A Role of the Bile Salt Receptor FXR in Atherosclerosis

This study reviews current insights into the role of bile salts and bile salt receptors on the progression and regression of atherosclerosis. Bile salts have emerged as important modifiers of lipid and energy metabolism. At the molecular level, bile salts regulate lipid and energy homeostasis mainly via the bile salt receptors FXR and TGR5. Activation of FXR has been shown to improve plasma lipid profiles, whereas Fxr(-/-) mice have increased plasma triglyceride and very-low-density lipoprotein levels. Nevertheless, high-density lipoprotein cholesterol levels are increased in these mice, suggesting that FXR has both anti-and proatherosclerotic properties. Interestingly, there is increasing evidence for a role of FXR in "nonclassical" bile salt target tissues, eg, vasculature and macrophages. In these tissues, FXR has been shown to influence vascular tension and regulate the unloading of cholesterol from foam cells, respectively. Recent publications have provided insight into the antiinflammatory properties of FXR in atherosclerosis. Bile salt signaling via TGR5 might regulate energy homeostasis, which could serve as an attractive target to increase energy expenditure and weight loss. Interventions aiming to increase cholesterol turnover (eg, by bile salt sequestration) significantly improve plasma lipid profiles and diminish atherosclerosis in animal models. Bile salt metabolism and bile salt signaling pathways represent attractive therapeutic targets for the treatment of atherosclerosi

The Online Evaluation of Courses: Impact on Participation Rates and Evaluation Scores

At one of Ontario’s largest universities, the University of Ottawa, course evaluations involve about 6,000 course sections and over 43,000 students every year. This paper-based format requires over 1,000,000 sheets of paper, 20,000 envelopes, and the support of dozens of administrative staff members. To examine the impact of a shift to an online system for the evaluation of courses, the following study sought to compare participation rates and evaluation scores of an online and paper-based course evaluation system. Results from a pilot group of 10,417 students registered in 318 courses suggest an average decrease in participation rate of 12–15% when using an online system. No significant differences in evaluation scores were observed. Instructors and students alike shared positive reviews about the online system; however, they suggested that an in-class period be maintained for the electronic completion of course evaluations.  À l’Université d’Ottawa, une des plus grandes universités de l’Ontario, les évaluations de cours impliquent quelques 6 000 cours et plus de 43 000 étudiants chaque année. Plus d’un million de feuilles de papier, 20 000 enveloppes et le soutien de quelques douzaines d’employés sont nécessaires à la tâche. Pour étudier les répercussions de la transition vers un système d’évaluation en ligne, l’étude présentée visait à comparer les taux de participation et les résultats d’évaluation d’un système en ligne et d’un système manuel (papier). Les résultats d’un groupe pilote composé de 10 417 étudiants, inscrits à 318 cours, suggèrent une diminution des taux de participation moyens de 12 à 15 % avec l’utilisation du système en ligne, mais aucune différence significative dans les résultats d’évaluation n’a été observée. Par ailleurs, professeurs et étudiants ont émis des commentaires positifs sur le système en ligne, mais ont suggéré de maintenir une courte période en classe pour que les étudiants remplissent l’évaluation de leur cours en ligne

Domain Specificity and Knwoledge Utilization In Diagnostic Explanation

This paper examines the performance of cardiologists, psychiatrists, and surgeons indiagnostic explanations of cases within and outside their domain. The protocols were analyzed by techniques of transforming a propositional representation into a semantic network. Some graph theoretic criteria for analyzing semantic networks are used for precision of analysis. The results show that the subjects interpret cases in terms of the familiar component of the problem, using specific domain knowledge. This is related to forward directed reasoning. Unfamiliar or uncertaincomponents of the disorder are either ignored or explained using backward reasoning strategies. Atendency to move from a forward driven strategy to a backward driven strategy and vice versa is alsoseen in sc.ne protocols. This sequence is repeated a number of times to form a chain consisting offorward/backward reasoning sequences. This has implications for how subsequent patientinformation is processed in order to make decisions for treatment and managemen

The Effects of Classroom Interventions on Off-Task and Disruptive Classroom Behavior in Children with Symptoms of Attention-Deficit/Hyperactivity Disorder:A Meta-Analytic Review

Children with attention-deficit/hyperactivity disorder (ADHD) often exhibit problem behavior in class, which teachers often struggle to manage due to a lack of knowledge and skills to use classroom management strategies. The aim of this meta-analytic review was to determine the effectiveness of several types of classroom interventions (antecedent-based, consequence-based, self-regulation, combined) that can be applied by teachers in order to decrease off-task and disruptive classroom behavior in children with symptoms of ADHD. A second aim was to identify potential moderators (classroom setting, type of measure, students' age, gender, intelligence, and medication use). Finally, it was qualitatively explored whether the identified classroom interventions also directly or indirectly affected behavioral and academic outcomes of classmates. Separate meta-analyses were performed on standardized mean differences (SMDs) for 24 within-subjects design (WSD) and 76 single-subject design (SSD) studies. Results showed that classroom interventions reduce off-task and disruptive classroom behavior in children with symptoms of ADHD (WSDs: MSMD = 0.92; SSDs: MSMD = 3.08), with largest effects for consequence-based (WSDs: MSMD = 1.82) and self-regulation interventions (SSDs: MSMD = 3.61). Larger effects were obtained in general education classrooms than in other classroom settings. No reliable conclusions could be formulated about moderating effects of type of measure and students' age, gender, intelligence, and medication use, mainly because of power problems. Finally, classroom interventions appeared to also benefit classmates' behavioral and academic outcomes

Actions of metformin and statins on lipid and glucose metabolism and possible benefit of combination therapy

Patients with diabetes type 2 have an increased risk for cardiovascular disease and commonly use combination therapy consisting of the anti-diabetic drug metformin and a cholesterol-lowering statin. However, both drugs act on glucose and lipid metabolism which could lead to adverse effects when used in combination as compared to monotherapy. In this review, the proposed molecular mechanisms of action of statin and metformin therapy in patients with diabetes and dyslipidemia are critically assessed, and a hypothesis for mechanisms underlying interactions between these drugs in combination therapy is developed

Z-scores of fetal bladder distention for the antenatal differential diagnosis of posterior urethral valves and urethral atresia

Objective: To construct reference values for fetal urinary bladder distension in pregnancy and use Z-scores as a diagnostic tool to differentiate posterior urethral valves (PUV) from urethral atresia (UA). Methods: This was a prospective cross-sectional study in healthy singleton pregnancies aimed at constructing nomograms of fetal urinary bladder diameter and volume between 15 and 35 weeks' gestation. Z-scores of longitudinal bladder diameter (LBD) were calculated and validated in a cohort of fetuses with megacystis with ascertained postnatal or postmortem diagnosis, collected from a retrospective, multicenter study. Correlations between anatomopathological findings, based on medical examination of the infant or postmortem examination, and fetal megacystis were established. The accuracy of the Z-scores was evaluated by receiver-operating-characteristics (ROC)-curve analysis. Results: Nomograms of fetal urinary bladder diameter and volume were produced from three-dimensional ultrasound volumes in 225 pregnant women between 15 and 35 weeks of gestation. A total of 1238 urinary bladder measurements were obtained. Z-scores, derived from the fetal nomograms, were calculated in 106 cases with suspected lower urinary tract obstruction (LUTO), including 76 (72%) cases with PUV, 22 (21%) cases with UA, four (4%) cases with urethral stenosis and four (4%) cases with megacystis-microcolon-intestinal hypoperistalsis syndrome. Fetuses with PUV showed a significantly lower LBD Z-score compared to those with UA (3.95 vs 8.83, P < 0.01). On ROC-curve analysis, we identified 5.2 as the optimal Z-score cut-off to differentiate fetuses with PUV from the rest of the study population (area under the curve, 0.84 (95% CI, 0.748–0.936); P < 0.01; sensitivity, 74%; specificity, 86%). Conclusions: Z-scores of LBD can distinguish reliably fetuses with LUTO caused by PUV from those with other subtypes of LUTO, with an optimal cut-off of 5.2. This information should be useful for prenatal counseling and management of LUTO

Performance of the FMF First-Trimester Preeclampsia-Screening Algorithm in a High-Risk Population in The Netherlands

OBJECTIVE: The aim of the study was to evaluate the performance of the first-trimester Fetal Medicine Foundation (FMF) screening algorithm, including maternal characteristics and medical history, blood pressure, pregnancy-associated plasma protein A and placenta growth factor, crown rump length, and uterine artery pulsatility index, for the prediction of preeclampsia in a high-risk population in the Netherlands. METHODS: This is a prospective cohort including nulliparous women and women with preeclampsia or intrauterine growth restriction in previous pregnancy. We screened patients at 11-14 weeks of gestation to calculate the risk for preeclampsia. The primary outcome was preeclampsia and gestational age at delivery. Performance of the model was evaluated by area under the receiver operating characteristic (ROC) curves (AUCs) and calibration graphs; based on the ROC curves, optimal predicted risk cutoff values for our study population were defined. RESULTS: We analyzed 362 women, of whom 22 (6%) developed preeclampsia. The algorithm showed fair discriminative performance for preeclampsia <34 weeks (AUC 0.81; 95% CI 0.65-0.96) and moderate discriminative performance for both preeclampsia <37 weeks (AUC 0.71; 95% CI 0.51-0.90) and <42 weeks (AUC 0.71; 95% CI 0.61-0.81). Optimal cutoffs based on our study population for preeclampsia <34, <37, and <42 weeks were 1:250, 1:64, and 1:22, respectively. Calibration was poor. CONCLUSIONS: Performance of the FMF preeclampsia algorithm was satisfactory to predict early and preterm preeclampsia and less satisfactory for term preeclampsia in a high-risk population. However, by addressing some of the limitations of the present study, the performance can potentially improve. This is essential before implementation is considered

Thin endometrial lining:is it more prevalent in patients utilizing preimplantation genetic testing for monogenic disease (PGT-M) and related to prior hormonal contraceptive use?

STUDY QUESTION: Is a thin endometrial lining before ovulation triggering more prevalent in patients utilizing preimplantation genetic testing for monogenic disease (PGT-M) compared to the regular IVF/ICSI population and is this associated with prior hormonal contraceptive use? SUMMARY ANSWER: Thin (1 year prior to treatment). Endometrial thickness was routinely measured on the day of hCG triggering or 1 day prior. The prevalence of an endometrial lining or 8 mm (20.0% vs 1.7%, mean difference 18.3%, 95% CI: 2.3, 34.3%). A trend towards lower birth weight and gestation- and gender-adjusted birth weight (z-score) was also found in this group. No statistically significant differences were detected in pregnancy rate, live birth rate, or incidence of preterm delivery or SGA. Within the control group, no statistically significant differences were found in outcomes between patients with an endometrial lining 8 mm. LIMITATIONS, REASONS FOR CAUTION: The study is retrospective. Various types of hormonal contraceptives were reported which possibly exert different effects on the endometrial lining. In relation to pregnancy outcome measures, numbers were very limited; therefore, no firm conclusions should be drawn. WIDER IMPLICATIONS OF THE FINDINGS: This study provides further insight into the role of prior hormonal contraceptive use as a possible contributor to the occurrence of thin endometrial lining during ART treatment. Future studies should provide more information on its clinical relevance, to determine whether PGT-M patients can be reassured, or should be counselled to stop hormonal contraceptive use and change to an alternative contraceptive method prior to PGT treatment. STUDY FUNDING/COMPETING INTERESTS: No specific funding was used and no conflicts of interests are declared. TRIAL REGISTRATION NUMBER: N/A

Phase I study of high-dose epirubicin and vinorelbine in previously untreated non-small-cell lung cancer stage IIIB-IV.

The aim of the study was to determine the maximum tolerated dose (MTD) for the combination of high-dose epirubicin and vinorelbine in chemotherapy-naive patients with inoperable non-small-cell lung cancer (NSCLC). Twenty-one patients with stage IIIB and IV NSCLC were treated in a single-centre study with escalating doses of epirubicin and vinorelbine given on an outpatient basis. The first dose level comprised epirubicin 100 mg m-2 on day 1 and vinorelbine 20 mg m-2 (days 1 and 8) given intravenously every 3 weeks. Escalating doses for epirubicin and vinorelbine were respectively 120 (day 1) and 20 (days 1 and 8), 120 (day 1) and 25 (days 1 and 8) and 135 (day 1) and 25 (days 1 and 8) mg m-2. Inclusion criteria were age < or = 75 years, ECOG performance score < or = 2 and normal renal, hepatic and bone marrow functions. Dose-limiting toxicities were thrombocytopenia grade II and neutropenia grade III on day 8, febrile neutropenia, and neutropenia lasting > 7 days. No dose-limiting toxicity (DLT) was observed at the first dose level; at the 135/25 mg m-2 dose level three out of six patients had a DLT which was considered as unacceptable. The only non-haematological toxicity reaching grade III was nausea/vomiting. One patient showed cardiac toxicity. No neurotoxicity and no treatment-related deaths were seen. The maximum tolerated dose of epirubicin and vinorelbine is 135 mg m-2 (day 1) and 25 mg m-2 (days 1 and 8) respectively, causing mainly haematological toxicity. The recommended dose of epirubicin and vinorelbine for phase II studies is found to be 120 mg m-2 and 20 mg m-2 respectively