Search PubMed⌕ Search

Biomedical subjects

Gen Sobue

Publications and source records attributed to Gen Sobue.

At least 91 records · Page 5Linked to original sources
PubMed2003

[Magnetic resonance spectroscopy and its clinical applications in multiple sclerosis].

Proton magnetic resonance spectroscopy(1H-MRS), which provides biochemical information in not only visible lesions on conventional MR imaging but also normal appearing white matter(NAWM), has extended the genesis of multiple sclerosis(MS) in several important directions. First, serial 1H-MRS studies reveal dynamic regional biochemical alterations in plaques during the course of the illness. Second, axonal damage may occur at early stage. Third, neuronal loss can be substantial in the gray matter. Fourth, NAWM shows widespread biochemical involvement prior to detection on MRI. Fifth, severities of neuroaxonal involvement significantly correlate with neurological dysfunction. 1H-MRS will provide more detailed information than conventional MRI, and could be beneficial in monitoring effects of therapeutic interventions in MS.

Adult↗
PubMed2003

Clinicopathologic and genetic features of early- and late-onset FAP type I (FAP ATTR Val30Met) in Japan.

Type I (transthyretin Val30Met) familial amyloid polyneuropathy (FAP ATTR Val30Met) has been reported in relation to two endemic foci in Japan. These cases are characterized by a relatively young age at onset, between the second and third decade, high penetrance rate, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. In contrast to these endemic cases, because of advances in DNA diagnosis, late-onset cases of FAP ATTR Val30Met with symptoms appearing at or over 50 years of age are now recognized to occur widely throughout Japan. These cases have a male preponderance, low penetrance rate, no relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. This type of FAP ATTR Val30Met has been overlooked because its clinical and genetic features differ from those of "typical" early-onset cases. Anticipation of age at onset is known to occur in pedigrees from the two endemic foci in Japan, with age at onset becoming younger in patients of successive generations. On the other hand, age at onset of patients in late-onset families seems to be uniformly late among the patient siblings when family history is present. Pathologic findings of the peripheral nervous system also differ in accordance with differences of clinical features. Loss of dorsal root and sympathetic ganglion neurons was severe in the early-onset cases, whereas it was only mild to moderate in the late-onset cases. Unmyelinated fibers in the biopsied sural nerve specimens of late-onset cases seemed to be relatively well preserved compared to those of previously reported early-onset cases.

Age of Onset↗
PubMed2003

[Successful early-stage corticosteroid treatment in a case of granulomatous angiitis of the central nervous system].

A 74-year-old woman presented with progressive mental deterioration following a low-grade fever and headache. Upon admission, she appeared lethargic, could not obey simple commands and was disoriented to time, place and person. She had low-grade fever and mild neck stiffness. The cerebrospinal fluid had an elevated protein content of 496 mg/dl, contrast-enhanced MRI revealed diffuse leptomeningeal enhancement, particularly in the occipital area, and a cerebral angiogram showed diffuse segmental narrowing of multiple intracranial arteries, especially in the distal portion of the right middle cerebral artery. A clinical diagnosis of granulomatous angiitis of the central nervous systems (GANS) was made, and corticosteroid therapy was initiated. The patient improved gradually, and corticosteroid therapy was tapered to the maintenance dose (prednisolone 0.4 mg/kg daily). An open brain biopsy showed multiple vessels containing granulomatous inflammation with giant cells. GANS is one of the most challenging neurologic disorders to diagnose because of its relative rarity and the lack of specificity of clinical signs and efficient, non-invasive, diagnostic tests. In this case, we were able to begin corticosteroid therapy in the early stage of the disease (before brain biopsy), and it yielded a good outcome.

Aged↗
PubMed2003

[Clinical phenotype of Charcot-Marie-Tooth disease (CMT) and familial amyloid polyneuropathy (FAP)].

A nationwide study of CMT and FAP has been performed. In FAP TTR Met30 families with late onset, neuropathy showed male preponderance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms, consistent with pathological findings. In contrast, families with early onset showed higher penetrance, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction. Demyelinating versus axonal phenotypes are major issues in CMT. CMT1A duplication caused mainly demyelinating phenotype, while axonal features were variably present. In CMT1B, two distinctive phenotypic subgroups were present: one showed exclusively axonal features; and another was exclusively demyelinating. CMTX showed intermediate slowing of MCV, predominantly axonal features, and relatively mild demyelinating pathology. Differing from CMT1B, these axonal and demyelinating features were concomitantly present in individual patients in variable extent. Median nerve MCVs were well maintained independently of age, disease duration, and severity of clinical and pathologic abnormalities. Amplitude of CMAPs was correlated significantly with distal muscle strength, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. CMT patients with demyelinating and/or axonal features, together with FAP patients with axonal feature and scattered distribution, are supposed to increase according to the development of genetic diagnosis for hereditary neuropathy that verifies late-onset, de novo and asymptomatic patients.

Adult↗
PubMed2003

[Development of therapeutics for spinal and bulbar muscular atrophy (SBMA)].

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a hereditary motor neuron disease that affects males, caused by the expansion of a polyglutamine (polyQ) tract in androgen receptor (AR). Female carriers are usually asymptomatic. The transgenic mouse (Tg) model carrying a full-length human AR with expanded polyQ has significant gender-related motor impairment. This phenotype is inhibited by castration, which prevents nuclear translocation of mutant AR. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, also rescues motor dysfunction and nuclear accumulation of mutant AR in the male Tg. Over-expression of a molecular chaperone HSP70, which renatures misfolded mutant AR, ameliorates neuromuscular phenotypes of the Tg by reducing nuclear-localized mutant AR. HSP70 appears to enhance the degradation of mutant AR via ubiquitin-proteasome pathway. These experimental approaches indicate the possibility of clinical application of drugs, such as leuprorelin, for SBMA patients.

Animals↗
PubMed2002

Expression of tumor necrosis factor-alpha in regenerating muscle fibers in inflammatory and non-inflammatory myopathies.

The expression level of tumor necrosis factor (TNF)-alpha is elevated in idiopathic inflammatory myopathies and Duchenne muscular dystrophy (DMD), but the precise role of TNF-alpha is unknown. To elucidate the possible role of TNF-alpha, we investigated the expression of TNF-alpha and its receptor in polymyositis (PM), dermatomyositis (DM), and DMD using in situ hybridization (ISH) and immunohistochemistry. We showed that TNF-alpha mRNA and protein were present in muscle fibers. TNF-alpha-positive fibers were observed in all cases of PM, DM and DMD, but were rare or absent in neurogenic disorders and normal controls. The proportion of TNF-alpha-positive fiber showed a significant positive correlation with the proportion of regenerating fibers that were positive for the developmental form of myosin heavy chain (MHC-d). The number of TNF receptor-positive fibers was small. Some muscle fibers expressed both TNF-alpha and its receptor simultaneously. Our results indicate that TNF-alpha is produced and expressed by muscle fibers and associated with muscle regeneration.

Adolescent↗
PubMed2002

Differentially expressed genes in sporadic amyotrophic lateral sclerosis spinal cords--screening by molecular indexing and subsequent cDNA microarray analysis.

To analyze the genes related to the pathophysiology of sporadic amyotrophic lateral sclerosis (SALS) we performed gene profiling of SALS spinal cords using molecular indexing combined with cDNA microarray. Eighty-four fragments were cloned in the first screening procedure with molecular indexing. Subsequent quantitative microarray screening revealed 11 genes which were differentially expressed in SALS. Real-time RT-PCR verified that the expression level of the following six genes was altered in SALS: dorfin, metallothionein-3, 30 kDa TATA-binding protein-associated factor, neugrin, ubiquitin-like protein 5 and macrophage-inhibiting factor-related protein-8. These results indicated that genes associated with the ubiquitin-proteasome system, oxidative toxicity, transcription, neuronal differentiation and inflammation might be involved in the pathogenesis of SALS.

Adult↗
PubMed2002

Mitochondrial localization of mutant superoxide dismutase 1 triggers caspase-dependent cell death in a cellular model of familial amyotrophic lateral sclerosis.

The mutations in superoxide dismutase 1 (SOD1) cause approximately 20% of familial amyotrophic lateral sclerosis cases. A toxic gain of function has been considered to be the cause of the disease, but its molecular mechanism remains uncertain. To determine whether the subcellular localization of mutant SOD1 is crucial to mutant SOD1-mediated cell death, we produced neuronal cell models with accumulation of SOD1 in each subcellular fraction/organelle, such as the cytosol, nucleus, endoplasmic reticulum, and mitochondria. We showed that the localization of mutant SOD1 in the mitochondria triggered the release of mitochondrial cytochrome c followed by the activation of caspase cascade and induced neuronal cell death without cytoplasmic mutant SOD1 aggregate formation. Nuclear and endoplasmic reticulum localization of mutant SOD1 did not induce cell death. These results suggest that the localization of mutant SOD1 in the mitochondria is critical in the pathogenesis of mutant SOD1-associated familial amyotrophic lateral sclerosis.

Amino Acid Substitution↗
PubMed2002

Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1.

Mutations of the superoxide dismutase 1 (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS). Intracytoplasmic aggregate formation consisting of mutant SOD1 is the histological hallmark of FALS. Since a previous report revealed that Hsp70 reduced aggregate formation and cell death in a cell model of FALS, here we examined the combined effects of Hsp70 and its cofactor, Hsp40, on a cell model of FALS. The combination of Hsp70 and Hsp40 reduced intracytoplasmic aggregates and markedly improved neurite outgrowth. They also prevented cell death to a relatively lesser extent. Neurite outgrowth was recognized almost exclusively in the cells without intracytoplasmic aggregates. Hsp70 and Hsp40 were upregulated in cells expressing mutant SOD1, and were colocalized with intracytoplasmic aggregates of mutant SOD1. These findings suggest that heat shock proteins (HSPs) promote neurite outgrowth by suppressing intracytoplasmic aggregate formation and restoring cellular dysfunctions. This is the first demonstration that overexpression of HSPs improved neurite outgrowth as it suppressed intracytoplasmic aggregate formation and cell death in a cultured neuronal cell model of FALS. These findings may provide a basis for the utilization of HSPs in developing a treatment for FALS.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse nuclear staining and nuclear inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.

Animals↗
PubMed2002

Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity.

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in the cerebral cortex, brainstem, and spinal cord. The cytopathological hallmark in the remaining motor neurons of ALS is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. In this paper we report that Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well as sporadic ALS. Dorfin physically bound and ubiquitylated various SOD1 mutants derived from familial ALS patients and enhanced their degradation, but it had no effect on the stability of the wild-type SOD1. The overexpression of Dorfin protected against the toxic effects of mutant SOD1 on neural cells and reduced SOD1 inclusions. Our results indicate that Dorfin protects neurons by recognizing and then ubiquitylating mutant SOD1 proteins followed by targeting them for proteasomal degradation.

Aged↗
PubMed2002

Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease.

The cellular distribution of malondialdehyde (MDA) was assessed immunohistochemically in brain specimens from young and normal elderly subjects as well as patients with Alzheimer's disease (AD). MDA was increased in the cytoplasm of neurons and astrocytes in both normal aging and AD, but was rarely detected in normal young subjects. By electron microscopic immunohistochemistry, neuronal MDA formed cap-like linear deposits associated with lipofuscin, while glial MDA deposits surrounded the vacuoles in a linear distribution. In the hippocampus, neuronal and glial MDA deposition was marked in the CA4 region but mild in CA1. By examination of serial sections stained with anti-MDA and antibodies against an advanced glycation end product, N(epsilon)-(carboxymethyl)lysine (CML), neuronal and glial MDA deposition was colocalized with CML in AD, but only neuronal MDA was colocalized with CML in normal aged brains. Glial MDA, although abundant in the aged brain, typically was not colocalized with CML. In AD cases, MDA was colocalized with tau protein in CA2 hippocampal neurons; such colocalization was rare in CA1. MDA also was stained in cores of senile plaques. Thus, while both MDA and CML accumulate under oxidative stress, CML accumulation is largely limited to neurons, in normal aging, while MDA also accumulates in glia. In AD, both MDA and CML are deposited in both astrocytes and neurons.

Adolescent↗
PubMed2002

Repair by Src kinase of function-impaired RET with multiple endocrine neoplasia type 2A mutation with substitutions of tyrosines in the COOH-terminal kinase domain for phenylalanine.

An oncogenic mutant of c-RET as a receptor-type tyrosine kinase, termed RET-MEN2A, displays both cell-transforming activity in vivo and strong catalytic activity in vitro. In this study, we compared the activities of mutant RET-MEN2A with substitutions of each of nine tyrosines for phenylalanine (Y1062F, Y1015F, Y981F, Y952F, Y928F, Y905F, Y900F, Y864F, and Y826F), which had been transfected into NIH 3T3 cells. In RET-MEN2A with the Y905F mutation, the cell-transforming activity was drastically reduced with a great reduction in the in vitro catalytic activity. Unexpectedly, we found that in vitro kinase activity was severely impaired in RET-MEN2A with Y981F, Y952F, or Y928F mutation, which displayed near-normal cell-transforming activity and only a partially impaired tyrosine phosphorylation level in vivo. Phosphoamino acid analysis actually demonstrated some increase in phosphotyrosine in the Y905F mutant but no or barely detectable increase in the Y981F, Y952F, or Y928F mutant after incubation for in vitro kinase assay. This suggested a crucial role of the Y981/Y952/Y928-linked structural integrity of the COOH end of the catalytic domain of RET in starting Y905 autophosphorylation. Interestingly, the apparent defect in intrinsic kinase activity in vitro in the Y981F, Y952F, or Y928F mutant, but not the reduction in activity in the Y905F mutant, could be partially repaired or restored by c-Src or, more extensively, by v-Src, which promoted Y905 phosphorylation in trans. A complex was shown to be formed between v-Src and RET-MEN2A through association of both with a cholesterol-rich membrane microdomain known as "a raft," possibly for efficient contact of submembranous domains of Src and RET to promote phosphorylation of Y905 of the latter. Finally, endogenous c-Src was shown to promote Y905 phosphorylation of the Y981F mutant in vivo. These results reveal a novel Src kinase-mediated repair mechanism of otherwise function-impaired mutant RET kinases.

3T3 Cells↗
PubMed2002

Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity.

Familial amyloid polyneuropathy (FAP) was once considered a disease peculiar to endemic areas, but it is now recognized not to be a rare disease among hereditary neuropathic disorders in Japan. FAP in Japan, the majority of which is caused by transthyretin (TTR)-related amyloid deposition, shows a wide spectrum of clinical pictures. This variability can be explained on the basis of the many causative gene mutations of TTR, but even in the same TTR type of FAP, the clinical phenotypes seem to vary in different kindreds or individuals. Especially in the case of the Val30Met TTR type, the sex ratio and the age at onset are considerably different between patients in endemic foci and those in nonendemic areas. It is also noteworthy that serious cardiac amyloidosis is commonly seen in patients with FAP of the non-Val30Met TTR type. In addition to TTR gene mutation, unknown factors may play an important role in the development of FAP. At present, liver transplantation is the only life-saving treatment, but this therapy is always associated with great stress for the patient and the donor, particularly in living-related transplantation. Less invasive treatments for this disease are required.

Amyloid↗
PubMed2002

Type I (transthyretin Met30) familial amyloid polyneuropathy in Japan: early- vs late-onset form.

BACKGROUND: Type I (transthyretin Met30) familial amyloid polyneuropathy (FAP TTR Met30) occurs in 2 endemic foci in Japan. We have also reported late-onset Japanese cases unrelated to an endemic focus and showing distinctive clinicopathologic features. OBJECTIVE: To compare clinical and geographic features of FAP TTR Met30 between patients with onset before and after 50 years of age. DESIGN AND SETTING: Clinical information was obtained through a nationwide survey by the Study Group for Hereditary Neuropathy in Japan. RESULTS: Families with early-onset disease in this study numbered 82, and those with late onset, 59. In families with late onset, neuropathy showed male preponderance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. Families with early onset showed higher penetrance, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. CONCLUSIONS: This study confirmed differences in clinical and geographic features between early- and late-onset FAP TTR Met30. Late-onset cases may be more prevalent and widespread than previously believed.

Adult↗
PubMed2002

Motor conduction studies in Miller Fisher syndrome with severe tetraparesis.

Some patients with Miller Fisher syndrome (MFS) have a severe tetraparesis such as that observed in Guillain--Barré syndrome (GBS). To determine whether pathophysiologic differences exist between the tetraparesis in MFS and that in GBS, we compared clinical and motor conduction findings in 4 MFS patients who developed severe tetraparesis with those in 5 MFS patients without tetraparesis, and 14 GBS patients. MFS patients with or without tetraplegia had normal motor conduction velocities, distal motor latencies, compound muscle action potential (CMAP) amplitudes, and F-wave latencies. CMAP amplitude tended to be lower in tetraparetic MFS patients than in MFS patients without tetraparesis, but not significantly. F-wave occurrence was slightly reduced in 1 MFS patient with tetraparesis and 1 MFS patient without tetraparesis. Motor conduction parameters were abnormal in 13 of 14 patients with GBS, and showed demyelinating features in 10. Our results suggest that the pathophysiology of tetraparesis in MFS differs from that in GBS.

Adult↗