Glucocorticoid receptor signaling is essential for mesoderm formation and muscle development in zebrafish

Glucocorticoid receptor (GR) signaling is thought to play a key role in embryogenesis, but its specific developmental effects remain unclear. Cortisol is the primary ligand for GR activation in teleosts, and in zebrafish (Danio rerio), the prehatch embryo content of this steroid is of maternal origin. Using early zebrafish developmental stages, we tested the hypothesis that GR signaling is critical for embryo growth and hatching. In zebrafish, maternal GR mRNA is degraded quickly, followed by zygotic synthesis of the receptor. GR protein is widely expressed throughout early development, and we were able to knockdown this protein using morpholino oligonucleotides. This led to a more than 70% reduction in mRNA abundance of matrix metalloproteinase-13 (mmp13), a glucocorticoid-responsive gene. The GR morphants displayed delayed somitogenesis, defects in somite and tail morphogenesis, reduced embryo size, and rarely survived after hatch. This correlated with altered expression of myogenic markers, including myogenin, myostatin, and muscle-specific myosin heavy chain and troponin genes. A key finding was a 70-90% reduction in the mRNA abundance of bone morphogenetic proteins (BMP), including bmp2a, bmp2b, and bmp4 in GR morphants. Bioinformatics analysis confirmed multiple putative glucocorticoid response elements upstream of these BMP genes. GR morphants displayed reduced expression of BMP-modulated genes, including eve1 and pax3. Zebrafish GR mRNA injection rescued the GR morphant phenotype and reversed the disrupted expression of BMP and myogenic genes. Our results for the first time indicate that GR signaling is essential for zebrafish muscle development, and we hypothesize a role for BMP morphogens in this process.     

A double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate XR in very heavy-drinking alcohol-dependent patients

Background: Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol‐dependent population of very heavy drinkers. Methods: In this double‐blind, placebo‐controlled trial, 224 alcohol‐dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. Results: No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy‐drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). Conclusions: This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy‐drinking alcohol‐dependent patients.     

Shear Bond Strength of Self-etching Adhesive Systems with Different pH Values to Bleached and/or CPP-ACP-treated Enamel

Purpose: To compare shear bond strengths of three different self-etching adhesive systems of different pH values to enamel bleached with carbamide peroxide, treated with casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), or treated with CPP-ACP subsequent to bleaching with carbamide peroxide. Materials and Methods: Thirty-six human third molars were cut into 4 sections and randomly assigned to 4 groups (n = 36): group I: no treatment; group II: bleaching; group III: CPP-ACP; group IV: bleaching and CPP-ACP. After surface treatments, the samples of each group were further divided into three subgroups (n = 12) based on the adhesive used. The adhesives Clearfil SE Bond (CSE), AdhesE (ADE), and Adper SE Plus (ADP) were applied, and resin composite cylinders with a diameter of 2 mm and a height of 4 mm were bonded to the enamel. Then the specimens were subjected to shear bond strength testing. Two-way ANOVA and a post-hoc Tukey's test were used for statistical analysis (α = 0.05). Results: There were significant differences between the adhesive systems (p < 0.001) and surface treatments (p < 0.001), but no significant interactions were observed between these variables (p = 0.78). The CSE adhesive system showed the highest bond strength, and the bleaching procedure reduced bond strengths (p = 0.001). Furthermore, there were no significant differences in shear bond strength values between the control and CPP groups. However, the differences between other groups were statistically significant (p < 0.05). Conclusion: Bleaching reduced shear bond strength to enamel, but CPP-ACP application did not affect the bond strength to intact and previously bleached enamel. The bond strength of adhesives with different pH values to enamel was material dependant.     

Histopathological changes of gastric mucosa following oral administration of fumonisin B1 in mice

Fumonisin B1 is a common secondary metabolite produced by Fusarium moniliforme that occurs in corn and corn-based foods. This mycotoxin is toxic to many species of laboratory and domestic animals and is known to induce a variety of diseases such as hepatic cancer and renal and hepatic dysfunction. The structure of fumonisin B1 (FB1) resembles sphingolipids so it can inhibit synthesis of ceramide, an enzyme in the sphingolipid biosynthetic pathway. This inhibition leads to the disruption of sphingolipid metabolism and increased levels of sphinganine and sphingosine (sphingoid bases) in the serum of treated animals. It is believed that the toxicity effect of fumonisin B1 is the result of these sphingoid bases. In the present research, mice were treated with FB1 to determine its pathological effects on gastric gland and gastric mucosa in the treated mice. For this purpose, the mice were randomly assigned into two groups, namely, control (n?=?14) and treatment (n?=?15). The treatment group was fed with prepared food containing FB1 (150 mg/kg) for a period of 4 months. One day after the last treatment, all animals in both groups were euthanized and their stomach were sampled and prepared for microscopic analysis. Histopathological analysis revealed a significant decrease in parietal cell number and a significant increase in the number of inflammatory cells in gastric mucosa. Also, atrophy of gastric glands was observed. The study confirmed that FB1 poisoning can have toxicopathological effects such as gastric gland atrophy and gastritis on mice gastric tissue.     

Proposing an ensemble learning model based on neural network and fuzzy system for keratoconus diagnosis based on Pentacam measurements

International Ophthalmology - The present study was done to evaluate efficiency of an ensemble learning structure for automatic keratoconus diagnosis and to categorize eyes into four different...     

Kidney Disease and Increased Mortality Risk in Type 2 Diabetes

Type 2 diabetes associates with increased risk of mortality, but how kidney disease contributes to this mortality risk among individuals with type 2 diabetes is not completely understood. Here, we examined 10-year cumulative mortality by diabetes and kidney disease status for 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index. Kidney disease, defined as urinary albumin/creatinine ratio ≥30 mg/g and/or estimated GFR ≤60 ml/min per 1.73 m², was present in 9.4% and 42.3% of individuals without and with type 2 diabetes, respectively. Among people without diabetes or kidney disease (reference group), 10-year cumulative all-cause mortality was 7.7% (95% confidence interval [95% CI], 7.0%–8.3%), standardized to population age, sex, and race. Among individuals with diabetes but without kidney disease, standardized mortality was 11.5% (95% CI, 7.9%–15.2%), representing an absolute risk difference with the reference group of 3.9% (95% CI, 0.1%–7.7%), adjusted for demographics, and 3.4% (95% CI, −0.3% to 7.0%) when further adjusted for smoking, BP, and cholesterol. Among individuals with both diabetes and kidney disease, standardized mortality was 31.1% (95% CI, 24.7%–37.5%), representing an absolute risk difference with the reference group of 23.4% (95% CI, 17.0%–29.9%), adjusted for demographics, and 23.4% (95% CI, 17.2%–29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes.In 2012, there were an estimated 346 million individuals with diabetes worldwide.¹ This number is expected to rise to >430 million by 2030.² Diabetes is associated with substantially increased risk of mortality, particularly due to cardiovascular disease.³Kidney disease, defined by increased urine albumin excretion and/or impaired GFR, is also strongly associated with increased risk of all-cause and cardiovascular mortality, both among persons with diabetes^4,5 and in the general population.^6–10 The critical effect of kidney disease on mortality in type 1 diabetes was emphasized in two recent reports.^11,12 Each study demonstrated that excess mortality was confined to the subgroup with kidney disease.The degree to which kidney disease captures risk of adverse health outcomes in type 2 diabetes has not been determined. The findings from type 1 diabetes may not extrapolate to type 2 diabetes because the latter is frequently associated with other comorbidities that affect mortality. This question has crucial public health implications because type 2 diabetes predominates among the 26 million US adults with diabetes^13,14 and identifying predictors of excess mortality in type 2 diabetes is essential in order to optimally target risk-reduction strategies. The primary objective of this study was to quantify and compare the excess risk of all-cause and cause-specific mortality among individuals with type 2 diabetes in presence or absence of kidney disease.