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Biomedical subjects

Seiji Kikuchi

Publications and source records attributed to Seiji Kikuchi.

At least 19 recordsLinked to original sources
PubMed2003

The prevalence and clinical characteristics of MS in northern Japan.

In Japan, there is a low prevalence rate (PR) of multiple sclerosis (MS; 0.8-4.0/100,000) but a relatively high frequency of "optic-spinal form" MS (OS-MS). There have been no intensive epidemiologic frequency studies, however, in over 30 years. We performed a province-wide prevalence study of MS in the Tokachi province of Hokkaido, the northernmost island of Japan, and compared the observed clinical features with other populations in Japan and Western countries. Prevalence was determined on March 31, 2001. The primary sources for the case ascertainment were 13 hospitals that treated patients with neurologic diseases including MS in Tokachi. Patients were classified according to Poser's criteria. The prevalence rate of clinically definite or laboratory-supported definite MS (LSDMS) was 8.57 per 100,000 [31/361,726; male/female ratio=1:2.9, and age at onset=29.1+/-14.2 (mean+/-SD) years]. Out of the 31 patients, 5 (16%) were classified as OS-MS. The prevalence rate of MS in the Tokachi province was the highest reported in Orientals to date, although still low in comparison with Western communities at a similar latitude. In contrast to the previous reports in Japan, there was a relatively low frequency of OS-MS in Hokkaido.

Adolescent↗
PubMed2003

Deficits of working memory during mental calculation in patients with Parkinson's disease.

Using the dual task paradigm, previous studies have suggested that working memory (WM) deficit is due to depleted attention resources in patients with Parkinson's disease (PD). The aim of this study is to establish whether the WM problems in PD are due to reduced attentional set-shifting resources rather than depletion of attention resources. The task design attempts to eliminate confounding of the deficits in dealing with novel material, a problem documented in PD, by concentrating on WM tasks of mental calculation that are familiar to subjects in daily living. We also administered attention tasks, the Trail Making Test (TMT) that relies primarily on attentional set-shifting and the Kana (Japanese syllabogram) Pick-out Test instead primarily depending on depleted attention resources for allocation. A total of 24 patients with PD and 24 normal controls participated in this study. The PD group showed deficits in mental calculation span and in attentional set-shifting in the TMT-b.Considering the common deficits in alternating processing of mental calculation and TMT-b in PD, the results suggested that the central executive dysfunction in PD during mental calculations was due to reduced attentional set-shifting resources for rapidly alternating operations, rather than the depletion of attentional resources.

Adult↗
PubMed2003

The writing of arabic numerals, kanji, and kana in brain-damaged patients.

This study investigated the neural mechanisms involved in the writing of Arabic numerals, kanji, and kana. Tasks involving writing numerals in Arabic, kanji, and, kana were administered to four patients with Gerstmann's syndrome and to five Wernicke aphasics. The results indicated that the ability to write Arabic numerals was well preserved in the Wernicke aphasics despite their serious phonological disturbances. The patients with Gerstmann's syndrome, who have a deficit with the concept of number, could write kanji numerals better than Arabic and kana numerals. Unlike Arabic numerals (ideogram) and kana (syllabogram), kanji (morphogram) have both semantic and phonetic values. The results suggested that Arabic numerals may be somesthetic and linked directly to the concept of number bypassing phonological analysis.

Aged↗
PubMed2003

Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons.

Proteasomal dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). We examined the effect of a selective proteasomal inhibitor, epoxomicin, on primary cultured mesencephalic neurons. Exposing rat cultured mesencephalic neurons to epoxomicin for 24 h resulted in neurotoxicity in a dose-dependent manner. Epoxomicin caused mitochondrial dysfunction, reduction in reduced glutathione (GSH), and increased generation of free radicals. Neuronal damage was significantly blocked by antioxidative/GSH-augmenting agents. Epoxomicin also increased the expression of Bax and decreased that of Bcl-2, which may cause mitochondrial dysfunction and release of free radicals. Dopaminergic neurons were preferentially resistant to the toxicity of epoxomicin. Inhibiting the synthesis of tetrahydrobiopterin (BH(4)), which has been reported to have antioxidative function, increased the susceptibility of dopaminergic neurons, whereas increasing BH(4) levels protected non-dopaminergic neurons. These findings suggest that BH(4) is at least in part a contributing factor to grand the resistance to dopaminergic neurons against epoxomicin neurotoxicity. Our results suggest that proteasome inhibition causes the neurotoxicity in mesencephalic neurons, but that is not sufficient to reproduce the selective damage to dopaminergic neurons, such as that seen in PD.

Animals↗
PubMed2003

Brefeldin A-induced neurotoxicity in cultured spinal cord neurons.

Brefeldin A (BFA) is a fungus metabolite that is known to cause the disassembly of the Golgi complex and apoptosis in exposed cells, both of which have been suggested as playing roles in the pathogenesis of neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS). This study showed that BFA caused neurotoxicity and apoptotic nuclear changes in cultured spinal neurons of rat spinal cord in a dose- and time-dependent manner. The spinal motor neurons were more vulnerable to this neurotoxicity. The cultured spinal neurons showed irreversible disassembly of the Golgi apparatus as early as 1 hr after exposure to BFA. BFA induced the expression and activation of caspase-12 beginning 8 hr after exposure. The level of the cleaved form of caspase-3 had increased 12 hr after the addition of BFA. Free radical generation and loss of mitochondrial membrane potential were observed in the later stages of neurotoxicity caused by BFA. Collectively, our data suggests that BFA is an excellent agent for reproducing the pathophysiological features of ALS. This in vitro model may be useful in attempts to study the mechanisms of this neurodegenerative disease and to examine therapeutic potentials.

Animals↗
PubMed2003

Glycation--a sweet tempter for neuronal death.

Glycation, one of the post-translational modifications of proteins, is a nonenzymatic reaction initiated by the primary addition of a sugar aldehyde or ketone to the amino groups of proteins. In the early stage of glycation, the synthesis of intermediates leading to the formation of Amadori compounds occurs. In the late stage, advanced glycation end products (AGE) are irreversibly formed after a complex cascade of reactions. Several AGEs have been characterized chemically, while other new compounds remain to be identified. To date, studies of the contribution of glycation to diseases have been primarily focused on its relationship to diabetes and diabetes-related complications. However, glucose-induced damage is not limited to diabetic patients. Although it does not cause rapid or remarkable cell damage, glycation advances slowly and accompanies every fundamental process of cellular metabolism. It has recently become clear that glycation also affects physiological aging and neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Glycation alters the biological activity of proteins and their degradation processes. Protein cross-linking by AGE results in the formation of detergent-insoluble and protease-resistant aggregates. Such aggregates may interfere with both axonal transport and intracellular protein traffic in neurons. In addition, glycation reactions lead to the production of reactive oxygen species. Conversely, glycation is promoted by oxidative stress. We speculate on the presence of synergism between glycation and oxidative stress. In this review, we provide an outline of glycation and propose some possible mechanisms of its cytotoxicity and defense systems against it.

Animals↗
PubMed2003

Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients.

Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN are present in brains of patients with multiple sclerosis (MS). The aim of this study was to investigate the role of OPN genes in the pathogenesis of MS. Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C genotype at the 8090th position in exon 6 was more prevalent in MS than in control (p<0.0001), and C allele was more prevalent in MS than in control (p<0.0001, OR=2.57, 95% CI=1.65-4.00). For the 9583rd position polymorphism in exon 7, patients with G/G genotype (age; 32.1+/-12.5 years, mean+/-S.D.) showed a later disease onset than G/A (age; 25.9+/-7.8 years, p=0.01) and A/A (age; 25.2+/-8.9 years, p=0.01) genotypes. There were no significant correlations between OPN gene polymorphisms and disease progression. Our results suggest that the 8090th polymorphism might be associated with susceptibility to MS, while the 9583rd polymorphism might be associated with age of onset of MS.

Adult↗
PubMed2003

Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis.

The molecular mechanisms for the interferon beta (IFNbeta) treatment of multiple sclerosis (MS) remain to be characterized. Using cDNA microarray technology, we have compared the gene expression profile of T and non-T cells derived from relapsing-remitting MS before and after treatment with IFNbeta-1b. IFNbeta treatment significantly altered expression of 21 genes out of 1263 at 3 and 6 months after treatment. These genes included nine with IFN-responsive promoter elements. Whereas there was no change in Th1 or Th2 marker genes, some of the changes were unexpected but coincided with the beneficial effect of IFNbeta in MS.

Adult↗
PubMed2003

Primary CD30/Ki-1 positive anaplastic large cell lymphoma of the central nervous system occurring in a patient with a seventeen-year history of essential thrombocythemia.

We present a rare case of central nervous system lymphoma that occurred in a patient who had essential thrombocythemia for 17 years. MRI examinations disclosed multiple ring-enhanced lesions that had shown bilateral spreading in the different period. Pathological examinations confirmed CD30/Ki-1-positive ALK negative anaplastic large cell lymphoma. The possible pathogenic mechanisms of this disease are discussed.

Brain Neoplasms↗
PubMed2003

Neurotoxicity of acetaldehyde-derived advanced glycation end products for cultured cortical neurons.

The Maillard reaction that leads to the formation of advanced glycation end products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients, in aging, and in neurodegenerative processes. We hypothesize that acetaldehyde (AA), one of the main metabolites of alcohol, may be involved in alcohol-induced neurotoxicity in vivo by formation of AA-derived AGEs (AA-AGEs) with brain proteins. Incubation of cortical neurons with AA-AGE produced a dose-dependent increase in neuronal cell-death, and the neurotoxicity of AA-AGE was neutralized by the addition of an anti-AA-AGE-specific antibody, but not by anti-N-ethyllysine (NEL) antibody. The AA-AGE epitope was detected in human brain of alcoholism. We propose that the structural epitope AA-AGE is an important toxic moiety for neuronal cells in alcoholism.

Acetaldehyde↗
PubMed2003

[Age-related working memory decline in patients with Parkinson's disease].

The purpose of this study was to investigate the age-related working memory(WM) decline in patients with Parkinson's disease(PD) using Baddeley's WM model. This model consists of the central executive (CE) and two slave systems, the phonological loop (PL) for the storage of verbal materials, and the visuospatial sketchpad(VSSP) for the storage of visuospatial information. The participants of this study were 22 PD, 11 old (age of 68-78, mean age, 70.5) and age of onset, duration of illness, medication time, and Yahr stage, global cognitive status-matched 11 young(age of 39-58, mean age, 51.5) PD, age- and educational years, global cognitive status-matched 22 normal control (NC), 11 old(age of 65-78, mean age, 70.4) and 11 young(age of 45-57, mean age, 52.4). Mental calculation span of digit sequences, digit forward and backward span, visual memory span were carried out. Age related decline of WM was found in both groups, but processing related differences were revealed between the two groups. NC group showed significant decline with aging in digit backward span. In contrast, in mental calculation span, PD groups showed significant deficit revealed in young PD group and declined significantly with aging and significant decline was not found in digit backward span. In term of the processing and difficulty of WM tasks, digit backward span that needs maintenance of digit sequences and re-ordering, was more difficult than mental calculation that needs maintenance of digit sequences, summation of the digit and updating of the results. There were not significant differences between four groups in digit forward span, visual memory span. The results indicated that the WM span in normal aging declined as task difficulty increased. Their performance decline may be caused by the CE dysfunction. On the other hand, PD showed a characteristic CE deficit observed in mental calculation even in young age and decline with aging. Such decline may be caused by peculiar processing related dysfunction of CE that assumes to be essential deficit of PD.

Adult↗
PubMed2003

[Susceptibility genes for multiple sclerosis].

Multiple lines of evidence support the role of genetic factors for susceptibility to multiple sclerosis (MS), although unknown environmental factors must play an important role in developing MS. In this paper, we review the reports studied for the possible associations between Japanese MS and candidate genes by using case-control method. As for HLA alleles, HLA-DRB1*1501 and -DPB1*0501 allele have been confirmed to be associated with conventional MS and opticospinal MS, respectively. Some polymorphisms of vitamin D receptor gene, estrogen receptor gene, CTLA-4 gene, and osteopontin gene were reported to be associated with conventional MS. Appropriate case ascertainment and collection as well as proper statistical method are needed to isolate the susceptibility genes for MS.

Alleles↗
PubMed2003

[IL-18 in multiple sclerosis].

IL-18, previously named interferon-gamma inducing factor, is produced by monocytes/macropharges, dendritic cells, B cells and other APC cells as well as by astrocytes, microglia. IL-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Caspase-1 regulates the cellular export of IL-18. Anti IL-18 antibodies prevent EAE. IL-18 directs autoreactive T cells and promotes autodestruction in CNS via induction of IFN-gamma by NK cells in EAE. IL-18 is expressed in MS plaque. Common IL-18 promoter polymorphisms influence the expression on IL-18. IL-18 is linked to raised IFN-gamma in MS and is induced by activated CD4(+) T cells via CD40-CD40 ligand interaction. IL-18 in MS is suppressed by treatments such as GA and IFN-beta.

Adjuvants, Immunologic↗
PubMed2002

An assessment of the association between IL-2 gene polymorphisms and Japanese patients with multiple sclerosis.

Interleukin-2 (IL-2) is a cytokine intimately involved with both the function and regulation of the immune system. Genetic analysis of experimental autoimmune encephalomyelitis (EAE) provides strong evidence supporting the candidacy of IL-2 as a susceptibility gene. We investigated the association of two single nucleotide polymorphisms (SNPs) at position -384 in the promoter region and +114 in the first exon of the IL-2 gene through a case-control study involving 113 Japanese patients with multiple sclerosis (MS) and 118 healthy controls. Our results showed no significant differences in the distribution of the two polymorphisms between MS patients and controls. Furthermore, no association was observed between IL-2 gene polymorphisms and clinical characteristics, such as clinical course and age at disease onset. Together, our findings suggest that IL-2 gene polymorphisms do not influence the susceptibility to MS or the clinical characteristics of MS in Japanese patients.

Adult↗
PubMed2002

Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vitro.

We have previously shown that advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate in diabetes, induced angiogenesis through overgeneration of autocrine vascular endothelial growth factor (VEGF). In the present study, effects of incadronate disodium, a nitrogen-containing bisphosphonate on AGE-elicited angiogenesis in vitro, were studied. Incadronate disodium was found to completely inhibit AGE-induced increase in DNA synthesis as well as tube formation of human microvascular endothelial cells (EC). Furthermore, incadronate disodium significantly prevented transcriptional activation of nuclear factor-kappaB and activator protein-1 and the subsequent up-regulation of VEGF mRNA levels in AGE-exposed EC. Farnesyl pyrophosphate, but not geranylgeranyl pyrophosphate, was found to completely restore the anti-angiogenic effects of incadronate disodium on EC. These results suggest that incadronate disodium could block the AGE-signaling pathway in microvascular EC through inhibition of protein farnesylation. Incadronate disodium may be a promising remedy for treatment of patients with proliferative diabetic retinopathy.

Animals↗