870
stage of tumour development, before cells become malignant. Such view raises the possibility that levels of calcium that can inhibit the growth of normal colonic epithelium may promote carcinogenesis in the long term by providing a selective growth advantage of carcinoma cells over normal cells and of adenoma cells over normal cells. At which stage in colorectal carcinogenesis do cells have a reduced response to the inhibitory effects of calcium? If initiated cells (ie, cells that are phenotypically normal but have mutations that predispose to adenomas) have a reduced response to calcium, then it could be that high levels of calcium promote even the earliest stage of colorectal carcinogenesis. In the mouse skin model of carcinogenesis, normal keratinocytes are inhibited by low levels of calcium, and one of the earliest phenotypic changes detected in mouse epidermal cells initiated (mutated) by chemical carcinogens is a reduced response to the inhibitory effect of calcium. Indeed, in this system resistance to the inhibitory effects of calcium was used as 4 a method to select chemically initiated cells from normal cells. is in caveat that the normal of calcium individual the addition My to the diet might suppress colonic cell turnover without any obvious adverse effects. However, if the patient has many initiated cells (as in familial adenomatous polyposis) or polyps, supplementary calcium might promote the selective outgrowth of abnormal cells. It is high-risk patients, such as those with familial adenomatous polyposis or with recurrent polyps, who are being targeted for dietary intervention-and in these individuals this strategy may do more harm than good. Long-term monitoring of patients taking part in dietary intervention trials will be essential. a
Department of Pathology and Microbiology, University of Bristol, Bristol BS8 1TD, UK
C. PARASKAVA
1. Bresalier RS, Kim YS. Diet and colon cancer. N Engl J Med 1985; 313: 1413-14 2. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Oglesby P. Dietary vitamin D and calcium and risk of colorectal cancer. a 19-year prospective study. Lancet 1985; i: 307-09. 3. Buset M, Lipkin M, Winawer S, Swaroop S, Fnedman E Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer Res 1986; 46: 5426-30. 4. Kruszewski FH, Hennings H, Tucker RW, Yuspa SH. Differences in the regulation of intracellular calcium in normal and neoplasuc keratinocytes are not caused by ras gene mutations. Cancer Res 1991; 51: 4206-12.
"Wearing-off" and &bgr;2-adrenoceptor in Parkinson’s disease
agonist
SIR,-"Wearing-off’ is a common difficulty in patients with Parkinson’s disease on long-term levodopa. It seems to be related to fluctuations in L-dopa concentrations in brain.’ Studies in rats suggest that &bgr;2 -adrenoceptor agonists enhance the transport of large neutral aminoacids, such as tyrosine and tryptophan 2,3and L-dopa’ to brain but we do not know whether the combined administration of P2-agonist and levodopa would raise the L-dopa concentrations in the human brain or reduce wearing-off. Our results suggest that a P2-agonist may indeed beneficially affect wearing-off in the levodopa-treated patients with Parkinson’s disease. We studied nine patients with wearing-off (two men, seven women; mean age 62 [54-69] years, disease duration 11 [5-20] years; Hoehn and Yahr stage 3; period of levodopa therapy 7 [4-14] years; daily dose 456 [300-800] mg with decarboxylase inhibitor). After a 2-week control observation period, patients were given the selective &bgr;2-agonist salbutamol5 6 mg daily in three divided doses for 2 weeks. The effect was assessed by measuring daily "on" levodopa effective "on-phase" latency after each dose; a diary charts was completed by the patient before and after salbutamol coadministration. "On-phase" periods and latency to turn "on" were averaged for the 2 control weeks and the 2 salbutamol weeks. The doses of levodopa, decarboxylase inhibitor, and other antiparkinsonian drugs (amantadine, anticholinergic agents, bromocriptine) used during the control period were unchanged. Co-administration of salbutamol significantly increased the mean daily total on phase (from 8-28 to 9-82 h; p < 002, Wilcoxon test) and shortened latency (from 74 to 59 min; p < 0-05) (figure). These preliminary results suggest that a &bgr;2-agonist may have an adjuvant effect in lessening wearing-off in patients on long-term
Effect of co-administration of salbutamol duration and latency.
on
"on-phase"
levodopa. However, &bgr;2 -agonists can sometimes induce or aggravate postural termor in parkinsonism-indeed one patient in our study complained of postural tremor after salbutamol. Blinded, placebocontrolled studies are now needed to evaluate both efficacy and safety. Department of Neurology, Aomori Prefectural Central Hospital, Aomori 030, Japan; and Third Department of Internal Medicine, and Department of Neurology, Institute for Neurological Diseases, Hirosaki University School of Medicine
RYOHEI HISHIDA KOZO KURAHASHI SHOKO NARITA TSUNEHARU BABA MUNEO MATSUNAGA
1. Mouradian MM, Juncos JL, Fabbrini G, Chase TN. Motor fluctuations in Parkinson’s disease pathogenetic and therapeutic studies. Ann Neurol 1987; 22: 457-79 2. Eriksson T, Carlasson A. Beta-adrenergic control of brain uptake of large neutral amino acids. Life Sci 1988; 42: 1583-89 3. Edwards DJ, Sorisio DA, Knopf S. Effects of the beta 2-adrenoceptor agonist clenbuterol on tyrosine and tryptophan in plasma and brain of the rat. Biochem Pharmacol 1989; 38: 1957-65. 4. Takao Y, Kamisaki Y, Omodani H, Itoh T. &bgr;-adrenergic regulation of large neutral ammo acid transport across the blood-brain barrier. Jpn J Pharmacol 1990, 52 (suppl 1): 324 (abstr). 5. McMahon DG, Sachdev D, Boddie HG, Ellis CJK, Kendal BR, Blackburn NA. A comparison of the effects of controlled-release levodopa (Madopar CR) with conventional levodopa in late Parkinson’s disease. J Neurol Neurosurg Psychiatry
1990; 53: 220-23.
Acid-base disturbances and heat-stress in the armed forces SiR,—There has been considerable interest lately in heat-stressrelated injury, especially when it happens in the armed forces. We have been investigating acid-base disturbance in Royal Marine recruits who collapsed during prolonged strenuous exercise such as speed-marching and the Royal Marines endurance course. Such recruits were brought immediately to the sick bay at the Commando Training Centre, Royal Marines in Devon, and were seen by a doctor within minutes of their collapse since a safety vehicle accompanies all such exercises. Our inclusion criteria were collapse, a core temperature above 38°C, or altered consciousness. After assessment of conscious level, the rectal temperature was noted by thermistor probe. Intravenous access was secured with two 14G peripheral cannulae. 30 ml blood was withdrawn and an intravenous infusion of a crystalloid such as Hartmann’s solution was started. Cooling measures such as tepid water bathing and fanning were also instigated. The recruits were admitted for at least 24 h. Arterial blood was taken concurrently and analysed immediately by ABL3 blood gas analyser, with correction for rectal temperature. Electrolytes, glucose, and lactate were measured in venous blood. The time of day, ambient temperature, humidity, and weather conditions were noted, and patients were asked about fluid intake over the previous 24 h. Resuscitation was not delayed by the blood sampling. One week after the event, the recruits returned for control arterial and venous blood samples to be taken, with informed consent.
Some of the results in the fourteen cases seen in one year (of a thousand recruits in training) were unexpected. Several recruits were initially unresponsive, with Glasgow coma scale (GCS) scores less than 8, but they recovered within minutes of the rapid infusion
871
of I or 2 litres of crystalloid. As many as 6 litres of crystalloid were infused in the first hour of treatment. There was no evidence that the patients with the lowest GCS had the most abnormal
biochemical findings. Two recruits had severe metabolic acidosis (serum pH 7.2 and 7-3), standard base deficits 13 and 16 mmol/1, serum bicarbonate 13 and 8 mmol/1, respectively. They also had serum lactate concentrations above 20 mmol/l (normal 0’6-2’4). There had been respiratory compensation for the acidosis, and the PACO, was below 3 kPa (normal 5-3). The other patients had milder biochemical abnormalities, despite core temperatures usually above 405°C. Nearly all had raised lactate concentrations (mean 5-21 mmol/1) but most were not acidaemic as they had compensated by hyperventilation. A few recruits had no base deficit, and thus no metabolic acidosis, yet were alkalaemic with serum pH values up to 76. These individuals thus had a primary respiratory alkalosis, and had hyperventilated, which, by reducing PaC02, could itself have helped to precipitate their collapse. All biochemical fmdings were normal one week later. Most research on acid-base disturbances in heatstroke has been in laboratory animals. Studies in patients with heatstroke have revealed a mixed picture of metabolic acidosis and respiratory alkalosisl-3 as one might expect. This is the first such study in fit young men undertaking the same strenuous exercise-the others were on older patients with coexisting disease, such as Mecca pilgrims, many of whom dehydrate themselves to reduce urine OUtput.2 There seems to be no single explanation for the collapse of very fit young men undergoing severe exertional exercise. "Heatstroke" and "heat exhaustion" have been used to classify patients with thermal stress on the basis of core temperature, but this classification is simplistic. There may be genetic predisposition
heatstroke-eg, in patients susceptible to malignant hyperpyrexia.4 Ambient temperature, hydration state, type and duration of exercise, type of clothing, and other factors may to
contribute. Most of these factors were standardised in our patients but the biochemical disorders found still varied widely. The armed forces have introduced many measures to avoid heat injury-for example, greater awareness, enforced water stops, loose-fitting clothing, timing exercises to avoid the hottest part of the day, and prompt treatment regimens. However, cases of heat injury have still occurred. A large prospective study should be undertaken to investigate these potentially life-threatening disorders. Department of Anaesthesia, Royal Naval Hospital, Plymouth PL1 3JY, UK
M. D. STONEHAM D. J. A. PRICE
Mustafa MK. Physiology of heat stroke: a review. In. Hales JRS, ed. Thermal physiology New York: Raven, 1984: 503-10. 2. Gumaa K, El-Mahrouky SF, Mahmoud N, Mustafa MKY, Khogali M. The metabolic status of heat stroke patients. In: Khogali M, Hales JRS, eds. Heat stroke and temperature regulation. Sydney: Academic Press, 1983: 157-69. 3 Tucker LE, Stanford J, Graves B, Swetnam J, Hamburger S, Anwar A Classical heatstroke: clinical and laboratory assessment South Med J 1985; 78: 20-25. 4. Hopkins PM, Ellis FR, Halsall PJ. Evidence for related myopathies in exertional heat stroke and malignant hyperthermia. Lancet 1991; 338: 1491-92. 1.
Khogali M,
Anti-HCV, anti-GOR, and autoimmunity SIR,-Dr Michel and colleagues (Feb 1, p 267) report that patients with autoimmune hepatitis type 2 (LKM-1) who are anti-HCV (hepatitis C virus) and anti-GOR positive, have less disease activity and respond less well to immunosuppression than do those who are anti-HCV and anti-GOR negative. They conclude that anti-GOR contributes to "a better differentiation of chronic hepatitis, a finding that has therapeutic implications". We have found that in autoimmune hepatitis type 2 or type 1 anti-HCV (clOO and 5-1-1) negative patients show more severe disease activity and better response to corticosteroids than do anti-HCV positive ones1 who are generally serum HCV-RNA positiveIn Michel’s paper, anti-GOR does not seem to add any therapeutic information-indeed, anti-GOR was strictly associated with anti-HCV positivity among patients with LKM-1-positive chronic hepatitis. Moreover, Michel et al found no anti-HCV or anti-GOR in autoimmune hepatitis type 1, whereas in our area anti-HCV and HCV-RNA is found in sera from patients with
antinuclear antibody (ANA, type 1) positive chronic hepatitis, and these patients behave like patients with HCV seropositive autoimmune hepatitis type 2 (LKM-1) in respect of disease activity and response to corticosteroids. Thus, in our experience, anti-HCV and HCV-RNA tests are enough to guide treatment decisions in cases of LKM-1 or ANA-positive chronic hepatitis. Division of Internal Medicine,
Ospedale V, Cervello, 90146 Palermo, Italy
SILVIO MAGRIN GIOVAMBATTISTA PINZELLO
Medical Clinic R,
ANTONIO CRAXI PIERO ALMASIO LUIGI PAGLIARO
University of Palermo 1. 2.
Magrin S, Craxi A, Fiorentino G, et al. Is autoimmune chronic active hepatitis a HCV-related disease?J Hepatol 1991; 13: 56-60. Magrin S, Craxi A, Fabiano C, et al Hepatitis C virus replication in "autoimmune" chronic hepatitis. J Hepatol 1991; 13: 364-67.
SIR,-Dr Michel and colleagues state that anti-GOR reflects HCV-specific autoimmunity in autoimmune liver disease. The assumption that anti-GOR is an autoantibody is based on the description of the GOR47-1 clone,l which was reported to contain no sequence homology with HCV. However, we have found an antigenic relation between GOR and HCV. We have identified a region of the HCV nucleocapsid protein that shares 47% aminoacid homology with the GOR epitope, allowing gaps for optimum alignment. The similarity of HCV residues 4-20 (IPKPQRKTKRNTNRRPQ) with GOR 15-29 (GRRGQKAKSNPNRPL) may have been missed previously because the regions are short and the degree of homology is low. Nevertheless, we have demonstrated, with the corresponding synthetic peptides
HCV4-2o and GOR15.29’ that HCV and
GOR do share
a common
epitope. A competitive binding experiment with a microtitre ELISA showed that 50% of the binding of anti-GOR to GOR15.29-coated wells could be inhibited by addition of0’ 12 ug/ml soluble GOR15.29 or 0-07 J-lg/ml soluble HCV 4.20’ Soluble HCV 4.20 peptide (0-6 J-lgfml) could also inhibit 50% of the antibody binding to HCV4.20-coated wells, but soluble GOR15.29’ even at 20 tg/ml, could inhibit only 25% of this binding. Absorbance values of 28 confirmed that anti-HCV seropositive plasma samples were highly correlated (f=0 88) on GOR15.29 and HCV4-20 peptide ELISA at a peptide coating concentration of 5 g/ml, but the antibody affinity was greater to the HCV peptide than to GOR. At a limiting peptide coating concentration of 1 J-lg/ml the absorbance of one such plasma sample was 1 ’7 with HCV4.20, compared with 0.1 with GOR15.29’ In an HCV seroconversion panel, both anti-GOR and anti-HCV 4.20 appeared simultaneously, substantially earlier than detection by a clOO based assay but later than detection by the UBI HCV enzyme immunoassay, which contains synthetic nucleocapsid as well as non-structural antigens.2 Our findings indicate that antibody elicited by HCV nucleocapsid protein during HCV infection is the source of the cross-reactive anti-GOR activity observed in autoimmune liver disease, non-Anon-B hepatitis, and blood donors-and the importance of such anti-GOR activity should be re-examined in this light. United Biomedical Inc, Hauppauge, NY 11788, USA
BARBARA HOSEIN XINDE FANG CHANG YI WANG
1. Mishiro S, Hoshi Y, Takeda K, et al. Non-A, non-B hepatitis specific antibodies directed at host-derived epitope: implication for an autoimmune process. Lancet 1990; 336: 1400-03. 2. Hosein B, Fang CT, Popovsky MA, et al. Improved serodiagnosis of hepatitis C virus infection with synthetic peptide antigen from capsid protein. Proc Natl Acad Sci USA 1991; 88: 3647-51.
SIR,-Dr Michel and colleagues state that two subgroups of type hepatitis are recognised-one related to HCV infection (as judged by both second generation ELISA and RIBA positivity and HCV viraemia), this being confined to adults;l,2 and 2 autoimmune
found in younger patients with "primary" autoimmune hepatitis but with no evidence of HCV infection.3 Anti-GOR is one
stage of tumour development, before cells become malignant. Such view raises the possibility that levels of calcium that can inhibit the growth of normal colonic epithelium may promote carcinogenesis in the long term by providing a selective growth advantage of carcinoma cells over normal cells and of adenoma cells over normal cells. At which stage in colorectal carcinogenesis do cells have a reduced response to the inhibitory effects of calcium? If initiated cells (ie, cells that are phenotypically normal but have mutations that predispose to adenomas) have a reduced response to calcium, then it could be that high levels of calcium promote even the earliest stage of colorectal carcinogenesis. In the mouse skin model of carcinogenesis, normal keratinocytes are inhibited by low levels of calcium, and one of the earliest phenotypic changes detected in mouse epidermal cells initiated (mutated) by chemical carcinogens is a reduced response to the inhibitory effect of calcium. Indeed, in this system resistance to the inhibitory effects of calcium was used as 4 a method to select chemically initiated cells from normal cells. is in caveat that the normal of calcium individual the addition My to the diet might suppress colonic cell turnover without any obvious adverse effects. However, if the patient has many initiated cells (as in familial adenomatous polyposis) or polyps, supplementary calcium might promote the selective outgrowth of abnormal cells. It is high-risk patients, such as those with familial adenomatous polyposis or with recurrent polyps, who are being targeted for dietary intervention-and in these individuals this strategy may do more harm than good. Long-term monitoring of patients taking part in dietary intervention trials will be essential. a
Department of Pathology and Microbiology, University of Bristol, Bristol BS8 1TD, UK
C. PARASKAVA
1. Bresalier RS, Kim YS. Diet and colon cancer. N Engl J Med 1985; 313: 1413-14 2. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Oglesby P. Dietary vitamin D and calcium and risk of colorectal cancer. a 19-year prospective study. Lancet 1985; i: 307-09. 3. Buset M, Lipkin M, Winawer S, Swaroop S, Fnedman E Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer Res 1986; 46: 5426-30. 4. Kruszewski FH, Hennings H, Tucker RW, Yuspa SH. Differences in the regulation of intracellular calcium in normal and neoplasuc keratinocytes are not caused by ras gene mutations. Cancer Res 1991; 51: 4206-12.
"Wearing-off" and &bgr;2-adrenoceptor in Parkinson’s disease
agonist
SIR,-"Wearing-off’ is a common difficulty in patients with Parkinson’s disease on long-term levodopa. It seems to be related to fluctuations in L-dopa concentrations in brain.’ Studies in rats suggest that &bgr;2 -adrenoceptor agonists enhance the transport of large neutral aminoacids, such as tyrosine and tryptophan 2,3and L-dopa’ to brain but we do not know whether the combined administration of P2-agonist and levodopa would raise the L-dopa concentrations in the human brain or reduce wearing-off. Our results suggest that a P2-agonist may indeed beneficially affect wearing-off in the levodopa-treated patients with Parkinson’s disease. We studied nine patients with wearing-off (two men, seven women; mean age 62 [54-69] years, disease duration 11 [5-20] years; Hoehn and Yahr stage 3; period of levodopa therapy 7 [4-14] years; daily dose 456 [300-800] mg with decarboxylase inhibitor). After a 2-week control observation period, patients were given the selective &bgr;2-agonist salbutamol5 6 mg daily in three divided doses for 2 weeks. The effect was assessed by measuring daily "on" levodopa effective "on-phase" latency after each dose; a diary charts was completed by the patient before and after salbutamol coadministration. "On-phase" periods and latency to turn "on" were averaged for the 2 control weeks and the 2 salbutamol weeks. The doses of levodopa, decarboxylase inhibitor, and other antiparkinsonian drugs (amantadine, anticholinergic agents, bromocriptine) used during the control period were unchanged. Co-administration of salbutamol significantly increased the mean daily total on phase (from 8-28 to 9-82 h; p < 002, Wilcoxon test) and shortened latency (from 74 to 59 min; p < 0-05) (figure). These preliminary results suggest that a &bgr;2-agonist may have an adjuvant effect in lessening wearing-off in patients on long-term
Effect of co-administration of salbutamol duration and latency.
on
"on-phase"
levodopa. However, &bgr;2 -agonists can sometimes induce or aggravate postural termor in parkinsonism-indeed one patient in our study complained of postural tremor after salbutamol. Blinded, placebocontrolled studies are now needed to evaluate both efficacy and safety. Department of Neurology, Aomori Prefectural Central Hospital, Aomori 030, Japan; and Third Department of Internal Medicine, and Department of Neurology, Institute for Neurological Diseases, Hirosaki University School of Medicine
RYOHEI HISHIDA KOZO KURAHASHI SHOKO NARITA TSUNEHARU BABA MUNEO MATSUNAGA
1. Mouradian MM, Juncos JL, Fabbrini G, Chase TN. Motor fluctuations in Parkinson’s disease pathogenetic and therapeutic studies. Ann Neurol 1987; 22: 457-79 2. Eriksson T, Carlasson A. Beta-adrenergic control of brain uptake of large neutral amino acids. Life Sci 1988; 42: 1583-89 3. Edwards DJ, Sorisio DA, Knopf S. Effects of the beta 2-adrenoceptor agonist clenbuterol on tyrosine and tryptophan in plasma and brain of the rat. Biochem Pharmacol 1989; 38: 1957-65. 4. Takao Y, Kamisaki Y, Omodani H, Itoh T. &bgr;-adrenergic regulation of large neutral ammo acid transport across the blood-brain barrier. Jpn J Pharmacol 1990, 52 (suppl 1): 324 (abstr). 5. McMahon DG, Sachdev D, Boddie HG, Ellis CJK, Kendal BR, Blackburn NA. A comparison of the effects of controlled-release levodopa (Madopar CR) with conventional levodopa in late Parkinson’s disease. J Neurol Neurosurg Psychiatry
1990; 53: 220-23.
Acid-base disturbances and heat-stress in the armed forces SiR,—There has been considerable interest lately in heat-stressrelated injury, especially when it happens in the armed forces. We have been investigating acid-base disturbance in Royal Marine recruits who collapsed during prolonged strenuous exercise such as speed-marching and the Royal Marines endurance course. Such recruits were brought immediately to the sick bay at the Commando Training Centre, Royal Marines in Devon, and were seen by a doctor within minutes of their collapse since a safety vehicle accompanies all such exercises. Our inclusion criteria were collapse, a core temperature above 38°C, or altered consciousness. After assessment of conscious level, the rectal temperature was noted by thermistor probe. Intravenous access was secured with two 14G peripheral cannulae. 30 ml blood was withdrawn and an intravenous infusion of a crystalloid such as Hartmann’s solution was started. Cooling measures such as tepid water bathing and fanning were also instigated. The recruits were admitted for at least 24 h. Arterial blood was taken concurrently and analysed immediately by ABL3 blood gas analyser, with correction for rectal temperature. Electrolytes, glucose, and lactate were measured in venous blood. The time of day, ambient temperature, humidity, and weather conditions were noted, and patients were asked about fluid intake over the previous 24 h. Resuscitation was not delayed by the blood sampling. One week after the event, the recruits returned for control arterial and venous blood samples to be taken, with informed consent.
Some of the results in the fourteen cases seen in one year (of a thousand recruits in training) were unexpected. Several recruits were initially unresponsive, with Glasgow coma scale (GCS) scores less than 8, but they recovered within minutes of the rapid infusion
871
of I or 2 litres of crystalloid. As many as 6 litres of crystalloid were infused in the first hour of treatment. There was no evidence that the patients with the lowest GCS had the most abnormal
biochemical findings. Two recruits had severe metabolic acidosis (serum pH 7.2 and 7-3), standard base deficits 13 and 16 mmol/1, serum bicarbonate 13 and 8 mmol/1, respectively. They also had serum lactate concentrations above 20 mmol/l (normal 0’6-2’4). There had been respiratory compensation for the acidosis, and the PACO, was below 3 kPa (normal 5-3). The other patients had milder biochemical abnormalities, despite core temperatures usually above 405°C. Nearly all had raised lactate concentrations (mean 5-21 mmol/1) but most were not acidaemic as they had compensated by hyperventilation. A few recruits had no base deficit, and thus no metabolic acidosis, yet were alkalaemic with serum pH values up to 76. These individuals thus had a primary respiratory alkalosis, and had hyperventilated, which, by reducing PaC02, could itself have helped to precipitate their collapse. All biochemical fmdings were normal one week later. Most research on acid-base disturbances in heatstroke has been in laboratory animals. Studies in patients with heatstroke have revealed a mixed picture of metabolic acidosis and respiratory alkalosisl-3 as one might expect. This is the first such study in fit young men undertaking the same strenuous exercise-the others were on older patients with coexisting disease, such as Mecca pilgrims, many of whom dehydrate themselves to reduce urine OUtput.2 There seems to be no single explanation for the collapse of very fit young men undergoing severe exertional exercise. "Heatstroke" and "heat exhaustion" have been used to classify patients with thermal stress on the basis of core temperature, but this classification is simplistic. There may be genetic predisposition
heatstroke-eg, in patients susceptible to malignant hyperpyrexia.4 Ambient temperature, hydration state, type and duration of exercise, type of clothing, and other factors may to
contribute. Most of these factors were standardised in our patients but the biochemical disorders found still varied widely. The armed forces have introduced many measures to avoid heat injury-for example, greater awareness, enforced water stops, loose-fitting clothing, timing exercises to avoid the hottest part of the day, and prompt treatment regimens. However, cases of heat injury have still occurred. A large prospective study should be undertaken to investigate these potentially life-threatening disorders. Department of Anaesthesia, Royal Naval Hospital, Plymouth PL1 3JY, UK
M. D. STONEHAM D. J. A. PRICE
Mustafa MK. Physiology of heat stroke: a review. In. Hales JRS, ed. Thermal physiology New York: Raven, 1984: 503-10. 2. Gumaa K, El-Mahrouky SF, Mahmoud N, Mustafa MKY, Khogali M. The metabolic status of heat stroke patients. In: Khogali M, Hales JRS, eds. Heat stroke and temperature regulation. Sydney: Academic Press, 1983: 157-69. 3 Tucker LE, Stanford J, Graves B, Swetnam J, Hamburger S, Anwar A Classical heatstroke: clinical and laboratory assessment South Med J 1985; 78: 20-25. 4. Hopkins PM, Ellis FR, Halsall PJ. Evidence for related myopathies in exertional heat stroke and malignant hyperthermia. Lancet 1991; 338: 1491-92. 1.
Khogali M,
Anti-HCV, anti-GOR, and autoimmunity SIR,-Dr Michel and colleagues (Feb 1, p 267) report that patients with autoimmune hepatitis type 2 (LKM-1) who are anti-HCV (hepatitis C virus) and anti-GOR positive, have less disease activity and respond less well to immunosuppression than do those who are anti-HCV and anti-GOR negative. They conclude that anti-GOR contributes to "a better differentiation of chronic hepatitis, a finding that has therapeutic implications". We have found that in autoimmune hepatitis type 2 or type 1 anti-HCV (clOO and 5-1-1) negative patients show more severe disease activity and better response to corticosteroids than do anti-HCV positive ones1 who are generally serum HCV-RNA positiveIn Michel’s paper, anti-GOR does not seem to add any therapeutic information-indeed, anti-GOR was strictly associated with anti-HCV positivity among patients with LKM-1-positive chronic hepatitis. Moreover, Michel et al found no anti-HCV or anti-GOR in autoimmune hepatitis type 1, whereas in our area anti-HCV and HCV-RNA is found in sera from patients with
antinuclear antibody (ANA, type 1) positive chronic hepatitis, and these patients behave like patients with HCV seropositive autoimmune hepatitis type 2 (LKM-1) in respect of disease activity and response to corticosteroids. Thus, in our experience, anti-HCV and HCV-RNA tests are enough to guide treatment decisions in cases of LKM-1 or ANA-positive chronic hepatitis. Division of Internal Medicine,
Ospedale V, Cervello, 90146 Palermo, Italy
SILVIO MAGRIN GIOVAMBATTISTA PINZELLO
Medical Clinic R,
ANTONIO CRAXI PIERO ALMASIO LUIGI PAGLIARO
University of Palermo 1. 2.
Magrin S, Craxi A, Fiorentino G, et al. Is autoimmune chronic active hepatitis a HCV-related disease?J Hepatol 1991; 13: 56-60. Magrin S, Craxi A, Fabiano C, et al Hepatitis C virus replication in "autoimmune" chronic hepatitis. J Hepatol 1991; 13: 364-67.
SIR,-Dr Michel and colleagues state that anti-GOR reflects HCV-specific autoimmunity in autoimmune liver disease. The assumption that anti-GOR is an autoantibody is based on the description of the GOR47-1 clone,l which was reported to contain no sequence homology with HCV. However, we have found an antigenic relation between GOR and HCV. We have identified a region of the HCV nucleocapsid protein that shares 47% aminoacid homology with the GOR epitope, allowing gaps for optimum alignment. The similarity of HCV residues 4-20 (IPKPQRKTKRNTNRRPQ) with GOR 15-29 (GRRGQKAKSNPNRPL) may have been missed previously because the regions are short and the degree of homology is low. Nevertheless, we have demonstrated, with the corresponding synthetic peptides
HCV4-2o and GOR15.29’ that HCV and
GOR do share
a common
epitope. A competitive binding experiment with a microtitre ELISA showed that 50% of the binding of anti-GOR to GOR15.29-coated wells could be inhibited by addition of0’ 12 ug/ml soluble GOR15.29 or 0-07 J-lg/ml soluble HCV 4.20’ Soluble HCV 4.20 peptide (0-6 J-lgfml) could also inhibit 50% of the antibody binding to HCV4.20-coated wells, but soluble GOR15.29’ even at 20 tg/ml, could inhibit only 25% of this binding. Absorbance values of 28 confirmed that anti-HCV seropositive plasma samples were highly correlated (f=0 88) on GOR15.29 and HCV4-20 peptide ELISA at a peptide coating concentration of 5 g/ml, but the antibody affinity was greater to the HCV peptide than to GOR. At a limiting peptide coating concentration of 1 J-lg/ml the absorbance of one such plasma sample was 1 ’7 with HCV4.20, compared with 0.1 with GOR15.29’ In an HCV seroconversion panel, both anti-GOR and anti-HCV 4.20 appeared simultaneously, substantially earlier than detection by a clOO based assay but later than detection by the UBI HCV enzyme immunoassay, which contains synthetic nucleocapsid as well as non-structural antigens.2 Our findings indicate that antibody elicited by HCV nucleocapsid protein during HCV infection is the source of the cross-reactive anti-GOR activity observed in autoimmune liver disease, non-Anon-B hepatitis, and blood donors-and the importance of such anti-GOR activity should be re-examined in this light. United Biomedical Inc, Hauppauge, NY 11788, USA
BARBARA HOSEIN XINDE FANG CHANG YI WANG
1. Mishiro S, Hoshi Y, Takeda K, et al. Non-A, non-B hepatitis specific antibodies directed at host-derived epitope: implication for an autoimmune process. Lancet 1990; 336: 1400-03. 2. Hosein B, Fang CT, Popovsky MA, et al. Improved serodiagnosis of hepatitis C virus infection with synthetic peptide antigen from capsid protein. Proc Natl Acad Sci USA 1991; 88: 3647-51.
SIR,-Dr Michel and colleagues state that two subgroups of type hepatitis are recognised-one related to HCV infection (as judged by both second generation ELISA and RIBA positivity and HCV viraemia), this being confined to adults;l,2 and 2 autoimmune
found in younger patients with "primary" autoimmune hepatitis but with no evidence of HCV infection.3 Anti-GOR is one
