Michael F. Azari

Mesenchymal Stem Cells for Treatment of CNS Injury

Brain and spinal cord injuries present significant therapeutic challenges. The treatments available for these conditions are largely ineffective, partly due to limitations in directly targeting the therapeutic agents to sites of pathology within the central nervous system (CNS). The use of stem cells to treat these conditions presents a novel therapeutic strategy. A variety of stem cell treatments have been examined in animal models of CNS trauma. Many of these studies have used stem cells as a cell-replacement strategy. These investigations have also highlighted the significant limitations of this approach. Another potential strategy for stem cell therapy utilises stem cells as a delivery mechanism for therapeutic molecules. This review surveys the literature relevant to the potential of mesenchymal stem cells for delivery of therapeutic agents in CNS trauma in humans.

Foot posture, leg length discrepancy and low back pain - Their relationship and clinical management using foot orthoses - An overview

Mechanical low back pain (LBP) is a very common, expensive, and significant health issue in the western world. Functional musculoskeletal conditions are widely thought to cause mechanical low back pain. The role of foot posture and leg length discrepancy in contributing to abnormal biomechanics of the lumbopelvic region and low back pain is not sufficiently investigated. This critical review examines the evidence for the association between foot function, particularly pronation, and mechanical LBP. It also explores the evidence for a role for foot orthoses in the treatment of this condition. There is a body of evidence to support the notion that foot posture, particularly hyperpronation, is associated with mechanical low back pain. Mechanisms that have been put forward to account for this finding are based on either mechanical postural changes or alterations in muscular activity in the lumbar and pelvic muscles. More research is needed to explore and quantify the effects of foot orthoses on chronic low back pain, especially their effects on lumbopelvic muscle function and posture. The clinical implications of this work are significant since foot orthoses represent a simple and potentially effective therapeutic measure for a clinical condition of high personal and social burden.

Novel therapeutic targets for axonal degeneration in multiple sclerosis

Multiple sclerosis (MS) is a devastating neurological condition that mainly affects young adults and is associated with long-standing morbidity. The pathophysiology of MS is believed to involve immune-mediated multifocal lesions in the CNS that are characterized by inflammation, demyelination, and axonal injury. Most research efforts to date have concentrated on the mechanisms of immune-mediated demyelination, whereas mechanisms of axonal injury, the major determinant of neurological deficits in MS patients, have been elusive beyond observational analyses. This review discusses current understanding of the pathology and novel clinical investigations of axonal injury in MS and the commonly used MS animal model, experimental autoimmune encephalomyelitis. The review focuses on the etiology and the induction of axonal degeneration through molecular signaling cascades downstream of myelin-associated inhibitory factors. Defining and eventually elucidating the signaling pathways elicited during the onset and progression of MS may provide novel therapeutic strategies to limit axonal degeneration in the acute phase of the disease. Furthermore, blocking or potentiating specific signaling pathways, particularly those that mediate axon retraction and promote disassembly of the tubulin network, may promote regrowth of damaged axons in CNS regions affected by many acute and chronic disease processes.

Effects of Nonpharmacological Interventions for Dizziness in Older People: Systematic Review

Background Nonpharmacological interventions have been shown to have some effectiveness in adults with dizziness; however, the effectiveness of these interventions in older people is unknown. Purpose The aim of this study was to determine the effects of conservative nonpharmacological interventions for dizziness in older people. Data Sources The Cochrane Central Register of Controlled Trials, PubMed, EMBASE, SCOPUS, CINAHL, AMED, Index to Chiropractic Literature, PsycINFO, and MANTIS were searched from inception to May 2014. Study Selection Two investigators independently screened controlled trials with participants who were more than 60 years old and experienced dizziness. Studies of participants with dizziness from a specific diagnosis, such as Ménière disease and benign paroxysmal positional vertigo, were excluded. Outcome measures from the selected studies included self-reported dizziness and postural balance. Data Extraction Two investigators independently extracted data on participants, interventions, comparison group, outcome measures, and results. The risk of bias of the included studies was assessed with Cochrane guidelines. Data Synthesis Seven articles consisting of 7 controlled trials were included. All studies involved some form of exercise, including vestibular rehabilitation exercises, postural balance exercises, and tai chi exercise, as the main intervention. The studies had a high risk of bias because of the lack of adequate randomization and allocation concealment, the lack of reporting on cointerventions, the lack of reporting on reasons for dropouts, and the lack of reporting on participant adherence. Limitations Heterogeneity among the included studies in interventions and outcome measures prohibited a meta-analysis. Only 2 studies reported a significant difference between the intervention group and the comparison group for self-reported dizziness. Conclusions There is insufficient evidence to determine the effectiveness of nonpharmacological treatments for dizziness in older people. Current evidence is hampered by a high risk of bias, and well-designed trials with adequate masking, randomization, and adherence are needed.

The influence of vibration on seated human drowsiness.

Although much is known about human body vibration discomfort, there is little research data on the effects of vibration on vehicle occupant drowsiness. A laboratory experimental setup has been developed. Vibration was applied to the volunteers sitting on the vehicle seat mounted on the vibration platform. Seated volunteers were exposed to a Gaussian random vibration, with 1–15 Hz frequency bandwidth at 0.2 ms−2 r.m.s., for 20-minutes. Two drowsiness measurement methods were used, Psychomotor Vigilance Test (PVT) and Karolinska Sleepiness Scale (KSS). Significant changes in PVT (p<0.05) and KSS (p<0.05) were detected in all eighteen volunteers. Furthermore, a moderate correlation (r>0.4) was observed between objective measurement (PVT) and subjective measurement (KSS). The results suggest that exposure to vibration even for 20-minutes can cause significant drowsiness impairing psychomotor performance. This finding has important implications for road safety.

Overcoming monocarboxylate transporter 8 (MCT8)-deficiency to promote human oligodendrocyte differentiation and myelination

Cell membrane thyroid hormone (TH) transport can be facilitated by the monocarboxylate transporter 8 (MCT8), encoded by the solute carrier family 16 member 2 (SLC16A2) gene. Human mutations of the gene, SLC16A2, result in the X-linked-inherited psychomotor retardation and hypomyelination disorder, Allan-Herndon-Dudley syndrome (AHDS). We posited that abrogating MCT8-dependent TH transport limits oligodendrogenesis and myelination. We show that human oligodendrocytes (OL), derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, express MCT8. Moreover, treatment of these cultures with DITPA (an MCT8-independent TH analog), up-regulates OL differentiation transcription factors and myelin gene expression. DITPA promotes hESC-derived OL myelination of retinal ganglion axons in co-culture. Pharmacological and genetic blockade of MCT8 induces significant OL apoptosis, impairing myelination. DITPA treatment limits OL apoptosis mediated by SLC16A2 down-regulation primarily signaling through AKT phosphorylation, driving myelination. Our results highlight the potential role of MCT8 in TH transport for human OL development and may implicate DITPA as a promising treatment for developmentally-regulated myelination in AHDS.

Characterization of the effects of vibration on seated driver alertness

Abstract Although performance of vehicle drivers under fatigue conditions has been investigated in many types of environments, there is insufficient research data about the effects of vibration specifically on levels of mental alertness in seated drivers. In addition to the paucity of research in this area, the study of drowsiness caused by whole body vibration is complex due to several confounding factors (such as lack of sleep, air temperature, health). Hence, we investigated the relationship between whole body vibration and driver drowsiness. A human vibration test setup was designed for this study. Ten subjects were exposed to low frequency sinusoidal and random whole body vibration in multi-axial vibration at 0.3 m/s2 (rms) for 20 minutes. Changes in drowsiness during vibration exposure were measured by recording electroencephalographic signals. Two brainwave spectrums (theta and beta waves) were used for analysis. Exposure to whole body vibration was found to be correlated with a reduction in alertness. Reduction in beta wave and increase in theta wave activity, caused by vibration, were found to be statistically significant. The data presented here quantify for the first time the drowsiness caused by whole body vibration and will help define the threshold limit for safe driving.

Association of Mild Leg Length Discrepancy and Degenerative Changes in the Hip Joint and Lumbar Spine

Objective The purpose of this study was to evaluate the correlation between mild leg length discrepancy (LLD) and degenerative joint disease (DJD) or osteoarthritis. Methods We evaluated standard postural lumbopelvic radiographs from 255 adults (121 women and 134 men) who had presented with spinal pain for chiropractic care. Symmetry of femoral head diameters was used to exclude magnification errors. Pearson’s partial correlation was used to control for age and derive effect sizes for LLD on DJD in the hip and lower lumbar motion segments. Krippendorff’s &agr; was used for intraobserver and interobserver reliability. Results A strong correlation was found between LLD and hip DJD in men (r = 0.532) and women (r = 0.246). We also found a strong correlation between LLD and DJD at the L5‐S1 motion segment in men (r = 0.395) and women (r = 0.246). At the L4‐5 spinal level this correlation was much attenuated in men (r = 0.229) and women (r = 0.166). Conclusions These findings suggest an association between LLD and hip and lumbar DJD. Cause–effect relationships between mild LLD and DJD deserve to be properly evaluated in future longitudinal cohort studies.

Characterisation of the correlation between standing lordosis and degenerative joint disease in the lower lumbar spine in women and men: a radiographic study

BackgroundDegenerative joint disease (DJD) in the lumbar spine is a common condition that is associated with chronic low back pain. Excessive loading of lumbar joints is a risk factor for DJD. Changes in lumbar lordosis significantly redistribute the forces of weight-bearing on the facet joints and the intervertebral discs. However, the relationship between lumbar lordosis and DJD has not been characterized in men and women.MethodsWe characterised the correlation between standing lumbar lordosis and DJD in standing radiographic images from 301 adult female and male chiropractic patients. DJD was rated using the Kellgren-Lawrence scale, and lordosis was measured using the Cobb angle. Linear and curvilinear correlations were investigated while controlling for age and sex.ResultsWe found a highly significant curvilinear correlation between lordosis and DJD of the lower lumbar spine in both sexes, but especially in women, irrespective of the effects of age. We found the effect size of lordosis on lower lumbar DJD to be between 17.4 and 18.1% in women and 12.9% in older men. In addition, lordosis of 65 (95% CI 55.3–77.7) and 68 (98% CI 58.7–73.3) degrees were associated with minimal DJD in the lower lumbar spine of women and men respectively, and were therefore considered ‘optimal’. This optimal lordotic angle was 73 (95% CI 58.8–87.2) degrees in older men.ConclusionsBoth hypo- and hyper-lordosis correlate with DJD in the lumbar spine, particularly in women and in older men. These findings may well be of relevance to spinal pain management and spinal rehabilitation.

Neck pain, concerns of falling and physical performance in community-dwelling Danish citizens over 75 years of age: A cross-sectional study

Aims: The aim of this study was to determine the associations between neck pain, concerns of falling and physical performance in older people. Methods: Cross-sectional study of 423 community-dwelling Danes aged 75 years and older. Measures consisted of self-reported neck pain, physical performance (Short Physical Performance Battery), self-reported psychological concerns related to falling (Falls Efficacy Scale International), depression (Major Depression Inventory), cognitive function (Mini Mental State Examination), self-reported low-back pain and self-reported history of falls. Associations between neck pain and fear of falling were determined using multivariable logistic regression modelling. Results: Bothersome neck pain that limits daily activities is significantly associated with concerns of falling (unadjusted odds ratio (OR) 3.29, 95% confidence interval (CI) 1.54–7.03) and impaired physical performance (unadjusted OR 2.26, 95% CI 1.09–4.69). However, these relationships became nonsignificant after adjusting for potential confounders. Bothersome neck pain and concerns of falling is attenuated by depression, and the relationship between bothersome neck pain and decreased physical performance is attenuated by concerns of falling, depression and previous history of falls. Conclusions: Bothersome neck pain in older people is associated with increased concerns of falling and decreased physical performance that are two known risk factors for falls in older people. However, these relationships are complicated by other variables, particularly depression.