Language：English   Publishing type：Research paper (scientific journal)  

DOI： Rheumatology International https://doi.org/10.1007/s00296-024-05593-6

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Alzheimer's Disease  

Background: An association between poor oral health and cognitive decline has been reported. Most of these studies have considered the number of teeth as a criterion, only a few studies have analyzed the relationship between occlusal status and Alzheimer’s disease (AD). Objective: To elucidate whether posterior occlusal contact is associated with AD, focusing on the Eichner classification, among an older population aged 65 years or older in Japan. Methods: This study used monthly claims data of National Health Insurance in Japan from April 2017 to March 2020. The outcome was newly diagnosed AD defined according to ICD-10 code G30. The number of teeth was estimated by dental code data, and occlusal contact was divided into three categories, namely A, B, and C, according to the Eichner classification. Multivariate Cox proportional hazards models were used to analyze the association between a new diagnosis of AD and the Eichner classification. Results: A total of 22,687 participants were included, 560 of whom had newly diagnosed AD during a mean follow-up period of 12.2 months. The AD participants had a lower proportion of Eichner A and a higher proportion of Eichner C. After adjusting for covariates, hazard ratios (95% confidence intervals) with Eichner B and C were 1.34 (1.01–1.77) and 1.54 (1.03–2.30), respectively. Conclusions: In older people aged ≥ 65 years old, reduced posterior occlusal contact as well as tooth loss have an impact on AD. This study emphasizes the importance of paying attention to occlusal contacts to reduce the risk of AD.

DOI： 10.3233/JAD-230449

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PubMed

Web of Science

Language：English   Publisher：Hematology (United Kingdom)  

Objectives: Chemotherapy, including bendamustine, usually causes lymphocytopaenia and hypogammaglobulinaemia as side effects in patients with haematological malignancies. Therefore, the possibility has been considered that these immunological adverse events induced by bendamustine may lead to infectious diseases. However, lymphocytopaenia and/or hypogammaglobulinaemia have not yet been shown to have a statistically significant association with infection in cancer patients who receive bendamustine. Methods: We retrospectively studied 27 patients with relapsed or refractory indolent follicular lymphoma who were treated with bendamustine and rituximab (BR). In order to elucidate relationships between immune-related laboratory parameters (i.e. peripheral blood leukocyte, neutrophil, lymphocyte and immunoglobulin G [IgG]) and infectious events, receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were performed. Results: Infectious diseases occurred in 11 patients (11/27, 41%), including 3 (3/27, 11%) with severe diseases. The area under the ROC curve (AUC) showed that the lowest IgG level during and after BR discriminated infectious events (cut-off value, 603 mg/dL) with 81.8% sensitivity and 68.8% specificity (AUC, 0.76; 95% CI, 0.52-0.90). Furthermore, a multivariate regression analysis revealed that the minimal serum IgG value during and after BR therapy was the only variable that was significantly associated with infection (odds ratio, 8.29; 95% CI, 1.19-57.62; p value, 0.03). Conclusion: Serum IgG ≤603 mg/dL during and after BR therapy was independently associated with an increased risk of infection. The monitoring of serum IgG during chemotherapy may help to predict the development of infection in blood cancer patients undergoing chemotherapy with bendamustine in combination with rituximab.

DOI： 10.1080/16078454.2022.2051863

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Background: To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient’s satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients. Methods: This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient’s satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment. Results: This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, “very satisfied” and “satisfied” were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50–64 years; OR 0.91; 65–74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas. Conclusions: In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.

DOI： https://doi.org/10.1186/s13075-022-02746-5

Language：English   Publisher：(一社)日本血液学会  

レニン-アルドステロン-アンジオテンシン系阻害剤(RAASi)を含む特定の降圧薬の偶発的使用が、TKI治療中の慢性骨髄性白血病(CML)の推算糸球体濾過量(eGFR)の変化に及ぼす影響を評価した。対象は当院のCML患者142名で、混合効果モデルを用いてeGFR変化率を推定し、TKI治療中の全てのeGFR測定値を遡及的に分析した。全体的に、使用した降圧薬の種類とeGFRの年間変化との間に有意な相互作用を認め、RAASi使用者が最も急速なeGFR減少(-5.5%/年)を示した。TKI別の分析では、イマチニブ(IMA)とボスチニブ(BOS)の間でのみ相互作用が有意であった。eGFRの年間減少率はRAASi使用者で最も顕著で、IMAとBOSでは-5.7と-10.1であった。以上より、上記TKIを服用している患者はeGFRを監視する必要があると考えられた。

Language：English   Publisher：Hypertension Research  

Renin-angiotensin system inhibitors have been shown to prevent cancer metastasis in experimental models, but there are limited data in clinical studies. We aimed to explore whether renin-angiotensin system inhibitors administered during the period of cancer resection can influence the subsequent development of metastasis by analyzing multiple individual types of primary cancers. A total of 4927 patients who had undergone resection of primary cancers at Kyushu University Hospital from 2009 to 2014 were enrolled and categorized into 3 groups based on the use of antihypertensive drugs: renin-angiotensin system inhibitors, other drugs, and none. Cumulative incidence functions of metastasis, treating death as a competing risk, were calculated, and the difference was examined among groups by Gray’s test. Fine and Gray’s model was employed to evaluate multivariate-adjusted hazards of incidental metastasis. In the multivariate-adjusted analysis, patients with skin and renal cancers showed statistically higher risks of metastasis with the use of renin-angiotensin system inhibitors (hazard ratio [95% confidence interval], 5.81 [1.07–31.57] and 4.24 [1.71–10.53], respectively). Regarding pancreatic cancer, patients treated with antihypertensive drugs other than renin-angiotensin system inhibitors had a significantly increased risk of metastasis (hazard ratio [95% confidence interval], 3.31 [1.43–7.69]). Future larger studies are needed to ascertain whether renin-angiotensin system inhibitors can increase the risk of metastasis in skin and renal cancers, focusing on specific tissue types and potential factors associated with renin-angiotensin system inhibitor use.

DOI： 10.1038/s41440-022-01038-4

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PubMed

Language：English   Publisher：International Journal of Hematology  

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, TKI-related chronic renal toxicity has been reported, particularly in patients with hypertension. We assessed whether incidental use of specific types of antihypertensive drugs, including renin–aldosterone–angiotensin system inhibitors (RAASis), affects the change in estimated glomerular filtration rate (eGFR) during TKI treatment. We retrospectively analyzed all eGFR measurements during TKI treatment for 142 CML patients at Kyushu University Hospital, estimating the rate of eGFR change using a mixed-effects model. Overall, a significant interaction was found between the type of antihypertensive medication used and the yearly change in eGFR (P < 0.01), with RAASi users exhibiting the most rapid decrease in eGFR (− 5.5%/year). The analysis by TKI used showed that the interaction was significant only in imatinib and bosutinib users (P < 0.01 and P = 0.04, respectively). The yearly rate of eGFR decrease was the most notable in RAASi users, at − 5.7 (− 6.6, − 4.9) and − 10.1 (− 12.3, − 7.9) for imatinib and bosutinib users, respectively. Our findings indicate that eGFR should be carefully monitored in patients taking these TKIs.

DOI： 10.1007/s12185-022-03433-6

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Language：English   Publisher：Nature Publishing Group  

がん切除時のレニン-アンジオテンシン系(RAS)阻害薬の投与が、その後の転移出現に影響を及ぼすか検討した。2009年1月1日～2014年12月31日に日本の単一施設で原発がんの切除を行い、90日以上の観察を行ったがん患者4927名(男性2654例、女性2273例、中央値66歳)の医療記録を解析した。RAS阻害薬投与群(1064例)、他の降圧薬投与群(975例)、降圧薬非投与群(2888例)に分類し、原発がんの種類別に転移リスクを評価した。多変量調整解析において、皮膚癌および腎癌の患者ではRAS阻害薬投与群で転移リスクが有意に増大し(ハザード比はそれぞれ5.81[95%CI 1.07～31.57]、4.24[95%CI 1.71～10.53])、膵癌患者では他の降圧薬投与群で転移リスクが有意に増大した(ハザード比3.31[95%CI 1.43～7.69])。皮膚癌と腎癌におけるRAS阻害薬による転移リスク増大については、特定の組織型およびRAS阻害薬使用の関連因子に注目して、さらに研究する必要があることが示された。

Language：English   Publishing type：Research paper (scientific journal)  

Renin-angiotensin system inhibitors have been shown to prevent cancer metastasis in experimental models, but there are limited data in clinical studies. We aimed to explore whether renin-angiotensin system inhibitors administered during the period of cancer resection can influence the subsequent development of metastasis by analyzing multiple individual types of primary cancers. A total of 4927 patients who had undergone resection of primary cancers at Kyushu University Hospital from 2009 to 2014 were enrolled and categorized into 3 groups based on the use of antihypertensive drugs: renin-angiotensin system inhibitors, other drugs, and none. Cumulative incidence functions of metastasis, treating death as a competing risk, were calculated, and the difference was examined among groups by Gray’s test. Fine and Gray’s model was employed to evaluate multivariate-adjusted hazards of incidental metastasis. In the multivariate-adjusted analysis, patients with skin and renal cancers showed statistically higher risks of metastasis with the use of renin-angiotensin system inhibitors (hazard ratio [95% confidence interval], 5.81 [1.07–31.57] and 4.24 [1.71–10.53], respectively). Regarding pancreatic cancer, patients treated with antihypertensive drugs other than renin-angiotensin system inhibitors had a significantly increased risk of metastasis (hazard ratio [95% confidence interval], 3.31 [1.43–7.69]). Future larger studies are needed to ascertain whether renin-angiotensin system inhibitors can increase the risk of metastasis in skin and renal cancers, focusing on specific tissue types and potential factors associated with renin-angiotensin system inhibitor use.

DOI： https://doi.org/10.1038/s41440-022-01038-4

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: Chemotherapy, including bendamustine, usually causes lymphocytopaenia and hypogammaglobulinaemia as side effects in patients with haematological malignancies. Therefore, the possibility has been considered that these immunological adverse events induced by bendamustine may lead to infectious diseases. However, lymphocytopaenia and/or hypogammaglobulinaemia have not yet been shown to have a statistically significant association with infection in cancer patients who receive bendamustine. Methods: We retrospectively studied 27 patients with relapsed or refractory indolent follicular lymphoma who were treated with bendamustine and rituximab (BR). In order to elucidate relationships between immune-related laboratory parameters (i.e. peripheral blood leukocyte, neutrophil, lymphocyte and immunoglobulin G [IgG]) and infectious events, receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were performed. Results: Infectious diseases occurred in 11 patients (11/27, 41%), including 3 (3/27, 11%) with severe diseases. The area under the ROC curve (AUC) showed that the lowest IgG level during and after BR discriminated infectious events (cut-off value, 603 mg/dL) with 81.8% sensitivity and 68.8% specificity (AUC, 0.76; 95% CI, 0.52-0.90). Furthermore, a multivariate regression analysis revealed that the minimal serum IgG value during and after BR therapy was the only variable that was significantly associated with infection (odds ratio, 8.29; 95% CI, 1.19-57.62; p value, 0.03). Conclusion: Serum IgG ≤603 mg/dL during and after BR therapy was independently associated with an increased risk of infection. The monitoring of serum IgG during chemotherapy may help to predict the development of infection in blood cancer patients undergoing chemotherapy with bendamustine in combination with rituximab.

DOI： https://doi.org/10.1080/16078454.2022.2051863

Language：English   Publishing type：Research paper (scientific journal)  

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, TKI-related chronic renal toxicity has been reported, particularly in patients with hypertension. We assessed whether incidental use of specific types of antihypertensive drugs, including renin–aldosterone–angiotensin system inhibitors (RAASis), affects the change in estimated glomerular filtration rate (eGFR) during TKI treatment. We retrospectively analyzed all eGFR measurements during TKI treatment for 142 CML patients at Kyushu University Hospital, estimating the rate of eGFR change using a mixed-effects model. Overall, a significant interaction was found between the type of antihypertensive medication used and the yearly change in eGFR (P < 0.01), with RAASi users exhibiting the most rapid decrease in eGFR (− 5.5%/year). The analysis by TKI used showed that the interaction was significant only in imatinib and bosutinib users (P < 0.01 and P = 0.04, respectively). The yearly rate of eGFR decrease was the most notable in RAASi users, at − 5.7 (− 6.6, − 4.9) and − 10.1 (− 12.3, − 7.9) for imatinib and bosutinib users, respectively. Our findings indicate that eGFR should be carefully monitored in patients taking these TKIs.

DOI： https://doi.org/10.1007/s12185-022-03433-6

Language：English   Publishing type：Research paper (scientific journal)  

This study aimed to show geographical differences in esophageal cancer mortality in Japan and reveal an association of esophageal cancer mortality with municipal socioeconomic deprivation level. Esophageal cancer mortality data in the Vital Statistics from 2013 to 2017 for each municipality and corresponding population data were analyzed. The deprivation level was derived from the municipal socioeconomic variables by principal component analysis. Municipalities were classified into five quintiles based on the deprivation level, and an association between the level and esophageal cancer mortality was evaluated using a Bayesian spatial model. As a result of regression analysis, the relative risk of esophageal cancer mortality tended to become larger as the deprivation level increased irrespective of sex, and the relative risk of esophageal cancer mortality was significantly higher in quintile 5 (most deprived) than quintile 1 (least deprived) among men and women. These results suggest that the deprivation level increases the risk of esophageal cancer mortality in Japan.

DOI： https://doi.org/10.3390/ijerph19095483

Language：English   Publisher：International Journal of Environmental Research and Public Health  

This study aimed to show geographical differences in esophageal cancer mortality in Japan and reveal an association of esophageal cancer mortality with municipal socioeconomic deprivation level. Esophageal cancer mortality data in the Vital Statistics from 2013 to 2017 for each municipality and corresponding population data were analyzed. The deprivation level was derived from the municipal socioeconomic variables by principal component analysis. Municipalities were classified into five quintiles based on the deprivation level, and an association between the level and esophageal cancer mortality was evaluated using a Bayesian spatial model. As a result of regression analysis, the relative risk of esophageal cancer mortality tended to become larger as the deprivation level increased irrespective of sex, and the relative risk of esophageal cancer mortality was significantly higher in quintile 5 (most deprived) than quintile 1 (least deprived) among men and women. These results suggest that the deprivation level increases the risk of esophageal cancer mortality in Japan.

DOI： 10.3390/ijerph19095483

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PubMed

Language：English   Publisher：Arthritis Research and Therapy  

Background: To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient’s satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients. Methods: This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient’s satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment. Results: This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, “very satisfied” and “satisfied” were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50–64 years; OR 0.91; 65–74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas. Conclusions: In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.

DOI： 10.1186/s13075-022-02746-5

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Background: We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen. Patients and Methods: Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m²/day), doxorubicin (10 mg/m²/day), and vincristine (0.4 mg/m²/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m²/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert's formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6. Results: In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation. Conclusion: The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.

DOI： 10.1016/j.clml.2020.03.008

Language：English   Publishing type：Research paper (scientific journal)  

Purpose Although several genetic factors may play a role in leisure-time exercise behavior, there is currently no evidence of a significant genomewide association, and candidate gene replication studies have produced inconsistent results. Methods We conducted a two-stage genomewide association study and candidate single-nucleotide polymorphisms (SNP) association study on leisure-time exercise behavior using 13,980 discovery samples from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, and 2036 replication samples from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center-2 study. Leisure-time physical activity was measured using a self-administered questionnaire that inquired about the type, frequency and duration of exercise. Participants with ≥4 MET·h·wk^-1 of leisure-time physical activity were defined as exhibiting leisure-time exercise behavior. Association testing using mixed linear regression models was performed on the discovery and replication samples, after which the results were combined in a meta-analysis. In addition, we tested six candidate genetic variants derived from previous genomewide association study. Results We found that one novel SNP (rs10252228) located in the intergenic region between NPSR1 and DPY19L1 was significantly associated with leisure-time exercise behavior in discovery samples. This association was also significant in replication samples (combined P value by meta-analysis = 2.2 × 10^-9). Several SNP linked with rs10252228 were significantly associated with gene expression of DPY19L1 and DP19L2P1 in skeletal muscle, heart, whole blood, and the nervous system. Among the candidate SNP, rs12612420 in DNAPTP6 demonstrated nominal significance in discovery samples but not in replication samples. Conclusions We identified a novel genetic variant associated with regular leisure-time exercise behavior. Further functional studies are required to validate the role of these variants in exercise behavior.

DOI： 10.1249/MSS.0000000000001712

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: To identify the determinant of patients’ perspectives of quality of life (QOL) and working status out of analysis-derived components underlying a set of assessment measures of the status of patients with rheumatoid arthritis (RA). Methods: From the NinJa database in Japan (2012–2014), 1455 RA patients with DAS28 > 3.2 were recruited. Components explaining RA status were derived from principal component analysis of 15 assessment measures. Multivariate regression was used to examine the relative contribution of each identified component to the EuroQOL-5 Dimension Questionnaire score and working status. Results: Among the identified components (patient symptoms, physical disability, evaluated symptoms, patient distress, inflammatory marker, and serological marker), patient distress showed highest contribution to EuroQOL for both male (44.6%) and female patients (39.3%). Physical disability was associated with significantly less participation in paid work in male (odds ratio [OR]; 0.63) and both household and paid work in female (OR; 0.82 and 0.54, respectively), though patient distress showed the strongest association with less participation in both household and paid work in female (OR; 0.64 and 0.45, respectively). Conclusion: The approach to latent patient distress using psychological screening tools, concurrently with the treatment to control the activity of arthritis, can be help to improve health-related QOL (HRQOL) including work participation.

DOI： 10.1080/14397595.2018.1428043

Language：English   Publishing type：Research paper (scientific journal)  

Background: Although beneficial associations have been reported between moderate alcohol intake and the serum lipid profile, it is unclear whether polymorphisms in alcohol-metabolizing enzymes can modify these associations. Here, we assessed the effects of ADH1B His48Arg (rs1229984), ALDH2 Glu504Lys (rs671), and their combination on these associations. Furthermore, we examined if the findings for ALDH2 could be replicated. Methods: We categorized 889 male participants in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study into two groups based on presence or absence of minor allele(s) or four groups based on genotype combinations. We performed regression analyses of serum lipid concentrations on alcohol intake, with multivariable adjustment. The replication study was conducted among 2,562 men in the Shizuoka part of the J-MICC Study. Results: The ALDH2 Glu=Lys or Lys=Lys groups showed significant decreases in serum low-density lipoprotein (LDL) cholesterol with increasing alcohol consumption; the coefficient per intake increase of 10 g=day was −2.49 mg=dL (95% confidence interval [CI], −3.85 to −1.13), and a significant interaction with the polymorphism was confirmed (P for interaction = 0.006). This inverse correlation was more evident among the ADH1B His=His + ALDH2 Glu=Lys or Lys=Lys groups (−3.24 mg=dL, 95% CI, −5.03 to −1.45). Serum triglycerides were positively associated with alcohol consumption in the ADH1B His=His group (P for interaction = 0.020). The stronger association between serum LDL cholesterol and alcohol consumption in the ALDH2 Glu=Lys or Lys=Lys groups was replicated. Conclusions: The ALDH2 Glu504Lys polymorphism can modify the association between alcohol intake and serum LDL cholesterol in Japanese men.

DOI： 10.2188/jea.JE20160189

Language：English   Publishing type：Research paper (scientific journal)  

Aim: The purpose of this study was to assess 5-year changes in physical function and factors associated with improvement among patients with rheumatoid arthritis (RA) in daily clinical practice, focusing on the effect of treatments, including biologic agents, in the early stage of disease course. Methods: The National Database of Rheumatic Diseases by iR-net in Japan (NinJa) was searched for patients with disease duration ≤ 2 years and modified health assessment questionnaire (mHAQ) > 0 between 2004 and 2007, so that 510 patients were included in the final analysis. Multivariate-logistic regression analyses were used to identify predictors of 5-year mHAQ disability score improvement. Results: Median mHAQ score was 0.40 at baseline and decreased to a median 0.17 after 5 years. Seventy-four percent of the patients were treated with methotrexate (MTX) and 25% with biologic agents, with early use of biologic agents (within 2 years of RA onset) increasing over time. Multivariate analyses identified higher baseline Disease Activity Score of 28 joints – C-reactive protein and early use of MTX (within 1 year of RA onset) and of biologic agents (within 2 years) as significantly associated with improved mHAQ; odds ratios of the early treatment were 1.83 (P = 0.01) for MTX and 2.23 (P = 0.04) for biologic agents, respectively. Conclusion: Five-year mHAQ improved in early RA patients in the NinJa database. In daily clinical management of RA, likewise in clinical trials, early administration of MTX or biologic agents is able to improve physical function outcome.

DOI： 10.1111/1756-185X.12877

Language：English   Publishing type：Research paper (scientific journal)  

Background and Objectives: Recent observational studies have suggested a positive association of white rice and protective associations of green tea and coffee with the risk of diabetes. However, none have examined the interaction between these dietary factors on the risk of diabetes. We prospectively investigated the effect modification of green tea and coffee on the association between rice and incident diabetes in elderly Japanese men and women. Methods and Study Design: Among subjects who participated in the baseline survey (2004-2007), 11717 (91 %) subjects responded to the follow-up survey (2010-2012). By using multiple logistic regression analysis, ORs of incident diabetes were calculated according to categories of cereal food, green tea, and coffee intakes, examining also the effect modification of green tea and coffee. Results: 464 new cases of diabetes were identified. Women, but not men, showed a positive association of rice intake (trend p=0.008) and an inverse association of green tea intake (trend p=0.02) with incident diabetes. Coffee showed no association with incident diabetes either in men or women. In the analysis stratified by green tea intake, the association between rice and diabetes disappeared among women with an intake of =7 cups/d of green tea (interaction p=0.08). Conclusions: Rice intake was associated with an increased risk of diabetes only in women, and women with a higher intake of green tea had a lower risk of diabetes. A high intake of green tea may be protective against increased risk of diabetes with a higher intake of rice in women.

DOI： 10.6133/apjcn.042016.04

Language：English   Publishing type：Research paper (scientific journal)  

Background: High-sensitivity C-reactive protein (hsCRP) levels are lower in Japanese compared with Western subjects. Since it is uncertain whether hsCRP is a potent predictor of mortality at low CRP concentrations, the present study examined associations with all-cause and cause-specific mortality in a large population of Japanese. Materials and Methods: Subjects were 4,737 men and 6,343 women aged 49-76 years participating in the baseline survey of an ongoing cohort study of lifestyle-related diseases between February 2004 and July 2006. Hazard ratios for all-cause and cause-specific mortality associated with hsCRP levels were estimated using Cox proportional hazards regression. Results: A total of 436 all-cause deaths occurred during a median followup of 8 years. The main cause of death was cancer. In men, hsCRP levels were positively associated with the risk of all-cause mortality as well as deaths from cancer and cardiovascular disease (CVD). All-cause mortality hazards for the 2nd (0.34-0.84 mg/L) and the 3rd (≥ 0.85 mg/L) tertiles of hsCRP were 1.27 (95% confidence interval [CI], 0.93-1.73) and 1.75 (1.30-2.37), respectively (p for trend=0.001). In women, increased risk of allcause and cause-specific mortality associated with elevated hsCRP levels was observed, but the associations were not statistically significant. Conclusions: HsCRP may be an independent predictor of all-cause, cancer and CVD mortality in apparently healthy Japanese men, but not women. The differential effect of hsCRP in predicting mortality risk by sex warrants further investigation.

DOI： 10.7314/APJCP.2016.17.5.2643

Language：English   Publishing type：Research paper (scientific journal)  

Objective: Inflammation is closely involved in the development of type 2 diabetes, and cigarette smoking acts as potent inducer of inflammation. We therefore investigated interactions between inflammation-related gene polymorphisms and cigarette smoking on glycated hemoglobin (HbA_1c) in the Japanese general population. Method: We conducted a cross-sectional study using data collected from 2619 Japanese (1274 males and 1345 females) 40-69 years of age who participated in baseline survey of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study (2005-2008). Eight polymorphisms in seven genes (interleukin [IL]-1β, IL-2, IL-4, IL-8, IL-10, IL-13 and tumor necrosis factor-α) were determined using the Invader assay. The interactions of smoking and gene polymorphisms on HbA_1c levels were analyzed using multiple linear and logistic regression models and analysis of covariance with adjustment for potential confounders. Results: Among the eight polymorphisms, only one significant interaction was detected for IL-1β T-31C (P < 0.0001). Among the subjects carrying TT genotype, current heavy smokers (≥20 cigarettes/day) had higher HbA_1c (5.83 [95% confidence interval 5.67-5.99] %) versus all other smoking status groups (never 5.49 [5.41-5.56] %, former 5.54 [5.43-5.65] %, current moderate [<20 cigarettes/day] 5.50 [5.30-5.69] %), whereas such differences were not observed in the subjects with C allele. The logistic regression analyses regarding high-normal HbA_1c levels showed a similar pattern of results. Conclusion: Smoking status did not interact with any other inflammation-related polymorphisms except for IL-1β T-31C. Heavy smokers harboring the TT genotype of IL-1β T-31C polymorphism show a greater adverse effect of smoking on HbA_1c levels among Japanese middle-aged subjects.

DOI： 10.1016/j.pmedr.2016.03.010

Language：English   Publishing type：Research paper (scientific journal)  

Hyperuricaemia is an undisputed and highly predictive biomarker for cardiovascular risk. SLC17A1, expressed in the liver and kidneys, harbours potent candidate single nucleotide polymorphisms that decrease uric acid levels. Therefore, we examined SLC17A1 polymorphisms (rs1165196, rs1179086, and rs3757131), which might suppress cardiovascular risk factors and that are involved in liver functioning, via a large-scale pooled analysis of the Japanese general population in a cross-sectional study. Using data from the Japan Multi-Institutional Collaborative Cohort Study, we identified 1842 participants of both sexes, 35-69-years-old, having the requisite data, and analysed their SLC17A1 genotypes. In men, logistic regression analyses revealed that minor alleles in SLC17A1 polymorphisms (rs1165196 and rs3757131) were associated with a low-/high-density lipoprotein cholesterol ratio >2.0 (rs1165196: odds ratio [OR], 0.703; 95% confidence interval [CI], 0.536-0.922; rs3757131: OR, 0.658; 95% CI, 0.500-0.866), and with homocysteine levels of >10.0 nmol/mL (rs1165196: OR, 0.544; 95% CI, 0.374-0.792; rs3757131: OR, 0.509; 95% CI, 0.347-0.746). Therefore, these polymorphisms had dominant negative effects on cholesterol homeostasis and hyperhomocysteinaemia, in men, independent of alcohol consumption, physical activity, or daily energy and nutrition intake. Thus, genetic variants of SLC17A1 are potential biomarkers for altered cholesterol homeostasis and hyperhomocysteinaemia in Japanese men.

DOI： 10.1038/srep15888

Language：English   Publishing type：Research paper (scientific journal)  

Programmed cell death ligand 1 (PD-L1) is expressed on both select diffuse large B-cell lymphoma (DLBCL) tumor cells and on tumor-infiltrating nonmalignant cells. The programmed cell death 1 (PD-1)/PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in the tumor microenvironment. The aim of this study was to determine the clinicopathological impact of PD-L1⁺ DLBCL. We performed PD-L1/PAX5 double immunostaining in 1253 DLBCL biopsy samples and established a new definition of PD-L1⁺ DLBCL. We also defined the criteria for microenvironmental PD-L1⁺ (mPD-L1⁺) DLBCL (ie, PD-L1^- DLBCL in which PD-L1⁺ nonmalignant cells are abundant in the tumor microenvironment). Of the 273 patients whose clinical information was available, quantitative analysis of PD-11 tumor-infiltrating lymphocytes (TILs) was performed. The prevalence rates of PD-L1⁺ and mPD-L1⁺ DLBCL were 11% and 15.3%, respectively. Both PD-L1⁺ and mPD-L1⁺ DLBCL were significantly associated with non-germinal center B-cell (GCB) type and Epstein-Barr virus positivity. The number of PD-11 TILs was significantly higher in GCB-type tumors and lower in mPD-L1- and PD-L1⁺ DLBCL. Patients with PD-L1⁺ DLBCL had inferior overall survival (OS) compared with that in patients with PD-L1- DLBCL (P 5 .0009). In contrast, there was no significant difference in OS betweenmPD-L1⁺ andmPD-L1^-DLBCL(P5.31). The expression of PD-L1 maintained prognostic value for OS in multivariate analysis (P 5 .0323). This is the first report describing the clinicopathological features and outcomes of PD-L1⁺ DLBCL. Immunotherapy targeting the PD-1/PD-L1 pathway should be considered in this distinct DLBCL subgroup.

DOI： 10.1182/blood-2015-02-629600

Language：English   Publishing type：Research paper (scientific journal)  

Background: A considerable interest has been drawn to potential protective effects of bilirubin against oxidative stress-related diseases. Smoking is known to be associated with lower concentrations of serum bilirubin, but other behavioral correlates of serum bilirubin have not been well studied. In this cross-sectional study, we examined the associations of behavioral and clinical factors with serum total bilirubin in Japanese men and women. Method: The study subjects comprised of 4802 men and 6414 women aged 49-76 years who participated in the baseline survey of an ongoing cohort study on lifestyle-related diseases in Fukuoka, Japan. With consideration to time of the day of blood sampling and fasting hours, the associations with smoking, alcohol intake, body mass index, physical activity, coffee, tea, blood pressure, glycated hemoglobin (HbA1c), HDL cholesterol and non-HDL cholesterol with serum bilirubin were evaluated by analysis of covariance and multiple linear regression analysis. Results: While smoking was negatively associated with serum bilirubin, alcohol consumption was positively associated with serum bilirubin in both men and women. Coffee consumption was associated with lower bilirubin concentrations in both sexes. In the multiple linear regression analysis, HDL cholesterol was positively and HbA1c was negatively associated with bilirubin in both men and women, and the associations were more evident in women. Conclusion: Smoking, alcohol use and coffee consumption were important behavioral correlates of serum bilirubin in Japanese men and women. Serum HDL cholesterol was a measurable clinical correlate of bilirubin in women.

DOI： 10.1186/1472-6823-13-39

Language：English   Publishing type：Research paper (scientific journal)  

Background: Inflammation has been implicated in the pathogenesis of cardiovascular disease, type 2 diabetes mellitus and cancer. Serum concentration of high-sensitivity C-reactive protein is a good biomarker of chronic low-grade inflammation. Few studies have evaluated relative importance of behavioral and clinical covariates of high-sensitivity C-reactive protein in Japanese population. Methods: The study subjects were men and women aged 49-76 years from the cohort study of lifestyle-related diseases between February 2004 and July 2006. Analysis of covariance and multiple linear regression analysis were used to estimate geometric means of high-sensitivity C-reactive protein and trends of association. Results: Smoking, body mass index, hypertension, type 2 diabetes mellitus, elevated non-high density lipoprotein cholesterol, prudent dietary pattern were independently associated with serum high-sensitivity C-reactive protein in both men and women. High-sensitivity C-reactive protein concentrations were lowest in men with a moderate intake of alcohol (< 30 mL/day). In men, smoking and body mass index accounted for 28 % and 26 % of the variation in high-sensitivity C-reactive protein, respectively, while body mass index accounted for 60 % of the variation of high-sensitivity C-reactive protein in women. Conclusions: Smoking and body mass index in men, and body mass index in women, were major correlates of serum high-sensitivity C-reactive protein in Japanese people.

DOI： 10.1515/cclm-2011-0839

Language：English   Publishing type：Research paper (scientific journal)  

We report the case of a 31-year-old woman who developed adult-onset Still's disease (AOSD) with a high level of serum interleukin (IL)-18. Although treated with high dose steroids, she suffered repeated remissions and her condition deteriorated. After we administered oral cyclosporine A (CsA), 200 mg/d, monitoring C2 and trough levels, her symptoms improved significantly. We decreased the dose of methylprednisolone slowly without noting a relapse. The use of CsA accompanied by C2 and trough level monitoring should be considered for refractory AOSD patients with high levels of serum IL-18.

Language：English   Publishing type：Research paper (scientific journal)  

A 58-year-old woman was diagnosed with Churg-Strauss syndrome (CSS) based on the symptoms of bronchial asthma, eosinophilia, mononeuritis multiplex and histological examination of the right sural nerve. Prior to treatment, the serum interleukin (IL)-5 level was high, and rearrangement of the T cell receptor (TCR) gene was identified. This is the first report of TCR gene rearrangement in a patient with CSS. The expanded T cell clone may be responsible for the overproduction of IL-5. Further studies are warranted to disclose a prevalence of TCR gene rearrangement in CSS patients and its pathophysiological roles in the development of this disease.

DOI： 10.1007/s10165-010-0341-3

Language：English   Publishing type：Research paper (scientific journal)  

We report a 29-year-old woman with a 2.5 year history of mixed connective tissue disease (MCTD) who developed idiopathic portal hypertension (IPH) and thrombocytopenia as a result of hypersplenism. She had recurrent esophagogastric variceal rupture. Hematological examination also revealed low levels of protein C activity. The liver biopsy specimen showed non-specific mild inflammation and no thrombi. However, portal vein thrombosis developed after splenectomy. This was a rare case of severe complications of IPH accompanying MCTD and protein C deficiency.

DOI： 10.2169/internalmedicine.49.3834

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To investigate the clinical characteristics of patients with Churg-Strauss syndrome (CSS), including symptoms, blood chemistry and immunological findings. Patients and methods: We retrospectively investigated the records of 11 patients (six female and five male) with CSS admitted to our hospital from September 2003 to October 2009. Results: Eight patients had preceding symptoms including bronchial asthma and allergic rhinitis. Seven patients showed eosinophilia. Nine patients had mononeuritis multiplex. Positive findings of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) were found in five patients. Neither clinical manifestations nor laboratory findings were correlated with positivity for MPO-ANCA. However, the MPO-ANCA-positive group showed a higher level of blood urea nitrogen and proteinuria than those negative for MPO-ANCA. Ten patients recovered after starting steroid or immunosuppressive therapy, although one patient died of unknown etiology. Conclusion: Although general assessments based on various factors such as medical history, clinical manifestation and laboratory studies are indispensable in CSS, MPO-ANCA might be useful as a predictor of renal dysfunction in patients with CSS.

DOI： 10.1111/j.1756-185X.2010.01479.x

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OBJECTIVE: To clarify the clinical usefulness of cerebrospinal fluid (CSF) interleukin-6 (IL-6) measurement in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), we studied CSF IL-6 levels in patients with NPSLE and analyzed the association between CSF IL-6 levels and other clinical findings of NPSLE. PATIENTS AND METHODS: We retrospectively analyzed records of 37 patients (33 females and four males) with NPSLE admitted to our hospital between January 2003 and December 2008. RESULTS: All patients showed neuropsychiatric symptoms. Fourteen patients showed abnormalities in brain magnetic resonance imaging (MRI) and 12 patients had abnormal findings in electroencephalography (EEG). Increased CSF cell counts and elevated levels of CSF IL-6 were found in 11 and 30 patients, respectively. Elevated levels of CSF IL-6 were not statistically correlated with specific abnormalities in the blood analysis, in increased CSF cell counts, and in abnormalities in the brain MRI and EEG. In addition, a group of NPSLE patients positive for antiphospholipid antibodies (aPL) showed lower CSF IL-6 than the patients negative for aPL. CONCLUSION: These results indicated that CSF IL-6 might be useful in diagnosis of NPSLE. However, general assessments of patients based on various factors (clinical manifestations, imaging findings and CSF examinations) are also required.

Language：English   Publishing type：Research paper (scientific journal)  

A 63-year-old-man was diagnosed in March 2002 with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis because of mononeuritis multiplex, interstitial pneumonia and a positive finding for myeloperoxidase (MPO)-ANCA. Although treated with prednisolone and oral cyclophosphamide, he suffered repeated remission and deterioration of his conditon, which was complicated by hypertrophic pachymeningitis and sinusitis. In July 2006, he was diagnosed with an exacerbation of ANCA-associated vasculitis because of pyrexia, general malaise, numbness in his face and legs, and elevated serum CRP level. Steroid pulse therapy was thus initiated and the patient's clinical symptoms improved. However, serum CRP levels elevated again (5.18 mg/dl) in September 2006.We began administration of rituximab (500 mg/body x 4 times) in November 2006 and his symptom and laboratory data signifficantly improved. The dose of prednisolone was slowly decreased without suffering a relapse. Rituximab has been administered every one year, and good disease control has been achieved. Diagnosis of Wegener's granulomatosis was made from the findings of a nodular lesion in the left lung. Rituximab should be considered for patients with refractory ANCA-associated vasculitis.

DOI： 10.2177/jsci.33.105

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