Biomedical subjects

Gen Sobue

Publications and source records attributed to Gen Sobue.

101 records · Page 6Linked to original sources

PubMed2002

Parallel expression of neurotrophic factors and their receptors in chronic inflammatory demyelinating polyneuropathy.

The mRNA levels of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6) were examined in sural nerves of 22 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The mRNAs for NGF, GDNF, LIF, and IL-6 were upregulated, whereas CNTF mRNA was downregulated significantly in the nerves. The NGF, GDNF, and CNTF, but not LIF mRNA expressions were parallel to those of the cognate receptors, suggesting that these cognate soluble receptors effectively present these factors to maintain and regenerate the axons. Furthermore, IL-6 mRNA expression was significantly parallel to both binding and signal-transducing receptor expression, implying a role of the IL-6 signal for non-neuronal cells in CIDP. These findings indicate that multiple neurotrophic growth factors and cytokines are expressed cooperatively with their concomitant receptors in the nerve lesions of CIDP and play an important role particularly in nerve repair.

Adult↗

PubMed2002

c-Jun N-terminal kinase pathway mediates Lactacystin-induced cell death in a neuronal differentiated Neuro2a cell line.

The ubiquitin-proteasome pathway is an intracellular protein degradation pathway responsible for degradation of many regulatory proteins that must be rapidly eliminated normally. Some recent studies reported that a proteasome dysfunction was involved in the pathogenesis of neurodegenerative diseases. Thus, there is now considerable interest in the possible role of proteasome in this regard. Here we show that inhibition of proteasomal function by Lactacystin-induced cell death in a neuronal differentiated Neuro2a (nN2a) cell line but not in an undifferentiated Neuro2a (N2a) cell line. Cell death was accompanied by both the activation of c-Jun N-terminal kinase, p38 and caspase-3. A pan-caspase inhibitor, Z-VAD-FMK, or SB203580, a p38 inhibitor could not inhibit cell death induced by Lactacystin, whereas nN2a cell lines with stable expression of the dominant negative mutant of c-Jun N-terminal kinase showed a remarkable suppression of cell death. Lactacystin-induced cell death is mediated through the c-Jun N-terminal kinase pathway but not the caspase-dependent pathway in a nN2a cell line. Our results shed light on the association among the proteasomal dysfunction, JNK pathway and neuronal cell death, leading to the elucidation of its possible role in the pathogenesis of neurodegenerative diseases.

Acetylcysteine↗

PubMed2002

Differential age-dependent trophic responses of nodose, sensory, and sympathetic neurons to neurotrophins and GDNF: potencies for neurite extension in explant culture.

The age-dependent trophic responses of sympathetic, sensory, and nodose neurons to the neurotrophins NGF, BDNF, and NT-3 and to glial cell line-derived neurotrophic factor (GDNF) were examined by an explant culture system. Superior cervical ganglia (SCG), dorsal root ganglia (DRG), and nodose ganglia (NG) were removed from rat embryos (E18), neonatals (< or = 1 day old), young adults (3-6 months old), and aged adults (> 24 months old). The ganglia were cultured with and without each neurotrophic factor; the neurite extension and neurite density were then assessed. The SCG from rats of all ages were significantly influenced by NGF, NT-3, and GDNF; the effects of NT-3 and GDNF were reduced after maturation. The DRG from embryos and neonates were influenced by all neurotrophic factors; however, the effects of BDNF and NT-3 disappeared after maturation. The GDNF showed little effect on adult DRG and no effect on aged DRG. The effect of NGF was preserved over all ages of DRG. The NG from embryonic rats were significantly responsive to BDNF and GDNF; their effects decreased in the neonatal NG, but a minimum effect remained in the aged NG. These results indicate that age-dependent profiles of trophic effects differ extensively among the lineages of the peripheral nervous system and also among the individual neurotrophic factors.

Aging↗

PubMed2002

Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis.

Familial amyotrophic lateral sclerosis (FALS)-linked mutations in copper-zinc superoxide dismutase (SOD1) cause motor neuron death through one or more acquired toxic properties. We analyzed the molecular mechanism underlying motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation. Using cDNA microarray, the differentially expressed genes were identified in the spinal cords of G93A mice, 30 being elevated and seven decreased. cDNA microarray analysis to monitor gene expression during neurodegeneration revealed an up-regulation of genes related to an inflammatory process, such as the tumor necrosis factor-alpha (TNF-alpha) gene, resulting from glial cell activation, together with the change in apoptosis-related gene expression, such as caspase-1. The increased expression of the inflammation- and apoptosis-related genes occurred at 11 weeks of age in the presymptomatic stage prior to motor neuron death. These results suggest a mechanism of neurodegeneration that includes an inflammatory response as an important component. Thus, ALS has paralleled other neurodegenerative disorders, such as Alzheimer's and prion diseases, in which the inflammatory process is believed to participate directly in neuronal death.

Amyotrophic Lateral Sclerosis↗

PubMed2002

X-Linked inhibitor of apoptosis protein is involved in mutant SOD1-mediated neuronal degeneration.

Mutations in the superoxide dismutase 1 (SOD1) gene cause the degeneration of motor neurons in familial amyotrophic lateral sclerosis (FALS). An apoptotic process including caspase-1 and -3 has been shown to participate in the pathogenesis of FALS transgenic (Tg) mouse model. Here we report that IAP proteins, potent inhibitors of apoptosis, are involved in the FALS Tg mouse pathologic process. The levels of X-linked inhibitor of apoptosis protein (XIAP) mRNA and protein were significantly decreased in the spinal cord of symptomatic G93A-SOD1 Tg mice compared with littermates. In contrast, the levels of cIAP-1 mRNA and protein were increased in symptomatic G93A-SOD1 Tg mice, whereas the levels of cIAP-2 mRNA and protein were unchanged. In situ hybridization showed that the expression of XIAP was remarkably reduced in the motor neurons of Tg mice, and the expression of cIAP-1 was strongly increased in the reactive astrocytes of Tg mice. Overexpression of XIAP markedly inhibited the cell death and caspase-3 activity in the neuro2a cells expressing mutant SOD1. Deletional mutant analysis revealed that the N-terminal domain of XIAP, the BIR1-2 domains, was essential for this inhibitory activity. These results suggest that XIAP plays a role in the apoptotic mechanism in the progression of disease in mutant SOD1 Tg mice and holds therapeutic possibilities for FALS.

Amyotrophic Lateral Sclerosis↗

PubMed2002

Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals.

Mutations of the neurofilament-light (NEFL/NF-L) gene were examined in 124 unrelated Japanese patients with Charcot-Marie-Tooth disease (CMT) without known gene mutations, and 248 normal Japanese individuals. A new method, which can detect basepair mismatches with RNase cleavage on agarose gel electrophoresis, coupled with DNA sequencing, identified 8 novel sequence variations in the NF-L gene. In these sequence variants, 5 variants were polymorphisms, including 3 single nucleotide polymorphisms (SNPs), and 3 other missense mutations (Pro22Thr, Asn97Ser and Ala148Val) were found in the patients with CMT phenotype. The variant alleles in the NF-L gene could influence the developing process of CMT phenotype and also might cause CMT phenotype.

Adult↗

PubMed2002

Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.

We investigated the disease progression and survival in 230 Japanese patients with multiple system atrophy (MSA; 131 men, 99 women; 208 probable MSA, 22 definite; mean age at onset, 55.4 years). Cerebellar dysfunction (multiple system atrophy-cerebellar; MSA-C) predominated in 155 patients, and parkinsonism (multiple system atrophy-parkinsonian; MSA-P) in 75. The median time from initial symptom to combined motor and autonomic dysfunction was 2 years (range 1-10). Median intervals from onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were 3, 5, 8 and 9 years, respectively. Patients manifesting combined motor and autonomic involvement within 3 years of onset had a significantly increased risk of not only developing advanced disease stage but also shorter survival (P < 0.01). MSA-P patients had more rapid functional deterioration than MSA-C patients (aid-requiring walking, P = 0.03; confinement to a wheelchair, P < 0.01; bedridden state, P < 0.01), but showed similar survival. Onset in older individuals showed increased risk of confinement to a wheelchair (P < 0.05), bedridden state (P = 0.03) and death (P < 0.01). Patients initially complaining of motor symptoms had accelerated risk of aid-requiring walking (P < 0.01) and confinement to a wheelchair (P < 0.01) compared with those initially complaining of autonomic symptoms, while the time until confinement to a bedridden state and survival were no worse. Gender was not associated with differences in worsening of function or survival. On MRI, a hyperintense rim at the lateral edge of the dorsolateral putamen was seen in 34.5% of cases, and a 'hot cross bun' sign in the pontine basis (PB) in 63.3%. These putaminal and pontine abnormalities became more prominent as MSA-P and MSA-C features advanced. The atrophy of the cerebellar vermis and PB showed a significant correlation particularly with the interval following the appearance of cerebellar symptoms in MSA-C (r = 0.71, P < 0.01, r = 0.76 and P < 0.01, respectively), but the relationship between atrophy and functional status was highly variable among the individuals, suggesting that other factors influenced the functional deterioration. Atrophy of the corpus callosum was seen in a subpopulation of MSA, suggesting hemispheric involvement in a subgroup of MSA patients. The present study suggested that many factors are involved in the progression of MSA but, most importantly, the interval from initial symptom to combined motor and autonomic dysfunction can predict functional deterioration and survival in MSA.

Activities of Daily Living↗

PubMed2002

Mortality and morbidity in peripheral neuropathy associated Churg-Strauss syndrome and microscopic polyangiitis.

OBJECTIVE: Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA) are commonly characterized by systemic necrotizing vasculitis and frequent occurrence of axonal neuropathy. We investigated whether the neuropathy in these 2 diseases reveals differences in clinicopathologic features and predicts survival and functional outcome. METHODS: We compared 30 patients with CSS associated neuropathy with 26 patients with MPA associated neuropathy in terms of clinical, laboratory, electrophysiologic, and outcome data. RESULTS: MPA cases showed a significantly higher age at onset, a higher male/female ratio, and more extensive systemic organ involvement than CSS. Inflammatory markers including antimyeloperoxidase antibody titers were also significantly higher in MPA. Both CSS and MPA showed similar neuropathic symptoms, electrophysiologic findings, and sural nerve biopsy findings representing acute axonal changes. Functional disability assessed by modified Rankin score, muscle strength, and nerve conduction variables were similar in CSS and MPA, both in the acute peak phase and during longterm followup. However, survival was significantly worse in MPA than CSS. CONCLUSION: Neuropathy associated CSS and MPA shared common neuropathic features throughout the course, but systemic organ involvement, inflammatory marker concentrations, and relapse rates were significantly higher in MPA, which showed a poorer survival rate.

Adult↗

PubMed2002

[An autopsied case of dentato-rubro-pallido-luysian atrophy with atypical pathological lesions].

In this paper, atypical pathological findings in a genetic diagnosed case of dentato-rubro-pallido-luysian atrophy (DRPLA) with mild degeneration in the common lesions of the disease is reported. The patient was 59-year-old woman with 31-year history of involuntary movement, ataxia and psychiatric disorders. Her CAG repeat number of DRPLA gene was 68/14. Besides the spongy degeneration in the third and fourth layers of the occipital cortex, severe degenerations were observed in the cerebellar cortex and white matter, inferior olive, posterior funicular nuclei of the medulla oblongata, posterior and lateral funicles of the spinal cord, and Clarke's nucleus. A wide spread distribution of the intracellular polyglutamine aggregation was also showed including both common and uncommon lesions. Genetic diagnosis disclosed a DRPLA case with lesions different from the conventional cases.

Brain↗

PubMed2002

Contrast-enhanced 2D cine phase MR angiography for measurement of basilar artery blood flow in posterior circulation ischemia.

BACKGROUND AND PURPOSE: Dizziness is a symptom that develops with internal ear disturbances and with dysfunctions of the brain stem and cerebellum, in particular with blood flow disturbances of the brain stem and cerebellum (posterior circulation ischemia [PCI]). Patients with PCI often present with various neurologic signs and symptoms. To examine the usefulness of contrast-enhanced 2D cine phase MR angiography in the diagnosis of PCI, we examined quantitative blood flow of the basilar artery in patients with PCI who had primarily complained of dizziness. METHODS: We quantitatively measured the blood flow volume rate of the basilar artery by using a contrast-enhanced 2D cine phase MR angiographic technique in 21 patients diagnosed with PCI and in 16 age- and sex-matched control participants. RESULTS: Maximum and mean average flow velocities of the basilar artery in the PCI group were significantly lower than those of the control group (29.2 +/- 9.2 cm/s versus 38.5 +/- 8.2 cm/s [P <.005] and 18.0 +/- 5.6 cm/s versus 22.6 +/- 5.0 cm/s [P <.01], respectively). The flow volume rates of the basilar arteries were also significantly lower in the PCI group (103.3 +/- 37.3 mL/min versus 148.8 +/- 40.0 mL/min [P <.001]). CONCLUSION: The flow volume rate of the basilar artery in patients with PCI during intermittent ischemic attacks with dizziness was chronically reduced compared with that in the control participants. This suggests that flow volume rates may influence the development of the clinical signs and symptoms of PCI. We think that contrast-enhanced 2D cine phase MR angiography is a valuable method for the diagnosis of PCI.

Adult↗

PubMedDate not supplied

Postgastrectomy polyneuropathy with thiamine deficiency is identical to beriberi neuropathy.

OBJECTIVE: We assessed whether postgastrectomy polyneuropathy associated with thiamine deficiency is clinicopathologically identical to beriberi neuropathy, including a biochemical determination of thiamine status. METHODS: Clinicopathologic features of 17 patients who had postgastrectomy polyneuropathy with thiamine deficiency were compared with those of 11 patients who had thiamine-deficiency neuropathy caused by dietary imbalance. RESULTS: The typical presentation for the two etiologies was as a symmetric sensorimotor polyneuropathy predominantly involving the lower limbs. A variety of clinical features, including neuropathic symptoms, progression, and coexistence of heart failure or Wernicke's encephalopathy, was seen similarly in both conditions. In both groups, the main electrophysiologic findings were those of axonal neuropathy, most prominently in the lower limbs. Sural nerve biopsy specimens also indicated axonal degeneration in both groups. Subperineurial edema was commonly observed. CONCLUSION: This study showed that thiamine-deficiency neuropathies due to gastrectomy and dietary imbalance are identical despite variability in their clinicopathologic features and suggested that thiamine deficiency can be a major cause of postgastrectomy polyneuropathy.

Beriberi↗