796
HLA GENE TRANSMISSION IN MYASTHENIA GRAVIS
could be obtained from 40 patients (95%). Hospital admission had been offered to all 40 patients within six weeks, but, surprisingly, only 10 (25%) accepted. 6 patients (15%) had been operated elsewhere whereas 24 (60%) refused operation because their symptoms had improved considerably in the meantime. So, in terms of fuzzy logic, our elective orthopaedic waiting list was bad for both surgeon and patient (0-25), embarrassing (0-15), yet "therapeutic" (0-6). We are waiting for a chip to tell us how to react. Orthopaedic Department, University Hospital, D-7800 Freiburg, Germany
MANFRED WILDNER MICHAEL WEBER
at onset 10 yr, tSlgnlflcantly deviated from the predictions by mendelian mode of inheritance, p0’028, tp=019; others showed no significant deviation
*Age
(p > 0 05)
Journals for
developing countries
SIR,-What do subscribers to medical journals do with them as they accumulate? Most medical practitioners in western countries subscribe to one or more journals voluntarily and receive others as a result of membership of a learned society. We also have libraries that are well supplied with journals and indexing services such as Index Medicus and its electronic offspring. We are submerged in paper and information. Disposal of old journals is therefore a serious difficulty and many subscribers are reluctant to merely throw them away or bum them. In the developing world major hospitals receive few, or no, journals, and in some countries there is not enough hard currency to subscribe to foreign journals. I know of a nutrition research institute in North Korea that has received no journals on a regular basis. None of us can produce work of quality and relevance in such isolation. This may be an extreme example, but medical schools that I know in developing countries have no journals on important subjects within the curriculum. The transfer of knowledge from the surfeited to the needy is worthwhile. It provides the recipient with knowledge and solves the donor’s disposal difficulties. For many years I have been sending journals to institutions in developing countries where I have worked and where I know the staff and their difficulties. But postage is expensive and I have been helped by representatives of a pharmaceutical company. I have approached the management of such companies to see if they would include distribution of such journals as one of their services. They have representatives visiting doctors, so the journals could be collected; they have shipments going to developed countries, which could include parcels of journals; and in the recipient country these parcels could be delivered to institutions and hospitals. I think that everyone would benefit. The donating doctors would feel that they are helping; the recipients would be getting materials that they would otherwise not see; the pharmaceutical company would get kudos from everyone. There has been considerable interest but no action. International agencies such as WHO or UNICEF could take part in the scheme, which could be wider than medicine and health. If such a project were undertaken by a national aid agency, the costs would be smaller and the benefits would be greater than most present arrangements. Importantly, benefits would be obvious, immediate, and real. Perhaps it is being done already-if so, neither I nor any of my acquaintances knows about it. Department of Child Health, University of Queensland, St Lucia Q 4067, Australia
ALAN DUGDALE
Distortion of HLA gene transmission in childhood-onset myasthenia gravis SIR,-Dr Cookson and colleagues’ report (Aug 15, p 381) was intriguing, since we have also seen and been perplexed by similar distortion of inheritance in Japanese children with myasthenia gravis. Childhood-onset myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions, and is distinct from congenital or neonatal myasthenia gravis.l Of children who develop this condition before three years of age, 51 % are DR9/DR13 heterozygous (or 79% DQ1/DQ3 heterozygous).2 We have shown that most DR9 and DQ3 came from mothers, whereas DR13 and DQ1 derived from fathers (table). In genetically normal very
Japanese, DR9 and DR13 haplotypes derive almost equally from both parents. One explanation is that the mother’s immune responses towards the fetus or infant vary according to the mother’s HLA, affecting the development of the child’s immune system. For example, mothers with DR9-DQ3 may have a different repertoire of antibodies from that ofDR13-DQl mothers, and some of the antibodies transfer to fetus or infant and affect the child’s immune development. Distortion of gene transmission such as that shown by Cookson and by us may at first seem perplexing since it implies that somatic genes from mother and father are not equivalent, but this would be possible in a diseased population, since various maternal conditions, even though clinically unremarkable, may well affect the child’s
development. Blood Transfusion Service, Saitama Medical School, Saitama 350, Japan
KAZUMASA MATSUKI HIROO MAEDA
Segawa Neurological Clinic for Children, Kanda, Chiyoda-ku, Tokyo
YOSHIKO NOMURA MASAYA SEGAWA
1.
Fukuyama Y, Hirayama Y, Osawa M. Epidemiological and clinical features of childhood myasthenia gravis in Japan. In: Japan Medical Research Foundation. Myasthenia gravis: pathogenesis and treatment. Tokyo: University of Tokyo Press, 1981: 19-27.
K, Juji T, Tokunaga K, et al. HLA antigens in Japanese patients with myasthenia gravis. J Clin Invest 1990; 86: 392-99.
2. Matsuki
Myocardial hibernation SIR,-"Hibernation" describes an impairment of contractile function in myocardial regions subjected to low coronary flow.’ This local reduction of myocardial contractility and the subsequent local decrease in O2 consumption can be seen as cardioprotective. In the affected region cardiac metabolism is reduced whereas in well-perfused areas normal contractile force persists to avoid pump failure. The mechanisms underlying the contractile dysfunction2 include mainly a decrease in Ca2+ transients. Anoxic contractile failure is caused by a reduction of intracellular Ca2 + transients secondary to anoxia-induced shortening of the action potential.3 This observation would explain why Allen et al4 found parallel action-potential shortening and contractile failure in ferret and guineapig ventricular muscle during metabolic inhibition. The hypothesis of a causal relation between action-potential duration (APD) and developed twitch tension is not new.s Lederer et al6 have shown that, in single cells, APD shortening and decrease in contraction (myocyte shortening) follow a similar time course. Furthermore, a metabolically induced APDshortening-and thus the concomitant decline in twitch tensionwere due to a sulphonylurea-sensitive increase of time-independent + K+ current (mediated by ATP-dependent K+ channels). Ischaemia-induced APD-shortening and early contractile failure could be attenuated and, in some cases, prevented by sulphonylureas in guineapig papillary muscles and sheep Purkinje fibres.’ Thus, if the APD is clamped by blocking the timeindependent KATP + current, contractile force is maintained during low coronary perfusion. In other words, myocardial hibernation is prevented. The mechanism applies only to early contractile failure during ischaemia and hypoxia. Conversely, during the later stages of complete ischaemia or anoxia, other factors may be important (eg, intracellular acidification, rise in free intracellular Mg2 +, inorganic phosphate).
HLA GENE TRANSMISSION IN MYASTHENIA GRAVIS
could be obtained from 40 patients (95%). Hospital admission had been offered to all 40 patients within six weeks, but, surprisingly, only 10 (25%) accepted. 6 patients (15%) had been operated elsewhere whereas 24 (60%) refused operation because their symptoms had improved considerably in the meantime. So, in terms of fuzzy logic, our elective orthopaedic waiting list was bad for both surgeon and patient (0-25), embarrassing (0-15), yet "therapeutic" (0-6). We are waiting for a chip to tell us how to react. Orthopaedic Department, University Hospital, D-7800 Freiburg, Germany
MANFRED WILDNER MICHAEL WEBER
at onset 10 yr, tSlgnlflcantly deviated from the predictions by mendelian mode of inheritance, p0’028, tp=019; others showed no significant deviation
*Age
(p > 0 05)
Journals for
developing countries
SIR,-What do subscribers to medical journals do with them as they accumulate? Most medical practitioners in western countries subscribe to one or more journals voluntarily and receive others as a result of membership of a learned society. We also have libraries that are well supplied with journals and indexing services such as Index Medicus and its electronic offspring. We are submerged in paper and information. Disposal of old journals is therefore a serious difficulty and many subscribers are reluctant to merely throw them away or bum them. In the developing world major hospitals receive few, or no, journals, and in some countries there is not enough hard currency to subscribe to foreign journals. I know of a nutrition research institute in North Korea that has received no journals on a regular basis. None of us can produce work of quality and relevance in such isolation. This may be an extreme example, but medical schools that I know in developing countries have no journals on important subjects within the curriculum. The transfer of knowledge from the surfeited to the needy is worthwhile. It provides the recipient with knowledge and solves the donor’s disposal difficulties. For many years I have been sending journals to institutions in developing countries where I have worked and where I know the staff and their difficulties. But postage is expensive and I have been helped by representatives of a pharmaceutical company. I have approached the management of such companies to see if they would include distribution of such journals as one of their services. They have representatives visiting doctors, so the journals could be collected; they have shipments going to developed countries, which could include parcels of journals; and in the recipient country these parcels could be delivered to institutions and hospitals. I think that everyone would benefit. The donating doctors would feel that they are helping; the recipients would be getting materials that they would otherwise not see; the pharmaceutical company would get kudos from everyone. There has been considerable interest but no action. International agencies such as WHO or UNICEF could take part in the scheme, which could be wider than medicine and health. If such a project were undertaken by a national aid agency, the costs would be smaller and the benefits would be greater than most present arrangements. Importantly, benefits would be obvious, immediate, and real. Perhaps it is being done already-if so, neither I nor any of my acquaintances knows about it. Department of Child Health, University of Queensland, St Lucia Q 4067, Australia
ALAN DUGDALE
Distortion of HLA gene transmission in childhood-onset myasthenia gravis SIR,-Dr Cookson and colleagues’ report (Aug 15, p 381) was intriguing, since we have also seen and been perplexed by similar distortion of inheritance in Japanese children with myasthenia gravis. Childhood-onset myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions, and is distinct from congenital or neonatal myasthenia gravis.l Of children who develop this condition before three years of age, 51 % are DR9/DR13 heterozygous (or 79% DQ1/DQ3 heterozygous).2 We have shown that most DR9 and DQ3 came from mothers, whereas DR13 and DQ1 derived from fathers (table). In genetically normal very
Japanese, DR9 and DR13 haplotypes derive almost equally from both parents. One explanation is that the mother’s immune responses towards the fetus or infant vary according to the mother’s HLA, affecting the development of the child’s immune system. For example, mothers with DR9-DQ3 may have a different repertoire of antibodies from that ofDR13-DQl mothers, and some of the antibodies transfer to fetus or infant and affect the child’s immune development. Distortion of gene transmission such as that shown by Cookson and by us may at first seem perplexing since it implies that somatic genes from mother and father are not equivalent, but this would be possible in a diseased population, since various maternal conditions, even though clinically unremarkable, may well affect the child’s
development. Blood Transfusion Service, Saitama Medical School, Saitama 350, Japan
KAZUMASA MATSUKI HIROO MAEDA
Segawa Neurological Clinic for Children, Kanda, Chiyoda-ku, Tokyo
YOSHIKO NOMURA MASAYA SEGAWA
1.
Fukuyama Y, Hirayama Y, Osawa M. Epidemiological and clinical features of childhood myasthenia gravis in Japan. In: Japan Medical Research Foundation. Myasthenia gravis: pathogenesis and treatment. Tokyo: University of Tokyo Press, 1981: 19-27.
K, Juji T, Tokunaga K, et al. HLA antigens in Japanese patients with myasthenia gravis. J Clin Invest 1990; 86: 392-99.
2. Matsuki
Myocardial hibernation SIR,-"Hibernation" describes an impairment of contractile function in myocardial regions subjected to low coronary flow.’ This local reduction of myocardial contractility and the subsequent local decrease in O2 consumption can be seen as cardioprotective. In the affected region cardiac metabolism is reduced whereas in well-perfused areas normal contractile force persists to avoid pump failure. The mechanisms underlying the contractile dysfunction2 include mainly a decrease in Ca2+ transients. Anoxic contractile failure is caused by a reduction of intracellular Ca2 + transients secondary to anoxia-induced shortening of the action potential.3 This observation would explain why Allen et al4 found parallel action-potential shortening and contractile failure in ferret and guineapig ventricular muscle during metabolic inhibition. The hypothesis of a causal relation between action-potential duration (APD) and developed twitch tension is not new.s Lederer et al6 have shown that, in single cells, APD shortening and decrease in contraction (myocyte shortening) follow a similar time course. Furthermore, a metabolically induced APDshortening-and thus the concomitant decline in twitch tensionwere due to a sulphonylurea-sensitive increase of time-independent + K+ current (mediated by ATP-dependent K+ channels). Ischaemia-induced APD-shortening and early contractile failure could be attenuated and, in some cases, prevented by sulphonylureas in guineapig papillary muscles and sheep Purkinje fibres.’ Thus, if the APD is clamped by blocking the timeindependent KATP + current, contractile force is maintained during low coronary perfusion. In other words, myocardial hibernation is prevented. The mechanism applies only to early contractile failure during ischaemia and hypoxia. Conversely, during the later stages of complete ischaemia or anoxia, other factors may be important (eg, intracellular acidification, rise in free intracellular Mg2 +, inorganic phosphate).
