[Treatment of immunologic nervous system diseases by using anti-adhesion molecule antibodies].
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Animals↗
Biomedical subjects
G Sobue
Publications and source records attributed to G Sobue.
Cervical spondylotic amyotrophy. Magnetic resonance imaging demonstration of intrinsic cord pathology.
STUDY DESIGN: Three case reports. OBJECTIVE: To elucidate the pathophysiology of cervical spondylotic amyotrophy. SUMMARY OF BACKGROUND DATA: Cervical spondylotic amyotrophy is the clinical syndrome in cervical spondylosis characterized by severe muscular atrophy in the upper extremities, with an absent or insignificant sensory deficit. Pathophysiology of this particular syndrome has not been well understood. METHODS: Three cases of cervical spondylotic amyotrophy are presented in which magnetic resonance imaging confirmed the intrinsic cord disease as the cause of the syndrome. RESULTS: The patients had segmental muscular atrophy of the proximal upper extremities, with an absent or insignificant sensory deficit. After initial disease progression, the symptoms stabilized for years. Sagittal T2-weighted magnetic resonance images showed multi-segmental linear high-signal intensity within the compressed spinal cord. These high-signal intensity lesions appeared to be located at the anterior horns on axial images. The spinal cord compression was less severe in the neck-neutral position, but spinal canal stenosis increased when the neck was extended. CONCLUSIONS: The results suggest that one pathophysiology of this syndrome may be multisegmental damage to the anterior horns caused by dynamic cord compression, possibly through circulatory insufficiency.
Aged↗
Clinicopathological features of chronic inflammatory demyelinating polyradiculoneuropathy in childhood.
The clinical, electrophysiological, and pathological findings, and the therapeutic characteristics in ten children with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), whose onset age was less than 16 years, were evaluated. The clinical progression pattern of the initial phase divided the patients into two groups. One group (six patients) showed a subacute progression for up to 2 months after onset and a subsided progression over 3 months. Three patients in this group had a preceding febrile episode. The other group (four patients) showed a chronic insidious progression for more than 3 months. The former group of patients revealed a favourable response to corticosteroid therapy as compared with the latter group. However, other clinical and laboratory features at the peak impairment were not distinguishable between these two groups. Motor dominant neuropathy was common to all patients, and only three cases showed sensory disturbance on the distal limbs. No cases revealed cranial nerve involvement. Motor and sensory nerve conduction and sural nerve biopsy studies revealed the demyelinating nature of the neuropathy. These clinicopathological features suggest that the subacute progression form frequently associated with prodromal episode and rather favourable corticosteroid response is characteristic in childhood CIDP, while the chronic insidious progression form is indistinguishable from the common adult CIDP.
Adolescent↗
Chronic inflammatory demyelinating polyradiculoneuropathy with diffuse and massive peripheral nerve hypertrophy: distinctive clinical and magnetic resonance imaging features.
We present 3 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with extensive and diffuse hypertrophy of the nerve roots and peripheral nerves. They exhibited slowly progressive sensory impairment and distally predominant limb weakness and muscular atrophy, and markedly enlarged palpable nerve trunks. They responded beneficially to corticosteroid. Magnetic resonance imaging demonstrated diffuse and extensive hypertrophy of the peripheral nerves in the four limbs and the spinal nerve roots, with gadolinium enhancement in the nerve roots but not in the peripheral nerves. These patients were considered to have a hypertrophic variant of CIDP.
Aged↗
Clustering of CMT1A duplication breakpoints in a 700 bp interval of the CMT1A-REP repeat.
The CMT1A-REP repeat is proposed to mediate unequal crossover leading to a 1.5 Mb duplication in chromosome 17p11.2-12 associated with Charcot-Marie-Tooth neuropathy type 1A (CMT1A). There is an apparent recombinational "hotspot" in the CMT1A-REP repeat since the majority of crossover breakpoints for CMT1A are located within a 1.7 kb interval. Further to characterize the crossover breakpoint region, we constructed PCR primers that specifically amplify the duplication breakpoint junctions in a series of Japanese and Caucasian CMT1A patients. We mapped the breakpoints in 89% of patients within a 700 bp interval of the CMT1A-REP repeat. This 700 bp region is 1.3 kb telomeric to a previously described mariner-like transposable element. Our observations further define the location of crossovers for CMT1A and provide additional evidence that this region is a recombinational "hotspot" within the CMT1A-REP repeat.
Asian People↗
Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy.
Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated nuclear inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR-bearing nuclear inclusions are present in SBMA.
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Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer's disease brain.
In the previous study [Takeda et al. (1996) Neurosci Lett 221: 17-21], we reported that the advanced glycation end products (AGEs) in the external space of neuronal perikarya (extraneuroperikaryal AGE deposits) were significantly abundant in the Alzheimer's brain. In this study, we investigated the spatial relationship of the extraneuroperikaryal AGE (carboxymethyllysine and pentosidine) deposits in astrocytes and microglial cells in the Alzheimer's disease brain using double immunolabelling for AGEs and astrocyte or microglial cell markers. Most of the extraneuroperikaryal AGE deposits were co-localized with glial fibrillary acidic protein-positive astrocytes. AGE deposit-bearing astrocytes also contained Gomori-positive granules. Furthermore, some of the extraneuroperikaryal AGE deposits were co-localized with microglial cells. These extraneuroperikaryal AGEs may activate astrocyte and microglia, and play a role in pathogenesis of Alzheimer's disease.
Aged↗
Expression of low-affinity neurotrophin receptor p75NTR in the peripheral nervous system of human neuropathies.
Expression of low-affinity neurotrophin receptor (p75NTR) was immunohistochemically examined in the peripheral nerve trunks, dorsal root ganglia, sympathetic nerve ganglia and spinal cords in various human neurological diseases manifesting peripheral neuropathies. p75NTR was expressed in the nerves with axonal degeneration, and was also prominent in the nerves with newly regenerating axons. In contrast, axonal pathology tended to reduce the expression of p75NTR in the neuronal perikarya of the dorsal root ganglion and sympathetic nerve ganglion neurons. In the ventral and lateral horn cells, the p75NTR immunoreactivity was not detected in the normal and diseased nerves except for amyloid polyneuropathy. These p75NTR expressions in the diseased human peripheral nervous tissues would be regulated by an underlying pathology-related process, and could play a role in peripheral nerve repair.
Aged↗
Tissue distribution of pathological lesions and Hu antigen expression in paraneoplastic sensory neuronopathy.
We investigated the distribution of lesions and Hu antigen expression in two autopsied cases of anti-Hu antibody-positive paraneoplastic sensory neuronopathy (carcinomatous subacute sensory neuropathy). Pathological changes in both patients were limited to the primary sensory neurons, some of the sympathetic ganglia and hippocampal regions. The lesions showed a multifocal distribution that differed among the spinal segmental levels and in the individual dorsal root ganglia as well as in the nerve fascicles. Western blot analysis of the patients' serum revealed that Hu antigens were extensively and widely expressed throughout the central nervous system, sensory and sympathetic ganglia and cancer cells, but not in the non-neural visceral tissues. Reverse transcriptase-polymerase chain reaction also showed that the Hu D, Hu C, Hel-N1 and Hel-N2 mRNAs were extensively and widely expressed through the neural tissues and cancer cells, but not in the visceral tissues. Thus, the distribution of antigen expression was very different from that of the lesions. Taken together with the distribution of lesions and Hu antigen expression, it is suggested that factors other than anti-Hu antibodies are also involved in the pathogenesis of this neuronopathy.
Adenocarcinoma↗
Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy.
Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of nuclear inclusions of spinal and bulbar muscular atrophy. Nuclear inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar nuclear inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural inclusions. These findings indicate that nuclear inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural nuclear inclusions.
Aged↗
Auditory and visual event-related potentials and flash visual evoked potentials in Alzheimer's disease: correlations with Mini-Mental State Examination and Raven's Coloured Progressive Matrices.
We investigated possible correlations among neurophysiological examinations [auditory and visual event-related potentials (A-ERPs, V-ERPs), and flash visual evoked potentials (F-VEPs)] and neuropsychological tests [Mini-Mental State Examination (MMSE) and Raven's Coloured Progressive Matrices (RCPM)] in 15 subjects with probable or possible Alzheimer's disease (AD) according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The P300 latency of A-ERPs was correlated with the scores of MMSE but not with those of RCPM. The P300 latency of V-ERPs was more significantly correlated with the scores of RCPM than with those of MMSE. The P2 latency of F-VEPs was more significantly correlated with the scores of RCPM than with those of MMSE. The P2 latency of F-VEPs was not correlated with the P300 latency of A-ERPs but was correlated with the P300 latency of V-ERPs. The close relationship among V-ERPs, F-VEPs and RCPM suggests that these examinations at least partly reflect the functions of visual association areas in AD. Furthermore, discrepancy between P300 latency by A-ERPs and V-ERPs suggests that the mechanism responsible for P300 generation is not identical between these two stimulus modalities.
Aged↗
Suppressive effects of 4-acetylaminophenylacetic acid (actarit) on experimental autoimmune encephalomyelitis in rats.
To elucidate the efficacy of 4-acetylaminophenylacetic acid (actarit), an anti-rheumatic drug, on neuroinflammatory diseases such as multiple sclerosis, the effects of actarit on both actively induced and adoptively transferred experimental autoimmune encephalomyelitis (EAE) were studied. Daily intraperitoneal administration of actarit during the effector phase of active EAE and transferred EAE suppressed the clinical manifestation and pathological findings of EAE at doses of 300 mg/kg or higher. The percentages of CD4 and CD25 positive cells in the infiltrating cells in the CNS were reduced by this treatment. Semi-quantitative cytokine analysis revealed that the mRNA expression of TNF-alpha and INF-gamma in spinal cords and spleens of actarit treated active EAE rats was significantly reduced compared with vehicle treated EAE rats. The mRNA expression of IL-10 on day 17 in spleens of actarit-treated EAE rats was significantly upregulated. Actarit is potentially useful for the treatment of neuroimmunological disorders, such as multiple sclerosis.
Amino Acid Sequence↗
Control of upright standing posture during low-frequency linear oscillation.
We examined the effects of anteroposterior movement of a sled on human upright standing. Each of six healthy men stood on the platform of a sled in the dark. The sinusoidal acceleration was provided, from 0.02 to 0.04 G, followed by 0.06 and 0.08 G, at a stroke length from 6 to 10 m and then to 14 m. Low acceleration (0.02 and 0.04 G) induced body sway, pivoting on the ankle joint. High acceleration (0.06 and 0.08 G) increased body sway, but the head-neck joint remained locked upright. The electromyographic recordings of the lower leg muscles revealed continuous tonic EMG activities of the gastrocnemius and tibialis anterior muscles at acceleration of 0.02 and 0.04 G, while reciprocal activation was observed at 0.06 and 0.08 G. During head movement, the neck muscles were slightly activated tonically at acceleration of 0.02 and 0.04 G, but they were markedly and tonically activated at 0.06 and 0.08 G. We speculate that the sled oscillation caused body sway in proportion to the acceleration, with the ankle joint playing a principal role. Analysis of neck movement also revealed that the head was held in a fixed upright position, indicating that the vestibulocollic reflex might tonically activate the neck muscles.
Acceleration↗
Nerve growth factor maintains regulation of intracellular calcium in neonatal sympathetic neurons but not in mature or aged neurons.
We examined the effects of nerve growth factor on the regulation of intracellular calcium levels of superior cervical ganglion neurons in terms of postnatal maturation and ageing. Rat superior cervical ganglion neurons from three age groups (neonatal: 0 to one-day-old, young adult: three to six-month-old, and aged: more than 24-month-old) were dissociated and cultured in the presence or absence of 100 ng/ml of nerve growth factor. Intracellular free calcium levels ([Ca2+]i) were measured using the fura-2 microfluorometry. Nerve growth factor treatment increased the resting [Ca2+]i of neonatal neurons, although it had no effect on those of mature and aged neurons. We further examined the effects of nerve growth factor on the transient increase of [Ca2+]i induced by methacholine (0.1 mM), caffeine (20 mM) or high-potassium medium (40 mM K+). Nerve growth factor pre-treatment significantly increased the population of neonatal superior cervical ganglion neurons which responded to methacholine, whereas almost all young adult and aged neurons responded to methacholine regardless of pre-treatment of nerve growth factor. Caffeine induced a cyclic alteration of [Ca2+]i (oscillation) in 45% of the neonatal superior cervical ganglion neurons when they were maintained without nerve growth factor, but nerve growth factor treatment suppressed the oscillation to 10% of neurons. In contrast to neonatal neurons, all of the young adult and aged neurons showed only a transient increase of [Ca2+]i in response to caffeine independent of nerve growth factor treatment. There was no significant effect of nerve growth factor on K+ depolarization-induced [Ca2+]i elevations at any of the ages studied. Nerve growth factor did not substantially alter the pattern of the transients induced by these three agents. Our results indicate that exogenous nerve growth factor is necessary to maintain normal acetylcholine receptor-mediated [Ca2+]i responses as well as Ca(2+)-induced Ca2+ release from intracellular calcium storage in neonatal superior cervical ganglion neurons. In mature superior cervical ganglion neurons, Ca2+ homeostasis becomes independent of exogenous nerve growth factor, and Ca2+ homeostasis and its independency are well preserved in aged neurons.
Aging↗
Expression of mRNAs for neurotrophins (NGF, BDNF, and NT-3) and their receptors (p75NGFR, trk, trkB, and trkC) in human peripheral neuropathies.
The steady-state mRNA levels of NGF, BDNF and NT-3, and the mRNA levels of their receptors p75NGFR, trk, trkB, and trkC were examined in various human peripheral neuropathies, to determine the correlation with myelinated fiber pathology and T cell and macrophage invasions in the diseased nerves. Steady state levels of p75NGFR mRNAs were significantly elevated in nerves with axonal pathology. In contrast, steady state levels of trkB and trkC mRNA levels were diminished. trk mRNA was not detected in the human nerves. The NGF, BDNF, and NT-3 mRNA levels were elevated in the diseased nerves. The increase in BDNF and NT-3 mRNA levels were proportional to the extent of invasion of the nerves by T cells and macrophages, but did not directly correlate with axonal nor demyelinating pathology, thus suggesting that inflammatory cell invasions are involved in the regulation of BDNF and NT-3 mRNA expressions. These neurotrophin and their receptor gene expressions in the diseased human nerves would be regulated by an underlying pathology-related process, and could play a role in peripheral nerve repair.
Brain-Derived Neurotrophic Factor↗
Somatic mosaicism of the expanded CAG trinucleotide repeat in mRNAs for the responsible gene of Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA).
The CAG trinucleotide repeats in mRNAs for the responsible genes of Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and X-linked spinal and bulbal muscular atrophy (SBMA) were examined in various neural and nonneural tissues of affected individuals. The tissue-specific variation of expanded CAG repeat alleles were apparent for mRNAs of all three genes. The expanded CAG repeats of the mRNA were shorter in the cerebellum than in other regions of the central nervous system in DRPLA and MJD, but not in SBMA, and were longer in the liver and colon in MJD. Transcripts of the responsible genes with expanded CAG repeats were detected in all tissues studied, and the tissue-specific variation in the CAG repeat size of the mRNA did not correlate with the tissue-specific severity of pathological involvement in these diseases.
Adult↗
Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6.
Using a molecular diagnostic approach, we investigated 101 kindreds with autosomal dominant cerebellar ataxias (ADCAs) from the central Honshu island of Japan, including spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease (MJD), dentatorubral and pallidoluysian atrophy (DRPLA) and spinocerebellar ataxia type 6 (SCA6). In our unselected series, MJD was the most common type of ADCA, accounting for 33.7% followed by DRPLA (19.8%), SCA2 (5.9%) and SCA6 (5.9%). No SCA1 mutations were identified. We analysed the clinical features of six molecular confirmed SCA6 kindreds: in each family, there was an expanded allele in the alpha1A-voltage dependent calcium channel comprising between 23 and 25 CAG repeats. The mean age at onset of symptoms was 43+/-13 years. The clinical features consisted predominantly of cerebellar ataxia, dysarthria and horizontal nystagmus, which was generally consistent with ADCA type 3. However several new clinical features were found in some patients: dramatic anticipation, rapid disease progression, severe ataxia associated with action tremor or action myoclonus, and very early onset, which are not described as the classical features of ADCA type 3.
Adult↗
A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).
Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.
Adult↗