Auditory and vestibular function in mitochondrial patients harbouring the m.3243A>G variant.

Hearing impairment is a frequent clinical feature in patients with mitochondrial disease harbouring the pathogenic variant, m.3243A>G. However, auditory neural dysfunction, its perceptual consequences and implications for patient management are not established.

Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers.

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.

Phase II Feasibility Study of the Efficacy, Tolerability, and Impact on the Gut Microbiome of a Low-Residue (Fiber) Diet in Adult Patients With Mitochondrial Disease.

Background And Aims: Gastrointestinal (GI) dysmotility is a common and debilitating clinical manifestation in patients with mitochondrial DNA (mtDNA)-related disease with no curative and few effective symptomatic therapies. A low-residue diet (LRD) has been shown to be effective at reducing bowel urgency, pain, and distension in functional GI-related conditions. We assessed tolerability and effects of an LRD on bowel habits in patients with mtDNA-related disease.

Amino acid divergence in the ligand-binding pocket of Vibrio LuxR/HapR proteins determines the efficacy of thiophenesulfonamide inhibitors.

The quorum-sensing signaling systems in Vibrio bacteria converge to control levels of the master transcription factors LuxR/HapR, a family of highly conserved proteins that regulate gene expression for bacterial behaviors. A compound library screen identified 2-thiophenesulfonamide compounds that specifically inhibit Vibrio campbellii LuxR but do not affect cell growth. We synthesized a panel of 50 thiophenesulfonamide compounds to examine the structure-activity relationship effects on Vibrio quorum sensing.

Interventions for promoting physical activity in people with neuromuscular disease.

Background: The World Health Organization (WHO) recommends that people of all ages take regular and adequate physical activity. If unable to meet the recommendations due to health conditions, international guidance advises being as physically active as possible. Evidence from community interventions of physical activity indicate that people living with medical conditions are sometimes excluded from participation in studies.

The DNA binding domain of the Vibrio vulnificus SmcR transcription factor is flexible and binds diverse DNA sequences.

Quorum sensing gene expression in vibrios is regulated by the LuxR/HapR family of transcriptional factors, which includes Vibrio vulnificus SmcR. The consensus binding site of Vibrio LuxR/HapR/SmcR proteins is palindromic but highly degenerate with sequence variations at each promoter. To examine the mechanism by which SmcR recognizes diverse DNA sites, we generated SmcR separation-of-function mutants that either repress or activate transcription but not both.

Purification of the Vibrio Quorum-Sensing Transcription Factors LuxR, HapR, and SmcR.

Quorum sensing is a cell density-dependent form of cellular communication among bacteria. This signaling process has been heavily studied in vibrios due to their diverse and complex phenotypes and relevance to human and aquaculture disease. Mechanistic studies of Vibrio quorum sensing have required optimization of protein purification techniques to examine the role of key proteins, such as the LuxR/HapR family of transcription factors that control quorum-sensing gene expression.

Measuring the effects of exercise in neuromuscular disorders: a systematic review and meta-analyses.

The benefit and safety of exercise training for patients with neuromuscular disorders (NMDs) has long been a contentious topic. This is, in part, due to recognised challenges associated with rare diseases including small and heterogenous patient populations. We performed a systematic review and meta-analyses to evaluate the effectiveness and safety of interventional exercise and establish minimal clinically important differences (MCID) in outcomes to facilitate clinical interpretation.

Species-Specific Quorum Sensing Represses the Chitobiose Utilization Locus in Vibrio cholerae.

The marine facultative pathogen forms complex multicellular communities on the chitinous shells of crustacean zooplankton in its aquatic reservoir. -chitin interactions are critical for the growth, evolution, and waterborne transmission of cholera. This is due, in part, to chitin-induced changes in gene expression in this pathogen.

Metabolic effects of bezafibrate in mitochondrial disease.

Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.

Twitter Activity Is Associated With a Higher Research Citation Index for Academic Thoracic Surgeons.

Background: Academic surgeons are encouraged to promote their work on social media. We hypothesized that thoracic surgeons who are active on Twitter have a higher research citation index (Hirsch index [h-index]) than their counterparts who are not.

Methods: Thoracic surgeons on CTSNet.

Analysis of the functional capacity outcome measures for myotonic dystrophy.

Objectives: Defining clinically relevant outcome measures for myotonic dystrophy type 1 (DM1) that can be valid and feasible for different phenotypes has proven problematic. The Outcome Measures for Myotonic Dystrophy (OMMYD) group proposed a battery of functional outcomes: 6-minute walk test, 30 seconds sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine-hole peg test. This, however, required a large-scale investigation, METHODS: A cohort of 213 patients enrolled in the natural history study, PhenoDM1, was analyzed in cross-sectional analysis and subsequently 98 patients were followed for longitudinal analysis.

shedding and seropositivity and its association with in-feed flavophospholipol in nursery pigs.

The objective of this study was to assess the impact of in-feed flavophospholipol on shedding and antibody response in nursery pigs. Weaned pigs were fed either a diet containing 4 ppm flavophospholipol ( = 16) or a non-medicated feed ( = 16) for 36 d. All pigs were orally challenged with a 2-mL dose of 10 colony-forming units (CFUs)/mL of Typhimurium on Days 7 and 8 of the trial.

fecal shedding in pigs from birth to market and its association with the presence of in palatine tonsils and submandibular lymph nodes at slaughter.

is an important cause of foodborne illnesses in humans. Food-producing animals, including swine, are a major source of in food products. This study investigated on farm fecal shedding in pigs at different production stages - from weaning to marketing - and its association with the presence of in tissues at slaughter.

Pathological mechanisms underlying single large-scale mitochondrial DNA deletions.

Objective: Single, large-scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large-scale mtDNA deletions in skeletal muscle.

Methods: We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large-scale mtDNA deletions.

Pathophysiology of exercise intolerance in chronic diseases: the role of diminished cardiac performance in mitochondrial and heart failure patients.

Objective: Exercise intolerance is a clinical hallmark of chronic conditions. The present study determined pathophysiological mechanisms of exercise intolerance in cardiovascular, neuromuscular, and metabolic disorders.

Methods: In a prospective cross-sectional observational study 152 patients (heart failure reduced ejection fraction, n=32; stroke, n=34; mitochondrial disease, n=28; type two diabetes, n=28; and healthy controls, n=30) performed cardiopulmonary exercise testing with metabolic and haemodynamic measurements.

Measuring Habitual Physical Activity in Neuromuscular Disorders: A Systematic Review.

Background: Free-living or habitual physical activity (HPA) refers to someone's performance in his or her free-living environment. Neuromuscular disorders (NMD) manifest through HPA, and the observation of HPA can be used to identify clinical risks and to quantify outcomes in research. This review summarizes and analyses previous studies reporting the assessment of HPA in NMD, and may serve as the basis for evidence-based decision-making when considering assessing HPA in this population.

Preliminary Evaluation of Clinician Rated Outcome Measures in Mitochondrial Disease.

Background: Currently there are no known cures and few effective treatments for mitochondrial disorders. It is also true there is a lack of knowledge about suitable clinician rated outcomes and how these change over time in this patient cohort.

Objective: We sought to evaluate the validity and responsiveness to change of clinician rated outcome measures in patients with m.

Perceived fatigue is highly prevalent and debilitating in patients with mitochondrial disease.

Perceived fatigue is a prominent symptom in patients with mitochondrial disease but to date its prevalence, impact and aetiology are poorly understood. Our aim was to determine the prevalence and assess for comorbidities associated with clinically relevant fatigue in patients with mitochondrial disease. A cross-sectional postal survey of patients with mitochondrial disease was undertaken using a validated self-completion, patient-reported outcome measures (response rate: 60%; n = 132).

Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression.

Complex I (CI) is the largest of the five multi-subunit complexes constituting the human oxidative phosphorylation (OXPHOS) system. Seven of its catalytic core subunits are encoded by mitochondrial DNA (ND (NADH dehydrogenase)1-6, ND4L (NADH dehydrogenase subunit 4L)), with mutations in all seven having been reported in association with isolated CI deficiency. We investigated two unrelated adult patients presenting with marked exercise intolerance, persistent lactic acidaemia and severe muscle-restricted isolated CI deficiency associated with sub-sarcolemmal mitochondrial accumulation.

Discrete gait characteristics are associated with m.3243A>G and m.8344A>G variants of mitochondrial disease and its pathological consequences.

Mitochondrial disease is complex and variable, making diagnosis and management challenging. The situation is complicated by lack of sensitive outcomes of disease severity, progression, contributing pathology and clinical efficacy. Gait is emerging as a sensitive marker of pathology; however, to date, no studies have quantified gait in mitochondrial disease.

Mitochondrial DNA deletions in muscle satellite cells: implications for therapies.

Progressive myopathy is a major clinical feature of patients with mitochondrial DNA (mtDNA) disease. There is limited treatment available for these patients although exercise and other approaches to activate muscle stem cells (satellite cells) have been proposed. The majority of mtDNA defects are heteroplasmic (a mixture of mutated and wild-type mtDNA present within the muscle) with high levels of mutated mtDNA and low levels of wild-type mtDNA associated with more severe disease.

Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease.

Background: Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown.

Methods And Results: Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.