841

before exerting its effect. It is first converted in the liver1 and gutl to its major circulating form, 25-hydroxycholecalciferol (25 OH D3), and for some years this was believed to be the final active form of the vitamin. But Fraser and Kodicek3 found that a further hydroxylation takes place and that this crucial reaction converts 25 OH D3 to an extremely potent steroid hormone. This hormone, 1,25-dihydroxycholecalciferol (1,25[OH]D), is produced only in the kidney and is the most potent single humoral agent regulating calcium metabolism. This

new

knowledge sparked

a

rapid expansion

in

research and inspired the organisation of several large international conferences. The latest, largest, and perhaps the most stimulating was held at Asilomar in California in January. The whole sphere of vitamin D was covered, but the most relevant to clinical medicine were the papers dealing with plasma assays for 1,25(OH)zD3 and those dealing with the physiological regulation of secretion of this seco-steroid by the kidney. Practical plasma assays based on a receptor protein from chick intestine have been devised 4and the pioneer assay has already been extensively exploited.6 The outstanding findings are: the very low levels in renal failure and in hypoparathyroidism; the moderate but not invariable increase of plasma 1,25(OH)zD3 in hyperparathyroidism; and the striking rise in plasma 1,25(OH)zD3 produced by phosphate deficiency, even in the absence of the para-

thyroid gland. The most exciting sections of the meeting were those dealing with the vexed question of the physiological regulation of 1,25(OH)zD3 production. The controversies over the role of parathyroid hormone in this regulation have enlivened meetings on vitamin D for some years, but if the arguments have diverted the acolytes, they have confused and perhaps irritated the clinicians. Fortunately, it has been possible to reconcile the differing views during the course of the past year of two and it has become clear that, although parathyroid hormone is of physiological importance, it is only one of several regulators of vitamin-D metabolism in the kidney.10 Thus, 1,25(OH)2D3 itself, plasma or dietary phosphate, and the circulating levels of plasma calcium are all known to be important. However, many workers suspected that this list was incomplete since it failed to explain the major changes in calcium absorption which are seen in normal health. These occur in the growth spurts in childhood, and during pregnancy and lactation. None of the known or suggested regulators of vitamin-D metabolism was really adequate to explain 1. Blunt, J. W., DeLuca, H. F., Schnoes, H. K. Biochemistry, 1968, 7, 3317. Tucker, G., Gagnon, R. E., Haussler, M. R. Archs Biochem. Biophys. 1973, 155, 47. 3. Fraser, D. R., Kodicek, E. Nature, 1970, 228, 764. 4 Brumbaugh, P. F., Haussler, D. R., Bursac, K. M., Haussler, M. R. Biochemistry, 1974, 13, 4091. 5 Eisman, J. A., Hamstra, A. J., Kream, B. E., DeLuca, H. F. Archs Biochem. Biophys. 1976, 176, 235. 6 Haussler, M. R., Baylink, D. J., Hughes, M. R., Brumbaugh, P. F., Wergedal, J. E., Shen, F. H., Nielsen, R. L., Counts, S. J., Bursac, K. M., McCain, T. A. Clin. Endocr. 1976, 5, suppl. p. 151s. 7 Garabedian, M., Holick, M. F., DeLuca, H. F., Boyle, I. T. Proc. natn. Acad. Sci. U.S.A., 1972, 69, 1673. 8 Galante, L., Colston, K. W., Evans, I. M. A., Byfield, P. G. H., Matthews, E. W., MacIntyre, I. Nature, 1973, 244, 438. 9 Fraser, D. R., Kodicek, E. Nature New Biol. 1973, 241, 163. 10 MacIntyre, I., Colston, K. W., Evans, I. M. A., Lopez, E., MacAuley, S. J., Piegnoux-Deville, J., Spanos, E., Szelke, M. Clin. Endocr. 1976, 5, suppl. p. 85S 2.

the changes in D metabolism in these real physiological situations. But the situation has now dramatically changed as a result of experiments by MacIntyre, Spanos, and their colleagues’1 at Hammersmith Hospital in London. Their initially surprising findings were that prolactin stimulates the chick kidney enzyme which produces the active metabolite of vitamin D. This inspired a transatlantic collaborative study12 by the groups at Hammersmith and Tucson which proved that the prolactin-induced enzyme effects were followed by the anticipated major increase of circulating 1,25(OH)2D3. Further, the fourfold enhancement of plasma 1,25(OH)zD3 levels during lactation, reported at Asilomar, strongly suggests that these results can be extended to mammals. And the close similarity of the aminoacid sequences of growth hormone and prolactin makes it very tempting to suggest that growth hormone will also be found to have a major influence. But in any event, it now seems almost certain that prolactin, and perhaps growth hormone, are deeply involved with the regulation of D metabolism, and that they may even explain the changes in calcium metabolism which occur in real life, in contradistinction to the

experimental laboratory. CIGARETTE SMOKING AND DIABETIC RETINOPATHY THERE is still considerable controversy about the relation between blood-glucose control and long-term diabetic complications.1 Although most people accept that good control from the outset may delay the onset and lessen the gravity of these complications 2we lack conclusive evidence that blood-glucose control hampers the development of retinopathy.4 The American Diabetic Association5 states that one of the goals of therapy should be "a serious effort to achieve levels of blood glucose as close to those in the non-diabetic as feasible." Few would argue with this, but such a policy is not easily put into practice. Long-term assessment of the degree of hyperglycaemia is very difficult and, despite the most careful and "physiological" use of modern insulins, long-lasting normoglycaemia is hard to secure in most in-

sulin-dependent patients. There is, however, a further factor that seems to be important in determining the progression of retinopathy and one which (in theory at least) might readily be modified or excluded-namely, cigarette smoking. Paetkau and her colleagues" in Edmonton, Alberta, have studied the smoking habits of diabetic patients after observing that many diabetics with proliferative retinopathy were heavy smokers and that a number of longstanding diabetics with little or no retinopathy were non-smokers. The Canadian group postulated that 11.

Spanos, E., Colston, K. W., Evans, I. M. A., Galante, L. S., MacAuley, S. J., Maclntyre, I. Mol. Cellular Endocr. 1976, 5, 163. 12. Spanos, E., Pike, J. W., Haussler, M. R., Colston, K. W., Evans, I. M. A., Goldner, A. M., McCain, T. A., Maclntyre, I. Life Sci. 1976, 19, 1751. 1. Cahill, G. F., Jr., Etzwiler, D. D., Freinkel, N. New Engl. J. Med. 1976, 294, 1004. 2. Knowles, H. C., Jr. Trans. Am. clin. clim. Ass. 1964, 76, 142. 3. Malins, J. M.Jl R. Coll. Physns, 1976, 10, 289. 4. Editorial. New Engl.J. Med. 1976, 295, 443. 5. Cahill, G. F., Jr., Etzwiler, D. D., Freinkel, N. Diabetes, 1976, 25, 237. 6. Paetkau, M. E., Boyd, T. A. S., Winship, B., Grace, M. ibid. 1976, 26, 46. 7. The Health Consequences of Smoking: report of the Surgeon General. U.S. Department of Health, Education and Welfare, Washington D.C., 1971.

842

smoking might be related to progression of diabetic retinopathy, from the simple background type to the proliferative type, and analysed the clinical records of non-smoking and smoking diabetics with retinopathy for the occurrence of background and proliferative disease as assessed by fluorescein angiography. A cigarette smoker was defined as a person who was regularly smoking one or more cigarettes a day at the time of the study or who had smoked within the past seven years. Pipe and cigar smokers were excluded, as were those who were heavily exposed to smoke in the environment. 181 patients with diabetic retinopathy were studied. Of these, 31 patients who had important visual loss as a result of macular exudates were analysed separately, leaving 80 with non-proliferative and 70 with proliferative changes. Paetkau and her colleagues found that the number of patients with proliferative retinopathy rose significantly with increasing tobacco consumption. In non-smokers there was no association between the duration of diabetes and proliferative retinopathy, but in smokers the number with proliferative retinopathy rose with increasing duration of diabetes. Cigarette smoking seemed not to be related to exudative maculopathy. Unfortunately, there were insufficient data for evaluation of control in relation to smoking; it was assumed that the spread of good to poor control was the among smokers and non-smokers. Paetkau et al. conclude that smoking may contribute to the development of proliferative retinopathy and that deterioration from the non-proliferative to the proliferative state seems to be a function of the combination of duration of the disease and exposure to tobacco. Their report does not tell us how the smoking habits of diabetics compare with those of non-diabetics: such data would obviously be of interest. It is also important to know whether retinopathy regresses when a patient stops smoking. Cigarette smokers are at increased risk of cardiovascular disease,7-9 as are diabetics. Heavy smokers have carboxyhaemoglobin levels as high as 13%,*’ and chronic exposure to low levels of carbon monoxide may hamper tissue oxygen supply in diseases where oxygen delivery to the tissues is already marginal. 10 An association has been suggested between proliferative retinopathy and hypoxia.11 Furthermore, nicotine is known to increase platelet stickiness,12 and patients with retinopathy have an increased tendency to platelet aggregation.’3 The lesson of this study seems clear. Diabetic retinopathy is a leading cause of blindness among middle-aged people. The place of pituitary ablation in the treatment ofprolisame

retinopathy is limited, and, although photocoagulation delays visual deterioration in patients with retinal neovascularisation,14 the long-term results of this therapy are not known and anything approaching a "cure" seems unlikely. The Joslin clinic in 195915 ferative

8.

Smoking and Health: a study of the effects of a reduction in cigarette smoking on mortality and morbidity rates. Department of Health and Social Security, 1972.

9. Ball, K., Turner, R. Lancet, 1974, ii, 822. 10. Sagone, A. L., Lawrence, T., Balcerzak, S. P. Blood, 1973, 41, 845. 11. Davis, M. D., Myers, F. L., Engerman, R. L., De Venecia, G. Magli, Y. L. in Symposium on the Treatment of Diabetic Retinopathy (edited by M. F. Goldberg and S. L. Fines); p. 47. U.S. Department of Health, Education and Weltare, Washington D.C., 1968. 12. Hawkins, R. L. Nature, 1972, 236, 450. 13. Dobbie, J. G., Kwaan, H. C., Colwell, J., Suwanwela, N. Archs Ophthal. 1974, 91, 107. 14. Lancet, 1976, ii, 77. 15. Joslin, E. P., Root, H. F., White, P., Marble, A. in The Treatment of Diabetes Mellitus; p. 440. Philadelphia, 1959.

stated, with regard to diabetic complications, that "careful control of diabetes with omission of smoking in all cases are points to be re-emphasised" and this advice is strongly reinforced by the Edmonton work. The next step (if enough diabetic smokers can still be found) should be a prospective study and an investigation of the interaction between diabetic control and cigarette smok-

ing. MYOSPHERULOSIS: AN IATROGENIC DISEASE? NOT for the first time, a disease classified in East Africa has proved to be prevalent in the mid-west of the United

States. This happened with the Burkitt lymphoma,’1 which was subsequently found to be widely distributed. The latest instance is myospherulosis, 4 in which muscle and subcutaneous tissue,skin/ and tissue from the paranasal sinuses,4,nose, and middle ear contain granulomatous nodules with Swiss-cheese-like holes. The lining and surrounds contain histocytes and highly vacuolated giant cells. The characteristic features, first recorded in Kenya, are the presence in the cyst-like spaces of sac structures filled with "spherules" and looking like "partly filled bags’ of marbles". The spherules are slightly larger than erythrocytes and lack a nucleus or any other organised contents, with a non-refractive thin sac wall often double-contoured.4 The sacs, "parentbodies", and spherules, and the debris which seems to be of the same type of material, are usually brown or brown-black in colour and small "brown bodies" with an intense brown colour are scattered through the debris or found in phagocytic cells. Sometimes the myospherulitic lesions are confined to a small area of the tissue removed; sometimes they are uniformly distributed. No budding forms, hyphse, or other features suggestive of a fungus have been found. A host of other possibilities have been eliminated by special staining techniques and the nature of the parent-bodies and the spherules" remains a mystery. All attempts at culture have been fruitless. The essential similarity of myospherulosis in Africa and the American mid-west was established by Dr D. H. Connor of the U.S. Armed Forces Institute of Pathology;4 then D. Kyriakos in St. Louis studied African material and confirmed the morphological identity.. But there were differences. McClatchie et al.,z who named the condition, and Hutt et al.8 described African patients, both children and adults, with tender painful superficial and deep nodules of the extremities and buttocks, most often on the right side of thebody and usually with no history of trauma. In St. Louis4 the sexes were equally affected, the youngest patient being 15 years old. The lesions were invariably in the paranasal sinuses and adjacent tissues including the middle ear, the feature common to all being previous surgical intervention in which gauze packing had been used for hamiostasis. The St. Louis cases had been appearing over a number of years and the condition was not confined to that city, so the cause is unlikely to be some peculiar local factor. The fact that all patients had had gauze 1. Dorfman, R. F. Cancer, 1965, 18, 418. 2. McClatchie, S., Warambo, M. W., Bremner, A. D.

Am.J.

clin. Path. 1969,

51, 699. 3. Hutt, M. S. R., Fernandes, B. J. J., Med. Hyg. 1971, 65, 182. 4. Kyriakos, M. Am. J. clin. Path. 1977,

Templeton, 67, 118.

A. C. Trans R. Soc. trop.

Cigarette smoking and diabetic retinopathy.

841 before exerting its effect. It is first converted in the liver1 and gutl to its major circulating form, 25-hydroxycholecalciferol (25 OH D3), and...
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