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H Mitsumoto

Publications and source records attributed to H Mitsumoto.

At least 55 records · Page 3Linked to original sources
PubMed1999

Neurotrophic factors and neuromuscular disease: I. General comments, the neurotrophin family, and neuropoietic cytokines.

Neurotrophic factors are growth factors or cytokines that are inducible polypeptides and permit intercellular communication. An explosion of information about neurotrophic factors is setting the stage for significant advances in neural disease therapy in the next century. The effects of these trophic factors are overlapping and pleiotropic, acting on many cell types and tissues to control proliferation and differentiation of developing neurons and to exert a variety of functions on mature neurons. Studies of receptors unique to several neurotrophic factor families have revealed exquisite mechanisms of signal transduction. Preclinical trials in neuromuscular disease were promising, but results from initial clinical trials have been disappointing; new and better designed clinical trials are under way. Laboratory investigators also are exploring techniques to deliver factors directly to the central nervous system by means of viral vectors or to exert neurotrophic signals on the nervous system using novel small molecules that stimulate neurotrophic factor or neuroimmunophilin receptors. Combination therapies, refined delivery techniques, and treatment timing may be the key for successful treatment with neurotrophic factors. In this two-part review, we discuss the neurobiology of neurotrophic factors, the characteristics of the major neurotrophic factors, and their therapeutic potential in neuromuscular disease.

Animals↗
PubMed1998

Neuronal pathology in the wobbler mouse brain revealed by in vivo proton magnetic resonance spectroscopy and immunocytochemistry.

Proton magnetic resonance spectroscopy (1H-MRS) was used to measure the in vivo signal of N-acetylaspartate (NAA), a putative neuronal marker, in the brain of the mutant wobbler mouse, a model of motor neuron disease. The ratio of NAA to creatine-phosphocreatine, an internal standard, was significantly lower in five affected wobbler mice (0.79+/-0.05; mean+/-s.d.) than in five unaffected littermates (0.98+/-0.10, p = 0.006). Ubiquitin and phosphorylated heavy neurofilament immunoreactivities were increased in cortical neurons of affected animals. This is the first demonstration of cerebral neuronal pathology in the wobbler mouse, supporting its use as a model of amyotrophic lateral sclerosis. In vivo IH-MRS and correlative postmortem study of wobbler mouse brain will allow temporal monitoring of neuronal degeneration and responsiveness to neuroprotective pharmacotherapies.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Physical therapy for a patient through six stages of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: This case report describes the use of Sinaki and Mulder's approach to staging amyotrophic lateral sclerosis (ALS) and functional outcome measures in designing a treatment program for a 59-year-old woman with ALS. CASE DESCRIPTION AND OUTCOMES: As the patient progressed from stage I through stage VI, over 12 months, the physical therapy goals changed from optimizing remaining function, to maintaining functional mobility, and finally to maximizing quality of life. DISCUSSION: Disease staging and the use of functional outcome measures provide a framework for physical therapy evaluation and treatment of patients with ALS throughout the disease process. Physical therapists can assist patients with ALS through the provision of education, psychological support, rehabilitation programs, and recommendations for appropriate equipment and community resources.

Activities of Daily Living↗
PubMed1997

Effect of noninvasive positive-pressure ventilation on survival in amyotrophic lateral sclerosis.

BACKGROUND: Noninvasive positive-pressure ventilation may benefit patients with amyotrophic lateral sclerosis and respiratory insufficiency. OBJECTIVE: To determine 1) whether patients tolerant of noninvasive positive-pressure ventilation have better survival than intolerant patients and 2) whether bulbar symptoms account for intolerance of noninvasive positive-pressure ventilation. DESIGN: Observational cohort study. SETTING: Tertiary care referral center. PATIENTS: 39 patients with amyotrophic lateral sclerosis who were treated with noninvasive positive-pressure ventilation. INTERVENTION: Noninvasive positive-pressure ventilation was started for patients with new orthopnea, new hypercapnia, or both. Patients were divided into two groups: those tolerant of and those intolerant of noninvasive positive-pressure ventilation. RESULTS: The risk for death from onset of respiratory insufficiency was higher for intolerant patients than for tolerant patients (relative risk, 3.1 [95% CI, 1.8 to 9.6]). Moderate or severe bulbar symptoms were more prevalent among intolerant patients than among tolerant patients (67% compared with 33%; P = 0.04). CONCLUSIONS: Among patients with amyotrophic lateral sclerosis, those who are tolerant of noninvasive positive-pressure ventilation have better survival than do those who are intolerant. Bulbar symptoms partially account for intolerance of noninvasive positive-pressure ventilation.

Aged↗
PubMed1997

Genetic transfer of the wobbler gene to a C57BL/6J x NZB hybrid stock: natural history of the motor neuron disease and response to CNTF and BDNF cotreatment.

Preclinical diagnosis of motor neuron disease (MND) in the wobbler mouse (wr/wr) has been impossible until recently. However, with the development of a new hybrid, the C57BL/6J x New Zealand Black (B6NZB) wr/wr mouse, the polymerase chain reaction (PCR) can be used to establish the preclinical diagnosis. We compared the clinical and histological features of MND and the effects of neurotrophic factor cotreatment between the hybrid B6NZB-wr/wr and the congenic C57BL/6J-wr/wr mice. Clinical assessments of body weight, grip strength, running speed, paw position, and walking pattern were made weekly from age 2 weeks through 8 weeks (n = 10, B6NZB-wr/wr; n = 15, C57BL/6J-wr/wr). Survival was analyzed (n = 7, each strain) as was C5 and C6 spinal cord motoneuron morphology and ventral root histometry (n = 7, each strain). For cotreatment, 8 B6NZB-wr/wr and 7 C57BL/6J-wr/wr mice received subcutaneous ciliary neurotrophic factor (1 mg/kg) and brain-derived neurotrophic factor (5 mg/kg) on alternate days, 6 days/week for 4 weeks. B6NZB-wr/wr mice could be distinguished from C57BL/6J-wr/wr mice at age 3 weeks by a more abnormal paw position (P < 0.01) and walking pattern (P < 0.05) and lower grip strength (P < 0.001) and running speed (P < 0.001). After 3 weeks, the changes continued to be greater in B6NZB-wr/wr mice. Although B6NZB-wr/wr mice were more severely affected early in the disease, their survival was comparable to C57BL/6J-wr/wr mice. Anterior horn cell vacuolar degeneration and myelinated fiber histometry were similar in both strains. The clinical response to CNTF/BDNF cotreatment was marked in both groups although it was weaker in B6NZB-wr/wr mice. Thus, the hybrid B6NZB-wr/wr mice have a more severe clinical phenotype and offer a unique opportunity to study the mechanisms of presymptomatic motor neuron degeneration and the effects of therapeutic agents for human MND.

Animals↗
PubMed1997

Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis.

Two new mutations in the gene encoding cytoplasmic Cu,Zn superoxide dismutase (SOD1) have been discovered in patients with familial amyotrophic lateral sclerosis (FALS). These mutations result in the truncation of most of the polypeptide segment encoded by exon 5, one by the formation of a stop codon in codon 126 (L126Z) and the other by inducing alternative splicing in the mRNA (splicing junction mutation). These two mutants of SOD1 result in a FALS phenotype similar to that observed in patients with missense mutations in the SOD1 gene, establishing that exon 5 is not required for the novel toxic functions of mutant SOD1 associated with ALS. These mutant enzymes are present at very low levels in FALS patients, suggesting elevated toxicity compared to mutant enzymes with single site substitutions. This increased toxicity likely arises from the extreme structural and functional changes in the active site channel, beta-barrel fold, and dimer interface observed in the mutant enzymes, including the loss of native dismutase activity. In particular, the truncation of the polypeptide chain dramatically opens the active site channel, resulting in a marked increase in the accessibility and flexibility of the metal ions and side chain ligands of the enzyme active site. These structural changes are proposed to cause a decrease in substrate specificity and an increase in the catalysis of harmful chemical reactions such as peroxidation.

Aged↗
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↗
PubMed1997

Riluzole--what is its impact in our treatment and understanding of amyotrophic lateral sclerosis?

Riluzole marks the beginning of pharmacotherapy for patients with ALS. Our task is to fully identify the impact of riluzole in ALS treatment. The ALS Clinical Assessment Research and Education (ALS CARE) is an ambitious database in North America created to establish the benchmarks for patient care and management. Such a program may allow us to analyze the use and impact of riluzole in the treatment of ALS. In the spring of 1997, just 1 year since the approval of riluzole, several more potential drugs for ALS are on the horizon. If a single medication is not sufficient to alter the disease course significantly, we must investigate drug combinations to determine potential additive or synergistic benefits. Although far from ideal, riluzole is allowing clinicians and researchers to lift a corner of the veil surrounding ALS to glimpse the possibility of effective treatment.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Advances in ALS.

Explore the source record for details and available documents.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Histometric effects of ciliary neurotrophic factor in wobbler mouse motor neuron disease.

We investigated the histological effects of ciliary neurotrophic factor on degenerating motor neurons, their axons, and skeletal muscles in 68 wobbler mice with motor neuron disease. Treatment consisted of recombinant rat or human ciliary neurotrophic factor (or a vehicle solution), 1-mg/kg subcutaneous injection, three times per week for 4 weeks after the clinical diagnosis. The number of motor neurons immunoreactive for calcitonin gene-related peptide was higher in mice receiving rat ciliary neurotrophic factor (p < 0.03), although the number of choline acetyltransferase-reactive neurons was the same in both treated and untreated control groups. Treatment did not prevent vacuolar degeneration of motor neurons. In mice treated with human ciliary neurotrophic factor, the percentage of axons undergoing acute axonal degeneration (myelin ovoids) was smaller in the entire C5 ventral root (p < 0.02) and in the musculocutaneous nerve (p < 0.04), and the number of myelinated nerve fibers was 30% higher in both nerves (p < 0.01 and p < 0.04, respectively) than in controls. In ciliary neurotrophic factor-treated mice, the biceps muscle weight was 20% greater, the mean muscle fiber diameter was 30% larger, and the number of atrophied muscle fibers was 75% lower than that in the vehicle-treated wobbler mice (p < 0.001 for all three results). The number of terminal axonal branching points and the mean length of motor end-plates were also higher in the ciliary neurotrophic factor-treated mice (p < 0.001 and p < 0.02, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of brain-derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease.

Brain-derived neurotrophic factor (BDNF) has been shown to promote the survival of developing motor neurons in vitro and to rescue motor neurons from axotomy-induced cell death in vivo. In this study, we examined the effects of exogenous BDNF on the progression of wobbler mouse motor neuron disease (MND). After clinical diagnosis at age 3 to 4 weeks, 20 affected mice received subcutaneous injections of recombinant human BDNF (5 mg/kg, n = 10) or vehicle (n = 10), three times a week for 4 weeks. In a separate experiment done to conduct a histometric analysis of the C-5 and C-6 ventral roots and to determine the number of myelinated nerve fibers, 7 wobbler mice received identical BDNF treatment. In the 10 BDNF-treated wobbler mice, grip strength declined at a slower rate (p < 0.03) and was twice as great as that of vehicle-treated animals at the end of treatment (p < 0.01). In vivo biceps (p < 0.01) and in vitro muscle twitch tensions (p < 0.02) were also greater than those of vehicle-treated mice. The biceps muscle weight was 20% greater (p < 0.05) and the mean muscle fiber diameter was significantly larger in BDNF-treated mice (p < 0.001) because the number of small (denervated) muscle fibers was markedly reduced. The number of myelinated motor axons at the cervical ventral roots studied in the additional 7 affected mice was 25% greater with BDNF treatment (p < 0.0001). This study establishes that exogenous BDNF administration can retard motor dysfunction in a natural MND and diminish denervation muscle atrophy and motor axon loss.

Animals↗
PubMed1995

Effect of cocaine on the contracture response to 1% halothane in patients undergoing diagnostic muscle biopsy for malignant hyperthermia.

Two case reports have cited the recreational use of cocaine as possible trigger of a malignant hyperthermia (MH) crisis. We evaluated whether toxic concentrations of cocaine altered the in vitro muscle response to halothane during contracture tests for MH. Twenty-two patients were studied. Muscle biopsies were obtained and first tested for MH susceptibility with 3% halothane and caffeine contracture testing. Ten patients were diagnosed as MH-susceptible and 12 as MH non-susceptible, in accordance with the North American Malignant Hyperthermia Group protocol. Then, muscle strips were exposed to 1% halothane in the presence and absence of 0.1 mmol.L-1 cocaine. Cocaine alone did not affect baseline muscle tension in either group. With 1% halothane, MH non-susceptible muscle showed no contracture with or without cocaine. In contrast, in the presence of 1% halothane, MH-susceptible muscle showed either no change in contracture (six patients), an increase (two patients), or a decrease (two patients) when exposed to cocaine. However, the overall effect of cocaine on muscle contracture in the presence of 1% halothane was insignificant in both groups. We conclude that cocaine, even at toxic levels, does not have a direct effect on skeletal muscle contractility and thus is safe for MH-susceptible patients.

Adult↗
PubMed1995

Treatment of myasthenia gravis by immunoadsorption of plasma.

We treated 16 patients with moderately severe to severe generalized myasthenia gravis (MG) by immunoadsorption (perfusion through a resin that adsorbs proteins) of 2,500 ml plasma on each of four alternate days. Fourteen patients who completed treatment all had significant improvement in strength (6 excellent, 6 good, and 2 fair), which began a mean of 42 hours after the first immunoadsorption, reached a maximum 4 days after the fourth immunoadsorption (mean, 250% of baseline strength), and returned to baseline over a mean of 2 months. Thirty-seven grams of plasma proteins were removed during each immunoadsorption, which required no replacement, compared with 175 grams during plasma exchange, which requires replacement with albumin. Serum or plasma concentration of all proteins fell, more so for most of the larger proteins than for the smaller ones: acetylcholine receptor antibody (AChR Ab) fell to a mean of 23% of original level, fibrinogen to 26%, C4 to 29%, IgM to 33%, IgG to 35%, CH50 to 41%, C3 to 42%, IgA to 54%, and albumin to 76%. All proteins, including AChR Ab, returned to their original levels within 1 to 3 weeks after the last immunoadsorption, while improvement in strength lasted a mean of 6 weeks longer. One seronegative patient had excellent improvement lasting more than a month. Activated complement C5a and white blood cell count rose during each immunoadsorption, while activated complement C3a fell, and each returned to its original level within hours. Eight patients had transient symptomatic hypotension attributable to withdrawal of blood more rapidly than it was returned; this hypotension was prevented or ameliorated by intravenous saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies↗