DIETARY FIBRE AND DIABETES

782 verts to

pure

122 µg pure immunoreactive

trypsin/1 or

5-3nmol

I.R.T./l serum.

If the biological (enzymic) activity is considered (in the absence of an international reference preparation for human trypsin) values in ;j!.g/I could be equated with enzymic activity units of Behring Institute pure trypsin/1 (µkatal/l). Since with all proteins, especially enzymes, the definition of "purity" is open to a wide variety of interpretations and since serumtrypsin is assayed bound to inhibitors, this figure is somewhat hypothetical. Nevertheless, the mean normal serum-I.R.T. value of 272 ug Ag5/1 could be given as 14.5 µkatal pure trypsin enzymic activity/I serum. These aspects should be taken into account when considering the clinical implications of published trypsin values5.6 and when comparing results from different centres. Hoechst UK Ltd, Walton Manor, Walton, Milton Keynes,

Buckinghamshire MK7 7AJ

T. P. WOOD

M. R. REDSHAW R. H. ROUSELI

DIALYSIS DEMENTIA, ALUMINIUM, AND TETRAHYDROBIOPTERIN METABOLISM

SIR,—Mr Leeming and Professor Blair (March 10, p. 556) suggest that dihydropteridine reductase (D.H.P.R.) inhibition may be a cause of aluminium neurotoxicity and hence of dialysis dementia. If aluminium is a major factor in the development of this disorder, there may be another metabolic explanation for the mechanism. Patients on chronic hæmodialysis have an excess of aluminium not only in the brain but also in other organs (including bone), the excess correlating with the duration of hoemodialysis. In particular, there is excess aluminium in the grey-matter. Synaptosomes, which are found only in grey-matter, store neurotransmitters, these are taken up for storage by an energy-requiring process involving A.T.P. Metal chelates are important in the storage and transport of neurotransmitters (and this may be clinically relevant in the development of parkinsonism in manganese toxicity, as well as in the trace-metal disturbances found in Huntington’s chorea). The formation of ternary complexes (A.T.P.-metal-noradrenaline) is important in catecholamine binding.2 Such complexes would incorporate free noradrenaline. Aluminium may play a part in this mechanism by forming ternary complexes3 thus reducing the free total noradrenaline available to the synaptosomes. One can only speculate as to the role of aluminium in forming these complexes with other neurotransmitter substrates. Catecholamine binding in conduction with the known loss of amines into the dialysate4 may explain the fluctuation of symptoms in relation to periods of dialysis and, in time, the gradual loss of this feature. Sites of catecholamine storage are all within grey-matter, the distribution being similiar to that of aluminium in encephalopathic brains. Any hypothesis incorporating a role for aluminium in the production of dialysis dementia must take into account the distribution of aluminium, and, in the context of Leeming and Blair’s proposition, the histochemical distribution of D.H.P.R. is obviously important. Further work should attempt to link aluminium deposition with known relative concentrations of stored neuroamines, and ternary complexes should be estimated in subcellular fractions from fresh biopsy or necropsy material.

DIETARY FIBRE AND DIABETES

SIR,—We are glad that Dr Williams and Dr James (March 17, p. 612) reaffirm our comment that, to be effective, fibre should be intimately mixed with the major carbohydrate portion of the food, though not necessarily all the carbohydrate portions. This does not mean that it must be cooked with the food, as illustrated by the effect of guar added to soup and consumed together with bread.’ Nevertheless the effect is best in the high-carbohydrate meals where guar has been added, as shown by the work of Dr Goulder (March 17, p. 612). Though we agree with the intuitive statement of Williams and James that long-term trials are necessary we do not feel that this follows from their published work showing that guar unmixed with the carbohydrate part of the meal is ineffective. Nor have they grounds at present for suggesting that "natural foods" may be more effective and less toxic as there is virtually no comparative data on this subject. On the contrary, wheat bran and high-fibre wheat products may reduce serum calcium2 and iron3 and in Iran are implicated in zinc deficiency with dwarfism, anaemia, cirrhosis, and hypogonadism,4 but at present no data exist on guar or other refined fibres in longterm use. However, it appears that there is a natural and a pharmacological aspect of fibre5 and both may have their place in therapy. We are disappointed in the stand which Williams and James take on sugar in the diabetic diet. As pointed out by Jenkins5 this would tend to reduce the action of any fibre. The successful development of a glycosidehydrolase inhibitor for the treatment of diabetes has been aimed specifically at reducing the effects of dietary sucrose on blood-sugar.6-8 Furthermore starches produce flatter blood-glucose responses than do sugars.9 Finally the use of low-starch/high-sugar foods is contrary to the fibre hypothesis.’" Dr Dewar and her colleagues (March 17, p. 612) report results on six subjects who were nauseated by guar and on whom urinary xylose-excretion measurements at 5 h revealed no difference from controls. The choice of a 5 h absorption test was unfortunate since previous data," cited by Dewar et al., show that in the first 2 h after ingestion there is a significant drop in xylose recovery with guar, while at 4-6 and 6-8 h a significant increase was seen such that over 8 h there was no significant difference. This indicated that there was a delay in absorption with no evidence of malabsorption. Thus at 5h the delayed xylose is continuing to appear and, with individual variation between subjects, the total xylose recovery in 5 h will certainly be misleading. In addition the presence of nausea in the subjects studied makes the interpretation of transit, absorption, and intestinal motility very difficult. Dewar et al. comment on the impossibility of using guar due to unpalatability, and they lament the time wasted by so many in unsuccessful attempts and the fact that investigators were not warned of this problem. We have successfully mixed guar with orange juice and soup and made bread with it,"-" and, 1.

Wolever, T. M. S., Taylor, R. H., Goff, D. V., Ahern, J. Lancet, 1979, i,

435. 2. Heaton, K. W., Pomare, E. W. ibid. 1974, i, 49. 3. Jenkins, D. J. A., Hill, M. J., Cummings, J. H. Am J. clin. Nutr. 1975, 28, 1408. 4. Reinhold, J. G., Faradji, B., Abaidi, P., Ismail-Beigi, F. J. Nutr. 1976, 106, 493. 5. Jenkins, D. J. A., Nineham, R., Craddock, C., Craig-McFeely, P., Donald-

J. Lancet, 1979, i, 434. J., Sherif, I. T., Noy, G. A., Alberti, K. G. M. M. Br. med. J. 1979, i, 220. 7. Taylor, R. H., Jenkins, D. J. A., Nineham, R. Gut, 1978, 19, 969. 8. Taylor, R. H, Jenkins, D. J. A., Nineham, R., Sarson, D., Bloom, S. R, Alberti, K. G. M. M. Gastroenterology (in the press). 9. Crapo, P. A., Reaven, G., Olefsky, J. Diabetes, 1977, 26, 1178. 10. Trowell, H. C. in Refined Carbohydrate Foods and Disease (edited by D. P Burkitt and H. C. Trowell); p. 246, London, 1978. 11. Jenkins, D. J. A., Wolever, T. M. S., Leeds, A. R., Gassul, M. A., Haisman, P., Dilawari, J., Goff, D. V., Metz, G. L., Alberti, K. G. M. M. Br. med J 1978, i, 1392. 12. Jenkins, D. J. A., Wolever, T. M. S., Haworth, R., Leeds, A. R., Hockaday, T. D. R. Lancet, 1976, ii, 1086. son, K., Leigh, T., Snook,

6. Walton, R.

Department of Neurology, Institute of Neurological Sciences, Glasgow GS1 4TF

IAN BONE

MYFANWY THOMAS

5 Adrian, T.E, and others Clin. Sci mol. Med 1978, 54, 13P. 6. Dandona, P., Elias, E., Beckett, A G. Br. med.J 1978, ii, 1125. 1. Rajan, K. S., Davis, J. M, Colburn, R. W. J. Neurochem. 1971, 18, 345. 2 Colburn, R W., Maas, J W. Nature, 208, 37 3 Kirshner, N. J. biol. Chem 1962, 237, 2311. 4. Wooton, I. D. P in Scientific Basis of Medicine: annual review; p. 234. Lon-

don, 1963.

783

though we have noticed a great increase in satiety, nausea and vomiting were not features. Of crispbread, we said that "the first palatable guar formulation therefore represents an imporadvance in food technology".’5 That very acceptable guar foods may be formulated for diabetics has been well shown.16 We therefore cannot accept the criticisms of Dewar and her tant

colleagues. However, while Williams and James’ contribution has been of great value in emphasising that fibre and carbohydrate must so Dewar’s work emphasises the need for more of nutritional experimentation by medical people and, for those who enter this area, a willingness to learn something of food science. One would have hoped that as many as seven people would not have been asked to eat a nauseating meal. Perhaps Dewar and her colleagues should have tasted this first and heeded the advice that "if it makes you sick, don’t doit".

be

combined,

knowledge

Department of Gastroenterology, Central Middlesex Hospital, London NW10

University Laboratory of Physiology,

frequency of lymph-node involvement changed with lymphography from 66% (45/68) to 93 c (63/68). This diagnostic procedure detected abnormal retroperitoneal nodes in 8 of 11 patients who, on clinical grounds, had been classified as stage 0, and retroperitoneal adenopathies were demonstrated in 10 stage ii, m, or IV patients who had no otherwise detectable

lymph-node swellings. Lymphography should

be included among the staging procedures recommended for c.L.L. to assess the true stage 0 since patients without peripheral adenopathies may well have abnormal retroperitoneal nodes. Lymphography should also be done in patients with more advanced C.L.L., for a proper assessment of disease extension and for accurate evaluation of response to treatment.

National Tumour Institute, 20133 Milan, Italy

RENATO MUSUMECI ARMANDO SANTORO ANTONIO CERTO SILVIO MONFARDINI

RODNEY H. TAYLOR DAVID V. GOFF THOMAS M. S. WOLEVER

Oxford

INHERITANCE OF TUBEROUS SCLEROSIS

Department of Gastroenterology,

HASHMEIN FIELDEN

Central Middlesex Hospital

SiR,-Professor Lowry and colleagues (Jan. 27, p. 216), on a family with two affected children with tuberous sclerosis and ostensibly normal parents, imply that non-penetrance of a dominant gene is an unlikely explanation and propose autosomal recessive inheritance or gonadal mosaicism as other possible mechanisms. We suggest that it is not necessary to invoke such explanations: the extreme variability of this gene is well documentedl-3 and minor manifestations of the heterozygote state are very easy to miss. The study of two families with tuberous sclerosis seen in our genetics clinic impressed on us the variable expression of the gene for this disease and the paucity of findings in known heterozygotes for this autosomal dominant disorder. The first family presented with two male half-sibs with seizures. Careful examination of the four boys in the family (two each from different fathers) revealed depigmented typical "ash-leaf’ spots in all four. The mother, who had no neurological complaints, also had many depigmented areas but these were visible only under ultraviolet light. The second family presented because of seizures in the 4-month-old female proband. Family history revealed one maternal aunt and a maternal half-aunt (maternal half-sib of the proband’s mother) with seizure disorders. Examination with Wood’s lamp of family members showed the proband’s mother and grandmother to have large depigmented areas over the sacrum. The aunts with seizures and the proband had many typical ash-leaf spots. Additionally, the full aunt of the proband also had adenoma sebaceum of the face. Unless careful detailed examination (including Wood’s lamp, dilated eye examination and computerised axial tomographic scan when necessary) is done on all family members when the diagnosis of tuberous sclerosis is suspected, underdiagnosis will occur. In both of our families the mothers (and the grandmother in family 2) would have been called normal without Wood’s lamp examination. Variability of expression in tuberous sclerosis is well documented.I-3 Our cases demonstrate the need to examine possible carriers in detail. It seems more likely to us that the family presented by Lowry et al.’ and that reported by Wilson et al.4 represent limited expression or non-penetrance of a dominant gene rather than genetically distinct entities.

commenting

STAGING FOR CHRONIC LYMPHOCYTIC LEUKÆMIA

SIR,-Several staging systems for chronic lymphocytic leukxmia (C.L.L.), based on clinical findings and laboratory data, have been proposed.’-3 Such classifications correlate well with prognosis and survival and provide a basis for treatment planning.’-5 Stage 0 and stage I carry significantly different prognoses,l.3.4 but the only characteristic difference between NODAL INVOLVEMENT AND STAGE MODIFICATION BY LYMPHOGRAPHY

*No. with enlarged lymph-nodes.

the two stages is the presence of enlarged lymph-nodes in stage t. We have been exploring a possible role for lymphography as an aid to the staging in C.L.L. 68 consecutive patients were evaluated between September, 1961, and August, 1978. The table summarises the frequency of nodal involvement and shows how lymphography affected staging (Rai system’). The 13. Jenkins, D. J. A., Wolever, T. M. S., Hockaday, T. D. R., Leeds, A. R., Haworth, R., Bacon, S., Apling, E. C., Dilawari, J. ibid. 1977, ii, 779. 14 Apling, E. C., Leeds, A. R., Wolever, T. M. S., Jenkins, D. J. A. ibid. 1977, ii, 975 Jenkins, D. J. A., Wolever, T. M. S., Nineham, R., Taylor, R. H., Metz, G. L., Bacon, S., Hockaday, T. D. R.Br. med. J. 1978, ii, 1744. 16 Tredger, J., Ransley, J. J. hum.Nutr. 1978, 32, 427. 1 Rai, K. R., Sawitsky, A., Cronkite, E. P., Chanana, A. D., Levy, R. N., Pasternaek, B.S. Blood, 1975, 46, 219. 2 Binet,J L., Leporrier, M., Dighiero, G., Charron, D., D’Athis, P., Vaugier, G, Merle Beral, H., Natali, J. C., Raphael, M., Nizet, M. G., Follezou, J. Y Cancer, 1977, 40, 855. 3 Rundles, R. W., Moore, J. O. ibid. 1978, 42, 941. 4 Phillips, E. A., Kempin, S., Passe, S., Miké, V., Clarkson, B. Clins Hœmat. 15

1977, 6, 203. 5 Santoro, A., Musumeci, R., Rilke, F., Franchi, F., Valagussa, P., Bajetta, E., Monfardini, S. Tumori, 1979, 65, 39.

Division of Medical Genetics, Children’s Orthopedic Hospital and Medical Center University of Washington School of Medicine, Seattle, Washington 98195, U. S.A.

VIRGINIA P. SYBERT

JUDITH G.

HALL

1 Marshall, D., Saul, G. B., Sachs, E., Jr. New Engl J Med. 1959, 261, 1102 2. Bundey, S., Evans, K. J. Neurol. Neurosurg. Psychiat 1969, 32, 591. 3. Lagos, J. C., Gomez, M. R. Mayo Clin. Proc. 1969, 42, 26. 4. Wilson, J., Carter, C. O. Lancet, 1978, i, 340.