Beneficial effects of raloxifene and atorvastatin on serum lipids and HDL phospholipids levels of postmenopausal women.

Selective oestrogen receptor modulators (raloxifene) and statins (atorvastatin) have been shown to reduce the risk of cardiovascular disease associated with the postmenopausal status. Their beneficial effects may be mediated partly by favourable changes in serum lipids and particular on HDL phospholipid composition. In the present study, individual administration of either raloxifene (Group A) or atorvastatin (Group B) or both (Group C) was compared for a period of 3 months and their effects on total lipids and HDL phospholipids were evaluated. The combined treatment of raloxifene and atorvastatin resulted in profound changes in the majority of serum lipids, including a significant reduction in total cholesterol and triglycerides (P<0.001), a rise in total phospholipids (P<0.01) and a reduction in LDL-C and Apo B levels (P<0.001). Furthermore, Apo A-I was elevated (P<0.001) whereas total HDL phospholipids were significantly increased (P<0.05). Specifically, HDL phosphatidylcholine levels were markedly increased (P<0.001) and HDL lysophosphatidylcholine, sphingomyelin and phosphatidylinositol levels were reduced (P<0.05). A further attempt to evaluate each treatment group was performed and the significance of these results is discussed.     

Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.

Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.     

Mutant huntingtin impairs immune cell migration in Huntington disease

In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.     

Emergence of sequence type 252 Enterobacter cloacae producing GES-5 carbapenemase in a Czech hospital

ST252 Enterobacter cloacae, producing GES-5 carbapenemase, was isolated in a Czech hospital. bla_GES-5 was part of a novel class 1 integron, In1406, which also included a new allele of the aadA15 gene cassette. In1406 was located on a ColE2-like plasmid, pEcl-35771cz (6953 bp).     

COPD Assessment Test: A Simple Tool to Evaluate Disease Severity and Response to Treatment

The COPD assessment test (CAT) is a short questionnaire designed to assess the impairment in health status of COPD patients. We aimed to determine the change of the CAT in COPD patients after 1 year of treatment and test the association between the score and clinical and lung function variables. Methods A cohort of 111 newly diagnosed COPD patients in primary care was evaluated at baseline and one year after the implementation of the recommended treatment according to the Global Initiative for the management of COPD (GOLD). Results Most of the patients (82%) were diagnosed with mild to moderate airflow limitation (mean FEV₁ 72 ± 21.5% predicted) and the CAT score increased in proportion with the GOLD stage of severity. The CAT significantly correlated with the number of exacerbations, visits to general practitioners and days of hospitalization both at the beginning and at 1 year follow-up. A strong negative correlation between the CAT score and FEV₁ predicted was also observed. The CAT was responsive to the application of treatment with a significant improvement in the mean score (95% confidence interval) following 12 months of treatment by –2.4 (–2.9, –1.9) despite the small decline in lung function indices. The number of exacerbations in the preceding year and FEV₁ were independent predictors of the CAT score in the general linear model. Conclusion The CAT questionnaire may serve as a simple, measurable tool complementary to spirometry in the assessment of severity and of response to treatment in unselected COPD patients in primary care.     

Candida albicans colonization on an intragastric balloon

Here we present the case of Candida albicans colonization on an intragastric balloon placed for weight loss. A 52‐year‐old obese woman achieved a BMI reduction of 10.9 kg/m² within 7 months as a result of a BioEnterics Intragastric Balloon and a well‐balanced, low‐calorie diet. During endoscopy for balloon removal, the balloon, which was well impacted in the gastric fundus, was found to be lime green in color with clusters of cone‐shaped cultures on its surface. Microbiology assessment revealed the presence of Candida albicans, although the patient was totally asymptomatic.     

An assessment of the translational relevance of Drosophila in drug discovery

Introduction: Drosophila melanogaster offers a powerful expedient and economical system with facile genetics. Because of the high sequence and functional conservation with human disease-associated genes, it has been cardinal in deciphering disease mechanisms at the genetic and molecular level. Drosophila are amenable to and respond well to pharmaceutical treatment which coupled to their genetic tractability has led to discovery, repositioning, and validation of a number of compounds.

Areas covered: This review summarizes the generation of fly models of human diseases, their advantages and use in elucidation of human disease mechanisms. Representative studies provide examples of the utility of this system in modeling diseases and the discovery, repositioning and testing on pharmaceuticals to ameliorate them.

Expert opinion: Drosophila offers a facile and economical whole animal system with many homologous organs to humans, high functional conservation and established methods of generating and validating human disease models. Nevertheless, it remains relatively underused as a drug discovery tool probably because its relevance to mammalian systems remains under question. However, recent exciting success stories using Drosophila disease models for drug screening, repositioning and validation strongly suggest that fly models should figure prominently in the drug discovery pipeline from bench to bedside.