Sex-specific influence of angiotensin type 2 receptor stimulation on renal function:a novel therapeutic target for hypertension

The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT 2 R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT 2 R stimulation on renal function in 11- to 12-week–old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT 2 R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT 2 R blockade (PD123319; 1 mg/kg per hour). Direct AT 2 R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1±2.4% versus females: 23.0±3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; P &lt;0.01). In addition, AT 2 R stimulation significantly increased sodium and water excretion to a similar extent in males and females ( P Group =0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT 2 R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT 2 R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT 2 R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women. </jats:p

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

Accumulating evidence suggests that the protective pathways of the renin–angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT 2 R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension, we examined the influence of the AT 2 R agonist, compound 21 (100–300 ng/kg per minute), on renal function in 18- to 19-week-old anesthetized male and female spontaneously hypertensive rats. AT 2 R stimulation significantly increased renal blood flow in female hypertensive rats ( P Treatment &lt;0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P &lt;0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT 2 R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any significant effect of AT 2 R stimulation on renal hemodynamic or excretory function in male hypertensive rats. Finally, gene expression studies confirmed greater renal AT 2 R expression in female than in male hypertensive rats. Taken together, acute AT 2 R stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in glomerular filtration rate in female hypertensive rats. Chronic studies of AT 2 R agonist therapy on renal function and arterial pressure in hypertensive states are now required to establish the suitability of AT 2 R as a therapeutic target for cardiovascular disease, particularly in women. </jats:p

The hepatic response following infection with Listeria monocytogenes

In the present study, we investigated the liver specific response upon infection with L. monocytogenes, a model pathogen for Gram-positive infections over a period of 5days. We used whole genome microarray chips to determine the temporal transcriptome at five observation points. Relative mRNA levels were validated for a representative subset of genes by quantitative Real-Time PCR. In the analysis of these data we followed a strict methodology. The quality of microarray data was ensured by several measures, including quality control tools developed and optimized at our institution. The biological effects of differentially expressed genes were investigated and interpretation of these results was followed by confirmatory experiments. In conclusion, this work allows a unique insight into regulatory networks of several biological processes and interconnections following an infection with L. monocytogenes. Based on our results and by integration of known literature, LXR-&#945; and related transcription factors are proposed to be fundamental for the regulation of hepatic and subsequently systemic response to pathogens.In der vorliegenden Studie untersuchten wir die Leber-spezifische Antwort nach Infektion mit L. monocytogenes, ein Gram-positives Modell-Bakterium über einen Zeitraum von 5 Tagen hinweg. Dabei machten wir Gebrauch von whole genome microarrays, mit dessen Hilfe das transiente Transkriptom zu fünf verschiedenen Zeitpunkten bestimmt wurde. Relative mRNA-Veränderungen wurden anhand einer repräsentativen Auswahl von Genen mittels quantitativer Echtzeit-PCR validiert. Die Analyse gewonnener Daten folgte einer strikten Methodologie. Die Qualität der microarray Daten wurde durch bioinformatische Programme, die an unserem Institut enwickelt und optimiert wurden, gesichert. Basierend auf dem Expressionsmuster differenziell regulierter Gene wurden biologische Rückschlüsse gezogen, die in subsequenten Experimenten untersucht und validiert wurden. Zusammenfassend bietet diese Arbeit einen einzigartigen Einblick in regulatorische Netzwerke verschiedenster biologischer Funktionen und Interaktionen nach Infektion mit L. monocytogenes. Basierend auf diesen Resultaten und eingebettet in bekannte Literatur, stellt sich eine herausragende Rolle für LXR und verwandte Transkriptionsfaktoren bei der hepatischen und subsequent auch systemischen Immunantwort dar

Renal Denervation Update From the International Sympathetic Nervous System Summit:JACC State-of-the-Art Review

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications

Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice

Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases

Sexual health and COVID-19: protocol for a scoping review.

BACKGROUND: Global responses to the COVID-19 pandemic have exposed and exacerbated existing socioeconomic and health inequities that disproportionately affect the sexual health and well-being of many populations, including people of color, ethnic minority groups, women, and sexual and gender minority populations. Although there have been several reviews published on COVID-19 and health disparities across various populations, none has focused on sexual health. We plan to conduct a scoping review that seeks to fill several of the gaps in the current knowledge of sexual health in the COVID-19 era. METHODS: A scoping review focusing on sexual health and COVID-19 will be conducted. We will search (from January 2020 onwards) CINAHL, Africa-Wide Information, Web of Science Core Collection, Embase, Gender Studies Database, Gender Watch, Global Health, WHO Global Literature on Coronavirus Disease Database, WHO Global Index Medicus, PsycINFO, MEDLINE, and Sociological Abstracts. Grey literature will be identified using Disaster Lit, Google Scholar, governmental websites, and clinical trials registries (e.g., ClinicalTrial.gov , World Health Organization, International Clinical Trials Registry Platform, and International Standard Randomized Controlled Trial Number Registry). Study selection will conform to the Joanna Briggs Institute Reviewers' Manual 2015 Methodology for JBI Scoping Reviews. Only English language, original studies will be considered for inclusion. Two reviewers will independently screen all citations, full-text articles, and abstract data. A narrative summary of findings will be conducted. Data analysis will involve quantitative (e.g., frequencies) and qualitative (e.g., content and thematic analysis) methods. DISCUSSION: Original research is urgently needed to mitigate the risks of COVID-19 on sexual health. The planned scoping review will help to address this gap. SYSTEMATIC REVIEW REGISTRATIONS: Systematic Review Registration: Open Science Framework osf/io/PRX8E

The influence of visual flow and perceptual load on locomotion speed

Visual flow is used to perceive and regulate movement speed during locomotion. We assessed the extent to which variation in flow from the ground plane, arising from static visual textures, influences locomotion speed under conditions of concurrent perceptual load. In two experiments, participants walked over a 12-m projected walkway that consisted of stripes that were oriented orthogonal to the walking direction. In the critical conditions, the frequency of the stripes increased or decreased. We observed small, but consistent effects on walking speed, so that participants were walking slower when the frequency increased compared to when the frequency decreased. This basic effect suggests that participants interpreted the change in visual flow in these conditions as at least partly due to a change in their own movement speed, and counteracted such a change by speeding up or slowing down. Critically, these effects were magnified under conditions of low perceptual load and a locus of attention near the ground plane. Our findings suggest that the contribution of vision in the control of ongoing locomotion is relatively fluid and dependent on ongoing perceptual (and perhaps more generally cognitive) task demands

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

*Shared first authorship (Dominguez-V M, Sampson J, Seppälä T)PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.Peer reviewe

Correction:Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

The original version of this Article did not contain details of Dutch Cancer Society (DCS) funding (grant number UL 2017-8223) in the Acknowledgements section. This has now been corrected in both the PDF and HTML versions of the Article

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes