1122

increased to 150 mg and after 2 more weeks his inappropriate sexual behaviour ceased. An 84-year-old man was noted to be hypersexual after admission to a nursing-home. He made sexual advances to female residents. He frequently attempted to fondle female staff, and when they refused fondling or interrupted his fondling of other residents, he became physically and verbally aggressive. The insidious development of cognitive impairment began at age 72. Alzheimer’s disease was diagnosed at age 74, on the basis of clinical examination and neuropsychological testing. He had no previous psychiatric history, but had undergone repair of an abdominal aortic aneurysm, had a history of hypothyroidism and was taking glyburide 2-5 mg daily for adult-onset diabetes. Small doses of thioridazine produced severe sedation and lethargy. MPA 200 mg was given. His hypersexual behaviour abated within 2 weeks. He was continued on MPA 200 mg every other week and his thioridazine (25 mg four times a day) was gradually discontinued over the next 3 weeks. Departments of Psychiatry

MYRON F. WEINER MARGO DENKE KATHRYN WILLIAMS ROBERT GUZMAN

and Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas 75235, USA 1.

Cooper AJ. Progestogens in the Psychiatry 1986; 31: 73-79.

treatment

of male

sex

offenders:

a

review.

Can J

LA, Bland WP, Ruskin P, et al. Antiandrogen treatment of aberrant sexual activity. Am JPsychiatry 1987; 144: 1511. 3. Cooper AJ. Medroxyprogesterone acetate (MPA) treatment of sexual acting out in men suffering from dementia. J Clin Psychiatry 1987; 48: 368-70. 4. Cooper AJ. Medroxyprogesterone acetate as a treatment for sexual acting out in organic brain syndrome. Am J Psychiatry 1988; 145: 1179.

These

observations

have

considerable

potential clinical

importance. Since polyomavirus infection

may precede CMV infection and since both viruses may take 10-14 days to isolate, the presence of typical features of viral cystitis should make one vigilant for the possibility of coincident CMV infection. This is important now that it has been shown that the early treatment of symptom-free patients with positive CMV surveillance cultures significantly improves survival in the first 100 days after BM T. 1,3 Polyomavirus infection may be a marker of early CMV disease.

DAVID I. MARKS KATE WARD MRC/LRF Leukaemia Unit,

Department of Haematology, Hammersmith Hospital, London W12 ONN, UK

JILL HOWS A. JOHN BARRETT JOHN M. GOLDMAN

1. Goodrich JM, Mon M, Gleaves CA, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N EnglJ Med 1991; 325: 1601-07. 2. Apperley JF, Rice SJ, Bishop JA, et al. Late-onset hemorrhagic cystitis associated with urinary excretion of polyomaviruses after bone marrow transplantation. Transplantation 1987; 43: 108-12. 3. Schmidt GM, Horak DA, Niland JC, et al. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants: the City of Hope-Stanford-Syntex CMV Study Group. N EnglJ Med 1991; 324: 1005-11.

2. Ross

Viral

(polyomavirus) cystitis heralding cytomegalovirus infection

SIR,-Cytomegalovirus (CMV) infection

are

often

seen

and

polyomavirus (BK) allogeneic bone-marrow in especially profoundly

after

transplantation (BMT),i immunosuppressed patients. In both, the infection seems to be due to reactivation of latent virus. There is no specific treatment for polyomavirus infection but early treatment of CMV infection seems to improve survival.’1 We describe here six patients with both infections after BMT for chronic myeloid leukaemia (table). In all cases the donor and/or recipient had been positive for CMV IgG pre-BMT. All six were receiving cyclophosphamide as part of their pre-transplant conditioning. All had graft-versus-host disease and were treated with high-dose intravenous methylprednisolone (1 g/m2), and two received monoclonal antibody against interleukin-2 receptor. Although the mean times to diagnosis of CMV infection and polyomavirus were similar, in four cases the polyomavirus was isolated before CMV was diagnosed (range 4-10 days, mean 6 days). Five patients had CMV isolated from multiple sites and all were treated with ganciclovir and CMV hyperimmune globulin;’ in two, CMV pneumonitis developed. Two patients with polyomavirus had no urinary symptoms, two had mild symptoms, and two required diamorphine for symptomatic control of severe nocturnal frequency. The mean duration of urinary symptoms was 2 weeks. These patients had other viral infections. One patient had adenovirus isolated from a gastric biopsy specimen and another had herpes simplex virus type I detected in throat gargle fluid. CLINICAL AND VIROLOGICAL DATA

BAL = bronchoalveolar lavage

Hyperhomocysteinaemia and recurrent or abruptio placentae

spontaneous abortion

SIR,-Hibbard (1964) was the first to report an association between spontaneous abortion and abruptio placentae and a maternal folate deficiency due to a defective folate metabolism.’ However, studies on this subject are conflicting. Homocysteine remethylation to methionine is dependent on both folate and vitamin B12’ Enzyme deficiencies involved in homocysteine remethylation and folate and vitamin B12 metabolism (and malnutrition and malabsorption of those vitamins) results in hyperhomocysteinaemia.2-4 Classic homocysteinuria is an autosomal recessively inherited metabolic disorder due to a deficiency of pyridoxine-dependent cystathionine synthase.4,5 This enzyme converts homocysteine into cystathionine, and its deficiency results in excess storage of homocysteine. Untreated homozygous women with classic homocysteinuria experience fetal loss rates of almost 50%,’ and increased perinatal mortality in obligate heterozygotes has also been reported.6 We hypothesised that even moderate hyperhomocysteinaemia might be a risk factor for recurrent spontaneous abortion and abruptio placentae, so we decided to measure homocysteine concentrations in non-pregnant women with a history of recurrent spontaneous abortion or abruptio placentae but no known risk factors for such events. Recurrent abortion was defined as two more more successive miscarriages (up to 16 weeks from the beginning of the last menstrual period) with confirmation by pregnancy test, ultrasound scan, or histopathological examination. Blood concentrations of vitamins relevant to homocysteine metabolism were also studied. On the 21 st day of the ovulatory cycle we did a standardised oral methionine loading test in 24 such women (mean age 31-8 [SD 4-8]), 14 had recurrent spontaneous abortion and 10 had a history of abruptio placentae. The controls were 15 normal women (mean age 31-4 [4’7]),7,8 All women had normal liver and kidney function. 6 patients in the study group had concentrations of total homocysteine 6 h after methionine loading more than 2 SD above the mean for controls (table). Their fasting homocysteine values were also increased, albeit not significantly. Cystathionine synthase activity was measured in cultured fibroblasts of all methionine intolerant patients, using a previously reported method with slight modificationand it ranged from 1 -8 to 18nmol/h per mg protein (normal 2-3-18 2), thus excluding heterozygosity for homocysteinuria in these patients. The mean fasting values of folate and especially vitamin B12 in serum were lower in the hyperhomocysteinaemic women, but not significantly in comparison with controls. A possible cause for hyperhomocysteinaemia in these 6 women may be diminished homocysteine remethylation, induced by, for

1123

FOLATE, B’2’ PYRIDOXINE, AND TOTAL HOMOCYSTEINE CONCENTRATIONS AND AFTER METHIONINE LOADING

I

Results as

I

(SD). PLP = pyridoxine, as pyridoxal phosphate. *Free plus protein-bound t6h after methionine loading (0 1 g/kg). mean

example, decreased concentrations of the active form of folate or vitamin B12 or by a deficiency in an enzyme involved in remethylation. The frequency of hyperhomocysteinaemia in this group (25%) should prompt further studies of, for instance, inborn errors of folate, vitamin B12, or homocysteine metabolism. It will also be interesting to relate use of periconceptual multivitamin preparations in subsequent pregnancies in these women to pre-existing methionine intolerance. Departments of Obstetrics and Gynaecology, Medicine (Division of Endocrinology), and Paediatrics,

University Hospital Nijmegen, 6500 HB Nijmegen, Netherlands

R. P. M. STEEGERS-THEUNISSEN GODFRIED H. J. BOERS HENK J. BLOM FRANS J. M. TRIJBELS TOM K. A. B. ESKES

1. Hibbard BM. The role of folic acid in pregnancy: with particular reference to anaemia, abruption and abortion. J Obstet Gynaecol Br Commonw 1964; 71: 529-42. 2. Stabler SP, Marcel PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 1988; 81: 466-74. 3. Brattstrom L, Israelsson B, Lindgarde F, et al. Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine &bgr;-synthase deficiency. Metabolism 1988; 37: 175-78. 4. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med 1989; 114: 473-501. 5. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine &bgr;-synthase deficiency. Am J Hum Genet 1985; 37: 1-31. 6. Burke G, Robinson K, Refsum H, Stuart B, Drumm J, Graham I. Intrauterine growth retardation perinatal death and maternal homocysteine levels. N Engl J Med 1992;

326: 69-70. 7. Boers GHJ, Fowler B, Smals AGH, et al. Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet 1985; 69: 164-69. 8. Steegers-Theunissen RPM, Boers GHJ, Trijbels JMF, Eskes TKAB. Derangement of homocysteine metabolism and neural-tube defects. N Engl J Med 1991; 324: 199-200.

Decline of endogenous &agr;-interferon with zidovudine SIR,-Professor Mildvan and colleagues (Feb 22, p 453) report that endogenous a-interferon concentrations in AIDS patients are reduced by zidovudine. We have also found this and demonstrated that the decline in interferon was associated with a parallel decrease in HIV p24 antigen values.Since we had the opportunity to study 3

patients in whom zidovudine

was given on alternate weeks, we could show that a significant decline in interferon values took place as early as 1 week after starting zidovudine and reached pretreatment values within 1 week of discontinuing this drug. We have also monitored interferon in 8 additional patients seen monthly or bimonthly by one of us (M. L.), and noted that despite continuous treatment with zidovudine 500 mg daily, the initial pronounced drop in interferon (> 4 fold) was not sustained. Interferon values started to rise in 28 weeks (1 patient), 18 weeks (1 patient), 14 weeks (4 patients), and 8 weeks (2 patients) despite continuous treatment with zidovudine. Mildvan and colleagues end their report with the misleading implication that endogenous interferon is known to be an HIV-

induced cytokine. HIV has proved incapable of inducing interferon in cultureto inhibit interferon production by potent inducersor to produce low concentrations of interferon.’ On the other hand, HIV-infected cells are efficient interferon inducers in culture.2 Epstein-Barr virus is also sensitive to zidovudine and can induce cx-interferon .5 Why zidovudine treatment has such a rapid effect on interferon remains unknown. We have shown that the drug does not impair ability of the cell to make interferon.1 Endogenous interferon in AIDS was discovered in 19816 and there were early suggestions that its sustained presence might have an important role in pathogenesis.’ These suggestions are now supported by Mildvan and colleagues’ finding that the presence of circulating interferon is associated with shortened survival. The adverse prognostic importance of &bgr;-2 microglobulin is well known. &bgr;-2 microglobulin can probably be regarded as a surrogate marker for a-interferon which is a powerful inducer of its synthesis and

release.8 Studies to definitively identify the interferon inducer and its cell of origin in AID S should now be encouraged. This information will greatly advance our understanding of the pathogenesis of this disease. Departments of Pediatrics and Medicine, St Lukes Roosevelt Medical Center, New York, NY 10019, USA

ELENA BUIMOVICI-KLEIN MICHAEL LANGE JOSEPH SONNABEND

1. Buimovici-Klein E, McKinley GF, Lange M, et al. Modulation of interferon levels by AZT treatment in HIV seropositive patients. J Exp Pathol (m press). 2. Gendelman HE, Baca LM, Kubrack CA, et al. Induction of IFN-alpha in peripheral blood cells by HIV-infected monocytes. J Immunol 1992; 148: 422-29. 3. Gendelman HE, Friedman RM, Joe S, et al. A selective defect of interferon-alpha production in human immunodeficiency virus-infected monocytes. J Exp Biol 1990; 172: 1433. 4. Szebeni J, Dieffenbach C, Wahl SM, et al. Induction of alpha interferon by human immunodeficiency virus type 1 on human monocyte-macrophage cultures. J Virol 1992; 65: 6362-64. 5. Lin JC, Zhang ZX, Smith MC, et al. Anti-human immunodeficency virus agent 3’-azido3’-deoxythymidine inhibits replicaton of Epstein-Barr virus. Antimicrob Agents Chemother 1988; 32: 265-67. 6. DeStefano E, Freidman RM, Friedman-Kien AE, et al. Acid-labile human leukocyte interferon in homosexual men with Kaposi’s sarcoma and lymphadenopathy. J Infect Dis 1982; 146: 451-55. 7. Preble OT, Rook AH, Quinnan GV, et al. Role of interferon in AIDS. Ann NY Acad Sci 1984; 437: 65-75. 8. Fellous M, Kamoun M, Gresser I, Bono R. Enhanced expression of HLA antigens and beta-2 microglobulin on interferon-treated human lymphoid cells. Eur J Immunol 1979; 9: 446.

Gastric intramucosal

pH monitoring

SIR,-Dr Gutierrez and colleagues (Jan 25, p 195) suggest that continuous monitoring and correction of low gastric intramucosal pH might improve survival in critically ill patients. They emphasised that differences in disease distribution between groups may have resulted in the 16% difference in survival (58% vs 42%) for patients entering intensive care with normal pH ( > 7-35). This is a vital concern since there was no difference in survival for those with initial gastric pH < 7 35 who were within the suggested target range for treatment. If Gutierrez et al have information on primary disease categories and emergency surgical status they could easily estimate expected mortality for protocol and control groups in both low and normal pH groups by using APACHE II scores. The study incorrectly assumes that the observed risk of death was equivalent to that found in APACHE II. However, application of the study criteria (scores between 15 and 25) to the APACHE II data file from thirteen US hospitals yields 1341 patients (mean age 60-5 years, 42-8 % postoperative). These US patients have a hospital survival rate of 72-3%, substantially higher than that observed in either of the two treatment or two control strata in the Argentinian trial. We urge Gutierrez et al to calculate a predicted risk of death, based on primary admitting disease and APACHE II score, and then to estimate a two-variable logistic regression analysis of outcome in each of the two gastric pH strata, the predictor variables being predicted risk of death and experiment control. Even if the predicted risk of death is off-calibrated because of differences in the availability of blood gas data, for example, in Argentina and the US, the hypothesis test on the experimental control variable would be a