Letter: Bone-marrow aspiration and biopsy.

COMMENTS AND CORRECTION

Comments submitted for publication must be typed doublespaced, and text length must not exceed 500 words. Complete references must be furnished, as specified in "Information for Authors" (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: we give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style. Internists, Primary Care, and Subspecialization TO THE EDITOR: While identifying problem areas in the provision of medical manpower, and dwelling at length on the problem of overspecialization, incredibly Dr. Petersdorf proceeds to endorse overspecialization in internal medicine (1). He states that "the medical consultant of the future will not be the general internist but the subspecialist" and suggests that "restructuring" of training programs will prepare the general internist for a role in primary care. In fact, many consultations can be effectively rendered by any well-trained, skilled, general internist. Most patients requiring medical consultation do not require the very special skills of procedural cardiologists and the like. However, skills unused cannot be long maintained and perhaps should not have been acquired. Undue involvement in primary care by the internist represents a further example of overspecialization and is quickly followed by erosion of consultant skills. As endorsed by the American Board of Internal Medicine, the present trend to train internists for primary care may well lead to a lack of consultant internists, whose replacement by subspecialists will simply aggravate the maldistribution of physicians in the U.S., through overspecialization ( 2 ) .

cal care could be avoided "if the specialist can maintain a reasonable degree of knowledge and skills in general medicine, and, more importantly, if specialists can be organized into groups"; he went on to say "the scope of medical science has long since passed the point where a single doctor could hope to encompass it all." Unfortunately, many medical residents have observed expert subspecialists with surprising weaknesses even in general medicine. Engstrom went so far as to warn against a faculty in medicine entirely composed of secondary physicians "who have a large protective buffer of house staff." It is possible that the medical knowledge explosion has reached the point that academic subspecialists can no longer afford to devote adequate time to keeping up in general medicine. In fact, Dr. Braunwald (3) sees an end to the "schizophrenic functions" of medicine and pediatric departments: that of general and specialty services. He believes that divisions of primary care and secondary or specialty care are likely to emerge. This implies loss of any primary functions of subspecialists and would force drastic changes in present medical training programs. As a medical intern attempting to decide on a career, I find the status of subspecialties confusing. Is subspecialty training meant to complement general medical practice or supersede it? Will it be possible to be a competent subspecialist and yet deliver effective primary care? Will subspecialty training be required for a career in academic medicine or a desirable group practice? In 1984, will one need to be a hematologist to perform legally a bonemarrow aspiration? Answers to these questions and meaningful delineation of the goals and purposes of subspecialty training are needed before intelligent decisions on the control of these programs can be made. CHRISTOPHER Y. THOMAS IV, MD

University of Cincinnati Medical Center Cincinnati, Ohio 45219

GERALD E. SINCLAIR, M.D.

Department of Medicine University of Saskatchewan Regina, Saskatchewan, S4S 5W9 Canada REFERENCES

1. PETERSDORF RG: Health manpower: numbers, distribution, quality. Ann Intern Med 82:694-701, 1975

REFERENCES

1. ENGSTROM W: Residency training in internal medicine, for what; subspecialty boards, what for? Ann Intern Med 70:621-633, 1969 2. ELKINTON JR: On the making and use of physicians (editorial). Ann Intern Med 70:635-638, 1969 3. BRAUNWALD E: Future shock in academic medicine. N Engl J Med 286:1031-1035, 1972

2. AMERICAN BOARD OF INTERNAL MEDICINE: Training and certify-

ing the internist for primary care. Ann Intern Med 82:707-708, 1975

TO THE EDITOR: Dr. Petersdorf suggests in his recent paper (Ann Intern Med 82:694-701, 1975) that too many internists are trained or are being trained in the subspecialties at the expense of the general internist pool. Perhaps this need not be the case. Dr. Engstrom (1) has stated "a subspecialty in medicine should be looked on as a professional 'hobby' and should be superimposed on general internal medicine." Dr. Elkinton (2) pointed out in an editorial that fragmented medi278

Nurse Practitioners TO THE EDITOR: As recent graduates of a medical school whose affiliated hospitals are involved in the training and employment of nurse practitioners in the clinics and emergency rooms, we have had the opportunity to observe and work along with many nurse practitioners. Thus, we read with great interest the article by Dr. Bates (Ann Intern Med 82:702-706, 1975). She accurately describes the problems of transition from performing routine nursing duties to participating in the diagnostic and therapeutic process. We take issue, how-

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ever, with several points. We do not believe that the nurse practitioner has an edge over the house officer in the common problems of primary care. Although nurse practitioners receive some formal classroom and clinical training, this should not be compared with the more extensive theoretical and clinical education that a physician receives during medical school and residency. To equate these two levels of education is to imply that the years of formal medical education are superfluous. It is inaccurate to state that house officers are not interested in "the mundane problems of chronically ill people." The great interest in, and competition for, primary care and family practice residency programs indicate that this is not the case. Our observation has been that interns and residents are able to care for more patients in a given clinic period than nurse practitioners. By virtue of their more extensive medical background they are not limited by the confines of protocols and, therefore, can order necessary diagnostic procedures more selectively. When these procedures are completed, residents are better prepared to interpret and act from the results. Nurse practitioners are used mainly in clinics where the patients, mostly of lower socioeconomic status, have little or no choice as to whether their care will be provided by a nurse practitioner or a physician. We wonder whether this is equitable. Funds currently earmarked for training and employing nurse practitioners might be better used to expand programs for physicians interested in primary care.

posed to rectal paraldehyde in the initial management of these patients. After induction of a calm state the patients required an average of 155 mg of diazepam and only 67 ml of paraldehyde. Although the specific data are not included in the article, the frequency of administered doses of diazepam required for maintenance appears to have been much greater than that required for paraldehyde. The protocol for diazepam stated that 5 to 10 mg be given intramuscularly at intervals of 1 to 4 hours as needed. This would suggest that the average total number of doses of diazepam given for maintenance of a calm state was somewhere between 15 and 30 doses. On the other hand, the protocol of 5 to 10 ml of rectal paraldehyde suggests the average total number of doses to be between 7 and 12 for maintenance. Since the overall duration of delirium tremens was virtually the same in all groups (56 hours), the frequency of "needed" doses of diazepam during maintenance may have been as much as 2 to 4 times greater than needed doses of paraldehyde. Thus rectal paraldehyde may give a smoother (that is, less picket-fence-like) response than parenteral diazepam when given by the dosage regimens described. Possibly optimal therapy for this condition might be obtained by a regimen of parenteral diazepam for induction and early maintenance, followed by rectal paraldehyde alone for the later maintenance period. MICHAEL C. RUDDY, M.D.

Department of Medicine Rutgers Medical School Piscataway, New Jersey 08854

LEWIS J. RUBIN, M.D.

Department of Medicine Duke University Medical Center Durham, North Carolina 27706

In comment: ROBERT S. KATZ, M.D.

Department of Medicine The Medical College of Virginia Richmond, Virginia 23219 Osteopaths Are Physicians TO THE EDITOR: The editorial "Federal Recognition of Chiropractic: A Double Standard" in the May issue (Ann Intern Med 82:712-713) mentions "The bringing together in one room of 11 Ph.D.'s, 7 osteopaths, 16 chiropractors, and 24 physicians." This seems to imply that osteopaths are not physicians. On the contrary, graduates of osteopathic medical schools deliver complete health care, both as primary physicians and in the medical and surgical specialties and subspecialties. Many osteopathic physicians are trained in AMA-approved postgraduate training programs. GARY C. GARFIELD, D.O.

59 East Park Street East Orange, New Jersey 07017

Dr. Ruddy's observations are quite correct. During maintenance of a calm state in delirium tremens our patients received an average of 9.8 doses of paraldehyde or 17.7 doses of diazepam. If diazepam had a shorter duration of action in these patients than paraldehyde, then equipotent diazepam doses would be required more frequently to achieve the same degree of oscillation. Alternatively, if the duration of actions of diazepam and paraldehyde were equal, giving smaller doses of diazepam more frequently would reduce the oscillation of effect. Unfortunately, neither our observations nor our review of the literature has provided a comparison of the duration of action of these sedatives during ethanol withdrawal. Maintenance of a calm state was accomplished easily with either drug in most patients. Undesired oscillation of effect was observed in two paraldehyde-treated patients and in three receiving diazepam who were given initially inadequate maintenance doses and required later larger doses to reestablish satisfactory sedation. We do not believe our results show a difference in efficacy between diazepam and paraldehyde in the maintenance of sedation after initial calming of the patient with delirium tremens. W. LEIGH THOMPSON, M.D., PH.D.

Diazepam or Paraldehyde for Delirium Tremens TO THE EDITOR: I read with great interest the recent study by Thompson, Johnson, Maddrey, et al (Ann Intern Med 82:175-180, 1975) of the treatment of delirium tremens by diazepam or paraldehyde. This study clearly shows the superior efficacy and safety of parenteral diazepam as op-

Department of Medicine Division of Clinical Pharmacology University Hospitals Cleveland, Ohio 44106 W I L L I S C. MADDREY, M.D.

Department of Medicine The Johns Hopkins University Baltimore, Maryland 21205 Comments


279

Echocardiography in Endocarditis and Aortic Regurgitation TO THE EDITOR: I enjoyed the excellent paper by DeMaria, King, Sale, et al, "Echography and Phonography of Acute Aortic Regurgitation in Bacterial Endocarditis" (Ann Intern Med 82:329-335, 1975). In Figure 4 of that paper, an echocardiogram shows thick diastolic echoes, supposedly representing aortic valve vegetations. These echoes viewed with their connecting systolic echoes appear very similar to a thickened anterior leaflet of the mitral valve. Such an effect can be produced if the transducer is directed midway between the mitral valve and the aortic root. The authors did not show an echocardiogram of the mitral valve from this patient (Patient 2) for comparison. Can the authors resolve this question? MARTIN JEFFREY FRANK, M.D.

Cardiology Department of Medicine George Washington University Medical Center Washington, D.C. 20005 In response: We thank Dr. Frank for his interest in our paper. The ability to scan from one cardiovascular structure to another by means of altering the angulation of the echographic transducer provides an excellent mechanism by which to identify cardiac anatomy. Figure 1 illustrates such an echo scan from the area of the mitral valve on the left, to the area of the aorta and the aortic leaflets on the right, in patients from our study. This echo illustrates both the anterior mitral leaflet with its fluttering motion and the aortic leaflets with the previously described vegetations. Thus this echographic scan renders it certain that the thick diastolic echoes noted in the previous echocardiogram actually were vegetations emanating from the aortic valve leaflets. ANTHONY N. DEMARIA, M.D. DEAN T. MASON, M.D.

Sacramento Medical Center University of California, Davis Sacramento, California 95817

with antacids because absorption of the anticholinergic is reduced. . . ." This remark was not referenced, which led to our investigating the clinical significance of this drug interaction. Dotevall and Walan (2) studied the effect of 1-hyoscyamine on duration of antacid action. Antacid administration alone produced a duration of pH — 3 for 28.9 ± 6 . 1 minutes, while concomitant dosing with the anticholinergic increased this pH limit to 71.1 ± 12.0 minutes (P < 0.01). Morrissey and associates ( 3 ) , using a gastrocamera procedure, found prolonged duration of antacid coating of the gastric mucosa after administration of 0.6 mg of atropine. In a 1971 review of peptic ulcer therapy by The Medical Letter on Drugs and Therapeutics ( 4 ) , it was concluded that the administration of an anticholinergic prior to an antacid produces an increased duration of antacid activity. Morrissey and Barreras (5) in their review of duodenal ulcer therapy recommend adding anticholinergics at bedtime if antacid therapy alone fails to control symptoms. In addition, we reveiwed a number of publications listing adverse drug interactions (6-9) and in no case was an interaction between antacids and anticholinergics listed. We agree that administration of an anticholinergic should precede antacid dosing. Lest the above statement by Littman and Pine be misinterpreted, we must conclude that anticholinergics and antacids may be used together, especially in cases refractory to antacid therapy alone. The physical incompatibility of these agents, in our opinion, has not been clinically proved. ROBERT C. BARGER, M.S., R.PH. JOHN F. MITCHELL, PHARM.D. Drug Information Service Providence Hospital Southfield, Michigan 48075 REFERENCES 1. LITTMAN A, PINE BH: Antacids and anticholinergic drugs. Ann Intern Med 82:544-551, 1975 2. DOTEVALL G, WALAN A: Antacids in the treatment of peptic ulcer. Acta Med Scand 182:529-537, 1967 3. MORRISSEY JF, HONDA T, TANAKA Y, et al: Gastric mucosal coating and gastric emptying time of antacids. Arch Intern Med 119: 510-517, 1967 4. Antacid therapy for peptic ulcer. Med Lett Drugs Ther 13:9396, 1971 5. MORRISSEY JF, BARRERAS RF: Drug therapy: antacid therapy. N Engl J Med 290:550-554, 1974 6. Adverse interactions of drugs. Med Lett Drugs Ther 15:77-80, 1973 7. AVERY GS: Check-list to potential clinically important interactions. Drugs 5:187-211, 1973 8. Evaluations of Drug Interactions, 1st ed. Wash., D.C, American Pharmaceutical Association, 1973 9. HANSTEN PD: Drug Interactions, 2nd ed. Philadelphia, Lea & Febiger, 1973

In comment: Figure 1. Echocardiographic scan from the area of the mitral valve (left) to that of the aorta and aortic leaflet (right): see text for explanation.

Antacids and Anticholinergics TO THE EDITOR: In their recent paper, Littman and Pine (1) stated that "anticholinergics should not be combined 280

We emphasized that full doses of an anticholinergic drug should be added to an antacid regimen for peptic ulcer "when there are clinical reasons for trying to get maximum neutralization of acid . . ." and when there are no contraindications. We said that anticholinergics should not be given combined with antacids and gave a number of reasons. Perhaps we should have made more clear that it is simultaneous administration we object to. As we pointed



out, there has n o t been m u c h investigation of the effect o n absorption, b u t t h e i n f o r m a t i o n that does exist justifies concern. As an example, G r o t e a n d W o o d s ( 1 ) selected single oral doses of atropine sulfate, h o m a t r o p i n e h y d r o b r o m i d e , a n d belladonna alkaloids that would kill 9 0 % o r m o r e of mice. M i x e d with a l u m i n u m hydroxide, t h e same doses of anticholinergics resulted in 1 0 % , 0 % , o r 1 7 % mortality respectively, indicating reduced absorption. I n later experim e n t s ( 2 ) , absorption of Pro-Banthine® was found n o t t o be strongly affected by administration with antacid. A major thesis of o u r review w a s that dosages of antacids a n d of anticholinergic drugs require individual a d justment a n d must be given separately. T i m i n g of dosage is extremely i m p o r t a n t if optimal effects a r e to b e pursued. T h e ideal time for antacids, based o n such p h a r m a c o l o g i c evidence as w e c a n muster, is a n h o u r after meals a n d m o r e often as n e e d e d ; t h e p r o p e r time for anticholinergics is a b o u t 3 0 minutes before meals to avoid d r y m o u t h while eating a n d to anticipate t h e secretory response. W h e n e v e r antacids a r e used w e believe a bedtime dose is i m p o r t a n t . W h e n a n anticholinergic drug is used a night dose is also needed, and it p r o b a b l y should b e given about a half h o u r before the antacid. A t best t h e present m e t h o d s for reducing gastric acidity leave m u c h to b e desired. A t t h e m o m e n t t h e brightest ray of h o p e is a n e w histamine H 2 - r e c e p t o r antagonist, cimetidine ( 3 , 4 ) . It appears to b e m o r e potent than earlier congeners, thus far without evident toxic potential. ARMAND LlTTMAN, M.D., PH.D., F.A.C.P. BRIAN H. P I N E ,

M.D.

Medical Service Edward Hines, Jr., Veterans Administration Hospital Hines, Illinois 60141 REFERENCES

1. GROTE [W, WOODS M: Studies on antacids. IV. Adsorption effects of various aluminum antacids upon simultaneously administered anticholinergic drugs. J Am Pharm Assoc 42:319-320, 1953 2. GROTE IW, WOODS M: Studies on antacids. VI. Adsorption effects of various aluminum antacids upon some simultaneously administered synthetic anticholinergic drugs. J Am Pharm Assoc 47:785-:'86, 1958 3. BRIMBLECOME

RW, DUNCAN WAM, DURANT GJ,

et al:

The

pharmacology of cimetidine, a new histamine H2-receptor antagonist. Br 1 Pharmacol 53:435-436, 1975 4. BRIMBLECOME RW, DUNCAN WAM, DURANT GJ, et al: Cimeti-

dine—a non-thiourea H2-receptor antagonist. J Int Med Res 3: 86-92, 1975

Improvement in Amyloidosis T O T H E EDITOR: T h e recent p a p e r b y C o h e n , Lessin, Hallal, et al ( 1 ) describing t h e r e m a r k a b l e response of a patient with renal amyloidosis to c h e m o t h e r a p y h a s p r o m p t e d m e to report a similar case seen t h r o u g h t h e past four years at this institution. A 55-year-old white man, presented in April 1971 complaining of abdominal distention, weight loss, and chest pain relieved by antacids. He had previously been in good health except for a benign right renal mass, which had been removed by nephrectomy in 1953. At examination he had hepatomegaly (22-cm liver span), splenomegaly (palpable 10-cm below the costal margin), and tender prostatic enlargement. Macroglossia, purpura, neurologic abnormality, and edema were not found. The cardiovascular system was normal. Laboratory tests

showed proteinuria (9 to 10 g / d a y ) , renal insufficiency (creatinine clearance 60 to 70 m l - m i n - 1 ) , and hypercholesterolemia (400 mg • dl" 1 ), but a normal serum albumin (4.3 g • dl - 1 ). The serum-protein electrophoresis pattern and quantitative immunoglobulin levels were likewise normal. Urinary protein electrophoresis was not done. Serum alkaline phosphatase was 180 IU (normal 30 to 100). A liver biopsy showed diffuse Congo red staining for amyloid with focal areas of yellow-green birefringence. A prostate biopsy section had similar staining characteristics, although less diffuse. The patient was treated symptomatically until October 1971, when pedal edema developed. At that time the serum albumin had fallen to 3 g • dl"1. The liver span was still 22 cm. A bone-marrow aspirate returned 10% plasma cells. The patient's urinary protein excretion was still 8 to 10 g/day, his creatinine clearance was 50 ml • min -1 , and his serum cholesterol was 400 mg • dl -1 . In early November 1971, the patient started taking melphalan, 4 m g / day. In March 1972, the melphalan was withdrawn because of no appreciable decrease in urinary protein excretion, although during the melphalan treatment the patient's creatinine clearance had risen to 95 ml • min - 1 and his serum cholesterol had fallen to 300 mg • dl -1 . At that time the patient was given a 2-month trial of cyclophosphamide, 200 mg/day, with no significant change in his clinical or laboratory status except for development of mild pancytopenia. Therefore, in July 1972, the melphalan treatment was resumed at a dose of 4 mg/day. This was continued for 2Vi months and reduced to 2 mg/day because of progressive leukopenia. By October 1972, the patient's urinary protein excretion had dropped to 7 g/day and by February of the next year was below 5 g/day. In April 1973, the melphalan was briefly withdrawn and later restarted at a dose of 2 mg every other day because of persistent pancytopenia. The urinary protein excretion, however, continued to fall until July 1973, and has remained between 0.5 and 2 g/day since then. The patient's creatinine clearance has remained between 80 and 100 ml • min - 1 since its initial rise in March 1972. His liver size and serum alkaline phosphatase did not begin to decrease until almost 2 years after starting melphalan treatment. By September 1973, however, the patient's liver size was normal and his alkaline phosphatase levels had fallen to the range of 120 to 140 I U and have remained there since. Symptomatically the patient has been virtually well on a maintenance dose of melphalan (2 mg every other day), although recently he has developed mild tingling paresthesias, which may represent disease progression. I believe that this patient's clinical i m p r o v e m e n t is directly attributable to m e l p h a l a n . A s f a r as I a m a w a r e this disease does n o t i m p r o v e spontaneously, a n d t h e p r i m a r y variety h a d n o t been r e p o r t e d to respond to t r e a t m e n t of any kind until t h e reports of success with m e l p h a l a n a p peared ( 1 , 2 ) . F u r t h e r m o r e , t h e time relation between t h e start of m e l p h a l a n t h e r a p y a n d t h e onset of this patient's recovery is quite suggestive of a cause-and-effect relation. H o w e v e r , this patient h a s n o t h a d a repeat liver biopsy to d o c u m e n t histologic resolution of t h e amyloid, n o r has h e ever h a d a biopsy of his r e m a i n i n g kidney t o confirm its involvement. T h e major reluctance t o using m e l p h a l a n routinely in the t r e a t m e n t of p r i m a r y amyloidosis has been its incrimination as a cause of leukemia ( 3 ) . This risk, therefore, must b e weighed against t h e morbidity a n d mortality of the steadily progressive underlying disease. M C D O N A L D K. H O R N E H I , C A P T , U S A F , M C

Department of Internal Medicine David Grant USAF Medical Center Travis Air Force Base, California 94535 REFERENCES 1. COHEN HJ, LESSIN LS, HALLAL J, et al: Resolution of primary Comments


281

amyloidosis during chemotherapy. Ann Intern Med 82:466-473, 1975 2. JONES NF, HILTON PJ, TIGHE JR, et al: Treatment of "primary"

renal amyloidosis with melphalan. Lancet 2:616-619, 1972 3. KYLE RA, PIERRE RV, BAYRD ED: Primary amyloidosis and

acute leukemia associated with melphalan therapy. Blood 44: 333-337, 1974

Age and Prognosis in Acute Leukemia

TO THE EDITOR: Schimpff and colleagues (1) have made an excellent contribution to the study of infection prophylaxis in patients with compromised host defenses. Their conclusions are somewhat suspect because of their failure to take into account group differences in age. Age is known to be one of the most significant prognostic factors in patients with acute nonlymphocytic leukemia. In reviewing the results presented in the paper, one cannot agree with the statement made by the authors that the "three experimental groups were similar with regard to . . . age." LAF + A* W + At Mean Age 43 45 Age > than 60/total 4/24(17%) 3/19(16%)

Wt 52 9/21(43%)

When one examines the morbidity, mortality, and remission data with the age differences of three groups in proper perspective, one could explain at least some of the differences on the basis of age alone. This unintentional selection factor must be considered as one of the explanations for the ward patients faring so poorly. JEROME W. YATES, M.D.

Medical Oncology Medical Center Hospital The University of Vermont Burlington, Vermont 05401 REFERENCE

1. SCHIMPFF SC, GREENE WH, YOUNG VM, et al: Infection pre-

vention in acute nonlymphocytic leukemia. Laminar air flow room reverse isolation with oral, nonabsorbable antibiotic prophylaxis. Ann Intern Med 82:351-358, 1975 In response: We agree with Dr. Yates that older age often confers a poorer prognosis upon patients with acute nonlymphocytic leukemia. In our study, patients who fulfilled all of the entrance criteria, (acute nonlymphocytic leukemia, noninfected, first or second induction, hospitalized less than 7 days, age 16 or less, and agreeable to isolation) were assigned to one of three experimental groups. Patients were all treated equivalently other than reverse isolation in a laminar air flow room or oral nonabsorbable antibiotics as dictated by the randomization. Despite this prospective, randomized approach to a controlled trial, the patients in one group had a mean age of 52 years (range, 21 to 73) compared with 43 (range, 20 to 70) and 45 (range, 20 to 72) years in the other two groups. The difference in age is not statistically significant but it is certainly possible that the difference is biologically significant. For that reason, we also analyzed various * LAF + A — laminar air flow room reverse isolation plus oral, nonabsorbable antibiotics. t W I A = routine hospital ward care plus oral, nonabsorbable antibiotics. t W = routine hospital ward care. 282

subgroups (for example, first induction therapy, type of induction therapy, ages less than 60 or 60 and older; see (1) Table 6, page 356). That analysis suggested that the trend in complete remission rates observed for the entire group (that is, LAF + A and W + A higher than W) was also observed for the patients less than 60 years of age (LAF + A, 12/20, 6 0 % ; W + A, 10/16, 6 3 % ; W, 3/12, 2 5 % ) . Similar results were found with other age cutoffs although the number of patients in each group becomes small. It is interesting than an equivalent fraction of patients in each group (70% to 7 5 % ) survived long enough to receive an adequate antileukemia trial (three courses of the same regimen requiring 30 or more days unless remission supervened) yet more remissions occurred in two of the three groups. The median time to remission was nearly 20 days sooner for the LAF + A and W + A patients compared with the W patients (see (1) Figure 5, page 357); the exact reason is not clear but one wonders if the reduced incidence of serious infections in the former two groups was not at least partially responsible. STEPHAN C. SCHIMPFF, M.D. PETER H. WIERNIK, M.D.

Baltimore Cancer Research Center National Institutes of Health Baltimore, Maryland 21201

Bone-Marrow Aspiration and Biopsy TO THE EDITOR: In a recent paper, "Bilateral Trephine Bone-Marrow Biopsies in Lymphoma and Other Neoplastic Diseases," (1) the authors state that "the superiority of bone-marrow biopsy over bone-marrow aspiration in defining extent of disease has been well established in Hodgkin's and non-Hodgkin's malignant lymphoma and carcinoma metastatic to bone marrow." A review of the quoted references shows that histologic sections were found to be superior to smears in evaluating the presence of malignant lymphoma or metastatic carcinoma in bone marrow. Histologic sections of bone marrow can be obtained by aspiration as well as biopsy. To the best of my knowledge no studies have been published comparing the yield of histologic sections obtained by aspiration, with histologic sections obtained by needle biopsy. Dr. Ioannides and I have carried out such a study § on 30 cadavers. Bone marrow was obtained by aspiration with a 16-gauge Osgood needle in one posterior superior iliac spine and by needle biopsy in the opposite iliac spine. Half the cases were biopsied with a 14-gauge Franklin-Silverman needle and half with an 11-gauge Jamshidi needle. The aspirated particles (10 ml of bone marrow) were processed and concentrated by a slightly modified, previously described method identical with that used in live patients (2). The weight of the concentrated aspirated particles was compared to the weights of the specimens obtained by biopsy. A morphometric point counting technique was used to ascertain the surface area of marrow available for examination in histologic sections. More marrow was secured and larger areas of marrow were seen in aspirated than in biopsied specimens. Biopsy by the Jamshidi needle was superior to the Franklin-Silverman needle. Cytologic details were sharper in histologic sections of aspirates than of biopsies. § IOANNIDES K, RYWLIN AM: A comparative study of histologic sections of bone marrow obtained by aspiration and needle biopsy. To be published.



Giemsa and Leder stains were far better in aspirates than in decalcified biopsies. Bone morphology could only be observed in biopsies. With proper technique excellent histologic sections can be obtained from aspirated bone marrow. Aspiration should not be equated with smears only. Whether needle biopsy yields more positive results than histologic sections of adequately aspirated and processed marrow in patients with malignant lymphoma or carcinoma has as yet not been investigated. More marrow is obtained by aspiration than by biopsy using the above mentioned techniques. It is important to aspirate more marrow (10 ml) than is usually recommended (1 to 2 m l ) . The aspirated particles must be concentrated before clotting of the marrow. Clot sections are inadequate and should be avoided. ARKADI M. RYWLIN, M.D.

Department of Pathology and Laboratory Medicine Mount Sinai Medical Center of Greater Miami Miami Beach, Florida 33140 REFERENCES

1. BRUNMNG RD, BLOOMFIELD CD, MCKENNA RW, et al: Bilateral

trephine bone-marrow biopsies in lymphoma and other neoplastic diseases. Ann Intern Med 82:365-366, 1975 2. RYWLIN AM, MARVAN P, ROBINSON MJ: A simple technic for

the preparation of bone-marrow smears and sections. Am J Clin Pathol 53:389-393, 1970

have had even poorer results because they either used unconfirmed positive fluorescent technique smears or the patients were on chemotherapy. We have just completed a review of our acid-fast bacilli smears and mycobacterial cultures for 1974, which yielded vastly different results that warrant reporting. Our hospital is a 667-bed Veterans Administration general hospital. In processing specimens, duplicate smears were prepared and stained by the fluorescent technique and the Kinyoun method. These stained smears were examined by two technologists who cross-examined all positive smears. We also required the smear to be positive by both the fluorescent technique and the Kinyoun method. All specimens were digested, decontaminated, concentrated, and cultured. All positive cultures were sent to a reference laboratory for confirmation. During the year 1974, 950 patients had 2994 specimens collected for acid-fast bacilli smears and culture. From these 2994 specimens, 154 cultures were positive for mycobacteria. Of these 154 culture positive specimens, 108 had been smear positive by both techniques yielding a 70% sensitivity rate. Only two "false-positive" smears occurred, both in patients on prolonged chemotherapy, which is well known to cause falsepositive smears. We find it hard to reconcile our findings of excellent sensitivity and specificity of the acid-fast bacilli smear with those of Boyd and Marr. Like all laboratory tests, acidfast bacilli smear and culture depend on many factors including the extent of disease, secretions containing enough organisms so they can be seen on smear and cultured (absence of chemotherapy), and the absence of other organisms that may appear acid fast, for example, Nocardia.

Diagnostic Smear of Acid-Fast Bacilli TO THE EDITOR: The reliability (specificity and sensitivity) of the acid-fast bacilli smear in the detection of tuberculosis has recently been questioned ( 1 ) . In the specimens reviewed by Boyd and Marr, smears were screened using the auramine-rhodamine fluorescent technique, a sensitive but nonspecific test. Positive smears were restained using the Kinyoun method, a refinement of the old Ziehl-Neelsen technique. This method is more specific but less sensitive than the fluorescent technique. To be considered positive, the smear had to be positive by both methods. Specimens were also cultured. Through paired sample techniques, they analyzed 4510 specimens. Fifty-eight smears were positive by both methods, and 32 ( 5 5 % ) occurred in patients who had negative cultures and thus were considered to be falsepositive (nonspecific). Only 26 of 118 ( 2 2 % ) culturepositive specimens were also smear-positive (nonsensitive). The false-positive to total positive rate was 5 5 % . To support their conclusions of a generalized decreasing reliability of the acid-fast facilli smear the authors quote Bayes' theorem and use data from four other studies to construct a Bayesian curve (2-5). Among the quoted studies, one is a personal communication unavailable for review ( 2 ) . Another used smears positive by either the fluorescent technique or the Ziehl-Neelsen technique, but not both smear techniques, which one would expect to decrease both sensitivity and specificity ( 3 ) . A third study had approximately a 70% sensitivity rate and a 6% false-positive to total positive smear rate ( 4 ) . However, in this study 19% of patients had already been on antituberculous chemotherapy for more than 1 month and the fluorescent technique-positive smears were not confirmed by the ZiehlNeelsen method so that this apparent lack of specificity is understandable. The fourth study failed to state whether specimens were from treated patients ( 5 ) . Thus the studies used to support their data are not comparable. They should

Even more important than these factors are the techniques of handling the specimens. The specimens should be fresh and properly decontaminated for culture. The technician must search diligently and knowingly for proper interpretation of the AFB smear. We attribute our excellent sensitivity and specificity to our technical help. Our data would seem to be supported as that to be generally expected from refinements on the previously quoted studies. ALLAN L. GOLDMAN, M.D.

Pulmonary Disease Section DEMETRIOS G. HALKIAS, PH.D.

Microbiology Section Veterans Administration Hospital Tampa, Florida 33612 REFERENCES

1. BOYD JC, MARR JJ: Decreasing reliability of acid-fast smear techniques for detection of tuberculosis. Ann Intern Med 82: 489-492, 1975 2. MESSA CJ, BLAIR EB, TULL AH, et al: Computer files and analy-

ses of laboratory data from tuberculous patients. Am Rev Resp Dis 108:813-818, 1973 3. NARAIN R, SUBBA RAO MS, CHANDRASEKHAR P, et al: Microscopy

positive and microscopy negative cases of pulmonary tuberculosis. Am Rev Resp Dis 103:761-773, 1971 4. CHAN W, CHIA M, LEE KL, et al: Bacteriological measures for

the detection of cases of pulmonary tuberculosis. Bull WHO 45: 551-558, 1971 5. TRUANT JP, BRETT WA, THOMAS W: Fluorescence microscopy

of tubercle bacilli stained with auramine and rhodamine. Henry Ford Hosp Med Bull 10:287-296, 1962

Goodpasture's Syndrome TO THE EDITOR: The recent paper by Mathew and associates (Ann Intern Med 82:215-218, 1975), reporting a case of Goodpasture's syndrome without clinical eviComments


283

dence of renal disease, raises several questions concerning interpretation of the data. The patient was an 18-year-old man with a history of hemoptysis, iron deficiency anemia, and hemosiderin-laden pulmonary macrophages, who was treated with corticosteroids with resolution of the hemoptysis. Despite the absence of hematuria, proteinuria, or renal functional impairment, the patient underwent three renal biopsies in 4 months, all of which failed to show evidence of glomerulitis by light microscopy. On the basis of IgG and IgM deposits (both continuous and interrupted) on the glomerular basement membrane and electron dense "linear" deposits on the endothelial side of the glomerular basement membrane and in the mesangium, the authors concluded that the patient had Goodpasture's syndrome. However, three points appear to have been overlooked. First, linear glomerular basement membrane fluorescence does not necessarily indicate the presence of anti-glomerular-basement-membrane antibody, for fluoresceinated antiserums to immunoglobulins can produce nonspecific linear fluorescence if not properly absorbed and rendered monospecific or if proper blocking controls are omitted. Unfortunately, the authors supplied no information on the source or specificity of their antiserums. Secondly, linear immunoglobulin deposition does not exclude immune complex disease. In systemic lupus erythematosus, for example, linear deposition of IgG can be seen in patients without clinical or histological evidence of glomerulitis, and when eluted shows no anti-glomerular-basement-membrane activity ( 1 ) . In addition, the "wire loop" lesions of systemic lupus erythematosus also may appear linear by immunofluorescence, but are seen by electron microscopy to be comprised of coalescent subendothelial dense deposits ( 2 ) . Thirdly, approximately 10% of patients at postmortem examination without histologic evidence of glomerulitis or concomitant malignancy have renal immunoglobulin deposition ( 3 ) . In the present case, without evidence of antiglomerular-basement-membrane antibody in either serum or renal biopsy eluate, linear fluorescence should not be the sole renal criterion on which the diagnosis of Goodpasture's syndrome is based. Furthermore, the ultrastructural changes in this case are more consistent with immune complex disease, for it lacks the homogeneously thickened glomerular basement membrane without dense deposits characteristic of Goodpasture's syndrome (4-6). The point in question is whether this patient does have Goodpasture's syndrome, and, from the data presented, this conclusion is not warranted. The authors appear to have reported a case of either idiopathic pulmonary hemosiderosis or an immune complex disease with similar presentation, as has been reported in systemic lupus erythematosus ( 7 ) . THOMAS R. POSKITT, M.D.

J Med 57:536-541, 1974 4. BURNS J, MACIVER AG:

Immuno-electron

microscopy of

the

glomerular basement membrane in Goodpasture's syndrome. Rev Eur Etud Clin Biol 16:48-50, 1971 5. POSKITT TR: Immunologic and electron microscopic studies in Goodpasture's syndrome. Am J Med 49:250-257, 1970 6. See Reference 2, p. 199 7. BYRD RB, TRANK G: Systemic lupus erythematosis presenting as pulmonary hemosiderosis. Chest 64:128-129, 1973

TO THE EDITOR: The recent paper by T. H. Mathew and associates, "Goodpasture's Syndrome: Normal Renal Diagnostic Findings," {Ann Intern Med 82:215-218, 1975), reports a patient with pulmonary hemorrhage and linear glomerular basement membrane deposits of immunoglobulins and complement. However, the methods used provide no firm evidence for their diagnosis of Goodpasture's syndrome. No anti-glomerular-basement-membrane activity of the fluorescein positive material was noted, circulating anti-glomerular-basement-membrane antibodies were not remarked upon, microelution of tissue sections was not done, no in vitro complement fixation by deposits was shown, monospecificity of the fluoresceinated antiserums was not commented upon, and no controls were described. Furthermore, an electron micrograph is said to show osmiophilic "linear" deposits, an extremely unusual finding for anti-glomerular-basement-membrane disease ( 1 ) . Normal glomerular basement membrane may well appear to have linear IgG deposits by fluorescence, and this may be markedly enhanced with false-positive stains for other material if tissue is not quickly processed, has "aged" in the freezer as a drying artifact, or after extracorporeal renal perfusion ( 2 ) . In short, not all that shows linear fluorescence is anti-glomerular-basement-membrane antibody, and that diagnosis should be reserved for those cases in which there is definite proof that anti-glomerular-basement-membrane antibodies are in fact deposited in the glomerular basement membrane. Perhaps, for the sake of brevity, it was necessary for the authors to omit from their paper the pertinent data allowing a definitive diagnosis of Goodpasture's syndrome. If such is the case, it would be most helpful to provide these data and substantiate their suggestion to "carry out renal biopsies in patients with apparent idiopathic pulmonary haemosiderosis." It would also be helpful in understanding the exact role of following normal serial renal biopsies as a parameter of a therapeutic response. W. K L I N E BOLTON, M.D.

Department of Medicine University of Virginia School of Medicine Charlottesville, Virginia 22901 REFERENCES 1. DUNCAN DA, DRUMMOND KN, MICHAEL AF, et al: Pulmonary

hemorrhage and glomerulonephritis: report of six cases and study of the renal lesion by the fluorescent antibody technique and electron microscopy. Ann Intern Med 62:920-938, 1965

Department of Medicine New England Center Hospital Boston, Massachusetts 02111

2. MARQUARDT H, WILSON CB, DIXON FJ: Isolation and immuno-

logical characterization of human glomerular basement membrane antigens. Kidney Int 3:57-65, 1973

REFERENCES 1. KOFFLER D, AGNELLO V, CARR RI, et al: Variable patterns of

immunoglobulin and complement deposition in the kidneys of patients with systemic lupus erythematosus. Am J Pathol 56:305312, 1969 2. GERMUTH FG, RODRIGUEZ E: Immunopathology

Glomerulus. Boston, Little, Brown and Company, 1973, pp. 123134 3. SUTHERLAND JC, VANN MARKHAM R, MARDINEY MR: Subclinical

immune complexes in the glomeruli of kidneys postmortem. Am 284

From the authors in reply:

of the Renal

Thank you for forwarding to me the letters by Dr. Bolton and Dr. Poskitt concerning our paper. The letters are sufficiently similar for me to reply to



both of them at once, although I shall ask my colleague, Dr. Hobbs, to reply to the specific points on the immunopathology. Both letters criticise a diagnosis of Goodpasture's Syndrome on the basis of "no concrete evidence for the diagnosis of Goodpasture's syndrome." Goodpasture's syndrome was, however, recognised clinically on the basis of the pulmonary features of idiopathic pulmonary hemosiderosis in association with a glomerular lesion long before the significance of linear deposits on fluorescent microscopy was recognised. As a clinician primarily, but one who has trained in pathology, the finding of clearcut strong linear IgG immunofluorescence in glomeruli in a patient with pulmonary manifestations but without overt renal disease is of considerable interest. There have been several reports of patients with recurrent episodes of lung hemorrhage over weeks, months, or years preceding an episode of fulminating glomerulonephritis, and the patients on whom we reported may run this risk in the future. Seven hundred renal biopsies are processed in this Department each year, and I can assure both Drs. Poskitt and Bolton that the strong linear immunofluorescence in our patient was quite different from the "nonspecific" faint linear deposits seen in some of the conditions they mention, such as lupus. I shall ask Dr. Hobbs to reply more specifically to the criticisms related to the immunological findings. Certainly the antiserums were properly absorbed; monospecific and proper controls were used. The lesions in the patient whom we described, and in a subsequent patient who presented in the same way and has now developed overt renal manifestations, were quite different from other minor faint linear deposits. As far as the electron microscopy is concerned, some publications to which they refer ( 1 , 2) illustrate what I would regard as necrotic basement membrane. I would agree that in the later stage in Goodpasture's syndrome the basement membrane is homogeneously thickened and dense. The homogenous dense thickening seen in Figure 5 of Dr. Poskitt's paper (2) is in my opinion characteristic of necrotic basement membrane and not specific for Goodpasture's syndrome. The only recent electron microscopy in this condition that they quote specifically (3) mentions dense deposits in the basement membrane. Two of the three biopsies from patients with Goodpasture's syndrome that we have examined have shown deposits in the basement membrane in areas where it was not necrotic and encased in collagen. In my view the patient on whom we reported represented "Goodpasture's syndrome" and the development of renal manifestations in a subsequent patient who presented in the same manner helps to confirm this view. PUISCILLA KlNCAID-SMITH, M.D., F.R.C.P., F.R.A.C.P. University Department of Medicine The Royal Melbourne Hospital Victoria, Australia 3050

REFERENCES 1. DUNCAN DA,

DRUMMOND KN,

MICHAEL AF,

et al:

Pulmonary

hemorrhage and glomerulonephritis. Ann Intern Med 62:920-938, 1965 2. POSKITT TR: Immunologic and electron microscopic studies in Goodpasture's syndrome. Am J Med 49:250-257, 1970 3. BURKHOLDER PM: Atlas of Human Glomerular Pathology. Hagerstown, Maryland, Harper & Row, 1974, p 224

We appreciate the opportunity to reply to the letters by Drs. Poskitt and Bolton, commenting upon the recent article by T. H. Mathew and associates entitled "Goodpasture's Syndrome: Normal Renal Diagnostic Functions," Ann Intern Med 82:215-218, 1975. This article was essentially a clinical presentation and the technical details were omitted. Samples taken for immunofluorescence are frozen at the bedside and within 48 hours are cut into serial 2-/A sections. They are processed in batches of 6 to 8 biopsies together with positive controls from lupus autopsies and negative controls. The sections are stained with fluoroscein labelled monospecific antisera to IgA, IgG, IgM, fibrinogen, albumin, and complement C3, as well as other substances, and viewed by epilumination on a Leitz Orthoplan. Antiserums to IgA and IgG, made by Hyland Laboratories, Burroughs Wellcome Co., and Hoechst Pharmaceutical Co., are routinely run in parallel with our own monospecific antiserums raised in sheep and purified by Dr. Cliff Hosking of the Royal Children's Hospital, Melbourne. In the case discussed in the article and the subsequent one referred to in Dr. Kincaid-Smith's letter, antiserums from all sources give similar reactions. In a total of 3000 renal biopsies examined by immunofluorescence in this fashion by me, only 3 have given this form of dramatic linear immunofluorescence. The linear nature is judged on the basis of a delicate, apparently continuous line when examined under oil immersion (see figure in original article). Dr. Poskitt's point that linear immune globulin deposition does not exclude immune complex disease surely means that linear deposition as judged even on oil immersion does not establish that the tested material is present as a linear arrangement of molecules. However, no current ultrastructural or immuno ultrastructural studies are capable of establishing this, so it is sufficient to say that there was no evidence of the form of gap that is usually seen in diseases such as membranous glomerulonephritis or systemic lupus erythematosus. The presence of so-called "antiglomerular-basement-membrane antibody" in the serum is not an essential component for the diagnosis of Goodpasture syndrome. Further, since the pathogenesis is not established, just as it is not for the other forms of glomerulitis, as one who routinely examines the biopsies by light and electron microscopy as well as immunofluorescence, I feel that it is inaccurate and clinically misleading to refer to glomerular disease on the basis of primary immunopathic processes and divide them into "anti-glomerular-basement-membrane" or "immune complex disease." These terms belong to experimental pathology and are accurate only for those models in which they are shown. I am surprised that Dr. Poskitt finds that "10% of patients at postmortem examination without histological evidence of a glomerulitis or concomitant malignancy have renal immune globulin deposition." Our series does not agree with this but we really were talking about biopsies in the original article and not sample variation in autolysis. I disagree with Dr. Bolton's similar point that "normal glomeruler basement membrane" may well appear to have linear IgG deposits by fluorescence. Some autofluorescence may occur but I have never seen normal renal tissue give anything like a specific immunofluorescence linear reaction for IgG. Microelution was not done in this case. The immunofluorescence samples obtained from single-core biopComments


285

sies are not generous and the best sample was obtained in the original biopsy. However, I would point out that the presence or absence of an elutable antiserum apparently to basement membrane is not to my mind the essential diagnostic point in Goodpasture syndrome. The ultrastructural aspects were adequately covered by Dr. KincaidSmith. The point of this case illustration and the subsequent case is that they illustrate the similarity between the syndromes of idiopathic pulmonary haemosiderosis and Goodpasture syndrome as has been seen and ignored in previous studies; in particular the one of Soergel and Sommers (1) where they deliberately exclude three cases of idiopathic pulmonary haemosiderosis that happened to also have a dramatic glomerulonephritis. J. B. HOBBS, PH.D., M.B., F.A.C.P.

Department of Anatomical Pathology The Royal Melbourne Hospital Victoria, Australia 3050 REFERENCE

1. SOERGEL KH, SOMMERS SC: Idiopathic pulmonary haemosiderosis and related syndrome. Am J Med 32:499-511, 1962

"Post Hoc" and Hypoprothrombinemia TO THE EDITOR: We read with great interest "WarfarinChloral Hydrate Interaction" by Udall (Ann Intern Med 81:341-344, 1974). The impression that warfarin and chloral hydrate can be given concomitantly without increasing the risks of hypoprothrombinemia or hemorrhagic complications appears to have been verified. We wish to report a recent experience where a single large dose of chloral hydrate given to a patient apparently stabilized on warfarin dramatically altered the anticoagulant response to the latter. A 17-year-old black man entered the San Francisco General Hospital with severe pain of the lower back of 4 days' duration. On admission, gingival bleeding was noted. Laboratory studies showed a prothrombin time of 51.5 seconds and a partial thromboplastin time of greater than 100 seconds. The hematocrit was 42%. No other evidence of bleeding was noted on physical examination. Electrolytes, renal function, and a urinalysis were all within normal limits. One dose of vitamin K (Aquamephyton®), 5 mg, was given. During the next 4 days, the prothrombin time progressively declined (51.5, 32.8, 30.3, to 20.5 seconds) and the partial thromboplastin time also declined from greater than 100 seconds (71.0, 86.7, to 54 seconds). One month before this admission, the patient had been hospitalized for treatment of a pulmonary embolus after a motorcycle accident. He was subsequently discharged on the following medications: warfarin, 15 mg daily, and diazepam, 5 mg every 6 hours. Two days before the most recent admission he took his last warfarin dose along with 30 mg of diazepam and "two cans" of beer. The next day the patient called for an ambulance because of severe back pain. He stated that the ambulance steward gave him a "foul-tasting, bitter liquid" that caused him to sleep for the next 8 to 10 hours. The next morning, he called the ambulance service again with complaints of severe back pain, "so bad, I couldn't move my bowels," at which time he was brought to the hospital. Upon questioning the patient, we elicited that he did not take any medications at home except for those stated above. A phone call to the ambulance service revealed that the patient had received a so-called "DT mix," apparently used to treat 286

alcoholics in delerium tremens (1). This mixture contained 3 g of chloral hydrate and 4 g of sodium bromide per dose. After reviewing the literature on anticoagulant drug interactions (2, 3 ) , we believe that chloral hydrate is the most likely cause of the increased anticoagulation. Sellers and Koch-Weser (4) showed that one g of chloral hydrate daily for a week potentiated the effect of warfarin by 4 0 % to 8 0 % . They proposed that the metabolite trichloroacetic acid displaced warfarin from plasma protein binding, thereby increasing the availability of free (unbound) warfarin for anticoagulation. Our patient's time course for hypoprothrombinemia and recovery of clotting factors follows quite nicely what one would predict, knowing the halflives for warfarin and the various vitamin-K-dependent clotting factors. The benzodiazepines have not been found to interfere with warfarin therapy ( 5 ) . There does not appear to be any data concerning bromide-warfarin interactions. It has been suggested that ethyl alcohol has effects on warfarin therapy, but no good clinical studies are available. The case presented illustrates that drugs that can cause a displacement of warfarin must be avoided in anticoagulated patients unless one can insure the daily continuance of each drug throughout the entire anticoagulation period. Any concoction, particularly those intended to sedate patients, of unknown ingredients should be scrutinized for content. RAYMOND E. GALINSKY, PHARM.D. PETER J. FORNI, PHARM.D. GORDON G. M C G U I R E , PHARM.D. THEODORE G. TONG, PHARM.D. NEAL BENOWITZ, M.D. CHARLES E. BECKER, M.D.

Acute Detoxification Unit San Francisco General Hospital San Francisco, California 94110 REFERENCES

1. GOLDBERT TM: Comparative evaluation of treatments of alcohol withdrawal syndromes. JAMA 201:113-116, 1967 2. SELLERS EM, KOCH-WESER J: Kinetics and clinical importance of displacement of warfarin for albumin by acidic drugs. Ann NY Acad Sci 179:213-225, 1971 3. SELLERS EM: Interaction of chloral hydrate and ethanol in man. I. Metabolism. Clin Pharmacol Ther 13:37-49, 1972 4. SELLERS EM, KOCH-WESER J: Potentiation of warfarin-induced

hypoprothrombinemia by chloral hydrate. N Engl J Med 283: 827-831, 1970 5. ORME M, BRECKENRIDGE A, BROOKS RV: Interactions of benzo-

diazepines with warfarin. Br. Med J 3:611-614, 1972 In comment: The major conclusion derived from the case reported by Galinsky and colleagues suffers a common fault associated with retrospective reports, causal relations drawn between two sequential events: in this instance the administration of chloral hydrate and excessive hypoprothrombinemia. The list of drugs that allegedly interfere with anticoagulant therapy has now grown very long, in part because of isolated reports and associations such as this ( 1 , 2 ) . The deduction that chloral hydrate caused warfarin potentiation in this case is essentially speculative and not very close to the mark in my opinion, now that the question is open for speculation. First, the statement that the patient was stabilized on warfarin is not supported by the information provided. To



the contrary, he received exceptionally high doses of warfarin (15 mg daily) without prothrombin testing for a month after initial hospitalization. He may have bled simply from an accumulative overdose of warfarin. This probability is supported by the development of a severe unexplained back pain, before chloral hydrate was given, which probably resulted from a retroperitoneal, mesenteric, or submucosal intestinal hemorrhage. Most patients in my experience with such hemorrhages suffer from back or abdominal pain. The patient's 42% hematocrit on admission does not exclude such bleeding because he was probably hemoconcentrated as a result of an alcoholic binge. Second, a "two beers" reply from a county hospital patient may be assumed to represent substantially more, often including wine and liquor. Alcohol was probably the analgesic chosen by the patient for the relief of back pain. This assumption is strongly supported by the action of the ambulance steward, practicing medicine without a license, who administered a foul-tasting elixir to prevent delerium tremens. Third, the authors neglected a pertinent report of the powerful influence of alcoholic-binge drinking compared with social drinking when they discounted the impact of alcohol on warfarin therapy. A single weekend of heavy imbibing has been shown repeatedly to potentiate anticoagulation very significantly ( 3 ) . Finally, the brief interval (less than 24 hours) between chloral hydrate administration in this case and the identification of marked prothrombinopenia was probably too short for additional free warfarin to exert an excessive prolongation of the prothrombin time. This effect usually occurs 30 to 48 hours after arresting the synthesis of vitamin-K-dependent clotting factors and the gradual dissipation of those factors already in the circulation. The most instinctive lessons from this case are [1] a better appreciation of the hazards of outpatient anticoagulation of county hospital patients because of the high prevalence of alcoholism and low prevalence of reliability among this population; [2] the need to monitor prothrombin times at weekly and bimonthly intervals shortly after hospital discharge to establish a safe warfarin maintenance dose and patient reliability; [3] an awareness that retroperitoneal, mesenteric, and submucosal intestinal hemorrhages are common causes of unexplained back pain and obstipation in patients receiving warfarin; and [4] the great advantage of controlled prospective clinical investigations compared with retrospective single-case reports in the correct identification of drugs which interfere, and the extent to which they interfere, with warfarin therapy.

for medical literature abstracts ( 1 ) . The "Annals" and other journals now print separate sets of abstracts to simplify their removal from the bound publication. We report here a simple method of cross-indexing, filing, and retrieval of these abstracts by the use of edge punch cards and a mechanical sorting machine*. These abstracts can be cross-indexed for four different headings and can be sorted for any combination of entries in a few minutes. The abstracts are simply cut out of the journal and affixed to single-hole punch cards (8.4 X 19 cm) with transparent tape. There is ample room for written notes on the cards as well. It is also a simple matter to photocopy graphs and tables from the article directly onto the punch cards. Coding of the headings allows maximal use of the 33 holes on one side of the card. With the use of two sets of 16 holes and four sorting rods, 14 400 separate and unique combinations can be defined. These codes are assigned to the headings according to the Medical Subject Headings for Index Medicus. As each new heading is needed the code is assigned by drawing at random four numbers from two sets of 16 counters. This code is then written in the margin of the book of Medical Subject Headings for reference. This code is transferred to the cards by notching out the margin of the desired hole with a hand punch. The sorting machine, Figure 1, consists of two trays that hold up to 4400 cards in position on either side of a 75-cm axle. The trays have holes corresponding to those in the punch cards. Sorting is accomplished simply by inserting rods in the required holes and turning on the machine. An electric motor rotates the trays on the axle and the properly notched cards are ejected by centrifugal force. All classifications are sorted simultaneously. Optional features of the machine include a catcher tray, which can keep the ejected cards in sequence, and a push button system for more easily inserting the sorting rods. As an illustration of the system, 700 cards were sorted for the code representing rheumatoid factor and 12 cards were produced. A quick inspection showed that 10 of the cards were related to rheumatoid factor and 2 were unrelated. These unwanted cards result from the superimposition of the two to four codes for the multiple cross-indexed * Littlcomputer, Denver, Colorado.

JOHN A. UDALL, M.D.

Division of Cardiology California College of Medicine University of California, Irvine Orange, California 92668 REFERENCES

1. KOCH-WESER J: Quinidine-induced hypoprothrombinemic hemorrhage in patients on chronic warfarin therapy. Ann Intern Med 68:511, 1968 2. UDALL JA: Quinidine and hypoprothrombinemia (letter). Ann Intern Med 69:403, 1968 3. UDALL JA: Drug interference with warfarin therapy. Clin Med 77:20, 1970

Mechanical Sorting of Abstracts TO THE EDITOR: Recent correspondence in the Letters section has emphasized the need for a personal filing system

Figure 1 . Mechanical sorting machine showing one tray partially filled with cards; sorting needles are inserted on the right. Comments


287

headings on each card. This unwanted fall-out has not been much of an annoyance and averages about 12% of the cards sorted. More restricted searches that use two or more headings simultaneously result in far fewer false cards. Thus a simple mechanical sorting machine can store up to 4400 abstracts and quickly retrieve any combination of over 14 000 headings. DAVID M I L L S , M.D.

Medical Service Veterans Administration Hospital Denver, Colorado 80220

1. BAKER DH, BRASHEAR RH: Cross-indexed file for medical literature. Ann Intern Med 80:557-559, 1974 Mithramycin for Hypercalcemia TO THE EDITOR: We take strong issue with a recent letter from A. W. Hopefl (Ann Intern Med 82:722, 1975) suggesting that mithramycin be reserved for the hypercalcemic patient who has not responded to "other more benign therapy" and used only by those experienced in chemotherapy. We have found mithramycin more reliable, yet no more toxic than other hypercalcemic agents, and strongly encourage its use early in the treatment of hypercalcemia. It is quite clear that the risks of hypercalcemia are greater than the risks of mithramycin if attention is paid to dose and frequency of administration. M.D. M.D. M.D. M.D. M.D.

Section of Oncology Division of Medicine Presbyterian-St. Luke's Hospital Chicago, Illinois 60612 Apology for "Hypercalcinuria" TO THE EDITOR: We apologize to your readers for the word "hypercalcinuria," which appeared repeatedly in our editorial in your April issue (Ann Intern Med 82:584-585). We would, however, like to make clear that we did not invent this word, which was the brainchild of your copy editor and was inserted despite our objections. "Hypercalciuria" and "hypercalcuria" have both appeared frequently in the past. We used the former as it seemed to carry the greater authority, having been used by, among others, Fuller Albright (1) in the first description of the idiopathic variety, the latest (13th) edition of Cecil-Loeb, the current Science Citation Index, and relevant articles in your own journal over the last 7 years (24 ) . Much to our surprise we found that the word had been changed to "hypercalcinuria" when the proofs reached us, but we altered the offending word back again and returned the proofs with an explanatory letter to the editor. We now see that our corrected proofs and covering letter (which we know from internal evidence to have reached your office) have been disregarded. May we suggest you provide your readers with an explanation for your use of this neologism? You should also point out to contributors that your despatch of proofs is a 288

OLIVER M. WRONG, M.D., F.R.C.P. TERRY G. FEEST, M.B.

Medical Unit University College Hospital Medical School London, WC1E 6JJ, England REFERENCES

1. ALBRIGHT F, HENNEMAN P, BENEDICT PH, et al: Idiopathic

REFERENCE

ROBERT E. SLAYTON, CHARLES PERLIA, JOHN SHOWEL, THOMAS HOELTGEN, JANET WOLTER,

charming Old-World affectation, and not to be taken seriously.

hypercalciuria. Proc R Soc Med 46:31-35, 1953 2. EPSTEIN FH: Bone and mineral metabolism in hyperthyroidism (editorial). Ann Intern Med 68:490-491, 1968 3. MUGGIA FM, HEINEMANN HO: Hypercalcemia associated with neoplastic disease. Ann Intern Med 73:281-290, 1970 4. SPERLING O, WEINBERGER A, OLIVER I, et al: Hypouricemia,

hypercalciuria, and decreased bone density; a hereditary syndrome. Ann Intern Med 80:482-487, 1974 Our copy editor apparently consulted his desk copy of Stedman's Medical Dictionary, 22nd ed.; Baltimore, Williams & Wilkins, 1972; p. 598, and did not notice that "hypercalcemia" is indicated as preferred in American usage to "hypercalcinuria." He might have consulted that Old-World lexikon, Sir Arthur Salusbury MacNalty's The British Medical Dictionary; London, Caxton, 1961; p. 707, and found that the "neologism," "hypercalcinuria," is there preferred to "hypercalciuria." What he did do is not known because he is no longer with us. What is clear, however, is that he should have respected the preference of Drs. Feest and Wrong. Their usage is supported by several modern American medical dictionaries, and, as is pointed out by Drs. Feest and Wrong, has been our accustomed usage. I apologize to Drs. Feest and Wrong. 1 hope that they have not been embarrassed among their colleagues as a consequence of our failure.—The Editor Correction: Error in Paper on Digoxin I wish to call attention to a typographical error in our paper, "Improved Computer-Assisted Digoxin Therapy," which appeared in the May 1975 issue (Ann Intern Med 82:619-627, 1975). The error is small, but considerably alters the meaning of the sentence in which it appears. The seventh sentence in the second paragraph of the paper (line 16, column 2, page 619) should read (with the correction in italic type): T h u s digoxin dosage regulation has another advantage as a starting point for the application of automated feedback methods to medicine: adequate "benchmark" data exist on the ncwfeedback performance of physicians. . . .* L E W I S B. SHEINER, M.D.

Department of Medicine School of Medicine University of California, San Francisco San Francisco, California 94143 Scene in Print: Kate Millett, Achtung! " . . . if one is searching records . . . to ascertain how many males there are, one simply 'subtracts' the word male from the word male or female, as the case may be, on each record. Males minus male gives a zero result, whereas female minus male is not zero (whatever else it is!)." [PAYNE LC, BROWN P T S : An Introduction

to

Medical

Automation, 2nd ed. Philadelphia, J. B. Lippincott Company, 1975, p. 127]



Letter: Needle aspiration biopsy for thyroid cancer.

Letter: Fatality after fine-needle aspiration biopsy of liver.

Percutaneous needle aspiration biopsy.

Fine-needle aspiration biopsy.

Percutaneous transthoracic aspiration needle biopsy.

Letter: Acid pulmonary aspiration.

Letter: Easier chest aspiration.

COMPUTERISED TOMOGRAPHY GUIDED TRANSTHORACIC ASPIRATION BIOPSY.

Position-controlled needle aspiration biopsy at mammography.

Transperitoneal percutaneous retroperitoneal lymph node aspiration biopsy.

Breast lymphoma: fine needle aspiration biopsy.

Fine-needle aspiration biopsy of salivary glands.

Percutaneous transperitoneal aspiration biopsy of pancreatic masses.

Fine-needle aspiration biopsy in gynecologic oncology.

Vitrectomy retinotomy aspiration biopsy of choroidal tumors.

Aspiration biopsy of carcinoma of the pancreas.

Positional precautions in needle aspiration lung biopsy.

Single pass fine-needle aspiration biopsy.

Complications of percutaneous transthoracic needle aspiration biopsy.

Fine needle aspiration biopsy in orbital tumours.

Combination of aspiration and non-aspiration fine needle biopsy for cytological diagnosis of thyroid nodules.

[(Gynecomastia as precancerous lesion: aspiration biopsy cytology and its histology)].

Transthoracic aspiration biopsy of pulmonary and mediastinal lesions.

Development of biopsy gun for aspiration and drug injection.