LETTERS AND CORRECTIONS "The power and the beauty of science do not rest upon infallibility, which it has not, but on corrigibility, without which it is nothi n g . " — H O W A R D E. GRUBER*

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. Is Bromocriptine

Teratogenic?

T o T H E EDITOR: The excellent and valuable review in the June issue by Drs. Spark and Dickstein, "Bromocriptine and Endocrine Disorders" (1), referred to the potential teratogenicity of this drug in humans because of the occurrence of "cleft lip" in the offspring of rabbits treated during pregnancy. We believe it is important for the assessment of the risks and benefits of any drug that full information be presented. To this end, we include the data on cleft palates from five studies in rabbits. The reader is also referred to the package insert for Parlodel® (bromocriptine mesylate; Sandoz Inc., East Hanover, New Jersey) for additional information. In the Yellow-Silver strain rabbits receiving 30 and 100 m g / kg«d of bromocriptine during the organogenetic phase (Days 6 to 18), cleft palate was found in none of 66 and three of 71 offspring, respectively. In a repeat study in this strain, cleft palate was found in none of 84 (100 mg/kg*d) and two of 55 (300 mg/kg«d); cleft palate was present in one of 168 offspring from the control dams. N o cleft palates were found in the New Zealand strain rabbit treated with 100 and 300 mg/kg«d, dosages 600 to 2000 times greater than the recommended human therapeutic dose. N o abnormalities were found when the drug was given during the preimplantation phase of pregnancy. Nor were any drug-related anomalies found in one primate and two rat studies. After critical review of these data, members of the EnTable 1 . Comparative Data on Incidence of Malformations

Malformation class

Parlodel (N = 781)

Reference 4 Reference 5 All Mother- (N = 10 454) Child Pairs (N = 50 282)

Any malformation

30.7*

45.3*

106.0*

Major malformation Minor malformation Tumors

19.2 10.2 1.3

27.7 17.9 3.3

41.0 65.0 0.9

Central nervous system Cardiovascular Musculoskeletal Respiratory Gastrointestinal Genitourinary Eye and ear Syndromes Miscellaneous

1.3 1.3 14.1 1.3 2.6 1.3 2.6 1.3 3.8

5.3 8.0 14.3 4.3 6.0 9.2 2.4 3.5

5.2 9.8 19.9 4.3 30.1 15.7 2.9 3.0 26.0

* Per 1000.

docrine and Metabolic Disease Division of the F D A concluded that there was no convincing evidence for bromocriptine-induced teratogenicity in animals. Because animal studies may not predict effects in humans, Sandoz initiated a worldwide surveillance of potential teratogenicity in offspring of bromocriptine-treated mothers. An interim report on this survey was summarized by Drs. Spark and Dickstein. T o date 905 pregnancies have been reported to Sandoz from which 781 live births have resulted. Twenty-four malformations were found in these children, giving an overall incidence of 3 . 1 % , a figure in the low portion of the 2 . 7 % to 6.5% range reported for the general population (2-5). We have classified the defects by body system and compared the results with those reported by Heinonen and colleagues (4) and Drew and associates (5) (Table 1). These data indicate that neither the type nor the incidence of malformations observed in infants born of mothers treated with Parlodel exceeds that reported in other populations. T h e same conclusion was reached by members of the F D A Fertility and Maternal Health Drugs Advisory Committee at their meeting on 1 June 1979. Although the worldwide surveillance program will be continued to gather additional data, it is reassuring that there is no reason to attribute a teratogenic effect to bromocriptine at present. We wish to emphasize that to date bromocriptine has only been approved in the United States for the treatment of amenorrhea-galactorrhea in the absence of demonstrable pituitary tumors. The recommendations given in the package insert should be carefully considered before the drug is prescribed. R I C H A R D L. E L T O N , P H . D . H A R R I S O N M. L A N G R A L L , M.D.

Sandoz Inc.; East Hanover, N J 07936 REFERENCES 1. SPARK RF, DICKSTEIN G. Bromocriptine and endocrine disorders.

Intern Med. 1979;90:949-56. 2. SMITHELLS RW. Environmental 1976;32:27-33.

teratogens

Ann

of man. Br Med Bull.

3. E K E L U N D H, K U L L A N D E R S, K A L L E N B. Major and minor malforma-

tions in newborns and infants up to one year of age. Acta Paediatr Scand. 1970;59:297-302. 4. K A U F M A N DW, ed. Birth Defects and Drugs in Pregnancy. Littleton, Massachusetts: Publishing Sciences Group Inc.; 1977:223. 5. D R E W JH, PARKINSON P, W A L S T A B JE, et al. Incidences and types of

malformations in newborn infants. Med J Aust.

Prolactinomas and the Multiple Endocrine

1977;2:945-9.

Adenomatosis

Type-I Complex

T o T H E EDITOR: T h e association of prolactinomas with the multiple endocrine adenomatosis type-1 complex, as suggested by Prosser's study (1) of three families, can be further substantiated by follow-up data from the original family described by Wermer (2) in 1954. Four of the seven sisters affected with the syndrome had roentgenogram evidence of an intrasellar mass when first evaluated. Recently O.P., now 64 years of age, was admitted to the * G R U B L R H E . T h e origin of the origin of species. Review of Darwin and the Mysterious Mr. X: New Light on the Evolutionists. By EISKI.UY L. The New York Times Book Review 1979 July 22: 16.

791

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hospital and a prolactin of 455 n g / m L (normal female value, less than 25 n g / m L ) found. T h e eldest sister, C.P., who previously had undergone pituitary irradiation, was contacted and her prolactin also was elevated at 73 n g / m L . Review of hospital records showed that W.B. had had radiation therapy directed at her pituitary gland in the 1960s and had died in the early 1970s. A stored serum sample taken after treatment also was elevated at 30 n g / m L . T h e fourth sister, F.S., had undergone pituitary surgery in the 1950s, and a mixed eosinophilic and chromophobe adenoma had been removed. She died a few years later; no prolactin determination is available. Although many pituitary tumors are now frequently found to secrete prolactin, the finding of elevated levels in three of the four sisters first described by Wermer (2) supports the association of prolactin-secreting adenomas as part of the multiple endocrine adenomatosis type-1 syndrome.

primary or secondary adrenal failure magnifies the problem. Several investigators have shown inappropriately high plasma A D H levels with water loading in patients with Addison's disease or in dog model systems (1). Indeed, a steady increase in A D H levels during water loading has been observed in a dog model system (2). The mechanisms that they propose seem quite plausible to us. We have no data that can clarify possible mechanisms. We wish to emphasize the point of the communication. As Rose and colleagues (3) noted, infusion of 5 % dextrose seems to cause more problems with water retention than does the infusion of saline. Adrenal crisis may occur, despite the administration of 1.5 to 2.0 mg of dexamethasone per day. LESLIE R. SHEELER, M.D. O. PETER SCHUMACHER, M.D. Cleveland Clinic; Cleveland, O H 44106

MICHAEL GOLDMAN, M.D. DONALD HOLUB, M.D.

REFERENCES

Presbyterian Hospital; New York, N Y 10032

1. M C D O N A L D K M , M I L L E R P D , A N D E R S O N RJ, B E R L T, SCHRIER RW.

REFERENCES

2. BOYKIN J, D E T O R R E N T E A, ERICKSON A, R O B E R T S O N G, SCHRIER

Hormonal control of renal water excretion. Kidney Int. 1976;10:38-45. RW. Role of plasma vasopressin in impaired water excretion of glucocorticoid deficiency. J Clin Invest. 1978;62:738-44.

1. PROSSER PR, K A R A M JH, T O W N S E N D JJ, FORSHAM P. Prolactin-secret-

ing pituitary adenomas in multiple endocrine adenomatosis, type 1. Ann Intern Med. 1979;91:41-4. 2. W E R M E R P. Genetic aspects of adenomatosis of endocrine glands. Am J Med. 1954;16:363-71.

3. R O S E LI, W I L L I A M S G H , J A G G E R PI, L A U L E R DP. The 48-hour adreno-

corticotrophin infusion test for adrenocortical insufficiency. Ann Med. 1970;73:49-54.

Intern

Hyponatremia During ACTH Infusions T o T H E EDITOR: Sheeler and Schumacher report in the May issue (1) three cases of severe hyponatremia (101, 109, and 116 m e q / L ) associated with infusions of A C T H in which a limited volume of 5 % dextrose in water was given intravenously as the carrier. Even assuming that renal water excretion was negligible, serum antidiuretic hormone ( A D H ) levels were maximal, and all three patients were small in size, the decrease in serum sodium concentration cannot be accounted for by the amount of water infused in any of these cases. Assuming a body weight of 50 kg, which is small for an adult, total body water would have had to increase by 7 to 9 L and not just the 1.5 to 2 L accounted for by the intravenous infusions. In fact, a body weight of 10 to 13 kg would be required if the decrease in serum sodium concentration were to be accounted for by the amount of water infused. Therefore, to explain completely the hyponatremia, either the amount of water infused was greater than indicated or these patients had a nonosmotic stimulus to thirst and A D H release with free access to water. Perhaps these patients were intravascularly volume depleted before the study. (Decreased intravascular volume is a strong nonosmotic stimulus to both thirst and A D H release.) Alternatively, could the infusion of A C T H in some way have produced a nonosmotic, volume-independent stimulus to both thirst and A D H release? MICHAEL GEHEB, M.D. MALCOLM COX, M.D. IRWIN SINGER, M.D. Philadelphia Veterans Administration Medical Center and Hospital of the University of Pennsylvania; Philadelphia, P A 19104 REFERENCE

1. SHEELER LR, SCHUMACHER OP. Hyponatremia during ACTH infusions. Ann Intern Med. 1979;90:798-9.

Indomethacin-lnduced Renal Failure T o T H E EDITOR: In their recent paper, Walshe and Venuto (1) ascribe a physiopathologic role to indomethacin in the induction of an acute deterioration in renal function. They conclude that the precipitation of such acute renal failure is more likely to occur in states perceived by the kidney as being salt depleted, as is their case with congestive cardiac failure. W e previously published a case report in 1976 (2) that lends support to their findings and conclusions. Our female patient had a histologically proven diagnosis of mesangiocapillary glomerulonephritis and high renin hypertension. She was admitted in severe congestive heart failure in July 1975. Her creatinine clearance at admission was 26 m L / m i n . Digitalis therapy produced a rapid improvement. In August, having complained of low back pain, she was started on indomethacin suppositories (400 m g / d ) . Three weeks later she was readmitted with acute deterioriation of chronic renal failure and malignant hypertension. Despite immediate withdrawal of indomethacin, her condition deteriorated to end-stage renal failure. As in the case reported by Walshe and Venuto (1), we were impressed by the close relation in time between the administration of indomethacin and the development of an acute deterioration of chronic renal failure. We argued then, in keeping with the authors' discussion, that the effect of indomethacin was probably mediated via its action as an inhibitor of prostaglandin synthetase activity. We wish to endorse and extend the authors' precautionary suggestion on the use of prostaglandin synthetase inhibitors in states characterized by severe renal ischemia with high levels of intrarenal vasconstrictors. In particular, the already established presence of a decrease in renal function should sound an alarm not to be ignored. J A C Q U E S L. B E R N H E I M , M . D .

In response: Geheb, Cox, and Singer make several excellent observations. T h e patients weighed 50, 52, and 56 kg, respectively. Oral intake was not restricted during the testing period. Limitations of space prohibited us from making the point that in doing this test in more than 50 subjects using normal saline 5 % dextrose as the carrier, the largest fall in serum sodium observed was 12 m e q / L . It seems that giving 5 % dextrose in water to patients with 792

Z E E V K O R Z E T S , M . B . , B.S.

Meir Hospital; Kfar-Saba, Israel. REFERENCES

1. W A L S H E JJ, V E N U T O RC. Acute oliguric renal failure induced by indomethacin: possible mechanism. Ann Intern Med. 1979;91:47-9. 2. B E R N H E I M JL, POKROY N, M Y E R S ED. Influence de l'indomethacine sur

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1'evolution d'une glomerulonephrite. Nouv Presse Med. 1976;38:2531-2.

Isoniazid and Reaction to Cheese

initial exposure to oral contraceptives.

T o THE EDITOR: Drs. Smith and Durack described in the April

Suite 2U, 445 East 68th Street; New York, N Y 10021

L O U I S E S. A C H E S O N , M . D .

1978 issue (1) an unusual reaction to cheese that was clearly related to isoniazid. The symptoms mimicked the reaction induced by foods containing monoamines in patients taking monoamine oxidase inhibitors. In their report, however, hypertensive crisis, a well-known and serious toxic effect associated with the latter condition, was not recorded. Further, because plasma isoniazid level was not monitored, overdosage cannot be ruled out. We wish to add another case of a patient who developed a reaction—including hypertension—to cheese while taking controlled doses of isoniazid. A 31-year-old Vietnamese man had been given isoniazid (2.5 mg/kg • d) and rifampin (7.5 mg/kg • d) for 1 year. He reported flushing and palpitations soon after meals, which included Swiss cheese on three occasions. No bowel movements were noted. He stopped cheese ingestion spontaneously. Similar reactions were not observed after meals that did not include cheese. Physical examination findings were normal. Casual blood pressure was 130/ 85 mm Hg and pulse 72/min. Hemoglobin, leukocyte count, platelet count, erythrocyte sedimentation rate, serum total protein, albumin, bilirubin, alkaline phosphatase, aspartate amino transferase, electrolytes, creatinine, and coagulation screen data were all within normal ranges. Challenge was done with 100 g of Swiss cheese. Fifteen minutes later, a red flush developed over his face, shoulders, and precordium, accompanied by chills and sweat. Blood pressure rose to 200/110 mm Hg and the pulse to 112/min 30 min after cheese ingestion. The attack lasted 1 h. Urinary hydroxyindoleacetic acid and vanillyl mandelic acid excretions over 24 h were both normal on the day of challenge and on the next 2 d. Isoniazid plasma concentration was 1.2 jag/ mL 3 h after administration, on fasting, of isoniazid and rifampin. The isoniazid index of inactivation calculated according to Vivien and colleagues (2) was 0.7. Isoniazid was withdrawn and the patient was left on rifampin therapy alone. Another challenge of Swiss cheese was then done. No reaction was observed.

This case is strikingly similar to that of Smith and Durack (1) except for the occurrence of hypertension and the lack of bowel movements. Therefore, in view of the risk of a hypertensive crisis, strict warnings on foods rich in monoamines should be given to those patients taking isoniazid who experience flushing after meals. This reaction does not appear to be related to overdosage of isoniazid. J. L. L E J O N C , M . D .

D . GUSMINI, M.D. P. B R O C H A R D , M . D .

Hopital Henri Mondor; 94010 Creteil, France REFERENCES

1. SMITH CK, D U R A C K DT. Isoniazid and reaction to cheese. Ann Intern Med. 1978;88:520-1. 2. V I V I E N JN, T H I B I E R R, L E P E U P L E A. Recent studies on isoniazid.

TubercRes.

Adv

1972;18:148-231.

Oral Contraceptive Pills and Endometrial Cancer T o T H E EDITOR: Horwitz and Feinstein (1) conclude from their

epidemiologic study of endometrial cancer that "no association exists between the use of oral contraceptive pills and the subsequent development of endometrial cancer." They correctly point out that a limitation of their data is that only a small number of patients and control subjects had previously used contraceptive pills. Their data may also be limited by the relatively short time from the introduction of contraceptive pills to the present. A typical latent period from exposure to known chemical carcinogens until detection of cancer is 20 to 40 years (2-4). Oral contraceptive pills were introduced in the early 1960s (higher estrogen pills in 1960 and "average" estrogen pills after 1963) (5). Thus, an excess of cancers resulting from oral contraceptive use might not yet be detectable. Horwitz and Feinstein's hypothesis ought to be considered unproven until one can study a group of women at least 20 years after their

REFERENCES

1. H O R W I T Z R l , FEINSTEIN A F . Case-control study of oral contraceptive pills and endometrial cancer. Ann Intern Med. 1979;91:226-7. 2. SELIKOFF IJ, H A M M O N D EC. Environmental cancer in the year 2000. In: American Cancer Society 7th National Cancer Conference Proceedings. Philadelphia: J.B. Lippincott Co.; 1973:687-96. 3. SELIKOFF IJ. The latent period of occupational cancers. In: LEVINSON C, ed. The New Multinational Health Hazards. Geneva: ICF; 1975:33-40. 4. MORRISON AS, C O L E P. Epidemiology of bladder cancer. Urol Clin North Am. 1976;3:13-29. 5. H A T C H E R RA, S T E W A R T G K , G U E S T F, F I N K L E S T E I N R, G O D W I N C.

Contraceptive 1976:42.

Technology

1976-1977. 8th ed. New York: Halsted Press;

Amitriptyline Ophthalmoplegia T o T H E EDITOR: Oculovestibular (caloric) testing is a useful

procedure to determine the integrity of the ocular motor system in a comatose patient. Absence of an oculovestibular response is considered to occur only in deep metabolic coma or in the near terminal stages of rostral-caudal deterioration from structural lesions. Mladinich and Carlow (1) have reported a case of total gaze paralysis in light coma due to amitriptyline poisoning. We report here a second such case with prompt resolution of the paralysis after physostigmine administration. A 52-year-old woman telephoned for an ambulance after taking an overdose of drugs. She was comatose upon arrival at the emergency department. Her purse contained amitriptyline and diuretics. At examination, she was afebrile with a blood pressure of 180/110 mm Hg, pulse 112/min, and respirations 20/min. At neurologic examination she made purposeful movements to noxious stimuli but did not open her eyes. Her pupils were both 4 mm and reactive to light. Fundi were normal. Oculocephalic and oculovestibular maneuvers elicited no ocular movements. Her reflexes were symmetrical with bilateral Babinski signs. Intravenous glucose and naloxone were without effect. Physostigmine, 2 mg intravenously, produced arousal within 5 min. She then regained full extraocular movements. She admitted to ingesting several 50-mg tablets of amitriptyline. A subsequent toxicologic screen on her urine was positive for amitriptyline; no other drugs were detected. Her recovery was uneventful.

The lack of eye movements to oculovestibular stimulation initially suggested profound brain stem damage. The purposeful movements and the appearance of the patient were more typical of metabolic coma, which was subsequently confirmed. Amitriptyline and phenytoin (2) are two drugs that can cause total ophthalmoplegia in light coma. Although amitriptyline has an antiserotonin effect (3), the fact that physostigmine promptly reversed the gaze paralysis indicates that cholinergic mechanisms in the nearby pontine reticular formation, and not serotoninergic mechanisms in the raphe nuclei, are involved with ocular motor movements. Total ophthalmoplegia, even in light coma, should suggest amitriptyline poisoning and a diagnostic and temporarily therapeutic trial of physostigmine. M I C H A E L S. S M I T H , M . D .

University of Arizona; Tucson, A Z 85724 REFERENCES

1. MLADINICH EK, C A R L O W TJ. Total gaze paresis in amitriptyline overdose. Neurology (Minneap). 1977;27:695. 2. SPECTOR R H , D A V I D O F F RA, S C H W A R T Z M A N RJ. Phenytoin-induced

ophthalmoplegia. Neurology

(Minneap).

1976;26:1031-4.

3. GOSSELIN RE, H O D G E HC, S M I T H R P , G L E A S O N MN. Clinical

ogy of Commercial 1976:228-9.

Products.

Toxoplasma Uveitis Without Retinochoroiditis? T o THE EDITOR: We have read with interest the recent correspondence (1) reporting a presumptive anterior uveitis without Letters and Corrections

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Toxicol-

Baltimore: Williams and Wilkins Co.;

793

apparent retinochoroiditis in acquired toxoplasmosis. Although there is now little doubt that the acquired disease can result in a retinochoroiditis (2-4), an isolated anterior uveitis caused by toxoplasmosis remains speculative. T h e anterior chamber reaction that commonly accompanies the retinochoroiditis observed in both congenital and acquired toxoplasmosis is thought to represent a "spillover" phenomenon, that is, a hypersensitivity reaction in the anterior uvea (iris and ciliary body) to an antigenic insult in the posterior segment (5). This reaction has been experimentally produced in rabbits recovering from toxoplasmic retinochoroiditis by the injection of a cell-free lysate of toxoplasma organisms into the vitreous (6). Moreover, Toxoplasma gondii organisms have never been recovered from the human ocular anterior segment (6). The role of hypersensitivity in toxoplasmosis has led to speculation that an isolated anterior uveitis as a complication of acquired toxoplasmosis might indeed exist and represent an immune phenomenon, based on an antigen-antibody complex reaction in the anterior uvea. We assume, however, that a reaction of this nature would be bilateral, unlike the reported case. Therefore, at present the sine qua non for the diagnosis of ocular toxoplasmosis remains a retinal lesion, usually at the posterior pole but also, at times, exclusively peripheral (making detection more difficult) (5). The case reported by D r . Handler raises several questions on diagnosis. First, the anterior chamber reaction, as described, appears more severe than that usually seen in toxoplasmosis, suggesting endophthalmitis rather than a simple anterior uveitis. Second, there is a lack of a complete description of the uveitis, for example, presence or quality of keratic precipitates; a mutton-fat type of keratic precipitate suggests a granulomatous uveitis, which would at least be consistent with toxoplasmosis. Last, the duration of the severe anterior reaction (at least 10 months) exceeds the duration of both systemic findings and elevated serologic titers. Under these circumstances, the ocular signs described would be more consistent with an ongoing untreated retinochoroidal focus rather than an acute immunologic reaction, manifested in part by an isolated anterior uveitis. Dr. Handler's case epitomizes both the challenges and frustrations of the ophthalmologist in his attempt to ascribe various causes to uveitis. Unfortunately, the concurrence of an isolated anterior uveitis and an elevated titer of antitoxoplasma antibodies does not necessarily signify a causal relation. ROBERT J. MASI, M.D. G. RICHARD O'CONNOR, M.D. Francis I. Proctor Foundation, University of California; San Francisco, C A 94143 REFERENCES

1. H A N D L E R RP. Ocular toxoplasmosis. Ann Intern Med. 1979;91:324. 2. SAARI M, V U O R R E I, N E I M I N E N H, R A I S A N E N S. Acquired toxoplasmic

chorioretinitis. Arch Ophthalmol.

1976;94:1485-8.

3. M A S U R H, J O N E S TC, L E M P E R T JA, C H E R U B I N I T D . Outbreak of toxo-

plasmosis in a family and documentation of acquired retinochoroiditis. Am J Med. 1978;64:396-402. 4. G U M P DW, H O L D E N RA. Acquired chorioretinitis due to toxoplasmosis.

Ann Intern Med. 1979;90:58-60. 5. O ' C O N N O R GR. Protozoan disease of the uvea. Int Ophthalmol Clin. 1977;17:163-76. 6. O ' C O N N O R GR. The influence of hypersensitivity on the pathogenesis of ocular toxoplasmosis. Trans Am Ophthalmol Soc. 1970;68:501-47.

specimen receipt. Our medical staff has been encouraged to consider the diagnosis in acutely febrile patients with evidence of respiratory infection, particularly if routine bacterial studies are negative. In addition direct fluorescent antibody studies have been offered on frozen sections of lower respiratory tissue using a Legionella-specific F I T C conjugate obtained from the Center for Disease Control. During the 3 summer months of 1979 we have diagnosed presumptive L. pneumophila infection in 11 of 47 patients studied. The cases seemed to fit into two distinct varieties. Eight patients presented with acute onset of fever and minimal to pronounced roentgenographic evidence of pneumonitis. Symptoms of chills, myalagia, headache, malaise, and diarrhea differed, but some combination of these complaints was noted by all patients. Immunoglobulin-G-specific L. pneumophila anti-bodies with a titer of 256 to 1024 were present in all patients on the initial serum, with IgM-specific antibody titers between 16 and 128. Routine bacterial cultures and mycoplasma serologic studies were negative. Leukocyte counts and differential were normal. All seven patients responded rapidly (usually within 36 h) to erythromycin, 500 mg four times daily, and were discharged within 4 to 5 d. Three patients had an atypical course that ultimately led to open-lung biopsy or percutaneous aspiration, at which time numerous Legionella bacilli were identified by both Dieterle and direct fluorescent antibody techniques. One patient had a 5week history of cough, low-grade fever, and diffuse pulmonary infiltrates. O n e febrile patient with pneumonitis developed a pulmonary cavity. The third patient developed discrete pulmonary nodules after an initial episode of pneumonitis followed by right upper quadrant pain and chemical changes simulating biliary obstruction. Percutaneous aspiration of a nodule produced inflammatory material containing many Legionella bacilli. All three patients recovered completely after 10 to 14 d of erythromycin therapy. Routine bacterial cultures of pulmonary tissues were negative, as were mycoplasma and respiratory viral serologic studies. A moderate neutrophilic leukocytosis was noted in these patients. We emphasize to our medical staff that we are learning as we accumulate information and prefer not to be rigid about diagnostic criteria. We conclude, thus far, from our findings that an initial IgG-specific Legionella antibody titer of 256 or an IgMspecific titer of 16 in a febrile patient with evidence of respiratory infection is strong evidence of active infection and indicates the need for specific treatment. All patients tested have not had any common epidemiologic features, and this leads us to conclude that the L. pneumophila infections have occurred endemically within the community and do not represent an epidemic or an "exotic" illness. There has been no evidence of person-to-person spread of the disease, and after a mild initial stir of excitement, Legionnaire's disease patients are now treated routinely in our hospital. With complete agreement that use of a monospecific antigen source may lead to an occasional false-negative result and the antibody titers and therapeutic responses could conceivably be coincidental, we believe strongly that rapid testing by the above or similar methods for L. pneumophila infections should be used until a "better" means of diagnosis is achieved. J O H N B. C A R T E R , M . D .

Louis A. Weiss Memorial Hospital; Chicago, I L 60640 REFERENCE

Legionnaires' Disease at a Community Hospital T o T H E EDITOR: In response to your April 1979 symposium on Legionnaire's disease (1), I wish to describe the services organized at our 375-bed community hospital for the diagnosis of that infection as well as to outline briefly our findings to date. We have been offering an immunofluorescent antibody test using IgG- and IgM-specific antibody determination with a Philadelphia-1 strain of Legionella pneumophila as the antigen substrate. Tests are done and results reported on the day of 794

1. I N T E R N A T I O N A L SYMPOSIUM ON L E G I O N N A I R E S ' D I S E A S E . Ann

Med.

Hairy-Cell Leukemia and Aplastic Anemia T o T H E EDITOR: W e have read with interest the article by Brearley and colleagues, "Hairy-Cell Leukemia Presenting A s Aplastic Anemia" (1). W e have had similar experiences while seeing patients on the service of Dr. Lung T. Yam. We wish to

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Intern

1979;90:491-703.

report one case in which the diagnosis of hairy-cell leukemia was not difficult but which behaved as a typical case of aplastic anemia. A 55-year-old white man was seen in July 1975 because of weakness, pancytopenia, and splenomegaly. Laboratory data showed a hemoglobin of 9.8 g/dL; hematocrit 31.3%, mean corpuscular volume 96 jam3; mean corpuscular hemoglobin concentration 31.7%; leukocyte count 3400/mm 3 with 15% neutrophils, 80% "lymphocytes" and hairy cells, 1% eosinophils, and 4 % monocytes, and five nucleated erythrocytes per 100 leukocytes. Tartrateresistant acid phosphatase test was positive. Platelet count was 55 000/mm 3 and reticulocyte count 0.3%. Bone marrow biopsy was typical of hairy-cell leukemia. Splenectomy was done in August 1975 with initial improvement of blood count. Two months after splenectomy, however, his hemoglobin was 6.8 g/dL; hematocrit 22.3%; mean corpuscular volume, 94 jam3; mean corpuscular hemoglobin concentration 31.1%; leukocyte count 17 700/mm 3 with 1% neutrophilic bands, 5 % neutrophils, 88% "lymphocytes" and hairy cells, and 6% monocytes; platelet count 51 000/mm 3 ; and reticulocyte count 0.5%. Studies failed to reveal evidence of blood loss, hemolysis, or megaloblastosis. Androgen therapy was begun, but no response was noted. The patient refused cytotoxic chemotherapy. During the past 4 years he has been receiving transfusions of four units of packed erythrocytes every 6 to 8 weeks. He has received about 100 units of blood and has developed stigmata of transfusion siderosis.

In this case the diagnosis of hairy-cell leukemia was made easily. The subsequent clinical course, however, was identical to that of aplastic anemia. Thus it appears from the report of Brearley and associates (1) and from our case that hairy-cell leukemia may infrequently present either as aplastic anemia, making the diagnosis difficult, or clinically behave as aplastic anemia, making therapy difficult. Conceivably a rare case may present as aplastic anemia. Hairy-cell leukemia should be added to the differential diagnosis in cases of aplastic anemia. C H A R L E S F. W I N K L E R , M . D .

A 53-year-old nonalcoholic Hopi woman with cryptogenic cirrhosis, suffered upper gastrointestinal bleeds in April 1978 and again in August 1979. Endoscopy revealed nonbleeding esophageal varices and superficially bleeding gastritis. After the April bleed, she was placed on cimetidine therapy, 300 mg orally every 6 h for 5 weeks. After the August bleed, she was restarted on cimetidine therapy, 300 mg orally every 8 h for 2 months. In December 1978 her platelet count was 57 000/mm 3 , at which time cimetidine was withdrawn (Table 1). Within 10 weeks, her platelet count had returned to normal. She was also found to be granulocytopenic and to have a Coombs' negative hemolytic process. These hematologic abnormalities resolved after cimetidine therapy was stopped. From April 1978 through April 1979, her liver function studies remained stable.

Our patient had granulocytopenia, thrombocytopenia, and a Coombs' negative hemolytic process associated with cimetidine therapy. As with the other reported cases of hematologic abnormalities associated with cimetidine, our patient's hematologic disorder may have been caused by the complicated underlying medical disease process and not by cimetidine (3). Freston (3) further states that "cimetidine-induced granulocytopenia has not been documented in a patient with uncomplicated peptic ulcer disease." Perhaps the potential toxicity of cimetidine is enhanced when other factors are present (cirrhosis, cancer, cytotoxic drugs, systemic lupus erythematosus, septicemia); as Hastings and coworkers (4) and Ippoliti and colleagues (5) point out, intensive antacid regimens are more appropriate than cimetidine in certain clinical settings. ROBERT RATE, M.D. MARK BONNELL, M.D. C A R O L C H E R V E N A K , R.PH. G A R Y P A V I N I C H , R.PH.

Keams Canyon Indian Hospital; Keams Canyon, A Z 86034

C L I F F O R D V. J E N N I N G S , M . D .

Veterans Administration Medical Center1; Louisville, K Y 40202 REFERENCES 1. L I T T L E J O H N GO, U R O W I T Z MB. Cimetidine, lupus erythematosus, and

REFERENCE 1. BREARLEY RL, C H A P M A N RM, BROZOVIC B. Hairy-cell leukemia pre-

senting as aplastic anemia. Ann Intern Med. 1979;91:228.

granulocytopenia. Ann Intern Med. 1979;91:317-8. Letter. 2. M C D A N I E L JL, STEIN JJ. Thrombocytopenia with cimetidine therapy. AT Engl J Med. 1979;300:864. Letter. 3. FRESTON JW. Cimetidine and granulocytopenia. Ann Intern Med. 1979;90:264-5. Editorial. 4. H A S T I N G S PR, SKILLMAN JJ, B U S H N E L L LS, SILEN W. Antacid titration

in the prevention of acute Gastrointestinal bleeding: a controlled, randomized trial in 100 critically ill patients. N Engl J Med. 1978;298:10415.

Cimetidine and Hematologic Effects T o T H E EDITOR: Recent observations on the hematologic abnormalities (1-3) associated with cimetidine prompt us to report an additional case and to add two cautionary thoughts.

5. IPPOLITI A F , S T U R D E V A N T RAL, ISENBERG JI, et al. Cimetidine versus

intensive antacid therapy for duodenal ulcer: a multicenter trial. Gastroenterology. 1978;74:393-5.

Table 1 . Laboratory Data

Date

4/78

8/78

9/78 12/27/78 1/15/79 1/30/79 3/1/79 4/23/79

Cimetidine Dose

After gastrointestinal bleed and before first course After gastrointestinal bleed and before second course 300 mg every 6 h Cimetidine withdrawn None None None None

Hemoglobin

Hematocrit

Leukocyte Count (PMNs*/ Lymphocytes)

Reticulocyte Count

Platelet Count

g/dL

%

no./mm*

%

no./mmz

4400 (66/30)

1.0

200 000

14.5

12

37

3800(61/33)

15.2

45 42 44 47 47

3800(45/51) 3100(60/38) 3600 (46/46) 3800(61/39) 3800(89/8)

15.6 15.8

Plasma-Free Hemoglobin

Serum Haptoglobin

mg/dL

670 000

3.9 4.0 4.7 5.2 4.3

57 000 77 000 78 000 122 000 181000

2.6 (0-0.9)f

0.3(0-15)f

< 1 0 (100-300)t

>100(100-300)t

* PMNs = polymorphonuclear neutrophilic leukocytes. t Numbers in parentheses indicate range of normal values; for plasma-free hemoglobin two different laboratories were used, and each had a different range of normal values. Letters and Corrections

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REFERENCE

Uric Acid Excretion

T o THE EDITOR: T h e article by Simkin and associates in the July issue (1) discussed a common problem in clinical medicine and provoked much conversation among the physicians here. Answers to the following questions may permit more complete acceptance of the spot uric-acid excretion ratio as clinically useful. W h a t literature is available on the time course—relative and absolute—of uric acid and creatinine release and excretion over a 24-h period? What correlation was obtained in a paired t test between spot ratio results and the 24-h collection excretion ratios in the persons studied? How does the use of spot clearance ratios (using serum creatinine and uric acid) appear to differ in patients with decreased renal function? Does the use of serum creatinine sufficiently correct for decreased glomerular filtration? How does the excretion ratio—spot and 24-h collections— apply in hyperuricemic patients? These are obviously the patients in whom the spot determination is useful, and this correlation is not discussed in Simkin's paper. GARY GREENBERG, M.D. B I J A Y K. J A Y A S W A L , M . D .

Glenville Health Association; Cleveland, O H 44108 REFERENCE 1. SIMKIN PA, H O O V E R PL, PAXSON CS, W I L S O N W F . Uric acid excretion:

quantitative assessment from spot, midmorning serum and urine samples. Ann Intern Med. 1979;91:44-7.

In reply: T o Drs. Greenberg and Jayaswal, I offer the following additional points. 1. We established only that the mean midmorning excretion rate of uric acid reflects the mean 24-h rate. Midmorning thus appears to be an appropriate time for a spot collection. Further study of diurnal patterns is warranted and should be facilitated by the availability of our method. 2. T h e close agreement of the mean midmorning and 24-h rates excludes the possibility that paired t analysis might reveal a significant difference between these methods. We must reiterate that our test measures uric acid excretion per decilitre of glomerular filtrate. This is not a ratio. 3. Clearance ratios are a qualitative reflection of how well the tubules handle a urate load, whereas we were interested in a quantitative assessment of how much uric acid is excreted. This is the main reason that the serum urate level does not enter the calculation. In addition, uric acid clearance best fits available data as an exponential function of the plasma urate concentration (1). This basic nonlinearity makes it difficult, if not impossible, to meaningfully evaluate renal handling of urate from uric acid clearance. The serum creatinine is not included to "correct for decreased glomerular filtration." A s stated in our paper, our test cannot be recommended when renal function is significantly impaired. Under such circumstances, it still may reflect fairly the burden of uric acid per tubule, but high values cannot be taken as evidence of increased overall excretion. 4. W e did not obtain 24-h collections in most of our hyperuricemic patients. 5. O u r approach to uric-acid excretion rests on two assumptions: Creatinine clearance measures the glomerular filtration rate; and we can accurately measure plasma creatinine, urinary uric acid, and urinary creatinine. T o the extent that these assumptions are correct, o u r method is virtually error-free. Most of the variability that we observe with the method is physiologic variation. Much important work remains to be done to define and perhaps to eliminate the sources of this physiologic variation. W e believe that the convenience and the inherent logic of our method make it a valuable tool in this continuing endeavor. P E T E R A. S I M K I N , M . D .

University of Washington; Seattle, W A 98195 796

1. SIMKIN PA. Uric acid excretion in patients with gout. Arthritis 1979:22:98-9.

Diabetic Ketoacidosis and Alcoholic Ketosis

T o T H E EDITOR: T h e data in the article "Hyperchloremic Acidosis during the Recovery Phase of Diabetic Ketosis" by Oh and colleagues in the December 1978 issue (1) fit well with our findings in patients with diabetic ketoacidosis (2) (Table 1). There are, however, differences in the pretreatment findings in both Oh's and our patients with diabetic ketoacidosis on the one hand, and those in our patients with alcoholic ketosis on the other (3) (Table 1). For the comparisons, we have omitted three of our original 21 patients with alcoholic ketosis (3) whose various blood specimens were not obtained simultaneously. Because the average ratio of plasma acetoacetate to 3-hydroxybutyrate probably differs in patients with diabetic ketoacidosis from that in alcoholic ketosis (4) and because neither we nor Oh measured acetoacetate, we d o not assume a value for acetoacetate. Serum bicarbonate concentrations have been calculated from the arterial blood p H and Pco 2 values. Our patients with alcoholic ketosis had nearly the same mean plasma (3-hydroxybutyrate + lactate) as did both our and O h ' s patients with diabetic ketoacidosis. Some other mean values in our patients with alcoholic ketosis, however, differed notably from those in both groups of patients with diabetic ketoacidosis. The alcoholic patients tended to have higher blood p H , lower serum K , lower serum CI , and higher serum H C O / than did the diabetic patients. We believe those features were due to the severe recurrent vomiting experienced by almost all of the alcoholic patients. T h e vomiting likely caused chloride depletion and metabolic alkalosis, coexisting with their ketoacidosis. As in Oh's patients with diabetic ketoacidosis, in both of our patient groups plasma (3-hydroxybutyrate + lactate) largely accounts for the "excess anion g a p , " that is, that exceeding the normal mean value of 12 m e q / L . (If, as Oh did, we add to the measured organic anions in the patients with diabetic ketoacidosis one fourth of their average 3-hydroxybutyrate concentration, to approximate mean plasma acetoacetate, it would add 2.7 m e q / L . T h e total estimated organic anions would then be 15.6 m e q / L , very close to the excess anion gap of 17.0.) In both Table 1 . Comparison of Admission Laboratory Data* in Patients with Diabetic Ketoacidosis and Alcoholic Ketosis

Variablef

Diabetic Ketoacidosis Oh et al. {N = 35)

Blood pH Serum N a + Serum K+ Serum Cl~ Plasma HCXV A HC03Anion gap§ Plasma lactate Plasma 3-hydroxybutyrate Plasma lactate + 3-hydroxybutyrate Excess anion gap ||

7.07 ± 0 135.5 ± 1.6 101.0 ± 1.4 9.4J 14.6 26.1 2.7 ± 0 . 3

10.3 ± 0 . 3

13.0 14.1

Our Series (N = 27) 7.17 133.0 4.9 97.3 6.7 17.3 28.9 2.1

±0.02 ± 1.2 ±0.2 ± 1.1 ±0.6 ±0.6 ± 1.1 ±0.1

Alcoholic Ketosis (N = 18)

7.35 135.2 4.1 90.9 16.5 7.5 27.8 3.9

± 0.05 ± 1.6 ±0.3 ± 3.9 ±2.4 ±2.4 ±2.5 ± 1.2

10.8 ± 0 . 6

9.3 ± 1.1

12.9 ± 0 . 6 17.0 ± 1.1

13.2 ± 1.6 15.8 ± 2 . 5

* Data given as mean ± S E M . t All units are in meq/L except for blood pH. X This and all succeeding values in this column refer to 15 patients. § Calculated as serum Na + - (Cl~ + HCO3-). || Calculated as anion gap — 12 meq/L.

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Rheum.

their and our patients with diabetic ketoacidosis, the measured organic acids closely approximate the AHCCV values (the decrease in plasma HCO,~ from the normal value of 24 m e q / L ) . In the alcoholic patients, in contrast, the mean (lactate + 3-hydroxybutyrate) of 13.2 m e q / L exceeded the AHCCV (7.5 m e q / L). This is because the alcoholic patients not only had subnormal plasma HC0 3 ~ due to ketoacidosis, but also hypochloremia (mean serum C I - of 90.9 m e q / L ) , presumably due to vomiting. MlLFORD FULOP, M.D. H E N R Y D. H O B E R M A N , PH.D., M.D.

Albert Einstein College of Medicine; Bronx, N Y 10461 REFERENCES 1. O H MS, C A R R O L L HJ, G O L D S T E I N DA, F E I N IA. Hyperchloremic aci-

dosis during the recovery phase of diabetic ketosis. Ann Intern Med. 1978;89:925-7. 2. F U L O P M. The ventilatory response in uncomplicated diabetic ketoacidosis. Crit Care Med. 1977;5:190-2. 3. F U L O P M, HOBERMAN H D . Alcoholic ketosis. Diabetes. 1975;24:785-90. 4. C O O P E R M A N MT, D A V I D O F F F, SPARK R, P A L L O T T A J. Clinical studies

of alcoholic ketoacidosis. Diabetes.

1974;23:433-9.

Computed Tomography in Cerebral Malignant Disease T o T H E EDITOR: In D r . Weisberg's recent comprehensive review of computed tomography (CT)(1), two areas were not addressed in regard to malignant disease—leptomeningeal carcinomatosis and progressive multifocal leukoencephalopathy. Both may mimic neurologic disorders and are frequently difficult diagnoses to establish (2-5). There is little in the literature on the usefulness of C T scanning in diagnosing leptomeningeal carcinomatosis, but a recent report noted that computed tomography detected intracranial meningeal spread in 4 4 % of these patients (6). The characteristic finding was subarachnoid contrast enhancement, and in two patients this finding was the first suggestion of the process. Progressive multifocal leukoencephalopathy is a progressive, usually fatal neurologic disorder associated primarily with chronic lymphocytic leukemia and lymphoma (4). Recent experience suggests that the C T scan may be the most specific diagnostic study available for identifying this disease (7, 8). T h e characteristic C T picture includes low-density lesions of central and convolutional white matter with scalloped lateral borders and failure to enhance with contrast material. Because the C T scan is being used increasingly as a screening study, its value in these entities should be appreciated by clinicians. Dr. Weisberg's perspective on the use of computed tomography in these disorders would be of interest. J A M E S B. R E U L E R , M . D . D O N A L D E, G I R A R D , M . D .

In reply: This letter raises several important diagnostic problems related to computed tomography. Computed tomography (CT) is a valuable supplementary study in the diagnosis of leptomeningeal carcinoma, but this diagnosis is almost always definitively established by careful cerebrospinal fluid (CSF) examination, which must include cytologic analysis. In one report (1) it is stated that "the computed tomography scan led to a C S F cytological examination and to the correct diagnosis [leptomeningeal carcinomatosis]." I take strong exception to this approach. Lumbar puncture should be done initially, then computed tomography should be done to detect parenchymal lesions. Our experience and that of Enzmann and associates (1) in leukemic and lymphomatous meningitis has shown falx and tentorial enhancement in only rare instances ( 3 % ) . In 5 0 % of a limited number of cases of carcinomatous meningitis, computed tomography showed subarachnoid enhancement, and, of these, one half also had parenchymal lesions. T h e subarachnoid enhancement is frequently seen at different window width settings on the scanner than is conventionally used to detect parenchymal lesions. In patients with leukemia who are neurologically asymptomatic or have only signs of meningeal involvement, I do not believe computed tomography is necessary. Two disorders that may be confused with parenchymal metastases from clinical and C T findings include progressive multifocal leukoencephalopathy and radiation necrosis. Progressive multifocal leukoencephalopathy appears as low-density areas with jagged borders located in white-matter regions. In all previously reported cases, no mass effect or enhancement has been seen, but both these findings have been seen in our experience and that of Heinz and colleagues (2). T h e peripheral edge of enhancement is more typical of progressive multifocal leukoencephalopathy than of intracranial metastases. Recent literature reporting enhancement and mass effect emphasizes that we are now detecting a wider spectrum of this disorder, perhaps at an earlier stage. With high-resolution C T scanners, the gray-white matter interphase is routinely defined. Therefore, excellent definition of low-density white matter on high-resolution scanners has led to the erroneous diagnosis of progressive multifocal leukoencephalopathy in certain cases. Radiation necrosis and areas of gliosis may appear as high-density enhancing lesions, with associated mass effect and surrounding edema. In these cases differentiation from metastatic recurrence is not possible based on C T characteristics without surgical biopsy. L E O N A. W E I S B E R G , M . D .

Tulane Medical School; New Orleans, L A 70112 REFERENCES 1. E N Z M A N N DR, K R I K O R I A N J, Y O R K E C, H A Y W A R D R. Computed to-

mography in leptomeningeal spread of tumor. / Comput Assist 1978;2:448-55.

Tomogr.

2. H E I N Z ER, D R A Y E R BP, H A G E N G E L L C, et al. Computed tomography

in white matter disease. Radiology.

1979;130:371-8.

D A V I D A. N A R D O N E , M . D .

Veterans Administration Hospital; Portland, O R 97201 REFERENCES

1. WEISBERG LA. Computed tomography in the diagnosis of intracranial disease. Ann Intern Med. 1979;91:87-105.

Internal Medicine as a Finely Honed Discipline

2. L I T T L E JR, D A L E AJD, O K A Z A K H. Meningeal carcinomatosis.

T o T H E EDITOR: I read with great interest Dr. Barondess' article (1) on the training of the internist. I thought it was most lucid and coherent. I also read the numerous comments it provoked (2, 3); most of them missed the whole point of his message. T o me, he seems to be saying that the discipline inherent in an inhospital training program for internists prepares them to handle not only the complicated in-bed case but also primary care in the office practice of internal medicine. His point is, I believe, that a disciplined mind is needed to be able to cope with the complexities of the modern practice of internal medicine, and he questions whether other training programs instill this discipline to the same degree as does an inhospital internal medicine training program. I support D r . Barondess in this belief. I have seen those trained in "general practice" or "primary care" as lacking the fine-honed discipline that can be seen in the in-

Neurol.

Arch

1974;30:138-43.

3. O L S O N ME, C H E R N I K NL, POSNER JB. Infiltration of the leptomeninges

by systemic cancer. Arch Neurol. 1974;30:122-37. 4. RICHARDSON EP. Our evolving understanding of progressive multifocal leukoencephalopathy. Ann NY Acad Sci. 1974;230:358-64. 5. R E U L E R JB, M E I E R D. Leptomeningeal carcinomatosis with normal CSF features. Arch Intern Med. 1979;139:237-8. 6. E N Z M A N N DR, K R I K O R I A N J, Y O R K E C, H A Y W A R D R. Computed to-

mography in leptomeningeal spread of tumor. / Comput Assist 1978;2:448-55.

Tomogr.

7. C A R R O L L BA, L A N E B, N O R M A N D, E N Z M A N N D. Diagnosis of progres-

sive multifocal leukoencephalopathy by computed tomography. gy. 1977;122:137-41.

Radiolo-

8. C O N O M Y JP, W E I N S T E I N MA, A G A M A N O L I S D, H O L T WS. Computed

tomography in progressive 1976;127:663-5.

multifocal

leukoencephalopathy.

AJR.

Letters and Corrections

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797

hospital-trained internist; for my personal physician I would certainly select the latter.

icine: guides and methods 1979;91:326-32.

for the clinician.

Ann

Intern

Med.

R O B E R T E. E C K A R D T , M . D . , P H . D .

7355 East Claremont Street; Scottsdale, A Z 85253 Correction: Dose of Amphotericin B REFERENCES

1. BARONDESS JA. The training of the internist: with some messages from practice. Ann Intern Med. 1979;90:412-7. 2. Training the internist. Ann Intern Med. 1979;91:124-7. Letters. 3. B A T E M A N WB J R , BLOOM HG, BOUFFORD JI. Training the internist.

Ann Intern Med. 1979;91:316. Letter.

T o T H E EDITOR: In our letter on the treatment and diagnosis of aspergillosis in a leukemic patient in the August issue (1), an unfortunate error was made in transcribing the letter from our manuscript. We indicated that amphotericin B was given in a dose of 40 mg q.o.d.; this appeared in print as 40 mg four times a day. BURT ADELMAN, M.D.

Peter Bent Brigham Hospital; Boston, M A 02115

Correction: Biosis Services

REFERENCE

T o T H E EDITOR: We were very pleased to see Biological Abstracts and BioResearch Index mentioned in the article by William Beatty, "Searching the Literature and Computerized Services in Medicine," in the August issue (1). We noted several factual errors, however, that we wish to point out. Mr. Beatty states that "Biological Abstracts has no cumulated indexes" (p. 330). H e implies that BioResearch Index also has no cumulated indexes. Both of these publications do have biannual cumulated indexes. In describing the coverage of BioResearch Index (p. 330), Mr. Beatty includes neither review nor meeting literature in his list. In fact, more than 5 0 % of the items indexed in BioResearch Index are taken from meeting literature (symposium papers, conference abstracts, and so forth), and nearly 1 5 % are taken from reviews. In Table 2 (p. 329), BIOSIS is listed with a description of several of our inhouse computerized search services. T h e description as it stands is correct but very incomplete. T h e BIOSIS computer-readable files are widely available throughout the world. Lockheed, SDC, BRS, and Can-ole are the four North American systems that provide online service. The ESA system and D I M D I system provide online service in Europe, and many more provide offline access both here and abroad. ROBERT MARCHISOTTO, PH.D.

Biosciences Information Service; Philadelphia, P A 19103 REFERENCE

1. A D E L M A N BA, B E N T M A N A, R O S E N T H A L P, S M I T H BR, B R I D G E S KR,

HOLMES W. Treatment of aspergillosis in leukemia. Ann Intern Med. 1979;91:323-4. Letter.

Correction: Grant Support T o T H E EDITOR: In my paper in the September issue (1), I inadvertently omitted that my study was supported in part by National Institutes of Health Grant N L M 02857 from the National Library of Medicine. P H I L R. M A N N I N G , M . D .

University of Southern California School of Medicine; Los Angeles, C A 90033 REFERENCE

1. M A N N I N G PR, DENSON TA. HOW cardiologists learn about echocardiography: a reminder for medical educators and legislators. Ann Intern Med. 1979;91:469-71.

Correction: Annotated Bibliography The page number and order of authors in Reference 87 of the annotated bibliography for cardiovascular diseases {Ann Intern Med. 1979;91:137-142) are incorrect. The correct reference is M O R G A N T, A D A M W, G I L L I E S A, W I L S O N M, M O R G A N G, C A R N E Y S.

1. BEATTY WK. Searching the literature and computerized services in med-

798

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Hypertension treated by salt restriction. Lancet.

1978;1:227-30.