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Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure. There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy. Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This first-in-human study of HD201 was designed to evaluate the pharmacokinetic (PK) equivalence between this biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab)*., Methods: In this randomized, blinded, single-dose comparative PK study, healthy male subjects were randomized to receive a single 6 mg/kg IV dose of HD201 or EU-trastuzumab. The primary PK end point was AUC 0-∞ . Equivalence was determined by using the predefined margins of 0.8 to 1.25. Other PK parameters were included as secondary end points., Findings: Baseline demographic characteristics for the 73 randomized subjects were similar across the 2 groups: median age 29 and 30 years old (ranges 19 - 45), median weight 78.6 and 81.7 kg (ranges 60.2 - 101). The 90% CIs for the geometric least squares mean of the AUC 0-∞ were included within the margins of 0.8 to 1.25. All other PK parameters were comparable for both HD201 and EU-trastuzumab. The proportions of subjects who experienced adverse events related to the study drug were 61.8% and 82.9% in the HD201 and EU-trastuzumab groups, respectively. The most frequently reported adverse events related to the study drug were infusion-related reactions. No subjects had positive results for antidrug antibodies after a single dose., Implications: This study reported the PK equivalence between HD201 and EU-trastuzumab. HD201 was well tolerated with no safety concerns after single-dose administration in healthy male subjects. EudraCT No.: 2012-000805-56., (Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.)

Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide.

Aim: Cardiovascular autonomic neuropathy (CAN) is a common but often overlooked complication of diabetes. Sympathetic C-fibers innervating sweat glands can be impaired early on in patients with diabetes. In this study, SUDOSCAN, a new non-invasive device that assesses sudomotor function was compared to methods generally used for the investigation of CAN., Patients: A total of 232 patients with diabetes were measured for heart rate variability (HRV) at rest and during moderate activity. Time and frequency domain analysis techniques, including measurement of the low-frequency (LF) domain component, were assessed during HRV testing. Ewing tests, as recommended by the French Health Authority, were also done. Electrochemical sweat conductance (ESC) was measured on the hands and feet, and a risk-score was calculated., Results: Using two abnormal Ewing tests as a reference for the area under the curve (AUC) of the receiver operating characteristics (ROC) curve for SUDOSCAN, the risk-score was 0.74, with a sensitivity of 92% and specificity of 49% for a risk-score cut-off value of 35%. For the ROC curve analysis using the LF power component during moderate activity at a threshold of 90 ms(2) (first quartile) as reference, the AUC was higher for the SUDOSCAN risk-score (0.77) compared with the standard Ewing tests [E:I ratio (0.62), 30:15 ratio (0.76) and blood pressure change on standing (0.55)]. Using a cut-off value of 35%, risk-score sensitivity and specificity were 88 and 54%, respectively., Conclusion: SUDOSCAN, which allows quick quantitative assessment of sudomotor function, may be used for early screening of CAN in everyday clinical practice before resorting to the more sophisticated and specific, but ultimately more time-consuming, Ewing tests., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Objective. The aim of this study was to compare SUDOSCAN, a new device to evaluate sweat function (reflecting peripheral small C-fiber status), with conventional measures of peripheral and cardiac neuropathy in patients with type 2 diabetes. Methods. 265 diabetic patients were tested for symptoms and clinical signs of neuropathy using Michigan Neuropathy Screening Instrument (MNSI), vibration perception threshold (VPT) using biothesiometer, and cardiac autonomic neuropathy (CAN) using Ewing's protocol. Sudomotor function was investigated with SUDOSCAN through measurement of electrochemical skin conductance (ESC) of hands and feet. Lower ESC is suggestive of sudomotor dysfunction. Results. Lower ESC at feet was significantly associated both with increasing symptoms (MNSI A) and increasing score on physical abnormalities (MNSI B). Lower ESC at feet was also significantly associated with increasing VPT by biothesiometry (P < 0.01), and with higher number of abnormal CAN results (P < 0.05). ESC was associated with postural fall in blood pressure (sympathetic abnormality) (P < 0.05), but not with heart rate variability (HRV) tests (parasympathetic abnormalities). Conclusions. Sudomotor dysfunction testing may be a simple test to alert physicians to peripheral nerve and cardiac sympathetic dysfunction. Ease of performance could make it useful in a busy diabetic clinic. Further studies with hard clinical outcomes are indicated.

Background: A new simple technique based on iontophoresis technology (EZSCAN, Impeto Medical, Paris, France) has recently been developed for the screening of diabetes. In the present study, we investigated the accuracy of this system for the diagnosis of diabetes mellitus in Chinese., Methods: We performed the EZSCAN test in diabetic and non-diabetic subjects. EZSCAN measures electrochemical conductance (EC) at forehead, hands and feet, and derives a diabetes index with a value ranging from 0 to 100. Diabetes mellitus was defined as a plasma glucose concentration of at least 7 mmol/l at fasting or 11.1 mmol/l at 2 hours after glucose load, or as the use of antidiabetic drugs., Results: The 195 study participants (51% men, mean age 52 years) included 75 diabetic patients (use of antidiabetic drugs 81%) and 120 non-diabetic subjects. EC (micro Siemens, μSi) was significantly (P < 0.001) lower in diabetic patients at the hands (44 vs. 61) and feet (51 vs. 69) locations, but not at the forehead (15 vs. 17, P = 0.39). When a diabetes index of 40 (suggested by the manufacturer) was used as the threshold, the sensitivity and specificity for the diagnosis of diabetes mellitus was 85% and 64%, respectively. In 80 patients who underwent an oral glucose tolerance test, EC at hands and feet and the diabetes index were significantly (P < 0.001) associated with both 2-hour post-load plasma glucose and serum glycosylated haemoglobin., Conclusions: EZSCAN might be useful in screening diabetes mellitus with reasonable sensitivity and specificity.

Objective: Assess the ability of a new device based on electrochemical principles using iontophoresis (the EZSCAN) to detect impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM)., Methods: Eligible Asian Indian subjects, n=212, had anthropometric and blood pressure measurements, followed by an OGTT, HbA1c, serum lipids tests and EZSCAN measurement., Results: Biochemically, 24 subjects were diagnosed with DM, 30 with IGT, 57 subjects had normal glucose tolerance (NGT) with metabolic syndrome (MS) and 101 had NGT without MS. Fasting plasma glucose (FPG) and HbA1c levels were highest in the DM group (p<0.0001 for both). HDL-C levels were different (p=0.015). FPG at a cut-off level of 7.0 mmol/L had a low sensitivity to detect DM (29%) EZSCAN had a 75% sensitivity to detect DM, 70% for IGT and 84% for NGT with MS at threshold >50%., Conclusions: FPG had low sensitivity to detect DM in the study group. EZSCAN demonstrated good sensitivity to detect IGT and DM and also identified NGT with MS. The concept of measuring ion fluxes through the skin appears to be a powerful method for early detection of MS, IGT and DM., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

In Western countries, it has been shown that coronary heart disease (CHD) is related to high serum total cholesterol (TC) levels. In less developed continents such as Asia and Africa, serum lipid levels are low and CHD incidence is much lower as compared with Western countries. With growing urbanization and industrialization in Asia, it has been shown that there is a concomitant rise in the level of serum TC and with it a rise in CHD. In all the Asian countries, serum TC levels are also higher in the urban compared with the rural population. Singapore, the only Asian country which is 100% urbanized since 1980, showed a rise of serum TC similar to that seen in the US and UK from the 1950s to the 1980s followed thereafter by a fall. This is reflected in the trend (rise followed by a fall) of CHD morbidity and mortality as well. In spite of a declining trend in serum TC level, CHD morbidity and mortality are still high in Singapore and comparable to the Western countries. The rest of the Asian countries show a different pattern from Singapore. In general, there is still a rising trend in serum TC level and in CHD mortality in most Asian countries. However, Japan is considered an exception in having a decreasing CHD mortality in spite of an increasing trend in serum TC. This may be attributed to a better control of other CHD risk factors such as hypertension and smoking. The rising trend in serum TC level remains a cause for concern, as this will emerge as a major problem for CHD morbidity and mortality in the future.

A total of 86 unrelated Malaysian patients with familial hypercholesterolaemia (FH) were studied for mutations in their low-density lipoprotein receptor (LDL-R) gene. Amongst them, 23 had a LDL-R gene mutation, while none having an Apolipoprotein B-3500 (Apo B-3500) mutation. Patients with the LDL-R gene defect appeared to have a higher level of low-density lipoprotein cholesterol (LDL-C), an increased incidence of xanthomas and coronary heart disease (CHD), but no relationships were found between the type of LDL-R gene mutations and their lipid levels or clinical signs of CHD. In contrast to Western data, our findings seemed to indicate a predominance of mutations in the ligand binding domain and an absence of Apo B-3500 gene mutation. The latter finding may offer a genetic basis as to why Asian patients with familial hypercholesterolaemia have lower LDL-C levels and less premature CHD than their Western counterparts.

The availability of treatment guidelines has revolutionised our approach to detection, evaluation and treatment of dyslipidaemias in adults. Such guidelines focus on lowering low-density lipoprotein-cholesterol (LDL-C), the primary risk factor for coronary heart disease, and provide physicians with specific goals to be attained by dietary and, if necessary, pharmacological therapy. However, the guidelines were published in 1993, which means that the pivotal findings from large intervention trials with statins were not included. This has led to calls for the guidelines to be amended to take into account the findings of these studies and other evolving issues such as the pathogenesis of the acute coronary event and the contribution of low HDL-C and other lipid parameters. More importantly, the mostly epidemiological basis of the guidelines has instilled the concept that the lower the LDL-C level after lipid-lowering intervention the better the result in terms of prevention of coronary events. Available data now refute this assumption. Indeed, maximal therapeutic benefit is already obtained with a decrease in LDL-C level of 20-30%, irrespective of baseline levels or LDL-C levels on treatment and, until now, there have been no data to suggest that decreases in LDL-C of > 30% give any additional benefit to patients in terms of improving their long-term outcome. The concept of absolute LDL-C treatment goals therefore needs to be revisited. A more appropriate goal of lipid-lowering therapy with statins is to ensure LDL-C levels are reduced by 20-30%, with statin dosages as used in the intervention trials. Furthermore, there are insufficient data to advise that LDL-C levels should be lowered to 2.6 mmol/l. This issue will be resolved only when the results of the appropriate intervention trials are published.

This study examined the action of cerivastatin, a new statin, in subjects with primary hypercholesterolaemia. The effects of two oral doses of cerivastatin (400 micrograms/day or 300 micrograms/day) were compared with placebo in 349 patients using a multicentre, randomized, double-blind, placebo-controlled study design. Cerivastatin treatment lasted 8 weeks and produced significant reductions in low density lipoprotein-cholesterol (LDL-C) levels from baseline compared with placebo. The reduction in LDL-C was significantly greater with 400 micrograms than with 300 micrograms cerivastatin. When responder rates were examined, the higher (400 micrograms/day) cerivastatin dose was found to be more effective in producing larger (> 40%) reductions in LDL-C levels. Cerivastatin treatment was well tolerated. Only two withdrawals due to adverse events during active treatment occurred, neither of which was considered to be due to the study medication. In addition, no clinically relevant increases in the levels of creatine phosphokinase and hepatic transaminases (alanine transaminase and aspartate transaminase) compared with placebo were seen in this study. In conclusion, cerivastatin treatment produced a significant lowering of LDL-C levels, with the higher dose providing the greatest benefit.

Lowering serum lipid levels prevents myocardial infarctions. But are we targeting the right lipoproteins in our preventive therapy? Are we getting the maximum benefit? Triglycerides certainly deserve more attention than they have yet received. Most of the trials of lipid-lowering therapy have ignored them and this omission may explain the divergence between the fall in morbidity predicted from the epidemiological evidence and the reductions observed in the clinical trials. The evidence that the statins reduce coronary morbidity and mortality, and that this reduction is associated with a fall in LDL cholesterol, is overwhelming. But the potential value of the statins may be limited by their relative inability to increase the concentration of cardioprotective HDL. The fibrates, either alone, or in combination with a statin, retain a central role in the management of patients with mixed hyperlipidaemia who are undoubtedly at high risk of premature coronary artery disease.

Dietary supplementation with n-3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) have been seen in humans after short-term n-3 fatty acid supplementation. We investigated long-term effects of dietary n-3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole-blood production of IL-1 beta, TNF-alpha and interleukin 1 receptor antagonist (IL-1Ra), the naturally occurring antagonist of IL-1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n-3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n-3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n-3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin-stimulated whole-blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL-1 beta and IL-1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long-term supplementation of fish oil does not affect ex vivo cytokine production in man.

Tissue levels of n-3 fatty acids reflect dietary intake, but quantitative data about rate of incorporation and levels as a function of intake are scarce. We fed 58 men 0, 3, 6, or 9 g/d of fish oil for 12 months and monitored fatty acids in serum cholesteryl esters, erythrocytes, and subcutaneous fat during and after supplementation. Eicosapentaenoic acid (EPA) in cholesteryl esters plateaued after 4-8 weeks; the incorporation half-life was 4.8 days. Steady-state levels increased by 3.9 +/- 0.3 mass % points (+/- SE) for each extra gram of EPA eaten per day. Incorporation of docosahexaenoic acid (DHA) was erratic; plateau values were 1.1 +/- 0.1 mass % higher for every g/d ingested. Incorporation of EPA into erythrocyte membranes showed a half-life of 28 days; a steady state was reached after 180 days. Each g/d increased levels by 2.1 +/- 0.1 mass %. C22:5n-3 levels increased markedly. Changes in DHA were erratic and smaller. EPA levels in adipose tissue rose also; the change after 6 months was 67% of that after 12 months in gluteal and 75% in abdominal fat. After 12 months each gram per day caused an 0.11 +/- 0.01 mass % rise in gluteal fat for EPA, 0.53 +/- 0.07 for C22:5n-3, and 0.14 +/- 0.03 for DHA. Thus, different (n-3) fatty acids were incorporated with different efficiencies, possibly because of interconversions or different affinities of the enzymatic pathways involved. EPA levels in cholesteryl esters reflect intake over the past week or two, erythrocytes over the past month or two, and adipose tissue over a period of years. These findings may help in assessing the intake of (n-3) fatty acids in epidemiological studies.

In a cohort of 70 unrelated patients living in Southern Belgium with autosomal dominantly inherited hypercholesterolemia, 11 had a hitherto undescribed mutation in exon 4. It consisted in a C-->A mutation at nucleotide 366, resulting in a stop codon at residue Cys122. This C122X mutation is expected to cause a class I receptor defect. The biochemical and clinical data collected from the patients carrying the mutation were consistent with a severe form of familial hypercholesterolemia (FH). Some differences between generations were noted. Amongst the C122X carriers, those born after 1926 had cardiovascular complications earlier than those born before 1926. This raises the possibility that changes in environmental factors during the course of the century have had an unfavorable impact on the prognosis of the disease. The mutation was found in 16% of the suspected FH patients and less frequently (less than 3% of suspected FH) in Northern Belgium. The haplotype of the chromosomes carrying the mutation was the same in all C122X families, but extensive genealogical studies failed to reveal a common ancestor. We conclude that C122X is an old and common cause of FH in Belgium. Screening for this mutation may be useful in the diagnosis of FH in Belgium.

Objective: To describe the serum total cholesterol, lipoprotein cholesterol and triglyceride concentrations in elderly people from the SENECA follow-up study and report on longitudinal changes in these lipid concentrations over a four-year follow-up period., Design: Longitudinal study including baseline measurements taken in 1988/1989 which were repeated in 1993., Subjects: In 1993 lipid concentrations were assayed in blood serum collected from 1181 elderly men and women, born from 1913 to 1918 and living in twelve small towns in ten European countries and one town in the USA. 1062 of these subjects had also participated in the baseline study., Results: Mean concentrations ranged from 4.91 to 6.72 mmol/l for total cholesterol, 1.15 to 1.64 mmol/l for HDL cholesterol, 3.04 to 4.47 mmol/l for LDL cholesterol and 1.03 to 1.79 mmol/l for triglycerides. Thirty-two per cent of European men and 18% of women had plasma total cholesterol concentrations below 5.16 mmol/l; 32% of men and 56% of women had HDL cholesterol concentrations exceeding 1.42 mmol/l. Total- and HDL-cholesterol concentrations, and the HDL:total cholesterol ratio were higher in women than in men. Despite large variations between towns no clear north-south gradient was observed. Yet, lowest values for LDL cholesterol tended to be located in the south, while the highest values for LDL cholesterol showed up in the north. Comparisons between the 1989 and 1993 surveys revealed a significant decrease in total cholesterol and an increase in the HDL:total cholesterol ratio without significant variation in HDL cholesterol or triglyceride concentrations., Conclusion: Though serum lipid concentrations varied widely across Europe, a marked decline in total cholesterol values along with an increase in the HDL:total cholesterol ratio occurred across the SENECA towns.

Objective: To assess the distribution of dietary vitamin A intake among Dutch women aged 16-50 and among pregnant women, and to evaluate the effect of the use of a vitamin A (1200 RE) containing multivitamin supplement in terms of nutritional and teratogenic risk., Study Design: Data from the 2nd Dutch national food consumption survey (1992) were used for calculation of the vitamin A intake among 1725 16-50 year old women and 58 pregnant women. Calculations were performed with and without simulation of the use of a supplement containing 1200 RE vitamin A., Results: Average vitamin A intake, based on a two-day dietary record method, compared quite well with recommended intake levels: 850 RE for the 16-50 year old non-pregnant (NP) women (RDA: 800 RE), and 990 RE for the pregnant (P) women (RDA: 1000 RE), respectively. The use of liver on one of the days under survey resulted in high intakes: 60% of the women in this subgroup exceeded the 'safe upper intake limit' of 3000 RE, while in 23% of the cases intakes were > 7500 RE. Those not consuming liver or liver products on the days under survey had relatively low average intakes [NP (n = 1472): 540 RE; P (n = 46): 720 RE]; about 70% of the non-liver users had intakes below the RDA. Including the daily use of a vitamin A containing multivitamin supplement with 1200 RE resulted in intakes > RDA, while only in 2% (NP), respectively 3% (P) of the cases the 'total' intake exceeded the 3000 RE level, but remained in all cases below 7500 RE/day. serving per day., Conclusion: The use of a vitamin A containing (maximum 1200 RE) multivitamin supplement can contribute to a controlled and adequate vitamin A intake and be considered as safe for pregnant women or women who wish to become pregnant, if the consumption of liver is completely avoided and the consumption of liver products is limited to maximum one.

Objective: To determine how much vitamin A is consumed through liver and liver products by non-pregnant and pregnant women aged 16-50 years, and to determine the implications for the use of multivitamin products., Design: Secondary analysis on data from representative database Dutch National Food Consumption Survey., Method: Data were obtained from a Dutch National Food Consumption Survey (1992, method published earlier) regarding 1725 non-pregnant and 58 pregnant women aged 16-50 years who did or did not consume liver and (or) liver products., Results: Average daily vitamin A intake (two consecutive days), was 850 retinol equivalents (RE) for non-pregnant and 990 RE for pregnant women, respectively (recommended daily allowances are 800 RE and 1000 RE). Average intakes of those not eating liver or liver products were 540 RE and 720 RE per day. In about 70% and 50% of the women respectively the intake was below the minimal requirement of 600 RE per day. The use of a vitamin A supplement providing 1200 RE per day among the non-liver users would in none of the cases have resulted in intakes higher than the threshold level of 7500 RE for teratogenic risks. Occasionally in 2-3% of the women, not using liver or liver products, maximum intake would exceed 3000 RE per day (the upper safe limit of intake according to the Dutch Health Council/Nutrition Council Committee). However, women using liver or liver products would be at risk of having too high intakes, above the threshold level of 7500 RE, irrespective of the use of vitamin supplements., Conclusion: Regular vitamin A supplements may be safely used by pregnant women who consume little or no liver or liver products.

Large-scale studies have demonstrated that obesity increases the risk of developing some forms of cancer. The association between obesity and cancer may result from factors such as fat distribution or sex hormone levels. Studies have also shown a relationship between a high-fat, low-fiber diet and cancer risk. High estrogen levels and low progesterone levels are associated with an increased risk of endometrial cancer. Obesity is known to raise estrogen levels and may lower progesterone levels. Obesity may increase the risk of breast cancer, but the evidence is less clear, since factors, such as age, country of origin, body-fat distribution, and family history, also play a major role in determining breast cancer risk. Sex hormones, insulin, and nutritional factors are also involved in the etiology of breast cancer. The incidence of lung cancer is inversely related to body weight.

To investigate the "metabolic" syndrome in different European populations, samples of 38-year-old healthy men were randomly selected from six centers: Gothenburg (Sweden), Warsaw (Poland), Deinze (Belgium), Verona (Italy), Lumiar (Portugal), and Ede (The Netherlands). In total, 515 men were studied. Anthropometric measurements and blood pressure levels were taken by one or two operators in each center after a common operator's training course. Each blood parameter was analyzed in one laboratory. There were significant intercenter differences in mean values for anthropometric parameters, blood pressure, serum lipids (except for low-density lipoprotein [LDL] cholesterol), and fasting insulin. In particular, fasting serum insulin showed the highest values in Sweden and The Netherlands and the lowest values in Italy and Portugal. In pooled men, fasting insulin was strongly related (P < .001) to body mass index (BMI), waist to hip (WHR) and waist to thigh (WTR) circumference ratios, serum lipids (except for LDL cholesterol), and blood pressure. On the contrary, there were relevant differences in the correlation of insulin with serum lipids and blood pressure when the data were evaluated for each center. However, generally both in each center and in all centers together all these correlations disappeared after adjustment for BMI, with the exception of the correlation with serum triglycerides. In pooled men, multiple regression analysis showed an independent association of fasting insulin, BMI, and WHR with serum triglyceride (P < .001). On the contrary, total, LDL, and high-density lipoprotein (HDL) cholesterol and blood pressure values showed independent associations with BMI and/or WHR but not with fasting insulin in multivariate models.2+ off

In adult patients with growth hormone deficiency, the fatty acid composition of abdominal and gluteal fat tissues was determined prior to and at several time points after administration of recombinant human growth hormone. Values obtained before growth hormone treatment were not different from those seen in a normal population. However, as in healthy individuals, significant differences were found in the composition of the fat sampled at the different sites. Administration of growth hormone had no effect on the composition. It is concluded that a change in fatty acid composition of fat tissue is unlikely to be a factor contributing to the reported increased cardiovascular mortality in hypopituitarism and that treatment with recombinant human growth hormone has no effect on that potential cardiovascular risk factor.

Fluvastatin sodium (Lescol; Sandoz) the first entirely synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor studied, is structurally distinct from the other HMG-CoA reductase inhibitors currently available, all of which are fungal metabolites and analogues of compactin. Fluvastatin's distinct structure may be responsible for the biopharmaceutical properties that result in its low systemic exposure and, subsequently, low incidence of peripheral adverse events, such as headache and myositis. Fluvastatin is rapidly absorbed from the gastrointestinal tract; has a 30-minute half-life, the shortest of any currently available HMG-CoA reductase inhibitor (lovastatin, 15 hours; pravastatin, 2 hours; simvastatin, 15.6 hours); is highly selective for the liver, undergoing extensive first-pass metabolism; has no active circulating metabolites; and does not penetrate the blood-brain barrier, unlike lovastatin and simvastatin. The low systemic exposure suggests that the occurrence of peripheral adverse events, such as myositis, central nervous system effects, and drug-drug interactions, may be less than what is currently observed with other HMG-CoA reductase inhibitors. Neither niacin nor propranolol had an effect on fluvastatin plasma levels when combined with fluvastatin. In contrast to other HMG-CoA reductase inhibitors, fluvastatin in combination with niacin resulted in no instances of myositis or other serious adverse events. Although the interaction of fluvastatin with cholestyramine resulted in a lower rate and extent of fluvastatin bioavailability, this reduction had no impact on clinical efficacy. Fluvastatin administered to patients chronically receiving digoxin had no effect on the area under the curve (AUC) of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanisms by which diabetes leads to various manifestations of tissue damage are not yet fully understood; however, different recent studies suggest that some of them may be mediated by modified lipoproteins, although other lipid abnormalities also have been described in diabetes patients. Principally, the modification consists of an oxidation of the lipoprotein particle [mainly low-density lipoprotein (LDL)]. The oxidized LDL is then rapidly internalized by macrophages, converting them to cholesterol-loaded foam cells. In diabetic patients, oxidation occurs through two pathways: enzymatic (vascular inflammation) and nonenzymatic (polyunsaturated fatty acids) that can be blocked either by acetyl salicylic acid or by antioxidants. Moreover, in diabetes patients, higher glucose levels can also lead to a direct (stimulated by metals) or an indirect (by generation of glycosylated proteins) generation of free radicals, which will also damage proteins and collagen in particular. Clinically, lipid peroxide concentrations are higher in diabetic than in nondiabetic subjects, particularly in patients with vascular complications and with high triglyceride levels. These lipid peroxide levels can be decreased by antioxidants, whose concentrations are lower in diabetic patients. Preliminary data also indicate that HMG CoA reductase inhibitors can decrease lipid peroxide concentrations.

Defects in the androgen receptor cause a spectrum of abnormalities in genetic males ranging from phenotypic women with testicular feminization to men with minor defects in fertility and/or virilization. The diagnosis of androgen resistance can be quite cumbersome, including analysis of the family history, karyotyping, endocrine studies, measurement of androgen binding in genital skin fibroblasts, and, in some instances, sequencing of mutant cDNAs. Furthermore, androgen-binding studies may be normal in patients with qualitative receptor abnormalities or mutations in the DNA-binding domain of the receptor. To circumvent these difficulties, we have used a recombinant adenovirus to deliver an androgen-responsive reporter gene (mouse mammary tumor virus-luciferase) to fibroblasts cultured from genital skin from 12 normal controls and from eight individuals with complete testicular feminization. Following incubation with androgen (2 nM mibolerone) for 72 h, luciferase activity in normal fibroblasts increased > 10-fold (range 11-200-fold) in a manner that corresponded with the level of androgen receptor detected in ligand-binding assays. By contrast, luciferase activity increased negligibly in fibroblasts from individuals with testicular feminization (average = 1.2-fold increase). This assay permits a direct assessment of endogenous androgen receptor function in cells and should be a powerful aid in the diagnosis of androgen resistance.

Serum lipoprotein(a) [Lp(a)], blood lipids, serum insulin and anthropometric parameters were determined in randomized samples of 38-year-old men living in six European cities: Ede (The Netherlands), Deinze (Belgium), Warsaw (Poland), Lumiar (Portugal), Verona and Naples (respectively in northern and in southern Italy). In total, 406 healthy men were studied. Serum Lp(a), blood lipids and serum insulin were measured in one laboratory. All the anthropometric and metabolic variables considered were statistically different among the participating sites, with the exception of Lp(a) serum levels. In spite of the lack of overall significant inter-center differences (Kruskal-Wallis test), the subjects from the two Italian cities had significantly lower Lp(a) serum levels than the subjects from Belgium and Portugal (Mann-Whitney U test, p < 0.01). In all cities the distribution of serum Lp(a) levels were highly skewed; the percentage of subjects with serum Lp(a) levels higher than 30 mg/dl (i.e., the commonly accepted risk level of cardiovascular disease) was 6% in both Verona and Naples (Italy), 12% in The Netherlands, 16% in Poland, 18% in Belgium and 19% in Portugal (for the last two cities, respectively, p < 0.02 and p < 0.01 vs Italian cities, chi-square test). Neither anthropometric (body mass index, waist/hip circumference ratio) nor metabolic (serum lipids and insulin) parameters showed any significant relationship with serum Lp(a) levels in any of the sites (Spearman's rank correlation). These data support the possibility of a difference in serum Lp(a) levels among different European countries.

The content of n-3 (omega 3) polyunsaturated fatty acids in fat tissue is an indicator of their long-term consumption. Therefore, a method for determining n-3 fatty acids in human fat tissue microbiopsies was validated and the stability of n-3 fatty acids in biopsies was checked under various conditions of storage. Methyl esters were prepared from 25 to 35 mg adipose tissue and separated by capillary gas chromatography. Recovery of added eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was 98-105%. The change after storage of fat samples at room temperature or at 4, -20, or -80 degrees C for 3 mo averaged +3.3% for EPA and +2.1% for DHA, with no effect of temperature. Storage at +20 or -80 degrees C for 7 mo yielded no perceptible change in EPA, DHA, or five other n-3 polyunsaturated fatty acids. EPA and DHA concentrations in adipose tissue aspirates are remarkably stable and deserve attention as biomarkers in epidemiological studies.

To evaluate the effects of obesity on the hypothalamo-pituitary-testicular axis, we compared total and free (FT) testosterone (T), androstenedione, dehydroepiandrosterone and its sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide, and estradiol levels in a group of 35 obese [body mass index (BMI), > 30] men (aged 17-61 yr) to levels in a nonobese control group. We observed a highly significant negative correlation (P < 0.001) between plasma (F)T levels and BMI and a significant positive correlation (P < 0.01) between E2 levels and BMI. There were no differences between the obese and the nonobese men in levels of androstenedione, dehydroepiandrosterone sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide. Insulin levels were significantly higher in obese men and were significantly (P < 0.02) correlated with the waist hip girth ratio. To evaluate the role of the hypothalamo-pituitary complex in the decreased (F)T levels in obese men, diurnal (0800-2000 h) LH pulsatility was studied in eight obese middle-aged men and eight age-matched controls. The pulsatility of plasma cortisol levels was also studied. Whereas LH pulse frequency was similar in the obese and control subjects, mean diurnal LH levels, mean diurnal LH pulse amplitude, and the sum of all diurnal LH pulse amplitudes and secretory masses were significantly lower in the obese than in the controls. Moreover, there was a highly significant correlation between the sum of LH pulse amplitudes and plasma (F)T levels. This decrease in LH pulse amplitude is not an isolated phenomenon of hypothalamo-pituitary dysfunction in obese men, because the pulse amplitude of plasma cortisol levels was also decreased. The decreased LH pulse amplitude together with the normal respond of Leydig cells to hCG stimulation reported in the literature suggest by inference that the decreased FT levels in obese men are the consequence of a hypogonadotropism. The decreased LH pulse amplitude and the decreased amplitude of cortisol pulses, and hence probably of ACTH pulses, point toward a general alteration of hypothalamo-pituitary function in obese men.

To investigate whether glucuronides of 17 beta-hydroxyandrogens are formed mainly in peripheral tissues or in splanchnic tissues, we compared androstanediol (AD) glucuronide (ADG) and dihydrotestosterone (DHT) glucuronide (DHTG) levels as well as the ratios of glucuronides over free steroids after transcutaneous DHT gel administration to levels and ratios found after oral administration of testosterone undecanoate. Whereas DHT and AD plasma levels were much higher after transcutaneous DHT gel administration, ADG and DHTG levels as well as glucuronide/free androgen ratios were an order of a magnitude higher after oral TU. This indicates that 17 beta-hydroxyandrogen glucuronides cannot be considered specific metabolites of androgen target tissues and are formed to a large extent in the splanchnic circulation.

Testosterone and its 5 alpha-reduced derivative 5 alpha-dihydrotestosterone exert different actions in the male during embryogenesis and in postnatal life. Nevertheless the two hormones bind to the same intracellular androgen receptor, and genetic and endocrinological studies in the Tfm mouse suggest that the actions of both hormones are mediated by this single receptor. Previous studies indicate that dihydrotestosterone binds more tightly to the androgen receptor but that the Bmax of binding of the two hormones is the same. To determine whether these differences in binding parameters could explain the mechanism by which the two hormones exert different physiological actions via the same receptor, we introduced a plasmid encoding the androgen receptor cDNA and a reporter plasmid encoding MMTV-CAT into Chinese hamster ovary cells. These cells do not express endogenous androgen receptor and do not convert testosterone to dihydrotestosterone. Therefore, it was possible to examine the relation between the concentration of each of the steroids and reporter gene expression. Both hormones enhanced CAT activity, but dihydrotestosterone was approximately 10 times as potent (half maximal of 0.018 nM) as testosterone (half maximal of 0.2 nM); the maximal activity achieved was the same for the two androgens. These findings are nearly identical to the apparent Kd values for the interaction of the two hormones with the androgen receptor. Although testosterone and dihydrotestosterone may influence the expression of other genes differently, these findings are compatible with a model system in which the differential effects can be explained as a consequence of different binding affinities to the receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

In some subjects with genetic and endocrine evidence of androgen resistance, no defect is demonstrable in the binding of androgen to its receptor in cultured genital skin fibroblasts. We have defined the molecular defect in the androgen receptor in four unrelated subjects in this category (termed receptor positive) with the phenotype of compete or incomplete testicular feminization. In these patients we detected amino acid substitutions in either exon 2 or exon 3, which encodes the DNA-binding domain of the androgen receptor. In one patient with incomplete testicular feminization, two separate mutations were present in exon 3. Introduction of these amino acid substitutions into the androgen receptor-coding segment leads to the expression of receptor proteins that bind ligand in a normal fashion but do not activate the transcription of the androgen-responsive mouse mammary tumor virus promoter. Mobility shift assays using androgen receptor fusion proteins produced in E. coli indicate that these mutations impair binding of the receptor to specific DNA sequences. In the subject with incomplete testicular feminization, a Ser-Gly substitution at amino acid residue 595 is able to partially restore DNA-binding activity to a mutant receptor protein that carries an Arg-Pro substitution at position 615. These findings indicate that mutations in amino acid residues crucial to the binding of the androgen receptor to target DNA sequences are a common cause of receptor-binding positive androgen resistance and that variable impairment of DNA binding can lead to distinctive phenotypes.

We have examined the associations between levels of plasma apolipoprotein (apo) AI, apo CIII and apo AIV and genetic variation in the apo AI-CIII-AIV gene cluster in 162 boys and young men from Belgium aged from 7 to 23 years. Genotypes were determined for six restriction enzymes XmnI, PstI, SstI, PvuIIA-CIII, PvuIIB-AIV and XbaI, and for the G to A substitution at -75 bp in the 5' region of the apo AI gene. The polymorphism most strongly associated with apo AI levels was the G to A substitution (P = 0.025, R2 x 100 = 3.6%) confirming previous observations. The polymorphism most strongly associated with apo CIII levels was that of PvuIIA-CIII (P = 0.023, R2 x 100 = 2.9%) in the apo CIII gene. This novel association must be interpreted with caution until it has been confirmed in an independent sample. The polymorphism associated with the largest effect on apo AIV levels was that detected with XbaI in the apo AIV gene, but this association was not statistically significant. Previously reported associations between the SstI polymorphism and triglyceride levels, and between the PstI polymorphism and apo AI levels, were weakly detected in the present sample. Our results show that variation associated with some of the polymorphisms in the apo AI-CIII-AIV cluster makes a small, but statistically significant, contribution to the determination of apo AI and apo CIII levels in this sample of young men and boys. These observations may, in part, explain reported associations between polymorphisms in this gene cluster, differences in plasma lipid and lipoprotein levels, and prevalence of coronary artery disease.

It has been proposed that subcutaneous fat patterning assessed by skinfolds is measuring different aspects of fat distribution compared to circumferences and circumference ratios. In this study in 510 men born in 1950 selected from six European towns we compared the associations between five skinfolds, eight circumferences and several skinfold and circumference ratios and metabolic risk factors after adjustment for body mass index (BMI). All skinfolds were independently of BMI positively related to diastolic blood pressure. Waist circumferences at most levels were independently of BMI positively related to blood pressure and triglycerides and negatively to HDL-cholesterol. Circumferences at the levels of chest, hips, thigh and arm were not related to any of the risk factors studied. Waist/thigh ratios were generally more strongly and more consistently related to risk factors than waist/hip ratios. The partial correlations of anthropometric variables with risk factors were relatively weak and never exceeded r = 0.20. The results give an indication, however, that subcutaneous fat patterning is related to different risk factors compared to waist/hip ratios. Moreover, waist/thigh and waist circumference alone (measured either as the minimal circumference or midway between the lower rib margin and the iliac crest) were stronger correlates of cardiovascular risk factors compared to waist/hip ratio.

Recent epidemiological studies have shown some beneficial health effects of the long chain (n-3) polyunsaturated fatty acids found in fatty fish. Although the results of these studies are often ambiguous and inconclusive, they have prompted many intervention trials to study the effects of n-3 fatty acids (FA) on the cardiovascular risk profile. However screening of the literature revealed that many of the beneficial effects of fish (oil) were obtained in intervention studies which had several serious shortcomings in their design. Therefore we started a placebo controlled randomised trial with increasing doses of n-3FA (respectively 0; 1.12; 2.24 and 3.37 g n-3 FA/day) and in order to have a maximum compliance this study was done in healthy monks. Fifty eight subjects took the fish oil capsules during 12 months and were thereafter followed for another 6 months. We couldn't detect any effect of n-3 FA supplementation on total cholesterol, HDL cholesterol, LDL cholesterol, apo A1, Lp(a), HbA1C, glucose, fibrinogen, factor VIII, antithrombin III, plasminogen activator inhibitor, tissue plasminogen activator and von Willebrand factor concentration, on bleeding time or on systolic or diastolic blood pressure. A pronounced significant dose dependent decrease of triglyceride levels was seen, while a slight but statistical significant decrease of apo B levels was observed in the highest fish oil dose. As the importance of triglycerides in the pathogenesis of atherosclerosis is still under discussion, the clinical relevance of these finding is not clear at the moment. It seems therefore improbable that the anti-atherosclerotic action of n-3 FA is due to an effect on the lipid, apoprotein, coagulation or fibrinolysis parameters as measured in our study. Hence further research must be focused on other parameters (prostaglandins) which can be influenced by n-3 FA and which probably play an equally important role in the atherosclerotic process.

Serum lipid levels are considered to be one of the main risk factors for cardiovascular diseases in middle-aged men and women. The significance, however, of serum lipid metabolism as a cardiovascular disease risk factor in the elderly has yet to be clarified. This paper focuses upon the serum lipid levels of groups of elderly people from 18 centres with diversified socioeconomic backgrounds in 11 European countries. Serum cholesterol was measured with an enzymatic colorimetric method by autoanalyser in one laboratory and accuracy was checked by participation in the quality control programme of the Centre for Disease Control, Atlanta, GA, USA. Mean (+/- SD) serum cholesterol levels ranged from 6.56 +/- 0.66 mmol/l (Bellinzona, Switzerland) to 5.22 +/- 0.68 mmol/l (Coimbra, Portugal) in men, and in women from 7.77 +/- 1.61 mmol/l (Elverum, Norway) to 5.86 +/- 1.07 mmol/l (Anogia-Archanes/Greece). The mean levels of high-density lipoprotein (HDL) cholesterol ranged from 1.40 +/- 0.58 mmol/l (Chateau Renault-Amboise, France) to 1.05 +/- 0.28 mmol/l (Elverum, Norway) in men and from 1.62 +/- 0.41 mmol/l (Padua, Italy) to 1.23 +/- 0.29 mmol/l (Anogia-Archanes, Greece; Vila Franca de Xira, Portugal) in women. The highest median serum triglyceride values were found in Norway (Elverum) (men: 1.50 mmol/l, women: 1.75 mmol/l), and one of the French groups (Chateau Renault-Amboise) had the lowest median values (men: 1.07 mmol/l, women: 1.15 mmol/l). Significant differences between participating centres and between sexes were found for the following variables: serum cholesterol, HDL, and the ratio total HDL cholesterol/total cholesterol. For triglycerides the differences were significant only between centres, not between the sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

In the context of the Euronut SENECA study of nutrition and the elderly, performed in 19 towns situated in 12 European countries, blood haemoglobin and haematocrit, and serum albumin were measured in a large sample of 70-75-year-old subjects. The mean haemoglobin (Hb) values for the different towns ranged from 144 g l-1 to 157 g l-1 for men and from 131 g l-1 to 150 g l-1 for women. The town haematocrit (Hct) means ranged from 43.0% to 48.9% for men and from 39.7% to 46.4% for women. No clear geographical pattern emerged for either Hb or Hct. The 95% ranges (2.5-97.5 percentile intervals) for Hb and Hct for all towns combined (without any claim of being representative of Europe) were very similar to those reported in the NHANES II study of the USA. Prevalences of anaemia, using the WHO definition (Hb less than 130 g l-1 for men and Hb less than 120 g l-1 for women) were 5.2% for men and 5.7% for women. The town mean serum albumins ranged from 40.3 g l-1 to 44.3 g l-1 for men and from 40.3 g l-1 to 43.2 g l-1 for women. No clear geographical pattern emerged. Mean values were somewhat lower than for younger adults and comparable to other published data. Most albumin values were in the normal range, with only 2.0% of both men and women having levels below 35 g l-1 and only 0.4% of men and no women having levels below 30 g l-1. These results show that these 70-75-year-old subjects who chose to participate in the study were in relatively good health as judged from their haemoglobin, haematocrit and serum albumin levels.

Fat biopsies were taken from 327 men aged 38 years from five different European communities in 1988-1989. Linoleic acid content varied widely (F = 110.6, p less than 0.001) and was lowest in men from Poland (8.6%) and highest in men from Belgium (16.7%). Adipose tissue content of alpha-linolenic acid was subject to less variation (F = 13.9, p less than 0.001) and was lowest in men from Italy (0.5%) and highest in men from Sweden and the Netherlands (0.9%). In analysis combining information from all centers, linoleic acid was negatively correlated to low density lipoprotein cholesterol (r = -0.15, p less than 0.01) and total cholesterol (r = -0.17, p less than 0.01). alpha-Linolenic acid was negatively correlated to serum triglycerides only (r = -0.14, p less than 0.05). These fatty acids were not related to body mass index, waist/hip ratio, or smoking habits. The authors conclude that there are major differences in the fatty acid composition of adipose tissue in different European populations but that these do not explain the significant differences in serum high density lipoprotein cholesterol and serum triglycerides among the different populations.

The authors studied 512 European men all born in 1950 from six different towns in the period October 1988 to May 1989. Anthropometric measurements were taken, including weight, height, and circumferences (waist, hip, thigh). Educational level, activity scores and information on smoking habits were obtained from a questionnaire. Higher educational level was associated with lower body mass index, waist/hip ratio, and waist/thigh ratio. The sports activity score was negatively related to waist/hip ratio (beta +/- standard error of the mean (SEM): -0.009 +/- 0.003) and waist/thigh ratio (-0.041 +/- 0.007), and this could be attributed to a negative relation with waist circumference and a positive relation to thigh circumference. Smoking habits were not related to body mass index but heavy smokers had larger waist circumferences (difference +/- SEM: 1.4 +/- 0.5 cm) as well as higher waist/hip ratios (difference +/- SEM: 0.014 +/- 0.005) and waist/thigh ratios (0.043 +/- 0.013) compared with men who never smoked. These associations between activity scores and smoking habits and fat distribution remained after adjustment for each other and for body mass index and educational level. The authors conclude that physical activity and smoking are independently related to indicators of fat distribution and may be potential confounders in the relations between fat distribution, risk factors, and disease.

A study on 512 38-year-old European men selected from 6 different towns was conducted. There were significant differences between the centers in averages of anthropometric variables (except for thigh circumference), serum lipids (except for LDL-cholesterol), and blood pressure. In the pooled material, body mass index (BMI) as well as waist circumference, waist/hip ratio and waist/thigh ratio and subscapular skinfold were positively correlated to serum triglycerides, total cholesterol, LDL-cholesterol, and blood pressure and negatively with HDL-cholesterol. After adjustment for BMI, waist, waist/hip, and waist/thigh were all still significantly correlated with serum triglycerides (P less than 0.001). In addition, waist/hip and waist/thigh ratio showed significant partial correlations with total cholesterol (r = 0.16, P less than 0.001, r = 0.10, P less than 0.05 respectively), and diastolic blood pressure (r = 0.10, P less than 0.05, r = 0.09, P less than 0.05 respectively). In addition, waist/hip was, independently of BMI, correlated to LDL-cholesterol (r = 0.12, P less than 0.01), and waist/thigh ratio with HDL-cholesterol (r = -0.12, P less than 0.01). The partial association between waist/thigh with HDL cholesterol became insignificant after adjustment for smoking habits and physical activity. Adjustment for differences in anthropometric measurements did not explain the differences in serum lipids and blood pressure between the centers. The authors conclude that indicators of body fat distribution are associated with unfavorable risk profiles for cardiovascular disease in European men covering a large geographical and cultural variety and a wide range of body measurements and cardiovascular risk factors.