Identification of Spliceogenic Variants beyond Canonical GT-AG Splice Sites in Hereditary Cancer Genes

Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.     

Systematic Review and Meta-Analysis of Mass Spectrometry Proteomics Applied to Human Peripheral Fluids to Assess Potential Biomarkers of Schizophrenia

Mass spectrometry (MS)-based techniques can be a powerful tool to identify neuropsychiatric disorder biomarkers, improving prediction and diagnosis ability. Here, we evaluate the efficacy of MS proteomics applied to human peripheral fluids of schizophrenia (SCZ) patients to identify disease biomarkers and relevant networks of biological pathways. Following PRISMA guidelines, a search was performed for studies that used MS proteomics approaches to identify proteomic differences between SCZ patients and healthy control groups (PROSPERO database: CRD42021274183). Nineteen articles fulfilled the inclusion criteria, allowing the identification of 217 differentially expressed proteins. Gene ontology analysis identified lipid metabolism, complement and coagulation cascades, and immune response as the main enriched biological pathways. Meta-analysis results suggest the upregulation of FCN3 and downregulation of APO1, APOA2, APOC1, and APOC3 in SCZ patients. Despite the proven ability of MS proteomics to characterize SCZ, several confounding factors contribute to the heterogeneity of the findings. In the future, we encourage the scientific community to perform studies with more extensive sampling and validation cohorts, integrating omics with bioinformatics tools to provide additional comprehension of differentially expressed proteins. The produced information could harbor potential proteomic biomarkers of SCZ, contributing to individualized prognosis and stratification strategies, besides aiding in the differential diagnosis.     

The Utility of Nasal Challenges to Phenotype Asthma Patients

Asthma is a heterogeneous disease in terms of both phenotype and response to therapy. Therefore, there is a great need for clinically applicable tools allowing for improved patient classification, and selection for specific management approaches. Some interventions are highly helpful in selected patients (e.g., allergen immunotherapy or aspirin desensitization), but they are costly and/or difficult to implement. Currently available biomarkers measurable in peripheral blood or exhaled air display many limitations for asthma phenotyping and cannot identify properly the specific triggers of the disease (e.g., aeroallergens or NSAID). The united airway concept illustrates the relevant epidemiological and pathophysiological links between the upper and lower airways. This concept has been largely applied to patient management and treatment, but its diagnostic implications have been less often explored. Of note, a recent document by the European Academy of Allergy and Clinical Immunology proposes the use of nasal allergen challenge to confirm the diagnosis of allergic asthma. Similarly, the nasal challenge with lysine acetylsalicylate (L-ASA) can be used to identify aspirin-sensitive asthma patients. In this review, we will summarize the main features of allergic asthma and aspirin-exacerbated respiratory disease and will discuss the methodology of nasal allergen and L-ASA challenges with a focus on their capacity to phenotype the inflammatory disease affecting both the upper and lower airways.     

Effect of areal density and fiber orientation on the deformation of thermomechanical bonds in a nonwoven fabric

This study proposes a novel method to mechanically characterize the performance of individual bonds in low‐density, thermomechanically bonded nonwoven fabrics. Commercial bicomponent, polyethylene/polypropylene (PE/PP), nonwoven fabric was laser cut into bowtie‐shaped specimens for uniaxial tensile testing so that the central region of each specimen contained an individual bond. Three groups, each composed of 20 specimens, were tested with their longitudinal axes oriented along the machine direction (MD), the cross direction (CD), and at 45° between these two directions (DD). Prior to testing, the intrinsic variation in areal density and fiber orientation in the region surrounding the individual bond were quantified via orientation and relative basis weight parameters. During testing, images of the specimens were acquired to determine the occurrence of fiber breakage, bond deformation, and bond cohesive failure. Maximum force, stiffness, and orientation parameters were found to be significantly different among the three specimen groups (p < 0.01) but the relative basis weight was not (p > 0.01). The stiffness and maximum load were linearly correlated with both the areal density and fiber orientation. Pre‐existing voids or windows within the bond lowered the maximum force for specimens with the longitudinal axes aligned with the MD. These voids had no influence on the maximum force achieved by the specimens aligned with the CD and DD. The bonds in these specimens were observed to deform less than the bonds in the specimens with the longitudinal axes aligned with the MD. The results indicate the importance of the fiber structure surrounding the bond on the tensile properties, deformation and failure mode of individual bonds within the nonwoven fabric. POLYM. ENG. SCI., 59:311–322, 2019. © 2018 Society of Plastics Engineers     

Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients

Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.     

New method for mode-field radius measurements in single-mode fibres based on harmonics detection

A new, easily implementable technique for mode-field radius measurement is described. It is based on a dynamical filtering and the detection of two harmonics of the fibre output radiation. The results are presented and discussed.     

In vitro cytotoxicity of guanylhydrazones (MGBG and PGBG) on cultured Chinese hamster ovary cells

Periosteum was obtained within 10 days of injury from the site of 17 adult tibial diaphyseal fractures during internal fixation. Osteogenic cells, non-osteogenic cells and vascular elements were identified in situ using a variety of techniques. In all cases, the periosteum was thickened with randomly distributed plaques of cartilage and bone. Cells covering newly formed bone trabeculae expressed osteocalcin. Lectin-binding revealed high vascularity. Few mast cells were observed. Macrophages and acid phosphatase positive cells, some multinucleate, were observed in abundance. These findings suggest that the repair of the adult human diaphyseal fracture is similar to that of experimental fractures in rapidity of onset, high vascularity and in bone and cartilage formation. They differ in the fact that chondrogenesis and osteogenesis appear to be simultaneous in human fractures but sequential in experimental fractures. The paucity of mast cells suggests that they probably play no significant role in the repair of the human fractures.     

Assessment of ventricular diastolic function in AIDS patients from Congo: a Doppler echocardiographic study

The aim of this study was to evaluate the effect of transdermal clonidine on hemodynamic and metabolic parameters in patients who have elevated blood pressure and non-insulin-dependent diabetes mellitus (NIDDM). After a 2-week run in placebo period, 20 NIDDM patients who had diastolic blood pressure in the range of 90 to 105 mm Hg underwent a randomized, single blind, placebo controlled, cross-over study of 4 week treatment with clonidine (transdermal patch 2.5 mg/week) or placebo (inactive patch). Compared with placebo, clonidine significantly reduced systolic (153 +/- 6 v 163 +/- 8) and diastolic (88 +/- 2 v 98 +/- 3.5 mm Hg, P = .001) blood pressure, left ventricular mass (94 +/- 11 v 99 +/- 12 g/m2, P < .01) and fasting glucose levels. Total glucose disposal (glucose clamp) was 6.5 +/- 1.5 with placebo and 7.1 +/- 1.6 mg/kg/min with clonidine (P < .01). Oxidative glucose disposal (indirect calorimetry) was also greater after clonidine. Plasma glucose, insulin, and C-peptide responses following oral glucose (75 g) were significantly lower after clonidine, as well as urinary albumin excretion. Transdermal clonidine is effective in reducing blood pressure in hypertensive NIDDM patients and is well tolerated. It may be useful to reduce the cardiovascular impact of hypertension in diabetes mellitus.     

Epithalamus calcifications in schizophrenia

This paper looks at how articulators can be of value in everyday NHS practice. A variation on the conventional classification of articulators is suggested with advice provided for the practitioner who wants to enhance his or her restorative work without immediately investing in high cost equipment. It is argued that rather than prolong chairside time, for specific types of treatment the use of an appropriate articulator and facebow can not only enhance the quality of the completed restoration, but also save on chairside time.