Congenital myopathy with hanging big toe due to homozygous myopalladin (MYPN) mutation

Background: Myopalladin (MYPN) is a component of the sarcomere that tethers nebulin in skeletal muscle and nebulette in cardiac muscle to alpha-actinin at the Z lines. Autosomal dominant MYPN mutations cause hypertrophic, dilated, or restrictive cardiomyopathy. Autosomal recessive MYPN mutations have been reported in only six families showing a mildly progressive nemaline or cap myopathy with cardiomyopathy in some patients. Case presentation: A consanguineous family with congenital to adult-onset muscle weakness and hanging big toe was reported. Muscle biopsy showed minimal changes with internal nuclei, type 1 fiber predominance, and ultrastructural defects of Z line. Muscle CT imaging showed marked hypodensity of the sartorius bilaterally and MRI scattered abnormal high-intensity areas in the internal tongue muscle and in the posterior cervical muscles. Cardiac involvement was demonstrated by magnetic resonance imaging and late gadolinium enhancement. Whole exome sequencing analysis identified a homozygous loss of function single nucleotide deletion in the exon 11 of the MYPN gene in two siblings. Full-length MYPN protein was undetectable on immunoblotting, and on immunofluorescence, its localization at the Z line was missed. Conclusions: This report extends the phenotypic spectrum of recessive MYPN-related myopathies showing: (1) the two patients had hanging big toe and the oldest one developed spine and hand contractures, none of these signs observed in the previously reported patients, (2) specific ultrastructural changes consisting in Z line fragmentation, but (3) no nemaline or caps on muscle pathology

NANOMATERIAL COATINGS FOR OSTEOINTEGRATED BIOMEDICAL PROSTHESES

Novel materials and methods, for preparation of coatings based on titanium dioxide for osteointegrated biomedical prostheses. The coatings are realized with nanomaterials having antibacterial properties, and have the purpose of promoting osteointegration of the implants, and, at the same time, reducing rejection attributable to inflammatory processes which derive from infections which may develop in the neighborhood of the implants. In particular, the present invention relates to an endo-osseous implant comprised of biocompatible metallic materials; characterized in that said implant comprises a coating comprised of nanocrystalline material comprising nanoparticles of formula (I) AOx- (L- Men+) i , (I) where AOx represents TiO2 or ZrO2; Men+ is a metallic ion having antibacterial activity, with n = 1 or 2; L is a bi functional organic molecule which can simultaneously bind to the metal oxide and to the metallic ion Men+; and i is the number of L-Men+ groups bound to one nanoparticle of AOx

Left Ventricular Reverse Remodeling Elicited by a Quadripolar Lead: Results from the Multicenter Per4mer Study

Background To understand the impact of a quadripolar left ventricular (LV) lead on reverse remodeling and phrenic nerve stimulation (PNS) in congestive heart failure patients treated by cardiac resynchronization therapy at 8-month follow-up (FU). Methods One hundred and fifty-eight patients received an LV Medtronic Performa lead (Medtronic Inc., Minneapolis, MN, USA) and were reevaluated at FU by echocardiography and measurement of electrical parameters. Results A targeted LV lead placement was achieved in 140 (89%) patients. Super responders and responders were 76 (50%) and 26 (18%), respectively, at FU; seven (4%) died and 13 (8%) were hospitalized for any cause. Nonischemic etiology was the only independent predictor of reverse remodeling. The configurations available only with the Performa leads reduced PNS occurrence at 8 [email protected] ms from 43 (27%) to 14 (9%) of patients at implantation, and from 44 (28%) to 19 (12%) at last FU, compared to configurations available with bipolar leads. Patients with detectable PNS had >10/16 pacing configurations with a PNS safety margin >2 V both at implantation and at FU. During FU 16 (10%) patients had an adverse event possibly related to the lead or to modification of the underlying heart disease but 99% of these events were fixed by reprogramming of the pacing vector. Conclusions Performa Lead enables an increased capability to achieve a targeted lead positioning in the broad clinical scenario of large- and small-volume implanting centers, with a relevant impact on the occurrence of reverse remodeling compared to literature data. The enhanced management of PNS resulted in a dislodgement rate of only 1%

Physicochemical characterisation of glycoconjugate vaccines for prevention of meningococcal diseases.

Bacterial capsular polysaccharides covalently linked to an appropriate carrier protein represent the best tool to induce a protective immune response against a wide range of bacterial diseases, such as meningococcal infections. We describe here the physico-chemical characterisation of glycoconjugate molecules designed to prepare a vaccine against Neisseria meningitidis serogroups A, C, W135 and Y. The use of a selective conjugation chemistry resulted in well characterised, reproducible and traceable glycoconjugate that can be consistently manufactured at large scale. A pool of physical and spectroscopic methods was used to establish glycosylation ratio, identity, molecular weight profiles, integrity of carrier protein and sites of glycosylation, assuring effective and consistent lots of vaccines

SCN5A mutation is associated with a higher Shanghai Score in patients with type 1 Brugada ECG pattern

Aims Brugada syndrome (BrS) is an inherited arrhythmic disease characterized by a coved ST-segment elevation in the right precordial electrocardiogram leads (type 1 ECG pattern) and is associated with a risk of malignant ventricular arrhythmias and sudden cardiac death. In order to assess the predictive value of the Shanghai Score System for the presence of a SCN5A mutation in clinical practice, we studied a cohort of 125 patients with spontaneous or fever/drug-induced BrS type 1 ECG pattern, variably associated with symptoms and a positive family history.Methods The Shanghai Score System items were collected for each patient and PR and QRS complex intervals were measured. Patients were genotyped through a next-generation sequencing (NGS) custom panel for the presence of SCN5A mutations and the common SCN5A polymorphism (H558R).Results The total Shanghai Score was higher in SCN5A+ patients than in SCN5A- patients. The 81% of SCN5A+ patients and the 100% of patients with a SCN5A truncating variant exhibit a spontaneous type 1 ECG pattern. A significant increase in PR (P = 0.006) and QRS (P = 0.02) was detected in the SCN5A+ group. The presence of the common H558R polymorphism did not significantly correlate with any of the items of the Shanghai Score, nor with the total score of the system.Conclusion Data from our study suggest the usefulness of Shanghai Score collection in clinical practice in order to maximize genetic test appropriateness. Our data further highlight SCN5A mutations as a cause of conduction impairment in BrS patients

The Role of COVID-19 in the Death of SARS-CoV-2-Positive Patients: A Study Based on Death Certificates

Background: Death certificates are considered the most reliable source of information to compare cause-specific mortality across countries. The aim of the present study was to examine death certificates of persons who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to (a) quantify the number of deaths directly caused by coronavirus 2019 (COVID-19); (b) estimate the most common complications leading to death; and (c) identify the most common comorbidities. Methods: Death certificates of persons who tested positive for SARS-CoV-2 provided to the National Surveillance system were coded according to the 10th edition of the International Classification of Diseases. Deaths due to COVID-19 were defined as those in which COVID-19 was the underlying cause of death. Complications were defined as those conditions reported as originating from COVID-19, and comorbidities were conditions independent of COVID-19. Results: A total of 5311 death certificates of persons dying in March through May 2020 were analysed (16.7% of total deaths). COVID-19 was the underlying cause of death in 88% of cases. Pneumonia and respiratory failure were the most common complications, being identified in 78% and 54% of certificates, respectively. Other complications, including shock, respiratory distress and pulmonary oedema, and heart complications demonstrated a low prevalence, but they were more commonly observed in the 30-59 years age group. Comorbidities were reported in 72% of certificates, with little variation by age and gender. The most common comorbidities were hypertensive heart disease, diabetes, ischaemic heart disease, and neoplasms. Neoplasms and obesity were the main comorbidities among younger people. Discussion: In most persons dying after testing positive for SARS-CoV-2, COVID-19 was the cause directly leading to death. In a large proportion of death certificates, no comorbidities were reported, suggesting that this condition can be fatal in healthy persons. Respiratory complications were common, but non-respiratory complications were also observed

TFG binds LC3C to regulate ULK1 localization and autophagosome formation

The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy

TFG binds LC3C to regulate ULK1 localization and autophagosome formation

The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy