1229
*°h of cohort
in
parentheses.
category is just 25 + g/day (about two drinks); there were very few truly heavy drinkers in the study. Shaper finds support for his hypothesis in his own study2 in which the initial inverse association between alcohol and reduced mortality disappeared when he excluded men who reported any TABLE II-MULTIVARIATE RELATIVE RISK OF NON-FATAL MYOCARDIAL INFARCTION AND CHD DEATH ACCORDING TO ALCOHOL INTAKE
previous cardiovascular-related disorder. However, this left only 6 cases in the baseline reference category. Shaper et al3 reported high correlations between alcohol consumption and both social class (f=0 72) and heavy smoking (y 0-71). With few non-drinkers and reduced variability in alcohol intake after statistical adjustment for highly correlated variables, the risk estimates would be relatively imprecise. We would be curious to see his fig 42 reprinted to include =
the 95% confidence intervals around each rate; we suspect that his data would be compatible with a wide range of possibilities. Harvard School of Public Health, and Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts 02775, USA
Liver enzymes and other laboratory tests pointed to hepatitis, probably type A, but the abnormal behaviour was unexplained. The laboratory tests did not suggest fulminant hepatitis with hepatic encephalopathy and a computed tomographic brain scan and cerebrosinal fluid (CSF) examination and culture were normal, as was an electroencephalogram. The jaundice reached a peak 6 days after admission and thereafter steadily resolved. Serological tests revealed hepatitis-A-virus-specific IgM, but were negative for hepatitis B virus and leptospira. His abnormal behaviour continued and psychiatric advice was sought. He appeared unkempt, anxious, depressed, and close to tears, with evidence of persecutory, grandiose, and self-referential delusions. He had auditory hallucinations. He described God as interfering with his thoughts but there was no other disorder of thought possession or passivity. He had only a vague recollection of recent events but otherwise cognition was intact. Paranoid schizophrenia was diagnosed and he was treated with haloperidol for 2 months. At psychiatric review 3 weeks after discontinuation of treatment he was well. Extrahepatic features of hepatitis A are uncommon, though meningoencephalitis has been described.2 Acute schizophrenia may be a feature of hepatic encephalopathy,3 but in this patient encephalopathy was excluded. The pattern of this man’s psychological disturbance suggested functional psychosis rather than an organic brain syndrome. The triggering of acute psychosis by infection apart, it has been suggested that a virus may cause a common type of schizophrenia,4 but this hypothesis remains
unproven.5 We thank Dr H. Pullen, Seacroft Hospital, for permission to report on this
MEIR STAMPFER ERIC RIMM
1
Stampfer MJ, Colditz GA, Willett WC, Speizer FI, Hennekens CH. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 1988; 319: 267-73. 2. Shaper AG, Wannamethee G, Walker M. Alcohol and mortality m British men: explaining the U-shaped curve. Lancet 1988; ii: 1267-73. 3. Shaper AG, Pocock SJ, Walker M, et al. British Regional Heart Study: cardiovascular nsk factors in middle-aged men in 24 towns. Br Med J 1981; 283: 179-86.
Schizophrenia triggered by hepatitis A SIR,-Psychological and other stresses, including infection, are said to be able to trigger acute psychosis. We describe a case of acute schizophrenia brought on by hepatitis A. A previously healthy 28-year-old man, resident in the UK since age 3, had a 4-day history of fever, anorexia, nausea, and abdominal pain, and a 1-day history of jaundice and agitation. His wife and three children had returned 2 weeks previously from India, where all the children had been unwell with diarrhoea. There was no history of alcohol ingestion. He had taken paracetamol in the recommended dose. A cousin was known to have had "delusions and shaking" but had not been admitted to hospital. On examination he was fully alert and had no abnormal neurological signs. However, he was agitated with abnormal postures and behaviour and was reluctant to answer questions.
patient. Infectious Diseases Unit, Seacroft Hospital, Leeds
DERMOT MAHER
Department of Psychiatry, St James’s University Hospital, Leeds LS9 7TF, UK
KEITH J. B. RIX
M, Gath D, Mayou R. Oxford textbook of psychiatry, 2nd ed. Oxford: Oxford University Press, 1989: 304. 2. Hadler S, Margolin H. Viral hepatitis. In: Evans AS, ed. Viral infections of humans: epidemiology and control, 3rd ed. New York: Plenum, 1989. 3. Read AE, Sherlock S, Laidlaw J, Walker JG. The neuro-psychiatric syndromes associated with chronic liver disease and an extensive portal-systemic collateral circulation. QJ Med 1967; 36: 135-50. 4. Crow TJ. A re-evaluation of the viral hypothesis: is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? Br J Psychiatry 1984; 145: 1. Gelder
243-53. 5. Hare EH.
Schizophrenia as an infectious disease. In: Kerr A, Contemporary issues in schizophrenia. London: Gaskell, 1986.
Sanith P, eds.
Calcipotriol for psoriasis SIR,-We disagree with Dr Long and Dr Marks (April 13, p 922) in their lack of enthusiasm for calcipotriol. This view was based on their negative experience with the naturally occurring form of vitamin D3, calcitriol. This is not surprising, however: low concentrations of calcitriol are known to be ineffective in psoriasis.1,2 Because calcipotriol is more than 100 times less potent than calcitriol in its effects on systemic calcium metabolism,3topical
1230
calcipotriol has been used in higher concentrations than calcitriol. Long and Marks seem unaware of controlled studies showing that calcipotriol ointment 50 pg/g is better than vehicle control.’ Now that calcipotriol has been shown to compare favourably with betamethasone 17-valerate, it may be possible to replace topical corticosteroids with calcipotriol in many patients with psoriasis. We should soon know how calcipotriol compares with dithranol: more than 400 patients have entered a multicentre trial designed to compare the efficacy and tolerability of the two agents. Calcipotriol is by far the best studied vitamin KD analogue. The results obtained in more than 3000 patients with psoriasis have shown calcipotriol to be both effective and well-tolerated. It represents a breakthrough in the topical treatment of psoriasis. Department of Dermatology, University of Aarhus, Marselisborg Hospital, DK-8000 Aarhus C, Denmark
KNUD KRAGBALLE
1. Van de Kerkhof
PCM, van Bokhoven M, Zultak M, Czarnetzki. A double-blind study of topical 1, 25-dihydroxy-vitamin D3 in psoriasis. Br J Dermatol 1989; 120: 661-64. 2. Henderson CA, Papworth-Smith J, Cunliffe WJ, Highet AS, Shamy HK, Czarnetzki BM. A double-blind, placebo-controlled trial of topical 1,25-dihydroxycholecalciferol in psoriasis. Br J Dermatol 1989; 121: 493-96. 3. Binderup L, Bramm E. Effect of a novel vitamin D analogue calcipotriol on cell proliferation and differentiation in vitro and calcium metabolism in vivo. Biochem Pharmacol 1988; 37: 889-95. 4. Kragballe K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol (MC 903). Arch Dermatol 1989; 125: 1647-52.
Inhibition of
hepatitis
B virus
by antisense
oligodeoxynucleotides SIR,-Hepatitis B virus (HBV) infection is a major cause of chronic liver disease and hepatocellular carcinoma world wide.1 Although interferon alpha is effective in about one-third of patients,2 other therapeutic strategies need to be explored. We analysed the effect of antisense oligodeoxynucleotides on HBV gene expression and replication. Transfection of human hepatoma cells with HBV-DNA3 (control) results in the synthesis and secretion of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Cotransfection of HBV-DNA with an oligodeoxynucleotide of antisense polarity (ATC-40) completely blocked HBsAg and HBeAg synthesis as well as HBV replication (figure). The same oligodeoxynucleotide of sense polarity (GAT-40) had no effect on viral antigen production or replication.
antisense data show that HBV-specific oligodeoxynucleotides can block viral gene expression and replication. Inhibition of both human immunodeficiency virus infection4 and lymphoma growths will have to await a clearer definition of the role of antisense oligodeoxynucleotides, either alone or in combination with other strategies.
These
Charlestown,
H. E. BLUM E. GALUN F. V. WEIZSÄCKER
Massachusetts 02129, USA
J. R. WANDS
Massachusetts General Hospital, Harvard Medical School, MGH Cancer Center,
1. Hoofnagle JH. Chronic hepatitis B. N Engl J Med 1990; 323: 337-39. 2. Perillo RP, Schiff ER, David GL, et al A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med 1990; 323: 295-301. 3. Blum HE, Galun E, Liang TJ, v Weizsacker F, Wands JR. Naturally occurring missense mutation in the polymerase gene terminating hepatitis B virus replication. J Virol 1991; 65: 1836-42. 4. Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990; 249: 1533-44. 5. McManaway ME, Neckers LM, Loke SL, et al. Tumour-specific inhibition of lymphoma growth by an antisense oligodeoxynucleotide. Lancet 1990; 335: 808-11.
Cortisol response to corticotropin and survival in septic shock SIR,—Dr Rothwell and colleagues (March 9, p 582) show a poor response to corticotropin in 13 patients with septic shock, all of whom died. They state that "the cause of this apparent adrenal
impairment is unclear". We offer a possible explanation. Cortisol plasma concentrations are usually raised in severe sepsis. Interleukin-1and tumour necrosis factor are lymphokines that play an important part in endotoxin-mediated septic shock. It has been suggested that these cytokines stimulate the ACTH-cortisol axis.l The degree of rise in blood cortisol tends to reflect the severity of sepsis. In Rothwell and colleagues’ report, total blood cortisol after stimulation shows no significant difference between survivors and non-survivors (1174 and 963 nmol/l, respectively). In our experience, the stimulation from already stimulated adrenal glands may result in
a smaller difference between the basal concentration and the 30-60-minute concentration than expected for the short corticotropin stimulation test. In addition, we do not agree that a trial of steroid replacement in severe sepsis with physiological doses of cortisol might be of value because cortisol plasma concentrations are already high in severe sepsis, as Rothwell et al recognise.
Departments of Internal Medicine and Microbiology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
ESTEBAN MARTÍNEZ ANGELES MARCOS
1. Michie HR, Manogue KR, Spnggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl Med 1988; 318: 1481-86. 2. Breder CD, Dmarello CA, Saper CB. Interleukin-1: Immuno-reactive innervation of the human hypothalamus. Science 1988; 240: 321-23.
vara
rtot
*°h of cohort
in
parentheses.
category is just 25 + g/day (about two drinks); there were very few truly heavy drinkers in the study. Shaper finds support for his hypothesis in his own study2 in which the initial inverse association between alcohol and reduced mortality disappeared when he excluded men who reported any TABLE II-MULTIVARIATE RELATIVE RISK OF NON-FATAL MYOCARDIAL INFARCTION AND CHD DEATH ACCORDING TO ALCOHOL INTAKE
previous cardiovascular-related disorder. However, this left only 6 cases in the baseline reference category. Shaper et al3 reported high correlations between alcohol consumption and both social class (f=0 72) and heavy smoking (y 0-71). With few non-drinkers and reduced variability in alcohol intake after statistical adjustment for highly correlated variables, the risk estimates would be relatively imprecise. We would be curious to see his fig 42 reprinted to include =
the 95% confidence intervals around each rate; we suspect that his data would be compatible with a wide range of possibilities. Harvard School of Public Health, and Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts 02775, USA
Liver enzymes and other laboratory tests pointed to hepatitis, probably type A, but the abnormal behaviour was unexplained. The laboratory tests did not suggest fulminant hepatitis with hepatic encephalopathy and a computed tomographic brain scan and cerebrosinal fluid (CSF) examination and culture were normal, as was an electroencephalogram. The jaundice reached a peak 6 days after admission and thereafter steadily resolved. Serological tests revealed hepatitis-A-virus-specific IgM, but were negative for hepatitis B virus and leptospira. His abnormal behaviour continued and psychiatric advice was sought. He appeared unkempt, anxious, depressed, and close to tears, with evidence of persecutory, grandiose, and self-referential delusions. He had auditory hallucinations. He described God as interfering with his thoughts but there was no other disorder of thought possession or passivity. He had only a vague recollection of recent events but otherwise cognition was intact. Paranoid schizophrenia was diagnosed and he was treated with haloperidol for 2 months. At psychiatric review 3 weeks after discontinuation of treatment he was well. Extrahepatic features of hepatitis A are uncommon, though meningoencephalitis has been described.2 Acute schizophrenia may be a feature of hepatic encephalopathy,3 but in this patient encephalopathy was excluded. The pattern of this man’s psychological disturbance suggested functional psychosis rather than an organic brain syndrome. The triggering of acute psychosis by infection apart, it has been suggested that a virus may cause a common type of schizophrenia,4 but this hypothesis remains
unproven.5 We thank Dr H. Pullen, Seacroft Hospital, for permission to report on this
MEIR STAMPFER ERIC RIMM
1
Stampfer MJ, Colditz GA, Willett WC, Speizer FI, Hennekens CH. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 1988; 319: 267-73. 2. Shaper AG, Wannamethee G, Walker M. Alcohol and mortality m British men: explaining the U-shaped curve. Lancet 1988; ii: 1267-73. 3. Shaper AG, Pocock SJ, Walker M, et al. British Regional Heart Study: cardiovascular nsk factors in middle-aged men in 24 towns. Br Med J 1981; 283: 179-86.
Schizophrenia triggered by hepatitis A SIR,-Psychological and other stresses, including infection, are said to be able to trigger acute psychosis. We describe a case of acute schizophrenia brought on by hepatitis A. A previously healthy 28-year-old man, resident in the UK since age 3, had a 4-day history of fever, anorexia, nausea, and abdominal pain, and a 1-day history of jaundice and agitation. His wife and three children had returned 2 weeks previously from India, where all the children had been unwell with diarrhoea. There was no history of alcohol ingestion. He had taken paracetamol in the recommended dose. A cousin was known to have had "delusions and shaking" but had not been admitted to hospital. On examination he was fully alert and had no abnormal neurological signs. However, he was agitated with abnormal postures and behaviour and was reluctant to answer questions.
patient. Infectious Diseases Unit, Seacroft Hospital, Leeds
DERMOT MAHER
Department of Psychiatry, St James’s University Hospital, Leeds LS9 7TF, UK
KEITH J. B. RIX
M, Gath D, Mayou R. Oxford textbook of psychiatry, 2nd ed. Oxford: Oxford University Press, 1989: 304. 2. Hadler S, Margolin H. Viral hepatitis. In: Evans AS, ed. Viral infections of humans: epidemiology and control, 3rd ed. New York: Plenum, 1989. 3. Read AE, Sherlock S, Laidlaw J, Walker JG. The neuro-psychiatric syndromes associated with chronic liver disease and an extensive portal-systemic collateral circulation. QJ Med 1967; 36: 135-50. 4. Crow TJ. A re-evaluation of the viral hypothesis: is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? Br J Psychiatry 1984; 145: 1. Gelder
243-53. 5. Hare EH.
Schizophrenia as an infectious disease. In: Kerr A, Contemporary issues in schizophrenia. London: Gaskell, 1986.
Sanith P, eds.
Calcipotriol for psoriasis SIR,-We disagree with Dr Long and Dr Marks (April 13, p 922) in their lack of enthusiasm for calcipotriol. This view was based on their negative experience with the naturally occurring form of vitamin D3, calcitriol. This is not surprising, however: low concentrations of calcitriol are known to be ineffective in psoriasis.1,2 Because calcipotriol is more than 100 times less potent than calcitriol in its effects on systemic calcium metabolism,3topical
1230
calcipotriol has been used in higher concentrations than calcitriol. Long and Marks seem unaware of controlled studies showing that calcipotriol ointment 50 pg/g is better than vehicle control.’ Now that calcipotriol has been shown to compare favourably with betamethasone 17-valerate, it may be possible to replace topical corticosteroids with calcipotriol in many patients with psoriasis. We should soon know how calcipotriol compares with dithranol: more than 400 patients have entered a multicentre trial designed to compare the efficacy and tolerability of the two agents. Calcipotriol is by far the best studied vitamin KD analogue. The results obtained in more than 3000 patients with psoriasis have shown calcipotriol to be both effective and well-tolerated. It represents a breakthrough in the topical treatment of psoriasis. Department of Dermatology, University of Aarhus, Marselisborg Hospital, DK-8000 Aarhus C, Denmark
KNUD KRAGBALLE
1. Van de Kerkhof
PCM, van Bokhoven M, Zultak M, Czarnetzki. A double-blind study of topical 1, 25-dihydroxy-vitamin D3 in psoriasis. Br J Dermatol 1989; 120: 661-64. 2. Henderson CA, Papworth-Smith J, Cunliffe WJ, Highet AS, Shamy HK, Czarnetzki BM. A double-blind, placebo-controlled trial of topical 1,25-dihydroxycholecalciferol in psoriasis. Br J Dermatol 1989; 121: 493-96. 3. Binderup L, Bramm E. Effect of a novel vitamin D analogue calcipotriol on cell proliferation and differentiation in vitro and calcium metabolism in vivo. Biochem Pharmacol 1988; 37: 889-95. 4. Kragballe K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol (MC 903). Arch Dermatol 1989; 125: 1647-52.
Inhibition of
hepatitis
B virus
by antisense
oligodeoxynucleotides SIR,-Hepatitis B virus (HBV) infection is a major cause of chronic liver disease and hepatocellular carcinoma world wide.1 Although interferon alpha is effective in about one-third of patients,2 other therapeutic strategies need to be explored. We analysed the effect of antisense oligodeoxynucleotides on HBV gene expression and replication. Transfection of human hepatoma cells with HBV-DNA3 (control) results in the synthesis and secretion of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Cotransfection of HBV-DNA with an oligodeoxynucleotide of antisense polarity (ATC-40) completely blocked HBsAg and HBeAg synthesis as well as HBV replication (figure). The same oligodeoxynucleotide of sense polarity (GAT-40) had no effect on viral antigen production or replication.
antisense data show that HBV-specific oligodeoxynucleotides can block viral gene expression and replication. Inhibition of both human immunodeficiency virus infection4 and lymphoma growths will have to await a clearer definition of the role of antisense oligodeoxynucleotides, either alone or in combination with other strategies.
These
Charlestown,
H. E. BLUM E. GALUN F. V. WEIZSÄCKER
Massachusetts 02129, USA
J. R. WANDS
Massachusetts General Hospital, Harvard Medical School, MGH Cancer Center,
1. Hoofnagle JH. Chronic hepatitis B. N Engl J Med 1990; 323: 337-39. 2. Perillo RP, Schiff ER, David GL, et al A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med 1990; 323: 295-301. 3. Blum HE, Galun E, Liang TJ, v Weizsacker F, Wands JR. Naturally occurring missense mutation in the polymerase gene terminating hepatitis B virus replication. J Virol 1991; 65: 1836-42. 4. Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990; 249: 1533-44. 5. McManaway ME, Neckers LM, Loke SL, et al. Tumour-specific inhibition of lymphoma growth by an antisense oligodeoxynucleotide. Lancet 1990; 335: 808-11.
Cortisol response to corticotropin and survival in septic shock SIR,—Dr Rothwell and colleagues (March 9, p 582) show a poor response to corticotropin in 13 patients with septic shock, all of whom died. They state that "the cause of this apparent adrenal
impairment is unclear". We offer a possible explanation. Cortisol plasma concentrations are usually raised in severe sepsis. Interleukin-1and tumour necrosis factor are lymphokines that play an important part in endotoxin-mediated septic shock. It has been suggested that these cytokines stimulate the ACTH-cortisol axis.l The degree of rise in blood cortisol tends to reflect the severity of sepsis. In Rothwell and colleagues’ report, total blood cortisol after stimulation shows no significant difference between survivors and non-survivors (1174 and 963 nmol/l, respectively). In our experience, the stimulation from already stimulated adrenal glands may result in
a smaller difference between the basal concentration and the 30-60-minute concentration than expected for the short corticotropin stimulation test. In addition, we do not agree that a trial of steroid replacement in severe sepsis with physiological doses of cortisol might be of value because cortisol plasma concentrations are already high in severe sepsis, as Rothwell et al recognise.
Departments of Internal Medicine and Microbiology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
ESTEBAN MARTÍNEZ ANGELES MARCOS
1. Michie HR, Manogue KR, Spnggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl Med 1988; 318: 1481-86. 2. Breder CD, Dmarello CA, Saper CB. Interleukin-1: Immuno-reactive innervation of the human hypothalamus. Science 1988; 240: 321-23.
vara
rtot
