Indicaxanthin from Opuntia ficus indica (L. Mill) Inhibits Oxidized LDL-Mediated Human Endothelial Cell Dysfunction through Inhibition of NF- \u3baB Activation

Oxidized low-density lipoproteins (oxLDL) play a pivotal role in the etiopathogenesis of atherosclerosis through the activation of inflammatory signaling events eventually leading to endothelial dysfunction and senescence. In the present work, we investigated the effects of indicaxanthin, a bioavailable, redox-modulating phytochemical from Opuntia ficus indica fruits, with anti-inflammatory activity, against oxLDL-induced endothelial dysfunction. Human umbilical vein cord cells (HUVEC) were stimulated with human oxLDL, and the effects of indicaxanthin were evaluated in a range between 5 and 20 \u3bcM, consistent with its plasma level after a fruit meal (7 \u3bcM). Pretreatment with indicaxanthin significantly and concentration-dependently inhibited oxLDL-induced cytotoxicity; ICAM-1, VCAM-1, and ELAM-1 increase; and ABC-A1 decrease of both protein and mRNA levels. From a mechanistic perspective, we also provided evidence that the protective effects of indicaxanthin were redox-dependent and related to the pigment efficacy to inhibit NF-\u3baB transcriptional activity. In conclusion, here we demonstrate indicaxanthin as a novel, dietary phytochemical, able to exert significant protective vascular effects in vitro, at nutritionally relevant concentrations

Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Reduced burnout in medical and health science students during the pandemic COVID-19 - a follow-up study of a single institution in Hungary

Abstract Background The coronavirus pandemic has significantly impacted lives worldwide, especially of medical and health science students. In Hungary, education has been relegated to the online space, with a substantial proportion of students having to attend medical secondments. Increased stress, uncertainty, and the presence of medical secondments can have an impact on students’ premature burnout. Methods In 2021, we conducted a follow-up survey among students of the University of Pécs studying medicine and health sciences in two data collection periods (from March to May and September to November). Our online questionnaire consisted of the Maslach Burnout Inventory General Survey for Students and our self-designed questionnaire. We used descriptive and paired two-sample t-tests for data analysis at a 95% confidence interval (p ≤ 0.05). Results We excluded from our survey respondents whose data we could not follow-up; finally, 183 students’ responses were analyzed. The majority of students were female (n = 148; 80.9%). Overall, there was a significant decrease in both exhaustion (EX) and cynicism (CY) scores (p = 0.001; p = 0.004). Female respondents had higher EX scores, but a significant decrease was observed for both genders (p ≤ 0.05). Excluding paramedic students, a significant decrease in EX scores was observed for the specialties we studied (p ≤ 0.05). General medicine students’ CY scores decreased; physiotherapy students’ profesisonal efficacy (PE) scores increased significantly (p ≤ 0.05). Students who were on medical secondments (n = 127; 69. 4%) were found to be more affected by burnout, but in all cases, these scores significantly improved (p ≤ 0.05). Students serving in the National Ambulance Service (n = 76; 41.5%), Hospitals (n = 44; 24.0%), or both (n = 7; 3.8%) had a significant decrease in their burnout score (p ≤ 0.05). Students who served in either a hospital or a hospital and National Ambulance Service had significantly improved CY and PE scores (p ≤ 0.05). Students concerned about their health had elevated EX and CY scores, which also improved (p ≤ 0.05). Conclusions In conclusion, medical secondments positively affected student burnout scores for medicine and health sciences students at our institution. This fact implies that it is necessary to have more internships in real-life settings during the training. Trial registration Our survey has been approved by the Medical Research Council (Case No IV/4573-1/2021/ECU)

From Cairo to Amsterdam: Hebrew Scrolls from the 11th to the 18th Centuries

Raccolta di saggi su rotoli manoscritti ebraici di epoca medievale e modern