Genome-wide association studies on bipolar disorders (BD) have revealed an additive polygenic contribution of common single-nucleotide polymorphisms (SNPs). However, these SNPs explain only 25% of ...the overall genetic variance and suggest a role of rare variants in BD vulnerability. Here, we combined high-throughput genotyping data and whole-exome sequencing in cohorts of individuals with BD as well as in multiplex families with a high density of affected individuals in order to determine the contribution of both common and rare variants to BD genetic vulnerability. Using polygenic risk scores (PRS), we showed a strong contribution of common polymorphisms previously associated with BD and schizophrenia (SZ) and noticed that those specifically associated with SZ contributed more in familial forms of BD than in non-familial ones. The analysis of rare damaging variants shared by affected individuals in multiplex families with BD revealed a single interaction network enriched in neuronal and developmental biological pathways, as well as in the regulation of gene expression. We identified four genes with a higher mutation rate in individuals with BD than in the general population and showed that mutations in two of them were associated with specific clinical manifestations. In addition, we showed a significant negative correlation between PRS and the number of rare damaging variants specifically in unaffected individuals of multiplex families. Altogether, our results suggest that common and rare genetic variants both contribute to the familial aggregation of BD and this genetic architecture may explain the heterogeneity of clinical manifestations in multiplex families.
Although autologous bone marrow cell (BMC) therapy has emerged as a promising treatment for acute myocardial infarction (AMI), trials reported mixed results. In the BONAMI trial, active smoking ...reduced cardiac function recovery after reperfused AMI. Therefore, we hypothesized that variability in the functionality of BMCs retrieved from patients with cardiovascular risk factors may partly explain these mixed results. We investigated the characteristics of progenitor cells in active smokers and non-smokers with AMI and their potential impact on BMC therapy efficacy.
Bone marrow and blood samples from 54 smoking and 47 non-smoking patients enrolled in the BONAMI cell therapy trial were analyzed.
The white BMC and CD45dimCD34+ cell numbers were higher in active smokers (P = 0.001, P = 0.03, respectively). In marked contrast, either bone marrow or blood endothelial progenitor CD45dimCD34 + KDR + cells (EPCs) were decreased in active smokers (P = 0.005, P = 0.04, respectively). Importantly, a multivariate analysis including cardiovascular risk factors confirmed the association between active smoking and lower EPC number in bone marrow (P = 0.04) and blood (P = 0.04). Furthermore, baseline circulating EPC count predicted infarct size decrease at three months post-AMI in non-smokers (P = 0.01) but not in active smokers. Interestingly, baseline circulating EPCs were no longer predictive of cardiac function improvement in the BMC therapy group.
These data suggest that circulating EPCs play an important role in cardiac repair post-AMI only in non-smokers and that active smoking-associated EPC alterations may participate in the impairment of cardiac function recovery observed in smokers after AMI, an effect that was overridden by BMC therapy.
Objectives
The French left atrial appendage (LAA) closure registry (FLAAC) aimed to assess the safety and efficacy of LAA closure in daily practice.
Background
LAA closure has emerged as an ...alternative for preventing thromboembolic events (TE) in patients with non‐valvular atrial fibrillation (NVAF). Clinical data in this field remains limited and few investigator‐initiated, real‐world registries have been reported.
Methods
This nationwide, prospective study was performed in 36 French centers. The primary endpoint was the TE rate after successful LAA closure.
Results
The FLAAC registry included 816 patients with a mean age of 75.5 ± 0.3 years, mean follow‐up of 16.0 ± 0.3 months, high TE (CHA2DS2‐VASc score: 4.6 ± 0.1) and bleeding risks (HAS‐BLED score: 3.2 ± 0.05) and common contraindications to long‐term anticoagulation (95.7%). Procedure or device‐related serious adverse events occurred in 49 (6.0%) patients. The annual rate of ischemic stroke/systemic embolism was 3.3% (2.4–4.6). This suggests a relative 57% reduction compared to the risk of stroke in historical NVAF populations without antithrombotic therapy. By multivariate analysis, history of TE was the only factor associated with stroke/systemic embolism during follow‐up (HR, 3.3 1.58–6.89, p = 0.001). The annual mortality rate was 10.2% (8.4–12.3). Most of the deaths were due to comorbidities or underlying cardiovascular diseases and unrelated to the device or to TE.
Conclusions
Our study suggests that LAA closure can be an option in patients with NVAF. Long‐term follow‐up mortality was high, mostly due to comorbidities and underlying cardiovascular diseases, highlighting the importance of multidisciplinary management after LAA closure.
Registration
NCT02252861.
There is growing evidence that autoantibodies (AAbs) against proteins expressed in the brain are playing an important role in neurological and psychiatric disorders. Here, we explore the presence and ...the role of peripheral AAbs to the α7-nicotinic acetylcholine receptor (nAChR) in inflammatory subgroups of psychiatric patients with bipolar disorder (BD) or schizophrenia (SCZ) and healthy controls. We have identified a continuum of AAb levels in serum when employing a novel ELISA technique, with a significant elevation in patients compared to controls. Using unsupervised two-step clustering to stratify all the subjects according to their immuno-inflammatory background, we delineate one subgroup consisting solely of psychiatric patients with severe symptoms, high inflammatory profile, and significantly increased levels of anti-nAChR AAbs. In this context, we have used monoclonal mouse anti-human α7-nAChR antibodies (α7-nAChR-mAbs) and shown that TNF-α release was enhanced upon LPS stimulation in macrophages pre-incubated with α7-nAChR-mAbs compared to the use of an isotype control. These findings provide a basis for further study of circulating nicotinic AAbs, and the inflammatory profile observed in patients with major mood and psychotic disorders.
In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. ...SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19.
The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar ...disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in
,
, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined
and
approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed
that the
C allele was sufficient to increase the
transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the
/
ratio was increased in schizophrenic patients carrying the
at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of
on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.
Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of
on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.
...the percentages of CD4+ T cells expressing IL-2+ or TNF-α were not different between the 2 groups. ...no difference was observed regarding the percentage of CD8+ T cells expressing IFN-γ, IL-2, or ...TNF-α between the 2 groups in response to the whole vaccine (data not shown). ...to protect patients with COPD from influenza, efforts should focus specifically on developing vaccines that boost both the humoral and the cell-mediated responses. Parameter Control COPD P value B cells (%) Naive B cells 52.7 (47.2-59.0) 66.9 (65.2-79.0) .018 Resting memory B cells 40.1 (32.4-44.5) 28.2 (15.3-31.0) .036 Activated memory B cells 3.41 (2.87-5.31) 3.62 (1.66-4.23) .454 Exhausted B cells 2.53 (1.47-3.50) 1.95 (1.26-2.93) .704 Marginal zone B cells 8.81 (5.93-12.5) 4.44 (3.63-8.93) .170 Switched B cells 36.4 (29.0-40.2) 24.4 (16.3-29.7) .029 CD4+CXCR5+CCR7loPD1hi T cells 9.00 (7.54-16.1) 10.5 (8.96-13.0) .282 CD4+CXCR5+ICOS+PD1hi T cells 0.81 (0.23-1.38) 0.47 (0.24-0.81) .560 Circulating lymphocytes 1.79 (1.10-3.30) 1.83 (1.20-3.80) .883 CD4+ T cells (%) Naive CD4+ T cells 40.3 (27.4-52.6) 49.7 (37.1-58.2) .198 Central memory CD4+ T cells 48.7 (33.2-58.3) 35.7 (27.4-45.3) .229 Effective memory CD4+ T cells 9.31 (5.87-22.2) 7.79 (4.89-18.2) .363 Exhausted CD4+ T cells 1.93 (1.39-3.01) 2.86 (1.97-3.99) .184 PD1+ CD4+ T cells 31.9 (18.4-38.3) 25.1 (16.5-36.2) .467 CD8+ T cells (%) Naive CD8+ T cells 43.7 (12.3-58.1) 39.9 (20.6-57.0) .705 Central memory CD8+ T cells 26.3 (17.1-49.8) 27.2 (21.7-47) .735 Effective memory CD8+ T cells 7.46 (4.88-10.7) 7.79 (4.8-13.1) .588 Exhausted CD8+ T cells 15.7 (6.7-27.6) 12.9 (3.7-37.8) .704 PD1+ CD8+ T cells 34.1 (28.4-46.0) 29.3 (21.0-37.4) .118 Cytotoxic capacity (%) Gz B+ CD8+ T cells 32.1 (13.4-39.9) 21.2 (6.1-47.2) .560 Pfp+ CD8+ T cells 10.9 (4.1-26.0) 10.93 (2.1-24.6) .533 Table E1 Main features in participants with COPD and in controls Data are mean ± SEM.BMI, Body mass index; CRP, C-reactive protein; DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity. Parameter FEV1 (% predicted) DLCO (% predicted) Emphysema score AU Hemagglutination-inhibiting antibody Delta A/California 07/2009 GMT 0.342 0.489 −0.219 Delta A/Texas/50/2012 GMT 0.112 0.243 −0.300 Delta B/Massachusetts/2/2012 GMT 0.209 0.160 0.155 In vitro IFN-γ production by T cells IFN-γ+ CD4+ T cells (%) (D0) −0.028 0.267 −0.363 IFN-γ (pg/mL) after Vaxigrip stimulation 0.247 0.574 −0.564 1 J.A. Wedzicha, T.A. Seemungal, COPD exacerbations: defining their cause and prevention, Lancet, Vol. 370, 2007, 786-796 2 W.A. Zwaans, P. Mallia, M.E. van Winden, G.G. Rohde, The relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease-a systematic review, J Clin Virol, Vol. 61, 2014, 181-188 3 G. Rohde, A. Wiethege, I. Borg, M. Kauth, T.T. Bauer, A. Gillissen, Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study, Thorax, Vol. 58, 2003, 37-42 4 K.D. Nath, J.G. Burel, V. Shankar, A.L. Pritchard, M. Towers, D. Looke, Clinical factors associated with the humoral immune response to influenza vaccination in chronic obstructive pulmonary disease, Int J Chron Obstruct Pulmon Dis, Vol. 9, 2014, 51-56 5 Z. Shahid, A. Kleppinger, B. Gentleman, A.R. Falsey, J.E. McElhaney, Clinical and immunologic predictors of influenza illness among vaccinated older adults, Vaccine, Vol. 28, 2010, 6145-6151 6 J.E. McElhaney, D. Xie, W.D. Hager, M.B. Barry, Y. Wang, A. Kleppinger, T cell responses are better correlates of vaccine protection in the elderly, J Immunol, Vol. 176, 2006, 6333-6339 7 Y.D. Mahnke, A. Saqr, S. Hazenfeld, R.C. Brady, M. Roederer, R.A. Subbramanian, Vaccine, Vol. 29, 2011, 8606-8614 8 J.J. Goronzy, C.M. Weyand, Understanding immunosenescence to improve responses to vaccines, Nat Immunol, Vol. 14, 2013, 428-436 9 C. Wehr, T. Kivioja, C. Schmitt, B. Ferry, T. Witte, E. Eren, The EUROclass trial: defining subgroups in common variable immunodeficiency, Blood, Vol. 111, 2008, 77-85
Purpose
Few data are available regarding the relation of left ventricular (LV) mechanical dyssynchrony to remodelling after acute myocardial infarction (MI) and stem cell therapy. We evaluated the ...1-year time course of both LV mechanical dyssynchrony and remodelling in patients enrolled in the BONAMI trial, a randomized, multicenter controlled trial assessing cell therapy in patients with reperfused MI.
Methods
Patients with acute MI and ejection fraction (EF) ≤ 45 % were randomized to cell therapy or to control and underwent thallium single-photon emission computed tomography (SPECT), radionuclide angiography, and echocardiography at baseline, 3 months, and 1 year. Eighty-three patients with a comprehensive 1-year follow-up were included. LV dyssynchrony was assessed by the standard deviation (SD) of the LV phase histogram using radionuclide angiography. Remodelling was defined as a 20 % increase in LV end-systolic volume index (LVESVI) at 1 year.
Results
At baseline, LVEF, wall motion score index, and perfusion defect size were significantly impaired in the 43 patients (52 %) with LV remodelling (all
p
< 0.001), without significant increase in LV mechanical dyssynchrony. During follow-up, there was a progressive increase in LV SD (
p
= 0.01). Baseline independent predictors of LV remodelling were perfusion SPECT defect size (
p
= 0.001), LVEF (
p
= 0.01) and a history of hypertension (
p
= 0.043). Bone marrow cell therapy did not affect the time-course of LV remodelling and dyssynchrony.
Conclusions
LV remodelling 1 year after reperfused MI is associated with progressive LV dyssynchrony and is related to baseline infarct size and ejection fraction, without impact of cell therapy on this process.
Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and ...dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA-DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes.
Epidemiology has repeatedly associated certain infections with a risk of further developing psychiatric diseases. Such infections can activate retro-transposable genetic elements (HERV) known to ...trigger immune receptors and impair synaptic plasticity of neuroreceptors. Since the HERV-W ENV protein was recently shown to co-cluster with pro-inflammatory cytokines in a subgroup of patients with schizophrenia or bipolar disorder, we questioned the influence of the COVID-19 pandemic on patients with psychosis spectrum disorders (PSD). Present results revealed that (i) SARS-CoV-2 serology shows high prevalence and titers of antibodies in PSD, (ii) HERV-W ENV is detected in seropositive individuals only and (iii) SARS-CoV-2 and HERV-W ENV positivity co-clustered with high serum levels of pro-inflammatory cytokines in psychotic patients. These results thus suggest that SARS-CoV-2 infection in many patients with psychotic disorders now admitted in the psychiatry department did not cause severe COVID-19. They also confirm the previously reported association of elevated serum pro-inflammatory cytokines and HERV-W ENV in a subgroup of psychotic patients. In the context of the COVID-19 pandemic, this cluster is only found in SARS-CoV-2 seropositive PSD cases, suggesting a dominant influence of this virus on HERV-W ENV and cytokine expression, and/or patients' greater susceptibility to SARS-CoV-2 infection. Further investigation on an interplay between this viral infection and the clinical evolution of such PSD patients is needed. However, this repeatedly defined subgroup of psychotic patients with a pro-inflammatory phenotype and HERV expression calls for a differential therapeutic approach in psychoses, therefore for further precision medicine development.
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