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This article discusses a study on X-linked chondrodysplasia punctata 1 (CDPX1), a rare congenital disorder that primarily affects males. The study examined seven male fetuses from six unrelated French families and found that all of them experienced fetal or neonatal demise between 18 and 29 weeks. Four of the fetuses displayed anomalies in the second trimester, including suspected or confirmed intracranial hemorrhage. The study identified genetic alterations in the ARSL gene as the cause of CDPX1 in these cases. This research provides new insights into the phenotype of CDPX1 and highlights the vulnerability of these fetuses to intracranial bleeding during the second trimester. [Extracted from the article]

Objective: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm.Methods: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings).Results: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects.Conclusion: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Background: Pain drawings (PDs) are an important component of the assessment of a patient with pain. The aim of this work is to present the test–retest reliability of a novel method of quantifying the extent and location of pain. Additionally, the association between PD variables and clinical features in patients with chronic neck pain (CNP) and chronic low back pain (CLBP) was explored. Methods: Fifty‐one patients with CLBP and 56 patients with CNP participated. Each patient shaded two consecutive PDs using a digital tablet. Software was developed to quantify the pain extent, to analyse the pain overlap between PDs and to produce pain frequency maps. Correlations were obtained between pain extent and clinical features including the level of pain intensity, disability, and psychological distress and cognitive function. Results: The intraclass correlation coefficients for pain extent in CLBP and CNP were very high: 0.97 (95% CI: 0.95–0.98) and 0.92 (95% CI: 0.87–0.98), respectively. The Bland Altman showed a mean difference close to zero: 5.4% pixels in CNP group and 3% pixels in the CLBP group. Significant correlations were observed between pain extent and pain intensity in CLBP and CNP and pain extent and disability in CNP. There was no relation between pain extent and the level of distress or cognitive function. Conclusions: A novel method for the acquisition of PD was presented. Test–retest reliability of reporting pain extent and pain location was supported in people with CNP and CLBP. Future research is needed to establish psychometric properties of PD. [ABSTRACT FROM AUTHOR]

Objective Whether or not a high risk of falls increases the risk of bleeding in patients receiving anticoagulants remains a matter of debate. Methods We conducted a prospective cohort study involving 991 patients ≥65 years of age who received anticoagulants for acute venous thromboembolism ( VTE) at nine Swiss hospitals between September 2009 and September 2012. The study outcomes were as follows: the time to a first major episode of bleeding; and clinically relevant nonmajor bleeding. We determined the associations between the risk of falls and the time to a first episode of bleeding using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time-varying covariate. Results Four hundred fifty-eight of 991 patients (46%) were at high risk of falls. The mean duration of follow-up was 16.7 months. Patients at high risk of falls had a higher incidence of major bleeding (9.6 vs. 6.6 events/100 patient-years; P = 0.05) and a significantly higher incidence of clinically relevant nonmajor bleeding (16.7 vs. 8.3 events/100 patient-years; P < 0.001) than patients at low risk of falls. After adjustment, a high risk of falls was associated with clinically relevant nonmajor bleeding [subhazard ratio ( SHR) = 1.74, 95% confidence interval ( CI) = 1.23-2.46], but not with major bleeding ( SHR = 1.24, 95% CI = 0.83-1.86). Conclusion In elderly patients who receive anticoagulants because of VTE, a high risk of falls is significantly associated with clinically relevant nonmajor bleeding, but not with major bleeding. Whether or not a high risk of falls is a reason against providing anticoagulation beyond 3 months should be based on patient preferences and the risk of VTE recurrence. [ABSTRACT FROM AUTHOR]

Screening for trisomy 21 relies primarily on first-trimester combined screening (FTCS), including maternal age and measurements of nuchal translucency and maternal serum markers ( -human chorionic gonadotropin and pregnancy-associated plasma protein-A), yielding a 90% detection rate with a 5% false-positive rate1. Among the 6254 cases with known testing outcome, 3201 (51%), 2496 (40%) and 557 (9%) had an invasive procedure, cell-free DNA (cfDNA) testing and no further test, respectively. Karyotyping or array-CGH results were grouped as normal, abnormal but detectable by cfDNA testing or abnormal and not detectable by cfDNA testing. [Extracted from the article]

Protein characterization plays a role in two key aspects of structural proteomics. The first is the quality assessment of the produced protein preparations. Obtaining well diffracting crystals is one of the major bottlenecks in the structure-determination pipeline. Often, this is caused by the poor quality of the protein preparation used for crystallization trials. Hence, it is essential to perform an extensive quality assessment of the protein preparations prior to crystallization and to use the results in the evaluation of the process. Here, a protein-production and crystallization strategy is proposed with threshold values for protein purity (95%) and monodispersity (85%) below which a further optimization of the protein-production process is strongly recommended. The second aspect is the determination of protein characteristics such as domains, oligomeric state, post-translational modifications and protein–protein and protein–ligand interactions. In this paper, applications and new developments of protein-characterization methods using MS, fluorescence spectroscopy, static light scattering, analytical ultracentrifugation and small-angle X-ray scattering within the EC Structural Proteomics in Europe contract are described. Examples of the application of the various methods are given. [ABSTRACT FROM AUTHOR]

The Structural Proteomics In Europe (SPINE) programme is aimed at the development and implementation of high-throughput technologies for the efficient structure determination of proteins of biomedical importance, such as those of bacterial and viral pathogens linked to human health. Despite the challenging nature of some of these targets, 175 novel pathogen protein structures (∼220 including complexes) have been determined to date. Here the impact of several technologies on the structural determination of proteins from human pathogens is illustrated with selected examples, including the parallel expression of multiple constructs, the use of standardized refolding protocols and optimized crystallization screens. [ABSTRACT FROM AUTHOR]

Objective To assess the reliability of the histological diagnosis of bladder cancer by assessing the interobserver variability of staging and grading in pTa/pT1 tumours and evaluating the clinical significance of discrepancies. Materials and methods All sections from 301 superficial bladder carcinomas were reviewed by one pathologist. The prognostic relevance of grade and stage from both the initial and review diagnosis were determined in 128 patients for whom there was long‐term follow‐up information. Results There were significant interobserver differences in both the grading and staging of tumours. From a total of 235 tumours that were initially considered pT1, the reviewer classified 35% as pTa, 56% as pT1, 6% as pT1‐ (at least pT1), and 3% as pT2–4. In 39% of all biopsies there were interobserver differences in tumour grade. The prognostic significance of grade and stage differed between the initial pathology report and the reviewer’s diagnosis. The reviewer’s staging allowed a better estimate of the risk of subsequent tumour progression than the initial staging. Progression was significantly more common in 49 tumours in which the reviewer agreed with stage pT1 than in 29 tumours that were down‐staged from pT1 to pTa (P = 0.0116). However, the initial tumour grade (P = 0.0386) but not the reviewer’s grade (P = 0.2645) was significantly linked to progression. Conclusions These results show that grading and staging by different pathologists have varying prognostic implications. If possible, biopsies from bladder tumours should be independently evaluated by two different pathologists before radical therapy is administered. [ABSTRACT FROM AUTHOR]

Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses., (© 2024 Wiley Periodicals LLC.)

A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene., (© 2022 Wiley Periodicals LLC.)

Deletions in the 12q21 region are rare and non-recurrent CNVs. To date, only 11 patients with deletions in this region have been reported in the literature. These patients most often presented with syndromic intellectual deficiency, ventriculomegaly or hydrocephalus, ectodermal abnormalities, growth retardation and renal and cardiac malformations, suggesting a recognizable microdeletion syndrome. We report three new patients with overlapping deletions of the 12q21 region, including the smallest deletion reported to date and the first case characterized by array CGH during pregnancy. We describe specific clinical findings and shared facial features as developmental delay, ectodermal abnormalities, ventriculomegaly or hydrocephalus, axial hypotonia or spastic diplegia, growth retardation, heart defect, hydronephrosis, ureteral reflux or horseshoe kidney, large thorax or pectus excavatum, syndactyly of 2-3 toes, pterygium coli or excess nuchal skin, large anterior fontanel, low set ears, prominent forehead, short-upturned nose with nostril hypoplasia, microretrognathia and hypertelorism. These new patients and a comprehensive review of the literature allow us to define a minimum critical region spanning 1.6 Mb in 12q21. By screening the critical region using prediction tools, we identified two candidate genes: SYT1and PPP1R12A., (© 2020 Wiley Periodicals LLC.)

The alpha-amylase from Tenebrio molitor larvae (TMA) has been crystallized in complex with the alpha-amylase inhibitor (alpha-AI) from the bean Phaseolus vulgaris. A molecular-replacement solution of the structure was obtained using the refined pig pancreatic alpha-amylase (PPA) and alpha-AI atomic coordinates as starting models. The structural analysis showed that although TMA has the typical structure common to alpha-amylases, large deviations from the mammalian alpha-amylase models occur in the loops. Despite these differences in the interacting loops, the bean inhibitor is still able to inhibit both the insect and mammalian alpha-amylase.