Harnessing in and ex vivo imaging to investigate motor nerve terminal injury and recovery in a mouse model of Guillain-Barré syndrome

The peripheral nerve disorder Guillain-Barré syndrome (GBS) accounts for the most common cause of acute acquired paralysis in the Western World. Circulating anti-ganglioside antibodies (Abs) are considered important mediators of this disease. Research conducted in a mouse model of GBS has the revealed the neuromuscular junction (NMJ) as a potential site of anti-ganglioside Ab-binding, due to this structure lying outside the blood-nerve barrier. The ganglioside composition of the neural and glial components of the NMJ determines which of these structures are bound and in the following subjected to complement-mediated injury. Some patients suffering from the acute motor axonal neuropathy (AMAN) forms of GBS recovery very rapidly from paralysis; it has been proposed that in these patients the injury was restricted to the distal motor axons and nerve terminals (NTs), which are able to regenerate over a short time-frame. To test this hypothesis, the mouse model of GBS was combined with in and ex vivo imaging of the NMJ in the ventral neck muscles of mice expressing cytosolic fluorescent proteins in their axons (cyan fluorescent protein: CFP) and Schwann cells (green fluorescent protein: GFP). Following confirmation of the stability of NMJs in these mice over time, optimisation of in vivo imaging procedures and determination of the most advantageous Abs for these kinds of investigations, 45 mice were subjected to a single in vivo topical application of anti-ganglioside Ab followed by a source of complement. Group A (n=15) received Ab that selectively bound to the NTs, group B (n=15) received Abs that bound both to the NTs and the perisynaptic Schwann cells (pSCs) and group C (control animals; n=15) only received complement. Evolution of the injury was documented by in vivo imaging, and following euthanasia the muscles were reimaged ex vivo both quantitatively and qualitatively, either immediately, or after 1, 2, 3 or 5 days of regeneration (each n=3 per group). Within 15 minutes of complement application, a rapid loss of CFP overlying the NMJ could be seen; in group A, the GFP signal remained unchanged, whereas in group B the GFP signal was also lost. In group C no changes to either CFP or GFP were observed. At 24h, 6% of the superficial NMJs in group A and 12% of the NMJs in group B exhibited CFP; the CFP-loss extended proximally until the axons formed little bundles. In both groups, CFP returned within the next five days (group A: 93.5%, group B: 94%; p=0.739), with the recovery of CFP being preceded by a return of GFP-positive cells overlying the NMJ in group B. Both in groups A and B, the pSCs exhibited processes which extended beyond the normal NMJ boundaries and very occasionally accompanied by axonal sprouts. This behavior was similar to that of pSCs challenged by traumatic denervation of their NMJ, albeit the changes observed in the Ab-mediated injury were lower in frequency and less dramatic when compared to those observed following traumatic denervation. The rate of motor NT-regeneration corresponds well to rates observed following the application of spider or snake toxins, which mediate selective injury to the NTs. Auxiliary investigations revealed that the loss of CFP at the NMJ correlated with a loss of axonal architectural proteins (neurofilament (NF) heavy and light) and a return of CFP at the NMJ was accompanied by a return of NF heavy. Ultrastructurally, the injured NTs resembled NTs undergoing degeneration following a traumatic denervation of the endplate and following five days of regeneration, the NMJs exhibited a physiological morphology. The results described above indicate that following a single anti-ganglioside Ab-mediated and complement-mediated attack, independent of whether there are healthy and mature pSCs overlying the NMJ, the murine NT is capable of recovering its architectural, axolemmal and ultrastructural integrity very rapidly. This data supports the notion that an equivalent mechanism may account for the rapid recovery seen in some clinical cases of AMAN

Fatigue, aging and the neuromuscular system

Bibliography: p. 400-445.The aim of this thesis was to investigate the relationship between chronic exercise activity, aging, the neuromuscular system and the symptom of fatigue in a series of studies. The hypothesis of the thesis was that in contrast to the accepted dogma that exercise is beneficial to an individual, increasing longevity and improving quality of life, excessive or chronic exercise activity may accelerate the aging process, lead to neuromuscular damage, and cause the development of pathological symptoms or levels of fatigue

Clinical and pharmacological studies in post-encephalitic Parkinsonism

Chapter I. General Introduction This chapter deals mainly with the control of skeletal muscle tone and the physiology of tremor. The clinical features and treatment of Parkinsonism are also discussed. Chapter II. Crises in Post-Encephalitic Parkinsonism. A study of 67 patients with post-encephalitic Parkinsonism revealed three types of crises: they can be described as oculogyric, sweating and breath-holding. The clinical accompaniments of oculogyric and sweating crises are described. Chapter III. Drug Therapy in the Crises of Post-Encephalitic Parkinsonism. The treatment of severe oculogyric and sweating crises in 11 patients with post-encephalitic Parkinsonism has been studied. The value of 200 mg. sodium phenobarbitone given intramuscularly or sodium amylobarbitone 200 to 300 mg. given orally was assessed. Neither of these forms of treatment affected the natural course of crises when these were in the category classified as "severe". Chapter IV. The Electroencephalogram in Post-Encephalitic Parkinsonism. Electroencephalographic study of 30 patients suffering from post-encephalitic Parkinsonism showed that over half of them have low voltage alpha rhythms. It would appear that in postencephalitic Parkinsonism the phenomenon of low voltage E.E.G.s is most frequently seen in patients who are known to be liable to oculogyric crises and in those who suffer from severe rigidity and who are incidentally often bedfast. Chapter V, Deformities in Post-Encephalitic Parkinsonism. The deformities of the hand in post-encephalitic Parkinsonism have been classified as Types I, II and III. Type I is the most common form. Talipes equino varus deformity is the common deformity of the foot in Parkinsonism. Scoliotic deformity of the spine, especially of the cervical spine, is common. The scoliosis is usually concave to the less rigid side. Chapter VI, Assessment of Drug Therapy in Parkinsonism. The relative therapeutic value of orphenadrine and "UK, 738" (Sandoz) were studied by means of a double blind trial, Orphenadrine 100 mg, thrice daily was found to be about three times as effective as "UK, 738" 4 mg, t,d,s. The methods of assessment of the efficacy of drug therapy in Parkinsonism are reviewed and the value of objective measurements is demonstrated. Chapter VII, The sites and mode of action of orphenadrine and other drugs used for the relief of rigidity and muscle weakness in Parkinsonism. Pharmacological studies with orphenadrine show that it has a definite neuromuscular blocking action in the frog and in the rat. In the cat, however, the neuromuscular blocking action is veiy much less. It is suggested that one of the ways by which orphenadrine reduces Parkinsonian rigidity is through its peripheral skeletal muscular relaxant property. The euphoric action noted in human subjects and the peripheral skeletal, muscular relaxant property contribute to the favourable effect of this drug on the muscle weakness and easy fatiguability in patients suffering from Parkinsonism. (Abstract shortened by ProQuest.)

Progressive resistance training during maintenance hemodialysis in patients with end stage renal disease

Background: The global incidence of end-stage renal disease (ESRD) continues to rise annually. Accompanying this rise is an increase in the number of patients on hemodialysis. These trends are being driven by an unprecedented burden of hypokinetic, non-communicable diseases, and particularly the type 2 diabetes-obesity pandemic. The progression of kidney disease is associated with an exponential increase in atherosclerotic cardiovascular disease (CVD) and associated mortality. CVD is the leading cause of hospitalization and death in this cohort. As the ESRD patient population continues to grow, greater efforts must be directed toward improving patient outcomes in this cohort, including morbidity, mortality and health-related quality of life (HRQoL). Aims: This thesis addresses several gaps related to the investigation and application of progressive resistance training (PRT) in the hemodialysis setting. The specific aims were: (i) to systematically review the extant literature on PRT in patients with ESRD, and to outline recommendations for robust clinical trials; (ii) to assess the feasibility and efficacy of including a novel customized resistance training device within a comprehensive intradialytic PRT intervention in a conventional hemodialysis unit; (iii) to investigate the effect of a 12-week intradialytic PRT intervention on measures of CVD risk, specifically, arterial stiffness (i.e. pulse wave velocity; PWV) and associated outcomes (i.e. hemodynamic, anthropometric, and hematologic). Research Program: The research program was undertaken from March 2011 to March 2015 and culminated in a clinical trial enrolling 22 participants conducted across four dialysis centers in Adelaide, South Australia. Conclusions: Chapter 7 presents general conclusions to the thesis, as follows: (i) According to the systematic review of the extance literature (Chapter 4) clinical trials are required to investigate a range of novel research questions related to the benefits and application of PRT in this cohort and its patient subgroups (e.g. diabetes, depression, dyslipidemia, etc.). Future studies must be of high methodological quality to inform clinical practice guidelines. (ii) According to the study presented in Chapter 5, PRT using the novel training device was feasible and improved measures of physical and psychological health and HRQoL. This device can be utilized in most dialysis centers. Future studies are required to evaluate dose-response effects of PRT prescriptions in subpopulations, and the application of PRT in standard dialysis practice. (iii) According to the study presented in Chapter 6, 12 weeks of low-to-moderate intensity intradialytic PRT did not change PWV, hemodynamic, anthropometric or hematologic measures in patients with ESRD. More research is needed to determine whether different intensities or durations of PRT can affect vascular health or other outcomes related to survival in this patient group

Reducing Muscular Fatigue in Trail Running - Mechanisms and Strategies

The aim of this thesis was to analyse strategies to reduce muscular fatigue in trail running and potentially draw conclusions on the underlying mechanisms. Trail running is a new and upcoming sport that induces a combination of fatigue and muscle damage in the main locomotor muscles. To obtain conclusive evidence on the effect of intervention studies a preliminary descriptive study was undertaken to characterise typical fatigue and damage. Subsequently a model was developed and validated that would allow the investigation of interventions in an applied field setting. A popular current strategy in trail running is the use of compression garments; therefore the effect of these on performance was studied as an intervention. Furthermore, prior heating is anecdotally considered beneficial and recent research has suggested a potential mechanism to link this with reduced muscle damage. Therefore a controlled laboratory study was conducted, examining the effects of passive heating on functional consequences of downhill running in an untrained population. In synopsis, the research conducted for this thesis provides descriptive evidence and a validated terrain model to further investigate fatigue reduction strategies in trail running. Additionally it adds to the current literature in disproving a positive effect of compression garments on performance and demonstrating the functional link between heating and eccentric-induced muscle damage reduction

Rehabilitation Engineering

Population ageing has major consequences and implications in all areas of our daily life as well as other important aspects, such as economic growth, savings, investment and consumption, labour markets, pensions, property and care from one generation to another. Additionally, health and related care, family composition and life-style, housing and migration are also affected. Given the rapid increase in the aging of the population and the further increase that is expected in the coming years, an important problem that has to be faced is the corresponding increase in chronic illness, disabilities, and loss of functional independence endemic to the elderly (WHO 2008). For this reason, novel methods of rehabilitation and care management are urgently needed. This book covers many rehabilitation support systems and robots developed for upper limbs, lower limbs as well as visually impaired condition. Other than upper limbs, the lower limb research works are also discussed like motorized foot rest for electric powered wheelchair and standing assistance device