Publications by authors named "Chieko Kato"

54 Publications

Intramammary infection caused by Staphylococcus aureus increases IgA antibodies to iron-regulated surface determinant-A, -B, and -H in bovine milk.

Vet Immunol Immunopathol 2021 May 31;235:110235. Epub 2021 Mar 31.

Dairy Hygiene Research Division, National Institute of Animal Health, National Agriculture and Food Research Organization, 4 Hitsujigaoka, Toyohira, Sapporo, Hokkaido, 062-0045, Japan. Electronic address:

The aim of this study was to identify virulence factors that have high immunogenicity. An in vivo-expressed Staphylococcus aureus antigen was identified by probing bacteriophage expression libraries of S. aureus with antibodies in bovine mastitis milk. Eighteen clones were isolated, and their proteins were identified as 5 characterised proteins (IsdA, Protein A, IsdB, autolysin, and imidazole glycerol phosphate dehydratase) and 13 hypothetical proteins. We focused on IsdA, IsdB, and IsdH as virulence factors that have a high immunogenicity and are capable of inducing a specific humoral immune response in S. aureus-infected quarters. The optical density (OD) values of IsdA and IsdB IgA and IgG antibodies in milk affected by naturally occurring mastitis caused by S. aureus increased significantly compared to those in healthy milk. In the experimental infection study, the OD values of IsdA- and B-specific IgA and IgG antibodies were significantly increased from 2 to 4 weeks after S. aureus infection compared to day 0 (P < 0.05). On the other hand, we demonstrated that milk from natural and experimental intramammary infections caused by S. aureus are associated with significantly higher IgA levels against IsdH (P < 0.05), but no significant change in IgG levels. Our findings facilitated our understanding of the pathogenicity of S. aureus in bovine mastitis, as well as the mechanisms by which specific humoral immune responses to S. aureus infection are induced. In addition, the results obtained could provide insight into how bovine mastitis can be controlled, for example, through vaccination.
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http://dx.doi.org/10.1016/j.vetimm.2021.110235DOI Listing
May 2021

Evaluating the usefulness of breast strain elastography for intraductal lesions.

J Med Ultrason (2001) 2021 Jan 3;48(1):63-70. Epub 2021 Jan 3.

Department of Ultrasound, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Purpose: Strain elastography for imaging lesion stiffness is being used as a diagnostic aid in the malignant/benign discrimination of breast diseases. While acquiring elastography in addition to B-mode images has been reported to help avoid performing unnecessary biopsies, intraductal lesions are difficult to discriminate whether they are malignant or benign using elastography. An objective evaluation of strain in lesions was performed in this study by measuring the elasticity index (E-index) and elasticity ratio (E-ratio) of lesions as semi-quantitative numerical indicators of the color distribution of strain. We examined whether ductal carcinoma in situ (DCIS) and intraductal papilloma could be distinguished using these semi-quantitative numerical indicators.

Methods: In this study, 170 ultrasonographically detected mass lesions in 162 cases (106 malignant lesions and 64 benign lesions)-in which tissue biopsy by core needle biopsy and vacuum-assisted biopsy, or surgically performed histopathological diagnosis, was performed-were selected as subjects from among 1978 consecutive cases (from January 2014 to December 2016) in which strain elastography images were acquired, in addition to standard B-mode breast ultrasonography, by measuring the E-index and E-ratio.

Results: The cut-off values for E-index and E-ratio in the malignant/benign discrimination of breast lesions were determined to be optimal values at 3.5 and 4.2, respectively, based on receiver operating characteristic (ROC) curve analysis. E-index sensitivity, specificity, accuracy, and AUC value (area under the curve) were 85%, 86%, 85%, and 0.860, respectively, while those for E-ratio were 78%, 74%, 74%, and 0.780, respectively. E-index yielded superior results in all aspects of sensitivity, specificity, accuracy, and AUC values, compared to those of E-ratio. The mean E-index values for malignant tumors and benign tumors were 4.46 and 2.63, respectively, indicating a significant difference (P < 0.001). E-index values of 24 DCIS lesions and 25 intraductal papillomas were 3.88 and 3.35, respectively, which showed a considerably close value, while the false-negative rate for DCIS was 29.2%, and the false-positive rate for intraductal papilloma was as high as 32.0%.

Conclusion: E-index in strain elastography yielded better results than E-ratio in the malignant/benign discrimination of breast diseases. On the other hand, E-index has a high false-negative rate and false-positive rate for intraductal lesions, a factor which should be taken into account when making ultrasound diagnoses.
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http://dx.doi.org/10.1007/s10396-020-01070-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882591PMC
January 2021

Author Correction: A spatial similarity of stereochemical environments formed by amino acid residues defines a common epitope of two non-homologous proteins.

Sci Rep 2020 Jul 1;10(1):11091. Epub 2020 Jul 1.

Institute of Neuroscience, Tokushima Bunri University, Kagawa, 769-2193, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-68279-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326963PMC
July 2020

A spatial similarity of stereochemical environments formed by amino acid residues defines a common epitope of two non-homologous proteins.

Sci Rep 2019 10 15;9(1):14818. Epub 2019 Oct 15.

Institute of Neuroscience, Tokushima Bunri University, Kagawa, 769-2193, Japan.

It is critical for development of high-quality antibodies in research and diagnostics to predict accurately their cross-reactivities with "off-target" molecules, which potentially induce false results. Herein, we report a good example of such a cross-reactivity for an off-target due to a stereochemical environment of epitopes, which does not simply depend on amino acid sequences. We found that significant subpopulation of a polyclonal peptide antibody against Bcnt (Bucentaur) (anti-BCNT-C antibody) cross-reacted with a completely different protein, glutamine synthetase (GS), and identified four amino acids, GYFE, in its C-terminal region as the core amino acids for the cross-reaction. Consistent with this finding, the anti-BCNT-C antibody strongly recognized endogenously and exogenously expressed GS in tissues and cultured cells by Western blotting and immunohistochemistry. Furthermore, we elucidated that the cross-reaction is caused by a spatial similarity between the stereochemical environments formed by amino acid residues, including the GYFE of GS and the GYIE of Bcnt, rather than by their primary sequences. These results suggest it is critical to comprehensively analyze antibody interactions with target molecules including off-targets with special attention to the physicochemical environments of epitope-paratope interfaces to decrease the risk of false interpretations of results using antibodies in science and clinical applications.
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http://dx.doi.org/10.1038/s41598-019-51350-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794283PMC
October 2019

Optimal lesion size index to prevent conduction gap during pulmonary vein isolation.

J Cardiovasc Electrophysiol 2018 12 5;29(12):1616-1623. Epub 2018 Oct 5.

Department of System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.

Introduction: A novel real-time lesion size index (LSI) that incorporates contact force (CF), time, and power has been developed for safe and effective catheter ablation. The optimal LSI was evaluated to eliminate gap formation during pulmonary vein isolation (PVI).

Methods And Results: Consecutive patients were enrolled, who underwent their first PVI using a fiber-optic CF-sensing catheter for atrial fibrillation between December 2016 and October 2017. The CF parameters, force-time integral (FTI), and LSI for 3095 ablation points in 34 patients were evaluated. The FTI and LSI in the lesions with gaps or dormant conduction (gaps/DC) were significantly lower than those in the lesion without gaps/DC (FTI: 140.5 ± 54.5 and 232.4 ± 121.4 g s, P < 0.0001; LSI: 4.0 ± 0.6 and 4.7 ± 0.9, P < 0.0001, respectively). On receiver operating characteristic curve analysis, the optimal LSI threshold was 4.05 (sensitivity, 63.4%; specificity, 76.3%). The LSI of <5.25 predicted a gap or DC with a high sensitivity (sensitivity, 97.6%; specificity, 25.7%). In the posterior wall, which was 37% thinner than the nonposterior wall, a lower LSI of <3.95 showed a relatively high sensitivity (92.3%) and specificity (65.6%).

Conclusions: The LSI can be used to predict gaps/DC during the PVI procedure. An LSI of 5.2 may be a suitable target for effective lesion formation. An LSI of 4.0 may be acceptable in the posterior wall, especially in areas adjacent to the esophagus.
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http://dx.doi.org/10.1111/jce.13727DOI Listing
December 2018

General anesthesia improves contact force and reduces gap formation in pulmonary vein isolation: a comparison with conscious sedation.

Heart Vessels 2017 Aug 4;32(8):997-1005. Epub 2017 Mar 4.

Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

Compared to conscious sedation (CS), the use of general anesthesia (GA) in pulmonary vein isolation (PVI) is associated with a lower recurrence rate of atrial fibrillation (AF). GA may improve catheter stability and mapping system accuracy compared to CS, but its influence on contact force (CF) parameters during ipsilateral PVI has not previously been investigated. The study population comprised 176 consecutive patients (107 in GA group and 69 in CS group) with AF who underwent their first PVI procedure. We retrospectively assessed CF parameters, force-time integral (FTI), FTI/wall thickness during anatomical ipsilateral PVI and long-term outcome after ablation. Complete PVI with single continuous circular lesions around the ipsilateral PVs was achieved in 54 patients (50.5%) in the GA group but only 24 patients (34.8%) in the CS group (P = 0.04). The distribution of gaps did not differ between the groups. All CF parameters were significantly higher in the GA group than in the CS group (average CF: 19.4 ± 8.7 vs. 16.7 ± 7.7 g, P < 0.0001; FTI: 399.0 ± 262.5 vs. 293.9 ± 193.4 gs, P < 0.0001; FTI/wall thickness: 155.5 ± 106.1 vs. 115.7 ± 85.5 gs, P < 0.0001). GA was associated with lower AF recurrence rate in patients with paroxysmal AF but not with persistent AF. Compared with CS, GA improves CF parameters, FTI and FTI/wall thickness, and reduced gap formation after ipsilateral PVI.
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http://dx.doi.org/10.1007/s00380-017-0961-zDOI Listing
August 2017

Optimal Force-Time Integral for Pulmonary Vein Isolation According to Anatomical Wall Thickness Under the Ablation Line.

J Am Heart Assoc 2016 Mar 15;5(3):e003155. Epub 2016 Mar 15.

Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

Background: Low contact force and force-time integral (FTI) during catheter ablation are associated with ineffective lesion formation, whereas excessively high contact force and FTI may increase the risk of complications. We sought to evaluate the optimal FTI for pulmonary vein (PV) isolation based on atrial wall thickness under the ablation line.

Methods And Results: Contact force parameters and FTI during anatomical ipsilateral PV isolation for atrial fibrillation and atrial wall thickness were assessed retrospectively in 59 consecutive patients for their first PV isolation procedure. The PV antrum was divided into 8 segments, and the wall thickness of each segment under the ablation line was determined using multidetector computed tomography. The FTI for each ablation point was divided by the wall thickness of the PV antrum segment where each point was located to obtain FTI/wall thickness. In total, 5335 radiofrequency applications were delivered, and 85 gaps in PV isolation ablation lines and 15 dormant conductions induced by adenosine were detected. The gaps or dormant conductions were significantly associated with low contact force, radiofrequency duration, FTI, and FTI/wall thickness. Among them, FTI/wall thickness had the best prediction value for gaps or dormant conductions by receiver operating characteristic curve analysis. FTI/wall thickness of <76.4 gram-seconds per millimeter (gs/mm) predicted gaps or dormant conductions with sensitivity (88.0%) and specificity (83.6%), and FTI/wall thickness of <101.1 gs/mm was highly predictive (sensitivity 97.0%; specificity 69.6%).

Conclusions: FTI/wall thickness is a strong predictor of gap and dormant conduction formation in PV isolation. An FTI/wall thickness ≈100 gs/mm could be a suitable target for effective ablation.
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http://dx.doi.org/10.1161/JAHA.115.003155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943282PMC
March 2016

Chronic Ischemia Induced by Woven Coronary Artery Anomaly with Typical Atrial Flutter: Insights from Multiple Imaging Devices.

Intern Med 2015 1;54(17):2185-9. Epub 2015 Sep 1.

Department of Cardiology, National Hospital Organization, Kanazawa Medical Center, Japan.

A 75-year-old man with a 120-bpm tachycardia and typical atrial flutter was admitted. Echocardiography showed a dilated left ventricle with anterior and apical wall akinesia. Tachycardia was terminated with cavotricuspid isthmus ablation. Multiple imaging findings revealed a woven coronary artery anomaly (WCAA) in the left anterior descending artery. Stress myocardial perfusion imaging was performed after ablation in the sinus rhythm and revealed stress-induced ischemia and a fixed low uptake in the WCAA territory. WCAA is generally regarded as a benign condition; however, compromised blood flow within the anomaly, caused by tachycardia-related diastolic shortening, may induce ischemia.
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http://dx.doi.org/10.2169/internalmedicine.54.4333DOI Listing
May 2016

[Diagnosis for Helicobacter pylori infection].

Nihon Shokakibyo Gakkai Zasshi 2015 Jun;112(6):994-9

Department of Gastroenterology, University of Toyama.

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http://dx.doi.org/10.11405/nisshoshi.112.994DOI Listing
June 2015

Coronary vessel floating sign and vasospastic angina in a patient with cardiac lymphoma.

Int J Cardiol 2014 Sep 8;176(1):e20-5. Epub 2014 Jul 8.

Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

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http://dx.doi.org/10.1016/j.ijcard.2014.06.081DOI Listing
September 2014

Retinoid X receptor agonists modulate Foxp3⁺ regulatory T cell and Th17 cell differentiation with differential dependence on retinoic acid receptor activation.

J Immunol 2013 Oct 26;191(7):3725-33. Epub 2013 Aug 26.

Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki-shi, Kagawa 769-2193, Japan;

Retinoic acid (RA) enhances TGF-β-dependent differentiation of Foxp3(+) inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4(+)CD25(-) T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-γ that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR-mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3(+) iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation.
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http://dx.doi.org/10.4049/jimmunol.1300032DOI Listing
October 2013

Early infantile growth and cardiovascular risks in adolescent Japanese women.

J Rural Med 2013 2;8(1):176-80. Epub 2013 Jul 2.

Department of Public Health, Graduate School of Medicine, Chiba University, Japan.

Objective: Early life events connected with the risk of later disease can occur not only in utero, but also in infancy. In study of the developmental origins of health and disease, the relationship between infantile growth patterns and adolescent body mass index and blood pressure is one of the most important issues to verify.

Materials And Methods: We analyzed the correlation of current body mass index and systolic blood pressure of 168 female college students with their growth patterns in utero and in infancy.

Results: Body mass index and systolic blood pressure in adolescence showed positive correlations with changes in weight-for-age z scores between 1 and 18 months but not with those between 18 and 36 months. Stepwise multiple regression analysis showed that both change in weight-for-age z scores from 1 to 18 months and body mass index at 1 month were significantly and independently associated with systolic blood pressure in adolescence. Body mass index at 36 months was positively correlated with body mass index in adolescence, while body mass index at birth was negatively correlated with body mass index in adolescence.

Conclusion: Our findings shows that restricted growth in utero and accelerated weight gain in early infancy are associated with the cardiovascular risk factors of high systolic blood pressure and high body mass index in adolescence. In Japan, an increasing proportion of low birth weight infants and accelerated catch-up growth after birth have been observed in recent decades. This might be an alarming harbinger of an increase in diseases related to the developmental origins of health and disease in Japan.
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http://dx.doi.org/10.2185/jrm.8.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309342PMC
February 2015

Influence of proton pump inhibitor treatment on Helicobacter pylori stool antigen test.

World J Gastroenterol 2012 Jan;18(1):44-8

Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu city, Oita 879-5593, Japan.

Aim: To investigate the effects of proton pump inhibitor (PPI) treatment on stool antigen test using the TestMate pylori enzyme immunoassay.

Methods: This study assessed 28 patients [16 men and 12 women; mean age (63.1 ± 5.9) years; range, 25-84 years] who underwent stool antigen test and urea breath test (UBT) before and after PPI administration.

Results: Using the UBT as the standard, the sensitivity, specificity and agreement of the stool antigen test in all 28 patients were 95.2%, 71.4%, and 89.3%, respectively, before PPI administration, and 88.9%, 90.9%, and 89.3%, respectively, after PPI treatment. Mean UBT values were 23.98% ± 5.33% before and 16.19% ± 4.75% after PPI treatment and, in 15 patients treated for ≥ 4 wk, were significantly lower after than before 4 wk of PPI treatment (12.58% ± 4.49% vs 24.53% ± 8.53%, P = 0.048). The mean optical density (A(450/630)) ratios on the stool antigen test were 1.16 ± 0.20 before and 1.17 ± 0.24 after PPI treatment (P = 0.989), and were 1.02 ± 0.26 and 0.69 ± 0.28, respectively, in the group treated for > 4 wk (P = 0.099).

Conclusion: The stool antigen test was equally sensitive to the UBT, making it a useful and reliable diagnostic method, even during PPI administration.
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http://dx.doi.org/10.3748/wjg.v18.i1.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251804PMC
January 2012

[Case report: a case of crowned dens syndrome during pneumonia treatment].

Nihon Naika Gakkai Zasshi 2011 Aug;100(8):2253-5

Department of General Medicine, Toyooka Public Hospital, Japan.

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http://dx.doi.org/10.2169/naika.100.2253DOI Listing
August 2011

Efficient induction of CCR9 on T cells requires coactivation of retinoic acid receptors and retinoid X receptors (RXRs): exaggerated T Cell homing to the intestine by RXR activation with organotins.

J Immunol 2010 Nov 29;185(9):5289-99. Epub 2010 Sep 29.

Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa, Japan.

The active vitamin A metabolite retinoic acid (RA) imprints gut-homing specificity on lymphocytes upon activation by inducing the expression of α4β7 integrin and CCR9. RA receptor (RAR) activation is essential for their expression, whereas retinoid X receptor (RXR) activation is not essential for α4β7 expression. However, it remains unclear whether RXR activation affects the RA-dependent CCR9 expression on T cells and their gut homing. The major physiological RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. Cell-surface CCR9 expression was often induced on a limited population of murine naive CD4(+) T cells by all-trans-RA or the RAR agonist Am80 alone upon CD3/CD28-mediated activation in vitro, but it was markedly enhanced by adding the RXR agonist PA024 or the RXR-binding environmental chemicals tributyltin and triphenyltin. Accordingly, CD4(+) T cells treated with the combination of all-trans-RA and tributyltin migrated into the small intestine upon adoptive transfer much more efficiently than did those treated with all-trans-RA alone. Furthermore, naive TCR transgenic CD4(+) T cells transferred into wild-type recipients migrated into the small intestinal lamina propria following i.p. injection of Ag, and the migration was enhanced by i.p. injection of PA024. We also show that PA024 markedly enhanced the all-trans-RA-induced CCR9 expression on naturally occurring naive-like regulatory T cells upon activation, resulting in the expression of high levels of α4β7, CCR9, and Foxp3. These results suggest that RXR activation enhances the RAR-dependent expression of CCR9 on T cells and their homing capacity to the small intestine.
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http://dx.doi.org/10.4049/jimmunol.1000101DOI Listing
November 2010

Comparison of monoclonal antibody-based stool antigen tests to determine the results of Helicobacter pylori eradication therapy.

Scand J Gastroenterol 2010 Dec 9;45(12):1431-4. Epub 2010 Aug 9.

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Objective: Stool antigen tests using monoclonal antibody are used to test the results of eradication therapy of Helicobacter pylori. A newly developed test using multiple monoclonal antibodies is considered to have higher sensitivity. The aim of this study was to examine whether monoclonal antibody-based stool antigen tests are equally applicable to determine the results of eradication therapy.

Materials And Methods: Stool specimens obtained from patients infected with H. pylori were diluted by human stool and tested by both Testmate pylori antigen enzyme immunoassay (TPAg EIA) and Premier Platinum HpSA PLUS (HpSA ELISA II). A total of 239 patients infected with H. pylori received eradication therapy and 5-8 weeks after finishing the treatment, stool samples were tested by TPAg EIA and HpSA ELISA II. On the same day of stool collection, all the patients received (13)C-urea breath test (UBT).

Results: After 5× dilution, optical density (OD) values of TPAg EIA were significantly reduced and three out of four stool specimens were tested negative after 10× dilution. By contrast, three specimens were tested positive even after 100× dilution by HpSA ELISA II. In the determination of eradication therapy, accordance between the two tests was 95.8%. Among 199 patients who tested negative by both stool antigen tests, 10 patients were positive by UBT. Overall accordance of TPAg EIA and HPSA ELISA II to UBT was 91.2% and 95.4%, respectively (NS).

Conclusions: Although reduction of OD values was seen in TPAg EIA, it did not seem to cause false negative results in stool samples after eradication therapy. Both TPAg EIA and HpSA ELISA II were equally useful to determine the results of eradication therapy comparing with UBT.
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http://dx.doi.org/10.3109/00365521.2010.510569DOI Listing
December 2010

Applicability of a monoclonal antibody-based stool antigen test to evaluate the results of Helicobacter pylori eradication therapy.

Jpn J Infect Dis 2009 May;62(3):225-7

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.

The (13)C-urea breath test (UBT) is widely used to examine the results of eradication therapy for Helicobacter pylori. We examined whether a stool antigen test can be used as efficiently as UBT. (i) Ninety-four patients infected with H. pylori underwent eradication therapy. Six or eight weeks after the completion of treatment, the results were evaluated by UBT and a stool antigen test (TPAg). In 77 out of 78 patients who had negative UBT results, the TPAg results were also negative. Among the 16 UBT-positive patients, 12 were also positive by TPAg. Agreement of UBT and TPAg was 94.7%. (ii) Twenty-two patients with peptic ulcers in the active stage also received eradication therapy followed by proton pump inhibitor (PPI) administration. TPAg and UBT were performed to examine the results of eradication therapy at the end of PPI administration and at least 7 days after its discontinuation. Of the 22 patients taking PPIs, TPAg evaluated the results of eradication therapy accurately in 21 patients. TPAg appears to be an accurate test for evaluating the results of H. pylori eradication therapy, and to be as efficient as (13)C-UBT. Use of the stool antigen test should be considered as an alternative, particularly in patients who have to take PPIs in order to avoid the risk of peptic ulcers.
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May 2009

GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity.

Int Immunol 2009 Apr 3;21(4):361-77. Epub 2009 Feb 3.

Laboratory of Biodefense Research, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki-shi, Kagawa, Japan.

Retinoic acid (RA) produced by intestinal dendritic cells (DCs) imprints gut-homing specificity on lymphocytes and enhances Foxp3(+) regulatory T-cell differentiation. The expression of aldehyde dehydrogenase (ALDH) 1A in these DCs is essential for the RA production. However, it remains unclear how the steady-state ALDH1A expression is induced under specific pathogen-free (SPF) conditions. Here, we found that bone marrow-derived dendritic cells (BM-DCs) generated with granulocyte-macrophage colony-stimulating factor (GM-CSF) expressed Aldh1a2, an isoform of Aldh1a, but that fms-related tyrosine kinase 3 ligand-generated BM-DCs did not. DCs from mesenteric lymph nodes (MLN) and Peyer's patches (PP) of normal SPF mice expressed ALDH1A2, but not the other known RA-producing enzymes. Employing a flow cytometric method, we detected ALDH activities in 10-30% of PP-DCs and MLN-DCs. They were CD11c(high)CD4(-/low)CD8alpha(intermediate)CD11b(-/low) F4/80(low/intermediate)CD45RB(low)CD86(high)MHC class II(high)B220(-)CD103(+). Equivalent levels of aldehyde dehydrogenase activity (ALDHact) and ALDH1A2 expression were induced synergistically by GM-CSF and IL-4 in splenic DCs in vitro. In BM-DCs, however, additional signals via Toll-like receptors or RA receptors were required for inducing the equivalent levels. The generated ALDH1A2(+) DCs triggered T cells to express gut-homing receptors or Foxp3. GM-CSF receptor-deficient or vitamin A-deficient mice exhibited marked reductions in the ALDHact in intestinal DCs and the T cell number in the intestinal lamina propria, whereas IL-4 receptor-mediated signals were dispensable. GM-CSF(+)CD11c(-)F4/80(+) cells existed constitutively in the intestinal tissues. The results suggest that GM-CSF and RA itself are pivotal among multiple microenvironment factors that enable intestinal DCs to produce RA.
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http://dx.doi.org/10.1093/intimm/dxp003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2660862PMC
April 2009

No association between the ryanodine receptor 3 gene and autism in a Japanese population.

Psychiatry Clin Neurosci 2008 Jun;62(3):341-4

Department of Neuropsychiatry, Graduate School of Medicine, Univerisity of Tokyo, Bunkyo, Tokyo, Japan.

Aim: Autism is a neurodevelopmental disorder with a complex genetic etiology. Chromosome 15q11-q14 has been proposed to harbor a gene for autism susceptibility because deletion of the region leads to Prader-Willi syndrome or Angelman syndrome, having phenotypic overlap with autism. Here we studied the association between autism and the ryanodine receptor 3 (RyR3) gene, which is located in the region. This is the first study, to our knowledge, that has investigated the association.

Methods: We genotyped 14 tag single nucleotide polymorphisms (SNPs) in 166 Japanese patients with autism and 375 controls.

Results: No significant difference was observed between the patients and controls in allelic frequencies or genotypic distributions of the 14 SNPs. Analysis after confining the subjects to males showed similar results.

Conclusions: The present study provides no positive evidence for the association between the RyR3 gene and autism in the Japanese population.
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http://dx.doi.org/10.1111/j.1440-1819.2008.01802.xDOI Listing
June 2008

Association study of the commonly recognized breakpoints in chromosome 15q11-q13 in Japanese autistic patients.

Psychiatr Genet 2008 Jun;18(3):133-6

Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Objective: Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility because deletions of the region lead to Prader-Willi syndrome and Angelman syndrome, whose phenotypes overlap with autism. These deletions generally occur with the use of three commonly recognized breakpoints (BP1, BP2, and BP3); therefore, it may be possible that genes located in the breakpoints are impaired and contribute to autism susceptibility. No study, however, has investigated the genetic association between the breakpoints and autism, to our knowledge. Here, we investigated the association between the common breakpoints of chromosome 15q11-q13 and autism in a Japanese population.

Methods: We genotyped 12 single nucleotide polymorphisms (SNPs) in 166 patients with autistic disorder and 415 healthy controls. The SNPs are located in two additional distal breakpoints (BP4 and BP5), involved in duplications and triplications of the region, as well as in BP1 and BP3.

Results: No significant difference was observed between the controls and patients in allelic frequencies or genotypic distributions of the 12 SNPs. In the analyses of the suggested five haplotypes, no significant difference between the controls and patients was observed in the distributions of any estimated haplotypes. When confining the patients to only males, a difference was observed in a two-marker haplotype in BP3 between the controls and patients (global permutation P value=0.006), although the statistical level became insignificant after correction for multiple testing.

Conclusion: This study provides no positive evidence of the association between the common breakpoints of chromosome 15q11-q13 and autism in the Japanese population.
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http://dx.doi.org/10.1097/YPG.0b013e3282fb0064DOI Listing
June 2008

Association study of the 15q11-q13 maternal expression domain in Japanese autistic patients.

Am J Med Genet B Neuropsychiatr Genet 2008 Oct;147B(7):1008-12

Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan.

Chromosome 15q11-q13 has been a focus of genetic studies of autism susceptibility, because cytogenetic abnormalities are frequently observed in this region in autistic patients. An imprinted, maternally expressed gene within the region may have a role in autistic symptomatology. In the present study, we investigated the association between autism and the maternal expression domain (MED) in the region, containing the UBE3A and ATP10C genes, and the upstream imprinting center (IC), which mediates coordinate control of imprinted expression throughout the region. We analyzed 41 single nucleotide polymorphisms (SNPs) in 166 patients with autism and 416 controls from a Japanese population. As a result, a statistically significant difference after correction for multiple testing was observed between the patients and controls in the genotypic distribution of SNP rs7164989 (SNP8 in this study) located in SNRPN, whose promoter corresponds to the IC (P = 0.018, corrected for multiple testing). In the analysis of a four-marker haplotype located in ATP10C, a statistically significant difference after correction for multiple testing was observed in the frequency of one haplotype between male patients and controls (permutation P = 0.033, corrected for multiple testing). Thus, the present study may suggest the association between autism and the MED or the upstream IC in chromosome 15q11-q13 in the Japanese population.
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http://dx.doi.org/10.1002/ajmg.b.30690DOI Listing
October 2008

No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population.

J Hum Genet 2007 24;52(12):985-989. Epub 2007 Oct 24.

Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.

The gamma-aminobutyric acid (GABA) receptor genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11-q13 have been major candidates for susceptibility genes for autism, a neurodevelopmental disorder with a complex genetic etiology. In this study, we first investigated the association between the GABA receptor genes and autism in a Japanese population by analyzing 11 single nucleotide polymorphisms (SNPs). Intron 3 of GABRB3 was densely mapped because the previous studies observed the association of the microsatellite 155CA-2 located in the region. We observed no significant difference in allelic frequencies or genotypic distributions of the 11 SNPs between patients and controls. A permutation test showed no significant global differences in estimated haplotype frequencies between patients and controls. Analysis after confining the subjects to males showed similar results. Thus, this study provides no positive evidence of an association between the GABA receptor genes and autism in a Japanese population. However, in a SNP (rs3212337) located near the microsatellite 155CA-2, a significant deviation from the Hardy-Weinberg equilibrium was observed in patients (p = 0.029, corrected for multiple testing). This finding may suggest further studies around the markers for more definitive conclusions.
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http://dx.doi.org/10.1007/s10038-007-0207-5DOI Listing
February 2008

Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice.

J Pharmacol Sci 2007 Sep;105(1):122-6

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.

We have recently reported that nobiletin, a citrus flavonoid, improves impaired memory in olfactory-bulbectomized (OBX) mice, which have been widely utilized as a useful paradigm that shares some major clinical features of Alzheimer's disease. Here, we examined the effects of nobiletin on OBX-induced cholinergic neurodegeneration in mice. OBX mice showed reduced acetylcholinesterase (AChE) staining and choline acetyltransferase (ChAT) expression in the hippocampus. An 11-day administration of nobiletin rescued OBX-induced decrease in the density of AChE-staining and ChAT expression in the hippocampus. These results suggest that nobiletin rescues OBX-induced cholinergic neurodegeneration, accompanied by improvement of impaired memory in OBX mice.
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http://dx.doi.org/10.1254/jphs.sc0070155DOI Listing
September 2007

Association study of monoamine oxidase and catechol-O-methyltransferase genes with smoking behavior.

Pharmacogenet Genomics 2007 Oct;17(10):867-72

Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Objective: The genes of catalytic enzymes of dopamine, including monoamine oxidase (MAOA and MAOB) and catechol-O-methyltransferase (COMT), have been major candidates for genes that affect smoking behavior. In this study, we investigated the relationship between smoking behavior and four polymorphisms of these genes, the MAOA variable number tandem repeat polymorphism, the MAOA 1460 T/C polymorphism, the MAOB intron 13 G/A polymorphism, and the COMT Val158Met polymorphism. The association between the MAOB polymorphism and personality traits was also explored.

Participants And Methods: The polymorphisms were genotyped in 451 healthy Japanese volunteers. Data on smoking habits were obtained from structured interviews. In addition to testing the association between each polymorphism and smoking status, epistatic and additive effects between two polymorphisms were also investigated.

Results: A significant association was observed between the COMT Val158Met polymorphism and smoking status. Male participants with the Val/Val genotype had a significantly higher risk of heavy smoking compared with those with other genotypes, although no significant association was observed in female participants. No evidence was obtained for an association between the MAO genes and smoking behavior, including epistatic or additive effects. No significant association was observed between the MAOB polymorphism and personality traits.

Conclusion: This study may suggest a role of the COMT Val158Met polymorphism in smoking behavior in Japanese individuals.
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http://dx.doi.org/10.1097/FPC.0b013e3282e9a51eDOI Listing
October 2007

Expression of an acyl-CoA synthetase, lipidosin, in astrocytes of the murine brain and its up-regulation during remyelination following cuprizone-induced demyelination.

J Neurosci Res 2007 Dec;85(16):3586-97

Mitsubishi Kagaku Institute of Life Sciences, Machida-shi, Tokyo, Japan.

Lipidosin is an 80-kDa protein with long-chain acyl-CoA synthetase activity expressed in the brain, adrenal gland, testis, and ovary, which are selectively damaged in X-linked adrenoleukodystrophy (X-ALD). Western blot analysis of the cerebrum and cerebellum revealed a gradual increase in the expression of lipidosin postnatally. Light microscopic immunohistochemistry using a panel of specific monoclonal antibodies showed that the lipidosin-immunopositive cells were ubiquitously distributed in the brain and were denser in the gray matter than in the white matter. Lipidosin immunoreactivity was colocalized with GFAP immunoreactivity but not with ubiquitin C-terminal hydrolase 1 (= PGP9.5) immunoreactivity, a neuronal marker, and lipidosin-producing cells detected by an antisense probe specific for lipidosin mRNA were also GFAP immunopositive. These data together with Western blot analysis of primary cultured astrocytes indicate that lipidosin is expressed in astrocytes. Immunoelectron microscopic analysis revealed that lipidosin immunoreactivity was widely distributed from perivascular endfeet to perisynaptic processes without being limited to peroxisomes. Lipidosin immunoreactivity was greatly increased in astrocytes in the area of remyelination following experimental demyelination induced by the administration of cuprizone to mice. These data suggest that lipidosin was involved in fatty acid metabolism during reconstruction of the myelin sheath.
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http://dx.doi.org/10.1002/jnr.21456DOI Listing
December 2007

Versatile roles of R-Ras GAP in neurite formation of PC12 cells and embryonic vascular development.

J Biol Chem 2007 Feb 19;282(6):3413-7. Epub 2006 Dec 19.

Mitsubishi Kagaku Institute of Life Sciences (MITILS), Machida, Tokyo 194-8511, Japan.

Ras GTPase-activating proteins (GAP) are negative regulators of Ras that convert active Ras-GTP to inactive Ras-GDP. R-Ras GAP is a membrane-associated molecule with stronger GAP activity for R-Ras, an activator of integrin, than H-Ras. We found that R-Ras GAP is down-regulated during neurite formation in rat pheochromocytoma PC12 cells by nerve growth factor (NGF), which is blocked by the transient expression of R-Ras gap or dominant negative R-ras cDNA. By establishing a PC12 subclone that stably expresses exogenous R-Ras GAP, it was found that NGF reduced endogenous R-Ras GAP but not exogenous R-Ras GAP, suggesting that down-regulation of R-Ras GAP occurs at the transcription level. To clarify the physiological role of R-Ras GAP, we generated mice that express mutant Ras GAP with knocked down activity. While heterozygotes are normal, homozygous mice die at E12.5-13.5 of massive subcutaneous and intraparenchymal bleeding, probably due to underdeveloped adherens junctions between capillary endothelial cells. These results show essential roles of R-Ras GAP in development and differentiation: its expression is needed for embryonic development of blood vessel barriers, whereas its down-regulation facilitates NGF-induced neurite formation of PC12 cells via maintaining activated R-Ras.
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http://dx.doi.org/10.1074/jbc.C600293200DOI Listing
February 2007

No association between the CNTF null mutation and schizophrenia or personality.

Psychiatr Genet 2006 Oct;16(5):217-9

Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

The ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that plays a critical role in neurodevelopment. On the basis of neurodevelopmental hypothesis, the CNTF gene has been a candidate locus for schizophrenia. Several studies have investigated the association between the null mutation of the gene and schizophrenia, however, with inconsistent results. In the present study, we investigated the association in 222 Japanese patients with schizophrenia and 237 controls. The association between the mutation and personality traits was also studied, to investigate the effect of the mutation in participants from the general population. As a result, no association was observed between the mutation and schizophrenia nor personality traits, evaluated by using the Revised NEO Personality Inventory scores. The present study did not provide evidence for the association between the CNTF gene and schizophrenia or personality traits in the Japanese population.
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http://dx.doi.org/10.1097/01.ypg.0000242189.05656.9dDOI Listing
October 2006

Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits.

Psychiatry Clin Neurosci 2006 Aug;60(4):524-6

Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of anxiety disorders and depression. Corticotropin-releasing hormone receptor 2 (CRHR2) is one of the receptors that mediate CRH signal. The purpose of the present study was to investigate the association between the CRHR2 gene and personality traits, evaluated using the Revised NEO Personality Inventory (NEO PI-R), in 243 healthy Japanese subjects. As a result, significant association was observed between the polymorphism in intron 2 (rs2267717) and Openness (P = 0.004, uncorrected, anova), while no relationship was observed concerning Neuroticism. The present result suggests an association between CRHR2 and the personality trait of Openness.
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http://dx.doi.org/10.1111/j.1440-1819.2006.01541.xDOI Listing
August 2006

No association between the Clara cell secretory protein (CC16) gene polymorphism and personality traits.

Prog Neuropsychopharmacol Biol Psychiatry 2006 Aug 9;30(6):1122-4. Epub 2006 Jun 9.

Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan.

Clara cell secretory protein (CC16) is an anti-inflammatory protein expressed in the respiratory tract. Several studies have suggested the association between CC16 and mental disturbances, such as schizophrenia, depression, and post-traumatic stress disorder. In the present study, we investigated the association between the CC16 gene A38G polymorphism and personality traits in 214 healthy Japanese subjects. Personality traits were evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and the State-Trait Anxiety Inventory (STAI). As a result, no significant association was observed between the genotypes and the scores of the NEO PI-R or the STAI. The present results suggest that CC16 may not have a major role in the development of personality traits.
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http://dx.doi.org/10.1016/j.pnpbp.2006.04.019DOI Listing
August 2006