OBJECTIVE -To assess coronary heart disease (CHD) risk within levels of the joint distribution of non-HDL and LDL cholesterol among individuals with and without diabetes.RESEARCH DESIGN AND METHODS -We used four publicly available data sets for this pooled post hoc analysis and confined the eligible subjects to white individuals aged Ն30 years and free of CHD at baseline (12,660 men and 6,721 women). Diabetes status was defined as either "reported by physician-diagnosed and on medication" or having a fasting glucose level Ն126 mg/dl at the baseline examination. The primary end point was CHD death. Within diabetes categories, risk was assessed based on lipid levels (in mg/dl): non-HDL Ͻ130 and LDL Ͻ100 (group 1); non-HDL Ͻ130 and LDL Ն100 (group 2); non-HDL Ն130 and LDL Ͻ100 (group 3); and non-HDL Ն130 and LDL Ն100 (group 4). Group 1 within those without diabetes was the overall reference group.RESULTS -Of the subjects studied, ϳ6% of men and 4% of women were defined as having diabetes. A total of 773 CHD deaths occurred during the average 13 years of follow-up time. A Cox proportional hazard model was used to estimate the relative risk (RR) of CHD death. Those with diabetes had a 200% higher RR than those without diabetes. In a multivariate model, CHD risk in those with diabetes did not increase with increasing LDL, whereas it did increase with increasing non-HDL: RR (95% confidence interval) for group 1: 5.7 (2.0 -16.8); group 2: 5.7 (1.6 -20.7); group 3: 7.2 (2.6 -19.8); and group 4: 7.1 (3.7-13.6).CONCLUSIONS -Non-HDL is a stronger predictor of CHD death among those with diabetes than LDL and should be given more consideration in the clinical approach to risk reduction among diabetic patients. Diabetes Care 28:1916 -1921, 2005P atients with diabetes have more than a 200% greater risk of cardiovascular diseases (CVDs) than nondiabetic individuals (1). Growing evidence suggests that dyslipidemia contributes significantly to the excess risk of CVD (2). Retrospective subgroup analysis and prospective studies have shown that lipid-lowering therapy can slow the progression of atherosclerosis and decrease the risk for cardiovascular events in patients with diabetes (3).Common characteristic features of diabetic dyslipidemia are the elevation of plasma triglycerides and triglyceride-rich VLDL cholesterol, reduced HDL cholesterol, and an increased number of small dense LDL cholesterol particles (2). Based on epidemiology studies linking diabetic dyslipidemia to coronary heart disease (CHD), together with preliminary evidence from the major statin trials, the American Diabetes Association (ADA) has updated guidelines that outline the priorities for the treatment of dyslipidemia among patients with diabetes (4). The National Cholesterol Education Program Adult Treatment Panel III (ATP III) defined diabetes as a CHD risk equivalent with an LDL treatment goal of Ͻ100 mg/dl (5). Although patients are divided into risk categories according to their levels of LDL, HDL cholesterol, and triglycerides, both the ADA and the ATP ...

Background Carnitine palmitoyltransferase 1(CPT1) is a rate-limiting step of mitochondrial β-oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT-1 activity by specific CPT-1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby posting concerns on the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 in order to evaluate it as a safe and effective therapeutic approach. Methods and Results Heterozygous CPT1b knockout mice (CPT1b+/−) were subjected to transverse aorta constriction (TAC)-induced pressure-overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by two weeks of transverse aorta constriction (TAC), CPT1b+/− mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b+/− mice exhibited exacerbated cardiac hypertrophy and remodeling compared with that in wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b+/− than in controlled mice. Moreover, the CPT1b+/− heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocytes apoptosis. Conclusions We conclude that CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be applied in the clinical use of CPT-1 inhibitors.

The results and rationale of using testicular and epididymal spermatozoa with intracytoplasmic sperm injection (ICSI) for severe cases of male infertility are reviewed. A total of 72 consecutive microsurgical epididymal sperm aspiration (MESA) cases were performed for congenital absence of the vas (CAV) and for irreparable obstructive azoospermia. ICSI was used to obtain normal embryos for transfer and fertilization in 90% of the cases. The overall fertilization rate was 46% with a normal cleavage rate of 68%. The pregnancy and delivery rates per transfer were 58 and 37% respectively. The delivery rate per cycle was 33%. In many cases, no epididymal spermatozoa were available and so testicular sperm extraction (TESE) was used for sperm retrieval. The transfer rate was lower with TESE (84 versus 96%) and the spermatozoa could not be frozen and saved for use in future cycles. However, there was little difference in pregnancy rates using epidiymal or testicular spermatozoa. The results were not affected by whether the obstruction was caused by CAV or failed vasoepididymostomy. Both fresh and frozen spermatozoa gave similar results; the only significant factor appeared to be the age of the female. Because of the consistently good results obtained using epididymal sperm with ICSI when compared with conventional IVF, and the similarly good results with testicular tissue spermatozoa, ICSI is mandatory for all future MESA patients. All CAV patients and their partners should be offered genetic screening for cystic fibrosis; hence pre-implantation embryo diagnosis should be available in any full service MESA programme. It is now clear that even with non-obstructive azoospermia, e.g. Sertoli-cell only, or maturation arrest, there are usually some small foci of spermatogenesis which allow TESE with ICSI to be carried out. This means that even in men with azoospermia due to absence of spermatogenesis or to a block in meiosis, there are usually a few spermatozoa available in the testes that are adequate for successful ICSI. Finally, it is likely that some forms of severe male factor infertility are genetically transmitted and although ICSI offspring have been shown to be completely normal, it is possible that the sons of these infertile couples will also require ICSI when they grow up and wish to have a family.

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