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Articles by K Suzuki
Total Records ( 8 ) for K Suzuki
  K Nakamura , Y Sekine , Y Ouchi , M Tsujii , E Yoshikawa , M Futatsubashi , K. J Tsuchiya , G Sugihara , Y Iwata , K Suzuki , H Matsuzaki , S Suda , T Sugiyama , N Takei and N. Mori
 

Context  Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown.

Objective  To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems.

Design  Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 (11C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652) and 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables.

Setting  Participants recruited from the community.

Participants  Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects.

Results  Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = –0.61; P = .004).

Conclusions  The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

  T Kohno , R Kakinuma , M Iwasaki , T Yamaji , H Kunitoh , K Suzuki , Y Shimada , K Shiraishi , Y Kasuga , G. S Hamada , K Furuta , K Tsuta , H Sakamoto , A Kuchiba , S Yamamoto , Y Kanai , S Tsugane and J. Yokota
 

Estrogen has been indicated to play an etiological role in the development of lung adenocarcinoma (ADC), particularly bronchioloalveolar carcinoma (BAC), a type of ADC that develops from a benign adenomatous lesion, atypical adenomatous hyperplasia (AAH). Polymorphisms in the CYP19A1 gene cause interindividual differences in estrogen levels. Here, 13 CYP19A1 single-nucleotide polymorphisms (SNPs) were examined for associations with lung AAH risk. AAH is detected as ground-glass opacity (GGO) by computed tomography (CT) examination, and this study consisted of 100 individuals diagnosed with GGO in their lungs among 3088 CT-based cancer screening examinees and 424 without. Minor allele carriers for the rs3764221 SNP showed an elevated risk for GGO [odds ratio (OR) = 1.72, P = 0.017]. Associations of this SNP with risks for lung AAH and BAC in the lungs were next examined using 359 ADC cases whose resected lung lobes were subjected to a histological examination for AAH accompaniment and the presence of BAC components and 330 controls without cancer. The ORs were also increased for lung ADC accompanied by AAH (OR = 1.74, P = 0.029) as well as lung ADC with BAC components (OR = 1.41, P = 0.091). The minor allele was associated with an increased circulating estradiol level (P = 0.079) in a population of 363 postmenopausal women without cancer. These results indicate that CYP19A1 polymorphisms are involved in the risk for lung AAH and BAC in the lungs by causing differences in estrogen levels.

  J Hirahashi , K Hishikawa , S Kaname , N Tsuboi , Y Wang , D. I Simon , G Stavrakis , T Shimosawa , L Xiao , Y Nagahama , K Suzuki , T Fujita and T. N. Mayadas
 

Background— Inflammation and thrombosis coexist in several disorders. Although it is recognized that leukocytes may induce a procoagulant state at sites of inflammation, the critical molecular determinants of this process remain largely unknown.

Methods and Results— To examine mechanisms of inflammation-induced thrombosis, we developed a murine model of thrombotic glomerulonephritis (TGN), a known cause of acute renal failure in patients. This model, induced by lipopolysaccharide and antibody to the glomerular basement membrane, led to rapid glomerular neutrophil recruitment, thrombotic glomerular lesions with endothelial cell injury, and renal dysfunction. In mice immunodepleted of neutrophils or lacking the leukocyte-specific integrin Mac-1, neutrophil recruitment, endothelial injury, glomerular thrombosis, and acute renal failure were markedly attenuated despite the robust generation of renal cytokines. Neutrophil elastase is a likely effector of Mac-1 because its activity was reduced in Mac-1–deficient mice and the phenotype in mice deficient in Mac-1 or neutrophil elastase was similar. Platelets accumulated in glomerular capillaries within 4 hours of TGN before evidence of thrombosis. Platelet immunodepletion before TGN markedly exacerbated hematuria (hemorrhage), inflammation, and injury, whereas thrombocytopenic Mac-1–deficient mice remained resistant to disease, indicating that initial glomerular platelet deposition protects the vessel wall from neutrophil-mediated sequelae. The subsequent thrombosis relied on the interaction of Mac-1 on recruited neutrophils with glycoprotein Ib on platelets as antibody-mediated disruption of this interaction attenuated TGN without affecting renal neutrophil accumulation.

Conclusions— These observations establish Mac-1 on neutrophils as a critical molecular link between inflammation and thrombosis and suggest it as an attractive target for antithrombotic therapy.

  P Kratsios , M Huth , L Temmerman , E Salimova , M Al Banchaabouchi , A Sgoifo , M Manghi , K Suzuki , N Rosenthal and F. Mourkioti
 

Rationale: Insight into the function of nuclear factor (NF)-B in the adult heart has been hampered by the embryonic lethality of constitutive NF-B inactivation.

Objective: The goal of the present study was therefore to gain insights into the role of NF-B pathway specifically in mouse cardiomyocytes by conditional deletion of the NF-B essential modulator (NEMO).

Methods and Results: Using a Cre/loxP system, we disrupted the Nemo gene in a cardiomyocyte-specific manner in the heart, which simulated gene expression changes underlying human heart failure and caused adult-onset dilated cardiomyopathy accompanied by inflammation and apoptosis. Pressure overload challenges of NEMO-deficient young hearts precociously induced the functional decrements that develop spontaneously in older knockout animals. Moreover, oxidative stress in NEMO-deficient cardiomyocytes is a critical pathological component that can be attenuated with antioxidant diet in vivo.

Conclusions: These results reveal an essential physiological role for NEMO-mediated signaling in the adult heart to maintain cardiac function in response to age-related or mechanical challenges, in part through modulation of oxidative stress.

  H. J Kimura , R Rocchi , M. A Landek Salgado , K Suzuki , C. Y Chen , M Kimura , N. R Rose and P. Caturegli
 

Interferon (IFN)- has been involved in the pathogenesis of Hashimoto thyroiditis. It is a cytokine released by infiltrating mononuclear cells that mediates its actions mainly through signal transducer and activator of transcription-1 (STAT1) but also through other transcription factors. To dissect the effect of IFN on thyroid morphology and function, we crossed transgenic mice that express IFN specifically in the thyroid gland to mice deficient in STAT1. Lack of STAT1 ameliorated the abnormal thyroid morphology and the primary hypothyroidism typical of IFN transgenic mice but not the suppressed iodine accumulation. Interestingly, lack of STAT1 alone decreased iodine accumulation, seemingly through expression of TGFβ. These results indicate that STAT1 is required to mediate some but not all of the phenotypic changes induced by IFN and that it also regulates iodine accumulation via TGFβ signaling.

  A Iwase , M Goto , T Harata , S Takigawa , T Nakahara , K Suzuki , S Manabe and F. Kikkawa
 

Context: Insulin resistance is considered as part of the pathogenesis of polycystic ovary syndrome (PCOS), and PCOS patients often show hyperinsulinemia. The influence of insulin on folliculogenesis in women with PCOS has not been fully investigated.

Objective: Our objective was to assess the induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with insulin treatment and effects of PTEN on IGF-I-induced granulosa cell proliferation as well as the correlation of PTEN levels with the concentration of insulin in follicular fluid in PCOS and non-PCOS patients.

Design, Setting, Patients, and Main Outcome Measures: A cell proliferation assay, real-time RT-PCR, and Western blotting for PTEN, Akt, and ERK1/2 were conducted in primary cultured granulosa cells under IGF-I stimulation with or without insulin pretreatment. Phosphorylation of Akt and ERK1/2 was also determined by Western blotting. We also measured the insulin concentration in follicular fluid and the levels of PTEN expression in granulosa cells collected at the time of oocyte retrieval of in vitro fertilization in PCOS (n = 13) and non-PCOS patients (n = 37).

Results: PTEN expression was induced by insulin. Pretreatment with insulin attenuated the IGF-I-induced Akt phosphorylation and cell proliferation but not ERK1/2 phosphorylation. A phosphatidylinositol 3-kinase inhibitor, LY294002, inhibited the IGF-I-induced cell proliferation. Suppression of insulin-induced PTEN expression using small interfering RNA recovered IGF-I-induced Akt phosphorylation. PTEN levels in granulosa cells, which tended to be higher in PCOS patients, were correlated with the insulin concentration in follicular fluid.

Conclusions: PTEN may influence the proliferation of human granulosa cells as well as disturbance of follicular growth in PCOS patients.

  S Miyagawa , Y Satoh , R Haraguchi , K Suzuki , T Iguchi , M. M Taketo , N Nakagata , T Matsumoto , K. i Takeyama , S Kato and G. Yamada
 

In most mammals, the sexually dimorphic development of embryos is typically achieved by the differentiation of the external genitalia. Hence, the sexual distinction of mammalian newborns is based on the external genital structure. Although it was shown in the 1940s and 1950s that androgen from the testes establishes the male sexual characteristics, the involvement of nongonadal and locally produced masculine effectors remains totally unknown. It is noteworthy that the disorders of fetal masculinization, including hypospadias, one of the most frequent birth defects, occur at a high frequency. Furthermore, their causative factors remain unclear. In this study, the involvement of the coordinated actions of androgen and the growth factor systems was genetically analyzed for the first time on mammalian reproductive organ formation. The results demonstrated that the Wnt/β-catenin pathway is indispensable masculine factor for the external genital development. The bilateral mesenchymal region adjacent to the urethral plate epithelium displayed a sexually dimorphic activity of Wnt/β-catenin signaling. Loss- and gain-of-function β-catenin mutants displayed altered sexual development of the external genitalia. These results indicate the novel functions of the Wnt/β-catenin pathway as a locally expressed masculine effector. This could be the first genetic study analyzing the roles of the genetic interactions between androgen and locally expressed growth factor signaling during the development of reproductive organs. These results also shed new insight on the reproductive genetics and the causative factors of genital disorders.

  K Suzuki , I Grigorova , T. G Phan , L. M Kelly and J. G. Cyster
 

The prominent display of opsonized antigen by follicular dendritic cells (FDCs) has long favored the view that they serve as antigen-presenting cells for B cells. Surprisingly, however, although B cell capture of antigen from macrophages and dendritic cells has been visualized, acquisition from FDCs has not been directly observed. Using two-photon microscopy, we visualized B cell capture of cognate antigen from FDCs. B cell CXCR5 expression was required, and encounter with FDC-associated antigen could be detected for >1 wk after immunization. B cell–FDC contact times were often brief but occasionally persisted for >30 min, and B cells sometimes acquired antigen together with FDC surface proteins. These observations establish that FDCs can serve as sites of B cell antigen capture, with their prolonged display time ensuring that even rare B cells have the chance of antigen encounter, and they suggest possible information transfer from antigen-presenting cell to B cell.

 
 
 
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