Aldosterone signaling through transient receptor potential melastatin 7 cation channel (TRPM7) and its α-kinase domain

We demonstrated a role for the Mg2 + transporter TRPM7, a bifunctional protein with channel and α-kinase domains, in aldosterone signaling. Molecular mechanisms underlying this are elusive. Here we investigated the function of TRPM7 and its α-kinase domain on Mg2 + and pro-inflammatory signaling by aldosterone. Kidney cells (HEK-293) expressing wild-type human TRPM7 (WThTRPM7) or constructs in which the α-kinase domain was deleted (ΔKinase) or rendered inactive with a point mutation in the ATP binding site of the α-kinase domain (K1648R) were studied. Aldosterone rapidly increased [Mg2 +]i and stimulated NADPH oxidase-derived generation of reactive oxygen species (ROS) in WT hTRPM7 and TRPM7 kinase dead mutant cells. Translocation of annexin-1 and calpain-II and spectrin cleavage (calpain target) were increased by aldosterone in WT hTRPM7 cells but not in α-kinase-deficient cells. Aldosterone stimulated phosphorylation of MAP kinases and increased expression of pro-inflammatory mediators ICAM-1, Cox-2 and PAI-1 in Δkinase and K1648R cells, effects that were inhibited by eplerenone (mineralocorticoid receptor (MR) blocker). 2-APB, a TRPM7 channel inhibitor, abrogated aldosterone-induced Mg2 + responses in WT hTRPM7 and mutant cells. In 2-APB-treated ΔKinase and K1648R cells, aldosterone-stimulated inflammatory responses were unchanged. These data indicate that aldosterone stimulates Mg2 + influx and ROS production in a TRPM7-sensitive, kinase-insensitive manner, whereas activation of annexin-1 requires the TRPM7 kinase domain. Moreover TRPM7 α-kinase modulates inflammatory signaling by aldosterone in a TRPM7 channel/Mg2 +-independent manner. Our findings identify novel mechanisms for non-genomic actions of aldosterone involving differential signaling through MR-activated TRPM7 channel and α-kinase

Applying systems thinking and human-centered design to development of intervention implementation strategies: an example from adolescent health research

Introducing innovative health interventions into clinic settings requires a comprehensive and creative approach to multiple implementation challenges. To optimize implementation of a sexual and reproductive health intervention for young women with depression, we applied systems thinking and human-centered design thinking methods to develop tools and strategies to address issues influencing intervention implementation in diverse clinics. We recruited staff from three clinics that provide sexual and reproductive health and behavioral health care to young women. Across five sessions (four video conference calls, one in-person workshop), we used systems mapping to identify key stakeholders and their relationships, processes, and challenges to care; formed clinic staff-investigator design teams; brainstormed about challenges that would influence intervention implementation and considered potential solutions; prioritized implementation challenges; and designed prototypes of solutions. Participants responded positively to the systems thinking perspective and collaborative design thinking process, which resulted in generalizable considerations about solving implementation challenges for clinic-based interventions

Variability of M giant stars based on Kepler photometry: general characteristics

M giants are among the longest-period pulsating stars which is why their studies were traditionally restricted to analyses of low-precision visual observations, and more recently, accurate ground-based data. Here we present an overview of M giant variability on a wide range of time-scales (hours to years), based on analysis of thirteen quarters of Kepler long-cadence observations (one point per every 29.4 minutes), with a total time-span of over 1000 days. About two-thirds of the sample stars have been selected from the ASAS-North survey of the Kepler field, with the rest supplemented from a randomly chosen M giant control sample. We first describe the correction of the light curves from different quarters, which was found to be essential. We use Fourier analysis to calculate multiple frequencies for all stars in the sample. Over 50 stars show a relatively strong signal with a period equal to the Kepler-year and a characteristic phase dependence across the whole field-of-view. We interpret this as a so far unidentified systematic effect in the Kepler data. We discuss the presence of regular patterns in the distribution of multiple periodicities and amplitudes. In the period-amplitude plane we find that it is possible to distinguish between solar-like oscillations and larger amplitude pulsations which are characteristic for Mira/SR stars. This may indicate the region of the transition between two types of oscillations as we move upward along the giant branch.Comment: 12 pages, 13 figures, accepted for publication in MNRAS. The normalized light curves are available upon reques

What counts as reliable evidence for public health policy: the case of circumcision for preventing HIV infection

<p>Abstract</p> <p>Background</p> <p>There is an ongoing controversy over the relative merits of randomized controlled trials (RCTs) and non-randomized observational studies in assessing efficacy and guiding policy. In this paper we examine male circumcision to prevent HIV infection as a case study that can illuminate the appropriate role of different types of evidence for public health interventions.</p> <p>Discussion</p> <p>Based on an analysis of two Cochrane reviews, one published in 2003 before the results of three RCTs, and one in 2009, we argue that if we rely solely on evidence from RCTs and exclude evidence from well-designed non-randomized studies, we limit our ability to provide sound public health recommendations. Furthermore, the bias in favor of RCT evidence has delayed research on policy relevant issues.</p> <p>Summary</p> <p>This case study of circumcision and HIV prevention demonstrates that if we rely solely on evidence from RCTs and exclude evidence from well-designed non-randomized studies, we limit our ability to provide sound public health recommendations.</p

Research into the efficacy and cost-effectiveness of brief, free of charge and anonymous sex counselling to improve (mental) health in youth: Design of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The capacity to form romantic relationships and sexual health of adolescents in the Netherlands are compromised by several factors, including young age of first intercourse and adolescent depression. Several thresholds like own expenses, trust and embarrassment prevent adolescents to seek help for their sexual problems. To overcome these thresholds, brief sex counselling has been developed. It has been used since 2006 within the Rotterdam-Rijnmond Public Health Service, but there is lack of information about the (cost-) effectiveness. In the current study we will evaluate the (cost-) effectiveness of brief sex counselling for sexual problems in adolescents and young adults between 18 and 25 years of age.</p> <p>Methods</p> <p>In a randomised controlled trial we will compare (1) brief sex counselling with (2) intensive sexological treatment, and (3) delayed treatment (waiting list). Embedded in this RCT will be a trial-based economic evaluation, looking at the cost-effectiveness and cost-utility of brief sex counselling versus the two other interventions. Four hundred fifty adolescents (aged 18-25) with sexual problems will be recruited among the persons who visit the Public Health Service (PHS) and through various websites. After a screening procedure, eligible participants will be randomly allocated to one of the three intervention groups. Primary outcome measure of the clinical evaluation is the severity of sexual problems. Other outcomes include psychological distress, especially depression. The economic evaluation will be performed from a societal perspective. Costs will be assessed continuously by a retrospective questionnaire covering the last 3 month. All outcome assessments (including those for the economic evaluation) will take place via the internet at baseline, and at 3, 6, 9, and 12 months after baseline.</p> <p>Discussion</p> <p>The proposed research project will be the first study to provide preliminary data about the effect and cost-effectiveness of brief sex counselling in youth in comparison with intensive sexological treatment and delayed treatment. It is anticipated that positive results in (cost-) effectiveness of the proposed intervention will contribute to the improvement of sexual health care for adolescents and young adults.</p> <p>Trial registration</p> <p>The study has been registered at the Netherlands Trial Register, part of the Dutch Cochrane Centre (NTR1952)</p

Excavator Wheel Drive Reconstruction.

Import 05/08/2014V této práci je popsán pomocný pohon kolesa rypadla a možnost jeho rozběhu softstartérem a frekvenčním měničem. V první části je probrán asynchronní motor s kotvou nakrátko, jeho popis a princip funkce. Další části se věnují softstartéru a frekvenčnímu měniči, jejich popisu, funkcím a možnostem řízení. Dále je zde provedeno měření jejich vlivu na síť. Poslední část je věnována návrhu rekonstrukce pohonu pro napájení s frekvenčním měničem.This thesis describes the auxiliary drive wheel excavators and the possibility of starting the softstarter and frequency converter. In the first part of the document the asynchronous motor with squirrel cage is discussed, its description and function. Other parts of the document are devoted to the soft starter and frequency converter, their description, function and management options. Furthermore, there is performed measurement of their effect on the network. The last section is devoted to the design of the reconstruction drive with the frequency converter.410 - Katedra elektroenergetikyvýborn

Intimate Partner Violence and Health Care-Seeking Patterns Among Female Users of Urban Adolescent Clinics

To assess the prevalence of intimate partner violence (IPV) and associations with health care-seeking patterns among female patients of adolescent clinics, and to examine screening for IPV and IPV disclosure patterns within these clinics. A self-administered, anonymous, computerized survey was administered to female clients ages 14–20 years (N = 448) seeking care in five urban adolescent clinics, inquiring about IPV history, reasons for seeking care, and IPV screening by and IPV disclosure to providers. Two in five (40%) female urban adolescent clinic patients had experienced IPV, with 32% reporting physical and 21% reporting sexual victimization. Among IPV survivors, 45% reported abuse in their current or most recent relationship. IPV prevalence was equally high among those visiting clinics for reproductive health concerns as among those seeking care for other reasons. IPV victimization was associated with both poor current health status (AOR 1.57, 95% CI 1.03–2.40) and having foregone care in the past year (AOR 2.59, 95% CI 1.20–5.58). Recent IPV victimization was associated only with past 12 month foregone care (AOR 2.02, 95% CI 1.18–3.46). A minority (30%) reported ever being screened for IPV in a clinical setting. IPV victimization is pervasive among female adolescent clinic attendees regardless of visit type, yet IPV screening by providers appears low. Patients reporting poor health status and foregone care are more likely to have experienced IPV. IPV screening and interventions tailored for female patients of adolescent clinics are needed

Cervico-vaginal immunoglobulin g levels increase post-ovulation independently of neutrophils

The prevalence of sexually transmitted infections (STIs) is often higher in females than in males. Although the reproductive cycle profoundly modulates local immunity in the female reproductive tract (FRT) system, significant gaps in our knowledge of the immunobiology of the FRT still exist. An intriguing and frequently observed characteristic of the FRT is the predominant presence of immunoglobulin (Ig) G in cervico-vaginal secretions. We show here that in the mouse, IgG accumulation was enhanced approximately 5-fold post-ovulation, and was accompanied by an influx of neutrophils into the FRT. To determine whether these two events were causally related, we performed short-term neutrophil depletion experiments at individual stages throughout the estrous cycle. Our results demonstrate that neutrophils were not necessary for cycle-dependent tissue remodeling and cycle progression and that cycle-dependent IgG accumulation occurred independent of neutrophils. We thus conclude that neutrophil influx and IgG accumulation are independent events that occur in the FRT during the reproductive cycle