Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial.

Background The sodium/glucose cotransporter 2 inhibitor empagliflozin has cardiorenal protective properties through mechanisms beyond glucose control. In this study we assessed whether empagliflozin modifies renal oxygenation as a possible mechanism of renal protection, and determined the metabolic, renal, and hemodynamic effects of empagliflozin in nondiabetic subjects. Methods and Results In this double-blind, randomized, placebo-controlled study, 45 healthy volunteers underwent blood and urine sampling, renal ultrasound, and blood-oxygenation-level-dependent magnetic resonance imaging before and 180 minutes after administration of 10 mg empagliflozin (n=30) or placebo (n=15). These examinations were repeated after 1 month of daily intake. Cortical and medullary renal oxygenation were not affected by the acute or chronic administration of empagliflozin, as determined by 148 renal blood-oxygenation-level-dependent magnetic resonance imaging examinations. Empagliflozin increased glucosuria (24-hour glucosuria at 1 month: +50.1±16.3 g). The acute decrease in proximal sodium reabsorption, as determined by endogenous fractional excretion of lithium (-34.6% versus placebo), was compensated at 1 month by a rise in plasma renin activity (+28.6%) and aldosterone (+55.7%). The 24-hour systolic and diastolic ambulatory blood pressures decreased significantly after 1 month of empagliflozin administration (-5.1 and -2.0 mm Hg, respectively). Serum uric acid levels decreased (-28.4%), hemoglobin increased (+1.7%), and erythropoietin remained the same. Conclusions Empagliflozin has a rapid and significant effect on tubular function, with sustained glucosuria and transient natriuresis in nondiabetic normotensive subjects. These effects favor blood pressure reduction. No acute or sustained changes were found in renal cortical or medullary tissue oxygenation. It remains to be determined whether this is the case in nondiabetic or diabetic patients with congestive heart failure or kidney disease. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03093103

Control of Cyclin C Levels during Development of Dictyostelium

Background: Cdk8 and its partner cyclin C form part of the mediator complex which links the basal transcription machinery to regulatory proteins. The pair are required for correct regulation of a subset of genes and have been implicated in control of development in a number of organisms including the social amoeba Dictyostelium discoideum. When feeding, Dictyostelium amoebae are unicellular but upon starvation they aggregate to form a multicellular structure which develops into a fruiting body containing spores. Cells in which the gene encoding Cdk8 has been deleted fail to enter aggregates due to a failure of early gene expression.Principal Findings: We have monitored the expression levels of cyclin C protein during development and find levels decrease after the multicellular mound is formed. This decrease is triggered by extracellular cAMP that, in turn, is working in part through an increase in intracellular cAMP. The loss of cyclin C is coincident with a reduction in the association of Cdk8 with a high molecular weight complex in the nucleus. Overexpression of cyclin C and Cdk8 lead to an increased rate of early development, consistent with the levels being rate limiting.Conclusions: Overall these results show that both cyclin C and Cdk8 are regulated during development in response to extracellular signals and the levels of these proteins are important in controlling the timing of developmental processes. These findings have important implications for the role of these proteins in controlling development, suggesting that they are targets for developmental signals to regulate gene expression.</p

CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation

Microcephaly, mental retardation and congenital retinal folds along with other systemic features have previously been reported as a separate clinical entity. The sporadic nature of the syndrome and lack of clear inheritance patterns pointed to a genetic heterogeneity. Here, we report a genetic analysis of a female patient with microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation. Karyotyping revealed a de novo pericentric inversion in chromosome 6 with breakpoints in 6p12.1 and 6q21. Fluorescence in situ hybridization analysis narrowed down the region around the breakpoints, and the breakpoint at 6q21 was found to disrupt the CDK19 gene. CDK19 was found to be expressed in a diverse range of tissues including fetal eye and fetal brain. Quantitative PCR of the CDK19 transcript from Epstein–Barr virus-transformed lymphoblastoid cell lines of the patient revealed ~50% reduction in the transcript (p = 0.02), suggesting haploinsufficiency of the gene. cdk8, the closest orthologue of human CDK19 in Drosophila has been shown to play a major role in eye development. Conditional knock-down of Drosophila cdk8 in multiple dendrite (md) neurons resulted in 35% reduced dendritic branching and altered morphology of the dendritic arbour, which appeared to be due in part to a loss of small higher order branches. In addition, Cdk8 mutant md neurons showed diminished dendritic fields revealing an important role of the CDK19 orthologue in the developing nervous system of Drosophila. This is the first time the CDK19 gene, a component of the mediator co-activator complex, has been linked to a human disease

Squalamine: An Appropriate Strategy against the Emergence of Multidrug Resistant Gram-Negative Bacteria?

We reported that squalamine is a membrane-active molecule that targets the membrane integrity as demonstrated by the ATP release and dye entry. In this context, its activity may depend on the membrane lipid composition. This molecule shows a preserved activity against bacterial pathogens presenting a noticeable multi-resistance phenotype against antibiotics such as polymyxin B. In this context and because of its structure, action and its relative insensitivity to efflux resistance mechanisms, we have demonstrated that squalamine appears as an alternate way to combat MDR pathogens and by pass the gap regarding the failure of new active antibacterial molecules

Participation and youth cultures

The 20th century has witnessed the emergence of specific youth subcultures which were in many respects unknown to pre-modern societies. Unfortunately, construction of indicators pertaining the cultural aspects of youth conditions is often vulnerable to many methodological problems, stemming from the impossibility of direct observation and the distortions implicit in self-reporting in survey contexts. These problems are further aggravated in an international framework, in that there are relatively few cross-country studies dedicated specifically to youth or in which youth sub-samples contain a sufficiently high number of cases to justify generalisation of findings. The fact that young people take actions differently with regard to familiy, citizenship or work compared to the generation of their parents and to the expectation of institutional actors may be either ascribed to different demand and constraints by which they are confronted, or it may be interpreted as different cultures of practice, of parenthood, work or citizenship. Culture is one way of understanding the meaning of practice as it evolves both individually and collectively. It embodies the sets of practices developed by groups, communities of societies. These sets of practices are the totality of social actions which are interlinked within a given social context and which share values, principles and norms. Thereby they represent the repertoire from which individuals construct meaning and relate it to specific forms of practice. The present chapter deals with two major trends in the field of youth culture: youth counter culture expressions in Italy, Austria, France, Ireland and Slovakia and young people\u2019s participation through the internet. We will discuss cases of apparently deviant or criminalized behaviour of young people such as urban riots and ask to what extent these need to be viewed and addressed as an expression of young people\u2019s participation

Current profile and management of gonococcal infections: A population-based study in Western France

International audienceObjective: To characterize the current profile of gonococcal infections in France, and to describe their management. Patients and method: A population-based retrospective study of all gonococcal infections documented by PCR in two French departments (Île-et-Vilaine, Morbihan), in 2014–2016. Cases were identified through hospital databases and the Rénago sentinel network. Results: We enrolled 245 patients (96 females, 149 males), with a median age of 25 years [interquartile range, 21–33]. The incidence rate was estimated at 4.54 per 100,000 inhabitants-year. Cases were diagnosed mostly by a general practitioner (n = 122, 49.8%) or a gynecologist (n = 45, 18.4%). The main clinical presentations included urethritis (n = 59), pelvic inflammatory disease (n = 40), cervicitis (n = 12), and anorectitis (n = 11). The main coinfections were Chlamydia trachomatis (n = 40) and HIV (n = 8). Ceftriaxone MIC was ≤ 0.12 mg/L in 146/147 patients with positive culture. Treatment was appropriate in 52/74 (70.2%) patients with available data. Conclusions: In France, general practitioners are at the front line in management of gonococcal infections. © 2020 Elsevier Masson SA