Neuronal intranuclear inclusions in spinocerebellar ataxia type 2.
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Humans↗
Biomedical subjects
K Iwabuchi
Publications and source records attributed to K Iwabuchi.
[ADL and actual life styles of all Japanese centenarians as determined by a visitation interview survey].
A visiting interview survey was performed on all centenarians living in Japan to investigate their Activities of Daily Life (ADL). 2,851 centenarians, 92.9% of all subjects completed the interview. They were divided into three groups, good ADL (almost independent in daily life), moderate ADL (almost independent in indoor life), and inferior ADL (bed fast) by the condition of ADL. Some factors of health conditions, family size, frequency of use of public welfare services, and life styles were compared among these three groups. Both the good and the moderate ADL groups accounted for about 20% each, and the inferior ADL group was about 60% of the subjects. The condition of ADL of men was better than that of women. The inferior ADL group showed a significantly higher percentage of chronic diseases. High ratios of cerebral vascular disease and dementia were seen in this group, and many had no teeth. While two thirds of all the centenarians lived at home, over 90% of the good ADL group lived at home. The mode of family size was three including the person oneself. An average of 21% of men and 27% of women used public health welfare services. However 40% of the centenarians in the inferior ADL group used those services. Men had better dietary habits for health than women. The good ADL group showed the most desirable dietary habits among the three groups and had the highest percentage of drinkers and smokers. Men practiced a greater number of ideal habits for longevity than women. Of the ADL groups, centenarians in the good ADL group had the highest percentage of ideal habits for longevity. The centenarians who maintained good ADL had the following characteristics: There were fewer people under medical treatment. They had maintained their own teeth. Almost all of them were living at their home with their family. They had continued good dietary habits and daily life for health and longevity. For the maintenance and improvement of ADL of centenarians, adequate social welfare support in a local area for centenarians and their family seemed to be vital in addition to health management and guidance of healthy life style of the aged.
Activities of Daily Living↗
Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15A13-15.
To date, three loci for autosomal recessive hereditary spastic paraplegia (ARHSP) linked to chromosomes 8p12-q13, 16qter, and 15q13-15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the "complicated" form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12-q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13-15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3-centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive spastic paraplegia, maps to chromosome 15q13-15.
Adolescent↗
Age-associated increase of basal corticosterone levels decreases ED2high, NF-kappaBhigh activated macrophages.
The proportion of cells with a high density of ED2 (ED2high cells) in peritoneal cells from old rats was significantly lower than that from young rats. The expression of major histocompatibility complex class II (MHC class II) molecules, the antigen presentation, production of interleukin (IL)-1beta and IL-6, and nuclear factor-kappaB activity in ED2high cells were markedly higher than those in cells with a low density of ED2 (ED2low cells), although no significant difference was observed in the expression of MHC class II molecules and the antigen presentation between ED2high cells from young and old rats. Meanwhile, basal corticosterone concentration in serum and glucocorticoid (GC) receptor mRNA expression in peritoneal cells increased significantly in old rats. The proportion of ED2high cells was increased by adrenalectomy in young rats. Furthermore, nuclear translocation of GC receptor was observed in ED2low cells, whereas GC receptor was detected in cytoplasmic extracts from ED2high cells. These results suggest that the decrease in functional ED2high macrophages with age results in the age-associated decline of immune responses, which is regulated, in part, by the basal GC concentration.
Adrenalectomy↗
Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study.
Spinocerebellar ataxia type 2 (SCA2) is associated with an expansion of CAG/polyglutamine-repeat of a gene of unknown function. We performed an immunohistochemical study to identify the immunolocalization of the disease protein ataxin-2 in normal and SCA2 patients. Although normal and expanded ataxin-2 were ubiquitously localized to the cytoplasm of neurons, ubiquitinated intranuclear inclusions were observed selectively in 1-2% of neurons of affected brain regions except the cerebellum. Triple-labeling immunofluorescence revealed that ataxin-2, expanded polyglutamine and ubiquitin were colocalized to these neuronal intranuclear inclusions (NIs), indicating that SCA2 shares morphological characteristics common to other neurological disorders associated with an expansion of CAG/polyglutamine-repeat. Lack of NIs in the cerebellar lesion, however, suggests the discrepancy between formation of NIs and neuronal degeneration in SCA2.
Ataxins↗
Glycosphingolipid-enriched signaling domain in mouse neuroblastoma Neuro2a cells. Mechanism of ganglioside-dependent neuritogenesis.
Differentiation and neuritogenesis of mouse neuroblastoma Neuro2a cells are induced by exogenous ganglioside but are not induced by nerve growth factor because its receptor is absent in these cells. In view of the emerging concept of the "glycosphingolipid-enriched domain" (GEM), we studied the mechanism of the ganglioside effect, focusing on the structure and function of such a domain. GEM in Neuro2a cells, separated as a low density membrane fraction, contains essentially all glycosphingolipids and sphingomyelin, together with five signal transducer molecules (c-Src, Lyn, Csk, Rho A, Ha-Ras). (3)H-Labeled Il(3)NeuAc-LacCer (GM3), Gb4Cer (globoside), and Il(3)NeuAc-Gg4Cer (GM1) added exogenously to cells were incorporated and concentrated in the low density GEM fraction. In contrast, more than 50% of glycerophospholipids and 30% of cholesterol were found in the high density fraction. (3)H-Labeled phosphatidylcholine added exogenously to cells was incorporated exclusively in the high density fraction. c-Src, the predominant signal transducer in the microdomain, was coimmunoprecipitated with anti-GM3 antibody DH2 or with anti-Csk; reciprocally, Csk was coimmunoprecipitated with anti-c-Src, indicating a close association of GM3, c-Src, and Csk. Brief stimulation of an isolated GEM fraction by the exogenous addition of GM3, but not lactosylceramide, caused enhanced c-Src phosphorylation with a concomitant decrease of Csk level in GEM. A decreased Csk/c-Src ratio in GEM may cause activation of c-Src because Csk is a negative regulator of c-Src. The effect of exogenous GM3 on c-Src activity was also observed in intact Neuro2a cells. Activation of c-Src was followed by rapid and prolonged (60 min) enhancement of mitogen-activated protein kinase activity leading to neuritogenesis. Thus, the ganglioside induction of neuritogenesis in Neuro2a cells is mediated by GEM structure and function.
Animals↗
Pertussis toxin-sensitive signal controls the trafficking of thymocytes across the corticomedullary junction in the thymus.
We investigated a role of chemokines in thymocyte trafficking. Genes encoding stromal cell-derived factor-1 and its receptor CXCR4 were detected in the cortex by in situ hybridization. Early immigrant cells did not express CXCR4, whereas their descendant CD44+CD25+CD4-CD8- cells did. CXCR4 expression was down-modulated when CD4+CD8+ double-positive cells became CD4+CD8- or CD4-CD8+ single-positive (SP) cells. Positively selected CD69+CD3intermediate cells gained CCR4, of which ligand, thymus activation-regulated chemokine, was expressed in the medulla. At the next developmental stage, CD69-CD3high cells lost CCR4 but gained CCR7. These results suggest that thymocytes use different chemokines along with their development. Blockade of chemokine receptor-mediated signaling by pertussis toxin perturbed the normal distribution of SP cells and resulted in the accumulation of SP cells in the cortex. Thus, a pertussis toxin-sensitive event controls the trafficking of SP cells across the corticomedullary junction.
Animals↗
A gustatory cyclic nucleotide-gated channels CNGgust, is expressed in the retina.
Cyclic nucleotide-gated (CNG) channels are essential proteins that contribute to the intracellular signal transduction of the senses of sight and smell. Recently, we found a novel CNG channel (CNGgust) in rat taste buds, and demonstrated its possible involvement in taste signal transduction. In the present study, we used RT-PCR and immunostaining to prove that this gustatory CNG channel is expressed in the outer segments of rat cone photoreceptor cells. The study strongly suggests that the senses of taste and sight share, at least in part, a common signal transduction pathway.
Animals↗
Endogenous substrates of sphingosine-dependent kinases (SDKs) are chaperone proteins: heat shock proteins, glucose-regulated proteins, protein disulfide isomerase, and calreticulin.
Protein kinases whose activity is detectable only in the presence of sphingosine (Sph) or N,N'-dimethyl-Sph (DMS), but not in the presence of 15 other sphingolipids, phospholipids, and glycerolipids tested (Megidish, T., et al. (1995) Biochem. Biophys. Res. Commun. 216, 739-747), have been termed "sphingosine-dependent kinases" (SDKs). We showed previously that a purified SDK (termed "SDK1") phosphorylates a specific Ser position of adapter/chaperone protein 14-3-3 isoforms beta, eta, and zeta but not tau or sigma (Megidish, T., et al. (1998) J. Biol. Chem. 273, 21834-45). In this study we found the following: (i) other SDKs with different substrate specificities are present in cytosolic and membrane extracts of mouse Balb/c 3T3 (A31) fibroblasts. (ii) The activation of these SDKs is specific to D-erythro-Sph and its N-methyl derivatives, the effect of L-threo-Sph or its N-methyl derivatives is minimal, and nonspecific cationic amphiphiles have no effect at all. An SDK separated as fractions "TN31-33" phosphorylated a 50 kDa substrate which was identified as calreticulin, as well as two endogenous substrates with molecular mass 58 and 55 kDa, both identified as protein disulfide isomerase (PDI). This SDK, which specifically phosphorylates calreticulin and PDI, both molecular chaperones found at high levels in endoplasmic reticulum, is tentatively termed "SDK2". Another SDK activity was copurified with glucose-regulated protein (GRP) and heat shock proteins (HSP). One GRP substrate had the same amino acid sequence as GRP94 (synonym: endoplasmin); another HSP substrate had the same amino acid sequence as mouse HSP86 or HSP84, the analogues of human HSP90. An SDK activity separated and present in "fraction 42" from Q-Sepharose chromatography specifically phosphorylated GRP105 (or GRP94) and HSP68 but did not phosphorylate PDI or 14-3-3. This SDK is clearly different from other SDKs in its substrate specificity and is tentatively termed "SDK3". Interestingly, substrates of all these SDKs so far identified are molecular chaperones or adapters capable of binding to enzymes and key molecules involved in signal transduction, maintaining tertiary structure of bioactive molecules, or maintaining cellular homeostasis in response to environmental stress. Thus, the essential role of Sph and DMS is to activate molecular chaperones, thereby providing a link to the mechanism by which SDK activity regulates cellular homeostasis and signal transduction.
3T3 Cells↗
Prevention of infection of influenza virus in DQ6 mice, a human model, by a peptide vaccine prepared according to the cassette theory.
We proposed a strategy (cassette theory) in which non-binding peptides for murine major histocompatibility complex (MHC) class II molecules are introduced into a MHC-binding component to render the resultant hybrid peptides bound to the MHC and thus immunogenic in animals carrying the relevant MHC. It was shown that 46F/HA127-133/54A(18mer) peptide which was prepared by introducing hemagglutinin (HA)127-133 of influenza virus into the H-2Ab binding component induced significant T cell responses and antibodies (Ab) specific for HA127-133 in H-2Ab mice. Further we found that the H-2Ab binding component had a supermotif for human class II molecules (i.e. HLA-DQ6). In the present study, a new peptide vaccine, H3-H3, was prepared by combining 46F/HA127-133/54A(18mer) as a carrier and HA127-133 attached to the C terminus of 46F/HA127-133/54A(18mer) as a hapten and the effect of vaccine was examined in DQ6 mice which carry HLA-DQ6 alone as MHC class II molecules and thus may be regarded as a model of the DQ6 positive individuals. Since 46F/HA127-133/ 54A(18mer) induced merely Ab against HA127-133, it was assumed that H3-H3 induced mainly HA127-133 specific Ab in DQ6 mice without undesirable Ab production against the carrier. Indeed, H3-H3 elicited T cell responses and induced HA127-133 specific Ab in DQ6 mice. Furthermore, administration of H3-H3 inhibited growth of influenza virus until 9 weeks after the last immunization in DQ6 mice.
Amino Acid Sequence↗
Short exposure of intestinal epithelial cells to TNF-alpha and histamine induces Mac-1-mediated neutrophil adhesion independent of protein synthesis.
Neutrophils play an important role in intestinal inflammation by interacting with intestinal epithelial cells. In this study, we evaluated neutrophil adhesion to intestinal epithelial cells using intestinal epithelial cell line HT29 stimulated with tumor necrosis factor alpha (TNF-alpha) and histamine for a short time (30 min). The TNF-alpha and histamine stimulation markedly increased neutrophil adhesion. The increased adhesion was inhibited by anti-CD11b and anti-CD18 monoclonal antibodies (mAbs), but not by anti-CD11a and anti-CD54 (ICAM-1) mAbs. It is interesting that flow cytometric analysis revealed that ICAM-1 expression on HT29 cells was not changed by TNF-alpha and histamine stimulation. Moreover, the increased adhesion was inhibited by proteinase K treatment but not cycloheximide treatment of HT29 cells. Together these observations suggest that short exposure of HT29 cells to TNF-alpha and histamine induces CD11b/CD18 (Mac-1)-dependent but CD11a/CD18 (LFA-1)-independent neutrophil adhesion to intestinal epithelial cells, and ICAM-1 is not likely to be involved in the interactions. Furthermore, epithelial cell ligand(s) for neutrophils is likely protein molecule(s) that is expressed on the cell by stimulation independent protein synthesis. However, it is also possible that neutrophil activating factor(s), which stimulates neutrophils to bind with epithelial ligands via Mac-1, is expressed by epithelial cells during stimulation.
Adenocarcinoma↗
Exposure of intestinal epithelial cell HT29 to bile acids and ammonia enhances Mac-1-mediated neutrophil adhesion.
OBJECTIVE: Bile acids and ammonia (NH3/NH4+) are cytotoxic metabolic products, which are known to influence intestinal epithelial functions such as colonic chloride secretion. In this study, we have investigated the effect of bile acids and ammonia on neutrophil-intestinal epithelial adhesive interaction. MATERIALS AND METHODS: Confluently cultured HT29 cells were treated with bile acids or ammonium chloride. Then, 51Cr-labeled neutrophils were added to HT29 cell monolayers, and neutrophil adhesion was assessed by gamma-scintillation counting. RESULTS: Treatment of HT29 cells with 0.1 mM CDCA (chenodeoxycholic acid), DCA (deoxycholic acid), CA (cholic acid) or ammonium chloride but not UDCA (ursodeoxycholic acid) for 30 min increased neutrophil adhesion about 4-folds (p<0.01). The increased adhesion was inhibited 82-91% by 10 microg/ml anti-CD11b and anti-CD18 mAbs (p<0.01), but not by anti-CD11a and anti-CD54 (ICAM-1) mAbs. Interestingly, flow cytometric analysis revealed that ICAM-1 expression on HT29 cells was not changed by bile acid- or ammonia-treatment. In addition, the increased adhesion was inhibited about 65 % by proteinase K-treatment (10 microg/ml, 1 min, p<0.05) but not cycloheximide-treatment (1 microg/ml, 30 min) of HT29 cells. CONCLUSIONS: These observations indicate that exposure of HT29 cells to bile acids or ammonia induces CD11b/CD18 (Mac-1) dependent- but CD11a/CD18 (LFA-1) independent-neutrophil adhesion to intestinal epithelial cells, and ICAM-1 is unlikely involved in the interactions. Furthermore, epithelial ligand(s) for neutrophils are protein molecule(s) which are expressed on the cell surface independent of protein synthesis.
Ammonia↗
Effects of lipophorin and 20-hydroxyecdysone on in vitro development of the larval endoparasitoid Venturia canescens (Hymenoptera: Ichneumonidae).
We previously reported that development of the embryos of the larval endoparasitoid Venturia canescens proceeded in the insect cell culture medium, MGM-450, and was promoted by the addition of a pupal extract from their host Galleria mellonella. The developmental promotion also was obtained by supplementing an equal amount of chicken egg yolk instead of the pupal extract to the medium. In this case, approximately 30% of the embryos developed into the second instar, but the value increased to more than 90% by treatment with 20-hydroxyecdysone. The medium supplemented with a G. mellonella pupal extract obtained by using Carlson's solution displayed growth-promoting ability, and in the extract, apolipophorin I was electrophoretically detected in large amounts. Both lipophorin purified from G. mellonella pupae and low density lipoprotein from chicken egg yolk acted as a growth-promoting substance for parasitoid development, although fetal bovine serum and 20-hydroxyecdysone were required as supplements to the medium for the expression of the ability. This indicated that lipophorin or lipophorin-transported lipids could act as a substance closely related to the growth-promoting factor(s) putatively involved in the host extract.
Journal Article↗
Antisense macrophage migration inhibitory factor (MIF) prevents anti-IgM mediated growth arrest and apoptosis of a murine B cell line by regulating cell cycle progression.
Macrophage migration inhibitory factor (MIF) is involved in the generation of cell-mediated immune responses. Recently it has been reported that MIF also plays a role in cell proliferation and differentiation. In the present study, using a B-cell line, WEHI-231, and its stable MIF-antisense transfectant, WaM2, as a representative transfectant, we investigated the mechanism underlying regulation of the cell growth by MIF. WaM2 cells produced less MIF than vector control or parental WEHI-231 cells. Reduced and increased proportions were seen in G1 and S-phase cells, respectively, in WaM2 as compared with WEHI-231. Growth arrest and apoptosis after stimulation via surface Ig (sIg) were less prominent in WaM2 cells than those in WEHI-231. However, the addition of recombinant rat MIF did not reverse the inhibition of the growth arrest and apoptosis induced in WaM2 by cross-linking sIg. Almost the same amount of p27kip1 expression was detected in WaM2 cells as those in WEHI-231 and vector control cells. Cross-linking of sIg elevated the p27kip1 level equally in these cells irrespective of the MIF-antisense expression. Taken together, it seems that MIF plays a role in inducing apoptosis in B cells upon IgM cross-linking by regulating the cell cycle via a novel intracellular pathway.
Animals↗
Combined clear and granular cell leiomyoma of soft tissue: evidence of transformation to a histiocytic phenotype.
AIMS: We present an unusual case of leiomyoma with a clear and granular cell pattern in which there was immunohistochemical evidence of transformation to a histiocytic phenotype. METHODS AND RESULTS: A 64-year-old man presented with mild scrotal swelling and pain. A local excision was performed after the clinical diagnosis of epidermal inclusion cyst. In the pathological specimen, another tumour nodule was identified which was composed predominantly of clear cells, with an occasional mixture of granular cells. Immunohistochemical analysis demonstrated positive staining for vimentin, lysozyme, CD68 and HAM56, but complete negativity for desmin, alpha-smooth muscle actin, HHF35, S100 protein, neurone-specific enolase and CD34. Ultrastructural study revealed dilated rough endoplasmic reticulum, glycogen granules, abundant vacuolar structures and also thin microfilaments with subplasmalemmal dense bodies. CONCLUSIONS: Based on these findings, we have interpreted it to be a rare case of leiomyoma with extensive clear cell and granular cell degeneration (combined clear and granular cell leiomyoma). This complete transformation of the immunohistochemical profile into the histiocytic phenotype has not been previously described in the literature.
Actins↗
Cerebrospinal fluid manganese concentrations in patients with symmetric pallidal hyperintensities on T1 weighted MRI.
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Adult↗
[Correlation of clinichopathological features and CAG repeats in SCA2].
Spinocerebellar ataxia type 2 (SCA2) is an inherited neurodegenerative disorder characterized clinically by cerebellar ataxia, slow eye movement, hyporeflexia, involuntary movement, dementia and sensory disturbance and neuropathologically by neuronal loss, mainly in the cerebellar cortex involving all three layers, the pontine nucleus, the inferior olivary nucleus, anterior horn, substantia nigra and thalamus. For making one's diagnosis, it is necessary to give careful consideration to two factors, (age at onset, disease duration). A distinctive neuropathological feature is having both simple atrophy (without degeneration) and numerical atrophy. SCA2 is associated with an expanded CAG repeat that encodes polyglutamine of a gene and a larger number of the repeat is associated with earlier onset and more severe symptoms and more severe neuronal degenerations.
Atrophy↗
Autosomal dominant spinocerebellar degenerations. Clinical, pathological, and genetic correlations.
Historical review on hereditary spinocerebellar degenerations (SCD) revealed that some CAG repeat diseases were formerly diagnosed under several different names because of their clinical and pathological heterogeneity. A genetic abnormality in these hereditary SCDs (often with expanded CAG repeat) corresponds to a definite prototypic combination of the principal lesions in the cerebellar, extrapyramidal, and oculomotor systems, which allows neuropathological differentiation between these entities. Variability of both clinical and pathological features is mainly related to the patient's age at onset, which is often correlated with the number of CAG repeat size. Several characteristics are suggestive of these SCD: preferential degeneration of specific systems, size reduction at cellular or tissue level not accompanied by glial reaction (simple atrophy or hypoplastic change) and presence of recently identified ubiquitin positive inclusions in neurons are characteristics of these SCDs. These features provide further insight into the phenotypic development of a genetic abnormality.
Atrophy↗