167 if only 5% of the age-group has diabetes, the lower limit of normal for glucose is approximately 180 mg. per 100 ml. The latter statement is more likely to be true. A more recent evaluation of the Bedford study by Keen3 failed to substantiate earlier claims of benefits from lowering blood-glucose in the " borderline diabetic ". All clinicians interested in prevention of vascular disease in patients with diabetes would like to believe that " treatment " of borderline diabetics is beneficial, but unfortunately this has not
Conversely,
been shown I should
to
be true.
to agree that " the problem of ’borderline diabetes ’ is difficult to handle, and one must hesitate before creating patients from volunteers who have a trivial and harmless abnormality ".
certainly like
Johns Hopkins Hospital, Baltimore, Maryland 21205, U.S.A.
THADDEUS E. PROUT.
SCREENING FOR CYSTIC FIBROSIS
SIR,-We read with interest Dr Raine’s paper (Oct. 27, 4 p. 997) but would like to stress that Hellsing and Kollberg used
a single radial immunodiffusion method not radioimmunoassay. Prosser et al.5 demonstrated quite clearly that similar results were obtained in cystic-fibrosis (c.F.) screening with test-strips and with more elaborate methods of albumin detection in meconium. Using both radial immunodiffusion as well as test-strips, Kollberg’s group
noticed a decreased albumin content in c.F. meconium stored at room temperature and mailed for several days. Diminished albumin concentration might have been brought about by remaining proteolytic activity. Prosser et al. found no change in albumin content during refrigerator storage. Approximately 10% of c.F. cases have no raised albumin content in meconium and this problem has not yet been solved. Department of Pædiatrics, University of Erlangen, Erlangen, and Department of Clinical Chemistry, University of Giessen, Giessen, Federal Republic of Germany.
FREQUENCY
U. STEPHAN C. BRÄUNING E. W. BUSCH.
OF CYSTIC-FIBROSIS GENE
SIR,-Mr Stuart and Dr Burdon (Dec. 21, p. 1521) speculate on the possibility that the high frequency of the cystic-fibrosis gene among Caucasians may be due to the heterozygotes having some advantage in biological fitness over normal homozygotes. They suggest that this might be due to increased resistance to typhus, once endemic in Europe, on the basis of the well-known immunological cross-reactivity between the causative organism, Rickettsia prowazeki, and certain strains of the species Proteus vulgaris, which is agglutinated by sera from cystic-fibrosis patients and heterozygotes.6However, there is no evidence that this agglutination is an immunological reaction. It appears microscopically to be associated with disorganisation and inhibition of the bacterial nagellse leading to clumping of the organisms.’ As such it is probably analogous to the effect on cilia of rabbit trachea and oyster or mussel gills. The cilia factor, although associated with IgG, is now known not to be IgG itself 11 and may well be the C3a component of complement.9 These and other observations, 3. 4. 5. 6. 7. 8. 9.
Proceedings of the 8th Congress of International Diabetes Foundation, Brussels, July 15-20, 1973. Hellsing, K., Kollberg, H. Scand. J. Lab. Invest. 1974, 33, 333. Prosser, R., Owen, H., Bull, F., Parry, B., Smerkinich, J., Goodwin, H. A., Dathan, J. Archs Dis. Childh. 1974, 49, 597. Cohen, F. L., Daniel, W. L. J. med. Genet. 1974, 11, 253. Balls, T., Crawfurd, M. d’A. Personal communication, 1974. Bowman, B. H., Barnett, D. R., Matalon, R., Davies, B. S., Beam, A. G. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 548. Conover, J. H., Conod, E. J., Hirschhorn, K. Lancet, 1973, i, 1194.
such as those on salivary and sweat gland secretions and sodium flux, suggest that all these phenomena are membrane rather than immunological effects. Although it is possible that a Proteus flagella antigen could also be the binding site for the cilia factor, this seems improbable. An alternative hypothesis is that heterozygotes for the cystic-fibrosis gene have increased resistance to tuberculosis. This would meet the requirement of a common disease recently endemic in Europe at least as well as typhus, and is suggested by indirect evidence from a family study demonstrating a significantly lower incidence of tuberculosis among the parents of cystic-fibrosis patients than among parents of controls. 10
on
Department of Genetics,
University of Leeds, Leeds LS2 9JT.
M. D’A. CRAWFURD.
ADJUVANT TREATMENT OF SEVERE MALARIA, INTRAVASCULAR COAGULATION, AND HEPARIN SIR,-I welcome the surprising conclusion of Dr Petchclai and colleagues (Jan. 4, p. 36) that increased intravascular coagulation does not contribute to cerebral symptoms and it is not a serious problem in acute falciparum malaria treated adequately in the endemic area." The conclusion is surprising because it directly conflicts with a paper,11 of FALCIPARUM
"
which Dr Petchclai was a co-author. This paper ends : "... we feel strongly that in addition to effective antimalarial drugs, adequate doses of heparin, steroids and low molecular weight dextran should be given at the earliest moment to patients with acute P. falciparum malaria who present with one or more severe clinical complications, or with early laboratory evidence suggesting DIC, namely increased burr cells, marked thrombocytopenia and elevated FDP, whether or not coagulopathy is evident." The paper reports 12 patients, all of whom received heparin (amongst other drugs). Haemoptysis was observed in 4 patients and severe gastrointestinal bleeding occurred in 8 of the 12 patients. 9 patients died. Although severe falciparum malaria may be associated with intravascular coagulation in regions of the microcirculation, its pathogenic significance remains uncertain; indeed, intravascular coagulation might be a protective reaction.12 Therapeutic defibrination by ancrod (’Arvin’) benefited neither patients with cerebral malaria 12 nor monkeys with knowlesi malaria.13 Experimental findings virtually excluded an important pathogenic role for fibrin in fatal simian knowlesi malaria and emphasise the danger of using potentially hsemorrhagic drugs such as heparin, which killed 2 monkeys.13 In human falciparum malaria, heparin has caused haemorrhage which may well have contributed to death. 11,14,15 In my opinion, heparin should not be used as adjuvant treatment in severe falciparum malaria. Cerebral oedema has been postulated as another important pathogenic factor in cerebral malaria although I am not aware of convincing clinical or pathological evidence supporting the hypothesis. It has been claimed that steroids benefit patients with cerebral malaria allegedly by relieving this oedema. In a controlled pilot study of 9 Ghanaian children with cerebral malaria, we observed no clear benefit from giving dexamethasone. 12 But, in contrast to heparin with its danger of lethal hxmorrhage, a short course of dexamethasone is unlikely to harm the patient 10. Crawfurd, M. d’A. Heredity, 1972, 29, 126. 11. Punyagupta, S., Srichaikul, R., Nitiyanant, P., Petchclai, B. Am. J. trop. Med. Hyg. 1974, 23, 551. 12. Reid, H. A., Nkrumah, R. K. Lancet, 1972, i, 218. 13. Reid, H. A., Sucharit, P. ibid. 1972, ii, 1110. 14. Borochovitz, D., Crosley, A. L., Metz, J. Br. med. J. 1970, ii, 710. 15. Smitskamp, H., Wolthuis, F. H. ibid. 1971, i, 714.
Conversely,
been shown I should
to
be true.
to agree that " the problem of ’borderline diabetes ’ is difficult to handle, and one must hesitate before creating patients from volunteers who have a trivial and harmless abnormality ".
certainly like
Johns Hopkins Hospital, Baltimore, Maryland 21205, U.S.A.
THADDEUS E. PROUT.
SCREENING FOR CYSTIC FIBROSIS
SIR,-We read with interest Dr Raine’s paper (Oct. 27, 4 p. 997) but would like to stress that Hellsing and Kollberg used
a single radial immunodiffusion method not radioimmunoassay. Prosser et al.5 demonstrated quite clearly that similar results were obtained in cystic-fibrosis (c.F.) screening with test-strips and with more elaborate methods of albumin detection in meconium. Using both radial immunodiffusion as well as test-strips, Kollberg’s group
noticed a decreased albumin content in c.F. meconium stored at room temperature and mailed for several days. Diminished albumin concentration might have been brought about by remaining proteolytic activity. Prosser et al. found no change in albumin content during refrigerator storage. Approximately 10% of c.F. cases have no raised albumin content in meconium and this problem has not yet been solved. Department of Pædiatrics, University of Erlangen, Erlangen, and Department of Clinical Chemistry, University of Giessen, Giessen, Federal Republic of Germany.
FREQUENCY
U. STEPHAN C. BRÄUNING E. W. BUSCH.
OF CYSTIC-FIBROSIS GENE
SIR,-Mr Stuart and Dr Burdon (Dec. 21, p. 1521) speculate on the possibility that the high frequency of the cystic-fibrosis gene among Caucasians may be due to the heterozygotes having some advantage in biological fitness over normal homozygotes. They suggest that this might be due to increased resistance to typhus, once endemic in Europe, on the basis of the well-known immunological cross-reactivity between the causative organism, Rickettsia prowazeki, and certain strains of the species Proteus vulgaris, which is agglutinated by sera from cystic-fibrosis patients and heterozygotes.6However, there is no evidence that this agglutination is an immunological reaction. It appears microscopically to be associated with disorganisation and inhibition of the bacterial nagellse leading to clumping of the organisms.’ As such it is probably analogous to the effect on cilia of rabbit trachea and oyster or mussel gills. The cilia factor, although associated with IgG, is now known not to be IgG itself 11 and may well be the C3a component of complement.9 These and other observations, 3. 4. 5. 6. 7. 8. 9.
Proceedings of the 8th Congress of International Diabetes Foundation, Brussels, July 15-20, 1973. Hellsing, K., Kollberg, H. Scand. J. Lab. Invest. 1974, 33, 333. Prosser, R., Owen, H., Bull, F., Parry, B., Smerkinich, J., Goodwin, H. A., Dathan, J. Archs Dis. Childh. 1974, 49, 597. Cohen, F. L., Daniel, W. L. J. med. Genet. 1974, 11, 253. Balls, T., Crawfurd, M. d’A. Personal communication, 1974. Bowman, B. H., Barnett, D. R., Matalon, R., Davies, B. S., Beam, A. G. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 548. Conover, J. H., Conod, E. J., Hirschhorn, K. Lancet, 1973, i, 1194.
such as those on salivary and sweat gland secretions and sodium flux, suggest that all these phenomena are membrane rather than immunological effects. Although it is possible that a Proteus flagella antigen could also be the binding site for the cilia factor, this seems improbable. An alternative hypothesis is that heterozygotes for the cystic-fibrosis gene have increased resistance to tuberculosis. This would meet the requirement of a common disease recently endemic in Europe at least as well as typhus, and is suggested by indirect evidence from a family study demonstrating a significantly lower incidence of tuberculosis among the parents of cystic-fibrosis patients than among parents of controls. 10
on
Department of Genetics,
University of Leeds, Leeds LS2 9JT.
M. D’A. CRAWFURD.
ADJUVANT TREATMENT OF SEVERE MALARIA, INTRAVASCULAR COAGULATION, AND HEPARIN SIR,-I welcome the surprising conclusion of Dr Petchclai and colleagues (Jan. 4, p. 36) that increased intravascular coagulation does not contribute to cerebral symptoms and it is not a serious problem in acute falciparum malaria treated adequately in the endemic area." The conclusion is surprising because it directly conflicts with a paper,11 of FALCIPARUM
"
which Dr Petchclai was a co-author. This paper ends : "... we feel strongly that in addition to effective antimalarial drugs, adequate doses of heparin, steroids and low molecular weight dextran should be given at the earliest moment to patients with acute P. falciparum malaria who present with one or more severe clinical complications, or with early laboratory evidence suggesting DIC, namely increased burr cells, marked thrombocytopenia and elevated FDP, whether or not coagulopathy is evident." The paper reports 12 patients, all of whom received heparin (amongst other drugs). Haemoptysis was observed in 4 patients and severe gastrointestinal bleeding occurred in 8 of the 12 patients. 9 patients died. Although severe falciparum malaria may be associated with intravascular coagulation in regions of the microcirculation, its pathogenic significance remains uncertain; indeed, intravascular coagulation might be a protective reaction.12 Therapeutic defibrination by ancrod (’Arvin’) benefited neither patients with cerebral malaria 12 nor monkeys with knowlesi malaria.13 Experimental findings virtually excluded an important pathogenic role for fibrin in fatal simian knowlesi malaria and emphasise the danger of using potentially hsemorrhagic drugs such as heparin, which killed 2 monkeys.13 In human falciparum malaria, heparin has caused haemorrhage which may well have contributed to death. 11,14,15 In my opinion, heparin should not be used as adjuvant treatment in severe falciparum malaria. Cerebral oedema has been postulated as another important pathogenic factor in cerebral malaria although I am not aware of convincing clinical or pathological evidence supporting the hypothesis. It has been claimed that steroids benefit patients with cerebral malaria allegedly by relieving this oedema. In a controlled pilot study of 9 Ghanaian children with cerebral malaria, we observed no clear benefit from giving dexamethasone. 12 But, in contrast to heparin with its danger of lethal hxmorrhage, a short course of dexamethasone is unlikely to harm the patient 10. Crawfurd, M. d’A. Heredity, 1972, 29, 126. 11. Punyagupta, S., Srichaikul, R., Nitiyanant, P., Petchclai, B. Am. J. trop. Med. Hyg. 1974, 23, 551. 12. Reid, H. A., Nkrumah, R. K. Lancet, 1972, i, 218. 13. Reid, H. A., Sucharit, P. ibid. 1972, ii, 1110. 14. Borochovitz, D., Crosley, A. L., Metz, J. Br. med. J. 1970, ii, 710. 15. Smitskamp, H., Wolthuis, F. H. ibid. 1971, i, 714.
