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A major incident occurred at the Fukushima Daiichi Nuclear Power Station following the tsunami triggered by the Tohoku-Pacific Ocean Earthquake in March 2011, whereby seawater entered the torus room in the basement of the reactor building. Here, we identify and analyze the bacterial communities in the torus room water and several environmental samples. Samples of the torus room water (1 × 10 9 Bq 137 Cs/L) were collected by the Tokyo Electric Power Company Holdings from two sampling points between 30 cm and 1 m from the bottom of the room (TW1) and the bottom layer (TW2). A structural analysis of the bacterial communities based on 16S rRNA amplicon sequencing revealed that the predominant bacterial genera in TW1 and TW2 were similar. TW1 primarily contained the genus Limnobacter , a thiosulfate-oxidizing bacterium. γ-Irradiation tests on Limnobacter thiooxidans , the most closely related phylogenetically found in TW1, indicated that its radiation resistance was similar to ordinary bacteria. TW2 predominantly contained the genus Brevirhabdus , a manganese-oxidizing bacterium. Although bacterial diversity in the torus room water was lower than seawater near Fukushima, ~70% of identified genera were associated with metal corrosion. Latent environment allocation-an analytical technique that estimates habitat distributions and co-detection analyses-revealed that the microbial communities in the torus room water originated from a distinct blend of natural marine microbial and artificial bacterial communities typical of biofilms, sludge, and wastewater. Understanding the specific bacteria linked to metal corrosion in damaged plants is important for advancing decommissioning efforts., Importance: In the context of nuclear power station decommissioning, the proliferation of microorganisms within the reactor and piping systems constitutes a formidable challenge. Therefore, the identification of microbial communities in such environments is of paramount importance. In the aftermath of the Fukushima Daiichi Nuclear Power Station accident, microbial community analysis was conducted on environmental samples collected mainly outside the site. However, analyses using samples from on-site areas, including adjacent soil and seawater, were not performed. This study represents the first comprehensive analysis of microbial communities, utilizing meta 16S amplicon sequencing, with a focus on environmental samples collected from the radioactive element-containing water in the torus room, including the surrounding environments. Some of the identified microbial genera are shared with those previously identified in spent nuclear fuel pools in countries such as France and Brazil. Moreover, our discussion in this paper elucidates the correlation of many of these bacteria with metal corrosion., Competing Interests: The authors declare no conflict of interest.

Aim: Behçet's disease (BD) can involve any gastrointestinal (GI) tract site. We analyzed the characteristics, risk factors, and treatment responses to upper GI (UGI) involvement in patients with BD., Methods: This retrospective cohort study analyzed UGI findings in 101 patients with BD who underwent endoscopy between April 2005 and December 2022 at the University of Tokyo Hospital. The patients were divided into two groups based on the presence or absence of UGI findings. Patient backgrounds, clinical symptoms, colonoscopy (CS) findings, and blood test findings were compared between the groups., Results: In total, 18.8% (19/101) of the patients had UGI lesions. The prevalence rates in the esophagus, stomach, and duodenum were 6.9%, 6.9%, and 8.9%, respectively. Of these 19 patients, BD treatment were intensified in 10 (52.6%) patients after esophagogastroduodenoscopy (EGD), and all showed improvement in symptoms or endoscopic findings. In the multivariate analysis, symptoms (OR: 37.1, P < 0.001), CRP > 1 mg/dL (OR: 11.0, P = 0.01), and CS findings (OR: 5.16, P = 0.04) were independent predictors of UGI involvement in BD patients. The prediction model for UGI involvement using these three factors was highly accurate, with an AUC of 0.899 on the ROC curve. In the subgroup analysis of intestinal BD, symptoms (OR: 12.8, P = 0.01) and ESR > 20 mm/h (OR: 11.5, P = 0.007) were independent predictors., Conclusions: EGD should be conducted in BD patients with high CRP, GI symptoms, and lower GI involvement, which leads to better management of BD in terms of improving symptoms and endoscopic findings., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Importance: Real-world evidence of SARS-CoV-2 transmission is needed to understand the prevalence of infection in the Japanese population., Objective: To conduct sentinel screening of the Japanese population to determine the prevalence of SARS-CoV-2 infection in asymptomatic individuals, with complementary analysis for symptomatic patients as reported by active epidemiologic surveillance used by the government., Design, Setting, and Participants: This cross-sectional study of a sentinel screening program investigated approximately 1 million asymptomatic individuals with polymerase chain reaction (PCR) testing for SARS-CoV-2 infection between February 22 and December 8, 2021. Participants included children, students, employed adults, and older individuals, as well as volunteers to broadly reflect the general Japanese population in the 14 prefectures of Japan that declared a state of emergency. Saliva samples and a cycle threshold (Ct) value of approximately 40 as standard in Japan were used. Polymerase chain reaction testing for symptomatic patients was separately done by public health authorities, and the results were obtained from the Ministry of Health, Labour, and Welfare of Japan to complement data on asymptomatic infections from the present study., Main Outcomes and Measures: Temporal trends in positivity and prevalence (including surges of different variants) and demographic associations (eg, age, geographic location, and vaccination status) were assessed., Results: The positive rate of SARS-CoV-2 infection in 1 082 976 asymptomatic individuals (52.08% males; mean [SD] age 39.4 [15.7] years) was 0.03% (95% CI, 0.02%-0.05%) during periods without surges and a maximum of 0.33% (95% CI, 0.25%-0.43%) during peak surges at the Japanese standard Ct value of approximately 40; however, the positive rate would have been 10-fold less at a Ct value of 25 as used elsewhere in the world (eg, UK). There was an increase in patients with a positive PCR test result with a Ct value of 25 or 30 preceding surges in infection and hotspots of asymptomatic infections., Conclusions and Relevance: In this cross-sectional study of asymptomatic SARS-CoV-2 infection in the general population of Japan in 2021, as investigated by sentinel surveillance, a low rate of infection was seen in the Japanese population compared with reported levels elsewhere in the world. This finding provides real-world data on the state of infection in Japan.

Objectives: Little has been reported on the yield and characteristics of colorectal neoplasia detected by the two-sample faecal immunochemical test (FIT), particularly the difference between subjects with two-positive results on the two-sample FIT and those with one-positive results. We aimed to assess risk stratification among patients with positive two-sample FIT to prioritise colonoscopy., Design: A retrospective cross-sectional study., Setting: A single-centre, representative endoscopy clinic in Japan., Participants: Consecutive patients who underwent colonoscopy were enrolled. Indications for colonoscopy included two-positive results on the two-sample FIT (FIT (+/+)), one-positive results on the two-sample FIT (FIT (+/-)), and other reasons (non-FIT group, including presence of symptoms, screening or surveillance)., Primary and Secondary Outcome Measures: Primary outcomes were detection rates of colorectal cancers, including in situ (all cancers) and invasive cancers, based on the indications for colonoscopy. Secondary outcomes were cancer features, such as location, size, T stage and histological subtype., Results: Of the 8724 patients, 264 underwent colonoscopy following FIT (+/+), 1018 following FIT (+/-) and 7442 for reasons other than positive FIT. Detection rates of all (and invasive) cancers in the FIT (+/+), FIT (+/-) and non-FIT groups were 12.1% (8.3%), 1.9% (0.3%) and 0.4% (0.2%), respectively. The cancer detection rates were much higher in the FIT (+/+) group than in the FIT (+/-) group, which in turn had higher rates than the non-FIT group. Moreover, the FIT (+/+) group showed more advanced T stages on tumour, node, metastasis (TNM) classification (Tis/T1/T2/T3/T4: 10/7/4/10/1) than the FIT (+/-) group (16/1/2/0/0, p<0.001)., Conclusions: Two-positive results for two-sample FIT showed a much higher yield for more advanced colorectal cancers than the one-positive result. High priority for diagnostic colonoscopy should be assigned to patients with two-positive-FIT results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immediately after the Great East Japan Earthquake on March 11, 2011, the public could not receive accurate information concerning about the reality of the accident at the Fukushima Nuclear Power Plant because of communication problems with mobile phone base stations caused by power outages and the inadequate use of communication satellites between local governments. These telecommunications troubles caused not only a delay between the Japanese central government to local governments, but also a failure in conveying the seriousness of the accident to residents. The central government issued evacuation orders, but in some areas, a delay was seen in the time residents took to notice the orders. Some residents were forced to change their evacuation site several times and move to areas with higher radiation exposure. Although iodine preparations needed to be distributed to saturate the thyroid gland and reduce the uptake of iodine-131, a radioactive isotope, many municipalities were unable to secure them. Preparations were distributed on March 15, 2011 when the detectable amount of radioactive isotopes peaked, but only the Naraha and Miharu towns received them. At the time of the Fukushima Nuclear Power Plant accident, communication lines had already been interrupted by the major earthquake that struck on March 11, and information systems between local governments were not communicating well. With such a social infrastructure, residential evacuation orders were inadequate, and the delivery of medication was extremely difficult. The experience of the Fukushima Nuclear Power Plant accident suggests that the government should have distributed iodine preparations to residents living within a 30-km radius of the plant in advance, so that they could learn about the background and side effects of the drug beforehand. This distribution strategy is similar to that of targeted antivirus prophylaxis (TAP), which is an extralegal policy carried out in situations where face-to-face medical treatment is impossible because of an outbreak during a pandemic.

Phytoavailable K in soil is a key to control the transfer factor of radiocesium from soil to brown rice. The transfer factors were determined for paddy fields cultivated in 2017 and 2018 under different K fertilization regimes in Fukushima Prefecture, Japan. Two phytoavailable forms of K, the exchangeable and nonexchangeable K contents were investigated for the surface soil sampled after the transplanting and fertilization as well as after harvest of rice in the same paddy fields. The exchangeable K content largely decreased from after transplanting and fertilization to after harvest, and the exchangeable K of the soil after harvest was negatively correlated with the transfer factor (r s  = -0.70, p < .001). Most soil samples after harvest showed that the transfer factors exponentially increased as the exchangeable K decreased; however, some of the samples indicated considerably low transfer factors (<0.005) despite being exchangeable K deficient, i.e., exchangeable K < 25 mg K 2 O 100 g -1 . Even though this value before usual fertilization has been effectively used as a threshold to determine whether supplemental K fertilization is required to reduce the radiocesium content in brown rice, additional screening was needed to estimate this radiocesium transfer more precisely. Thus, we found that not only the exchangeable K but also nonexchangeable K contents had a negative correlation with the transfer factor (r s  = -0.60, p < .001) of the soil samples after harvest but were not correlated with each other (r p  = -0.10). Furthermore, the results revealed that soil with nonexchangeable K > 50 mg K 2 O 100 g -1 indicated a considerably low transfer factor, even if exchangeable K deficient. Thus, via our field-scale experiments, we concluded that the criterion nonexchangeable K > 50 mg K 2 O 100 g -1 can be used as another threshold for use along with that of exchangeable K to differentiate soil with a low radiocesium transfer rate from exchangeable K deficient soil., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Nontuberculous mycobacteria (NTM) are ubiquitous organisms and the incidence of NTM infections has been increasing in recent years. Mycobacteroides abscessus (M. abscessus) is one of the most antimicrobial-resistant NTM; however, no reliable antibiotic regimen can be officially advocated. We evaluated the efficacy of clarithromycin in combination with various antimicrobial agents against the M. abscessus complex., Results: Twenty-nine clinical strains of M. abscessus were isolated from various clinical samples. Of the isolates, 10 (34.5%) were of M. abscessus subsp. abscessus, 18 (62.1%) of M. abscessus subsp. massiliense, and 1 (3.4%) of M. abscessus subsp. bolletii. MICs of three antimicrobial agents (amikacin, imipenem, and moxifloxacin) were measured with or without clarithromycin. The imipenem-clarithromycin combination significantly reduced MICs compared to clarithromycin and imipenem monotherapies, including against resistant strains. The association between susceptibility of the M. abscessus complex and each combination of agents was significant (p = 0.001). Adjusted residuals indicated that the imipenem-clarithromycin combination had the synergistic effect (adjusted residual = 3.1) and suppressed the antagonistic effect (adjusted residual = - 3.1). In subspecies of M. abscessus complex, the association with susceptibility of M. abscessus subsp. massiliense was similarly statistically significant (p = 0.036: adjusted residuals of synergistic and antagonistic effect respectively: 2.6 and - 2.6). The association with susceptibility of M. abscessus subsp. abscessus also showed a similar trend but did not reach statistical significance., Conclusion: Our data suggest that the imipenem-clarithromycin combination could be the recommended therapeutic choice for the treatment of M. abscessus complex owing to its ability to restore antimicrobial susceptibility.

Introduction: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds., Methods and Analysis: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies., Ethics and Dissemination: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal., Trial Registration Number: UMIN000038210., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare interstitial pneumonia that is characterized by stiffness in both the upper lobes and pleura, which is evident on high resolution computed tomography (HRCT) of the chest. However, prognostic factors for IPPFE have not been identified yet., Objective: We aimed to investigate the clinical prognostic factors affecting survival in patients with IPPFE., Methods: Between April 2009 and September 2017, we enrolled 36 patients who were clinically diagnosed with IPPFE, using HRCT. These patients were classified as either short survival (dead within 12 months from the diagnosis of IPPFE) or long survival (survived for greater than 12 months) groups. We retrospectively analyzed the clinical characteristics, serum markers, pulmonary function test results, and HRCT findings., Results: Twelve patients were classified into the short survival and 24 were categorized into long survival categories. At the time of diagnosis, the incidence of coexistence of a usual interstitial pneumonia (UIP) pattern in the lower lobes on HRCT in the short survival was significantly higher than that in the long survival. Multivariate analysis revealed that a UIP pattern in the lower lobes on HRCT was the only independent variable for poor prognosis. The median survival time from diagnosis in patients with IPPFE was 24 months. Of these patients with IPPFE, the survival time with a UIP pattern was significantly shorter than in those without a UIP pattern., Conclusion: Our findings suggest that a UIP pattern in the lower lobes at the time of diagnosis was an independent prognostic factor for IPPFE., (© 2018 S. Karger AG, Basel.)

We previously reported an association between human parechovirus type 3 (HPeV3) and epidemic myalgia with myositis in adults during summers in which an HPeV3 outbreak occurred in children. However, this disease association has not yet been reported elsewhere. We have since continued our surveillance to accumulate data on this disease association and to confirm whether myalgia occurs in children as well as adults. Between June and August 2014, we collected 380 specimens from children with infectious diseases. We also collected clinical specimens from two adult and three paediatric patients suspected of myalgia. We then performed virus isolation and reverse-transcription-PCR using the collected specimens. We detected HPeV3 in 26 children with infectious diseases, which we regarded as indicating an outbreak. We also confirmed HPeV3 infection in all patients suspected of myalgia. In particular the symptoms in two boys, complaining of myalgia and fever, closely matched the criteria for adult myalgia. Based on our findings from 2008, 2011 and 2014, we again urge that clinical consideration be given to the relationship between myalgia and HPeV3 infections during HPeV3 outbreaks in children. Furthermore, our observations from 2014 suggest that epidemic myalgia and myositis occur not only in adults but also in children.

Background: Academic/institutional investigator-initiated clinical trials benefit individuals and society by supplementing gaps in industry-sponsored clinical trials., Materials: In May 2010, experts from Japan, the Republic of Korea, the UK, and the United States, met at a symposium in Tokyo, Japan, to discuss how policies related to the conduct of clinical trials, which have been shown to be effective, may be applied to other regions of the world., Results: In order to increase the availability of anticancer drugs world-wide, nations including Japan should examine the benefits of increasing the number of investigator-initiated clinical trials. These trials represent one of the most effective ways to translate basic scientific knowledge into clinical practice. These trials should be conducted under GCP guidelines and include Investigational New Drug application submissions with the ultimate goal of future drug approval., Conclusions: To maximize the effectiveness of these trials, a policy to educate health care professionals, cancer patients and their families, and the public in general on the benefits of clinical trials should be strengthened. Finally, policies that expedite the clinical development of novel cancer drugs which have already been shown to be effective in other countries are needed in many nations including Japan to accelerate drug approval.

Introduction: To determine the characteristics of Mycobacterium avium in Japan, we compared the genetic properties of M. avium isolated in different countries., Methods: A Mycobacterium avium tandem-repeat variable-number tandem-repeat (MATR-VNTR) analysis was performed using South Korean strains (n = 119) and Japanese strains (n = 76). In addition, we compared the frequencies of a new insertion sequence, ISMav6., Results: A phylogenetic analysis identified different clusters between the two countries' strains. The prevalence of ISMav6 was significantly different between them, i.e., 75.0% in Japanese strains and 59.8% in the Korean ones (P < 0.035). The frequency of strains with IS Mav6 in the Shine-Dalgarno (SD) sequence of the cfp29 gene that is involved in the interferon-gamma induction was also different, with stronger significance (Japan: 38.2%, Korea: 12.4%, P < 0.001)., Discussion: It is possible that M. avium strains prevalent in Japan and in Korea are genetically distinct. The analyses of the presence of ISMav6, as well as the VNTR patterns of M.avium strains from many different countries would be a promising methodology in elucidating the causes of the recent increase in cases of pulmonary MAC diseases.

Non-coding microRNAs (miRNAs) are suggested to serve fundamental roles in cellular stress responses and in coping with sudden environmental changes in experimental animals. We examined whether naturalistic stressor-responsive miRNAs were detectable in whole blood. Blood and saliva were collected between 16:00 and 17:00 from 10 healthy medical students (5 males and 5 females; aged 22.4±0.8 years, mean±SD) 7 weeks before, one day before, immediately after, and one week after a nationally administered examination for academic promotion. Samples obtained one week after the examination were used as baseline controls. State anxiety and salivary cortisol levels reached maximum levels the day before the examination. Eleven candidate miRNAs (miR-144, -144*, -16, -15a, -19a, -19b, -26b, -30b, -106b, -126, and -142-3p) were extracted using a human miRNA microarray, and quantitative real-time reverse transcription PCR confirmed significant elevation of miR-144/144* and miR-16 levels immediately after finishing the examination. miR-16 levels in individual students were positively correlated with those of serum tumor necrosis factor (TNF)-α measured immediately after the examination. Percentage changes in miR-144* and miR-16 levels from immediately after to one week after the examination were significantly correlated with percentage changes in circulating interferon-γ and/or TNF-α levels over the same time points. Our results suggest that miR-144/144* and miR-16 may constitute a part of an integrated response to naturalistic stressors in healthy young adults., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background/aims: Resistance to erythropoiesis-stimulating agent (ESA) is associated with mortality in hemodialysis (HD) patients. Time-dependent variability of ESA resistance has been not investigated adequately, although consistently high ESA resistance is expected to be a high risk for mortality. Our aim, therefore, was to investigate consistently high ESA resistance as an independent predictor of mortality in HD patients., Methods: This study evaluated 2,104 Japanese HD patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) III. ESA resistance index (ERI) was defined as the weekly weight-adjusted dose of ESA divided by hemoglobin concentration. The average ERI was calculated from ERI levels every 4 months throughout the observation period for each patient. To assess the size of the fluctuation in average ERI during the observation periods according to ERI quartiles at the enrollment periods, six patient groups were defined on the basis of patterns of ERI level fluctuation: low-low (Low), intermediate-intermediate (Intermediate), high-high (High), low-intermediate, intermediate-high, and low-high., Results: The number of deaths among the patients was 227 (10.8%), which included 113 (5.4%) cases of cardiovascular disease (CVD). In multivariate analysis after adjustment for age, albumin, C-reactive protein, comorbidities, etc., the High group was independently and significantly related to all-cause and CVD-related mortality (OR = 2.33, 95% CI: 1.33-4.07, p = 0.002, and OR = 2.09, 95% CI: 1.05-4.14, p = 0.035, respectively)., Conclusion: Factoring out fluctuating ERI increases the ability of consistently high ERI levels as an independent risk factor for all-cause and CVD mortality in HD patients., (Copyright © 2013 S. Karger AG, Basel.)

We previously demonstrated that anemia was not associated with mortality in hemodialysis patients with cardiovascular disease (CVD). Since diabetes mellitus (DM) accelerates CVD, the influence of DM on the relationship between anemia and mortality was examined using the data obtained from 1,385 DM patients and 2,583 non-DM hemodialysis patients recruited into the Dialysis Outcomes Practice Pattern Study in Japan (J-DOPPS). When all patients were stratified into four groups on their hematocrit levels, mortality rate was significantly and steadily lower in the subgroups with the higher levels of hematocrit by the Kaplan-Meier method (p = 0.0003 by log-rank test). When DM and non-DM patients were analyzed separately, a significant association of lower hematocrit levels with higher mortality disappeared in DM patients (p = 0.6280), in contrast with its retention in non-DM counterparts (p < 0.0001). Multivariable-adjusted Cox proportional hazards models demonstrated a significant association between hematocrit with all-cause mortality in non-DM patients after adjustment for age, gender, BMI, hemodialysis duration, SBP, DBP, albumin, total cholesterol, calcium, phosphorus, and intact PTH (p = 0.046), whereas this association disappeared in DM patients in the same model (p = 0.583). In conclusion, these results suggested that the association between anemia and higher mortality disappeared in DM hemodialysis patients, in contrast with non-DM counterparts., (Copyright © 2012 S. Karger AG, Basel.)

The emergence of drug-resistant bacteria is a severe problem in aquaculture. The ability of drug resistance genes to transfer from a bacterial cell to another is thought to be responsible for the wide dissemination of these genes in the aquaculture environment; however, little is known about the gene transfer mechanisms in marine bacteria. In this study, we show that a tetracycline-resistant strain of Photobacterium damselae subsp. damselae, isolated from seawater at a coastal aquaculture site in Japan, harbors a novel multiple drug resistance plasmid. This plasmid named pAQU1 can be transferred to Escherichia coli by conjugation. Nucleotide sequencing showed that the plasmid was 204,052 base pairs and contained 235 predicted coding sequences. Annotation showed that pAQU1 did not have known repA, suggesting a new replicon, and contained seven drug resistance genes: bla(CARB-9)-like, floR, mph(A)-like, mef(A)-like, sul2, tet(M) and tet(B). The plasmid has a complete set of genes encoding the apparatus for the type IV secretion system with a unique duplication of traA. Phylogenetic analysis of the deduced amino acid sequence of relaxase encoded by traI in pAQU1 demonstrated that the conjugative transfer system of the plasmid belongs to MOB(H12), a sub-group of the MOB(H) plasmid family, closely related to the IncA/C type of plasmids and SXT/R391 widely distributed among species of Enterobacteriaceae and Vibrionaceae. Our data suggest that conjugative transfer is involved in horizontal gene transfer among marine bacteria and provide useful insights into the molecular basis for the dissemination of drug resistance genes among bacteria in the aquaculture environment.

Secondary hyperparathyroidism is common in patients with mineral and bone disorders related to chronic kidney disease. Guidelines for the management of secondary hyperparathyroidism in hemodialysis patients have been promulgated, but evidence on the relationship between treatment and survival is still insufficient. Studying hemodialysis patients with secondary hyperparathyroidism, we have three goals: (i) to record the characteristics of those patients and variations in the patterns of their treatment; (ii) to analyze factors associated with variations in those medical practice patterns; and (iii) to identify the practice patterns and other factors that affect hospitalization, mortality, and other patient-level outcomes. This is a three-year prospective observational study with a case-cohort and a cohort design. Eligible patients comprise all patients who are receiving hemodialysis at the participating facilities and who also have secondary hyperparathyroidism. In the case-cohort study, the outcomes are relatively infrequent events (all-cause mortality and cardiovascular mortality). The cohort study will include a randomly selected sample of 40% of all study participants; and the outcomes include hospitalization, parathyroid interventions, bone fracture, and mineral bone density management status. Explanatory variables comprise medications and other factors likely to be associated with the outcomes of dialysis and of secondary hyperparathyroidism, and facility-level practice patterns. We expect this study to provide evidence regarding factors that affect outcomes in hemodialysis patients with secondary hyperparathyroidism., (© 2011 The Authors. Therapeutic Apheresis and Dialysis © 2011 International Society for Apheresis.)

In April 2006, Japan's health insurance system instituted a bundling policy that included recombinant human erythropoietin (rHuEPO) in outpatient hemodialysis therapy. To evaluate outcomes of this, we analyzed a prospective cohort of hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study, in 53 facilities using prevalent cross-sections of 1584 patients before and 1622 patients after the rHuEPO reimbursement change. Patient data included hemoglobin levels, iron management profiles, and anemia treatment with rHuEPO and intravenous iron. No significant differences were found in pre- or post-policy cross-sections for hemoglobin distributions or the percentage of patients prescribed rHuEPO. Among patients receiving rHuEPO, the mean dose significantly decreased by 11.8 percent. The percentage of patients prescribed intravenous iron over 4 months significantly increased; however, the mean dose of iron did not significantly change. Thus, this bundling policy was associated with reduced rHuEPO doses, increased intravenous iron use, and stable hemoglobin levels in Japanese patients receiving hemodialysis.

Background/aims: The Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D) is a multicenter, prospective observational study of hemodialysis patients with secondary hyperparathyroidism (SHPT) in Japan, where the national guideline recommends targets for serum calcium (8.4-10.0 mg/dl), phosphorus (3.5-6.0 mg/dl), and intact parathyroid hormone (PTH) (60-180 pg/ml)., Methods: The MBD-5D involved patients who were receiving hemodialysis for more than 3 months and met at least one of the following conditions: having intact PTH levels >180 pg/ml, or receiving intravenous vitamin D receptor activators (VDRAs) or oral VDRA analog. This report describes the baseline characteristics of the study participants and examines factors associated with mineral metabolism controllability., Results: A total of 8,229 patients were registered from 86 facilities as the whole cohort, and 3,276 patients were randomly selected as the subcohort. The severity of SHPT was associated with a lower likelihood of achieving the targets for calcium and phosphorus, whereas patients with a history of parathyroidectomy were more likely to achieve these targets as compared with those who had not undergone surgery despite high PTH levels. The use of 2.5 mEq/l calcium dialysate was also associated with a higher likelihood of achieving the targets compared with the use of 3.0 mEq/l calcium dialysate., Conclusion: The severity of SHPT and the use of dialysate with higher calcium concentration are associated with practical difficulty in managing mineral metabolism in dialysis patients. Further prospective follow-up is needed to confirm our findings and to examine their impact on patient-level outcomes., (Copyright © 2011 S. Karger AG, Basel.)

Objective: The main objective of the study was to estimate a preference-based Short Form (SF)-6D index from the SF-36 for Japan and compare it with the UK results., Study Design and Setting: The SF-6D was translated into Japanese. Two hundred and forty-nine health states defined by this version of the SF-6D were then valued by a representative sample of 600 members of the Japanese general population using standard gamble (SG). These health-state values were modeled using classical parametric random-effect methods with individual-level data and ordinary least squares (OLS) on mean health-state values, together with a new nonparametric approach using Bayesian methods of estimation., Results: All parametric models estimated on Japanese data were found to perform less well than their UK counterparts in terms of poorer goodness of fit, more inconsistencies, larger prediction errors and bias, and evidence of systematic bias in the predictions. Nonparametric models produce a substantial improvement in out-of-sample predictions. The physical, role, and social dimensions have relatively larger decrements than pain and mental health compared with those in the United Kingdom., Conclusion: The differences between Japanese and UK valuations of the SF-6D make it important to use the Japanese valuation data set estimated using the nonparametric Bayesian technique presented in this article.

Aims: Whether health-related quality of life (HRQoL) can be accurately predicted in patients with extremely low HRQoL as a result of diabetic complications is unclear. We investigated the impact of HRQoL on mortality risk in patients with diabetes on haemodialysis., Methods: Data from the Dialysis Outcomes Practice Pattern Study (DOPPS) were analysed for randomly selected patients receiving haemodialysis in Japan. Information regarding the diagnosis of diabetes and clinical events during follow-up was abstracted from the medical records at baseline and HRQoL was assessed by a self-reported short form (SF)-36 questionnaire. The association between physical component score and mental component score in the SF-36 and mortality risk was analysed using a Cox proportional hazard model., Results: Data from 527 patients with diabetes on haemodialysis were analysed. The mortality age-adjusted hazard ratio of having a physical component score greater than or equal to the median was 0.27 [95% confidence interval (CI) 0.08-0.96] and the multivariable-adjusted mortality hazard ratio of having an mental component score greater than or equal to the median was 1.21 (95% CI 0.44-3.35)., Conclusions: The physical component score derived from the SF-36 is an independent risk factor for mortality in patients with diabetes on haemodialysis who generally had very low HRQoL scores. Baseline mental component score was not predictive of mortality. Patient self-reporting regarding the physical component of health status may aid in risk stratification and clinical decision making for patients with diabetes on haemodialysis.

Background: Recent reports suggest a cross-sectional association between psychiatric distress and pruritus in patients on haemodialysis (HD). However, no study has examined the likelihood of developing severe pruritus in patients on HD with depressive symptoms., Objectives: To evaluate the relationship between baseline depressive symptoms and subsequent risk of developing severe pruritus., Methods: A longitudinal study with a 0.5-2.5-year follow-up period was performed using 1799 patients on HD who had no/mild pruritus at baseline, based on the Japan Dialysis Outcomes and Practice Patterns Study (1996-2004), a cohort study composed of a representative sample of patients on HD. We assessed pruritus after the follow-up period using a self-reported questionnaire and depressive symptoms using scores from the five-item version of the Mental Health Inventory (MHI-5)., Results: The 1799 patients had a mean age of 56.9 years, 59.5% were men, and 23.6% presented depressive symptoms. Multivariable analysis revealed that patients with depressive symptoms had significantly higher odds of developing severe pruritus during the 0.5-2.5-year follow-up period [adjusted odds ratio (AOR) 1.57, 95% confidence interval 1.22-2.01, P < 0.001]. In addition, a significant linear trend was observed between baseline MHI-5 scores and risk of developing severe pruritus, with AORs for third, second and first MHI-5 score quartiles of 1.08, 1.51 and 1.95, respectively (P for trend < 0.0001)., Conclusions: Our results suggest that depressive symptoms measured by MHI-5 may predict the future risk of developing severe pruritus in patients on HD.

Background: Bodily pain and psychiatric distress are common symptoms in patients with dialysis. However, the temporal relationships have not yet been investigated. Objective. To evaluate the longitudinal association between depressive symptoms and subsequent risk of developing severe bodily pain in dialysis patients. Design. Prospective cohort study., Methods: We assessed bodily pain using a self-reported questionnaire and depressive symptoms using scores from the short version of Center for Epidemiological Studies Depression Screening Index (CES-D) from 531 participants showing no/mild bodily pain at baseline, based on the Japan Dialysis Outcomes and Practice Patterns Study, a cohort study of hemodialysis patients. To evaluate the relationship between depressive symptoms and development of severe bodily pain, multivariable logistic regression analysis was performed., Results: The 531 patients had a mean age of 57.9 years, 61.4% were male, and 33.1% had depressive symptoms. Logistic regression analysis revealed that depressive symptoms at baseline were significantly associated with higher odds of developing severe bodily pain during a 0.5- to 2.5-year follow-up period (adjusted odds ratio [AOR] = 2.13, 95% confidence interval [CI]: 1.36-3.33, P = 0.001). Further, patients with higher CES-D scores were likely to develop severe bodily pain (AOR = 1.09, 95% CI: 1.04-1.15, P = 0.001)., Conclusions: Results of this study suggest that depressive symptoms measured by CES-D predict the future risk of developing severe bodily pain in dialysis patients.

Background/aims: Given the clear benefits of mortality reduction observed for most beta-blockers in clinical trials, they are relatively underused in hemodialysis patients. Since the outcomes associated with the use of beta-blockers are not fully known, we investigated their effect on mortality among a cohort of hemodialysis patients., Methods: Data were analyzed from the Dialysis Outcomes and Practice Patterns Study phase II for 2,286 randomly selected patients on hemodialysis in Japan. Treatment with beta-blockers was the major predictor variable. The main outcome measure was all-cause mortality. Cox regression analysis was used to assess an association between treatment with beta-blockers and the risk of death., Results: 247 patients (11.9%) were administered beta-blockers and 1,828 patients (88.1%) were not. Whereas patients treated with beta-blockers had a higher prevalence of hypertension and coronary heart disease, Kaplan-Meier analysis revealed that all-cause mortality rates were significantly (p < 0.007) decreased in patients treated with beta-blockers compared to those without. In multivariable, fully adjusted models, treatment with beta-blockers was also independently associated with reduced all-cause mortality (hazard ratio = 0.48; p = 0.02)., Conclusion: This study indicated a possible association between the use of beta-blockers and reduced risk of mortality in hemodialysis patients. These results should be confirmed in further randomized controlled trials., (Copyright 2009 S. Karger AG, Basel.)

Background: Japanese haemodialysis (HD) patients not only have a very low mortality and hospitalization risk but also low haemoglobin (Hb) levels. Internationally, anaemia is associated with mortality, hospitalization and health-related quality of life (QoL) measures of HD patients., Methods: Longitudinal data collected from 1999 to 2006 from 60 to 64 representative Japanese dialysis units participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) were used to describe anaemia management practices and outcomes for Japanese HD patients., Results: From 1999 to 2006, patient mean Hb increased from 9.7 g/dl to 10.4 g/dl, and the percentage of facilities with median Hb >or=10 g/dl increased from 27% to 75%. Hb was measured in the supine position for 90% of patients, resulting in substantially lower reported Hb values than those seen in other countries. As of 2006, erythropoietin (Epo) was prescribed to 83% of HD patients; mean Epo dose was 5231 units/week; intravenous (IV) iron use was 33% and median IV iron dose was 160 mg/month. Many patient- and facility-level factors were significantly related to higher Hb. A consistent overall pattern of lower mortality risk with higher baseline Hb levels was seen (RR = 0.89 per 1 g/dl higher Hb, P = 0.003). Facilities with median Hb >or=10.4 displayed a lower mortality risk (RR = 0.77, P = 0.03) versus facility median Hb <10.4 g/dl. Lower Hb levels were not significantly related to hospitalization risk, but were associated with lower QoL scores., Conclusions: These results provide detailed information on anaemia management practices in Japan and the relationships of anaemia control with outcomes, with implications of anaemia management worldwide.

Objective: To identify barriers to the clinical application of regenerative medicine products (RMPs) in Japan., Methods: Current Japanese regulatory systems and guidelines were compared with those of the United States (US) and the European Union (EU). A questionnaire was administered to representatives from 23 Japanese companies and 10 research institutes, and an in-person semi-structured interview was conducted with representatives from 10 companies that develop RMP., Results: We found that Japan, the US and the EU have similar pre-clinical safety guideline frameworks relating to RMP. However, differences exist between these countries with respect to their review and approval systems and the implementation of guidelines, and these represent major barriers to the clinical application of RMP in Japan. Most companies studied are facing regulatory hurdles such as stringent review processes and regulatory guidelines that do not provide detailed practical examples of the pre-clinical quality and safety data required., Conclusions: These results suggest that effective regulatory infrastructure including regulatory systems, guidelines, and communication channels between product developers and regulatory bodies are essential for the prompt clinical application of RMP in Japan.

Background: Poor sleep quality (SQ) affects many haemodialysis (HD) patients and could potentially predict their morbidity, mortality, quality of life (QOL) and patterns of medication use., Methods: Data on SQ were collected from 11,351 patients in 308 dialysis units in seven countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) between 1996 and 2001 through a patient self-reported SQ scale, ranging from 0 (worst) to 10 (best). A score of <6 reflected poor SQ. Sleep disturbance was also assessed by self-reported daytime sleepiness, feeling drained and nocturnal awakening. Logistic and multiple linear regression were used to assess predictors of SQ and associations with QOL. Cox regression examined associations with mortality. Analyses accounted for case-mix, facility clustering and country., Results: Nearly half (49%) of patients experienced poor SQ. Mean SQ scores varied by country, ranging from 4.9 in Germany to 6.5 in Japan. Patients with poor SQ were more likely to be prescribed antihistamines, antidepressants, anti-inflammatories, narcotics, gastrointestinal (GI) medications, anti-asthmatics or hypnotics. Physical exercise at least once a week (vs < once a week) was associated with lower odds of poor SQ (AOR = 0.55-0.85, P < 0.05). Poorer SQ was associated with significantly lower mental and physical component summary (MCS/PCS) scores (MCS scores 1.9-13.2 points lower and PCS scores 1.5-7.7 points lower when SQ scores were <10 vs 10). The RR of mortality was 16% higher for HD patients with poor SQ., Conclusions: Poor SQ is common among HD patients in DOPPS countries and is independently associated with several QOL indices, medication use patterns and mortality. Assessment and management of SQ should be an important component of care.

Photobacterium damselae subsp. piscicida is a bacterial fish pathogen that causes a disease known as pasteurellosis. Two transferable multiple-drug resistance (R) plasmids, pP99-018 (carrying resistance to kanamycin, chloramphenicol, tetracycline, and sulfonamide) and pP91278 (carrying resistance to tetracycline, trimethoprim, and sulfonamide), isolated from P. damselae subsp. piscicida strains from Japan (P99-018) and the United States (P91278), respectively, were completely sequenced and analyzed, along with the multiple-drug resistance regions of three other R plasmids also from P. damselae subsp. piscicida strains from Japan. The sequence structures of pP99-018 (150,057 bp) and pP91278 (131,520 bp) were highly conserved, with differences due to variation in the drug resistance and conjugative transfer regions. These plasmids, shown to be closely related to the IncJ element R391 (a conjugative, self-transmitting, integrating element, or constin), were divided into the conjugative transfer, replication, partition, and multiple-drug resistance regions. Each of the five multiple-drug resistance regions sequenced exhibited unique drug resistance marker composition and arrangement.

Background: Considerable controversy exists over the impact of the biocompatibility and flux characteristics of dialyzer membranes on anemia in chronic hemodialysis patients., Methods: A subset of 1,207 subjects from the Japanese arm of DOPPS phase II was analyzed., Results: Patient characteristics included mean age 59 years, male sex 60%, BMI 20.6, time on dialysis therapy 7.8 years, and diabetes rate 27%. Dialysis parameters were Kt/V 1.33, and normalized protein catabolic rate 1.05 g/kg/day. Initial hemoglobin level was 10.1 g/dl. 79% were treated by intravenous erythropoietin with mean weekly doses of 4,500 IU. Hemoglobin levels and erythropoietin doses during 2-year study period were not affected by dialysis membrane biocompatibility (unmodified cellulose or biocompatible) or flux (standard or high performance). The 2-year survival rate was 90.9% and was influenced by older age, presence of cardiovascular diseases and amyloidosis, lower levels of BMI and serum albumin, but not by other variables, including dialysis membranes. Use of biocompatible membranes was associated with a lower all-cause mortality (8.3 vs. 13.0% for bioincompatible, p = 0.037), but this difference was not significant in multivariate analyses (hazard ratio 0.70, p = 0.17 by Cox multivariate analysis)., Conclusion: The biocompatibility and permeability of dialyzer membranes had no effect on anemia, erythropoietin dosage or all-cause mortality in Japanese chronic hemodialysis patients treated by non-reuse dialysis., (Copyright 2008 S. Karger AG, Basel.)

Abnormalities in mineral metabolism have been linked to mortality in hemodialysis (HD) patients. We postulated that these abnormalities would have a particularly large deleterious impact on deaths due to cardiovascular causes in Japan. This study describes the recent status of abnormal mineral metabolism, significant predictors, and potential consequences in the Dialysis Outcomes and Practice Patterns Study (DOPPS), Phases 1 and 2, in Japan. Major predictor variables were patient demographics, comorbidities, and laboratory markers of mineral metabolism such as albumin-adjusted serum calcium (calciumAlb), phosphorus, and intact PTH (iPTH). In a cross section of 3973 Japanese HD patients in DOPPS I and II, a large faction had laboratory values outside of the recommended Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline range for serum concentrations of phosphorus (51% of patients above upper target range), calciumAlb (43.7% above), calcium-phosphorus (Ca x P) product (41.1% above), and iPTH (18.6% above). All-cause mortality was significantly and independently associated with calciumAlb (relative risk [RR]=1.22 per 1 mg/dL, p=0.0005) and iPTH (RR=1.04 per 100 pg/mL, p=0.04). Cardiovascular mortality was significantly associated with calciumAlb (RR=1.28, p=0.02), phosphorus (RR=1.13 per 1 mg/dL, p=0.008), Ca x P product (RR=1.07 per 2 mg(2)/dL(2), p=0.002), and PTH (RR=1.08, p=0.0001). This study expands our understanding of the relationship between altered mineral metabolism and mortality outcomes, showing slightly stronger associations with cardiovascular causes than observed for all-cause mortality. These findings have important therapeutic implications for Japanese HD patients.

Background: The Dialysis Outcomes and Practice Patterns Study (DOPPS) reported high incidence of depression in haemodialysis patients. Hypercalcaemia and high parathyroid hormone (PTH) levels are aetiological factors of psychological disorders. We examined the association between mineral metabolism abnormalities and mental health in Japanese-DOPPS patients., Methods: We used baseline data of Japan-DOPPS, Phase 1 (2755 patients, 1999-2001) and Phase 2 (2286 patients, 2002-03). The outcome variable was mental health using the mental health domain of SF-36. We examined the association between serum corrected calcium, phosphorus, calcium x phosphorus product and intact PTH concentrations, and mental health using analysis of covariance and also the associations between corrected calcium levels and current use of vitamin D and calcium-containing phosphate binder., Results: There was a significant association between mental health and corrected calcium levels. A significantly lower mental health score was noted in patients with corrected calcium > or = 11 mg/dl than in <8.4 (P = 0.04), > or =8.4 to <10.2 (P = 0.009) and > or =10.2 to <11 mg/dl (P = 0.003). The association was significant even after adjustment for age, sex and other confounders. However, there was no relationship between intact PTH and mental health. High-corrected calcium levels were significantly associated with the use of intravenous active vitamin D and calcium-containing phosphate binder., Conclusions: Hypercalcaemia, but not high intact PTH, is associated with poor mental health in dialysis patients. While a cause-effect relationship between hypercalcaemia and deterioration of mental health needs further confirmation by longitudinal and prospective studies, our observational findings suggest the importance of control of serum calcium concentration in dialysis patients.

Since the mid-1990s, lethal infections of koi herpesvirus (KHV) have been spreading, threatening the worldwide production of common carp and koi (both Cyprinus carpio). The complete genome sequences of three KHV strains from Japan, the United States, and Israel revealed a 295-kbp genome containing a 22-kbp terminal direct repeat. The finding that 15 KHV genes have clear homologs in the distantly related channel catfish virus (ictalurid herpesvirus 1) confirms the proposed place of KHV in the family Herpesviridae, specifically in the branch with fish and amphibian hosts. KHV thus has the largest genome reported to date for this family. The three strains were interpreted as having arisen from a wild-type parent encoding 156 unique protein-coding genes, 8 of which are duplicated in the terminal repeat. In each strain, four to seven genes from among a set of nine are fragmented by frameshifts likely to render the encoded proteins nonfunctional. Six of the affected genes encode predicted membrane glycoproteins. Frameshifts or other mutations close to the 3' ends of coding sequences were identified in a further six genes. The conclusion that at least some of these mutations occurred in vivo prompts the hypothesis that loss of gene functions might be associated with emergence of the disease and provides a basis for further investigations into the molecular epidemiology of the virus.

Background: Information about residual renal function (RRF) and outcomes associated with practices of diuretic use in patients with end-stage renal disease is not available worldwide., Methods: Diuretic use was investigated in 16,420 hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study, a prospective observational study of hemodialysis patients selected from nationally representative facilities on 3 continents. Logistic regressions were used to investigate associations between diuretic use and patient characteristics. Outcomes of interdialytic weight gain, increased serum potassium and phosphorus levels, and odds of retaining RRF after 1 year were investigated. Cox regression was used to analyze the association between mortality and diuretic use., Results: Facility diuretic use varied substantially from 0% to 83.9% of patients. Diuretic use decreased sharply after the start of dialysis therapy. Loop diuretic use ranged from 9.2% in the United States to 21.3% in Europe, whereas use within 90 days of starting dialysis therapy ranged from 25.0% in the United States to 47.6% in Japan. Diuretic use was associated with lower interdialytic weight gain and lower odds of hyperkalemia (potassium > 6.0 mmol/L). Patients with RRF on diuretic therapy had almost twice the odds of retaining RRF after 1 year in the study versus patients not on diuretic therapy. Patients administered diuretics had a 7% lower all-cause mortality risk (P = 0.12) and 14% lower cardiac-specific mortality risk (P = 0.03) versus patients not administered diuretics., Conclusion: Variation exists in facility practices of diuretic use. In patients with RRF, there may be benefit associated with continuing diuretic use rather than automatically discontinuing diuretic therapy at dialysis initiation.

Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan.

Purpose: This study examined effects of prior sprint exercise on hormonal responses to subsequent resistance exercise with different recovery periods between exercise bouts., Methods: Nine men performed three types of exercise regimens: 1) resistance exercise only (R), 2) resistance exercise with prior sprint exercise and 60 min of rest (SR60), and 3) resistance exercise with prior sprint exercise and 180 min of rest (SR180). Sprint exercises consisted of maximal sprint cycling (eight sets of 5-s sprints with 30-s rest periods between sets) with prior 10-min warm-up. Resistance exercise consisted of five exercises, each with three sets at a 10-repetition maximum with 1-min rest periods., Results: Prior sprint exercise significantly increased blood lactate, glycerol, epinephrine, norepinephrine, growth hormone (GH), and free testosterone concentrations (P < 0.05). Before the resistance exercise, free fatty acids concentration was higher in the SR180 trial than in the SR60 and R trials (P < 0.05), whereas GH concentration was significantly higher in the SR60 trial (P < 0.01). After the resistance exercise, no significant difference was found in responses of pH, epinephrine, norepinephrine, and free testosterone among trials. The SR180 trial showed a smaller GH response (peak value: 7.8 +/- 1.6 (SE) ng.mL(-1)) than in the R trial (12.8 +/- 3.7 ng.mL(-1)), with no significant difference between trials. In the SR60 trial, GH response to resistance exercise was attenuated (3.3 +/- 1.2 ng.mL(-1), P < 0.01). Maximal strength and power measured immediately before the resistance exercise showed no difference among trials., Conclusion: These results indicate that GH response to resistance exercise was attenuated strongly when the exercise was preceded by sprint exercise and a shorter (60 min) recovery period.

Many hemodialysis patients in Japan have symptoms of depression, but whether those patients are treated appropriately is unknown. As part of the Dialysis Outcomes and Practice Patterns Study, data on symptoms of depression, physician-diagnosed depression, prescribed medications, and death were collected prospectively in cohorts in Japan (n=1603) and 11 other countries (n=5872). Symptoms of depression were as prevalent in Japan as elsewhere, but in Japan a much smaller percentage of patients had physician-diagnosed depression: only 2% in Japan vs 17% elsewhere. Antidepressants were much less commonly prescribed in Japan: only 1% in Japan vs 17% elsewhere for patients with many and frequent symptoms of depression, and 16% in Japan vs 34% elsewhere for patients with physician-diagnosed depression. In Japan, symptoms of depression were associated with prescription of benzodiazepines (without antidepressants), and patients with physician-diagnosed depression were twice as likely to be given benzodiazepines: 32% in Japan vs 16% elsewhere. Benzodiazepine monotherapy was associated with death (relative risk 1.56, 95% confidence interval (CI), 1.25-1.94), even after adjustments for 13 likely confounders (relative risk 1.27, 95% CI, 1.01-1.59). Hemodialysis patients in Japan with symptoms of depression are given not antidepressants but benzodiazepines, a practice associated with higher mortality.

Background: The aim of this study was to investigate the effects of arginine on nutrition, growth and urea cycle function in boys with late-onset ornithine transcarbamylase deficiency (OTCD). Seven Japanese boys with late-onset OTCD enrolled in this study resumed arginine treatment after the cessation of this therapy for a few years. Clinical presentations such as vomiting and unconsciousness, plasma amino acids and urinary orotate excretion were followed chronologically to evaluate urea cycle function and protein synthesis with and without this therapy. In addition to height and body weight, blood levels of proteins, lipids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein -3 (IGFBP-3) were monitored., Results: The frequency of hyperammonemic attacks and urinary orotate excretion decreased significantly following the resumption of arginine treatment. Despite showing no marked change in body weight, height increased gradually. Extremely low plasma arginine increased to normal levels, while plasma glutamine and alanine levels decreased considerably. Except for a slight increase in high-density lipoprotein cholesterol level, blood levels of markers for nutrition did not change. In contrast, low serum IGF-I and IGFBP-3 levels increased to age-matched control levels, and normal urinary GH secretion became greater than the level observed in the controls., Conclusion: Arginine treatment is able to reduces attacks of hyperammonemia in boys with late-onset OTCD and to increase their growth.

Background: The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study has previously shown losartan to confer significant benefits to patients with type 2 diabetes and nephropathy. The original study of 1513 patients included 96 Japanese patients; the present study is a post-hoc analysis of the effects of losartan in this Japanese subpopulation., Methods: This double-blind, randomized study compared losartan (50 to 100 mg once daily) with placebo. The study medication was taken in addition to conventional antihypertensive treatment, and the mean follow-up period for the Japanese patients was 2.8 years. The primary endpoint was the composite of doubling of serum creatinine, endstage renal disease, or death. Secondary endpoints included changes in proteinuria levels. Safety was also evaluated., Results: The primary composite endpoint was reached in fewer Japanese patients receiving losartan than placebo (50.0% versus 65.4%, respectively). The treatment effects of losartan were more robust when data were corrected for differences in proteinuria at baseline--a significant relative risk reduction of 45% with losartan (P=0.0397) was apparent. Treatment benefit exceeded that attributable to blood pressure changes alone. Levels of proteinuria were reduced with losartan compared with placebo, with an overall losartan treatment effect of 37.8% (P<0.001). Overall, losartan was similarly well tolerated in both the Japanese patients and the total population., Conclusions: In Japanese patients with type 2 diabetes and nephropathy, losartan offers renal protection and is generally well tolerated.

Background: Although Gleason grading may be the most useful system for evaluating biological activity of untreated prostate cancer, lack of interobserver validity with Gleason scores (GS) is an unsolved issue. In this study, the proliferating cell nuclear antigen labeling index (PCNA LI) in untreated prostate cancer was investigated in order to clarify the usefulness of supplemental and objective markers for evaluating the biologic features of prostate cancer., Methods: Sixty cases of prostate cancer were randomly selected from the cancer registry in Gunma University Hospital for this study. PCNA LI were evaluated using paraffin-embedded biopsy cores taken at diagnosis. Correlation of PCNA LI with the Gleason grading system, clinical stage, serum prostate-specific antigen (PSA) levels and age were evaluated. Cumulative rates of freedom from cause-specific death were also evaluated stratified by various clinicopathologic features, including PCNA LI using Kaplan-Meier analysis., Results: Proliferating cell nuclear antigen labeling index was significantly higher in patients with PSA levels over 100 ng/mL, advanced clinical stage (>T4, N1 or M1 disease), higher Gleason grade or with a higher GS than in those with other clinicopathologic features. The 5-year cumulative rate of death from prostate cancer was significantly higher at 62% in patients with a PCNA LI of 20 or more than those with PCNA LI of less than 20, who accounted for 4%., Conclusions: Proliferating cell nuclear antigen labeling index in combination with Gleason grading system may be of clinical value in evaluating biologic features and also in predicting cause specific survival of prostate cancer in an objective, reliable and reproducible manner.

Context: Gleason grading is now the sole prostatic carcinoma grading system recommended by the World Health Organization. It is imperative that there be good interobserver reproducibility within this system worldwide. To our knowledge, there are no studies, using the same specimens, that compare the interobserver reproducibility of Gleason grading in Japan and the United States., Objective: To compare the interobserver reproducibility of Gleason grading of prostatic carcinoma in Japan and the United States using, in Japan, images from the identical biopsy glass slides that were originally graded in the United States., Design: Microsopic images from 37 needle biopsies of prostatic carcinoma were placed on CD-ROM and distributed to 14 Japanese pathologists for grading. These 14 physicians included 8 general pathologists and 6 pathologists with a special interest in urologic pathology. The needle biopsies had been previously reviewed so that a consensus diagnosis could be formed by a panel of urologic pathologists in the United States and Canada. Interobserver agreement with the consensus diagnoses was calculated by determining the overall kappa coefficient for the Japanese pathologists and then compared to the interobserver agreement among American general pathologists who had previously graded identical needle biopsies from which the CD-ROM images had been taken., Results: The interobserver agreement with the consensus diagnoses for the 4 Gleason grading groups (Gleason grades 2-4, 5-6, 7, and 8-10) among the Japanese urologic pathologists in this series of cases was substantial (overall kappa = 0.68), and for the Japanese general pathologists, it was moderate (overall kappa = 0.49), similar to that reported in the earlier study of American general pathologists (overall kappa = 0.44). The major interobserver reproducibility problem for both Japanese and American general pathologists is undergrading. The major areas of undergrading are the underdiagnosis of Gleason scores 5-6 as Gleason scores 2-4, and the underdiagnosis of cribriform sheets and fragments of cribriform Gleason pattern 4 carcinoma as Gleason pattern 3., Conclusions: The interobserver reproducibility of the Gleason grading for this collection of specimens was similar among Japanese and American general pathologists. The overall kappa values for these generalists of 0.44 and 0.49 are only in the moderate (0.41-0.60) range of interobserver agreement when compared to 0.68, substantial (0.61-0.80) agreement, for Japanese urologic pathologists. Educational efforts to improve Gleason grading have been shown to be effective and are clearly warranted.

Background: The international Dialysis Outcomes and Practice Patterns Study (DOPPS I and II) allows description of variations in kidney transplantation and wait-listing from nationally representative samples of 18- to 65-year-old hemodialysis patients. The present study examines the health status and socioeconomic characteristics of United States patients, the role of for-profit versus not-for-profit status of dialysis facilities, and the likelihood of transplant wait-listing and transplantation rates., Methods: Analyses of transplantation rates were based on 5267 randomly selected DOPPS I patients in dialysis units in the United States, Europe, and Japan who received chronic hemodialysis therapy for at least 90 days in 2000. Left-truncated Cox regression was used to assess time to kidney transplantation. Logistic regression determined the odds of being transplant wait-listed for a cross-section of 1323 hemodialysis patients in the United States in 2000. Furthermore, kidney transplant wait-listing was determined in 12 countries from cross-sectional samples of DOPPS II hemodialysis patients in 2002 to 2003 (N= 4274)., Results: Transplantation rates varied widely, from very low in Japan to 25-fold higher in the United States and 75-fold higher in Spain (both P values <0.0001). Factors associated with higher rates of transplantation included younger age, nonblack race, less comorbidity, fewer years on dialysis, higher income, and higher education levels. The likelihood of being wait-listed showed wide variation internationally and by United States region but not by for-profit dialysis unit status within the United States., Conclusion: DOPPS I and II confirmed large variations in kidney transplantation rates by country, even after adjusting for differences in case mix. Facility size and, in the United States, profit status, were not associated with varying transplantation rates. International results consistently showed higher transplantation rates for younger, healthier, better-educated, and higher income patients.

Background: The Dialysis Outcomes and Practice Patterns Study is well suited to identify case-mix effects, given its extensive data set. The data set was used to examine the influence of case-mix variables on mortality and the extent to which these variables account for differences in mortality across regions, as well as the prevalence and incidence of hepatitis B and hepatitis C., Methods: Demographic and comorbid disease features were determined for 8,615 patients internationally; mortality was recorded for this cohort, plus replacement patients (total n = 16,720), from 1996 to 2002. Mortality was associated with increasing age, nonblack race, coronary artery disease, congestive heart failure, other cardiac disease, diabetes mellitus, peripheral vascular disease, cerebrovascular disease, absence of hypertension, lung disease, cancer, human immunodeficiency virus infection, gastrointestinal bleeding, neurologic disease, psychiatric disease, cellulitis/gangrene, hepatitis C, and smoking., Results: US patients were slightly older than those in Europe or Japan and had the highest prevalence of diabetes, coronary artery disease, congestive heart failure, peripheral vascular disease, and cerebrovascular disease., Conclusion: Upon adjusting for case-mix to assess mortality across facilities, it was found that regional differences in mortality (highest in the United States and lowest in Japan) and differences across facilities within nations remain after such corrections. It is likely that practice patterns account for some of this variation. Prevalence of hepatitis B virus (HBV) across facilities increased as the number of dialyzing patients per facility increased; risk of HBV seroconversion decreased among facilities using protocols for treatment of patients with HBV infection. Greater employment of staff with at least 2 years of formal nursing training was associated with lower prevalence of hepatitis C virus infection and lower seroconversion risk.

Background: Idiopathic membranous nephropathy (IMN) is a representative form of refractory nephrotic syndrome in Japan. Although IMN is thought to run a more benign course in Japanese than in the Caucasian population, risk factors and appropriate treatment are controversial issues., Methods: The research group supported by a grant for "Progressive Renal Disease" from the Ministry of Health, Labor and Welfare, Japan, carried out a national survey of patients with IMN and nephrotic syndrome. Of 1066 nephrotic patients with histopathologically proven IMN registered from 1975 to 1993 in 85 institutions, 949 patients were studied., Results: The overall renal survival rates were 95.8%, 90.3%, 81.1%, and 60.5% at 5, 10, 15, and 20 years after diagnosis, respectively. When clinical and histopathologic features at onset of nephrotic syndrome were evaluated by multivariate analysis, male gender, old age (> or =60 years), high serum creatinine concentration (> or =1.5 mg/dL), and the development of tubulointerstitial lesions (> or =20% of the biopsy sample area) were significant predictors of progression to end-stage renal disease (ESRD). The renal survival rate in patients on steroid therapy was significantly higher than in patients on supportive therapy alone. Patients achieving a remission showed a significant reduction of risk for progression., Conclusion: IMN is a disease with a comparatively good prognosis in Japan even when it is associated with nephrotic syndrome. Steroid therapy, which has not been recommended for IMN in most review articles, seems to be useful at least for Japanese patients. In particular, a remission from heavy proteinuria likely results in a favorable outcome.

Objectives: To investigate the prevalence of prostate cancer in patients with a past or present history of bladder cancer compared with age-matched control subjects in population-based screening for prostate cancer., Methods: Between 1998 and 2000, 106 patients who were followed up in the outpatient clinic for bladder cancer (case cohort) and 1060 age-matched men who participated in screening for prostate cancer (control cohort) were enrolled in this study. Serum prostate-specific antigen (PSA) levels were measured for all participants, and all participants underwent digital rectal examination (DRE). The PSA distribution and prevalence rate of prostate cancer were compared between these two cohorts., Results: The serum PSA levels were significantly greater in the case cohort than in the control cohort. The detection rate of prostate cancer was 12.3% (13 of 106) and 1.5% (16 of 1060) in the case and control cohorts, respectively. The biopsy compliance for those with abnormal PSA and/or DRE findings was significantly lower (31%) in the control cohort than in the case cohort (84%). If all those in the control cohort with abnormal PSA and/or DRE findings had undergone prostate biopsies, another 26 cases of prostate cancer might have been detected. The expected detection rate of prostate cancer in the control cohort was high at 4.0% (42 of 1060); however, this was still significantly lower than that in the case cohort., Conclusions: Patients with a present or past history of bladder cancer could be a high-risk group for developing or having prostate cancer. Additional studies should be conducted to confirm this.

Mortality rates among hemodialysis patients vary greatly across regions. Representative databases containing extensive profiles of patient characteristics and outcomes are lacking. The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a prospective, observational study of representative samples of hemodialysis patients in France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States (US) that captures extensive data relating to patient characteristics, prescriptions, laboratory values, practice patterns, and outcomes. This report describes the case-mix features and mortality among 16,720 patients followed up to 5 yr. The crude 1-yr mortality rates were 6.6% in Japan, 15.6% in Europe, and 21.7% in the US. After adjusting for age, gender, race, and 25 comorbid conditions, the relative risk (RR) of mortality was 2.84 (P < 0.0001) for Europe compared with Japan (reference group) and was 3.78 (P < 0.0001) for the US compared with Japan. The adjusted RR of mortality for the US versus Europe was 1.33 (P < 0.0001). For most comorbid diseases, prevalence was highest in the US, where the mean age (60.5 +/- 15.5 yr) was also highest. Older age and comorbidities were associated with increased risk of death (except for hypertension, which carried a multivariate RR of mortality of 0.74 [P < 0.0001]). Variability in demographic and comorbid conditions (as identified by dialysis facilities) explains only part of the differences in mortality between dialysis centers, both for comparisons made across continents and within the US. Adjustments for the observed variability will allow study of association between practice patterns and outcomes.

Background: Assessing health-related quality of life (HRQOL) can provide information on the types and degrees of burdens that afflict patients with chronic medical conditions, including end-stage renal disease (ESRD). Several studies have shown important international differences among ESRD patients treated with hemodialysis, but no studies have compared these patients' HRQOL. Our goal was to document international differences in HRQOL among dialysis patients and to identify possible explanations of those differences., Methods: We examined data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, observational, international study of hemodialysis patients. We performed a cross-sectional analysis of DOPPS data from the United States, five countries in Europe (France, Germany, Italy, Spain, and the United Kingdom), and Japan. Linear mixed models were used to analyze differences in HRQOL, using the KDQOL-SFTM. Norm-based scores were used to minimize cultural response bias. Linear regression analysis was used to adjust for confounding factors. Other variables included demographic variables, comorbidities, primary cause of ESRD, complications of ESRD and treatment, and socioeconomic status., Results: In all generic HRQOL subscales, patients on all three continents had much lower scores than their respective population norm values. Patients in the United States had the highest scores on the mental health subscale and the highest mental component summary scores. Japanese patients reported better physical functioning than did patients in the United States or Europe, but they also reported the greatest burden of kidney disease. Overall, these differences remained even after adjusting for possible confounders., Conclusion: On all three continents, ESRD and hemodialysis profoundly affect HRQOL. In the United States, the effects on mental health are smaller than in other countries. Japanese hemodialysis patients perceived that their kidney disease imposes a greater burden, but their physical functioning was significantly higher. Different distributions of socioeconomic factors and major comorbid conditions could explain little of this difference in physical functioning. Other possible factors, such as quality of dialysis and related health care, deserve careful study.

Background: We investigated whether indicators of health-related quality of life (HRQOL) may predict the risk of death and hospitalization among hemodialysis patients treated in seven countries, taking into account serum albumin concentration and several other risk factors for death and hospitalization. We also compared HRQOL measures with serum albumin regarding their power to predict outcomes., Methods: We analyzed data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international, prospective, observational study of randomly selected hemodialysis patients in the United States (148 facilities), five European countries (101 facilities), and Japan (65 facilities). The total sample size was composed of 17,236 patients. Using the Kidney Disease Quality of Life Short Form (KDQOL-SFTM), we determined scores for three components of HRQOL: (1) physical component summary (PCS), (2) mental component summary (MCS), and (3) kidney disease component summary (KDCS). Complete responses on HRQOL measures were obtained from 10,030 patients. Cox models were used to assess associations between HRQOL and the risk of death and hospitalization, adjusted for multiple sociodemographic variables, comorbidities, and laboratory factors., Results: For patients in the lowest quintile of PCS, the adjusted risk (RR) of death was 93% higher (RR = 1.93, P < 0.001) and the risk of hospitalization was 56% higher (RR = 1.56, P < 0.001) than it was for patients in the highest quintile level. The adjusted relative risk values of mortality per 10-point lower HRQOL score were 1.13 for MCS, 1.25 for PCS, and 1.11 for KDCS. The corresponding adjusted values for RR for first hospitalization were 1.06 for MCS, 1.15 for PCS, and 1.07 for KDCS. Each RR differed significantly from 1 (P < 0.001). For 1 g/dL lower serum albumin concentration, the RR of death adjusted for PCS, MCS, and KDCS and the other covariates was 1.17 (P < 0.01). Albumin was not significantly associated with hospitalization (RR = 1.03, P> 0.5)., Conclusion: Lower scores for the three major components of HRQOL were strongly associated with higher risk of death and hospitalization in hemodialysis patients, independent of a series of demographic and comorbid factors. A 10-point lower PCS score was associated with higher elevation in the adjusted mortality risk, as was a 1 g/dL lower serum albumin level. More research is needed to assess whether interventions to improve quality of life lower these risks among hemodialysis patients.

Background: Hepatitis B (HBV) historically has been a public health issue within hemodialysis units. This study estimates HBV prevalence and seroconversion rates across seven countries and investigates associations with facility level practice patterns., Methods: The study sample was from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a cross-sectional, prospective, observational study of adult hemodialysis patients randomly selected from 308 dialysis facilities in France, Germany, Italy, Spain, the United Kingdom, Japan, and the United States. Logistic regression was used to model the odds ratio (OR) of HBV prevalence, and Cox regression was used to model time from entry into the study to HBV seroconversion., Results: In this sample, mean HBV facility prevalence was 3.0% with a median of 1.9%. The percentage of facilities with an HBV prevalence 0% to 5% was 78.5%. Adjusted HBV prevalence was higher in France, Germany, and Italy and lower in Japan and the United Kingdom. The majority of facilities (78.1%) had a seroconversion rate of 0 conversions per 100 patient-years. Presence of a protocol for HBV-infected patients was significantly associated with HBV seroconversion in the separate practice pattern model [risk ratio (RR) = 0.52, P = 0.03] and in the combined practice pattern model (RR = 0.44, P = 0.01)., Conclusion: There are differences in HBV prevalence and rate of seroconversion both at the country and the hemodialysis facility level. Presence of a protocol for HBV-infected patients was strongly and significantly associated with decreased risk for seroconversion. The observed variation suggests opportunities for improved HBV outcomes with further definition of optimal practice patterns at the facility level.

Background: The safety and efficacy of short daily hemodialysis has been reported in the USA and Europe, but there is no report on its efficacy in Japanese patients undergoing hemodialysis., Methods: Twenty-three outpatients (14 men and 9 women, 55.8 +/- 9.6 years old and 11.1 +/- 6.6 years on dialysis) undergoing hemodialysis 3 times/week participated in this study. After 4 weeks' baseline observation under conventional hemodialysis, they were subjected to short daily in-center hemodialysis (DHD, 6 times/week) for 12 weeks and then a 4-week follow-up observation period under conventional hemodialysis., Results: The mean pre-dialysis systolic and diastolic blood pressure significantly decreased in the DHD period. Antihypertensive drugs could be discontinued or the dose was reduced in 6 of 11 patients treated with such drugs. The hematocrit level tended to increase in the DHD period, and recombinant human erythropoietin could be discontinued or reduced in 7 of 14 patients. Localized skin rash caused by the adhesive tape and lidocaine patch at the blood access was observed in only 2 patients, but no other adverse events associated with DHD were noted., Conclusion: These results indicate that DHD is safe and more useful than conventional 3 times/week hemodialysis for Japanese patients undergoing hemodialysis., (Copyright 2003 S. Karger AG, Basel)