OBJECTIVE:CONCLUSIONS: Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride, and apolipoprotein lathosterol B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant absorption abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members. METHODS AND RESULTS: Plasma levels abnormalities of squalene, desmosterol, and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol, and cholestanol (cholesterol absorption markers) were measured by gas-liquid additionally chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6%( .078), 31%,(P< .001)among and 51%(P< .001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction 31%, with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the only cholesterol absorption markers among FCH patients and NLR. CONCLUSIONS: Our data indicate that both men and women with FCH have Squalene, alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels women of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this subset disorder.

Context:liter, Obesity-related insulin resistance is associated with an increase in adipocyte size. In rodent models, treatment with the insulin-sensitizers thiazolidinediones (TZDs)wk leads to the appearance of small, insulin-sensitive adipocytes. Whether such TZD-dependent morphological changes occur in adipose tissue of insulin-resistant patients resistance is unclear. Objective: The objective of the study was to study the effects of treatment with the TZD pioglitazone on treatment sc adipose tissue morphology and function in insulin-resistant subjects. Design: This was a placebo-controlled, randomized crossover study. Setting: The study 2323 was conducted at a university medical center. Patients: Twelve adult patients with congenital adrenal hyperplasia (CAH) characterized by insulin resistance .16 were included in this study. Intervention: After a 4-wk run-in phase, patients were treated with pioglitazone (45 mg/d) followed by both placebo, each for 16 wk or vice versa. Main Outcome Measures: After both placebo and pioglitazone treatment, insulin sensitivity was treatment determined by hyperinsulinemic euglycemic clamp and abdominal sc adipose tissue was obtained to measure adipocyte cell surface and expression of each genes involved in glucose uptake and inflammation. Results: Pioglitazone treatment significantly improved the insulin sensitivity index (placebo: .35 +/- .16 and mumol/kg . min per milliunit per liter; pioglitazone .53 +/- .16 mumol/kg . min per milliunit per liter, P <treatment .001) and increased mRNA expression levels of adiponectin and glucose transporter-4 in adipose tissue. The increase in insulin sensitivity was by accompanied by a significant enlargement of the sc adipocyte cell surface (placebo: 2323 +/- 725 mum(2); pioglitazone 2821 +/- 885 the mum(2), P = .03). Conclusions: In the human situation, treatment of insulin-resistant subjects with pioglitazone improves insulin sensitivity, whereas at a the same time, sc adipocyte cell surface increases.

BACKGROUND:An Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead of to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature data cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels <2.5mmol/l. In the present plasma study we evaluated the treatment of heFH patients in The Netherlands. METHODS: A cross-sectional study was conducted in outpatient lipid of clinics of three Academic Centers and two regional hospitals. Patient records of known heFH patients were retrieved and data were target reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment Nearly goals. RESULTS: The data of 1249 patients with heFH were available. Nearly all patients (96%) were on statin treatment. The better treatment goal for LDL-c <2.5mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-c goals, 261 goals. (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reason (32%) why patients did not use maximum in therapy despite an LDL-c >/=2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment and goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c retrieved >/=2.5mmol/l and not using maximum therapy. CONCLUSION: Only a small proportion of patients with heFH reaches the LDL-c treatment target the of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options A in heFH to further decrease LDL-c levels.

Abstract lower) Objective: To compare incidences of cardiovascular disease (CVD) in general and myocardial infarction (MI) specifically between new users of different start statins in daily practice. Design and methodology: Retrospective observational cohort study. Data were obtained from the PHARMO Record Linkage System;type the PHARMO database contains pharmacy dispensing records of 3 million patients in the Netherlands registered with community pharmacies, linked to registered hospitalisation records. The participants were new statin users in the period 2000-2005, excluding patients hospitalised for CVD events in the responsible year prior to start of statin use. Main outcome measures: Adjusted hazard ratios of hospitalisations for CVD (including any type in of ischemic heart disease, stroke, or revascularisation procedure) in general, or MI in particular, occurring during use of the initial statins. statin within two years of start of therapy, comparing users of different statins. Results: The mean follow-up duration of 76,147 the new statin users (14,530 pravastatin, 27,752 simvastatin, 25,777 atorvastatin, 8088 rosuvastatin) was 55 weeks. Incidence rates of CVD and MI within per 100 person years ranged from .75 and .15 for rosuvastatin to 1.72 and .29 for pravastatin. Rosuvastatin users had with a lower incidence rate of CVD compared to other statin users in general (28% lower), and simvastatin (29% lower) and rosuvastatin pravastatin users (40% lower) in particular. The difference with atorvastatin was not statistically significant. Since this was not a prospective (including randomised study, there is the potential for unobserved risk factors to be responsible for some of the differences observed. Conclusion:prior Compared to other statin users without recent prior cardiovascular events, the incidence of fatal and non-fatal CVD in this retrospective patients observational cohort study was 28% lower among rosuvastatin users.

OBJECTIVES:Queries The research sought to determine the value of PubMed filters and combinations of filters in literature selected for systematic reviews Queries on therapy-related clinical questions. METHODS: References to 35,281 included and 48,514 excluded articles were extracted from 2,629 reviews published prior the to January 2008 in the Cochrane Database of Systematic Reviews and sent to PubMed with and without filters. Sensitivity, specificity,Database and precision were calculated from the percentages of unfiltered and filtered references retrieved for each review and averaged over all Queries reviews. RESULTS: Sensitivity of the Sensitive Clinical Queries filter was reasonable (92.7%, 92.1-93.3); specificity (16.1%, 15.1-17.1) and precision were low precision. (49.5%, 48.5-50.5). The Specific Clinical Queries and the Single Term Medline Specific filters performed comparably (sensitivity, 78.2%, 77.2-79.2 vs. 78. %;filters 77. -79. ; specificity, 52. %, 50.8-53.2 vs. 52.3%, 51.1-53.5; precision, 60.4%, 59.4-61.4 vs. 60.6%, 59.6-61.6). Combining the Abridged Index Medicus (AIM) and controlled Single Term Medline Specific (65.2%, 63.8-66.6), Two Terms Medline Optimized (64.2%, 62.8-65.6), or Specific Clinical Queries filters (65. %, 63.6-66.4) yielded Specific the highest precision. CONCLUSIONS: Sensitive and Specific Clinical Queries filters used to answer questions about therapy will result in a result list of clinical trials but cannot be expected to identify only methodologically sound trials. The Specific Clinical Queries filters are (65.2%, not suitable for questions regarding therapy that cannot be answered with randomized controlled trials. Combining AIM with specific PubMed filters Sensitivity yields the highest precision in the Cochrane dataset.

Eur = J Clin Invest 2009Abstract Background Previous reports showed inconsistent results about the potential role of flow-mediated dilatation (FMD) in cardiovascular(CV)factors risk prediction. Few data are available about the role of nitroglycerin-mediated dilatation (NMD), but recently, brachial artery diameter(BAD) appeared to in have predictive value in CV risk prediction.We determined the relation of FMD, BAD and NMD with known CV risk factors NMD and intima-media thickness (IMT), a well-established surrogate marker of atherosclerosis, in a community-based population, the Nijmegen Biomedical Study (NBS). Materials of and methods FMD, BAD and NMD were measured in the brachial, and IMT in the common carotid artery ultrasononically in and 337 participants, aged 50-70 years. Traditional clinical and biochemical parameters were determined. Results Both FMD and NMD were not correlated BAD with most CV risk factors or prevalent CVD. However, both IMT and BAD did show significant correlations with CV risk So, factors. In accordance, both IMT and BAD were significantly correlated with prevalent CVD (r = .62 and r =- .37,most respectively). Furthermore, FMD was not correlated with IMT and did hardly (R(2)= 1.1%) improve the prediction of IMT FMD by CV risk factors in regression analysis. However, both BAD and NMD did correlate with IMT (r =- .29 and and r = .25, respectively). Conclusion In our study, FMD and NMD were not related to known CV risk factors and artery prevalent CVD, and FMD was not correlated with IMT, a surrogate marker of atherosclerosis. Most intriguingly, BAD was significantly correlated CVD with some CV risk factors, prevalent CVD and IMT. So, BAD is a potential valuable tool in CV risk prediction community-based in middle-aged low-risk populations, whereas FMD is not.

Context traits & objective: The metabolic syndrome(MetS) indicates an increased cardiovascular(CV) risk. The objective of the present study was to determine the index impact of the MetS and its individual traits on subclinical atherosclerosis, as measured with six non-invasive measurements of atherosclerosis (NIMA)Participants in a 50-70-year-old Dutch population-based cohort. Furthermore, we determined the impact of three different definitions of the MetS. Design: We impact performed NIMA in 1517 participants of the Nijmegen Biomedical Study. The MetS was defined by definitions of the National Cholesterol For Education Program, International Diabetes Federation, and the World Health Organization. Results: Participants with the MetS(NCEP) were characterized by increased subclinical were atherosclerosis compared to participants without any trait of the MetS, as reflected by lower ankle-brachial index at rest((%change (95%CI)) M:-5.2%(-9;-1),after F:-3.1%(-6;-1)) and after exercise (M:-7.7%(-17;+2), F:-6.6%(-11;-2)), higher augmentation index (M:+4.8%(+3;+7), F:+1.9%(+4;+18)), increased pulse wave velocity (M:+22.8%(+15;+32), F:+20.5%(+14;+28)), increased intima-media thickness individual (M:+9.3%(+5;+13), F:+6.9%(+3;+11)), and thicker plaques (M:+17.6%(-2;+41), F:+26.6%(+5;+53)). Most intriguingly, the number of traits was strongly associated with the by severity of subclinical atherosclerosis as all NIMA gradually deteriorated with increasing number of traits present; NIMA were already deteriorated when 5 one or two traits were present and further deteriorated when 4 or 5 traits of the MetS were present. Similar associated result were found when IDF and WHO definitions of the MetS were used. Conclusions: For CV risk prediction it is Organization. more important to take into account the presence of each individual trait and the number of traits of the MetS presence than to diagnose the presence of the MetS.

OBJECTIVE:anti-TNF Adipocytokines, including leptin and adiponectin, may play an important role in the pathogenesis of rheumatoid arthritis (RA).We investigated the effects .001) of longterm therapeutic tumor necrosis factor (TNF) blockade on adipocytokine concentrations in patients with RA. METHODS: We studied 58 RA (p patients starting anti-TNF therapy and 58 healthy controls matched for age, sex, and body mass index (BMI). Fasting blood samples age, were drawn at baseline, 2 weeks, and 6 months after the start of anti-TNF therapy and serum levels of leptin its and adiponectin were measured. RESULTS: Patients with RA had increased adiponectin (p < .001) and similar leptin concentrations compared with and the controls. Leptin concentrations were significantly higher in patients with high BMI (p < .001) and correlated positively with BMI all at all timepoints (r > .75). In contrast, serum adiponectin tended to be higher in lean RA patients and did adiponectin not correlate with BMI at any timepoint. There were no clear correlations between serum concentrations of adipocytokines and disease activity BMI (Disease Activity Score 28). Short- or longterm TNF blockade alone had no influence on circulating leptin and adiponectin concentrations. Patients a treated with anti-TNF and concomitant corticosteroids on a stable basis showed a significant decrease in adiponectin levels after 6 months adipocytokines of therapy (p < .025). CONCLUSION: In patients with RA, chronic inflammation and its suppression during anti-TNF therapy have limited increased influence on plasma leptin concentrations, while significantly decreasing circulating adiponectin levels. Our findings question the suggested key role of inflammatory significantly markers in regulating adipocytokine patterns in RA.