Vitamin E in a mitochondrial myopathy with proliferating mitochondria

logistic regression suggested that the major factor contributing to illness was consumption of cooked food from the market (adjusted odds ratio 3-2, 95% CI 1-6-6-2). This finding was consistent with the age and sex distribution of the cases, since it was mostly adult males who wandered and socialised in the market place, whereas women usually went there only to shop. Environmental factors such as presence of latrine, amount of available water, and source of drinking water tional

identified as risk factors. Furthermore, no association recorded between attack rates in the camp sections and person/latrine ratios in those sections (Spearman’s rank correlation 0-012). Of the 36 stool specimens that were analysed at Kamuzu Central Hospital, Lilongwe, 5 were positive on culture for Shigella dysenteriae type 1 (Sdl). 8 other specimens were analysed at Pasteur Institute, Paris. Polymerase chain reaction was used to detect enterohaemorrhagic toxins VT1 and VT2, and for invasivity gene.2-4 A DNA fragment of 130 nucleotides corresponding to the amplified VT1 toxin gene fragment was obtained in all specimens. No amplification was obtained for VT2 or invasivity genes. These findings suggested the presence of enterohaemorragic E coli and the absence of Sdl in these patients. We now highly suspect E coli 0175:H7 to be the causative agent of the Lisungwi outbreak, although some cases may have been due to Sdl. were not was

Figure: Distribution of T, relaxation times of bathing fluid Arrow=the exception.

did

reveal a cause for the long relaxation times. The recipient had an uneventful recovery from the transplantation and is doing well at present. Our observation suggests that at least one successful transplant has been performed with a UW-perfused donor liver that had been bathed in saline instead of UW. We have been unable to find a published rationale for preferring UW over saline and the bathing fluid. The hepatic capsule tolerates saline well, as is known from general surgery when the abdominal cavity is flushed with saline. Furthermore, bathing donor livers in saline instead of in UW is cost-effective since saline costs less than 1 % of the price of UW ($250 per litre). We feel that the use of UW for bathing purposes should be reconsidered. not

R F Wolf, E H P Deketh Departments of Radiology and Surgery, University Hospital, 9700 RB, Groningen,

This investigation was supported by Medecins Sans Frontieres. We thank Dr Patricia Campbell, ARC, for kindly sharing her clinical data with us.

C Paquet, W Perea Epicentre, 8

rue

St Sabin, 75011 Paris, France

F Grimont, M Collin Pasteur Institute, Paris

M Guillod Médecins Sans Frontières, Paris

Netherlands

1

Aetiology of haemorrhagic colitis epidemic in

2

Africa 3

SiR-Isaacson and colleagues (April 10, p 961) suggest that of the recent epidemics of haemorrhagic colitis in eastern and southern parts of Africa could be caused by Escherichia coli type 0157. We report a bloody diarrhoea outbreak in a Mozambican refugee camp in Malawi that supports this some

Ministry of Health, Malawi. Bloody diarrhoea situation in the Central Region: report from the Regional Health Office, July, 1992. Lilongwi: MOH, 1992. Pollard DR, Johnson WM, Lior H, et al. Rapid and specific detection of verotoxin genes in Escherichia coli by the polymerase chain reaction. J Clin Microbiol 1990; 28: 540-45. Tyler SD, Johnson WM, Lior H, et al. Identification of verotoxin type 2 variant B subunit genes in Escherichia coli by the polymerase chain reaction and restriction fragment length polymorphism analysis. J Clin Microbiol 1991; 29: 1339-43.

4

Lampel K, Jagow J, Truckess M, Hill W. Polymerase chain reaction for detection of invasive Shigella flexneri in food. Appl Environ Microbiol 1990; 56: 1536-40.

hypothesis. Between Jan 1 and Dec 1, 1992, more than 20 000 cases of bloody diarrhoea were notified in the central and southern regions of Malawi (population 5 million). Case fatality rates changed from 5% to 10% in the districts.1 In the Lisungwi refugee camp (60 000 Mozambicans), 772 cases presented with bloody diarrhoea associated with cramping abdominal pain between July and December, 1992 (attack rate 12-8 per 1000; case fatality rate 4-7%). Fever was uncommon. The duration of illness ranged from 3 days to 4 weeks (mean 8 days) and antibiotics were ineffective. Adults (> 15 years) were 3-7 times more affected than children, and adult males were more affected than females (sex ratio M/F 2-3). These patterns were constant throughout the outbreak. Although attack rates differed widely in sections of the camp, cases did not seem to cluster about water points. To identify risk factors associated with bloody diarrhoea, we conducted a case-control study. 125 cases were matched for age, sex, and section of residence with 125 controls selected at random from the camp population. The questionnaire included demographic and socioeconomic characteristics, environmental factors, and food consumption habits. Condi-

Vitamin E in

proliferating

mitochondrial mitochondria

a

myopathy with

boy with high plasma lactate (10mmol/L, range 7-4-14-0, n=6), was handicapped by a severe myopathy, had never walked independently, and became wheel-chair bound at age 24 months. He had a deficiency of the adenine nucleotide translocator in muscle, which was accentuated by a 2-20-fold increase in other mitochondrial activities. Because complex IV showed the lowest (2-fold) increase in activity, we postulated that the enzyme was inhibited by perixodation of fatty acids in cardiolipinwhich was supported by the observation that the amount of protein in complex IV was about 5 times increased, as assessed by the immunoreactivity of its subunits.1 Although there were no clinical signs of vitamin E deficiency in this normally fed boy, he received orally 500 mg vitamin E (DL ot-tocopherol acetate) twice a day. After 3 weeks, the dose was decreased from 1 0 to 06 g per day. Within 8 weeks, his muscle SIR-A

endurance power increased such that he was no longer severely 175

of the following criteria: (1) a recent positive clinical history of chest pain; (2) characteristic changes in the electrocardiogram; or (3) peak elevation of serum enzymes (creatine kinase, aspartate aminotransferase, lactic dehydrogenase). Our patient had a recent history of chest pain (beginning 11h before admission) with a rise in serum enzymes (peak values for creatine kinase on the day after admission) and changes in the electroencephalogram (ECG) suggestive of myocardial infarction. In view of the pattern of enzyme release1 and the recent history of chest pain, we believe that a recent myocardial infarction had taken place. The ECG pattern and evolution after acute myocardial infarction vary. Our patient was admitted 11 h after onset of chest pain. At that time a rise in the ST segment probably did return to the baseline. Furthermore, we think that Hillis and MacIntyre’s conclusion that the coronary vasoconstrictive effects of sumatriptan are less than that of serotonin or the ergot alkaloids is premature. Firstly, their angiographic studies of sumatriptan were small,2,3 and postmarketing experience with sumatriptan is much less than with ergot alkaloids. Secondly, whereas Hillis and MacIntyre and co-workers showed a moderate reduction of coronary artery diameter induced by sumatriptan in patients without substantial coronary atherosclerosis/,3 serotonin has a vasodilatory effect on normal human coronary arteries.4 Thirdly, it is incorrect to compare coronary vasoconstrictive effects of subcutaneous or intravenous sumatriptan in patients without coronary artery stenosis of 50% or more2,3 with the effects of intracoronary serotonin in patients with angina, most of whom had substantial coronary stenoses.Finally, any conclusion about the comparative effects on the coronary artery diameter of sumatriptan and ergot alkaloids should be based on pharmacodynamic study with both drugs in one study

handicapped. He could play unassisted in the streets, and needed his wheel-chair only for long distances. His muscle energy metabolism, measured by in-vivo magnetic resonance spectroscopy of the natural phosphor isotope 31 with hydrogen imaging to locate the right muscle group,!,3 showed an increase of the creatine phosphate to ATP ratio in resting muscle from 1 70 before therapy, to 1 86 after 10 weeks, and to 1 93 after 10 months. This ratio in controls is 3-19 (range 2 84-3-50, n = 20). The rate of creatine phosphate resynthesis after exercise, which reflects the rate of oxidative phosphorylation, increased from 19 to 33% of the average rate in 20 controls after 10 weeks of therapy, and after 10 months to 38%. The lowest control value was 66% of the mean. Plasma lactate during vitamin E therapy decreased (not significantly) to 7-5

mmol/L (6-2-9-3, n = 6). The beneficial effect of vitamin E was probably related to its ability to act as a scavenger of free radicals. Since these reactive oxygen species are continuously generated by mitochondria during normal metabolism,4 it is feasible that our patient with his increased mitochondrial activities produced such a high concentration of free radicals that the normal protection

mechanisms became insufficient. Polyunsaturated fatty acids in cardiolipin became peroxidised and inhibited the mitochondrial inner membrane enzymes that depend on cardiolipin for activity, such as complex IV. Possibly the peroxidised cardiolipin caused a further deterioration of the deficient adenine nucleotide translocator, and after therapy the functioning of the translocator became more efficient. An additional explanation is that vitamin E stabilised membranes by inhibition of phospholipase A2,s and thereby increased the number of adenine nucleotide translocators in muscle mitochondria. The fact that mitochondrial energy metabolism improved considerably implies that the patient may have been affected more from his secondary defect-ie, the free radical production by his proliferating mitochondria-than from his primary defect, the deficiency of the adenine nucleotide translocator in muscle. Henk D Bakker Het Emma Kinderziekenhuis, Children’s Academic Medical Centre, 1105 AZ Amsterdam, Netherlands

population. J P Ottervanger, B H Ch Stricker Netherlands Centre for Monitoring of Adverse Reactions to Drugs, PO Box 5406, 2280 HK Rijswijk, Netherlands

Hearse DJ.

3

MacIntyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS. The effect of i.v. sumatriptan, a selective 5-HT1-receptor agonist, on central haemodynamics and the coronary circulation. Br J Clin

Hans R Scholte

401-05.

Department of Biochemistry, Erasmus University, Rotterdam

Jeroen A L Jeneson Het Wilhelmina Kinderziekenhuis,

University Children’s Hospital, Utrecht 4

Bakker HD, Scholte HR, van den Bogert C, et al. Deficiency of the adenine nucleotide translocator in muscle of a patient with myopathy and lactic acidosis: a new mitochondrial defect. Pediatr Res 1993; 33: 412-17. 2 Wiesner R, Ludwig P, Schewe T, Rapoport SM. Reversibility of the inhibition of cytochrome c oxidase by reticulocyte lipoxygenase. FEBS Lett 1981; 123: 123-26. 3 Jeneson JAL, Nelson SJ, VigneronDB, et al. Two-dimensional 31Pchemical shift imaging of intramuscular heterogeneity in exercising human forearm muscle. Am J Physiol 1992; 263: C357-64. 4 Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Res 1979; 59: 527-605. 5 Douglas CE, Chan AC, Choy PC. Vitamin E inhibits platelet phospholipase A2. Biophys Biochim Acta 1986; 876: 639-45. 1

Sumatriptan and

chest

pain

SIR-In their June 19 commentary Hillis and MacIntyre suggest that our case of transmural myocardial infarction (April 3, p 861) can be explained by a previous myocardial infarction, before administration of sumatriptan. However, we think that this explanation is highly improbable. In general, the diagnosis of acute myocardial infarction is based on at least two

176

Myocardial enzyme leakage. J Mol Med 1977; 2: 185-200. MacIntyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS. Effect of subcutaneous sumatriptan, a selective 5HT1 agonist, on the systemic, pulmonary, and coronary circulation. Circulation 1993; 87:

1 2

5

Pharmacol 1992; 34: 541-46. Golino PP, Piscione F, Willerson JT, et al. Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients. N Engl J Med 1991; 324: 641-48. McFadden EP, Clarke JG, Davies GJ, Kaski JC, Haider AW, Maseri A. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med 1991; 324: 648-54.

CAPD with

dialysis solution containing glucose polymer SiR-Stein and colleagues (May 1, p 1159) suggest that continuous ambulatory peritoneal dialysis (CAPD) patients managed with a 4 times per day glucose regimen could be managed by 3 (or even 2) exchanges with dialysis solution containing glucose polymer. Mistry et aP reported that the net ultrafiltration obtained with a glucose-polymer solution during 6 and 12 h exchanges was 315 and 506 mL, respectively. Assuming an infusion volume of 2 L and an average ultrafiltration of 500 mL per exchange, the total daily drain volume for a 3 exchange per day glucose polymer regimen would be 7-5 L. This regimen would yield a daily Kt/V for urea of 0-179. Similarly, the corresponding drain volume and Kt/V for urea