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Biomedical subjects

I Nonaka

Publications and source records attributed to I Nonaka.

At least 199 records · Page 11Linked to original sources
PubMed1996

Analysis of lymphoproliferative cytokines produced by thymic myoid cells.

Lymphoproliferative activities produced by cloned thymic myoid cell 871207B were analysed by immunological and biochemical methods. The lymphoproliferative activities were separated into two fractions by DEAE-Sepharose CL-6B chromatography: one is in the fraction passed through the column and the other in the fraction eluated from the column with a low concentration of NaCl. The eluated fraction induced the proliferation of interleukin-1 (IL-1)-dependent D10N4 M cells. This activity was abrogated by an anti-IL-1 alpha antibody, but not an anti-IL-1 beta antibody. Expression of IL-1 alpha mRNA was also detected in 871207B cells. The thymocyte proliferative activity found in the fraction passed through the DEAE-Sepharose column was further separated into three fractions by heparin-Sepharose column chromatography: (1) the fraction passed through the column, (2) the fraction weakly bound to the column, and (3) the fraction firmly bound to the heparin column. The fraction passed through the heparin column sustained the growth of IL-6-dependent MH60.BSF-2 cells. IL-6-specific mRNA was found in 871207B cells. The thymocyte proliferative activity of the fraction firmly bound to the heparin column was neutralized with an anti-IL-7 antibody. The biological activity of the fraction weakly bound to the column remained to be elucidated. These results suggest that thymic myoid cells produce IL-1 alpha, IL-6, IL-7 and unidentified lympho-stimulatory factors, all of which play significant roles in many steps of T-cell development in the thymus.

Animals↗
PubMed1995

Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy.

Severe childhood autosomal recessive muscular dystrophy (SCARMD) is a progressive muscle-wasting disorder common in North Africa that segregates with microsatellite markers at chromosome 13q12. Here, it is shown that a mutation in the gene encoding the 35-kilodalton dystrophin-associated glycoprotein, gamma-sarcoglycan, is likely to be the primary genetic defect in this disorder. The human gamma-sarcoglycan gene was mapped to chromosome 13q12, and deletions that alter its reading frame were identified in three families and one of four sporadic cases of SCARMD. These mutations not only affect gamma-sarcoglycan but also disrupt the integrity of the entire sarcoglycan complex.

Amino Acid Sequence↗
PubMed1995

Genetic analysis of Japanese patients with myophosphorylase deficiency (McArdle's disease): single-codon deletion in exon 17 is the predominant mutation.

We report molecular genetic analysis of 11 Japanese patients with myophosphorylase deficiency (McArdle's disease). Four reported mutations, frequently observed in patients with McArdle's disease, in exons 1, 5, 14 and 17 were investigated. Seven patients out of 11 were homozygous for a single-codon deletion at codon 708/709 in exon 17 and one patient was heterozygous for a single-codon deletion with an unknown mutant allele. In contrast, the predominant mutation reported in US and UK patients (CGA to TGA at codon 49 in exon 1), accounting for 75% and 83% of the cases, respectively, was not found in any of the Japanese patients. Results suggest that the predominant mutation in Japanese patients is a single-codon deletion at codon 708/709 in exon 17 (found in 73% of our patients) and differs from the most common mutation in US or UK patients.

Adolescent↗
PubMed1995

The molecular genetic basis of myophosphorylase deficiency (McArdle's disease).

Glycogen phosphorylase catalyzes the first step of glycogen catabolism. Hereditary defects of muscle phosphorylase lead to a myopathy characterized by exercise intolerance, cramps, and myoglobinuria (McArdle's disease). We have identified ten mutations in the myophosphorylase gene in patients with McArdle's disease. Relatively common mutations include: a nonsense mutation, CGA(Arg) to TGA at codon 49, observed in 30 of 40 American patients; deletion of a single codon 708/709, observed in 4 of 7 Japanese patients; and a missense mutation, GGC(Gly) to AGC(Ser) at codon 204, observed in 5 of 40 American patients. Apparently rare mutations include: a splice-junction mutation, G to A, at the first nt of intron 14; a deletion of G at codon 510; a mutation, ATG to CTG, in the translation initiation codon; and missense mutations, AAG(Lys) to ACG(Thr) at codon 542, CTG(Leu) to CCG(Pro) at codon 396, CTG(Leu) to CCG(Pro) at codon 291, and GAG(Glu) to AAG(Lys) at codon 654. As most mutations can be screened for using genomic DNA, patients can now be diagnosed reliably using peripheral blood cells, thus avoiding muscle biopsy. Although these findings define the wide spectrum of genetic lesions causing McArdle's disease, the clinical heterogeneity of this disorder remains to be explained.

Base Sequence↗
PubMed1995

Mitochondrial DNA mutation and muscle pathology in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.

We sought a relationship between abnormalities of mitochondrial DNA (mtDNA) and muscle pathology in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) at the single fiber level, using histochemistry, in situ hybridization, and single fiber PCR. Most type 1 ragged-red fibers (RRF) showed positive cytochrome c oxidase (COX) activity at the subsarcolemmal region, while type 2 RRF showed little COX activity. However, there was no difference in the amount of total (mutant and wild-type) mtDNAs and the proportion of mutant mtDNA between type 1 RRF and type 2 RRF. These observations suggest that mitochondrial proliferation and nuclear factors affect muscle pathology, including COX activity, in MELAS. Total mtDNAs were greatly increased in RRF. The proportion of mutant mtDNA was significantly higher in RRF than in non-RRF. The amount of both wild-type and mutant mtDNAs was increased in RRF in MELAS, which fact does not support the contention of a replicative advantage of mutant mtDNA. The proportion of mutant mtDNA was significantly higher in the strongly succinate dehydrogenase-reactive blood vessels (SSV) than in non-SSV. The similar morphological behavior in these vessels and fibers suggests that increased mutant mtDNA is responsible for mitochondrial proliferation and dysfunction in both tissues. It seems likely that systemic vascular abnormalities involving cerebral vessels lead to the evolution of strokelike episodes in MELAS.

Arteries↗
PubMed1995

Muscle fiber degeneration in distal myopathy with rimmed vacuole formation.

In 11 patients with distal myopathy with rimmed vacuole formation (DMRV), a well-known autosomal recessively inherited disorder, the rimmed vacuole formation appears to be the main pathological change accounting for the progressive muscle fiber degeneration. To gain a better understanding of the pathophysiology of the vacuole formation, we applied Congo red and immunohistochemical stains to muscle biopsies from these patients and the results were compared with those of patients with inclusion body myositis (IBM). The vacuoles in DMRV contained Congophilic amyloid material and deposits immunoreactive for beta-amyloid protein, both the NH2 and COOH termini of beta-amyloid protein precursor, ubiquitin, and tau protein. These results were similar to those seen in our present cases of IBM as well as in previously reported cases. Therefore, there may be no pathogenetic differences in the formation of rimmed vacuoles in DMRV and IBM. Nevertheless, the degenerative process involved in rimmed vacuole formation in various diseases may share a common pathogenetic mechanism with that in amyloid-plaque formation in Alzheimer's disease brain as has been proposed previously.

Adult↗
PubMed1995

Reducing bodies in distal myopathy with rimmed vacuole formation.

A 42-year-old woman with distal myopathy with rimmed vacuoles had intracytoplasmic inclusion bodies similar to those described in reducing body myopathy. Since these inclusions were found in fibers with high acid phosphatase activity and occasional rimmed vacuoles, their formation appeared to correlate with active myofibrillar degeneration, but their origin remains unknown.

Adult↗
PubMed1995

Tau protein immunoreactivity in muscle fibers with rimmed vacuoles differs from that in regenerating muscle fibers.

To determine whether tau protein found in muscle fibers with rimmed vacuoles and in regenerating fibers was phosphorylated, we examined eight muscle biopsy samples containing rimmed vacuoles (from five patients with distal myopathy with rimmed vacuole formation and three patients with inclusion body myositis) and three muscle biopsy samples from patients with Duchenne muscular dystrophy containing numerous regenerating fibers. Although both rimmed vacuolated and regenerating fibers had increased immunoreactivity against tubulin and tau protein, tau protein in the former was more highly phosphorylated than that in the latter. While very few microtubules in muscle fibers with rimmed vacuoles were recognizable by electron microscopy, regenerating fibers, especially immature ones, contained numerous microtubules. Since tau protein found in vacuolated fibers is hyperphosphorylated, it can be considered to have reduced ability to bind tubulin molecules. Thus, the tau protein cannot stabilize microtubules, resulting in their depolymerization even in the presence of tubulin molecules.

Adolescent↗
PubMed1995

Dystrophin-positive muscle fibers following C2 myoblast transplantation into mdx nude mice.

To determine when and how the dystrophin-positive muscle fibers are formed after myoblast transplantation into dystrophin-negative muscles, the tibialis anterior (TA) muscle from mdx nude mouse was chronologically examined after C2 myoblast transplantation by immunohistochemical and glucose 6-phosphate isomerase (GPI) isoenzyme analyses. The host TA muscle transplanted with C2 myoblasts became necrotic with accumulation of basic fibroblast growth factor in the necrotic areas. This may stimulate concomitant proliferation of the host satellite cells and C2 myoblasts. Small dystrophin-positive muscle fibers appeared in the necrotic areas 3 days after transplantation. This TA muscle contained two different kinds of homodimer GPI isoenzymes but did not contain the heterodimer, suggesting rare fusion of host and donor cells. The dystrophin-positive muscle fibers in the necrotic areas rapidly increased in number and in size by 7 days, but they were smaller than the original host muscle fibers. They had central nuclei, indicating that they were regenerating fibers. The presence of heterodimer GPI isoenzyme in these muscles indicated that the regenerating fibers were mosaic host/donor muscle fibers. The dystrophin-positive muscle fibers are probably formed first by fusion of donor cells with each other and then later by the fusion of host satellite and donor cells.

Animals↗
PubMed1995

Fatal reducing body myopathy. Ultrastructural and immunohistochemical observations.

Two female infants who developed normally during infancy began to have progressive muscle hypotonia and weakness from 2 years 10 months and 2 years 3 months of ages, respectively. Both patients had rapidly progressive muscle weakness with death from respiratory failure at 4 years 11 months and 3 years 9 months, respectively. In addition to mild inflammation in their muscle biopsies, the most striking finding was the presence of numerous reducing bodies (RB) in almost all degenerating fibers. By electron microscopy, these bodies consisted of fine granular material, usually located around the degenerating nucleus. These bodies showed no immunohistochemical reaction to antibodies against structural, cytoskeletal and membrane proteins and a histone-specific antibody against nuclei and chromosomes. They were occasionally positively stained with a ubiquitin antibody. Although the origin of these bodies remains unknown, they appeared to be related to active myofibrillar degeneration, probably resulting from primary nuclear degeneration.

Cell Nucleus↗
PubMed1995

Limb-girdle muscular dystrophy: clinical and pathologic reevaluation.

To better define limb-girdle muscular dystrophy (LGMD), we examined 58 patients clinically and pathologically who fulfilled the criteria for LGMD and had normal dystrophin expression in their muscle biopsies. Only 27.6% of patients had evidence of inheritance. The onset of disease varied from 2 to 58 years of age, averaging 17.2 years. The disease progression also differed from patient to patient. In addition to evidence of muscle fiber necrosis and regeneration, in all muscle biopsies there were fibers with architectural changes of disorganized intermyofibrillar networks including moth-eaten (100%), lobulated (40%), whorled (17%) and targetoid (8%) fibers. The lobulated fibers which have never been reported in Duchenne muscular dystrophy (DMD) were seen in the advanced stages of LGMD, although the significance of such fibers remains unknown. On immunohistochemical examination, dystrophin-associated proteins (DAPs) and laminin were normally expressed along the surface membrane of muscle fibers, including the lobulated fibers.

Adult↗
PubMed1995

Muscle and intramuscular nerve pathology in congenital hypomyelination neuropathy.

Two patients had delayed development and generalized muscle hypotonia and weakness since early infancy. Their muscle biopsies showed slight variation in fiber size without group atrophy, and no clear evidence of an active demyelinating process in the intramuscular nerves. The most striking finding by light microscopy was the absence of myelinated fibers in the intramuscular nerve bundles. Ultrastructurally, the axons were devoid of myelin sheath or had very thin myelin sheaths, and the axons were surrounded by multilayered basal lamina forming an atypical onion bulb with no suggestions of myelin destruction. A sural nerve biopsy from one of the patients showed similar findings. Unlike the Déjèrine-Sottas type of hereditary motor and sensory neuropathy, there was no evidence of demyelination and remyelination in the muscle pathology, suggesting that the poor myelination in congenital hypomyelination neuropathy is due to a true "hypo"-myelination and not the result of demyelination.

Biopsy↗
PubMed1995

Immunophenotyping of congenital myopathies: disorganization of sarcomeric, cytoskeletal and extracellular matrix proteins.

We have studied the expression and distribution patterns of the intermediate filament proteins desmin and vimentin, the sarcomere components titin, nebulin and myosin, the basement membrane constituents collagen type IV and laminin, and the reticular layer component collagen type VI in skeletal muscle of patients with "classic" congenital myopathies (CM), using indirect immunofluorescence assays. In all biopsy specimens obtained from patients with central core disease (CCD), nemaline myopathy (NM), X-linked myotubular myopathy (XLMTM) and centronuclear myopathy (CNM), disease-specific desmin disturbances were observed. Vimentin was present in immature fibres in severe neonatal NM, and as sarcoplasmic aggregates in one case of CNM, while the amounts of vimentin and embryonic myosin, observed in XLMTM, decreased with age of the patients. Abnormal expression of myosin isoforms was found in several CM biopsies, although the organization of myosin and other sarcomere components was rarely disturbed. Basement membrane and reticular layer proteins were often prominently increased in severe cases of CM. We conclude that (i) desmin is a marker for individual types of CM and might be used for diagnostic purposes; (ii) the expression patterns of the differentiation markers desmin, vimentin and embryonic myosin in XLMTM, point either to a postnatal muscle fibre maturation or to a variable time-point of maturational arrest in individual patients; (iii) the correlation between the distribution patterns of extracellular matrix proteins and clinical presentation points to a role of these proteins in pathophysiology of CM.

Adolescent↗
PubMed1995

Congenital hypomyelination neuropathy: decreased expression of the P2 protein in peripheral nerve with normal DNA sequence of the coding region.

Congenital hypomyelination neuropathy (Lyon type) is characterized by a non-progressive clinical course and a histopathological formation of atypical onion-bulb. We have studied the immunohistochemical expression of the major peripheral myelin proteins including P0 protein, myelin basic protein (MBP) and P2 protein in three such patients. No significant difference was observed between the patients and the controls, as to the P0 and MBP staining. In contrast, P2 protein antiserum scarcely stained the patients' nerve fibers except for a few scattered adequately myelinated fibers. Assuming the pathogenetic contribution of the extremely decreased P2 protein to the disease, we investigated P2 protein gene by sequencing all coding regions but failed to detect any change in the nucleotide sequence. Further investigation including the analysis of promoter region of P2 protein gene is needed to elucidate the mechanism of congenital hypomyelination neuropathy.

Base Sequence↗