Laurie Gutmann

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial

Background: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. Methods: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. Results: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. Conclusions: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis. GLOSSARY: ALS = amyotrophic lateral sclerosis; ALSFRS-r = revised ALS functional rating scale; AUC = area under the curve; DVT = deep venous thromboses; IGF-1 = insulin-like growth factor type I; MMT = manual muscle testing; PE = pulmonary embolisms.

Myokymia and neuromyotonia 2004.

Myokymia and neuromyotonia are related clinical phenomena that result from hyperexcitability of peripheral nerve motor axons.Whether they are really separate and distinct clinical entities or just reflect a difference in the severity of the same underlying electrophysiological abnormality remains undetermined. Both may occur in a generalized or focal fashion and reflect a generalized or focal alteration in the microenvironment or membrane of the peripheral nerve. Other related terms include facial myokymia, generalized myokymia, myokymia with impaired muscular relaxation, syndrome of continuous muscle-fiber activity, Isaacs’ syndrome, neurotonia, Morvan’s syndrome, and Morvan’s fibrillary chorea [1, 5.6, 9.12, 13, 14, 15]. Alterations of peripheral nerve voltage gated K+channels (VGKC) have recently been associated with several examples of both phenomena, e. g. VGKC antibodies in generalized neuromyotonia (Isaacs’ syndrome) [21] and persistent facial myokymia [11]. Adding to the confusion surrounding the two clinical phenomena are the terms myokymic and neuromyotonic discharges – the spontaneous repetitive discharges arising from the hyperexcitable axon membrane – that reflect the underlying pathophysiology of myokymia and neuromyotonia [6]. Myokymic and neuromyotonic discharges

Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy

We sought to determine whether acute resistance exercise (RE)-induced gene expression is modified by RE training. We studied the expression patterns of a select group of genes following an acute bout of RE in naïve and hypertrophying muscle. Thirteen untrained subjects underwent supervised RE training for 12 wk of the nondominant arm and performed an acute bout of RE 1 wk after the last bout of the training program (training+acute). The dominant arm was either unexercised (control) or subjected to the same acute exercise bout as the trained arm (acute RE). Following training, men (14.8 ± 2.8%; P < 0.05) and women (12.6 ± 2.4%; P < 0.05) underwent muscle hypertrophy with increases in dynamic strength in the trained arm (48.2 ± 5.4% and 72.1 ± 9.1%, respectively; P < 0.01). RE training resulted in attenuated anabolic signaling as reflected by a reduction in rpS6 phosphorylation following acute RE. Changes in mRNA levels of genes involved in hypertrophic growth, protein degradation, angiogenesis, and metabolism commonly expressed in both men and women was determined 4 h following acute RE. We show that RE training can modify acute RE-induced gene expression in a divergent and gene-specific manner even in genes belonging to the same ontology. Changes in gene expression following acute RE are multidimensional, and may not necessarily reflect the actual adaptive response taking place during the training process. Thus RE training can selectively modify the acute response to RE, thereby challenging the use of gene expression as a marker of exercise-induced adaptations.

Axonal channelopathies An evolving concept in the pathogenesis of peripheral nerve disorders

Abnormalities of peripheral nerve Na sup + and K sup + channels result in clinical manifestions unrelated to axonal degeneration or demyelination.Na sup + channel blockade causes weakness and sensory loss associated with slowed conduction and decreased motor and sensory action potential amplitudes. K sup + channel abnormalities result in high frequency repetitive action potentials (e.g., myokymia). Ion channel abnormalities may also play an important role in electrophysiologic changes seen in demyelinating disorders. NEUROLOGY 1996;47: 18-21

Resistance exercise training influences skeletal muscle immune activation: a microarray analysis.

The primary aim of this investigation was to evaluate the effect of training on the immune activation in skeletal muscle in response to an acute bout of resistance exercise (RE). Seven young healthy men and women underwent a 12-wk supervised progressive unilateral arm RE training program. One week after the last training session, subjects performed an acute bout of bilateral RE in which the trained and the untrained arm exercised at the same relative intensity. Muscle biopsies were obtained 4 h postexercise from the biceps brachii of both arms and assessed for global transcriptom using Affymetrix U133 plus 2.0 microarrays. Significantly regulated biological processes and gene groups were analyzed using a logistic regression-based method following differential (trained vs. untrained) gene expression testing via an intensity-based Bayesian moderated t-test. The results from the present study suggest that training blunts the transcriptional upregulation of immune activation by minimizing expression of genes involved in monocyte recruitment and enhancing gene expression involved in macrophage anti-inflammatory polarization. Additionally, our data suggest that training blunts the transcriptional upregulation of the stress response and the downregulation of glucose metabolism, mitochondrial structure, and oxidative phosphorylation, and it enhances the transcriptional upregulation of the extracellular matrix and cytoskeleton development and organization and the downregulation of gene transcription and muscle contraction. This study provides novel insight into the molecular processes involved in the adaptive response of skeletal muscle following RE training and the cellular and molecular events implicating the protective role of training on muscle stress and damage inflicted by acute mechanical loading.

When is myokymia neuromyotonia

The term neuromyotonia has recently become popular in describing a syndrome (also referred to as Isaacs’ syndrome) characterized by generalized muscle stiffness and persistent contraction related to underlying spontaneous repetitive firing of motor unit potentials. A recent review of this disorder by Vincent was published in Muscle & Nerve. In the literature, the terms neuromyotonia, myokymia, and myokymic and neuromyotonic discharges are not used in any consistent fashion. In the past, the term generalized myokymia was also applied to this syndrome. Gardner-Medwin and Walton referred to it as myokymia with impaired muscle relaxation. Myokymia and neuromyotonia describe similar clinical circumstances, and myokymic and neuromyotonic discharges are related. Other terms that have been used to refer to the syndrome of neuromyotonia include generalized myokymia, myokymia with impaired relaxation, syndrome of continuous muscle-fiber activity, Isaacs’ syndrome, neurotonia, Morvan’s syndrome, and Morvan’s fibrillary chorea. These interrelated clinical terms need to be distinguished from the electrophysiological phenomena of myokymic and neuromyotonic discharges. The origin and appropriate use of these terms are reviewed.

Skeletal muscle gene expression in response to resistance exercise: sex specific regulation

BackgroundThe molecular mechanisms underlying the sex differences in human muscle morphology and function remain to be elucidated. The sex differences in the skeletal muscle transcriptome in both the resting state and following anabolic stimuli, such as resistance exercise (RE), might provide insight to the contributors of sexual dimorphism of muscle phenotypes. We used microarrays to profile the transcriptome of the biceps brachii of young men and women who underwent an acute unilateral RE session following 12 weeks of progressive training. Bilateral muscle biopsies were obtained either at an early (4 h post-exercise) or late recovery (24 h post-exercise) time point. Muscle transcription profiles were compared in the resting state between men (n = 6) and women (n = 8), and in response to acute RE in trained exercised vs. untrained non-exercised control muscle for each sex and time point separately (4 h post-exercise, n = 3 males, n = 4 females; 24 h post-exercise, n = 3 males, n = 4 females). A logistic regression-based method (LRpath), following Bayesian moderated t-statistic (IMBT), was used to test gene functional groups and biological pathways enriched with differentially expressed genes.ResultsThis investigation identified extensive sex differences present in the muscle transcriptome at baseline and following acute RE. In the resting state, female muscle had a greater transcript abundance of genes involved in fatty acid oxidation and gene transcription/translation processes. After strenuous RE at the same relative intensity, the time course of the transcriptional modulation was sex-dependent. Males experienced prolonged changes while females exhibited a rapid restoration. Most of the biological processes involved in the RE-induced transcriptional regulation were observed in both males and females, but sex specificity was suggested for several signaling pathways including activation of notch signaling and TGF-beta signaling in females. Sex differences in skeletal muscle transcriptional regulation might implicate a mechanism behind disproportional muscle growth in males as compared with female counterparts after RE training at the same relative intensity.ConclusionsSex differences exist in skeletal muscle gene transcription both at rest and following acute RE, suggesting that sex is a significant modifier of the transcriptional regulation in skeletal muscle. The findings from the present study provide insight into the molecular mechanisms for sex differences in muscle phenotypes and for muscle transcriptional regulation associated with training adaptations to resistance exercise.

RESISTANCE TRAINING EXERCISE AND CREATINE IN PATIENTS WITH CHARCOT-MARIE-TOOTH DISEASE

Resistance exercise and creatine supplementation independently improve strength and function in patients with certain neuromuscular diseases. The purpose of this study was to examine the effects of resistance training with and without creatine supplementation on muscle, strength, and function in patients with Charcot–Marie–Tooth (CMT) disease. Twenty patients with CMT consumed 5 g/day creatine or placebo while participating in resistance training for 12 weeks. Energy metabolites, muscle fiber type and size, strength, and timed activities of daily living were measured before and after training. There were no differences between creatine or placebo groups for any outcome. For the groups combined, exercise training increased type I muscle fiber diameter (48.2 ± 14.2 μm vs. 55.4 ± 14.8 μm), strength, and activities of daily living (ADL) times. Thus, patients respond to resistance training with muscle fiber adaptations, and improvements in strength and function. Creatine was not beneficial.

Microarray Analysis Reveals Novel Features of the Muscle Aging Process in Men and Women

To develop a global view of muscle transcriptional differences between older men and women and sex-specific aging, we obtained muscle biopsies from the biceps brachii of young and older men and women and profiled the whole-genome gene expression using microarray. A logistic regression-based method in combination with an intensity-based Bayesian moderated t test was used to identify significant sex- and aging-related gene functional groups. Our analysis revealed extensive sex differences in the muscle transcriptome of older individuals and different patterns of transcriptional changes with aging in men and women. In older women, we observed a coordinated transcriptional upregulation of immune activation, extracellular matrix remodeling, and lipids storage; and a downregulation of mitochondrial biogenesis and function and muscle regeneration. The effect of aging results in sexual dimorphic alterations in the skeletal muscle transcriptome, which may modify the risk for developing musculoskeletal and metabolic diseases in men and women.

Admission neutrophil–lymphocyte ratio predicts 90 day outcome after endovascular stroke therapy

Objective Immune dysregulation influences outcome following acute ischemic stroke (AIS). Admission white blood cell (WBC) counts are routinely obtained, making the neutrophil–lymphocyte ratio (NLR) a readily available biomarker of the immune response to stroke. This study sought to identify the relationship between NLR and 90 day AIS outcome. Methods A retrospective analysis was performed on patients who underwent endovascular therapy for AIS at West Virginia University Hospitals, Morgantown, West Virginia. Admission WBC differentials were analyzed as the NLR. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS) score and outcome by the modified Rankin Scale (mRS) score at 90 days. Univariate relationships between NLR, age, NIHSS, and mRS were established by correlation coefficients; the t test was used to compare NLR with recanalization and stroke location (anterior vs posterior). Logistic regression models were developed to identify the ability of NLR to predict mRS when controlling for age, recanalization, and treatment with IV tissue plasminogen activator (tPA). Results 116 patients were reviewed from 2008 to 2011. Mean age of the sample was 67 years, and 54% were women. Mean baseline NIHSS score was 17 and 90 day mRS score was 4. There was a significant relationship between NLR and mRS (p=0.02) that remained when controlling for age, treatment with IV tPA, and recanalization. NLR ≥5.9 predicted poor outcome and death at 90 days. Conclusions This study shows that the NLR, a readily available biomarker, may be a clinically useful tool for risk stratification when evaluating AIS patients as candidates for endovascular therapies.