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Biomedical subjects

I Nonaka

Publications and source records attributed to I Nonaka.

At least 235 records · Page 13Linked to original sources
PubMed1994

Autosomal recessive distal muscular dystrophy: normal expression of dystrophin, utrophin and dystrophin-associated proteins in muscle fibers.

We examined 19 muscle biopsies from 14 patients with autosomal recessive distal muscular dystrophy (DisMD) histochemically and immunohistochemically to characterize the histologic features of this disease and to determine whether dystrophin and dystrophin-associated proteins (DAPs) are normally present in the muscles of patients with this disorder. The common histologic features in DisMD were active muscle fiber necrosis and regeneration with variation in fiber size, predominantly in the gastrocnemius muscle. There were occasional disorganizations of the intermyofibrillar network such as moth-eaten appearance, lobulated, whorled and targetoid fibers. In one half of the patients, small angular fibers and scattered rimmed vacuoles were also found. On immunohistochemical examination, dystrophin, DAPs, spectrin and laminin were normally expressed along the surface membrane of muscle fibers, even in the advanced stages of the disease. In contrast, dystrophin was absent and DAPs reduced in the sarcolemma of Duchenne muscular dystrophy (DMD) muscles. The overall histochemical features in DisMD were similar to those seen in DMD, though dystrophin and DAPs were normally expressed even in severely affected gastrocnemius muscle. A defect in an as yet unidentified protein rather than in DAPs and dystrophin is probably responsible for the muscle fiber necrosis in DisMD.

Adolescent↗
PubMed1994

Point mutations in mitochondrial tRNA genes: sequence analysis of chronic progressive external ophthalmoplegia (CPEO)

We have sequenced all mitochondrial tRNA genes from 9 Japanese patients with chronic progressive external ophthalmoplegia (CPEO) who had no detectable large mtDNA deletions nor mutations previously reported, and identified 6 different base substitutions in 6 patients. Since 5 of the 6 substitutions were homoplasmic in distribution and recognizable in some normal controls, they were thought to be polymorphisms in normal individuals. One mutation at nucleotide (nt) 12311 in the tRNA(Leu(CUN)) gene was not present in 90 normal controls nor in 103 patients with other mitochondrial myopathies. This mutation was in a heteroplasmic state, and the mutated site was conserved among other species during evolution, suggesting a disease-related mutation. However, the significance of this mutation has to be studied further. In Japanese CPEO patients without large deletions, a point mutation in the mitochondrial tRNA gene is not likely to be a frequent cause.

Adult↗
PubMed1994

Multiplicity of abnormal dystrophin in Becker muscular dystrophy. A Becker muscular dystrophy gene frequently produced two smaller sizes of dystrophin.

Dystrophin is a muscle cytoskeletal protein with a molecular mass (MM) of approximately 420 kDa and an isoelectric point (pI) of approximately 5.5, which is abnormal in size and/or abundance in Becker muscular dystrophy (BMD). We investigated the abnormality of dystrophin molecule in muscles biopsied from 23 BMD patients using the two-dimensional gel electrophoresis (TDGE). We found 7 protein spots which reacted specifically with the monoclonal anti-dystrophin antibody (mAb) A1C raised against N-terminal domain of the normal dystrophin. These spots were focused on the two-dimensional gel at the same position as the normal dystrophin (#1), at the position with MM approximately 480 kDa/pI approximately 5.35 (#2), the position with MM approximately 400-330 kDa/pI approximately 5.51-5.47 (#3), the position with MM approximately 300 kDa/pI approximately 5.4 (#4), the position with MM approximately 235-250 kDa/pI approximately 5.53-5.5 (#5), the position with MM approximately 165 kDa/pI approximately 6.0 (#6), and the position with MM approximately 160 kDa/pI approximately 5.75 (#7). These spots were classified into five patterns in individuals, that is, #1 alone in 3 patients, #3 alone in 1, the combination of #3 and 5 in 17, the combination of #1, 3 and 5 in 1 and the combination of #1, 2, 4, 6 and 7 in 1. The combination of #3 and 5 was observed in 17 of 23 patients (75%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Immunohistochemical analysis of perforin and granzyme A in inflammatory myopathies.

Perforin (PF) and granzyme A (GA) are candidates suspected of being cytolytic proteins of the granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. We analysed PF and GA in muscles from patients with inflammatory myopathies. Five cases of polymyositis (PM), two cases of inclusion body myositis (IBM), and five cases of dermatomyositis (DM) were studied immunohistochemically using anti-PF and GA antibodies raised against each synthetic peptide of human PF and mouse GA, together with a panel of monoclonal antibodies reactive for lymphocyte subsets. In PM and IBM, PF positive cells were colocalized with GA positive cells and occasionally invaded into the non-necrotic muscle fibres. The percentage of PF positive cells among the endomysial CD8 positive cell population was 9.9% (PM) and 12.5% (IBM), and the majority of the endomysial CD8 positive cells were alpha/beta T cells. In contrast, in DM, both PF and GA positive cells were very few in all cases. Only few inflammatory cells were CD16+ or CD57+ NK cells among these diseases. Our results suggest that PF and GA are secreted mainly from alpha/beta T cells, and may play a key role in muscle fibre damage in at least some PM and IBM, but not in DM.

Aged↗
PubMed1994

Selective defect in dystrophin-associated glycoproteins 50DAG (A2) and 35DAG (A4) in the dystrophic hamster: an animal model for severe childhood autosomal recessive muscular dystrophy (SCARMD).

To determine if dystrophin and dystrophin-associated glycoproteins (DAGs) are involved in muscle fiber necrosis in the dystrophic hamster, we examined NSJ-my/my (homozygous dystrophic) hamsters introduced from the BIO14.6 strain, by immunohistochemical and immunoblotting methods. Antibodies against dystrophin, utrophin and DAGs including 50DAG (A2), 43DAG (A3a) and 35DAG (A4) were employed for the examination. Dystrophin was stained strongly and utrophin stained very faintly along the sarcolemma of the dystrophic hamster, similar to the control. On the other hand, in the dystrophic hamster 50DAG (A2) and 35DAG (A4) were selectively defective, and 43DAG (A3a) was also decreased, although to a lesser degree. Since these results were almost identical to those seen in severe childhood autosomal recessive muscular dystrophy (SCARMD), the dystrophic hamster appears to be an animal model of SCARMD in which defects in DAGs may result in muscle fiber necrosis despite normal dystrophin expression.

Animals↗
PubMed1994

Human mitochondria and mitochondrial genome function as a single dynamic cellular unit.

rho 0 HeLa cells entirely lacking mitochondrial DNA (mtDNA) and mitochondrial transfection techniques were used to examine intermitochondrial interactions between mitochondria with and without mtDNA, and also between those with wild-type (wt) and mutant-type mtDNA in living human cells. First, unambiguous evidence was obtained that the DNA-binding dyes ethidium bromide (EtBr) and 4',6-diamidino-2-phenylindole (DAPI) exclusively stained mitochondria containing mtDNA in living human cells. Then, using EtBr or DAPI fluorescence as a probe, mtDNA was shown to spread rapidly to all rho 0 HeLa mitochondria when EtBr- or DAPI-stained HeLa mitochondria were introduced into rho 0 HeLa cells. Moreover, coexisting wt-mtDNA and mutant mtDNA with a large deletion (delta-mtDNA) were shown to mix homogeneously throughout mitochondria, not to remain segregated by use of electron microscopic analysis of cytochrome c oxidase activities of individual mitochondria as a probe to identify mitochondria with predominantly wt- or delta-mtDNA in single cells. This rapid diffusion of mtDNA and the resultant homogeneous distribution of the heteroplasmic wt- and delta-mtDNA molecules throughout mitochondria in a cell suggest that the mitochondria in living human cells have lost their individuality. Thus, the actual number of mitochondria per cell is not of crucial importance, and mitochondria in a cell should be considered as a virtually single dynamic unit.

DNA, Mitochondrial↗
PubMed1994

Expression of dystrophin-associated protein 35DAG (A4) and 50DAG (A2) is confined to striated muscles.

A monoclonal antibody MA4-2 against a dystrophin-associated protein 35DAG (A4) was established and applied to examine the distribution of 35DAG in monkey tissue and its expression in DMD patients. In immunoblotting after two-dimensional gel electrophoresis of crude skeletal muscle extracts, MA4-2 reacted exclusively with an apparent single spot located in a similar position to rabbit 35DAG in each animal examined. 35DAG was detected only in striated muscles (quadriceps femoris and cardiac muscles), but not in other tissues examined, including smooth muscle (aorta, uterus), brain, nerve, lung, and liver. This distribution pattern is the same as that of 50DAG but different from that of 43DAG (A3a) [Mizuno et al. (1993) J. Biochem. 114, 936-941]. In Duchenne muscular dystrophy muscles, 35DAG was distinctly present, but greatly reduced in amount. This is also the case with 50DAG. On the basis of these results, it is concluded that 35DAG and 50DAG are striated muscle-specific and may be important in the pathogenesis of Duchenne muscular dystrophy.

Animals↗
PubMed1994

A histochemical study of the biceps brachii muscle cross-innervated by intercostal nerves. 6 cases of brachial plexus injuries operated with nerve-crossing.

Direct nerve-crossing of intercostal nerves from the lateral thorax to the musculocutaneous nerve was performed in 6 patients after spinal nerve root avulsion with brachial plexus palsy. Elbow flexion power was regained well enough to move against gravity and some resistance in all cases. The muscles were examined histochemically 4 (1-9) years after the operation. The intercostally-innervated biceps brachii muscle showed motor predominance of slow-twitch Type 1 fiber regeneration much more than that of fast-twitch Type 2 fiber in 5 of our patients. Our study suggests that the motor nerves of slow-twitch fibers may have priority in peripheral nerve regeneration over those of fast-twitch fibers.

Adolescent↗
PubMed1994

[Muscle pathologic diagnosis--mechanism in muscle fiber degeneration].

In various neuromuscular diseases, the most significant muscle degeneration is muscle fiber necrosis as seen in Duchenne muscular dystrophy (DMD). A certain membrane instability is probably responsible for muscle fiber necrosis, because defects in membrane proteins have been proposed to associate with progressive muscular dystrophies including dystrophin in DMD, a 50 KD subunit of dystrophin associated glycoprotein (DAG) in severe childhood autosomal recessive muscular dystrophy (SCARMD), and subunit M of laminin (merosin) in congenital muscular dystrophy and dy mouse. The vulnerable muscle surface membrane may permit extracellular calcium influx into the sarcoplasm resulting in focal myofibrillar hypercontraction (opaque fiber) and activation of proteases such as calpain and cathepsins. The muscle fiber then undergoes necrosis and allows macrophage invasion, followed by muscle fiber regeneration. Focal myofibrillar degeneration involving rimmed vacuole (RV) formation is an another striking muscle fiber degeneration seen in various neuromuscular diseases including inclusion body myositis (IBM) and distal myopathy with rimmed vacuole formation (DMRV). Abnormal accumulation of ubiquitin, beta-amyloid protein precursor and tau protein has been described in IBM by Askanas et al. The similar findings are also recognizable in DMRV and in an experimentally induced myopathy after long-term chloroquin administration to rat. Therefore, if we clarify the pathomechanism of degenerative process involved in the rimmed vacuole formation, the results may provide some insights into the understanding the process involved in amyloid plaque formation in Alzheimer's disease.

Animals↗
PubMed1994

[A patient of late-onset nemaline myopathy with mononuclear cell infiltration].

We described a 50-year-old woman with late-onset nemaline myopathy with focal mononuclear cell infiltrates in her muscle biopsy. She developed difficulty in climbing stairs, and elevating her arms for 5 months after the onset of the disease. On admission, neurological examination revealed moderate weakness and atrophy in the proximal limb and neck muscles. Laboratory studies were within normal limits except mildly elevated serum CK and aldolase levels. Electromyography showed myopathic changes in the right triceps and quadriceps muscles examined. A biopsy from the left biceps brachii muscle revealed increased variation in fiber size, with numerous basophilic atrophic fibers. There were some foci of mild mononuclear cell infiltration. Most of basophilic fibers contained nemaline bodies on modified trichrome stain. On electron microscopy numerous nemaline bodies were present in fibers with marked myofibrillar degeneration. Azathioprine and prednisolone administration was not effective to improve her condition. As mononuclear cell infiltration has been occasionally described in the previously reported patients of adult-onset nemaline myopathy, inflammatory process may have some roles in formation of nemaline bodies on the way of acute myofibrillar degeneration.

Female↗
PubMed1994

[Muscle fiber involvement in Lowe syndrome].

Although it is well known fact that patients with Lowe syndrome have a delay in developmental milestones, muscle hypotonia and weakness, no detailed pathologic study to explain the muscle symptoms is available. In two patients with Lowe syndrome aged 22 years and 14 years, respectively, the biopsied biceps brachii muscles showed no significant morphologic changes except for small caliber fibers measuring almost 1/3 of the normal size. Although the muscle fiber type distribution is normal with no increase in undifferentiated type 2 C fibers, there remains a possibility of a certain defective neural influence on developing muscle fibers or metabolic defect. The muscle fiber immaturity is probably responsible for muscle weakness and hypotonia in this syndrome.

Adolescent↗
PubMed1994

[Significance of rimmed vacuoles in neuromuscular disorders--a comparative immunohistochemical study of inclusion body myositis and distal myopathy with rimmed vacuole formation].

Of 3,403 muscle biopsies from patients with a variety of neuromuscular disorders, 87 (2.6%) had at least three muscle fibers with rimmed vacuoles in a single low power field (magnificantion x 20). The rimmed vacuole formation may be a crucial pathologic findings to understand the pathogenesis of inclusion body myositis (IBM), distal myopathy with rimmed vacuole formation (DMRV), Marinesco-Sjögren syndrome and oculopharyngodistal myopathy, because the muscle fibers in these biopsies showed no striking necrotic and denervating changes. Since Congo red positive material and ubiquitin- and beta-amyloid protein-positive deposits were found in muscle fibers with rimmed vacuoles in DMRV and various neuromuscular disorders besides IBM, these findings may have no disease-specific significance and may be not helpful in differentiating DMRV from IBM.

Diagnosis, Differential↗
PubMed1994

[A case of glycogen storage disease with normal acid maltase accompanied with the abnormal platelet function].

Glycogen storage disease with normal acid maltase first reported by Danon et al. was characterized clinically by mental retardation, cardiomyopathy, and proximal myopathy. Since the first report, 17 patients have been reported including 5 patients from Japan. In this paper we described a 26-year-old man who had dilatated cardiomyopathy with a pacemaker implanted at age 22 years. He was admitted to our hospital complaining of easy fatigability in February 1992. Neurological findings showed that he had mental retardation. Serum CK, GOT, GPT and aldolase levels were elevated. Histopathological study of biopsied skeletal muscle showed intracytoplasmic vacuoles with increased acid phosphatase and slightly increased PAS positive material. Electron microscopic study revealed numerous glycogenosomes (autophagic vacuoles containing glycogen). These pathological findings were similar to acid maltase deficiency, but activities of carbohydrate metabolic enzyme including acid maltase activity were normal in the biopsied muscle. From these results, he was diagnosed as having glycogen storage disease with normal acid maltase. We also found abnormal platelet function and glycogen accumulation in the platelets, which have not been previously described. The disease is probably a systemic disorder affecting not only skeletal and cardiac muscles, but platelets.

Adult↗
PubMed1994

[Dystrophin-related protein in diaphragm, limb and myoblast transferred muscles of mdx mouse].

Expression of the dystrophin-related protein (DRP or Utrophin) was examined with Western blot and immunohistochemical methods in diaphragm, limb and also in myoblast transferred muscles of the mdx mouse. Although we have hypothesized that progressive fibrosis in the diaphragm of the mdx mouse has been due to a smaller amount of DRP expression compared with limb muscles, we could not find any difference in the amount of DRP or in the DRP localization pattern between the two muscle sites. In limb muscles treated with myoblast transfer, dystrophin-positive muscle fibers had no DRP on their surface membrane, although dystrophin-negative muscle fibers were DRP-positive. These findings suggest that excessive expression of DRP is suppressed in the normalized muscle fiber with dystrophin. It also appears that the histological differences seen in the different muscles of the mdx mouse are not due to the amount of DRP present.

Animals↗
PubMed1994

[Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes with delayed and decreased cerebral blood flow on cerebral angiography--a case report].

A 9-year-old girl was admitted to our hospital because of fever, headache, vomiting, and convulsive seizures. On admission, she was proved to have homonymous hemianopsia as well as elevated lactate and pyruvate levels in both serum and cerebrospinal fluid. Muscle biopsy study showed scattered ragged-red fibers and strongly succinatedehydrogenase-reactive blood vessels (SSV), suggesting systemic vascular involvement. She had a point mutation at nucleotide pair 3,243 in mitochondrial DNA extracted from muscle and blood samples. Brain CT and MRI showed a large abnormal area mimicking cerebral infarction in the region of the occipital cerebral artery. The cerebral lesion was assumed to be caused by vascular abnormality because of delayed and decreased cerebral blood flow together with vascular changes in her muscle biopsy.

Cerebral Angiography↗
PubMed1994

Three new mutations in patients with myophosphorylase deficiency (McArdle disease).

We report three new mutations in patients with myophosphorylase deficiency (McArdle disease). A splice-junction mutation (G-to-A transition at the 5' end of intron 14) and a missense mutation (CTG to CCG at codon 291, changing an encoded leucine to a proline) were identified in Caucasian patients who were heterozygous for a common mutation reported elsewhere (CGA [Arg] to TGA [stop]) at codon 49. The splice-junction mutation destroyed the consensus sequence at the 5' splice site, and a cryptic splice site 67 bp upstream was recognized instead. As a result, there was a 67-bp deletion in the 3'-terminal region of exon 14 in the transcript, resulting in a frameshift with premature translation termination. A deletion of a single codon, 708/709 (TTC, specifying phenylalanine) was identified in Japanese patients. Two affected siblings were homozygotes, and their parents were heterozygotes. A third, unrelated patient was heterozygous for the same mutation, while the myophosphorylase gene on the other allele was only faintly expressed.

Adolescent↗
PubMed1993

Accumulation of mtDNA with a mutation at position 3271 in tRNA(Leu)(UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function.

A new mitochondrial DNA (mtDNA) mutation of tRNA(Leu)(UUR) at nucleotide position 3271 (MELAS3271) was determined to be involved in the pathogenic process of mitochondrial diseases MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) using intercellular transfer of patient-derived mtDNA to mtDNA-less HeLa cells (rho 0 HeLa cells). Cybrid clones containing imported mtDNA exclusively from a MELAS patient with MELAS3271 mtDNA were isolated, and the influence of MELAS3271 mtDNA on mitochondrial translation activity and mitochondrial respiratory complex I enzyme activity were examined. Accumulation of more than 87% MELAS3271 mutant mtDNA in the cybrid clones induced both low complex I activity and abnormal mtDNA-encoded polypeptide synthesis including at least complex I subunit ND6. suggesting involvement of the new MELAS-associated mutation in the pathogenesis.

Blotting, Southern↗