Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five references may be used. 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. Anniversary and Advertisements TO THE EDITOR: I was angered and disappointed to read Dr. Moser's editorial on the need for drug advertising in medical journals (1). I was angered because Dr. Moser's short-sighted perspective avoided some of the more critical issues of the controversy and disappointed because it typified the complacency of the medical profession toward this important topic. Dr. Moser emphasizes that without drug advertisement the cost of the Annals would increase from $25 to $37 per year and that "this is what justifies the incorporation of drug advertising in this journal." I hope Dr. Moser is not naive enough to think that the $12 difference per issue is made up by the drug companies digging deeply into their profits. Millions of dollars each year are spent on medical and pharmaceutical journal advertising, direct mail advertising, promotional sales, and field-selling devices. The cost of this barrage of drug company advertising is passed on directly to the consumer via exorbitant drug prices. And, as usual, it is the people who can least afford it, the poorest and the sickest, who suffer the most. The average physician does not pay $25 out of his pocket for the Annals. Most physicians write off journals as tax-deductible and therefore end up paying much less than the full subscription fee. There is already a less-than-half special rate for "those who need it most", that is, students and house officers, and increases for these persons could be offset by help from medical student societies and housestaff associations. Dr. Moser contends that the techniques used by the drug companies play an important role in educating the prescribing habits of the physician. I beg Dr. Moser to keep in mind that the pharmaceutical industry is not an organization devoted to acts of charity or goodness but is a business designed to secure a profit. Traditional business attitudes and Madison Avenue gimmicks are involved that can work to the detriment of health care. Numerous drug advertisements stress aspects of drugs that are often irrelevant, misleading, and plagued by distortions of medical terminology. The drug advertising onslaught has resulted in two interrelated evils. First, there is a general tendency for physicians to overprescribe. For example in Canada, a country of 22 million people, six million tablets of diazepam are prescribed per week (2). Too often drug companies invent a new drug and then proceed to elaborate common complaints into distinct diseases for which the drug would be the quick, easy solution. We are all aware of the plethora of drugs designed for "poor eaters," the "troublemakers at school," the "nervous stomach," or the "bed wetter." Second, the infusion of multiple brand names for single generic compounds has only served to complicate our already immense body of knowledge, denying any possibility for an international uniformity of drug names. This rape of the healthcare system comes about by the power of the drug firms to market a product under a unique trade name. This forms the basis for our irrational and unsafe drug-naming system. In summary, I do not share Dr. Moser's opinion that "drug advertisements in peer review journals are a vital part of contin-

uing pharmacologic education." Instead, I suggest that to a large degree the medical profession has itself to blame for not assuming the responsibility for providing itself with an objective, reliable, and scientific method for continuing drug education after medical school. Unfortunately this void has been filled by the drug industry, and the conflict lies in the priority of this latter system, which is to generate profit. The alternative would be to establish, with the aid of the universities and the government, a central, easily accessible, continuing drug education program that could provide the most reliable and scientific information. This would unify our body of medical knowledge and at the same time eliminate the evils inherent in our existing drug education. I challenge Dr. Moser to use the influence of the Annals and the American College of Physicians to pursue such an alternative for the sake of the medical profession, the health-care system, and the people we serve. E R I C E. LETOVSKY

Senior Medical Student Faculty of Medicine McGill University Montreal, Quebec, Canada REFERENCES 1. MOSER RH: Advertising and our journal. Ann Intern Med, 87:114-115, 1977 2. K A T Z M: Summary publication drug symposium, in Drug Information for the Health Care Team, McGill University, Montreal, Quebec, Canada, 30-31 May 1975, p. 14

TO THE EDITOR: The old advertisements and the accompanying commentaries in the 50th anniversary issue are almost a persuasive argument for a return to interspersed advertising! Congratulations on such an imaginative collection of old goodies for our enjoyment! H A R R Y L. A R N O L D , JR., M . D .

The Schoch Letter 888 South King St. Honolulu HI 96813 Sterility of Blood Collection Tubes TO THE EDITOR: Data in a recent article, "The Microbiology of Evacuated Blood Collection Tubes" (Ann Intern Med 86:186188, 1977), indicated that about 9% of the sterile, yellow-stoppered Vacutainer tubes tested contained viable bacteria. The sterility of yellow-stoppered Vacutainer tubes manufactured by Becton, Dickinson and Company is assured through an extensive control program. Therefore, we were disturbed and very concerned when we were informed in July 1976 that laboratories had detected bacterial contamination in some of our yellowstoppered tubes. We then initiated an extensive investigation. This letter makes public the results of our investigation so that readers of the article can arrive at their own interpretation and conclusions. The sterility test procedures described in the Materials and Methods section of the referenced article were recommended to the collaborative laboratories and were probably used in most laboratories. However, the author fails to point out that in one laboratory reporting six positive tubes these procedures were not followed. At that laboratory the rubber stoppers were removed manually in a hospital laboratory environment, and then various locations were swabbed and the swabs placed in culture Letters and Corrections

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media. The anticoagulant inside the tubes was aspirated and inoculated into culture media. The six positive cultures reported by that laboratory were detected in October 1975, which was about 6 months before the reported collaborative study was initiated. The author also failed to mention the results of an extensive evaluation program that was conducted. Becton, Dickinson and Company uses a closed system for sterility testing of yellowstoppered Vacutainer tubes. Our test procedures and equipment were made available to the institutions originally reporting contamination in these tubes, as well as the Mayo Clinic. Two of the laboratories conducted additional sterility testing using our recommended procedures. Shelf stocks from seven different hospital sources were cultured, and all were found by these laboratories to be sterile. Becton, Dickinson and Company also tested over 1700 tubes representing about 50 different production lots, and all were found to be sterile. In addition, a duplicate set of the tubes reported in the Addendum of the subject publication were received from the Mayo Clinic and tested by Becton, Dickinson and Company. All of these tubes were found to be sterile. It has been our experience that when laboratories are not specifically equipped and experienced in sterility testing they frequently report a high level of contamination. This is not intended as a derogatory statement; rather it is a simple statement of fact that sterility testing is a highly complex field that requires specialized equipment, sound procedures, and technical experience. Significantly, with a test base of about 2000 tubes tested by four different laboratories no test positives were detected. This may be compared to the original data base of 103 tubes in the reported collaborative study. In addition, the organisms reportedly detected in the collaborative studies are all extremely sensitive vegetative bacteria. It is quite unlikely that these sensitive organisms could survive a sterilization cycle that reliably destroys highly resistant bacterial spores. Becton, Dickinson and Company is extremely concerned with any report indicating that our products fail to comply with label claims. We have reviewed our production records, including sterilization operations and testing, and are confident that our yellow-stoppered Vacutainer tubes are indeed sterile. Furthermore, based on extensive testing conducted by our laboratories as well as some participants in the collaborative study, our confidence in the sterility of our tubes is confirmed.

ing a substantial portion of the lot must occur for it to be detected by testing a randomly selected small sample size. Fifth, and most important, the absense of contamination in tests of lots of tubes submitted at a later date to my laboratory by the manufacturer does not exclude the possibility that contamination had occurred in an earlier production lot of tubes. As impressive as the company's quality control data are, the fact remains that there was a well-documented report of contamination in one lot of sterile tubes. Although the procedures used by one laboratory differed somewhat from that specified in the protocol, these differences are attributable to that laboratory's attempts to establish the site of contamination in the tubes in question. Cultures of the inner surfaces of the tubes themselves and the anticoagulant contained therein were consistently negative; however, cultures of the inner surfaces of their stoppers yielded a variety of Gram-negative bacilli. These findings were duly reported at the time by the laboratory's director to a representative of Becton, Dickinson and Company, J O H N A. W A S H I N G T O N , II, M . D .

Mayo Clinic Rochester, M N 55901 Antibiotics and Streptococcal Pharyngitis TO T H E EDITOR: On page 497 of the April 1977 issue, Dr. Pantell states that antibiotics do not alter the symptomatic course of streptococcal pharyngitis. He cites a 1951 reference by Brink and associates; we have read the 1951 reference and do not agree that the article justifies the conclusions that Dr. Pantell alleges. From the management of several hundred cases over our combined careers, neither of us agrees with this conclusion. Admittedly our clinical experience is anecdotal, although extensive. We would therefore like to see further personal or literature documentation on this issue from Dr. Pantell. F.T. D A R V I L L , M . D . , F.A.C.P. TlMM ZlMMERMANN, M.D.

P.O. Box 636 Mount Vernon, W A 98273

T H E O D O R E J. M E D R E K , M . D .

Corporate Medical Director Becton, Dickinson and Company Rutherford, NJ 07070 B. C. W O O L E Y , P H . D .

Corporate Director of Quality Assurance Becton, Dickinson and Company Lyndhurst, NJ 07071 In


As I stated in my report of the collaborative study, the possibility of contamination during processing of the cultures of the sterile tubes cannot be excluded. Nevertheless, one cannot dismiss the possibility that the findings were real. First, the groups of bacteria isolated from the sterile tubes were different from those isolated from the nonsterile tubes. Second, clinical microbiology laboratories routinely perform sterility tests on all kinds of products and devices used in their laboratories and hospitals, and there were certainly no problems uniquely associated with culturing evacuated tubes. Third, isolated incidents of lot-specific contamination of sterile products or devices are not infrequently reported in the literature or by the Food and Drug Administration (FDA Enforcement Report) and the Center for Disease Control (Morbidity and Mortality Weekly Report), despite apparently adequate safeguards and quality-control measures taken by their manufacturers. Fourth, sterility testing can obviously be done on only a small sample of any given lot of a manufactured product, so that a contamination problem affect632

TO THE EDITOR: Tompkins, Burnes, and Cable (1) suggest three different strategies for dealing with acute pharyngitis whose cost, barring complications, varies from $14.50 to $28.00 per illness. With government cooperation, an even more efficient alternative could be made available—self-medication. If oral penicillin were made available without prescription and promoted to the public as the treatment of choice for sore throat, this would in fact constitute "strategy B" but at a cost of only $3.00 per illness, the cost of the medication alone. I think it would be a good idea, and, though it may shock some of my colleagues, I believe it can be defended. In so doing, I should also like to comment on the second editorial in that issue, the stance of which is in clear opposition to "strategy B" (2). The editorial's author, Dr. Pantell, states that antibiotics do not alter the symptomatic course of streptococcal pharyngitis. Careful examination of the study he cites in proof (3) leads only to the contrary conclusion. As an example, one need only compare the prevalence of fever and sore throat on Days 1 and 3 in those given penicillin and those given nothing. The differences are definitely significant—P < 0.02 for fever (chi-square, Yates' correction = 5.638) and P < 0.001 for sore throat (chisquare = 12.588). Moreover, the penicillin rendered all cultures negative by Day 3, which casts serious doubt on the convention that 10 days' treatment is necessary for streptococcal eradication. It is further claimed that the mortality rate is higher than Tompkins, Burnes, and Cable (1) had estimated. In fact, the study cited (4) indicates that only 2 % of the penicillin-related

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fatalities are from oral penicillin. Of course, the relative use of parenteral and oral forms is uncertain. However, if we counterbalance the physicians preference for the needle with the availability of penicillin over the counter in many areas of the world, it seems reasonable to assume that most fatal reactions are caused by parenteral medication and that the oral fatality rate is about 4 X 1 0 5 , which qualifies oral penicillin as a safe drug. Warning patients not to take oral penicillin if they have a history of specific allergy should further halve the mortality rate. Moreover, increasing public reliance on oral self-medication should keep many people out of the hands of their physicians and spare them the risk of parenteral penicillin, thus further increasing the safety margin. I would therefore discount the safety factor. The editorial states that a 24- to 48-hour delay in treatment does not increase the rheumatic fever risk, citing a policy statement rather than an objective study. I suspect, however, that the original support for this contention came from the study of Cantazaro, Rammelkamp, and Chamovitz (5), wherein the rheumatic fever attack rate was actually higher in those treated early, thus suggesting that the early- and late-treated patients were not comparable with respect to the disease treated and possibly certain host factors. Therefore, I contend that the effects of time of treatment are not known. Not only is oral self-medication cheap and safe, but it would also lessen the contagion of physicians' waiting rooms and spare both parents and children the trauma of an office visit. "Strategy A " would still be available to those who desired it, while others would be spared the misery of awaiting treatment until culture results are reported. I R A D . S T E I N , M . D . , F.A.C.P.

642 Summit Road Union, NJ 07083 REFERENCES 1. T O M P K I N S RK, B U R N E S DC, C A B L E WE: An analysis of the cost-effec-

tiveness of pharyngitis management and acute rheumatic fever prevention. Ann Intern Med 86:481-492, 1977 2. P A N T E L L R H : Cost-effectiveness of pharyngitis management and prevention of rheumatic fever (editorial). Ann Intern Med 86:497-499, 1977 3. B R I N K WR, R A M M E L K A M P C H J R , D E N N Y FW, W A N N A M A K E R LW:

Effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis and pharyngitis. Am J Med 10:300-308, 1951 4. IDS0E O, G U T H E T, W I L L C O X RR, D E W E C K AL: Nature and extent of

penicillin side-reactions with particular reference to fatalities from anaphylactic shock. Bull WHO 38:159-188, 1968 5. C A N T A Z A R O FJ, R A M M E L K A M P CH, C H A M O V I T Z MC: Prevention of

rheumatic fever by treatment of streptococcal infections. TV Engl J Med 259:51-57, 1958

mean duration of soreness by 19 h and fever by 23 h when compared with an untreated group. However, only five cases in the untreated group showed evidence of streptococcal infection by means of significant antistreptolysin titer rise, making this study difficult to interpret. Comparable studies have not been done in children. Penicillin is effective in significantly shortening the course of scarlet fever (3). The above studies traced the natural history of untreated streptococcal pharyngitis, but the clinically relevant question is whether treating early, before throat culture results are known, offers superior symptomatic relief. Brink and associates (1) found early treatment (within 24 h) shortened the duration of soreness by about 12 h when compared to a late treatment (12 to 24 h) group. Merenstein and Rogers (4) studied 32 patients with streptococcal pharyngitis and found no significant difference in either general well-being or in duration of time reported to being "completely well" between early- and late-treated groups. Although patients treated early reported fewer sore throats and fever 12 to 24 h after presenting, there was no difference at 48 to 72 h. Even if the above studies had shown indisputably the advantage of early treatment with penicillin, the clinical implications would be questionable, since no study has been done comparing other symptomatic regimens. Gargles, cold liquids, aspirin, or acetaminophen may be more effective and certainly safer than penicillin. Dr. Stein has done a good job in pointing out some of the uncertainties confronting clinicians who treat pharyngitis, but he does not really defend his recommendation for self-medication. The National Ambulatory Survey reveals that streptococcal pharyngitis comprises only 10% of the pharyngitis presenting to physicians (5). Self-medication would therefore result in significant overuse of penicillin, placing patients unnecessarily at risk and encouraging the emergence of penicillin-resistant strains of bacteria. Even physician treatment with penicillin before culture results are known requires clinicians to make highly inaccurate decisions about the presence of streptococci in the pharynx based on clinical signs. About half of the patients treated on clinical grounds will unnecessarily receive penicillin. Waiting for the result of a throat culture is not synonymous with ignoring the patient. Pharyngitis can be treated early with safe, symptomatic remedies; penicillin should be reserved for purposes in which efficacy has been demonstrated, that is, in documented streptococcal illness. R O B E R T H. P A N T E L L , M . D .

Departments of Pediatrics and Medicine Stanford University School of Medicine Stanford, CA 94305 REFERENCES

In reply: Drs. Darvill, Zimmermann, and Stein have posed an important question: Is penicillin efficacious in altering the symptomatic course of streptococcal pharyngitis? As the purpose of clinical trials is to confirm or reject hypotheses generated from clinical experience, I shall rely on them in this reply. Careful examination of Brink's study (1) comparing penicillin and no-treatment of exudative streptococcal pharyngitis reveals Stein's calculations to be in error and the chi-square statistic (x2 = 4.8, P < 0.05) significant only for soreness and not for fever. However, use of the chi-square statistic is inappropriate for comparing curves that describe the course of an illness, since only one arbitrarily selected point is used for the comparison. The Mantel-Haenszel procedure is appropriate here and reveals no significant difference for the symptom course. More importantly, however, no clinically significant differences were noted for soreness, anorexia, malaise, or headache. Although 24 h after observation the penicillin group seemed to have fewer febrile patients than the untreated group (67% versus 86%), by 36 h only 50% of patients in either group who were originally febrile had persistent fever. Brumfitt and Slater (2) found that penicillin reduced the


Effect of penicillin and aureoymycin on the natural course of streptococcal tonsillitis and pharyngitis. Am J Med 10:300-308, 1951 2. BRUMFITT W, SLATER JDH: Treatment of acute sore throat with penicillin: a controlled trial in young soldiers. Lancet 1:8-11, 1957 3. H A I G H T T H : Erythromycin therapy of respiratory infections. I. Controlled studies on the comparative efficacy of erythromycin and penicillin in scarlet fever. J Lab Clin Med 43:15-30, 1954 4. MERENSTEIN JH, ROGERS K D : Streptococcal pharyngitis: early treatment and management by nurse practitioners. JAMA 227:1278-1282, 1974 5. U N I T E D STATES D E P A R T M E N T O F H E A L T H , E D U C A T I O N , A N D W E L -

FARE: National Ambulatory Medical Care Survey: 1973 Summary. Vital and Health Statistic Series 13, No. 21. D H E W Publication No. (HRA) 76-1772. Rockville, Maryland, United States Department of Health Education and Welfare, National Center for Health Statistics, October 1975

Hepatitis B Antigen in Pleural Effusion and Ascitic Fluids TO T H E EDITOR: Merrill, Farris, and Rounds (Ann Intern Med 87:120, 1977) claimed to have isolated for the first time hepatitis B (HBs) antigen from a pleural effusion complicating a case of acute hepatitis. However two other cases of HBs antigen in Letters

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pleural fluid have already been reported by De Flora and Forci (1) and Cocchi and Silenzi (2). Furthermore, since the authors did not give any details of the technique used to collect the pleural fluid, it is difficult to exclude the possibility of contamination of this fluid with HBs-positive blood. We wish to report the following case. A 66-year-old woman was hospitalized for investigation of jaundice. At physical examination hepatomegaly and ascites were revealed. Liver enzyme, gammaglobulin, and bilirubin values were elevated. Liver biopsy showed features of chronic active hepatitis with cirrhosis. Blood samples were positive for HBs antigen by electroimmunodiffusion at a titer of 1:256. Antigen e was also present. During her hospitalization, she developed a right pleural effusion. Pleural and ascitic fluids were collected, and the following precautions were taken to avoid contamination with blood (by a method analogous with the collection of cerebrospinal fluid): the aspirates were collected in fractions and only the later fractions tested for the presence of HBs antigen. In addition, in none of these fractions were erythrocytes detected by microscopic examination. Hepatitis B antigen was present in both pleural and ascitic fluids at a titer of 1:4. JEAN-PIERRE CAPRON, M.D. ARSENE PAPAZIAN, M.D. JEAN-LOUIS DUPAS, M.D. PHILIPPE D A N I E L , M . D .

Clinique Medicale A Centre Hospitalier Universitaire Laboratoire de Virologie Faculte de Medecine 80 000-Amiens, France

Table 1. Percutaneous Cholangiography in Cholestatic Jaundice

Diagnosis Dilated biliary ducts Choledocholithiasis Choledocholithiasis after cholecystectomy Choledochostenosis Primary bile duct carcinoma Pancreatic carcinoma Metastasis Chronic pancreatitis Parasitosis Total Nondilated biliary ducts Virus hepatitis Drug-induced cholestasis Alcoholic hepatitis Liver cirrhosis Primary biliary cirrhosis Secondary sclerosing cholangitis Others Total Unclassified cases

TO T H E EDITOR: Regarding the article by Drs. Ferguson and Smith, "Cryptococcosis and Cushing's Syndrome" {Ann Intern Med 87:65-66, 1977), I believe that the first report in the English language since 1950 of cryptococcosis in the presence of Cushing's syndrome secondary to endogenous steroid excess was by Dyson in The New England Journal of Medicine 261:169, 1959. Does it matter who is first? JOSEPH D. SAPIRA, M . D .

College of Medicine University of South Alabama Mobile, A L 36617

Thin-Needle Cholangiography TO T H E EDITOR: "Skinny"-needle percutaneous transhepatic cholangiography seems to come to age in the diagnosis of cholestatic jaundice. The recent paper by Pereiras and associates (1) shows admirable results in 131 patients. They certainly have the best published success in cases of intrahepatic cholestasis with nondilated ducts, 96% good visualization achieved with up to seven passes through the liver but no greater morbidity. We have used this procedure for the last 2 years in 150 cases, all with biochemical evidence of cholestasis. We follow the same technique of Okuda and colleagues (2) but can rarely withdraw bile through the needle, even from dilated ducts, because of the high viscosity of the bile and the narrow caliber of the needle. Our results are summarized in Table 1. We have had very good results in cases with extrahepatic obstruction. Our results are not as good in cases with nondilated biliary ducts, probably because we seldom try more than five passes. 634





7 6 17 25 24 10 1 111

5 4 16 22 18 7 1 88

4 3 3 3 3 1 4 21 18

1 1 0 0 1 0 0 3 11


71 85 70 80

14 61

Departments of Medicine and Radiology Medical School of Lisbon Lisbon 4, Portugal REFERENCES 1. PEREIRAS R J R , C H I P R U T RO, G R E E N W A L D RA, SCHIFF ER: Percutaneous transhepatic cholangiography with the "skinny" needle. A rapid, simple, and accurate method in the diagnosis of cholestasis. Ann Intern Med 86:562-568, 1977 2. O K U D A K, T A N I K A W A K, EMURA T, K U R A T O M I S, JINNOUCHI S, U R ABE K, SUMIKOSHI T, K A N D A Y, FUKUYAMA Y, M U S H A H, M O R I H, SHIMOKAWA Y, YAKUSHITI F, MATSUURA Y: Nonsurgical, percutaneous transhepatic cholangiography—diagnostic significance in medical problems of the liver. Am J Dig Dis 19:21-36, 1974

Panniculitis and Pancreatic Disease TO T H E EDITOR: Subcutaneous nodular fat necrosis associated with pancreatic diseases is an entity distinct from other forms of panniculitis. Rubinstein and associates (1) have further associated this cutaneous marker of pancreatitis with their finding of alpha,-antitrypsin deficiency in two patients. We believe, however, that their patients had clinical features of nodular fat necrosis of pancreatic disease rather than relapsing febrile nonsuppurative panniculitis (Weber-Christian disease). Their patients developed the classic subcutaneous nodules on the legs and trunk that occasionally drained an odorless fluid. At autopsy panniculitis with fat necrosis was revealed. Szymanski and Bluefarb (2) reported five cases of nodular fat necrosis associated with pancreatitis or adenocarcinoma of the pancreas. They first recognized the histologic features of fat necrosis with "ghost" cells whose thick "shadowy" walls do not enclose the nucleus. This unique histologic feature and the association with pancreatic disease has justified separating nodular fat necrosis from other forms of panniculitis in current textbooks (3, 4). Weber-Christian disease can clinically resemble nodular fat necrosis, but its relapsing febrile course, the usual nonsuppurative nodules, and the absence of pancreatic disease distinguish it, in most cases. Foam cells can be seen histologically, but "ghost" cells are not found. Although "ghost" cells were not included in the brief description of pathologic changes, we be-

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J. P I N T O CORREIA, M . D . E R M E L I N D A CAMILO, M . D . A. G A R G A T E , M . D .

REFERENCES 1. D E FLORA S, FORCI F: Hepatitis B surface antigen in pleural fluid. Lancet 1:1269, 1977 2. COCCHI P, SILENZI M: Pleural effusion in HBS Ag-positive hepatitis. / Pediatr 89:329-330, 1976

Cryptococcosis and Cushing's Syndrome


lieve that the two cases presented by Rubinstein and associates (1) represent the nodular fat necrosis of pancreatic disease rather than relapsing febrile nonsuppurative panniculitis (WeberChristian disease). R O B E R T A. M C D O N A L D , M . D . N I C H O L A S L O W E , M.B., M.R.C.P.

Department of Medicine University of Wisconsin Madison, WI 53706


1. FEIGENBAUM H: Echocardiographic diagnosis of pericardial effusion. Am J Cardiol 26:475-479, 1970 2. GRAMIAK R, WAAG RC: Cardiac Ultrasound. St. Louis, C.V. Mosby Company, 1975, p. 112 3. GREENE DA, KLEID SJ, NAIDU S: Unusual echocardiographic manifes-

tation of pericardialfluid.Am J Cardiol 39:112-115, 1977 In reply:


ciency with severe panniculitis. Report of two cases. Ann Intern Med 86:742-744, 1977 2. SZYMANSKI FJ, BLUEFARB SM: Nodular fat necrosis and pancreatic disease. Arch Dermatol 83:224-229, 1961 3. DEMIS DJ, et al: Clinical Dermatology. Hagerstown, Maryland, Harper and Row Publishers, Inc., 1977, Unit 8-5 4. LEVER WF, SCHAUMBURG-LEVER G: Histopathology of the Skin, 5th

ed. Philadelphia, J.B. Lippincott Company, 1975, pp. 231-234

We fully agree with Dr. Sasse. Furthermore, his second reference is the chapter about echocardiographic evaluation of pericardial effusion written by one of us. The mentioned technique is routinely performed for this type of evaluation in our laboratory. Specifically, in our Cases 2 and 3, the sonolucence behind the epicardium of the left ventricular posterior wall disappeared on sweeping to the posterior left atrial wall. In Case 1, we do not have a sweep, but there was no sonolucence behind the left atrial wall, and the right atrial angiogram corroborated the echocardiographic findings. JOSE M E L L E R , M . D .



L O U I S E. T E I C H H O L Z , M . D . , F.A.C.P.

I do not believe that classification of panniculitis is important. If patients with idiopathic panniculitis (Weber-Christian disease) can have pancreatitis and visceral fat necrosis that includes peripancreatic tissues, if there is a distinct syndrome of primary pancreatic disease with secondary panniculitis, and if, as I believe, that histologic criteria for panniculitis are not highly accurate, it is clear that this overlap will make it difficult to classify many cases. Furthermore, many believe, and I agree, that Weber-Christian disease is not a homogeneous disorder but is more of a syndrome with a number of entities included. What is needed are clues to mechanisms, and this is what led us to report the two instances of severe panniculitis (however they are classified) associated with severe (PiZZ) alpha,-antitrypsin deficiency. H E R B E R T M. R U B I N S T E I N , M . D . , F.A.C.P.

Loyola University Stritch School of Medicine May wood, IL 60153 Pericardial Echocardiography TO T H E EDITOR: Millman and colleagues maintain, in "Pericardial Tumor or Fibrosis Mimicking Pericardial Effusion by Echocardiography" (Ann Intern Med 86:434-436, 1977), that their echocardiograms "represent true findings and not 'falsepositives' because they were taken in standard position and were taken using the usual method for evaluation of the pericardium." However, the main criterion used was a sonolucent space between the apparent posterior epicardium and pericardium according to a 1970 reference (1). More recent publications have stressed the need for sweeping the transducer from the posterior left ventricular wall to the posterior left atrial wall where the sonolucence due to pericardial effusion disappears, while other sonolucencies are unrelated to the pericardial reflections posterior to the posterior left atrial wall (2). Cases of pericardial effusion posterior to the posterior left atrial wall are so rare that they are still subjects of published case reports (3). Transducer sweeping from the posterior left ventricular wall to the posterior left atrial wall is standard technique for evaluating and diagnosing pericardial effusion; it would be of interest to know the results of such sweeps in the cases reported by Millman and co-workers. If the sonolucencies described disappeared behind the posterior left atrial wall in all three patients, the evidence for "mimicking pericardial effusion" would be stronger than the published report. L E W I S SASSE, M . D . , F.A.C.P.

Southern California Permanente Medical Group Los Angeles, CA 90027

Division of Cardiology The Mount Sinai Hospital New York, N Y 10029 Cellular Proliferation and Hypokalemia TO T H E EDITOR: The occurrence of hypokalemia with the blast crisis of acute myeloid leukemia has been described by Mir and co-workers (la), and accounts of hypokalemia in other leukemic states have been reported by correspondents to Annals of Internal Medicine (lb, lc). A recent report (2) in the pediatric literature describing eight cases shows that this phenomenon is not confined to adult patients with leukemia. Although the mechanisms responsible for the development of hypokalemia have not been fully delineated, current evidence suggests that it results from renal potassium wasting or intracellular movement of potassium. Some hypokalemic leukemic patients manifest increased renal potassium excretion that may be caused either by the large sodium content or the strong concentration of negatively charged anions presented to the renal tubules by some antibiotic preparations (3). The kaliuretic effect of lysozyme (lb) that has also recently been demonstrated in the isolated perfused kidney (4) and possibly the effect of increased aldosterone production in the volume-contracted patient are additional causes of hypokalemia. In other patients, however, balance studies fail to show renal potassium wasting, and in these patients intracellular potassium sequestration is undoubtedly playing an important role ( l c ) . With rapid production of large numbers of cells, many of which are immature, there is increased sequestration of the dominant intracellular cation, potassium. Thus, Na + — K + ATPase activity is higher in leukemic leukocytes than in normal leukocytes, and the augmented enzyme activity and higher potassium content parallel the morphologic immaturity of the leukemic cells (5) (though whether this increased enzyme activity is a primary event is undetermined). Furthermore, soon after therapy of megaloblastic anemia with either B12 or folate, significant (and occasionally fatal) hypokalemia may develop that coincides with the onset of reticulocytosis, rise in platelet count, rise in erythrocyte potassium content, and fall in urinary potassium concentration (6). Hypokalemia may also occur during correction of iron deficiency anemia, and younger erythrocytes contain higher potassium concentrations than older ones (7). When one considers the essential requirement for potassium in protein synthesis and growth, the intracellular shift of this cation becomes more understandable. We suggest, therefore, that the cause of hypokalemia in conditions associated with enhanced cellular proliferation is multifactorial, engendered in some instances by the assault on the Letters and

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kidneys of potential toxins and in many others by the essential metabolic and chemical demands of the proliferative state itself. F R E D J. S C H I F F M A N , M . D .

National Cancer Institute Bethesda, M D 20014 R O B E R T L. S C H I F F M A N , M . D . R O B E R T M. R O S A , M . D .

Beth Israel Hospital Boston, M A 02215 REFERENCES IA.

M I R MA, B R A B I N B, T A N G OT, L E Y L A N D MJ, D E L A M O R E IW: Hypo-

k a l e m i a in acute myeloid leukaemia. Ann Intern Med 82:54-57, 1975 1B. G R E E N B E R G E R JS, R O S E N T H A L DS, M O L O N E Y WC: Hypokalemia in

leukemia. Ann Intern Med 82:854, 1975 lc.

K O S M I D I S P, JAMSEK M, A X E L R O D AR: Hypokalemia in leukemia.

Ann Intern Med 82:854-855, 1975 2. O ' R E G A N S, K A P L A N BS, C H E S N E Y RW, A Y O U B JIG, D R U M M O N D

KN: Hypokalemia in children with leukemia in relapse. Am J Dis Child 130:937-940, 1976 3. CHESNEY RW: Drug-induced hypokalemia. Am J Dis Child 130:10551056, 1976 4. M A S O N DY, H O W E S DT, T A Y L O R CR, R O S S BD: Effect of human

lysozyme (muramidase) on potassium handling by the perfused rat kidney. / Clin Pathol 28:722-727, 1975 5. BLOCK JB, B O N T I N G SL: Sodium-potassium activated ATPase and ca-

tion transport in normal and leukemic human leukocytes. Enzymol Biol Clin 4:183-198, 1964 6. JAMES G W III, A B B O T T L D J R : Metabolic studies in pernicious anemia. I. Nitrogen and phosphorus metabolism during vitamin B12-induced remission. Metabolism 1:259-270, 1952 7. JOYCE CRB: Uptake of potassium and sodium by parts of packed human blood cell column. Q J Exp Physiol 43:299-309, 1958

Factor VIII and Renal Disease TO THE EDITOR: Recent studies (1-3) have indicated that levels of factor VIII are increased in chronic renal disease. One study (3) in which patients were seen over a period of 4 years showed that increased factor VIII levels at the time of diagnosis were associated with deteriorating renal functions, progressive renal disease, and poor prognosis. To explore these prognostic implications, we measured factor VIII levels in 32 patients (mostly children) who underwent percutaneous renal biopsies for nephrosis, disseminated lupus erythematosus with renal involvement, and vasculitis (anaphylactoid purpura) with renal involvement. The investigation of each child included factor VIII procoagulant activity by the partial thromboplastin time or thromboplastin generation time methods; factor VHI-related antigen by the Laurell technique; clinical diagnosis; pertinent clinical data such as proteinuria, hematuria, hypertension, and renal insufficiency; and histologic classification by percutaneous renal biopsy. The mean age of these children was 11 x/2 years with a range of 2 to 28 years (six patients were older than 16 years of age, all with disseminated lupus erythematosus. Of the 32 patients studied, 15 had steroid-responsive nephrotic syndrome and were biopsied because of frequent relapses. Nine of these 15 had elevated factor VIII procoagulant activity, and nine had elevated factor VIII antigen levels. In this group, 13 had minimal-change lesions on histologic examination. Factor VIII levels were not helpful in separating the minimalchange lesions from other histologic types. Ten patients in the series had disseminated lupus erythematosis, seven of whom had elevated VIII activity levels and eight of whom had elevated antigen levels. A s with the previous group, VIII levels were not helpful in distinguishing between these patients in terms of histologic type or clinical signs. A third group of patients included seven who had vasculitis (that is, anaphylactoid purpura). Of these, five had elevated factor VIII antigen levels and two had elevated activity levels. Figure 1 shows the results of factor VIII activity and antigen levels in these three patient groups. Except for VIII antigen levels in the vasculitis patients, the distribution of the factor VIII levels was similar in all groups. 6 3 6


Figure 1 . Percent of factor VIII activity {circle symbol) and factor VIII antigen {square symbol) levels in patients with renal disease. dle=disseminated lupus erythematosus.

Ekberg, Nilsson, and Linell (3) studied a large number of patients, 70% of whom were older than 12 years of age and only 5% of whom had minimal-change lesion. In their study, the data indicate that factor VIII levels were associated with a poor outlook in terms of deteriorating renal function. In our patients, too, decreased creatinine clearance and evidence of renal insufficiency were associated with elevated VIII levels (eight of nine patients in this clinical category had increased factor VIII). This relation also held for both proteinuria (17 of 20 patients with proteinuria had elevated VIII) and nephrotic syndrome (nine of 12 had increased VIII). However, we cannot conclude that the patients with high VIII levels will fare worse than those with normal levels. The factor VIII levels of the groups of patients in Figure 1 were all elevated similarly. Children with steroid-responsive nephrosis and minimal-change lesions generally have a better outlook than those patients with disseminated lupus erythematosus and vasculitis (4). Thus, the prognostic relation between factor VIII renal disease in childhood is not upheld by our observations. The reason for, or significance of, elevated factor VIII in children with minimalchange lesions is not clearly understood. Prospective studies to delineate this observation further are underway. D A N I E L R. A M B R U S O , M . D . D E N N I S P. D U R A N T E , M . D . R A W L E M. M C I N T O S H , M . D . W I L L I A M E. H A T H A W A Y , M . D .

Department of Pediatrics University of Colorado Medical Center Denver, CO 80262 REFERENCES 1. T H O M S O N C, F O R B E S CD, P R E N T I C E CRM, K E N N E D Y AC: Changes in

blood coagulation and fibrinolysis in the nephrotic syndrome. Q J Med 63(171):399-407, 1974 2. EKBERG M, NILSSON IM: Factor VIII and glomerulonephritis. Lancet 1:1111-1113, 1975

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3. E K B E R G MR, NILSSON IM, L I N E L L F: Significance of increased factor

VIII in early glomerulonephritis. Ann Intern Med 83:337-341, 1975 4. R U B I N MI, BARATT TM: Prognosis, in Pediatric Nephrology, edited by R U B I N MI. Baltimore, Williams & Wilkins Co., 1975, pp. 468-470

Osteopenia TO THE EDITOR: We have read with great interest the excellent review of Thomson and Frame, "Involutional Osteopenia: Current Concepts" (Ann Intern Med 85:789-803, 1976). We wish to describe some of our findings and our hypothesis on the pathogenesis of postmenopausal osteoporosis. 1. In accord with the findings of Urist and Vincent we have found that urinary excretion of androgen metabolites is lower in patients with postmenopausal osteoporosis than in matched control subjects (1). 2. Conjugated dehydroepiandrosterone in the plasma of osteoporotic patients is significantly decreased (2). 3. The decreased calcitonin sensitivity in male rats after castration is well known; we have confirmed this observation and shown that calcitonin sensitivity is also decreased in isolated adrenal sex-hormone deficiency (3). The decrease is greatest when both castration and adrenalectomy are done. While oestrogens fail to restore normal sensitivity, both virilising and nonvirilising androgens do. 4. After intravenous calcium load the peak and duration of hypercalcaemia is consequently higher and longer in patients with osteoporosis than in control subjects. The difference is most striking at 60 minutes. The calcium-tolerance curve returns to normal in osteoporosis after 7 days on dehydroepiandrosterone sulphate (Bonapace, Milan, Italy), 100 mg/day orally, or nortestosterone phenylpropionate (Richter, Budapest, Hungary), 2 X 25 mg/week intramuscularly, but remains unchanged in control subjects (4, 5). We think that these findings confirm our supposition that androgen deficiency lowers calcitonin sensitivity in human postmenopausal osteoporosis. Our hypothesis for postmenopausal osteoporosis is that bone is protected by an unexplained oestrogen effect and by an androgen-dependent calcitonin action. Oestrogen deficiency per se does not lead to pathologic bone resorption, but combined oestrogen-androgen deficiency results in postmenopausal osteoporosis. I. H O L L 6 , M . D . , D . M E D . SCI.

J. Szucs, M.D. M. BOROSS

pausal period may alter calcitonin production or biologic effect and thus eventuate in involutional osteopenia is interesting. However, there is evidence against their hypothesis. With regard to androgens and their possible etiologic role in the development of involutional osteopenia, the following facts seem to counter their idea, [a] Skeletal receptors for androgens have yet to be identified in man, although clinical studies with these agents suggest they may exist, [b] Although there may be plasma differences for the weak androgen dehydroepiandrosterone between osteoporotics and nonosteoporotics, the data of Riggs and colleagues (1) have shown that the plasma levels of the far more potent androgen, testosterone, are similar in the two groups. This has also been confirmed with the recent finding that the postmenopausal ovary maintains or increases its secretion of testosterone well into the menopausal period (2). [c] In Gordan's long-term study of patients on estrogen and anabolic agents (3), the fracture incidence for the anabolic agent was five times that of patients taking estrogens. Similarly, there seem to be few data that substantiate a role for calcitonin as a factor in the genesis of involutional osteopenia, [a] To date, there has been no study to confirm that pharmacologic levels of calcitonin have altered the development of osteoporosis, [b] Although there is evidence that in young animals or man physiologic levels of calcitonin may alter bone remodeling, there has been no evidence suggesting that this hormone has any sustained biologic effect in the normal adult, [c] Calcitonin secretion levels may be set in tandem with that of parathyroid hormome, the two calciotropic hormones determining plasma calcium levels, but there is no proof of this thesis. Riggs and associates (1) have shown, using an amino terminal assay for parathyroid hormone, that most patients with osteoporosis have low levels of the hormone, which increases with the use of estrogens or anabolic steroids. Thus, it is not unexpected that calcitonin secretion may be depressed in osteoporosis. The chronic hyposecretion of calcitonin may well prevent a normal response to acute calcium loading, and this response may be normalized with the introduction of an anabolic steroid. Our suggestion would be that if sex steroids alter calcitonin levels in involutional osteopenia, this is an indirect response mediated by alteration of parathyroid hormone secretion and not by a direct effect of the steroids themselves on calcitonin secretion or effect. In summary, if hormonal factors are playing any part in the genesis of involutional osteopenia, the major abnormalities are with secretion of parathyroid hormone and estrogens. We do not believe that alterations of calcitonin and androgen secretion or effectiveness can account for involutional bone loss.


First Department of Medicine and Gerontologic Research Group Semmelweis University Medical School 1083 Budapest, Koranyi Sandor u 2 / A , Hungary

D A V I D L. T H O M S O N , M . D . B O Y F R A M E , M . D . , F.A.C.P.

Department of Medicine Henry Ford Hospital Detroit, MI 48202


1. H O L L 6 I, F E H E R T: Studies on postmenopausal osteoporosis. I. Urinary excretion of 17-ketosteroid fractions in postmenopausal osteoporosis. Acta Med Acad Sci Hung 20:233-235, 1964 2. H O L L 6 I, F E H E R T, SZUCS J: Serum dehydroepiandrosterone, androster-

one and Cortisol level in primary postmenopausal and other type osteoporosis. Acta Med Acad Sci Hung 27:155-160, 1970 3. H O L L 6 I, BOROSS M, SZUCS J: Effect of sex hormone deficiency on calci-

tonin-induced hypocalcaemia. Akt Geront 8:609-616, 1975 4. H O L L 6 I, S z u c s J, STECZEK K: Effect of norandrosterone-decanoate on

calcium tolerance curves of patients with primary osteoporosis. Data on the mode of action of anabolic compounds in osteoporosis. Endokrinologie 58:326-330, 1971 5. H O L L 6 I, SZALAY F, STECZEK K, S z u c s J: Terheleses serum-calcium-

REFERENCES 1. R I G G S BL, J O W S E Y J, K E L L Y PJ, A R N A U D CD: Role of hormonal fac-

tors in the pathogenesis of postmenopausal osteoporosis. Isr J Med Sci 12:615-619, 1976 2. J U D D HL, J U D D GE, LUCAS WE, Y E N SSC: Endocrine function of the

postmenopausal ovary: concentrations of androgens and estrogens in ovarian and peripheral vein blood. / Clin Endocrinol Metab 39:10201024, 1974 3. G O R D A N GS, V A U G H A N C: Clinical Management

of the


Acton, Massachusetts, Publishing Sciences Group, Inc., 1976, p. 94

Correction: Resorcinol and Hypothyroidism

gorbe postmenopausal osteoporosisban. Diagnosztikai eljaras. Magy Belorv Arch 28:194-198, 1975



We welcome the hypothesis of Dr. Hollo and colleagues. Their theory that a decrease of androgenic steroids in the postmeno-

TO THE EDITOR: The article by Dr. Katin and colleagues, "Resorcinol-Induced Hypothyroidism in a Patient on Chronic Hemodialysis'* (Ann Intern Med 86:447-449, 1977), was certainly of great interest. However, they stated that "the T3R stabilized at a lower than normal level, probably a reflection of decreased binding proteins (albumin, 3.5 g/dl and total proteins, 5.7 g / Letters

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dl)." Since, according to their article, T3R was meant to represent T3 resin uptake, the quoted sentence is obviously in error. As is widely known, the technique of the T3 resin uptake is such that with a decrease in thyroid hormone-binding proteins there is an increase in the T3 resin uptake, and with an increase in the thyroid hormone-binding proteins there is a decrease in the T3 resin uptake (1). Because of existing confusion between the T3 resin uptake and the T3 by radioimmunoassay and confusion in the technique of the T3 resin uptake, the incorrect statements made by Dr. Katin and colleagues should not go unnoticed or uncorrected. E D W A R D B. R U B Y , M . D .

Intern Med 86:754-783, 1977) provides an exhaustive literature review of drug dosing in the presence of renal failure. However, the paper contains two erroneous statements. The authors state that any drug dose used with normal renal function would need to be divided by the ratio of the normal half-life to the observed biological (renally impaired) half-life to find the dose in renal failure. They further state that any interval between drug doses used in patients with normal renal function would be multiplied by the ratio of the normal half-life to the renally impaired half-life to find the dosing interval in renal failure. Apparently the errors in the manuscript were oversights.

Endocrinology and Metabolism Second General Hospital APO New York 09180


Department of Pharmaceutical Services Hutzel Hospital Detroit, MI 48201

REFERENCE 1. INGBAR SH, W O E B E R KA: The thyroid gland, in Textbook of Endocrinology, 5th ed., edited by WILLIAMS RH. Philadelphia, W.B. Saunders Company, 1974, pp. 137-140



Thanks also to William Fineman, M.D., Albert Einstein Medical Center, Northern Division, Philadelphia, for bringing this to our attention. Measurements of thyroid-binding globulin, thyroid-binding protein albumin, and a repeat T3 by radioimmunoassay should have been made to clarify this matter. A possible explanation for the low T3 resin uptake is impaired conversion of T4 to T3 in patients with chronic renal failure on hemodialysis, as described by Lim and co-workers in 1975 (1). M I C H A E L J. K A T I N , M . D .

Department of Nephrology Lankenau Hospital Philadelphia, P A 19151 REFERENCE 1. L I M VS, F A N G VS, R E F E T O F F S, K A T Z AI: T 3 hypothyroidism in uremia: impaired T 4 to T 3 conversion. International Congress of Nephrology, Florence, Italy, Abstract No. 636, 1975

Correction: Drug Treatment of Asthma TO T H E EDITOR: I wish to make a correction in our paper in the July 1977 issue, "Drug Therapy in the Management of Asthma" (Ann Intern Med 87:68-74, 1977). In the paragraph on inhaled glucosteroids (p. 72) we stated that lipid-soluble steroids are poorly absorbed when swallowed. It is true that they do not reach the systemic circulation to a notable degree. However, the probable mechanism is that the sparingly soluble steroid is slowly absorbed, which allows the liver to convert most of the drug to pharmacologically inactive polar metabolites. This is supported for beclomethasone by the work of Martin, Harrison, and Tanner (Reference 37 in our paper).

TO T H E EDITOR: I wish to bring to your attention a printing error regarding the use of methenamine mandelate and metronidazole in renal failure in the article by Bennett and associates (Ann Intern Med 86:754-783, 1977). In Table 1 the first two lines on ineffectiveness in renal failure under "Toxic Effects and Remarks" for metronidazole on pp. 758-759 actually apply to methenamine mandelate on pp. 756-757. A L A N D. TICE, M . D .

Veterans Administration Hospital Brown University Providence, RI 02908 In


I am grateful to Dr. Cornelis for pointing out the transpositions of words that result in erroneous statements in "Guidelines for Drug Therapy in Renal Failure." The sentence on p. 755 should read, "With any ideal drug excreted entirely by the kidney according to first-order kinetics, any dose used with normal renal function would need to be divided by the ratio of the observed biological half-life to normal half-life to find the dose in renal failure. Likewise, any interval between doses used in patients with normal renal function would be multiplied by the same ratio to find the appropriate dose interval in renal failure." The printing error pointed out by Dr. Tice is also known to us, and he is quite correct that the first two lines on ineffectiveness in renal failure apply to methenamine mandelate, not to metronidazole. W I L L I A M M. B E N N E T T , M . D .

Department of Medicine University of Oregon Health Sciences Center Portland, OR 97201 Correction: Editor of Book

P A U L P. V A N A R S D E L , JR., M . D .

Department of Medicine (RM-13) University Hospital Seattle, WA 98195

TO T H E EDITOR: The June issue (p. 837) contained a book review by Dr. Michael T. Shaw, Management of the Patient with Cancer, published by the W.B. Saunders Co. The review mistakenly identified the editor of the book as Thomas F. Nelson, Jr.—the correct name is Thomas F. Nealon, Jr.

Correction: Drugs and Renal Failure TO T H E EDITOR: The article by Bennett and co-authors (Ann


November 1977 • Annals of Internal Medicine • Volume 87 • Number 5

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V I N C E N T A. D E G E N N A R O , M . D .

2 Hawthorne Place Boston, M A 02114

Sterility of blood collection tubes.

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