5, 1944. 10. Furcolow, M. L., and Grayston, J. T. Occurrence of histoplas- mosis in epidemics: etiologic studies. Am. Rev. Tuberc. 68:307- 320, 1953. 11. Parrott. T., Jr., Taylor, G., Poston, M. A., and Smith, D. T. Epidemic of histoplasmosis in Warrenton, North Carolina. South. M. J. 48:1147-1150, 1955. 12. Feldman, H. A., and Sabin, A. B. Pneumonitis of unknown etiology in group of men exposed to pigeon excreta. J. Clin. In- uestipation 27:533, 1948. 13. Dickie, H. A., Ackerman, H., and Murphy, M. Unpublished data. 14. Dickie, H. A. Personal communication. 15. Wilcox, K. R., Jr., Waisbren, B. A., and Martin, J. Walworth, Wisconsin, epidemic of histoplasmosis. Ann. Int. Med. 49:388-418, 1958. 16. Dickie. H. A., Bayley, H., and Poser, R. F. Unpublished data. 17. Edwards, P. Q., Ajello, L., Moore, J., Jacobs, C. F., and Aronson, D. L. Soil sampling in urban focus of histoplasmin sensitivity. Am. Rev. Resp. Dis. 81:747-751, 1960. 18. Jacobs, C. F., and Hamilton A. P. Personal communication. 19. Engelke, O. K., Hemphill, P. M., Bushell, E., and McKinney, E. B. Survey of tuberculin and histoplasmin reactors among school children of Washtenaw County, Michigan. Am. J. Pub. Health S0: 368-376, 1960. 20. Curtis, A. C., et al. Personal communication. 21. Englert, E., Jr., and Phillips, A. W. Acute diffuse pulmonary granulomatosis in bridge workers. Am. J. Med. 15:733-740, 1953. 22. Ajello, L., Briceno-Maaz, T., Campins, H., and Moore, J. C. Isolation of Histoplasma capsulatum from oil bird (Steatornis caripensis) cave in Venezuela. Mycopathologia 12:199-206, 1960. CONSTRICTIVE PERICARDITIS DUE TO HISTOPLASMA CAPSULAT UM* CHARLES F. WOOLEY, M.D.,t AND DON M. HosIER, M.D,$ COLUMBUS, OHIO THE progressive increase in knowledge of the clini- cal spectrum of histoplasmosis in man, coupled with the infrequency of a specific etiologic diagnosis in patients with chronic constrictive pericarditis, con- tributes to the interest of the following case report. CASE REPORT A 14-year-old high-school girl was admitted for the 1st time to Children's Hospital for evaluation of recurrent edema on November 1, 1959. She had been in good health until February, 1956, when, at 11 years of age, she was admitted to another hospital with a 2-week history of anorexia, malaise, nonproductive cough, chest discomfort and abdominal pain. Fever was present, with daily elevations of temperature to 104 to 105°F. Pertinent findings included orthopnea, dyspnea at rest and signs of pleural and pericardial effusions. There was a slight leukocytosis initially; the erythrocyte sedimentation rate was 30 mm. per hour. Antistreptolysin-O titers and the test for C-reactive protein were within normal *From the departments of Medicine (Cardiologp) and Pediatrics, Ohio State University College of Medicine and the Children's Hospital. iFellow, Central Ohio Heart Association. $Associate professor of pediatrics, Ohio State University College of Medicine. limits. Serial electrocardiograms showed ST-segment and T-wave changes consistent with pericarditis. Pericardio- centeses on successive days yielded 300 ml. and 350 ml. of serous fluid, with a specific gravity of 1.020 and 10,000 red cells and 1400 white cells per cubic millimeter. Gram stain, culture and stains for acid-fast bacilli and cultures for pyogens were negative. Therapy included rest, digitalis, penicillin and cortisone. The duration and amount of therapy were not recorded. The course was one of progres- sive improvement; fever gradually subsided, no murmurs de- veloped, the cardiac silhouette returned to normal over a period of 4 weeks, and electrocardiograms manifested per- sistence of the precordial T-wave inversion. The child was admitted to the same institution in Feb- ruary, 1957, for re-evaluation. No mention of the physical findings was made; however, an electrocardiogram revealed persistent myocardial changes and x-ray study of the chest showed a normal cardiac silhouette. At the time of the initial admission to Children's Hospital on November 1, 1959, the patient's complaint was that of recurrent pedal edema of approximately 9 or 10 months' duration and the more recent development of intermittent edema of the face and hands. Since the time of the initial illness, she had been troubled with easy fatigability. During the year preceding admission she had attended school full time; however, she was unable to participate in any vigorous activities. Symptoms included orthopnea requiring 2 pillows for relief and dyspnea on exertion. There was no paroxysmal dyspnea, chest pain or hemoptysis. i 4 F

, . . Vol. 264 No. 24 PERICARDITIS DUE TO HISTOPLASMA- WOOLEI' AND HOSIER The family history revealed no significant abnormality. The family lived on a farm, which was not worked by the family, and the patient had not actively participated in ani- mal care or handling. Physical examination showed a well developed, well nourished girl weighing 52.1 kg. (115 pounds) who was moderately orthopneic. There was minimal distention of the neck veins and of the veins of the upper extremities. No pulsatile activity was noted in the neck veins. The lungs were clear to percussion and auscultation. The heart was not enlarged. The rhythm was regular. The heart sounds were distant and of poor quality. No murmurs were noted, and no adventitious sounds were appreciated. The liver was palpable at the right costal margin; the spleen was not pal- pable. Peripheral pulses were all normal. There was + + pretibial edema bilaterally. A suggestion of some periorbital fullness was noted; there was no edema of the upper extremi- ties or the face. The temperature was 98.6°F:, the pulse 80, and the respi- rations 20. The blood pressure was 110/70 in both arms and 135/100 in both legs. The hemoglobin was 13.6 gm. per 100 ml., and the white- cell count 8500, with a normal differential. The sedimenta- tion rate was ?5 mm. per hour. Urinalysis was within nor- mal limits, as were the blood urea nitrogen, electrolytes and serum proteins. Agglutination studies for typhoid 0 and H, paratyphoid A and B, salmonella B, E and C, Proteus OX 19 and hrucella were all negative. X-ray study of the chest (Fig. 1) showed deposits of calcium in the hilar re- FIGURE 1. Posteroanterior View of the Chest before Opera- tion. The heart size is normal. The contour of the right atrium is slightly distorted, with an area of linear calcification in the pericardium in the same area. The pulmonary artery is slightly prominent. Deposits of calcium are present in the hilar and peripheral lung fields bilaterally. gions and peripheral lung fields bilaterally. There was a streak of calcium superimposed on the right and posterior borders of the pericardium, with speckled deposits of calcium overlying the margin of the left ventricle. The transverse diameter of the heart was within normal limits. Fluoroscopy and cinefluorographic studies of the heart showed normal pulsations in the region of the aorta and the pulmonary artery; pulsations of the remainder of the left cardiac border were very sli,,ht. On the right side the streak of calcium noted on the plain films was seen just above the diaphragm; the movement was very slight throughout this area and along the entire right cardiac border. An electrocardiogram 1231 showed low voltage in the limb leads and inverted T waves in Leads 1, 2, 3, aVF and V, through V,,. Skin tests were negative at 48 hours for purified protein derivative, 1st and 2d strengths, positive at 24 and 48 hours for histoplasmin, 1:-100 dilution, and negative for bruceller- gen and coccidioidin. The histoplasmin collodion agglutina- tion test was negative. The histoplasmin complement-fixation test of Saslaw and Campbell,' employing whole-yeast phase antigen, was ++-b + at 1: 5 dilution, + + + + at 1: 10 dilution, +-}- + at 1: 20 dilution, + at 1:40 dilution and negative at 1:80 and 1:160 dilutions. The control was FIGURE 2. Low-Power Photomicrograph of the Pericardium (Hematoxylin and Eosin Stain), Showing the Margin be- tween the Central Area of Caseation Necrosis and the Outer Fibrous Wall. Note the granulomatous inflammatory reaction with Lang- hans-type giant cells. negative. Studies performed at the Ohio State Public Health Laboratory showed a positive Kolmer complement-fixation test (yeast phase, ground suspension) at 1: 16 dilution and a negative complement-fixation test for histoplasmin. At catheterization of the right side of the heart the mean pressure in the right atrium was 11 mm. of mercury, the pressure curve being M shaped. The pressure in the right ventricle was 30/12, with a characteristic early diastolic dip and plateau pattern. The pulmonary-artery pressure was 19/14, the left-brachial-artery pressure 137/80. At surgery the pericardium was obviously constricting the heart. The heart was small, and the pulsatile activity was markedly reduced. After the initial incision of the anterior pericardium, the heart bulged into the incision. While the pericardium was being removed from the apex of the left ventricle, a cavity was entered that contained approxi- mately 5 ml. of green, grumous material, which was removed with the remainder of the pericardium. The myocardium appeared normal, and there was no evidence of myocardial replacement by fibrosis. The surgical procedure proceeded without incident, and the postoperative course was unre- markable. After operation cinefluorographic studies of the heart showed excellent pulsation along both cardiac borders. Cul- tures of the pericardium and the material obtained at surgery were negative for pyogens, acid-fast bacilli and fungi. Histologic sections of the pericardium disclosed a chronic granulomatous inflammatory reaction, with areas of casea- tion necrosis (Fig. 2). Methenamine silver stains on serial sections showed multiple round to oval bodies in areas of caseation necrosis morphologically consistent with Histo- plasma capsulatum (Fig. 3). Slides, including methenamine silver stains, made from the blocks of the surgical specimen were reviewed by Dr. Henry C. Sweany, director of research, Missouri State Sanatorium, who noted typical yeast bodies in 4 of 5 slides, and con- sidered the diagnosis positive for H. capsulatum. Six weeks after the operative procedure the electrocardio- gram was normal. X-ray study of the chest showed a slight increase in heart size as compared to preoperative films; however, the heart size was within normal limits. The pa- tient remained well 1 year later.

1232 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 DlscussloN Pericardial calcification associated with histoplasmin sensitivity has previously been recorded,z-5 with ac- companying suggestions that histoplasmosis may be a cause of pericardial calcification and perhaps of constrictive pericarditis. Within the spectrum of clini- cal histoplasmosis chronic fibrous mediastinitis with caval obstruction,s myocarditisT and endocarditis$ have been reported. FIGURE 3. Oil-Immersion Photomicrograph (Comori's Me- thenamine Silver Stain). This photograph was taken in the area of caseation necrosis similar to that demonstrated in Figure 2. Note the multiple round to oval black-staining bodies morphologically consistent with H. capsulatum organisms. Apparently, neither pericardial effusion nor calcific constrictive pericarditis due to H. capsulatum has previously been documented e That this should occur is not surprising in view of the known facts regarding the pathogenesis10 and ever-broadening spectrumll of histoplasmosis in the human being. Nor is it sur- prising that routine studies of surgical or autopsy material have not yielded information implicating histoplasmosis as a cause of constrictive pericarditis. In addition to the necessity for multiple tissue sections and a variety of special stains, it must be appreciated that H. capsulatum occurring extracellularly in ne- crotic tissue differs histologically from the intracellu- lar forms in viable tissue.l' Undoubtedly, the use of skin testing, serologic studies, appropriate culture technics and special his- tologic studies of pathological specimens will show that histoplasmosis has been an unrecognized cause of pericarditis, pericardial effusion and constrictive pericarditis. SUMMARY A case of constrictive pericarditis due to Histo- plasma capsulatum is presented. Surgery for constrictive pericarditis was performed three years after an acute illness manifested by fever, pleural` effusions, pericarditis and pericardial effusion requiring pericardiocentesis. Diagnostic studies gave hemodynamic and cine- fluorographic evidence of pericardial constriction, multiple pulmonary calcifications, histoplasmin sen- sitivity, serologic studies consistent with a previous histoplasmosis infection and organisms in the peri- cardial tissue morphologically compatible with H. capsulatum. We are indebted to Dr. William A. Newton, associate pro- fessor of pediatrics and pathology, for the histopathologic studies and photomicrographs and to Dr. Samuel Saslaw, pro-" fessor of medicine, and Dr. Phillip Pratt, assistant professor of pathology. Dr. Michael L. Furcolow, chief, Communicable Disease Center, Kansas City, Kansas, was most helpful, and Dr. Henry Sweany, director of research, Missouri State Sanatorium, reviewed the pathological material. t 0 REFERENCES 1. Saslaw, S., and Campbell, C. C. Use of yeastphase antigens in 2. complement fixation test for histoplasmosis. I. Preliminary results with rabbit sera. J. Lab. & Clin. Med. 33:811-818, 1948. Billings, F. T., Jr., and Couch O. A., Jr. Pericardial calcification 3. and histoplasmin sensitivity. Ann. Int. Med. 42:654-658, 1955. McNerney, J. J. Histoplasmin sensitivity associated with pericardial 4. calcification. Am. Heart J. 52:609-611, 1956. Lamb, L. E. Electrocardiographic findings of pericarditis and histo- 5. plasmin sensitivity. Am. Heart J. 53:301-304, 1957. Hurwitz, J. K., and Pastor, B. H. Pericardial calcification asso- 6. ciated with histoplasmosis. New Eng. J. Med. 260:543, 1959. Salyer, J. M., Harrison, H. N., Winn, D. F., Jr., and Taylor, 7. R. R. Chronic fibrous mediastinitis and superior vena caval ob- struction due to histoplasmosis. Dis. of Chest 35:364-377, 1959. Saphir, O. Non-rheumatic inflammatory diseases of heart. In 8. Pathology of the Heart. Edited by S. E. Gould. 1023 pp. Spring- field, Illinois: Thomas, 1953. P. 806. Merchant, R. K., Louria, D. B., Geisler, P. H., Edgcomb, J. H., 9. and Utz, J. P. Fungal endocarditis: review of literature and report of three cases. Ann. Int. Med. 48:242-266, 1958. Spodick, D. H. Acute Pericarditis. 182 pp. New York: Grune , 0 1959. P. 117. 10. Sweany, H. C. Pathogenesis of histoplasmosis in human body. In 11. Histohlasmosis. Edited by H. C. Sweany. 538 pp. Springfield, Illinois: Thomas, 1960. Pp. 268-291. Conrad, F. G., Saslaw, S., and Atwell, R. J. Protean manifesta- tions of histoplasmosis as illustrated in twenty-three cases. Arch. Int. Med. 104:692-709, 1959. 12. Binford, C. H. Histoplasmosis: tissue reactions and morphologic variations of fungus. Am. J. Clin. Path. 25:25-36, 1955.

. i Vol. 264 No. 24 ANOMALOUS PULMONARY VENOUS CONNECTION -KALMANSOHN ET AL. 1233 PARTIAL ANOMALOUS PULMONARY VENOUS CONNECTION WITH UNUSUAL VARIATIONS * ROBERT B. KALMANSOHN, M.D.,t JAMES V. MALONEY, JR., M.D.,$ AND RICHARD W. KALMANSOHN, M.D.t LOS ANGELES S INCE the development of effective surgical meth- ods for treating congenital heart lesions there has been a renewed emphasis on clinical diagnosis. Anomalous pulmonary venous connection is one of the conditions in which the typical clinical syndrome has been clarified in recent years.l-' We have studied 2 patients who presented unusual clinical variants of the syndrome. CASE REPORTS CASE 1. A 10-year-old boy was first seen on May 13, 1958, with the complaints of wheezing, dyspnea and ankle edema. The symptoms were progressive and of 2 months' duration. Since the age of 5 years, he had had episodes of wheezing, which were attributed to allergy. A heart mur- mur was detected at the age of 9 months during a hospital admission for pertussis. Otherwise, the past history was noncontributory, without mention of maternal rubella, other congenital anomalies, cyanosis, squatting or clubbing. FIGURE 1. Preoperative Posteroanterior Roentgenogram in Case 1, Demonstrating an Abnormal Shadow in the Left Upper Lobe (See Insert). Physical examination revealed an asthenic boy who was underdeveloped physically, but not mentally. He was orthop- neic and had grossly audible wheezes. The temperature was 98.6°F. (37°C.) by mouth, the respirations 40, and the pulse 104 and regular. The neck veins were distended, without visible pulsation. The chest was asymmetrically deformed, with a prominence of the left hemithorax, par- ticularly in the parasternal area. A Grade 3, low-pitched, 'From the departments of Medicine and Surgery, University of Cali- fornia Medical Center. Supported in part by grants-in-aid (H-2812 and HTS-5357) from the United States Public Health Service. Dr. Maloney's work was supported by the Scholar Program of the John and Mary R. Markle Foundation. tClinical instructor in medicine, University of California School of Medicine. $Associate professor of surgery, University of California School of Medicine. continuous murmur with late systolic accentuation was maximally audible at the pulmonic area and was associated with a thrill in the same area; the murmur was transmitted too the back, neck and apex. The pulmonic 2d sound was markedly accentuated and moderately split. Subcrepitant rales were audible anteriorly and posteriorly over the lower- lung fields. The liver, palpable 2 fingerbreadths below the right costal border, was firm, nontender and nonpulsatile. All peripheral pulses were easily palpated; the blood pres- sure taken at rest was 103/70 in the right arm and 165/80 in the right leg. There was + + peripheral edema. FIGURE 2. Postoperative Posteroanterior Roentgenogram in Case 1, Demonstrating the Abnormal Shadow Now Angulated Owing to Surgical Correction. Laboratory data included a sedimentation rate of 5 mm. per hour (Wintrobe method), hemoglobin of 16.5 gm. per 100 ml., a white-cell count of 12,640, with a normal differ- ential, urinary specific gravity of 1.006, with a + to -}- + test for protein, and an electrocardiogram suggestive of biventricular hypertrophy and enlargement of the right atrium; the vectorcardiogram was interpreted as indicating enlargement of the right ventricle, and the phonocardiogram showed a continuous murmur, with an accentuated 2d sound. Chest roentgenograms showed gross cardiomegaly, bilateral pleural effusions, and marked enlargement of the main and secondary branches of the pulmonary artery. A hilar dance was present on chest fluoroscopy. It was subsequently noted, in retrospect, that there was a shadow in the left upper lobe that did not follow normal vascular patterns. After surgical correction this shadow became angulated, which probably indicated the new course of the vein since it was transposed to the left atrial ap- pendage (Fig. 1 and 2). The patient was treated for congestive heart failure for a 2-week period. When cardiac compensation had been restored arterial oxygen saturation was 90.9 per cent (Van Slyke). The clinical impression was a patent ductus arteri- osus, with marked pulmonary hypertension but with a predominant left-to-right shunt. On June 3 a left-sided thoracotomy was performed, and a patent ductus arteriosus was divided. The ductus was 1.4 cm. in diameter, and the pulmonary-artery pressure appeared approximately the same as the aortic pressure. The pul- monary-artery pressure was 40 to 50 mm. of mercury after the division of the ductus and 65 mm. of mercury at the end of the operation. It was found that the vein draining I n Q I I

1234 THE NEW ENGLAND JOURNAL OF MEDICINE both divisions of the left upper lobe joined the innominate vein. The anomalous vein was divided from its attachment to the innominate vein and anastomosed to the left atrial appendage. After operation the patient had transient sys- temic hypertension and gastrointestinal bleeding of unknown origin. One year later the ventricular enlargement had re- gressed, as demonstrated by the physical examination, an electrocardiogram and x-ray studies. The patient was symp- tom free and without the need of medication. No heart murmurs were audible. CASE 2. An 11-year-old boy was first seen in June, 1958, because of a heart murmur first discovered in the preceding month. There was no history of rheumatic fever, congenital anomalies or cardiovascular disability. FIGURE 3. Posteroanterior Roentgenogram in Case 2, Show- ing the Changes Described in the Text. Physical examination showed an obese boy in no apparent distress. He had a moderately high-arched palate, normal neck veins and clear lungs. The blood pressure was 120/70 in the arms, with a higher record in the legs. The pulse was 80, and the rhythm was regular; the left heart border was in the mid-clavicular line in the 5th interspace. There was a palpable thrust in the 4th interspace at the left para- sternal line. The aortic 2d sound was equal in intensity to the pulmonic, which was moderately split and fixed in all phases of respiration. There was a Grade 3, low-pitched, ejection-type systolic murmur, maximal at the pulmonic area, which was transmitted to the 3d and 4th interspaces to the left of the sternum. Chest fluoroscopy and roentgenography showed exag- gerated hilar pulsations, a prominent main pulmonary ar- tery, hyperemia of the lung fields and enlargement of the right ventricle and possibly of the right atrium (Fig. 3). An electrocardiogram showed a pattern of right-bundle- branch block. Catheterization of the right side of the heart demonstrated a pressure of 30/0 in the right ventricle and 25/10 in the main pulmonary artery; oxygen saturation studies showed a step-up from 65 per cent in the superior vena cava to 79 to 83 per cent in the right atrium, with the latter saturation persisting in the right ventricle and the pulmonary artery. In August, 1958, at thoracotomy under hypothermia, no June 15, 1961 evidence of a defect of the atria] septum was found. Instead, the right and left inferior pulmonary veins drained into a 3d atrial chamber posterior to the right atrium. This chamber drained into the right atrium. Because it was thought that there was insufficient time under hypothermia to correct the defects completely, the chest was closed, and the patient was rescheduled for operation with the use of extracorporeal circulation. On August 12, 1959, a bilateral thoracotomy was per- formed. A flap was cut out of the atrial septum and used as part of the wall between the left atrium and the 3d chamber on the one hand and the right atrium on the other. Then, a continuous silk suture starting at the caudal area of the 3d atrial chamber was used, and the 2 edges were sewn together so that the anomalous veins and coro- nary sinus were displaced to the left. This suture line then included the flap in the atrial septum previously described, so that a solid wall was formed between the 2 chambers on the left and the chamber on the right.* This was done with the use of anoxic cardioplegia, the aortic clamp being released at 10-minute intervals. The patient made an un- eventful recovery. DISCUSSION We could find only 1 mention in the literature of an association of anomalous venous connection and patent ductus arteriosus. Zieglers reported a nine- month-old patient with these anomalies; no clinical details were given, and surgical correction was not mentioned. Reference has been made in the litera- ture to only two types of anomalous connection of pulmonary veins that could be recognized in the posteroanterior roentgenograms of the chest' - that is, the so-called "figure-of-eight" type of drainage into a persistent left superior vena cava or vertical vein and the type in which all or some of the right pul- monary veins drain into the inferior vena cava. Thus, we have described a third type that may be recog- nized on the conventional posteroanterior film of the chest. We have been unable to find a case similar to Case 2. Five patients with partial anomalous pul- monary venous connection of both lung fields have been described3,',s; 4 patients had associated septal defects, and the fifth' had anomalous connection of the right lower lobe and the entire left lung. Be- cause of the significant amount of blood draining anomalously, a normal life span was probably not to be anticipated.s,lo,l' In retrospect, there was little reason to suspect this anomaly rather than a defect of the interatrial septum: the clinical findings - that is, evidence of a left-to-right shunt at an atrial level - are the same; the patient's habitus, although unusual in association with an ostittm-secundum type of septal defect, is not unheard of in that con- dition, since the shunt was, in reality, at the atrial level; the site of oxygen step-up is similar in these two conditions; and angiocardiography and dye- dilution studies would probably not have been of value. An anomalous vein draining part of a lobe as an "An illustrated operative description in a similar case has been pre- sented elsewhere.l d .

Vol. 264 No. 24 SMOKING AND LUNG CANCER - WYNDER isolated finding would probably not be of great clinical or prognostic significance. However, when combined with a patent ductus arteriosus and pul- lnonary hypertension, it might have assumed greater significance. SLTMMARY Two patients with unusual types of anomalous pul- monary venous connections are described. The first had a patent ductus arteriosus with pulmonary hy- pertension and an anomalous vein draining both divisions of the left upper lobe into the left in- nominate vein; the second had anomalous veins draining both lower lobes into a fifth chamber be- hind the right atrium. All anomalies were corrected in both patients. REFERENCES 1235 1. Longmire, W. P., Jr., Burroughs, J. T., and Maloney, J. V., Jr. Total pulmonary venous connection. Surgery 44:572-577, 1958. Bruwer, A. J. Posteroanterior chest roentgcnogram in 2 types of anomalous pulmonary venous connection. J. Thoracic Surg. 32:119- 134, 1956. 3. Brody, H. Drainage of pulmonary veins into right side of heart. Arch. Path. 33:221-240, 1942. 4. Guntheroth, W. G., Nadas, A. S., and Gross. R. E. Transposition of pulmonary veins. Circulation 18:117-137, 1958. 5. Steinberg, L, and Finby, N. Clinical and an$iocardiographie fea- tures of congenital anomalies of pulmonary circulation: classifica- tion and review. Angiology 7:378-395, 1956. 6. Levinson, D. C., et al. Transposed pulmonary veins: correlation of clinical and cardiac catheterization data. Am. J. Med. 15:143-157, 1953. 7. Gilman, R. A., Skowron, C. A. R., Musser, B. G., and Bailey, C. P. Partial anomalous venous drainage. Am. J. Surg. 94:688-694, 1957. 8. Ziegler, R. F. Importance of patent ductus arteriosus in infants. Am. Heart J. 43:553-572, 1952. 9. Ellis, F. H., Jr., Callahan, J. A., DuShane, J. W., Edwards, J. E., and Wood, E. H. Partial anomalous venous pulmonary venous con- nections involving both lungs with interatrial communication: report of two cases treated surgically. Proc. Stajf Meet., Mayo Clin. 33: 65-74, 1958. 10. Healey, J. E., Jr. Anatomic survey of anomalous pulmonary veins: their clinical significance. J. Thoracic Surg. 23:433-444, 1952. I1. Hughes, C. W.. and Rurnore, P. C. Anomalous pulmonary veins. Arch. Path. 37:364-366, 1944. SPECIAL ARTICLES AN APPRAISAL OF THE SMOKING-LUNG-CANCER ISSUE* ERNEST L. WYNDER, M.D. t NEW YORK CITY A A DEBATE with Dr. Little on the relation of lung cancer to smoking is a welcome oppor- tunity to clarify the issue and some of the different points of view that undoubtedly still exist. This dis- cussion permits us to review the evidence and to judge the extent to which the case has been estab- lished or remains still unproved. It is the task of the independent researcher, as well as that of the tobacco industry, to determine the facts as they are and then to let the facts speak for themselves. There are fields of human endeavor in which facts can be suppressed and at times submerged forever. Not so, however, in science. Here, facts may be destructively criticized and misrepresented, but if indeed they are facts, they will eventually be accepted, as the history of scientific progress testifies. It is this aspect of science that has always appealed to me as one of its greatest assets. Any scientist welcomes constructive criticism, Destructive criticism, however, from whatever source does not aid scientific progress. If one negates the value of statistics as part of scientific proof, disre- gards animal evidence as at least aiding human data and sets a goal for acceptable proof that is based upon impossible conditions, the very aim to resolve a given issue is paralyzed. 'From the Section of Epidemiology, Division of Preventive Medicine, Sloan-Kettering Institute. Presented at a meeting of the New England States Chapter, Ameri- can College of Chest Physicians, Boston, lYovember 18, 1960. tAssociate professor of preventive medicine, Sloan-Kettering Division of Cornell University Medical College. The issue that we set out to debate is whether smoking, particularly of cigarettes, increases the risk of lung cancer. The issue is not whether we under- stand the basic mechanism of carcinogenesis, as cer- tainly we do not. The issue is not whether other exog- enous or endogenous factors influence the develop- ment of lung cancer, as undoubtedly they do. The issue is not that lung cancer may occur in nonsmokers, as may, though exceedingly rarely, happen. The issue is whether in the absence of smoking the present incidence of lung cancer would be reduced. The issue is not whether cigarette smoking influences the development of all or even the majority of cases of lung cancer. The issue is whether it influences any. From the point of view of preventive medicine, if smoking leads to the development of even a single case of lung cancer, it is clearly the task of physicians and the tobacco industry to acknowledge this fact and to undertake steps to prevent such an occurrence. I propose, in agreement with a large portion of responsible scientific opinion, that smoking of ciga- rettes at least to some extent increases the risk that cancer of the,lung will develop. Dr. Little, I suspect, holds that it has not been established that such a relation exists to any degree. I should like to outline the existing evidences, pre- slfmptive, statistical, epidemiologic, pathological, bio- logic and chemical, that, taken together, in my opinion demonstrate beyond any reasonable doubt that smoking of cigarettes increases the risk of lung I tl I

1236 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 cancer and that, in fact, it is to be regarded as a causative factor of this disease. PRESUMPTIVE EVIDENCE There has been a real increase in the incidence of lung cancer that cannot be accounted for by improved diagnostic tools. This increase can be explained by any number of environmental factors that have increased during the last few decades, in- cluding cigarettes. The increase has been primarily in men and not in women, which makes it difficult to give a major role to air pollution, but is in line with cigarette consumption, since males in the cancer age have smoked far more and over a longer period than women. Clinicians have observed that the vast majority of their patients with lung cancer are heavy cigarette smokers. They have also observed that heavy cigarette smoking may lead to chronic cough and that upon cessation of smoking, such a cough frequently disappears. Certainly, therefore, it is known that the suspected factor comes into immediate contact with the tissue where cancer develops. In fact, upon deep inhalation, up to 90 per cent of the smoke con- densate is retained by the lung. From elementary chemistry it is known that one can produce carcino- genic polycyclic hydrocarbons by burning any or- ganic matter such as tobacco. None of these points, of course, prove that smoking does affect the develop- ment of lung cancer, but they do make one suspect that it may; certainly, it would not cause a surprise if statistical and epidemiologic data bore out this pre- sumptive evidence. I conceive of no criticism that can be directed against this presumptive evidence. STATISTICAL AND EPIDEMIOLOGIC EVIDENCE Statistical evidence is based upon more than 25 retrospective studies conducted in 9 countries and totaling more than 6000 patients with lung cancer, as well as 3 prospective studies carried out in the United States and England. It is a fact that not a single statistical study has been reported that has not shown that patients with lung cancer smoke con- siderably more than control patients.1,2 It is, of course, conceivable that all these studies have been in error, but if a bias or a statistical error has been com- mitted, it is difficult to see how it could apply to all these studies carried out among different study and control groups and by various technics. What is furthermore important, if an error or bias has been committed, it has to be of a magnitude similar to the difference between the smoker and nonsmoker to acquire lung cancer. It is this point of magnitude that Berkson has failed to respect properly. In the Hammond and Horn3 study among those who smoked more than 40 cigarettes per day, 12 per cent died from cancer of the lung. If an industry had an in- crease in risk so large that in 12 per cent of its workers cancer would develop because of industrial exposure, surely this industry would have to suspend its op- eration. The Hammond and Horn study also showed that among those who give up cigarette smoking, lung cancer is significantly reduced. Although it may be relatively simple to propose a factor that could account for a 50 per cent difference in risk of a disease to develop in groups it is far more difficult to propose a bias or statistical interpretation that could account for an increased risk of over 6000 per cent, as one finds in the heaviest-smoking group of the Hammond and Horn study. Fisher' and others have proposed that a constitu- tional factor exists that leads to both lung cancer and cigarette smoking. There is no evidence of the existence of constitutional factors of such magnitude as to account for the different risk of smokers and nonsmokers. Furthermore, a study among Seventh Day Adventists has shown that in a group of people, even though they live in smog-filled Los Angeles, the risk of lung cancer is significantly lower than that in the general population.5 One would have to propose that the constitutional factor makes a person smoke cigarettes, causes lung cancer and prevents his joining the Seventh Day Adventists Church. Fur- thermore, this constitutional factor would have to have increased in recent years, would have to be sex linked and should be absent in countries where lung cancer is uncommon. None of the studies showing a difference of lung- cancer risks between different countries have ruled out smoking as a factor in the development of lung cancer, though several have suggested that air pol- lution may be an additional factor. Much emphasis has been placed upon the observation by Eastcott6 and Dean,7 who propose that since British immi- grants have more lung cancer than the New Zealand or South African natives, an air-pollution factor in their native England has an important role. The main objection to these studies is not so much that they give practically no specific information about the immigrants themselves in terms of smoking habits or occupation but that the differences that were found between the two population groups were far smaller than the differences that every single study has found between nonsmokers and heavy smokers in whom lung cancer develops (Fig. 1). It must be clear even to the most elementary statistician that a 75 per cent difference cannot account for a difference of several thousand per cent.e Of particular interest are the comparisons between the lung-cancer risks and smoking habits between men and women. Our own studies,9 as well as that by Haenszel, Shimkin and Miller,10 have clearly shown that the present sex ratio is consistent with the long-term smoking habits of the two sexes. I consider this an important point in the epidemiologic proof for the t I . .

. . Vol. 264 No. 24 SMOKING AND LUNG CANCER - WYNDER role of smoking in the causation of lung cancer. In general, the present incidence of lung cancer in var- ious countries is consistent with cigarette consumption some thirty years ago. Greater differences may be accounted for by other factors. For instance, in a study that Dr. Hirayama and I recently completed in Japan we showed that the difference in rates of lung cancer in the two countries can be explained by the differences in cigarette consumption, together with differences in the practice of inhalation. A re- cent study that we conducted in Venice together with Professor Ferrari shows that in this city, even though it has little air pollution, lung cancer is the most common cancer among males and that patients with lung cancer smoke significantly more cigarettes than the control population. Thus, both studies are in agreement that smoking represents an important factor in the development of lung cancer. I Ndlmon oq GIIan,NbMa,IkESn/RvW BC 2 EmttMt, U R, 8>n ImmproNS,/Na. Zwbnd Ban 6,000 3n45S4 , DW,UK.Bmn lmmiqranrvS.G}rkm8em 38 650 aw.( 4 Own,Mnks, 201ClqoreMS PM Ocy/Nan-Smokrs . 3 DoRSWn,hWMS,250mPS.OS/,Smo4n/Nan-SmW.n t P O - 5,000 sf 40 GpvM r q, NwnnanE 8 Nan, AAaMS,20 gp I SmohraMOn Smalrs 6C HamiaM B t1mn,/4els, 40-Ciqvatn Pv Du,/Nm- Smakss. 4,000 ~ 3,000 , ~ 2,0 4 1.000 oC ® ®. s. ae l r 1 V I All lung cunnf osa seen PrwM eroncRUyenic carcinoms d tRe lung FIGURE 1. Relative Di$erences in Mortality from Lung Cancer, Urban-Rural and Immigrant-Native, Compared with Those among Smokers and Nonsmokers. Another important point is the rarity with which epidermoid or anaplastic lung cancer occurs in a nonsmoking person. In fact, it is so. rare as to be useful as an important differential diagnostic tool. The point to be stressed, which has often been over- looked, is that the statistical differences encountered are so significant as in fact to spoil every statistician or epidemiologist who subsequently has to study other diseases and related factors. To explain differ- ences of such magnitude on the basis of error demands errors of similar magnitude. Such errors have so far not been established. I conceive of no other way to interpret the massive statistical and epidemiologic evidence except that smoking does increase the risk of lung cancer and that, in fact, it is a causative factor of this disease. PATHOLOGICAL EVIDENCE The pathological evidence brought forth by Auer- bach, Chang and Cowdry and others may be sum- marized to show that there is an increase in abnormal 1237 cellular pathology, including metaplasia, hyperplasia and carcinoma in situ of human bronchi, the fre- quency of which is related to the number of cigarettes a person has smoked.11,12 It is not necessary to inter- pret these findings in terms of subsequent cancer or to say that these conditions may be produced by other agents or diseases of the lung. The fact is that these pathological findings are certainly not normal and FIGURE 2. Human Major Bronchial Tree, Compared with Skin of Average Mouse. are found more commonly in smokers than in non- smokers. That such findings could be expected is clear to the clinician who knows that a cough in a smoker is an indication that the bronchial epithelium has been changed in such a way as no longer to be independently able to rid itself of impending material. Pathologically, therefore, the bronchi of the smoker show changes that at the very least are not normal. BIOLOGIC EVIDENCE Cigarette-smoke condensate has been proved to be carcinogenic to mouse epidermis, rabbit epidermis and the hilus of rats. It has thus been shown to produce cancer in three species of animals.l9-15 Experiments to cause lung cancer by exposure of mice or rats to cigarette smoke have produced no bronchogenic carcinoma, but neither have experi- ments with benzpyrene mist.16 Seemingly, it has so far not been possible to introduce a sufficient amount of cigarette smoke into the lungs of these animals if they are merely placed in a smoke-filled cage. Unless one can find an animal that will inhale cigarettes as man does, it may be impossible to duplicate the hu- man findings. We have been criticized for applying an unusually high amount of smoke condensate to the backs of mice. The average mouse receives about 10 gm. of smoke condensate a year compared to at least 300 gm. for the average patient with lung cancer. The majority of the cases occur in the major bronchial tree, whose surface is only about six times larger than iir m kt N I'

1238 THE NEW ENGLAND JOURNAL OF DIEDICINE June 15, 1961 that of the average mouse's skin (Fig. 2). Thus, the dose is within range of the dose relation for man as far as these laboratory animals are concerned. The fact, however, is that cigarette smoke is car- cinogenic to laboratory animals, and such evidence, if one is to judge from recent decisions by the Public Health Service regarding aminotriazole and stil- bestrol, should in itself make cigarette smoke suspect. There is a considerable body of opinion that any material, particularly if it produces epidermoid cancer in animals, should be avoided by man and is to be regarded as carcinogenic to man until proved other- wise. I believe that neither positive nor negative ani- CHAIN OF EVIDENCE PRESUMPTIVE EPIDEMIOLOGIC CHEMICAL BIOLOGIC STATISTICAL PATHOLOGICAL FIGURE 3. Chain of Evidence of Relation of Smoking to Lung Cancer. mal experiments can offer conclusive proof that man will react similarly. The main purpose of the animal experiment is to permit a study of the mechanism of the carcinogenesis of a particular substance. The fact that in the present case, however, the animal experi- ments are in agreement with the human data cer- tainly gives added emphasis to both data. CHEbIICAL EVIDENCE The purpose of the chemical study is to give an explanation for the biologic findings and to determine the agent or agents responsible for the biologic ac- tivity established for the laboratory animal. Initial work suggested that higher polycyclic hydrocarbons were important factors, accounting for at least some of the biologic activity.l' It has been suggested that since no one has chemically identified all the agents that lead to cancer there is no chemical proof of carcinogenesis. Certainly, chemical proof is not neces- sary to prove biologic carcinogenicity. It would be like arguing that a woman is not pregnant simply because one does not know who the father is. In our attempt to account for the biologic activity in chemical terms, Dr. Hoffmann and I have made good progress. We are regarding the polycyclic hydro- carbons as the major initiating carcinogens in tobacco- smoke condensate, in the absence of which the total activity would be drastically reduced. We have also found powerful promoting substances, particularly some of the phenols, that have an important role, together with the initiating carcinogens, in accounting for much of the carcinogenic activity.'$ A chemical explanation of the biologic findings is thus near at hand. The total sum of evidence, therefore, includes chemical evidence that explains at least in part the positive biologic findings and pathological evidence that is in line with the statistical and epidemiologic evidence, and all these evidences are in agreement with the presumptive evidence (Fig. 3). I doubt whether in the field of chronic disease there is such complete proof, proof of such great magnitude and proof of so many different studies carried out in different parts of the world as in this particular field. CAUSATION AND CAUSATIVE FACTORS For reasons stated I regard smoking as a causative factor of cancer of the lung in the absence of which the incidence of lung cancer would be dramatically reduced. I regard smoking as a causative factor be- cause the available evidence is in agreement with the postulates that Dr. Day and I have advanced to establish proof for a causative factor of chronic disease : The greater and more prolonged the exposure to the factor, the greater the risk of the population involved. A removal or a reduction of the factor for a given population group should be followed by a reduction in the incidence of disease. The epidemiologic pattern should be consistent with the distribution of the factor. All these postulates have been met by the cigarette- smoking factor. The use of the term causative factor does not mean that we pretend to know the details of the mechanism of carcinogenesis. Knowledge of causative factors does not necessitate knowledge of the precise mechanism of causation. Certainly, one regards sunlight as a cause of skin cancer without understanding the basic cause of this disease, and radiation as a cause of leukemia without knowing its precise mode of action. In the present understanding of chronic disease causative factors need not be essential ones. By causative factor we mean a factor that increases the risk that a given disease will de- velop and in the absence of which the disease would occur less frequently. One need not know the precise mechanism of a disease to prevent it. Did not John Snow suggest methods of preventing cholera years before the true cause of this disease was discovered? Did not Ignaz Semmelweiss successfully combat child- bed fever long before the bacterial origin of this ill- ness was known? Did not Jenner conquer smallpox, and did not Lind triumph over scurvy long before w

Vol. 264 No. 24 SMOKING AND LUNG CANCER-WYNDER 1239 d I . the pathogenesis of these diseases was understood, and did not Percival Pott clearly interpret the relation of coal tar and scrotal cancer a hundred and forty years before its experimental confirmation, a relation whose full pathogenesis remains unknown today? Many will accept from history what they will deny at present - a concept that should not apply to science. Should it not be regarded as a truism that a disease can be prevented without specific knowledge of its pathogenesis? I suggest that few reasonable scientists would demand such proof, and certainly no student of preventive medicine would expect it before introducing available preventive measures. Science demands, of course, discovery of causative factors as well as an understanding of the cause itself. Work must proceed in both directions, but when preventive measures are at hand, a full understanding of pathogenesis is not necessary before one proceeds to utilize them. "A CONTROVERSIAL ISSUE" The issue of the lung-cancer-smoking problem has been widely studied. I know of no other chronic disease that has been studied epidemiologically and statistically in such detail and with such uniform results as smoking and lung cancer. The tobacco industry would like to give the impression that scien- tific evidence is divided on this issue. I do not consider this to be the fact. Certainly, Eastcott, in New Zealand, and Dean, in South Africa, have pre- sented evidence that air pollution may play a part in the development of lung cancer without in any way, however, ruling out the cigarette factor. Berk- son39 has indeed suggested that the statistical re- lation may be artificial, without, however, giving evidence that could account for the magnitude of differences in risk of smokers and nonsmokers, and Fisher' has claimed that a constitutional factor could account for the high risk of lung cancer among smokers, without, however, giving evidence of the existence of such a factor, which could account for the great magnitude of difference between smokers and nonsmokers for lung cancer to develop. A num- ber of reputable scientists have testified that they do not believe smoking to be a cause of cancer of the lung, but few of them have done research on the subject under discussion. It is true in virtually any field of human endeavor that one finds people who will take an opposing view to any proposed evidence. This was true in the days of Semmelweiss, as well as the days of Pasteur, and in previous centuries just as it is true today. It is often said that in the majority of smokers cancer of the lung does not develop. This, of course, is true. But neither do all radiologists get leukemia, nor all sailors cancer of the skin. Does this, therefore, mean one should not protect oneself against radiation or against sunlight? The fact is that in a great number of smokers lung cancer does develop and that some 30,000 Americans acquire lung cancer each year - certainly, enough cases to warrant deep concern. In the evaluation of the present evidence the in- dividual scientist no longer stands alone. The present data have been considered by several groups specifi- cally convened for this purpose. It goes without saying that health authorities, because of the im- portance of the subject matter, both from the per- sonal and from the economic point of view, have given this matter more than the usual attention. Can the tobacco industry regard these authorities, as they regard some of the private investigators, as enthu- siasts or even as fanatics? These authorities include the Surgeon General of the United States, the State Health Commissioner of New York State, the British Medical Research Council, a specially convened United States study group and a special study group of the World Health Organization that considered etiologic factors of lung cancer. These authorities wrote as follows: Surgeon General Burney: "The weight of evidence at present implicates smoking as the principal etiological factor in the increased incidence of lung cancer. . Unless the use of tobacco can be made safe, the in- dividual person's risk of lung cancer can best be reduced by the elimination of smoking."20 New York State Commissioner of Health Hilleboe: "From the practical standpoint, we believe there is al- ready enough evidence incriminating cigarette smoking to justify advising the public that the available evidence is consistent with the view that cigarette smoking is one of the causative factors in lung cancer and that stopping cigarette smoking may, therefore, be a means of lowering the incidence of lung cancer."" Study Group Sponsored by the World Health Organiza- tion: "The study group unanimously agreed that there was no reason to modify the conclusions reached by these experts that the sum total of the evidence available today was most reasonably interpreted as indicating that ciga- rette smoking is a major causative factor in the increasing incidence of human carcinoma of the lung."a The British Medical Research Council: "Evidence from many investigations in different countries indicates that a major part of the increase is associated with tobacco smoking, particularly in the form of cigarettes. In the opinion of the Council, the most reasonable interpretation of this evidence is that the relationship is one of direct cause and effect.ste Recently, Dr. Kotin, a member of the Tobacco Industry Research Council, together with Dr. Falk,24 wrote as follows: The statement recently made by a study group ap- pointed to examine the scientific evidence on the effects of tobacco smoking on health to the effect that "The sum total of scientific evidence establishes beyond reason- able doubt that cigarette smoking is a causative factor in the rapidly increasing incidence of human epidermoid carcinoma of the lung" represents a more or less uni- versally accepted viewpoint with which we concur. Drs. Kotin and Falk thus agree that smoking is a causative factor in lung cancer. The mechanism that they propose may be different from that sug- gested by me and my associates, but this is of little immediate importance to the student of preventive medicine. As far as preventive measures are con-

1240 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 cerned, one is not so much interested in how a given factor increases the risk of a disease as long as one knows that, in its absence, the disease will occur less frequently. It is therefore a fact that several responsible health authorities in this country and abroad have stated after examining all the available evidence that smok- ing, especially of cigarettes, is to be regarded as a causative factor of lung cancer. Because of man's apparent innate desire to continue smoking and because of the large-scale efforts of the tobacco industry and related organizations to present these products to man, I am sure that cigarettes will be smoked at least for the foreseeable future. On the basis of present evidence, however, the problem of lung cancer not only will remain but also will increase in importance. It is for this reason that efforts leading toward safer smoking products must be combined. Obviously, the cigarette industry, in denying the existence of the problem, is preventing the type of crash program of industry and independent researchers that should exist in this field. It is my hope that this debate will help to clarify the present issue by reviewing where research stands today and where it must move in the future. Of those who will not accept existing evidence, I should like to know what evidence would be ac- ceptable. If one criticizes epidemiology for being statistical, if one criticizes animal research for being unrelated to the human problem and if one criticizes chemical identification of carcinogens as not having any bearing to the human disease, I should like to ask if there is a form of evidence that would be accepted as being conclusive. If it were humanly pos- sible we would at once set up a study that could yield such evidence. If it is humanly impossible, it is not a constructive kind of suggestion that would advance scientific knowledge. In this sense I should like to stress again the fact that, as the history of preventive medicine clearly demonstrates, an understanding of causation of disease is not necessary to introduce preventive measures. I believe, in agreement with the majority of public- health authorities, that available evidence is so strong that the case has been proved and that preventive measures must be introduced. I am deeply concerned with the fate of a great industry. I am similarly con- cerned, however, with the thousands of people in whom cancer of the respiratory tract will develop each year. I am finally concerned about how the problem can be solved. For these reasons my col- leagues and I are actively engaged in the task of producing safer smoking products since obviously the public will continue to smoke regardless of how strong the evidence. Here, it seems to me, the tobacco industry and private researchers have a common goal. I strongly believe that by facing the issue squarely and joining forces, they can succeed in solving the problem for the benefit of all. . REFERENCES 1. Cornfield, J., et al. Smoking and lung cancer: recent evidence and discussion of some questions. J. Nat. Cancer Inst. 22:173-203, 1959. 2. Doll, R. Smoking of tobacco. In Monographs on Neoplastic Disease at Various Sites. Vol. 1. Carcinoma of the Lun Edited by J. R. Bignall. 314 pp. Edinburgh: Livingstone, 1958. Pp. 60-80. 3. Hammond, E. C., and Horn, D. Smoking an death rates - report on forty-four months of follow-up of 187,783 men. I. Total mortality. J.A.M.A. 166:1159-1172, 1958. Smoking and death rates - report on forty-four months of follow-up of 187,783 men. II. Death rates by cause. Ibid. 166:1294-1308, 1958. 4. Fisher, R. A. Cigarettes, cancer and statistics. Centennial Rev. Arts & Sc. (Michigan State Univ.) 2:151-166, Spritig, 1958. 5. Wynder, E. L., Lemon, F. R., and Bross, I. J. Cancer and coro- nary artery disease among Seventh-Day Adventists. Cancer 12:1016- 1028, 1959. 6. Eastcott, D. F. Epidemiology of lung cancer in New Zealand. Lancet 1:37-39, 1956. 7. Dean, G. Lung cancer among white South Africans. Brit. M. J. 2:852-857, 1959. 8. Wynder, E. L., and Hammond, E. C. Study of air pollution car- cinogenesis. I. Analysis of epidemiological evidence. Cancer (in press ) . 9. Wynder, E. L., Bross, I. J., Cornfield, J., and O'Donnell, W. E. Lung cancer in women: study of environmental factors. New Eng. J. Med. 2SS:1111-1121, 1956. 10. United States Department of Health, Education, and Welfare, Public Health Service. Haenszel, W., Shimkin, M. B., and Miller, H. P. Tobacco Smoking Patterns in the United States. 463 pp Washington, D. C.: Government Printing Office, 1956. (Public Health Monograph No. 45, Publication No. 426.) 11. Auerbach, 0., et al. Changes in bronchial epithelium in relation to smoking and cancer of lung: report of progress. New Eng. J. Med. 256:97-104, 1957. 12. Chang, S. C. Microscopic properties of whole mounts and sections of human bronchial epithelium of smokers and nonsmokers. Cancer 10:1246-1262, 1957. 13. Wynder, E. L., Graham, E. A., and Croninger, A. B. Experi- mental production of carcinoma with cigarette tar. Cancer Research 14:855-864, 1953. 14. Graham, E. A., Croninger, A. B., and Wynder, E. L. Experi- mental production of carcinoma with cigarette tar. IV. Successful experiments with rabbits. Cancer Research 17:1058-1066, 1957. 15. Blacklock, J. W. S. Production of lung tumors in rats by 3:4 benzpyrene, methylcholanthrene and condensate from cigarette smoke. Brit. J. Cancer 11:181-191, 1957. 16. Leuchtenberger, C., Leuchtenberger, R., and Doolan, P. F. Corre- lated histological, cytological, and cytochemical study of tracheo- bronchial tree and lungs of mice exposed to cigarette smoke. I. Bronchitis with atypical epithelial changes in mice exposed to Varette smoke. Cancer 11:490-506, 1958. 17. ynder, E. L., and Hoffmann, D. Study of tobacco carcinogenesis. VII. Role of higher polycyclic hydrocarbons. Cancer 12:1079-1086, 1959. 18. Idem. Present status of laboratory studies on tobacco carcinogenesis. Acta path. et microbiol. Scandinav. (in press). 19. Berkson, J. Statistical study of association between smoking and lung cancer. Proc. Staff Meet., Mayo Clin. 30:319-348, 1955. 20. Burney, L. E. Smoking and lung cancer: statement of Public Health Service. J.A.M.A. 171:1829-1837, 1959. 21. New York State Department of Health, Bureau of Cancer Control. Hilleboe, H. E. Cigarette Smoking and Lung Cancer. 32 pp. New York: The Department, 1959. 22. Epidemiology of cancer of lung: report of study group. Tech. Rep. Warld Health Organ. 192:1.13, 1960. 23. Great Britain, Medical Research Council. Tobacco smoking and cancer of lung: official statement. Brit. M. J. 1:1523, 1957. 24. Kotin, P., and Falk, H. L. Role and action of environmental gents in pathogenesis of lung cancer. II. Cigarette smoke. Cancer 13:250-262, 1960. t t © .

Vol. 264 No. 24 SMOKING AND LUNG CANCER-LITTLE SOME PHASES OF THE PROBLEM OF SMOKING AND LUNG CANCER CLARENCE C. LITTLE, Sc.D.* ELLSWORTH, MAINE .4 1 0 MY object in discussing the subject of smoking in relation to lung cancer is quite different from that of Dr. Wynder. His purpose is to present data that have convinced him that smoking is a major - perhaps the major - cause of lung cancer. This he has done before many groups over a period of years. He does so with complete conviction and with en- thusiasm. He professes little interest in the broad question of lung-cancer etiology outside smoking whereas the fact that the disease develops in non- smokers as well as in smokers seems of basic sig- nificance to me. One cannot properly disregard re- search on the total mechanism of cancer formation in favor of dealing with an assumed environmental agent not active in some cases. It is my purpose to present certain of the reasons why all such data (which are at times based on rather superficial, scattered and indirect observations) fail to convince other scientists and medical men that a cause-and-effect relation between tobacco use and bronchogenic carcinoma has been established. This does not mean that certain existing studies have not produced suggestive findings. It merely pro- poses that the many problems raised by such studies are not yet solved and that much more research in depth is needed before definitive answers will be avail- able. In the process of this brief discussion there will be some mention of methods for qualitatively more ac- curate and scientific levels of research than those now employed by some investigators. To expect, as Dr. Wynder and some others do, that those still unconvinced should state the exact and specific evidence that would "convince" them is being completely unrealistic. If one could define such specific evidence the problem would be already solved. The following suggestions, however, may in- dicate some steps toward clearing the tangle of con- fused and conflicting opinions now prevalent. No effort will be made to follow a definite classi- fication of evidence, but certain pertinent fields of interest are convenient focal points in an even brief consideration of the entire situation. PATHOLOGY From the pathological aspect, areas of epithelial metaplasia in the lungs have been flatly interpreted by a minority group of pathologists as being pre- cancerous areas significantly associated with smoking. "Scientific director, Tobacco Industry Research Committee; director emeritus, Jackson Memorial Laboratory. 1241 However, similar lesions have been found in infants, in children and in nonsmokers. It is known that several diseases, many of which are commonly as- sociated with childhood years, will produce such lesions in bronchial epithelium. This shows that the origin of these lesions may be independent of smoking. These lesions have also been found in large num- bers in the trachea, over which all inhaled smoke must pass but in which cancer is clinically rare. The epithelial tissues of the trachea and the bronchi are very similar. Therefore, one must ask, and there is no satisfactory answer, if smoking does cause lung cancer, why is it that the trachea does not form cancer as the lung does? Though some claim that these epithelial lesions in the lung occur in greater numbers in smokers than in nonsmokers, it has also been shown that this is true of persons who are afflicted with pneumonia. Therefore, the increase in the lesions is not distinctly diagnostic of any effect of tobacco. Added to these facts, pathologists need to make concerted efforts to improve and agree upon criteria for classification of human lung tumors into types such as adenoma and squamous-cell cancer so that studies of relative rates of incidence and of possible environmental and other influences on such rates could be made more meaningful. Thus, there are basic gaps in pathological obser- vations and interpretations indicating that the evi- dence in this field falls far short of being adequate or conclusive. To clear up the existing discrepancies and disagree- ments among pathologists is one prerequisite to fur- ther progress based upon more significant definitions. AN7MAL EXPERIMENTATION Dr. Wynder was one of the first to report the pro- duction of skin cancers in certain strains of mice painted repeatedly with strong concentrations of tobacco-smoke condensates. This type of work has been accepted by some as "evidence" of a causative relation between smoking and human cancer of the lung. However, proponents of this kind of data ignore or depreciate the more applicable research in which the lungs of animals have been exposed for long periods to whole smoke - which is the accused material - without the production of any malignant tumors. Here, the lung of an animal is being challenged, not the skin, and whole smoke is being used, not a ma- chine-made concentrate. There have been many such experiments here and abroad, and none have

1242 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 been able to produce carcinoma of the lung in animals. More than once the cry has gone up, "Why not remove the harmful substance from tobacco smoke and make it safe?" No one has proved that tobacco smoke can cause lung cancer. How, then, can an un- identified material be "removed" from a substance not yet shown to be carcinogenic? Production of neoplasia by exposure to whole smoke would seem to be a reasonable requirement to raise the level of extrapolative interpretation beyond that of nonscientific speculation and to provide some sort of basic knowledge from which to proceed to further experimental analysis. The skin-painting work with tobacco-smoke con- densates on animals has been used to erect a whole superstructure of estimated quantitative degrees of risk of lung cancer from smoke in human beings. This sort of extrapolation from animals to human beings exceeds scientific limits. The results of this animal skin-painting work were obtained by use of concentrated chemical material in which no substance known to be carcinogenic to man has been demonstrated. Furthermore, no substances have been detected in the smoke concentrate that are present in amounts, either alone or in combina- tion, sufficient to account for biologic activity on the skins of laboratory animals. The material used has been obtained by methods of machine smoking that differ radically from the process of human smoking. If one claims that a substance that produces a biologic reaction on the skin of a laboratory animal should be removed from use by human beings, there are many substances that fall in this category even though they have been used by and applied to man with impunity for years. For instance, invert sugar, egg albumen and even tomato juice have been re- ported as having produced cancers in animals in laboratory experiments. STATISTICS It is the statistical data that comprise the great bulk of the material on which rest the dogmatic claims of "proof" of a cause-and-effect relation between smok- ing and lung cancer. Supporters of the tobacco-guilt hypothesis say: "Look at the great number of epidemiologic studies, all showing a statistical association between cigarette smoking and the development of lung cancer in some individuals. Is not this proof of causation?" Quantity in this statistical area is not proof or corroboration. Indeed, one would expect that all statistical studies similarly set up would show a sta- tistical association if one of them did - but such an association is not proof of causation by any means. Most statisticians, recognizing the secondary and indirect nature of epidemiologic evidence based on death certificates, agree that such evidence alone can- not properly be considered final or conclusive in es- tablishing causation. It may be, and in this case is, suggestive and challenging. It demands and is re- ceiving proper consideration by those who require ad- ditional and more direct evidence pro or con the theory of tobacco guilt. It was a statistical finding that was chiefly respon- sible for stimulating the present intensive study of smoking and health. That finding was the increas- ing number of recorded deaths from lung cancer, par- ticularly among white males, during recent decades. However, there was and still is wide divergence of opinion about how much of the reported increase in lung-cancer mortality is real and how much is ap- parent, resulting from improved diagnostic technics, greater attention to the disease on the part of physi- cians, aging of the population and better methods of classifying and reporting causes of death. One important fact of which one can be sure is that the numerical increase in reported lung-cancer mortality is not an exact measure of change in the real attack rate. One cannot be sure how much, if any, the actual mortality from this cause has been increasing. Involvement of tobacco use in mortality is based on the statistical association of smoking habits with the rate of death. Such an association has been re- ported for "excessive" cigarette smoking by a num- ber of epidemiologic studies. This is the keystone in the arch of accusations against smoking by those who call it the "major" cause of lung cancer and a num- ber of other diseases. Hardly a disease has escaped the mass of statistics dealing with smoking. Causes of death that have been related by statistical studies to excessive ciga- rette smoking include general mortality, lung cancer, cancer of the mouth, pharynx, larynx and esophagus, stomach cancer, bladder cancer, kidney cancer, cancer of the pancreas and prostate, malignant lymphoma and other forms of cancer combined, bronchitis, emphysema, pneumonia and other respiratory dis- eases, coronary-artery disease, general arteriosclero- sis, hypertension, cerebrovascular disease and gen- eral mortality from diseases of the heart and circulation, peptic ulcer and cirrhosis of the liver. Furthermore, other medical literature relates ciga- rette smoking to eye trouble, nose and ear ailments, miscarriages, sterility and other disturbances of the reproductive organs and a host of actions on the nervous, endocrine and digestive systems of man. One's credulity has to be strained to believe that these diseases, most of which have existed since medical experience began, are now being caused by cigarette smoking, which, in the past fifty or sixty years, has become a widespread custom. This long list of diverse and unrelated causes of death brings one to the first major area of disagree- ment among the statisticians themselves. I , 0 .

Vol. 264 No. 24 SMOKING AND LUNG CANCER-LITTLE 1243 0 One point of view holds that excessive cigarette smoking introduces one or more specific contact carcinogens. But if this is true, how does one ac- count for the association of smoking with other non- contact diseases? Those who claim that cigarettes are the "major" cause of lung cancer - assuming a contact carcinogen - certainly should not accuse cigarettes of similarly causing, for example, prostatic cancer, even though a statistical association is shown between this disease and cigarettes. To answer this, another point of view proclaims that excessive smoking produces that hackneyed medical umbrella - "general debility" - under which so many variable and unexplained afflictions have crouched for years, protected from the chilling rain of scientific definition and analysis. There are certain unresolved conflicts of opinion among the statisticians who point the finger of guilt at smoking. One such conflict involves the com- parison between inhalers and noninhalers of ciga- rette smoke. British scientists have found, in a survey of smok- ing habits of a large number of doctors, virtually no difference in lung-cancer incidence between the two categories. What difference they did find was that the inhalers seemed to have slightly less lung cancer than the noninhalers. Some investigators in the United States believe that there is a greater proportional incidence of lung cancer among inhalers, but they have not pro- duced firm data to establish this theory. Obviously, someone is wrong. Both cannot be right. Since replies from the British physicians concern- ing their habits of inhalation were collected in the same way and by the same persons who collected information about the number of cigarettes smoked,' the duration of the smoking habit and the periods of interruption of the habit, the degree of accuracy of all this information needs verification by further studies. This is all the more essential since a highly detailed degree of quantitative and comparative significance has been given to these figures by many eager statisticians. Another difference in observational results is seen in the supposed effect of the continued smoking of cigarettes. Some data appear to show a "protective" effect of cigar and pipe smoking, if these kinds of tobacco use are added to cigarette smoking, regard- less of whether the latter is light, medium or heavy. In other words, people who smoke all three types of tobacco - cigarettes, cigar and pipe - acquire less lung cancer, according to these data, than smokers of cigarettes alone. The variation in the claimed "excess risk" of lung cancer among cigarette smokers as calculated from statistical studies is another example of con- flicting opinion. Contrary to many generalizations made about these statistical studies, they do not all show the same thing. Depending upon which study is ex- amined, one finds that the relative risk of lung cancer among cigarette smokers may be fractionally higher, or may be three or four or five or six or nine times, and so on, up to thirty-six times the risk among nonsmokers. Similarly, there is a wide difference of opinion concerning the relative quantitative role of cigarette smoking in the etiology of bronchogenic carcinoma, even amo,ng those who believe in the guilt of tobacco. These estimates, based on the same statistical data, of how much of the lung-cancer incidence can be attributed to cigarettes vary from as high as 90 per cent, or almost totality, downward by degrees to less than 10 per cent, or almost nothing. Since the same statistical data are available to all, it is evident that such estimates are more a reflection of the degree of interpretive zeal and enthusiasm that each interpreter possesses than they are of scientific significance. All the guesses cannot be right, and if only one is, who can say which one it is? There are certain other examples of conflicting data and interpretations that will perhaps be help- ful in encouraging a balanced and comprehensive basis for evaluation of many aspects of statistical investigation. One is the relatively higher mortality among males from all the common respiratory diseases. Some statisticians and epidemiologists accept this as a constitutional or genetic difference between the sexes. The largely unbalanced X chromosome in males would provide an increased opportunity for direct expression of certain genes that might influence susceptibility. The balanced X chromosomes of the female would decrease this opportunity. Others believe that no real difference exists be- tween the sexes and that when women have smoked as long and as much as men they will show an equal mortality from lung cancer. There are two lines of statistical evidence that strongly favor the existence of a real sex difference in susceptibility. One is direct and consists of the fact that the lung-cancer mortality difference be- tween the sexes has been widening in recent years instead of closing. On the theory that relatively more and more women are completing the hypothesized cancer-latency period of twenty to thirty or more years of smoking, the gap should narrow. The second line of evidence, which is indirect, is the persistently greater susceptibility of men to other respiratory ailments in which exposure of both sexes to infection and other causes is more nearly equal. Another area of disagreement concerning the statistical data is the duration of the aforementioned hypothesized latent period before the carcinogenic changes attributed to smoking are supposed to become evident. Estimates vary over a range of from

1244 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 ten or fifteen to thirty or forty years. Since about 90 per cent of heavy smokers at eighty years of age or over do not have lung cancer, and since many people report that they started to smoke at the age of twelve, there seems to be no valid reason why, if it is convenient to do so, the latent period should not be extended from early adolescence throughout the life span. This could be a great statistical satis- faction, a large "back door" of uncertainty through which to escape when necessary. There are also differences in defining what may properly be classed as "heavy," "moderate" or "light" cigarette smoking. The "pack-a-day" criterion, as recorded from the recollection of smokers or their families or friends, is only an approximate estimate and not a scientific measurement. It is obvious that a person who smokes 20 cigarettes a day to the shortest convenient butt length may draw into his mouth an amount of smoke equal to that of a smoker who daily smokes 60 cigarettes down to two thirds of their length. The only thing common to smokers of a given number of cigarettes a day - assuming that the figures are accurate - is that they lighted the same number of cigarettes. This brings up another device used in some of the statistical studies: that of translat- ing quantities of cigar and pipe tobacco used into terms of packages of cigarettes. This kind of non- scientific conjecture merely serves to complicate and confuse interpretation of the differences reported in all the statistical studies between the effects of ciga- rettes, cigars and pipes. In summation of the statistical aspect, it is fair to expect that the epidemiologists should provide certain essential refinements in their technics and conclusions before they seek to define the problems that their preliminary findings have raised. Among the questions they should settle are the following: Is inhalation a necessary factor in the apparent association between smoking and lung cancer? Is the claimed increase in risk from smoking a steady, cumulative process, or is there a threshold of smoking up to which no such increase is significant ? How are estimates of the relative etiologic potency of smoking versus age, sex, air pollution, previous infections, genetic factors and so forth derived? Much more needs to be known about the types of persons who are prone to cancer or cardiovascular disease. OTIiER FACTORS Factors other than smoking cannot and should not be overlooked in the search to find the etiology of lung cancer. A socioeconomic difference has been observed in lung-cancer incidence in many areas. The lower the economic level, the higher the rate of lung cancer. This difference is worthy of continued attention and study. Malnutrition and dietary deficiencies, already ap- parently involved in some degree in the etiology of cancer of the buccal cavity and the tongue, comprise one subject to be investigated. Stress and strain as an unbalancing and continuing element in life form another possible factor to be kept in mind. Another factor to be considered is the possible role of previous or current respiratory infectious processes, with their accompanying lesions, and disturbances or disruptions of the continuity of function of certain areas of the lung. There is an amazing symmetrical divergence between the curve of recorded increase of lung-cancer mortality and the curve of decreasing death rate from respiratory infections. This may or may not prove to be a coincidence, but it is certainly deserving of further study. There have been reports in the literature indicating a strong link between the decline in deaths from tuberculosis - a disease said to afflict, unknowingly, virtually all persons in civilized countries - and the increase in those from lung cancer. The consistently higher statistical incidence of lung cancer in urban populations as compared with rural is considered evidence of the need for further study of air pollutants as a potential factor of im- portance. There is already an increasing body of research evidence that there are significant psychoemotional differences between compulsive, excessive smokers on the one hand and confirmed nonsmokers on the other. Exact experimental science is apt to shy away from the effects of the relatively intangible and complex factors that determine differences between human beings. Yet in an involved and new type of intense human living, the mind and body are meeting chal- lenges to the more simple and basic inter-relations that were all that was necessary for successful sur- vival under previous, less involved environmental conditions. This situation may be temporarily ignored by those who dislike the existence of unknown or little understood elements in human health problems. It will, however, be firmly and persistently insistent until it is faced and an attitude of attempting its analysis is adopted. It is an integral part of the problems at hand. It is true that these problems require the develop- ment of new skills and patience in approaching them statistically, pathologically and experimentally. These steps, however, are inherent in the problems and are not the product of destructive criticism as hinted by Dr. Wynder. These steps are not a "negation" of statistical evidence, but are a plea for its refinement and n . 0

Vol. 264 No. 24 SMOKING AND LUNG CANCER - LITTLE 1245 . V maturation. They do not "disregard" animal evi- dence but urge the use of at least the same material and the same organs that are involved in lung cancer and other diseases under investigation. They further urge that pathologists clarify their own con- cepts of these diseases and of their possible histologic precursors before the incidence of such diseases and conditions is recorded, tabulated, analyzed and inter- preted with unjustified confidence and misleading finality. Many public-health educators today are advocat- ing and conducting active propaganda campaigns against smoking. No one can fairly deny them this right. All critical scientists and medical men, however, should agree that public education in this field should be balanced and should present all the facts both pro and con tobacco in order that the reader may base his or her decision on the whole evidence, not on a selected or partial presentation. Unfortunately, and by what seems to be deliberate selection, the majority of educational material being distributed is not balanced or complete. Negative evidence, gaps in knowledge and fallibility of super- ficial data are not mentioned. Dr. Wynder cites various health groups and in- dividuals who are convinced of the theory of tobacco guilt. He does not consider in detail the editorial comment in the Journal o f the American Medical Association, the views of the distinguished statisticians Berkson and Sir Ronald Fisher and many others who are not convinced. In so doing he presents an ex- ample of a selective attitude rather than of balanced evidence. No new specially convened groups, boards of re- view, committees or commissions - no matter how "big" and impressive the "names" of their individual members - can make incomplete or superficial data more meaningful. Resolutions and pronunciamentos based on such data will not resolve the problem - much less solve it. Presentation of selected evidence has created a superstructure of material that is based on a funda- mentally weak foundation of incompletely and in- directly gathered information, on uncertain and debatable pathological interpretation, and on non- scientific extrapolation of animal data from con- centrates of tobacco smoke on mouse skins to whole smoke in human lungs. The relative role, if any, that smoking may have is submerged and forgotten in a dedicated effort to isolate tobacco as the cause of lung cancer. Even if one is an evangelist in this field, one should remember the very similar situation regarding alcohol that, not so many years ago, gave to this country the unfor- gettable experience of "prohibition." If one is not such an evangelist, one is bound to do all that one reasonably can to prevent the public from being cajoled into premature judgment based on incomplete and inadequate knowledge. To develop a public attitude that may later be tragically and bitterly faced with disillusionment in individual ex- perience is a grave responsibility. This is especially true when "fear" is used as a motivating factor in establishing the attitude of the public. Unfortunately, this has occurred in certain propaganda efforts. This is not only unfortunate; it is cruel and unwise. Those ready to assume such a responsibility may believe that they have the right to do so. Those not ready to accept as final proof the existing data also have a right to their attitude. Those not yet decided about what their judgment will be have a right to consider all available evidence and to hear suggestions of what might be done in further research. They also have the right to suspend judgment just as long as they may wish. The situation involving tobacco is not a contro- versy or a debate. Efforts to arouse emotion, create propaganda and cater to publicity will only create the danger of a controversy and retard scientific investigation. Lung cancer, indeed all cancer, is a challenge, an unsolved problem. Its etiology will probably long be an open question. As such, greater co-operation and exchange of ideas among experimenters, statisticians and clinicians are the goals to be focused on and to be attained. Bml.locnnpxy Berkson, J. Statistical study of association between smoking and lung cancer. Proc. Staf/ Meet., Mayo Clin. 30:319-348, 1955. Smoking and lung cancer: some observations on two recent reports..J. Am. Statist. A. 53:28-38, 1958. Statistical investigation of smoking and cancer of lung. Proc. StaB Meet., Mayo Clin. 34:206-224a, 1959. Statistics and tobacco. J.A.M.A. 172:967-969, 1960. Doll, R., and Hill, A. B. Mortality of doctors in relation to their smoking habits: preliminary report. Brit. M. J. 1:1451-1455, 1954. Lung cancer and other causes of death in relation to smoking: second report on mortality of British doctors. Ibid. 2:1071-1081, 1956. Fisher, R. A. Dangers of cigarette smoking. Brit. M. 1. 2:43 and 297, 1957. Cigarettes, cancer and statistics. Centennial Rev. Arts & Sc. (Michigan State Univ.) 2:151-166, Spring 1958. Lung cancer and` cigarettes? Nature (London) 182:108, 1958. Cancer and smoking. Ibid. 182:596, 1958. Smoking: The cancer controaersy: Some attempts to assess the evidence. 47 pp. Edinburgh: Oliver & Boyd, 1959. Talbott, J. H. Smoking and lung cancer. J.A.M.A. 171:2102-2104, 1939.

1246 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 MEDICAL PROGRESS INTESTINAL ABSORPTION - ASPECTS OF STRUCTURE, FUNCTION AND DISEASE OF THE SMALL-INTESTINE MUCOSA (Concluded) * LEONARD LASTER, M.D.,t AND FRANZ J. INGELFINGER, M.D.$ BETHESDA, MARYLAND, AND BOSTON, MASSACHUSETTS .. t MALABSORPTION It is apparent from the preceding discussion that intestinal absorption is the net result of many inter- dependent physicochemical and biochemical reactions. Since these reactions are potentially vulnerable to disruption by one or more pathologic processes, the general mechanisms that may be responsible for mal- absorption are numerous and varied. These mecha- nisms have been well described and categorized in recent reviews,ll'-12' and this discussion will not enter upon malabsorption caused by impaired digestive function, deranged motility, excessive secretion (exu- dative enteropathy) or inadequate small-bowel ab- sorptive surface curtailed by inflammation, infiltration or ablation. Instead, emphasis will be placed on certain aspects of the small-bowel disorders that pre- sumably impair absorption by altering the finer morphologic properties and biochemical reactions es- sential for normal intestinal function. The Intestinal Lesion in the Primary Malabsorption States Description. A major achievement of the past decade has been the demonstration that the small- bowel mucosa is extensively altered in so-called pri- mary malabsorption states, such as celiac disease, idio- pathic steatorrhea (nontropical sprue) and tropical sprue.128 The recognition and delineation of the in- testinal lesion were greatly facilitated by the develop- ment of technics for obtaining biopsies of intestinal mucosa by means of peroral intubation.l2e-131 In its severest form the lesion is striking and obvious (Fig. 7) 12D,132-135 The mucosal surface is completely or al- most completely flattened, and if villi are present at all they are extremely short and blunted. Although the degree of abnormality varies, there is a constant feature of the intestinal lesion - a significant reduc- tion in the amount of epithelial surface. A method has been developed for quantitatively estimating the length of the surface epithelium in microscopical sections of biopsy specimens by random counts of the epithelial cells in specific areas of a grid pattern that is superimposed on the microscopical field.132 A *From the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, the Evans Memorial, Massachusetts Me- morial Hospitals, and the Department of Medicine, Boston University School of Medicine. fChief, Castroenterology Unit, National Institute of Arthritis and Metabolic Diseases. jProfessor of medicine, Boston University School of Medicine; asso- ciate physician-in-chief, Massachusetts Memorial Hospitals. number is obtained that is believed to be a direct function of epithelial length and a square-root func- tion of epithelial area. The mean value of counts performed on a series of biopsies from patients with primary malabsorption was approximately half that obtained for control specimens, and there was no overlap in the ranges of the values for the two groups.132 FIGURE 7. An Extreme Example of the Intestinal Lesion in the Primary Malabsorption States. In primary malabsorption states the surface epithe- lial cells of the intestinal mucosa usually appear flattened, their cytoplasm tends to be vacuolated, and their nuclei vary in size and shape. The nuclei, which are more apically situated than usual, may be frag- mented. According to Fone et a1.133 the intercellular borders and basement membrane of the epithelium are indistinct, and the brush borders are reduced in width and frequency are not visible by light micros- copy. Abnormal epithelial cells are often seen fre- quently at the apices of broad, flat villi, but they are. not found near the openings of or within the crypts of Lieberkiihn.138 Although the crypt epithelium is not strikingly altered, the crypts have been described as hyperplastic, elongated, shaped like a corkscrew, infrequent and widely spaced, or arranged in a disorderly fashion and scattered in an expanded lamina propria.l2s,1s2,133,13r The shortening of the villi and the elongation of the crypts have been used to provide an index of mucosal abnormality. In control specimens the villi are, on the whole, about twice as long as the crypts are deep, !

Vol. 264 No. 24 INTESTINAL ABSORPTION - LASTER AND INGELFINGER 1247 but in abnormal specimens the ratio of villus length to crypt depth may be as low as 0.2.134 According to three different reports the rate of epithelial-cell mitosis in the crypts is somewhat greater than norma1.23,129,134 . The lamina propria appears densely infiltrated. Some find plasma cells predominating,132,133 and others report lymphocytes12B, or eosinophilsl3s as the major cells. Interstitial edema of the lamina propria is described,129 but the edema is inconstant and more related, perhaps, to conditions of fixation than to actual pathological changes.132 The application of electron microscopy to the study of the mucosal lesion has been confined mainly to the epithelial columnar absorbing cells. Zetterqvist and Hendrix8 find the microvilli of these cells to be much shorter, less symmetrical and less numerous than in biopsies of normal mucosa, whereas the remaining cell structures appear normal. Hartman et al.7 de- scribe similar changes in the microvilli and note in addition that extensive areas of mucosa may be devoid of epithelium in biopsies from patients with untreated tropical sprue. These authors are uncertain whether the epithelial loss precedes, or occurs as a conse- quence of, the biopsy procedure, but they believe that it represents an abnormality in the attachment of the epithelium to its basement membrane. No other re- ports have described this finding. Opinions about the width of the entire mucosal layer in sprue differ, depending on whether "width" is measured as the distance from the muscularis mucosae to the tips of the villi or to their bases. If the measurement is made to the bases of villi, the mucosal width consistently appears increased,129 but if the measurement is made to the tips of villi, mucosal width may be reduced or norma1,132 and it may be normal even in the severest lesions. In some patients with primary malabsorption the intestinal lesion is less striking. 129,132,133 Villi are pres- ent, but they are shorter than normal and broad and sometimes appear to be fused at their tips. Changes in the lining epithelium are less marked or absent, and the infiltration of the lamina propria may be indistinguishable from that seen in control biopsies. The crypts show little elongation, or they may ap- pear hyperplastic. These moderate abnormalities, in contrast to the obvious severe lesion, may be difficult to identify. Shiner and Doniach129 designate the severe lesion as subtotal villous atrophy and the milder lesion as partial villous atrophy, but Rubin et al.132 will accept the term "atrophy" only if it is narrowly defined to indicate a decrease in the number of epithelial cells, rather than a reduction in mucosal thickness or "a loss of pre-existing epithelial elements." Some of the discrepancies in the published descrip- tions and interpretations of the intestinal lesion may be related to pitfalls in the handling of biopsy specimens. If a sample of mucosa is not sectioned in a plane perpendicular to its surface a normal biopsy may appear remarkably similar to the severe lesion of primary malabsorption.131 Similarly, if the microvilli are not sectioned at a proper angle, they may appear abnormally short under the electron microscope. The appearance of intestinal biopsies is influenced by the time that elapses between excision of the tissue and its fixation for electron microscopy. Zetterqvist' found that if specimens of mouse jejunum were not fixed until forty minutes after death, the number of cytoplasmic vacuoles in the epithelial cells greatly exceeded nor- mal, and the inner partitions of the mitochondria were destroyed. Variations in the tonicity of the fix- ing solution were also capable of producing artifacts in the biopsy specimens. Since views of tissue samples with the electron microscope cover minute areas, it is important to know the site on a villus from which a particular section is derived. Columnar epithelial cells on the villi have a well defined pat- tern of microvilli, but immature cells in the crypts tend to have rudimentary microvilli. Because of this it is possible that an examination of a normal biopsy specimen with the electron microscope could, if it were limited to crypt cells, lead to the erroneous impression that the microvilli were abnorma1.132 Location and specificity. The extent of the mucosal lesion along the small intestine varies. The duodeno- jejunal area is characteristically involved, but the incidence of ileal abnormalities is uncertain. Multiple biopsies taken from the entire length of the small intestine of each of 2 patients with idiopathic steator- rhea failed to reveal any normal areas, although the degree of abnormality decreased somewhat as distal regions were approached.138 Shiner13' obtained a biopsy from the upper small intestine of a patient with idiopathic steatorrhea who subsequently came to laparotomy and whose terminal ileum was also biopsied. Similar "changes of mucosal atrophy" were seen in all the specimens. In other patients with idio- pathic steatorrhea, however, the distal jejunum and ileum appeared to be norma1,134,138 and it has been customary to regard the mucosal lesion as a"proxi- maP' intestinal lesion. Rubin138 suggests that in celiac disease and in idiopathic steatorrhea the proximal small bowel is severely and often irreversibly damaged whereas the distal small bowel is less severely damaged and is more likely to revert to normal during treat- ment. Caution is necessary in such interpretations of biopsy results, however, because mucosal samples taken from the jejunum on the same day from areas only inches apart have shown distinct differences in the degree of their abnormality.138 A lesion of the intestinal mucosa is an extremely frequent and probably an invariable finding in pri- mary malabsorption states. In biopsies from 26 pa- tients with celiac disease and 16 patients with idio- pathic steatorrhea, each specimen revealed reduction in epithelial surface with varying degrees of blunting 1I

h THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 1248 or loss of villi.73z In a British study of 22 patients with idiopathic steatorrhea 20 biopsies showed subtotal vil- lous atrophy, and 2 showed partial villous atrophy.12° In another study from England133 biopsies were ob- tained from 58 patients with clinical diagnoses of idiopathic steatorrhea. Of these, 27 showed severe flattening of the mucosa, 27 showed mild abnormali- ties, and 4 were normal. Because of this high inci- dence of characteristic pathologic changes in celiac disease and idiopathic steatorrhea, a definitive diag- nosis of these conditions should not be attempted without a mucosal biopsy.13z In cases of tropical sprue jejunal biopsies were obtained at surgery from 6 patients,135 and by intubation technic from 9 pa- tients140; in each case mild to moderate abnormalities were encountered. The intestinal lesions seen in celiac disease of chil- dren and idiopathic steatorrhea of adults are so similar in appearance that they have been regarded as identical. This similarity favors the hypothesis that celiac disease and idiopathic steatorrhea are juvenile and adult phases of the same disease.136 There are, however, two stumbling blocks to the acceptance of the histologic lesion as specific for these disorders. In the first place the mucosal abnormalities seen in tropical sprue appear quite similar or identical to those seen in celiac disease and in idiopathic steator- rhea,13z.1'° and yet clinically tropical sprue may be an entirely different disease. Secondly, abnormalities resembling those seen in primary malabsorption are also found in biopsies from patients with other dis- eases. Most authors believe, however, that this oc- curs only infrequently. Rubin et a1.132 failed to detect the characteristic mucosal lesion in any biopsies from 73 control patients. These included 19 subjects without obvious disease of the gastrointestinal tract and 54 subjects with a variety of such diseases. Sev- eral biopsies of ileal mucosa performed via an ileos- tomy in a patient with regional enteritis were found to contain lesions "with a marked resemblance to the celiac-sprue lesion."13z Shiner and Doniach129 re- ported partial or subtotal villous atrophy in 2 of 11 patients with post-gastrectomy steatorrhea, in 5 of 7 patients with "non-classifiable steatorrhea," and in all of 3 patients with "post-operative steatorrhea." Yesner, Schwartz and Spiro141 concluded that flattened, coalesced villi seem to be characteristic of sprue but that atrophic duodenal mucosa with blunted villi occurs in other types of chronic diarrhea. Fone et al.133 believe that markedly flattened intestinal mucosa signifies juvenile or adult celiac disease, but mild abnormalities may represent more than one etiologic group, including, for example, "chronic jejunitis with various degrees of mucosal atrophy." Thus, it appears that the histologic abnormality of the intes- tinal mucosa is highly characteristic of, but not ab- solutely specific for, the primary malabsorption states. Pathogenesis. Neither the immediate pathogenesis nor the underlying cause of the intestinal lesion is understood. As discussed in the first section of this re- port (under "Renewal of Small-Intestine Epitheli- um" ) the appearance of the small-bowel mucosa at a given time represents a balance between the processes of epithelial proliferation and differentiation in the crypts, and the processes of aging and extrusion of cells on the villi. In idiopathic steatorrhea the immediate cause of the intestinal lesion may involve disturbances in differentiation and turnover of the epithelium. As evidence in favor of this concept Padykula et al.'3 have presented histochemical observations that in idiopathic steatorrhea the intestinal epithelial cells apparently fail to acquire normal complements of enzymes that develop intracellularly during differenti- ation - namely, esterase, succinic dehydrogenase and phosphatases. These studies also demonstrated in- creased mitotic activity of the epithelium. It is not yet possible, however, to exclude other types of dis- turbance, such as an accelerated epithelial aging and extrusion, as an immediate cause of the mucosal lesion of the primary malabsorption states. Possible underlying causes for the mucosal lesion include nutritional deficiencies and exposure to toxic substances. Gross forms of malnutrition, such as those in pancreatic insufficiency or starvation, do not neces- sarily produce an intestinal lesion resembling that seen in idiopathic steatorrhea.132 If a deficiency of a specific nutrient impairs the capacity of the intestinal mucosa to maintain its rapid rate of renewal this nutrient remains to be identified. On the other hand, there is some basis for suspecting folic acid deficiency. The administration of folic acid to patients with tropical sprue results not only in hematologic remis- sion but also in a more normal appearance of the intestinal epithelium.l'0 Administration of the folic acid antimetabolite, aminopterin, to rats is capable of grossly disrupting the structure and metabolism of the intestinal epithelium and of reducing significantly the capacity of the small intestine to absorb a sugar such as xylose."2 Finally, oral tolerance tests for assessing folic acid absorption in patients with tropical sprue1'3 and idiopathic steatorrheal" have indicated that malabsorption of folic acid occurs extremely often in these disorders. It is now well established that gluten, a protein fraction of such cereal grains as wheat, rye and barley, is clinically injurious to a large majority of patients with celiac disease or idiopathic steatorrhea. The question of whether gluten has a direct toxic action on the intestinal inucosa of these patients to produce the characteristic histologic abnormality has been evalu- ated experimentally.138 Studies were carried out on 2 adults who had idiopathic steatorrhea in clinical re- mission. Multiple biopsies obtained from each patient revealed characteristic lesions of the proximal small- bowel mucosa, but the mucosa of the distal ileum was completely normal. While the patients were on

I Vol. 264 No. 24 INTESTINAL ABSORPTION - LASTER AND INGELFINGER gluten-free diets wheat flour was instilled repeatedly into the ileum through an indwelling tube. Both pa- tients suffered clinical relapses, and biopsies taken during the nine days of the experiment revealed that the characteristic mucosal lesion developed in ileal areas that had previously been normal. Similar ex- periments with 2 control subjects failed to produce either clinical or morphologic changes. These findings suggest that patients with celiac disease and idiopathic steatorrhea suffer from a specific metabolic defect that permits a toxic effect of wheat gluten on the intestinal mucosa.138 The nature of the metabolic de- fect remains unidentified. This preliminary hypothesis fails to explain why in patients with tropical sprue, who do not appear so specifically sensitive to wheat gluten, mucosal lesions indistinguishable from those seen in celiac disease and in idiopathic steatorrhea develop. Duration. What is the natural history of the mucosal lesion in the primary malabsorption states? The clinical condition of the patient, the duration of the disease and the degree of abnormality of the mucosal biopsy do not correlate with one another. Equally abnormal intestinal lesions have been found in a thirty-four-year-old adult with celiac disease and in a three-year-old child with juvenile celiac disease.136 Mild to moderate histologic changes have been found in biopsies from severely ill patients, and patients in apparent clinical remission often have markedly ab- normal mucosal biopsies.136 In many patients the lesion appears to persist, apparently irreversibly, throughout the course of the disease and despite im- provement in clinical status.129,13E Functional ab- normalities may also persist. Adolescent and adult subjects who appear clinically to have outgrown celiac disease of early childhood are frequently found to have subclinical impairment of their capacities to absorb fats and sugars when quantitative estimations of these functions are performed.145 Although the anatomic lesion may not disappear completely, it can at times improve markedly. Two children with celiac disease were treated with gluten-free diets for ap- proximately eight months, and serial intestinal biopsies showed marked increases in the length of epithelial surface, as determined by the random-count technic, as well as definite improvement in the general histo- logic appearance of the biopsy specimens.138 Treat- ing tropical sprue also results in improvement in the intestinal abnormality,lz9 and indeed "one may an- ticipate reversal of the mucosal lesions if the nutri- tional defects have been of short duration."146 Im- provement was also seen in preliminary studies of the ultrastructural mucosal abnormalities that occur in celiac disease.$ One adult patient was biopsied before and after a remission was induced by the elimination of gluten from the diet, and a second patient was biopsied while in a similar remission. Studies with the electron microscope of the specimens suggested that 1249 when the disease was in relapse the brush border was absent but that, with the onset of remission, the brush border of the columnar cells regenerated. It appears a priori that the extreme reduction in intestinal surface area that results from the mucosal lesion would be an important factor contributing to the decreased absorptive capacity of patients with primary malabsorption.7 The appearance of a biopsy specimen, however, does not correlate with the degree of functional impairment that occurs in a given patient. The morphologic abnormalities may be ex- tremely marked, and yet steatorrhea may be minimal. It may be necessary to determine the length of small bowel that is involved to explain such observations.132 Biopsy instruments that permit sampling from the entire length of the small intestine during a single intubation should prove helpful in this endeavor.l'T,1'$ It is also possible that the degree and extent of in- volvement of a specific region of the small intestine determines the severity of the functional derange- ments. For example, it is believed that in man most of the sugar that is absorbed is taken up before the chyme reaches the ileum, whereas vitamin B12 is absorbed in the ileum. Finally, it is possible that in the primary malabsorption states an underlying ab- normality of metabolism affects the structure and function of the small-bowel epithelium independently and that a biochemically disturbed columnar cell may not be detectable by light or even by electron micros- copy.138 Gluten and Malabsorption An important contribution to knowledge of intes- tinal malabsorption was the discovery by Dicke, in 1950, of a direct relation between the manifestations of celiac disease and the ingestion of certain cereal grains.149 He incriminated wheat, rye, barley and oats, but the inclusion of oats has since been ques- tioned.15°.151 A similar intolerance for cereal grains occurs in idiopathic steatorrhea15=-15' but not in trop- ical sprue. Reports implicating the cereal grains in malabsorption states other than those classified as "primary" have been extremely rare.156 These obser- vations suggest that celiac disease and idiopathic steatorrhea share a common pathogenetic mechanism that is activated by the ingestion of a toxic substance in cereal grains. The toxic substance. In an attempt to characterize the toxic substance in cereal grains, Dicke, Weijers and van de Kamer evaluated the clinical status and determined the daily fecal excretion of fat in children with celiac disease during control periods when their diets were free of cereal grains and during test pe- riods when various fractions of wheat flour were added to the diets. Contrary to medical opinion pre- vailing at the time, the starch-containing fraction of wheat proved quite harmless, but the protein fraction consistently induced relapses. By separating the major

• 1250 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 wheat-flour proteins from one another, the Dutch workers were able to incriminate a component of gluten known as gliadin.1'a When wheat flour, which contains approximately 50 to 75 per cent carbohydrate and about 10 to 15 per cent protein,1's is extracted with water and neu- tral salt solution, a rubbery mass of prote.in remains behind. This is gluten. It does not dissolve when added to water, but it does become sticky and doughy, a property of importance in baking. If it is extracted with 60 to 70 per cent ethyl alcohol about half of it goes into solution.14e The half that dissolves is glia- din; the remainder is glutenin. Depending on the methods employed, gliadin can be fractionated into few or many constituents.l't Gliadin is classified as a "prolamine" because it is usually rich in the amino acids proline (12 per cent) and glutamic acid in the form of glutamine (36 to 43 per cent) - that is, with its free carboxyl group bound to ammonia (Fig. 8) .19,158 In a search for the struc- tural properties of gliadin that made it harmful to celiac patients, attention was given to its high gluta- mine content. A preparation of gliadin was subjected to mild acid hydrolysis under conditions that were known to deamidate it.l'9,159 The treatment removed practically all the ammonia from the glutamine mole- cules but did not destroy more than 10 per cent of the peptide bonds holding the glutamine molecules with- in the gliadin structure. The product, deamidated gliadin, was assumed to be essentially the same as un- treated gliadin except that its glutamine content had been converted to glutamic acid (Fig. 8). When de- amidated gliadin was fed to children with celiac dis- ease it had no ill-effects. Thus, the toxic action of gliadin appeared to depend on its glutamine content. However, when the free amino acid glutamine was tested in appropriate dosage, it too proved harmless to patients with celiac disease, suggesting that the toxic factor in gliadin was a glutamine-containing peptide 14s This pioneering work has been confirmed in a number of laboratories.151 Evidence has been pub- lished indicating that the toxic factor is water soluble, that it has a molecular weight of 15,000 or less and that it retains its toxicity after its antigenic proper- ties have been destroyed by autoclaving.leo One group has isolated the toxic factor as an "acid pep- tide fraction" of gliadin and has found that treatment of this fraction to destroy many of its disulfide bonds does not eliminate its toxicity.lsl Modern methods of protein analysis undoubtedly permit an even more precise characterization of the toxic peptide than has been achieved so far, but the need to test experi- mental fractions of gliadin by feeding them to patients and determining the effect on fecal excretion of fat delays the research immeasurably. An animal assay for the toxic effect of gliadin would expedite the isolation of the harmful peptide, but no such assay is available at present. Rats that received 2 per cent of their protein intake in the form of wheat gluten were reported to have doubled their daily fecal excretion of neutral fat,i62 but the over- lapping nature of the control and experimental data tends to preclude use of this observation for assay purposes. 1. Schematic representation of an amino acid 0 II t H2N\ ~C~ CH OH Glutamine 0 H2N\C C\OH CH2 CH2 C=O sO - amide bond NH2 3. Hypothetical peptide containing two glutamine residues P C C N C \ ~ \C/ H2N \C/ \CH \NH CH II I II 0 CH2 - 0 R J CH2 C= 0 i NH2 4. Deamidated form of the peptide shown in 3 above II 0 peptide bond OH* i C=0 I CH2 Rl O R2 0 CH2 NH /C\ /C\ ~N\ ~C\ CH OH H2N C CH NH C CH NH C 0 CH2 0 R3 0 CH2 I C=o I OH* FiGUxE 8. Deamidation of a Peptide. In formula 4 two -OH groups (marked with asterisks) have replaced two -NH, groups of the compound shown in formula 3. Another observation seemed, when it was first re- ported, to provide not only a diagnostic test for gluten- intolerant patients but also a means of assaying wheat fractions for toxicity. It was observed that feeding gliadin to human subjects resulted in a much greater rise in blood glutamine levels of patients with celiac disease than of control subjects.'4" More extensive

Vol. 264 No. 24 INTESTINAL ABSORPTION-LASTER AND INGELFINGER evaluation of this "gliadin tolerance test" showed, however, that there was too great an overlap of the data from subjects with and those without celiac disease for the test to be of diagnostic value.163,16' In contrast to findings in patients with no celiac disease the rise in blood glutamine levels in those with the disease has been described as due almost entirely to glutamine bound in peptide form rather than to free glutamine."9 This finding constitutes evidence that patients with celiac disease do not digest ingested gliadin completely and that they absorb a glutamine- containing peptide fraction of gliadin. However, in another report of similar studies the rise in blood glutamine in patients with celiac disease was attrib- uted to free rather than to peptide-bound gluta- mine.184 Nature of gluten intolerance. If a glutamine-con- taining peptide does accumulate in patients with gluten-induced steatorrhea, what mechanisms account for this accumulation? Several studies by Frazer and his colleagues160 bear on this question. The digestive actions of gastric and pancreatic enzymes seem to be normal in patients with celiac disease. Gluten, incu- bated in vitro with pepsin and then with trypsin, yields a peptide-containing digest that is still toxic to gluten-intolerant patients. Further incubation of this digest with an extract of hog-intestine mucosa produces a mixture that no longer has ill-effects when fed to patients with celiac disease.l°°,1°5 Assuming that these preliminary observations can be confirmed, gluten-intolerant patients appear to be deficient in an intestinal-mucosa peptidase that normally functions to catalyze the degradation of peptide derivatives of wheat gliadin past the point of having properties toxic to man. When solutions containing either gluten or its derivatives were perfused in vitro through the lumen of a segment of animal intestine no alteration of intestinal motility resulted, but when the solutions were applied to the outer, serosal surface of a seg- ment, peristaltic contraction of the muscle layers was completely inhibited.188 Digestion of gluten with pep- sin and trypsin did not destroy this inhibitory effect on peristalsis in vitro, but additional incubation of the digest of gluten with small-intestine mucosa from rat or man did eliminate the inhibitory properties. Whether these in vitro studies are applicable to the action of gluten in vivo is uncertain. In the clinical studies of the toxicity of wheat flour149 the injurious factor was localized to gliadin, which is alcohol sol- uble rather than water soluble, but in the studies of the effect of wheat gluten on isolated intestinal seg- ments it was found that aqueous extracts of gluten had ten times the depressant activity of peptic-tryptic digests of gluten.1G' A direct evaluation of the theory that gluten-intol- erant patients are deficient in a digestive enzyme would entail first the isolation and identification of the still hypothetical noxious peptide and, second, the 1251 demonstration that extracts of normal human small- intestine mucosa can digest the peptide but that the capacity of intestinal extracts from gluten-intolerant patients to digest the peptide is reduced or lacking. Findings of this nature would lend support to pre- mature statements that describe the "primary malab- sorption syndrome" as an inborn error of inetabo- Iism.11T The postulation of an inborn error of metabolism relies heavily on the belief that there is a hereditary predisposition to celiac disease and idiopathic steator- rhea. This belief is supported not only by a general clinical impression but also by three systematic studies of the genetics of celiac disease. In the older two stud- ies"',16$ no account was taken of the therapeutic, and possibly diagnostic, value of a gluten-free diet, and the criteria for making the diagnosis of celiac disease or idiopathic steatorrhea in relatives of index patients did not include quantitative determination of fecal fat excretion. These factors were considered in the third study, but biopsy of the intestinal mucosa was not included in the diagnostic evaluation of index patients and their relatives.1G9 Despite these limita- tions, the three studies do reveal that the incidence of celiac disease and idiopathic steatorrhea is higher in the near relations of index patients than it is in the general population. Carter et al.,lss who found the risk in the general population to be about 1 in 3000, demonstrated that 5 of 205 brothers and sisters, 2 of 85 fathers, 1 of 580 aunts and uncles and 1 of 806 cousins of index patients had definite celiac disease or idiopathic steatorrhea. The authors considered it unlikely that this family concentration was due simply to a common environment. A rapid and simple screening test for gluten intolerance would not only expedite the identification of the toxic component of gluten but also permit more extensive and more definite genetic studies than are feasible by the use of available diagnostic tools. An inborn error of metabolism is not the only con- ceivable explanation for gluten intolerance. It is quite possible that an allergic reaction is involved as a con- tributory or sole factor, since cereal-grain proteins are known to be antigenic in animals.15° On occasion a child who has been on a gluten-free diet has re- sponded to the ingestion of even a minute quantity of gluten in a manner so fulminating that the response has been termed "gliadin shock."170 The beneficial action of adrenocortical steroids in idiopathic steator- rhea may be another indication that an allergic re- action is involved. Clinical observations have sug- gested that foodstuffs other than cereal grains may produce the picture of celiac disease.lsl Conventional clinical attempts to implicate allergic mechanisms in celiac disease have not been successful. Skin tests with gluten were negative, and a particular tendency to allergic manifestations in general was not detected in these children.ll° 11

1252 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 Bergert' 1 has performed a number of studies to implicate an allergic process in celiac disease. He has found that the antigenic behavior of cereal pro- teins in vitro tends to parallel their capacity to affect patients with celiac disease. For example, antibodies produced by immunization of animals with extracts of various cereal grains give many crossreactions with wheat, rye, barley and oats, which are harmful to pa- tients with celiac disease. Corn, which is not injurious to such patients, does not crossreact with the other grains. Furthermore, by the use of complement-fixa- tion tests Berger found that both normal subjects and patients with celiac disease have antibodies in the blood that react with alcoholic extracts of wheat, barley and oats. When gliadin is fed to these subjects the antibodies disappear from the blood of the pa- tients with but do not decrease in the blood of those without celiac disease. Berger believes that such ob- servations indicate a fundamental difference in the immunologic behavior of the antibodies in the subjects with celiac disease. Biochemical Abnormalities Associated with Malabsorp- tion A number of abnormalities have been detected in patients with primary malabsorption, but it is difficult to decide whether the findings reflect cause or effects of the disease states. Of 53 children with celiac dis- ease, 30 were found to excrete in the urine a com- pound with chromatographic properties of phos- phorylethanolamine, but studies of 576 control sub- jects without known celiac disease revealed only 16 who excreted this compound in the urine.1T= Most patients with the inborn error of metabolism, hypo- phosphatasia (deficient or absent activity of alkaline phosphatase), excrete phosphorylethanolamine in the urine.173 The significance of the excretion of this compound by patients with celiac disease is not known. In 1954 Boscott and Cooke17} reported that pa- tients who have steatorrhea and macrocytic anemia frequently excrete p-hydroxyphenylacetic acid in the urine, but that normal persons excrete this compound only rarely. On the basis of their study, they con- cluded that the presence of p-hydroxyphenylacetic acid in the urine was the result of deranged tyrosine metabolism and a deficiency of ascorbic acid. Boscott and Cooke17' also detected indoleacetic acid in the urine of patients with steatorrhea. Since then, Haverback et al.17' have confirmed the finding and have identified the compound as indole-3-acetic acid. These workers detected increased urinary ex- cretion of indole-3-acetic acid not only in primary malabsorption states but also in secondary steatorrhea such as that due to pancreatic disease. The urinary excretion of another indole, 5-hydroxyindoleacetic acid, is moderately higher than normal in some pa- tients with primary malabsorption. Urinary excretion of both indo]e-3-acetic acid and 5-hydroxyindoleacetic acid may fall toward normal during a remission re- sulting from treatment with a gluten-free diet.17s'1'° The abnormal excretion of these indoles in malab- sorption states has been attributed to disturbances in the metabolism of tryptophane by enteric bacteria and is not considered specific for primary malabsorp- tion.lrs Finally, patients with tropical sprue absorb greater quantities of intact sucrose than control subjects do.17' Normally, sucrose is split into glucose and fructose during digestion and does not appear in the blood intact unless unusually large quantities are fed. The cleavage of the disaccharide into its component mono- saccharides is catalyzed by the enzyme sucrase, which is present in the normal intestinal mucosa. Santini et al.t'' have shown that the intestinal mucosa of pa- tients with untreated and treated tropical sprue con- tains less sucrase activity than that of control subjects, a finding that seems to explain the excessive absorp- tion of unsplit sucrose by patients with tropical sprue.l'' The significance of biochemical abnormalities, such as excessive urinary excretion of phosphorylethanol- amine, in patients with primary malabsorption is dif- ficult to appreciate until the underlying mechanisms responsible for primary malabsorption are better identified. Elucidation of these mechanisms, in turn, must wait upon clarification of the basic processes re- sponsible for normal intestinal absorption and for membrane transport in general. We are indebted to Miss Joyce Lynn Sills (Fig. 2 through 5) and Mr. Howard Bartner (Fig. 1 and 7), of the Medical Arts Section, National Institutes of Health, for the drawings. Figures 3,"T 4 and 5` were based to some extent on drawings in other publications. REFERENCES 117. Adlersberg, D., et al. Symposium on malabsorption syndrome. J. Mount Sinai Hosp. 24:177-424, 1957. 118. Gordon, R. S., Jr., Bartter, F. C., and Waldmann, T. Idiopathic hypoalbuminemias: Clinical Staff Conference at National Institutes of Health. Ann. Int. Med. 51:553-576, 1959. 119. Sheldon, W. Celiac disease. Pediatrics 23:132-145, 1959. 120. Symposium: malabsorption syndrome. In Proceedings of the World Congress of Gastroenterology: And the fifty-ninth annual meeting of the American Gastroenterological Association: Washington, D. C., U.S.A.: Mav 25th through 31st, 1958. Vol. 1. 714 pp. Baltimore: Williams & Wilkins, 1959. Pp. 558-657. 121. Symposium on disorders of small intestine (excluding duodenum). Proc. Roy. Soc. Med. 52:1-46, 1959. 122. Tropical Sprue: Studies of the U.S. Army's Sprue Team in Puerto Rico. Edited by W. H. Crosby. 355 pp. (Army Institute of Re- search, Walter Reed Army Medical Center.) Washington, D. C.: Government Printing Office, 1959. 123. Volwiler, W. Gastrointestinal malabsorptive syndromes. D3L' Disease-a-Month., pp. 1-35, March, 1959. 124. Malabsorption syndromes: symposium: papers read at annual Congress of British Institute of Radiology, December 10, 1959. Brit. J. Radiol. 33:201-242, 1960. 125. Spencer, R. P. The Intestinal Tract: Structure, function and pathology in terms of the basic sciences. 411 pp. Springfield, Illinois: Thomas, 1960. 126. van de Iiamer, J. H., and Weijers, H. A. Malabsorption syndrome. Federation Proc. 20:335-344, 1961. 127. Symposimn on absorption mechanisms and malabsorption syndrome. Am. J. Clin. Nutrition B:1S1-205 1960. 128. Paulley, J. W. Histologic and ~psychologic findings in idiopathic steatorrhea. In Proceedings of the World Congress of (,astro- enterology: And the fifty-ninth annual meeting of the American Gastroenterological Association: Washington, D. C., U.S.A.: May 25th through 31st, 1958. Vol. 1. 714 pp. Baltimore: Williams & Wilkins, 1959. Pp. 469-476.

Vol. 264 No. 24 MEDICAL INTELLIGENCE - POST 129. Shiner, M., and Doniach, I. Histopathologic studies in steatorrhea. In Proceedings of the World Congress on Gastroenterology: And the fi(ty-ninth annual meeting of the American Gastroenterological Association: Washington, D. C., U.S.A.: May 25th through 31st, 1958. Vol. 1. 714 pp. Baltimore: Williams & Wilkins, 1959. Pp. 586-607. 130. Smith, R. B. W., Sprinz, H., Crosby, W. H., and Sullivan, B. H., Jr. Peroral small bowel mucosal biopsy. Am. J. Med. 25:391-394, 1958. 131. Brandborg, L. L., Rubin, C. E., and Quinton, W. E. Multipurpose instrument for suction biopsy of esophagus, stomach, small bowel, and colon. Gastroenterology 37:1-16, 1959 132. Rubin, C. E., Brandborq, L. L., Phelps, P. C., and Taylor, H. C., Jr. Studies of celiac disease. I. Apparent identical and specific nature of duodenal and proximal jelunal lesion in celiac disease and idiopathic sprue. Gastroenterology 38:28-49, 1960. 133. Fone, D. J., et al. Jejunal biopsy in adult coeliac disease and allied disorders. Lancet 1:933-939, 1960. 134. Thurlbeck, W. M., Benson, J. A., Jr., and Dudley, H. R., Jr. Histopathologic changes of sprue and their significance. Am. J. Clin. Path. 34:108-117. 1960. 135. Butterworth, C. E., Jr., and Perez-Santiago, E. Jejunal biopsies in sprue. Ann. Ine. Med. 48:8-29, 1958. 136. Rubin, C. E., et al. Studies of celiac disease. II. Apparent irre- versibility of proximal intestinal pathology in celiac disease. Gastro- enterology 38:517-532, 1960. 137. Bolt, R. J., Pollard, H. M., and Standaert, L. Transoral small- bowel biopsy as aid in diagnosis of malabsorption states. New Eng. J. Med. 259:32-34, 1958. 138. Rubin, C. E. Celiac disease and idiopathic sprue: some reflections on reversibility, gluten, and intestine. Gastroenterology 39:260, 1960. 139. Shiner, M. Small intestinal biopsies by oral route: histopathologic changes in malabsorption syndrome. J. Mount Sinai Hosp. 24:273- 285, 1957. 140. Butterworth, C. E., Smith, R. B. W., and Perez-Santiago, E. Pathologic findings in jejunal specimens obtained by peroral intubation biopsy in patients with malabsorption. In Proceedings of the World Congress on Gastroenterology: And the fifty-ninth annual meeting of the American Gastroenterological Association: Washington, D. C., U.S.A.: May 25th through 31st, 1958. Vol. 1. 714 pp. Baltimore: Williams & Wilkins, 1959. Pp. 629-639. 141. Yesner, R., Schwartz, R. D., and Spiro, H. M. Duodenal biopsy in diarrhea and steatorrhea. Yale J. Biol. & Med. 32:361-369, 1960. 142. Zamcheck, N. Dynamic interaction among body nutrition, gut mucosal metabolism and morphology and transport across mucosa. Federation Proc. 19:855-864, 1960. 143. Butterworth, C. E., Jr., Nadel, H., Perez-Santiago, E., Santini, R., Jr., and Gardner, F. H. Folic acid absorption, excretion, and leukocyte concentration in tropical sprue. J. Lab. & Clin. Med. 50:673-681, 1957. 144. Cox, E. V., Meynell, M. J., Cooke, W. T., and Gaddie, R. Folic acid excretion test in steatorrhea syndrome. Gastroenterology 35: 390-397, 1958. 145. Gerrard, J. W., Ross, C. A. C., Astley, R., French, J. M., and Smellie, J M. Coeliac disease: is there natural recovery? Quart. J. Med. 24:23-32, 1955. 146. Gardner, F. H. Tropical sprue. New Eng. J. Med. 258:791-796 and 835-842, 1958. 147. Ross, J. R., and Moore, V. A. Small intestinal biopsy capsule utilizing hydrostatic and suction principles. Gastroenterology 40: 113-119, 1961. 148. Flick, A. L., Quinton, W. E., and Rubin, C. E. Peroral hydraulic biopsy tube for multiple sampling at any level of gastrointestinal tract. Gastroenterology 40:120-126, 1961. 149. Weijen, H. A., and van de Kamer, J. H. Celiac disease and wheat sensitivity. Pediatrics 25:127-134, 1960. MEDICAL INTELLIGENCE ANURIA AS A PRESENTING SYMPTOM IN UNSUSPECTED LEUKEMIA JERROLD POST, M.D.* NI:W HAVEN, CONNECTICUT E LEVATED serum uric acid and increased uric acid excretion are frequently present in the myelo- proliferative disorders. During treatment of leukemia with radiation, alkylating agents and certain anti- 'Intern, Medical Service, Grace-New Haven Hospital. 1253 150. Moulton, A. L. C. Place of oats in cocliac diet. Arch. Dis. Childhood 34:51-55, 1959. 151. Frazer, A. C. Present state of knowledge on celiac syndrome. Pediat. 57:262-276, 1960. 152. uffin, J. M., Carter, D. D., Johnston, D. H., and Baylin, G. J. "Wheat-free" diet in treatment of sprue. New Eng. J. Med. 250:281, 1954. 153. French, J. M., Hawkins, C. F., and Smith, N. Effect of wheat- gluten-free diet in adult idiopathic steatorrhoea: study of 22 cases. Quart. J. Med. 26:481-499, 1957. 154. Sleisenger, M. H., Law, D. H., Kowlessar, O. D., Pert, J. H., and Almy, T. P. Effects of gluten-gliadin-free diet on patients with non-tropical sprue. Tr. A. Am. Physicians 71:100-109, 1958. 155. Scudamore, H. H., and Green, P. A. Secondary malabsorption syndromes of intestinal origin. Postgrad. Med. 26:340-351, 1959. 156. Bailey, C. H. The Constituents of Wheat and Wheat Products. 332 pp. New York: Reinhold, 1944. 157. Holme, J., and Briggs, D. R. Studies on physical nature of gliadin. Cereal Chem. 36:321-340, 1959. 158. Pace, 4. Chemical aspects of wheat proteins. In Society of Chemical Industry, London. The Physico-Chemical Properties of Proteins: With special reference to wheat proteins. 92 pp. Edited by J. Pace. New York: Macmillan, 1959. (S.C.1. Monograph, No. 6.) Pp. 26•38. 159. Vickery, H. B. Rate of hydrolysis of wheat gliadin. J. Biol. Chem. 53:495-511, 1922. 160. Frazer, A. C., et al. Gluten-induced enteropathy: effect of partially digested gluten. Lancet 2:252-255, 1959. 161. Van Roon, J. H., Haex, A. J Ch., Seeder, W. A., and de Jong, J. Clinical and biochemical analysis of gluten toxicity. I. Experientia 16:209, 1960. 162. Ribeiro, E., Sobrinho-Simoes, M., and Mesquita, A.-M. Effect of dietary gluten on fecal fat in rat. Metabolism 6:378-380, 1957. 163. Payne, W. W., and jenkinson, V. Test for coeliac disease. Arch. Dis. Childhood 33:413-416, 1958. 164. Alvey, C., Anderson, C. M., and Freeman, M. Wheat gluten and coeliac disease. Arch. Dis. Childhood 32:434-437, 1957. 165. Frazer, A. C. On growth defect in coeliac disease. Proc. Roy. Soc. Med. 49:1009-1013, 1956. 166. Schneider, R., Bishop, H., Shaw, B., and Frazer, A. C. Effect of wheat gluten on peristaltic reflex. Nature (London) 187:516, 1960. 167. Thompson, M. W. Heredity, maternal age, and birth order in etiology of celiac disease. Am. J. Human Genet. 3:159-166, 1951. 168. Boyer. P. H., and Andersen, D. H. Genetic study of celiac disease. J. Dis. Child. 91:131-137, 1956. 169. Carter, C., Sheldon, W., and Walker, C. Inheritance of coeliac disease. Ann. Human Genet. 23:266-278, 1959. 170. Krainick, H. G., et al. Further investigations on harmful effect of wheat flour in celiac disease. I. Acute gliadin reaction (gliadin shock). Hela. paediat. aeta 13:432-454, 1958. 171. Berger, E. On allergic pathogenesis of celiac disease. Bibl. paediat. Supp. 67:1-55, 1958. 172. Fisher, O. D., and Neill, D. W. Excretion of ethanolanvne- phosphoric acid in coeliac disease. Lancet 1:334, 1955. 173. Fraser, D. Hypophosphatasia. Am. J. Med. 22:730-746, 1957. 174. Boscott, R. J., and Cooke, W. T. Ascorbic acid requirements and urinary excretion of p-hydroxyphenylacetic acid in steatorrhoea and macrocytic anaemia. Quart. J. Med. 23:307-322, 1954. 175. Haverback, B. J., Dyce, B., and Thomas, H. V. Indole metabolism in malabsorption syndrome. New Eng. J. Med. 262:754-757, 1960. 176. Kowlessar, O. D., Williams, R. C., Law, D. H., and Sleisenger, M. H. Urinary excretion of 5-hydroxyindolacetic acid in diarrheal states, with special reference to nontropical sprue. New Eng. J. Med. 259:340, 1958. 177. Santini, R., Jr., Aviles, J., and Sheehy, T. W. Sucrase activity in intestinal mucosa of patients with sprue and normal subjects. Am. J. Digest. Dis. 5:1059-1062, 1960. metabolites, uricosuria may rise to dangerous pro- portions. This is assumed to be due to an accentuation of hyperuricemia because of increased nuclear de- struction. In 1958 Kritzler' reported 3 cases of anuria after antileukemia therapy and referred to 7 similar cases. The following case is of interest since anuria was the presenting symptom in a patient with pre- viously unsuspected and untreated leukemia. CASE REPORT L.L. (G.-N.H.H. 48-65-20), a 78-year-old man, was ad- mitted to the private service of Grace-New Haven Hospital on January 17, 1961, with a chief complaint of not having urinated for 2 days. When seen in this hospital for the 1st time in 1958 because of an episode of sharp left-upper- quadrant pain the following significant findings were noted: 3d-degree heart block; total white-cell count of 15,000, with 80 per cent granulocytes; and a normal intravenous pyclo- gram. The impression at discharge was diverticulitis. The patient did well until the summer of 1960, when he experi- enced an episode of sharp right-upper-quadrant pain, at-

1254 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 tributed to acute cholecystitis in view of a cholecystogram that revealed no function. He recovered from this attack without incident. Four days before admission he again suf- fered an episode of sharp right-upper-quadrant pain. On the morning before admission he had a further episode of right-sided abdominal pain, lower and more medial. Until this time he had urinated 8 to 10 times daily. After the 2d episode of abdominal pain he did not urinate for 36 hours and felt somewhat nauseated and anorectic. He was seen in the emergency room, where catheterization revealed no urine in the bladder. An intravenous pyelogram showed no function. On admission to the floor he did not appear acutely or chronically ill. The liver edge was felt 3 cm. below the right costal margin. The following significant negative findings were noted: there was no lymphadenopathy or splenomegaly; the kidneys were not palpable and there was no costovertebral-angle tenderness; the prostate was smooth, firm and not enlarged; and no ecchymoses or tophi were present. The temperature was 99°F., the pulse 40, and the respira- tions 16. The blood pressure was 180/90. Shortly after admission cystoscopy was performed. The bladder contained approximately 150 ml. of smoky urine and many 1-mm. stones. Although initially the ureteral orifices were obstructed by similar calculi, retrograde pyelograms showed no abnormalities. The urologist's impression that these were uric acid stones was later confirmed by chemical analysis. The white-cell count on admission was 40,700, with 52 per cent granulocytes, 8 per cent band forms, 3 per cent lymphocytes and 43 per cent cells in the mononuclear series, many immature forms being seen. The hematocrit was 40 per cent, and the platelet count was 62,000. On bone- marrow aspiration a cellular specimen was obtained that contained predominantly cells in the mononuclear series, the majority of which were mature, but some granulocytic and erythroid elements were also present. The serum uric acid was 15.2 mg., and the blood urea nitrogen 51 mg. per 100 ml. The serum carbon dioxide was 22.1 milliequiv., the chloride 105 milliequiv., the sodium 137 milliequiv., and the potassium 5.1 milliequiv. per liter. The serum calcium and phosphorus were 9.7 mg. and 6.7 mg. per 100 ml. respectively. Liver-function tests were within normal limits except for a bromsulfalein retention of 14.7 per cent and cephalin flocculations of + + + and ++++ in 24 and 48 hours. The globulin fraction of the serum protein was slightly elevated. On the basis of the peripheral blood and the bone mar- row a diagnosis of subacute monocytic leukemia was made. The patient maintained a good output of urine on a regi- men of forced fluids. After a transient rise, the blood urea nitrogen gradually fell toward normal, as did the serum uric acid. Because of fear of increased uricosuria, no specific therapy was directed at the leukemic process, and after a 10-day hospital course, he was discharged, completely asymptomatic. DISCUSSION Weisberger and Persky2 state that the incidence of uric acid stones in patients with the myelopro- liferative disorders is seventy-five times higher than that in the normal population. In a study of 283 such patients they found renal calculi in 5.3 per cent. Emphasizing the fact that, as a rule, in patients with these disorders in whom stones develop, they do so under treatment, they present 5 cases of untreated leukemia with renal calculi. Ureteral obstruction was not present in any of these untreated cases. In the differential diagnosis of anuria bilateral ureteral obstruction with stones is routinely consid- ered. Anuria as a consequence of obstruction by uric acid calculi may be a rare presenting symptom of the myeloproliferative disorders. I am indebted to Dr. Paul Calabresi for helpful advice in the preparation of this paper and to Dr. Robert Gordon for permission to present the case history. REFERENCES 1. Kritzler, R. A. Anuria complicating treatment of leukemia. Am. J. Med. 25:532-538, 1958. 2. Weisberger, A. S., and Persky, L. Renal calculi and uremia as com- plications of lymphoma. Am. J. M. Sc. 225:669-673, 1953. HAZARDS TO HEALTH Effectiveness of Seat Belts in Preventing Motor-Vehicle In juries ROBERT G. FRAZIER, M.D.* EVANSTON, ILLINOIS A PPROXIMATELY 1,200,000 persons in the United States are injured, and about 40,000 die per year from automobile accidents. Despite this the passenger automobile is becoming increasingly important as an essential instrument of modern living, as shown by the increase from 37,000,000 automobiles in the United States in 1946 to 62,- 000,000 in 1958 and an estimated 82,000,000 in 1966.1 In the face of pleas for funds to fight the many diseases that still threaten health and happiness it is soberin; to think that automobile accidents alone are either the first, second, third or fourth leading cause of death in all age groups from five to thirty- four years.' Reduction of this high fatality rate may be ap- proached in several ways. One way of interest to the physician in his capacity as counselor to patients and families, and often as community adviser, is the use of the sa f ety belt. The following studies refer only to the lap-type seat belt, which is the only one easily available in this country, although the shoulder-loop type is well adapted to, and fre- quently used in, European cars. The risk of death or injury in an automobile ac- cident is to a large extent dependent on the fre- quency of ejection. Two other major variables that influence both the frequency of ejection and the risk of fatal injury are the severity of the accident and the seat position occupied. In one study of injury- producing accidents, 13.6 per cent of adult occupants were ejected, and the fatality rate was five times greater in this group than that for occupants who were not ejected.2 It was estimated in this study that prevention of ejection could have resulted in a 25 per cent reduction in mortality. This study was performed in the years 1953-1956. In 1956 im- proved door locks were included in most standard American cars. Subsequent studies have shown that this little known fact has reduced the risk of oc- cupant ejection about 48 per cent and that of danger- ous injuries by 29 per cent.' 'Secretary, American Academy of Pediatrics.

I / Vol. 264 No. 24 26.6 per cent in the control group to 10.2 per cent in the group wearing safety belts. In both cate~ories this is a reduction of about 60.0 ler cent, which in the luoderate-to-fatal group was si'gnificant at the 98.0 per cent level. As might be expected a companion study in which the control group suffered ejection showed that moderate-to-fatal injuries weree reduced 80 per cent among safety-belt users. An analysis of the reasons for the difference between 35 per cent improvement in major-to-fatal grade injuries in the first study discussed and the 60 to 80 per cent improvement in the small studv of matched accidents has recently been made avail- able.t The two groups of cases for the small study of matched accidents were not collected under the same conditions so that the 81 cars whose occupants wore seat belts came from a group of less severe accidents than the cars in the control group. The 60 per cent improvement in injuries was therefore labeled "maximum improvement" on the assumption that the bias weighted the figures in favor of seat belts. Quotations of this data have tended to leave out this qualifying term, which was difficult to define or quantitate. It is apparent that the best answer now available regarding the effectiveness of the seat belt is the average figure of 35 per cent reduction in major-to- fatal injuries found in the large California study first discussed.' In this discussion of injury and death from motor- vehicle accidents it should also be noted that rear- seat occupants have far less risk of ejection, and that the fatality rate is about half that of front-seat occupants. The more favorable injury experience of children may in part be related to the frequency with which they occupy the rear seat. In a large study of accidents in which at least 1 person was injured, 52 per cent of the children, 71 per cent of the adolescents and 80 per cent of the adults were injured.1 In this study the safest seat area - the rear seat - was occupied by 50 per cent of children four to eleven years of age but by only 12 per cent of adults. Infants up to four years of age tended to occupy more hazardous seat areas than older children. The center and right front seats or un- usual seating areas were occupied by 73 per cent of this group. Although different types of safety belts have been developed for small children, as yet there are no reported experimental studies on their effec- tiveness. Armed with this evidence of the effectiveness of safety belts, one naturally wonders how widely they are used. A California study in 1958 showed seat belts available for 1 or more occupants in 3.5 per cent of automobiles involved in a series of 54,348 accidents.' However, in only 33 per cent of the *The statistical significance of the figure u relfected in the value of p<0.01. "i'he confidence limits (±2 S.E.) of this analysis show that the ilersonal comniunication from Robert A. 1Vult. Uirccn'r. A°~"""'t'" reduction may be as low as 9 per cent or as high as 60 per cent. Crash Injury Research, Cornell University Medical College. MEDICAL INTELLIGENCE -FRAZIER 1255 One study of safety-belt effectiveness compared injuries among 933 drivers and occupants of the right front seat who used belts and 8,784 drivers and occupants of the right front seat who did not.` These accidents were on rural highways. After accounting for the influence of speeds of cars, ac- cident type and seats occupied the authors con- cluded that users of safety belts sustained 35 per cent fewer "major-fatal" grade injuries than non- users.* In this study the safety belt did not prove to be a panacea. The rate of "any injury" was about the same in both groups. But for each seated position examined it reduced the proportion of "major-to- fatal" grade injuries. Directional analysis of these accidents (that is, a breakdown in terms of front- front, front-rear, rollover, angled or lateral im- pacts) showed that the expected and observed num- ber of major-to-fatal injuries in front-front and front-rear accidents were almost identical in the belt and nonbelt groups, whereas in rollover and angled impact accidents the observed total of major-to-fatal injuries in belt users was less than half that in the control or nonbelt group. This suggests that safety belts may function most effectively in preventing ejection since it is known that rollover and angled or lateral impacts result in ejection more frequently than front-front or front-rear collisions. It also supports the evidence from simulated accidents us- ing anthropomorphic dummies restrained in lap- type seat belts during barrier crashes that such a restraint provides negligible protection against injury under severe accident conditions owing to insufficient clearance of head and chest and the interior struc- tures in front of an occupant in the front seat.5 How- ever, only about 33 per cent of accidents are front- to-front or front-to-rear. Twenty per cent are roll- over, and the remainder are angled or lateral im- pacts. In the latter types a safety belt provides the best known protection from ejection during impact and from violent dislocation within the automobile. An earlier study that, though unpublished, is often quoted because of the highly favorable figures on the effect of the seat belt now merits re-examina- tion.s Data from two groups of automobile accidents were matched for several factors, the only variable being the presence or absence of safety belts. The experimental group comprised 81 cars with 97 oc- cupants using safety belts. The control group in- cluded 81 cars and 139 occupants without safety belts. No members of either the experimental or the control group were ejected from the car. The frequency of any injury was reduced from 75.5 per cent in the control group to 29.9 per cent in the group wearing safety belts. Injuries ranging from moderate to fatal in severity were reduced from i.

~. 1256 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 automobiles equipped with belts were all the installed belts worn by the occupants. Public inertia and ignorance in this matter as well as specific objections to seat belts, or the opinion that local driving is safer than highway driving, have delayed their wide acceptance. Studies show that only 0.2 per cent of injury-producing accidents are followed by fire and only 0.3 per cent involve submersion. In any event the safety belt should make it possible for the occupant to cope better with these emergencies by virtue of a lesser degree of injury. The risk of local driving is reflected in the fact that in 1958, 47 per cent of all deaths oc- curred at travel speeds below 40 m.p.h., and 66 per cent took place within 25 miles of the driver's home.s Other factors that may influence acceptance are expense of belts and installation, comfort, clutter in the car and time to buckle and unbuckle. A more important factor raised by some is the re-emphasis on the fact that safety belts are not a complete answer and that industry as well as the public has a continuing responsibility to foster engineering and design improvements in the passenger automobile that will increase the occupants' safety. In the mean- time, faced with the evidence that has been pre- sented, several states have considered or are con- CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL Weekly Clinicopathological Exercises FOUNDED BY RICHARD C. CABOT BENJAMIN CASTLEMAN, M.D., Editor BETTY U. KIBBEE, Assistant Editor .,, CASE 42-1961 PRESENTATION OF CASE A forty-nine-year-old woman entered the hospital because of hematemesis. Ten years previously the patient was admitted to a sanatorium because of tuberculosis of the right lung. She was treated with streptomycin and pneumothorax and was discharged after one year. An x-ray film of the chest one year before entry showed a pleural effusion on the right side; examinations of the sidering laws requiring seat belts, and the auto- mobile industry can surely meet this trend with an improved and less expensive belt installation. Demonstrated improvements in automobile design of public-health significance should be recommended by authoritative bodies and, if necessary, required by appropriate legislation. Certainly, physicians can more effectively guide their patients and foster their health if they are informed on this subject, have critically evaluated the evidence, and make their thoughts known. 1801 Hinman REFERENCES 1. Moore, J. 0., and Lilienfeld, R. Child in injury-producing auto- mobile accidents. Traffic Safety (March), 1960. P. 16. 2. Tourin, B. Ejection and automobile fatality. Pub. Health Rep. 73: 381-391, 1958. 3. Crash in,'~uries and their prevention. New York State J. Med. S8: 1704-1723, 1958. 4. Tourin, B., and Garrett, J. W. Safety Belt Effectiveness in Rural Cali ornia Accidents: Prepared by Automotive Crash Injury Research of rnell University, New York 21, New York, February, 1960. 5. Mathewson, J. H., and Severy, D. M. Automobile impact research. Tr. National Safety Council 28:93-101, 1954. 6. Annual Report, Automotive Crash Injury Researcb: For the period 1 April 1956 to 31 March 1957. Prepared by Cornell University Medical College, Department of Health and Preventive Medicine, New York 21, New York, 1957. 7. Tourin, B., and Garrett, J. W. A Report on Safety Belts to the CaG ornia Legislature: Automotive Crash Injury Research. Prepared by Cornell University, New York 21, New York, February, 1960. 8. Automobile Seat Belts: Report of the Special Subcommittee on Traf- ftc Safety, House of Representatives. Washington, D. C. August 30, 1957. (Submitted by Mr. Harris, chairman.) sputum and gastric washings were negative. Isoniazid and para-aminosalicylic acid, 10 gm. daily, were given. Because of intermittent anorexia, flatulence and epigastric pain six weeks before admission the dosage of para-aminosalicylic acid was decreased to 5 gm. daily, and she improved. During the two weeks before entry she experienced anorexia, weight loss, weakness and epigastric pain, accompanied by an in- crease in abdominal girth, swelling of the ankles and darkening of the urine. The pain usually occurred after eating, was twice followed by vomiting and was aggravated by milk. Twelve hours before entry marked weakness and vertigo developed, and a black stool was passed. She vomited a large amount of blood just before admission. There was no history of alcoholism. Physical examination revealed a moderately obese, pale, acutely ill woman. Slight icterus was visible in the skin and sclerae. Breath sounds were decreased throughout the right side of the chest; the left side of the chest was clear. A Grade 3 systolic mur- mur, which was not transmitted, was audible over the entire precordium and was loudest in the pulmonic area. The abdomen was protuberant, taut and dull to percussion; a fluid wave and shifting dullness were present. No organs or masses were palpable. There was moderate epigastric tenderness, without rebound tenderness or guarding. The outstretched hands showed a liver flap, and + pitting edema of the knees was observed.

Vol. 264 No. 24 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 1257 The temperature was 99°F., the pulse 120, and the respirations 20. The blood pressure was 120 systolic, 90 diastolic. The urine gave a negative test for protein and sugar; the specific gravity was 1.023; the sediment contained 2 white cells and an occasional red cell per high-power field; a culture demonstrated coliform organisms; an azuresin test showed less than 0.3 mg. per 100 ml. Examination of the blood revealed a hemoglobin of 7.2 gm. per 100 ml., a hematocrit of 27 per cent and a white-cell count of 21,150, with 77 per cent neutrophils. The bleeding time was two and a half minutes, and the coagulation time seven and three-fourths minutes. The prothrombin content was 24 per cent. The nonprotein nitrogen was 41 mg., the fasting glucose 118 mg., the total bilirubin 3.6 mg. (the direct 2.5 mg., and the indirect 1.1 mg. ), and the total protein 4.7 gm. (the albumin 2.4 gm., and the globulin 2.3 gm.) per 100 ml. The alkaline phos- phatase was 11.1 Bodansky units, the thymol turbidity 20 units, and the transaminase 250 units; the cephalin flocculation was ++++ in forty-eight hours. The sodium was 134 milliequiv., the potassium 3.6 milli- equiv., the chloride 99 milliequiv., and the carbon dioxide 33 milliequiv. per liter. A Hinton test was negative. A stool specimen gave a++++ guaiac test. X-ray films of the chest demonstrated pleural thickening and blunting of the costophrenic angle on the right side, with retraction of the upper trachea to the right. A film of the abdomen showed a gen- eralized increase in density and a calcified mesenteric lymph node; the liver shadow appeared large. An upper gastrointestinal series (Fig. 1) revealed an ulcer crater, 2 by 3 cm., on the lesser curvature of the stomach just below the fundus. Nasogastric intubation yielded dark-brown fluid that intermittently gave a positive guaiac test and con- tained free acid; a cytologic examination for malignant cells was unsatisfactory. Black and bloody stools were FIGURE 1. Fluoroscopic Spot Filrn of the Gastric Ulcer, De- fining Mucosal Folds Radiating from the Edge of the Crater. passed for several days, during which the patient re- mained drowsy, with slurred speech, and the liver flap increased. The icterus remained unchanged, and the total bilirubin on the seventh hospital day was 4.5 mg. per 100 ml. On the next day, after multiple transfusions of blood, the hemoglobin was 11 gm. per 100 ml. An abdominal paracentesis yielded 3000 ml. of serous, yellow fluid; a culture and cyto- logic examination for malignant cells were negative. Neomycin was given orally. On the tenth hospital day the patient became more alert and began to take food by mouth. Subsequently, the ascitic fluid and peripheral edema gradually reappeared, and she was given spironolactone and mercurial diuretics. Begin- ning on the twenty-fourth hospital day she became progressively less responsive. The blood pressure fell to 80 systolic; the hematocrit was 28 per cent. Further transfusions of blood were given. She died on the twenty-sixth hospital day. DIFFERENTIAL DIAGNOSIS DR. BRIANT L. DECKER*: Ten years before her final hospital admission this patient had pulmonary tuberculosis, for which she was treated with antibiotics and pneumothorax. Nine years later she apparently had a recurrence and received isoniazid (INH) and para-aminosalicylic acid (PAS) until the time of admission. Six weeks before entry she began to have epigastric pain and anorexia, and four weeks later weight loss, jaundice, ascites and edema occurred. The episode that brought her into the hospital was an upper gastrointestinal hemorrhage twelve hours before admission, and she died with liver failure and hemorrhage. May we see the x-ray films now, Dr. Weber? DR. ALFRED L. WEBER: The films of the chest demonstrate displacement of the trachea to the right, as described, and also displacement of the esophagus, heart and mediastinal structures into the right chest cavity. A homogeneous density along the lateral chest wall obscures the right costophrenic angle. This density could be the result of fluid or pleural adhe- sions. The right leaf of the diaphragm is not well outlined. There are increased markings in the right- lower-lung field and possibly also in the right-upper- lung field that might represent fibrosis. The films from the gastrointestinal series (Fig. 1) show a large ulcer, approximately 2 by 3 cm., at the lesser curvature of the stomach. The margin of the lesser curvature near the ulcer crater is fairly sharply defined, and mucosal folds radiating from the ulcer crater are visible. The mucosa adjacent to the ulcer appears thickened. I see no positive radiologic evi- dence of a tumor near the ulcer crater. The distal portion of the stomach, the duodenal cap and loop and the visttalized segments of the small bowel appear "Associate physician, Massachusetts General Hospital; instructor in medicine, Harvard Medical School. I 1t

1258 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 nornlal. The fundus is not well seen, but I have the is usually about 3.7 gm., whereas in cirrhosis the impression that the mucosal folds are thickened. The average is about 1.2 gm. per 100 ml., and the specific lower esophagus is not adequately demonstrated, burt gravity is generally a little higher in the former. the fluoroscopist reported no evidence of varices. The Could this patient have had amyloidosis secondary film of the abdomen suggests enlargement of the liver. to tuberculosis? Against that diagnosis is the absence A calcified lymph node is evident in the left flank. of evidence of renal involvement. Although the liver DR. DECI:ER: Do you see any evidence of calcifica- may be very large in patients with amyloidosis, the tion in relation to the pericardium? course is more prolonged, and there is little derange- DR. WEBER: No. ment of hepatocellular function. It also seems un- DR. DECr;FR: The symptoms, physical findings and likely that a tumor was the cause of this woman's laboratory tests in this case all point•to an apparently illness. The character of the ascitic fluid was not that rapidly developing cirrhosis with hepatocellular dis- found with peritoneal metastases, and the cytologic ease. I say "apparently" because the patient may examination was negative. The gastric ulcer might have had cirrhosis at the time of the right-sided have been cancerous, but that diagnosis seems im- pleural effusion a year before admission. Of course, probable in the presence of free hydrochloric acid. the right-sided pleural effusion may have been a Furthermore, metastases to the liver would probably manifestation of an unrecognized ascites, but the not produce such severe parenchymatous involvement. prolonged pneumothorax therapy is probably a better The question of thrombosis of the hepatic veins explanation. Tests done in an attempt to determine comes up, and I don't know how to rule it out com- tuberculous activity at that time were negative, but pletely. That condition could have contributed to h ' d'ffi 1 b h 1 d i p no mention is made of results of culture or guinea-g inoculation of the pleural fluid. It was apparently assumed that she had recurrent tuberculosis since treatment with INH and PAS was begun. Although PAS frequently causes marked gastric symptoms, I could find no evidence in the literature that it has ever produced peptic ulceration, nor could my pul- monary consultant recall such a case. However, in a recent study made by the United States Public Health Servicel hepatitis developed in 2 of 1400 pa- tients receiving INH and PAS. In that series and also in a co-operative study of patients receiving PAS and INH by the United States Veterans Administration and the Armed Forces,2 1 patient in each group died as a result of toxic hepatitis and acute yellow atrophy. There were no liver complications in the patients receiving INH alone, and the patient who recovered from hepatitis after discontinuation of INH and PAS was subsequently given INH without ill-effect. How- ever, it is known that large doses of INH have damaged the liver in laboratory animals. I doubt that tuberculosis could have been respon- sible for the whole picture in this case. Although there was a calcified mesenteric lymph node, the character of the ascitic fluid and the evidence of severe hepatocellular disease were not consistent with tuberculous peritonitis. Constrictive pericarditis sec- ondary to tuberculosis could produce this effect, but there were no symptoms of heart failure, and dilated cervical veins, a gallop rhythm or a paradoxical pulse is not mentioned. The evidence of severe parenchy- mal liver disease is also against that possibility, and the development of cirrhosis secondary to constrictive pericarditis or heart failure is more insidious than it was in this case. It would be helpful to have a more precise description of the ascitic fluid because in con- gestive heart failure, constrictive pericarditis and thrombosis of hepatic veins the protein concentration t e patlent s I cu ty, ut t e apparent y rapl de- velopment of the parenchymatous disease makes it unlikely. Thrombosis of the hepatic veins most fre- quently occurs in conjunction with suppurative ab- dominal infections, cancer or cirrhosis. I found one report3 of thrombosis of hepatic veins in a patient with chronic ulcerative pulmonary tuberculosis. In the acute form of the disease the course may be brief, with the rapid development of abdominal pain, ascites, vomiting and shock. The chronic form may have a course of months or years, with death eventu- ally due to hepatic failure. The most likely explanation of this patient's illness is cirrhosis of the liver, either the so-called florid form of the Laennec type or the postnecrotic type, both of which are characterized by a rapid downhill course. The absence of a history of alcoholism favors the latter. A peptic ulcer is a fairly frequent accompani- ment of either type and has been reported in from 5 to 19 per cent of patients with cirrhosis.' The low prothrombin content, the low serum albumin, the moderate rise in the alkaline phosphatase, the +++-I- cephalin flocculation and the elevated trans- aminase in this case are consistent with either type of cirrhosis, but the considerably elevated thymol tur- bidity of 20 units is perhaps more typical of post- necrotic than of portal cirrhosis. In my opinion, this patient died in hepatic coma, with hemorrhage from a gastric ulcer. I shall say that the liver disease was a rapidly developing cirrhosis, probably the postne- crotic type and perhaps precipitated by drug toxicity. She also had pulmonary tuberculosis of questionable activity. DR. HELN;N S. PITrMArr : Do we have more infonna- tion about how much PAS and INH this woman had received? DR. DAVID PAINE: During the year spent at the Middlesex County Sanatorium ten years ago she re-

a Vol. 264 No. 24 CASE RECORDS OF THE MASSACHUSETTS GENERAL IIOSPITAI. ceived streptomycin daily for forty-two days, but no PAS or INH. Her second admission there, nine years later, was for only twenty-five days. At that time PAS, 10 gm. daily, and INH, 300 mg. a day, were started. DR. KURT J. ISSELBACHER: PAS and INH have been studied separately as far as their toxicity is con- cerned, and although a cholestatic type of jaundice is said to occur occasionally with PAS therapy,5 in most of the reported cases with liver damage, there was evidence of hepatocellular damage and necrosise•7 and not just cholestasis. The patients in whom jaundice develops in association with PAS treatment usually have manifestations of hypersensitivity antedating the appearance of the jaundice, whereas this patient apparently had no hypersensitivity phenomena. There are numerous reports of toxic hepatitis following INH treatment, and the changes in the liver were compa- rable to those seen in viral hepatitis and to the lesions that result from iproniazid (Marsalid) treatment." Re- garding the present case, there is a recent reports of a patient in whom hepatic damage developed during PAS and INH therapy, and in that case the hepatic necrosis progressed to postnecrotic cirrhosis, with death due to bleeding esophageal varices. The present case may be another example of subacute or chronic liver disease subsequent to acute liver damage. I suspect that there was a significant degree of hepato- cellular necrosis and inflammation, with perhaps mini- mal fibrosis. I might point out that I do not share Dr. Decker's confidence that we can distinguish postnecrotic from Laennec's cirrhosis by means of liver-function tests. DR. PITrMAN : Does the concurrent administration of pyridoxine with INH have any effect on its liver toxicity? DR. ISSELBACHER: Not to my knowledge. DR. WARREN POINT: Dr. Decker and Dr. Issel- bacher have brought up several interesting points, one of which is the question of acute versus chronic liver disease. In this case I would lean toward chronic liver disease decompensated by a bleeding gastric ulcer in a patient who may have had the disease for longer than we realize, as Dr. Decker intimated, although I wouldn't go so far as to say that the pleural effusion was on that basis. My reason for favoring chronic liver disease is the fact that abdominal fluid and ankle edema did develop along with the jaundice, whereas in a patient with acute hepatitis jaundice and the signs of liver failure usually appear before the develop- ment of edema and ascites. I don't know how to settle the problem of whether this was a drug-induced disease or another kind of chronic liver disease because, as Dr. Issel- bacher stated, toxicity due to INH in most cases results in acute hepatitis, although one wonders how often chronic liver disease is brought about by various drugs. We really don't know the natural history of these drug intoxications. My final comment about the question of drug toxicity is that I suspect that postnecrotic cirrhosis was found, and that the pathol- ogist was unable to ascertain the etiology of the lix rr disease. Regarding the third question of the nature of the ulcer, I agree with Dr. Decker's premise of a benign gastric ulcer decompensated by events and by medi- cation, with hemorrhage leading to liver failure and eventually to death. I might add that the abdominal tap afforded an opportunity to find out if the spleen or the liver was enlarged by palpation, and there is no mention of such an examination. That informa- tion would certainly help in deciding whether the patient had chronic or acute liver disease and its structural status. DR. ISSELBACHER: The minimal elevation of the bilirubin also supports your reasoning. I would expect the bilirubin to have been higher if the sole finding was an acute, fulminant, toxic hepatitis. DR. KENNETH T. BIRD: Dr. Paine' reported the 1 fatal case of hepatic necrosis associated with PAS therapy that we have seen at the Middlesex County Sanatorium. In that patient manifestations of hyper- sensitivity developed within three weeks after PAS therapy was started. Unfortunately, an additional dose of PAS was given six days later, while the patient was still in the throes of a moderately severe hyper- sensitivity reaction, and massive acute hepatic necrosis ensued, leading to death. Post-mortem examination showed a fairly severe, diffuse, patchy necrosis involv- ing about three fifths of the liver. When hepatitis develops in a patient receiving PAS one should in- stinctively think of a hypersensitivity reaction to the drug, but in our experience the reaction almost in- variably has occurred within a maximum of eight weeks after the institution of the therapy. Dermal hy- persensitivity has appeared after many months of PAS therapy, but it apparently is the only type of hypersen- sitivity phenomenon with such a delayed onset. The iatrogenic diseases caused by PAS are multiple and basically are toxic or allergic in nature. If this is a case of toxic hepatitis due to PAS therapy, it will be unique in our experience since the patient had received PAS for many months with no hypersensitivity phe- nomena preceding the development of jaundice. DR. BENJAMIN CASTLEMAN: What about the ulcer? DR. BIRD: People with tuberculosis frequently have other associated diseases, including peptic ulcer. We have not seen a case in which PAS precipitated an ulcer. The patients in whom a peptic ulcer developed during PAS therapy usually have had a suggestive history or a previously delnonstrable ulcer. It is note- worthy, however, that the PAS solution is fairly acidic. An interesting sidelight is that when aluminum hy- droxide antacids are given to a person on PAS therapy in an attempt to control irritative gastrointestinal symptoms, which occur in about 5 per cent of the Ili

1260 THE NEW ENGLAND JOURNAL OF MEDICINE cases, the combination of the aluminum compound with PAS forms an insoluble complex, with a secondary decrease in the blood level of PAS. How- ever, I don't believe that PAS has ever been the cause of a peptic ulcer, nor do I know of any evidence to incriminate INH. CLINICAL DIAGNOSES Liver impairment, unknown origin. Gastric ulcer, ? carcinoma. Pulmonary tuberculosis. DR. BRIANT L. DECKER'S DIAGNOSES Cirrhosis, probably postnecrotic type, ? precipitated by drug toxicity. Hepatic coma. Gastric ulcer, with hemorrhage. Pulmonary tuberculosis. PATHOLOGICAL DISCUSSION DR. CASTLEMAN : The autopsy showed that this patient did have active tuberculosis in the right lung, with many caseous nodules and tuberculous granula- tion tissue, and sections stained for tubercle bacilli were positive. There was a large, benign ulcer with many bleeding points in its base that had perforated a few days before death (Fig. 2). The liver was reduced to half the normal size, weighing a little over 600 gm. There were large, depressed, apparent scars producing lobules, giving the impression of the hepar lobatum of syphilis (Fig. 3). Grossly, a postnecrotic or toxic cirrhosis was cer- tainly suggested. On section, two types of tissue were evident: fairly uniform areas with some very ill defined septa; and gray areas, comprising more than half the liver. A closer scrutiny of the gray areas showed whitish-yellow nodules of regeneration. Micro- scopically, in the areas of apparent scarring we found no liver cells, but only the bile ducts, with intervening hemorrhage (Fig. 4 and 5). The liver parenchyma of each of the lobules that had a bile duct had disap- peared. Connective-tissue stains confirmed the fact that there was no scarring whatsoever. Stains for reticulum fibers (Fig. 6) revealed the collapsed framework of the liver lobules from which the cells had "fallen out," in contrast to the normal reticulum pattern of the liver lobules containing viable cells. When the liver cell becomes necrotic and disappears, the two reticulum fibers on each side of it collapse, leaving merely the remnant of the reticulum framework. Therefore, this patient had subacute atrophy of the liver, which would eventually have become a postnecrotic cirrhosis. It wasn't yet a true cirrhosis because there was no scar- ring. I suppose that this could be called subacute hepatic necrosis and atrophy. The question whether it was related to the drug therapy must be left open. The process probably had a duration of no more than June 15, 1961 FIGURE 2. Large Gastric Ulcer. Note the perforation and openings of eroded vessels in its base. ~EW~~~1/H~/1~1/~1111/lUI~I IIIIII~U/IMII/UII{Hlllitllll /~ Illllllt/~ll FIGURE 3. Small, Multinodular Liver Weighing 600 Gm. three months. Acute infectious hepatitis could pro- duce the same picture ; the patient had received no transfusions or injections. In the absence of any other factor we probably should implicate the drug therapy as at least a partially responsible agent. DR. ISSELBACHER: How much inflammation was present in the liver? DR. CASTLEMAN: It was still active, but not acute. I

Vol. 264 No. 24 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL FIGURE 4. Bands of Collapsed Parenchyma in Which Re- maining Bile Ducts Are Present (X30). 1261 FIGURE 6. Collapsed Reticulum Fibers in the Atrophic Part of the Liver (Above), in Contrast to the Reticulum Pattern of the Normal Liver Cells (Below) (X90). DR. HARRIET L. HARDY: If that is true, what was the cause of death? DR. CASTLEMAN : Peritonitis as a result of the per- forated ulcer. DR. HARDY: Not liver failure? DR. CASTLEMAN : The patient had liver failure, and I am sure that it was an aggravating factor. A PHYSICIAN :Were there any varices? DR. CASTLEMAN : No. DR. ISSELBACEIER: The question has been raised in the past whether such a patient has hepatitis of the viral or the toxic type or whether INH might have activated a latent viral hepatitis. However, in ex- perimental studies in animals INH does not seem to be a factor in causing viral hepatitis.s ANATOMICAL DIAGNOSES FIGURE 5. Broad Area of Collapsed Parenchyma, Showing Bile Ducts and Hemorrhage (X35). Subacute hefiatic necrosis and atrophy, ? due to para-amiuosalicylic acid or isoniazid. Acute gastric ulcer, with hemorrhage and perfora- tion. Acute peritonitis. Pulmonary tubt•rculosis, active, right.

1262 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 REFERENCES I. Curtis, H., ct al. Sequential use of paired combinations of isoniazid, streptomycin, para-aminosalicylic acid and pyrazinamide: United States Public Health Service Tuberculosis Therapy Trial. Am. Rev. Resp. Dis. 80:627-640, 1959. 2. Storey, P. B. Comparison of isoniazid-cycloserine with isoniazid-PAS in therapy of cavitary pulmonary tuberculosis. X. Report of Veterans Administration-Armed Forces cooperative study. Am. Rev. Resp. Dis. 81:868-880. 1960. 3. Kelsey, M. P., and Comfort, M. IV. Occlusion of hepatic veins: review of 20 cases. Arch. Int. Med. 75:175-183, 1945. 4. Clarke. J. S. Influence of liver upon gastric secretion. Am. J. Mcd. 29:740-747, 1960. 5. Popper, H., and Schaffner, F. Drug-induced hepatic injury. Ann. Int. afed. 51:1230-1252. 1959. 6. Bellamy, w. E., Jr., Mauck. H. P., Jr.. Hennigar, G. R., and wigod, M. Jaundice associated with administration of sodium p-ammosalicylic acid: review of literature and report of case. Ann. 1 nt. .{fed. 44: 7G4-772, 1956. 7. Alt, 1V. J.. and Spengler, J. R. Secere systemic reactions to para- aminosalicylic acid: case report and review of literature. Ann, 1nt. Med. 45:5-11-547, 1956. 8. lferritt. A. D., and Fetter, B. F. Toxic hepatic necrosis (hepatitis) due to isoniazid: report of case with cirrhosis and death due to hemorrhage from esophageal varices. Ann. Int. Med. 50:804-810. 1959. 9. Paine, D. Fatal hepatic necrosis associated with aminosalicylic acid: revie.+ of literature and report of case. J.A..11.:L 167:285-289. 1958. CASE 43-1961 PRESEtiT ATION OF CASE A forty-nine-year-old printing press operator was admitted to the hospital because of vomiting and hiccuping. During the six months before entry progressive weakness, loss of weight and increase in abdominal girth occurred. Two weeks before admission the patient experienced the sudden onset of postprandial vomiting, pain in the lower portion of the abdomen and back, fever and increased thirst. The symptoms continued for two days and recurred after a two-day remission, persisting until the day of entry. Eight days before admission the temperature was 103°F.; the urine gave a++++ test for protein, and the sedi- ment contained numerous white cells. Chlorampheni- col and promazine afforded no improvement, and he was conFned to bed during the following week because of ~veakness. Four days before entry persistent hiccup- ing began, with no relief with atropine. There was no history of constipation, diarrhea or abdominal surgery. His dietary habits had been poor, with heavy ingestion of alcohol, for thirty years. Physical examination revealed a well nourished man in no distress. Scattered, coarse rhonchi were audible throughout the chest and were most prevalent at the lung bases. The heart was normal. The abdomen was tense and protuberant, with a large, nontender mass filling the entire left half. The mass did not tnove with respiration; one observer thought it could be indented slightly and interpreted it as cystic; no Ilttid wave was elicited. On percussion the entire left side of the abdomen was dull, and the bowel sounds Nvere depressed throughout. There was no guarding or rebound tenderness. One examiner reported that the liver edge was sharp, nontender and palpable 3 cm. below the ri;ht costal margin; others could not palpate any oll-ans. "1'he telnperature was 101°F., the pulse 120, and the respirations 20. The blood pressure %vas 120 systolic, 80 diastolic. The urine gave a + test for protein; the sediment contained 6 white cells and a rare red cell per high- power field; a culture was negative. Examination of the blood revealed a hemoglobin of 11.9 gm. per 100 ml., a hematocrit of 35 per cent and a white-cell count of 17,600, with 65 per cent neutrophils, 10 per cent band forms, 20 per cent lymphocytes and 5 per cent monocytes. The fasting glucose was 117 mg., the urea nitrogen 16 mg., the bilirubin 0.7 mg., and the total protein 6.2 gm. (the albumin 3.6 gm., and the globulin 2.6 gm. ) per 100 ml. The sodium was 132 milliequiv., the potassium 5.2 milliequiv., the chloride 85 milliequiv., and the carbon dioxide 33 milliequiv. per liter. The prothrombin content was 70 per cent. The amylase was 14 Russell units, the transaminase 130 units, and the alkaline phosphatase 7.5 Bodansky units. The cephalin flocculation was negative in forty-eight hours; a bromsulfalein test showed 30 per cent retention in forty-five minutes. Tests for febrile agglutinins were negative; a sputum culture grew out moderate pneumococci; a tuberculin skin test (first-strength PPD) was negative. A stool specimen gave a negative guaiac test, and a culture was negative. An electrocardiogram showed sinus tachvcardia at a rate of 125, but was otherwise nor- mal. The x-ray film of the chest was normal. Diffuse haziness on the film of the abdomen obscured all visceral detail. The barium-enema examination (Fig. 1) denlonstrated a huge abdominal mass that dis- -.~ FtGURE 1. Film from the Barium-Enema Examination, De- fining U/ueard Displacement of the Transverse Colon and Lateral Displacement of the Descending Colon-

Vol. 264 No. 24 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 1263 FIGURE 2. Intravenous Pyelogram, Showing Delayed Excre- tion from the Hydronephrotic Left Kidney. placed the transverse colon upward and the descend- ing colon laterally; in some areas the lumen of the colon was compressed to 0.5 cm. in diameter; the colon was intrinsically normal. The intravenous pyelo- graphic study (Fig. 2) demonstrated upward displace- ment of the stomach; there was delayed excretion of contrast material on the left side, with a markedly dilated collecting system and a sharp cutoff just distal to the ureteropelvic junction; the remainder of the left ureter was not visualized; on the right side the upper collecting system appeared normal, and the ureter was slightly displaced laterally. Despite streptomycin and sulfathalidine, daily ele- vations of the temperature to between 101 and 103°F. continued. A sigmoidoscopic examination was nega- tive. On the fourth hospital day the white-cell count was 29,400. The abdominal mass increased in size and became better delineated. The hiccuping subsided spontaneously. After one transfusion of blood the hematocrit rose to 41 per cent. A bone-marrow aspirate showed a very cellular marrow, with marked myeloid predominance; no malignant cells were seen. An operation was performed on the twelfth hospital d ay. DIFFERENTIAL DIAGNOSIS DR. CHARLES G. MIXTER, JR.*: This forty-nine- year-old patient had a debilitating disease of at least six months' duration, culminating in a two-week febrile period associated with nausea and vomiting. 'Assistant in surgery, Massachusetts General Hospital; instructor in surgery, Harvard Medical School. The striking physical finding was a huge left-sided abdominal mass. The laboratory data were consistent with prolonged ~-omiting. There was moderate hepatic dysfunction, but it probably had no relation to the large mass, which was the paramount problem. The elevation of the transaminase may have reflected the hepatic disturbance or some tissue breakdown. The fever and the elevated white-cell count were probably either the direct result of the mass because of inflam- Ination or tissue breakdown or due to infection in the blocked kidney, since a large number of white cells were present in the urine on one occasion. I attribute the nausea and vomiting to pressure of the mass on the relatively fixed portion of the duodenum or jejunum in the region of the ligament of Treitz. I hope to gain more information from the x-ray films. DR. Louis «'ENER: On the film of the abdomen a diffuse haze obscures most of the detail, and the organ outlines on the left side cannot be delineated. The barium-enema examination (Fig. 1) demonstrates displacement of the colon upward and laterally by a soft-tissue density in the left upper quadrant of the abdomen. An intravenous pyelogram (Fig. 2) reveals fairly normal function of the right kidney and mild displacement to the right of the ureter at the level of the third and fourth lumbar vertebras; the left kidney shows slow function, and the calyxes are moderately dilated on the five-minute film. On subsequent films the entire collecting system on the left side is tre- mendously enlarged, with a sharp cutoff immediately below the ureteropelvic junction and no demonstra- tion of the ureter below that point. A lateral film (Fig. 3) taken at that time, however, shows a large left kidney in the retroperitoneal space, with the left ureter displaced forward, but only slightly. DR. MIxTER : Can you detect any calcium in the mass? DR. WENER: No. DR. MIxTER: On the basis of the x-ray films I can eliminate from consideration at least three organs, the liver, the stomach and the spleen, all of which should depress rather than elevate the colon if involved by tumor. A large intra-abdominal mass of this type is unusual in a male. If it is seen in a female, of course, a number of conditions connected with the pelvic or- gans come to mind. An intra-abdominal process seems less likely than a retroperitoneal lesion in view of the displacement of the left ureter on the x-ray films. However, among the intra-abdominal processes that one might think of, the foremost is an inflammatory lesion such as diver- ticulitis and possibly regional enteritis, with abscess formation. Such abscesses often develop slowly, can reach a huge size and may show no connection with the bowel on x-ray films, but the long history in this case rules out that possibility. Mesenteric and dermoid cysts arise in the abdomen, although they are usually

1264 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 FIGURE 3. Lateral Film from the Intravenous Pyelographic Study, Showing Only Slight Forward Displacement of the Left Ureter (Arrow). more movable than the mass in this patient. Such a cyst may become very large, but I doubt if it would displace the ureter this much. Distortion of both the transverse and descending colon in this manner could be caused by such a cyst, but I prefer to go on to other diagnoses. An echinococcal cyst can be dis- missed since there is no statement that the patient had been in an area where that disease is endemic. One condition that should be mentioned, although an infrequent occurrence in this age group, is a duplica- tion of the bowel, which can assume huge propor- tions. An interesting feature of that situation is the fact that the normal bowel may be stretched out over the duplicated segment in such a way that it appears :narrow on the x-ray films, as in this case. Another 'intra-abdominal process that could attain this size is ' a pseudomyxoma peritonaei. ~ It seems more likely that the lesion in this patient ,'was in the retroperitoneal space, tilting the kidney and spreading out the ureters in the manner shown on the x-ray films. I believe that we can rule out an aneurysm because no mention is made of pulsations in the mass, and the course was too long for a rup- tured aneurysm. An inflammatory process can be dis- carded because no primary source is suggested, and the mass was not tender. It wasn't in the location where one would expect to find a perinephric abscess. A cold abscess could occur in this area, but I do not recall ever having seen one of this size, and the nega- tive tuberculin test is against that diagnosis. It is not often recalled, but pancreatic tumors, particularly if in the tail, occasionally burrow under the mesocolon and present in the lower abdomen, pushing the trans- verse colon upward, although they usually push it downward and anteriorly. For this reason a pancre- atic cyst might be considered, but it seems unlikely in the absence of a history of pancreatitis or of trauma. A papillary cystadenoma of the pancreas is an unusual tumor of a cystic nature that does reach a large size and should be mentioned in passing. True retroperitoneal tumors, which assume many forms, are generally believed to arise from the urogen- ital tract. I shall confine my attention to the more common ones. Cysts of various types are frequently seen in the retroperitoneum, but the long story and the debilitating course militate against that possibility in this case. I believe that the process was a retro- peritoneal tumor, but can only hazard a guess as to the type. In order of statistical frequency, one would list lymphoma, rhabdomyosarcoma, lipoma or liposar- coma, and finally teratoma. My diagnosis in this case is not very firm, I admit, but I think that the patient had a lymphoma of the retroperitoneal space, prob- ably with hemorrhage and necrosis within it resulting in the increase in size and the elevated temperature. DR. JACK R. DREYFUSS: Dr. Wener, on the basis of the x-ray films, particularly the lateral film, can you make a statement about whether the lesion was retroperitoneal or intra-abdominal in position? DR. WENER: Several factors on the films suggest that it was within the peritoneal cavity, one of which is the very faint delineation of the left psoas shadow. Secondly, if it was a retroperitoneal tumor the left ureter should be displaced far anteriorly rather than lying in a relatively normal position, as seen on the lateral projection. The position of the ureter suggests that the mass was located anteriorly and not pos- teriorly. CLINICAL DIAGNOSIS Retroperitoneal tumor, probably liposarcoma. DR. CHARLES G. MIxTER, ,jR.'S, DIAGNOSIS 0 co W Lymphoma, retroperitoneal space, with hemorrhage ~ and necrosis. a L.

Vol. 264 No. 24 CASE RECORDS OF PATHOLOGICAL DISCUSSION THE MASSACHUSETTS GENERAL HOSPITAL 1265 DR. RICHARD B. COHEN: Dr. Glotzer, will you describe the course of this patient? DR. DONALD J. GLOTZER: Our preoperative diag- nosis was a retroperitoneal tumor, probably a liposar- coma, and we believed that the fever was due to necrosis within it. I must admit that we were dis- quieted by the position of the left kidney and upper ureter, but the radiologists whom we consulted did not seem to consider that finding a decisive factor for or against a retroperitoneal location. At exploration we encountered a large mass occupy- ing the entire left side of the abdomen, pushing the descending colon forward and splaying out its mesen- tery. The mass was fixed, but it felt somewhat cystic. There appeared to be a cleavage plane between the colon with its mesentery and the mass, and we chose to separate them, reasoning that even if the process was malignant removal of the colon would not effect a cure. As we were debating whether to aspirate the mass because of its cystic consistency, we inadvertently entered it. It contained a large amount of purulent material with an odor suggestive of coliform organ- isms, although a gram stain at the time did not show any organisms. We submitted a piece of the cyst wall to the pathologist for frozen-section examination, which revealed no evidence of neoplasia and no spe- cific type of lining. Therefore, our working diagnosis was an infected cyst. We excised the mass, which extended up to the left kidney and renal artery and over the aorta and iliac vessels. It was not ad- herent to the pancreas or the kidney. The hydrone- phrotic left kidney was not removed since we have seen return of excellent function in such kidneys once the obstruction has been relieved. DR. DREYFUSS: Actually, Dr. Glotzer, the radiol- ogist who originally interpreted these films thought that the mass was probably retroperitoneal despite the fact that the left ureter was only slightly forward of its normal position. However, I think that the very lack of marked forward displacement of the left ureter is significant and rules against a retroperitoneal mass. DR. CLAUDE E. WELCH : We debated between the two probable diagnoses - a retroperitoneal sarcoma and a mesenteric cyst. Perhaps because of the x-ray report we decided on a retroperitoneal sarcoma, but none of us had seen a mesenteric cyst that had become this large and infected. DR. COHEN : Couldn't a large mesenteric cyst bulge both anteriorly and posteriorly and perhaps affect the kidney? DR. DREYFUSS: It certainly could. DR. COHEN: Most of the pertinent findings in this case have been presented by Dr. Glotzer, who found the very large cyst at operation and was able to view it intact. We received the collapsed cyst, which was an unimpressive mass of fibrous tissue comprising its wall. It was acutely inflamed, with no specific identi- fiable characteristics. There was no sign of neoplasia, and it is probable that it was a mesenteric cyst. Mesen- teric cysts are grouped into three categories: the neo- plastic, which rarely attain such size; the congenital; and the infectious. The congenital cysts are perhaps the most interesting. They derive from chylous lymphatic elements or from sequestered embryonic intestinal remnants, perhaps of a diverticulum that has been sequestered during the development of the gut. When they reach this size the lining has usually been destroyed by infection and compression, and it is dif- ficult to assign an etiology. Occasionally, there is a small connection between the cyst and the bowel. ANATOMICAL DIAGNOSIS Mesenteric cyst, infected. ~ ~

1266 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 The New England Journal of Medicine Official Organ of THE MASSACHUSETTS MEDICAL SOCIETY OWNED BY THE SOCIETY AND PUBLISHED WEEKLY UNDER THE JURISDICTION OF THE COMMITTEE ON PUBLICATIONS Richard M. Smith, M.D., Chairman James M. Faulkner, M.D. Joseph M. Hayman, Jr., M.D. Lawrence R. Dame, M.D. Lamar Soutter, M.D. Joseph Garland, M.D., EDITOR Assocta7e EDITORS Joseph Stokes III, M.D. Robert J. Haggerty, M.D. Robert O'Leary, ASSISTANT EntroR Milton C. Paige, Jr., BUSINESS MANAOPR EDITORIAL BOARD Henry R. Viets, M.D. Vernon P. Williams, M.D. Thomas H. Lanman, M.D. Benjamin Castleman, M.D. Donald Munro, M.D. Robert W. Buck, M.D. Dwight O'Hara, M.D. Herrman L. Blumgart, M.D. Fletcher H. Colby, M.D. Frank N. Allan, M.D. Robert L. Goodale, M.D. Langdon Parsons, M.D. Chester M. Jones, M.D. Mark Aisner, M.D. Harvey R. Morrison, M.D. Dale G. Friend, M.D. Maxwell Finland, M.D. Richard Warren, M.D. THE GREAT DEBATE IN Novenyber, 1960, Drs. Ernest L. Wynder and Clarence C. Little appeared before the New England States Chapter of the American College of Chest Physicians, assembled in Boston, to present their sepa- rate and opposing views on the cigarette smoking-lung cancer issue. As is generally known Dr. Wynder, of the Sloan-Kettering Institute, is making a career of cancer and its causes and has become a dominant figure in the crusade against immoderate cigarette smoking. Clarence Little, a doctor of science, director emeritus of the Jackson Memorial Laboratory in Bar Harbor, Maine, is scientific director of the Tobacco Industry Research Committee and devotes his highly developed talents to a defense of what many cherish as man's second or perhaps third best friend. The addresses that were delivered before the thoracologists are published as speciall articles in this issue of the Journal and may be read seriatim, if not simultaneously. Both authors are dedicated, sincere proponents of their points of view, each upholding what he believes to be the truth and nothing but the truth, each ready to admit that the whole truth has . . , . not yet been revealed to aspiring man. MANUSCRIPTS, including references or bibliography, should be typewritten double spaced and submitted as origi- nal copy. References should conform to the style of the Index Medicus (listing name and initials of author, title of article, journal, volume number, first and last pages and year), and should be cited numerically in the order in which they appear in the text; the number should be limited to the absolute minimum. Acceptable case reports will usually be published in the "Medical Intelligence" section of the Journal. Such reports should include only the pertinent details of each case and reference to articles reporting closely related cases. A complete review of the literature is rarely desirable. 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Proprietary names of pharmaceutical products must be accompanied by the chemical, or generic or official names, and the quantity of all active substances must and the rec- ommended dose should be stated. Copy should be factual, conservative and in good taste. ALTHOUGH all advertising material accepted is intended to conform to ethical medical standards, acceptance does not imply endorsement by the Journal. SUBSCRIPTION TERMS: $8.00 per year in advance, postage aid, for the United States (residents, interns and medical students, 5.00 per )ear) ; Canada, $9.00 per year (Boston fundsl: foreign, $10.50 per year. Long-term rates: United States, 2 years $15.06, 3 years $22.00; Canada, 2 years $17.00, 3 years $25.00; foreign, 2 years $20.00, 3 years $29.50. MICROFILM volutnes available to regular subscribers through Univer- sity Microfilms, 313 N. First Street, Ann Arbor, Michigan. COMMUNICATIONS should be addressed to the New England Journal oJ Medicine, 8 Fenway, Boston 15, Massachusetts. Telephone CO 6-7510. John J Byrne D M It is especially difficult for editors, who, unlike Pathe Weekly, see much but know little, to present a fair appraisal of these opposing points of view. More- over, since the editors of the Journal have on oc- casion revealed their own suspicion that one side of this controversy is probably the one to which to cleave, it is perhaps not completely judicious for them to offer any extraneous comments at this time that might seem to favor either faction. It is enough to say that most of the evidence is statistical and demonstrates a close association between heavy cigarette smoking and lung cancer. However, it is generally believed that statistics in the hands of a master can be made to prove almost anything. Dr. Wynder seeks to show, not by the adroit deployment of small clusters of statistics but by swinging the heavy artillery into action, that a strong causal relation be- tween cigarette smoking and bronchogenic cancer must in fact exist. Dr. Little's strategy is based, at least partly, on demonstrating that Dr. Wynder's statistics are inconclusive. Many conscientious observers believe that there are strong indications in favor of a causal relation in the vast majority of cases, and no acceptable evidence that disproves it; others remain unconvinced or have taken a determined stand behind Dr. Little. Certain facts stand out - that the stakes are high in terms of life and death, that smoking has been indicted as a sometimes lethal agent and that nonsmoking is almost certainly harmless. Each individual must choose his own course, whether to woo the lady nicotine or abjure the filthy weed, while the search for truth continues. J

Vol. 264 No. 24 EDITORIALS URBAN HISTOPLASMOSIS AT the time of its first description fifty-five years ago, histoplasmosis was considered to be a rare and highly virulent infection. As is so often true, more sensitive diagnostic tests, in this case x-ray examina- tion of the chest and the demonstration of delayed hypersensitivity to histoplasmin and other immuno- logic technics, have demonstrated over the last fifteen years that infection with Histoplasma capsulatum is common in highly endemic areas such as the Missis- sippi Valley. Although it is rare in New England, French et al.' have described histoplasmosis that was almost certainly acquired in Vermont and far from the broad Mississippi. It also is evident that bird and bat droppings harbor the fungus and promote its growth - a discovery that has disclosed some fascinating facets to the epidemiol- ogy of this disease. The risk of stirring up sleeping dust in places where H. capsulatum spores abound has been amply demonstrated, and the list of high-risk retreats now includes bat-infested belfrys, storm cel- lars, caves, silos, chicken coops and other closed places frequented by birds. Hitherto, the infective sites have been far removed from the usual habitats of modern, urban cliff dwellers, whose closest contact with birds is usually an occasional pigeon in the park or a "muddy sparrow, mean and small." However, elsewhere in this issue of the Journal, Furcolow et al. point out that even urbanites can no longer avoid infection in an endemic area by letting someone else clean out the chicken coop. The epidemic that these authors describe was traced to an 11-acre historical park that had been neglected and had become more attractive to starlings than human beings. Subsequent re-explora- tion of this wooded area by boy scouts and other ad- venturesome groups led to a high rate of positive histoplasmin skin tests. With little supporting evidence and without wish- ing to sound false alarms, the Journal would also remind its urban readers of a possible hazard to those who spend their summer months at the cool end of window air conditioners whose warm end serves as a roost for pigeons and certain other loitering birds. That this arrangement leads to an unhealthy exchange of ectoparasites has already been demon- strated,2 and there is reason to believe that such organisms as psittacosis virus and H. capsulatum could pass through the finest of air filters and infect an un- suspecting susceptible host on the other side. There- fore, it seems reasonable to encourage manufacturers to find ways of convincing pigeons that they should look elsewhere for their roosts. REFERENCES 1. French, E. E., Jillson, 0. F., and Crespell, L. S. Histoplasmosis in lifelong resident of New England. New Eng. J. Med. 249:270-272, 1953. 1267 2. McGinniss. G. F. Avian-mite dermatitis. New Eng. J. Med. 261:396, 1959. COST OF MEDICAL CARE A BELIEF seems to be prevalent in these rousing days of rising costs and buoyant currency that some- how or other the care of sickness comes too high and that the doctors, who are responsible for the care, are also re$ponsible for the cost. In a nation that is continuing to prosper for a while despite the increas- ing roll of thunder on its horizons, the profession of medicine is sharing in the prosperity, and this too many of its fellow Americans seem unable to abide. It is perhaps again worth noting that the Adminis- tration's Anderson-King bill, linking eldercare to Social Security, - anathema to the organized pro- fession - provides only for payment of hospital and nursing-home charges for those gentle souls who have passed sixty-five, leaving them to settle with their doctors according to their own devices. The Bureau of Labor Statistics, United States De- partment of Labor, is responsible for the following figures indicating, if nothing else, the relative modesty of physicians' fees: ITEM PER CENT INCREASE 1936-1960 All Items 113.3 Hospital Rates 370.1 Men's Haircuts 276.0 Shoe Repairs 186.1 Movie Admissions 155.4 Public Transportation 146.4 Food 138.9 Laundry Services 135.3 Auto Repairs 101.8 Dentists' Fees 101.0 General Practitioners' Fees 89.9 SurQeons' Fees 74.4 REGARDING GAMMA GLOBULIN UNDER the Massachusetts Department of Public Health heading in this issue of the Journal, Drs. Gellis and McComb call attention to the conflicting recom- mendations on the dose of gamma globulin for the pre- vention of infectious hepatitis in infants and children. At a time when many local supplies of gamma globu- lin have been depleted as a result of its extensive use by physicians attending professional meetings in Atlantic City, where infectious hepatitis is reputed to have been transmitted by eating of raw shellfish, this recommendation to continue using the well established, smaller dose of 0.01 ml. per pound of body weight is especially timely. Following such recommendation will further extend supplies vitally needed for modification or prevention

1268 THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 of measles and for the occasional susceptible patient exposed to rubella in the first trimester of pregnancy. It also re-emphasizes the fact that the use of gamma globulin should be restricted to those conditions for which it has been shown to be of benefit, and not used indiscriminately for nonspecific or hoped-for effects in other infections. CORRESPONDENCE Letters to the Editor are welcomed and will be published, if found suitable, as space permits. Like other material sub- mitted for publication, they should be typewritten double spaced, should be of reasonable length and will be subject to the usual editing. IODIDE MUMPS The Governor has commissioned Dr. Wm. J. Dale, of Boston, as Surgeon-General of the Massachusetts f orces. Boston M. & S. J. June 20, 1861 MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH CONSERVATION OF GAMMA GLOBULIN The 1961 edition of the "Red Book" of the American Academy of Pediatrics distinguishes between the adult and the child dose for the first time in its recommendations for the prevention of infectious hepatitis. This amounts to two and a half times more for adults than for children per pound of body weight. These recommendations re- semble those of Krugman et al. ( J.A.M.A. 174:823-830, 1960) and do not take into account ten years of satisfactory experience and published reports by many workers using the dosage of 0.01 ml. per pound of body weight first advocated by Stokes et al. ten years ago. In the Krugman trials this dose did not show the satisfactory results of previous published reports; the lot of globulin used was not tested at any other dosage level. When a higher dosage was employed in the next trial, the gamma globulin used was from a different commercial source. We firmly believe that ten years of experience should not be abruptly discarded on the basis of a single clinical trial, and work now in progress shows that gamma-globulin lots manufactured by the cold ethanol process developed by Cohn are quite uniform in potency. It is common knowledge that the antibodies in such material remain stable long beyond their dating period. The Krugman lot in question was not made by the Cohn method. To our knowledge this is true of no other commercial source of gamma globulin. We have had the experience of having had a different lot number from the same source fail to prevent or modify measles in several cases just before and after its expiration date in 1960. For us this was an un- usual experience, occurring seventeen years after satisfac- tory dosages for the prevention and modification of measles had been in effect and no thought of dosage increase was considered. We earnestly urge that in the face of a nation-wide increase in cases of hepatitis, this expensive and scarce material be used at the dosage level of 0.01 ml. per pound of body weight for the prevention of infectious hepatitis in both children and adults. SYDNEY S. GELLIS, M.D. Professor of Pediatrics and Chairman, Department of Pediatrics Boston University School of Medicine Director of Pediatrics, Boston City Hospital JAhIES A. MCCoXIB, D.V.M. Director, Biological Laboratories Massachusetts Department of Public Health To the Editor: Regarding the article "Iodide `Mumps,"' by Dr. John E. Carter in the May 11 issue of the Journal, I can vouch for the accuracy of his observations from my own personal recent experience. About three months ago I underwent sialography for chronic recurrent parotitis due to a stenosis of Stensen's duct. About 1 ml. of an iodine-containing radiopaque medium trickled down my throat. About twelve hours later, while in the company of a fellow pathologist, I noticed a peculiar sensation near my throat. On raising my hand to the area I found that both submandibular glands were enlarged and rather tender. They increased in size considerably over the next two hours, and the tenderness and discomfort was acute. I also experienced a profound feeling of malaise and lassi- tude. At no time did the right parotid gland become enlarged or tender, and the left parotid gland, already slightly larger and somewhat tender from the sialadenitis, did not change appreciably. These symptoms abated somewhat by the following morning, but did not really disappear for almost forty-eight hours. About six weeks later another sialograrn was taken. A smaller amount of iodine-containing radiopaque medium was used, and I should estimate that less than 0.5 ml. was in- gested. This amount was sufficient to produce the identical syndrome in about twelve hours, albeit to a lesser degree. WILLIAbI B. OBER, M.D. New York City To the Editor: The Medical Intelligence item, "Iodide `Mumps,"' calls attention to an unusual development after iodide therapy, which is worth bearing in mind, in view of the fact that iodine, in one form or another, is an im- portant weapon in the therapeutic armamentarium. The author pointed out that there were few, if any, other reports of acute, painful salivary-gland swelling after injec- tion of small amounts of iodide. So that the record may be complete, I should like to submit a brief account of a similar episode in an asthmatic patient described by a Pennsylvania physician, when he requested an opinion con- cerning the reason for "this peculiar reaction" (J.A.M.A. 147: 359, 1951). The physician wrote, "On several occasions I have prescribed potassium iodide. Each time after about 36 hours and only after a dosage of 0.3 cc. three times a day had been reached, his parotid and submaxillary glands would swell and become tender. His appearance would be that of a person with mumps. On withdrawal of the medication this swelling would recede." A consultant replied, "This is not in the nature of an allergic phenomenon, but rather an exaggerated response of the normal physiologic effect of the drug." If one accepts the consultant's opinion the cases described by Dr. Carter should not be labeled as iodine idiosyncrasy, assuming drug idiosyncrasy to be an inherent qualitative abnormal response to a drug. Nor should these cases be labeled manifestations of "lodism," if one accepts the definition of iodism found in Dorland's Medical Dictionary (twenty-third edition). And, for that matter, the case reported by Waugh (author of reference 5 in Carter's paper) as one of "severe iodism" does not actually appear to be true iodism, judging from Waugh's account of the case (Arch. Int. Med. 93:299-303, 1954). Might the reaction described by Dr. Carter be better termed a case of drug "side effect" or perhaps, of drug "intolerance"? "Side effect" has been defined as "any undesirable, non- toxic, non-allergic, directly-caused response," and "intoler- ance" as " a quantitative deviation from the normal" (CP

Vol. 264 No. 24 CORRESPONDENCE 1269 13:92-98, 1956). Intolerance is considered to be a reaction representing an accentuation of a normal pharmacologic action of a drug. Long Beach, California GEORGE X. TRIMBLE, M.D. Director of Medical Education Memorial Hospital of Long Beach CORTICOSTEROIDS IN ASPIRATION PNEUMONITIS To the Editor: In the April 6 issue of the Journal a letter by Theodore S. Smith, M.D., comments on the lack of mention of the use of corticosteroids in the treatment of a fatal case of aspiration pneumonitis reported in the Novem- ber 24, 1960, issue of the Journal. Dr. Smith gave the impression that this form of therapy for such a complication was first reported by Dr. R. Tovell's Hartford group in the fall of 1960. The letter of reply from the Committee on Maternal Welfare quotes Dr. Chester White as stating that the use of corticosteroids in this condition was originated by Dr. Bannister in Dr. Tovell's Hartford group. Dr. White sug- gested that it is experimental, and Dr. Marcus, the other committee anesthesiologist, stated that he was unfamiliar with this method of treatment, but if true it would be a welcome addition. I find these statements very surprising since I thought that by now this was a widely used procedure, as it is in Canada. I first used it four years ago after a discussion of the problem with Dr. R. A. Gordon, of Toronto. In 1958 Dr. Gordon's Toronto group first presented their results with this therapy in the Canadian Anaesthetists' Society Journal (5:438, 1958). Many other Canadian anesthetists have used corticosteroids in the treatment of this complication, with uniformly successful results. Dr. Tovell's group is to be congratulated for its work in helping to prove and popularize the value of corticosteroids in this relation. E. A. GAIN, M.D. Director, Department of Anaesthesia University Hospital Edmonton, Alberta FIRST DESCRIPTION To the Editor: I hope this discussion does not go on ad infinitum, but may I be allowed to push "A First Descrip- tion . . . etc." back in time a bit? The use of sperm and testes to produce antibodies, so ably utilized recently by the late Jules Freund and his col- leagues, has its origins in the last century. Both Land- steiner and Metchnikoff described antibodies to sperm in 1899. However, it remained for a pupil of Metchnikoff named Metalnikoff to record the first "autoantibody." In a rough translation his statement is as follows: When one injects spermatozoa of a guinea pig under the skin or into the peritoneum of another guinea pig, one notices that after the first injection the serum of the inoculated guinea pig becomes weakly toxic, not only for the spermatozoa of other guinea pigs, but also for those of the inoculated animal himself. The autotoxicity increases greatly after the second and third injection. (Annals L'Institut Pasteur 14:586, 1900). I hope that this quotation will receive its due credit as the first description of an autoantibody. JOH\ BAUbt, M.D. Dallas, Texas TREATMENT OF EXTRAPYRAMIDAL SYMPTOMS To the Editor: In the Current Concepts in Therapy, "Complications from Psychotherapeutic Drugs. I.," which appeared in the February 9 issue of the Journal, reference was made to the treatment of extrapyramidal symptoms secondary to the administration of prochlorperazine. Only anti-Parkinsonian drugs, caffeine and barbiturates were mentioned. Last year I reported, in a paper, "Neuromuscular Reac- tions: Secondary to the Administration of Prochlorperazine: Some Notes on Diagnosis and Management" in the American Practitioner and Digest of Treatment (11:962, 1960), 2 acute cases and referred to 7 others treated with meperidine hydrochloride intramuscularly, with amazingly fast and com- plete relief of symptoms. Since the publication of the paper I have had the oppor- tunity of treating another 4 such patients. Three of these, employees of a hospital, were admitted with nausea and vomiting as a complication of severe upper-respiratory-tract infections. 4Our routine treatment in these cases consists of symptomatic therapy, using only acetylsalicylic acid, nose drops, throat gargles and cough syrup when needed. In addition prochlorperazine, 10 mg. intramuscularly every six to eight hours, as needed for nausea is prescribed. If the patient is not vomiting, a 15-mg. sustained-release capsule is used instead of the intramuscular route. Extrapyramidal symptoms developed in 2 of the patients receiving the medication intramuscularly after 30 mg. and 40 mg. respectively, and in 1 after 60 mg. had been ad- ministered by mouth. All of them complained of difficulty in speech, pain in the muscles of the right side of the neck, deviation of the mandible toward the right and anxiety. All the symptoms were sudden in onset, and when seen they had been com- plaining for about fifteen minutes. Physical examination in each case was negative except for contraction of the muscles of the right side of the neck and deviation of the mandible to the right. Meperidine was administered intramuscularly in a 50-mg. dose, and the time checked. All the symptoms disappeared with complete recovery in forty, sixty and one hundred and twenty seconds. The treatment had to be repeated once six hours later in the patient receiving the sustained-release form of medication, again with complete relief in forty seconds. The fourth somewhat more dramatic case was that of a twenty-nine-year-old schizophrenic patient who was trans- ferred from the general ward to our medical ward with the diagnosis of luxation of the mandible. This patient had been receiving 10 mg. of thiopropazate dihydrochloride three times daily when he came to the attention of the attending physician because he "had his mouth wide open" (as did the first patient in my previous report). I saw him that evening because of stertorous breathing, profuse sweating and a pulse rate of 120. He was sitting on the bed with his mouth wide open, the mandible in contact with the chest and eyes rolling upward, and was unable to talk at all. The stertorous breathing was impressive, and there was early cyanosis about the fingernails and perioral region. The blood pressure was 130 systolic, 70 diastolic, the pulse 120, and the temperature 96.4°F. by rectum. There was con- traction of the muscles of the oropharynx and marked re- traction of the tongue. The patient was able to understand commands given and was co-operative with the examiner. A tracheotomy was thought to be necessary, but while the tracheotomy tray was awaited the patient was given 50 mg. of meperidine intramuscularly as a trial. Five minutes later he was able to move the mandible to an intermediate posi- tion. The breathing was still stertorous, but the cyanosis had completely disappeared. At this time another 50 mg. of meperidine was administered, and after another five minutes he was able to close his mouth with only slight deviation of the mandible to the right. Breathing was still somewhat labored but much improved, and the pulse was down to 100, with no change in blood pressure. For the first time he was able to talk, asking for water with only one word. At this time another 50-mg. dose of meperidine was administered intramuscularly. Fifteen minutes after the first injection he was able to talk distinctly, the respirations were 18 per minute, with normal excursion, and he was able to open and close his mouth freely. The pulse remained at 100, and the blood pressure was 128 systolic, 82 diastolic. This man took the longest time to respond to medication, probably because he weighed about 95.2 kg. (210 pounds) and only 50 mg. of meperidine was given, for the diagnosis was not certain.

THE NEW ENGLAND JOURNAL t)1' 'MP.DICINE June 15, 1961 1270 This treatment has been proved effective only in acute extrapyramidal symptoms, and it is not known whether the same results will be obtained in the less dramatic and long standing cases. A series is now being run on the patients who can be located but the results are not as yet conclusive. I am unable to offer any logical explanation for the amazing effect of meperidine in this type of reaction, and hope that someone may be able to enlighten me. I also hope that this note will help others in treating acute cases and encourage pharmacologic and physiopathological studies with these drugs. L. M. PEREZ, M.D. Personnel Physician BOOK REVIEW Clinical Vectorcardiography and Electrocardiography. By Edward Massie, A.M., M.D., F.A.C.P., F.A.C.C.; and Thomas J. Walsh, M.D.,.F.A.C.C. 4°, cloth, 605 pp., with 471 illustrations and 31 tables. Chicago: The Year Book Publishers, Incorporated, 1960. $27.50. This textbook, containing a lucid and detailed description of modern vectorcardiographic and electrocardiographic views, is divided into four major sections. The first deals concisely with basic considerations on cellular depolarization, reference systems and instrumentation. The second part, the abnormal electrocardiogram and vectorcardiogram, con- siders the ventricular hypertrophies, bundle-branch blocks, myocardial infarctions and other types of heart disease. The third section describes the arrythmias, and the final portion provides further illustrations pertinent to the pre- vious text. Each chapter begins with a discussion of the ex- pected vector deviations, which are clarified by excellent diagrams. The electrocardiographic findings are then re- viewed along these lines, and this is followed by a discussion of the actual vectorcardiographic recordings. Certain exceptions may be taken to the authors' views. Although they refer to the corrected vectorcardiographic lead systems of Frank and others, their data have been ob- tained with the cube system. Whereas this provides valuable information and does not affect the principles outlined, some of their data may not apply to the more modern lead sys- tems. For example, the wide ranges in direction of initial and final vectors limit the clinical usefulness of the cube system. This could explain their finding that only 75 per cent of cases with diaphragmatic infarction show a direction of the 0.02-second vector outside the range of normal. In this regard it is unfortunate that in the section on myocardial infarction no data on autopsied cases are given. The section on congenital heart disease is treated some- what summarily. The data are often derived from pooled series from various authors, resulting in some questionable conclusions. For example, the statement that "ordinarily pulmonic stenosis is not an isolated anomaly" is incorrect. Also, the incidence of hypertrophy of the left ventricle in defects of the ventricular septum, given as 23 per cent, appears much too low. Analysis of data in congenital heart disease is very much dependent on the age group, a factor not analyzed in this section. The reviewer marvels at the excellent quality of the vector- cardiographic tracings. In fact, the text is replete with accurate, schematic illustrations.. which facilitate comprehen- sion of this often difficult and, to many, boring subject. The book leaves one with a feeling of clarity and satisfaction, a commendable achievement. The logical arrangement and its scope recommend it to all those interested or experienced in vectorcard.osraphy and electrocardiography. PAUL G. HUGENFtOLTZ, M.D. fessor emeritus of obstetrics and gynecology, Yale University School of Medicine, and curator, Yale Medical Memorabilia, Yale University. 8°, cloth, 220 pp., with 53 illustrations. Hamden, Connecticut: The Shoe String Press, Incorpo- rated, 1960. $6.00. Complications in Surgery and Their Management. Edited by Curtis P. Artz, M.D., F.A.C.S., associate professor of surgery, University of Mississippi School of Medicine; and James D. Hardy, M.D., F.A.C.S., professor of surgery and chairman, Department of Surgery, University of Mis- sissippi School of Medicine. 4°, cloth, 1122 pp., with 272 illustrations and 32 tables. Philadelphia: W. B. Saunders Company, 1960. $23.00. The Memoirs of Ray Lyman Wilbur 1875-1949. Edited by Edgar Eugene Robinson and Paul Carroll Edwards. 8°, cloth, 702 pp., with 16 illustrations. Stanford, California: Stan- ford University Press, 1960. $10.00. Medical Examination Review Book. Three volumes. Vol. 1. Comprehensive. 8°, paper, 204 pp. $12.00. Vol. 2. Clinical Medicine. 8°, paper, 162 pp. $6.00. Vol. 3. Basic Sciences. 8°, paper, 176 pp. $6.00. Second printing. Flushing, New York: Medical Examination Publishing Company, Incorpo- rated, 1960. A Textbook of Clinical Pathology. Edited by Seward E. Miller, M.D., professor of internal medicine, University of Michigan Medical School, director, Institute of Industrial Health, and professor of industrial health, University of Michigan School of Public Health. Sixth edition. 4°, cloth, 915 pp., with many illustrations, some in color. Baltimore: The Williams and Wilkins Company, 1960. $15.00. NOTICES UNIVERSITY OF VERMONT COLLEGE OF MEDICINE SEMINAR A seminar on the basic concepts of cardiac excitation and conduction, under the sponsorship of the University of Ver- mont College of Medicine and the Vermont Heart Associa- tion, will be held in Burlington, Vermont, September 16 and 17. Guest speakers will be Drs. E. T. Angelakos, B. F. Hoff- man, R. Langendorf, A. J. Linenthal, D. Scherf, H. H. Swain and W. Trautwein. Further information may be obtained from Borys Surawicz, M.D., or Eugene Lepeschkin, M.D., Department of Experi- mental Medicine, University of Vermont College of Medi- cine, Burlington, Vermont. AMERICAN CANCER SOCIETY, INCORPORATED The annual scientific session of the American Cancer Society will be held in the Biltmore Hotel, New York City, October 23 and 24. The theme of the session will be "The Physician and the Total Care of the Cancer Patient." Further information may be obtained from the Professional Education Section, American Cancer Society, 521 West 57th Street, New York 19, New York. BOOKS RECEIVED The receipt of the following books is acknowledged, and this listing must be regarded as a sufficient return for the courtesy of the sender. Books that appear to be of particular interest will be reviewed as space permits. Additional infor- mation in regard to all listed books will be gladly furnished on request. The Doctors of Yale College 1702-1£315 and the Founding of the Medical Institution. By Herbert Thorns, M.D., pro- AMERICAN SOCIETY FOR MICROBIOLOGY The American Society for Microbiology announces a series of annual meetings to be known as "The Interscience Con- ference on Antimicrobial Agents and Chemotherapy." The first meeting in this series will be held at the Commodore Hotel, New York City, October 31 and November I and 2. (Concluded on page xxvi)

Vol. 264 No. 24 ADVERTISING SECTION M I LD-MODERATE-SEVERE GASTROINTESTINAL DISORDERS Pro-Banthine Brand of propantheline Dromide One characteristic of Pro-Banthine which has won it general medical acceptance is its versa- tility. Pro-Banthine has proved highly useful in the management of gastrointestinal disorders varying widely in both symptoms and severity. In peptic ulcer and in other disorders char- acterized by hyperacidity, hypermotility or spasm of the enteric tract, Pro-Banthine con- trols symptoms with a consistency attested in more than 375 published reports. This therapeutic proficiency results not merely from the high level of pharmaco- dynamic activity of Pro-Banthine but also from a favorable balance of its actions on both au- tonomic ganglia and parasympathetic effector organs. The total effect of this activity permits doubling or tripling the usual dosage to relieve severe or intractable conditions without unduly extending or aggravating secondary actions. Less than a satisfactory responsel to Pro- Banthine may often be simply a result of less than adequate dosage. ' TABLETS AMPULS Pro-Banthine, brand of propantheline bro- mide, is supplied in tablets of 15 mg. for oral administration in conditions such as peptic ulcer, gastritis, duodenitis, pylorospasm, biliary dyskinesia and spastic colon, and in ampuls of 30 mg. for intramuscular or intravenous administration in conditions such as ureteral spasm and pancreatitis in which prompt and vigorous effects are required or when nausea and vomiting preclude oral administration. Usual adult dosage: One tablet four times daily. Up to four tablets may be administered four times daily for severe manifestations. When emotional factors prevail - PRO-BANTHINE© with DARTAL® 8rand ot propanthelina bromide with thioproparata dihYdrochloride (Not more than four tablets daily.) or PRO-BANTHiNE° with Phenobarbital I. Krantz, J. C., Jr., and Carr, C. J.: The Pharmacologic Prin- ciples of Medical Practice, Baltimore, The Williams & Wilkins Company, 1958, p. 843. xxv ii G. o. S E A R L E& e o., c ti t e A G O 80, 1 L L I N O I S. Research in the Service of Medicine

xxvi THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 TUFTS UNIVERSITY SCHOOL OF MEDICINE COURSES FOR GRADUATES REVIEW OF RECENT ADVANCES IN INTERNAL MEDICINE October 2-7, 1961 at the NEW ENGLAND CENTER HOSPITAL The following subjects will be covered: HEMATOLOGY: Dr. William Dameshek, Chairman KIDNEY AND ELECTROLYTES: Dr. William B. Schwartz, Chairman GASTROENTEROLOGY: Dr. James F. Patterson, Chairman ENDOCRINOLOGY: Dr. Edwin B. Astwood, Chairman ALLERGY-PULMONARY DISEASE: Dr. Robert P. McCombs, Chairman INFECTIOUS DISEASE: Dr. Louis Weinstein, Chairman CARDIOLOGY: Dr. Samuel Proger, Chairman Tuition - $100.00 For further information write to: Assistant Dean, Courses for Graduates, Dept. A, 171 Harrison Avenue, Boston 11, Mass. SPECIAL ANNOUNCEMENT FOR Journal Subscribers We have an arrangement with the publishers of The Practitioner that permits us to offer this publication to subscribers to The New England Journal of Medicine in the U. S. A. and Canada for only $6.50 per year. Use order form at right. Articles appearing in the June, 1961 issue include - MINOR SURGERY OF THE HANDS By Robert H. C. Robins, M.B., F.R.C.S. Orthopaedic Surgeon, Royal Cornwall Inftrmary, Truro INFECTIONS OF THE HAND By Edward Hamlin, Jr., M.D. Associate Clinical Professor of Surgery, Harvard Medical School; Visiting Surgeon, Massachusetts General Hospital, Boston, Massachusetts THE MANAGEMENT OF INJURIES OF THE HANDS By Athol Parkes, M.B., F.R.C.S.Ed. Assistant Orthopaedic Surgeon, Western In(trmary, Glat- gow; Surgeon in Charge, Peripheral Nerve Injury and Hand Injury Clinics, Western Infirmary and Killearn Hot- pitals, Glasgow MINOR SURGERY OF THE FEET By Robert Roaf, M.Ch.Orth., F.R.C.S., F.R.C.S.Ed. Director of Clinical Studies and Research, Robert Jones and Agnes Hunt Orthopaedic Hospital, Ottvestry; Lecturer in Orthopaedic Surgery, University of Lirterpool THE PROBLEM OF FOOTWEAR By T. T. Stamm, M.B., F.R.C.S. lJrthopaedic Surgeon, Guy's Hotpital INDICATIONS FOR CHIROPODY By John R. Hall, F.Ch.S. President, The Society of Chiropod'uts CONGENITAL ABNORMALITIES OF THE HANDS AND FEET By Alexander Innes, M.B.E., M.B., F.R.C.S. Surgeon, United Birmingham Hospitals; Orthopaedic Surgeon, Children's Hospital, Birmingham, and Warwick- shire Orthopaedic Hospital for Children (Concluded from page 1270) Further information and hotel reservations may be ob- tained from the American Society for Microbiology, 19875 Mack Avenue, Detroit 36, Michigan. SOCIETY MEETINGS AND CONFERENCES Further information concerning conferences, hospital rounds and clinics in the Greater Boston area, formerly published in this weekly calendar, may be obtained from the Postgraduate Medical Institute, 22 Fenway, Boston 15, KE 6-8812. JUNE 16-18, JULY 1-4 and NOVEMBER 19-22. International College of Surgeons. Page 255, issue of February 2. JUNE 16-23. Trudeau School of Tuberculosis and Other Pulmonary Diseases, Saranac Lake, New York. Page 732, issue of April 6. Juxe 16-28. Consultation Clinics for Grippled Children in Massachu- setts. Page 1163, issue of June 1. ~uNE 22. Association of Foreign Medical Graduates, Boston. Page 12'10, issue of June 8. JUNE 22-26. American College of Chest Physicians, New York City. lPae 1008, issue of May 11. UNE 24. National Conference on Disaster Medical Care, New York City Page 1168, issue of June 1. JuNE 24. The International Cardiovascular Society, New York City. Pa e 1008, issue of May 11. yuxE 24 and 25. Postgraduate Seminar on Diagnosis and Management of Rheumatic Diseases, New York City. Page 952, issue of May 4. JUNE 25. A.M.A. Session on School Health, New York City. Page 1168, issue of June 1. JUNE 25-30. Annual Meeting of the American Medical Association, New York City. JUNE 27. Northwestern University Medical Alumni Luncheon, New York City. Page 892, issue of April 27. JUNE 27-29. Society for Investigative Dermatology, New York City. Page 470, issue of March 2. JULY 3-AucusT 4. International Congress of Biophysics, Stockholm, Sweden. Page 104, issue of July 14. JULY 10-14. Third International Congress of Dietetics, London, Eng- land. Page 1250, issue of June 16. JULY 12 and 13. Rocky Mountain Cancer Conference, West Denver, Colorado. Page 1008, issue of May 11. Avt:UST 6-18. Course in Medical Genetics, Bar Harbor, Maine. Page 520, issue of March 9. SEPTEStBER 4-7. Tenth International Congress on Rheumatoid Diseases, Rome, Italy. Page 660, issue of September 29. SEPTEMBER 14-16. New England Society of Anesthesiologists, Ports- mouth, New Hampshire. Page 892, issue of April 27. SEPTEMBER 14-17. Second International Symposium on Chemotherapy, Naples, Italy. Page 660, issue of September 29. SEPTEMBER 16 and 17. University of Vermont College of Medicine Seminar, Burlington, Vermont. Page 1270. OcroReR 12 and 13. Congress of Neurological Surgeons, New York City. Page 1114, issue of .fay 25. OC[OBER 15-20, Fourth International Congress of Allergology, New York City. Page 206, issue of January 26. OCTOBER 23 and 24. American Cancer Society, Incorporated, New York City. Page 1270. OcroBER 31 and NovEMBER I and 2. American Society for Microbiology, New York City. Page 1270. NOVEMBER 2-4. Inter-Society Cytology Council, Memphis, Tennessee. Page 952, issue of May 4. NoveMBER 6-9. Southern Medical Association, Dallas, Texas. Page 780, issue of April 13. NOVEMBER 7-9. New England Postgraduate Assembly, Boston. Page 712, issue of October 6. NovEMBER 27-29. American Society of Hematology, Los Angeles, California. Page 1220, issue of June 8. DECEMBER 6-8. Neuroendocrinology Symposium, Miami, Florida. Page 1168, issue of June 1. . ........................................................... NEW ENGLAND JOURNAL OF MEDICINE 8 Fenway Boston 15, Massachusetts Please enter my order for a year's subscription to The Practitioner at the special price of $6.50. 0 bA (0A so~ Name ................................................................................... 7) to Address .................................................................................. (~' City .................................................... State ........................ [3 Check or Money Order enclosed. Make checks or money orders payable to the NEW ENGLAND JOURNAL OF MEDICINE. : . ..... ........... ............................................

r Vol. 264 No. 24 new pre-eminence In the prevention, detection and automatic treatr»ent ADVERTISING SECTION oF Cardiac Arrest, the E l ectrodyn e PMS-5 I • Only Electrodyne offers an instrument of this type. • Full S" electrocardioscope for greater visibility. • Simplicity of operation, functional appearance. ~ , Electrodyne Company, Inc. 80 Endicott Street, Norwood, Massachusetts, U. S. A. The reputation of Electrodyne instruments has established leadership in the field of medical electronics for the preventive detection and treatment of Cardiac Standstill, Ventricular Fibrillation and Cardiac Arrhythmias. Proudly we present our latest and most refined instrument for the prevention, detection and automatic treatment of ventricular standstill through the application of efficacious electrical impulses through the intact chest or directly to the heart Engineered for unexcelled. valuable time-saving simplicity of operation, only Electrodyne offers an instrument of this type. Monitoring heart action visually and audibly, it in- stantly signals Cardiac Arrest and automatically provides external stimulation. Any Cardiac Arrhythmia is instantly recognizable on the highly visible large 5" Electrocardio- scope which presents a continuous display of the electro• cardiogram. Please write for an informative file of technical specifica• tions on this and other fine Electrodyne equipment.

u our ow- ac patient back on the payroll Soma's prompt relief of pain and stiffness can get your low-back patients back to work in days instead of weeks Soma is unique because it combines the properties of an effective muscle relaxant and an independent analgesic in a single drug. Unlike most other muscle relaxants, which can only relax muscle tension, Soma attacks both phases of the pain-spasm cycle at the same time. Thus with Soma, you can break up both pain and spasm fast, effectively . . . help give your patient the two things he wants most: relief from pain and rapid return to full activity. Soma is notably safe. Side effects are rare. Drowsiness may occur, but usually only with , higher dosages. Soma is available in 350 mg. tablets. Usual dosage is 1 tablet q.i.d. The muscle relaxant with an independent pain-relieving action 0 (carisoprodol, Wallace) 1~I Wallace Laboratories, Cranbury, New Jersey

® ® ® owl ® a win ::, t~~ -. M1~5 \, f AO ® ,. ; <I# !!MI,9I E- ' RMMFAR.M~ +v~ : ~ ~ How you can help save ' your patients a month's pay f-R Kestler reports in J.A.M.A. (April 30, 1960) that conventionally treated low-back syndrome pa- tients required an average of 41 days for full recovery (range: 3 to 90 days). The addition of Soma therapy in this comparative inves- tigation reduced the average to R' 11.5 days (range: 2 to 21 days). With Soma, patients averaged full recovery 30 days sooner. \ { 0 ®r

patients are happier when doctors choose FLEET®ENEMA R.eady-to-Use Squeeze Bottle I

Vol. 264 No. 24 ADVERTISING SECTION because it's so easy to give... and so easy on the patient Patients prefer FLEETO"ENEMA because it's so simple and easy to take-completely without the discomfort of old-style enemas. Nurses enjoy its safe, sure administra- tion. No more preparation and cleanup! And physicians rely on its predictable, thorough cleansing action. Pre-lubricated, anatomically correct 2-inch rectal tube avoids injury Check valve regu- lates flow Just 4 fl1 oz. of pre- cisely formulated solution* provides thorough cleansing without irritation or discomfort Compact squeeze bottle unit-no loose or moving parts 2M *100 cc. contains: 16 Gm. sodium biphosphate and 6 Cm. sodium phosphate in 4t/s-fl. oz. squeeze bottle. Pediatric size, 2t/a fl. oz. Also available: FLEET OIL RETENTION ENEMA, 41/4-fl. oz. ready-to-use unit containing Mineral Oil U.S.P. 1. Ready to use...no preparation nec- essary...just remove protective cover 2. Easy to adminisler... just squeeze bottle with one hand ... no contact with rectal area 0 0 3. Disposable... replace used enema unit in original container and dis- card ... eliminates cleanup and sterilization FLEET-~' ENEMA Ready-lo-Use Squeeze Bottle C. B. FLEET CO., Iuc. Lynchburg, Virginia

THE NEW ENGLAND JOURNAL OF MEDICINE BALDPATE, Inc. George town.. Mass. Fleetwood 2-2131 30 miles north of Boston For the treatment of psychoneuro- ses, personality disorders, psycho- ses, alcoholism and drug addiction. Definitive psychotherapy, somatic thera- pies, pharmacotherapy. Milieu-therapy un- der direction of trained occupational and recreational therapists. Accredited by joint Commission on Ac- crcditaton of Hospitals. HARRY C. SOLO\ION, M.D. Consulting Psirhiatrist PATRICK J. QUIRK, M.D. .Iledicaf Superintendent THE LEARY LABORATORY Established 1929 43 BAY STATE ROAD BOSTON, MASSACHUSETTS All Branches of Laboratory Medicine 7-DAY COVERAGE KEnmore 6-2121 CLIN ICAL CHEMISTRY Service to the lledica! Profession Boston Medical Laboratory, Inc. Norbert Benotti - Joseph Benotti Directors 19 Bay State Road, Boston 15, Mass. CO m rn ml weat t h 6-3402 PSYCHIATRISTS - Staff openings for Board-eligible and Board-certified neurologists or psychiatrists. Large New England mental hospital. Salary $11,000 to $12,500. Contact Supt. of Brattleboro Retreat, Brattleboro, Vermont. B472-22-8t WANTED - Full-time child psychia- trist to work with 12-man mental health team in all-purpose medical group. Op- portunity to participate in ongoing re- search program with full-time behavioral scientists on the problem of aggression in children. Address A493, New Eng. J. Med. 22-tf YOUNG INTERNIST or PRACTI- TIONER to associate with a general practitioner in Monadnock area. Excel- lent hospital facilities, terms to be ar- ranged. Address A293, New Eng. J. Med. 5-tf RESIDENCIES in INTERNAL MED- ICINE, university appointment, salary $3,495-$5,315, fully approved, research and teaching opportunities, 1200-bed ~,general hospital, Southwest. Must be graduate of approved U. S. or Canadian `medical school. Address A294, New Eng. .J. Med. 14-40t HOUSE OFFICERS-Positions avail- -•able immediately. 230-bed general hos- pital, north of Boston. Standard E.C.- F.M.G. certificate required. Generous stipend and allowances. Write: Adminis- trator, Bon Secours Hospital, Methuen, Massachusetts. B436-17-tf GENERAL SURGEON - ASSOCI- ATE, S U B S E Q U E N T partnership. Young surgeon for expanding surgical clinic, salary commensurate with educa- tion and experience. Exceptional oppor- tunities for advancement. Near Boston, Massachusetts. Address A397, New Eng. J. Med. 21-8t FOR RENT - WEST MEDFORD. Four-room doctor's office, fully equipped, air conditioned, excellent location. Ad- dress A 197, New Eng. J. Med. 18-eow-tf UNITED LIMB & BRACE CO., Inc., manufacturers of artificial limbs. 15 Berkeley Street, Boston. HA 6-4018. B517-6-tf PATHOLOGY RESIDENCY - Four- year approved program, pathologic anat- omy and clinical pathology; affiliated Baylor University College of Medicine. Stipend $3,495-$5,315. Must be U. S. citizen or graduate of U. S. or Canadian medical school. Bela Halpert, M.D., Veterans Administration Hospital, Hous- ton, Texas. B373-10-20t APPROVED ROTATING INTERN- SHIPS in unique university affiliated education program available July 1, 1961. Residency-level training in major disciplines. Stipends range from $250- $300 per month, depending on marital status. Apply, Director of Medical Edu- cation, Pittsfield Affiliated Hospitals, 379 East Street, Pittsfield, Massachusetts. B467-21-4t AVAILABLE - Roslindale Square, most modern office building. Suite of medical offices available, $80 per month. BEacon 2-9488. B489-24-2t APPROVED ROTATING INTERN- SHIPS (4). 301-bed fully accredited general hospital, 12,000 admissions per year, good clinical material, excellent teaching program. E.C.F.M.G. certifica- tion required for foreign graduates. $350 per month plus full maintenance, family housing available, 30 miles from Pittsburgh. Apply: Coordinator of Medi- cal Education, Westmoreland Hospital. Greensburg, Pa. B277-21-tf B O A R D CERTIFIED, university trained pediatrician, leaving Army this summer, desires group or associate type practice in New York, Connecticut, New Jersey, or Washington, D. C. area. Ad- dress A392, New Eng. J. Med. 21-4t INTERNIST, Board eligible or certi- fied for 5-man department of established specialty group in excellent hospital as- sociation. Younger man preferred. Salary two years, then partnership in 20-man group. Furnish complete autobiography in initial reply. Address A341, New Eng. J. Med. 13-14t FOR RENT - Beacon Street, Brook- line, front private entrance two- or four- room, ultra-modern suites, parking, LA- scll 7-5776. B369-10-tf June 15, 1961 ACCOUNTS RECEIVABLE MANAGEMENT • Billing • Bookkeeping • Collections Medical Clearing Bureau 110 Tremont Street Boston, Mass. HUbbard 2-2151 PERKINS SCHOOL LANCASTER, MASS. Devoted to the scientific understanding and education of children of retarded develop- ment. Five homelike and attractive buildings surrounded by 85 acres of campus and gar- dens. FRANKLIN H. PERKINS, M.D. VACATION COVERAGE. Responsi- ble, energetic Board-eligible surgeon avail- able to cover your general or surgical practice part or all of July, August, Sep- tember. Massachusetts license. Experi- ence. Address A401, New Eng. J. Med. 22-3t NEEDED - GENERAL PRACTI- TIONER. A community of 4,000 needs a physician. It is located on an inter- state expressway 35 miles north of Boston. It is a New England town in the center of both summer and winter playgrounds with residents commuting to nearby busi- nesses. It is an aggressive community with no unemployment and a steadily growing population. A centrally located home and office will be provided. For information contact address A402, New Eng. J. Med. 22-4t PEDIATRICIAN - Certified with cardiology and pulmonary training de- sires academic and/or group association in which previous experience is utilized. Address A403, New Eng. J. Med. 22-4t PEDIATRICIAN WANTED for ex- panding 3-man department in private group clinic located in excellent hospital. No house calls. Midwest. $30,000 for two years' service, then opportunity for partnership. Traveling expenses paid for applicants invited for personal interview. Address A406, New Eng. J. Med. 22-6t GENERAL PRACTITIONER WANTED to associate with surgeon- general practitioner serving a population of 15,000, excellent hospital, completely equipped two-man clinic, salary or part- nership. 1%• hours from Boston. Address A240, New Eng. J. Med. 22-tf ANESTHESIOLOGIST exceptionally qualified for academic or clinical position seeks director or comparable senior posi- tion. Curricttlum vitae available. Address A356, New Eng. J. Med. 14-em-3t (Additional advertisements on pages xxxvii and xlvi)

iiidepression- : for greater emotional stability in the aging patient T~ofranil Tablets of 10 mg, for geriatric use During the declining years, frustration aris- ing from declining capacity to participate in social and family activities often leads to depression, manifested frequently in unpredictable swings of mood.l The value of Tofranil in restoring the de- pressed elderly patient to a more normal frame of mind has received strong support from recent studies.1-3 Under the influence of Tofranil, such symptoms as irascibility, hostility, apathy and compulsive weeping are often strikinglyt elieved with the result that life becomes easier both for the pa- tient and those around him. Since the dosage requirements of etderly patients are lower than those of the non- geriatric patient, Tofranil is made available in a special low dosage 10 mg. tablet designed specifically for geriatric use. Full product information regarding dos- age, side effects, precautions and contra- indications available on request. References: 1. Cameron, E.: Canad. Psychiat. A. J., Special Supplement 4:S160, 1959. 2. Christe, P.: Schweiz. med. Wchnschr. 90:586, 1960. 3. Schmied, J., and Ziegler, A.: Praxis 49:472,1960. Tofranil®, brand of imipramine hydrochloride: Triangular tablets of 10 mg. for geriatr c use: also available, round tablets of 25 mg , and ampuls for intramuscular administration only, each containing 25 mg. in 2 cc. ot solut on (1.25 per cent). Geigy Pharmaceuticals Division of Geigy Chemical Corporation Ardsley, New York To•sa7.a1

xxxiv THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 • Just Published ! ... from LITTLE, BROWN Antoniades' HORMONES IN HUMAN PLASMA In recognition of great recent interest in the use of human plasma to obtain hormones for clinical use, 33 of the country's leading biologists - biochemists - physical- chemists - physiologists - pharmacologists - clinicians - have pooled their knowledge to present ... ... the latest methods of identifying and measuring hor- mones in human plasma ... technics for preparing hormones from human blood for clinical purposes ... an examination of the nature in which these hormones exist and ways in which their physical-chemical and physiological properties can be determined .-. analyses of the protein interaction of non-protein hormones such as steroid hormones, epinephrine and norepinephrine Many illustrations and tables, together with numerous references round out a comprehensive, up-to-date study in a rapidly expanding field. 667 pp. 100 illus. and tables $25.00 Order through your bookstore, or directly from: LITTLE, BROWN AND COMPANY 34 Beacon Street, Boston 6, Massachusetts N a A Hard Working Handle holds your instrument cost down One Welch Allyn handle powers all these Welch Allyn instrument heads - and many more. Add in- struments as you need them with no more expense fbr handles. No battery replacements - this handle has recharge- able batteries. Beryllium copper collar spring for permanent snug instrument fit. Positive-off rheostat prevents turning on power accidentally. Ask your dealer to show you Welch Allyn's 717 handle. Handles also available for use with standard dry cell batteries. McGILL UNIVERSITY POSTGRADUATE COURSE IN ANAESTHESIA A postgraduate Revision and Refresher Course will take place at McGill University, Montreal, Monday September 11th to Saturday September 16th, inclusive. The course has been arranged for those sitting examinations and for General Practitioners engaged in the practice of Anaesthesia. Lectures on important aspects of Anaesthesia will be given from midday until 5:30 daily, each lasting, 30 minutes. The mornings may be spent either in clinical observation or as a study period in the Medical Library. The fee for the course is $35.00. Those interested should apply to Dr. R. G. B. Gilbert, Chairman of the Department of Anaes- thesia, McGill University, 3801 University Street, Montreal 2, when a programme and application blank will be forwarded. 01148395

I Vol. °fi•4 No. 2-} ADVERTISING SECTION DE$ITIN®O OINTMENT with HYDROCORTISONE [17°] anti-inflammatory, antipruritic hydrocortisone .... enhanced by time-tested soothing, healing Desitin Ointment formula .... controls pain, itching and inflamma- tion as it promotes healing in: eczematoid dermatitis (allergic, in- fantile, nummular, etc.), seborrheic dermatitis, anogenital pruritus, neuro- dermatitis, contact dermatitis (poison ivy, oak, sumac). formula of Desitin HC Oint- ment with Hydrocortisone: Hydrocortisone (alc.) 1%, Norwegian Cod Liver Oil (rich in unsaturated fatty acids and vitamins A and D), zinc oxide, talcum, petrola- tum, and lanolin. Applied 2 to 4 times daily. Supplied: in tubes of 1/2 oz. and 1 oz. Request samples on Rx blank or letterhead DESITIN CHEMICAL COMPANY 812 Branch Avenue, Providence 4, R. i. '° " NOTE: DESITIN OINTMENT, as such, is of course available as always. xxxv I

THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 Proven in over six years of clinical use and more than 750 published clinical studies Effective for relief of anxiety and tension Outstandingly Safe simple dosage schedule produces rapid, dependable tranquilization without unpredictable excitation no cumulative effects, thus no need for difficult dosage readjustments does not produce ataxia, change in appetite or libido does not produce depression, Parkinson-like symptoms, jaundice or agranulocytosis does not impair mental efficiency or normal behavior Miltown® meorobamate (Wallace) Usual dosage: One or two 400 mg. tablets t.i.d. Supplied: 400 mg. scored tablets, 200 mg. sugar-coated tablets; in bottles of 50. lllso supplied in sustained-release capsules... Meprospan® Available as Meprospan-400 (blue-topped sustained• release capsules containing 400 mg. meprobamate), and Meprospan-200 (yellow-topped sustained-release capsules containing 200 mg. meprobamate). ,WA1 0 WALLACE LABORATORIES / Cranbury, N. J. CM_q23•

Vol. 264 No. 24 ADVERTISING SECTION xxxvii ELECTROENCEPHALOGRAPHY (EEG) Records correlated by Neurologist 24-hour service available Beacon Center for Electroencephalography 350 Beacon St., Boston 16, Mass. KEnmore 6-1364 Jeanette Landau, Director WESTWOOD LODGE Incorporated WESTWOOD, MASSACHUSETTS Telephone NO 7-0168 For the study and treatment of nervous and emotional disorders. Homelike therapeutic atmosphere with modern treatment techniques. Intensive individual and group psychotherapy; biophysiological treatment methods (electro- shock, electrocoma, insulin stimulation, with- drawal treatment for addicts, carbon dioxide, etc. ); occupational, music and recreational therapy; tennis court. M. Brunner-Orne, M.D., Superintendent W. J. Hammond, Administrator a A. L. Clark, M.D., P.r)chiatrist S. M. Bunker, M.D., Psychiatrist WASHINGTONIAN HOSPITAL 41 MORTON STREET Jamaica Plain, Boston, Mass. MEDICAL AN D PSYCHIATRIC TREAT.IIENT CENTER For: ALCOIIOL AN D DRUG ADDICTS Male and Female Patients Night Hospitalization Available In-Patients and Out-Patients Service JOSEPH THIMANN, M.D. Executice and Medical Director JA 4-1540 - 1541 - 1542 NEEDED - YOUNG GENERAL PHYSICIAN by four-man group in growing rural program in West Virginia. Modern clinic facilities, regularly visiting specialist consultant staff, scheduled training and vacation periods, founda- tion sponsorship, no investment required. Starting net income range $14,000-$16,- 000 depending on qualifications. Address A349, New Eng. J. Med. 13-16t OPENING AN OFFICE? Largest display of examining and pediatric tables in Greater Boston area ($56 and up). One stop for all your office needs, exec- utive and secretarial desks and chairs, waiting-room seating, etc. Long-term financing available. Let us help you plan an efficient and attractive office. Consult our Office Planning and Decorating Service. Only 15 minutes from Downtown Boston via Southeast Expressway. Quincy Medical Supply Co., 13 School Street, Quincy, Massachusetts. GRanite 9-4440. B338-6-27t WANT A LOCUM TENENS? A full-time assistant professor (Board quali- fied in Internal Medicine) at a promi- nent northeastern medical school is studying various aspects of private prac- tice. Available for 2 to 4 week periods, June or July, in return for income plus use of your appointments and facilities. Address A317, New Eng. J. Med. 23-2t RADIOLOGIST, certified, available full or part time. Prefers New England. Address A411, New Eng. J. Med. 22-4t RESIDENT PHYSICIANS - 500- bed, general teaching hospital. New staff quarters including apartments for house staff with families (nominal charge). Sti- pends from $3,000 to $6,000 plus full single maintenance. Approved training programs in medicine, surgery, anesthesi- ology, pathology, radiology, psychiatry, chest and pediatrics. Several remaining openings in: Radiology, modern, well- equipped department, two full-time radi- ologists. $3,000-$3,600. Anesthesiology, two full-time anesthesiologists, five at- tendings. Optional university or hospi- tal affiliation. $3,000-$3,600. Medicine $3,000. Pathology, all fields of pathology including forensic medicine. $3,000-$4,- 8d0. Psychiatry, extensive teaching pro- gt'am, 6 full-time psychiatrists plus large, aetively participating attending staff. 126- t3ed remodeled facility. Active outpatient p,Fbgram. $4,200-$6,000. Apply: Director, GYasslands Hospital, Valhalla, New York. ~ B416-15-12t ORTHOPEDIC SURGEON WANT- ED. Well-established, expanding 20-man group located in excellent hospital. Board eligible or certified. Salary for two years, then partnership. Excellent professional situation. Address A324, New Eng. J. Med. 18-9t INTERNIST for expanding program of Upper New York State medical group. Address A236, New Eng. J. Med. 21-tf PEDIATRICIAN for expanding pedi- atric service in all-purpose, rural New York medical group. Address A220, New Eng. J. Med. 17-tf FOR SALE - Combination 9-room home and 5-room, fully-equipped, mod- ern, air-conditioned office. Centrally lo- cated. One mile from new 76-bed hos- pital. Excellent practice, established 15 years. Leaving to specialize. Telephone Palmer, Massachusetts, ATlas 3-3211. B396-13-tf WANTED - PEDIATRICIAN, cer- tified or Board eligible, to join a 2- member group in a medium-sized com- munity in southern New England. Area accessible to New York and New Haven academic centers. Address A417, New Eng. J. Med. 23-2t FOR SALE - Physician's home and office in Boston suburb. Excellent loca- tion and near all transportation. $27,500. Address A418, New Eng. J. Med. 23-2t WANTED - RECENT MODEL of binocular microscope. Telephone Boston Industrial Medical Center, COpley 7- 7272. B454-23-3t PRACTICE, OFFICE and HOME - Extremely active well-established general medical practice available due to ill- ness. Also excellent opportunity for pedi- atrician or obstetrician to serve South Shore area of approximately 15,000 popu- lation, only 30 minutes from Boston. Waiting room and spacious office with separate entrance. Six-month-old custom styled and tastefully decorated 3-bedroom tri-level home. Realistically priced at $27,900. Telephone B. W. Caswell at GRanite 2-5737. B478-23-2t WE BUY USED examining-room equipment. Examination tables, instru- ment cabinets, etc. Also office desks and swivel chairs. Quimsco, 13 School Street, Quincy, Massachusetts. GRanite 9-4440. B346-6-22t LENOX, MASSACHUSETTS - Fur- nished professional suite now available for rent. Prime location with private en- trance. Parking area. Waiting room, of- fice, large examining room, laboratory, and ceramic lavatory. Excellent oppor- tunity. Write Sammis & Burbank, 184 North Street, Pittsfield, Massachusetts. B479-23-4t IMMEDIATE OPENINGS available for full-time house staff physicians to serve in 200-bed municipal hospital. Salary $10,348 to $11,596 plus fringe benefits. Minimum tenure one year. Con- necticut license required. Contact Myron E. Freedman, M.D., Director of Medical Education, J. J. McCook Memorial Hos- pital, Hartford, Connecticut. B470-21-6t ANESTHESIOLOGIST - Board cer- tified or eligible for 170-bed J.C.A.H. approved Massachusetts hospital within I hour's drive of Boston. Fee-for-service basis. About 3,000 anesthesias adminis- tered per year. Good opportunity for 1 or more young men to establish practice. Address A412, New Eng. J. Med. 23-5t PEDIATRICIAN - Board certified or eligible. Opportunity in well-estab- lished twelve-man specialty group with own building, erected 1958. Near New York City in expanding suburban north shore Long Island town serving area of 100,000. Early partnership. Please fur- nish resume indicating training, experi- ence, military and marital status. Ad- dress A414, New Eng. J. Med. 23-2t PEDIATRIC RESIDENCY available July, 1961 or thereafter. University af- filiated general hospital in New England with full-time director of medical edu- cation, chief pediatric residency, and co- ordinator of pediatric education approved for 2 years' training. Good opportunity for the acquisition of practical and thed- retical knowledge necessary for certifica- tion and practice of pediatrics. Stipend plus maintenance allowance. Address A416, New Eng. J. Med. 23-3t YOUNG INTERNIST, Board quali- fied, wanted for association with Board internist, one hour from Boston. Growing hospital facilities and potential academic association make attractive future. Would consider one month locum tenens in July or August for trial by applicant. Ad- dress A413, New Eng. J. Med. 23-3t (Additional advertisements on pages xxxii and xlvi)

xxxvtrl mmo \\\Ew BOOK Announcement From YEAR BOOK MEDICAL PUBLISHERS Davenport's PHYSIOLOGY OF THE DIGESTIVE TRACT NEW - Here is a clear-cut description, excellently illustrated, of the function of the normal human digestive tract, showing first the mechanism available for propulsion and secretion, then demon- strating aliments in the process of being digested and absorbed with reference to how and to what extent the mechanism of motility, secretion and their control are actually used. By HORACE W. DAVENPORT, Ph.D., Professor and Chairman, Dept. of Physiology, University of Michigan. 224 pages; illustrated. MacFate's INTRODUCTION TO THE CLINICAL LABORATORY NEW - The physician who does his own laboratory work or has it performed by an office assistant will find Dr. MacFate's new book a quick and authoritative reference. It deals with essentials such as the equipping, setting up and care of the labora- tory; obtaining specimens from the patient; preserving specimens; systems of measurement; characteristics of principal blood com- ponents; common microorganisms and fungi, with related test procedures; discarding of specimens and dangerous chemicals; safety precautions and first aid procedures in laboratory accidents, etc. By ROBERT P. MACFATE, Ch.E., M.S., Ph.D., Chief, Divi- sion of Iaboratoriea, City of Chicago Board of Health. 450 pages; illustrated. $10.00. THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 in pso~iasis ~ J pmma benzene hexachloride widely prescribed clinically proven/cosmetically elegant "Psoriasis is, today, incurable, but, psoriasis can be a very manageable disease."1 In a recent study of 214 chronic psoriatics treated with ALPHOSYL "...every patient manifested some favorable response.r'1 Available: Bottles of 8 n. oz. 1. Welsh, A. L.: Report. Conference on the Management of Chronic Dermatoses, University of Cincinnati College of Medicine. Cincinnati, ohio, November 4•5, 1959. Available: Alphosyi Lotion in 8 oz. bottles. REED & CARNRI CK /A'enrtworth. New deraey *Kwel Barness' MANUAL OF PEDIATRIC PHYSICAL DIAGNOSIS NEW 2nd EDITION - Dr. Barness' revision includes new procedures, charts of normal growth rate and other modifications required to keep this highly instructive manual up to date. Here in concise, excellently organized presentation are the special tips, techniques and fine points necessary to a searching, miss-nothing physical examination of the pediatric patient - from head to toes. By LEWIS A. BARNESS, M.D., Associate Professor of Pediatrics, University of Pennsylvania Medical School. 208 pages; illustrated. ....................ORDER FORM.................... ~ YEAR BOOK MEDICAL PUBLISHERS Year Book Medical Publishers, Inc., 200 East Illinois Street, Chicago 11, III. Please send and bill subject to 10 days' examination E] Physiology of the Digestive ~ Introduction to the Clinical Tract, Ready in June Laboratory, $10.00 Q Pediatric Physical Diagnosis, Ready in June Name ............................................................... Street ...................................................... City .............................. Zone ..... State .................. N.E. 6-61 .:. .(HEAD AND PUBIC LICE) ~ K r X _. t~ I . _.i allantoin and special coal tar extract AVAILABLE: Bottles of 2 and 16 fI. oz. ~-= For External Use 0nly . ,... S e.. ~ „~~,- ..:. .. ......._ ..,-_. x ~.~~.. . v il allantoin/hexachlorophene/special coal tar extract CREAM AND SHAMPOO CLEARS SCALP SEBORRHEAS FROM CRADLE CAP TO DANDRUFF AVAILABLE: Sebical Cream and Shampoo 2 oz. tubes. 01148399

Parkinson's disease does not have to mean a retreat from living or reluctance to face family and friends. Treatment with "COGENTIN often causes a diminution or disappearance of the typical parkinsonian facies. It has the ability to control severe tremor and may control sialorrhea better than atropine."1 Severe rigidity, contractures, and frozen states also respond to COGENTIN.2 Its prolonged action permits 24-hour control of symptoms with one bedtime dose.3 Os148-100 Before prescribing or administering Coaexxtrr, the physician should consult the detailed information on use accompanying the package or available on request. S. upplied: Tablets COGENTIN (quarterscored), 2 mg., bottles of 100 and 1000. New dose form: Injection COGENTIN, 1 mg. per cc., ampuls of 2 cc., boxes of 6. References: 1. Finkel, M. J.: M. Times 86:1391, 1958. 2. Doshay, L. J., and Boshes, L.: Postgrad. Med. 27:602, 1960. 3. A. M. A. Council on Drugs: New and Nonofficial Drugs 1960, Philadelphia, J. B. Lippincott Company, 1960, p. 264. COGENTIN is a trademark of Merck & Co., Inc. M©D MERCK SHARP & DOHME Division of Merck & Co.. INC., West Point, Pa. : .~ ` V

Allergic orK- inflammalary f/are-up! .4-= Female, 41; Dx: dermatitis venenata. Contactant: calamine-antihistamine lotion applied for contact dermatitis-Rx Celestone Tablets, 0.6 mg. Photo- graph prior to Rx. Step•down dosage of 1 tab. q.i.d. for 2 days, I tab. t.i.d. for 2 days, I tab. b.i.d. for 2 days and 1 tab. daily for 8 days. Results: condition com- pletely cleared. Side Effects: none. Photograph after 72 hours of Celestone therapy. (Photographs courtesy of M. M. Nierman, M. D., Calumet City, III.)

Rapid remission with new Celestone the first major advance in corticosteroid therapy in over 21/2 years Clinical worth: CELESTONE provides greatly enhanced antiallergic and anti- inflammatory effects with significantly lower mg. dosages. Its efficacy and safety have been established by 20 months of pre-introductory clinical trials in such steroid-responsive disorders as: • bronchial asthma • pollenosis (severe hay fever) • allergic/ inflammatory dermatoses • inflammatory eye diseases • rheumatoid arthritis Exceptional utility: From simple derma- toses to the more severe steroid-responsive conditions, the unexcelled anti-inflamma- tory effect of CELESTONE provides rapid clinical improvement with average daily dosages of from 2 to 8 tablets. Ease of use: CELESTONE has simple-to- follow dosage schedules for all steroid- responsive disorders based on a single tablet strength, 0.6 mg. Patients may be switched easily from other corticosteroids to CELESTONE with proper dosage adjust- ments. Safety-speed factor: CELESTONE is partic- ularly valuable for short-term therapy of acute inflammatory episodes because in- flammation is resolved quickly, thus help- ing to avoid certain corticoid side effects such as: • weight loss • sodium and water • anorexia retention • vertigo • muscle weakness • severe headache • potassium excretion Improved response: CELESTONE also offers the advantage of providing an opportunity to restore "lost" or diminished control in patients receiving other steroids. For complete details, consult latest Schering literature available from your Schering Representative or the Medical Services Department, Schering Corporation, BloomTeld, New Jersey. Bibliography: 1. Goldman, L.: Investigation of a New Steroid in Dermatology. Paper presented at First Symposium on the Clinical Application of Betamethasone: A New Corticosteroid, New York City, May 8, 1961. 2. Nierman, M. AI.: The Use of Betamethasone in Dermatology. Ibid. 3. Gant, J. t2., and Gould, A. H.: Betamethasone: A Clinical Study. Ibid. 4. Frank, L.: The Place of Betamethasone in Dermatologic Practice. Ibid. 5. Hampton, S. F.: Betamethasone-A New Steroid in Allergy: A Preliminary Report. Ibid. 6. Bukantz, S. C.: Observations on the Use of Bctamethasone in the Intractable Asthmatic Child. Ibid. 7. Bedell, H.: A New Systemic Steroid in the Treatment of Allergies in Office Practice. Ibid. 8. Schwartz. E.: Clinical Evalu- ation of Betamethasone in Chronic Intractable Bronchial Asthma. Ibid. 9. Kammerer, W. H.: Observations on the Effects of Betamethasone in Rheumatoid Arthritis. Ibid. 10. Cohen, A., and Goldmn, J.: Management of Rheumatoid Arthritis with a New Steroid. Ibid. 11. Gordon, D. M.: Betamethasone-A New Corticosteroid in Ophthalmology. Ibid. 12. Abrahatnson, I. A., Jr.: A Clinical Evaluation of Betamethasone. Ibid. ..»t (5 N ~ ~ ~ ~ ~ (betamethasone) Tablets, 0.6 rng. N E~ONE

THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 "Outstanding Contrihution"1 in Cholangiography Rapid Optimal Opaci fication: Within 15 minutes, Cholografin outlines hepatic and common ducts even after cholecystec- tomy, reveals biliary ducts in about 25 minutes, and com- pletely opacifies the gallbladder within 21/2 hours." High Diagnostic Accuracy: Accuracy in diagnosing bile duct disease in postcholecystec- tomized patients is reported to be 86%.' In another series,' Cholografin permitted diagnos- tic interpretation in almost 70% of patients with chronic chole- cystitis. "With Little RiskfS No hepatic or renal toxicity, no delayed re- actions have been observed s Cholografin "is the method of choice"` for gallbladder visuali- zation in infants. ~ cholografiSodium/ Methylglueamine Duografin Squibb Diatrizoate and lodipamide Methylglucamines for rapid visualization of biliary and renal tracts in routine examinations or differential diagnosis Supply: Cholografin Methylglucarnine Squibb Iodipamide Methylglucamine Injection U.S.P. is sup- plied in 20 cc. sizes, with sufficient excess for sensitivity testing. Cholografin Sodium Squibb lodipamide Sodium Injection N.F. is supplied in cartons containing two 20 cc. ampuls with sufficient excess for sensitivity testing. Duograftn is supplied in bottles of 50 cc. For full information, see your Squibb Product Reference or Product Brief. References: (1) Cohn, E. M.: Am. J. Gastroenterol. 35:115 (Feb.) 1961. (2) Jones, hL D.; Sakai, H.; and Rogerson, A. G.: J. Pediat. 53:172 (Aug (3) Machella : Gastroenterology 34:1050 ) 1958 T E , . . . . (June) 1958. (4) Orloff, T. L.: Am. J. Roentgenol. 80:618 (Oct.) ~ SQ,UI88 . ~,....,~.,.,. ., , a,., , ,. .. . .,...s• Mil=_slarvVAm n •r 7 - r•. yueuu Vuuticr- 152:91 (July) 1960. (6) McClenahan, J. L.: Pennsylvania M. J. ~ o ' ~ ~ 62:100 (Feb.) 1959. 'CMOLOORAIIN•®ANO'GUOORAfIN'®AMElCUI9lTRADEMANRt. (./t•ePr2Cetess(rt.grQ(dlent

Vol. 264 No. 24 ADVERTISING SECTION xliii in Ob-Gyn practice: prevent bacterial insult to traumatized cervicovaginal tissue FURACI brand of nitrofurazone a safe, single agent with singular benefits From a recent study reporting the lowered inci- dence of postoperative morbidity following the use of FURACIN Vaginal Suppositories in operative gynecology-"Certainly a single agent is to be pre- ferred to a combination of agents, providing com- parable results are obtained:'• L. ® Used beJore and after cervicovaginal surgery, de- livery, radiation therapy and certain office proce- dures, FuRACtN controls infection, hastens healing, reduces discharge, malodor and discomfort. FURACIN VAGINAL SUPPOSITORIES: FURACIN 0.3% in a water-miscible base. Box of 12, each 2 Gm. suppository hermetically sealed in yellow foil. FURACIN CREAM: FURACIN 0.2°,>o in a water-miscible cream base. Tube of 3 oz. with plastic plunger-type applicator. •Crimea, H. G.,.nd Geiger, C.1.: Am. J.Obe.. & Gynec. 79:4t1, 1960. EATON LABORATORIES Division of The Norwich Pharmacal Company NORWICH, NEW YORK ~

ROCHr--:; LABORATORIES a = Division of HoBmann-La Roche Inc. Assure balanced nutritional support from the very first days of life with W-PENTA DROPS-- dependable vitamin formu/ations:.

5-year study' with LU?LJDThT demonstrates: long-term anticoagulation in office management of outpatients is practical and effective A 5-year study' of long-term anticoagulation with COUMADIN (warfarin sodium) in office practice patients has demonstrated that such treatment reduces the prob- ability of further infarctions in the postinfarct patient and is effective in preventing a first infarction in patients with angina. An earlier report2 noted that long-term anticoagulant therapy with warfarin sodium can be carried out, along with the necessary prothrombin time determinations, as part of general office practice. "The most significant advantage is the great ease in maintaining patients in a therapeutic range. It has been rewarding to find, month after month, patients varying no more than three or four seconds in their prothrombin times on their established dosage of Warfarin sodium [COUMADIN ]."1 T ® the original and only warfarin responsible for establish- ing this drug as closely approaching the ideal anti- coagulant3.4 and as "the best anticoagulant available W--,~ FOR ORAL, INTRAVENOUS OR INTRAMUSCULAR USE today.rrsOver179,000,000dosesadministeredtodate. the -proven anticoagulan t for long-term maintenance Full range of oral and parenteral dosage forms-COUMADiN* (warfarin sodium) is available as: Scored tablets-2 mg., lavender; 5 mg., peach; 71/2 mg., yellow; 10 mg., white; 25 mg., red. Single Injection Units-one vial, 50 mg., and one 2 cc. ampul Water for Injection; one vial, 75 mg., and one 3 cc. ampul Water for Injection. Average Dose: Initial, 40-60 mg. For elderly and/or debili- tated patients, 20-30 mg. Maintenance, 5-10 mg. daily, or as indicated by prothrombin time determinations. 1. Nora, J. J.: M. Times, May, 1961. 2. Nora, J. J.: J.A.M.A. 174:118, Sept. 10, 1960. 3. Baer, S., et al.: J.A.M.A. 187:704, June 7, 1958. 4. Moser, K. M.: Dis- ease-a-Month, Chicago, Yr. Bk. Pub., Mar., 1960, p. 13. S. Meyer, O. 0.: Postgrad. Med. 24:110, Aug., 1958. 'Manufactured under license from the Wisconein Alumni Research Foundation Complete Information and Reprints on Request ~. ENDO LABORATORIES Richmond Hill 18, New York

xlvi THE NEW ENGLAND JOURNAL OF MEDICINE WANTED - Pathologist, Board certi- fied. Large, general hospital eleven miles from George Washington Bridge. Excel- lent equipment. Clinical and research fa- cilities. Approved residency program. Ap- proved school for medical technologists. Salary open. Apply: Rufus R. Little. M.D., Superintendent, Bergen Pine County Hospital, Paramus, New Jersey. B429-16-eow-5t NORTH WEYMOUTH - 3-room office suite, furnished for physician, now available. Call PResident 3-6256. B331-5-tf DOCTOR, ARE YOU looking for a medical secretary, technician, or office nurse? We provide thoroughly screened applicants at no cost to you. For courte- ous confidential service, telephone RIch- mond 2-0130, Massachusetts Medical Bureau, Boston, Massachusetts. B452-19-6t CARDIOLOGIST-INTERNIST, uni- versity trained, with extensive catheter- ization experience, currently practicing adult and pediatric cardiology desires po- sition or practice opportunity. Address A405, New Eng. J. Med. 22-tf PEDIATRICIAN, Board eligible, avail- able in July, seeks association with pedi- atrician in suburban community near New York. Address A419, New Eng. J. Med. 23-3t OBSTETRICIAN - GYNECOLOGIST to join active obstetrics-gynecology serv- ice of medical group in mid-eastern New York State ; expanding, decentralized program with academic environment fea- tured. Address A219, New Eng. 1. Med. 17-tf TISSUE TECHNICIAN, excellent training, male, married, wants to locate in New England area. Please write to George Meimaridis, 12 Day Street, Cambridge 40, Massachusetts. B475-22-4t GENERAL PRACTITIONER to join private clinic in Cambridge, Massachu- setts. City practice. Address A102, New Eng. J. Med. 19-tf WANTED - FAMILY DOCTOR. Wonderful opportunity to leave conven- tional drudgery and accept challenge is offered by ambitious clinic in Colorado to family doctor with special interests in obstetrics and anesthesia. Address A404, New Eng. J. Med. 22-eow-2t MEDICAL MANAGEMENT - Sal- ary $1,000 per month. Ample fringe benefits. Desirous of obtaining American medical graduates who have completed their internships to provide medical management in a 248-bed general hos- pital in Chicago, Illinois. Good variety _-of clinical material. Contact Brother Dominic, C.F.A., Administrator, Al- exian Brothers Hospital, 1200 West Be]- den Avenue, Chicago 14, Illinois. Tele- ••phone Dlversey 8-6500. B485-24-1t ~ PEDIATRICIAN - Board certified „or eligible, to associate with pediatrician in 13-man medical group in Monadnock area. Apply: Keene Clinic, Keene, New Hampshire. B492-24-2t INTERNIST - University trained, Board certified. Active division of well- established group of specialists in resi- dential suburb of Detroit. Excellent op- portunity for teaching and research avail- able. Close association with completely- equipped modern hospital. Starting salary, $20,000 and up. Opportunity for partnership without investment. Forward complete resume to address A409, New Eng. J. Med. 22-e3w-3t MEDICAL DIRECTOR - Certified internist, also certified in a subspecialty, desires position as medical director in field of occupational medicine or insur- ance medicine. Trained at Mayo Clinic and in university. Background includes clinical investigation. Experience includes private practice. Address A421, New Eng. J. Med. 24-3t WANTED - GENERAL PRACTI- TIONER, Board certified otolaryngolo- gist and obstetrician-gynecologist. Es- tablished 12-man clinic in northern West Virginia near University Medical Center. No investments, excellent income, incre- ments and fringe benefits. Address A423. New Eng. J. Med. 24-1t WANTED - INTERNIST, Board cer- tified or eligible, to associate with busy general practitioner and surgeon in New Hampshire town serving recreational area of 25,000. New hospital under construc- tion. No full-time internist in town. Must be willing to do some general prac- tice. State full particulars in reply. Ad- dress A425, New Eng. J. Med. 24-3t INTERNIST WANTED for immedi- ate opening. Model rural medical center; Maine coast. Excellent university hospi- tal background, Board qualifications, and desire to combine teaching-level medicine with country living, mandatory. Special interest in malignancy and blood dis- eases desirable. Full-time staff, unusual benefits. Please send complete personal and professional data initial communica- tion. Address A426, New Eng. J. Med. 24-3t AVAILABLE FELLOWSHIP in pul- monary diseases. Medical school ap- pointment in Boston, Massachusetts, in- cludes pulmonary physiology research, clinical work, and teaching. Maurice S. Segal, M.D., Department T, Boston City Hospital, Boston 18, Massachusetts. B484-24-3 t INTERNIST WANTED to take over busy practice in Caribou, Maine. Well- equipped office available immediately in clinic building adjacent to accredited hospital. Will lend equipment to occu- pant. Nothing to purchase. Excellent opportunity. Contact, H. D. Warren, M.D., 27 North Main Street, Caribou, Maine or call GY 6-5161. B480-23-2t PATHOLOGY RESIDENCY - 1 or 2 years starting July 1, 1961. 260-bed hospital, 25 miles from Boston. Graduate of United States or Canadian school, or E.C.F.M.G. qualified. Stipend $250 per month plus room and board. Contact Head of Pathology Department, Brock- ton Hospital, Brockton, Massachusetts. B465-24-2t June 15, 1961 WANTED - RESEARCH PHYSI- CIAN with clinical facilities to test new phenobarbital drug which is free from side effects. Financial honorarium available. Write to Frederic Damrau, M. D., 2 Tudor City Place, New York 17, N. Y. B486-24-1 t WANTED - DIETITIAN, prefera- bly registered, or at least well qualified to handle 272-bed general hospital. Sal- ary at least $25 to $30 per day with room and board. Beautiful nurses' home with all private rooms nicely furnished. Re- sponsible for preparing menus and spe- cial diets and supervising personnel in entire department. Purchasing is done through full-time purchasing agent. Write giving full qualifications to Dover General Hospital, Jardine Street, Dover, New Jersey, c/o C. T. Barker, Director. B488-24-3t WANTED - Supervisory psychiatrist ($11,856 to $14,300 ) , senior physicians ($11,440 to $13,780), for progressive program for mentally retarded and men- tally ill children. Imaginative, industrious physicians, who must be interested in clinical or basic research and who wish to make a personal contribution in a lib- eral atmosphere, should write for details to Personnel OfFice, Pineland Hospital & Training Center, Box C, Pownal, Maine. B490-24-4t URGENTLY NEEDED - A general practitioner for the Woodsville (New Hampshire)-Wells River (Vermont) area. New hospital facilities available in the community. Address inquiries to Harry M. Rowe, M. D., Wells River, Vermont. B491-24-1 t PATHOLOGIST - Age 40, certified P.A.O.C.P., seeks position in community hospital, Northeast, semirural. Address A424, New Eng. J. Med. 24-4t POSITIONS AVAILABLE for quali- fied physicians in psychiatric and medical services of a 1700-bed psychiatric hospi- tal located in New York State's beautiful Finger Lakes region. Requirements: li- censure in any state; age, not over 60. Salary range, $10,635-$13,730 plus 15% if certified by an American Specialty Board. Excellent fringe benefits. Write Manager, Veterans Administration Hos- pital, Canandaigua, New York. B493-24-6t MEDICAL OFFICES - Just two suites for doctors left in new professional building on main street in Lexington, Massachusetts, with plenty of off-street parking. Telephone VOlunteer 2-2721 or VOlunteer 2-1539. B483-24-2t PHYSICIAN, starting medical resi- dency in one of Boston's hospitals in July 1961 after three years of Navy general and industrial medicine, desires part- time position to supplement income. Ad- dress A420, New Eng. J. Med. 24-2t ORTHOPEDIC SURGEON to head seven-man department in large hospital based group. Partnership in three years. Address A422, Nezu Eng. J. Med. 24-4t (Additional advertisements on pages xxxii and xxxvii) 01148407

Vol. 264 No. 24 ADVERTISING SECTION menstrual irregularity... just "functional"? ... or another case of hidden hypothyroidism? Menstrual irregularity is often the chief complaint - sometimes the only complaint -of the patient with mild hypothyroidism. Although the clinical picture in such cases is frequently unclear, and the results of diagnostic tests are often inconclusive, many of these patients respond well to a therapeutic trial of Proloid. Proloid- preferred therapy whenever thyroid is indicated- establishes and maintains a euthyroid state safely and smoothly. An exclusive double assay assures unvarying metabolic potency from tablet to tablet, from prescription to prescription, year after year. Full dosage information, available on request, should be consulted before initiating therapy. predictable; safe economical• makers of Tedrat Gelusil Peritrate Mandelamine. m xlvii '1 (. ,,,

xlviii AS IN THIS CASE:" Fundus of 62-year-old female who has THE NEW ENGLAND JOURNAL OF MEDICINE June 15, 1961 When blood pressure must come down had severe hypertension for ", many years. Photo shows effect of ~~ pressure at a-v crossings and various types of hemorrhage.  When you see eyeground changes like this- with such hypertensive symptoms as dizziness and headache-your patient is a candidate for Serpasil- Apresoline. With this combination the antihyper- tensive action of Serpasil complements that of Apresoline to bring blood pressure down to near- normal levels in many cases. Side effects can be reduced to a minimum, since Apresoline is effec- tive in lower dosage when given with Serpasil.  "Hydralazine [Apresoline] in daily doses of 300 mg. or less, when combined with reserpine, produced a significant hypotensive effect in a large majority of our patients with fixed hypertension of over three years' duration."2 Complete information sent on request. REFERENCES: 1. Bedell, A. J.: Clin. Symposia 9:135 (Sept.-Oct.) 1957. 2. Lee, R. E., Seligman, A. M., Goebel, D., Fulton, L. A., and Clark, M. A.: Ann. Int. Med. 44:456 (March) 1956. suPPUED: Tablets #2 (standard-strength), each containing 0.2 mg. Serpasil and 50 mg. Apresoline hydrochloride. Tablets #1 (half-strength), each containing 0.1 mg. Serp.asil and 25 mg. Apresoline hydrochloride. / -2 MK ^(I ~~ Z ' ~ hydrochloride (reserpine and hydralazine hydrochloride CIBA)

4 Vol. 264 No. 24 ADVERTISING SECTION Diagnosis: Sinusitis ..-iy I_j C' J j ,3r. THE SUPERIOR SYSTEMIC ANTI•INFLAMMATORY ENZYME What now? for one thing to control in;7un1,mation, swelling and oain in SINUSITIS, :=;ST;,'i1v1A, ocl.;i_tr in- i3n]n7utlon, C;ilur fraUn)d In rhinitis, sinusitiS and asthma, breathing is improved and mucus more easily expelled from clogged passages when Chymar is used to thin secretions. Patients have been able to discontinue use of nose drops, antihistamines and corticosteroids completely. Others have been able to breathe normally for the first time in years.' Chymar hastens the absorption of blood in traumatized tissues and shortens the course of ophthalmic inflammation.2 Twenty-four hours will often see a vast improvement in ocular trauma and inflammation when Chymar is used as soon as possible.3 ~ r S 1. Parsons, D. J.: Clin. Med. 5:1491, 1958. the systemic route to ~ 2. Fullgrabe, E. A.: Ann. New York Acad. /aster ~ Sc. 68:193, 1957. 3. Jenkins, B. H.: J.M.A. healing at Georgia 45:431, 1958. any location ARMOUR PHARMACEUTICAL COMPANY KANKAKEE, ILLINOIS • A Leader in Biochemiral Research .......................CHYMAR . .......... Chymar Aqueous and Chymr (rn oll) contain crystallized cNamotreps,n, a proleda4 enzyme with systemic anti-inflammatory properhn. Each [[ Of Ch.mar contLns SJ00 Armour Units of chymotrypsin, 0.18% methyl paraben- 00:"; proDat pu+un 1 aluminum monpslearate. Q.s. sesame od. Eaah « of Chemar Aoueovs conla.ns 5:(A Armour Units of chymolrypsin, 0.9 e sodium ahlorrde. 0 i ; uk•um aae!ate. C'-1 ; thimerosal, O.s. Water for Iniecbon. ACTION: Reduces rnEammatcn of a n f,cw rrucn and prevents edema eecept that Of Cardrac or renal or,g,n. hastens absGrpl on of cbod and lymph ealnvasaln: helps to liquefy tb-cY tenacwus mucon saret ons rntan localcirculation;promolnneabnt.reducnwrn INDICATIOhS CnrmaraIna<ated.n rnpiratory conddrons such as asthma. broncndn. s,nusd,s and rn,n.bs ,n arr.Cenlal Irauma ta speed relluctronof hemalomas.brwsnaedcentus.ons -nnamma!nrr, ^er-.a- Iosntoamelrprateacuternflammat,En,nconluntlGnw,InstJndardlhffap- narne(olueccond,hons thenpeutrca0y of m conrunetan .,tn anl,bal<s in pel.K ,nrammatory Ouease: in sur¢ral procedures as biopvn. 6 I suraery, nernq repa~n nemorrr•o,dec- lomin, plastK surgery And Ihrombophlep.tn in pe01K YkerS a1d u/.fr)Lre <Whi ai an adluncttod.el.antrswsmOdKS.antaUns.etc inaenl0arnar.asoraersatepm~dyn'~ts, Urcnit-s and proslablrs. ,n e1e cunc-tans as acul. conruncl.ta. luumat4 edema, hematomas. and eye surgery, in dental and oul sur¢ery as Iraclures Of Ine mandible maadU. alveo4clomies. d<nure hlhna. a'd mWripre e.tracFonsi and in obstebics as in epi siolom~n, preast enlor¢emenl, and tnromppDhrep~t~s PRECAUTIONS: Chyrnar andChsmarAOueousaretor,nlramuKUrar,nlNt~Dnonly Altnou¢hsensitrvitylochymD- Irypsrn is uncommon, reactions to antr-rnllammlGry ent,mn nAvr beerl observed. The usual remedHl agenls eprnephrrne. conccotroprn RP• ACTHAR GeL. anthrslamine, ammDphylhne, elc i should be readily a.L4bte in case of untoward rea[trons Precau- bons -seralch testing fpr CAymar in pJ.. scnlch or mhadermal testing lor Chymar AOUeous~ should be eaerused in Inoie paUenls wdn known or susDected allerg,es or sensrUvrlres. As wilh any farergn prptNn, palienls may develop sensitivity from repealed rnleclrpns. It is. therefore, lKommended that Ihe abpve precautrons be considered prior to administralron. In lurlher treatmenl of those pat,enls in whom a previous •n- leclron of chymotrypsin produced signs of possible sensrtivrly. such as localized edema and erythema at rnlec0on sdes ur6carral conjunctrvrtrs, etc . parl,cular care must be esercised. INCOMPATIBILITIES: With usual agents, none knawn-eg, compatible with antibiotics and anesthelics. DOSAGE: 0.5 cc, to 10 ccc deep intramuscularly once or twice daily, depending on severity of condrtion. Decrease frequency as course Of condition is allered. In chronic or recurrent condit,ons. 0.5 ccc to 1.0 cc. once or twice weekly. SUPPLIED: Chymar in Oil 5 cc. vials and Chymar Aqueous 1 and 5 ccc vuls:5000 Armour Units of prpteolytic aclnrty per cc. •Highly Purified. 0 May, 1961, A.P. Co.

June 15, 1961 Weight problem? Start the reducing program right, .keep it going right with Esidrix° F Esidrix-Ke Recent studies show that the diuretic action of Esidrix improves results of weight-reducing programs 2 ways: 1. As an adjuvant in initiating treatment: Esidrix induces greater weight losses in the first few days than a conventional regimen.' This weight loss may be signifi- cant in itself (depending on the degree of fluid retention). But more than that, the quick loss of even a few pounds builds confidence in the weight-reducing pro- gram, inspires determination to follow it faithfully. 2. As an adjuvant in maintenance treat- ment: Esidrix eliminates retained water- with consequent weight losses-to break through the weight plateaus so often en- countered in antiobesity programs. (See schematic graph below.) The new weight loss cheers the patient and helps over- come his tendency to eat too much. (Adapted from Einhorn and Kalb1) Esidrix` (hydrochiorothiazide cIBA) Photograph used with patient's permission. For complete information about Esidrix and Esidrix-K (including dosage, side effects, and cautions), see Physicians' Desk Refer- ence, or write CIBA, Summit, N. J. Referenees: 1. Ray. R. E: To be published. 2. Ein• horn, H. P., and Kalb, S. W.: Clin. Med. 7:1995 (Oct.) 1960. Supplied: EsIDRIx Tablets, 25 mg. (pink, scored) and 50 mg. (yellow, scored). EsIDRIx-K Tablets 25/500 (white, coated), each containing 25 mg. Esidrix and 500 mg. potassium chloride. NEW STRENGTH ESIDRIX-K NOW AVAILABLE: ESIDRIX-K Tablets 50/1000 (white, coated), each containing 50 mg. Esidrix and 1000 mg. potassium chloride. 01148411 2f2921 MR., C 1 13 A SUMMIT-NEW JERSEY

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