Seftel Hc

Influence of specific mutations at the LDL-receptor gene locus on the response to simvastatin therapy in Afrikaner patients with heterozygous familial hypercholesterolaemia.

Simvastatin, an inhibitor of HMG CoA reductase, lowers the plasma total cholesterol and LDL-cholesterol concentration in familial hypercholesterolemic patients. The efficacy of the drug shows considerable inter-individual variation, however. In this study we have assessed the influence of certain LDL-receptor gene mutations on this variation. A group of 20 male and female heterozygotic familial hypercholesterolemic patients, all Afrikaners and each bearing one of two different LDL receptor gene mutations, FH Afrikaner-1 (FH1) and FH Afrikaner-2 (FH2), was treated with simvastatin (40 mg once daily) for 18 months. The average reduction in total plasma cholesterol was 35.3% in the case of the FH2 men but only 23.2% in that of the FH1 men (P = 0.005); the reduction in LDL cholesterol concentrations was also greater in the FH2 group (39% as opposed to 27.1%, P = 0.02). The better response of the FH2 group was also evident when men and women were considered together. Female FH1 patients responded better to simvastatin treatment, however, than did males with the same gene defect. Mutations at the LDL-receptor locus may thus play a significant role in the variable efficacy of the drug. The particular mutations in the males of this group may have contributed up to 35% of the variance in total cholesterol response and 29% of the variance in LDL-cholesterol response to simvastatin treatment.

Pathogenesis of non-insulin-dependent diabetes mellitus in the black population of southern Africa

Non-insulin-dependent diabetes mellitus (NIDDM) is an important health problem in the black population of southern Africa. Whether the primary cause of NIDDM is insulin secretory dysfunction or peripheral insulin resistance is unknown. In westernised populations it is believed that insulin resistance and hyperinsulinaemia occur in the early stages of disease, followed later by progressive impairment of insulin secretion. However, we suggest that in the southern African black population a decrease in the mass of functioning beta cells is an important event, making these people vulnerable to the deleterious effects of insulin resistance induced by obesity and other factors. These abnormalities are, in turn, associated with insulin receptor down-regulation. An accelerated decline in beta-cell function then follows in susceptible individuals, ultimately producing striking insulinopenia. Insulinopenic NIDDM in black southern Africans may partly explain why this population has a comparatively low incidence of macrovascular complications and also predicts a short-lived therapeutic response to oral sulphonylureas in most patients.

Clinical Characteristics and Outcome of Hyperglycaemic Emergencies in Johannesburg Africans

In this prospective analysis we investigated the clinical characteristics of black South African diabetic patients admitted to hospital with hyperglycaemic emergencies. The study cases were selected from the medical admissions to an urbanized, Johannesburg academic hospital over a period of 12 months. Only patients with severe diabetic ketoacidosis (DKA) or hyperosmolar non‐ketotic hyperglycaemia (HNKH) as defined in the text were included. Over the study period, we identified 58 patients with severe DKA (M: 32, F: 26) and 24 with HNKH (M: 14, F:10). Thirty‐two of the patients with DKA (55.2 %) were classified as having non‐insulin dependent (Type 2) diabetes mellitus (NIDDM). Compared to the 26 subjects with insulin‐dependent (Type 1) diabetes mellitus (IDDM), the NIDDM patients were older (51.7 vs 27.7 years) and had a significantly higher body mass index (BMI) (29.4 vs 23.5 kg m−2, p = 0.002), and glucose levels 47.5 vs 34 mmol l−1 p = 0.004). Mortality from DKA was 6.8 % and from HNKH 16.6 %. Infection was the leading precipitating factor for both DKA and HNKH, followed by first presentation and non‐compliance. We conclude that the majority of urban African patients admitted to hospital with DKA have NIDDM. Mortality from DKA among the black Africans in Johannesburg is low and comparable to the mortality in western Europe. © 1997 John Wiley & Sons, Ltd.

The first 24 hours of acute pancreatitis: Changes in biochemical and endocrine homeostasis in patients with pancreatitis compared with those in control subjects undergoing stress for reasons other than pancreatitis

Abstract As a group, 20 patients with acute pancreatitis showed alterations in biochemical and endocrine homeostasis that differed from the metabolic reactions observed in 13 control patients undergoing stress for reasons other than pancreatitis. In patients with acute pancreatitis, hyperglycemia was associated with inappropriately low serum insulin levels (p

Platelet function in familial hypercholesterolaemia in south africa and the effects of probucol

Patients with Familial Hyperlipoproteinaemia Type II showed evidence of increased platelet aggregability when compared to normal controls. This abnormality was not influenced by oral therapy with probucol whether or not the serum cholesterol levels were lowered during the study period. Probucol assays indicated adequate compliance during the study period but did not demonstrate any uptake of the drug by platelets. In vitro studies also failed to demonstrate any inhibition of platelet function at therapeutic drug levels although higher levels were inhibitory.

Characteristics of South African Bantu who have suffered from myocardial infarction

Abstract Thirty cases of myocardial infarction in Bantu subjects were analyzed in respect to a number of clinical, personal, biochemical and pathologic characteristics. The findings varied considerably, but in comparison with control groups, the Bantu cases of infarction showed a marked predominance of males, had a higher incidence of hypertension, diabetes and obesity, a higher educational, occupational and economic status, were less active physically, and were more often habituated to a diet relatively high in animal protein and fat. In the majority of cases in which blood lipid components were determined, levels were found to be elevated. Fifteen of the 30 patients were examined post mortem. In 6 cases the lesion occluding the coronary arteries was largely atherosclerotic, with or without superimposed thrombosis. In another 6, coronary atherosclerosis was mild, and the occlusive lesion consisted mainly of thrombus. In 3 cases the occlusion was due to a combination of moderate atheroma with thrombosis or subintimal hemorrhage. When the Bantu cases of infarction were classified according to the type of diet consumed, the following correlation emerged. Those living on a diet high in animal protein and fat were relatively advanced socioeconomically, were largely sedentary and had high blood lipid levels; and, in cases coming to necropsy, the coronary occlusion was due mainly to atherosclerosis. Subjects on a diet low in animal protein and fat were of low socioeconomic status, were relatively active physically and had low or normal blood lipid levels (for Bantu); and at necropsy the occlusive lesion was predominantly thrombotic. The bearing of these findings on the problem of ischemic heart disease in white populations is discussed.

Lack of effect of high dose vitamin E on xanthoma regression in homozygous familial hypercholesterolaemia

There is increasing evidence that oxidative modification of low-density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Homozygous familial hypercholesterolaemia (HFH) is characterized by premature, severe atherosclerosis. Drugs available at present are ineffective in lowering the markedly elevated LDL levels in this condition; antioxidant therapy to protect the LDL against oxidation may be of benefit. Probucol, the only drug shown to induce xanthoma regression in HFH, is a potent antioxidant, but it also lowers high-density lipoprotein cholesterol (HDL-C) levels, causing some concern. Vitamin E is a naturally occurring antioxidant that does not affect HDL-C levels. We have therefore evaluated the effect of long-term high dose vitamin E on xanthoma regression in HFH. Ten subjects with HFH, mean age 17 years (range 4-34), received vitamin E (400-1000 mg/dl alpha-tocopherol acetate/day) for a period of 23 months (range 12-27). There was a 4.2-fold increase in the mean serum vitamin E level (mean (S.D.) 49.7 (19.9) to 177.9 (45.6) mumol/l; P < 0.005), but no change in serum lipid or lipoprotein concentrations. Although there was an increase in the in vitro resistance of LDL to oxidation as determined by the duration of the lag phase during copper-mediated oxidation (116 (8.34) vs. 141.5 (9.23) min; P < 0.005) there was no xanthoma regression; in fact they progressed in 4 subjects. Unlike probucol, high dose long-term vitamin E has no demonstrable effect on xanthoma regression in HFH.

Clonidine and the Hormonal Responses to Graded Exercise in Healthy Subjects

The aim of this study was to assess the acute effects of clonidine, an alpha 2-adrenergic agonist, on hormonal responses to graded exercise in 8 healthy young men. After fasting overnight, each subject was tested on 2 mornings, 1 week apart. On one occasion he was given 200 micrograms clonidine orally and on the other identical placebo tablets, the order being randomized in a double-blind fashion over the 2 days. Thereafter each subject performed 2 successive treadmill runs, equivalent to 60 and 100%, respectively, of maximal aerobic power. Clonidine pretreatment blunted the maximal increase in plasma catecholamines by more than 60% of the control response (p less than 0.01), without significantly altering the rise of plasma cortisol or ACTH. Furthermore, clonidine significantly reduced the exercise-induced maximal rise in plasma glucose, without modifying the slight decline in mean plasma insulin or increase in pancreatic glucagon levels. The drug did not affect the maximal increments in plasma growth hormone or prolactin occurring after exercise. It was concluded that a single dose of clonidine suppressed peripheral sympathetic responses, without altering central (pituitary) alpha-adrenergic-mediated hormonal responses, to short-term exercise in healthy men.

Intravenous fat tolerance in obese Africans with varying grades of carbohydrate tolerance

An intravenous fat tolerance test (IVFTT) was performed and fasting plasma lipid values determined in 12 healthy normal weight, 18 obese non-diabetic, 9 obese chemical diabetic and 10 obese symptomatic diabetic African subjects. Their insulin responses to an oral glucose load were also determined. Mean plasma triglyceride levels were similar in the normal weight and obese non-diabetic groups but were significantly raised in the two diabetic groups, being highest in the symptomatic diabetics. The fractional removal-rate of an intravenous injection of the fat emulsion Intralipid was significantly less in each of the obese diabetic groups compared with the normal weight or obese non-diabetic group. There was a significant negative correlation in all but the symptomatic diabetic group between the fasting triglyceride level and the rate constants for the IVFTT. These results suggest that the rate of triglyceride clearance is an important determinant of the basal plasma triglyceride concentration in urban African subjects.

Metabolic studies in acute asthma before and after treatment.

We studied the metabolism and hormone profile of 9 patients with moderately severe acute asthma before treatment, and again 10 min after intravenous aminophylline (250 mg) or the selective beta-adrenergic stimulant hexoprenaline (5 microgram) intravenously. Compared with basal values in normal subjects the untreated asthmatics had statistically significant raised mean plasma pancreatic glucagon, free fatty acid (FFA) and glucose levels in the plasma and a significantly depressed mean plasma potassium level. Insulin, growth hormone, cortisol, thyrotropin and ketone body levels were normal. The only significant changes after therapy were a further fall in plasma potassium in the hexoprenaline-treated patients and a rise in the mean lactate concentration of the group as a whole. The clinical implications of these findings are briefly considered.