Muscle-specific function of the centronuclear myopathy and Charcot-Marie-Tooth neuropathy-associated dynamin 2 is required for proper lipid metabolism, mitochondria, muscle fibers, neuromuscular junctions and peripheral nerves

The ubiquitously expressed large GTPase Dynamin 2 (DNM2) plays a critical role in the regulation of intracellular membrane trafficking through its crucial function in membrane fission, particularly in endocytosis. Autosomal-dominant mutations in DNM2 cause tissue-specific human disorders. Different sets of DNM2 mutations are linked to dominant intermediate Charcot-Marie-Tooth neuropathy type B, a motor and sensory neuropathy affecting primarily peripheral nerves, or autosomal-dominant centronuclear myopathy (CNM) presenting with primary damage in skeletal muscles. To understand the underlying disease mechanisms, it is imperative to determine to which degree the primary affected cell types require DNM2. Thus, we used cell type-specific gene ablation to examine the consequences of DNM2 loss in skeletal muscle cells, the major relevant cell type involved in CNM. We found that DNM2 function in skeletal muscle is required for proper mouse development. Skeletal muscle-specific loss of DNM2 causes a reduction in muscle mass and in the numbers of muscle fibers, altered muscle fiber size distributions, irregular neuromuscular junctions (NMJs) and isolated degenerating intramuscular peripheral nerve fibers. Intriguingly, a lack of muscle-expressed DNM2 triggers an increase of lipid droplets (LDs) and mitochondrial defects. We conclude that loss of DNM2 function in skeletal muscles initiates a chain of harmful parallel and serial events, involving dysregulation of LDs and mitochondrial defects within altered muscle fibers, defective NMJs and peripheral nerve degeneration. These findings provide the essential basis for further studies on DNM2 function and malfunction in skeletal muscles in health and disease, potentially including metabolic diseases such as diabete

Lesions associated with mineral deposition in the lymph nodes and lungs of cattle: a case-control study of environmental health hazard.

This report focuses on the state of health of the cattle raised in the district of Taranto - city of Italy rated as environmentally at risk. Representative samples of lungs, bronchial and mediastinal lymph nodes of cattle from district of Taranto's slaughterhouses were collected. After a macroscopic examination, samples with marked lesions were processed for light microscopy. Samples were also observed with polarized light microscopy, scanning electron microscopy and with microanalysis. The macroscopic examination revealed that 60 out of 183 samples showed marked lesions. Lung alterations were characterized by thickening of the alveolar septa and by the latter's modifying action on the alveolar spaces, foci of fibrosis and bronchopulmonary inflammation. For 51 out of the 60 samples observed, the histological examination confirmed the presence of pneumoconiosis and lymph nodal anthracosis. Energy-dispersive X-ray microanalysis of lung samples identified a wide range of elements including silicon, aluminium, titanium, iron, carbon and small amount of the other metals. In the lymph-nodes the same kind of metals with a different levels of distribution was observed. Our survey on cattle farmed in areas at high risk of pollution may be helpful to the estimation of the exposure risk for man to environmental contaminants and to the evaluation of the occurrence of the pathological manifestations as well

Vitamin D: Mechanism of action and biological effects in uterine fibroids

Uterine fibroids (UFs) are the most common benign gynecological tumors. It was esti-mated that fifty percent of women presenting with UFs has symptomatology that negatively in-fluences their quality of life. Pharmacological and/or surgical treatments are frequently required, depending on the woman’s desire to preserve fertility, with a high impact on healthcare costs. Generally, the use of currently available pharmacological treatments may lead to side effects. Therefore, there is a growing interest in a natural and safe approach for UFs. In recent years, epi-demiological studies reported a vitamin D deficiency in patients with UFs raised interest in the potential biological effects of vitamin D supplementation. In vitro studies proved vitamin D efficacy in inhibiting UFs growth by targeting pathways involved in the regulation of various biological processes, including proliferation, extracellular matrix (ECM) remodeling, DNA repair, signaling and apoptosis. However, clinical studies supported only in part the beneficial effects of vitamin D supplementation in reducing UFs growth and tumor volume. Randomized controlled trials and large population studies are mandatory as the potential clinical benefits are likely to be substantial

Invertibility Conditions for Floating-Point Formulae

Automated reasoning procedures are essential for a number of applications that involve bit-exact floating-point computations. This paper presents conditions that characterize when a variable in a floating-point constraint has a solution, which we call invertibility conditions. We describe a novel workflow that combines human interaction and a syntax-guided synthesis (SyGuS) solver that was used for discovering these conditions. We verify our conditions for several floating-point formats. One implication of this result is that a fragment of floating-point arithmetic admits compact quantifier elimination. We implement our invertibility conditions in a prototype extension of our solver CVC4, showing their usefulness for solving quantified constraints over floating-points

Diffusion MRI Findings in Encephalopathy Induced by Immunosuppressive Therapy after Liver Transplantation

Neurological complications are common after liver transplantation, as they affect up to one-third of the transplanted patients and are associated with significant morbidity. The introduction of calcineurin inhibitors, cyclosporine A and tacrolimus, in immunosuppressive regimens significantly improved the outcome of solid-organ transplantation even though immunosuppression-associated neurotoxicity remains a significant complication, particularly occurring in about 25% of cases after liver transplantation. The immunosuppressant cyclosporine A and tacrolimus have been associated with the occurrence of major neurological complications, diffuse encephalopathy being the most common. The biochemical and pathogenetic basis of calcineurin inhibitors-induced neurotoxicity are still unclear although several mechanisms have been suggested. Early recognition of symptoms could help reduce neurotoxic event. The aim of the study was to evaluate cerebral changes through MRI, in particular with diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) maps, in two patients undergoing liver transplantation after immunosuppressive therapy. We describe two patients in which clinical pictures, presenting as a severe neurological condition, early after orthotopic liver transplantation during immunosuppression therapy, showed a different evolution in keeping with evidence of focal-multifocal lesions at DWI and ADC maps. At clinical onset, DWI showed hyperintensity of the temporo-parieto-occipital cortex with normal ADC values in the patient with following good clinical recovery and decreased values in the other one; in the latter case, MRI abnormalities were still present after ten days, until the patient's exitus. The changes in DWI with normal ADC may be linked to brain edema with a predominant vasogenic component and therefore reversible, while the reduction in ADC is due to cytotoxic edema and linked to more severe, nonreversible, clinical picture. Brain MRI and particularly DWI and ADC maps provide not only a good and early representation of neurological complications during immunosuppressant therapy but can also provide a useful prognostic tool on clinical outcome of the patient

Should the visceral peritoneum at the bladder flap closed at caesarean sections a post partum sonographic and clinical assessment?

Objective. To compare cesarean section (CS) using open or closed visceral peritoneum of the bladder flap (BF) in relation to fluid collection in vesico-uterine space (VUS) by ultrasound (US) and clinical outcome. Material and methods. A prospective cohort of repeat CS in 474 in advanced first and second stage of labor was studied. All women underwent a Misgav Ladach CS, in local combined anesthesia. These were divided into two groups by surgical management of the BF at the time of CS: Group I (n?262), with visceral peritoneum left open and Group II (n?212), with visceral peritoneum closed. An US check for the fluid collections in the VUS was done in the third post-operative day. The two groups were also clinically compared for: intra-operative estimated blood loss, the need for post-CS pain killers, febrile morbidity and duration of hospital stay. Results. Visceral peritoneum (VP) closure resulted in a significant increase blood collections in the VUS (p50.05). VP closure resulted in a significantly higher morbidity in all the following parameters. Rate of BFHs, post-operative fever, need for post-operative analgesia, require antibiotic administration and prolonged hospitalisation (p50.05). Conclusions. VP suturing of women requiring CS for dystocia is associated to increased rate of blood collection in the VUS, which could possibly explain the higher rate of puerperal complications in these patients. These data clearly indicate that suturing the VP of the BF in women undergoing CS for dystocia is contraindicated. This data could be probably extrapolated to all cesarean deliveries

Uterine fibroid pseudocapsule studied by transmission electronmicroscopy.

OBJECTIVE: The fibroid pseudocapsule is a structure which surrounds the uterine fibroid, separates it from the uterine tissue and contains a vascular network rich in neurotransmitters like a neurovascular bundle. The authors examined the composition of the fibroid pseudocapsule using electron microscopy. STUDY DESIGN: Twenty non-pregnant patients were submitted to laparoscopic myomectomy by the intracapsular method and samples of the removed pseudocapsules were analyzed using transmission electron microscopy. RESULTS: At the ultrastructural level the pseudocapsule cells have the features of smooth muscle cells similar to the myometrium. So, the pseudocapsules are part of the myometrium which compresses the leiomyoma. CONCLUSION: This ultrastructural feature suggests that when removing fibroids their pseudocapsules should be preserved. This study confirms preliminary evidence that pseudocapsules contain neuropeptides together with their related fibers, as a neurovascular bundle. The surgeon's behavior should be directed to carefully control and spare this muscular surrounding tissue during fibroid excision, in order to preserve the myometrium as much as possible

Caesarean Section in the World: a new ecological approach

Introduction. This study aimed to estimate the most recent caesarean section rates in the world and examine the association between these rates and old and new indicators of health care. Methods. Authors analyzed the Caesarean Section (CS) rates, also in geo-economic and economic groups, and correlated them to maternal and neonatal mortality, to births attended by skilled health personnel and to births among adolescents. Analysis of covariance and piecewise regressions were used for the statistical analysis. Results. In 47.2% of the countries, the CS rate exceeded 15%. Countries of Latin America and the Caribbean along with Europe, North America and Oceania had the highest values. The analysis showed an inverse association between CS rates and Maternal Mortality (MMR) and Neonatal Mortality (NMR) for all geographical areas except for Europe. The greatest association was observed in lower-middle-income countries. In developing countries only 50% of cases, occur in medical facilities and only half of these are seen by medical, nursing and obstetrical staff. Age of the mother appears to influence the outcome and choice of delivery type. Countries where an high ABR rate is present have low CS use. Conclusions. To best evaluate the consequences of the increasing rate of CS, it would be useful to identify the most sensitive outcome indicators

Combining Decision Procedures for Sorted Theories

Abstract. The Nelson-Oppen combination method combines decision procedures for theories satisfying certain conditions into a decision pro-cedure for their union. While the method is known to be correct in the setting of unsorted first-order logic, some current implementations of it appear in tools that use a sorted input language. So far, however, there have been no theoretical results on the correctness of the method in a sorted setting, nor is it obvious that the method in fact lifts as is to logics with sorts. To bridge this gap between the existing theoretical results and the current implementations, we extend the Nelson-Oppen method to (order-)sorted logic and prove it correct under conditions sim-ilar to the original ones. From a theoretical point of view, the extension is relevant because it provides a rigorous foundation for the application of the method in a sorted setting. From a practical point of view, the extension has the considerable added benefits that in a sorted setting the method’s preconditions become easier to satisfy in practice, and the method’s nondeterminism is generally reduced.