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P Nigel Leigh

Publications and source records attributed to P Nigel Leigh.

At least 19 recordsLinked to original sources
PubMed2006

Electrical injury and amyotrophic lateral sclerosis: a systematic review of the literature.

Electrical injury may act as a potential precipitating or risk factor for amyotrophic lateral sclerosis (ALS). A systematic review of the literature was undertaken to assess the relationship between electrical injury and the development of ALS. Information for the review was obtained using five medical databases, and from manual searching of individual papers. Patients presenting with a neurological syndrome after electrical injury, including lightning, were included and classified into four categories: ALS; progressive upper motor neurone (UMN) syndrome; progressive lower motor neurone (LMN) syndrome; and non-progressive syndrome. Linear regression and chi2 testing were used for analysis of the data. 96 individuals, comprising 44 with ALS, 1 with a progressive UMN syndrome, 7 with a progressive LMN syndrome and 44 with a non-progressive syndrome, were identified from 31 papers with publication dates between 1906 and 2002. The median interval between electrical injury and disease onset was 2.25 years for all progressive syndromes and just over 1 week for the non-progressive syndrome. The more severe the shock (excluding lightning), the more likely individuals were to have a non-progressive motor syndrome. A non-progressive spinal cord syndrome is associated with more severe electrical injury. Overall, the evidence reviewed does not support a causal relationship between ALS and electric shock.

Amyotrophic Lateral Sclerosis↗
PubMed2005

ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth.

Rac and its downstream effectors p21-activated kinase (PAK) family kinases regulate actin dynamics within growth cones to control neurite outgrowth during development. The activity of Rac is stimulated by guanine nucleotide exchange factors (GEFs) that promote GDP release and GTP binding. ALS2/Alsin is a recently described GEF that contains a central domain that is predicted to regulate the activities of Rac and/or Rho and Cdc42 activities. Mutations in ALS2 cause some recessive familial forms of amyotrophic lateral sclerosis (ALS) but the function of ALS2 is poorly understood. Here we demonstrate that ALS2 is present within growth cones of neurons, in which it co-localizes with Rac. Furthermore, ALS2 stimulates Rac but not Rho or Cdc42 activities, and this induces a corresponding increase in PAK1 activity. Finally, we demonstrate that ALS2 promotes neurite outgrowth. Defects in these functions may therefore contribute to motor neuron demise in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Comparison of two percutaneous radiological gastrostomy tubes in the nutritional management of ALS patients.

Patient care and minimizing complications post gastrostomy have to date received little attention in ALS patients. We compare the complications associated with pigtail and mushroom type percutaneous radiological gastrostomy tubes in this patient group. Patients requiring PRG received either Wills-Oglesby or the skin level Entristar. Retrospective review of the clinical notes was performed capturing demographic data, peristomal infection, tube displacement, tube failure, nutritional status, site of disease onset, and survival. Thirty-five patients (Group 1) had the Wills-Oglesby tube of which 14 (40%) tubes required replacement. The Entristar tube was inserted in 29 patients (Group 2) where 8 (28%) required replacement (NS). The incidence of infection was significantly lower with the Entristar tube, (p<0.001). The mean time to tube removal in Group 2 was 223 days (SD 147; range 71-494 days) due to 'buried bumper syndrome'. We conclude that the Entristar skin level gastrostomy tube is associated with a reduction in peristomal infection, tube failure and blockage compared with the Wills-Oglesby tube.

Adult↗
PubMed2005

Living with motor neurone disease: lives, experiences of services and suggestions for change.

Palliative care involves the complete, holistic care of people with progressive illness and their families. People living with motor neurone disease (MND) require a range of multidisciplinary palliative care services. However, there are significant gaps in our understanding of these people's lives, experiences of services and their suggestions for service change. The present study addressed the following questions: (1) What are the lived experiences of people living with MND? (2) What are people's experiences of services? and (3) Can improvements to care be identified? A qualitative research design was adopted using semi-structured interviews. The topic guide was developed from existing literature. The study was based in three boroughs in London, UK. People living with MND and professionals were drawn from a database at King's College Hospital, and additionally, through 'snowball' sampling. Nine people with MND, five carers/family members and 15 professionals took part in the interviews. These interviews were audio-taped, transcribed and checked for accuracy against the original recordings. Themes within the interviews were coded and grouped. The analysis was facilitated with the NVIVO computer software package. The findings are presented within three substantive groups: (1) the impact of MND on people's lives (the physical impacts of the illness, including increasing disability; social issues, including restrictions on social activities; and adjustments to people's lives, including methods of coping with the illness); (2) experiences of services (accessing service entitlements, information sources, professionals' attitudes and approaches, and professionals' knowledge and understanding of MND); and (3) suggestions for service change (better information and communication, including information on service entitlements; improved knowledge amongst professionals about MND; and some suggestions for service restructuring). This study brings a fresh approach to understanding the impacts of MND and the ways in which services can be improved to meet people's needs. The paper concludes with methodological considerations, the implications of the findings for practitioners and policy makers, and suggestions for further research.

Activities of Daily Living↗
PubMed2004

A novel somatodendritic marker defined by a peptide derived from the ALS2 protein.

We characterized an antibody raised against a peptide derived from the ALS2 protein, the product of a gene linked to recessive juvenile forms of amyotrophic lateral sclerosis, defining the ALS2 RLD-derived antigen (ARDA). In cultured rat cortical neurons, ARDA is localized in perikarya and neurites, but absent from nuclei. Double immunostaining of rodent cultured neurons and spinal cord sections for ARDA and MAP2, a marker of dendrites, or tau and phosphorylated neurofilaments, markers of axons, demonstrated that the ARDA antigen was localized in the somatodendritic compartment and excluded from axons. ARDA was also selectively localized to the somatodendritic compartment of motor neurons in human spinal cord. The ARDA antigen therefore represents a novel somatodendritic marker for embryonic and adult neurons.

Amino Acid Sequence↗
PubMed2004

Entristar skin-level gastrostomy tube: primary placement with radiologic guidance in patients with amyotrophic lateral sclerosis.

PURPOSE: To retrospectively review the authors' experience with a radiologic method of primary insertion of a skin-level gastrostomy tube (Entristar; Tyco Healthcare, Mansfield, Mass) in patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: Over a 12-month period (September 2002 through September 2003), 25 patients with ALS (mean age, 62.4 years; age range, 41-83 years; 15 men, 10 women) who had bulbar impairment and a body mass index of less than 20 kg/m(2) or weight loss of greater than 10% were selected for placement of an enteral feeding tube. Patients with overnight oxygen desaturation or respiratory acidosis were referred for placement of the Entristar tube with radiologic guidance. This procedure was performed with local anesthesia and without sedation by using a modified percutaneous lateral fluoroscopic technique that aided tube insertion in patients with elevation of the hemidiaphragm and a "high" stomach position. Technical success and immediate and delayed procedure complications were recorded. RESULTS: The Entristar tube was successfully inserted in all 25 patients. Pneumoperitoneum as an early complication was documented in one patient, and one patient developed a pelvic abscess that required drainage. Follow-up for a median of 112 days (range, 14-343 days) revealed superficial wound infections in four patients and weight gain in two patients; weight gain necessitated tube replacement in one patient. There were no procedure-related deaths. CONCLUSION: Radiologically guided insertion of the Entristar skin-level gastrostomy tube is a safe procedure in patients with ALS that allows the creation of a permanent feeding gastrostomy without the need for sedation or endoscopy.

Adult↗
PubMed2004

Gigaxonin is associated with the Golgi and dimerises via its BTB domain.

Mutations in the gigaxonin gene cause giant axonal neuropathy. The amino-terminus of gigaxonin contains a BTB domain but no binding partners for this domain have so far been identified. Here, we demonstrate that the gigaxonin BTB domain forms homodimers. Other BTB-bearing proteins have also been shown to dimerise via their BTB domains with the dimers then capable of interacting with other ligands. Thus, the gigaxonin BTB domain may function in a similar manner. We also demonstrate that gigaxonin is expressed in a wide variety of neuronal cell types where a significant proportion exists in cell bodies. Confocal microscope studies of gigaxonin-transfected COS-7 cells and cultured neurones revealed that a proportion of gigaxonin localises to the Golgi and endoplasmic reticulum.

Animals↗
PubMed2004

Degradation properties of polyglutamine-expanded human androgen receptor in transfected cells.

Spinal and bulbar muscular atrophy is an inherited motor neuronopathy caused by the expansion of a polyglutamine sequence in the androgen receptor. Recent evidence suggests that the presence of a long polyglutamine stretch may impair the regulation of the steady-state levels of disease-causing proteins. We compared the degradation characteristics of androgen receptors with 20 or 51 glutamine residues in transfected HEK293 cells. Both forms accumulated after treatment with lactacystin, demonstrating degradation by the ubiquitin-proteasome pathway. The half-life of the two forms of the androgen receptor was approximately 6 h, as determined by cycloheximide chase. These results suggest that the presence of an expanded polyglutamine sequence does not influence degradation rates directly and that differential regulation of steady-state levels of the androgen receptor in neurons would require neuron-specific, polyglutamine-dependent, factors.

Acetylcysteine↗
PubMed2004

A novel central motor conduction abnormality in D90A-homozygous patients with amyotrophic lateral sclerosis.

Patients with amyotrophic lateral sclerosis (ALS) who are homozygous for the D90A SOD1 mutation have been noted to have central motor abnormalities distinct from those of patients with idiopathic ALS. We stimulated the motor cortex of ten patients homozygous for the D90A SOD1 mutation, using transcranial magnetic stimulation (TMS), and recorded the response evoked in the right first dorsal interosseous muscle when the muscle was at rest and when voluntarily active. A subgroup of patients had two distinct evoked responses when the cortex was stimulated at high intensity with the muscle at rest. When the muscle was modestly contracted, the first of these responses disappeared, whereas the second response was facilitated. Both fast and slow components of the corticospinal tract were usually intact and excited by TMS in these patients. We propose that there is an abnormality of intracortical or intraspinal inhibition in a subgroup of D90A SOD1 ALS patients, which suppresses fast-conducted activity when the muscle is active. Apart from further defining the phenotype of familial ALS, these findings may have importance in understanding the pathogenesis of central motor abnormalities in these patients.

Adult↗
PubMed2004

p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis.

Neurofilament middle and heavy chains (NFM and NFH) are heavily phosphorylated on their carboxy-terminal side-arm domains in axons. The mechanisms that regulate this phosphorylation are complex. Here, we demonstrate that p38alpha, a member of the stress-activated protein kinase family, will phosphorylate NFM and NFH on their side-arm domains. Aberrant accumulations of neurofilaments containing phosphorylated NFM and NFH side-arms are a pathological feature of amyotrophic lateral sclerosis (ALS) and we also demonstrate that p38alpha and active forms of p38 family kinases are associated with these accumulations. This is the case for sporadic and familial forms of ALS and also in a transgenic mouse model of ALS caused by expression of mutant superoxide dismutase-1 (SOD1). Thus, p38 kinases may contribute to the aberrant phosphorylation of NFM and NFH side-arms in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

Adult↗
PubMed2004

Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial.

In November 2002, an advisory board meeting was convened by Novartis Pharma to provide recommendations and rationale for clinical trials designed to evaluate new treatments, such as TCH346, for amyotrophic lateral sclerosis (ALS). In terms of selecting appropriate outcome measures, the panel recommended the use of the ALS Functional Rating Scale (ALSFRS-R) to measure primary endpoints. A review of other key issues in this area including regional variations in the epidemiology, diagnosis and management of ALS, defining patient populations and doses of trial medication, and accommodating the likelihood of co-medication with pre-existing treatment in trial design, are discussed.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Protective effects of estrogens on polyglutamine-expanded androgen receptor aggregation in mice.

Spinal and bulbar muscular atrophy is a motor neuronopathy caused by a polyglutamine expansion in the androgen receptor (AR). Only males are affected as the development of pathology requires high levels of circulating androgens. Androgens promote aggregation of the AR into characteristic intracellular inclusions. As a potential factor contributing to the protection of female carriers, we assessed the effects of estrogens on AR aggregation in transfected neuronal cells using a filter retardation assay. Pre-treatment of mouse neuroblastoma Neuro2a cells expressing an AR with 51 glutamine residues with 10 microM 17beta- or 17alpha-estradiol prevented induction of AR aggregation by testosterone. Western blot analysis showed that the protective effects of estrogens occurred in the absence of a change in AR processing. We conclude that estrogens protect polyglutamine-expanded AR from aggregation through a non-genomic mechanism possibly involving estrogen binding to the AR.

Animals↗
PubMed2003

Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D16S3137 and a three-point LOD score of 3.85 for markers D16S415 and D16S3137. Haplotype analysis revealed no recombination > approximately 30 cM, (flanking markers at D16S3075 and D16S3112). The maximum two-point LOD score for family 2 was 1.84 at D16S415, and the three-point LOD score was 2.10 for markers D16S419 and D16S415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D16S3396 and D16S3112). The region shared by both families on chromosome 16q12 corresponds to approximately 4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.

Adult↗