CLASSIFICATION OF DIABETES MELLITUS

1202 ratio. The ideal ratio was achieved for our IgM R.I.A. by antigen titration and by titration of the second antibody, which determined the final dilution of both preparations. Detection of measles-specific IgG antibodies in C.S.F. of controls.-Dr Halonen and his colleagues state that they detected measles-specific IgG in c.s.F. in 80% of controls whereas our controls did not have any c.s.F. measles-antibody activities at a dilution above 1/2. Details of their study, including a definition of the control group and the serum/c.s.F. measles-antibody ratios, are not yet published, so we cannot evaluate their findings. Our controls had low measles-antibody titres in serum when tested by R.I.A. and by ha-magglutination inhibition, so we would not expect to find measles antibodies in their C.S.F.

Connolly et al.2 and Thomson et a1.,3 but not Najera et al.,4 having reported, using different methods, the presence of measles-specific IgM in serum and c.s.F. of S.S.P.E. The response is not as pronounced as it is after acute measles infection: in our experience the median titre of measles-specific IgM in acute measles is 15-30 times higher than it is in s.s.P.E. In addition this response is not always detectable during S.S.P.E. in serum or c.s.F. Thomson et a1.3 demonstrated specific IgM activity in serum in 40% of their cases, using the insensitive immunofluorescence technique. However, no serial studies were done. We found in our nine patients from whom we had more than one pair of serum and c.s.F. specimens a significant fluctuation of measles-specific IgM. This fluctuation led, in patients 5-7, to undetectable or hardly measurable specific IgM titres in serum or c.s.F., but no s.s.P.E. patient never had specific IgM activity in serum or c.s.F. Our R.I.A. would seem to be up to 10 times more sensitive than the one used by the Finnish workers. This could account for the observed differences: with a tenfold less sensitivity we would not have detected the specific IgM response in many of our S.S.P.E. patients. Two points seem clear-there is a fluctuating IgM response in s.s.P.E. and the ability to detect this depends on the assay sensitivity and, perhaps, on what stage of the disease the test is done. W. R. KIESSLING Institut für Virologie W. W. HALL und Immunbiologie, 8700 Würzburg, West Germany V. TER MEULEN

ANTIARRHYTHMIC ACTION OF LIGNOCAINE IN EARLY MYOCARDIAL INFARCTION

SIR,-A sate and effective lignocaine regimen for the prehospital prevention of arrhythmias in myocardial infarction is highly desirable since the risk of life-threatening arrhythmias is greatest during the first few hours. We were interested to read that Dr Sheridan and his colleagues (April 16, p. 824) advocate a regimen for giving lignocaine outside hospital which produced side-effects in three of nine patients. Such sideeffects as they report are to be expected in association with the plasma-lignocaine concentrations they found.’ In a larger population convulsions would probably occur in some patients, an added danger to the myocardium. We suggest that intramuscular lignocaine should be given in two doses an hour apart. This would reduce the height of the second plasma peak (the very transient first peak from intravenous bolus administration causes few side-effects) and would have the added benefit of prolonging the effective plasma con-

London SE1 7EH

2. Connolly, J. H., Haire, M., Hadden, D. S. M. Br. 3. Thomson, D., Connolly, J. H., Underwood, B.

FELICITY REYNOLDS C. APS med. J. 1971, i, 23. O., Brown, F. J. clin. Path.

1975, 28, 543. Najera, R., Gracia, Saiz, A., Herrea, I., Valenciano, L. Ann. Inst. Pasteur, 1972, 123, 565. 1. Aps, C., Bell, J. A., Jenkins, B. S., Poole-Wilson, P. A., Reynolds, F. Br. med. J. 1976, i, 13.

4.

1. Tattersall, R. B., Fajans, S. S. Diabetes, 1975, 24, 44. Irvine, W. J. Adv. Med. 1977, 13 (in the press). Barbosa, J., King, R., Goetz, F., Noreen, H., Yunis, E. Y. Archs intern. Med. (in the press). 4. Rubinstein, P., Suciu Foca, N., Nicolson, J., Fortino, M., Molinaro, A., Harisiadis, L., Hardie, M., Reemtsma, K., Allan, F. J. exp. Med. 1976, 143, 2. 3.

centration. Department of Pharmacology, St. Thomas’s Hospital Medical School,

CLASSIFICATION OF DIABETES MELLITUS Dr. Barbosa (April 23, p. 906) enjoyed my paper of March 19 (p. 638). I take his point that some patients developing insulin-independent diabetes at a young age are probably best described as having type-III diabetes (maturity-onset diabetes in the young, MoDY’), and in a follow-up article2 I have made this distinction. The observation that MODY may be associated with A3 and BW153 would indeed support its being a separate disease entity from type u. Dr Barbosa also makes a point about a possible relation between the seasonal variation in the incidence of juvenile insulin-dependent diabetes and antigen B8. A lot more needs to be done in defining a useful marker for susceptibility to diabetogenic viral infection. Perhaps I should not have emphasised the report by Rubinstein et al." on the frequency of intra HLA A/B recombinations: although there is little confirmation so far, it is an intriguing hypothesis. Dr Cudworth and Dr Woodrow (April 30, p. 949) seem keen to interpret some of the equivocal findings of themselves and others with the benefit of hindsight. The genetic studies which they cite (except for that pertaining to MODY) provide very indirect evidence about the heterogeneity of diabetes, which is what happens if the propositi are subdivided according to the age of onset of diabetes. If Dr Cudworth and Dr Woodrow had really appreciated that the age of onset was not of major importance in relation to type-I diabetes, why did they not analyse the family histories of their diabetic patients with this in mind? They would have found interesting answers.s The fact that 21% of 38patients with late-onset insulin-dependent diabetes had islet-cell antibodies6.7 means very little unless we know the duration of diabetes. Likewise, they concluded from inadequate data that there was no relation between HLA-B8 and persistence of I.C.A. The clinical distinction between juvenile-onset, insulin-dependent and maturity-onset, insulindependent diabetes has been recognised for decades. The introduction of the numerical classification is only of value when it better defines the three types of primary diabetes which would otherwise require long verbal descriptions. Dr Cudworth and Dr Woodrow dismiss our work on the significance of I.C.A. in diabetes treated with oral hypogtycxmic agents by stating that "anyone treating diabetics knows that a few patients of type can be managed with a sulphonylurea for a time". Perhaps, they w1l1 find our May 14 paper more convincing.s One such patient got diabetes at age 18 years and was controlled on oral hypogtycaemic agents for 7 years before requiring insulin. He was I.C.A. positive. This casts doubt on the arbitrary choice of a period of 2 years’ satisfactory control after the diagnosis of diabetes without the use of insulin in defining a state of MODY in patients under the age of 25.9 Presumably patients with MODY are I.c.A. negative; if they are I would expect some of the patients labelled by Fajans et a].’as MODY to be in fact in an early stage of type Ia or ib diabetes, with slow progression to insulin dependency. Dr Cudworth and Dr Woodrow suggest that a small group of type-I diabetics with an associated autoimmune disease, persistent I.C.A. and, possibly, a high frequency of B8 may have a separate pathogenesis from the rest of type i. Types la, b, and c form a spectrum autoimmunity being predominantly responsible in type Ia and viral infection being predominantly respon-

SIR,-Iwas pleased that

1277. W. J., Toft, A. D., Fulton, D., Prescott, R. J., Clarke, B. F., Duncan, L. J. P. Lancet (in the press). 6. Cudworth, A. G., Woodrow, J. C. Br. med. J. 1976, ii, 846. 7. Cudworth, A. G. Br. J. Hosp. Med. 1976, 16, 247. 8. Irvine, W. J., McCallum, C. J., Gray, R. S., Duncan, L. J. P. Lancet, 1977, 5.

Irvine,

9.

Fajans, S. S., Floyd, J. C., Tattersall, R. B., Williamson, J. R., Peck, S., Taylor,C. I. Archs intern. Med. 1976, 136, 194.

i, 1025.

1203 sible in type ic, while in type tb, both viral infection and autoimmunity play a part. No, we have not proved it, but this does seem to be the most feasible working hypothesis at present. Although Lendrum et a1. 10 have suggested that all insulindependent diabetics have I.e.A., I believe that there is a substantial minority who do not. My purpose is to focus attention on this group (ic) so that future studies will concentrate on establishing its existence. Within the spectrum of pathogenesis, there is good evidence for Ia and Ib but less for K. One cannot fit this spectrum to the "a" and "b" concept of Bottazzo and Doniach." There is no need to expect that thyrogastric antibodies should be more common in patients with l.c.A. The common type tb diabetes is associated, irrespective of age at study, with an increased prevalence of thyrogastric antibodies, and therefore they do have a diathesis towards making organ-specific autoantibodies.12 Nobody has suggested that they must make thyrogastric antibodies before they can make I.e.A. Patients are only likely to do that if the diathesis is very strong. Also, nobody has claimed that C.I.A. on its own causes diabetes,13 but it is a useful marker pointing to autoimmune processes in type ta and b diabetes. Immune complexes have been detected in the sera of 7 out of 13 newly diagnosed untreated type-i diabetics, compared with none in age and sex-matched controls, 14 which may be relevant to antibody-dependent cell-mediated

cytotoxicity.11 The application of the concept of autoimmunity to the study of diabetes is a significant advance in our understanding of at

However, as you point out, one wonders how meaningful plasma-noradrenaline concentrations are as a reflection of peripheral vasoconstrictor tone. A. J. H. CRITCHLEY CHRISTINE P. WEST

JULIAN

Royal Infirmary, Edinburgh EH3 9YW

ADHERENT AMNIOTIC-FLUID CELLS AND NEURAL-TUBE DEFECTS

SIR,-Dr Gosden and Dr Brock (April 30, p. 919) have refined their technique* of determining if rapidly adhering cells in second-trimester amniotic fluid are diagnostic of neural-tube defects and if they might give a warning about other types of fetal malformation. We find that even simple cell-counts, without refined morphological classification of rapidly adhering cells, are of definite diagnostic value. Our routine amnioticfluid cell-culture protocolZ provides for plating of 5 ml volumes of uncentrifuged amniotic fluid in 10 cm2 plastic petri dishes which contain three microscopic glass slides and 10 ml of culture media. We routinely count the cells attached within 20-24 h to one of these slides after simultaneous fixation and staining.3 The accompanying figure shows that, with these proportions of fluid to medium and surface area, there is a wide range ov cell-counts which is similar for both clear and macroscopically bloody fluids. However, two instances of high cell-

least some of the disease processes that go to make up the syndrome of diabetes. It has also provided the only in-vitro test we have for potential diabetes (types ia and b).16 Endocrine Unit and

Immunology (Therapeutics), Royal Infirmary, Edinburgh EH3 9YW

Laboratories

W. J. IRVINE

PERIPHERAL VENOUS PLASMA-CATECHOLAMINE ESTIMATIONS

SIR,-We were interested in your editorial on plasma-noradrenaline in essential hypertension (May 21, p. 1088) and the paper by Dr Sever and his colleagues in the same issue. However, we would like to put into perspective those studies which use peripheral venous blood to estimate plasma-catecholamine. There are very powerful mechanisms for both the extraneuronal and the neuronal uptake of catecholamines by the tissues.I.2 Celander and Mellander3 showed that over 90% of the catecholamines in blood are removed in one passage through the vascular beds of the hind limb. This high clearance of physiological concentrations of plasma catecholamines 4 by skin, muscle, and other tissues has been confirmed by Vane and others. Thus the term circulating catecholamines may be misleading, and antecubital blood may merely reflect the noradrenaline washed out of the tissues drained by this superficial vein. Although they present medical and ethical problems, arterial or right-atrial samples would give an overall view of the amount of noradrenaline which escapes uptake and passes out of the tissues into the circulation, but here the uptake of noradrenaline by lung tissue4 must be taken into consideration. 10.Lendrum, R., Walker, G., Cudworth, A. G., Theophanides, C., Pyke, D. A., Bloom, A., Gamble, D. R. Lancet, 1976, ii, 1273. 11.Bottazzo, F., Doniach, D. ibid. p. 800. 12.Irvine, W. J., Clarke, B. F., Scarth, L., Cullen, D. R., Duncan, L. J. P.ibid. 1970, ii, 163. 13.Gamlen, T. R., Aynsley-Green, A., Irvine, W. J., McCallum, C. J. Clin. exp. Immun. 1977, 28,192. 14.Irvine, W. J., Al-Khateeb, S. F., Di Mario, U., Edmond, B., Gray, R. S., Campbell, L. J. P. ibid. (in the press). 15.Huang, S-W.,MacLaren,N.K.Science,1976, 192, 64. 16 Irvine, W. J. Lancet, 1977, ii, 1097. 1 Iversen, L. L. Br. med. Bull. 1973, 29, 130. 2 Gillespie, J. S. ibid. p. 136. 3 Celander, O., Mellander, S.Nature, 1955, 176, 973. 4 Vane, J RBr. J. Pharmacl.1969, 35, 209.

Distribution of counts of adherent cells in 104 amniotic fluid.

specimens of

(845 and >900) in clear fluids were from fetuses with neural-tube defects (anencephaly and large spina bifida); these defects were detected by raised af-fetoprotein concentrations and were confirmed at abortion. In contrast, the two counts exceeding 500 cells/slide in grossly bloody fluids were from normal pregnancies. In retrospect, we agree with Dr Gosden and Dr Brock that in these two instances cells with "small cense nuclei and streak cytoplasm" prevailed which appear to be characteristic of heavy blood contamination. Probably few prenatal-diagnosis teams have the experience of Dr Gosden and Dr Brock in the evaluation of amniotic fluids in pregnancies affected with neural-tube detects; and most laboratories cannot be as confident in the interpretation of the bewildering spectrum of morphological appearances seen among rapidly adhering cell types. Our results indicate that with clear amniotic fluids, routine cell-counts 24 h after plating can alert even less experienced laboratories to the possibility of fetal abnormality. Such a routine would in addition foster greater proficiency in the recognition of unusual cell types, the potential significance of which Dr Gosden and Dr Brock have described. counts

Division of Genetic Pathology and Center for Inherited Diseases, University of Washington, Seattle, Washington 98195, U.S.A.

EILEEN M. BRYANT HOLGER HOEHN

1.

Sutherland, G. R., Brock, D. J. H., Scrimgeour, J. B. J. med. Genet. 1975,

2.

12, 135. Wolf, U. in Methods in Medical Cytogenetics (edited by H. G. Schwarzacher U. Wolf). Heidelberg, 1974.

3.

Hoehn, H., Bryant, E. M., Karp, 8, 746.

L.

E., Martin, G. M. Pediat. Res. 1974,