Pioglitazone Decreases Plasma Cholesteryl Ester Transfer Protein Mass, Associated With a Decrease in Hepatic Triglyceride Content, in Patients With Type 2 Diabetes

Thiazolidinediones reduce hepatic steatosis and increase HDL cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes. We included 78 men with type 2 diabetes (aged 56.5 +/- 0.6 years; HbA1c 7.1 +/- 0.1%) who were randomly assigned to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebo, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL cholesterol levels and CETP mass were measured, and hepatic triglyceride content was assessed by proton magnetic resonance spectroscopy. RESULTS Pioglitazone decreased hepatic triglyceride content (5.9 [interquartile range 2.6-17.4] versus 4.1 [1.9-12.3]%, P <0.05), decreased plasma CETP mass (2.33 +/- 0.10 vs. 2.06 +/- 0.10 microg/ml, P <0.05), and increased plasma HDL cholesterol level (1.22 +/- 0.05 vs. 1.34 +/- 0.05 mmol/l, P <0.05). Metformin did not significantly change any of these parameters. A decrease in hepatic triglyceride content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL cholesterol levels. These results in patients with type 2 diabetes fully confirm recent findings in mic

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD

Thyrotrophin and thyroxine support immune homeostasis in humans

The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross-control and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute-phase proteins, monocyte-platelet interactions and cytokine production capacity) in two large independent cohorts of healthy volunteers of Western European descent from the Human Functional Genomics Project (500FG and 300BCG cohorts), we identified a crucial role of the thyroid hormone thyroxin (T4) and thyroid-stimulating hormone (TSH) on the homeostasis of lymphocyte populations. TSH concentrations were strongly associated with multiple populations of both effector and regulatory T cells, whereas B-cell populations were significantly associated with free T4 (fT4). In contrast, fT4 and TSH had little impact on myeloid cell populations and cytokine production capacity. Mendelian randomization further supported the role of fT4 for lymphocyte homeostasis. Subsequently, using a genomics approach, we identified genetic variants that influence both fT4 and TSH concentrations and immune responses, and gene set enrichment pathway analysis showed enrichment of fT4-affected gene expression in B-cell function pathways, including the CD40 pathway, further supporting the importance of fT4 in the regulation of B-cell function. In conclusion, we show that thyroid function controls the homeostasis of the lymphoid cell compartment. These findings improve our understanding of the immune responses and open the door for exploring and understanding the role of thyroid hormones in the lymphocyte function during disease

Limited effects of growth hormone replacement in patients with GH deficiency during long-term cure of acromegaly

The aim of this study was to assess the effects of replacement with recombinant human growth hormone (rhGH) in patients with GH deficiency (GHD) after treatment of acromegaly. Intervention study. Sixteen patients (8 men, age 56 years), treated for acromegaly by surgery and radiotherapy, with an insufficient GH response to insulin-induced hypoglycaemia, were treated with 1 year of rhGH replacement. Study parameters were assessed at baseline and after 1 year of rhGH replacement. Study parameters were cardiac function, body composition, bone mineral density (BMD), fasting lipids, glucose, bone turnover markers, and Quality of Life (QoL). During rhGH replacement IGF-I concentrations increased from −0.4 ± 0.7 to 1.0 ± 1.5 SD (P = 0.001), with a mean daily dose of 0.2 ± 0.1 mg in men and 0.3 ± 0.2 mg in women. Nonetheless, rhGH replacement did not alter cardiac function, lipid and glucose concentrations, body composition or QoL. Bone turnover markers (PINP and β crosslaps) levels increased (P = 0.005 and P = 0.021, respectively), paralleled by a small, but significant decrease in BMD of the hip. The beneficial effects of rhGH replacement in patients with GHD during cure from acromegaly are limited in this study

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Association between skin diseases and severe bacterial infections in children: case-control study

BACKGROUND: Sepsis or bacteraemia, however rare, is a significant cause of high mortality and serious complications in children. In previous studies skin disease or skin infections were reported as risk factor. We hypothesize that children with sepsis or bacteraemia more often presented with skin diseases to the general practitioner (GP) than other children. If our hypothesis is true the GP could reduce the risk of sepsis or bacteraemia by managing skin diseases appropriately. METHODS: We performed a case-control study using data of children aged 0–17 years of the second Dutch national survey of general practice (2001) and the National Medical Registration of all hospital admissions in the Netherlands. Cases were defined as children who were hospitalized for sepsis or bacteraemia. We selected two control groups by matching each case with six controls. The first control group was randomly selected from the GP patient lists irrespective of hospital admission and GP consultation. The second control group was randomly sampled from those children who were hospitalized for other reasons than sepsis or bacteraemia. We calculated odds ratios and 95% confidence intervals (CI). A two-sided p-value less than 0.05 was considered significant in all tests. RESULTS: We found odds ratios for skin related GP consultations of 3.4 (95% CI: [1.1–10.8], p = 0.03) in cases versus GP controls and 1.4 (95% CI: [0.5–3.9], p = 0.44) in cases versus hospital controls. Children younger than three months had an odds ratio (cases/GP controls) of 9.2 (95% CI: [0.81–106.1], p = 0.07) and 4.0 (95% CI: [0.67–23.9], p = 0.12) among cases versus hospital controls. Although cases consulted the GP more often with skin diseases than their controls, the probability of a GP consultation for skin disease was only 5% among cases. CONCLUSION: There is evidence that children who were admitted due to sepsis or bacteraemia consulted the GP more often for skin diseases than other children, but the differences are not clinically relevant indicating that there is little opportunity for GPs to reduce the risk of sepsis and/or bacteraemia considerably by managing skin diseases appropriately