Autonomic nervous system responses to strength training in top-level weight lifters

In athletes, spectral analysis of HR variability (HRV) has been shown capable to detect the adaptational changes in sympatho-vagal control attending physical training. So far, studies investigated autonomic nervous system (ANS) changes occurring with endurance training, whereas adaptations to markedly different exercise modes, for example, strength training, have never been investigated. We assessed the changes in cardiac ANS parameters during long-term training in weight lifters of the Italian team preparing for the European Championship, where athletes competed for obtaining the pass for Olympic Games. We investigated nine athletes. Subject trained 3 sessions/day, 6 days a week. The intensity of strength exercises varied from 70% to 95% 1 RM. Training load (TL) was calculated as: volume (min)  7 intensity (%1RM).All ANS parameters were significantly and highly correlated on an individual basis to the dose of exercise with a second-order regression model (r2 ranged from 0.96 to 0.99; P < 0.001). The low-frequency (LF) component of HRV and LF/HF ratio showed an initial increase with the progression of TL and then a decrease, resembling a bell-shaped curve with a minimum at the highest TL. The high-frequency (HF) component of HRV and R-R interval showed a reciprocal pattern, with an initial decrease with progression of TL followed by an increase, resembling an U-shaped curve with a maximum at the highest TL. These adaptations were at the opposite to those previously reported in endurance athletes. These results suggest that in Olympic weight lifters, ANS adaptations to training are dose-related on individual basis and that ANS adaptations are mainly sport-specific

Autosomal-dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations

Robotic-assisted, laparoscopic, and open radical cystectomy: surgical data of 1400 patients from The Italian Radical Cystectomy Registry on intraoperative outcomes

Introduction: The Italian Radical Cystectomy Registry (Registro Italiano Cistectomie - RIC) aimed to analyse outcomes of a multicenter series of patients treated with radical cystectomy (RC) for bladder cancer. Material and methods: An observational, prospective, multicenter, cohort study was performed to collect data from RC and urinary diversion via open (ORC), laparoscopic (LRC), or robotic-assisted (RARC) techniques performed in 28 Italian Urological Departments. The enrolment was planned from January 2017 to June 2020 (goal: 1000 patients), with a total of 1425 patients included. Chi-square and t-tests were used for categorical and continuous variables. All tests were 2-sided, with a significance level set at p <0.05. Results: Overall median operative-time was longer in RARCs (390 minutes, IQR 335-465) than ORCs (250, 217-309) and LRCs (292, 228-350) (p <0.001). Lymph node dissection (LND) was performed more frequently in RARCs (97.1%) and LRCs (93.5%) than ORCs (85.6%) (p <0.001), with extended-LND performed 2-fold more frequently in RARCs (61.6%) (p <0.001). The neobladder rate was significantly higher (more than one-half) in RARCs. The median estimated blood loss (EBL) rate was lower in RARCs (250 ml, 165-400) than LRCs (330, 200-600) and ORCs (400, 250-600) (p <0.001), with intraoperative blood transfusion rates of 11.4%, 21.7% and 35.6%, respectively (p <0.001). The conversion to open rate was slightly higher in RARCs (6.8%) than LRCs (4.3%). Intraoperative complications occurred in 1.3% of cases without statistically significant differences among the approaches. Conclusions: Data from the RIC confirmed the need to collect as much data as possible in a multicenter manner. RARCs proves to be feasible with perioperative complication rates that do not differ from the other approaches

Dysregulation of the Expression of Asparagine-Linked Glycosylation 13 Short Isoform 2 Affects Nephrin Function by Altering Its N-Linked Glycosylation

BACKGROUND N-linked glycosylation, which is a post-translational modification process, plays an important role in protein folding, intracellular trafficking and membrane targeting, as well as in regulating the protein function. Recently, we identified a missense variant (p.T141L) in the short isoform 2 of the X-linked gene asparagine-linked glycosylation 13 (ALG13-is2), which segregated with focal segmental glomerulosclerosis and PCCD in a large Australian pedigree; however, any evidence of its pathogenicity was demonstrated. ALG13 gene encodes, through alternative splicing, 2 glycosyltransferase isoforms, which catalyse the second sugar addition of the highly conserved oligosaccharide precursor in the endoplasmic reticulum (ER). Mutations in the long isoform 1 were associated with epilepsy. METHODS AND RESULTS Here, we show a different expression of the 2 isoforms depending on the tissue. Specifically, the long isoform is highly expressed in lungs, ovaries, testes, cerebellum, cortex, retina, pituitary gland, and olfactory bulbs, while the short isoform is highly expressed in mouse podocytes and in human podocyte cell lines, at both mRNA and protein levels. The silencing of ALG13-is2 by specific siRNAs induces an altered N-linked glycosylation pattern of nephrin, as demonstrated by the presence of an additional immunostaining band of about 130 kD. In knock-down cells, immunofluorescence analysis shows perturbed organization of the cytoskeleton and altered localization of nephrin on the cellular membrane. We also demonstrated that the altered pattern of N-linked glycosylation induces an over-expression of binding immunoglobulin protein and calreticulin, suggesting ER stress. CONCLUSIONS These results provide preliminary evidence that ALG13-is2 could be an important modifier of renal filtration defects

Common variants in the regulative regions of GRIA1 and GRIA3 receptor genes are associated with migraine susceptibility

<p>Abstract</p> <p>Background</p> <p>Glutamate is the principal excitatory neurotransmitter in the central nervous system which acts by the activation of either ionotropic (AMPA, NMDA and kainate receptors) or G-protein coupled metabotropic receptors. Glutamate is widely accepted to play a major role in the path physiology of migraine as implicated by data from animal and human studies. Genes involved in synthesis, metabolism and regulation of both glutamate and its receptors could be, therefore, considered as potential candidates for causing/predisposing to migraine when mutated.</p> <p>Methods</p> <p>The association of polymorphic variants of <it>GRIA1</it>-<it>GRIA4 </it>genes which encode for the four subunits (GluR1-GluR4) of the alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor for glutamate was tested in migraineurs with and without aura (MA and MO) and healthy controls.</p> <p>Results</p> <p>Two variants in the regulative regions of <it>GRIA1 </it>(rs2195450) and <it>GRIA3 </it>(rs3761555) genes resulted strongly associated with MA (P = 0.00002 and P = 0.0001, respectively), but not associated with MO, suggesting their role in cortical spreading depression. Whereas the rs548294 variant in <it>GRIA1 </it>gene showed association primarily with MO phenotype, supporting the hypothesis that MA and MO phenotypes could be genetically related. These variants modify binding sites for transcription factors altering the expression of <it>GRIA1 </it>and <it>GRIA3 </it>genes in different conditions.</p> <p>Conclusions</p> <p>This study represents the first genetic evidence of a link between glutamate receptors and migraine.</p

High prevalence of chitotriosidase deficiency in Peruvian Amerindians exposed to chitin-bearing food and enteroparasites

The human genome encodes a gene for an enzymatically active chitinase (CHIT1) located in a single copy on Chromosome 1, which is highly expressed by activated macrophages and in other cells of the innate immune response. Several dysfunctional mutations are known in CHIT1, including a 24-bp duplication in Exon 10 causing catalytic deficiency. This duplication is a common variant conserved in many human populations, except in West and South Africans. Thus it has been proposed that human migration out of Africa and the consequent reduction of exposure to chitin from environmental factors may have enabled the conservation of dysfunctional mutations in human chitinases. Our data obtained from 85 indigenous Amerindians from Peru, representative of populations characterized by high prevalence of chitin-bearing enteroparasites and intense entomophagy, reveal a very high frequency of the 24-bp duplication (47.06%), and of other single nucleotide polymorphisms which are known to partially affect enzymatic activity (G102S: 42.7% and A442G/V: 25.5%). Our finding is in line with a founder effect, but appears to confute our previous hypothesis of a protective role against parasite infection and sustains the discussion on the redundancy of chitinolytic function

Results From the Global Rheumatology Alliance Registry

Funding Information: We acknowledge financial support from the ACR and EULAR. The ACR and EULAR were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: © 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.Objective: Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID-19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. Methods: Data were derived from the COVID-19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID-19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. Results: The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67-0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%-83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. Conclusion: We were able to predict ARDS with good sensitivity using information readily available at COVID-19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID-19 disease progression.publishersversionepub_ahead_of_prin

High Differentiation among Eight Villages in a Secluded Area of Sardinia Revealed by Genome-Wide High Density SNPs Analysis

To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not “a priori” be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates

Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment

Environmental effects of ozone depletion, UV radiation and interactions with climate change : UNEP Environmental Effects Assessment Panel, update 2017

Peer reviewe