Mechanisms of radiation injury to the central nervous system: implications for neuroprotection

The central nervous system (CNS) is a major dose-limiting organ in clinical radiotherapy (XRT). The underlying mechanisms of radiation-induced injury in this organ remain unclear. For many years, research has focused on identifying the major target cells of damage, and depletion of target cells due to reproductive or clonogenic cell death was believed to be the primary cause of tissue damage and organ failure. There is now an increasing body of data indicating that the response of the CNS after XRT is a continuous and interacting process. This review addresses some of the recent advances in our understanding of the mechanisms of CNS radiation damage. Specifically, the focus is on apoptotic cell death, and cell death and injury mediated by secondary damage. These potentially reversible components of the injury response provide important targets for neuroprotective interventions.     

Electrical stimulation of peripheral and central pathways for the relief of musculoskeletal pain

One method for the treatment of chronic musculoskeletal pain involves stimulation of the peripheral or central nervous system. Such stimulation includes transcutaneous electrical nerve stimulation, dorsal column stimulation, and deep brain stimulation. This review discusses the clinical use of electrical stimulation for the relief of musculoskeletal pain, and describes the results of studies conducted in our laboratory suggesting that such stimulation reduces pain transmission along sensory-discriminative pathways.     

Ligaments: a source of work-related musculoskeletal disorders.

The mechanical and neurological properties of ligaments are reviewed and updated with recent development from the perspective which evaluates their role as a source of neuromusculoskeletal disorders resulting from exposure to occupational activities. Creep, tension-relaxation, hysteresis, sensitivity to strain rate and strain/load frequency were shown to result not only in mechanical functional degradation but also in the development of sensory-motor disorders with short- and long-term implication on function and disability. The recently exposed relationships between collagen fibers, applied mechanical stimuli, tissue microdamage, acute and chronic inflammation and neuromuscular disorders is delineated with special reference to occupational stressors.     

Spinal cord injury: a model of central neuropathic pain

The condition of pain after spinal cord injury (SCI) affects the life quality of nearly 70% of individuals with SCI. Clinical studies over the past decade have provided important insights into the complexities of the clinical and psychosocial characteristics of this debilitating consequence of SCI. The use of experimental models developed to study at-level or below-level pain has provided an appreciation for the mechanism(s) responsible for the onset and progression of these conditions. Important to the studies related to SCI pain has been the focus on the molecular, biochemical, anatomical, and functional consequences of SCI that have identified potential therapeutic targets for the design of novel treatment strategies.     

Individual factors and musculoskeletal disorders: a framework for their consideration.

Individual factors have been variously defined as non-work, demographic, physiological or psychological factors. They may represent a variety of important constructs at different relevant levels that may not be initially evident in their measurement. These include: work-related factors e.g., job assignment, duration of exposure, work style, anthropometric mismatches, and differential responses to job demands; concomitant external or internal exposures e.g., sports, smoking, and endogenous hormones; and physical, psychological and social vulnerabilities e.g., prior injury, depression, socio-economic status. Such factors operate in different ways in the development, course and response to interventions of musculoskeletal disorders. Newer framings of their contribution to musculoskeletal disorders are providing new insights into the role of such factors as some among many which contribute to the burden of MSK disorders in working age populations. As researchers, practitioners and policy makers, we need to consider them in order to reduce burden, to protect the vulnerable and to match interventions to different groups of people most appropriately.     

Biomechanics of musculoskeletal pain: dynamics of the neuromatrix.

Pain, due to mechanical stimuli, is a normal, indeed healthy, response of animals to potential or actual damage to tissues. Mammals in general, and humans in particular, have evolved a highly sophisticated system of pain perception, which is characterized in humans by complementary but distinct neural processing of the intensity and location of a noxious stimulus, and a motivational/emotional or affective response to the stimulus. The peripheral and central neurons that comprise this system, which has been called the 'neuromatrix', dynamically (temporally) respond and adapt to noxious biomechanical stimuli. However, phenotypic variability of the neuromatrix can be large, which can result in a host of musculoskeletal conditions that are characterized by altered pain perception, which can and often does alter the course of the condition. This neural plasticity has been well recognized in the central nervous system, but it has only more recently become known that peripheral nociceptors also adapt to their altered extracellular matrix environment. This work reviews the biomechanics of pain focusing on the relevant stimulus that initiates responses by nociceptors to the cognitive perception of pain.     

Mechanisms regulating GABAergic inhibitory transmission in the basolateral amygdala: implications for epilepsy and anxiety disorders

Summary. The amygdala, a temporal lobe structure that is part of the limbic system, has long been recognized for its central role in emotions and emotional behavior. Pathophysiological alterations in neuronal excitability in the amygdala are characteristic features of certain psychiatric illnesses, such as anxiety disorders and depressive disorders. Furthermore, neuronal excitability in the amygdala, and, in particular, excitability of the basolateral nucleus of the amygdala (BLA) plays a pivotal role in the pathogenesis and symptomatology of temporal lobe epilepsy. Here, we describe two recently discovered mechanisms regulating neuronal excitability in the BLA, by modulating GABAergic inhibitory transmission. One of these mechanisms involves the regulation of GABA release via kainate receptors containing the GluR5 subunit (GluR5KRs). In the rat BLA, GluR5KRs are present on both somatodendritic regions and presynaptic terminals of GABAergic interneurons, and regulate GABA release in an agonist concentration-dependent, bidirectional manner. The relevance of the GluR5KR function to epilepsy is suggested by the findings that GluR5KR agonists can induce epileptic activity, whereas GluR5KR antagonists can prevent it. Further support for an important role of GluR5KRs in epilepsy comes from the findings that antagonism of GluR5KRs is a primary mechanism underlying the antiepileptic properties of the anticonvulsant topiramate. Another mechanism regulating neuronal excitability in the BLA by modulating GABAergic synaptic transmission is the facilitation of GABA release via presynaptic α_1A adrenergic receptors. This mechanism may significantly underlie the antiepileptic properties of norepinephrine. Notably, the α_1A adrenoceptor-mediated facilitation of GABA release is severely impaired by stress. This stress-induced impairment in the noradrenergic facilitation of GABA release in the BLA may underlie the hyperexcitability of the amygdala in certain stress-related affective disorders, and may explain the stress-induced exacerbation of seizure activity in epileptic patients.     

Mechanisms of reoxygenation injury in myocardial infarction: implications of a myoglobin redox cycle

The addition of ascorbate to ischemic rat hearts prevents the myocardial damage associated with reoxygenation. H2O2 oxidizes myoglobin (Mb+2) to higher oxidation states (Mb+4 and Mb+5) which are rapidly reduced by ascorbate. It is proposed that the operation of a myoglobin redox cycle, in which H2O2 causes the two-electron oxidation of myoglobin, is a critical determinant of reperfusion injury. Conversely, the reduction of myoglobin, in one-electron steps, may represent an essential protective mechanism against such injury in the heart.     

Cloning, characterization, and functional studies of a human 40-kDa catecholamine-regulated protein: implications in central nervous system disorders

Catecholamine-regulated proteins (CRPs) have been shown to bind dopamine and other structurally related catecholamines; in particular, the 40-kDa CRP (CRP40) protein has been previously cloned and functionally characterized. To determine putative human homologs, BLAST analysis using the bovine CRP40 sequence identified a human established sequence tag (EST) with significant homology (accession #BQ224193). Using this EST, we cloned a recombinant human brain CRP40-like protein, which possessed chaperone activity. Radiolabeled dopamine binding studies with recombinant human CRP40 protein demonstrated the ability of this protein to bind dopamine with low affinity and high capacity. The full-length human CRP40 nucleotide sequence was elucidated (accession #DQ480334) with RNA ligase-mediated rapid amplification of complementary DNA ends polymerase chain reaction, while Northern blot hybridization suggested that human CRP40 is an alternative splice variant of the 70-kDa mitochondrial heat shock protein, mortalin. Human SH-SY5Y neuroblastoma cells treated with the antipsychotic drug, haloperidol, exhibited a significant increase in CRP40 messenger RNA expression compared to untreated control cells, while other dopamine agonists/antagonists also altered CRP40 expression and immunolocalization. In conclusion, these results show that we have cloned a splice variant of mortalin with a novel catecholamine binding function and that this chaperone-like protein may be neuroprotective in dopamine-related central nervous system disorders.     

A direct comparison of local-global integration in autism and other developmental disorders: implications for the central coherence hypothesis

The weak central coherence hypothesis represents one of the current explanatory models in Autism Spectrum Disorders (ASD). Several experimental paradigms based on hierarchical figures have been used to test this controversial account. We addressed this hypothesis by testing central coherence in ASD (n = 19 with intellectual disability and n = 20 without intellectual disability), Williams syndrome (WS, n = 18), matched controls with intellectual disability (n = 20) and chronological age-matched controls (n = 20). We predicted that central coherence should be most impaired in ASD for the weak central coherence account to hold true. An alternative account includes dorsal stream dysfunction which dominates in WS. Central coherence was first measured by requiring subjects to perform local/global preference judgments using hierarchical figures under 6 different experimental settings (memory and perception tasks with 3 distinct geometries with and without local/global manipulations). We replicated these experiments under 4 additional conditions (memory/perception*local/global) in which subjects reported the correct local or global configurations. Finally, we used a visuoconstructive task to measure local/global perceptual interference. WS participants were the most impaired in central coherence whereas ASD participants showed a pattern of coherence loss found in other studies only in four task conditions favoring local analysis but it tended to disappear when matching for intellectual disability. We conclude that abnormal central coherence does not provide a comprehensive explanation of ASD deficits and is more prominent in populations, namely WS, characterized by strongly impaired dorsal stream functioning and other phenotypic traits that contrast with the autistic phenotype. Taken together these findings suggest that other mechanisms such as dorsal stream deficits (largest in WS) may underlie impaired central coherence.     

Mechanisms of immunity in hydatid disease: implications for vaccine development

The Echinococcus organisms, the cause of echinococcosis (hydatid disease), are parasitic helminths with life cycles involving a carnivorous definitive host (usually dog or fox) and an intermediate host (human, ungulate, or rodent). They are complex multicellular pathogens that, despite being under constant barrage by the immune system, are able to modulate antiparasite immune responses and persist and flourish in their mammalian hosts. Understanding how the immune system deals with these parasites is a major challenge. Recent application of modern molecular and immunological approaches has revealed insights on the nature of immune responses generated during the course of hydatid infection, although many aspects of the Echinococcus-host interplay remain unexplored. This review summarizes current understanding of the immunology of echinococcosis, indicates areas where information is lacking, and shows how knowledge of host protective immunity has been translated into the design and development of anti-Echinococcus vaccines for application in intermediate hosts.     

A national survey of musculoskeletal impairment in Rwanda: prevalence, causes and service implications

Background

Accurate information on the prevalence and causes of musculoskeletal impairment (MSI) is lacking in low income countries. We present a new survey methodology that is based on sound epidemiological principles and is linked to the World Health Organisation''s International Classification of Functioning.

Methods

Clusters were selected with probability proportionate to size. Households were selected within clusters through compact segment sampling. 105 clusters of 80 people (all ages) were included. All participants were screened for MSI by a physiotherapist and medical assistant. Possible cases plus a random sample of 10% of non-MSI cases were examined further to ascertain diagnosis, aetiology, quality of life, and treatment needs.

Findings

6757 of 8368 enumerated individuals (80.8%) were screened. There were 352 cases, giving an overall prevalence for MSI of 5.2%. (95% CI 4.5–5.9) The prevalence of MSI increased with age and was similar in men and women. Extrapolating these estimates, there are approximately 488,000 MSI diagnoses in Rwanda. Only 8.2% of MSI cases were severe, while the majority were moderate (43.7%) or mild (46.3%). Diagnostic categories comprised 11.5% congenital, 31.3% trauma, 3.8% infection, 9.0% neurological, and 44.4% non-traumatic non infective acquired. The most common individual diagnoses were joint disease (13.3%), angular limb deformity (9.7%) and fracture mal- and non-union (7.2%). 96% of all cases required further treatment.

Interpretation

This survey demonstrates a large burden of MSI in Rwanda, which is mostly untreated. The survey methodology will be useful in other low income countries, to assist with planning services and monitoring trends.     

Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy

Retinitis pigmentosa (RP) is a group of retinal degenerative diseases that are characterised primarily by the loss of rod photoreceptor cells. Mutations in rhodopsin are the most common cause of autosomal-dominant RP (ADRP). Here, we propose a new classification for rhodopsin mutations based on their biochemical and cellular properties. Several different potential gain-of-function mechanisms for rhodopsin ADRP are described and discussed. Possible dominant-negative mechanisms, which affect the processing, translocation or degradation of wild-type rhodopsin, are also considered. Understanding the molecular and cellular consequences of rod-opsin mutations and the underlying disease mechanisms in ADRP are essential to develop future therapies for this class of retinal dystrophies.     

Epimuscular myofascial force transmission: A historical review and implications for new research. International society of biomechanics Muybridge award lecture,Taipei, 2007

Elements of what we call myofascial force transmission today have been on peoples mind for a long time, usually implicitly, sometimes quite explicitly.A lot is there to be learned from the history of our knowledge on muscle and movement.There is little doubt about the presence and effectiveness of the mechanism and pathways of epimuscular myofascial force transmission. However, we should learn much more about the exact conditions at which such transmission is not only of fundamental biomechanical interest, but also quantitatively so important that it has to be considered for its effects in health and disease. Even if the quantitative effects in terms of force would prove small, one should realize that this mechanism will change the principles of muscular function drastically.A new vision on functional anatomy, as well as the application of imaging techniques and 3-D reconstruction of in vivo muscle, will aid that process of increased quantitative understanding, despite usual limitations regarding the mechanics in such experiments. I expect it is fair to say that without understanding myofascial force transmission we will never be able to understand muscular function completely.     

Mechanisms of prion-induced modifications in membrane transport properties: implications for signal transduction and neurotoxicity.

Prion-related encephalopathies are associated with the conversion of a normal cellular isoform of prion protein (PrP(c)) to an abnormal pathologic scrapie isoform (PrP(Sc)). The conversion of this single polypeptide chain involves a reduction in the alpha-helices and an increase in beta-sheet content. This change in the content ratio of alpha-helices to beta-sheets may explain the diversity in the proposed mechanisms of action. Many of the pathogenic properties of PrP(Sc), such as neurotoxicity, proteinase-resistant properties and induction of hypertrophy and proliferation of astrocytes, have been attributed to the peptide fragment corresponding to residues 106-126 of prion (PrP[106-126]). In particular, the amyloidogenic and hydrophobic core AGAAAAGA has been implicated in modulation of neurotoxicity and the secondary structure of PrP[106-126]. Because of some similarities between the properties of PrP[106-126] and PrP(Sc), the former is used as a useful tool to characterize the pharmacological and biophysical properties of PrP(Sc) in general and of that domain in particular, by various laboratories. However, it is important to note that by no means can PrP[106-126] be considered a complete equivalent to PrP(Sc) in function. Several hypotheses have been proposed to explain prion-induced neurodegenerative diseases. These non-exclusive hypotheses include: (i) changes in the membrane microviscosity; (ii) changes in the intracellular Ca(2+) homeostasis; (iii) superoxide dismutase and Cu(2+) homeostasis; and (iv) changes in the immune system. The prion-induced modification in Ca(2+) homeostasis is the result of: (1) prion interaction with intrinsic ion transport proteins, e.g. L-type Ca(2+) channels in the surface membrane, and IP(3)-modulated Ca(2+) channels in the internal membranes, and/or (2) formation of cation channels. These two mechanisms of action lead to changes in Ca(2+) homeostasis that further augment the abnormal electrical activity and the distortion of signal transduction causing cell death. It is concluded that the hypothesis of the interaction of PrP[106-126] with membranes and formation of redox-sensitive and pH-modulated heterogeneous ion channels is consistent with: (a) PrP-induced changes in membrane fluidity and viscosity; (b) PrP-induced changes in Ca(2+) homeostasis (and does not exclude changes in endogenous Ca(2+) transport pathways and Cu(2+) homeostasis); (c) PrP role as an antioxidant; and (d) the PrP structural properties, i.e. beta sheets, protein aggregation, hydrophobicity, functional significance of specific amino acids (e.g. methionine, histidine) and regulation with low pH.     

Reducing the costs of work-related musculoskeletal disorders: targeting strategies to chronic disability cases.

Musculoskeletal disorders impose a significant direct cost burden on health care systems in the US and Canada and account for even greater indirect losses of productivity. The overall prevalence of musculoskeletal disorders is high, but a disproportionate share of costs is associated with a small number of cases with chronic pain. This is especially true for cases of occupational back pain, the single most common and costly musculoskeletal disorder in the workplace. A number of studies identify workplace characteristics associated with prolonged disability among cases of work-related back pain. These characteristics include: failure to receive job accommodations, receipt of disability benefit payments, and employment in high-risk industries or jobs that require heavy lifting. Research on the predictors of high-cost cases is limited, however, because of the lack of high-quality data and the need for a multidisciplinary approach. A new study, the Arizona State University Healthy Back Study, addresses some of these issues and promises new insights into effective strategies to reduce the proportion of high-cost claims.