Publications by authors named "Atsushi Takahashi"

860 Publications

Impact of the objective response to and number of cycles of platinum-based first-line chemotherapy for metastatic urothelial carcinoma on overall survival of patients treated with pembrolizumab.

Int J Urol 2021 Sep 20. Epub 2021 Sep 20.

Department of Urology, University of Toyama, Toyama, Japan.

Objectives: To investigate the impact of the number of cycles and objective response to chemotherapy on overall survival in patients with metastatic urothelial carcinoma treated with pembrolizumab.

Methods: This multicenter, retrospective study included 755 patients from 59 institutions with advanced, chemoresistant urothelial carcinoma who received pembrolizumab. The associations of the overall survival with the number of cycles and best objective response were investigated using Cox multiple regression analysis.

Results: Overall, 391 patients received standard first-line chemotherapy and pembrolizumab as a second-line treatment, and were included in the final analysis. Of the 391 patients, 185 received less than four cycles, 134 received four to six cycles and 72 received more than six cycles of first-line chemotherapy. An objective response (complete or partial response) to chemotherapy was observed in 145 patients (37.1%). Univariate analysis showed that the overall survival of patients who received more than six cycles or responded to chemotherapy (complete or partial response) was significantly longer than that of patients who received less than four cycles or did not respond to chemotherapy (stable or progressive disease). At multivariate levels, no correlations were observed between overall survival and the number of cycles of or the response to chemotherapy.

Conclusions: Therapeutic benefit of pembrolizumab can be expected irrespective of the objective response to and number of cycles of platinum-based first-line chemotherapy.
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http://dx.doi.org/10.1111/iju.14686DOI Listing
September 2021

A case report of fibrolamellar hepatocellular carcinoma, with particular reference to preoperative diagnosis, value of molecular genetic diagnosis, and cell origin.

Surg Case Rep 2021 Sep 17;7(1):208. Epub 2021 Sep 17.

Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan.

Background: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a liver tumor that occurs almost exclusively in young adults without underlying liver disease. In spite of its distinct clinical characteristics and specific imaging findings, preoperative diagnosis is often difficult due to the extremely low incidence of the tumor. Although FL-HCC shows particular morphological features on H&E-stained tissue sections, differential diagnosis from ordinary HCC, especially the scirrhous variant of HCC, and intrahepatic cholangiocarcinoma needs additional immunohistochemical (IHC) analyses and/or molecular genetic testing.

Case Presentation: A 21-year-old male patient was referred to our hospital for further evaluation of a large liver mass. Abdominal ultrasound examination, contrast-enhanced computed tomography, and magnetic resonance imaging revealed a well-defined hypervascular lobulated liver mass, 11 × 11 cm in diameter, with a central scar and calcification, in segments 5/8. Under the diagnosis of FL-HCC, we carried out extended anterior sectorectomy, including a part of segment 4. On microscopic examination, the tumor was composed of proliferating polygonal cells with abundant eosinophilic granular cytoplasm containing nuclei with vesicular chromatin and enlarged nucleoli, in an abundant stroma. Collagen fibers arranged in a parallel lamellar pattern were seen in the tumor stroma. These findings, together with the results of subsequent IHC analyses using HAS, CK7, and CD 67, we made the diagnosis of FL-HCC, which was further confirmed by detection of the DNAJB1-PRKACA fusion gene in the tumor cells by RT-PCR.

Conclusion: FL-HCC shows distinct imaging appearances. Although it also has characteristic morphological features, combined use of IHC and/or molecular genetic studies are necessary for the final diagnosis.
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http://dx.doi.org/10.1186/s40792-021-01295-4DOI Listing
September 2021

Suboptimal diabetic control and psychological burden after the triple disaster in Japan: the Fukushima Health Management Survey.

BMJ Open Diabetes Res Care 2021 Sep;9(1)

Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical University School of Medicine, Fukushima, Japan

Introduction: A triple disaster struck eastern Japan in March 2011. We investigated the psychological distress and post-traumatic stress disorder (PTSD) symptoms caused by the disaster in people without or with diabetes mellitus.

Research Design And Methods: This cross-sectional analysis examined the 16 097 evacuees (1820 (11.3%) with and 14 277 (88.7%) without diabetes mellitus) included in the Fukushima Health Management Survey. Non-specific mental health distress was assessed using the Kessler-6 Scale, and traumatic symptoms were evaluated using the PTSD Checklist. Logistic regression analyses were used to estimate the OR and 95% CI associated with symptoms, adjusted for diabetes-related and disaster-related factors.

Results: In the age-adjusted and sex-adjusted logistic models, suboptimal diabetic control (hemoglobin A1c (HbA1c) ≥7%) was associated with both psychological distress and possible PTSD. In the same models, current smoking, evacuation, and sleep dissatisfaction were associated with psychological distress and possible PTSD. In the multivariate-adjusted logistic models, HbA1c ≥7% was associated with psychological distress, independent of job change, evacuation, or sleep dissatisfaction.

Conclusion: After the triple disaster, non-specific mental health distress was associated with suboptimal diabetic control. Thus, patients with diabetes, especially those with suboptimal diabetic control, may be vulnerable to postdisaster psychological burden.
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http://dx.doi.org/10.1136/bmjdrc-2020-002007DOI Listing
September 2021

TAFRO syndrome complicated by porto-sinusoidal vascular liver disease with portal hypertension: a case report.

Clin J Gastroenterol 2021 Sep 6. Epub 2021 Sep 6.

Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Porto-sinusoidal vascular liver disease (PSVD) is a disorder that can cause portal hypertension without liver cirrhosis. TAFRO syndrome is a systemic inflammatory disorder with a background of immunological abnormalities. We report a case of TAFRO syndrome complicated by PSVD with portal hypertension. A 39-year-old man developed refractory ascites and esophageal varices. Lymph node histology revealed multicentric Castleman disease-like features. Intravenous methylprednisolone and tocilizumab therapy improved ascites and renal dysfunction, but the patient developed severe infections. The diagnosis of TAFRO syndrome in patients complicated by PSVD with portal hypertension encourages the consideration of appropriate treatment for these patients.
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http://dx.doi.org/10.1007/s12328-021-01515-2DOI Listing
September 2021

Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases.

Biomedicines 2021 Aug 13;9(8). Epub 2021 Aug 13.

Department of Animal Pharmaceutical Science, School of Pharmaceutical Science, Kyusyu University of Health and Welfare, Nobeoka 882-8508, Japan.

Circulating full-length osteopontin (FL-OPN) is elevated in plasma from patients with various infectious diseases, such as adult T-cell leukemia, (TB), hepatitis virus infection, leptospirosis, acquired immune deficiency syndrome (AIDS), AIDS/TB, and coronavirus disease 2019 (COVID-19). Proteolysis of OPN by thrombin, matrix metalloproteases, caspase 8/3, cathepsin D, plasmin, and enterokinase generates various cleaved OPNs with a variety of bioactivities by binding to different target cells. Moreover, OPN is susceptible to gradual proteolysis. During inflammation, one of the cleaved fragments, N-terminal thrombin-cleaved OPN (trOPN or OPN-Arg [OPN-R]), induces dendritic cell (DC) adhesion. Further cleavage by carboxypeptidase B2 or carboxypeptidase N removes Arg from OPN-R to OPN-Leu (OPN-L). Consequently, OPN-L decreases DC adhesion. In particular, the differences in plasma level over time are observed between FL-OPN and its cleaved OPNs during inflammation. We found that the undefined OPN levels (mixture of FL-OPN and cleaved OPN) were elevated in plasma and reflected the pathology of TB and COVID-19 rather than FL-OPN. These infections are associated with elevated levels of various proteases. Inhibition of the cleavage or the activities of cleaved products may improve the outcome of the therapy. Research on the metabolism of OPN is expected to create new therapies against infectious diseases.
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http://dx.doi.org/10.3390/biomedicines9081006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394573PMC
August 2021

Therapeutic options to reduce intravesical recurrence in newly diagnosed Ta high-grade bladder cancer according to risk stratification: A multicenter retrospective study.

Int J Urol 2021 Aug 3. Epub 2021 Aug 3.

Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Objectives: To evaluate the risk factors for intravesical recurrence in patients with newly diagnosed Ta high-grade non-muscle-invasive bladder cancer and the optimal management to reduce the risk of recurrence.

Methods: We retrospectively evaluated Ta high-grade bladder cancer in patients who were newly diagnosed by transurethral resection from January 2007 through October 2018. Using multivariate analyses, we evaluated the risk factors and therapeutic options affecting intravesical recurrence and stratified the patients according to the risk numbers.

Results: We included 390 patients and the median follow-up period was 31 months after the initial transurethral resection. According to multivariate analysis, having a previous history of upper urinary tract carcinoma, and multiple and sessile tumors were risk factors for intravesical recurrence (P = 0.001, P = 0.02 and P = 0.01, respectively). Risk groups were stratified according to these risk factors into favorable, intermediate and poor. In the entire cohort, induction and immediate intravesical instillation therapy were treatment options to reduce intravesical recurrence (P < 0.01 and P = 0.02, respectively). Analyses in each risk group showed that a second transurethral resection was the only therapeutic option to reduce intravesical recurrence in the favorable group (P = 0.048), whereas induction intravesical instillation therapy was effective in the intermediate and poor risk groups (P = 0.01 and P < 0.01, respectively), as was immediate intravesical instillation for the poor risk group (P < 0.001).

Conclusions: Sessile, multiple tumors and a history of upper urinary tract carcinoma are risk factors for intravesical recurrence in Ta high-grade bladder cancer patients.
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http://dx.doi.org/10.1111/iju.14657DOI Listing
August 2021

Angiographic flow velocity predicts lower limb outcomes after endovascular therapy: Application of the frame count method.

Vasc Med 2021 Jul 21:1358863X211025613. Epub 2021 Jul 21.

Cardiovascular Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Introduction: Several factors related to lesion characteristics and endovascular therapy (EVT) procedures have been reported to affect primary patency after EVT. However, it is unknown why these factors were associated with primary patency. We hypothesized patency failure was related to poor blood flow in affected arteries.

Methods: This retrospective study included 131 consecutive patients who had received EVT with bare metal stents for peripheral artery disease caused by femoropopliteal artery lesions. Based on the tertile post-EVT flow velocity of the superficial femoral artery (SFA), patients were divided into high ( = 43), middle ( = 44), and low ( = 44) flow velocity groups. Flow velocity was measured using the frame count method. We measured incidence of major adverse limb events (MALE), composed of target lesion revascularization (TLR), non-TLR, and major amputation.

Results: At a median follow-up period of 22.7 months, MALE had occurred in 7 (16.3%), 10 (22.7%), and 29 (65.9%) of patients from the high, middle, and low SFA flow velocity groups, respectively ( < 0.001). Kaplan-Meier analysis showed incidence of MALE was significantly higher in the patients of low SFA flow velocity (log-rank test χ = 38.8, < 0.001). Multivariate analysis found low SFA flow velocity to be an independent predictor for MALE (hazard ratio: 4.42; 95% CI: 2.27 to 8.60; < 0.001) as was ankle-brachial index.

Conclusion: Post-EVT SFA flow velocity for femoropopliteal artery lesions treated with bare metal stents is an independent predictor of limb patency. The frame count method for assessing arterial flow velocity is convenient and has potential for wide applications in EVT.
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http://dx.doi.org/10.1177/1358863X211025613DOI Listing
July 2021

Novel metastatic burden-stratified risk model in de novo metastatic hormone-sensitive prostate cancer.

Cancer Sci 2021 Sep 10;112(9):3616-3626. Epub 2021 Jul 10.

Department of Urology, Kagoshima University, Kagoshima, Japan.

The metastatic burden is a critical factor for decision-making in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low- and high-burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T-stage were associated with poor OS in low-burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high-burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression-free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden-stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation.
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http://dx.doi.org/10.1111/cas.15038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409413PMC
September 2021

Consumption of barley ameliorates the diabetic steatohepatitis and reduces the high transforming growth factor β expression in mice grown in α-minimum essential medium as embryos.

Biochem Biophys Rep 2021 Sep 30;27:101029. Epub 2021 May 30.

Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, 4-4-37 Takeda, Kofu, Yamanashi, 400-8510, Japan.

Non-alcoholic fatty liver disease (NAFLD), which includes the subtype non-alcoholic steatohepatitis (NASH), is a major complication of type 2 diabetic mellitus (T2DM), even among non-obese patients. However, the exact cause of NAFLD/NASH in non-obese patients with T2DM is unclear. We studied a non-obese mouse model of T2DM created through the malnourishment of embryos by culture for 48 h in α-minimum essential medium (MEM) at the two-cell stage. We compared the development of steatohepatitis in these MEM mice with control mice that were similarly cultured in standard potassium simplex-optimized medium (KSOM). We also studied the effects of 10 weeks of consumption of barley, which contains large amounts of the soluble fiber β-glucan, on the steatohepatitis of the adult MEM mice. The size of lipid droplets, the area of fibrosis, and the mRNA expression of the transforming growth factor beta () gene in the liver were higher in adult MEM mice fed a rice-based diet than in KSOM mice fed the same diet. However, barley consumption reduced the area of fibrosis and TGFB expression in MEM mice. In conclusion, adult mice that are cultured in MEM at the two-cell embryo stage develop steatohepatitis and T2DM, accompanied by higher hepatic TGFB expression, than KSOM controls. Furthermore, the consumption of barley during adulthood ameliorates the steatohepatitis and reduces the TGFB expression.
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http://dx.doi.org/10.1016/j.bbrep.2021.101029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181192PMC
September 2021

High FIB4 index is an independent risk factor of diabetic kidney disease in type 2 diabetes.

Sci Rep 2021 Jun 3;11(1):11753. Epub 2021 Jun 3.

Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical University, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) may be linked to development of chronic kidney diseases (CKD). The FIB4 index, a noninvasive liver fibrosis score, has been reported to predict CKD in non-diabetic patients, but there are no reports yet in diabetic cases. Therefore, we evaluated the prognostic impact of FIB4 index on the risk of developing diabetic kidney disease (DKD) in Japanese patients with type 2 diabetes in a retrospective cohort study. We assessed patients with type 2 diabetes with an eGFR ≥ 60 mL/min/1.73 m and without dipstick positive proteinuria (≥ 1 +) at their first visit to our department. Participants were divided into two groups based on the FIB4 index at their first visit: FIB4 index > 1.3 and FIB4 index ≤ 1.3. The primary endpoint was defined as a decrease in eGFR < 60 mL/min/1.73 m or the onset of proteinuria during the course of treatment. The average age of all 584 type 2 diabetic participants (360 [61.6%] men) was 55 ± 11 years. There were 187 patients in the FIB4 index group > 1.3 (32.0%) and the median observation period was 6.0 (3.8-11.0) years. Kaplan-Meier survival analysis indicated that the risks of developing DKD, eGFR < 60 and proteinuria were all higher in FIB4 index > 1.3 patients than in FIB4 ≤ 1.3 patients. In the Cox regression analysis, an FIB4 index > 1.3 was a significant predictor for onset of DKD (HR 1.54, 95% CI 1.15-2.08) and proteinuria (HR 1.55, 95% CI 1.08-2.23), but not for an eGFR < 60 (HR 1.14, 95% CI 0.79-1.99). To the best of our knowledge, this is the first study to demonstrate that an FIB4 index > 1.3 has a prognostic impact on the development of CKD and proteinuria in type 2 diabetic patients. This warrants further investigation of the prognostic impact of the development of DKD or proteinuria.
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http://dx.doi.org/10.1038/s41598-021-88285-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175689PMC
June 2021

High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia.

Int J Mol Sci 2021 May 7;22(9). Epub 2021 May 7.

Department of Respiratory Medicine, Sendai City Hospital, Miyagi 982-8502, Japan.

Numbers of patients with coronavirus disease 2019 (COVID-19) have increased rapidly worldwide. Plasma levels of full-length galectin-9 (FL-Gal9) and osteopontin (FL-OPN) as well as their truncated forms (Tr-Gal9, Ud-OPN, respectively), are representative inflammatory biomarkers. Here, we measured FL-Gal9, FL-OPN, Tr-Gal9, and Ud-OPN in 94 plasma samples obtained from 23 COVID-19-infected patients with mild clinical symptoms (CV), 25 COVID-19 patients associated with pneumonia (CP), and 14 patients with bacterial infection (ID). The four proteins were significantly elevated in the CP group when compared with healthy individuals. ROC analysis between the CV and CP groups showed that C-reactive protein had the highest ability to differentiate, followed by Tr-Gal9 and ferritin. Spearman's correlation analysis showed that Tr-Gal9 and Ud-OPN but not FL-Gal9 and FL-OPN, had a significant association with laboratory markers for lung function, inflammation, coagulopathy, and kidney function in CP patients. CP patients treated with tocilizumab had reduced levels of FL-Gal9, Tr-Gal9, and Ud-OPN. It was suggested that OPN is cleaved by interleukin-6-dependent proteases. These findings suggest that the cleaved forms of OPN and galectin-9 can be used to monitor the severity of pathological inflammation and the therapeutic effects of tocilizumab in CP patients.
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http://dx.doi.org/10.3390/ijms22094978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125627PMC
May 2021

Radioactivity and radionuclides in deciduous teeth formed before the Fukushima-Daiichi Nuclear Power Plant accident.

Sci Rep 2021 May 14;11(1):10335. Epub 2021 May 14.

Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

The Fukushima-Daiichi Nuclear Power Plant (FNPP) accident in March of 2011 released substantial amounts of radionuclides into the environment. We collected 4,957 deciduous teeth formed in children before the Fukushima accident to obtain precise control data for teeth formed after the accident. Radioactivity was measured using imaging plates (IP) and epidemiologically assessed using multivariate regression analysis. Additionally, we measured Sr, Cs, and natural radionuclides which might be present in teeth. Epidemiological studies of IP showed that the amount of radioactivity in teeth from Fukushima prefecture was similar to that from reference prefectures. We found that artificial radionuclides of Sr and Cs, which were believed to have originated from past nuclear disasters, and natural radionuclides including K and daughter nuclides in the U and Th series contributed to the generation of radioactivity in teeth. We also found no evidence to suggest that radionuclides originating from the FNPP accident significantly contaminated pre-existing teeth. This is the first large-scale investigation of radioactivity and radionuclides in teeth. The present findings will be indispensable for future studies of teeth formed after the FNPP accident, which will fall out over the next several years and might be more contaminated with radionuclides.
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http://dx.doi.org/10.1038/s41598-021-89910-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121844PMC
May 2021

A Right Angle Guide for Distal Tuberosity Osteotomy With Medial Open Wedge High Tibial Osteotomy for Varus Knee Osteoarthritis.

Arthrosc Tech 2021 Apr 12;10(4):e1007-e1016. Epub 2021 Mar 12.

Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, Sendai City, Japan.

Medial open wedge high tibial osteotomy (OWHTO) is usually performed with proximal tuberosity osteotomy or setting the osteotomy line proximal to the tuberosity. However, OWHTO can result in patellofemoral complications due to postoperative patella infera. A new OWHTO technique, biplanar osteotomy with a distal tuberosity osteotomy, was reported in 2004 to prevent postoperative patella infera. To ensure that the 2 osteotomy lines maintain perpendicular, we describe the OWHTO procedure with a distal tuberosity osteotomy technique using a TriS Medial HTO Plate System (Olympus Terumo Biomaterials Corp., Tokyo, Japan) and a right angle guide we developed. In this Technical Note, we describe the procedure and advantages, risks, and limitations, as well as the pearls and pitfalls based on our experience.
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http://dx.doi.org/10.1016/j.eats.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084846PMC
April 2021

Relationship between physical activity/exercise habits and the frequency of new onset of lifestyle-related diseases after the Great East Japan Earthquake among residents in Fukushima: the Fukushima Health Management Survey.

J Radiat Res 2021 May;62(Supplement_1):i129-i139

Radiation Medical Science Center for the Fukushima Health Management Survey, Fukushima Medical University, Fukushima-city, Fukushima, Japan.

The effect of exercise habits on the increased incidence of lifestyle-related diseases among residents of the evacuation area in Fukushima Prefecture after the Great East Japan Earthquake is not well characterized. This study examined the influence of exercise habits on the frequency of new onset of lifestyle-related diseases in the aftermath of the earthquake using data from the Fukushima Health Management Survey (FHMS). Of the 32 289 individuals (14 004 men and 18 285 women) aged 40-90 years who underwent one or more health examinations in both 2011-12 and 2014-15, those who knew whether they had any lifestyle diseases and who responded to a questionnaire about their exercise and physical activity habits were included (dyslipidemia, 8017; hypertension, 7173; and diabetes mellitus, 13140 individuals). The association between the frequency of new onset of lifestyle-related diseases in 2014-15 and the presence or absence of persistent exercise and physical activity habits (active lifestyle) was examined using the FHMS data. The frequency of new onset of dyslipidemia was significantly lower in the active lifestyle group than in the sedentary lifestyle group (P = 0.008). On univariate and multivariate logistic regression analyses, the presence of active lifestyle, obesity and the experience of evacuation showed a significant association with new onset of dyslipidemia, independent of age, sex or follow-up period. Thus maintaining physical activity and exercise habits may help prevent the new onset of dyslipidemia among residents of the evacuation area in the Fukushima Prefecture after the earthquake.
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http://dx.doi.org/10.1093/jrr/rraa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114221PMC
May 2021

Pembrolizumab for treating advanced urothelial carcinoma in patients with impaired performance status: Analysis of a Japanese nationwide cohort.

Cancer Med 2021 05 1;10(10):3188-3196. Epub 2021 May 1.

Department of Urology, University of Tsukuba, Ibaraki, Japan.

Background: The benefits of pembrolizumab in patients with advanced urothelial carcinoma (UC) and impaired performance status (PS) remain unknown. This study assessed the safety and efficacy of pembrolizumab in patients with platinum-refractory UC and Eastern Cooperative Oncology Group PS ≥2 to identify which subgroups may benefit from this drug.

Methods: This retrospective nationwide cohort study collected clinicopathological information for 755 patients from 59 institutions. The overall response rate (ORR) and overall survival (OS) were compared among the patients with PS 0-1, 2, and 3-4. Multivariate analysis was conducted to identify factors predicting OS in patients with PS ≥2.

Results: The numbers of patients with PS 0-1, 2, and 3-4 were 602, 98, and 55, respectively; the ORRs in these groups were 29.5, 15.3, and 9.1%, respectively, and the median OS times were 14.3, 3.1, and 2.4 months, respectively. In multivariate Cox regression analysis, a neutrophil-lymphocyte ratio (NLR) ≥3.5 (hazard ratio [HR] = 1.897) and liver metastasis (HR = 2.072) were associated with OS in the PS ≥2 subgroup. The median OS of patients with PS ≥2 without either risk factor was 6.8 months, compared with 3.1 months for patients with one risk factor and 2.3 months for patients with both risk factors.

Conclusions: PS ≥2 portended worse ORR and OS than PS ≤1 despite a comparable safety profile. Among the patients with impaired PS, patients with NLR <3.5 and no liver metastasis may most greatly benefit from pembrolizumab therapy.
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http://dx.doi.org/10.1002/cam4.3863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124127PMC
May 2021

Genome-wide association study of epilepsy in a Japanese population identified an associated region at chromosome 12q24.

Epilepsia 2021 Jun 29;62(6):1391-1400. Epub 2021 Apr 29.

Department of Neurodevelopmental Disorder Genetics, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, Aichi, Japan.

Objective: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population.

Methods: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data.

Results: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24.

Significance: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.
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http://dx.doi.org/10.1111/epi.16911DOI Listing
June 2021

Vascular Responses to First-Generation Sirolimus-Eluting Stents and Bare-Metal Stents Beyond 10 Years.

Circ Rep 2021 Mar 30;3(4):201-210. Epub 2021 Mar 30.

Department of Cardiovascular Medicine, Tsuchiura Kyodo General Hospital Tsuchiura Japan.

There are limited data regarding differences in vascular responses between first-generation sirolimus-eluting stents (1G-SES) and bare-metal stents (BMS) >10 years after implantation. We retrospectively investigated 223 stents (105 1G-SES, 118 BMS) from 131 patients examined by optical coherence tomography (OCT) >10 years after implantation. OCT analysis included determining the presence or absence of a lipid-laden neointima, calcified neointima, macrophage accumulation, malapposition, and strut coverage. Neoatherosclerosis was defined as having lipid-laden neointima. OCT findings were compared between the 1G-SES and BMS groups, and the predictors of neoatherosclerosis were determined. The median stent age at the time of OCT examinations was 12.3 years (interquartile range 11.0-13.2 years). There were no significant differences in patient characteristics between the 1G-SES and BMS groups. On OCT analysis, there was no difference in the prevalence of neoatherosclerosis and calcification between 1G-SES and BMS. Multivariable logistic regression analysis revealed that stent size, stent length, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use were significant predictors of neoatherosclerosis. In addition, uncovered and malapposed struts were more prevalent with 1G-SES than BMS. After >10 years since implantation, the prevalence of neoatherosclerosis was no different between 1G-SES and BMS, whereas uncovered struts and malapposition were significantly more frequent with 1G-SESs.
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http://dx.doi.org/10.1253/circrep.CR-21-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024020PMC
March 2021

A size-adaptive 32-channel array coil for awake infant neuroimaging at 3 Tesla MRI.

Magn Reson Med 2021 09 8;86(3):1773-1785. Epub 2021 Apr 8.

Institute of Medical Physics and Radiation Protection, Department of Life Science Engineering, TH Mittelhessen University of Applied Sciences, Giessen, Germany.

Purpose: Functional magnetic resonance imaging (fMRI) during infancy poses challenges due to practical, methodological, and analytical considerations. The aim of this study was to implement a hardware-related approach to increase subject compliance for fMRI involving awake infants. To accomplish this, we designed, constructed, and evaluated an adaptive 32-channel array coil.

Methods: To allow imaging with a close-fitting head array coil for infants aged 1-18 months, an adjustable head coil concept was developed. The coil setup facilitates a half-seated scanning position to improve the infant's overall scan compliance. Earmuff compartments are integrated directly into the coil housing to enable the usage of sound protection without losing a snug fit of the coil around the infant's head. The constructed array coil was evaluated from phantom data using bench-level metrics, signal-to-noise ratio (SNR) performances, and accelerated imaging capabilities for both in-plane and simultaneous multislice (SMS) reconstruction methodologies. Furthermore, preliminary fMRI data were acquired to evaluate the in vivo coil performance.

Results: Phantom data showed a 2.7-fold SNR increase on average when compared with a commercially available 32-channel head coil. At the center and periphery regions of the infant head phantom, the SNR gains were measured to be 1.25-fold and 3-fold, respectively. The infant coil further showed favorable encoding capabilities for undersampled k-space reconstruction methods and SMS techniques.

Conclusions: An infant-friendly head coil array was developed to improve sensitivity, spatial resolution, accelerated encoding, motion insensitivity, and subject tolerance in pediatric MRI. The adaptive 32-channel array coil is well-suited for fMRI acquisitions in awake infants.
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http://dx.doi.org/10.1002/mrm.28791DOI Listing
September 2021

Association between lifestyle habits and the prevalence of abdominal obesity after the Great East Japan Earthquake: The Fukushima Health Management Survey.

J Epidemiol 2021 Apr 3. Epub 2021 Apr 3.

Radiation Medical Science Center for the Fukushima Health Management Survey, Fukushima Medical University.

Background: The proportion of overweight individuals living in the evacuation zone of Fukushima increased after the Great East Japan Earthquake. However, the change in the prevalence of abdominal obesity has not been reported. Lifestyle habits and changes in these habits after the disaster might have affected the onset of abdominal obesity; however, the association between the two is unclear.

Methods: This study evaluated 19,673 Japanese participants of the Fukushima Health Management Survey. We used data from general health check-ups conducted in 13 municipalities between 2008 and 2010. Follow-up examinations were performed from June 2011 to March 2013. Changes in the proportion of individuals with abdominal obesity before and after the disaster were compared. Then, lifestyle habits affecting these changes were assessed.

Results: We found that 34.2% and 36.6% of participants (P < 0.001), both evacuees (37.0% and 42.1% (P < 0.001)) and non-evacuees (32.8% and 34.0% (P < 0.001)), had abdominal obesity before and after the disaster, respectively. Abdominal obesity was positively associated with smoking cessation, snacking after dinner and non-breakfast skipping after the disaster and alcohol drinking before and after the disaster (all P < 0.05). Smoking cessation was positively associated with abdominal obesity in both evacuees and non-evacuees and in both men and women (all P < 0.01).

Conclusions: The prevalence of abdominal obesity increased among residents in the area affected by nuclear disaster. It might be associated with not only lifestyle habits before the disaster but also changes in these habits after the disaster, especially smoking cessation.
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http://dx.doi.org/10.2188/jea.JE20200597DOI Listing
April 2021

Simultaneous determination of polybrominated diphenyl ethers and hexabromocyclododecane in plastic waste by short-column gas-chromatography-quadrupole mass spectrometry and electron capture detector.

Chemosphere 2021 Aug 18;277:130301. Epub 2021 Mar 18.

Center for Material Cycles and Waste Management Research, National Institute for Environmental Studies (NIES), 16-2 Onogawa, Tsukuba, 305-8506, Japan.

To avoid recycling plastic waste containing polybrominated diphenyl ethers (PBDEs) or hexabromocyclododecane (HBCD), which are listed in the Stockholm Convention on Persistent Organic Pollutants (POPs), a simple method to determine their contents at the time of waste disposal is needed. Herein, we developed a rapid analytical method using a gas chromatograph coupled with quadrupole mass spectrometry or electron capture detection to simultaneously detect PBDEs and HBCD in plastic waste. PBDEs and HBCD were ultrasonically extracted from plastic samples using toluene. The dissolved polymer matrix was then removed using n-hexane and 44% HSO-impregnated silica gel before analysis of the extract. A run time of less than 10 min was achieved using a custom, short GC column (5 m). The detection limits of the method were below the upper threshold of the low POP content limits defined by the Basel Convention (<1000 mg kg for both PBDEs and HBCD). The accuracy of the method was confirmed by analyzing seven polymer reference materials. The determined PBDE and HBCD concentrations in most of these reference materials were within 30% of the certified values; the coefficients of variation in triplicate analysis were also within 30%. The concentrations of PBDEs and HBCD in actual plastic waste measured by this method were comparable with those obtained by more sophisticated and expensive methods, such as GC-high-resolution MS for PBDEs and liquid chromatography-tandem mass spectrometry for HBCD. Hence, the method developed herein is a less expensive alternative for identifying PBDE- and HBCD-containing wastes.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130301DOI Listing
August 2021

Association of equol with obesity in postmenopausal women.

Menopause 2021 03 15;28(7):807-810. Epub 2021 Mar 15.

Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan.

Objective: Equol, which is an active metabolite of isoflavone, has a beneficial impact on metabolic diseases such as dyslipidemia and hyperglycemia. However, the effect of equol on obesity remains uncertain. This study was performed to determine the association between equol and obesity in postmenopausal women.

Methods: We evaluated 386 women in their 50s-60s who underwent health check-ups from February 2018 to January 2019 at Watari Hospital Health Center in Fukushima, Japan. Overweight and visceral obesity were defined as a body mass index ≥25 kg/m2 and waist circumference ≥ 90 cm, respectively. Participants were asked to complete a questionnaire about their ordinary lifestyle. Participants were defined as equol producers when urinary equol level was 1.0 μM or more. The proportion of individuals with obesity (overweight and visceral obesity) and lifestyle factors were compared between equol producers and nonproducers. In addition, the association between equol and obesity was examined using logistic regression analysis with adjustment for lifestyle factors.

Results: Of the 386 participants, 106 (27.5%) women were equol producers. The proportions of women who were overweight (13.2% vs 25.7%) and had visceral obesity (6.6% vs 20.7%) were significantly lower in the equol-producing group than in the nonproducing group. Multivariable logistic regression analysis showed that equol production was significantly associated with overweight (odds ratio =0.47, 95% confidence interval: 0.25-0.88) and visceral obesity (odds ratio =0.30, 95% confidence interval: 0.13-0.68).

Conclusions: Equol is significantly associated with obesity in postmenopausal women.
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http://dx.doi.org/10.1097/GME.0000000000001761DOI Listing
March 2021

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in urological malignancies: a multi-center retrospective study.

J Bone Miner Metab 2021 Jul 11;39(4):661-667. Epub 2021 Mar 11.

Departments of Urology, Oral Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.

Introduction: We evaluated the incidence and risk factors for antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in prostate and kidney cancer patients.

Materials And Methods: We retrospectively reviewed the clinical data of 547 patients from 13 hospitals. Prostate and kidney cancer patients with bone metastases who were treated with a bone-modifying agent (BMA) between January 2012 and February 2019 were enrolled. Exclusion criteria were BMA use for hypercalcemia, a lack of clinical data, a follow-up period of less than 28 days and a lack of evaluation by dentists before BMA administration. The diagnosis and staging of ARONJ were done by dentists.

Results: Two-hundred eighteen patients were finally enrolled in the study, including 168 prostate cancer patients and 50 kidney cancer patients. Of them, 49 (29%) prostate cancer patients and 18 (36%) kidney cancer patients needed tooth extraction prior to BMA initiation. The mean follow-up period after BMA initiation was 552.9 ± 424.7 days (mean ± SD). In the cohort, 23% of the patients were diagnosed with ARONJ in the follow-up period. The 1-year cumulative incidences of ARONJ were 9.4% and 15.4% in prostate and kidney cancer patients, respectively. Multivariate analysis indicated that kidney cancer, tooth extraction before BMA and a body mass index (BMI) ≥ 25 kg/m were significant predictors for ARONJ.

Conclusion: ARONJ is not a rare adverse event in urological malignancies. Especially, kidney cancer, high BMI patients and who needed tooth extraction before BMA were high risk for developing ARONJ.
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http://dx.doi.org/10.1007/s00774-021-01207-4DOI Listing
July 2021

[Tumor Shrinkage as a Prognostic Factor of Metastatic Renal Cell Carcinoma in the Era of Molecular Targeted Therapy].

Hinyokika Kiyo 2021 Feb;67(2):57-61

Hakodate Goryoukaku Hospital.

We evaluated the impact of tumor shrinkage (TS) induced by molecular targeted therapy as the first-line systemic therapy on the survival of patients with metastatic renal cell carcinoma (mRCC). A total of 67 patients with mRCC who received first-line molecular targeted therapy were included in this study. Sixty patients were evaluable by response evaluation criteria in solid tumors. Patients underwent the first evaluation at 8-12 weeks after the start of the therapy. Twenty patients had TS ≧30%, 32 from 30% to -20%, and 8 ≦-20%. The median overall survival periods of patients who achieved TS ≧30%, from 30% to -20%, and ≦-20% at first evaluation were 41.0, 35.0, and 11.5 months, respectively. Univariate and multivariate analyses showed that TS of≧0%, in addition to negative C-reactive protein and the absence of bone metastasis were good predictors of overall survival. The patients who achieved 0% or more at the initial evaluation had longer survival than those who had no tumor reduction (40.0 months vs 12.0 months, p<0. 001). These findings suggest that early TS affects overall survival in real practice. We should consider alternative therapies for patients who have not achieved tumor reduction at the initial evaluation.
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http://dx.doi.org/10.14989/ActaUrolJap_67_2_57DOI Listing
February 2021

Risk factors and prognostic impact of post-discharge bleeding after endovascular therapy for peripheral artery disease.

Vasc Med 2021 Jun 1;26(3):281-287. Epub 2021 Mar 1.

Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

This study evaluated the incidence, predictors, and impact of bleeding requiring hospitalization following successful endovascular therapy (EVT) for peripheral artery disease. Platelet inhibition after EVT reduces the risk of major adverse limb events but increases the risk of bleeding. The incidence of post-discharge bleeding after EVT, its independent predictors, and its prognostic importance in clinical practice have not been fully addressed. We evaluated 779 consecutive patients who underwent EVT. We found that 77 patients (9.9%) were hospitalized for major bleeding during follow-up after EVT (median 39 months, range 22-66 months), with almost half (48.1%) of the bleeding categorized as gastrointestinal bleeding. Significant predictors of post-discharge bleeding were hemodialysis (hazard ratio (HR), 3.12; 95% CI: 1.93 to 5.05; < 0.001) and dual antiplatelet therapy (DAPT) use (HR, 1.87; 95% CI: 1.03 to 3.41; = 0.041). During follow-up, the all-cause mortality-free survival rate was significantly worse in patients who had experienced major bleeding than in those who had not (log-rank test χ = 54.6; < 0.001). Cox proportional hazards analysis showed that major bleeding (HR, 2.78; 95% CI: 1.90 to 4.06; < 0.001) was an independent predictor of all-cause death after EVT. Hospitalization for post-discharge bleeding after EVT is associated with a substantially increased risk of death, even after successful EVT. We concluded that patients' predicted bleeding risk should be considered when selecting patients likely to benefit from EVT, and that the risk should be considered especially thoroughly in hemodialysis patients.
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http://dx.doi.org/10.1177/1358863X21992863DOI Listing
June 2021

Real-World Safety Profile of Atrial Fibrillation Ablation Using a Second-Generation Cryoballoon in Japan: Insight From a Large Multicenter Observational Study.

JACC Clin Electrophysiol 2021 05 24;7(5):604-613. Epub 2021 Feb 24.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Objectives: This study sought to investigate the incidence and characteristics of the real-world safety profile of second-generation cryoballoon ablation (2nd-CBA) in Japan.

Background: Pulmonary vein isolation using second-generation cryoballoons is an accepted atrial fibrillation ablation strategy.

Methods: This multicenter observational study included 4,173 patients with atrial fibrillation (3,807 paroxysmal) who underwent a 2nd-CBA in 18 participating centers. The baseline data and details of all procedure-related complications within 3 months post-procedure in consecutive patients from the first case at each center were retrospectively collected.

Results: Adjunctive ablation after the pulmonary vein isolation was performed in 2,745 (65.8%) patients. Complications associated with the entire procedure were observed in 206 (4.9%) total patients, and in the multivariate analysis, the age (odds ratio: 1.015; 95% confidence interval: 1.001 to 1.030; p = 0.035) and study period were predictors. Air embolisms manifesting as ST-segment elevation and cardiac tamponade requiring drainage occurred in 63 (1.5%) and 15 (0.36%) patients, respectively. Six (0.14%) patients had strokes/transient ischemic attacks, among whom 5 underwent ablation under an interrupted anticoagulation regimen. No atrioesophageal fistulae occurred; however, 10 (0.24%) patients had symptomatic gastric hypomotility. Esophageal temperature monitoring did not reduce the incidence, and the incidence was significantly higher in patients with adjunctive posterior wall isolations or mitral isthmus ablation than those without (p = 0.004). Phrenic nerve injury occurred during the 2nd-CBA in 58 (1.4%) patients; however, all were asymptomatic and recovered within 13 months. One patient died of aspiration pneumonia.

Conclusions: This study had a high safety profile of 2nd-CBA despite including the early experience and high rate of adjunctive ablation. Care should be taken for air embolisms during 2nd-CBA.
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http://dx.doi.org/10.1016/j.jacep.2020.11.016DOI Listing
May 2021

Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes.

Hum Mol Genet 2021 May;30(8):716-726

Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.

Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P < 1.0 × 10-4) in an independent case-control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stages 1 and 2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, P = 1.62 × 10-9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11-1.23, and rs140508424 within PALM2 on chromosome 9, P = 4.19 × 10-8, OR = 1.61, 95% CI 1.36-1.91. However, the association of these two loci was not replicated in Korean, European or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (P = 2.17 × 10-6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.
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http://dx.doi.org/10.1093/hmg/ddab044DOI Listing
May 2021

Mice derived from in vitro αMEM-cultured preimplantation embryos exhibit postprandial hyperglycemia and higher inflammatory gene expression in peripheral leukocytes.

Biosci Biotechnol Biochem 2021 Apr;85(5):1215-1226

Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Kofu, Yamanashi, Japan.

We examined whether peripheral leukocytes of mice derived from in vitro αMEM-cultured embryos and exhibiting type 2 diabetes had higher expression of inflammatory-related genes associated with the development of atherosclerosis. Also, we examined the impact of a barley diet on inflammatory gene expression. Adult mice were produced by embryo transfer, after culturing two-cell embryos for 48 h in either α minimal essential media (α-MEM) or potassium simplex optimized medium control media. Mice were fed either a barley or rice diet for 10 weeks. Postprandial blood glucose and mRNA levels of several inflammatory genes, including Tnfa and Nox2, in blood leukocytes were significantly higher in MEM mice fed a rice diet compared with control mice. Barley intake reduced expression of S100a8 and Nox2. In summary, MEM mice exhibited postprandial hyperglycemia and peripheral leukocytes with higher expression of genes related to the development of atherosclerosis, and barley intake reduced some gene expression.
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http://dx.doi.org/10.1093/bbb/zbab023DOI Listing
April 2021
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