Biomedical subjects
Publications and source records attributed to K Arima.
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We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.
Aceruloplasminemia (ACP) is an inherited disorder of iron metabolism caused by the lack of ceruloplasmin activity; the neuropathological hallmarks are excessive iron deposition, neuronal loss, bizarrely deformed astrocytes, and numerous 'grumose or foamy spheroid bodies (GFSBs)'. We histopathologically examined two autopsied ACP brains, and observed for the first time that GFSBs form in clusters at the ends of perivascular astrocytic foot processes. Both the deformed astrocytes and the GFSBs contained ferric iron and were intensely immunolabelled with antibodies against the antioxidant proteins ferritin and manganese superoxide dismutase (Mn SOD). Ceruloplasmin is largely produced by perivascular astrocytes in the central nervous system and exhibits a ferroxidase activity that inhibits iron-associated lipid peroxidation and hydroxyl radical formation; therefore, the lack of ceruloplasmin causes direct oxidative stress on astrocytes. The intense immunolabelling of ferritin and Mn SOD most likely reflects a defensive response to iron-mediated oxidative stress. This study suggests that astrocytes play key roles in iron trafficking and the detoxification of iron-mediated free radicals at the blood-brain barrier and in the parenchyma in ACP brain. The antioxidative ability of astrocytes is one of their essential neuroprotective effects, and the decompensation of this ability may lead to secondary neuronal cell death in ACP.
In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.
Resolution process of cerebroparenchymal amyloid beta-protein (Abeta) deposition has become of increasing interest in the light of recent advance in the Abeta-vaccination therapy for Alzheimer's disease (AD). However, the neuropathological features of degraded and disappearing senile plaque remain poorly characterized, especially in the natural course of the disease. To clarify the natural removal processes of Abeta burden in the brain with AD, we devised a triple-step staining method: Bodian for dystrophic neurites, anti-glial fibrillary acidic protein for astrocytes, and anti-Abeta. We thus examined 24 autopsied AD brains. A novel form of senile plaques, termed 'remnant plaques', was identified. Remnant plaques were characterized by mesh-like astroglial fibrils within the entire plaque part, Abeta deposit debris exhibiting weak Abeta immunoreactivity, and only a few slender dystrophic neurites. In remnant plaques, amyloid burden was apparently decreased. The density of remnant plaques increased significantly with disease duration. Dual-labelling immunohistochemistry revealed many Abeta-immunoreactive granules in astrocytes and a modest number in microglia, both of which accumulated in senile plaques. We consider amyloid deposits of diffuse and neuritic plaques to be shredded by astrocytic processes from the marginal zone of plaques, and to gradually disintegrate into smaller compartments. Cerebroparenchymal Abeta deposits undergo degradation. After a long-standing resolution process, diffuse and neuritic plaques may finally proceed to remnant plaques. Astrocytes are actively engaged in the natural Abeta clearance mechanism in advanced stage AD brains, which may provide clues for developing new therapeutic strategies for AD.
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The incidence of allergic diseases has dramatically increased in recent decades, especially in urban and industrialized areas. It is important socially as well as medically to establish more useful strategies to overcome allergic disorders. Bronchial asthma is a complex disease characterized by airway inflammation involving a Th2-cytokine, interleukin (IL)-13. A substantial body of evidence has accumulated pointing to the pivotal role of IL-13 in the pathogenesis of bronchial asthma, based on mainly analyses of mouse models. In addition to such analyses, the high expression of IL-13 in lesions and genetic association of several genes coding IL-13 signaling molecules with bronchial asthma have raised the possibility that IL-13 plays a pivotal role in the onset or exacerbation of human bronchial asthma. Therefore, IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic agent for bronchial asthma. In this article, we describe how IL-13 is involved in the pathogenesis of bronchial asthma and then how therapeutic agents to block IL-13 signals are developed for bronchial asthma.
BACKGROUND: Although it is thought that both Th1- and Th2-type inflammations are involved in the pathogenesis of atopic dermatitis (AD), it is controversial which immune response is more involved in regulating the clinical severity of AD. We recently found that the squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 are novel biomarkers of bronchial asthma, downstream of IL-4 and IL-13. OBJECTIVE: We examined whether SCCA1 and SCCA2 could also serve as biomarkers of AD, reflecting its Th2-type immune responses, and whether the expression level of SCCA was correlated with clinical severity of AD. METHOD: We compared the expression of SCCA1 and SCCA2 at the mRNA and protein levels in both involved and uninvolved skin of AD patients and in normal control skin. We next analysed induction of SCCA by IL-4 or IL-13 in keratinocytes. Finally, we compared the serum level of SCCA with laboratory parameters reflecting Th2-type inflammation and clinical severity in AD patients. RESULTS: SCCA1 and SCCA2 were highly expressed in involved skin of AD patients, compared with their uninvolved skin, at both mRNA and protein levels. SCCA protein was dominantly expressed in suprabasal keratinocytes in the epidermis of AD patients. Either IL-4 or IL-13, but not IFN-gamma or TNF, induced production of SCCA in keratinocytes. These result suggest that SCCA is induced in AD skin, probably due to direct actions of IL-4 and/or IL-13 on keratinocytes. Serum levels of SCCA were well correlated with eosinophil numbers and serum lactate dehydrogenase levels, and weakly with serum IgE levels, in AD patients. Furthermore, serum levels of SCCA were strongly correlated with clinical severity. CONCLUSIONS: Th2-type inflammation dominantly regulates the clinical severity of AD, and SCCA is a relevant biomarker of AD, reflecting both Th2-type inflammation and clinical severity.
The objective of this study was to detect autoantibodies against granzyme B cleavage products in sera from patients with primary Sjögren's syndrome (SS). Cell lysates derived from human salivary gland (HSG) cell lines were incubated with granzyme B. The susceptibility to the generation of cleavage fragments of SS autoantigens was assayed by immunoblotting using sera from 57 primary SS patients, 17 primary SS patients with malignant lymphoma (ML), 28 systemic lupus erythematosus (SLE) patients, and 20 healthy controls. A 27 kD protein was recognized by serum autoantibodies in 8 (14.0%) of 57 primary SS patients, 5 (29.4%) of 17 SS patients with ML, 2 (7.1%) of 28 SLE patients, but not in 20 normal subjects. This protein was recognized by anti-SSB (La) monoclonal antibodies. Granzyme B-treated recombinant La protein was also shown to migrate as a discrete 27 kD protein by SDS PAGE. Blocking studies demonstrated the existence of an apoptosis-specific B cell epitope present in sera from 2 of 8 primary SS patients and in 2 of 5 primary SS patients with ML which recognized the 27 kD protein. Granzyme B-induced La fragments are generated during cytotoxicity in vitro. This is the first report describing autoantibodies in sera from primary SS patients that specifically recognize fragments of the La protein that are produced by the granzyme B protease.
OBJECTIVES: To characterise serum concentrations of various cytokines and detection by magnetic resonance imaging (MRI) of synovial hypervascularity in patients with remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome before and after corticosteroid treatment. METHODS: Vascular endothelial growth factor(165) (VEGF(165)), tumour necrosis factor alpha (TNFalpha), and interleukin 1beta (IL1beta) were measured by enzyme linked immunosorbent assay (ELISA) in serum samples from three patients with RS3PE syndrome. As controls, serum samples from 26 healthy volunteers, 12 patients with rheumatoid arthritis, 10 patients with systemic lupus erythematosus, 13 patients with polymyositis/dermatomyositis, 13 patients with vasculitis syndrome, and 6 patients with mixed connective tissue disease were also analysed. Synovial hypervascularity of patients with RS3PE syndrome was estimated by rate of enhancement (E-rate) in a dynamic MRI study. RESULTS: Serum concentrations of VEGF(165) (mean (SD) 2223.3 (156.3) pg/ml) were significantly higher in patients with active RS3PE syndrome than in controls before corticosteroid treatment. TNFalpha and IL1beta levels were similar in patients and controls. Synovial hypervascularity in affected joints and subcutaneous oedema decreased during corticosteroid treatment, in parallel with the fall in serum VEGF(165). CONCLUSIONS: VEGF promotes synovial inflammation and vascular permeability in patients with RS3PE syndrome, suggesting that RS3PE can be classified as a VEGF associated disorder.
The squamous cell carcinoma antigen 1 (SCCA1) and SCCA2 are unique serpins that can inhibit cysteine proteinases. SQN-5, their mouse ortholog, has already been identified, and its inhibitory property has been characterized; however, its biological role has remained undefined. Furthermore, no other mouse homolog of SQN-5 has been known. We characterize three mouse members of SCCA-related molecules including SQN-5 in this article. Serpinb3a (SQN-5) and Serpinb3b, but not Serpinb3c, were functional, inhibiting both serine and cysteine proteinases with different inhibitory profiles due to the difference of two amino acids in their reactive site loops. Serpinb3a was ubiquitously expressed in most tissues, whereas expression of Serpinb3b was limited to keratinocytes. Keratinocytes secreted both SCCA-related proteins, Serpinb3a and Serpinb3b. These results indicate that Serpinb3a and Serpinb3b may play different roles by inhibiting intrinsic or extrinsic proteinases with different expression distributions and different inhibitory profiles.
OBJECTIVE: Three critical periods have been suggested for the development of obesity during childhood: fetal, ages 4-6 y, and adolescence. The prevalence of obesity in elementary school children is increasing in Japan, and the present study examines whether this rising prevalence occurs during the elementary school period (age 6-11 y) or is occurring prior to entry into elementary school. DESIGN: Repeated cross-sectional sampling of cohorts of children for the prevalence of obesity. SETTING AND PARTICIPANTS: The data from 81 264 first grade and 87 849 seventh grade children (94 and 87% of the total populations, respectively) between 1989 and 2002 in Kagoshima City were analyzed. Data were also obtained from nationwide surveys published by the Ministry of Japan between 1989 and 2001. MEASUREMENTS: Obesity was defined by the body mass index for an age- and sex-specific 95th percentile cutoff point in Japanese children. Trends in obesity and odds ratios of the prevalence of obesity were also determined. RESULTS: The period 1989-2001/2 showed significant increases in the prevalence of obesity for both genders, in both first and seventh grades, and in both Kagoshima City and nationwide. The odds ratios for the prevalence of obesity of 12-y-old children calculated against the prevalence of obesity within the same cohort at 6 y old revealed that a significant risk for development of obesity during the elementary school years applied only to boys from around 1993 onward in Kagoshima City and applied throughout the study period in nationwide Japan. CONCLUSION: Obesity prevalence increases for boys during elementary school years but does not significantly increase for girls. A rising trend for becoming obese before starting elementary school was present for both boys and girls over the period 1989-2001. Educational programs to improve nutrition and physical activity, especially for boys, are becoming increasingly necessary.
Interleukin-13 (IL-13) is a Th2-type cytokine, secreted from CD4(+) T cells, mast cells, basophils and eosinophils. The human IL-13 gene locates at 5q31, generating a cluster with other Th2-type cytokines such as IL-4 and IL-5. Although the homology between IL-13 and IL-4 at the amino acid level is only about 25%, the IL-13 structure determined by NMR is very similar to that of IL-4. Both cytokines share their receptors and signal pathways, giving these two cytokines similar biological properties. However, the important role of IL-13 in the pathogenesis of bronchial asthma has recently been recognized, based mainly on analyses of mouse models. IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic reagent for bronchial asthma. In this article, we summarize the signal transduction pathway of IL-13, the pathological roles of IL-13 in bronchial asthma and the reagents to inhibit IL-13 signals that are now under development.
The tau N279K mutation was identified in four separately ascertained families in the United States, Japan, and France and in another recently discovered affected individual in Japan. The authors analyzed genealogical and clinical records and DNA samples. Average age at onset was 43 years; survival time was 7 years. All families exhibited similar clinical features, with parkinsonism, dementia, and supranuclear palsy uniformly seen. A founder effect indicated by a shared disease haplotype was seen only in two Japanese families. The N279K mutation can develop independently in different parts of the world.
The incidence of allergic diseases has dramatically increased in recent decades, and it is socially and medically important to establish more useful strategies to overcome allergic disorders. Various kinds of drugs are utilized for allergic patients; however, some cases are unresponsive to these drugs and in others there are undesired adverse effects. On the other hand, a substantial body of evidence has accumulated pointing to the pivotal role of Th2-cytokines, interleukin (IL)-4, and IL-13, in the pathogenesis of bronchial asthma. The evidence is categorized as (1) expression of these cytokines in the bronchial lesions, (2) genetic association of the signaling molecules of these cytokines, (3) analyses of mouse models. In addition, the molecular mechanism of the signal transduction of these cytokines has also been well characterized. Based on such information, IL-4 and IL-13 have emerged as promising means of improving allergic states, and several IL-4/IL-13 antagonists have been developed, among which soluble IL-4 receptor is now in human trials. Identifying the structure of the IL-13 variant and of the IL-4/IL-13-inducing genes would be of great use. It is expected that in the near future, several drugs will emerge based on these strategies, which will give us wider choice in treating patients, depending on the pathogenesis of the diseases.
Radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) therapy are currently used for the treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the usefulness of combination therapy of PEI and RFA (PEI-RFA). Seventy-three patients with biopsy-proven HCC and liver cirrhosis underwent RFA after a bolus injection of ethanol into HCC. The volume of coagulated necrosis in the liver caused by PEI-RFA was estimated and compared with that by RFA alone. Coagulated necrosis areas in the liver of patients treated with PEI-RFA were significantly larger than those of patients treated with RFA alone. In PEI-RFA group, the volume of coagulated necrosis was significantly correlated with the amounts of ethanol injected into HCC. No major complications were observed during and after the PEI-RFA treatment. These results indicate that PEI-RFA is more effective than RFA alone and can make dramatic improvement of therapeutic effects in RFA therapy for HCC with fewer sessions of treatments. Therefore, PEI-RFA is considered to be a practical and promising option and may open up new avenues for the treatment of HCC.