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Biomedical subjects

Yoshihide Sunada

Publications and source records attributed to Yoshihide Sunada.

18 recordsLinked to original sources
PubMed2006

Acute disseminated encephalomyelitis associated with oral polio vaccine.

A 27-year-old woman presented with acute paresis after taking an oral polio vaccine (OPV). Deep tendon reflexes were preserved, needle electromyography showed no neurogenic changes, and there were no lesions on spine magnetic resonance imaging (MRI), suggesting that motor neurons of the spinal cord were not affected. Brain MRI showed abnormal lesions in the tegmentum of the upper pons, left cerebral peduncles, truncus of the corpus callosum, and right parietal lobe. Cerebrospinal fluid revealed mild pleocytosis. The most probable diagnosis was acute disseminated encephalomyelitis associated with OPV.

Acute Disease↗
PubMed2006

Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.

Caveolin-3, the muscle-specific isoform of caveolins, plays important roles in signal transduction. Dominant-negative mutations of the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) with loss of caveolin-3. However, identification of the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient muscle has remained elusive. Myostatin, a member of the muscle-specific TGF-beta superfamily, negatively regulates skeletal muscle volume. Here we report that caveolin-3 inhibited myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophosphorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of caveolin-3 in P104L mutant caveolin-3 transgenic mice caused muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a myostatin target gene. Introduction of the myostatin prodomain, an inhibitor of myostatin, by genetic crossing or intraperitoneal administration of the soluble type II myostatin receptor, another inhibitor, ameliorated muscular atrophy of the mutant caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that caveolin-3 normally suppresses the myostatin-mediated signal, thereby preventing muscular atrophy, and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in a mouse model of LGMD1C. Myostatin inhibition may be a promising therapy for LGMD1C patients.

Animals↗
PubMed2006

Bone marrow transplantation improves outcome in a mouse model of congenital muscular dystrophy.

We examined whether pathogenesis in dystrophin-deficient (mdx) mice and laminin-alpha2-deficient (dy) mice is ameliorated by bone marrow transplantation (BMT). Green fluorescent protein (GFP) mice were used as donors. In mdx mice, BMT failed to produce any significant differences in muscle pathology, although some GFP-positive fibers with restored dystrophin expression were observed. In contrast, in the dy mice, BMT led to a significant increase in lifespan and an increase in growth rate, muscle strength, and respiratory function. We conclude that BMT improved outcome in dy mice but not mdx mice.

Animals↗
PubMed2006

Generation of muscle aquaporin 4 overexpressing transgenic mouse: its characterization at RNA and protein levels including freeze-fracture study.

We generated the muscle aquaporin 4 (AQP4) overexpressing transgenic mice in order to investigate the skeletal muscle pathology at RNA and protein levels. At RNA level, the AQP4 mRNA expression of soleus, EDL and cardiac muscles in Tg mice was statistically significantly higher than that in wild mice by the real-time reverse transcription polymerase chain reaction method. At protein level examinations, we used the immunoblot, immunohistochemistry and freeze-fracture electron microscopy. The immunoblot showed the single band of 31kDa with anti-AQP4 antibody in the extracts of soleus and EDL muscles of wild mice but not in extract of wild cardiac muscle; while the reaction band was noted in cardiac muscle of Tg mice and the reaction band was stronger in the extracts of soleus and EDL muscles of Tg mice. The immunohistochemistry showed that the expression of AQP4 at the myofiber surface of soleus and EDL muscles of Tg mice was more marked than that of wild mice and, interestingly, the AQP4 expression of these muscles of Tg mice appeared to be more remarkable in type 1 slow twitch myofibers as judged by the positive slow myosin immunostaining of adjacent serial sections. The immunofluorescence staining with anti-AQP4 antibody of cardiac muscles of wild mice revealed the scarcely immunopositive myofibers; whereas the immunostaining cardiac muscles of Tg mice contained the numerous AQP4 immunopositive myofibers. The freeze-fracture electron microscopy demonstrated that the orthogonal array densities in soleus and EDL muscle plasma membranes of Tg mice were significantly higher than those of wild mice and that the orthogonal array like particle density of cardiac muscle plasma membranes of Tg mice appeared to be more numerous than that of cardiac myofibers of wild mice. Finally the clinical phenotype of Tg mice appeared to be similar to that of wild mice. Further physiological examination with devices may suggest some about the physiological difference.

Animals↗
PubMed2006

Peripheral myelin protein 22 is expressed in human central nervous system.

We studied the expression of peripheral myelin protein 22 (PMP22) gene in the human central nervous system (CNS). Northern blot analysis was performed with polyA+ RNA blots containing several parts of the human brain and the spinal cord using human PMP22 cDNA as a probe. As two alternative PMP22 transcripts have been reported and since exon 1A-containing transcripts are associated with myelin formation, the exon 1A fragment was also used to examine this transcript. Total PMP22 mRNA was significantly detected in most parts of brain and spinal cord, while exon 1A-containing transcripts were detected in the medulla, spinal cord and corpus callosum. PMP22-like immunoreactivity was identified in motor neurons and preganglionic sympathetic neurons in the spinal cord. PMP22 was also detected in pia mater of the spinal cord. These results suggest that PMP22 might play an important role in human CNS.

Brain↗
PubMed2006

VEGF 164 gene transfer by electroporation improves diabetic sensory neuropathy in mice.

BACKGROUND: Diabetic neuropathy is the most common cause of peripheral neuropathy and a serious complication of diabetes. Vascular endothelial growth factor (VEGF) stimulates angiogenesis and has neurotrophic and neuroprotective activities. To examine the efficiency of VEGF 164 electro-gene therapy for neuropathy, intramuscular VEGF 164 gene transfer by electroporation was performed to treat sensory neuropathy in diabetic mice. METHODS: VEGF 164 was overexpressed in the tibial anterior (TA) muscles of streptozotocin-induced diabetic mice with hypoalgesia, using a VEGF 164 plasmid injection with electroporation. From 2 weeks after electro-gene transfer, the nociceptive threshold was measured weekly using the paw-pressure test. The TA muscles, sciatic nerve, liver and spleen were histochemically examined at 4 weeks after electro-gene transfer. RESULTS: Two weeks after electro-gene transfer into the bilateral TA muscles, the elevated nociceptive threshold was decreased to a normal level in all treated mice. Improvement of the hypoalgesia continued for 14 weeks. When the VEGF 164 plasmid was injected with electroporation into a unilateral TA muscle, recovery from hypoalgesia was observed in not only the ipsilateral hindpaw, but also the contralateral one, suggesting that VEGF circulates in the blood. No increase in the number of endoneurial vessels in the sciatic nerve was found in the VEGF 164 plasmid-electroporated mice. CONCLUSIONS: These findings suggest that VEGF 164 electro-gene therapy completely recovered the sensory deficits, i.e. hypoalgesia, in the diabetic mice through mechanisms other than angiogenesis in the endoneurium of the peripheral nerve, and may be useful for treatment for diabetic sensory neuropathy in human subjects.

Animals↗
PubMed2006

[Medullary tegmentum lesion in a patients having intractable hiccups, nausea, and syncope].

A 61-year-old female, having intractable hiccups, nausea, and syncope. Her systolic blood presure decreased by 30 mmHg on sitting position from supine position. Sinus arrest lasting more than three seconds were detected 52 times per day by 24 hour Holter electrocardiography. Brain MRI disclosed a small hyperintense lesion in the medullary tegmentum on T2-weighted images. She was diagnosed as having a relapse of multiple screlosis and her symptoms were improved by administration of high dose methylprednisolone (1,000 mg per day x 3 days) intravenously. In a patients, a stimulative lesion in the medullary tegmentum was suspected where the reflex centers of hiccups, nausea and blood pressure to exist. We are able to confirm a small hyperintense lesion in such a particular region by brain MRI. In case of syncope accompanied with intractable hiccups and nausea, we should consider a stimulative lesion in the medullary tegmentum. Moreover, sinus arrest other than orthostatic hypotension may be involved in the pathophysiology of syncope in correlation with the medullary tegmentum lesion.

Female↗
PubMed2004

Mechanism of taxane neurotoxicity.

The two taxanes (paclitaxel and docetaxel) are widely employed in standard antineoplastic practice. Although these agents are now well established, some toxic side effects have been reported. Toxicity of these agents includes bone marrow suppression (principally neutropenia), hypersensitivity reactions, cutaneous reactions, edema and neurotoxicity. The most prominent neurotoxicity is a sensory neuropathy. Controlling neuropathy is crucial for maintaining the quality of life of patients because it is usually persistent and hard to manage. The precise mechanism for taxane-induced neuropathy is still unknown. The taxanes are known to promote aggregation of intracellular microtubules. Abnormal aggregation of microtubules in the neuronal cells may cause this neuropathy. In addition, the taxanes have been suggested to have intrinsic toxicity and directly injure the cells. A better understanding of the mechanism for this neuropathy may improve the quality of life of patients who undergo taxane antineoplastic therapy.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Techniques for the neurological examination of taxane-induced neuropathy.

Taxanes are considered to be the key drugs in the treatment of breast cancer. Although physicians who treat patients with breast cancer have rarely seen patients with neuropathy as an adverse effect of treatment before the advent of taxanes, patients with breast cancer who are treated with taxanes frequently exhibit peripheral neuropathy. As peripheral neuropathy often causes deterioration of the quality of life of patients, it is very important to precisely assess the extent of peripheral neuropathy at an early stage. Clinical oncologists should be familiar with the techniques of neurological examination. In this article we describe the basic techniques for the neurological examination of patients with taxane-induced peripheral neuropathy. In the hope of facilitating the precise evaluation of taxane-induced peripheral neuropathy, the items of neurological examinations in this article are described with reference to the physician neuroexamination form (PNEF) designed by BioNumerik Pharmaceuticals Inc.

Antineoplastic Agents, Phytogenic↗
PubMed2004

[Limb-girdle muscular dystrophy; update].

Sixteen different forms of limb-girdle muscular dystrophies (LGMDs) have emerged from recent molecular genetic studies, six forms with a dominant trait and ten forms with a recessive trait. Among 1,420 Japanese patients with muscular dystrophy analyzed at NCNP, LGMD is the secondly largest category (19%) following dystrophinopathy (56%). Within LGMDs, the occurrence of LGMD2A (calpainopathy), LGMD2B (dysferlinopathy), and LGMD2C-F (sarcoglycanopathy) is 26%, 18%, and 6.6%, respectively, however, causative genes have not been specified in about 50% of the LGMD patients. LGMD2A patients show atrophy prominent in shoulder and pelvic girdle muscles without calf muscle hypertrophy, and abundant lobulated fibers in muscle biopsy. Four major mutations unique to the Japanese population, have been identified. Pathogenesis attributes to a loss of proteolytic activity of mutant calpain-3. Dysferlin, the defective protein in LGMD2B, is a ferlin family molecule possessing six C2 domains probably mediating the resealing mechanism of the damaged sarcolemma. Mutations in the dysferlin gene result in Miyoshi distal myopathy and distal anterior compartment myopathy other than LGMD2B. Among four sarcoglyconopathies, LGMD2D is the most common form, whereas LGMD2F has not yet been reported. In sarcoglycan-deficient skeletal muscle, matrix metalloproteinases may be involved in the beta-dystroglycan processing which underlies the pathogenesis of sarcoglycanopathy.

Humans↗
PubMed2003

Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.

The effect of endogenous nitric oxide synthase (NOS) on cardiac contractility and architecture has been a matter of debate. A role for NOS in cardiac hypertrophy has recently been demonstrated by studies which have shown hypertrophic cardiomyopathy (HCM) with altered contractility in constitutive NOS (cNOS) knockout mice. Caveolin-3, a strong inhibitor of all NOS isoforms, is expressed in sarcolemmal caveolae microdomains and binds to cNOS in vivo: endothelial nitric oxide synthase (eNOS) in cardiac myocytes and neuronal nitric oxide synthase (nNOS) in skeletal myocytes. The current study characterized the biochemical and cardiac parameters of P104L mutant caveolin-3 transgenic mice, a model of an autosomal dominant limb-girdle muscular dystrophy (LGMD1C). Transgenic mouse hearts demonstrated HCM, enhanced basal contractility, decreased left ventricular end diastolic diameter, and loss and cytoplasmic mislocalization of caveolin-3 protein. Surprisingly, cardiac muscle showed activation of eNOS catalytic activity without increased expression of all NOS isoforms. These data suggest that a moderate increase in eNOS activity associated with loss of caveolin-3 results in HCM.

Animals↗
PubMed2003

Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development.

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal-recessive disorders in Japan, is characterized by congenital muscular dystrophy associated with brain malformation due to a defect during neuronal migration. Through positional cloning, we previously identified the gene for FCMD, which encodes the fukutin protein. Here we report that chimeric mice generated using embryonic stem cells targeted for both fukutin alleles develop severe muscular dystrophy, with the selective deficiency of alpha-dystroglycan and its laminin-binding activity. In addition, these mice showed laminar disorganization of the cortical structures in the brain with impaired laminin assembly, focal interhemispheric fusion, and hippocampal and cerebellar dysgenesis. Further, chimeric mice showed anomaly of the lens, loss of laminar structure in the retina, and retinal detachment. These results indicate that fukutin is necessary for the maintenance of muscle integrity, cortical histiogenesis, and normal ocular development and suggest the functional linkage between fukutin and alpha-dystroglycan.

Animals↗
PubMed2003

Full-length dystrophin cDNA transfer into skeletal muscle of adult mdx mice by electroporation.

We showed that a LacZ expression plasmid (pCAG-lacZ) injection followed by electroporation increased the expression of the LacZ gene in the skeletal muscles of adult mdx mice up to ninefold higher as compared with simple intramuscular DNA injection. When full-length mouse dystrophin plasmid (pCAG-dys) and pCAG-lacZ were co-transfected by electroporation, 56% of dystrophin-positive fibers were stained for beta-galactosidase activity suggesting most of these myofibers are not revertants but transfected ones. Our data indicate that electroporation in vivo could introduce large full-length dystrophin cDNA into skeletal muscle of adult mdx mice.

Age Factors↗
PubMed2003

Fukuyama-type congenital muscular dystrophy (FCMD) and alpha-dystroglycanopathy.

Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. Through positional cloning, we identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein O-linked mannose beta1, 2-N-acetylglucosaminy ltransferase (POMGnT1), respectively. Recent studies have revealed that posttranslational modification of alpha-dystroglycan is associated with these congenital muscular dystrophies with brain malformations. In this review Fukuyama-type congenital muscular dystrophy (FCMD), other CMDs with brain malformations, and their relation with alpha-dystroglycan are discussed.

Animals↗
PubMed2002

Characterization of parkin in bovine peripheral nerve.

The autosomal recessive juvenile parkinsonism is caused by the mutations of the gene encoding a novel protein called parkin. It has been reported that parkin is expressed in the central nervous system and functions as a ubiquitin-protein ligase (E3) which suppresses neuronal cell degeneration by ubiquitinating misfolded proteins. Thus far, however, it remains unknown if parkin is expressed and functions in the peripheral nervous system. In order to begin to address to this question, we investigated the expression of parkin in bovine peripheral nerve. Reverse transcription polymerase chain reaction analysis demonstrated the presence of parkin transcript in bovine peripheral nerve. The obtained bovine parkin cDNA sequence was identical to that of human except a single nucleotide. Immunoblot analysis demonstrated the expression of parkin protein in bovine peripheral nerve. Immunohistochemical analysis demonstrated the localization of parkin in the axoplasm of myelinated nerve fibers, the Schwann cell cytoplasm and the Schwann cell outer membrane. Furthermore, fractionation analysis indicated the presence of two fractions of parkin in bovine peripheral nerve, the cytosolic fraction and the cell membrane-bound fraction. All together, these results point to diverse roles of parkin in not only the central but also the peripheral nervous system.

Animals↗
PubMed2002

Deficiency of a 180-kDa extracellular matrix protein in Fukuyama type congenital muscular dystrophy skeletal muscle.

Abnormalities of the proteins constituting the extracellular matrix have been shown to play important roles in the molecular pathogenesis of muscular dystrophies. In the present study, we have established a monoclonal antibody against a human skeletal muscle extracellular matrix protein. The antibody M1 recognized a single 180-kDa protein (p180) by immunoblot analysis of normal human skeletal muscle and gave a strong and continuous signal along the sarcolemma by immunohistochemical analysis. Furthermore, p180 could be solubilized either under a strong alkaline condition, or in the presence of EDTA or detergents such as Triton X-100, indicating that p180 was an extracellular matrix protein. Interestingly, p180 was deficient in the skeletal muscle of the patients with Fukuyama-type congenital muscular dystrophy (FCMD), but not other muscular diseases, by both immunohistochemical and immunoblot analyses. We presume that the deficiency of p180 in FCMD is caused specifically by the primary deficiency of fukutin, the causative protein of FCMD, and plays an important role in muscle cell degeneration in this disease.

Animals↗
PubMed2002

[A patient with muscular torticollis caused by nodular fasciitis in the sternocleidomastoid muscle (SCM)].

Nodular fasciitis is a benign pseudosarcomatous proliferative lesion which is frequently misdiagnosed as malignant tumor clinically and microscopically. It usually occurs as a rapidly enlarging subcutaneous mass on the upper extremities, especially on the forearm. Here we report a patient showing muscular torticollis caused by nodular fasciitis in the sternocleidomastoid muscle (SCM). A 17-year-old woman was hospitalized because of rapidly progressive torticollis. The right SCM was markedly enlarged and firm on palpation. Muscle biopsy taken from the right SCM revealed massive proliferation of spindle shaped fibroblasts infiltrating into the endomysium. These findings coincided with the intramuscular nodular fasciitis. However, different from typical nodular fasciitis, no apparent nodule formation was found in this patient. Instead, diffuse proliferative lesion extended widely into the neck soft tissue. To our knowledge, this is the first report of muscular torticollis caused by nodular fasciitis involving the SCM.

Adolescent↗