COMMENTS

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. Medical Ethics TO THE EDITOR: Medical ethics is a charged field, but I read with alarm Dr. Ingelfinger's "The Unethical in Medical Ethics" (1) and noted these points: it was received and accepted on the same day, 14 May 1975; most other articles in the August issue were received much earlier and accepted only after substantial delays; and Dr. Ingelfinger is associated with a major journal that is generally thought to be a competitor of "The Annals." The rapid publication of this paper, which cannot have been critically reviewed, can, from the viewpoint of other authors in the journal, only seem to be unfair. And "to be unfair is to be unethical" ( 1 ) . The tenor of the article speaks for itself. Specifically, I would point to the standard devices of style and the arguments in just one area, where the author spoke of "prisoners as a privileged class." Half of that section was devoted to noting the lack of an ultimate source for Mitford's quotation: "Criminals in our penitentiaries are fine experimental material—and much cheaper than chimpanzees." Doctor Ingelfinger at no stage addressed himself to the premise, which is of course true, even if provocative. That the original source is not available has no relevance at all to the content of the statement. The rest of that section of the paper managed to compare prisoners with draftees. By carefully intertwining separate arguments about these separate classes of people, he concluded that prisoners "should not be excluded as subjects for experiments that may help save lives of others required to make greater sacrifices." A nice slug of emotion that may just slip past our logical defenses. The comment is relevant only if prisoners and draftees are mutually exclusive categories to be compared validly with each other. This cannot be done. I have addressed myself to Dr. Ingelfinger's method, for it is this that I regard as far more important than his arguments. But my real worry is that even a great clinical scientist, editor, and educator should be in just the same position as the rest of us when it comes to the discussion of medical ethics. However, he is not: the structure of the medical press gives undue emphasis to the views of the clinical scientist. In a topic as tremendously important as the discussion of medical ethics, this is a most dangerous advantage for a person of that vocation. ROGER J. LEWIS, M.D. 900

Harlem Hospital Center 135th Street and Lenox Avenue New York, New York 10037 REFERENCE

1. INGELFINGER FJ: The unethical in medical ethics. Ann Intern Med 83:267-270, 1975

TO THE EDITOR: I think that Dr. Ingelfinger has overreacted to the sensationalism that is part of the criticism of medical experimentation standards [Reference 1, above]. Medical research is already the beneficiary of a hefty amount of well-tolerated propaganda to help correct any imbalance (1). In particular, I am disturbed by Dr. Ingelfinger's appeal to the concept of "distributive justice" to defend research on prisoners. Although he is not completely explicit, the argument that risks should be divided as equally as possible among the military-exempt prisoners and the men in combat suggests that the rate of morbidity and mortality on the battlefield provides a reasonable standard of acceptable risk in medical experiments on prisoners, at least those experiments directed to solving military medical problems. During some of the more brutal wars of recent history, these standards would be rather lax. I, too, do not accept the point of view that omnipresent overt duress excludes prisoners from all medical studies; however, Dr. Ingelfinger's attempt to circumvent the argument with the concept of distributive justice is ill-founded. It is hard to resist pointing out that the far larger population of military-exempt people consists of American women, who perhaps should then be approached as the appropriate group for such experimentation. Perhaps, Dr. Ingelfinger's article was intended as a crusading piece rather than a balanced assessment. ROBERT R. LIVINGSTON

University of Pennsylvania Medical School Philadelphia, Pennsylvania REFERENCE 1. GREENBERG DS: "Progress" in cancer research—don't say it isn't

so. N Engl J Med 292:707-708, 1975

In comment: As Daniel Callahan has written, ethicists or would-be ethicists who criticize medicine, and those who in turn belabor the critics "dote on each other's excesses" ( 1 ) . But this is only natural; otherwise, one would have to discuss the basic need for medical ethics or for medicine, topics only a few (for example, Ivan Illich) would tackle. There is no question of trying to balance the morbidity and mortality risks of prisoners participating in an experiment, and of those exposed to military action; the question is whether prisoners should be expected to share, even to a small degree, military risks. And I find it unfortunate that

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Dr. Lewis is not more distressed by the use of an inflammatory canard. FRANZ J. INGELFINGER, M.D. New England Journal of Medicine 10 Shattuck Street Boston, Massachusetts 02115 REFERENCE 1. CALLAHAN D: The ethics backlash. Hastings Center Rep 5(4): 18, 1975

This journal strives to publish papers as rapidly as the adequacy of acceptable manuscripts, the capacities of our staff, and the intervals of our publishing schedule permit. I heard Dr. Ingelfinger read his paper at the Annual Session of the College in April and formed a preliminary judgment on the desirability of publishing it if he were to give us the privilege of considering it for publication. He took up the option offered to all presenters of papers at the Annual Session and sent the manuscript to us. My reading of the manuscript on its arrival confirmed for me my earlier judgment that Dr. Ingelfinger's views were worth adding to public debate on these serious issues and that his views were argued clearly and in detail, with documentary support; further, the manuscript was ready for publication without revision. Doctor Ingelfinger is not the sole recipient of prompt editorial action in this office, some others of less eminence, or none, having gotten similarly prompt readings of their papers. The implication that he received "advantageous" treatment because he is an eminent clinical investigator is without basis in fact; we have rejected, sometimes promptly, plenty of papers, scientific and polemic, from authors in the same "Establishment" Certainly Dr. Lewis is entitled to a view on whether a manuscript read by me, alone, has been "critically reviewed."—The Editor

Renal Vein Thrombosis TO THE EDITOR: In the July issue, Llach, Arieff, and Massry (1) reported from a careful, prospective study that they had detected an alarmingly high incidence (33%) of renal vein thrombosis in patients with the nephrotic syndrome, which in most cases was secondary to membranous and membranoproliferative glomerulonephritis. Of equal concern was the finding that the majority of patients had no symptoms, laboratory findings, or radiographic clues on intravenous pyelography to suggest that renal vein thrombosis was present. They point out that the prognosis, as far as rapid deterioration of renal function is concerned, is not as ominous as has been previously reported in renal vein thrombosis. Their study, however, does not allow evaluation of the extent of venous occlusion, as they do not present detailed angiographic findings or criteria for establishing the diagnosis of renal vein thrombosis, leaving some doubt as to the interpretation of the findings. The authors also point out that renal vein thrombosis may occur in the absence of the nephrotic syndrome, and that the latter in all likelihood may be the cause, rather than the result, of renal vein thrombosis. It is therefore possible that renal vein thrombosis has little effect on the course of the primary disease, except in its more extreme

instances. The authors' study offers the opportunity to evaluate the long-term effect of renal vein thrombosis on the course of membranous and membranoproliferative glomerulonephritis. Unfortunately, the follow-up was relatively short in terms of the particular renal disease (4 to 24 months), and they do not present the follow-up data in the group without renal vein thrombosis. Should this information be available, it might add significantly to our understanding of the long-term functional effect of renal vein thrombosis on the course of patients with the nephrotic syndrome. Lastly, of their 30 patients with either membranous or membranoproliferative glomerulonephritis, there was a 40% incidence of renal vein thrombosis and a 26.6% incidence of pulmonary embolism (4 of 12 with and 4 of 18 without renal vein thrombosis), suggesting that prophylactic anticoagulation might be considered in patients with nephrotic syndrome secondary to these and possibly other causes. DONALD E. BUTKUS, M.D.

Nephrology Service Fitzsimons Army Medical Service Denver, Colorado 80240 REFERENCE 1. LLACH F, ARIEFF AI, MASSRY SG: Renal vein thrombosis and nephrotic syndrome. A prospective study of 36 adult patients. Ann Intern Med 83:8-14, 1975

In reply: We agree that the incidence of the thromboemboli phenomenon reported in our article is very high. Others have recently reported that renal vein thrombosis was noted in 30% of patients with membranous glomerulonephritis (1). Our diagnosis of renal vein thrombosis was made with the inferior vena cavagram and selective right and left catheterization. No vasoconstrictor agents were used. This is not a difficult method in trained hands, and the interpretation of results was not a problem. There was complete or almost complete obstruction of the renal vein in all reported cases, with different patterns of collateral circulation, so that the diagnosis was unequivocal. We agree that the follow-up period of patients with renal vein thrombosis was short, and that the follow-up data in the group of patients without renal vein thrombosis would have been most informative. We are currently evaluating in another prospective study our nephrotic syndrome population at USC Medical Center for [a] frequency of thromboembolic phenomena as assessed by a routine inferior vena cavagram and ventilation perfusion lung scan; [b] effect of the renal vein thrombosis on renal function; and [c] long-term effects of oral anticoagulant therapy. At present, we can confirm a similar incidence of renal vein thrombosis and other thromboembolic phenomena in our new patients with nephrotic syndrome due to membranous or membranoproliferative glomerulonephritis. FRANCISCO LLACH, M.D. ALLEN ARIEFF, M.D., F.A.C.P. SHAUL G. MASSRY, M.D., F.A.C.P.

School of Medicine LAC-USC Medical Center 2025 Zonal Avenue Los Angeles, California 90033 Comments

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REFERENCE

1. TREW PA, BIAVA CG, JACOBS RP, et al: Renal vein thrombosis

(RVT) and membranous glomerulonepathy: incidence and relationship (abstract). 7th Annual Meeting of American Society of Nephrology

Renal Effects of Urography in Diabetes Mellitus TO THE EDITOR: The recent paper, "Acute Renal Failure After Excretory Urography in Diabetic Patients" by DiazBuxo and associates (Ann Intern Med 83:155-158, 1975), prompts us to report a similar case that we have seen at our institution. A 58-year-old black woman with diagnoses of rheumatic heart disease, aortic stenosis, and congestive heart failure was admitted to the Medical College of Pennsylvania Hospital on 9 August 1975 for cardiac evaluation. She had a 30-year history of diabetes mellitus, for which she was taking insulin. Her only other medications were digoxin and furosemide. At admission her blood urea nitrogen (BUN) level was 37 mg/dl and her serum creatinine concentration was 2 mg/dl. Her 24-hour urine output was 1440 ml. On 12 August 1975 right and left cardiac catheterization with coronary angiography (200 ml of meglumine and sodium diatrizoate [76%] dye) was performed uneventfully. However, after the study oliguria was observed, although the patient did not develop any severe arrhythmia or hypotension. Mannitol (25g) and furosemide (Lasix®, 120 mg intravenously) were given, which failed to increase her urine output. Her 24-hour urine outputs were 19 ml, 55 ml, and 124 ml for the next 3 days. Urinalysis, which was negative before cardiac catheterization, now showed trace protein, 5 to 10 leukocytes/high power field, and a few tubular cells. Her blood urea nitrogen level increased to 57 mg/dl and serum creatinine concentration went up to 3.3 ml/dl. The patient developed a diuresis on the fourth day after cardiac catheterization, with gradually increasing urine output and a return of the patient's BUN and serum creatinine to the original levels of 35 mg/dl and 2 mg/dl, respectively, by the eighth day after the initial study. Our case and the report of Diaz-Buxo and co-workers indicate that acute oliguric renal failure is not uncommon after the use of contrast materials. Diabetic patients, especially those with some degree of renal impairment, are potentially poor-risk patients for not only excretory urography, but also for various angiographic studies in which large amounts of contrast materials are often used. After undergoing contrast studies, a diabetic patient should be closely monitored for urine output, renal function, and complications associated with acute oliguric renal failure. BRAJESH N. AGARWAL, M.D. FRANKLIN CABEBE, M.D. CYNTHIA MCCORMICK, MEDICAL STUDENT

Department of Nephrology The Medical College of Pennsylvania Philadelphia, Pennsylvania 19129

TO THE EDITOR: We wish to confirm the frequent occurrence of oliguric renal failure after urography in diabetic patients, as described by Diaz-Buxo and associates in a recent issue. We have seen two such patients in the past 2Vi months. Both patients were elderly men (74 and 80 years) with longstanding diabetes mellitus (20 and 33 years), nephropathy, cataracts, and advanced peripheral vascular disease. Their disease was currently controlled on diet alone. One patient was hypertensive (180/120 mm Hg) and the other normotensive (110/70 mm Hg). Both patients were without fluid intake for greater than 12 hours before the study, and both received meglumine diatrizoate as the contrast agent. Oliguria was self-limited and persisted for 2 and 3 days, respectively. It was not influenced by the use of mannitol or furosemide. The renal failure was reversible (Table 1), and renal function returned toward pre-urography levels. Both patients were asymptomatic except for the observation of decreased urine volume (lowest urine volumes were 45 ml and 105 ml per 24 hours, respectively) within 48 hours of the excretory urogram. These cases are remarkably similar to the ones previously reported by Diaz-Buxo and co-workers, and they lend support to the concept that the diabetic patient is at risk for the development of renal failure from urography. Since both of our patients had rising blood urea nitrogen levels before urography, this is a factor to be considered in deciding when and whether to do such contrast studies in the diabetic patient. ROBERT MATZ, M.D., F.A.C.P. FERNANDO CAMACHO, M.D. ROBERT SABLE, M.D. DAVID SEINFELD, M.D.

Department of Medicine Montefiore-Morrisania Affiliation 168th Street and Gerard Avenue Bronx, New York 10452

Hemolysis from Hot Dialysate TO THE EDITOR: We read the paper by Berkes and associates (Ann Intern Med 83:363-364, 1975) with considerable interest and would like to describe the case of a patient who had a similar problem in our hemodialysis unit recently. A 43-year-old black man had been on hemodialysis for 2 years after developing malignant hypertension. His blood pressure had been well controlled during this period. One hour into a routine hemodialysis, the patient complained of feeling warm. This sensation became worse over a period of 10 minutes, at which time the air conditioner in the room was adjusted. Five minutes later he began to perspire, and it was noted that the bath temperature was 47 °C and the dialysate was steaming. The blood in the lines was returned to the patient, and he was changed to another machine. Five hours

Table 1 . Clinical Data

Patient

Blood Urea Nitrogen Before Urography

After Urography, Maximal

62->87 39-*49

126 80

After Urography, Last

Before Urography

After Urography Maximal

Last

9.2 11.2

4.1 2.4

**f#r/r//

1 2 902

mg/cu 86 54

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3.2 3.2

later, at the end of dialysis, the patient noted only weakness and a "washed out" feeling. During the next 2 days he continued to feel tired, vomited greenish material, and had watery diarrhea. During the next dialysis 3 days later, there was difficulty maintaining the patient's blood pressure. It was then noted that his hematocrit level was 10% whereas it had been 21% 14 days before. Predialysis laboratory data on that occasion included blood urea nitrogen, 131 mg/dl; Na, 143 meq/ litre; K, 3.9 meq/litre; CI, 96 meq/litre; COa, 16 meq/litre; Ca, 9.9 mg/dl; P, 2.6 mg/dl; creatinine, 22.6 mg/dl; serum glutamic oxalacetic transaminase (SGOT), 8 IU/ml; serum glutamic pyruvic transaminase (SGPT), 107 IU/ml; bilirubin, 0.8 mg./dl (direct, 0.05, indirect, 0.75); lactic dehydrogenase (LDH), 2559 IU/litre; G-6-PD, normal; Coombs' test (direct and indirect), negative; alkaline phosphatase, 1.4 KA units/dl; haptoglobin, less than 40 mg/dl; leukocyte count, 25,300, with segs, 68%; bands, 4%; lymphs, 23%; monos, 2%; and eosinophils, 2%; 2 nucleated erythrocytes; amylase, 370 Somogyi units/dl; and lipase, 3.0 IU/ml. The patient was transfused to his usual hematocrit level of 20% to 22%. An upper gastrointestinal series was normal, and stool guaiac was negative. Seven days later the patient's hematocrit was 17%, and he was again transfused with two units of deglycerolized blood. Three weeks after the hyperthermic incident the patient's hematocrit was stable at 24.0%; bilirubin, 0.3 mg/dl; LDH, 419 IU/litre (normal 100 to 300); and haptoglobin, 78 mg/dl. The high LDH level, low haptoglobin level, and negative guaiac support hemolysis as the explanation for the rapid drop in. hematocrit. The probable cause of this hemolysis is consistent with the hypothesis set forth by Berkes and associates that temperatures between 47 °C and 51 °C cause a "chronic" form of hemolysis. Our patient also experienced nausea, vomiting, and diarrhea, which cleared rapidly after admission. The SGPT level returned to normal in 2 days, but the amylase and lipase levels remained elevated. There was no clinical or radiologic evidence of pancreatitis. B. HECHT, M.D. P. BERKMAN, M.D. M. E. RISCH, R.N.

Renal Division Department of Medicine Washington Hospital Center Washington, D.C. 20010 Alkalosis and Urate Clearance TO THE EDITOR: We read with interest about the increased prevalence of hyperuricaemia and gouty arthritis in patients with Bartter's syndrome (Ann Intern Med 83:56-59, 1975), but the authors' conclusions that systemic alkalosis can decrease the clearance of uric acid, and that physicians should be aware of this inhibitory effect of alkalosis on urate clearance, do not seem justified by the evidence presented. This evidence was obtained in a careful study of five patients with normal renal function, and the results were given in Table 2 of the paper. Systemic alkalosis was induced by substituting 100 meq sodium bicarbonate for 100 meq sodium chloride in the diet, and the significant rise in serum uric acid and fall in uric acid clearance observed were attributed to the alkalosis. Unfortunately, the creatinine clearance also fell during the period on sodium bicarbonate, and, although the fall was not significant, it may nevertheless be important. We have tabulated the coefficients for correlations of serum COz, serum K, and creatinine clearance with serum uric acid and uric acid clearance, using all the observations presented for the five patients with normal renal function

Table 1. Correlations of Serum C02v Serum K, and Creatinine Clearance with Serum Uric Acid and Uric Acid Clearance in Five Patients*

Serum C0 2 (no. = 9) Serum K (no. = 9 ) Creatinine clearance (no. = 10)

Serum Uric Acid

Uric Acid Clearance

+ 0.68 (P < 0.05) - 0.59 (P < 0.1) — 0.66 (P < 0.05)

- 0.69 (P < 0.05) + 0.49 + 0.82 (P < 0.005)

* Two observations per patient.

(Table 1). Serum C0 2 correlated significantly with serum uric acid and uric acid clearance, findings consistent with the authors' interpretation. However, creatinine clearance also correlated significantly with serum uric acid and uric acid clearance, and the positive relation between creatinine clearance and uric acid clearance was particularly impressive. Using partial correlations, this relation remained significant when serum C0 2 was held constant (r = +0.73, P < 0.05), whereas the correlation between serum C0 2 and uric acid clearance with creatinine clearance held constant, while still negative, was not significant (r = — 0.46, P > 0 . 0 1 ) . (Scatter diagrams suggested that the relationships with uric acid clearance were log-linear, and uric acid clearance was log transformed for partial correlations.) While examining changes in these variables within subjects, we found that changes in creatinine clearance correlated with changes in serum uric acid (r = —0.95, P < 0.02, n = 5) and in uric acid clearance (r = +0.97, P = 0.005, n = 5), although these correlations were heavily influenced by the results for their Patient 10. Nevertheless, changes in serum uric acid and uric acid clearance could not be related to changes in serum COz or serum K. Clearly, the changes in uric acid homeostasis in this study cannot be attributed with certainty to the altered acid-base status, and, if any causal inference is justified, the rise in serum uric acid and fall in urate clearance are more readily explained by the fall in creatinine clearance. Although current concepts of uric acid homeostasis maintain that excretion and clearance of uric acid are independent of the filtered load (1), we have recently found a highly significant positive correlation between creatinine clearance and uric acid clearance in healthy subjects (paper in preparation). Since this relation is evident in the data of Dr. Meyer and colleagues in their article in the July "Annals," it clearly warrants further evaluation. It remains possible that acid-base status may influence uric acid homeostasis. Systemic acidosis lowers serum uric acid (2), although this was attributed to redistribution and not to altered renal urate handling. However, the evidence that alkalosis is the principal factor, or even an important factor, in producing the hyperuricaemia of Bartter's syndrome seems weak, and other factors mentioned in the paper (extracellular fluid volume changes or angiotensin II) may equally be involved. It is also possible that aldosterone itself influences uric acid homeostasis. A direct role for mineralocorticoids in diuretic-induced hyperuricaemia has been proposed (3), and there is a positive relation between plasma uric acid and aldosterone excretion in healthy subjects (4). We suggest that the pathogenesis of hyperuricaemia in Bartter's syndrome needs further study. LAWRENCE RAMSAY, M.R.C.P. (UK) DAVID LEVINE, M.R.C.P. (UK) JOHN SHELTON, B.SC. Comments

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ROBERT BRANCH, M.R.C.P. ( U K ) RICHARD AUTY, M.R.C.P. ( U K )

Department of Medicine University of Glasgow Glasgow, Scotland G i l 6NT REFERENCES

1. STEELE TH, RIESELBACH RE: The renal mechanism for urate homeostasis in normal man. Am J Med 43:868-875, 1967 2. ZWEIFLER AJ, THOMPSON GR: Correction of thiazide hyperuricaemia by potassium chloride and ammonium chloride. Arthritis Rheum 8:1134-1144, 1965 3. GRIEBLE HG, JOHNSTON LC, FULLER JB: Treatment of arterial

hypertensive disease with diuretics. Arch Intern Med 110:33-44, 1962 4. RAMSAY LE, AUTY RM, HORTH CE, et al: Plasma uric acid level

related to the urinary excretion of aldosterone and of electrolytes in normal subjects. Clin Sci Mol Med, in press In reply: The induction of metabolic alkalosis in subjects with normal renal function was accomplished by substitution of 100 meq of sodium bicarbonate for 100 meq of dietary sodium chloride so as to avoid stimulation of the renin-angiotensinaldosterone systems. Since body weight and urinary sodium excretion (and presumably the volume of extracellular fluid) did not change, it appears that alkalosis was the basis for the decrease in creatinine clearance that occurred in most of the patients. A correlation of creatinine clearance with uric acid clearance present in our data and noted by Ramsay and co-workers in their unpublished observations is consistent with the possibility, but it does not establish the point that a decrease in the clearance of creatinine, such as that observed in our studies, can decrease the clearance of uric acid. Indeed, a decrease in the clearance of uric acid with alkalosis in two patients who either showed no change (Patient 13) or who showed a trivial decrease (Patient 14) in the clearance of creatinine suggests that the decrease in the clearance of uric acid did not necessarily depend on a decrease in creatine clearance. In any event, whatever the role of glomerular filtration in the clearance of uric acid, the conclusion from our studies that alkalosis can lead to a decrease in the clearance of uric acid should still be valid. As Ramsay and associates point out and as we noted in our discussion, there are a number of factors that could contribute to the development of hyperuricemia in Bartter's syndrome. In any potential multifactorial disorder it is difficult to be certain about the relative importance of any single factor. We, therefore, do not conclude, as they allege, that alkalosis is the "principal factor," but only that it may be important as a factor in the development of hyperuricemia by patients with Bartter's syndrome. JOHN R. GILL, JR., M.D. FREDERIC C. BARTTER, M.D.

National Heart and Lung Institute National Institutes of Health Bethesda, Maryland 20014

Amyloidosis and Behcet's Disease TO THE EDITOR: The recent paper by Rosenthal and colleagues (1) reports three patients with systemic amyloidosis and Behcet's disease. They quote a previous paper by us 904

(2) describing three cases of renal involvement in Behcet's disease. As our paper was published in a local journal in Rumania and some peculiar aspects differentiate our patients from those of Rosenthal and colleagues, we believe it worthwhile to summarize our findings. In our patients, the renal involvement manifested itself from 2 to 9 years after the first sign of the disease. They all had massive proteinuria (4 to 12 g/24 h), hypoproteinemia (4.2 to 5.2 g/dl), hyper as globulinemia, hypergammaglobulinemia, and hypercholesterolemia (325 to 385 mg/dl). Once installed, the renal involvement dominated the evolution of at least two cases. In Case 1, the patient had important and diuretic resistant oedema and died because of severe uremia and septic complications some months after the appearance of the oedema. The patient in Case 2 reached an advanced stage of uremia 2 years after his first oedema. We had anatomical data on the kidneys in only two cases. In Case 2, the renal biopsy showed extensive deposits of amyloid within the glomeruli, the small arteries, and arterioles. In Case 1, the autopsy showed the same involvement of the kidney and also showed large deposits of amyloid in the small arteries and arterioles of the myocardium, lungs, intestine, and spleen. Most impressive was the massive obliterating thrombosis found in most of the large veins (inferior caval, renal, portal, primitive and internal iliac, and femoral) and also in some smaller veins of the kidneys and the lungs. The intima of the affected veins was usually absent, and their media showed an excess of collagen. Abundant granular deposits of calcium were found in the thrombi, some pulmonary alveoli walls, and the media of some pulmonary veins. Some of these findings differentiate our patients from those of Rosenthal and colleagues. Effectively, their Patient 3 had only traces of an intermittent proteinuria; clinical features were never dominated by renal involvement, and their patients had a normal renal function when they died (Patients 1 and 3) or were last seen. Except for the thrombosis of inferior caval vein in their Patient 2, no mention was made of any venal structural changes or calcifications. However, in our opinion, the thrombosis of the main renal veins and even those of the smaller intrarenal veins may be an alternative explanation of the nephrotic syndrome in some particular cases. As for the extrarenal symptoms, all of our patients had the classic triad as well as recurrent arthralgia, fever, recidivant thrombophlebitis, and aseptic pustulae at the puncture site. Case 2 had also a severe meningoencephalitis syndrome, which subsided progressively under corticosteroid therapy. Both Cases 1 and 2 had a Staphylococcus aureus septicemia, which in Case 1 was complicated by a purulent pericarditis and many small pulmonary suppurative focuses. Although one can accept amyloidosis as an intrinsic manifestation of Behcet's disease, the association of a tenacious pyodermitis in all our cases made us think that amyloidosis was secondary to a chronic suppuration. In any event, it would be useful to make an early and precise diagnosis of amyloidosis, or renal vein thrombosis, because the steroids, which are indicated for some of the other manifestations of the disease (ocular, cerebral, articular), may have adverse effects on the evolution of both above-mentioned associated conditions. VINCENT BERONIADE, M.D., D.SC.

Department of Medicine Nephrology-Hypertension Section University of Montreal, Hotel-Dieu of Montreal Montreal, Quebec, Canada REFERENCES

1. ROSENTHAL T, BANK H, ALADJEM M, et al: Systemic amyloidosis

in Behcet's disease. Ann Intern Med 83:220-223, 1975 2. NESTOR G, BERONIADE V, CARNARU S, et al: Behcet's disease with

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renal involvement (with reference to three anatomo-clinical cases). Med Interna (Bucarest) 21:1511-1518, 1969

Jimson Weed Seeds TO THE EDITOR: Mikolich, Paulson, and Cross (1) recently called attention to an anticholinergic syndrome due to ingestion of Jimson seeds by teen-agers for a hallucinogenic effect. Their report brings to mind other misadventures with Jimson weed. Roueche (2) described the poisoning of five persons who shared a meal that included home-grown tomatoes from stalks grafted onto a Jimson weed plant. Both plants are members of the nightshade family. The graft was made to produce a frost-resistant tomato that would ripen in late fall. Unfortunately, the fruit was filled with belladonna alkaloids. In an excellent but obscure five-paragraph report, three practitioners in Oxford, Ohio (3) described a farmer with "cornpicker's pupil," a unilateral wide dilatation of the pupil that suggested serious neurologic disease. When no organic cause could be found, a more detailed history revealed that when the farmer climbed under his cornpicking machine to unclog it, dust from Jimson weed, which also grew in the field, entered his eye and produced mydriasis that lasted 4 days. ROBERT W. MILLER, M.D.

Epidemiology Branch National Cancer Institute Bethesda, Maryland 20014 REFERENCES

1. MIKOLICH JR, PAULSON GW, CROSS CJ: Acute anticholinergic

syndrome due to Jimson seed ingestion.. Clinical and laboratory observation in six cases. Ann Intern Med 83:321-325, 1975 2. ROUECHE B: Something a little unusual, in Annals of Epidemiology, edited by ROUECHE B. Boston, Little, Brown and Company, 1967, pp. 285-302 3. GOLDEY JA, DICK DA, PORTER WL: Cornpicker's pupil. A clinical

note regarding mydriasis from Jimson weed dust (stramonium). Ohio State Med J 62:921, 1966 TO THE EDITOR: The paper by Mikolich, Paulson, and Cross supplements other reports published in 1975 about Jimson weed ingestion. Jimson weed "highs" have been described recently in Delaware ( 1 ) , Maryland ( 2 ) , New York ( 3 ) , and Oregon ( 4 ) . Collectively, these case reports focus attention on a newly popularized use of Jimson weed seeds for psychedelic purposes. Previous reports of toxicity in the American medical literature involve not only consumption of Asthmador®, but also accidental ingestion of the Jimson weed by children and ingestion of tomatoes grafted onto the Jimson weed. Renewed interest by adolescents in the writings of Carlos Castaneda may have stimulated experimentation with Jimson weed. In The Teachings of Don Juan: A Yaqui Way of Knowledge ( 5 ) , Castaneda discuses his experiences with the hallucinatory effects of Datura stramonium while in Mexico. Any patient presenting with a syndrome of hallucinations presumably secondary to belladonna poisoning must have it differentiated from those of lysergic acid diethylamide (LSD) effects and schizophrenia. Findings of mydriasis, tachycardia, and fever can occur with LSD, but the severity of pupillary dilatation unresponsive to light and the fever suggest atropine toxicity. In addition, the type of hallucination with stramonium is generally simple, discrete

objects or persons, as contrasted to the often magnified and spectacular distortions described by LSD-users. With schizophrenia, the physical signs of atropinelike poisoning are absent. Also, a sudden onset of bizarre behavior occurs with drug poisoning, while a history of gradual and progressive abnormal behavior preceding a psychotic episode would favor schizophrenia. The increasing number of reports of Jimson weed ingestion indicates greater interest and abuse of this wildly growing herb, which is freely available. This recent popularity among adolescents may signify future widespread experimentation. DONALD A. MAHLER, M.D.

Department of Medicine Dartmouth Medical School Hanover, New Hampshire REFERENCES

1. MAHLER DA: The Jimson weed high. JAMA 231:138, 1975 2. ODERDA GM: Jimson weed. JAMA 232:597, 1975 3. ORR R: Reversal of Datura stramonium delirium with physostigmine: report of three cases. Anesth Analg (Cleve) 54:158, Jan-Feb 1975 4. New drug on the scene? Newsweek, p. 13, March 10, 1975 5. CASTANEDA C: The Teachings of Don Juan: A Yaqui Way of Knowledge. University of California Press, 1968

Evaluation, Profiling, and Screening TO THE EDITOR: Korvin, Pearce, and Stanley conclude their paper in the August issue, "Admissions Screening: Clinical Benefits" by stating that " despite the significant number of abnormal laboratory results encountered in an admissions screening program, these have little beneficial impact on patient care" ( 1 ) . The biggest problem with their study is that the application of a panel of tests, laboratory or other, to patients upon admission to hospital is not "screening." The World Health Assembly in 1971 recognized the existing confusion in terminology and set forth the following definition of screening for disease, the aim of which is to discover latent and unrecognized disease. Screening, when used in the detection of either early or established disease, implies medical investigation that does not arise from a request for health care resulting from a specific complaint. In other words, screening is undertaken when tests or examinations are carried out on people who may be either well or ill, but who, if ill, are not suffering from the disease for which screening is being done. Screening aims at sorting out individuals who probably have a disease from those who probably do not (2). Unfortunately, the misuse of the word "screening" has persisted, and recently Sackett and Holland (3) writing in Lancet sought to clarify terminology by offering the following definitions. Screening is the testing of apparently healthy volunteers from the general population for the purpose of separating them into groups with high and low probabilities for a given disorder. The objective of screening is unique: the early detection of those diseases whose treatment is either easier or more effective when undertaken at an earlier point in time. Case-finding is the testing of patients who have sought health care for disorders which may be unrelated to their chief complaints. The encounter is initiated by the patient and the purpose here is a comprehensive assessment of health. In contrast, diagnostic testing is the application of tests to patients who have actively sought health Comments

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services in order to identify the exact cause for their chief complaints. Since the 1000 patients that Korvin and associates tested were being admitted to hospital, it is clear that they were not being "screened." Therefore, it was unreasonable for the authors to evaluate the outcome of their testing regimen in terms of screening objectives (the detection of unrecognizable disease). The editorial by Delbanco and Noble in the same issue (4) is similarly confusing because these authors state that "screening is directed at an apparently well population" and then they note that "Korvin points to disappointing results from screening a particular hospital population." By virtue of their own definition, the hospital population was not "screened." According to Delbanco and Noble, Korvin's study was one of admission diagnostic evaluation and not of admission screening. Delbanco and Noble state the objective of screening as the identification of unrecognized disease. They state the objective of diagnostic evaluation as the diagnosis and resolution of patient problems. Rather than assessing new diagnoses, Korvin and coworkers should have evaluated the true objective of diagnostic evaluation before drawing conclusions as to impact on patient care. Those of us who are advocates of admission profiling look to this laboratory tool as a means of "diagnostic testing" and perhaps "case-finding." In this setting, admission profiling facilitates efficient laboratory utilization and most certainly has a beneficial impact on patient care. ROBERT S. GALEN, M.D., M.P.H.

Department of Pathology College of Physicians and Surgeons Columbia University New York, New York 10032 REFERENCES 1. KORVIN CC, PEARCE RH, STANLEY J: Admissions screening: clinical benefits. Ann Intern Med 83:197-203, 1975 2. WILSON JMG, HILLEBOE HE: Mass Health Examination. Geneva, World Health Organization (Public Health Paper No. 45), 1971 3. SACKETT DL, HOLLAND WW: Controversy in the detection of disease. Lancet 2:357-359, 1975 4. DELBANCO TL, NOBLE J: The periodic health examination revisited (editorial). Ann Intern Med 83:271-272, 1975

In reply: The objective of our study was to determine whether or not the performance of a battery of unsolicited, common laboratory tests on every admission to a general hospital would show a significant number of patients suffering from unrecognised diseases. This study would fall within the definition of screening by the World Health Assembly (1971) and within the definition of case-finding of Sackett and Holland (1975). However, our conclusions would not be changed by redefinition of the term used to describe the procedure. The performance of a battery of tests neither revealed a significant number of patients with unsuspected disease nor resulted in any significant change in the pattern of care. This observation should hold salient interest to those concerned with cost-benefit analysis of such procedures. Improved efficiency of laboratory use through the use of admission profiling has yet to be convincingly shown. Our own observations raise questions about its beneficial impact on patient care. 906

C. C. KORVIN, M.B., B.S., F.R.C.P.(C) R. H. PEARCE, PH.D

Department of Pathology The University of British Columbia Vancouver 8, Canada Dr. Galen points out semantic difficulties that apply to the many discussions that address the problem of periodic health examination and screening. If we have added to the confusion, we hope that his response adds some further clarity. However, semantics must not be allowed to obscure data that may have relevance to further practice. His use of yet another term, "admission profiling" (one more semantic point to digest) may conceivably prove helpful in itself, but the conclusion that such practice "most certainly has a beneficial impact on patient care" is founded on no data of which we are aware. Indeed, data and analyses of Korvin (1) and Spitzer (2) and colleagues are at odds with such an assumption. It would seem that it is much more important for those interested in health care research to work together to figure out how to conduct a practice rationally, rather than to worry too much about what to call what! THOMAS L. DELBANCO, M.D.

Beth Israel Hospital Boston, Massachusetts 02215 JOHN NOBLE, M.D.

The North Carolina Memorial Hospital Chapel Hill, North Carolina 27515 REFERENCES 1. KORVIN C, PEARCE RH, STANLEY J: Admissions screening: clinical benefits. Ann Intern Med 83:197-203, 1975 2. BROWN BP, SPITZER WO: Unanswered questions about the periodic health examination. Ann Intern Med 83:257-263, 1975

Additional

TO THE EDITOR: Although proved results are sparse, periodic health examinations should be continued if an ongoing effort is made to study their effectiveness. Emphasis must be placed on determining the optimal frequencies and content while selectively discontinuing unproductive aspects of the examination. One troublesome area has been the proliferation of data resulting from "biochemical profiles." Doctors are becoming aware that some "abnormal values" are just variations of the statistical distribution, and do not necessarily require further investigation. In our opinion it would be premature to discontinue biochemical profiling. Alcoholism and alcohol-related health problems (cirrhosis, D.T.'s accidents, homicides, suicides,) can probably be considered the country's third most important health hazard among adults in urban America. Our experience has shown that many abusers of alcohol who cannot be detected on the basis of history or physical examination will have elevations of serum glutamic oxalacetic transaminase (1). Other observers have noted the value of the gammaglutamlyltranspeptidase test (2). Use of liver enzyme testing with periodic health examinations may alert physicians to patients who should be advised to modify their drinking behavior. The periodic health examination presents an ideal opportunity for health education. We are just beginning to

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learn how to translate health education into behavior modification, which will increase the effectiveness of preventive medicine. W. R. CUNNICK, M.D. Deputy Chief Medical Director Metropolitan Life 1 Madison Avenue New York, New York 10010 REFERENCES 1. CUNNICK WR, CROMIE JB, CORTELL R, et al: Value of biochemi-

cal profiling in a periodic health examination program: analysis of 1000 cases. Bull NY Acad Med 48:5-22, 1972 2. ROLLASON

JG,

PINCHERLE

G,

ROBINSON

D:

Serum

gamma

glutamyl transpeptidase in relation to alcohol consumption. Cltn Chim Acta 39:75-80, 1972

Systemic Contraceptives and the Liver TO THE EDITOR: The "pill-associated benign hepatic neoplasms" have evoked considerable interest, as evidenced by still another report, by Stauffer and associates {Ann Intern Med 83:301-306, 1975). We believe that several points raised in that report do, however, require clarification. Stauffer and colleagues consider as a homogeneous group all of the "pill-associated hepatic neoplasms," referring to the occurrence in young women using oral contraceptives as a syndrome. This melee consists of at least two distinct clinicopathologic entities, focal nodular hyperplasia and liver cell adenoma, which unfortunately have not generally been well recognized and accurately diagnosed by pathologists. Critical histopathologic review of the reported cases shows that only the three cases reported by Mays, Christopherson, and Barrow (1) and two cases (Patients 2 and 3) reported by Ameriks and associates (2) as "hepatic adenomas" appear to represent focal nodular hyperplasia (3). The great majority of the literature cases lack the histopathologic documentation necessary to be unequivocally designated as focal nodular hyperplasia or liver cell adenoma. Patients 1 and 2 reported by Stauffer and co-workers appear by their photographs and histopathologic descriptions, that is, vacuolated hepatocytes in pseudorosette formation, absence of bile ducts, and centrally coalescing fibrous tracts, to be examples of liver cell adenoma. Why then do the authors arbitrarily imply the term "focal nodular hyperplasia." Focal nodular hyperplasia connotes a distinct pathologic entity (4) and is not descriptive of any syndrome. Patient 3 presented with intrahepatic hemorrhage but no lesion was identified. The authors correctly concluded that rupture of a pre-existing adenoma can not be excluded. However, spontaneous intrahepatic hemorrhage and subsequent rupture has been described (4). We do not, therefore, believe it justified to refer to this patient as a variant of a "syndrome." Sorensen and Baden (5) reviewed literature reports of 141 patients with focal nodular hyperplasia and 69 patients with liver cell adenoma. No patient with focal nodular hyperplasia presented with a complication; the single case of ruptured focal nodular hyperplasia reported by Mays and associates (1) is thus far the only exception to the totally benign clinical course of focal nodular hyperplasia.

Thirty-six per cent of the patients with liver cell adenoma presented with complications related to tumor necrosis and hemorrhage. Sorensen and Baden (5) and Knowles and Wolff (4) in independent reviews concluded that liver cell adenoma and focal nodular hyperplasia must be distinguished both for prognostic and therapeutic reasons. Although liver cell adenoma should probably be surgically resected for the possibility of bleeding and rupture, the indication for resection of asymptomatic focal nodular hyperplasia is relative: it is not necessarily indicated if a major hepatic resection would be required (4, 5). In summary, we agree with Stauffer and associates that the term "benign hepatoma" is to be avoided. We do however believe it imperative to distinguish focal nodular hyperplasia from liver cell adenoma, Stauffer's Patients 1 and 2 representing liver cell adenoma. We believe that an association between focal nodular hyperplasia and oral contraceptive use may be merely coincidental, especially in view of its usual occurrence in young women (4). The possible association between oral contraceptive use and liver cell adenoma is moot because of the poor histopathologic documentation of the literature cases. Hopefully, better histopathologic substantiation in the future and strict adherence to a standard nomenclature will result in concrete clinicopathologic correlations. DANIEL M. KNOWLES, M.D. MARIANNE WOLFF, M.D.

Department of Pathology College of Physicians and Surgeons Columbia University New York, New York 10032 REFERENCES 1. MAYS ET, CHRISTOPHERSON WM, BARROW GH: Focal nodular

hyperplasia of the liver: possible relationship to oral contraceptives. Am J Clin Pathol 61:735-746, 1974 2. AMERIKS J A, THOMPSON NW, FREY CF, et al: Hepatic cell

adenomas, spontaneous liver rupture and oral contraceptives. Arch Surg 110:548-557, 1975 3. KNOWLES

DM

II,

WOLFF

M,

CASARELLA WJ:

Hepatic

In reply: The letter by Knowles and Wolff regarding our report of focal nodular hyperplasia and intrahepatic hemorrhage, both occurring in young women on oral contraceptives raises three major points: [1] nomenclature, [2] etiologic relation of the tumors to oral contraceptives, and [3] the relation of intrahepatic hemorrhage to focal nodular hyperplasia. We do not dispute the fact that there appear to be two distinct clinicopathologic entities, that is, focal nodular hyperplasia and liver cell adenomas. Edmondson (1), in his discussion of benign epithelial tumors, identifies the distinguishing features between liver cell adenoma and focal nodular hyperplasia. Grossly, liver cell adenomas are usually solitary and encapsulated tumors. Microscopically, the predominant feature relates to proliferation of liver cells arranged in cords or tubules with a paucity of Comments

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adenomas (letter). Arch Surg 110:1154-1155, 1975 4. KNOWLES DM II, WOLFF M: Focal nodular hyperplasia of the liver: a clinicopathologic study and review of the literature. Hum Pathol, in press 5. SORENSEN TIA, BADEN H: Benign hepatocellular tumors. Scand J Gastroenterol 10:113-119, 1975

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portal tracts, bile ducts, or central veins. He states that no changes are seen in arteries and veins. In his description of focal nodular hyperplasia these tumors are more hyperplastic nodules with sharply circumscribed borders but without a true capsule. They commonly have prominent fibrous trabeculae and interlobular connective tissue that may contain proliferating bile ducts. In contrast to liver cell adenoma, focal nodular hyperplasia may show changes in the media and subintimal area of blood vessels. On occasion this is associated with hyperplastic changes in fibroblasts, leading to obliteration of the involved vessel. As we stated in the description of the tumors occurring in our cases, there were features suggestive of liver cell adenoma, as well as focal nodular hyperplasia. Although there was some pseudorosette formation and hepatocellular changes consistent with an hepatic adenoma, the predominant lesion related to changes in the vasculature with associated fibroblastic proliferation. In view of this, we opted to call our cases examples of focal nodular hyperplasia rather than liver cell adenoma. Upon reviewing the article by Ameriko and co-workers ( 2 ) , which was published while our paper was in press, the same difficulty in nomenclature was encountered. In fact, some of their cases, in our opinion, more closely resemble focal nodular hyperplasia than liver cell adenoma. The evidence correlating oral contraceptives and the onset of liver tumors is circumstantial and statistical, as was stated in the article. Certainly, the phenomena of liver cell adenoma and focal nodular hyperplasia occurred prior to introduction of oral contraceptives, and there have been reports of these occurring in individuals not on oral contraceptives ( 3 ) . However, a primary point of our article is that there is an increased incidence of these tumors in young women on oral contraceptives. Prospective studies are needed to establish with certainty that use of oral contraceptives may induce formation of liver tumors. The third point relates to Patient 3 in our report, who had intrahepatic hemorrhage. Knowles and Wolff relate that this has been previously described, although their reference indicates that this report is in press, and we cannot comment on unpublished reports. We prefer to describe our third case as a variant of the syndrome, in that we did not identify an area of focal nodular hyperplasia in this patient. Since this manuscript was published, a fourth case has been observed at this medical center in which intraheptic hemorrhage occurred in a woman on oral contraceptives and small fragments of abnormal liver tissue were identified at the borders of the intrahepatic hemorrhage. This would tend to support our speculation that Patient 3 did indeed have hemorrhage from an area of focal nodular hyperplasia. In conclusion, we believe there is a possible association between oral contraceptive use and formation of hepatic tumors. Subtle differences in the histologic appearance from one tumor to the next may reflect either the different stage in evolution of the tumor or a differing host response to inducing agents such as estrogens. If the association of these tumors and oral contraceptives is confirmed, then certainly we are warranted in calling this a syndrome. JOHN Q. STAUFFER, M.D.

Gastroenterology Section Department of Medicine State University Hospital of the Upstate Medical Center Syracuse, New York 13210 908

REFERENCES

1. EDMONDSON HA: Tumors of the Liver and Intrahepatic Bile Ducts: Benign Epithelial Tumors. Washington, D.C., Armed Forces Institute of Pathology, 1958, pp. 193-206 2. AMERIKO J A, THOMPSON NW, FREY CF, et al: Hepatic cell

adenomas, spontaneous liver rupture and oral contraceptives. Arch Surg 110:548-557, 1975 3. DAVIS JB, SCHENKEN JR, ZIMMERMAN O: Massive hemoperitineum

from rupture of benign hepatocellular adenoma. Surgery 73:181184, 1973

Relative Frequencies of Anaerobes TO THE EDITOR: In the UCLA Conference on the management of anaerobic infections (Ann Intern Med 83:375-389, 1975) by Finegold and coworkers it is erroneously stated (p. 384) that Bacteroides fragilis is the second most frequent isolate from blood cultures at the Mayo Clinic (personal communication from myself is cited). In fact, anaerobes are isolated from approximately 13% of positive cultures, representing approximately 20% of bacteremic patients (excluding those with Propionibacterium) at the Mayo Clinic and affiliated hospitals. During the years of 1970 through 1972 bacteroidaceae represented the second most frequent Gram-negative bacillary isolate from blood cultures ( 1 ) . Bacteroidaceae represented the etiologic agent in 78% of patients with clinically significant anaerobic bacteremia ( 2 ) . JOHN A. WASHINGTON II, M.D.

Section of Clinical Microbiology Mayo Clinic Rochester, Minnesota 55901 REFERENCES

1. WASHINGTON J A II: Anaerobic bacteria, in Antibiotics and Infection, edited by SMITH IM, DONTA ST, RABINOVICH S. Flushing,

New York, Spectrum Publications, 1974, pp 71-84 2. WILSON WR, MARTIN WJ, WILKOWSKE CJ, et al: Anaerobic

bacteremia. Mayo Clin Proc 47:639-646, 1972

In reply: We apologize for the errors indicated by Dr. Washington and appreciate having this correction made. EDWARD J. HARDER, M.D. SYDNEY M. FINEGOLD, M.D.

Veterans Administration Wadsworth Hospital Center Los Angeles, California 90073

Isoproterenol, Asthma, and the Heart TO THE EDITOR: The recent paper by Shim and Williams, "Cardiac Response to Repeated Doses of Isoproterenol Aerosol" (Ann Intern Med 82:208-211, 1975), suggests that the frequent administration of aerosolized isoproterenol has no harmful effects in asthmatics. We wonder if this suggestion is justified by their data. Regarding patient selection, the designation of "moderate-to-severe asthma" based on the patient's subjective assessment of himself is not in keeping with the clinical data and is not the usual way of categorizing severity. Patients 4, 5, and 10 were

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on no corticosteroids and Patients 7, 8, and 13 were on no medications at all (Table 1). The predicted values for the peak expiratory flow rate are not included with the other data (Table 1) making an assessment of the severity of the obstruction impossible. Patients ranged from ages 17 to 67 with "no history of hypertension or heart disease," thereby excluding some of the patients who might be expected to show an increased risk from aerosolized isoproterenol. Although the authors acknowledge that hypoxia or acidosis may be important in assessing cardiac effects of isoproterenol, they provide no arterial blood gas data, which would seem essential in this study. Isoproterenol has been shown to result in hypoxia from altered ventilationperfusion relations (1) and to increase myocardial oxygen consumption. Also, cardiac effects from fluorocarbon propellants might only be manifest with hypoxia (2). Finally, the most important time to look for an adverse effect from isoproterenol may have been missed. In those patients with a paradoxical response associated with overuse (3) as well as those who show an idiosyncratic response to isoproterenol, (4) it is only 45 minutes to an hour after the last dose that the adverse reactions occur. The mechanism of the adverse reactions might involve a metabolic end-product with beta blocking properties, such as postulated by Paterson and colleagues (5) or a different mechanism. However, the effects on blood gases and pulmonary function variables that would predispose to a cardiac problem may not be manifest until an appropriate time interval has elapsed from the last dose. Thus, we would like to suggest that the authors' results should not be generalized, and, as they have previously stated, "this study should not be interpreted as advocating an excessive use of isoproterenol..." MARK R. STEIN, M.D.

Patients with hypertension or heart disease were excluded from this study because it would have required at least a dozen patients in each category to draw any meaningful conclusion. Blood gas was analyzed only on those with PEFR less than 150 litre/min before treatment. Of 6 patients studied none had Pao 2 lower than 52 mm Hg and none had an elevated PCo 2 . The only patient (Patient 1) in our series who had an increased heart rate after isoproterenol aerosol did so when Pao 2 was 70 mm Hg, whereas he had no change in heart rate when Pao 2 was 52 mm Hg. Hypoxia and acidosis are commonly seen in another group of patients, chronic obstructive pulmonary disease, who are also treated with aerosol isoproterenol. In another study 21 patients with chronic obstructive pulmonary disease and cardiac arrhythmia were treated with 2 puffs of isoproterenol aerosol ( 1 ) . None had worsening of arrhythmia. Cardiac effects of fluorocarbon propellants are seen at the level of hypoxia (asphyxia) not likely to be encountered in patients with asthma unless one is exposed to a much higher concentration of fluorcarbon for several minutes (2). Worsening of airways obstruction after administration of isoproterenol aerosol must be quite a rare phenomenon. Except for a few cases, most reports do not have adequate control for comparison. By definition airway obstruction in asthma is variable. It is also well known that patients with asthma are highly susceptible to suggestion. It is unwise to draw conclusions regarding airways obstruction based on data that are not compared double-blind to response to placebo. In another study 22 patients with asthma had been treated with 2.5 mg of isoproterenol (we used 2.0 mg) every hour at least 4 times ( 3 ) . There was a progressive bronchodilator effect in all of them and no adverse effect was reported. CHANG SHIM, M.D.

SHELDON L. SPECTOR, M.D., F.A.C.P.

Section of Allergy and Clinical Immunology National Jewish Hospital and Research Center Denver, Colorado 80206 REFERENCES

M. HENRY WILLIAMS, JR., M.D.

Chest Service Department of Medicine Albert Einstein College of Medicine Bronx, New York 10461

1. GAZIOGLU K, CONDEMI J J, HYDE RW, et al: Effect of isoproterenol

on gas exchange during air and oxygen breathing in patients with asthma. Am J Med 50:185-190, 1971 2. HARRIS WS: Toxic effects of aerosol propellants on the heart. Arch Intern Med 131:162-166, 1973 3. REISMAN RB: Asthma induced by adrenergic aerosols. J Allergy 46:162-177, 1970 4. SPECTOR SL: Idiosyncratic Bronchoconstriction Following Isoproterenol (abstract). Proceedings of the World Congress on Asthma Bronchitis & Conditions Allied, New Delhi, India, November 9-15, 1974, in press

REFERENCES 1. SCHER S, SHIM C, WILLIAMS MH JR: Effect of bronchodilator

agents on arrhythmia (abstract), ATS/CTS Annual Meeting, Montreal, Canada, May 1975 2. SILVERGLADE A: Cardiac toxicity of aerosol propellants (editorial). JAMA 222:827-829, 1972 3. MCFADDEN ER JR, KISER R, DEGROOT WJ: Acute bronchial

asthma. N Engl J Med 288:221-225, 1973

5. PATERSON JW, CONOLLY ME, DAVIES DS, et al: Isoprenaline

resistance and the use of pressurized aerosols in asthma. Lancet 2:426-429, 1968

In reply: The patients had been classified to have moderate-tosevere asthma on the basis of their past asthma history and not of their current status. The predicted value for peak expiratory flow rate (PEFR) depends on age, sex, and height. The mean predicted value for the patients was 457 litre/min (SD, 7 8 ) . The PEFR before treatment represented a mean of 37.1% predicted.

"Band" Test in Connective Tissue Disease TO THE EDITOR: In their recent "Brief Communication" Levitin, Weary, and Giuliano (1) reported a positive immunofluorescent "band" test in the clinically normal skin in three of six patients with mixed connective tissue disease and in five of six patients with systemic lupus erythematosus. Although the authors did not state whether they took light-exposed or light-protected clinically normal skin, the high prevalence of the band in the lupus erythematosus group suggests that light-exposed skin was probably used. Positive "band" tests have been found more frequently in light-exposed than in light-protected clinically normal skin Comments

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from patients with lupus erythematosus ( 2 ) . We suggested (3) that this higher prevalence of the band in light-exposed skin explained the finding of Caperton, Bean, and Dick (4) of a high prevalence of the band and consequently no correlation between a positive "band" test in clinically normal systemic lupus erythematosus skin and an increased prevalence of kidney involvement. Bean and colleagues using light-exposed skin found a band in 67% of systemic lupus erythematosus patients without renal involvement and in 70% of systemic lupus erythematosus patients with renal involvement. Our overall prevalence in light-protected skin was only 36.4%, but kidney involvement was three times as frequent in the "band"-positive than in the "band"negative group ( 5 ) . We mentioned (3) that in view of the high prevalence of a band in light-exposed clinically normal systemic lupus erythematosus skin, this might be the best site from which to test skin for diagnostic rather than prognostic purposes. However, this would be possible only after a large enough study of patients with the various connective tissue diseases other than systemic lupus erythematosus had confirmed that a band in light-exposes clinically normal skin is specific for systemic lupus erythematosus. The authors' findings of a band in three of six patients with mixed connective tissue disease from presumably light-exposed skin cast some doubt on the validity of using light-exposed clinically normal skin to confirm a diagnosis of systemic lupus erythematosus. THOMAS K. BURNHAM, M.B., B.S.

Department of Dermatology Henry Ford Hospital Detroit, Michigan 48202 REFERENCES 1. LEVITIN PM, WEARY PE, GIULIANO VJ: The immunofluorescent

"band" test in mixed connective tissue disease. Ann Intern Med 83:53-55, 1975 2. BAART DE LA FAILLE-KUYP, CORMANE RH: The occurrence of

certain serum factors in the dermal-epidermal junction and vessel walls of the skin in lupus erythematosus and other (skin) diseases. Acta Derm Venereal 48:578-588, 1968 3. BURNHAM TK: Immunofluorescent test for lupus erythematosus: relation to renal disease. JAMA 223:798-799, 1973 4. CAPERTON EM, BEAN SF, DICK FR:

Immunofluorescent

skin

test in systemic lupus erythematosus. Lack of relationship with renal disease. JAMA 222:935-937, 1972 5. BURNHAM TK, FINE G: The immunofluorescent "band" test for

lupus erythematosus. III. Employing clinically normal skin. Arch Dermatol 103:24-32, 1971

In reply: We thank Dr. Burnham for his comments. Our skin biopsies in patients with mixed connective tissue disease and systemic lupus erythematosus were taken from the upper arm, a relatively light-exposed area. It is possible that the specificity of the immunofluorescent band test in systemic lupus erythematosus might be enhanced by biopsy of only light-protected clinically normal skin. PETER M. LEVITIN, M.D.

910

Medical Teaching Service The Moses H. Cone Memorial Hospital The University of North Carolina School of Medicine Greensboro, North Carolina 27401 P E Y T O N E. W E A R Y , M . D . V I N C E N T J. G I U L I A N O , M . D .

Departments of Medicine and Dermatology University of Virginia School of Medicine Charlottesville, Virginia 22901

Review of "VD Epidemic" TO THE EDITOR: I am grateful to Dr. Duncan for some of the favorable comments he made about my book The VD Epidemic, reviewed by him in the September 1975 issue of the "Annals." On the other hand, a few of his comments puzzle me. I do not understand, for example, why the need for a book like mine is much less now than it was five years ago. Doctor Duncan states that in that interval the National Institutes of Health have funded three centers of research in venereal disease, but I don't really see that this is relevant to most potential readers of my book. (Or it is simply that Baylor College of Medicine has received a center and that Dr. Duncan is thereby happy?) Also, Dr. Duncan finds it "disquieting" that there are references from Medical Tribune and Medical World News. He should not be disquieted, in my view, because there are cogent reasons for reading those two journals. To begin with, I have found them generally accurate, and certainly more up to date than the ordinary medical literature. If one wants to keep up with what is going on in venereal disease, it is hard to do so by simply reading the traditional literature, because a good bit of the work never gets published there, and if it does, the publication is likely to be long delayed. For one writing a book, therefore, reliable and up-to-date coverage is important, and the two periodicals in question supply it. Finally, he describes as "most disquieting" my reference to the spread of gonorrhea by toilet seats. Again, I am puzzled. I described in my book some experiments by a Swedish physician named Henning, in which he succeeded is growing live gonococci from a variety of inanimate objects, including a toilet seat, after smearing on a suspension of them some hours before. I also point out that two other Swedish scientists have grown gonococci from towels soiled by urethral discharge from infected men. (The latter reference is from the British Medical Journal, presumably not as "disquieting" as Medical Tribune.) I go on to say: "One suspects that the Swedish doctor may be right in theory, but that in practice the toilet seat is usually an innocent by-sitter." Perhaps folks in the "northeast" are less readily disquieted than our southern colleagues. Louis LASAGNA, M.D.

Department of Pharmacology University of Rochester School of Medicine and Dentistry Rochester, New York 14642

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