Effect of demyelinating ulnar nerve injury on strength and fatigue

PURPOSE: The aim of the current study was to examine the effect of ulnar nerve conduction block on the strength and fatiguability of the first dorsal interosseous muscle (FDI). METHODS: Eight controls and nine patients presenting with ulnar nerve conduction block (CB) performed index finger abduction (FDI contraction) maximal voluntary contractions (MVC’s) using a custom-built hand dynamometer to assess strength. Isometric FDI contractions held at 70% MVC until failure were used to assess fatiguability. Affected and healthy sides were tested to allow for comparison within individuals. RESULTS: CB affected side demonstrated significant decreases in strength and muscle endurance versus the unaffected side and controls. The extent of CB was positively correlated with the decrements in strength and endurance. CONCLUSION: The decrement in strength was due to an inability to recruit all of the available muscle fibres in the limb affected by CB. The decrease in endurance was possibly a result of frequency-dependent conduction block during sustained muscle contractio

Impacts of Diabetic Neuropathy on the Human Neuromuscular System

Diabetes mellitus (DM) imparts vascular and metabolic stressors that cause damage and dysfunction to the human nervous system. The disorder associated with this dysfunction is termed diabetic polyneuropathy (DPN). Although DPN has been associated with muscle weakness and atrophy, the extent of its impacts on the neuromuscular system is not well understood. The five studies presented in my thesis investigated how DPN affects the neuromuscular system in humans, from the motor neuron to skeletal muscle contractile properties, using a combination of electromyography (EMG), dynamometry and magnetic resonance imaging (MRI) techniques. The purpose of Studies 1 and 2 was to determine whether the neurogenic loss of motor units underlies the muscle weakness and atrophy associated with DPN, and to investigate how these changes may differ in an upper and lower limb muscle. I determined DPN patients feature reduced motor unit estimates (MUNEs) compared to controls, and progression of motor unit loss in DPN may follow a length-dependent pattern. The purpose of Study 3 was to assess the stability of neuromuscular transmission in patients with DPN compared with healthy controls, using a novel set of electrodiagnostic parameters obtained via quantitative EMG. I determined DPN patients have less stable neuromuscular transmission, and the feature intermittent conduction failure at a relatively low contraction intensity. The purpose of Study 4 was to investigate skeletal muscle contractile properties and morphology in DPN patients associated with the severity of muscle denervation. I determined DPN patients possess slowed muscle, with greater proportional amounts of non-contractile muscle tissue compared to controls. The purpose of Study 5 was to explore the fatigability of DPN patients during a sustained, maximal voluntary contraction (MVC). I determined DPN patients have less endurance than controls, and their increased fatigability may be associated with neuromuscular transmission failure. Overall these foundational explorations greatly expand our knowledge of how DPN can impact the neuromuscular system in humans. Furthermore, the studies contained within my thesis may help direct further useful studies and strategies to understand, and direct clinical support in those with DPN

Acute changes in forearm vascular compliance during transient sympatho-excitation

The study of vascular regulation often omits important information about the elastic properties of arteries under conditions of pulsatile flow. The purpose of this study was to examine the relationship between muscle sympathetic nerve activity (MSNA), vascular bed compliance, and peripheral blood flow responses in humans. We hypothesized that increases in MSNA would correlate with reductions in vascular compliance, and that changes in compliance would correspond with changes in peripheral blood flow during sympatho-excitation. MSNA (microneurography), blood pressure (Finopres), and brachial artery blood flow (Doppler ultrasound), were monitored in six healthy males at baseline and during the last 15 s of voluntary end-inspiratory, expiratory apneas and 5 min of static handgrip exercise (SHG; 20% maximum voluntary contraction) and 3 min of post-exercise circulatory occlusion (SHG + PECO; measured in the non-exercising arm). A lumped Windkessel model was employed to examine vascular bed compliance. During apnea, indices of MSNA were inversely related with vascular compliance, and reductions in compliance correlated with decreased brachial blood flow rate. During SHG, despite increased MSNA, compliance also increased, but was unrelated to increases in blood flow. Neither during SHG nor PECO did indices of MSNA correlate with forearm vascular compliance nor did vascular compliance correlate with brachial flow. However, during PECO, a linear combination of blood pressure and total MSNA was correlated with vascular compliance. These data indicate the elastic components of the forearm vasculature are regulated by adrenergic and myogenic mechanisms during sympatho-excitation, but in a reflex-dependent manner

Effect of Acute High-intensity Interval Exercise on Whole-body Fat Oxidation and Subcutaneous Adipose Tissue Cell Signaling in Overweight Women

International Journal of Exercise Science 13(2): 554-566, 2020. Exercise-induced alterations in adipose tissue insulin and/or β-adrenergic signaling may contribute to increases in whole-body fat oxidation following acute exercise. Thus, we examined changes in insulin (Akt, AS160) and β-adrenergic (PKA) signaling proteins in subcutaneous adipose tissue and whole-body fat oxidation in overweight women following acute high-intensity interval exercise (HIIE). Overweight females completed two experimental sessions in a randomized order: 1) control (bed rest) and 2) HIIE (10 x 4 min running intervals at 90% HRmax, 2-min recovery). Subcutaneous abdominal adipose tissue biopsies were obtained from 10 participants before (pre-), immediately (0hr) after (post-), 2hr post-, and 4hr post-exercise. Plasma glucose and insulin levels were assessed in venous blood samples obtained at each biopsy time-point from a different group of 5 participants (BMI-matched to biopsy group). Fat oxidation rates were estimated using the respiratory exchange ratio (RER) in all participants using indirect calorimetry pre-, 2hr post-, and 4hr post-exercise. RER was decreased (p \u3c 0.05) at 2hr post-exercise after HIIE (0.77 ± 0.04) compared to control (0.84 ± 0.04). Despite higher plasma glucose (p \u3c 0.01) and insulin (p \u3c 0.05) levels at 0hr post-exercise versus control, no significant interaction effects were observed for Akt or AS160 phosphorylation (p \u3e 0.05). Phosphorylation of PKA substrates was unaltered in both conditions (p \u3e 0.05). Collectively, altered β-adrenergic and insulin signaling in subcutaneous adnominal adipose tissue does not appear to explain increased whole-body fat oxidation following acute HIIE

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Remodelling of Cortical Actin Where Lytic Granules Dock at Natural Killer Cell Immune Synapses Revealed by Super-Resolution Microscopy

Super-resolution 3D imaging reveals remodeling of the cortical actin meshwork at the natural killer cell immune synapse, which is likely to be important for secretion of lytic granules

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London