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At least 649 records · Page 36Linked to original sources
PubMed1994

Treatment of ALS with high dose pulse cyclophosphamide.

Autoimmune abnormalities have been described in sporadically acquired amyotrophic lateral sclerosis (ALS), but ALS patients do not benefit from conventional immunosuppressive therapy. Because Multifocal Motor Neuropathy causes a syndrome mimicking the lower motor neuron involvement in ALS and responds to high dose cyclophosphamide, we tested whether ALS patients would respond to the same treatment. Eighteen patients with classical ALS initially received a high loading dose of intravenous cyclophosphamide (3 g/m2) followed by 6-monthly injections of 750-1000 mg/m2. We monitored isometric strength, fine motor coordination and pulmonary function monthly for 3 months prior to the study, during the treatment phase, and for 6 months after treatment. Treatment subjects were matched to control subjects from the WALS natural history data base and compared on the basis of decline rate (megaslopes). Treatment did not alter the course of ALS.

Adult↗
PubMed1995

The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies.

Because of its multi-faceted potential as a neurotrophic factor, insulin-like growth factor I (IGF-I) has been given to hundreds of ALS patients world-wide. Unlike some patients with post-polio syndrome and fragile elderly males, it is unclear whether any of these patients possess disturbances in IGF signaling. We found that about 25% of ALS patients in a controlled trial of human growth hormone (hGH) had lower or higher than normal IGF-I serum levels. Many ALS patients do have some of the characteristics of type II diabetes mellitus, where IGF-I therapy is also under way. In addition, in type I diabetes significant increase in a circulating molecule that binds IGF-I, IGF-I binding protein 1 (IGFBP-1), occurs along with reduced IGF-I, when neuropathic complications are prominent. We have studied the response of IGFBPs in ALS patients to subcutaneous rhIGF-I and found transient induction of IGFBP-1. Studies related to the IGFBPs have not been done in familial ALS (FALS) patients. However, the gene for another IGFBP, BP-2, co-localizes with the gene for juvenile ALS (ALSJ) on chromosome 2. IGF-I has been given to several models of motor neuron degeneration in the mouse, including motor neuron disease and wobbler, with beneficial effects. However, it is also not known whether any accepted genetic mouse model of motor neuron degeneration possesses any disturbance in the IGF signaling system.

Amyotrophic Lateral Sclerosis↗
PubMed1996

The amyotrophic lateral sclerosis (ALS) patient perspective on misdiagnosis and its repercussions.

We studied the rate of initial "misdiagnosis', along with factors than might distinguish such patients, in 64 patients with amyotrophic lateral sclerosis (ALS) who completed a survey of 34 questions. Announcement of the survey was made by electronic newsletter and users group bulletin board directed at ALS patients. The questionnaire was distributed to interested ALS patients via electronic mail (e-mail), and 64 ALS patients (81% from the USA) returned their completed questionnaires via reply e-mail or postal mail. Seventeen patients (27% of total group) indicated at least 1 prior misdiagnosis, most commonly spinal stenosis/radiculopathy; 5 listed unnecessary and costly surgical treatments (laminectomy, endarterectomy). Misdiagnosis appeared to be more common in patients above age 60 and may be more common in patients originating in cities versus smaller communities. Mean time from onset of first symptom until definitive diagnosis of ALS was prolonged in patients with initial misdiagnosis (19 months) compared with non-misdiagnosed patients (10 months). Such a previous misdiagnosis may decrease a patient's chance of acceptance into multicenter ALS drug trials.

Adult↗
PubMed1995

Structure and regulation of the ALS gene.

The mouse ALS gene spans at least 6 kb. It contains 2 exons which encode a protein highly homologous to human and rat ALS. It was localized to mouse chromosome 17 by flourescent in situ hybridization. The 5' flanking region lacks a TATA box but contains GC boxes that may be recognised by transcription factors such as Spl. Hepatic ALS mRNA is decreased in rats following hypophysectomy, and restored by stimulated ALS promoter activity in a rat hepatoma cell line, but not in 3T3-F442A mouse preadipocyte fibroblasts, suggesting that utilisation of the ALS promoter is cell-type specific. The rat hepatoma system is a promising system to study the regulation of ALS gene expression, and the signalling pathways of CH regulation.

Animals↗
PubMed2004

Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motoneurons in the spinal cord and brain stem. We have characterized motoneuron death in transgenic mice carrying the mutant human copper/zinc superoxide dismutase, as a model for familial ALS. Previous studies have shown the involvement of mitochondria in nerve cell demise in these animals. We report here an early cleavage of caspase-12, residing in the endoplasmic reticulum (ER), in the spinal cord during the course of the disease. Apart from caspase-12, caspase-9, and caspase-3 were activated in the transgenic ALS mice. Staining with an antibody for nitrotyrosine, as a marker for oxidative stress, showed a large increase in the ALS mice. The results indicate that oxidative and ER induced stress causing caspase-12 activation are involved in neuronal death and disease progression in ALS. Caspase-12 and the ER pathway for cell death may constitute potential novel targets for the treatment of ALS.

Adaptation, Physiological↗
PubMed2004

Quantitative EEG analysis for assessment to 'plan' a task in amyotrophic lateral sclerosis patients: a study of executive functions (planning) in ALS patients.

An attempt has been made to study the ability of patients with amyotrophic lateral sclerosis (ALS) to 'plan' a task. Electroencephalogram (EEG) data corresponding to 'planning of a movement task' is analyzed in comparison with a normal relaxed state. The study was conducted on 12 patients with ALS (6 males, 3 females, mean age 46.75 years) and on same number of controls (10 males, 2 females, mean age 48.75 years) to evaluate a difference in the ability to 'plan' a movement task between them. Patients with ALS were divided in two groups defined by unclear/clear speech. It has been observed that patients with ALS having unclear speech (Group I) showed considerable reduction (p<0.0001) in 'planning' a movement task, whereas patients with ALS having clear speech (Group II) showed no deficit in 'planning' a movement task (p=0.0577), both in comparison with age-matched controls. Apart from supporting the earlier reports of a possible extended neuronal degeneration across wide area of the frontal lobes, the findings reveal a possible reduction in planning, an executive function of the prefrontal cortex of brain, and also reveal that speech impairment may be associated with cognitive deficits in patients with ALS.

Adult↗
PubMed2006

Al(III)-binding ability of an octapeptide and its phosphorylated derivative.

A synthetic octapeptide, H-GlyGluGlyGluGlySerGlyGly-OH, and its phosphorylated Ser derivative were synthetized and their solution speciation and binding modes in their complexes with Al(III) were measured. One goal of the work was find a lead compound for the design of a selective peptide-based Al(III) chelator. pH-potentiometry was used to characterize the stoichiometry and the stability of the species formed in the interactions of the metal ion and the peptides, while multinuclear NMR was applied to characterize the binding sites of the metal ion in the complexes. CD spectroscopy revealed a difference in the conformational behaviour of the phosphorylated peptide as compared with its non-phosphorylated parent derivative. The Al(III) is presumed to enhance aggregation through the -PO3H(-)-Al(3+)-PO3(2-)-Al(3+)- intermolecular bindings between the peptide chains. The results of molecular dynamics calculations supported the experimentally obtained secondary structures and the binding position of Al(III).

Aluminum↗
PubMed2006

GABA(A)-receptor mRNA expression in the prefrontal and temporal cortex of ALS patients.

There is evidence that excitotoxic cell death is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Electrophysiological and histological studies support the pathophysiological concept of an impaired inhibitory, namely GABAergic, control of the motoneurons in the cerebral cortex of ALS patients. Recently, pathological, neuropsychological and functional imaging data have challenged the view that ALS is a disorder restricted to the motor system. The aim of our study was to investigate the expression of the most abundant GABA(A)-receptor subunit mRNAs and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) in the prefrontal, temporal, occipital and cerebellar cortex of ALS patients compared to tissue of control persons. We performed in situ hybridization histochemistry (ISH) on human post-mortem cortex sections of ALS patients (n=5) and age-matched controls with no history of neurological disease (n=5). In the prefrontal and temporal cortex of ALS patients, we detected significantly reduced mRNA expression of the alpha1-subunit, while the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) was significantly upregulated in these regions. In the occipital and cerebellar cortex, we did not see disease-specific differences of the mRNA expression of the investigated subunits.

Aged↗
PubMed2006

Targeted stem cell transplantation strategies in ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that results in paralysis and ultimately death due to respiratory failure. Transplantation of neural precursor cells (NPCs) derived from the central nervous system is a promising therapeutic strategy for treatment of brain and spinal cord disorders such as ALS. ALS is a particularly challenging disease for designing relevant therapies, and presently no effective treatment exists. Despite such daunting challenges, a number of the potential benefits of NPC transplantation coincide with the neuropathological obstacles associated with ALS, including neuronal and glial replacement and non-replacement functions such as delivery of trophic support. Knowledge of the underlying disease-specific pathways involved in neurodegeneration and the contributions of different cellular subtypes to the disease go hand-in-hand with advances in NPC transplantation biology, and will aid in targeting cell-specific therapies to neurodegenerative disorders such as ALS. It is with these multiple cell targets that NPC transplantation may lend itself well to understanding and possibly slowing disease processes. A number of studies have already demonstrated the potential benefits of cell transplantation in ALS models. Lastly, practical issues such as timing and method of cell delivery, immune suppression, and the need for combinatorial approaches with non-cell based strategies must all be considered for eventual translation to the clinic.

Cell Division↗
PubMed2005

Variants in candidate ALS modifier genes linked to Cu/Zn superoxide dismutase do not explain divergent survival phenotypes.

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; approximately 25% are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. A4V ALS cases typically have a very short survival (1-1.5 years versus 3-5 years for other dominant SOD1 mutations). A recent study of A4V carriers identified a common haplotype around the SOD1 locus, suggesting the hypothesis that genetic variations within the haplotypic region might accelerate the course of A4V cases. By contrast, SOD1(D90A/D90A) ALS cases have a very slow progression (>10 years), raising the reciprocal hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1(D90A/D90A) mutations. In the present study, DNA sequencing of four genes within the haplotypic region shared in A4V and D90A ALS patients revealed 15 novel variants, but none result in changes in amino acid sequences specifically associated with SOD1(D90A/D90A) or SOD1(A4V) ALS. We conclude that mutations within coding regions of genes around the SOD1 locus are not responsible for the more aggressive and more benign natures of the SOD1(A4V) and SOD1(D90A/D90A) mutations, respectively.

Amyotrophic Lateral Sclerosis↗
PubMed2006

High erythropoietin and low vascular endothelial growth factor levels in cerebrospinal fluid from hypoxemic ALS patients suggest an abnormal response to hypoxia.

Animal studies have highlighted the potentially neuroprotective role of vascular endothelial growth factor (VEGF). Low levels of this growth factor have been found in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). VEGF (and other proteins, such as erythropoietin (EPO)) are produced in response to hypoxia via a common pathway involving a specific transcription factor (hypoxia-inducible factor, HIF) and a hypoxia responsive element (HRE) in the respective genes' promoter regions. In this study, we report finding the expected, high levels of VEGF and EPO in CSF from hypoxemic neurological controls, whereas EPO (but not VEGF) levels are high in the CSF from hypoxemic ALS patients. Hence, the VEGF levels in CSF from patients with ALS were significantly lower than those seen in hypoxemic controls. There was a trend towards higher CSF levels of EPO in hypoxemic ALS patients than in hypoxemic controls. Our results suggest that VEGF may not be produced in sufficient amounts in chronically hypoxic ALS patients and that this dysfunction may participate in the pathogenesis of the disease. The high EPO levels in hypoxemic ALS patients nevertheless suggest an intact common oxygen-sensor pathway.

Adult↗
PubMed2005

Field ion microscopy and 3-D atom probe analysis of Al3Zr particles in 7050 Al alloy.

Field ion microscope images have been used to measure the local evaporation field of a Al3Zr particle in 7050 Al alloy. Using the matrix Al evaporation field (19 V/nm) as a reference, the evaporation field of Al3Zr has been estimated to be 36 V/nm, similar to the theoretical value for the field evaporation of Al2+ or Zr3+ ions. A strong local magnification effect from the large difference in evaporation fields between the particle and matrix has been found to cause a severe distortion of the apparent particle morphology in a three-dimensional atom probe reconstruction when using parameters based on the Al matrix. Use of the measured evaporation field for Al3Zr has allowed accurate reconstruction of the morphology of the particle. A simple worst-case analysis predicts that trajectory overlaps increase with increasing cross-section of particle, and the calculated overlaps agree well with experimental estimates of approximately 1.4-2.0 nm for variations in the particle cross-section from 7 to 12 nm. The chemical composition of Al3Zr in a 7050 Al alloy has been measured to be 64.8-67.7 at% Al, 23.6-24.8 at% Zr, 6.9-9.1 at% Zn, 0.4-0.7 at% Cu, 0.5-1.2 at% Mg, with a (Al+Zn)/Zr ratio close to 3. Specimen analysis temperatures of either 25 or 80 K show little effect on the measured chemical compositions of the particle.

Alloys↗
PubMed2006

XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice.

Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons. The cause for nerve cell demise is not clear but involves activation of the caspase family of cysteine proteases. We have shown that ER stress and caspase-12 activation occur in ALS transgenic mice carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. In these mice, we found that the antiapoptotic proteins, X-linked Inhibitor of Apoptosis Protein (XIAP) and the related protein, MIAP2 were decreased. To study the role of this, we generated double transgenic mice expressing XIAP in ALS spinal cord neurons using the Thy1 promoter. Overexpression of XIAP inhibited caspase-12 cleavage and reduced calpain activity in the ALS mice. XIAP also reduced the breakdown of calpastatin that is an inhibitor of calpain. In the double transgenic mice, life span was increased by about 12%. These data support the view that XIAP has beneficial effects in ALS and extends survival. The neuroprotective effect of XIAP involves inhibition of caspases and the stabilization of the calpastatin/calpain system that is altered in the ALS mice.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Al(3+)-mediated changes on membrane fluidity affects the activity of PI-PLC but not of PLC.

We investigated whether Al(3+)-mediated changes in membrane fluidity can affect the activity of prokaryotic enzymes phospholipase C (PLC) and phospholipase C-phosphatidyl inositol specific (PI-PLC) in liposomes of phosphatidyl choline (PC), PC:phosphatidyl inositol (PI), or PC and polyphosphoinositides (PPI). Al(3+) (10-100 microM) promoted membrane rigidification, evaluated with the probes 1,6-diphenyl-1,3,5-hexatriene and Laurdan, and followed the order: PC:PPI>PC:PI>PC. Al(3+) (25 and 50 microM) did not affect PLC-mediated hydrolysis of PC, PI and PIP(2), but stimulated PIP hydrolysis (48.6%). PI-PLC did not affect PC, PI, and PIP concentrations, but caused a 67% decrease in PIP(2). Al(3+) significantly inhibited PIP(2) hydrolysis in a concentration-dependent (25-50 microM) manner. Results suggest that the inhibition of PIP(2) hydrolysis by Al(3+) could be partially due to a higher lipid packing induced by Al(3+) which could affect the interaction between the enzyme and its substrate.

Aluminum↗
PubMed2000

Six important themes in amyotrophic lateral sclerosis (ALS) research, 1999.

My assignment was to identify the 6 most important ALS papers published in 1999 but, great to relate, there were too many excellent candidates. Rather than confining the search to individual papers, six major themes seemed appropriate for discussion: 1) The study of transgenic mice that carry a mutated human gene for superoxide dismutase-1 (SOD1) has led to many far-reaching advances in ALS research. The mice are regarded as the best test system to evaluate potential therapies, including creatine. Inconsistencies between efficacy in mice and people are noted, however. 2) Transgenic mice have also been used to evaluate the role of glutamate toxicity in the pathogenesis of ALS, a dominant theory. 3) The role of mitochondria in the pathogenesis of ALS is gathering increasing attention. 4) The role of neurofilaments in the pathogenesis of ALS has provided new twists in mice and people. 5) Motor neuropathy is the most important differential diagnosis of ALS. 6) Gene therapy, as exemplified by the use of stem cells, has been applied successfully to animal models of other inherited diseases of the central nervous system.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Hyperintense and hypointense MRI signals of the precentral gyrus and corticospinal tract in ALS: a follow-up examination including FLAIR images.

In amyotrophic lateral sclerosis (ALS) patients, hyperintense signals at the subcortical precentral gyrus in brain fluid attenuated inversion recovery (FLAIR) MR images have been found more frequently than in controls. Quantitative analysis has revealed a significant increase of the FLAIR-magnetic resonance imaging (MRI) signal at the subcortical precentral gyrus of ALS patients compared to healthy controls. In addition, hypointense signals at the rim of the precentral gyrus in FLAIR and T2-weighted images have been shown in ALS patients. In 17 ALS patients, we evaluated hyperintense signals in T2-, T1-, proton density-weighted and FLAIR MR images, and hypointense signals in T2-weighted and FLAIR images 15.7+/-3.0 months after the initial examination by visual scoring. In FLAIR images, a quantitative analysis was added. The visual scores of hyperintense signals along the corticospinal tract did not change significantly in all sequences. However, the quantitative evaluation of FLAIR images revealed a significant increase of the signal intensity at the subcortical precentral gyrus (p<0.005). In addition, the frequency of the visually evaluated hypointense signals at the precentral gyrus increased significantly (p<0.05). The change of MR results did not correlate with the change of clinical parameters. In ALS patients, the increase of the quantified MRI signal at the subcortical precentral gyrus in FLAIR images and the increase of hypointense signals at the rim of the precentral gyrus corroborate the hypothesis that these signals are related to the upper motor neuron degeneration in ALS. Their specificity and clinical relevance have to be clarified further.

Adult↗
PubMed1997

A brief quality-of-life measure for ALS clinical trials based on a subset of items from the sickness impact profile. The Syntex-Synergen ALS/CNTF Study Group.

We previously demonstrated a significant relationship (P<0.0001) between maximum voluntary isometric contraction (MVC) plus pulmonary function scores (the Tufts Quantitative Neuromuscular Exam Combination Megascore (TQNE CM)), and the Sickness Impact Profile (SIP) in a cohort of 524 ALS patients. Because the 136-item SIP questionnaire can be difficult to administer in this population, we examined SIP subscales and clinically derived item sets in relation to the TQNE CM in an effort to define a briefer measure of quality of life for use in clinical trials. Two 'Mini-SIP' indices performed as well as the overall SIP in reflecting the impact of muscle weakness on ALS patients' quality of life: a combination of two SIP subscales ('SIP-33'), and a 19-item set of questions independently chosen by a panel of ALS specialists ('SIP/ALS-19'). Either index potentially could be useful in ALS clinical trials. The SIP/ALS-19 is currently being used in a National ALS data base, providing an opportunity to evaluate its utility prospectively against other QOL measures in ALS patients.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Home care of patients with amyotrophic lateral sclerosis (ALS).

Optimal home care maximizes function and quality of life for patients with ALS. We designed a survey to study home care in the ALS population. Ninety-eight patients with ALS completed our survey. Of these, 24 receive non-hospice home care, nine hospice home care, and seven both hospice and non-hospice home care. Fifty-eight patients receive no outside help. Patients receiving hospice are older than those receiving non-hospice home care (68.9 vs. 57.7 years, P<0.05). Patients with home care assistance have a mean ALS Functional Rating Scale (ALS FRS) score of 13, and those without home care assistance have a mean score of 26 (P<0.0001). Patients receiving non-hospice home care assistance have a median of 16 h/week of care, while those with hospice receive 5.5 h/week (P=0.05). Patients on Medicaid receive more hours of home care than those with any other insurance (median 61 vs. 3.4 h/week with Medicare and 5 h/week with commercial insurance, P=0.008). Primary caregivers spend a median of 11 h/day caring for patients despite having home care assistance. Forty-two and 48% of primary caregivers feel physically and psychologically unwell, respectively. Home care received by patients with ALS often is inadequate and too late to relieve the burden placed on family caregivers.

Adult↗