Effect of diacutaneous fibrolysis on the muscular properties of gastrocnemius muscle

Diacutaneous fibrolysis is a noninvasive technique that has been shown to be effective in the treatment of musculoskeletal disorders such as shoulder pain, lateral epicondylalgia, patellofemoral pain syndrome and carpal tunnel syndrome. However, while diacutaneous fibrolysis is applied to soft tissue, its effects on muscular properties are unknown. The purpose of the present study was to evaluate the effects of diacutaneous fibrolysis on muscle properties as measured by tensiomyography and myotonometry in asymptomatic subjects. An analytical descriptive study was performed. A single session of diacutaneous fibrolysis on the gastrocnemius muscle was applied to one limb (treated limb group) and the other limb was the control (control limb group). Subjects were assessed with tensiomyography and myotonometry before treatment (T0), after treatment (T1) and 30 minutes later (T2). The primary outcomes were tensiomyography and myotonometry variables. The treated limb group showed a statistically significant increase (p<0.05) in tensiomyography parameters. A decrease in rigidity and increase in relaxation was also observed on myotonometry at T1, with some of the effects being maintained at T2. Rigidity and relaxation at T1 were statistically significant between groups (p<0.05). A single session of diacutaneous fibrolysis to the gastrocnemius muscle of asymptomatic subjects produced immediate changes in muscle properties. These changes were maintained 30 minutes after the application of the technique

Prebreakdown and Breakdown Behaviour of Low Pour Point Dielectric Liquids Under Negative Lightning Impulse Voltage

In this article, some investigations on the prebreakdown and breakdown phenomena of low pour point insulating liquids under negative lightning impulse (LI) voltage are reported. The tested liquids include mineral oil (MO), a typical synthetic ester (TSE), and two low-pour point synthetic esters. These liquids underwent accelerated thermal aging. The nonaged and aged samples were subjected to LIs using a point-plane electrode arrangement. The discussions are focused on the initiation of partial discharges, propagation of streamers, and breakdown behavior in the nonaged and aged liquids. The investigated parameters include inception voltage, LI breakdown voltage, streamer acceleration voltage, and streamer velocity. The results are supported by the oscillographs of the light activity that is recorded during the discharge process. The prebreakdown phenomenon noticed in the TSE vis-à-vis mineral insulating oil is in line with the existing literature. Importantly, it is noticed that the inception and breakdown voltages of the nonaged low pour point synthetic esters are similar to nonaged MO. In addition, the inception and breakdown voltages of the aged low pour point synthetic esters are noticed to be higher than that of the aged MO. These results add to the arguments in favor of replacing MOs in power transformers

Analysis of Breakdown Voltage of Low Pour Point Synthetic Ester Insulating Liquids under Lightning Impulse Voltage of both Polarities

In this article, lightning impulse breakdown behaviour of two low pour point synthetic ester liquids is presented in comparison to a typical synthetic ester at both positive and negative polarities. Traditional mineral insulating oil has been also considered for reference purposes. A detailed breakdown behaviour analysis of the four test liquids under a non-uniform field (medium gap, point-plane electrode system) and quasi-uniform field (smaller gap, U-plane electrode system) is envisaged. The lightning impulse breakdown measurements based on the source voltage waveforms and light activity during the discharge process are presented. The Weibull breakdown failure rates and streamer velocity during the breakdown of different liquids for all the cases (+/- polarities and both electrode configurations) are reported in support of the discussions. In the case of non-uniform fields, the lightning breakdown voltage of the low pour point liquids is found to be higher than typical synthetic esters and is comparable to mineral oil under both polarities. While in the case of quasi-uniform field, the lightning breakdown voltage of the low pour point liquids is found to be lower than mineral oil and comparable to the typical synthetic ester under both polarities. These findings add to limited knowledge on the application of esters in cold countries and allow insulation designers to estimate the behaviour of the low pour point synthetic ester liquids under lightning conditions

The synovial and blood monocyte DNA methylomes mirror prognosis, evolution and treatment in early arthritis

Identifying predictive biomarkers at early stages of early inflammatory arthritis is crucial for starting appropriate therapies to avoid poor outcomes. Monocytes and macrophages, largely associated with arthritis, are contributors and sensors of inflammation through epigenetic modifications. In this study, we investigated associations between clinical features and DNA methylation in blood and synovial fluid (SF) monocytes in a prospective cohort of early inflammatory arthritis patients. Undifferentiated arthritis (UA) blood monocyte DNA methylation profiles exhibited significant alterations in comparison with those from healthy donors. We identified additional differences both in blood and SF monocytes after comparing UA patients grouped by their future outcomes, good versus poor. Patient profiles in subsequent visits revealed a reversion towards a healthy level in both groups, those requiring disease-modifying antirheumatic drugs (DMARDs) and those that remitted spontaneously. Changes in disease activity between visits also impacted DNA methylation, partially concomitant in the SF of UA and in blood monocytes of rheumatoid arthritis patients. Epigenetic similarities between arthritis types allow a common prediction of disease activity. Our results constitute a resource of DNA methylation-based biomarkers of poor prognosis, disease activity and treatment efficacy in early untreated UA patients for the personalized clinical management of early inflammatory arthritis patients

Congenital leptin deficiency and leptin gene missense mutation found in two colombian sisters with severe obesity

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

Modulation of Statin-Activated Shedding of Alzheimer APP Ectodomain by ROCK

BACKGROUND: Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate α-secretase-type shedding of the α-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPP(α)). Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases—Rho A, B, and C—as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs). Several cell-surface molecules are substrates for activated α-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved. METHODS AND FINDINGS: We found that both atorvastatin and simvastatin stimulated sAPP(α) shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPP(α) shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPP(α) shedding. CONCLUSION: Together, these data suggest that statins exert their effects on shedding of sAPP(α) from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1

Drosophila Araucan and Caupolican Integrate Intrinsic and Signalling Inputs for the Acquisition by Muscle Progenitors of the Lateral Transverse Fate

A central issue of myogenesis is the acquisition of identity by individual muscles. In Drosophila, at the time muscle progenitors are singled out, they already express unique combinations of muscle identity genes. This muscle code results from the integration of positional and temporal signalling inputs. Here we identify, by means of loss-of-function and ectopic expression approaches, the Iroquois Complex homeobox genes araucan and caupolican as novel muscle identity genes that confer lateral transverse muscle identity. The acquisition of this fate requires that Araucan/Caupolican repress other muscle identity genes such as slouch and vestigial. In addition, we show that Caupolican-dependent slouch expression depends on the activation state of the Ras/Mitogen Activated Protein Kinase cascade. This provides a comprehensive insight into the way Iroquois genes integrate in muscle progenitors, signalling inputs that modulate gene expression and protein activity

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors

Association between T2-related co-morbidities and effectiveness of biologics in severe asthma

Acknowledgments The authors thank Mr. Joash Tan (BSc, Hons), of the Observational and Pragmatic Research Institute (OPRI), and Ms Andrea Lim (BSc, Hons) of the Observational Pragmatic Research Institute (OPRI) for their editorial and formatting assistance that supported the development of this publication. Funding statement: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. AstraZeneca UK LimitedPeer reviewe