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Biomedical subjects

Y Harati

Publications and source records attributed to Y Harati.

At least 19 recordsLinked to original sources
PubMed2003

Occurrence of amyotrophic lateral sclerosis among Gulf War veterans.

BACKGROUND: In response to Gulf War veterans' concerns of high rates of ALS, this investigation sought to determine if Gulf War veterans have an elevated rate of ALS. METHODS: A nationwide epidemiologic case ascertainment study design was used to ascertain all occurrences of ALS for the 10-year period since August 1990 among active duty military and mobilized Reserves, including National Guard, who served during the Gulf War (August 2, 1990, through July 31, 1991). The diagnosis of ALS was confirmed by medical record review. Risk was assessed by the age-adjusted, average, annual 10-year cumulative incidence rate. RESULTS: Among approximately 2.5 million eligible military personnel, 107 confirmed cases of ALS were identified for an overall occurrence of 0.43 per 100,000 persons per year. A significant elevated risk of ALS occurred among all deployed personnel (RR = 1.92; 95% CL = 1.29, 2.84), deployed active duty military (RR = 2.15, 95% CL = 1.38, 3.36), deployed Air Force (RR = 2.68, 95% CL = 1.24, 5.78), and deployed Army (RR = 2.04; 95% CL = 1.10, 3.77) personnel. Elevated, but nonsignificant, risks were observed for deployed Reserves and National Guard (RR = 2.50; 95% CL = 0.88, 7.07), deployed Navy (RR = 1.48, 95% CL = 0.62, 3.57), and deployed Marine Corps (RR = 1.13; 95% CL = 0.27, 4.79) personnel. Overall, the attributable risk associated with deployment was 18% (95% CL = 4.9%, 29.4%). CONCLUSIONS: Military personnel who were deployed to the Gulf Region during the Gulf War period experienced a greater post-war risk of ALS than those who were not deployed to the Gulf.

Adult↗
PubMed2001

Current management of ALS: comparison of the ALS CARE Database and the AAN Practice Parameter. The American Academy of Neurology.

BACKGROUND: The American Academy of Neurology (AAN) ALS Practice Parameter was published in April 1999. The ALS CARE Database has been collecting data on the management of patients with ALS in North America since 1996. OBJECTIVE: To compare the management of patients with ALS in North America as recorded in the ALS CARE Database with the recommendations of the AAN ALS Practice Parameter. METHODS: Data were analyzed from 2018 patients at enrollment and from 373 of these patients who died between enrollment and May 1999. RESULTS: Eighty-two percent of the enrolled patients reported that they had been given enough information about ALS. Only 54% of patients with drooling were receiving medication for this problem. Only 41% of those who reported being depressed most of the time were receiving antidepressant medications. Only 28% of those with dyspnea and only 9.2% of those with a forced vital capacity <40% predicted were receiving noninvasive positive pressure ventilator support. Only 30% of those with moderate to severe dysphagia had a gastrostomy tube. Half of the patients who died did so at home, but only 47% of them received residential hospice services. Although 89% of patients who died were recorded as having done so peacefully, 17% were reported to have had breathing difficulties (i.e., respiratory distress), 8% anxiety, 3.3% pain, and 2.5% choking. Advance directives were in place for 90% of the patients who died, and in 97% of cases these directives were followed. CONCLUSIONS: These findings indicate that in the 3-year period prior to the publication of the AAN Practice Parameter, many but not all patients received the care that is recommended in that parameter; there were deficiencies, particularly in the key areas of gastrostomy and noninvasive positive pressure ventilation.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To determine the efficacy of IV immunoglobulin (IVIg) given patients with untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A randomized, double-blind, multicenter, investigator-initiated study compared IVIg (Aventis Behring LLC, King of Prussia, PA) with placebo (5% albumin). On days 1, 2, and 21, IVIg (1 g/kg) or placebo was given. The primary outcome measure was the change in muscle strength from baseline to day 42, using the average muscle score (AMS). Secondary outcome measures included change from baseline AMS at days 10 and 21, the Hughes' functional disability scale, forced vital capacity (FVC), and nerve conduction studies (NCS) of four motor nerves (median, ulnar, peroneal, and tibial). RESULTS: The patients (n = 33) were randomized. Of these, 30 (14 women, 16 men, aged 54 +/- 20 years, range 13 to 82) received IVIg and 23 were given placebo (12 women, 11 men, aged 50 +/- 18 years, range 23 to 73). Baseline AMS values of the groups were similar (IVIg 7.06 +/- 1.31 versus placebo 7.28 +/- 1.18, p = 0.53). There were two dropouts in placebo group and one in the IVIg group. Mean AMS improved at day 42 comparing IVIg with placebo (0.63 versus -0.1, p = 0.006). Improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIg, 11 subjects improved by the functional disability scale; none worsened. This differed (p = 0.019) from those in the placebo-treated group (two improved, two got worse, remainder unchanged). Forced vital capacity did not improve with IVIg treatment. IVIg improved ulnar motor distal latency (p = 0.005), tibial distal compound muscle amplitude (p = 0.003), and peroneal nerve conduction velocity (p = 0.03). CONCLUSIONS: IVIg improves strength in patients with untreated CIDP by day 10 with continued benefit through day 42; more than one third improve by at least a functional grade on a disability scale. This study provides data supporting IVIg as the initial treatment for CIDP.

Adolescent↗
PubMed2000

A "dystrophic" variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene.

OBJECTIVES: To identify the disease-causing mutation and its molecular consequence for a clinically distinct type of myotonic myopathy. BACKGROUND: The authors encountered a unique myotonic disorder of early onset in a 37-year-old man and his 47-year-old sister. METHODS: After examining known loci of inherited myotonic disorders, the authors looked for mutations within the CLCN1 gene using single strand conformation polymorphism and direct sequencing. To investigate the disease mechanism, reverse transcriptase PCR analyses of total RNA were performed. RESULTS: In the proband and his affected sister, two novel mutations comprising a compound heterozygous state in the CLCN1 gene were identified: 1) a base (G) insertion in exon 7 generating a premature termination codon (fs289X) in the D5 domain, and 2) a C-to-T substitution in exon 23 resulting in a missense mutation (P932L). These mutations accompanied a clinical phenotype that is distinguishable from recessive myotonia congenita by progressive generalized muscle weakness, severe distal muscle atrophy, joint contractures, high serum creatine kinase levels, and conspicuous myopathic changes on muscle histopathology. Reverse transcriptase PCR analyses detected only the P932L mutant mRNA in skeletal muscle, suggesting that the fs289X mRNA is degraded rapidly. CONCLUSIONS: These data suggest that fs289X is a null mutation, rendering the patients with the compound heterozygous genotype of fs289X/P932L to exclusively express P932L homomeric channels that may have caused the "dystrophic" phenotype.

Adult↗
PubMed2000

Motor unit number estimation, ALS and clinical trials.

Motor unit number estimation (MUNE) techniques have evolved substantially over the past decade and have been applied, with increasing frequency, to the study of amyotrophic lateral sclerosis (ALS). As major clinical therapeutic trials in motor neuron disease continue to appear, the need for a clear quantitative method of following motor unit physiology in the living subject grows ever more pressing. In this article, we review the major modern techniques of MUNE and the data supporting their reproducibility and utility in patients with ALS, with particular attention to their role in evaluating the efficacy of new therapeutic interventions.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Somatic sequence variation at the Friedreich ataxia locus includes complete contraction of the expanded GAA triplet repeat, significant length variation in serially passaged lymphoblasts and enhanced mutagenesis in the flanking sequence.

The vast majority of Friedreich ataxia patients are homozygous for large GAA triplet repeat expansions in intron 1 of the X25 gene. Instability of the expanded GAA repeat was examined in 23 chromosomes bearing 97-1250 triplets in lymphoblastoid cell lines passaged 20-39 times. Southern analyses revealed 18 events of significant changes in length ranging from 69 to 633 triplets, wherein the de novo allele gradually replaced the original over 1-6 passages. Contractions and expansions occurred with equal frequency and magnitude. This behavior is unique in comparison with other large, non-coding triplet repeat expansions [(CGG)(n)and (CTG)(n)] which remain relatively stable under similar conditions. We also report a rare patient who, having inherited two expanded alleles, showed evidence of contracted GAA repeats ranging from nine to 29 triplets in DNA from two independent peripheral blood samples. The GAA triplet repeat is known to adopt a triplex structure, and triplexes in transcribed templates cause enhanced mutagenesis. The poly(A) tract and a 135 bp sequence, both situated immediately upstream of the GAA triplet repeat, were therefore examined for somatic mutations. The poly(A) tract showed enhanced instability when in cis with the GAA expansion. The 135 bp upstream sequence was found to harbor a 3-fold excess of point mutations in DNA derived from individuals homozygous for the GAA triplet repeat expansion compared with normal controls. These data are likely to have important mechanistic and clinical implications.

Base Sequence↗
PubMed1998

A mild case of Friedreich ataxia: lymphocyte and sural nerve analysis for GAA repeat length reveals somatic mosaicism.

Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease, characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, Babinski sign, loss of position and vibration senses, cardiomyopathy, and carbohydrate intolerance. It is the most common inherited ataxia, and is associated with a GAA triplet repeat expansion in the first intron of the X25 gene on the long arm of chromosome 9. We present a case whose clinical diagnosis was initially confounded by the mildness of the ataxic phenotype and a family history of multiple sclerosis. Evaluation of the X25 gene revealed that the patient was homozygous for the GAA triplet repeat expansion, pathognomonic of FRDA. Investigation of her sural nerve biopsy revealed a significantly smaller expansion size, constituting the first direct demonstration of somatic mosaicism involving the nervous system in FRDA. We speculate that a similar contraction in pathologically affected tissues could be the molecular basis for the mildness of the ataxia.

Adult↗
PubMed1998

Side effects of immunosuppressant therapies used in neurology.

This article provides an overview of the clinically relevant complications of the main immunosuppressants currently used in the treatment of neurologic disorders with suspected or established immune etiology. The most serious complications are discussed in detail, including pathophysiology and preventative measures. An intimate knowledge of these complications proves helpful in the day to day practice of the neurologist supervising immunotherapy.

Humans↗
PubMed1998

Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of tramadol in treating the pain of diabetic neuropathy. BACKGROUND: The pain of diabetic neuropathy is a major cause of morbidity among these patients and treatment, as with other small-fiber neuropathies, is often unsatisfactory. Tramadol is a centrally acting analgesic for use in treating moderate to moderately severe pain. METHODS: This multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group study consisted of a washout/screening phase, during which all analgesics were discontinued, and a 42-day double-blind treatment phase. A total of 131 patients with painful diabetic neuropathy were treated with tramadol (n=65) or placebo (n=66) tramadol, which were administered as identical capsules in divided doses four times daily. The primary efficacy analysis compared the mean pain intensity scores in the tramadol and placebo groups obtained at day 42 of the study or at the time of discontinuation. Secondary efficacy assessments were the pain relief rating scores and a quality of life evaluation based on daily activities and sleep characteristics. RESULTS: Tramadol, at an average dosage of 210 mg/day, was significantly (p < 0.001) more effective than placebo for treating the pain of diabetic neuropathy. Patients in the tramadol group scored significantly better in physical (p=0.02) and social functioning (p=0.04) ratings than patients in the placebo group. No statistically significant treatment effects on sleep were identified. The most frequently occurring adverse events with tramadol were nausea, constipation, headache, and somnolence. CONCLUSIONS: The results of this placebo-controlled trial showed that tramadol was effective and safe in treating the pain of diabetic neuropathy.

Activities of Daily Living↗
PubMed1997

Moving toes and myoclonus associated with hereditary neuropathy with liability to pressure palsy (HNPP).

A 22-year-old male awoke with right foot drop and numbness. Nerve conduction studies, sural nerve biopsy, and molecular genetic analysis were consistent with hereditary neuropathy with liability to pressure palsy (HNPP). Two months later he developed involuntary flexion/extension movements of the right toes with associated intermittent dystonic flexion of the right foot. Over the next 2 months these movements spread to the left foot and hand and myoclonus of the left trapezius and rhomboid appeared. This is the first case report of moving toes syndrome and segmental myoclonus in association with HNPP. The temporal and topographic patterns of spread of the abnormal movements suggest a central mechanism probably induced by peripheral pathology.

Adult↗
PubMed1996

Localization of myotonic dystrophy protein kinase in skeletal muscle and its alteration with disease.

Myotonic dystrophy (DM) is an autosomal dominant disorder which affects skeletal muscle, heart, eye lens, brain, and endocrine functions. The disease-causing mutations are expansions of the triplet repeat CTG in the 3' untranslated region of a locus which encodes a serine/threonine protein kinase that represents a new family of protein kinases. A monoclonal antibody to a recombinant DM protein kinase (mAb DM-1) reacts specifically with the 64 kDa isoform of DM protein kinase in type I fibers in skeletal muscle, the fiber type which characteristically atrophies in the disease. Within type I fibers of normal muscle the isoform may be localized with mAb DM-1 to the triad region. In the DM disease state, the enzyme is redistributed to the pathologically characteristic peripheral sarcoplasmic masses. In markedly affected human distal myotonic muscle, the levels of the 64 kDa DM kinase isoform are elevated relative to slow skeletal myosin heavy chain. These results suggest that, consistent with the dominant clinical phenotype, the localization and accumulation of the 64 kDa isoform are altered in the heterozygous disease state.

Acrylic Resins↗
PubMed1996

Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis.

Numerous studies of amyotrophic lateral sclerosis have suggested that increased intracellular calcium is a common denominator in motoneuron injury. In experimental models, IgG from patients with amyotrophic lateral sclerosis enhanced calcium entry and induced apoptotic cell death in vitro as well as increased intracellular calcium and induced ultrastructural alterations of the motor nerve terminals in mice in vivo. To determine whether similar increases in intracellular calcium and altered morphology are present in motor nerve terminals of amyotrophic lateral sclerosis patients in vivo, muscle biopsy specimens from 7 patients with amyotrophic lateral sclerosis, 10 nondenervating disease control subjects, and 5 patients with denervating neuropathies were analyzed with ultrastructural techniques, employing oxalate-pyroantimonate fixation to preserve in situ calcium distribution. Motor nerve terminals from amyotrophic lateral sclerosis specimens contained significantly increased calcium, increased mitochondrial volume, and increased numbers of synaptic vesicles compared to any of the disease control groups, without exhibiting excess Schwann envelopment specific to denervating terminals. These results parallel the effect of amyotrophic lateral sclerosis IgG passively transferred to mice, and provide the first demonstration that neuronal calcium is, in fact, increased in amyotrophic lateral sclerosis in vivo.

Adult↗
PubMed1996

Cumulative reduction in serum cholinesterase following repeated therapeutic plasma exchange.

STUDY OBJECTIVE: To investigate the magnitude of serum cholinesterase reduction following repeated therapeutic plasma exchange in patients with neuromuscular disease. DESIGN: Serum cholinesterase activity was measured immediately before and after each plasma exchange in open-label fashion and then analyzed using an analysis of variance model. SETTING: Inpatient neurology and allergy and immunology clinics at a university-affiliated hospital. PATIENTS: 50 consecutive patients with neuromuscular disease. INTERVENTIONS: All patients underwent repeated therapeutic plasma exchange, with each subject receiving up to a maximum of six plasma exchanges. MEASUREMENTS AND MAIN RESULTS: Serum cholinesterase activity was determined spectrophotometrically. Analysis of variance revealed a significant reduction in serum cholinesterase following each therapeutic plasma exchange (p < 0.0001), a significant and consistent reduction across the six treatments (p < 0.0001), and a significant interaction between (before versus after exchange) and treatment number (p < 0.0001). Mean serum cholinesterase before repeated therapeutic plasma exchange was 4817 U/L, but it decreased to a mean of 929 U/L following six plasma exchanges. CONCLUSIONS: There is a significant reduction in serum cholinesterase following repeated therapeutic plasma exchange. It is suggested that drugs metabolized by serum cholinesterase (e.g., succinylcholine, mivacurium) be used with caution in the period immediately following repeated therapeutic plasma exchange.

Anesthesia↗
PubMed1996

Diabetes and the nervous system.

Hyperglycemia and its vascular complications affect the entire nervous system, contributing to increased morbidity and mortality. Chronic hyperglycemia is not only a known and major risk factor for cerebral vascular diseases but also the presence of hyperglycemia at the time of a cerebrovascular event may adversely influence the outcome. It also affects the treatment of some neurodegenerative disorders, and there are suggestions that diabetes may in fact suffer from a "chronic diabetic encephalopathy." Its varied effects on the peripheral nervous system result in several forms of diabetic neuropathies, the exact pathogenesis of which is still obscure. There is, however, some new information that may link metabolic and vascular hypotheses.

Blood Glucose↗
PubMed1996

Clinical trials of riluzole in patients with ALS. ALS/Riluzole Study Group-II.

Two double-blinded, placebo-controlled clinical trials of riluzole have now been carried out in more than 1,100 patients with ALS. The results of both studies show a modest benefit in prolonging survival that is statistically significant. These results led to the availability of this drug by the Food and Drug Administration for use in the United States beginning in early 1996. This is the first drug that has been available for ALS. It begins a new era in both basic and clinical research in an attempt to find a cure for this disease.

Adult↗
PubMed1995

Altered muscle calcium channel binding kinetics in autoimmune motoneuron disease.

While skeletal muscle is not apparently affected directly in amyotrophic lateral sclerosis (ALS), immunoglobulin G fractions purified from patients with ALS (ALS IgG) bind dihydropyridine (DHP)-sensitive L-type voltage-gated calcium channel (VGCC) antigen isolated from skeletal muscle in ELISA and Western immunoblot, and alter VGCC function in vitro. To determine whether muscle VGCC properties are altered in ALS, VGCC-enriched subsarcolemmal membrane fractions were prepared from biopsied quadriceps muscle of patients with ALS, with other neurologic diseases, or without apparent muscle disease, and tested for DHP binding with [3H]PN200-110. ALS muscle VGCCs possessed eightfold higher binding affinities for [3H]PN200-110 than did VGCCs from muscle fractions of most other patients, independent of denervation-induced increases in DHP binding site number. Similarly elevated DHP binding affinities were observed in specimens from patients with autoimmune motor neuropathies, suggesting that ALS and immune mediated motoneuron disease share skeletal muscle L-type VGCC alterations.

Amyotrophic Lateral Sclerosis↗