Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments

The mechanism of risk reduction obtained by blood pressure-lowering pharmacological treatment remains unclear. We explored the amount of risk reduction attributable to the apparent effect of antihypertensive medicines on blood pressure by using the capture approach. Five randomized, placebo or nil controlled trials with a total of 28,997 subjects and 1,935 cardiovascular fatal or non-fatal events from the INDANA database met the eligibility criteria. Computations were performed on the original individual records using multiple Cox's proportional hazard regression models designed for meeting the assumed treatment mode of action and comparing relevant assumptions. For coronary event, the results are inconclusive essentially because the risk reduction is mild. However, for stroke the risk reduction adjusted for baseline risk factors is 34% (P<0.0001). The part explained by the effect of treatment on systolic blood pressure is 49% of this reduction, with 95% confidence interval not including 100%. This result suggests that the apparent effect on blood pressure is not the only cause of stroke risk reduction in hypertensive subjects submitted to an antihypertensive medicine.     

Development and validation of the ORACLE score to predict risk of osteoporosis

OBJECTIVE: To develop and validate a composite index, the Osteoporosis Risk Assessment by Composite Linear Estimate (ORACLE), that includes risk factors and ultrasonometric outcomes to screen for osteoporosis. SUBJECTS AND METHODS: Two cohorts of postmenopausal women aged 45 years and older participated in the development (n = 407) and the validation (n = 202) of ORACLE. Their bone mineral density was determined by dual energy x-ray absorptiometry and quantitative ultrasonometry (QUS), and their historical and clinical risk factors were assessed (January to June 2003). Logistic regression analysis was used to select significant predictors of bone mineral density, whereas receiver operating characteristic (ROC) analysis was used to assess the discriminatory performance of ORACLE. RESULTS: The final logistic regression model retained 4 biometric or historical variables and 1 ultrasonometric outcome. The ROC areas under the curves (AUCs) for ORACLE were 84% for the prediction of osteoporosis and 78% for low bone mass. A sensitivity of 90% corresponded to a specificity of 50% for identification of women at risk of developing osteoporosis. The corresponding positive and negative predictive values were 86% and 54%, respectively, in the development cohort. In the validation cohort, the AUCs for identification of osteoporosis and low bone mass were 81% and 76% for ORACLE, 69% and 64% for QUS T score, 71% and 68% for QUS ultrasonometric bone profile index, and 76% and 75% for Osteoporosis Self-assessment Tool, respectively. ORACLE had the best discriminatory performance in identifying osteoporosis compared with the other approaches (P < .05). CONCLUSION: ORACLE exhibited the highest discriminatory properties compared with ultrasonography alone or other previously validated risk indices. It may be helpful to enhance the predictive value of QUS.     

TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity

The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and β-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.     

Gene constellation of live influenza A vaccines

Summary The genotypic composition of several H₃N₂ vaccinal strains made from PR/8/34 and different wild isolates has been determined. The results suggested that specific gene constellations at the level of the 3 largest RNA fragments, coding the 3 polymerase proteins are responsible for their consistent attenuation.Part of this study was supported by a grant from the Institut pour l'Encouragement de la Recherche Scientifique dans l'Industrie et l'Agriculture (I.R.S.I.A.).     

Connexins protect mouse pancreatic β cells against apoptosis

Type 1 diabetes develops when most insulin-producing β cells of the pancreas are killed by an autoimmune attack. The in vivo conditions modulating the sensitivity and resistance of β cells to this attack remain largely obscure. Here, we show that connexin 36 (Cx36), a trans-membrane protein that forms gap junctions between β cells in the pancreatic islets, protects mouse β cells against both cytotoxic drugs and cytokines that prevail in the islet environment at the onset of type 1 diabetes. We documented that this protection was at least partially dependent on intercellular communication, which Cx36 and other types of connexin channels establish within pancreatic islets. We further found that proinflammatory cytokines decreased expression of Cx36 and that experimental reduction or augmentation of Cx36 levels increased or decreased β cell apoptosis, respectively. Thus, we conclude that Cx36 is central to β cell protection from toxic insults.     

Epidemiology,risk factor,species distribution,antifungal resistance and outcome of Candidemia at a single French hospital: a 7‐year study

Candidemia remains a major cause of disease worldwide and is associated with a high mortality rate. We conducted a retrospective study of candidemia at Nantes Hospital, France, between 2004 and 2010. A total of 191 episodes (n = 188 patients) were reviewed. Incidence, demographics, risk factors, antifungal management, species identification, in vitro susceptibility and 12 weeks survival were analysed. Global incidence of candidemia was 0.37‰ admissions. Higher incidences were observed in haematology (6.65‰) and intensive care units (2‰). Central venous catheter and antibiotic exposure were the most frequent risk factors (77% and 76% respectively). Candida albicans was the predominant species (51.8%) followed by C. parapsilosis (14.5%), C. glabrata (9.8%), C. tropicalis (9.8%) and C. krusei (4.1%). However, species distribution differed significantly between medical units with frequency of C. tropicalis being higher in haematology compared to other medical units. Fluconazole and caspofungin were the main antifungals given as first‐line therapy. Although not significant, 12 weeks mortality rate was 30.9%, being higher for C. tropicalis (44.4%) than for C. parapsilosis (16%). Acquired azole or echinocandin resistance was noted in some isolates, underlining the need for systematic antifungal susceptibility testing in patients with candidemia. These epidemiological findings will be of interest for antifungal stewardship at our hospital.     

Interest of biochemical markers of bone turnover for long-term prediction of new vertebral fracture in postmenopausal osteoporotic women

Objective: To analyse the interest of baseline levels and short-term (3-months) changes in serum osteocalcin (BGP), serum bone-specific alkaline phosphatase (BALP) and urinary C-telopeptide of type I collagen/creatinine ratio (U-CTX) to predict 3-years changes in bone mineral density (BMD) and spinal deformity index (SDI) in postmenopausal osteoporotic women. Methods: Data were derived from a cohort of 603 osteoporotic women corresponding to the placebo arm of a 3-years prospective, double-blind study. Results: Baseline values of BALP, BGP and U-CTX were negatively and significantly correlated with baseline spinal BMD. Significant correlations were also observed between the changes in BMD observed after 36 months at the spine and baseline BALP (r=0.20, P=0.0001), BGP (r=0.09, P=0.05) and U-CTX (r=−0.11, P=0.02). At 3 years, 71 women (15.9%) showed an increase in their SDI, corresponding to the occurrence of at least one new vertebral deformity. Baseline values of the four bone turnover markers (BTM) were not significantly related to the occurrence of new vertebral deformities. However, when considering the changes in the BTM observed after 3-months of follow-up, BGP (P=0.003) and U-CTX (P=0.047) were identified as significant predictors of an increase of SDI. The associated odds ratios (95% confidence interval (CI)) were 10.922 (2.218–53.78) for unit changes of log BGP and 1.369 (1.003–1.867) for unit changes of log U-CTX. The relative risk (RR) (IC 95%) of having a new vertebral fracture over 36 months was 0.31 (0.15–0.65) when being in the lowest quartile of 3-months changes in BGP as compared with the highest. Conclusion: We conclude that two sequential measurements of BGP and U-CTX performed at 3-months intervals could be of interest to identify postmenopausal osteoporotic women with the highest risk to present new vertebral deformities.