103 research outputs found

    The PPARδ Ligand GW501516 Reduces Growth but Not Apoptosis in Mouse Inner Medullary Collecting Duct Cells

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    The collecting duct (CD) expresses considerable amounts of PPARδ. While its role is unknown in the CD, in other renal cells it has been shown to regulate both growth and apoptosis. We thus hypothesized that PPARδ reduces apoptotic responses and stimulates cell growth in the mouse CD, and examined the effect of GW501516, a synthetic PPARδ ligand, on these responses in mouse IMCD-K2 cells. High doses of GW501516 decreased both DNA and protein synthesis in these cells by 80%, but had no overall effect on cell viability. Although anisomycin treatment resulted in an increase of caspase-3 levels of about 2.59-fold of control, GW501516 did not affect anisomycin-induced changes in active caspase-3 levels. These results show that a PPARδ ligand inhibits growth but does not affect anisomycin-apoptosis in a mouse IMCD cell line. This could have therapeutic implications for renal diseases associated with increased CD growth responses

    Troglitazone Induces Extracellular Matrix and Cytoskeleton Remodeling in Mouse Collecting Duct Cells

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    Peroxisome proliferator-activated receptor (PPARγ) has been shown to have a protective role in the nephron through its ability to inhibit a transforming growth factor- (TGF-β) mediated fibrotic response. In contrast, PPARγ was also shown to induce a mesenchymal transformation in epithelial intestinal cells. A fibrotic response in the collecting duct has only recently been established; however, the entire collecting duct has not been fully examined. Inner medullary collecting duct cells (IMCD-K2) and mouse cortical collecting duct cells (M1), representing the cortical and medullary collecting duct, were exposed to 5–10 μM troglitazone for 24 hours. Troglitazone resulted in an elongated morphology, 60% decreases in E-cadherin and β-catenin, a 35% decrease in α-catenin, and a 1.5-fold increase in fibronectin. These effects were not reversed with PPARγ antagonists or affected with PPARγ overexpression. Our results indicate that troglitazone induced a mesenchymal-like transformation in M1 and IMCD-K2 epithelial cells independently of PPARγ

    Troglitazone Induces Extracellular Matrix and Cytoskeleton Remodeling in Mouse Collecting Duct Cells

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    Peroxisome proliferator-activated receptor (PPARγ) has been shown to have a protective role in the nephron through its ability to inhibit a transforming growth factor- (TGF-β) mediated fibrotic response. In contrast, PPARγ was also shown to induce a mesenchymal transformation in epithelial intestinal cells. A fibrotic response in the collecting duct has only recently been established; however, the entire collecting duct has not been fully examined. Inner medullary collecting duct cells (IMCD-K2) and mouse cortical collecting duct cells (M1), representing the cortical and medullary collecting duct, were exposed to 5–10 μM troglitazone for 24 hours. Troglitazone resulted in an elongated morphology, 60% decreases in E-cadherin and β-catenin, a 35% decrease in α-catenin, and a 1.5-fold increase in fibronectin. These effects were not reversed with PPARγ antagonists or affected with PPARγ overexpression. Our results indicate that troglitazone induced a mesenchymal-like transformation in M1 and IMCD-K2 epithelial cells independently of PPARγ

    Endothelial Gata5 transcription factor regulates blood pressure

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    Despite its high prevalence and economic burden, the aetiology of human hypertension remains incompletely understood. Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP). GATA5 is expressed in microvascular endothelial cells and its genetic inactivation in mice (Gata5-null) leads to vascular endothelial dysfunction and hypertension. Endothelial-specific inactivation of Gata5 mimics the hypertensive phenotype of the Gata5-null mice, suggestive of an important role for GATA5 in endothelial homeostasis. Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways. Consistent with a role in human hypertension, we report genetic association of variants at the GATA5 locus with hypertension traits in two large independent cohorts. Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension

    International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg−1 per day starting dose of oral corticosteroids to treat bullous pemphigoid

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    BackgroundEuropean guidelines propose a 0 center dot 5 mg kg(-1) per day dose of oral prednisone as initial treatment for bullous pemphigoid (BP). We assessed the safety and efficacy of this regimen depending on BP extent and general condition of the patients.MethodsIn a prospective international study, we consecutively included all patients diagnosed with BP. Patients received a 0 center dot 5 mg kg(-1) per day dose of prednisone, which was then gradually tapered 15 days after disease control, with the aim of stopping prednisone or maintaining minimal treatment (0 center dot 1 mg kg(-1) per day) within 6 months after the start of treatment. The two coprimary endpoints were control of disease activity at day 21 and 1-year overall survival. Disease severity was assessed according to the Bullous Pemphigoid Disease Area Index (BPDAI) score.ResultsIn total, 198 patients were included between 2015 and 2017. The final analysis comprised 190 patients with a mean age of 80 center dot 9 (SD 9 center dot 1) years. Control of disease activity was achieved at day 21 in 119 patients [62 center dot 6%, 95% confidence interval (CI) 55 center dot 3-69.5]; 18 of 24 patients (75%, 95% CI 53 center dot 3-90 center dot 2), 75 of 110 patients (68 center dot 8%, 95% CI 59 center dot 2-77 center dot 3) and 26 of 56 patients (46.4%, 95% CI 33 center dot 0-60 center dot 3) had mild, moderate and severe BP, respectively (P = 0 center dot 0218). A total of 30 patients died during the study. The overall Kaplan-Meier 1-year survival was 82 center dot 6% (95% CI 76 center dot 3-87 center dot 4) corresponding to 90 center dot 9%, 83 center dot 0% and 80 center dot 0% rates in patients with mild, moderate and severe BP, respectively (P = 0 center dot 5). Thresholds of 49 points for BPDAI score and 70 points for Karnofsky score yielded maximal Youden index values with respect to disease control at day 21 and 1-year survival, respectively.ConclusionsA 0 center dot 5 mg kg(-1) per day dose of prednisone is a valuable therapeutic option in patients with mild or moderate BP whose general condition allows them to be autonomous.</p

    Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

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    <div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div

    Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

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    INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD

    Plasticity of the Intrinsic Period of the Human Circadian Timing System

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    Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light (∼450 lux; ∼1.2 W/m2) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration

    Broad and narrow personality traits as markers of one-time and repeated suicide attempts: A population-based study

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    <p>Abstract</p> <p>Background</p> <p>Studying personality traits with the potential to differentiate between individuals engaging in suicide attempts of different degrees of severity could help us to understand the processes underlying the link of personality and nonfatal suicidal behaviours and to identify at-risk groups. One approach may be to examine whether narrow, i.e., lower-order personality traits may be more useful than their underlying, broad personality trait dimensions.</p> <p>Methods</p> <p>We investigated qualitative and quantitative differences in broad and narrow personality traits between one-time and repeated suicide attempters in a longitudinal, population-based sample of young French Canadian adults using two multivariate regression models.</p> <p>Results</p> <p>One broad (Compulsivity: OR = 2.0; 95% CI 1.2–3.5) and one narrow personality trait (anxiousness: OR = 1.1; 95% CI 1.01–1.1) differentiated between individuals with histories of repeated and one-time suicide attempts. Affective instability [(OR = 1.1; 95% CI 1.04–1.1)] and anxiousness [(OR = .92; 95% CI .88–.95)], on the other hand, differentiated between nonattempters and one-time suicide attempters.</p> <p>Conclusion</p> <p>Emotional and cognitive dysregulation and associated behavioural manifestations may be associated with suicide attempts of different severity. While findings associated with narrow traits may be easier to interpret and link to existing sociobiological theories, larger effect sizes associated with broad traits such as Compulsivity may be better suited to objectives with a more clinical focus.</p
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