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Summary Introduction: T-helper cell type 1 (Th1) polarization of the immune response has been documented in patients with chronic immune thrombocytopenia (ITP). Interleukin (IL)-10 is the most important factor regulating Th1 and T-helper type 2 cytokine synthesis. This study evaluated the impact of IL-10 polymorphisms on both susceptibility to, and severity of, chronic ITP. Methods: We analyzed -1082(G/A), -812(C/T), and -592(C/A) IL-10 polymorphisms in 90 patients with adult chronic ITP and 202 race- and sex-matched healthy controls. Results: No significant differences in the genotype or haplotype frequencies were observed between the patient with chronic ITP and the control group. However, more patients with the -592AA genotype showed a severe thrombocytopenic state (platelet count <10 × 109/l) than those with the -592CC/CA genotypes (44.1% vs. 19.6%, P = 0.01). Furthermore, more patients with the ATA/ATA haplotype showed a severe thrombocytopenic state than those without the ATA/ATA haplotype (44.1% vs. 19.6%, P = 0.01). Conclusion: According to our data, patients with low producer type of IL-10 polymorphisms have more severe thrombocytopenia, suggesting that IL-10 gene polymorphisms may reflect the severity of ITP. [ABSTRACT FROM AUTHOR]

In order to explore the implementation of bereavement care in hospice/palliative care settings in Japan, a self-administered questionnaire was sent to all 54 government-approved hospice/palliative care units (PCUs) in May of 1999 (recovery rate 93%). Results showed that bereavement follow-up is performed in 37 institutes (74%) and memorial cards and services are most frequently provided. Memorial cards are provided mainly by nurses, and memorial services involve many health care professionals as well as volunteers. Religious workers tended to be involved in memorial services and social group meetings. Individually oriented interventions such as telephone contacts, personal visits and personal counselling were reportedly used less often. The need for individual-oriented programmes was recognized, and many institutes were considering the expansion of their programmes to include them. However, the difficulties of implementing such care at hospice/PCUs were also raised. Two socio-cultural factors possibly affecting bereavement care in Japan, namely, the roles of family and religious (Buddhist) ceremonies were discussed. It was pointed out that the spirit of bereavement care may be embodied in existing religious ceremonies. We conclude that it is necessary to develop bereavement care programmes based on common, basic hospice care tenets while making full use of existing local resources and taking into account regional values. [ABSTRACT FROM AUTHOR]

The purpose of this study is to determine whether adding intravenous methylprednisolone pulse (IVMP) to primary adjunctive prednisolone with intravenous immunoglobulin (IVIG) improves treatment resistance and coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) with a high risk of treatment resistance. This multicenter, prospective, observational study was conducted at 28 hospitals in Japan from October 2016 to June 2020. For patients predicted to be resistant to treatment based on a Kobayashi score ≥ 5 and total bilirubin ≥ 1.0 mg/dL, each hospital independently decided to add IVMP followed by prednisolone, prednisolone alone, or nothing to the primary IVIG therapy. In total, 2856 consecutive KD patients were enrolled; of these, 399 (14.0%) were predicted to be treatment resistant. Patients who were resistant to the primary treatment and required additional treatment comprised 59%, 20%, and 26% of the IVIG-alone group, IVIG-plus-prednisolone group, and IVIG-plus-IVMP group, respectively (P < .0001). The CAA incidence (Z score ≥ 2.5) at month 1 was similar among the treatment groups (6.7%, 4.8%, and 7.3%, respectively; P = .66). CAA occurred more frequently in patients who needed third- or later-line therapy.Conclusions: Primary adjunctive corticosteroid therapy improved the treatment response and suppressed inflammation. However, the study found no benefit of adding IVMP to prednisolone therapy. Patients receiving IVIG alone achieved coronary outcomes comparable to those of patients receiving primary adjunctive corticosteroid therapy although they were more likely to require additional rescue treatment. KD inflammation should be resolved no later than the third line of additional treatment to reduce the risk of CAA.Trial registration: University Hospital Medical Information Network Clinical Trials Registry in Japan ( https://www.umin.ac.jp/ctr/index.htm ) under code UMIN000024937., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In the 1990s, the concepts of hikikomori and modern-type depression (MTD) emerged in Japan. Hikikomori is a condition of social avoidance or isolation, characterized by staying at home and being physically isolated for at least six months. MTD is characterized by depressive symptoms-mainly in stressful work or school situations during adolescence and early adulthood-which tend to rapidly reduce or disappear after leaving the stressful situation. We hypothesized that childhood maltreatment can form MTD traits that lead to hikikomori., Methods: As a first step, we conducted a multigroup path analysis between childhood maltreatment, MTD traits, and physical isolation in the hikikomori group. This study utilized the nine-item Patient Health Questionnaire (PHQ-9), Home Environment Questionnaire (HEQ), 22-item Tarumi Modern-Type Depressive Trait Scale (TACS-22), 25-item Hikikomori Questionnaire (HQ-25), and Hamilton Depression Rating Scale (HDRS). The HQ-25 contains three factors: physical isolation, lack of socialization, and lack of emotional support., Results: The hikikomori group included 92 patients and the control group comprised 137 healthy individuals. All total and subscale scores of PHQ-9, HEQ, TACS-22, HQ-25, and HDRS were significantly higher in the hikikomori group than in the control group. The risk model of childhood maltreatment for physical isolation via MTD traits obtained good fit with a goodness-of-fit index of.982., Limitations: The study's limitations were its sample selection bias, cross-sectional design, and use of self-report scales., Conclusions: Our findings support the hypothesis that childhood maltreatment is an important risk factor for hikikomori via MTD traits., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has forced people to make major life changes, and there is concern that depressive tendencies have increased in pregnant women during the pandemic. This study used the Edinburgh Postnatal Depression Scale (EPDS), administered in the second trimester, to investigate the effect of COVID-19 on the mental health of Japanese women during pregnancy and to provide early intervention., Methods: The study included 1,320 pregnant women (663 pre-COVID-19 and 657 during COVID-19) with similar background characteristics and compared the results for the COVID-19 period (September 2020-August 2021) and control period (September 2018-August 2019). Women treated for psychiatric disorders were excluded. The EPDS cutoff score was 13., Results: The median EPDS scores were 3 (1-6) points during the control period and 3 (1-5) points during the pandemic (p = 0.166) for the control and pandemic periods. Fourteen patients (2.1%) during the control period and 20 (3.0%) during the pandemic scored ≥13 points; however, the difference was not significant (odds ratio, 1.455; 95% confidence interval: 0.692-3.143)., Conclusions: COVID-19 did not change mid-pregnancy EPDS scores at a single Japanese center.

Background: A severe form of pathological social withdrawal, 'hikikomori,' has been acknowledged in Japan, spreading worldwide, and becoming a global health issue. The pathophysiology of hikikomori has not been clarified, and its biological traits remain unexplored., Methods: Drug-free patients with hikikomori ( n  = 42) and healthy controls ( n  = 41) were recruited. Psychological assessments for the severity of hikikomori and depression were conducted. Blood biochemical tests and plasma metabolome analysis were performed. Based on the integrated information, machine-learning models were created to discriminate cases of hikikomori from healthy controls, predict hikikomori severity, stratify the cases, and identify metabolic signatures that contribute to each model., Results: Long-chain acylcarnitine levels were remarkably higher in patients with hikikomori; bilirubin, arginine, ornithine, and serum arginase were significantly different in male patients with hikikomori. The discriminative random forest model was highly performant, exhibiting an area under the ROC curve of 0.854 (confidential interval = 0.648-1.000). To predict hikikomori severity, a partial least squares PLS-regression model was successfully created with high linearity and practical accuracy. In addition, blood serum uric acid and plasma cholesterol esters contributed to the stratification of cases., Conclusions: These findings reveal the blood metabolic signatures of hikikomori, which are key to elucidating the pathophysiology of hikikomori and also useful as an index for monitoring the treatment course for rehabilitation., Competing Interests: The authors have no conflicts of interest to declare related to this study., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 healthy individuals in Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT 50 ; assessed using infectious virions) with various determinants were examined and the potency of sera against variants of concerns was determined. Significant rise in NT 50 s was seen in sera on day 28 post-1st dose. A moderate inverse correlation was seen between NT 50 s and ages, but no correlation seen between NT 50 s and adverse effects. NT 50 s and SARS-CoV-2-S1-binding-IgG levels on day 28 post-1st dose and pain scores following the 2nd dose were greater in women than in men. The average half-life of NT 50 s was ~ 68 days, and 23.6% (49 out of 208 individuals) failed to show detectable neutralizing activity on day 150. While sera from elite-responders (NT 50 s > 1,500: the top 4% among the participants) potently to moderately blocked all variants of concerns examined, some sera with low NT 50 s failed to block the B.1.351-beta strain. Since BNT162b2-elicited immunity against SARS-CoV-2 is short, an additional vaccine or other protective measures are needed., (© 2021. The Author(s).)

Objectives: To test the performance of the Son risk score, which was created to predict coronary artery abnormalities from baseline variables in North American patients with Kawasaki disease., Study Design: The dataset from Post RAISE, the largest prospective cohort study of Japanese patients with Kawasaki disease to date, was used for the present study. With high risk defined as ≥3 points, sensitivity, specificity, positive predictive value, and negative predictive value for coronary artery abnormality development were calculated. To evaluate the effect of each risk factor in the Son score, the OR and 95% CIs were calculated using logistic regression analysis with the presence of coronary artery abnormality at 1 month after disease onset., Results: Post RAISE enrolled 2628 consecutive patients with Kawasaki disease, and 304 patients had a high-risk score, of whom 15.1% showed coronary artery abnormality. At the cutoff ≥3 points, the sensitivity was 37.7%, and the specificity was 87.2%. The maximum z score at baseline ≥2.0 (OR 3.5, 95% CI 2.3-5.2) and age <6 months at disease onset (OR 3.2, 95% CI 1.9-5.4), were significantly associated with coronary artery abnormality development. However, a high concentration of C-reactive protein was not associated with coronary artery abnormality. The area under the receiver operating characteristic curve for the Son score was 0.65 (95% CI 0.59-0.71)., Conclusions: The Son score had insufficient sensitivity and good specificity in a Japanese cohort of patients with Kawasaki disease. Among the variables comprising the Son score, a large baseline z score and young age at disease onset were significant, independent predictors of coronary artery abnormality development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

More than 60% of the 1,700 infectious diseases that affect human come from animals and zoonotic pandemics, after starting from sporadic phenomena limited to rural areas, have become a global emergency. The repeated and frequent zoonotic outbreaks such as the most recent COVID-19 pandemic can be attributed also to human activities. In particular, the creation of enormous intensive domestic animal farms, the indiscriminate use of antibiotics, the destruction of forests, the consumption of the meat of wild animals and the illegal animal trade are all factors causing the insurgence and the transmission of zoonotic diseases from animals to humans. The purpose of this study was to explore the knowledge of the One Health concept including the zoonotic risk potentially derived from illegally traded pet animals and wildlife among adolescents in 6 different countries (Italy, Austria, Slovenia, Germany, Mauritius, and Japan). A representative sample of 656 students was recruited and all participants took an anonymous questionnaire. Data were analyzed by ANOVAs to estimate the prevalence of correct health prevention behaviors and to identify the influential factors for these behaviors. After two theoretical-practical lectures, the same anonymous questionnaire was administered for the second time in order to assess the efficacy of the program. The proportion of students who did not know that many diseases affecting humans come from animals is 28.96% while 32.16% of them did not know what a zoonosis is. The circularity of the One Health concept related to the transmission of diseases from animals to humans and vice-versa is not understood from a large prevalence of the adolescents with 31.40 and 59.91% of wrong responses, respectively. Furthermore, rabies is not considered as a dangerous disease by 23.02% of the adolescents. After two theoretical-practical classroom sessions, the correct answers improved to 21.92% according to the different question. More than a third of the student cohort investigated showed a profound ignorance of the zoonotic risks and a poor understanding of the One Health concept. The authors believe that the teaching of health prevention with a One Health approach and a practical training should be included in every school curriculum., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zucca, Rossmann, Dodic, Ramma, Matsushima, Seet, Holtze, Bremini, Fischinger, Morosetti, Sitzia, Furlani, Greco, Meddi, Zambotto, Meo, Pulcini, Palei and Zamaro.)

Background: Microvascular decompression (MVD) is the most effective procedure for hemifacial spasm (HFS). MVD results from nonspecialized or low-volume institutes are not always reliable. Most studies on MVD for HFS are retrospective and single centered; to the best of our knowledge, no prospective, multicenter studies exist., Objective: To evaluate short- and long-term outcomes and complications in patients who underwent MVD for HFS in specialized Japanese institutions, in this multicenter, prospective, cohort study., Methods: Included patients had undergone MVD for HFS in study centers between April 2012 and March 2015. Patients' postoperative grade of involuntary movements and complications were recorded postoperatively at 7 d (short-term) and at 1 (mid-term) and 3 (long-term) yr., Results: A total of 486 patients (150 men, 336 women; mean age 53.9 yr with 181 patients over 60 yr) were enrolled during the study period. Neuromonitoring was used in 96.3% of the cases. The complete cure rate of symptom relief, mortality rate, and complication rate at short-term follow-up were 70.6%, 0%, and 15%, respectively. The long-term follow-up was completed by 463 patients (95.3%); the complete cure rate of symptom relief and complication rate were 87.1% and 3.0%, respectively., Conclusion: Our study revealed that under expert guidance and intraoperative neuromonitoring, the long-term curative effect rate of MVD for HFS is high, while complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with HFS, including elderly patients., (© Congress of Neurological Surgeons 2021.)

Objective: To investigate the characteristics of materials used as prostheses for microvascular decompression surgery (MVDs) in Japan and their possible adverse events (AEs) to determine preferable materials for MVDs., Methods: A questionnaire was sent to all members of the Japanese Society for MVDs, and answers were obtained from 59 institutions., Results: Among a total of 2789 MVDs, 1088 operations for trigeminal neuralgia, 1670 for hemifacial spasm, and 31 others, including 117 reoperations, were performed between April 2011 and March 2014. Nonabsorbable material was used in 96.5% of MVDs, including polytetrafluoroethylene (PTFE) (80.5%), polyurethane (11.9%), expanded PTFE (2.1%), and silk thread (1.47%). The use of absorbable materials, including fibrin glue (87.5%), cellulose (13.5%), gelatin (4,77%), and collagen (1.76%), was reported. The major combinations were PTFE with fibrin glue (58.7%) followed by PTFE alone (7.60%). Eighty-eight AEs in 85 (3.2%) cases were reported among 2672 first operations. AEs included 51 central nervous system dysfunctions, 15 wound infections/dehiscence, and 10 others, which were presumed to be related to the intraoperative procedure. Among relatively high-, moderate-, and low-volume centers, there were no significant differences in the frequency of AEs (P = 0.077). Tissue-prosthesis adhesion and/or granuloma formation were reported in 13 cases of 117 reoperations. The incidence of adhesion-related recurrence was 11.1% of all reoperations., Conclusions: The number of AEs was quite low in this survey, and intradural use of any prosthesis reported in this paper might be justified; however, further development of easily handled and less-adhesive prosthesis materials is awaited., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The RAISE study showed that additional prednisolone improved coronary artery outcomes in patients with Kawasaki disease at high risk of intravenous immunoglobulin (IVIG) resistance. However, no studies have been done to test the steroid regimen used in the RAISE study. We therefore aimed to verify the efficacy and safety of primary IVIG plus prednisolone., Methods: We did a multicentre, prospective cohort study at 34 hospitals in Japan. We included patients diagnosed with Kawasaki disease according to the Japanese diagnostic criteria, and excluded those who were treated at other hospitals before being transferred to a participating hospital. Patients who were febrile at diagnosis received primary IVIG (2 g/kg per 24 h) and oral aspirin (30 mg/kg per day) until the fever resolved, followed by oral aspirin (5 mg/kg per day) for 2 months after Kawasaki disease onset. We stratified patients using the Kobayashi score into predicted IVIG non-responders (Kobayashi score ≥5) or predicted IVIG responders (Kobayashi score <5). For predicted non-responders, each hospital independently decided whether to add prednisolone (intravenous injection of 2 mg/kg per day for 5 days) to the primary IVIG treatment, according to their respective treatment policy, and we further divided these patients based on the primary treatment received. The primary endpoint was the incidence of coronary artery abnormalities determined by two-dimensional echocardiography at 1 month after the primary treatment in predicted non-responders treated with primary IVIG plus prednisolone. Coronary artery abnormalities were defined according to the criteria of the Japanese Ministry of Health and Welfare and of the American Heart Association (AHA). This study is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000007133., Findings: From July 1, 2012, to June 30, 2015, we enrolled 2628 patients with Kawasaki disease, of whom 724 (27·6%) were predicted IVIG non-responders who received IVIG plus prednisolone as primary treatment. 132 (18·2%) of 724 patients did not respond to primary treatment. Among patients with complete data, coronary artery abnormalities were present in 40 (incidence rate 5·9%, 95% CI 4·3-8·0) of 676 patients according to the AHA criteria or in 26 (3·8%, 2·5-5·6) of 677 patients according to the Japanese criteria. Serious adverse events were reported in 12 (1·7%) of 724 patients treated with primary IVIG plus prednisolone; two of these patients had hypertension and bacteraemia that was probably related to prednisolone. One patient died possibly due to severe inflammation from the Kawasaki disease itself., Interpretation: Primary IVIG plus prednisolone therapy in this study had an effect similar to that seen in the RAISE study in reducing the non-response rate and decreasing the incidence of coronary artery abnormalities. A primary IVIG and prednisolone combination therapy might prevent coronary artery abnormalities and contribute to lowering medical costs., Funding: Tokyo Metropolitan Government Hospitals and the Japan Kawasaki Disease Research Center., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The p.R4810K (rs11273543, c.14429G > A) variant of the RNF213 gene is associated with increased risk of Moyamoya disease (MMD), which is an idiopathic progressive intracranial vascular steno-occlusive disease, in Asian populations. Numerous variant association studies for this MMD variant have been performed in Japan to date. Since another genetic study that utilized approximately 140,000 single nucleotide polymor (SNPs) has indicated that there still are genetic differences among mainland Japanese, there is a possibility that the variant distribution in patients with MMD and normal individuals varies between different Japanese regions. Additionally, the majority of variant association studies have used Sanger sequencing, which is labor-intensive, time-consuming, and costly. In this study, we analyzed the frequency of the variant genotype in patients with MMD and normal individuals in Kyushu using pyrosequencing, which is an accurate, cost-effective, and automated method. We found differences in the genotype frequencies in familial patients from Kyushu and normal populations in Tohoku compared with west Japan, which suggested that there were differences in the frequency of the variant among different regions in Japan.

Purpose: Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effect of orteronel with or without prednisolone in Japanese patients with castration-resistant prostate cancer (CRPC)., Methods: We conducted a phase 1 study in men with progressive and chemotherapy-naïve CRPC. Patients received orteronel orally at doses of 200-400 mg twice daily (BID) with or without oral prednisolone (5 mg BID). Dose-limiting toxicity (DLT) was assessed during Cycle 1 (28 days). Patients could continue study treatment until any of criteria for treatment discontinuation were met. Gonadotropin-releasing hormone therapy was continued in patients without prior orchidectomy., Results: Fifteen patients were enrolled and administered at least one dose of orteronel. No DLTs were reported during Cycle 1 in this study. Adverse events (AEs) were reported in all 15 patients. Most common AEs (>30%) were hyperlipasemia (47%), hyperamylasemia (40%), and constipation (33%). Acute pancreatitis (Grades 2 and 3) and pancreatitis (Grade 1) were complicated in three patients during the study. Dose-dependent increase in plasma orteronel concentrations was indicated over the 200-400 mg BID dose range. Prednisolone coadministered did not alter PK of orteronel. Serum testosterone was rapidly suppressed below the lower limit of quantification across all doses. Of 15 subjects, 13 achieved at least a 50% reduction from baseline in prostate-specific antigen., Conclusions: Orteronel at doses up to 400 mg BID was tolerable in Japanese CRPC patients. The present results support further evaluation of orteronel with or without prednisolone.

Aim: The aim of this study was to elucidate the clinical characteristics and risk factors for amniotic fluid embolism (AFE)., Methods: We performed a retrospective case study analysis of patients using medical records and autopsy records. The diagnosis of AFE was based on the presence of clinical symptoms using Clark's criteria and autopsy results. We analyzed patient records from a 29-year period in three hospitals affiliated with the Nippon Medical School in Japan., Results: Ten diagnoses of AFE were found in the records. First, we classified AFE patients into two types based on the initial presenting symptoms: post-partum hemorrhage and cardiopulmonary collapse. Fifty percent of the patients initially presented with post-partum hemorrhage and disseminated intravascular coagulation. Most were diagnosed with post-partum hemorrhage or uterine atony at AFE onset. Similarly, 50% presented with cardiopulmonary arrest or pulmonary arrest as initial symptoms, and most were diagnosed with eclampsia. Second, risk factors for AFE included advanced maternal age, multiparity, increased intrauterine pressure and disruptions of the uterine vasculature. Third, the case fatality rate was 70%. Fourth, squamous cells were observed in maternal central venous blood of five patients., Conclusion: AFE patients were classified into two types based on presenting signs and symptoms. Knowledge of the various initial symptoms of AFE enables a correct diagnosis., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Purpose: Our purpose was to identify the causal factors for the perfusion distribution obtained with ASL-MRI by comparing ASL-MRI with clinical information and other MRI findings in moyamoya disease., Methods: Seventy-one patients with moyamoya disease underwent ASL-MRI and other MRI, including fluid-attenuated inversion recovery imaging (FLAIR) and three-dimensional time-of-flight magnetic resonance angiography (MRA) on 3.0-Tesla MRI system. Cerebral blood flow (CBF) values (ASL values) for the cerebral hemispheres (142 sides) were measured on CBF maps generated by ASL-MRI. Relationships between the ASL values and the following 9 factors were assessed: sex, family history, revascularization surgery, age at MR exam, age at onset, the steno-occlusive severity on MRA (MRA score), degree of basal collaterals, degree of leptomeningeal high signal intensity seen on FLAIR, and size of ischemic or hemorrhagic cerebrovascular accident lesion (CVA score)., Results: Patients with a family history had significantly higher ASL values than those without such a history. There were significant negative correlations between ASL values and age at MR exam, MRA score, and CVA score., Conclusions: ASL-MRI may have cause-and-effect or mutual associations with family history, current patient age, size of CVA lesion, and intracranial arterial steno-occlusive severity in Moyamoya disease., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

A survey on adult community-acquired pneumonia was conducted jointly by multiple centers nationwide to verify the Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia in Adults (JRS2005). The efficacy and safety of piperacillin (PIPC) were investigated at the same time. PIPC is recommended as the initial treatment for patients with suspected bacterial pneumonia and pneumococcal pneumonia in JRS2005. Overall, 552 and 333 patients were registered for safety and efficacy analysis in this study, respectively. The majority of the cases in which PIPC was used had moderate disease (63.7 %), and the most common daily dosage was 4 g (73.6 %). The efficacy rate was 83.5 % overall, 81.1 % in patients with suspected bacterial pneumonia, and 92.8 % in patients with pneumococcal pneumonia. The efficacy rate with a daily dosage of 4 g was 84.9 %, and the efficacy rates achieved with a daily dosage of 4 g in patients who had mild and moderate suspected bacterial pneumonia were 90.0 and 82.6 %, respectively. The most commonly isolated causative organisms were Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae), and the bacterial eradication rates were high (97.2 and 100 %, respectively). The incidence of adverse drug reactions was 5.62 %, among which the main events were hepatic dysfunction and decreased white blood cell count. In conclusion, this study showed that PIPC is safe and effective at 4 g/day for mild-to-moderate adult community-acquired pneumonia.

An epidemic situation of pandemic (H1N1) 2009 was investigated from August 1 to March 31 in Iki City, an isolated island with a population of about 30,000. All members of the Iki Physicians' Association participated in the investigation. Daily reports of patients with influenza were made to the local health center. During the outbreak, 2,024 individuals were clinically diagnosed as having influenza, or with the rapid diagnostic test. The prevalence was highest among patients 10-19 years of age (26.8%), followed by patients 9 years and under (21.3%). The prevalence was lowest in patients over 60 years (0.4%). Of the 2,024 patients, 1,443 (71.3%) were 19 years of age or younger. Only seven of the 2,024 were admitted to the hospital, and there were no deaths. When the first outbreak occurred, many individual classes and some schools were closed, and subsequently the number of cases rapidly decreased. A second outbreak occurred three weeks later. The same procedures were taken and the outbreak came to an end. A vaccination program for A (H1N1) pdm09 virus was implemented according to the Japanese National Ministry of Health guidelines, one time for persons aged 13 years or over and twice for those 12 years or younger. To test for antibodies to pandemic A (H1N1) pdm09 after the outbreak, 358 serum samples were collected from Aug to Nov 2009, and the HI titer was measured. 205 (57.3%) were HI titer > or = 1:40. The factor most closely related to a 40 HI titer > or = 1:40 was A (H1N1) pdm09 vaccination, followed by symptomatic influenza. Asymptomatic influenza accounted for 11%. In conclusion, 71.3% of 2,024 A (H1N1) pdm09 patients were 19 years of age or younger. From an epidemiological perspective, school and class closures were considered to be very effective in controlling the spread of the disease.

Introduction: The Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia (CAP) in Adults (JRS 2005) was published as a revision of the Basic Concept for the Management of CAP in Adults (JRS 2000). To evaluate the JRS 2005 criteria for differentiating between disease types and assessing the status of antimicrobial agent use in initial treatment, we conducted a prospective survey., Subjects and Methods: The survey was conducted from July 2006 to March 2007 as a nationwide joint study by 200 institutions. The study subjects included patients aged ≥16 years of age who had CAP, and patients who met the inclusion criteria were consecutively enrolled. Disease type differentiation based on JRS 2005 and JRS 2000 was conducted. Disease type diagnosis was also performed based on test results. The sensitivity and specificity of disease type differentiation were calculated. The antimicrobial agents used in the initial treatment were classified as recommended or non-recommended based on JRS 2005. The validity of non-recommended antimicrobial agent use was investigated., Results: A total of 1875 patients were analyzed. Differentiation of atypical pneumonia using the JRS 2005 criteria had higher sensitivity and lower specificity than differentiation using the JRS 2000 criteria. The antimicrobial agents recommended by JRS 2005 were used as initial treatment in a low number of cases. The efficacy of the recommended antimicrobial agents was similar to that of the non-recommended agents., Conclusions: JRS 2005 is advantageous in terms of reducing the number of items used in disease type differentiation. The recommended antimicrobial agents used for the initial treatment are believed to be appropriate., (Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: The Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia (CAP) in Adults (JRS 2005) were published to revise the Basic Concept for the Management of CAP in Adults (JRS 2000). Revisions in JRS 2005 mainly focused on the criteria for the assessment of pneumonia severity and the differentiation between bacterial pneumonia and atypical pneumonia. To evaluate the JRS 2005 criteria for the assessment of pneumonia severity, we conducted a prospective survey., Subjects and Methods: The survey was conducted from July 2006 to March 2007 as a nationwide joint study by 200 institutions. The study subjects included patients aged ≥16 years of age who had CAP. The severity at initial consultation was determined using the criteria established by JRS 2005, JRS 2000, and Infectious Diseases Society of America Guidelines (IDSA-GLs). The survival outcome 30 days after the start of the initial antimicrobial agent treatment was confirmed., Results: A total of 1875 patients were analyzed. The numbers of cases of pneumonia assessed as being moderate and severe were significantly lower when the JRS 2005 criteria were used than when the JRS 2000 criteria were used. Thus, the severity of pneumonia could be determined more appropriately using the JRS 2005 criteria. Furthermore, the severity-dependent prediction of fatal outcomes or mortality according to these criteria was similar to that determined using the IDSA-GLs., Conclusions: Determining severity on the basis of JRS 2005 can resolve nearly all the problems encountered with JRS 2000; these criteria were found to be useful and rapidly and easily applicable in clinical practice., (Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

We retrospectively investigated air-leak syndrome (ALS), including pneumothorax and mediastinal/s.c. emphysema, following allogeneic hematopoietic SCT. Eighteen patients (1.2%) developed ALS among 1515 undergoing SCT between 1994 and 2005 at the nine hospitals participating in the Kanto Study Group on Cell Therapy. The median onset of ALS was at 575 days (range: 105-1766) after SCT and 14 patients (77.8%) had experienced late onset noninfectious pulmonary complications (LONIPC) before ALS. Chronic GVHD (cGVHD) was the strongest risk factor for ALS (odds ratio 13.5, P=0.013 by multivariate analysis). Repeat SCT, male sex and age <38 years at the time of transplantation were also significant risk factors for ALS. Patients with ALS had a significantly worse survival rate than those without ALS (61.5 vs 14.9% at 3 years; P=0.000). The main cause of death was respiratory complications in 8 of the 18 patients. In conclusion, ALS is a rare complication of SCT that is more likely to occur in relatively young male patients with cGVHD and/or LONIPC. It is possible that better understanding and treatment of LONIPC may lead to prevention of ALS.

Objective: To evaluate the clinical usefulness of the QuantiFERON TB-2G (QFT-2G) test in patients with non-tuberculous mycobacterial (NTM) disease without a previous history of tuberculosis (TB)., Methods: The study consisted of 214 patients with NTM disease who satisfied the diagnostic guidelines of the American Thoracic Society., Results: The causative microorganism was Mycobacterium avium in 83 patients, M. intracellulare in 80, M. kansasii in 33, M. marinum in 12, M. szulgai in 3, M. abscessus in 2 and M. chelonei in 1. The positive response rate of QFT-2G test result was 2% in 163 patients with M. avium-intracellulare complex (MAIC) disease, 52% in 33 with M. kansasii disease, 58% in 12 with M. marinum disease, 33% in 3 with M. szulgai disease, 0% in two with M. abscessus disease and 0% in one with M. chelonei disease. The positivity of the QFT-2G test was 52% in patients with NTM disease, thought to be because NTM possesses common M. tuberculosis-specific antigens., Conclusions: Although QFT-2G may be a useful diagnostic method to differentiate TB from MAIC disease, there are several problems to be resolved before it can be used as a diagnostic method for NTM disease (M. kansasii disease), including the determination of the positive cut-off level for QFT-2G test.

Objective: The aim of this study was to investigate the pathophysiology of hospital-acquired pneumonia (HAP) and the clinical efficacy of its first-line treatment and to examine the validity of "the Japanese Respiratory Society (JRS) Guidelines for management of HAP"., Methodology: The observational survey was conducted during the period of June 2002-May 2004 and patients with HAP were prospectively surveyed using the consecutive enrollment method. A total of 1,356 patients from 254 hospitals nationwide were analyzed. Clinical response to first-line antibiotics was evaluated at the end of the medication., Results: The 30-day mortality rate was 19.8%. Patients were classified into four groups according to the JRS guideline criteria. There were remarkable variances in the number of cases of each group. Mild/moderate pneumonia with no risk factors (group I) accounted for 0.3% of all cases. The mortality rate tended to be higher, as clinical conditions became more serious (group II < III < IV). Alternatively, though categorized in the same group (group III), there was a difference in the mortality rate by the severity of pneumonia (severe cases 32.2% vs. moderate cases 11.0%). First-line medication using carbapenems accounted for 61.7% of total cases. The efficacy rate of guideline-concordant therapy was significantly higher than that of guideline-discordant therapy (54.2% vs. 41.7%)., Conclusions: This is the first nationwide study on HAP in Japan. The clinical characteristics and prognosis of HAP were elucidated. Review of the current classification of the disease is required and these results provide valuable information for the next revision of the guidelines.

Although patients with risk factors for tuberculosis have increased with the increased use of immunosuppressive therapy, there have been few reports about differences in clinical findings between immunocompromised patients and nonimmunocompromised patients with pulmonary tuberculosis. Therefore, we investigated differences between the clinical features of immunocompromised patients with pulmonary tuberculosis and those of nonimmunocompromised patients in the past decade. We analyzed findings in 840 patients (312 immunocompromised and 528 nonimmunocompromised) with pulmonary tuberculosis who were found to be culture-positive for Mycobacterium tuberculosis between January 1997 and December 2006. The characteristic clinical findings of the immunocompromised patients, compared with findings in the nonimmunocompromised group, were as follows: (1) an increase in the number of patients with respiratory symptoms during the period of follow-up of underlying diseases; (2) an increase in the number of patients in a hyponutritional state and with a negative response for the tuberculin skin test; (3) an increase in the number of microbiologically smear-positive sputum specimens; (4) an increase in the number of patients with atypical radiological findings, such as a few cavities or calcification, bilateral and expansive consolidation, miliary shadows, and mediastinal and/or hilar lymphadenopathy ; (5) an increase in the number of patients with misdiagnosed pneumonia at admission; and (6) an increase in the mortality rate. We concluded that, among the immunocompromised patients with pulmonary tuberculosis, there were many patients with atypical radiological findings and with smear-positive findings for acid-fast bacilli examination that was carried out to isolate M. tuberculosis (which had become infectious). We must perform the acid-fast bacilli examination for patients who have a fever and continuous cough, and antituberculous drugs should be administered as soon as possible when the results are positive.

Objective: Palliative care of the terminally ill requires not only treatment of physical pain, but also care for a patient's spiritual and social needs. In Japan, where many customs correlate closely with the seasons of fall, winter, spring, and summer, seasonal events carry significance for patients who have reached a terminal stage of disease. This study determined how Japanese hospice patients evaluate a program that celebrates seasonal events and considers the modality and significance of season events at hospices., Methods: A questionnaire survey was conducted for 1 year between August 2000 and July 2001 at a hospice located in the suburbs of Tokyo, Japan. Of the original 48 instruments, a total of 43 instruments were returned (response rate: 89.6%)., Results: Results showed that 72.1% of respondents participated in seasonal events, and the majority of participants positively evaluated their experiences of seasonal events. Positive aspects included being able to get a feeling for the seasons (74.2%) and being able to interact with staff and volunteers (51.6%). Negative aspects included that the events were too long (9.7%) and tiring (6.5%), and that the events made one feel sad (6.5%). Reasons for participating in seasonal events included seeming fun (71.0%), recreative (58.1%), and being entertaining (48.4%)., Significance of Results: Overall findings suggest that there is significance in celebrating the seasons with a monthly event at hospices. Further research is needed on the modality and experiences of celebrating the seasons at hospices in other nations.

Changes in nasopharyngeal bacterial flora in adults with acute upper respiratory tract infection on administration of antimicrobial agents were investigated, and how these changes contrasted with those in children. Many patients with acute sinusitis due to allergies, and patients with malignancy and diabetes mellitus were included in the investigation. The detection rates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, the major bacteria of acute otitis media (AOM), were 22%, 10%, and 7% respectively, which were significantly lower than those for children. Gram stain examination of nasopharyngeal swab samples showed a significant relation between leukocyte infiltration and the detection amount of S. pneumoniae (P = 0.0086). A significant relation (P = 0.0134) was also observed when H. influenzae was simultaneously detected. No significant change in the three major AOM bacteria present in nasopharyngeal bacterial flora after administration of antimicrobial agents was observed. However, all S. pneumoniae and H. influenzae detected after antimicrobial agent administration had the beta-lactam-resistance gene. It was observed that a significant improvement in leukocyte infiltration occurred 6 to 10 days after antimicrobial agent administration. In contrast, a significant improvement in children was observed at 2 to 5 days. In the adult subjects, this improvement was probably due to spontaneous remission rather than the effect of the antimicrobial agents. Although investigation of the long-term administration of antimicrobial agents was also conducted, its benefits for the patients were not elucidated.

Background: The difficulty of treatment for pulmonary Mycobacterium avium complex (MAC) in Japan., Objectives: To investigate the clinical and microbiological effects of treatment according to the guidelines proposed by the American Thoracic Society and the Japanese Society for Tuberculosis and prospective follow-up studies after the completion of treatment of patients with pulmonary MAC disease., Methods: Analysis of the microbiological effects with regard to sputum conversion rate and the sputum relapsing rate and the clinical effects with regard to clinical symptoms and radiological findings for patients with pulmonary MAC disease treated with a regimen consisting of rifampicin, ethambutol, streptomycin, and clarithromycin over 24 months and follow-up over 12 months., Results: Sixty-five patients with pulmonary MAC disease were enrolled in this trial. In 39 patients, negative sputum conversion was observed within 6 months after the initiation of this regimen, 16 relapsed, and 20 experienced clinical worsening within 1 year after the completion of treatment. Although retreatment with the same regimen or a regimen including new quinolones was carried out for these patients, we could not achieve negative sputum conversion and/or clinical improvement., Conclusions: We believe that the dose of clarithromycin for pulmonary MAC disease may be increased and recommend surgery for patients with a localized lesion at early-stage MAC disease to prevent a high rate of relapse., (Copyright (c) 2006 S. Karger AG, Basel.)

Background: The urinary antigen detection kit for Streptococcus pneumoniae was tested., Objectives: It was our aim to evaluate the usefulness of the immunochromatographic membrane test by doing a large prospective study of community-acquired pneumonia (CAP) in Japan., Methods: We prospectively evaluated the use of the S. pneumoniae urinary antigen detection kit and analyzed the treatment and clinical effect seen in patients with positive test kit results. One hundred and fifty-six patients with CAP admitted to our hospital between October 2001 and September 2003 were evaluated., Results: In 49% of these CAP patients, the causative microorganisms were isolated. S. pneumoniae was suspected to be the causative microorganism in 15%, but positive results of the urinary antigen detection kit indicated S. pneumoniae to be a probable microorganism in 28%, even though antibiotics had previously been administered to half of the patients. The kit was particularly useful for diagnosing patients with poor quality sputum in whom antibiotics treatment nevertheless had to be selected. Antibiotics appropriate for S. pneumoniae (mainly penicillin) were given. The treatment was found to have excellent clinical results in 89% of the CAP patients., Conclusions: The S. pneumoniae urinary antigen detection kit was considered to be useful in selecting treatment since there was a high level of clinical effectiveness when the most suitable antibiotics were immediately administered to positive patients. The use of the S. pneumoniae urinary antigen kit is rapid and simple compared with conventional microbiological procedures., (Copyright (c) 2006 S. Karger AG, Basel.)

A nationwide study was undertaken to determine the susceptibility to penicillin and serotypes of Streptococcus pneumoniae in Japan. S. pneumoniae was isolated from 114 adult patients with community-acquired pneumonia over 22 months at 20 hospitals and medical centres in different regions in Japan. All but five isolates were from sputum. Forty-eight isolates (42.1%) were susceptible, 40 (35.1%) showed intermediate resistance (MIC, 0.12-1.0 microg/ml) and 26 (22.8%) were resistant (MIC, >or=2.0 microg/ml) to penicillin G. All isolates were susceptible to ceftriaxone (breakpoint 1 microg/ml), imipenem (4 microg/ml) and vancomycin (4 microg/ml). Most were resistant to erythromycin, clarithromycin and azithromycin; only two were resistant to levofloxacin. Differences were found in the distribution of serotypes among isolates showing susceptibility to penicillin (predominant types 3, 6B, and 19F), intermediate resistance (6B, 14, 19F, and 23F) and full resistance (19F and 23F). PFGE typing showed that 14 of the 25 strains of serotype 19F had a single DNA profile, pattern A, a pattern closely similar to that of the Taiwan multidrug-resistant 19F clone. Twelve pattern A strains were not susceptible to penicillin but carried the macrolide resistance gene mef(A). The DNA profiles of the 15 strains of 23F were also heterogeneous but six were highly similar (pattern b) yet distinct from the Spanish multidrug-resistant 23F clone although possibly related to the Taiwan multidrug-resistant 23F clone. The pattern b strains were not susceptible to penicillin and also harboured either mef(A) or erm(B). Our results indicate that multidrug-resistant pneumococci are spreading rapidly in Japan. Efforts to prevent the spread of the pandemic multidrug-resistant serotypes should be intensified.

X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by mutations in Bruton's tyrosine kinase (BTK). Patients typically become symptomatic during infancy or early childhood and develop recurrent bacterial infections. We report a Japanese case of XLA diagnosed in a patient who was 27 years of age and who had no history of severe infection. The patient's serum immunoglobulin (Ig) G, IgA, and IgM levels were 132,7, and 17 mg/dL, respectively. The percentage of positive cells for CD19 and CD20 was 0.03% and 0.02%, respectively. The patient's brother and sister had no abnormalities. Flow cytometric analysis showed a partially reduced expression of BTK protein in the patient's peripheral monocytes. Sequencing of the BTK. gene revealed a missense mutation (230C>T,T33I). Given this data, this patient was diagnosed as having rare, late onset XLA with a missense mutation in the BTK gene.

Background: A high frequency of drug-resistant pneumococci has been reported in Asian countries. Few data on the drug-resistance or serotype of pneumococcal strains responsible for community-acquired pneumonia (CAP), however, are available for the past two decades in Japan., Methodology: Susceptibility to antibiotics and the genotype of antibiotic-resistant genes and serotypes of Streptococcus pneumoniae isolates from 114 adult patients with CAP were examined in a nationwide study in Japan between 2001 and 2003., Results: Most of the cases were non-bacteraemic pneumonia and the case fatality rate was 4.4%. The most frequent genotype of the pbp gene was pbp1a + 2x + 2b (gPRSP; 36.8%) followed by pbp 2x (28.1%) and of the macrolide-resistant gene, it was ermB (50.0%). The most common serotype was 19F (29.1%), followed by serotype 23F (13.2%), 6B (12.3%) and 3 (11.4%). The coverage of serotypes of isolates by a 23-valent pneumococcal polysaccharide vaccine (PPV) would be 82.5% in these patients with CAP. Most of strains with serotypes 19F and 23F were gPRSP. A cluster of serotype 3 strains associated with the pbp 2x and ermB gene was also noted., Conclusion: A high frequency of altered pbp gene mutations or of macrolide-related genes and a high serotype coverage by the 23-valent PPV found in our study of pneumococcal pneumonia facilitates attempts to increase the coverage rate of the 23-valent PPV in adults older than 65 years in Japan.

Carcinogenicity and chronic toxicity of 1,4-dichloro-2-nitrobenzene (DCNB) were examined by feeding each group of 50 F344 rats and 50 BDF1 mice of both sexes a DCNB-containing diet at a concentration of 0 (control), 320, 800 or 2,000 ppm (w/w) for 2 yr. In rats, incidences of hepatocellular adenomas and carcinomas and their combined incidence were increased in the 2,000 ppm-fed males, together with increased incidence of basophilic cell foci in the 800 and 2,000 ppm-fed males. A dose-related increase in combined incidences of renal cell adenomas and carcinomas was noted. Incidence of Zymbal gland adenomas tended to increase in the 2,000 ppm-fed males. In mice, incidences of hepatocellular adenomas in the 800 and 2,000 ppm-fed females and hepatocellular carcinomas in the 2,000 ppm-fed males and in the 800 and 2,000 ppm-fed females were increased. Incidence of hepatoblastomas was increased in all DCNB-fed males and in the 2,000 ppm-fed females. Signs of chronic toxicity were characterized by centrilobular hypertrophy of hepatocytes with nuclear atypia in mice, increased relative liver weight in rats, a dose-related increase in incidences of chronic progressive nephropathy with advanced grades of severity in male rats, and decreased hemoglobin concentration and hematocrit accompanied by increased bone marrow hematopoiesis in female rats. Carcinogenic activity of DCNB was evaluated for the three different tumors, and sensitive signs of the chronic toxicity were dis-

The incidence of chronic lymphocytic leukemia (CLL) is low in Asian countries including Japan, while CLL is the most common type of leukemia in the west. To elucidate which factors contribute to the low frequency of CLL in Japan, we investigated immunoglobulin (Ig) heavy chain gene usage and somatic hypermutation status in 44 Japanese patients with CLL. Only one of these patients used V(H)1-69. The finding is in striking contrast to data from western countries, where the frequency of CLL expressing V(H)1-69 ranges from 12 to 21%.

Subchronic inhalation toxicity of p-dichlorobenzene (p-DCB) was examined by exposing BDF1 mice and F344 rats of both sexes (6 h/d and 5 d/wk) to inhalation of 25, 55, 120, 270 or 600 ppm (v/v) p-DCB vapor for 13 wk. The exposure to p-DCB vapor retarded the growth rate in the male mice, and induced hepatotoxicity in the mice and rats of both sexes and renal and hematological toxicity in the male rats. Hepatotoxicity was characterized by increased liver weight, hepatocellular hypertrophy, and increased serum levels of total cholesterol. Liver necrosis and increased serum levels of AST and ALT were observed in the exposed mice, whereas these changes, which indicate hepatocellular death, did not occur in any of the exposed rats. p-DCB-induced renal lesions occurred only in the male rats. Hyaline droplets were observed in the proximal tubular epithelial cells, and were stained positively with anti-alpha2u-globulin, suggesting excessive accumulation of alpha2u-globulin in the epithelial cells. Granular casts were formed in the tubular lumen, resulting from the necrotic desquamation of the renal tubular epithelium. Papillary mineralization in the renal pelvis and increased serum levels of BUN and creatinine were noted. These renal changes indicated alpha2u-globulin nephropathy. Decreases in red blood cell counts, hemoglobin concentration, hematocrit and mean corpuscular volume and increased spleen weight occurred in the exposed male rats. The NOAEL was 120 ppm for the hepatic endpoint in mice and for the renal endpoint in rats. The maximum tolerated dose for a 2-yr bioassay inhalation study of rodent carcinogenicity was estimated to be 300 ppm, based on the present results.

The Japanese Respiratory Society (JRS) published the guidelines for the management of community-acquired pneumonia in 2000. The guidelines set up nine parameters and criteria for the differential diagnosis of atypical pneumonia and bacterial pneumonia based on clinical symptoms, physical signs and laboratory data. To evaluate the performance of these guideline criteria, 91 cases of Chlamydia pneumoniae (53 cases were pure-C. pneumoniae and 38 cases were mixed-C. pneumoniae pneumonia), 103 cases of Mycoplasma pneumoniae (86 cases were pure-M. pneumoniae and 17 cases were mixed-M. pneumoniae pneumonia) and 144 cases of bacterial (Streptococcus pneumoniae and/or Haemophilus influenzae) pneumonia were analyzed. The accordance rate for a suspected atypical pneumonia with the guideline criteria was 84.8% for pure-M. pneumoniae pneumonia and 60.3% for pure-C. pneumoniae pneumonia, but only 9.0% for bacterial pneumonia, 12.1% for mixed-C. pneumoniae pneumonia and 16.6% for mixed-M. pneumoniae pneumonia. Overall, the sensitivity and specificity of the criteria in the JRS guidelines were 75.5% and 90.9%, respectively. Our results indicated that the differentiation of pneumonia in the JRS guidelines is useful for the diagnosis of M. pneumoniae pneumonia, but difficult to apply to the diagnosis of C. pneumoniae pneumonia.

We aimed to investigate the transitional pattern of the clinical features of pulmonary Mycobacterium-avium complex (MAC) disease, especially with regard to the clinical effect of treatment, in patients treated before and after the implementation of the 1998 guidelines of the Japanese Society for Tuberculosis for combined chemotherapy for pulmonary MAC disease. The clinical findings and treatments of 220 patients with pulmonary MAC disease during the past 10 years were compared by dividing the patients into two groups, each encompassing a 5-year period. During the past 5 years, we have carried out combined chemotherapy with rifampicin, ethambutol, an aminoglycoside (streptomycin or kanamycin), and clarithromycin (CAM) following the guidelines for the treatment of pulmonary MAC disease proposed in 1998, and we have achieved positive results; both the sputum conversion rate and clinical improvement of the outcome in patients with primary infectious type rose significantly. Although there were no significant differences in the background or in microbiological and radiological findings in the two groups, significant improvement was seen in the sputum conversion rate and in improvement of the clinical effect of treatment. The results of this combined chemotherapy were unsatisfactory, however, when compared with its clinical effect on pulmonary tuberculosis. Therefore, we anticipate the development of new companion drugs for pulmonary MAC disease that are as active as CAM.

Rosuvastatin is a new statin that has been shown to produce substantial dose-dependent reductions in low-density lipoprotein cholesterol (LDL-C) in Western and Japanese hypercholesterolemic patients. Rosuvastatin efficacy and safety were assessed in an open-label, dose-titration trial of 37 Japanese patients with heterozygous familial hypercholesterolemia. After an 8-week dietary lead-in period, patients received rosuvastatin on the following schedule: 10 mg/day during weeks 0-6; 20 mg/day during weeks 6-12, and 40 mg/day for weeks 12-18. Mean percentage reductions from baseline in LDL-C (49.2-56.7%), total cholesterol (39.4-45.4%), and non-high-density lipoprotein cholesterol (non-HDL-C) (46.7-54.3%) were highly significant at each dose (p < 0.0001). Similar significant reductions in triglycerides (18.2-25.0%; p < 0.006) and increases in HDL-C (9.6-13.6%; p < 0.005) were observed. Rosuvastatin was well tolerated. Two patients withdrew from the study because of adverse events unrelated to the study treatment. No patients had clinically significant elevations in liver transaminases. Two patients exhibited a single increase in creatine kinase (one unrelated to study treatment, the other possibly related) with no muscle symptoms. Rosuvastatin produced significant beneficial changes in all lipid parameters in Japanese patients with heterozygous familial hypercholesterolemia and was well tolerated.

In order to better characterize the toxicity of N,N-dimethylformamide (DMF) and to provide its basic toxicity data for risk assessment of workers exposed to DMF, F344 rats and BDF1 mice of both sexes were exposed by inhalation (6 h/d x 5 d/wk) to 100, 200, 400, 800 or 1,600 ppm DMF for 2 wk, and 50, 100, 200, 400 or 800 ppm DMF for 13 wk. Three male and 7 female rats died during the 2-wk exposure to 1,600 ppm DMF, but no death of the exposed rats or mice occurred under any other exposure conditions. Massive, focal and single cell necroses were observed in the liver of DMF-exposed rats and mice. The massive necrosis associated with the centrilobular fibrosis occurred at the highest exposure concentration. The single cell necrosis was associated with fragmentation of the nucleoli as well as an increased mitotic figure. The 13-wk exposures of rats and mice to DMF were characterized by increases in the relative liver weight and the incidence of the centrilobular hepatocellular hypertrophy as well as increased serum levels of AST, ALT, LDH, total cholesterol and phospholipid. Lower confidence limits of the benchmark dose yielding the response with a 10% extra risk (BMDL10) were determined for the relative liver weight and the incidence of hepatocellular hypertrophy of the 13-wk exposed animals. The BMDL10 resulted in 1 ppm for the increased relative liver weight of male rats and mice and 17 ppm for the hepatocellular hypertrophy of male mice.

We performed a nationwide survey of 1,258 patients to assess the treatment of community-acquired pneumonia in Japan. Cases were classified as bacterial pneumonia in which the causal organism was unknown (Type A) or presumed (Type B), atypical pneumonia (Type C), severe pneumonia (Type D), or pneumonia in certain specific morbid states (Type E). Our objectives were to assess the actual use of antimicrobials and to determine the usefulness of the "Guidelines on Respiratory Infections--Basic Concepts in the Medical Care of Community-Acquired Pneumonia in Adults", developed by the Guideline-Drafting Committee of the Japanese Respiratory Society (JRS), in differentiating these categories of patients. We also hoped to elicit constructive opinions that would contribute to future revisions of these guidelines. The findings showed that pneumonia was classified as "bacterial pneumonia in which the causal organism was unknown" in approximately half (50.2%) of the patients studied. The next most common classification was "severe pneumonia", followed by "atypical pneumonia", "bacterial pneumonia in which the causal organism was presumed", and "pneumonia in certain specific morbid states", in that order. Our results suggest that the JSR guidelines, including the methods for differentiating between bacterial pneumonia and atypical pneumonia, are useful and appropriate, and that antimicrobial agents were generally selected in accordance with the guidelines. We also identified a number of issues to be addressed in future updates of the guidelines, including criteria for physiological assessment, handling of cases in which physical findings and laboratory test results are not in agreement, age-related issues (especially the treatment of patients 65 years of age and older), the differentiation between bacterial pneumonia and atypical pneumonia, the weighing of underlying diseases and complications, and guidelines regarding the use of adjuvant therapy.

From October 2001 to September 2002, we collected the specimen from 370 patients with lower respiratory tract infections in 16 institutions in Japan, and investigated the susceptibilities of the isolated bacteria to various antibacterial agents and antibiotics and patients' characteristics. Of 458 strains that were isolated from specimen (mainly from sputum) and assumed to be bacteria causing in inflammation, 456 strains were investigated. The breakdown of the isolated bacteria were: Staphylococcus aureus 69, Streptococcus pneumoniae 72, Haemophilus influenzae 85, Pseudomonas aeruginosa (non-mucoid) 44, P. aeruginosa (mucoid) 13, Klebsiella pneumoniae 32, Moraxella subgenus Branhamella catarrhalis 32, and others. Of 69 S. aureus strains, those with 4 micrograms/mL or more of MIC of oxacillin (methicillin-resistant S. aureus: MRSA) occupied 43.5%. Vancomycin and arbekacin showed the most potent activities against MRSA as observed in 2000. The frequency of S. pneumoniae exhibiting low sensitivity to penicillin (penicillin-intermediate S. pneumoniae: PISP + penicillin-resistant S. pneumoniae: PRSP) was 59.7% and both rates of PISP and PRSP were the highest after 1992. Carbapenems had strong activities against S. pneumoniae. Especially, panipenem and imipenem inhibited the growth of all 72 strains at 0.125 and 0.5 microgram/mL, respectively. Generally, all drugs had strong activities against H. influenzae with MIC90s of 16 micrograms/mL or less. The drug that had the strongest activity against H. influenzae was levofloxacin, which inhibited the growth of 80 of the 85 strains at 0.063 microgram/mL. Against P. aeruginosa mucoid strain, meropenem had a strong activity with MIC90 of 0.5 microgram/mL while, against non-mucoid strain, tobramycin had a strong activity with MIC90 of 2 micrograms/mL. K. pneumoniae showed good susceptibilities to all drugs except ampicillin and minocycline, and the MIC90s were 4 micrograms/mL or less. Particularly, cefmenoxime, cefpirome, and imipenem had the strongest activity (MIC90: 0.125 microgram/mL), and cefozopran had a strong activity, inhibiting the growth of all strains at 0.25 microgram/mL. Also, all drugs generally had strong activities against M. (B.) catarrhalis. MIC90s of all drugs were 4 micrograms/mL or less. The drug that had the strongest activity was minocycline and levofloxacin inhibiting all 32 strains at 0.063 microgram/mL. Most of the patients with respiratory infection were aged 70 years or older, accounting for approximately a half of the total (40.5%). As for the incidence by the diseases, bacterial pneumonia and chronic bronchitis were the highest, being noted in 39.2% and 37.3% of all the patients, respectively. The bacteria frequently isolated from the patients with bacterial pneumonia were S. aureus (19.3%) and S. pneumoniae (19.9%). In contrast, H. influenzae (22.0%) were frequently isolated from the patients with chronic bronchitis. Before the drug administration, the bacteria frequently isolated from the patients were S. pneumoniae (20.8%) and H. influenzae (21.5%). S. pneumoniae and H. influenzae decreased after the initiation of drug administration while S. aureus increased. The isolation frequency of P. aeruginosa was higher after than before the initiation of drug administration. The bacteria were frequently isolated from the patients who had already treated with cephems were S. aureus and P. aeruginosa. From the patients who had already treated with macrolides, S. pneumoniae was the most frequently isolated while S. aureus was the most frequently isolated from the patients pre-treated with quinolones.

A survey was conducted to determine the antimicrobial activity of fluoroquinolones and other antimicrobial agents against 8,474 clinical isolates obtained from 37 Japanese medical institutions in 2000. A total of 25 antimicrobial agents were used, comprising 4 fluoroquinolones, 13 beta-lactams, minocycline, chloramphenicol, clarithromycin, azithromycin, gentamicin, amikacin, sulfamethoxazole-trimethoprim, and vancomycin. A high resistance rate of over 85% against fluoroquinolones was exhibited by methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Isolates showing resistance to fluoroquinolones among methicillin-resistant coagulase-negative Staphylococci, Enterococcus faecalis, and Pseudomonas aeruginosa from UTI accounted for 30-60%. However, many of the common pathogens were still susceptible to fluoroquinolones, such as Streptococcus pneumoniae (including penicillin-resistant isolates), Streptococcus pyogenes, methicillin-susceptible S. aureus (MSSA), methicillin-susceptible coagulase-negative Staphylococci, Moraxella catarrhalis, the Enterobacteriaceae family, and Haemophilus influenzae (including ampicillin-resistant isolates). About 85% of P. aeruginosa isolated from RTI were susceptible to fluoroquinolones. In conclusion, this survey of sensitivity to antimicrobial agents clearly indicated trend for increasing resistance to fluoroquinolones among MRSA, Enterococci, and P. aeruginosa isolated from UTI, although fluoroquinolones are still effective against other organisms and P. aeruginosa from RTI as has been demonstrated in previous studies.

We have held practical classes called chozaigijutsu-konwakai(Konwakai) for pharmacists working in drugstores every month since December 1994. Konwakai is composed of lectures and practice. The practice is carried out for pharmacists to obtain a better understanding of prescriptions and compounding them in exercises. In this study, we analyzed the answers to questionnaires distributed at the end of each konwakai to all participants. It was found that the age of participants as well as the length of compounding experience varied markedly, indicating that pharmacists of various generations are interested in konwakai. Regarding the contents of lectures and practice, the answers indicated that the practice was particularly useful, suggesting the importance of exercise for learning techniques in compounding. Since there were many requests for consultations on routine work, frequent communications between pharmacists in the hospital and drugstores appears necessary. In conclusion, regular meetings including practical classes such as konwakai are very important for pharmacists in drugstores that receive prescriptions from hospitals. Further efforts to improve the konwakai should be maid in the future.

By retrospectively analyzing 288 patients with de novo myelodysplastic syndrome (MDS), we sought to determine the prevalence and clinical characteristics of bone marrow eosinophilia and basophilia that were detected at presentation. Bone marrow eosinophilia and basophilia were defined as a differential count of each cell type exceeding 5.0% and 1.0%, respectively. Of 288 patients with MDS, 36 (12.5%) fulfilled this criterion for bone marrow eosinophilia (MDS-Eos); 34 patients (11.8%) showed basophilia (MDS-Bas), and 11 (3.8%) satisfied both criteria (MDS-EosBas). The remaining 229 patients had neither eosinophilia nor basophilia in their bone marrow (MDS(-/-)) at presentation. Cytogenetic analysis was carried out on unstimulated bone marrow cells obtained from 264 patients. When the cytogenetic categorization of the IPSS (International Prognostic Scoring System) for MDS was applied, significantly higher numbers of MDS-Eos and MDS-Bas patients had chromosomal abnormalities carrying intermediate or poor prognosis, compared with the MDS(-/-) patients. Specific chromosomal abnormalities and complex karyotypes were associated with MDS-Eos and/or MDS-Bas. In accordance with these results, the overall survival rate was significantly lower, and the evolution to acute myelogenous leukemia (AML) occurred more frequently in the MDS-Eos and MDS-Bas than in the MDS(-/-) patients. Multivariate analysis demonstrated that bone marrow basophilia was an independent risk factor for evolution to AML. Our study indicates that bone marrow eosinophilia and basophilia in patients with MDS predict a poorer prognosis.

Acute myeloid leukaemia (AML) with trilineage dysplasia (AML/TLD) is de novo AML recognized by the morphological dysplasia of three mature cell lines in the presence of leukaemic blasts. We studied the karyotypes of AML/TLD of patients with de novo AML, except for those with the French-American-British classification M3, who were enrolled onto the Japan Adult Leukaemia Study Group (JALSG)-AML 92 trial. Morphological and cytogenetic analyses were performed in 559 patients and TLD phenotype was found in 155 patients (27.7%). The 511 patients with informative morphological and cytogenetic data were classified into three groups according to karyotype: favourable, intermediate and adverse risk groups (92, 375 and 44 patients respectively). Normal karyotype was the most frequent as a total, and among both the non-TLD and TLD patients (164 patients 45.3% and 78 patients 52.7% respectively). All but one patient with AML/TLD was classified into the intermediate or adverse cytogenetic risk group. TLD phenotype was associated with lower remission rate and shorter overall survival but it did not influence disease-free survival. Although we did not find any specific cytogenetic abnormalities for AML/TLD, the rarity of favourable karyotypes among TLD patients indicates the biological difference between AML/TLD and AML/non-TLD.

Objective: To evaluate the clinical features, etiology, and prognosis of patients who required long-term mechanical ventilation (LMV) of over three months for respiratory failure following underlying disease, and observation of their clinical course until death., Patients: Thirty-seven patients (27 males, 10 females) treated in the internal and medical intensive care unit at Kawasaki Medical School Kawasaki Hospital over the 16-year period from April 1985 to March 2001 were retrospectively studied., Results: Many of these patients were elderly males with respiratory disease such as pulmonary emphysema or old pulmonary tuberculosis, which had developed into acute respiratory failure resulting in respiratory tract infection and initiation of mechanical ventilation. The survival rates of one year, three years and five years after the start of mechanical ventilation were 60%, 30%, and 16%, retrospectively, and the prognoses were poor. Respiratory tract infection was the most common and serious complication. Specifically, ventilator-associated pneumonia (VAP) was a complication in 21 patients and also the main-cause of death. VAP was observed 2.3 years after the initiation of mechanical ventilation with significant differences in the following risk factors being observed between VAP (+) and VAP (-) groups: chronic obstructive pulmonary disease, duration of mechanical ventilation, prior antibiotics, aspiration of gastric contents and use of histamine-type II receptor antagonist. The causative pathogens of VAP were Pseudomonas aeruginosa and Staphylococcus aureus, which were frequently isolated from tracheal aspirates. All patients with VAP caused by MRSA died shortly after contracting the infection., Conclusions: This study has demonstrated that appropriate treatment for respiratory tract infections such as VAP and the prevention of nasocomial infection due to MRSA is of paramount importance for patients requiring long-term mechanical ventilation of over three months.