Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries

Blood flow reduction induces inward remodeling of resistance arteries (RAs). This remodeling occurs in ischemic diseases, diabetes and hypertension. Nonetheless, the effect of flow reduction per se, independent of the effect of pressure or metabolic influences, is not well understood in RA. As angiotensin II is involved in the response to flow in RA, we hypothesized that angiotensin II may also be involved in the remodeling induced by a chronic flow reduction. We analyzed the effect of angiotensin I-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) on inward remodeling induced by blood flow reduction in vivo in rat mesenteric RAs (low flow (LF) arteries). After 1 week, diameter reduction in LF arteries was associated with reduced endothelium-dependent relaxation and lower levels of eNOS expression. Superoxide production and extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation were higher in LF than in normal flow arteries. Nevertheless, the absence of eNOS or superoxide level reduction (tempol or apocynin) did not prevent LF remodeling. Perindopril and candesartan prevented inward remodeling in LF arteries. Contractility to angiotensin II was reduced in LF vessels by perindopril, candesartan and the ERK1/2 blocker PD98059. ERK1/2 activation (ratio phospho-ERK/ERK) was higher in LF arteries, and this activation was prevented by perindopril and candesartan. ERK1/2 inhibition in vivo (U0126) prevented LF-induced diameter reduction. Thus, inward remodeling because of blood flow reduction in mesenteric RA depends on unopposed angiotensin II-induced contraction and ERK1/2 activation, independent of superoxide production. These findings might be of importance in the treatment of vascular disorders

Alteration in flow (shear stress)-induced remodelling in rat resistance arteries with aging: improvement by a treatment with hydralazine

AIMS: The link between aging and vascular diseases remains unclear, especially in resistance arteries. As a decreased vasodilator capacity of the endothelium is usually described in aging, we hypothesized that arteriolar remodelling in response to a chronic increase in blood flow might be altered. In addition, we tested the capacity of a vasodilator treatment with hydralazine to restore remodelling, as we have previously shown that hydralazine has a potent effect on the process. METHODS AND RESULTS: Mesenteric resistance arteries (350 microm diameter) from 3- and 24-month-old rats were exposed to high blood flow (HF) and normal blood flow (NF), for 2 weeks by sequential ligating second-order arteries in vivo. In HF arteries, diameter increased by 21% when intraluminal pressure was 100 mmHg, in association with a rise in superoxide production in young rats. On the other hand, both diameter and superoxide levels failed to increase in old rats. Hydralazine restored HF-induced remodelling in old rats in association with an increased superoxide production and a decreased superoxide dismutase (SOD) expression. The SOD-mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (TEMPOL) prevented the effect of hydralazine on the arterial diameter. In old rats, hydralazine increased the arterial diameter in HF arteries without increasing eNOS expression. Furthermore, hydralazine also restored HF remodelling in eNOS knockout mice. CONCLUSION: Thus, flow remodelling in resistance arteries failed to occur in aging but it could be restored by hydralazine via a reactive oxygen species-dependent mechanism. These findings may have serious pathophysiological consequences in situations requiring flow-dependent remodelling such as ischaemic and metabolic diseases, more frequent in the elderly

Search for varying constants of nature from astronomical observation of molecules

The status of searches for possible variation in the constants of nature from astronomical observation of molecules is reviewed, focusing on the dimensionless constant representing the proton-electron mass ratio $\mu=m_p/m_e$. The optical detection of H$_2$ and CO molecules with large ground-based telescopes (as the ESO-VLT and the Keck telescopes), as well as the detection of H$_2$ with the Cosmic Origins Spectrograph aboard the Hubble Space Telescope is discussed in the context of varying constants, and in connection to different theoretical scenarios. Radio astronomy provides an alternative search strategy bearing the advantage that molecules as NH$_3$ (ammonia) and CH$_3$OH (methanol) can be used, which are much more sensitive to a varying $\mu$ than diatomic molecules. Current constraints are $|\Delta\mu/\mu| < 5 \times 10^{-6}$ for redshift $z=2.0-4.2$, corresponding to look-back times of 10-12.5 Gyrs, and $|\Delta\mu/\mu| < 1.5 \times 10^{-7}$ for $z=0.88$, corresponding to half the age of the Universe (both at 3$\sigma$ statistical significance). Existing bottlenecks and prospects for future improvement with novel instrumentation are discussed.Comment: Contribution to Workshop "High Performance Clocks in Space" at the International Space Science Institute, Bern 201

Arthritis in primary Sjögren&#039;s syndrome: Characteristics, outcome and treatment from French multicenter retrospective study

Objective To describe the characteristics and the outcome of primary Sjögren Syndrome (pSS) associated arthritis and to compare the efficacy of different therapeutic regimen. Methods We conducted a retrospective study using Club Rhumatisme and Inflammation (CRI) and French Internal Medicine Society (SNFMI) networks. All patients with a diagnosis of pSS and at least one episode of clinical and/or echographic synovitis were included. Patients with synovitis (cases) were compared to pSS patients without synovitis (controls). Results 57 patients (93% women) were included with a median age of 54 years [45–63]. Patients with synovitis had more frequently lymph node enlargement (12.3% vs. 1.8%, p = .007) and a higher ESSDAI score (8 [6–12] vs. 2 [1–4], p &lt; .0001). There was no difference concerning CRP levels, rheumatoid factor and cyclic citrullinated peptide (CCP)-antibodies positivity. Among 57 patients with synovitis, 101 various treatment courses have been used during the follow-up of 40 [22.5–77] months. First treatment course consisted in steroids alone (3.5%), steroids in association (79%) with hydroxychloroquine (HCQ) (49%), methotrexate (MTX) (35%), rituximab (RTX) (5.3%) or other immunosuppressive drugs (7%). HCQ, MTX, and RTX were associated with a significant reduction of tender and swollen joint count, and a significant steroids-sparing effect. No difference could be shown for the joint response between these treatment regimens. Conclusion pSS articular manifestations may include synovitis which could mimic rheumatoid arthritis but differ by the absence of structural damage. Even if the use of HCQ, MTX, and RTX seem to be effective for joint involvement, the best regimen remains to be determined

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. Results: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92–0.95, p = 4.13E−13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02–1.06, p = 1.26E−05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95–0.99, p = 8.05E−04). Conclusions: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations