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Rhodes JM. Cholesterol crystal embolism: an important “new” diagnosis for the general physician. Lancet 1996; 347: 1641. Coburn JW, Agre KL. Renal thromboembolism, atheroembolism, and other acute diseases of the renal arteries. In: Schrier RW, Gottschalk CW, eds. Diseases of the kidney. 5th ed. Boston: Little Brown and Company, 1993: 2129–30. Mayo RR, Swartz RD. Redefining the incidence of clinically detectable atheroembolism. Am J Med 1996; 100: 524–29. Pierce JR, Wren MV, Cousar B. Cholesterol embolism: diagnosis antemortem by bone marrow biopsy. Ann Intern Med 1978; 89: 927–38.

Desmosterolosis: a new inborn error of cholesterol biosynthesis SIR—Irons and co-workers1,2 showed that the blood and tissues of infants with Smith-Lemli-Opitz (SLO) syndrome contained reduced amounts of cholesterol and greatly increased concentrations of a cholesterol precursor, 7dehydrocholesterol. This discovery showed that an inborn error of metabolism affecting a step in the synthesis of cholesterol from lanosterol could give rise to a characteristic pattern of malformation. The discovery of the biochemical defect has also led to successful prenatal diagnosis.3,4 We reasoned that other defects in the pathways from lanosterol to cholesterol may lead to syndromes similar to SLO. We have therefore used gas-chromatography/mass-spectrometry (GC-MS) to analyse neutral sterols in plasma and tissue samples for aborted fetuses, stillbirths, and infants who have features similar to those seen in SLO. We have shown that formalin fixation does not have any obvious effect on tissue sterol profiles and thus stored tissues can be analysed. The second pregnancy of unrelated parents was uneventful with the premature birth, at 34 weeks’ gestation, of an infant with marked craniofacial dysmorphism and ambiguous genitalia who died within an hour. The first pregnancy of this Scottish mother and American father of English extraction resulted in a normal daughter. At necropsy the infant was found to have macrocephaly, a hypoplastic nasal bridge, a cleft palate with unusual gingival nodules, total anomalous pulmonary venous drainage, malrotation of the gut, and renal hypoplasia. The gonadal tissue was found to be ovarian bilaterally. The skeletal survey showed rhizomelic shortening of all four limbs with shortened and malformed ribs. The brain showed an immature gyral pattern and poorly developed corpus callosum. Chromosome analysis of skin fibroblasts showed a normal female karyotype. GC-MS analysis of the neutral sterols in formalin-fixed brain tissue revealed that instead of just one major sterol (cholesterol), there were two compounds present in large amounts— cholesterol (23%) and a sterol with the retention time and mass spectrum identical to those of desmosterol (cholesta5,22-dien-3β-ol) (77%). In age-matched control samples, desmosterol accounted for less than 15% of brain sterols. The kidney and liver of the infant also contained increased amounts of desmosterol (43% [controls <2%] and 48% [controls <2%], respectively). Plasma from the infant’s parents showed slightly raised desmosterol concentrations: father, desmosterol 40 µmol/L, cholesterol 8·6 mmol/L; mother, desmosterol 12 µmol/L, cholesterol 4·7 mmol/L; controls, desmosterol 0·87–6·3 µmol/L, cholesterol 3·3–6·0 mmol/L). The accumulation of desmosterol in the tissues of this infant strongly suggests a defect in the enzyme responsible for saturation of the C24–C25 double bond during synthesis of cholesterol from lanosterol. The parents’ slightly raised plasma desmosterol concentrations are consistent with their being heterozygous for the enzyme deficiency. The gene for this enzyme is thought to be located on chromosome 20. The

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abnormalities displayed by this infant can be seen in several syndromes related to the severe form of SLO syndrome (type II). Sterol-
24 reductase, the enzyme that we believe was deficient in this infant, is inhibited by triparanol. This drug, which produces accumulation of desmosterol in vivo is highly teratogenic in rats; the abnormalities which are produced include facionasal dysplasia, renal anomalies, anophthalmia, and neural tube defects.5 We believe that the multiple malformations seen in this infant were the result of a genetically determined enzyme deficiency in one of the last stages of cholesterol biosynthesis. This case demonstrates the importance of normal endogenous cholesterol production in the developing human brain, craniofacies, heart, skeleton, and urogenital system. *Peter Clayton, Kevin Mills, Jean Keeling, David FitzPatrick *Biochemistry Unit, Institute of Child Health, London WC1N 1EH, UK; Department of Paediatric Pathology, Edinburgh Sick Children’s NHS Trust, Edinburgh; and Department of Clinical Genetics, Molecular Medicine Centre, Western General Hospital, Edinburgh

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Irons M, Elias ER, Salen G, Tint GS, Batta AK. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet 1993; 3: 1414. Tint GS, Irons M, Elias ER, et al. Defective cholesterol synthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 1994; 330: 107–13. McGaughran JM, Clayton PT, Mills KA, Rimmer S, Moore L, Donnai D. Prenatal diagnosis of Smith-Lemli-Opitz syndrome. Am J Med Genet 1995; 56: 269–71. Mills K, Mandel H, Montemagno R, Soothill P, Gershoni-Baruch R, Clayton PT. First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency). Pediatr Res 1996; 39: 816–19. Roux C. Action teratogene du triparanol chez l’animal. Arch Fr Pediatr 1964; 21: 451–64.

Cimetidine and immunoreactivity SIR—Many kinds of alterations to cellular immunity have been identified in patients undergoing a cardiac operation with a cardiopulmonary bypass (CPB). Natural killer (NK) cell cytotoxic activity is depressed after CPB.1 NK cells have an intrinsic ability to recognise and destroy some infected and some tumour cells. In addition, they release interferon- and other cytokines, which are important for cell-mediated immune responses.2 An impaired immunoreactivity increases the risk of septic multiorgan failure.3 Meanwhile, it has been reported that cimetidine increases immunoreactivity by inhibition of suppressor T lymphocytes or by activation of interleukin-2 production.4 Matsumoto5 also reported that cimetidine activated cellular immunity and increased survival time in colon cancer patients. These reports prompted us to investigate whether or not perioperative administration of cimetidine preserves cellular immunity after CPB, especially in relation to NK cell activity. 20 patients undergoing either coronary artery bypass grafting or heart valve replacement were studied with their informed consent. In this prospective randomised trial, the patients were divided into two groups of equal size. All patients received the same anaesthesia. Group A patients, with a mean age of 64·4 (SD 2·5) years, received an infusion of 400 mg of cimetidine intravenously over 20 min soon after induction of anaesthesia, before CPB. In addition, group A patients were given a 33 mg/h continuous intravenous infusion of cimetidine, starting 2 h after CPB and continuing up until the 5th postoperative day (day 5). Group B patients, with a mean age of 62·1 (2·6) years, received conventional postoperative therapy. Blood samples were taken preoperatively and on days 1 and 7. NK cell activity was measured soon after sampling by a chromium-51-release

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assay with the K562 cell line as the target. The MannWhitney U test was used for intergroup comparison. Results are presented as mean (standard error). There were no significant differences in age, sex ratio, or CPB time between the two groups. Furthermore, there were no differences in NK cell activity preoperatively (group A 44·0 [3·66]%, group B 44·4 [2·66]%, p=0·931) or on day 7 (group A 42·6 [4·18]%, group B 38·7 [4·81]%, p=0·548). The NK cell activity on day 1, however, in group A was 27·7 (4·93)% and in group B was 8·90 (1·96)% (p=0·0023). Although the number of patients reported in this study was too small to permit evaluation of the clinical effectiveness of cimetidine, our study raises the possibility that perioperative administration of cimetidine preserves cell-mediated immune response and decreases susceptibility to infection. *Junya Katoh, Kouji Tsuchiya, Wataru Sato, Masato Nakajima, Yoshinao Iida Department of Cardiovascular Surgery, Yamanashi Central Hospital, Kofu, Yamanashi 400, Japan

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Nguyen DM, Mulder DS, Shennib H. Effect of cardiopulmonary bypass on circulating lymphocyte function. Ann Thorac Surg 1992; 53: 611–16. Lydyard P, Grossi C. Cells involved in the immune response. In: Roitt I, Brostoff J, Male D, eds. Immunology. London: Mosby, 1996: 2,7–8. Markewitz A, Faist E, Lang S, Endres S, Fuchs D, Reichart B. Successful restoration of cell-mediated immune response after cardiopulmonary bypass by immunomodulation. Thorac Cardiovasc Surg 1993; 105: 15–24. Sahasrabudhe DM, McCune CS, O’Donnell RW, Henshaw EG. Inhibition of suppressor T lymphocytes (Ts) by cimetidine. J Immunol 1987; 138: 2760–63. Matsumoto S. Cimetidine and survival with colorectal cancer. Lancet 1995; 346: 115.

Figure: Diffuse infiltration of skin with hypochromic patches

Erythrodermic diffuse cutaneous leishmaniasis with Sézary syndrome SIR—Cutaneous presentations of leishmaniasis vary with Leishmania species involved and the patient’s immune status.1 In immunocompetent patients, dermotropic Leishmania cause localised cutaneous leishmaniasis. Diffuse cutaneous leishmaniasis is rare and characterised by diffuse cutaneous leishmanial nodules. It is seen in East Africa associated with L aethiopica or in south America with L amazonensis. In immunocompromised patients, diffuse cutaneous leishmaniasis has been associated with species normally responsible for localised lesions, such as L major,2 L braziliensis,3 or L infantum.4 We report a patient with erythrodermic diffuse cutaneous leishmaniasis due to L major and associated with Sézary syndrome. A 60-year-old man was admitted to the Institut Marchoux, Bamako, Mali, in December, 1992. He was from Mali and never travelled outside the country. He presented with an infiltration of the entire skin (figure). The skin was thickened and erythematous, with hypochromic patches of a coppery colour which were disseminated over the whole body. Itching was severe. His general condition was poor, and he had lymphadenopathy in his axillae, groins, and neck. White-cell count was 94106/L, with 86% lymphocytes. Most lymphocytes had nuclei characteristic of small Sézary cells, and showed a CD2+, CD4+, CD5+, CD3, CD7, CD8, CD25 phenotype. CD3 was expressed intracytoplasmically. PCR amplification of TCR genes from DNA extracted from blood showed bi-allelic clonal rearrangement (V2-J1/2 and V4-J1/2), confirming the presence of a clonal T-cell population.

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HTLV-I and HTLV-II serology was negative by ELISA and western blot. PCR was negative for HTLV-I proviral DNA sequences on the DNA extracted from the skin and from the peripheral blood mononuclear cells (PBMC), with three different primer sets of the HTLV-1 LTR, pol, and tax genes. The patient was HIV-1 and HIV-2 seronegative. Cultures of the patient’s PBMCs led to a cytopathic effect with syncytia formation and cell lysis after culture, both of PBMCs alone and after 4 weeks of co-culture with phytohaemagglutinin-stimulated PBMCs from an HIVseronegative person. Electron microscopy of this culture showed a herpes-like virus. DNA from PBMCs, from the coculture and from affected skin, was positive for human herpesvirus (HHV-6) and HHV-7 viral DNA sequences and negative for HHV-8. Skin biopsies showed, in the upper dermis, a diffuse blandlike infiltrate of foamy histiocytes, which contained numerous Leishmania amastigotes. Under these aggregates, there was a nodular and diffuse infiltrate of lymphocytes, mainly CD3+, UCHL-1+ T-cells, with rare CD20+ Blymphocytes which reached the deeper dermis. Smears taken from several sites showed Leishmania amastigotes. Isoenzyme characterisation on starch-gel electrophoresis showed the parasite to be L major zymodeme MON-74. Antileishmanial serology (fluorescent antibody technique and counterimmunoelectrophoresis) was negative. A bone-marrow sample was negative for Leishmania, but showed diffuse infiltration with small Sézary cells. Treatment with meglumine antimoniate was started, but the patient soon died. The association between cutaneous leishmaniasis and Sézary syndrome, reported here for the first time, resulted in

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