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Background: Diesel exhaust particles (DEP) synergistically aggravate acute lung injury related to lipopolysaccharide (IPS) in mice, but the camponents in DEP responsible far this have not been identified. A study [...]

With the constant rich operation of two-stroke engines, common design criteria for three-way catalysts fail. The increasing popularity of vehicles powered by two-stroke engines for cheap and convenient transportation in [...]

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10−9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10−10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10−9), TRANK1 (Pbest=2.1 × 10−9) and ODZ4 (Pbest=3.3 × 10−9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for ‘within Japanese comparisons’, Pbest~10−29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for ‘trans-European-Japanese comparison,’ Pbest~10−13, R2~0.27%). This ‘trans population’ effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD ‘risk’ effect are shared between Japanese and European populations.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novocopy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10−9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novoCNVs (e.g., MBD5deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novoCNVs and variable expressivity of CNVs.

Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n=54) and age-matched male healthy controls (n=40). Subsequently, post-mortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.

X-ray microscopy enables high-resolution analysis of thick specimens such as several microns in aqueous and atmospheric pressure environments in fields of biological and material sciences. Most commonly, zone plates (ZPs) are used as optical elements in combination with the use of synchrotron radiation (SR) as an x-ray source. It is realized at the x-ray microscopy station at BL-12 of Ritsumeikan SR center. The highest spatial resolution is 45 nm. This X ray microscope has been applied in biology, medicine, and material science. Various specimens can be clearly observed. We report some applied researches of our X-ray microscope.

Recently, genomics and proteomics have been utilized as advanced tools for investigation of cellular signaling pathways and molecular interactions, and elucidated promiscuous networks composed of numerous interactions among pathways. However, some of these interactions are considered to be simply contributing to background ‘noise’ and others are as ‘crosstalk’ biologically-relevant to cellular physiology, leading to synergy effects more than additive responses in an entire organism. Effort is now required to determine which interactions truly contribute to final physiological output. A receptor is the prime example of connectors among the networks. It functions, not simply as a signaling gateway, but also as an active trader by forming inter-receptor dimers. Furthermore, various receptors can modulate the function of the other receptors by input to common intracellular signaling pathways, establishing functional crosstalk among networks. Our findings by combined analyses of gene polymorphisms of two separate genes present evidences that such is the case with human body in a clinical setting: 1) an integrated effect of epidermal growth factor receptor (EGFR) and protease activated receptor-1 (PAR-1) on susceptibility to airway hyperresponsiveness (AHR), and 2) a crosstalk effect between muscarinic acetylcholine receptor (mAChRs) and β2 adrenoceptor (β2AR) on bronchodilatory response to anticholinergic agents in patients with COPD. These results indicate that these interactions are unlikely to be ‘noise’ but functionallyrelevant ‘crosstalk’ in a human body. This review attempts to highlight the clinically-relevant ‘crosstalk’ paradigm in a human body which provides us a novel insight necessary to investigate pathophysiology in common multifactorial diseases and to develop new drugs.

The pathogenesis of inflammatory bowel disease (IBD) is complicated and even several therapeutic strategies have been developed, they are not adequate for achieving mucosal remission in all IBD patients. Several reports have described the role of carbon monoxide (CO) in protection against chronic intestinal inflammation. CO has recently emerged as a potent immunomodulatory entity, anti-inflammatory agent, and homeostasis of physiological condition. CO reduces lipopolysaccharide-induced proinflammatory cytokines in macrophages via the effect of MAPK pathways. Interleukin-6, one of the important cytokines in the pathogenesis of IBD is also regulated by CO. Epithelial cell restitution is reported to be important factor to control IBD and CO has been reported to enhance colonic epithelial restitution through FGF15/19 expression in colonic myofibroblasts. CO also reduced mucosal damage and inflammation in several experimental animal colitis models such as interleukin-10-/- mouse model, TCR-/- mouse model, dextran sodium sulfate colitis model, and trinitrobennzen sulfonic acid colitis model. Taken together, CO has anti-inflammatory and enhancement of restitution examined in vitro model and in vivo experimental colitis model. These results indicate that CO may have a potential to be one of the therapeutic strategies in IBD patients.

Methylglyoxal is a reactive dicarbonyl compound produced from cellular glycolytic intermediates that reacts nonenzymatically with proteins to form products such as argpyrimidine at arginine residues. Abnormal accumulation of methylglyoxal and methylglyoxalderived advanced glycation end products (AGEs) occurs under hyperglycemic conditions and has been implicated in endothelium dysfunction, arterial stiffening, and microvascular complications in diabetes. However, the role of methylglyoxal in the healing process of diabetic gastric ulcers has not been fully investigated. Recently, methylglyoxal modification of peroxiredoxin-VI was found to be associated with delayed healing of diabetic gastric ulcers. Thus, inhibition of methylglyoxal modification might have therapeutic potential for the treatment of such ulcers. In this review, we present what is currently known regarding the role of methylglyoxal in the healing of diabetic gastric ulcers.

Fructooligosaccharides (FOS) are prebiotic supplements that can enhance immunological responses in the host to activate mucosal immunity, probably through regulation of gastrointestinal microflora. An area that has not been investigated, however, is the therapeutic potential of prebiotics on allergic airway diseases. The purpose of this study is to evaluate the effects of dietary supplementation with FOS on a murine model of airway inflammation induced by the house dust mite allergen Dermatophagoides farinae(Der f). Male C3H/HeN mice were intratracheally administered with Der f and were fed a diet containing 0% or 2.5% FOS ad libitum. Supplementation with FOS alleviated mite allergen-related airway inflammation characterized by eosinophilic inflammation and goblet cell hyperplasia, which was evidenced by cytological and histological examinations. In addition, the FOS-supplemented diet reduced the serum allergen-specific IgG1level as compared with a control diet in the presence of the mite allergen. Moreover, FOS tended to suppress the expression of IL-5 and eotaxin in the lungs, which is enhanced by mite allergen. These results suggest that dietary supplementation with FOS can prevent/improve airway inflammation induced by the mite allergen. This effect can be at least partially associated with the inhibition of allergen-specific Ig production and probably with that of IL-5 and eotaxin expression.

We have previously demonstrated the protective role of interleukin (IL)-6 against septic lung injury induced by lipopolysaccharide (LPS) using IL-6 knock-out (−/−) mice. This protection is mediated, at least partly, through the inhibition of the enhanced local expression of proinflammatory cytokines. In the present study, we addressed whether IL-6 regulates oxidative stress in the lung generated by LPS exposure using IL-6 (−/−) and corresponding wild type (WT) mice. Intraperitoneal LPS (1 mg/kg) challenge induced transcriptional expressions of inducible nitric oxide synthase and heme oxygenase −1 in the lung of mice with both genotypes. In the presence of LPS, these expressions were significantly greater in IL-6 (−/−) than in WT mice. Immunohistochemistry also showed that LPS induced a significant increase in 8-hydroxy-2′-deoxyguanosine formation in the lung as compared to vehicle. Furthermore, the formation was more intense in IL-6 (−/−) than in WT mice in the presence of LPS challenge. In the presence of LPS, lipid peroxidation in the lung was significantly greater in IL-6 (−/−) than in WT mice. These data suggest that the possible mechanisms in which endogenous IL-6 protects against septic lung injury induced by LPS involve, at least in part, its antioxidative properties.

Epidemiological and experimental studies have suggested that diesel exhaust particles (DEPs), which generate reactive oxygen species, may be involved in the recent increase in the prevalence of lung diseases. Cacao liquor proanthocyanidins (CPs) are naturally occurring polyphenols with antioxidative activities. We carried out a study in mice to investigate the effects of dietary supplementation of CPs on lung injury induced by intratracheal administration of DEPs (500 μg/body). Dietary supplementation with 1.0% CPs inhibited DEP-induced lung injury, characterized by neutrophil sequestration and edema. Immunohistochemical analyses showed that CPs prevented enhanced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 caused by DEPs in the lung injury. Numerous adducts of nitrotyrosine, N-(hexanonyl) lysine, 4-hydroxy-2-nonenal, and 8-OHdG were also observed immunohistochemically in the lungs of mice treated with DEPs. However, these indicators of oxidative stress were barely visible in mice pretreated with CP supplementation. In addition, the level of thiobarbituric acid reactive substances in the lung was decreased by CP supplementation in the presence of DEPs. These results suggest that CPs inhibit DEP-induced lung injury by reducing oxidative stress, in association with a reduction in the expression of adhesion molecules.

Effects of nano-sized materials (nanomaterials) on subjects with predisposing inflammatory disorders have not been well elucidated. This study examined the effects of pulmonary exposure to TiO2nanomaterials on lung inflammation induced by lipopolysaccharide (LPS) and consequent systemic inflammation with coagulatory disturbance in mice, in particular regarding their size-dependency. Also, gene expression pattern in the lung was compared among the experimental groups using cDNA microarray analysis. ICR male mice were divided into 8 experimental groups that intratracheally received vehicle, three sizes (15, 50, 100 nm) of TiO2nanomaterials (8 mg/kg), LPS (2.5 mg/kg), or LPS plus nanomaterials. Twenty four h after the treatment, these nanomaterials exacerbated the lung inflammation and vascular permeability elicited by LPS, with an overall trend of amplified lung expressions of cytokines such as interleukin (IL)-1β, macrophage chemoattractant protein (MCP)-1, and keratinocyte chemoattractant (KC). LPS plus nanomaterials, especially of a size less than 50 nm, elevated circulatory levels of fibrinogen, IL-1β, MCP-1, and KC, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. cDNA microarray analyses revealed that there was no difference in gene expression pattern between the LPS group and the LPS + nanomaterial. These results suggest that nanomaterials exacerbate lung inflammation related to LPS with systemic inflammation and coagulatory disturbance, and that the exacerbation is more prominent with smaller nanomaterials than with larger ones.

Ambient particulate matter (PM) exacerbates allergic airway diseases. Our previous study showed that diesel exhaust particles, the main constituents in urban PM, enhance airway hyperresponsivness in mice. In addition, health effects of PM with a diameter of less than 100 nm, called nanoparticles, have been reported, and we have also demonstrated that carbon nanoparticles exacerbate antigen-related airway inflammation. The present study investigates the effects of pulmonary exposure to two sizes of carbon nanoparticles on lung physiology and lung expression of Muc5ac in the presence or absence of antigen in mice. Nanoparticles alone or ovalbumin (OVA) alone moderately enhanced cholinergic airway reactivity, as assessed by total respiratory system resistance (R) and Newtonian resistance (Rn). In the nanoparticle + OVA groups, all the parameters for lung responsiveness, such as R, compliance, elastance, Rn, tissue damping, and tissue elastance, were worse than those in the vehicle group, the corresponding nanoparticle groups or the OVA group. The lung mRNA level for Muc5ac was significantly higher in the OVA group than in the vehicle group, and further increased in the nanoparticle + OVA groups than in the OVA or the nanoparticle groups. These data suggest that carbon nanoparticles can enhance lung hyperresponsiveness, especially in the presence of antigen. The effects may be mediated, at least partly, through the enhanced lung expression of Muc5ac.

Bioactivity of cell wall component(s) of fungi has not been fully elucidated, especially in vivo. We isolated Candida soluble beta-D-glucan (CSBG) from Candida albicans (C. albicans). We investigated the effects of airway exposure to CSBG on the immune systems in the airways in mice. CSBG exposure induced neutrophilic and eosinophilic inflammation in the lung, which was concomitant with the increased local expression of proinflammatory cytokines including tumor necrosis factor - α, interleukin (IL)-1 β, IL-6, macrophage inflammatory protein -1 α, macrophage chemoattractant protein -1, RANTES (regulated on activation and normal T cells expressed and secreted), and eotaxin. The lung inflammation with enhanced expression of proinflammatory proteins caused by CSBG was directly related to its structure, since structurally degraded products of CSBG by formic acid induced negligible responses in the lung. CSBG enhanced nuclear localization of phosphorylated signal transducer and activator of transcription (STAT)-6 in the lung. These results suggest that airway exposure to CSBG induces lung inflammation, at least partly, via the enhanced expression of proinflammatory cytokines and the activation of STAT-6 pathway, and can be a proper murine model for fungal lung inflammation.

Multiple attempts have been made to replace biliary defects with a variety of materials. Recently, successful biliary reconstruction using the Gore-Tex vascular graft has been reported experimentally and clinically We designed a new artificial bile duct consisting of collagen sponge and polypropylene mesh. We presently evaluated the feasibility of using this prosthesis as a scaffold for bile duct tissue regeneration in a canine model. Our prosthesis, a sponge made from porcine dermal collagen, is reinforced with a polypropylene mesh cylinder. We used the prosthesis to reconstruct the middle portion of the common bile duct in seven beagle dogs to evaluate its efficacy. While one dog died of biliary stricture 8 months after operation, six survived without problems to scheduled time points for tissue evaluation at 1 to 12 months. All prostheses had become completely incorporated into the host. A confluent epithelial lining was observed within 3 months. In cholangiograms the prosthesis displayed long-term patency in the six dogs and provided satisfactory bile drainage for up to 12 months. Our graft thus shows promise for repair of biliary defects and should lead to development of a new treatment for biliary reconstruction.

Abstract.ObjectiveInterleukin (IL)-8 has been reported to participate in neutrophil infiltration inHelicobacter pylori (H. pylori)-induced gastritis in humans. In this study, we investigated the anti-inflammatory actions beyond the suppression of acid secretion by proton pump inhibitors (PPI), such as omeprazole and lansoprazole, on IL-8 production by gastric epithelial cells (MKN45) and human umbilical vein endothelial cells (HUVEC) and on the transendothelial migration of polymorphonuclear neutrophils (PMN).Materials and methodsMKN45 and HUVEC were stimulated withH. pyloriwater extract (HPE) and IL-1β, respectively, and nuclear factor kappa B (NFκB) activation and subsequent IL-8 production was assessed in the absence or presence of PPI. We also assessed the effect of PPI on IL-8-induced PMN transendothelial migration and on the alteration of cytoplasmic calcium concentration in formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN.ResultsHPE and IL-1β induced a significant increase in IL-8 production by MKN45 and HUVEC, respectively, along with NFκB activation, which was significantly inhibited by PPI. PPI also inhibited the IL-8-induced transendothelial migration of PMN and the fMLP-induced cytosolic calcium increase in PMN.ConclusionsPPI attenuate PMN-dependent gastric mucosal inflammation partly by interfering with NFκB activation in vascular endothelial cells and gastric epithelial cells, and partly by modulating the calcium concentration of PMN.

There is a growing body of evidence that oxidative stress mediated by reactive oxygen species plays an important role in the pathogenesis of various kinds of allergic and non-allergic inflammation. These data suggest that blocking reactive oxygen species should be useful for amelioration of allergic or non-allergic inflammation in the respiratory and intestinal tracts. In addition, the modulation of oxidative stress-related molecules, such as inducible nitric oxide synthase and redox-sensitive transcriptional factors, may be useful for the regulation of these inflammatory responses. In this review, we have summarized the recent advances in the prevention of allergic or non-allergic inflammation, especially the diesel exhaust particle-induced respiratory allergic response and dextran sulfate sodium-induced intestinal inflammation in rodents.

In order to establish a reliable method for the detection of human herpesvirus‐6 (HHV‐6) B antigens in peripheral blood mononuclear cells (PBMCs) collected from HHV‐6 infected patients, we created a polyclonal antibody against the HHV‐6 B U90 protein (IEA/ex3) and used it to examine the expression of this protein in virus‐infected cells and patients' PBMCs. This antibody reacted with 170 and 195 kDa proteins in HHV‐6 B‐infected cord blood mononuclear cells. The IEA/ex3 antigen was detected in cord blood mononuclear cells at 6 hr post‐infection, and the number of infected cells reached its maximum at 48 hr post‐infection. The antigen stained in a punctate pattern and partially localized to the promyelocytic leukemia (PML) protein body. We also examined 60 PBMC samples from 60 febrile children (3–19 months old) and detected IEA/ex3 antigen in the PBMCs by laser‐scanning microscopy. HHV‐6 was isolated from 31 of the 60 samples. The sensitivity and specificity of the antigen detection were 84% (26/31) and 97% (28/29), respectively, in the samples with virus detected. The mean number of antigen‐positive PBMCs was 409/106cells in 20 samples with viral isolation. A significant correlation (r = 0.566; P= 0.008) was observed between the viral load and number of antigen‐positive cells. Although IEA/ex3 antigen was detected by laser‐scanning microscopy in PBMCs (without cultivation) collected from six patients with isolated virus, it was detected in only one sample by conventional fluorescence microscopy. Increasing the intensity by cultivation (24 hr) resulted in a higher detection rate (5/6) even by conventional fluorescence microscopy, which is available in most hospital laboratories. J. Med. Virol. 75:86–92, 2005. © 2005 Wiley‐Liss, Inc.

Objective: Over-expression of matrix metalloproteinases (MMPs) can accelerate tissue destruction and disrupt subsequent tissue repair. A dextran sulfate sodium (DSS) colitis model was established to examine the effects of MMP inhibition, by an orally active MMP inhibitor ONO-4847, on colonic inflammation. Materials and methods: Acute colitis was induced in female BALB/c mice by giving 8% DSS orally in drinking water for 7 days. The animals were randomized into groups receiving different concentrations of ONO-4847 or vehicle by oral gavage every day. mRNA levels of 4 MMPs and a tissue inhibitor of MMP (TIMP-1) were measured by RT-PCR in intestinal tissue isolated from mice after DSS administration. Colonic mucosal injury and inflammation were evaluated clinically, biochemically, and histologically. The clinical disease activity index (DAI), including body weight loss, stool consistency, and blood in feces, was examined. Moreover, mucosal tumor necrosis factor (TNF)-α and interferon (IFN)-γ were determined by immunoassay. Results: The intestinal expression of MMP-3, −7, 9, and −12 and TIMP-1 mRNA was upregulated after DSS administration. Shortening of the colon was significantly reversed by ONO-4847 at a dose of 30 mg/kg. DAI in DSS-treated mice was significantly lower in the ONO-4847-treated mice compared with the control mice. Histological study also showed a reduced infiltration of inflammatory cells, especially neutrophils, and reducedmucosal cell disruption in ONO-4847-treated mice compared with the control mice. The increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by co-administration with ONO-4847. ONO-4847 also inhibited increases in the mucosal TNF-α and IFN-γ content after DSS administration. Conclusion: Improvements in DSS colitis in response to ONO-4847 suggest that activation of MMPs contributes to the initiation/amplification of colonic inflammatory injury by mechanisms including oxidative damage as well as enhancement of inflammatory cytokine release.

Family-based linkage disequilibrium (LD) mapping has been suggested as a powerful and practical alternative to linkage analysis. We have performed a genome-wide LD survey of susceptibility loci for schizophrenia in a Japanese population. We first typed 119 schizophrenic pedigrees (357 individuals) using 444 microsatellite markers, and analyzed the data using the pedigree disequilibrium test. This analysis revealed 14 markers demonstrating significant transmission distortion. To corroborate these findings, the statistical methods were changed to the extended transmission disequilibrium test (ETDT), using 80 independent complete trios (schizophrenic proband and both parents), with 68 derived from initial pedigrees and 12 newly recruited trios. ETDT supported two markers for continued association, D11S987 on 11q13.3 (P = 0.00009) and D16S423 on 16p13.3 (P = 0.002). We scrutinized the most significant genomic locus on 11q11-13 by adding 26 new markers for analysis. Results of three-marker haplotype analysis in the region showed evidence of association with schizophrenia (most significant haplotype P = 0.0005, global P = 0.022). Although the present study may have missed other potential genomic intervals because of the sparse mapping density, we hope that it has identified promising anchor points for further studies to identify risk-conferring genes for schizophrenia in the Japanese population. In addition, we provide useful information on genomic LD structures in Japanese populations, which can be used for LD mapping of complex diseases. © 2004 Wiley-Liss, Inc.

The pathogenesis of Sjögren's syndrome (SS) is poorly understood. In this study we used an in-house mouse spleen cDNA microarray to analyse genes in spleens from MRL/lpr (an SS mouse model) mice. We have previously demonstrated that GRAPgenes were up-regulated in salivary glands of the same mice. The microarray analysis showed that seven out of 2304 genes were highly expressed in spleens from the MRL/lprmice, one of which was the GRAPgene. In other words, the GRAPgene is highly expressed in the salivary glands and spleen of MRL/lpr mice. We also carried out immunohistochemical studies. Mouse and human Grb-2-related adaptor protein (GRAP) antigens were expressed on ductal cells and infiltrating lymphocytes in salivary glands of MRL/lprmice and SS patients, but only weakly in controls (MRL/+ mice and individuals with salivary cysts). These results suggest that the GRAPgene might have a role in the pathogenesis of SS.

A process for the recycling of wasted optical fiber is proposed in this work. By reducing optical fiber, which consists of highly purified silica with a plastic coating, high-purity silicon is obtained. For the preliminary approach for this purpose, the reduction of the silica inside the optical fiber into silicon was carried out using an arc-plasma furnace. As a result, silicon was formed without the addition of carbon as a reducing agent. However, because the coating material was thermally decomposed and gasified in the early stage of the reaction, the quantity of carbonaceous compounds present as the reductant was deficient, resulting in the formation of silicon carbide or silicon monoxide as byproducts. Further addition of carbon showed no significant effect on the yield of silicon but increased the amount of silicon carbide. In contrast, the silicon carbide was found to improve the yield of silicon when it was recycled back into the reactant medium with the unreacted optical fiber.

Diffusion tensor imaging (DTI) is a magnetic resonance (MR) technique used to analyze diffusion anisotropy of the central nervous system (CNS) and can demonstrate subtle white matter anatomy. In particular, tractography is expected to be a unique, non-invasive tool to provide more pertinent insights into brain structure and orientation not accessible with conventional MRI. Data collection was performed in a normal volunteer on a 1.5-T MRI system using several techniques including six axis single-shot echo planar imaging (EPI), over six axis EPI, and periodically rotated overlapping parallel lines with enhanced reconstruction techniques. Tractography was generated by a continuous tracking method with our original software, Volume-One (for viewing volumetric image data) and VizDT-II (for analysis of DTI data). Using these data, estimated tracts were generated in arcuate fibers of cerebrum, cingulum, superior longitudinal fasciculus, uncinate fasciculus, inferior longitudinal fasciculus, corpus callosum, fornix, anterior thalamic radiation, central thalamic radiation, thalamo-parietal fibers, optic radiation, superior cerebellar peduncle, middle cerebellar peduncle, inferior cerebellar peduncle and intrinsic commissure paths of the hipoccampous. DTI including tractography allows differentiation between complex white matter tracts. The information regarding the detailed relationship may be useful for diagnosis of the location and extent of brain lesions, and preoperative planning.

Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction (PROPELLER) is one of the newer magnetic resonance imaging (MRI) methods developed to correct motion artifacts. PROPELLER uses a radial scan variation of the fast spin-echo sequence and spatial inconsistencies to be corrected using self navigation and an averaging effect for low spatial frequencies. We report and assess the imaging findings in a restless patient with Creutzfeldt-Jakob disease with a point mutation at codon 180 in prion protein DNA using PROPELLER diffusion-weighted MRI.

Electroconvulsive therapy is an effective treatment for severe and medication-resistant depression. There have been no reports describing how a volatile anaesthetic affects haemodynamic responses, seizure duration, and recovery characteristics during electroconvulsive therapy. We carried out a repeated-measure crossover study to compare the effects on haemodynamic responses, seizure duration, and recovery characteristics of the following types of anaesthesia in electroconvulsive therapy: propofol alone, sevoflurane alone, and propofol combined with sevoflurane.We recruited 50 patients requiring electroconvulsive therapy for depression. For anaesthesia induction, 1.5 mg/kg propofol (condition P), 5% sevoflurane in oxygen following a vital capacity rapid inhalation induction (condition S), or 1.5 mg/kg propofol followed by 5% sevoflurane in oxygen (condition PS) was administered. Succinylcholine 1.5 mg/kg was then given. Electrical stimulation was administered after fasciculation. Measurements were obtained before anaesthesia induction (baseline), prior to succinylcholine administration, prior to electroconvulsive therapy, and at the peak after electroconvulsive therapy.After electroconvulsive therapy, peak heart rate and peak mean arterial pressure were highest in condition S. Whereas recovery time was longest in condition PS, motor seizure duration was significantly shorter than in either condition P or S. Electroencephalographic seizure duration was significantly shorter in condition PS than in condition P and significantly shorter in condition S than in condition P.Sevoflurane anaesthesia alone is most disadvantageous in terms of haemodynamics. Propofol-sevoflurane anaesthesia is advantageous in terms of haemodynamics, but disadvantageous in terms of seizure duration and recovery time. Propofol alone is most advantageous in terms of seizure duration.

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A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D2 and serotonin 5-HT3 receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT3 receptor along with moderate to high binding affinity for the dopamine D2 receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D2 receptor while keeping a potent serotonin 5-HT3 receptor binding affinity. As a result of structure−affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D2 and serotonin 5-HT3 receptors was much more potent than that of metoclopramide (dopamine D2 receptor; 23.3 nM vs 444 nM, serotonin 5-HT3 receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D2 and serotonin 5-HT3 receptors, while the corresponding (S)-53 had a potent serotonin 5-HT3 receptor binding affinity and a moderate dopamine D2 receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D2 and serotonin 5-HT3 receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D2 and serotonin 5-HT3 receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID50 values of 27.1 μg/kg, po and 136 μg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.

We describe the clinical features and MRI findings of a patient with hypereosinophilia-induced encephalopathy associated with human T-cell lymphotropic virus type 1.Initial diffusion-weighted images revealed hyperintense spots in the border zone, and the apparent diffusion coefficient of the lesions increased over a three-week follow-up period. MRI findings, particularly those of the diffusion-weighted images, are of diagnostic value and are helpful in terms of understanding the pathophysiology of this disease.

We present the contrast-enhanced dynamic MR imaging appearance of cerebral arteriovenous malformations (AVM) following gamma knife radiosurgery and discuss the implications of this finding with respect to treatment. Dynamic MR images obtained in our three AVM patients following radiosurgery revealed slowly enhancing lesions. This pattern is not observed in all cases involving AVMs following gamma knife radiosurgery. When it is present, a haemangioma-like lesion should be considered.

We describe a patient with a rare association of a parietal arteriovenous malformation (AVM) and an ipsilateral persistent primitive hypoglossal artery (PPHA). A 27-year-old woman was treated by surgical removal, followed by gamma-knife radiosurgery. Only seven cases of intracranial AVM associated with PPHA have been reported in the literature.Although AVM associated with persistent carotid-basilar anastomosis has no distinguishing features compared with ordinary AVM, early recognition of the association is of significance to minimize neurological deficits during diagnostic angiography, interventional radiology (embolization) and surgery. The present report adds to the growing literature regarding AVMs associated with carotid-basilar anastomoses.

Electroconvulsive therapy (ECT) is commonly associated with acute hyperdynamic cardiovascular responses, and we hypothesize that intravenous lignocaine can blunt this response. We have measured the effect of lignocaine 1.5 mg/kg IV on heart rate and mean arterial pressure during electroconvulsive therapy. Furthermore, we also assessed seizure duration using both the cuff method and two-lead electroencephalography.We studied 25 patients using a randomized, double-blind, placebo-controlled crossover study design. Patients in the control group were given intravenous saline 0.075 ml/kg, and those in the lignocaine group were given intravenous lignocaine 2% 1.5 mg/kg, and this treatment was conducted one minute before intravenous propofol 1.5 mg/kg to induce unconsciousness. Succinylcholine 1.5 mg/kg was then administered intravenously and electrical stimulation was administered after fasciculation. Measurements were taken at the baseline, prior to succinycholine, prior to electroconvulsive therapy and at the peak response after electroconvulsive therapy.Intravenous lignocaine significantly reduced the increases in heart rate after electroconvulsive therapy, as compared with the placebo. The use of intravenous lignocaine was, however, associated with a remarkably shortened seizure duration.Due to the reduction in seizure duration, routine administration of intravenous lignocaine may not be advisable since it may interfere with the psychotherapeutic efficacy of electroconvulsive therapy. However, intravenous lignocaine medication for electroconvulsive therapy is potentially useful for reducing tachycardia in high-risk patients and reducing the severity of propofol injection pain in comparison with a placebo.

Abstract: It is known that metallurgical phenomena such as recovery, recrystallization, grain growth, and aging are due to the diffusion of constituent atoms in materials. The heat treatments that cause these phenomena are conducted defining both time and temperature. In the diffusion process, it is the diffusion distance that is defined by both time and temperature. Therefore, the authors surmise that there must be a relationship between the change of material properties as a result of heat treatment and the diffusion distances of constituent atoms. Under this assumption, diffusion distances of constituent atoms at recovery, recrystallization, grain growth, and aging in aluminum and copper alloys were examined. As a result, it was found that these phenomena take place at the fixed diffusion distances peculiar to the materials and phenomena. Therefore, the relationship between time and temperature was decided in terms of the fixed diffusion distances. In this respect, empirically used “normalized annealing time” turns out to mean the diffusion distance.

AbstractAdrenocorticotropic hormone (ACTH) and another pro-opiomelanocortin-derived neuropeptide, β-endorphin (β-End), are stimulated by corticotropin-releasing hormone (CRH) at the anterior pituitary. CRH and β-End have predominantly proinflammatory effects in peripheral inflammatory sites. We have supposed that inflammatory stimuli develop ACTH as well as β-End. In this study, we investigated the expression of ACTH in inflamed synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and at inflammatory joints with adjuvant-induced arthritis (AA) in female Lewis (LEW/N) rats. The expression of ACTH immunostaining was significantly greater in synovium of RA patients than in that of OA patients (P< 0.0001), and correlated with the extent of inflammatory mononuclear cell infiltration. Extensive and intense intracellular ACTH immunostaining, which correlated with the advance in arthritis score, was observed in the synovial lining layer, inflammatory mononuclear cells, and fibroblast-like cells of synovium and chondrocytes in LEW/N rats with AA. In addition, we performed double immunostaining of the same sections from arthritic joints in rats with anti-ACTH and anti-CRH antibodies. ACTH and CRH colocalized in inflammatory mononuclear cells and fibroblast-like cells. ACTH may play a role in the pathogenesis of RA as well as CRH.

Magnetic resonance imaging (MRI) is useful to diagnose dural sinus thrombosis. However, the representative appearance of dural sinus thrombosis on diffusion-weighted MRI has not been established. This study was aimed at determining whether cytotoxic or vasogenic edema is more predominant in the affected cerebral parenchyma and assessing the time courses and prognosis of dural sinus thrombosis lesion. The studies on sixteen patients with dural sinus thrombosis who underwent diffusion-weighted MRI were retrospectively reviewed. The diagnosis was confirmed by digital subtraction angiography in 11 patients and magnetic resonance angiography in five patients. Diffusion-weighted images with echo-planar imaging were obtained using two or three b values, with the highest b value of up to 1,000 s/mm2. A region of interest was placed on an area of abnormal signal intensity to calculate apparent diffusion coefficients (ADCs). Nine of the 16 patients had lesions with an increased ADC, whereas, three of these nine patients also had lesions with a decreased ADC. Among 11 patients who underwent initial MRI within 7 days of their last episode, eight had lesions with an increased ADC, of whom three had lesions mixed with both decreased and increased ADC areas. Follow-up studies of these three patients revealed the development of hemorrhagic infarction in two and subcortical hemorrhage in one. Vasogenic edema develops more predominantly and earlier in dural sinus thrombosis, though cytotoxic edema was also associated with the pathological changes in the early phase. Decrease of ADC value is presumed to reflect severe pathological conditions and indicate possible future development of infarction or hemorrhage.

BACKGROUND: Helicobacter pylori infection and non-steroidal anti-inflammatory drugs are two major causes of gastric ulceration but interactions between H pylori and these drugs in gastric mucosal injury are unclear. AIMS: We studied the influence of experimental H pylori infection on gastric mucosal injury induced by aspirin. SUBJECTS: Male Mongolian gerbils free of specific pathogens were used. METHODS: H pylori ATCC43504 culture broth was administered by oral gavage at seven weeks of age. After three weeks, acidified aspirin (400 mg/kg) was administered orally, and three hours later the total area of gastric erosions, myeloperoxidase (MPO) activity (an index of neutrophil accumulation), thiobarbituric acid reactive substances (TBARS, an index of lipid peroxidation), and KC/GRO (a chemoattractive cytokine in rodents) were measured in gastric mucosa. To determine the role of neutrophils in these circumstances, antigerbil neutrophil rabbit serum (ANS) was administered to some animals 18 hours before aspirin. RESULTS: Aspirin caused more extensive haemorrhagic erosions (33.1 (12.3) mm2) associated with greater MPO activity (1887.7 (598.5) microU/mg protein) and TBARS (0.33 (0.14) nmol/mg protein) and KC/GRO concentrations (28.3 (9.5) pg/mg protein) in infected than in uninfected gerbils (13.7 (2.3); 204.0 (68.9); 0.12 (0.06); 3.1 (0.8), respectively) Pretreatment with ANS inhibited the increases in gastric erosions, MPO activity, and TBARS but not KC/GRO concentration. The reduction in aspirin induced mucosal injury by administration of ANS was much greater in H pylori infected animals (65%) than in uninfected animals (31%). CONCLUSIONS: H pylori infection potentiates aspirin induced gastric mucosal injury by mechanisms that include accumulation of activated neutrophils.

Diesel exhaust particles (DEP) contain quinones that are capable of catalyzing the generation of reactive oxygen species in biological systems, resulting in induction of oxidative stress. In the present study, we explored sulfhydryl oxidation by phenanthraquinone, a component of DEP, using thiol compounds and protein preparations. Phenanthraquinone reacted readily with dithiol compounds such as dithiothreitol (DTT), 2,3-dimercapto-1-propanol (BAL), and 2,3-dimercapto-1-propanesulfonic acid (DMPS), resulting in modification of the thiol groups, whereas minimal reactivities of this quinone with monothiol compounds such as GSH, 2-mercaptoethanol, and N-acetyl-l-cysteine were seen. The modification of DTT dithiol caused by phenanthraquinone proceeded under anaerobic conditions but was accelerated by molecular oxygen. Phenanthraquinone was also capable of modifying thiol groups in pulmonary microsomes from rats and total membrane preparation isolated from bovine aortic endothelial cells (BAEC), but not bovine serum albumin (BSA), which has a Cys34 as a reactive monothiol group. A comparison of the thiol alkylating agent N-ethylmaleimide (NEM) with that of phenanthraquinone indicates that the two mechanisms of thiol modification are distinct. Studies revealed that thiyl radical intermediates and reactive oxygen species were generated during interaction of phenanthraquinone with DTT. From these findings, it is suggested that phenanthraquinone-mediated destruction of protein sulfhydryls appears to involve the oxidation of presumably proximal thiols and the reduction of molecular oxygen.

A 5 month old girl had typical clinical features of acute myocarditis just after the febrile period of exanthem subitum and died immediately. She had been healthy, with normal development, and there was no family history of particular note. Myocardial postmortem findings were compatible with acute myocarditis. Although the isolation of human herpesvirus 6 (HHV-6) was not attempted, positive IgM antibody to HHV-6 was detected in the patient's serum. Moreover, HHV-6 variant B DNA was detected in several tissues, including myocardium, by the polymerase chain reaction (PCR). In contrast, antibody responses to human herpesvirus 7, another causal agent of exanthem subitum, were not found, and enteroviral RNA was not detected in myocardial tissues by reverse transcription PCR. Apoptotic changes were seen in infiltrating cells within the myocardial tissues by means of the TUNEL method. HHV-6 antigen was not detected in several tissues (including myocardium) by immunohistochemical analysis. In conclusion, HHV-6 may have been the causative agent of fatal acute myocarditis in this infant.

To investigate the role of telomerase activity in colorectal adenoma-carcinomas, telomerase activity, human telomerase RNA component (hTERC) and human telomerase reverse transcriptase (hTERT) mRNA were quantitatively analyzed in human cancerous and precancerous colorectal tissues. Sixty-six colorectal tumor specimens, including 10 invasive carcinomas, 6 mucosal carcinomas and 50 adenomas were evaluated. Ten specimens of normal tissue were also included in the study. Telomerase activity was assayed by semiquantitative fluorescence using the TRAP-ezeTM telomerase detection kit. Analysis of the expression of each telomerase subunit gene was performed by real-time PCR amplification. There was a positive correlation between histological atypia and telomerase activity (ρ = 0.700, p < 0.0001), hTERT mRNA expression (ρ = 0.603, p < 0.0001), and hTERC expression (ρ = 0.290, p < 0.05). There was also a positive correlation between the levels of hTERT mRNA and telomerase activity (r = 0.455, p < 0.01). Significant differences in the levels of hTERT mRNA were shown between normal tissues and the adenomas (p < 0.05) and between the mucosal carcinomas and invasive carcinomas (p < 0.05). The values of hTERC expression in neoplastic tissues were significantly higher than in the normal tissues; however, there were no significant differences between the adenomas and the carcinomas. In summary, although upregulation of hTERC expression is an early event in adenoma development, hTERT mRNA expression is gradually upregulated during the adenoma-carcinoma sequence and may be a rate-limiting determinant of telomerase activity.