Showing papers by "Martin R Turner published in 2012"

A proposed staging system for amyotrophic lateral sclerosis.

Abstract: Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, with a median survival of 2-3 years. Although various phenotypic and research diagnostic classification systems exist and several prognostic models have been generated, there is no staging system. Staging criteria for amyotrophic lateral sclerosis would help to provide a universal and objective measure of disease progression with benefits for patient care, resource allocation, research classifications and clinical trial design. We therefore sought to define easily identified clinical milestones that could be shown to occur at specific points in the disease course, reflect disease progression and impact prognosis and treatment. A tertiary referral centre clinical database was analysed, consisting of 1471 patients with amyotrophic lateral sclerosis seen between 1993 and 2007. Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration. Milestones occurred at predictable proportions of the disease course. Diagnosis occurred at 35% through the disease course, involvement of a second region at 38%, a third region at 61%, need for gastrostomy at 77% and need for non-invasive ventilation at 80%. We therefore propose a simple staging system for amyotrophic lateral sclerosis. Stage 1: symptom onset (involvement of first region); Stage 2A: diagnosis; Stage 2B: involvement of second region; Stage 3: involvement of third region; Stage 4A: need for gastrostomy; and Stage 4B: need for non-invasive ventilation. Validation of this staging system will require further studies in other populations, in population registers and in other clinic databases. The standardized times to milestones may well vary between different studies and populations, although the stages themselves and their meanings are likely to remain unchanged.

Neuroimaging in amyotrophic lateral sclerosis.

Abstract: The catastrophic system failure in amyotrophic lateral sclerosis is characterized by progressive neurodegeneration within the corticospinal tracts, brainstem nuclei and spinal cord anterior horns, with an extra-motor pathology that has overlap with frontotemporal dementia. The development of computed tomography and, even more so, MRI has brought insights into neurological disease, previously only available through post-mortem study. Although largely research-based, radionuclide imaging has continued to provide mechanistic insights into neurodegenerative disorders. The evolution of MRI to use advanced sequences highly sensitive to cortical and white matter structure, parenchymal metabolites and blood flow, many of which are now applicable to the spinal cord as well as the brain, make it a uniquely valuable tool for the study of a multisystem disorder such as amyotrophic lateral sclerosis. This comprehensive review considers the full range of neuroimaging techniques applied to amyotrophic lateral sclerosis over the last 25 years, the biomarkers they have revealed and future developments.

Does interneuronal dysfunction contribute to neurodegeneration in amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is typically regarded as a sporadic neurodegenerative disorder that results in a catastrophic failure of the motor system, with characteristically variable involvement of upper and lower motor neuronal populations. A wide range of evidence from clinical, histological, genetic, neurophysiological, neuroimaging and neuropsychological studies, suggests that a loss of central nervous system inhibitory neuronal influence is a contributing factor in ALS pathogenesis. This loss of inhibitory function points intuitively to an ‘interneuronopathy’, with natural differences in cortical and spinal inhibitory networks reflected in the hitherto unexplained variable compartmentalization of pathology within upper and lower motor neuron populations. An excitotoxic final common pathway might then result from unopposed glutamatergic activity. If correct, therapies aimed specifically at supporting interneuronal function may provide a novel therapeutic strategy.

Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS

Abstract: Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation.

Young-onset amyotrophic lateral sclerosis: historical and other observations

Abstract: There is a wide range of age at initial symptom onset in amyotrophic lateral sclerosis despite a mean age of 65 years in population-based studies. 'Young-onset' amyotrophic lateral sclerosis typically refers to patients younger than ∼45 years and accounts for about 10% of cases in contemporary series. A review of published cases of amyotrophic lateral sclerosis from 1850 to 1950 revealed a far higher proportion of cases with young onset (>50%), with a steady decline to the contemporary figure. It is possible that this is not solely explained by increases in life expectancy. While there is still a rich variation in phenotypes among cases of young-onset amyotrophic lateral sclerosis, bulbar onset was found to be significantly under-represented in analysis of a large patient database, with implications for age-related vulnerabilities pertaining to focality of symptom onset. The timing of initiating pathological processes in relation to the emergence of symptoms is discussed, including the potential role of very early development and the interaction of epigenetic and environmental factors.

Cardiovascular fitness as a risk factor for amyotrophic lateral sclerosis: indirect evidence from record linkage study

Abstract: Background Amyotrophic lateral sclerosis (ALS) appears to be a sporadic disorder in 95% of cases. Although few personal characteristics associated with developing ALS are known, identification of those at risk is essential to any vision of early intervention. There is persistent anecdotal observation that those with ALS are premorbidly physically ‘fitter’, although such observations are susceptible to bias. Hospital admission for coronary heart disease (CHD) might serve as an objective marker of reduced cardiovascular fitness. Methods A record linkage study of two large databases of hospital admissions, the Oxford Record Linkage Study (ORLS) and an English national record linkage dataset of Hospital Episode Statistics was undertaken. The ratio of the rate of ALS in people without a record of CHD to that in those with a record of CHD was calculated, factoring out premature death in both cohorts. Similar analysis for Parkinson9s disease (PD) and multiple sclerosis (MS) was undertaken. Results In the English population, the rate ratio for ALS in the non-CHD cohort, compared with the CHD cohort, was 1.14 (95% CI 1.05 to 1.22); for PD it was 0.95 (95% CI 0.93 to 0.98); and for MS 0.95 (95% CI 0.88 to 1.04). The ORLS data yielded similar findings. Conclusions Those without a record of CHD were at modestly higher risk of ALS, but not for PD or MS. This lends support to the assertion that ALS arises within a population who may have relatively higher levels of cardiovascular fitness.

Fractional anisotropy in the posterior limb of the internal capsule and prognosis in amyotrophic lateral sclerosis.

Abstract: Patients: The study involved 21 patients with amyotrophic lateral sclerosis and 3 patients with primary lateral sclerosis. Results: Correlation was observed between fractional anisotropy and progression rate for a region of the corticospinal tract spanning the posterior limb of the internal capsule, with a left hemisphere emphasis. Posterior limb of the internal capsule fractional anisotropy showed potential to distinguish those patients with rapid progression. Axial diffusivity significantly increased in this region in a paired t test analysis of baseline and follow-up diffusion tensor imaging, in keeping with axonal damage. No correlations were noted for the corpus callosum. Conclusions:Posterior limb of the internal capsule fractional anisotropy is a candidate prognostic marker in amyotrophic lateral sclerosis, with potential to identify incident cases with more rapid progression.

Essential Role for Thymosin β4 in Regulating Vascular Smooth Muscle Cell Development and Vessel Wall Stability

Abstract: Rationale:Compromised development of blood vessel walls leads to vascular instability that may predispose to aneurysm with risk of rupture and lethal hemorrhage. There is currently a lack of insight into developmental insults that may define the molecular and cellular characteristics of initiating and perpetrating factors in adult aneurismal disease. Objective:To investigate a role for the actin-binding protein thymosin β4 (Tβ4), previously shown to be proangiogenic, in mural cell development and vascular wall stability. Methods and Results:Phenotypic analyses of both global and endothelial-specific loss-of-function Tβ4 mouse models revealed a proportion of Tβ4-null embryos with vascular hemorrhage coincident with a reduction in smooth muscle cell coverage of their developing vessels. Mechanistic studies revealed that extracellular Tβ4 can stimulate differentiation of mesodermal progenitor cells to a mature mural cell phenotype through activation of the transforming growth factor-beta (TGFβ) pathway and t...

RNA-binding proteins as a point of convergence of the PI3K and p38 MAPK pathways

Abstract: Understanding the mechanisms by which signal transduction pathways mediate changes in RNA abundance requires the examination of the fate of RNA from its transcription to its degradation. Evidence suggests that RNA abundance is partly regulated by posttranscriptional mechanisms affecting RNA decay and this in turn is modulated by some of the same signalling pathways that control transcription. Furthermore, the translation of mRNA is a key regulatory step that is influenced by signal transduction. These processes are regulated, in part, by RNA-Binding Proteins (RBPs) which bind to sequence specific RNA elements. The function of RBPs is controlled and co-ordinated by phosphorylation. Based on the current literature we hypothesize that RBPs may be a point of convergence for the activity of different kinases such as PI3K and MAPK which regulate RBP localisation and function.

Pten Loss in CD4 T Cells Enhances Their Helper Function but Does Not Lead to Autoimmunity or Lymphoma

Abstract: PTEN, one of the most commonly mutated or lost tumor suppressors in human cancers, antagonizes signaling by the PI3K pathway. Mice with thymocyte-specific deletion of Pten rapidly develop peripheral lymphomas and autoimmunity, which may be caused by failed negative selection of thymocytes or from dysregulation of postthymic T cells. We induced conditional deletion of Pten from CD4 Th cells using a Cre knocked into the Tnfrsf4 (OX40) locus to generate OX40(Cre)Pten(f) mice. Pten-deficient Th cells proliferated more and produced greater concentrations of cytokines. The OX40(Cre)Pten(f) mice had a general increase in the number of lymphocytes in the lymph nodes, but not in the spleen. When transferred into wild-type (WT) mice, Pten-deficient Th cells enhanced anti-Listeria responses and the clearance of tumors under conditions in which WT T cells had no effect. Moreover, inflammatory responses were exaggerated and resolved later in OX40(Cre)Pten(f) mice than in WT mice. However, in contrast with models of thymocyte-specific Pten deletion, lymphomas and autoimmunity were not observed, even in older OX40(Cre)Pten(f) mice. Hence loss of Pten enhances Th cell function without obvious deleterious effects.

Nerve fibre degeneration in the brain in amyotrophic lateral sclerosis

Abstract: NERVE FIBRE DEGENERATION IN THE BRAIN IN AMYOTROPHIC LATERAL SCLEROSIS1 Author: Smith MC Year published: 1960 Number of times cited: 95 Martin R Turner from Oxford University, comments on the first ‘tractography’ study in amyotrophic lateral sclerosis, and a landmark in the construct of a multi-system cerebral neurodegeneration An advertisement in The New Scientist dated 9 May 1957 read: “Technician or junior technician required for histology in neuropathological work. Some knowledge of photography an advantage. Salary according to experience. Apply in writing stating age and experience to Dr Marion Smith, National Hospital for Nervous Diseases, Queen Square, London WC1”. Three years later the Glasgow trained neuropathologist (1910–1998) and President of the British Neuropathological Society published …

An Emerging Role of RNA-Binding Proteins as Multifunctional Regulators of Lymphocyte Development and Function

Abstract: Sequence-specific RNA-binding proteins (RBP) and the regulation of RNA decay have long been recognized as important regulators of the inflammatory response. RBP influence gene expression throughout the lifespan of the mRNA by regulating splicing, polyadenylation, cellular localization, translation, and decay. Increasing evidence now indicates that these proteins, together with the RNA decay machinery that they recruit, also regulate the development and activation of lymphocytes. The activity of RBP is regulated by the same signal transduction pathways that govern lymphocyte development and differentiation in response to antigen and cytokine receptor engagement. Roles for these proteins in regulating the diverse functions of lymphocytes are becoming increasingly apparent.

Magnetic resonance imaging of pathological processes in rodent models of amyotrophic lateral sclerosis.

Abstract: Non-human models of neurodegenerative diseases have potential for the identification of key pathways in pathogenesis and for the more rapid assessment of therapeutic candidates. While there are legitimate concerns about the physiological differences between the rodent and human motor systems, mice expressing the 'G93A' superoxide dismutase-1 gene mutation are a predictable and robustly-characterized model for amyotrophic lateral sclerosis (ALS). This model has provided evidence for an important role of inflammatory processes during the pre-clinical phase, a stage currently inaccessible for human study in what is largely a sporadic disease. While magnetic resonance imaging is now an established and leading modality for the identification of ALS biomarkers in humans, it can also be increasingly applied to rodent models to probe structural, functional and biochemical changes throughout the course of the disease, with additional potential to generate surrogate markers for the efficacy of therapeutic interventions. Targeted MRI contrast agents, through tagging of various cell types and even individual molecules, will deliver an era of in vivo molecular neuroimaging, with greater specificity for the most relevant pathological processes. These are potentially important steps towards the ultimate goal of human therapeutic translation.

Motor neurone disease is a clinical diagnosis

Abstract: As non-neurophysiologists we enjoyed this informative review of electromyography (EMG), and benefit enormously from the service provided by our local colleagues. We suggest, however, that EMG is neither ‘essential’ nor ‘diagnostic’ for motor neurone disease (MND). Rather, for at least the 85% of cases with classical amyotrophic lateral sclerosis, MND is a clinical diagnosis. The average delay in diagnosis of MND from the onset of symptoms has stubbornly remained around 1 year over the last two decades.1 Over-reliance on investigations, including neurophysiology, excluding implausible mimic conditions may be a contributory factor. The first …

Teaching Video NeuroImages: Acute Adie syndrome

Abstract: A healthy 30-year-old woman reported acute painless enlargement of the right pupil, associated with mild ipsilateral photophobia and blurring. An enlarged right pupil was observed, constricting poorly to light and with segmental vermiform movements ([figure][1]). Generalized deep tendon hyporeflexia

Teaching NeuroImages: somatic muscle fasciculations detected by electrocardiography

Abstract: A routine EKG during admission for gastrostomy in a chronically hypertensive 75-year-old patient with amyotrophic lateral sclerosis (ALS) demonstrated repetitive small depolarizations (figure). The patient had no cardiac pacemaker and was not taking any medication. A study of 550 routine EKGs revealed somatic muscle fasciculation potentials in 1%, in association with a range of lower motor neuron pathology, …

A new mechanism of gene regulation mediated by noncoding RNA.

Abstract: Cytokines play a critical role in innate and adaptive immunity, acting as messenger molecules that regulate the growth, survival, and function of cells. The revolution in recombinant DNA techniques in the late 1970s led to the molecular cloning of cDNAs encoding a number of cytokines. By the mid-1980s, many of these had been identified and were revealed to be relatively small secreted proteins with diverse primary structures. The pleiotropic actions of cytokines, which underpin the complex interaction between the immune system and other tissues, were only beginning to be appreciated. With the identification of their gene sequences, it was possible to examine how the expression of cytokines was regulated at the molecular level. It was widely appreciated that answering this question would give insights into how the immune response was coordinated and how altered regulation of cytokines might contribute to disease. The factors controlling gene expression at the molecular level were only starting to be understood (e.g.,theidentification of promotersandenhancers that regulate gene transcription in tissue-specific and inducible manners). However, the mechanisms by which these factors functioned remained poorly defined. Accordingly, the publication of the paper we highlight in this commentary coincided with the discovery of NF-kB and predated the identification of NFAT and STAT transcription factors, which are among the most often encountered regulators of cytokine gene transcription.

Compositions and Methods for Preventing or Treating Influenza Virus Infection

Abstract: The invention includes compositions and methods for regulating PI3K p110 delta as an anti-retroviral therapy. The invention includes inhibiting p110 delta, a component of PI3K p110 delta signaling pathway, or any combination thereof in a cell as an anti-retroviral therapeutic approach for treating a retroviral infection, for example HIV. The invention includes a method of modulating PI3K p110 delta in a cell infected with a retrovirus by contacting the cell with an effective amount of a composition comprising an inhibitor of PI3K p110 delta.