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Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor is recommended as an initial treatment for young patients. However, immunosuppressive therapy (IST) with cyclosporine and anti-thymocyte globulin may be a viable option even when an HLA-identical sibling donor is available.We constructed a Markov model to simulate the 10-year clinical course of patients aged 21-40 years with newly diagnosed severe aplastic anemia. Immediate BMT and IST were compared as an initial treatment assuming the availability of an HLA-identical sibling donor. Transition probabilities after treatment were determined based on a registry data analysis for BMT and a long-term prospective study for IST.Quality-adjusted life years (QALYs) after treatment selection were 6.77 for BMT and 6.74 for IST. One-way sensitivity analysis revealed that the utility for being alive without GVHD after BMT, that for being alive with partial response after IST, and the response rate after initial IST strongly affected the results.BMT and IST produced similar QALY for young patients with severe aplastic anemia. An estimation of the response rate to the initial IST may enable an individualized comparison between BMT and IST.

Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by anemia with reticulocytopenia and a marked reduction in erythroid precursors. Given its rarity, the true incidence is largely unknown, and epidemiological data representing the general population, with a description of the full spectrum of etiologies, are scarce. An epidemiological study on PRCA in Japan conducted 30 years ago estimated the annual incidence as 0.3 per million. To update the data and investigate the incidence and demographics of PRCA, we conducted a nationwide epidemiological study using the Japanese Society of Hematology (JSH) Hematologic Disease Registry, a hematologic disease registration database managed by the JSH and the Diagnosis Procedure Combination (DPC) study data available at a website of the Ministry of Health, Labor, and Welfare (MHLW) of Japan. A total of 1055 patients with newly diagnosed acquired PRCA were identified between 2012 and 2019, and the average annual incidence was calculated at 1.06 (95% confidence interval [CI], 0.83-1.28) per million. The median age was 73 (range, 18-99) years. The female-to-male ratio was 1.5:1, and the female predominance was most prominent in the child-bearing age group. Sixty-nine percent of acquired PRCA was idiopathic. The incidence of PRCA was approximately 20% of that of aplastic anemia (AA) during the same period. Approximately 0.98 patients per million per year (95% CI, 0.89-1.07) required hospitalization for the treatment of PRCA. These results are expected to contribute to the discussion of resource allocation for PRCA in the aging population in many countries, including Japan.

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.

The Abstract Template is flexible to accommodate Empirical Results or Narrative style submission types. First, determine whether your presentation content fits within the Empirical Results style or Narrative style. Next, remove the section from the below template that does not fit your submission type and complete the appropriate section of the template accordingly. Please ensure that you follow the below format and instructions for your submission. Background Text: ‘Ikigai’, subjective well-being which is the Japanese concept to a good life plays important role for a long and active aging. We examined the cross-sectional association between ‘Ikigai’ and participation in community support activities in the elderly aged 65-74 for building community social capital in the current active aging policy of Japan. Methods Text: The target population was all residents aged 65-74 years without disabilities in a municipality, Japan. The self-administered questionnaires were mailed to 5,163 individuals in 2018. A Total of 2,283 persons responded (response rate, 44.2%). Participants provided information on basic characteristics, ‘Ikigai’, perceived health, and intention to participate in community support activities for the elderly, the children care, and the disabled. Results Text: A total of 1,089 (47.7%) persons showed positive intention to participate in community support activities for the elderly. Respondents who had ‘Ikigai’ were 1,796 (78.7%). Respondents who had ‘Ikigai’ were more likely to participate in community support activities for the elderly than those who did not. The same trends were shown in community support activities for the children care or the disabled. Conclusions Text: Elderly people who had ‘Ikigai’ were more likely to participate in community support activities. ‘Ikigai’ may have an important role for making mutual ties and good life for active aging in the community. Key messages Text: ‘Ikigai’ may have an important role for active aging in the community.

Background Text: Information and Communication Technology (ICT) use has penetrated the daily lives of individuals as well as the activities of public organizations. We examined the cross-sectional association between ICT use and participation in community support activities in the elderly aged 65-74 for building community social capital in the current active aging policy of Japan. Methods Text: The target population was all residents aged 65-74 years without disabilities in a municipality, Japan. The self-administered questionnaires were mailed to 5,163 individuals in 2018. A Total of 2,283 persons responded (response rate, 44.2%). Participants provided information on basic characteristics, ICT use, and intention to participate in community support activities for the elderly. Results Text: A total of 1,089 (47.7%) persons showed positive intention to participate in community support activities for the elderly. Respondents who used a smartphone daily were 768 (33.6%). The proportion of participants with positive intention to participate in community support activities was 55.9% for those who used smartphones daily, whereas 42.8% for those who did not. Respondents who used the website, LINE, or QR codes were more likely to participate in community support activities than those who did not. Conclusions Text: Elderly people who utilize ICT frequently were more likely to participate in community support activities. ICT use among the elderly may be useful for building relationships of mutual assistance in the community. Key messages Text: ICT helps mutual assistance among the elderly in communities.

We would like to thank Luu et al 1 for their comments on our recent publication in the Annals of the Rheumatic Diseases , entitled ‘First external validation of sensitivity and specificity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies with a Japanese cohort’.2 We are pleased to know similar validation studies of the new criteria3–7 have been carried out to strengthen our contention. Although Luu et al 1 argue that earlier studies have been published before ours, they were …

The diagnosis of myelodysplastic syndromes (MDS) is based on morphology and cytogenetics. However, limited information is currently available on the interobserver concordance of the assessment of dysplastic lineages (10% or ≥10% in bone marrow (BM)). The revised International Prognostic Scoring System (IPSS-R) described a new threshold (2%) for BM blasts. However, the interobserver concordance of the categories (0-≤2% and2-5%) has limited data. The purpose of the present study was to investigate the assessment of dysplastic lineages and IPSS-R reproducibility. Our study was divided into two Steps. In each Step, the microscopic examinations were performed separately by two morphologists. Regarding the category of BM blasts ≤2% and2-5%, interobserver agreement was more than 'moderate' in all pairs (kappa test: 0.43-0.90). Regarding dysgranulopoiesis (dysG) and dyserythropoiesis (dysE) in BM, interobserver agreement was more than 'moderate' in all pairs (kappa test, dysG: 0.45-0.96, dysE: 0.45-0.81). Regarding the category of dysmegakaryopoiesis (dysMgk) in BM, interobserver agreement was more than moderate in 4 out of 5 pairs (kappa test: 0.58-1.00), and was fair for one pair (kappa test: 0.37). We consider that high interobserver concordance may be possible for the BM blast cell count (≤2% or2-5%) and dysplasia (10% or ≥10%) of each lineage.

Objectives To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria to classify juvenile IIMs (JIIMs) in an Asian paediatric population. Methods Sixty-eight JIIM patients and 49 non-JIIM patients diagnosed at seven major paediatric rheumatology centres in Japan between 2008 and 2015 were enrolled. Retrospective data were collected, and each patient’s data form was submitted. The expert group reviewed the forms and re-examined the diagnoses. The EULAR/ACR criteria were then applied and the probability of having JIIM was determined for each case. The sensitivity and specificity of the EULAR/ACR criteria were compared with those of other existing criteria. Results The sensitivity/specificity of the EULAR/ACR classification criteria were 92.1/100% with muscle biopsy data (n = 38); 86.7/100% without muscle biopsy data (n = 30) and 89.7/100% in our total cohort (n = 68). The sensitivity of Bohan and Peter’s criteria and Tanimoto’s criteria were 80.9 and 64.7% in our total cohort, respectively. Among 68 physician-diagnosed JIIM patients, seven cases (three JDM and four overlap myositis) were not classified as JIIM because the probability did not reach the cut-off point (55%). The three JDM patients all presented with only one of the three skin manifestations that are listed in the criteria: Gottron’s sign. Conclusion Our validation study with Japanese JIIM cases indicates that the EULAR/ACR classification criteria for IIM generally perform better than existing diagnostic criteria for myositis.

Introduction: Sentinel surveillance in Japan is used to estimate national influenza incidence under the assumption that Sentinel Medical Institutions (SMIs) are randomly selected. The current method might lead to overestimation when SMIs are recruited on a voluntary basis. Aims & Objectives: We aimed to improve influenza incidence estimation using auxiliary information without this assumption. Materials and Method: We used reports of influenza from SMIs in 2015, together with the number of all disease outpatients in September 2014 at all medical institutions from the Survey of Medical Institutions of Japan, as auxiliary information. The influenza incidence was estimated by the method using auxiliary information and the current method (without auxiliary information). Result and Conclusion: Influenza incidence rate per 1,000 population in 2015 estimated by using auxiliary information and by the current method was 63.7 (95% Confidence Interval (CI), 61.0-66.3) and 96.5 (95% CI, 93.0-100.0), respectively. The ratio of these estimates was 0.66. Our findings suggest that influenza incidence estimated by using the number of all disease outpatients as auxiliary information is more accurate than estimates by the current method.

The objective of this study is to develop clinical practice guideline (CPG) for Sjögren's syndrome (SS) based on recently available clinical and therapeutic evidences.The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS.The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG.The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.

The Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes has been conducting prospective registration, central review, and follow-up study for patients with aplastic anemia and myelodysplastic syndrome (MDS) since 2006. Using this database, we retrospectively analyzed the prognosis of patients with MDS. As of May 2016, 351 cases were registered in this database, 186 of which were eligible for the present study. Kaplan–Meier analysis showed that overall survival (OS) curves of the five risk categories stipulated by the revised international prognostic scoring system (IPSS-R) were reasonably separated. 2-year OS rates for the very low-, low-, intermediate-, high-, and very high-risk categories were 95, 89, 79, 35, and 12%, respectively. In the same categories, incidence of leukemic transformation at 2 years was 0, 10, 8, 56, and 40%, respectively. Multivariate analysis revealed that male sex, low platelet counts, increased blast percentage (>2%), and high-risk karyotype abnormalities were independent risk factors for poor OS. Based on these data, we classified Japanese MDS patients who were classified as intermediate-risk in IPSS-R, into the lower risk MDS category, highlighting the need for careful assessment of treatments within low- and high-risk treatment protocols.

Purpose To evaluate the risk factors and prevalence of hyponatremia among epilepsy patients in relation to use of antiepileptic drugs (AEDs). Methods We retrospectively reviewed 14,620 adult patients (aged 18–103 years) and classified them into the following 3 groups: patients without AED treatment (n = 2165, Group I), patients receiving antiepileptic drugs other than carbamazepine (n = 7442, Group II), and patients treated with carbamazepine (n = 5013, Group III). This study did not include the patients receiving oxcarbazepine or eslicarbazepine acetate because these AEDs are not marketed in Japan. Severe hyponatremia was defined as a serum sodium level Results In Groups I, II, and III, the mean sodium level was 140, 139, and 137 mEq/L, respectively. The highest frequency of severe hyponatremia was observed in Group III (7%), and it was much higher than in Group I (0.8%) or Group II (1.2%). In Groups II and III, old age, low body weight, and concomitant use of phenobarbital, benzodiazepines, or antipsychotics were risk factors for hyponatremia. In Group III, the sodium level decreased as the carbamazepine dose increased. At a carbamazepine dose exceeding 600 mg/day, there was 10.9-fold higher prevalence of hyponatremia, and the risk was potentiated by concomitant use of valproate. Conclusion The serum sodium level should be monitored carefully when patients are receiving AED polypharmacy combined with antipsychotics. In particular, concomitant administration of valproate enhances the risk of hyperammonemia in patients receiving carbamazepine. These findings may help clinicians to avoid hyponatremia in patients with epilepsy.

ObjectiveTo externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort.MethodsThis study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees.ResultsWhen the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto’s criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter’s criteria to diagnose those diseases except for ADM (88.4%/88.3%).ConclusionsOur study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients.

Although rheumatologists, neurologists and dermatologists see patients with polymyositis (PM) and dermatomyositis (DM), their management appears to vary depending on the physician's specialty. The aim of the present study was to establish the treatment consensus among specialists of the three fields to standardize the patient care. We formed a research team supported by a grant from the Ministry of Health, Labor and Welfare, Japan. Clinical questions (CQ) on the management of PM and DM were raised. A published work search on CQ was performed primarily using PubMed. Using the nominal group technique, qualified studies and results in the published work were evaluated and discussed to reach consensus recommendations. They were sent out to the Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association for their approval. We reached a consensus in 23 CQ and made recommendations and a decision tree for management was proposed. They were officially approved by the three scientific societies. In conclusion, a multidisciplinary treatment consensus for the management of PM and DM was established for the first time.

Extracellular adenosine regulates inflammatory responses via the A2A adenosine receptor (A2AR). A2AR deficiency results in much exaggerated acute hepatitis, indicating nonredundancy of adenosine-A2AR pathway in inhibiting immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. An A2AR agonist abolished NKT-cell-dependent induction of acute hepatitis by concanavalin A (Con A) or α-galactosylceramide in mice, corresponding to downregulation of activation markers and cytokines in NKT cells and of NK-cell co-activation. These results show that A2AR signaling can downregulate NKT-cell activation and suppress NKT-cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-galactosylceramide induced more severe hepatitis in A2AR-deficient mice than in WT controls. Transfer of A2AR-deficient NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT-cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway.

Background: The sentinel surveillance system in Japan provides estimates of nationwide influenza incidence. Although prefectural influenza incidences can be estimated using data from the current surveillance system, such estimates may be imprecise. Methods: We calculated the numbers of sentinel medical institutions (SMIs) needed in the surveillance system to estimate influenza incidences in prefectures, under the assumption that the standard error rates in 75% of influenza epidemic cases are less than 10%. Epidemic cases observed in 47 prefectures during the 2007/2008, 2008/2009, and 2009/2010 seasons, respectively, were used. Results: The present total number of SMIs was 6669. With respect to current standards, the increases required in prefectures ranged from 0 to 59, and the total increase required in the number of SMIs was 1668. Conclusions: We used sentinel surveillance data for Japan to calculate the number of SMIs required to estimate influenza incidence in each prefecture.

Completely bio-derived cholinium ionic liquids (ILs) such as choline acetate (ChOAc) are reported to be less expensive, more biocompatible, and more biodegradable and bio-renewable in comparison with the imidazolium ILs that are conventionally used for the pretreatment of lignocellulosic biomass. We demonstrated here, for the first time, that the cholinium-IL-assisted pretreatment of lignocellulosic biomass is enhanced by ultrasound irradiation in comparison with conventional heating. The cellulose saccharification ratio of bamboo powder was approximately 55% when pretreated thermally in ChOAc at 110 °C for 60 min. Conversely, after ultrasonic pretreatment in the same IL at 25 °C for 60 min, 92% of cellulose was hydrolyzed to glucose. Moreover, X-ray diffractometry and Fourier-transform infrared spectrometry analyses revealed that the cellulose crystallinity of pretreated bamboo powder was lower in case of ultrasonic pretreatment in ChOAc than in case of thermal pretreatment in the same IL.

Infectious disease surveillance systems provide information crucial for protecting populations from influenza epidemics. However, few have reported the nationwide number of patients with influenza-like illness (ILI), detailing virological type. Using data from the infectious disease surveillance system in Japan, we estimated the weekly number of ILI cases by virological type, including pandemic influenza (A(H1)pdm09) and seasonal-type influenza (A(H3) and B) over a four-year period (week 36 of 2010 to week 18 of 2014). We used the reported number of influenza cases from nationwide sentinel surveillance and the proportions of virological types from infectious agents surveillance and estimated the number of cases and their 95% confidence intervals. For the 2010/11 season, influenza type A(H1)pdm09 was dominant: 6.48 million (6.33-6.63), followed by types A(H3): 4.05 million (3.90-4.21) and B: 2.84 million (2.71-2.97). In the 2011/12 season, seasonal influenza type A(H3) was dominant: 10.89 million (10.64-11.14), followed by type B: 5.54 million (5.32-5.75). In conclusion, close monitoring of the estimated number of ILI cases by virological type not only highlights the huge impact of previous influenza epidemics in Japan, it may also aid the prediction of future outbreaks, allowing for implementation of control and prevention measures.

The aim of this study was to describe age, gender distribution, and age at onset of systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), and systemic sclerosis (SSc) in Japan. We used epidemiological information on 21,405, 6,327, and 10,058 patients with SLE, PM/DM, and SSc, respectively, in a Japanese nationwide registration database of patients with intractable diseases. All three diseases occur predominantly in women, with the female-to-male ratio being 8.2:1, 2.6:1, and 7.7:1 for SLE, PM/DM, and SSc, respectively. The most susceptible age for SLE is 15–44 and 20–39 years for males and females, respectively. For PM/DM it is 45–64 and 40–64 years and for SSc, 50–69 and 40–59 for men and women, respectively. The basic descriptive epidemiological characteristics of SLE, PM/DM, and SSc in Japan, such as gender distribution, present age, and age at onset, were surveyed nationwide for fiscal 2007. It was found that these characteristics were similar to those in Western populations. Our finding provides new information on the natural history of disease development.

Immunosuppressive signaling via the A2A adenosine receptor (A2AR) provokes a mechanism that protects inflamed tissues from excessive damage by immune cells. This mechanism is desirable not only for preventing uncontrolled tissue destruction by overactive immune responses, but also for protecting tumor tissues from antitumor immune responses. In aforementioned circumstances, T cell priming may occur in an environment containing high concentrations of extracellular adenosine. To examine qualitative changes in T cells activated in the presence of adenosine, we asked whether different functional responses of T cells are equally susceptible to A2AR agonists. In this study, we demonstrate that A2AR signaling during T cell activation strongly inhibited development of cytotoxicity and cytokine-producing activity in T cells, whereas the inhibition of T cell proliferation was only marginal. Both CD8+ and CD4+ T cells proliferated well in the presence of A2AR agonists, but their IFN-γ-producing activities were susceptible to inhibition by cAMP-elevating A2AR. Importantly, the impaired effector functions were maintained in T cells even after removal of the A2AR agonist, reflecting T cell memory of the immunoregulatory effect of adenosine. Thus, although the adenosine-rich environment may allow for the expansion of T cells, the functional activation of T cells may be critically impaired. This physiological mechanism could explain the inefficiency of antitumor T cells in the tumor microenvironment.

Differences in Lifestyle and Perceived Health in Different Occupations in a Community: Akiko OHTA, et al. Department of Public Health, Gunma University School of Medicine—It has been reported that morbidity and mortality vary according to occupation. To clarify factors which account for these differences, lifestyle, social network, job satisfaction and perceived health were measured in 1,165 men 40- 59 years old residing in a rural village in Gunma, Japan. Comparisons were made of four occupational groups: agricultural and forestry workers, the self-employed, blue-collar workers, and white-collar workers. Agricultural and forestry workers had less obesity, good social networks with relatives and local community, lower job satisfaction, and less subjective physical symptoms and psychological complaints. The self-employed had higher job satisfaction but felt their jobs were hard. Blue- collar workers had lower job satisfaction, felt that their job was hard, and had the most subjective physical symptoms and psychological complaints. White-collar workers were the most obese, ate more Western-style foods, had more physical exercise, higher job satisfaction, did not feel the job was hard, had stronger marriage ties, and had fewer subjective physical symptoms and psychological complaints. These differences may account for differences in morbidity and mortality by occupation, and will provide useful information for health care planning in the respective occupational group. For example, improved health care will be needed for blue-collar workers who had the poorest perceived health in the community. (J Occup Health 1998; 40: 325-333)

The intensity and duration of host responses are determined by protective mechanisms that control tissue injury by dampening down inflammation. Adenosine generation and consequent effects, mediated via A2A adenosine receptors (A2AR) on effector cells, play a critical role in the pathophysiological modulation of these responses in vivo. Adenosine is both released by hypoxic cells/tissues and is also generated from extracellular nucleotides by ecto-enzymes e.g. CD39 (ENTPD1) and CD73 that are expressed by the vasculature and immune cells, in particular by T regulatory cell. In general, these adenosinergic mechanisms minimize the extent of collateral damage to host tissues during the course of inflammatory reactions. However, induction of suppressive pathways might also cause escape of pathogens and permit dissemination. In addition, adenosinergic responses may inhibit immune responses while enhancing vascular angiogenic responses to malignant cells that promote tumor growth. Novel drugs that block A2AR-adenosinergic effects and/or adenosine generation have the potential to boost pathogen destruction and to selectively destroy malignant tissues. In the latter instance, future treatment modalities might include novel 'anti-adenosinergic' approaches that augment immune clearance of malignant cells and block permissive angiogenesis. This review addresses several possible pharmacological modalities to block adenosinergic pathways and speculates on their future application together with impacts on human disease.

BACKGROUND: Drug-resistant bacteria have been increasing together with advancement of antimicrobial chemotherapy in recent years. In Japan, the target diseases in the National Epidemiological Surveillance of Infectious Diseases (NESID) include some drug-resistant bacterial infections.METHODS: We used the data in the NESID in Japan, 2001-2005. Target diseases were methicillinresistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and multi-drug-resistant Pseudomonas aeruginosa (MDRPA) infections. The numbers of patients reported by sentinel hospitals (about 500) on a monthly basis were observed.RESULTS: The numbers of patients per month per sentinel hospital of 2001-2005 were 3.37-3.98 in MRSA, 0.96-1.19 in PRSP, and 0.11-0.13 in MDRPA infections. The sex ratios (male / female) of patients were 1.69-1.82, 1.34-1.43, and 1.71-2.52, respectively. More than 50% of all patients were adults aged 70 years or older in MRSA and MDRPA infections, but more than 60% were children under 10 years in PRSP infections. The number of patients per sentinel hospital in MRSA infections showed little variation between months, but evidenced a large variation in PRSP and MDRPA infections. The annual trend in the number of patients per sentinel hospital was increasing significantly for the 5-year period in MRSA and PRSP infections, but not in MDRPA infections.CONCLUSIONS: We revealed sex-age distributions of the patients reported to NESID in Japan, 2001- 2005. An increasing incidence of MRSA and PRSP infections and monthly variation in PRSP and MDRPA infections were observed for the 5-year period. Extended observation would be necessary to confirm these trends and variations.J Epidemiol 2007; 17: S42-S47.

BACKGROUND: The method for estimating incidence of infectious diseases from sentinel surveillance data has been proposed. In Japan, although the annual incidence rates of influenza and pediatric diseases estimated using the method were reported, their weekly incidence rates have not.METHODS: The weekly sex- and age-specific numbers of cases in the sentinel medical institutions in the National Epidemiological Surveillance of Infectious Diseases in Japan in 2002-2005 were used. Annual and weekly incidence rates of influenza and 12 pediatric diseases were estimated by the above-mentioned method, under the assumption that sentinels are randomly selected from all medical institutions.RESULTS: The annual incidence rate of influenza in 2002-2005 was 57.7-142.6 per 1,000 population. The highest weekly incidence rate was 7.4 at week 8 in 2002, 14.9 at week 4 in 2003, 14.1 at week 5 in 2004, and 21.2 at week 9 in 2005. The annual incidence rate per 1,000 population of 0-14 years old in 2002-2005 was less than 5.0 for pertussis, rubella and measles, 293.2-320.8 for infectious gastroenteritis, and 5.3-89.6 for 8 other diseases. The highest weekly incidence rate was less than 1.0 for exanthem subitum, and was more than 5.0 for infectious gastroenteritis, hand-foot-mouth disease and herpangina.CONCLUSION: We estimated annual and weekly incidence rates of influenza and pediatric diseases in Japan in 2002-2005, and described their temporal variation.J Epidemiol 2007; 17: S32-S41.

BACKGROUND: A method for determining epidemics in small areas from the sentinel surveillance data has been proposed and applied in the National Epidemiological Surveillance of Infectious Diseases (NESID) in Japan. We observed epidemics of influenza and 11 pediatric diseases by the method in the NESID in Japan during 1999-2005.METHODS: We assumed that an epidemic in a public health center area began in a week when the number of cases reported to the NESID per sentinel clinic and hospital in the area in the week exceeded a given value, and that the epidemic ended when the number was lower than another given value. The proportion of public health center areas with epidemics (epidemic area proportion) by week in fiscal 1999-2005 was calculated. Total public health center area-weeks observed were about 30,000 each year.RESULTS: The mean epidemic area proportion in the 7 years was 6.0% for influenza and 0.2-7.4% for pediatric diseases. The proportion increased in pharyngoconjunctival fever and group A streptococcal pharyngitis, decreased in measles and was less than 1.0% in pertussis and rubella. In influenza, the height of the peak in the weekly epidemic area proportion varied between 6 and 90% in the 7 years and the week of the peak varied widely. In some pediatric diseases, the height of the peak varied, while the week of the peak was relatively constant.CONCLUSION: The frequency and temporal change were described in the epidemics of influenza and pediatric diseases in public health center areas from the NESID data in Japan, 1999-2005.J Epidemiol 2007; 17: S14-S22.

BACKGROUND: In 1999 the Communicable Disease Prevention Law of Japan was completely revised into the "New" Infectious Disease Control Law, which reiterated the importance of surveillance and information dissemination and re-organized the surveillance system. This paper is an attempt to illustrate the potential impact of the new surveillance system through a description of the existing surveillance system and data before and after the revision.METHODS: After a historical review of surveillance system in Japan, the current surveillance system is described. Data sets of actual case numbers reported and incidence rate per 1,000,000 population are compared before and after the revision.RESULTS: Comparison of the data between the 2 periods revealed that most of the diseases have had declining trends after the new law was enacted with several exceptions. However, although no major break in continuity is observed in seriously perceived disease, in milder diseases there are striking gaps between the numbers reported in the mandatory and sentinel reporting framework. Sentinel reporting framework maintained the continuity of data without major gaps.CONCLUSIONS: From this perspective, the new surveillance system with two different frameworks of mandatory reporting for severe diseases and sentinel reporting for milder diseases seems to be working well. But continuous efforts should be made for evaluation and improvement of surveillance system and risk communication through the research on data analysis and effective communication method.J Epidemiol 2007; 17: S3-S13.

BACKGROUND: Observing the epidemics of vector-borne diseases is important. One or more cases of 6 vector-borne diseases were reported to the National Epidemiological Surveillance of Infectious Diseases in Japan in 2000-2005.METHODS: The reports of those cases were available. The incidence was observed by region of acquired infection, prefecture reporting, and week and year of diagnosis.RESULTS: The incidence rate per year per 1,000,000 population was 0.36 for dengue fever, 0.04 for Japanese encephalitis, 0.38 for Japanese spotted fever, 0.08 for Lyme disease, 0.74 for malaria, and 3.50 for scrub typhus. There were no cases of dengue fever or malaria derived from domestic infections. The yearly incidence rate increased for dengue fever and Japanese spotted fever, and declined for malaria and scrub typhus. The proportion of cases reported in Tokyo was 44% for dengue fever and 37% for malaria. The number of prefectures reporting one or more cases of Japanese spotted fever increased in western Japan. The cases of scrub typhus increased in autumn-winter in prefectures of eastern Japan, and increased both in autumn-winter and spring in western prefectures.CONCLUSIONS: The study reveals the epidemiologic features of both temporal and geographic distributions of cases of 6 vector-borne diseases in Japan, 2000-2005.J Epidemiol 2007; 17: S48-S55.

A cross-sectional study with a self-administered questionnaire was conducted in order to examine the association between low back pain and smoking. The subjects analyzed were 6,891 adults aged 40-69 yr, who lived in a downtown district in Isesaki City, Gunma, Japan. There was a positive association between cigarette smoking and low back pain in men. The age-adjusted odds ratios of low back pain were 1.32 (95% confidence interval (Cl) 1.10, 1.57) for 1-20 cigarettes smoked per day and 1.40 (95% Cl 1.11, 1.76) for 21 or more. The association had similar strength after adjustment for alcohol consumption, physical exercise, body mass index, non-musculoskeletal disease, education, occupation, and whether living with parents, living with a child or children, or living alone. The multivariate odds ratios for low back pain were 1.29 (95% Cl 1.03, 1.62) for 1-20 cigarettes smoked per day and 1.36 (95% Cl 1.03, 1.80) for 21 or more. In conclusion, smoking was significantly related to low back pain, even if adjusted for other potential risk factors.

This study aimed to describe the geographical spread and temporal accumulation of cases during the 2009 influenza A (H1N1) epidemic in Japan. Using a method adopted by the National Epidemiological Surveillance of Infectious Diseases (NESID) to identify epidemics, we described the frequency and temporal change of the 2009 influenza A (H1N1) epidemic among designated public health center areas in Japan. We calculated the proportion of public health center areas with an epidemic by week from 1999 to 2010. The 2009 influenza A (H1N1) epidemic had several distinguishing features compared with previous seasonal influenza epidemics. For example, the 2009 epidemic started in autumn and peaked at week 49, almost 10 weeks earlier than that of previous seasonal influenza epidemics. Additionally, the 2009 epidemic had the highest total number of public health center areas reporting an epidemic within a season, but only the second highest proportion of areas with an epidemic in the peak week (78.5%). The duration of the epidemic was 17 weeks, which was longer than that of previous epidemics. The present study results shed light on the epidemiology of the 2009 influenza A (H1N1) pandemic and provide useful information to create strategies to prevent future pandemics.

To investigate the effect of determining birthdays by social factors on the distribution of daily live births.We obtained data on live births tabulated by date and birthplace (hospitals, clinics, and maternity homes) between 1981 and 2010 in Japan from the National Vital Statistics System. This study analyzed the variations in live births for each day of the week, as well as for several specific days observed to have a systematic variation in the number of live births. We determined the ratio of the mean daily live births on those specific days to the overall daily average each month (the birth number ratio). The standardized deviation (the ratio of the deviation to the standard deviation for the day of week) regarding the birth number ratio of each specific day was also determined.The birth number ratio in hospitals and clinics was highest on Tuesdays and lowest on Sundays. Hospitals showed a large difference in the birth number ratio between weekdays and weekends, although the difference in the birth number ratio between weekdays and Saturdays was smaller in clinics than in hospitals. The birth number ratio during the first three days of the New Year was lower than that on Sundays. Until approximately 1995, the standardized deviation on February 29th and April 1st (the end of the Japanese school year) showed abnormally low values, while those on March 1st and April 2nd showed significantly high values. Following that time period, the significant variations on February 29th (only on Sundays), April 1st (only on Sundays), March 1st, and April 2nd almost completely disappeared. Maternity homes showed equivalent results until the 1980s or the middle of the 1990s.The variations in the days of the week were inconsistent with nationwide policies for consultation in each setting. These results indicate that some birth dates were set for institutional reasons or maternal preferences (i.e., the day after the leap day or the next school year) by using or avoiding obstetric intervention. The abnormal variation on leap days and on April 1st might be related to fictitious reporting. More recent variations in the birth number ratio on specific days suggest that some individuals may avoid obstetric intervention. The results of this study indicate that determining birthdays by social factors may have been practiced in maternity homes until approximately 1990.

It is thought that prominent production of inflammatory cytokines and expression of adhesion molecules on the endothelial cells activated by unkown pathogens induce the formation of the vasculitis in Kawasaki disease (KD) . To study the anti-inflammatory effect of salicylazosulfapyridine (SASP) on the cardiovasculitis of KD, we examined the effect of SASP on IL-6 production by human coronary artery endothelial cells (HCAEC) . We used HCAEC because IL-6 production by HCAEC was greater than by human umbilical vein endothelial cells. SASP at less than 0.5 mM suppressed IL-6 production by LPS-induced HCAEC, and higher concentrations of SASP affected cell viability. On the other hand, SASP did not suppress IL-6 production by the cells stimulated with cytokines such as TNFα, IL-1 β and IL-4. Sulfapyridine and 5-aminosalicylic acid, which are degradation products of SASP, did not suppress IL-6 production.These results show that SASP may have a direct inhibitoy effect on HCAEC activated by external substances such as LPS, which may be an effective agent in the cardiovasculitis of KD.

Tissue hypoxia plays a key role in establishing an immunosuppressive environment in vivo by, among other effects, increasing the level of extracellular adenosine, which then signals through A2A adenosine receptor (A2AR) to elicit its immunosuppressive effect. Although the important role of the adenosine–A2AR interaction in limiting inflammation has been established, the current study revisited this issue by asking whether hypoxia can also exert its T-cell inhibitory effects even without A2AR. A similar degree of hypoxia-triggered inhibition was observed in wild-type and A2AR-deficient T cells both in vitro and, after exposure of mice to a hypoxic atmosphere, in vivo. This A2AR-independent hypoxic T-cell suppression was qualitatively and mechanistically different from immunosuppression by A2AR stimulation. The A2AR-independent hypoxic immunosuppression strongly reduced T-cell proliferation, while IFN-γ-producing activity was more susceptible to the A2AR-dependent inhibition. In contrast to the sustained functional impairment after A2AR-mediated T-cell inhibition, the A2AR-independent inhibition under hypoxia was short lived, as evidenced by the quick recovery of IFN-γ-producing activity upon re-stimulation. These data support the view that T-cell inhibition by hypoxia can be mediated by multiple mechanisms and that both A2AR and key molecules in the A2AR-independent T-cell inhibition should be targeted to overcome the hypoxia-related immunosuppression in infected tissues and tumors.

Extracellular adenosine regulates inflammatory responses via the A2A adenosine receptor (A2AR). A2AR deficiency results in much exaggerated acute hepatitis, indicating nonredundancy of adenosine-A2AR pathway in inhibiting immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. An A2AR agonist abolished NKT-cell-dependent induction of acute hepatitis by concanavalin A (Con A) or α-galactosylceramide in mice, corresponding to downregulation of activation markers and cytokines in NKT cells and of NK-cell co-activation. These results show that A2AR signaling can downregulate NKT-cell activation and suppress NKT-cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-galactosylceramide induced more severe hepatitis in A2AR-deficient mice than in WT controls. Transfer of A2AR-deficient NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT-cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway.

Murdochite-type (Mg 6− x Li x )MnO 8 (0.0 ≤ x ≤ 0.3) was synthesized at 973 K in a flow of pure oxygen gas using a solid state reaction. The cell constants, the (Mg, Li)–O(1) distance, and the Mn–O(1) distance monotonously decrease with increasing x . The variation of the effective magnetic moment (μ eff ) calculated from the magnetic measurement indicates that both the Mn 4+ and the Mn 5+ ions coexist in (Mg 6− x Li x )MnO 8 (0.0 ≤ x ≤ 0.2). The binding energies of the Mg 2s 1/2 , Li 1s 1/2 , Mn 2p 3/2 , and O 1s 1/2 levels of (Mg 6− x Li x )MnO 8 were determined by X-ray photoelectron spectroscopy (XPS), and they are independent of the composition.

The A2A adenosine receptor (A2AR)-mediated immunosuppression is firmly implicated in the life-saving down-regulation of collateral tissue damage during the anti-pathogen immune response and in highly undesirable protection of cancerous tissues during anti-tumor immune response. Therefore, depending on specific clinical situation there is a need to either weaken or strengthen the intensity of A2AR signal. While the A2AR-mediated immunosuppression was shown to be T cell autonomous in studies of effector T cells, it was not clear how A2AR stimulation affects regulatory T cells (Treg). Here we show in parallel assays that while A2AR stimulation on T cells directly inhibits their activation, there is also indirect and longer-lasting T cell inhibitory effect through modulation of Treg. A2AR stimulation expanded CD4(+) CD25(hi) FoxP3(+) cells, which also express CD39, CD73, and CTLA-4. Treg cultured with A2AR agonist showed increased expression of CTLA-4 and stronger immunosuppressive activity. There was a significant increase of Treg cell number after A2AR stimulation. The CD4(+) FoxP3(+) population contained those induced from CD4(+) CD25(-) cells, but CD4(+) FoxP3(+) cells predominantly derived from CD4(+) CD25(+) natural Treg. Thus, A2AR stimulation numerically and functionally enhanced Treg-mediated immunosuppressive mechanism. These data suggest that the A2AR-mediated stimulation of lymphocytes using A2AR agonists should be considered in protocols for ex vivo expansion of Treg before the transfer to patients in different medical applications.

Activation of immune cells is under control of immunological and physiological regulatory mechanisms to ensure adequate destruction of pathogens with the minimum collateral damage to innocent bystander cells. The concept of physiological negative regulation of immune response has been advocated based on the finding of the critical immunoregulatory role of extracellular adenosine. Local tissue oxygen tension was proposed to function as one of such physiological regulatory mechanisms of immune responses. In the current study, we utilized in vivo marker of local tissue hypoxia pimonidazole hydrochloride (Hypoxyprobe-1) in the flowcytometric analysis of oxygen levels to which lymphocytes are exposed in vivo. The level of exposure to hypoxia in vivo was low in B cells and the levels increased in the following order: T cells < NKT cells < NK cells. The thymus was more hypoxic than the spleen and lymph nodes, suggesting the variation in the degree of oxygenation among lymphoid organs and cell types in normal mice. Based on in vitro studies, tissue hypoxia has been assumed to be suppressive to T cell activation in vivo, but there was no direct evidence demonstrating that T cells exposed to hypoxic environment in vivo are less activated. We tested whether the state of activation of T cells in vivo changes due to their exposure to hypoxic tissue microenvironments. The parallel analysis of more hypoxic and less hypoxic T cells in the same mouse revealed that the degree of T cell activation was significantly stronger in better-oxygenated T cells. These observations suggest that the extent of T cell activation in vivo is dependent on their localization and is decreased in environment with low oxygen tension.

BACKGROUND: Epidemics of infectious diseases usually start in small areas and subsequently become widespread widely. Although a method for detecting epidemics in public health center (PHC) areas has been proposed and used in the National Epidemiological Surveillance of Infectious Diseases in Japan, wide-area epidemics have not been fully investigated.METHODS: Using the abovementioned method, we defined an epidemic as that occurring for a week in at least one PHC area in a prefecture and a wide-area epidemic as that when the number of people living in epidemic PHC areas exceeds 30% of the prefectural population. The number of weeks of an epidemic or wide-area epidemic for influenza and 11 pediatric diseases was observed in 47 prefectures in Japan from 1999 through 2005.RESULTS: Epidemics and wide-area epidemics of influenza occurred for an average of 7.0 and 4.3 weeks in a year in a prefecture, respectively. The proportion of wide-area epidemics in epidemic weeks was 62%. The average number of wide-area epidemic weeks for pediatric diseases varied among diseases; it was more than 4 weeks for infectious gastroenteritis and herpangina and less than 1 week for pertussis, rubella, and measles. The proportion of wide-area epidemics in epidemic weeks was 28-41% for infectious gastroenteritis, hand-foot-mouth disease, and herpangina and less than 20% for other diseases.CONCLUSIONS: The frequency of wide-area epidemics of influenza and pediatric diseases in various prefectures was observed. Epidemics of infectious diseases such as influenza and herpangina occurring in small areas were likely to spread to wide areas.J Epidemiol 2007; 17: S23-S31.

We here propose a new index, the difference-change contribution proportion, to quantify contributions of age and cause of death to differences in age-adjusted overall mortality disparities between two groups over time. The present study was conducted with the aim of elucidating age and cause of death contributions to the recent decrease in disparity in life expectancy between males in Okinawa and mainland Japan. The longer-term goal is to apply the findings to developing appropriate preventive measures against diseases for Okinawa people.Changes in disparity between age-adjusted overall mortality of male populations of Okinawa and Japan nationwide during a 15-year period, between 1985 and 2000, were measured and difference-change contribution proportions for age-adjusted overall mortality were computed.Causes of death that showed high difference-change contribution proportions included cerebral infarction (24.26%), cardiac failure (18.45%), other cerebrovascular diseases (15.11%), malignant gastric neoplasms (11.89%), ischemic heart disease (11.06%), hepatic disease (10.93%), suicide (5.71%), and diabetes (5.36%). Of these, cerebral infarction, cardiac failure, other cerebrovascular diseases, malignant gastric neoplasm, ischemic heart disease, and diabetes indicated high difference-change contribution proportions among seniors 65 years old and above, while hepatic disease and suicide ranked highly among the middle-aged.The results of this study revealed the extent of age and cause of death contributions to the decreasing disparity observed between populations of Okinawa and Japan nationwide in male age-adjusted overall mortality. The causes of death and the age revealed by this study are critical to taking preventive measures against diseases. Moreover, this study confirmed that the difference-change contribution proportion is a useful method to quantify contributions of age and cause of death to changes in variation regarding life expectancy.