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In June 2016, the Ministry of the Environment of Japan announced a program "EXTEND2016" on the implementation of testing and assessment for endocrine active chemicals, consisting of a two‐tiered strategy. The aim of the Tier 1 screening and the Tier 2 testing is to identify the impacts on the endocrine system and to characterize the adverse effects to aquatic animals by endocrine disrupting chemicals detected in the aquatic environment in Japan. For the consistent assessment of the effects on reproduction associated with estrogenic, anti‐estrogenic, androgenic, and/or anti‐androgenic activities of chemicals throughout Tier 1 screening to Tier 2 testing, a unified test species, Japanese medaka (Oryzias latipes), has been used. For Tier 1 screening, the in vivo Fish Short‐Term Reproduction Assay (OECD test guideline No. 229) was conducted for 17 chemicals that were nominated based on the results of environmental monitoring, existing knowledge obtained from a literature survey, and positive results in reporter gene assays using the estrogen receptor of Japanese medaka. In the 17 assays using Japanese medaka, adverse effects on reproduction (i.e., reduction in fecundity and/or fertility) were suggested for 10 chemicals, and a significant increase of hepatic vitellogenin in males, indicating estrogenic (estrogen receptor agonistic) potency, was found for eight chemicals at the concentrations in which no overt toxicity was observed. Based on these results, and the frequency and the concentrations detected in the Japanese environment, estrone, 4‐nonylphenol (branched isomers), 4‐tert‐octylphenol, triphenyl phosphate, and bisphenol A were considered as high priority candidate substances for the Tier 2 testing. For Tier 1 screening, the Fish Short‐Term Reproduction Assay (OECD TG 229) using Japanese medaka was conducted for 17 chemicals nominated based on the results of environmental monitoring, literature survey, and results in reporter gene assays using Japanese medaka estrogen receptor. Adverse effects on reproduction were suggested for 10 out of 17 chemicals. Based on these results, and the frequency and the concentrations detected in the Japanese environment, estrone, 4‐nonylphenol (branched isomers), 4‐tert‐octylphenol, triphenyl phosphate, and bisphenol A were considered as high priority candidate substances for the Tier 2 testing. [ABSTRACT FROM AUTHOR]

Under the Organisation for Economic Co‐operation and Development (OECD), the Ministry of the Environment of Japan (MOE) added Japanese medaka (Oryzias latipes) to the test guideline fish short‐term reproduction assay (FSTRA) developed by the United States Environmental Protection Agency (US EPA) using fathead minnow (Pimephales promelas). The FSTRA was designed to detect endocrine disrupting effects of chemicals interacting with the hypothalamic–pituitary–gonadal axis (HPG axis) such as agonists or antagonists on the estrogen receptor (Esr) and/or the androgen receptor (AR) and steroidogenesis inhibitors. We conducted the FSTRA with Japanese medaka, in accordance with OECD test guideline number 229 (TG229), for 16 chemicals including four Esr agonists, two Esr antagonists, three AR agonists, two AR antagonists, two steroidogenesis inhibitors, two progesterone receptor agonists, and a negative substance, and evaluated the usability and the validity of the FSTRA (TG229) protocol. In addition, in vitro reporter gene assays (RGAs) using Esr1 and ARβ of Japanese medaka were performed for the 16 chemicals, to support the interpretation of the in vivo effects observed in the FSTRA. In the present study, all the test chemicals, except an antiandrogenic chemical and a weak Esr agonist, significantly reduced the reproductive status of the test fish, that is, fecundity or fertility, at concentrations where no overt toxicity was observed. Moreover, vitellogenin (VTG) induction in males and formation of secondary sex characteristics (SSC), papillary processes on the anal fin, in females was sensitive endpoints to Esr and AR agonistic effects, respectively, and might be indicators of the effect concentrations in long‐term exposure. Overall, it is suggested that the in vivo FSTRA supported by in vitro RGA data can adequately detect effects on the test fish, O. latipes, and probably identify the mode of action (MOA) of the chemicals tested. Fish short‐term reproduction assay (OECD, TG229) with Japanese medaka (Oryzias latipes) was conducted for 16 reference chemicals including 4 estrogen receptor (Esr) agonists, 2 Esr antagonists, 3 androgen receptor (AR) agonists, 2 AR antagonists, 2 steroidogenesis inhibitors, 2 progesterone receptor agonists, and a negative substance, and confirmed the usability and the validity of the TG229 protocol. [ABSTRACT FROM AUTHOR]

This article discusses the relationship between locomotive syndrome (LS) and large joint symptoms in patients with rheumatoid arthritis (RA). LS refers to a condition that limits mobility due to musculoskeletal disorders and can lead to being bedridden. The study found that RA patients with large joint symptoms, especially in the lower limbs, were more likely to develop LS. The prevalence of LS was higher among RA patients compared to the general Japanese population. The findings suggest that addressing large joint symptoms in RA patients may help prevent LS and improve their quality of life. The study also highlights the importance of prompt treatment for large joint disabilities, including drug treatment and surgical options, in preventing LS in RA patients. Additionally, age, particularly in early-onset RA patients, is a significant factor related to LS. [Extracted from the article]

Introduction: Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA). Frailty is the intermediate condition between being healthy and disabled, and can lead to negative health outcomes. Adverse events (AEs) due to RA drugs are expected to be higher in frail patients. The present study aimed to investigate the relationship between frailty and MTX discontinuation due to AEs in RA patients. Methods: Of 538 RA patients who visited us between June and August 2020 as part of the retrospective T-FLAG study, 323 used MTX. After 2 years of follow-up, we investigated AEs leading to MTX discontinuation. Frailty was defined as a Kihon Checklist (KCL) score ≥ 8. Cox proportional hazards regression analysis was performed to identify factors associated with MTX discontinuation due to AEs. Results: Of the 323 RA patients (251 women, 77.7%) who used MTX, 24 (7.4%) discontinued MTX due to AEs during the 2-year follow-up period. Mean ages in the MTX continuation/discontinuation groups were 64.5 ± 13.9/68.5 ± 11.7 years (p = 0.169), Clinical Disease Activity Index was 5.6 ± 7.3/6.2 ± 6.0 (p = 0.695); KCL was 5.9 ± 4.1/9.0 ± 4.9 points (p < 0.001); and the proportion of frailty was 31.8%/58.3% (p = 0.012). MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02–5.37) even after adjusting for age and diabetes mellitus. AEs included liver dysfunction (25.0%), pneumonia (20.8%), and renal dysfunction (12.5%). Conclusions: Because frailty is a significant factor contributing to MTX discontinuation due to AEs, the latter should be carefully monitored in frail RA patients who use MTX. Key Points • Of the 323 rheumatoid arthritis (RA) patients (251 women, 77.7%) who used methotrexate (MTX), 24 (7.4%) discontinued MTX due to adverse events (AEs) during the 2-year follow-up period. • MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02–5.37) even after adjusting for age and diabetes mellitus, and neither the MTX dose, folic acid supplementation, nor GC co-therapy were factors in MTX discontinuation. • Frailty is a predominant factor in MTX discontinuation among established, long-term pretreated RA patients, and the occurrence of AEs due to MTX should be carefully monitored when frail RA patients use MTX. [ABSTRACT FROM AUTHOR]

Background: Tricuspid regurgitation pressure gradient (TRPG) measurement by echocardiography is recommended as the most objective examination to detect portopulmonary hypertension (PoPH). This study aimed to identify factors associated with a high TRPG in patients with cirrhosis and develop a scoring model for identifying patients who are most likely to benefit from echocardiography investigations. Results: A total of 486 patients who underwent echocardiography were randomly allocated to the derivation and validation sets at a ratio of 2:1. Of the patients, 51 (10.5%) had TRPG ≥ 35 mmHg. The median brain natriuretic peptide (BNP) was 39.5 pg/mL. Shortness of breath (SOB) was reported by 91 (18.7%) patients. In the derivation set, multivariate analysis identified female gender, shortness of breath, and BNP ≥ 48.9 pg/mL as independent factors for TRPG ≥ 35 mmHg. The risk score for predicting TRPG ≥ 35 mmHg was calculated as follows: − 3.596 + 1.250 × gender (female: 1, male: 0) + 1.093 × SOB (presence: 1, absence: 0) + 0.953 × BNP (≥ 48.9 pg/mL: 1, < 48.9 pg/mL: 0). The risk score yielded sensitivity of 66.7%, specificity of 75.3%, positive predictive value of 25.5%, negative predict value of 94.3%, and predictive accuracy of 74.4% for predicting TRPG ≥ 35 mmHg. These results were almost similar in the validation set, indicating the reproducibility and validity of the risk score. Conclusions: This study clarified the characteristics of patients with suspected PoPH and developed a scoring model for identifying patients at high risk of PoPH, which may be used in selecting patients that may benefit from echocardiography. [ABSTRACT FROM AUTHOR]

Aims: This retrospective study compared the survival between elderly and non‐elderly patients. Methods: A total of 5545 treatment‐naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively. Results: There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p < 0.001). In both elderly and non‐elderly patients, the median albumin‐bilirubin score significantly improved over time and the diagnosis of HCC was made slightly earlier over time. The median overall survival (OS) in elderly patients was 52.8, 42.0, and 45.6 months in the early, middle, and late period, respectively, without a significant improvement (p = 0.17) whereas the OS in non‐elderly patients was significantly improved (p < 0.001). The percentage of elderly patients receiving curative treatments did not significantly increase (p = 0.43), while that of non‐elderly patients did (p = 0.017). Non‐liver‐related death in elderly patients significantly differed among periods (p = 0.023), while liver‐related death did not (p = 0.050). Liver‐ and non‐liver‐related death in non‐elderly patients significantly differed among periods (p < 0.001, p = 0.005). Conclusions: Survival in elderly patients was not improved despite an improvement in their liver function. Curative treatments should be conducted when appropriate after evaluating each elderly patient. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) patients often exhibit finger/wrist joint symptoms and reduced grip strength. This study aimed to validate grip strength as a measure of frailty in RA patients. Subjects were 424 female RA patients (mean age ± standard deviation, 66.8 ± 14.5 years). Frailty was defined as a score of ≥ 8 points on the Kihon Checklist (KCL). Finger/wrist joint symptoms were defined based on tender or swollen joints. Associations between frailty and grip strength were determined using receiver operating characteristic (ROC) curve analysis and multivariable logistic regression analysis. There were 179 subjects with frailty (42.2%). Multivariable logistic regression analysis revealed that frailty was significantly associated with grip strength independently of finger/wrist joint symptoms. In ROC curves, cut-off scores of grip strength for frailty in subjects without and with finger/wrist joint symptoms were 17 kg (sensitivity, 62.1%; specificity, 69.0%) and 14 kg (sensitivity, 63.2%; specificity, 73.0%), respectively. The results of the present study suggest that grip strength in female RA patients is associated with frailty, with a cut-off score of 17 kg (equivalent to Cardiovascular Health Study criteria, < 18 kg) when RA patients have no finger/wrist joint symptoms. However, when RA patients have finger/wrist joint symptoms, it may be considered to reduce the cut-off score of grip strength. [ABSTRACT FROM AUTHOR]

Aim: The identification of new prognostic factors able to stratify hepatocellular carcinoma patients candidate to first‐line therapy is urgent. In the present work we validated the prognostic value of the lenvatinib prognostic index. Methods: Data of Eastern and Western patients treated with lenvatinib as first‐line for Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma were recollected. The lenvatinib prognostic index was composed by three classes of risk according with our previous study. The "low risk" group includes patients with prognostic nutritional index (PNI) >43.3 and with previous transarterial chemoembolization. The "medium risk" group includes patients with PNI >43.3, but without previous transarterial chemoembolization and patients with PNI <43.3, albumin‐bilirubin grade 1 and Barcelona Clinic Liver Cancer stage B. The "high risk" group includes patients with PNI <43.3, albumin‐bilirubin grade 2, and patients with PNI <43.3, albumin‐bilirubin grade 1 and Barcelona Clinic Liver Cancer stage C. Results: A total of 717 patients were included. The median overall survival was 20.7 months (95% CI 16.1–51.6) in patients with low risk (n = 223), 16.7 months (95% CI 13.3–47.0) in patients with medium risk (n = 264), and 10.7 months (95% CI 9.3–12.2) in patients with high risk (n = 230; HR 1, 1.29, and 1.92, respectively; p < 0.0001). Median progression‐free survival was 7.3 months (95% CI 6.3–46.5) in patients with low risk, 6.4 months (95% CI 5.3–8.0) in patients with medium risk ,and 4.9 months (95% CI 4.3–5.5) in patients with high risk (HR 1, 1.07, 1.47 respectively; p = 0.0009). Conclusion: The lenvatinib prognostic index confirms its prognostic value on an external cohort of hepatocellular carcinoma patients treated with Lenvatinib. [ABSTRACT FROM AUTHOR]

Background: We clarified the safety and efficacy of preoperative chemoradiotherapy for locally advanced rectal cancer using a multidrug regimen (S-1 + oxaliplatin + bevacizumab). Methods: This multicenter phase II trial involved 47 patients with locally advanced rectal cancer. All patients received S-1 orally (80 mg/m2/day on days 1–5, 8–12, 15–19, and 22–26) and infusions of oxaliplatin (50 mg/m2 on days 1, 8, 15, and 22) and bevacizumab (5 mg/kg on days 1 and 15). The total radiation dose was 40 Gy delivered in daily fractions of 2 Gy via the four-field technique. The primary endpoint was the pathological complete response rate. The secondary endpoints were safety (incidence of adverse events) and clinical response, relapse-free survival, overall survival, local recurrence, R0 resection, downstaging, and treatment completion rates. Results: All 47 patients received chemoradiotherapy, and 44 patients underwent curative resection. Two patients refused surgery and selected a watch-and-wait strategy. The pathological complete response rate was 18.2% in patients who underwent curative resection. The clinical response rate was 91.3% in 46 patients. Concerning hematotoxicity, there was one grade 4 adverse event (2.1%) and seven grade 3 events (14.9%). Diarrhea was the most frequent non-hematotoxic event, and the grade 3 event rate was 25.5%. Conclusions: Although preoperative chemoradiotherapy for patients with locally advanced rectal cancer using the S-1 + oxaliplatin + bevacizumab regimen did not achieve the expected pathological complete response rate, this regimen led to an improved clinical response rate. [ABSTRACT FROM AUTHOR]

Background: Subclinical diastolic dysfunction in patients with Type 1 diabetes mellitus (T1DM) caused by myocardial injury due to diabetic cardiomyopathy leads to a high risk of death and heart failure. This myocardial injury extends not only to the left ventricle (LV) but also to the left atrium (LA). However, LA function in children and young adults with T1DM has not been extensively studied. Objective: Therefore, the aim of this study was to assess LA dysfunction in pediatric and adult patients with T1DM using LA strain analysis with echocardiography. Subjects: Fifty‐three patients (median age: 23 [range: 5–41] years) with T1DM. Methods: We divided the patients into three age groups (D1: 5–14 years, D2: 15–24 years, D3: 25–41 years); 53 age‐ and sex‐matched controls were divided into three corresponding groups (C1, C2, and C3). LA and LV functions were evaluated using echocardiography. Results: LA reservoir strain was lower in the D2 and D3 groups than in the C2 and C3 groups (P = 0.001, P = 0.004, respectively). LA conduit strain was lower in the D2 group than in the C2 group (P = 0.002). LA stiffness was significantly greater in the D3 group than in the C3 group (P < 0.001). Conclusions: In patients with T1DM, LA phasic function decreased in adolescents and young adults, and LA stiffness increased in adult patients aged >30 years. LA phasic function and LA stiffness can be potentially used as early markers for diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Serum zinc (Zn) levels and the branched chain amino acid/tyrosine molar ratio (BTR) were reported to decrease with the progression of various chronic liver diseases. We investigated the impact of BTR and Zn on the incidence of malignancies in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). A total of 179 Japanese NAFLD patients who underwent liver biopsy were enrolled. Hepatocellular carcinoma (HCC) and extrahepatic malignancies developed in 7 (3.9%) and 10 (5.6%) patients, respectively, during the follow-up period (median 7.9 years). Patients with low BTR levels (<5.0) and Zn deficiency (<70 μg/dL) had significantly higher incidences of HCC and extrahepatic malignancies (P < 0.001 and 0.026), respectively. Multiple logistic regression analyses revealed the following risk factors: liver fibrosis (F3–4) (hazard ratio [HR] 24.292, 95% confidence interval [CI] 2.802–210.621, P = 0.004) and BTR < 5.0 (HR 5.462, 95% CI 1.095–27.253, P = 0.038) for HCC, and serum Zn level <70 μg/dL (HR 3.504, 95% CI 1.010–12.157, P = 0.048) and liver inflammation (A2–3) (HR 3.445, 95% CI 0.886–13.395, P = 0.074) for extra-hepatic malignancies. In conclusion, serum BTR and Zn levels were useful for predicting HCC and extrahepatic malignancies in NAFLD, respectively. [ABSTRACT FROM AUTHOR]

The article focuses on the study of the association between locomotive syndrome (LS) and methotrexate (MTX) discontinuation due to adverse events in rheumatoid arthritis (RA) patients. It informs that LS is a condition of reduced mobility due to disorders of the musculoskeletal system. It notes that as RA causes cartilage degeneration, and destruction of bones and joint structure, RA patients are more likely to develop LS, and complications of RA, or RA drugs, are also expected to increase.

2); then, a guidewire was advanced toward the bile duct through the stent mesh of the enteral stent and stent B was placed successfully using the stent-in-stent technique (Fig. Herein we report the first case of afferent loop syndrome with cholangitis and liver abscess treated by simultaneous metal stent placement using the stent-in-stent technique. B Video 1 b We performed simultaneous endoscopic metallic stent placements using the stent-in-stent technique for afferent loop obstruction with cholangitis and liver abscess due to a recurrent tumor after a pancreatoduodenectomy. [Extracted from the article]

The 6,6-quinolone scaffold of the viridicatin-type of fungal alkaloids are found in various quinolone alkaloids which often exhibit useful biological activities. Thus, it is of interest to identify viridicatin-forming enzymes and understand how such alkaloids are biosynthesized. Here an Aspergillal gene cluster responsible for the biosynthesis of 4′-methoxyviridicatin was identified. Detailed in vitro studies led to the discovery of the dioxygenase AsqJ which performs two distinct oxidations: first desaturation to form a double bond and then monooxygenation of the double bond to install an epoxide. Interestingly, the epoxidation promotes non-enzymatic rearrangement of the 6,7-bicyclic core of 4′-methoxycyclopenin into the 6,6-quinolone viridicatin scaffold to yield 4′-methoxyviridicatin. The finding provides new insight into the biosynthesis of the viridicatin scaffold and suggests dioxygenase as a potential tool for 6,6-quinolone synthesis by epoxidation of benzodiazepinediones. [ABSTRACT FROM AUTHOR]

Many patients with coagulation disorders are infected with hepatitis C virus (HCV) that advances to end stage liver disease, resulting in an increased number of deaths. The efficacy of ribavirin and peginterferon combination therapy for chronic HCV infection in patients with coagulation disorders has not been clarified fully. The aim of this study was to evaluate the efficacy and tolerability of combination therapy in this patient population compared with patients who are infected with HCV and do not have coagulation disorders. A total of 226 consecutive chronic hepatitis C patients were treated with combination therapy and divided into two groups: patients with (n = 23) and without coagulation disorders (n = 203). Clinical characteristics, sustained virological response rates obtained by an intention-to-treat analysis, and combination therapy discontinuation rates were compared between the two groups. The sustained virological response rates did not differ significantly between patients with and without coagulation disorders (65.2% vs. 47.8% by intention-to-treat analysis). According to a multivariate analysis, age, alanine aminotransferase, gamma-glutamyltransferase, and HCV genotype were associated significantly with a sustained virological response, whereas whether a patient had a coagulation disorder did not affect the sustained virological response. In conclusion, combination therapy for chronic hepatitis C was comparably effective between patients with and without coagulation disorders and did not result in adverse bleeding. J. Med. Virol. 85:228-234, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

One of the most effective methods for reducing exposure is the use of air cleaners. In this study, a dose mitigation of a commonly-used Japanese air cleaner under conditions in which aerosols are continuously supplied was investigated. Although the values of the EERC during an operation of air cleaner decreased, values of the f increased with the use of air cleaner. An effective dose was calculated on the basis of our experimental results, resulting in the dose mitigation of about 40 % by the air cleaner. Air cleaners can be regarded as an effective tool for the dose mitigation under with conditions in which aerosols are continuously supplied. [ABSTRACT FROM AUTHOR]

Abstract   Bacillus cereus is known as a serious bacterial pathogen in neutropenic patients. B. cereus is often resistant to β-lactams, including penicillins and cephalosporins. We report a case of fatal pneumonia caused by B. cereus in a patient with newly diagnosed acute myeloid leukemia (AML) during remission induction therapy. Cefepime was started for febrile neutropenia (FN) initially and was switched to panipem/betamipron, when fulminant pneumonia supervened. The isolated strain was resistant not only to cefepime but also to panipenem/betamipron. This is the first report of fulminant infection caused by carbapenem-resistant B. cereus in a neutropenic patient. B. cereus should be kept in mind as a target of empirical treatment when neutropenic patients develop pneumonia [ABSTRACT FROM AUTHOR]

A repertoire of T cells with diverse antigen receptors is selected in the thymus. However, detailed mechanisms underlying this thymic positive selection are not clear. Here we show that the CCR4-NOT complex limits expression of specific genes through deadenylation of mRNA poly(A) tails, enabling positive selection. Specifically, the CCR4-NOT complex is up-regulated in thymocytes before initiation of positive selection, where in turn, it inhibits up-regulation of pro-apoptotic Bbc3 and Dab2ip. Elimination of the CCR4-NOT complex permits up-regulation of Bbc3 during a later stage of positive selection, inducing thymocyte apoptosis. In addition, CCR4-NOT elimination up-regulates Dab2ip at an early stage of positive selection. Thus, CCR4-NOT might control thymocyte survival during two-distinct stages of positive selection by suppressing expression levels of pro-apoptotic molecules. Taken together, we propose a link between CCR4-NOT-mediated mRNA decay and T cell selection in the thymus. The CCR4-NOT complex catalyzes mRNA deadenylation and hence regulates protein translation. Here the authors show that CNOT3 regulation of this complex is needed for positive selection of thymocytes via a mechanism involving inhibition of pro-apoptotic gene expression. [ABSTRACT FROM AUTHOR]