FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy.

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.

A systematic review of viral transmission risk to healthcare staff comparing laparoscopic and open surgery.

BACKGROUND: Throughout the United Kingdom, there have been sweeping changes to the practice of medicine due to the COVID-19 pandemic. For the surgical speciality, there have been changes to both elective and emergency practice. Concern regarding potential aerosolisation during invasive procedures have been raised - including the use of pneumoperitoneum to facilitate laparoscopy. The aim of this study is to systematically review the data available to date regarding the potential risk posed to theatre staff by laparoscopy. METHOD: A systematic review and meta-analysis was carried out in accordance with PRISMA guidelines. Only publications in peer-reviewed journals were considered. PubMed, Ovid Embase, SCOPUS, and Cochrane Library were searched. The search period was between 1st January 1980 and 27th April 2020. Bias was assessed using the ROBINS-I tool. RESULTS: 4209 records were identified, resulting in 9 unique studies being selected. The included studies examined viral DNA aerosoliation generated by electrosurgery and CO2 laser ablation, with one study examining viral DNA aerosolisation following laparoscopy. Each of these demonstrated that viral DNA (Hepatitis B Virus and Human Papilloma Virus) was detectable in the surgical smoke plume. CONCLUSION: The data and analysis reported in this study reflect the most up-to-date evidence available for the surgeon to assess risk towards healthcare staff. It was constrained by heterogeneity of reporting for several outcomes and lack of comparable studies. There is currently insufficient data to recommend open or a minimally invasive surgical approach with regard to theatre team safety in the COVID-19 era.

Birdlike growth and mixed-age flocks in avimimids (Theropoda, Oviraptorosauria).

Avimimids were unusual, birdlike oviraptorosaurs from the Late Cretaceous of Asia. Initially enigmatic, new information has ameliorated the understanding of their anatomy, phylogenetic position, and behaviour. A monodominant bonebed from the Nemegt Formation of Mongolia showed that some avimimids were gregarious, but the site is unusual in the apparent absence of juveniles. Here, a second monodominant avimimid bonebed is described from the Iren Dabasu Formation of northern China. Elements recovered include numerous vertebrae and portions of the forelimbs and hindlimbs, representing a minimum of six individuals. Histological sampling of two tibiotarsi from the bonebed reveals rapid growth early in ontogeny followed by unexpectedly early onset of fusion and limited subsequent growth. This indicates that avimimids grew rapidly to adult size, like most extant birds but contrasting other small theropod dinosaurs. The combination of adults and juveniles in the Iren Dabasu bonebed assemblage provides evidence of mixed-age flocking in avimimids and the onset of fusion in young individuals suggests that some of the individuals in the Nemegt Formation bonebed may have been juveniles. Regardless, these individuals were likely functionally analogous to adults, and this probably facilitated mixed-age flocking by reducing ontogenetic niche shift in avimimids.

Cellular rescue in a zebrafish model of congenital muscular dystrophy type 1A.

Laminins comprise structural components of basement membranes, critical in the regulation of differentiation, survival and migration of a diverse range of cell types, including skeletal muscle. Mutations in one muscle enriched Laminin isoform, Laminin alpha2 (Lama2), results in the most common form of congenital muscular dystrophy, congenital muscular dystrophy type 1A (MDC1A). However, the exact cellular mechanism by which Laminin loss results in the pathological spectrum associated with MDC1A remains elusive. Here we show, via live tracking of individual muscle fibres, that dystrophic myofibres in the zebrafish model of MDC1A maintain sarcolemmal integrity and undergo dynamic remodelling behaviours post detachment, including focal sarcolemmal reattachment, cell extension and hyper-fusion with surrounding myoblasts. These observations imply the existence of a window of therapeutic opportunity, where detached cells may be "re-functionalised" prior to their delayed entry into the cell death program, a process we show can be achieved by muscle specific or systemic Laminin delivery. We further reveal that Laminin also acts as a pro-regenerative factor that stimulates muscle stem cell-mediated repair in lama2-deficient animals in vivo. The potential multi-mode of action of Laminin replacement therapy suggests it may provide a potent therapeutic axis for the treatment for MDC1A.

Meta-analysis of patient-reported outcomes after laparoscopic versus open inguinal hernia repair.

BACKGROUND: Inguinal hernia repair is a common low-risk intervention. Patient-reported outcomes (PROs) are being used increasingly as primary outcomes in clinical trials. The aim of this study was to review and meta-analyse the PROs in RCTs comparing laparoscopic versus open inguinal hernia repair techniques in adult patients. METHODS: A systematic review and meta-analysis was carried out in accordance with PRISMA guidelines. Only RCTs in peer-reviewed journals were considered. PubMed, Ovid Embase, Scopus and the Cochrane Library were searched. In addition, four trial registries were searched. The search interval was between 1 January 1998 and 1 May 2018. Identified publications were reviewed independently by two authors. The review was registered in the PROSPERO database (CRD42018099552). Bias was assessed using the Cochrane Collaboration risk-of-bias tool. RESULTS: Some 7192 records were identified, from which 58 unique RCTs were selected. Laparoscopic hernia repair was associated with significantly less postoperative pain in three intervals: from 2 weeks to within 6 months after surgery (risk ratio (RR) 0·74, 95 per cent c.i. 0·62 to 0·88), 6 months to 1 year (RR 0·74, 0·59 to 0·93) and 1 year onwards (RR 0·62, 0·47 to 0·82). Paraesthesia (RR 0·27, 0·18 to 0·40) and patient-reported satisfaction (RR 0·91, 0·85 to 0·98) were also significantly better in the laparoscopic repair group. CONCLUSION: The data and analysis reported in this study reflect the most up-to-date evidence available for the surgeon to counsel patients. It was constrained by heterogeneity of reporting for several outcomes.

A dinosaur community composition dataset for the Late Cretaceous Nemegt Basin of Mongolia.

Dinosaur community composition data for eleven fossil localities in the Late Cretaceous Nemegt Basin of Mongolia are compiled from field observations and records in the literature. Counts were generated from skeletons and represent numbers of individuals preserved in each locality. These data were used in the analyses of Funston et al. [1] "Oviraptorosaur anatomy, diversity, and ecology in the Nemegt Basin" in the Nemegt Ecosystems Special Issue of Palaeogeography, Palaeoclimatology, Palaeoecology, where the results are discussed.

A systematic review and meta-analysis of the post-operative adverse effects associated with mosquito net mesh in comparison to commercial hernia mesh for inguinal hernia repair in low income countries.

PURPOSE: Abdominal wall hernia is a common surgical condition, with more than 20 million estimated to be repaired each year. Mesh repair is the standard for most repairs; however, the mesh material itself may be a barrier to care, the cost prohibitively high for some populations and healthcare systems. The aim of this systematic review and meta-analysis was to produce a pooled comparison between the adverse event rate associated with mosquito net mesh and commercial hernia mesh. METHODS: A systematic review was carried out in accordance with PRISMA guidelines. PubMed, Ovid Embase/Medline, SCOPUS, Web of Science and the Cochrane library were searched. In addition, the ISRCTN register, ClinicalTrials.gov, ICTR Platform and EU Clinical Trials Register were searched. RESULTS: Five randomised controlled trials (RCTs) were identified. The RCTs were deemed to have similar sample populations after inspection of their sample parameters. Therefore, the adverse effects were compared individually (reoccurrence, haematoma, seroma, infection, and serous discharge) and pooled. A total of 313 mosquito net meshes were included in the study, there was no significant difference between the intervention and control groups for pooled adverse effects or individually. CONCLUSIONS: There is not a significant difference between the commercial mesh group and the mosquito net mesh group for pooled [odds ratio 0.93 (0.63, 1.35)] and individual adverse event rates. However, the 95% confidence intervals of these results are still wide. To reduce this uncertainty sample sizes must increase in future studies.

Muscular dystrophy modeling in zebrafish.

Skeletal muscle performs an essential function in human physiology with defects in genes encoding a variety of cellular components resulting in various types of inherited muscle disorders. Muscular dystrophies (MDs) are a severe and heterogeneous type of human muscle disease, manifested by progressive muscle wasting and degeneration. The disease pathogenesis and therapeutic options for MDs have been investigated for decades using rodent models, and considerable knowledge has been accumulated on the cause and pathogenetic mechanisms of this group of human disorders. However, due to some differences between disease severity and progression, what is learned in mammalian models does not always transfer to humans, prompting the desire for additional and alternative models. More recently, zebrafish have emerged as a novel and robust animal model for the study of human muscle disease. Zebrafish MD models possess a number of distinct advantages for modeling human muscle disorders, including the availability and ease of generating mutations in homologous disease-causing genes, the ability to image living muscle tissue in an intact animal, and the suitability of zebrafish larvae for large-scale chemical screens. In this chapter, we review the current understanding of molecular and cellular mechanisms involved in MDs, the process of myogenesis in zebrafish, and the structural and functional characteristics of zebrafish larval muscles. We further discuss the insights gained from the key zebrafish MD models that have been so far generated, and we summarize the attempts that have been made to screen for small molecules inhibitors of the dystrophic phenotypes using these models. Overall, these studies demonstrate that zebrafish is a useful in vivo system for modeling aspects of human skeletal muscle disorders. Studies using these models have contributed both to the understanding of the pathogenesis of muscle wasting disorders and demonstrated their utility as highly relevant models to implement therapeutic screening regimens.

Involvement of opioid signaling in food preference and motivation: Studies in laboratory animals.

Motivation is a complex neurobiological process that initiates, directs, and maintains goal-oriented behavior. Although distinct components of motivated behavior are difficult to investigate, appetitive and consummatory phases of motivation are experimentally separable. Different neurotransmitter systems, particularly the mesolimbic dopaminergic system, have been associated with food motivation. Over the last two decades, however, research focusing on the role of opioid signaling has been particularly growing in this area. Opioid receptors seem to be involved, via neuroanatomically distinct mechanisms, in both appetitive and consummatory aspects of food reward. In the present chapter, we review the pharmacology and functional neuroanatomy of opioid receptors and their endogenous ligands, in the context of food reinforcement. We examine literature aimed at the development of laboratory animal techniques to better understand different components of motivated behavior. We present recent data investigating the effect of opioid receptor antagonists on food preference and effort-related decision making in rats, which indicate that opioid signaling blockade selectively affects intake of relatively preferred foods, resulting in reduced willingness to exert effort to obtain them. Finally, we elaborate on the potential role of opioid system manipulations in disorders associated with excessive eating and obesity.

Failure of oral penicillin as secondary prophylaxis for rheumatic heart disease: a lesson from a low-prevalence rheumatic fever region.

Our patient is an 18-year-old Caucasian woman from the UK who developed severe mitral stenosis on a history of childhood acute rheumatic fever (ARF) and rheumatic heart disease (RHD). She had been reporting of her oral penicillin secondary prophylaxis regimen since diagnosis. At the age of 15 years, a new murmur was discovered during routine cardiac follow-up. An echocardiogram confirmed moderate-severe mitral stenosis. One year later, her exercise tolerance significantly deteriorated and she subsequently underwent balloon valvuloplasty of her mitral valve to good effect. Our case emphasises the evidence base supporting the use of monthly intramuscular penicillin injection to prevent ARF recurrence and RHD progression; it also emphasises the reduced efficacy of oral penicillin prophylaxis in this context. It particularly resonates with regions of low rheumatic fever endemicity. The long-term cardiac sequelae of ARF can be devastating; prescribing the most effective secondary prophylaxis regimen is essential.

Decreased anti-regenerative effects after spinal cord injury in spry4-/- mice.

Previously, we have demonstrated a role for fibroblast growth factor (Fgf) in spinal cord regeneration in both zebrafish and mouse. We have shown that exogenous Fgf2 treatment attenuates astrocytic gliosis and induces glia cells to become progenitors that undergo neurogenesis as well as differentiating into bipolar astrocytes that support axonal regeneration (Goldshmit et al., 2012, 2014). One of the downstream signaling target genes of Fgf is spry4, which acts as a feedback inhibitor for Fgf signaling. In this study we examined the effects of increased endogenous Fgf signaling, in spry4-/- mice, on the early events that occur after spinal cord injury (SCI). We demonstrate that in spry4-/- mice inflammatory responses, such as tumor necrosis factor α (TNFα) secretion and macrophage/neutrophil invasion into the lesion site are reduced. In addition, astrocytic gliosis is attenuated and neuronal survival is increased. These results further support a pro-regenerative role of Fgf after SCI, and suggest that increased endogenous Fgf signaling after SCI may contribute to functional recovery and therefore presents this pathway as a target for new therapy development.

Analysing regenerative potential in zebrafish models of congenital muscular dystrophy.

The congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of muscle disorders. Clinically hypotonia is present from birth, with progressive muscle weakness and wasting through development. For the most part, CMDs can mechanistically be attributed to failure of basement membrane protein laminin-α2 sufficiently binding with correctly glycosylated α-dystroglycan. The majority of CMDs therefore arise as the result of either a deficiency of laminin-α2 (MDC1A) or hypoglycosylation of α-dystroglycan (dystroglycanopathy). Here we consider whether by filling a regenerative medicine niche, the zebrafish model can address the present challenge of delivering novel therapeutic solutions for CMD. In the first instance the readiness and appropriateness of the zebrafish as a model organism for pioneering regenerative medicine therapies in CMD is analysed, in particular for MDC1A and the dystroglycanopathies. Despite the recent rapid progress made in gene editing technology, these approaches have yet to yield any novel zebrafish models of CMD. Currently the most genetically relevant zebrafish models to the field of CMD, have all been created by N-ethyl-N-nitrosourea (ENU) mutagenesis. Once genetically relevant models have been established the zebrafish has several important facets for investigating the mechanistic cause of CMD, including rapid ex vivo development, optical transparency up to the larval stages of development and relative ease in creating transgenic reporter lines. Together, these tools are well suited for use in live-imaging studies such as in vivo modelling of muscle fibre detachment. Secondly, the zebrafish's contribution to progress in effective treatment of CMD was analysed. Two approaches were identified in which zebrafish could potentially contribute to effective therapies. The first hinges on the augmentation of functional redundancy within the system, such as upregulating alternative laminin chains in the candyfloss fish, a model of MDC1A. Secondly high-throughput small molecule screens not only provide effective therapies, but also an alternative strategy for investigating CMD in zebrafish. In this instance insight into disease mechanism is derived in reverse. Zebrafish models are therefore clearly of critical importance in the advancement of regenerative medicine strategies in CMD. This article is part of a Directed Issue entitled: Regenerative Medicine: The challenge of translation.

Influence of diabetes on the maintenance of sinus rhythm after a successful direct current cardioversion in patients with atrial fibrillation.

AIM: To determine independent risk factors for recurrence of atrial fibrillation (AF) after a successful direct current (DC) cardioversion in patients with and without diabetes. DESIGN: We retrospectively analysed the outcome in patients recently diagnosed with persistent AF. METHODS: Of 364 patients included, 289 had a successful direct current (DC) cardioversion. We compared 42 (14.5%) patients known to have diabetes to 247 (85.5%) without. Patients were reviewed in outpatient clinic with assessment of heart rhythm clinically and by electrocardiogram. Median follow-up after DC cardioversion was 74 days [interquartile range (IQR) 69-78 days]. RESULTS: When reviewed in outpatient clinic, only 63.7% (185 of 289) were still in sinus rhythm (SR). Of the group without diabetes, 66.8% (165 of 247) remained in SR vs. 45.2% (19 of 42) of the group with diabetes (P = 0.005). Binary logistic regression analysis showed duration of AF (P < 0.0001) and the presence of diabetes (P = 0.019) have been independent risk factors for recurrence of AF. DISCUSSION: Presence of diabetes and the longer duration of AF were independent risk factors for the recurrence of AF after a successful DC cardioversion.

Non-attendance at secondary prevention clinics: the effect on lipid management.

BACKGROUND: Secondary prevention of coronary artery disease is effective in reducing morbitiy and mortality. Our aim was to assess lipid management following non-attendance to a hospital based secondary prevention clinic. METHODS: Data were collected over 5 years on statin usage and total cholesterol levels for patients with coronary artery disease following attendance at a cardiac nurse led outpatient clinic. Lipid levels were taken from a central laboratory database, for both patients discharged from clinic and non-attenders. RESULTS: From 935 inpatients discharged from hospital, 248 (29%) defaulted from outpatient follow up. Lipid lowering drug usage was similar (72% vs. 74% for non-attenders, p=NS). Attenders at the nurse led outpatient clinic were more likely to achieve a total cholesterol <5 mmol/L at discharge than non-attenders (70% vs. 43%; p < 0.001), with a lower mean total cholesterol (4.75 +/- 0.06 mmol/L vs. 5.33 +/- 0.08 mmol/L; p < 0.001). Non-attenders subsequently had a greater number of cholesterol measurements than those who were discharged from the hospital based clinic (range 0-12, c2 23.8 on 12 df p < 0.005). Lipid profiles in hospital non-attenders remained inferior with fewer achieving a total cholesterol <5 mmol/L (61% vs. 78%; p < 0.001), and having greater mean total cholesterol levels (4.85 +/- 0.06 mmol/L vs. 4.52 +/- 0.05 mmol/L; p < 0.001). CONCLUSIONS: Patients defaulting from hospital follow up have higher total cholesterols with fewer at target level compared to attenders. Though non-attenders receive subsequent lipid measurement, inferior lipid profiles persist compared to patients who completed hospital follow up to be discharged. Further implementation strategies are needed with regard to lipid management in this patient group.

Myosin heavy chain expression in zebrafish and slow muscle composition.

In the zebrafish embryo, two distinct classes of muscle fibers have been described in the forming myotome that arise from topographically separable precursor populations. Based entirely on cross-reactivity with antibodies raised against mammalian and chick myosin heavy chain isoforms slow twitch muscle has been shown to arise exclusively from "adaxial" myoblasts, which migrate from their origin flanking the notochord to form a single layer of subcutaneous differentiated muscle cells. The remainder of the myotome differentiates behind this migration as muscle fibers recognized by anti-fast myosin heavy chain (MyHC) antibodies. To identify unambiguous molecular markers of cell fate in the myotome, we have characterized genes encoding zebrafish fast and slow MyHC. Using phylogenetic and expression analysis, we demonstrate that these genes are definitive molecular markers of slow and fast twitch fates. We also demonstrate that zebrafish embryonic slow twitch muscle co-expresses both slow and fast twitch MyHC isoforms, a property that they share with primary fibers of the amniote myotome.

Troponin T: how high is high? Relationship and differences between serum cardiac markers according to level of creatine kinase and type of myocardial infarction.

Cardiac troponins have emerged over recent years as the "gold standard" serum biochemical marker for the diagnosis and management for patients with acute myocardial infarction (MI). The relationship between old (creatine kinase; CK) and new (troponin T; TT) markers of myocardial injury were examined in this study of 392 consecutive patients admitted to a district hospital with a diagnosis of an acute MI. Significant correlation of serum TT and peak CK levels were seen (R = 0.58, p<0.0001) in all types of MI. A significant relationship was also seen according to type of MI (Q wave or non-Q wave MI) or peak CK level. The regression equation (TT (microg/l) = 0.0027 (peak CK) + 1.1160 (IU/l)) may be used by clinicians to estimate TT release from a known peak CK result and thus provide some guidance on equivalence between the two tests. Our findings provide physicians with a benchmark reference range between the two cardiac markers, according to level of peak CK.

Secondary prevention for coronary artery disease.

BACKGROUND: Secondary prevention of coronary artery disease is effective in reducing morbidity and mortality, but deficiencies in implementation and prescription bias have been identified. AIM: To assess progress in secondary prevention measures for coronary heart disease and whether there was a difference between patient subgroups with angina, post myocardial infarction or revascularization. DESIGN: Retrospective analysis. METHODS: Between 1997 and 2001, data were collected on prophylactic prescribing, demographic and lifestyle information, at baseline and 1 year following attendance at a hospital-based, cardiac-nurse-led out-patient clinic. RESULTS: Patients (n = 945) were entered into the database at hospital discharge and 619 (72%) attended at 1 year. Aspirin and statin prescribing increased, though ACE inhibitor use was less. Mean total cholesterol at baseline reduced to 4.92 +/- 0.11 mmol/l (p < 0.001) in 2000, with a further reduction to 4.59 +/- 0.08 mmol/l at the 1-year visit in 2001 (p < 0.001). The proportion of patients with total cholesterol < 5 mmol/l increased to 38% in 2000, reaching 70% in 2001. Smokers at baseline were similar at around 30%, although this had reduced to 10% in 2001 (p < 0.001). No change in weight was seen for patients with BMI >or=30 (p = NS). No significant differences were seen between patient subgroups (p = NS). DISCUSSION: Secondary prevention measures are improving, especially in prophylactic prescribing, lipid management and smoking cessation, although scope for further improvement remains. No difference was seen between the patient subgroups. Lifestyle measures need to be addressed to gain maximum benefit in addressing overall cardiovascular risk.