Notes

Bivariate link coefficients inside family-type clustered research.
30 log ng/mg creatinine in patients with functional severe glaucoma (visual field mean deviation ≤ -6 dB) compared with mild glaucoma (mean deviation > -6 dB; P = 0.040) and lower UME by 0.05 log ng/mg creatinine with each 10 μm thinning of the circumpapillary retinal nerve fiber layer thickness as the index of structural severity of glaucoma (P = 0.011). In conclusion, significant association between glaucoma and lower urinary 6-sulfatoxymelatonin was found. In addition, patients with functional and structural severe glaucoma were significantly associated with lower urinary 6-sulfatoxymelatonin levels. Our results indicate the possibility of a circadian disruption in patients with glaucoma. This article is protected by copyright. All rights reserved.AIM To study the clinical characteristics and incidence of microvascular complications among childhood and adolescent onset type 1(T1DM) and type 2 diabetes (T2DM) seen at a tertiary care diabetes centre in India. METHODS From our electronic medical records, we retrieved clinical and biochemical details of 4555 individuals with childhood and adolescent onset diabetes (diagnosed below the age of 20 years) seen between 1992 and 2017. T1DM was diagnosed if there was history of ketoacidosis or fasting C-peptide 1.0pmol/ml, or response to oral hypoglycemic agents for more than two years. We calculated the incidence rates of retinopathy (presence of at least one definite microaneurysm by retinal photography), nephropathy (urinary albumin excretion ≥30μg/mg of creatinine) and neuropathy (vibration perception threshold ≥20V) per 1000 person-years of follow up. RESULTS Among the 4555 individuals with childhood and adolescent-onset diabetes, 71.4% had T1DM, 19.5% T2DM and 9.1% other forms of diabetes. Age at first visit and duration of diabetes were significantly higher in T2DM when compared to T1DM. The age adjusted incidence of retinopathy was 52.9/1000 person years (Confidence Intervals (CI) 42.9-62.8) in T1DM and 49.8/1000 person years (CI 30.8-68.8) in T2DM; nephropathy, 6.2 (CI 3.3-9.0) and 13.8 (CI 5.6-22.0); and neuropathy, 8.8(CI 3.6-14.0) and 24.0 (CI 9.8-38.2) in T1DM and T2DM respectively. CONCLUSION The incidence of microvascular complications is high among childhood and adolescent-onset T1DM and T2DM and this calls for more aggressive control of diabetes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion-Almeida type (MFDGA). MFDGA-associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss-of-function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss-of-function are self-evident, the mechanisms by which missense variants are disease-causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss-of-function. Only four of 19 assessed missense variants cause EFTUD2 loss-of-function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre-messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory-based validation of bioinformatic predictions for EFTUD2 missense variants. © 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.Mutations in histidyl-tRNA synthetase (HARS1), an enzyme that charges transfer RNA with the amino acid histidine in the cytoplasm, have only been associated to date with autosomal recessive Usher syndrome type III and autosomal dominant Charcot-Marie-Tooth disease type 2W. Using massive parallel sequencing, we identified bi-allelic HARS1 variants in a child (c.616G>T, p.Asp206Tyr and c.730delG, p.Val244Cysfs*6) and in two sisters (c.1393A>C, p.Ile465Leu and c.910_912dupTTG, p.Leu305dup), all characterized by a multisystem ataxic syndrome. All mutations are rare, segregate with the disease, and are predicted to have a significant effect on protein function. Functional studies helped to substantiate their disease-related roles. Indeed, yeast complementation assays showing that one out of two mutations in each patient is loss-of-function, and the reduction of messenger RNA and protein levels and enzymatic activity in patient's skin-derived fibroblasts, together support the pathogenicity of the identified HARS1 variants in the patient phenotypes. Thus, our efforts expand the allelic and clinical spectrum of HARS1-related disease. © 2020 Wiley Periodicals, Inc.Human adults are better at recognizing upright bodies than inverted bodies. This inversion effect is also found for objects with which they have expertise, which is called the expert effect. This study aims to investigate its evolutionary and developmental aspects by testing humans' closest relatives, chimpanzees, and preschool children. Chimpanzees show the inversion effect to chimpanzee bodies, but it is not clear how they perceive other species' bodies. We tested 7 chimpanzees in matching-to-sample tasks on touch screens using upright and inverted stimuli, and examined their accuracy and response time. In a previous study, they did not show the inversion effect for bipedal humans in unfamiliar postures, but here in this study they showed it to bipedal humans with familiar postures or crawling postures. This suggests the existence of the expert effect in non-human primates, and that visual or embodied experience is needed to invoke it. It is also supported by the inversion effect they exhibit for horses who share quadrupedal postures, but which they have never seen. Additionally, for conspecifics, the inversion effect was shown regardless of the postures. We tested 33 preschool children using a similar method. They showed the inversion effect to human bodies, but not houses, suggesting the configural processing for bodies, which is found to be stable at the preschool stage. They also showed the inversion effect for chimpanzees and horses, indicating the important role of experience in shaping the ways of object processing. This article is protected by copyright. All rights reserved.Emerging evidence suggests that the microbiota-gut-brain axis affects a variety of complex behaviors, including social, emotional, and depressive-like behaviors. Peyer's patches (PPs), a well-characterized gut-associated lymphoid tissue, are the entry site for luminal antigens and the initiation site for antigen-specific immune responses. However, few studies have explored the composition of lymphoid tissue-resident commensal bacteria (LRCs) in stress-associated disorders. Male C57BL/6 mice exposed to chronic social stress were analyzed for microbiome on the interior of PPs and changes in inflammation. Susceptible mice (SUS) exhibited a composition of bacteria inside PPs that was distinct from that of control (CON) and resilient (RES) mice, including an increase in Candidatus Arthromitus (SFB) and a decrease in Lactobacillus. The CD4+ CD25+ Foxp3+ T cells were significantly reduced in SUS mice. Relative mRNA levels of IL-2 were significantly reduced in SUS mice, and the mRNA levels of Bcl-6, IFN-γ, IL-6, and the IgA protein levels in the ileum were significantly increased. Moreover, in the prefrontal cortex of SUS mice, IL-6 and TNF-α were increased, whereas IL-10 was decreased. The correlational analyses revealed that social interaction ratio was negatively correlated with SFB and positively associated with Lactobacillus and four other candidate protective organisms. These results pointed the possibility that the changes in the LRCs induced by chronic social defeat stress were ultimately associated with the inflammation of the brain and exacerbation of depressive-like behaviors. © 2020 Federation of American Societies for Experimental Biology.Spontaneous bleeding is rare in patients with factor XI deficiency and significant bleeding usually occurs after a trauma or a surgical procedure. It is difficult to maintain hemostatic balance in these patients. In the present case report, a 68-year-old male patient with no chronic disease was scheduled for elective cardiopulmonary bypass surgery. Eight units of fresh-frozen plasma (FFP) were slowly infused and the operation was initiated with the activated partial thromboplastin time (aPTT) of 34.5, which was 108.7 in the preoperative period. Tranexamic acid bolus was administered before the skin incision and continued throughout the operation. Intraoperative aPTT was measured intermittently and a total of six units of FFP were administered. After 76 minutes of cross-clamp time, the patient was separated from cardiopulmonary bypass without any problem. There is no consensus regarding the management of bleeding during cardiac surgery in patients with factor XI deficiency. The common approach includes normalizing the factor levels via FFP infusion or factor concentrates in the preoperative period, proceeding with surgery following the replacement, and close monitoring of perioperative factor levels and aPTT values. © 2020 Wiley Periodicals, Inc.Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus-specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross-species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. MRTX1719 research buy The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity. © 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.
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