Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: A case report

Background: Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine-tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype. Case presentation: A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co-segregation in the family. As a result, a novel homozygous mutation (c.346C > G, p.Leu116Val) in115G-L-W117motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation. Conclusions: We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved115G-L-W117motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient

Advanced Ultrasonic Non-destructive Evaluation for Metrological Analysis and Quality Assessment of Impact Damaged Non-crimp Fabric Composites☆

Abstract Composite materials are nowadays massively utilized in a very large number of industrial applications. Thus, it has become essential to characterize the service behaviour they can provide depending on their working conditions. In this paper, the study of the influence of impact conditions on damage generation in high performance composite materials, consisting of non-crimp fabric composite laminates, is carried out through the application of an advanced ultrasonic non-destructive evaluation technique, known as full volume ultrasonic scanning. This technique is based on the pulse-echo immersion testing method and allows for the quantitative analysis of the internal material structure in the entire composite volume. The aim of the ultrasonic non-destructive evaluation analysis is the metrological characterization of the non-crimp fabric composite laminates in terms of actual thickness estimation and stacking sequence fiber orientation verification as well as their quality assessment in terms of impact damage development within the whole composite material volume

Integration of reverse engineering and ultrasonic non-contact testing procedures for quality assessment of CFRP aeronautical components

Abstract Nowadays, the quality assurance of aeronautical components is a very crucial issue. Diverse defects can be generated during composite material components manufacturing such as voids, delamination, cracks, etc. The identification of these defects requires the use of different types of inspection methods. In this paper, two diverse non-contact inspection techniques, i.e. a laser-based reverse engineering method and an ultrasonic testing procedure, are integrated to provide a complete quality assessment of carbon fibre reinforced polymer components for applications in the aeronautical field. A custom made software code was developed in order to create a user interface allowing for the visualization and analysis of the reverse engineering and ultrasonic information for the detection of geometrical and internal flaws of the component under inspection

Non-contact Reverse Engineering Modeling for Additive Manufacturing of Down Scaled Cultural Artefacts

Abstract In recent years, reverse engineering has achieved a relevant role in the cultural heritage field. The availability of 3D digital models of artefacts opens the door to a new era of cultural heritage: virtual museum creation, artefact cataloguing, conservation, planning and simulation of restoration, monitoring of artefacts subjected to environmental degradation, virtual reconstruction of damaged or missing parts, reproduction of replicas, etc. In this paper, two different non-contact reverse engineering scanning systems were utilized for 3D data acquisition of a cultural heritage artefact. The digital data acquisition and processing procedures of the scanned geometry have been illustrated and compared to evaluate the performance of both systems in terms of data acquisition time, processing time, reconstruction precision and final model quality. Finally, additive manufacturing technologies were applied to reconstruct a down scaled copy of the artefact

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy

INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. OBJECTIVES This study aimed to assess the genetic background of HCM in a cohort of Polish patients. PATIENTS AND METHODS Twenty–nine Polish patients were analyzed by a next–generation sequencing panel including 404 cardiovascular genes. RESULTS Pathogenic variants were found in 41% of the patients, with ultra–rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3

Study of USH1 Splicing Variants through Minigenes and Transcript Analysis from Nasal Epithelial Cells

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital profound deafness, vestibular areflexia and prepubertal retinitis pigmentosa. The first purpose of this study was to determine the pathologic nature of eighteen USH1 putative splicing variants found in our series and their effect in the splicing process by minigene assays. These variants were selected according to bioinformatic analysis. The second aim was to analyze the USH1 transcripts, obtained from nasal epithelial cells samples of our patients, in order to corroborate the observed effect of mutations by minigenes in patient’s tissues. The last objective was to evaluate the nasal ciliary beat frequency in patients with USH1 and compare it with control subjects. In silico analysis were performed using four bioinformatic programs: NNSplice, Human Splicing Finder, NetGene2 and Spliceview. Afterward, minigenes based on the pSPL3 vector were used to investigate the implication of selected changes in the mRNA processing. To observe the effect of mutations in the patient’s tissues, RNA was extracted from nasal epithelial cells and RT-PCR analyses were performed. Four MYO7A (c.470G>A, c.1342_1343delAG, c.5856G>A and c.3652G>A), three CDH23 (c.2289+1G>A, c.6049G>A and c.8722+1delG) and one PCDH15 (c.3717+2dupTT) variants were observed to affect the splicing process by minigene assays and/or transcripts analysis obtained from nasal cells. Based on our results, minigenes are a good approach to determine the implication of identified variants in the mRNA processing, and the analysis of RNA obtained from nasal epithelial cells is an alternative method to discriminate neutral Usher variants from those with a pathogenic effect on the splicing process. In addition, we could observe that the nasal ciliated epithelium of USH1 patients shows a lower ciliary beat frequency than control subjects

Update on hypertrophic cardiomyopathy and a guide to the guidelines

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 individuals worldwide. Existing epidemiological studies might have underestimated the prevalence of HCM, however, owing to limited inclusion of individuals with early, incomplete phenotypic expression. Clinical manifestations of HCM include diastolic dysfunction, left ventricular outflow tract obstruction, ischaemia, atrial fibrillation, abnormal vascular responses and, in 5% of patients, progression to a 'burnt-out' phase characterized by systolic impairment. Disease-related mortality is most often attributable to sudden cardiac death, heart failure, and embolic stroke. The majority of individuals with HCM, however, have normal or near-normal life expectancy, owing in part to contemporary management strategies including family screening, risk stratification, thromboembolic prophylaxis, and implantation of cardioverter-defibrillators. The clinical guidelines for HCM issued by the ACC Foundation/AHA and the ESC facilitate evaluation and management of the disease. In this Review, we aim to assist clinicians in navigating the guidelines by highlighting important updates, current gaps in knowledge, differences in the recommendations, and challenges in implementing them, including aids and pitfalls in clinical and pathological evaluation. We also discuss the advances in genetics, imaging, and molecular research that will underpin future developments in diagnosis and therapy for HCM

Modelling urban turbulent heat exchanges between the urban canopy and the atmosphere: differences between CFD and surface energy balance models

Urban microclimate models were initially designed to improve weather forecasting and climate modelling. They have been used to assess the large scale deployment mitigation techniques for many years. However, urban climate models necessarily introduce many simplifications and approximations, despite the increase in available computational resources. Here, we present a comparison between the wind velocity computed with a 2-D urban canopy parameterization, and with a computational fluid dynamic model (CFD) by means of FLUENT-ANSYS in 2-D and 3-D. The urban canopy parameterization is the urban tile of the Community Land Model (Oleson et al. 2010). We considered an urban canyon in Milan in peak summer conditions, having equal height and width, and subject to wind having two possible velocities (2, or 4 m s-1). In both cases, we modelled the canyon considering or neglecting the natural convection. In the considered conditions, although urban canopy parameterizations are not capable of distinguishing the wind direction within the urban fabric, they get the magnitude of wind velocity, achieving intermediate values between those computed with 2-D and 3-D CFD modelling