Search

Survival Sepsis Campaign (SSC) guidelines have recommended broad-spectrum antibiotics prescriptions to cover the possible pathogenic microorganisms. However, mortality from sepsis is still high, as about one quarter of cases are thought to result in death. We analyzed nationwide health claims data of universal health insurance systems in Japan. Our aim was to describe the antibiotics prescriptions and underlying conditions of Japanese sepsis patients. In addition, we analyzed the factors associated with 30-day mortality. A total of 1188 patients aged ≥15 years were entered, of which 80.1% were ≥65 years old. Broad-spectrum antibiotics were prescribed for 53.8%. Carbapenem, Piperacillin Tazobactam and Anti-pseudomonas Cephalosporin were prescribed for 30.8%, 13.0% and 12.2% of the patients, respectively. (Some patients were counted twice) The overall 30-day mortality rate was 21.3%. Risk factors associated with 30-day mortality were examined by Cox proportional hazards regression analysis. Age of ≥85 years, malignancy, chronic kidney disease (CKD), shock and respiratory failure were selected as risk factors, but broad-spectrum antibiotics was not included. Sepsis is mostly observed in those aged 65 years and over. The rates of broad-spectrum antibiotics were restricted, and antibiotics were also not necessarily prescribed on the basis of SSC guidelines. However, broad-spectrum antibiotics did not improve the treatment outcome. Aging and underlying conditions like malignancy, CKD, shock and respiratory failure were poor prognostic factors., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The detection of SARS-CoV-2 RNA by real-time reverse transcription-polymerase chain reaction (rRT-PCR) is used to confirm the clinical diagnosis of COVID-19 by molecular diagnostic laboratories. We developed a multiplex rRT-PCR methodology for the detection of SARS-CoV-2 RNA., Methods: Three genes were used for multiplex rRT-PCR: the Sarbecovirus specific E gene, the SARS-CoV-2 specific N gene, and the human ABL1 gene as an internal control., Results: Good correlation of C q values was observed between the simplex and multiplex rRT-PCR methodologies. Low copies (<25 copies/reaction) of SARS-CoV-2 RNA were detected by the novel multiplex rRT-PCR method., Conclusion: The proposed multiplex rRT-PCR methodology will enable highly sensitive detection of SARS-CoV-2 RNA, reducing reagent use and cost, and time required by clinical laboratory technicians., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Recent contacts with active TB (tuberculosis) patients were screened for latent tuberculosis infection (LTBI) because of their greater relative risk for developing active TB. QuantiFERON®-TB Gold Plus (QFT-Plus) offers two TB-specific antigen tubes (TB1 and TB2). TB1 elicits CD4 T-cell responses, and TB2 is designed to elicit both CD4 and CD8 T-cell responses. These mechanisms could be useful for estimating the role of CD8 T-cell immune responses to TB-specific antigens. To estimate the QFT-Plus capability to diagnose LTBI, a prospective cross-sectional study was conducted. A total of 412 TB contacts (median age 44 years) were enrolled. The positivity rates of QFT-Plus, TB1 and TB2 were 7.5%, 6.3% and 7.2%, respectively. TB2 showed a higher positivity rate compared to TB1, but without significant difference. The interferon (IFN)-γ productions of TB1 and TB2 were well correlated (r = 0.934, P < 0.001). The ratio of IFN-γ production between TB1 and TB2 showed a median (interquartile range) of IFN-γ [QFT-Plus TB2] /IFN-γ [QFT-Plus TB1] of 1.09 (0.91-1.36). CD8 T-cell immune response to TB-specific antigens varied among subjects. CD8 T-cell potentially boosts IFN-γ productions in QFT-Plus and results in the detection of more persons with LTBI. However, there was no significant difference in the positivity rates of QFT-Plus TB1 and TB2 in our TB contact investigation. The contribution of CD8 T-cells might be small for the diagnosis of LTBI. The analysis of IFN-γ production in both TB1 and TB2 would lead to further analysis of the TB immune response, and especially that caused by CD8 T-cells., Competing Interests: Declaration of Competing Interest All authors: No potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The Macrolides (MLs), clarithromycin and azithromycin, are key drugs for non-tuberculous mycobacteria (NTM) diseases treatment. A three antibiotics regimen including MLs, rifampicin (RFP) and ethambutol (EB) has been recommended for the treatment of NTM diseases in ATS/IDSA guideline. However, anti-biotics are not necessarily prescribed in compliance with the guideline. Inappropriate regimens are risk of introducing MLs resistance. Therefore, we planned this study to evaluate the current Japanese NTM diseases treatment conditions. We used the national database (NDB) from 2011 to 2014. A total of 183 patients were entered into the study. The patients number increased at an accelerating rate in patients aged ≥55 years. Patients aged ≥55 years made up 91.3% of the total NTM diseases. Male and female patients were 61 and 122, respectively, a female/male ratio of 2.00. Clarithromycin, RFP, EB and fluoroquinolones were frequently prescribed, with the numbers of prescriptions being 125, 66, 57 and 45, respectively. The regimen of MLs, RFP and EB recommend by ATS/IDSA guideline 2007 was only followed by 25.1% of the patients. MLs monotherapy was as high as 30.6% of NTM diseases and would be a risk factor leading to an increase of MLs resistance and poor treatment outcome. Without effective NTM disease therapy, the increase of MLs-resistant NTM diseases would be a burden for Japanese health care facilities., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Pneumonia is the third leading cause of death in Japan. Mortality increases at an accelerating rate in elderly patients aged ≥65 years. Elderly patients tend to have underlying conditions affecting pneumonia treatment. The national database (NDB) associated with medical services under Japanese universal health insurance is available for research purposes. Our NDB randomly sampled 10% of hospitalized patients every October from 2011 to 2014. In this NDB, we analyzed pneumonia epidemiology in patients aged ≥15 years and 30-day mortality in Japanese hospitals. This study also investigated the factors affecting treatment outcome. A total of 9386 patients were entered. The number of patients from age 65 years and older increased greatly, representing 85% of the total. The thirty-day mortality rate among all patients was 11.7%. Mortality rates at age 15-64, 65-74, 75-84, and ≥85 years were 9.5%, 12.0%, 8.3%, and 14.9%, respectively, showing significant differences (P < 0.001). The underlying conditions varied among age groups. Male gender, age, heart failure, chronic kidney disease (CKD), consciousness disorder, shock and respiratory failure are risk factors for 30-day mortality. Pneumonia develops mainly in people aged 65 years and older in Japan, and treatment outcome is generally poor in elderly patients. The underlying conditions were seen to affect the 30-day mortality rate. CURB-65 and ADROP, a modification of CURB-65 in Japan, have already estimated these risk factors, and heart failure and CKD might be additional factors for estimating pneumonia severity., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Individuals with recent contact with active tuberculosis (TB) patients were screened for latent tuberculosis infection (LTBI) considering their greater relative risk for developing active TB. QuantiFERON®-TB Gold Plus (QFT-Plus) assay offers two TB-specific antigen tubes (TB1 and TB2). TB2 is designed to elicit both CD4 and CD8 T-cell responses. This mechanism could lead to increased sensitivity as compared to the QuantiFERON®-TB Gold In-Tube (QFT-GIT) assay. Our objective was to compare the LTBI diagnostic capability of QFT-Plus with that of QFT-GIT., Methods: A total of 412 TB contacts (median age 44 years) were prospectively enrolled. We conducted both QFT-Plus and QFT-GIT assays concurrently. We also analyzed production of interferon-γ (IFN-γ) in response to TB-specific antigens., Results: The positivity rates in QFT-Plus and QFT-GIT were 7.5% (95% confidence interval (CI), 5.4-10.5) and 5.8% (CI, 3.9-8.5), respectively, showing a significant difference (P < 0.05). The median (inter-quartile range [IQR]) of IFN-γ [QFT-Plus] /IFN-γ [QFT-GIT] was 1.41 (1.00-2.00). QFT-Plus produced 1.4 times IFN-γ., Conclusions: QFT-Plus revealed significantly higher positivity rate compared with QFT-GIT, which might be attributed to increased IFN-γ production. The cut-off in both QFT-Plus and QFT-GIT was 0.35 IU/mL. These effects might resulted in the higher positivity rate in QFT-Plus., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and developing active tuberculosis. QuantiFERON ® -TB Gold Plus (QFT-Plus) has two TB-specific antigens tubes (TB1 and TB2). TB1 elicits CD4 T-cell response, and TB2 elicits both CD4 and CD8 T-cells responses, with expected increased sensitivity. The aim of this study was to estimate the prevalence of LTBI in renal transplant recipients in Japan. We conducted a cross-sectional study by using two interferon-γ release assays (IGRAs), QFT-Plus and T-SPOT ® .TB (TSPOT). One hundred thirty-five recipients were prospectively enrolled. The median age was 49 years (range: 20 to 79). The positivity rates of QFT-Plus and TSPOT were 5.9% (95%CI 3.0-11.3) and 3.7% (95%CI 1.6-8.4), respectively, with no significant difference. The concordance rate was 95.5% (κ coefficient, 0.76). Age of 60 years and higher was related to the higher positivity rate in both QFT-Plus and TSPOT. The positivity rates of TB1 and TB2 were 5.1% (95%CI 2.5-10.2) and 5.9% (95%CI 3.0-11.2), respectively, with no significant difference. The concordance rate was 99.3% (κ coefficient, 0.93). TB2 did not show a higher positivity rate compared with TB1. The estimated prevalence of LTBI by using the both IGRAs was 3.7-5.9% in renal transplant recipients. These results were equivalent to the IGRAs positivity rate in the general Japanese population, even under the condition of immunosuppressive therapy. In consideration of the higher risk of developing active TB from LTBI, we can use both IGRAs as acceptable tools for LTBI diagnosis in renal transplant recipients., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Inactivated quadrivalent influenza vaccine (IIV4) has been used as seasonal influenza vaccine since 2016 in Japan. This study examined the safety of IIV4 in comparison with the AH1pdm monovalent vaccine used for novel influenza in 2009. Questionnaire surveillance associated with adverse events (AEs) was conducted at Chiba University Hospital, Japan. After being vaccinated, all health care workers (HCWs) were given a daily AEs check sheet on which they recorded solicited events, the same surveillance program used after AH1pdm vaccination in 2009. The frequency of injection site AEs with IIV4 was significantly higher than with the monovalent vaccine, but there was no significant difference with systemic AEs. Injection site and systemic AEs were reported as 83.7% and 25.5%, respectively, with IIV4. The grades of AE, mild, moderate and severe, were 67.2%, 16.4% and 0.1% with IIV4, respectively, indicating that almost all of the AEs reported with IIV4 were mild or moderate. Systemic AEs with IIV4 and monovalent vaccine were reported to be 25.5% and 23.1%, respectively, with the difference not being significant. The grade of AEs with IIV4, mild, moderate and severe, was 19.1%, 5.6% and 0.9%, respectively. The ratio of HCWs reporting AEs peaked at around 80% on day 1, then decreasing to less than 5% by day 7. AEs with IIV4 were reported more frequently compared with the AH1pdm monovalent vaccine. However, in consideration of the grade and duration of AEs, IIV4 was a well-tolerated, safe vaccine.

Cured or completed cases in newly diagnosed sputum smear-positive pulmonary tuberculosis (TB) is 47.7% in Japan in 2016. Aging of TB patients and their underlying conditions could affect treatment outcome. We analyzed the association between the isolation of microorganisms from sputum at admission and the 180-day mortality rate of the sputum smear-positive pulmonary TB patients in Chiba-East Hospital in Japan. Total subjects were 761 (median age: 63 years). Sputum test for microorganisms was conducted in 708 patients. Microorganisms other than the normal oral flora were isolated in 128 cases (18.1%). Details of the isolated microorganisms were as follows: methicillin-resistant Staphylococcus aureus 23 cases, Klebsiella pneumoniae 17 cases, Pseudomonas aeruginosa 16 cases. Mortality was significantly elevated in the patients with those microorganisms than the others (39.8% vs. 10.2%) (P < 0.01). Fifty-one of 128 patients with those microorganisms died, and 10 of them died of infectious disease, which is the most frequent cause of deaths. The factors associated with the isolation of those microorganisms were as follows: respiratory failure (adjusted odds ratio (aOR):2.5 [95% confidence interval (CI) 1.3-4.7]), performance status 3 or 4 (aOR:2.9 [95% CI 1.6-5.4]), serum albumin <3.0 mg/dL (aOR:2.1 [95% CI 1.3-3.6], age of 65 years or older (aOR:2.0 [95% CI 1.2-3.4]). Those strains were isolated from one of sixth patients. Patients with those microorganisms did not always develop infectious diseases; however, treatment outcomes were poor, with higher mortality. The isolations of microorganisms were associated with various underlying conditions, leading to death. Thus, attention should be paid to TB patients with the above factors., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Rheumatoid arthritis (RA) is an immune mediated inflammatory disorder, and immune suppressive drugs are prescribed. RA patients receiving treatments are in a kind of immunosuppressive condition that presents increased risk of developing active tuberculosis. Accurate diagnosis of latent tuberculosis infection (LTBI) is recommended for RA. QuantiFERON ® -TB Gold Plus (QFT-Plus), a novel IGRA, has two tubes (TB1 and TB2). TB2 is designed to elicit both CD4 and CD8 T-cell responses, with expected increased sensitivity. We conducted a cross-sectional study to compare two IGRAs, QFT-Plus and T-SPOT ® .TB (TSPOT), in RA. One hundred fifty-two RA patients (median age: 66.5 yrs) were enrolled. QFT-Plus and TSPOT were concurrently conducted. Lymphocyte subsets (CD4 T-cell and CD8 T-cell) were also measured. The positivity rates of QFT-Plus and TSPOT were 9.7% and 4.5%, respectively, with the difference being significant (P < 0.01). The positivity rates in TB1 and TB2 were 9.1% and 7.1%, respectively; the difference was not significant (P = 0.18). Patients with CD4 T-cell ≥650/μL and CD8 T-cell ≥400/μL had significantly higher positivity rates in both QFT-Plus and TSPOT in comparison with other groups (P < 0.01 and P < 0.05, respectively). QFT-plus demonstrated a higher positivity rate than TSPOT. However, there was little additional effect for detecting LTBI by TB2. Lymphocyte subsets were strongly associated with immune response in both QFT-Plus and TSPOT. LTBI should not be ruled out even with a negative IGRA result in patients with CD4 T-cell <650/μL or CD8 T-cell <400/μL., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to < 6 years), then increased in the later stage [17.3% in ≥ 11 years, p = 0.001 (vs. ≥ 2 to < 6 years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for < 2 years and 17.4 vs. 3.1% for ≥ 2 to < 6 years, p = 0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and progressing to active tuberculosis (TB). This study was conducted in National hospital for tuberculosis and renal transplantation (RT) in Japan. The purpose is to compare two interferon-γ release assays (IGRAs), QuantiFERON ® -TB Gold in Tube (QFT) and T-SPOT ® .TB (TSPOT), in patients after renal transplantation for detecting latent TB infection (LTBI). Total 92 renal transplant recipients (median age 46 years, range 17-75) were prospectively enrolled, and QFT and TSPOT were concurrently examined. Total subjects were 92 patients (median age 46 years, range 17-75). The positive rate in QFT and TSPOT were 6.5% (95% confidence interval (CI) 3.0-13.5) and 2.2% (95% CI 1.0-7.6), respectively. There was a significant difference in IGRAs positivity (P < 0.05). The negative rate in QFT and TSPOT were 91.3% (95% CI 83.8-95.5) and 95.7% (95% CI 89.3-98.3), respectively. There was no significant difference in IGRAs negativity. No patients among either IGRAs negative patients developed active TB during median follow-up of 994 days. Neither QFT nor TSPOT reaches estimated TB infection rate in Japan, especially elderly recipients aged 60 year-old or more. Therefore, both IGRAs might underestimate LTBI owing to immune suppressive therapy and aging. Physicians for renal transplantation need to understand the characteristics of both IGRAs and pay attention to the possibility of developing active TB even in patients of negative IGRAs results., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

QuantiFERON-TB gold in-tube has been used for screening latent tuberculosis infection in newly employed health care workers in Japan. There have been a few studies concerning quality control. We retrospectively analysed QuantiFERON-TB gold in-tube results in a hospital in Japan. Interferon-γ values in three blood collection tubes for QuantiFERON-TB gold in-tube were analysed in association with the positivity rate. The data set consisted of health care workers aged 20-29 years during the 7 years between 2010 and 2016. The yearly QuantiFERON-TB gold in-tube positivity rate was 0.9%, 16.4%, 3.0%, 39.3%, 2.8%, 0.9% and 1.5%, and was extremely high in 2011 and 2013. The interferon-γ values in the tuberculosis antigen tube were elevated in these two years, as indicated by higher median and wider interquartile range. The interferon-γ value in the negative control tube was also higher in 2011. The higher interferon-γ values in collection tubes (tuberculosis antigen tube and/or negative control tube) resulted in higher QuantiFERON-TB gold in-tube positivity rate. The distribution of interferon-γ in tuberculosis antigen tube and negative control tube, as evaluated by median and interquartile range, proved to be an effective index for the quality control of QuantiFERON-TB gold in-tube., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Corynebacterium striatum was recently recognized as a potential pathogen of various infectious diseases. However, the clinical entity of this microorganism has not been clearly identified. Therefore, we analyzed C. striatum isolates from blood culture and explored their clinical determinants., Methods: We reviewed the medical records of all patients from whom C. striatum isolates were recovered from blood culture for analysis of the patients' backgrounds and clinical course including response to antimicrobial therapy and prognosis., Results: During the 5-year study period (January 2010 to December 2014), 24 C. striatum strains were isolated from blood samples, and the frequency of C. striatum bacteremia increased. The majority of the strains were multidrug resistant. All of the tested strains were susceptible to only vancomycin. The age at onset of C. striatum bacteremia encompassed all adult age groups, and at least one underlying condition was documented in all patients. Thirteen of the 24 patients were cured using appropriate antibiotics (true infection group); however, 11 of the 24 patients were cured using inappropriate antibiotic therapy or no antibiotics (contamination group). Malignancy and neutropenia significantly increased the odds of true C. striatum bloodstream infection., Conclusions: The Corynebacterium species is often considered a contaminant when isolated in culture. Instead, particularly when the strain is isolated from blood, the species should be considered clinically relevant and identified to the species level; in addition, antimicrobial susceptibility testing is recommended., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Setting: National hospital for tuberculosis (TB) and rheumatoid arthritis (RA) in Japan., Objective: To compare two interferon-γ release assays (IGRAs), QuantiFERON ® -TB Gold In-Tube (QFT) and T-SPOT ® .TB (T-SPOT), in RA patients for detecting latent tuberculous infection (LTBI)., Design: QFT and T-SPOT were conducted concurrently in 230 prospectively enrolled RA patients., Results: There were no active TB patients. The percentage of QFT- and T-SPOT-positive patients was respectively 8.3% and 5.7%. In patients aged ⩾60 years, these proportions were respectively 12.3% and 7.2%. The percentage of QFT positivity and T-SPOT positivity at age <60 years was respectively 2.2% and 3.3%. After multivariate logistic analysis for QFT positivity, age ⩾60 years and TB suspected based on chest X-ray were selected as independent factors, with adjusted odds ratios of respectively 4.73 and 3.25. No factors were selected for T-SPOT positivity., Conclusion: QFT had a higher positivity rate. In the light of the previous estimated rate of LTBI in Japan, both IGRAs underestimate LTBI, and neither IGRA has enough capability to detect LTBI.

Chronic kidney disease (CKD) is an increased risk for the development of active tuberculosis, but few studies have analyzed the treatment outcome of pulmonary tuberculosis among CKD patients. A retrospective cohort study was conducted at Chiba-East Hospital in Chiba, Japan. Our study estimated the treatment outcomes in smear-positive pulmonary tuberculosis in relation to CKD and its stages. Total subjects were 759 patients (12-99 years) hospitalized between 2007 and 2012. Patients suffering from multi-drug-resistant tuberculosis were excluded. Patients with CKD were 19.3% aged <65 years (n = 384), and 49.6% aged ≥ 65 years, respectively (P < 0.001). Successful treatment was 52.7% in CKD (n = 260) and 67.3% in non-CKD (n = 499) (P < 0.001). Death was 25.4% in CKD and 12.4% in non-CKD (P < 0.001). Treatment outcome was especially poor in patients with low estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m(2), as successful treatment was 20.0%, and death was 50.0%, significantly lower than in other CKD and non-CKD patients. After multivariate logistic regression analysis, eGFR<30 ml/min/1.73 m(2) was an independent factor affecting successful treatment and death, and its adjusted odds ratios (aOR) were 0.20 (95% confidence interval (CI) 0.07-0.50) and 2.99 (95%CI 1.20-7.51), respectively. Other factors affecting successful treatment were serum albumin <3.0 mg/dl, steroid therapy for underlying disease and cardiovascular disease, with aOR (95%CI) of 0.28 (0.20-0.39), 0.32 (0.16-0.63) and 0.49 (0.28-0.86), respectively. Several factors were associated with poor treatment outcome of smear-positive pulmonary tuberculosis. Advanced stage of CKD with eGFR of <30 ml/min/1.73 m(2) was a risk factor for poor treatment outcome., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: We aimed to investigate the incidence and clinical characteristics of nontuberculous mycobacterial (NTM) pulmonary disease as a complication of chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: We conducted a retrospective study of 10 cases (5.6%) complicated by NTM pulmonary disease among 180 CTEPH patients., Results: Isolated species of avium (n=5), kansasii (n=2), intracellulare (n=1), abscessus (n=1) and fortuitum (n=1) were detected. NTM-infected lesions were observed in 33 of 180 (18.3%) lung segments obtained from the 10 patients, and complete obstruction due to chronic pulmonary thromboembolism was detected in 65 of the 180 segmental pulmonary arteries (36.1%). The NTM-infected segments in the CTEPH patients were significantly associated with obstructed rather than unobstructed pulmonary artery segments [25 of 65 (38.5%) vs. 8 of 115 (6.9%), p<0.01]. Cavitary, nodular, ectatic and ground-glass lesions were seen in 14, 22, seven and four of the 180 segments, respectively. Thirteen of the 14 cavitary (92.9%) lesions were located in non-perfused segments. Five patients with NTM disease underwent pulmonary endarterectomy (PEA). Of the 18 assessable NTM-infected segments in six NTM-treated patients, 17 were located in non-perfused segments and one was located in a previously perfused segment. All NTM-infected segments improved among three segments reperfused with PEA. In contrast, only eight (57.1%) NTM-infected segments improved among 14 continuously non-perfused segments. A lower body mass index was found to be a significant risk factor for NTM disease in the CTEPH patients., Conclusion: This is the first report to document NTM-disease complications in patients with CTEPH. Reperfusion in cases of NTM lesions may improve the response to NTM drug therapy.

Japanese Ministry of Health, Labour and Welfare issued new criteria for admission and discharge of tuberculosis patients in 2007. The criteria for admission are extended for the patients of the risk of Mycobacterium tuberculosis transmission and of the possible risk of treatment failure. The criteria for discharge are consisted of the 3 factors, (1) symptoms (cough, fever, etc.) are free after the standard chemotherapy of more than 2 weeks, (2) three different sputum smears are negative for acid-fast bacilli after the standard chemotherapy of more than 2 weeks, (3) patients are estimated to adhere to the chemotherapy after discharge and understand the infection control of M. tuberculosis. Although the criteria were simple, the goal was to treat tuberculosis patients successfully and improve treatment outcomes. For the effective operation of these criteria, the network of primary care facilities for early diagnosis and treatment after discharge, tuberculosis treatment facilities for hospitalization and local government including health care center is important. Four speakers proposed the problems and revealed their own resolutions. Three speakers from tuberculosis treatment facilities were positive for the shortening of hospitalization length by modifying the discharging criteria, however 1 speaker from the Tokyo Metropolitan Government emphasized that the regional medical system should be established for the treatment of discharged tuberculosis patient. 1. Reconsideration of admission and discharge criteria for tuberculosis patients: Kazunari TSUYUGUCHI (Department of Infectious Diseases, Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center) According to the present guideline in Japan, three consecutive negative sputum results for smear or culture are required for discharge of tuberculosis (TB) patients, making their duration of hospitalization extremely long. On the other hand, most of the TB ward in Japan consists of big rooms without air conditioning which carries a potential risk of nosocomial transmission and reinfection. In order to establish effective TB control, suspected or confirmed TB patient should be isolated in a single room equipped with the capacity for airborne infection isolation during hospitalization, as long as sputum smear or culture remains positive. It is reasonable to discharge patients to home before sputum conversion if effective chemotherapy is provided and all household members have been previously exposed. Rapid drug sensitivity testing will be helpful in assuring the effectiveness of chemotherapy for prompt discharge and detecting multidrug-resistance immediately. 2. Reconsideration of admission and discharge criteria for tuberculosis patient in Japan : Taku NAKAGAWA, Kenji OGAWA (Department of Pulmonary Medicine, National Hospital Organization Higashi Nagoya National Hospital) Admission criteria for tuberculosis patient are based on the positive result of sputum AFB smear test in principle. But admission criteria should be applied flexibly depending on the extent and severity of illness, socioeconomic background of the patient, and adherence to treatment in cooperation with the public health center. The Japanese Tuberculosis Society published "Guidelines for Admission and Discharge of Tuberculosis Patient" in January 2005. This guideline was consistent with the notice from Ministry of Health, Labour and Welfare. Improvement of management of patients with tuberculosis is most important, but bacteriological conversion is not necessary to release isolation from the hospital. The patients treated with standard regimen over two weeks and having improvement of clinical symptoms may be able to go home back in the absence of compromised person. As a result of putting this guideline into practice, there were no problems about infectiousness for tuberculosis. But the modified notice from Ministry of Health, Labour and Welfare based on bacteriological conversion was made public in September 2007. This modified notice brought in a prolonged period of hospitalization and created confusion in clinical practice. Based on the result of our study for infectiousness, it is appropriate to use the guideline in January 2005. 3. Consideration of the standard for leaving TB hospital: Masako WADA (Chemotherapy Research Institute, Kaken Hospital) In Japan, infectious pulmonary tuberculosis patients are ordered to receive chemotherapy in admission to tuberculosis treatment facilities according to Infectious Diseases Control Law. Infectious pulmonary tuberculosis is defined as sputum smear positive for acid-fast bacilli (AFB) even it is questionable. And there consecutive negative sputum smear for AFB is needed as a criteria for discharge. In this study we defined our own admission criteria as follows, medical service is needs owing to serious pulmonary tuberculosis, meningitis and other complications. We simulated the cost for hospitalization. During study period 170 patients were admitted and only 36 patients (21%) were needed hospitalization on our own criteria. The other 134 patients were admitted because of infectiousness. The average hospital stay was 63.0 days and 64.8 days, respectively. Total cost of patients cares were 26 million yen and 100 million yen respectively. On the points of saving medical costs, Infectious Diseases Control Law should be revised. 4. Recent problems in tuberculosis hospitalization and countermeasures related to patients support in urban area: Michihiko YOSHIDA (Infectious Control Section, Health and Safety Division, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Govenment) Standard treatment for tuberculosis led to a shortening of hospitalization days. After discharge most patients are treated as outpatient. In the outpatient, the decreased numbers and the bias in the geographical distribution of tuberculosis hospitals impair patients' accessibility and may lead to increase of drop out cases. And there is possible poor adherence to treatment in such as foreign-born patients from high burden countries, so intensive intervention will,be needed for successful treatment. On the other hand, in the tuberculosis hospitals, there are noninfectious tuberculosis patients with chronic complications such as psychiatric disorders and dialysis. In most cases, these patients cannot be transferred to other hospitals or welfare facilities. To resolve these problems, it is necessary to build community DOTS system including the public health centers, tuberculosis hospitals and related community resources such as clinics and welfare facilities. Also, in the near future, it is necessary to review and rebuild tuberculosis medical system comprehensively at the national level.

A 50-year-old man with chronic renal failure (hemodialysis treatment) and interstitial pneumonia (IP) was referred to our hospital for exacerbation of IP. We immediately administered a mechanical ventilation, broad spectrum antibiotics, steroid pulse therapy, and endoxan pulse therapy in the intensive care unit, but alveolar opacities became worse. Subsequently, an intrapulmonary cavity appeared in the left middle lung field on the chest X-ray and we also administered amphotericin B. However he died of tension pneumothorax on the tenth day of hospitalization. In an autopsy the rupture of the intrapulmonary cavity of the left S3 region was detected and we diagnosed as invasive pulmonary mucormycosis by Grocott stain of the cavitary lesion. We report a rare case that complicated by fatal tension pneumothorax during treatment with a ventilator in invasive pulmonary mucormycosis and review the literature.

The immunogenicity of pandemic influenza A H1N1 virus (A/H1pdm) vaccine might be modified by prior seasonal trivalent influenza vaccine (sTIV) administration. We conducted a retrospective analysis of immunogenicity of 243 health care workers (number of sTIV-positive [sTIV(+)] subjects, 216; number of sTIV(-) subjects, 27) by hemagglutination inhibition. There was no significant difference in the ratios of antibody titers of ≥40 (41.2% versus 48.1%; P = 0.49) and fold increases in geometric mean titer (3.8 versus 4.5; P = 0.37). sTIV injected 7 to 10 days prior to A/H1pdm vaccine administration did not interfere with the immunogenicity of the latter.

Pandemic influenza A (H1N1) virus (AH1pdm) emerged in April 2009. An inactivated, split-virus, unadjuvanted AH1pdm vaccine was manufactured in Japan, and vaccination was initiated with top priority for healthcare workers (HCWs) on October 19, 2009. A retrospective cohort study was conducted to evaluate the effectiveness of a single-dose vaccine for HCWs in a hospital in Japan. A total of 1,567 (84.5%) of 1,854 HCWs were vaccinated. Thirty-seven were infected with AH1pdm before the vaccine became available, and were excluded. The other 250 were not vaccinated for personal reasons. We analyzed the influenza infection rate with or without vaccination and related adverse events. Among the 1,817 HCWs without previous infection, 37 were infected with AH1pdm; 13 (5.2%) of 250 unvaccinated HCWs became infected, which was a significantly higher rate than the 24 (1.5%) of 1,567 vaccinated HCWs (P=0.001). Multivariate analysis revealed that age of 20-29 years was a risk factor for infection (adjusted odds ratio [aOR], 3.7; P<0.001), and that vaccination was a preventive factor (aOR, 0.20; P<0.001). Adverse events occurred in 549 of 1,060 HCWs, but most were mild. Although vaccination was carried out during AH1pdm epidemic expansion, the single-dose AH1pdm vaccine proved effective in HCWs, and severe adverse events were rare.

A phase III observational study evaluating a single-dose of an inactivated, split-virus, unadjuvanted AH1pdm vaccine in HCW was conducted. A safe and effective vaccine was needed after the emergence of AH1pdm in April 2009. We analyzed the immunogenicity and safety of the vaccine. A total of 409 subjects were enrolled and given 15 μg hemagglutinin antigen by s.c. injection. Antibody titers were measured using hemagglutination-inhibition antibody assays before vaccination and 28 days after. The co-primary immunogenicity end-points were the proportion of subjects with antibody titers of 1:40 or more, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in geometric mean titer. We collected 389 pair samples. Antibody titers of 1:40 or more were observed in 148 of 389 subjects (38.0%, 95% CI: 33.2-42.9). The immunogenicity was also confirmed in other end-points, but was not sufficient and was lower than in previous reports. A total of 96 of adverse events was reported: 51 local events and 57 systemic events. There were 12 subjects with both local and systemic events. Nearly all events were mild to moderate except in four subjects. A single 15-μg dose of AH1pdm vaccine did not induce sufficient immunogenicity in HCW, with mild-to-moderate vaccine-associated adverse events. We need to consider further improvement of the AH1pdm vaccine program in HCW for the prevention of nosocomial infection, as well as for the benefit of HCW., (© 2010 The Societies and Blackwell Publishing Asia Pty Ltd.)

Generally, the primary lesion of a mold infection is in the airway, an extravascular site. Therefore, the antifungal drug concentration at the actual tissue lesion of a mold infection is as important as in the blood compartment. Although our antifungal armamentarium has expanded recently, polyenes are still often needed in clinical practice because of their potent fungicidal activity and the rarity of resistance. Nevertheless, the distribution of amphotericin B (AmB) in infected lung tissue has not yet been evaluated. Using high-performance liquid chromatography analysis, we determined the concentrations of AmB in plasma and infected and uninfected tissues of resected lung simultaneously, in a patient with pulmonary aspergillosis treated with liposomal amphotericin B (L-AmB). The AmB concentration in the infected lesion of the lung was approximately 5.2 times higher than that in plasma and 3.7 times higher than in uninfected lung tissue. L-AmB accumulated in the infected lesion of the lung at a higher concentration. Although our data are from only one patient, they may be useful in helping to develop better strategies for the use of L-AmB against pulmonary fungal infections., (Copyright © 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Tuberculosis (TB) control in a low socio-economic society is an important program for urban area of industrialized countries. Some construction workers live in Hanba, a kind of dormitory housings that have crowded living conditions, and possibly give rise to Mycobacterium tuberculosis transmission. The pulmonary tuberculosis detection rate by chest X-ray screening in Hanba is higher than the general population, and therefore TB incidence among Hanba construction worker is also estimated to be as high as that of homeless., Purpose: To analyze the ratio of the TB patients from Hanba in Chiba City from 1993 through 2006, and analyze the treatment outcome and speculate the factors affecting them, especially the effects of the inpatients DOTS (Directly Observed Treatment Short-course) policy introduction after 2001., Methods: TB registration records in the Public Health Center, Chiba City, Japan, were retrospectively analyzed., Results: Pulmonary TB patients from Hanba were 121 (male: 121, female: 0), representing 3.8% of the total 3179 TB patients from 1993 through 2006. Restricting to male patients aged 40-59 years-old, TB patients from Hanba were 78, representing 10.7% of 729 male TB patients of the same age groups. All of TB patients from Hanba developed pulmonary TB (PTB) and treatment outcome of chemotherapy was cured or completed: 69 (57%), defaulted or failed: 43 (36%), and died 9 (7%) respectively. When compared with PTB in Chiba and Japan, defaulted or failed was higher. In the multi-variated analysis, extensive lesions more than one lung (Adjusted odds ratio [AOR]: 0.13, 95% confidence interval [CI]: 0.04-0.37, P < 0.001) and smear-positive (AOR: 0.17, 95% CI: 0.04-0.65, P = 0.009) were negative factor for cured and completed. However, hospitalization during initial period of treatment was positive factor (AOR: 7.92, 95% CI: 1.73-36.2, P = 0.008). After inpatients DOTS introduction, the rate of cured or completed increased from 50% to 67%, and the rate of failed or defaulted decreased from 46% to 22% (P < 0.05)., Conclusion: TB patients from Hanba, a kind of dormitory housings for construction workers, occupied 3.8% of total TB patients in Chiba City. Higher rate of defaulted or failed cases leads to poor treatment outcome in TB patients of Hanba construction workers who were possibly associated with an elevated risk of urban tuberculosis. DOTS might improve adherence to treatment and result in a decrease of failed or defaulted cases.

Fistula between the gallbladder and colon is a rare condition. Even more infrequent is spontaneous resolution of the fistula. We encountered a case of cholecystocolic fistula associated with xanthogranulomatous cholecystitis (XGC) that was diagnosed definitively using CT, MRI, and colonoscopy. An 82-year-old woman with no remarkable medical history presented with fever and right hypochondralgia that had continued for 8 days. Abdominal ultrasound showed a hyperechoic area as air in the lumen of the gallbladder with a hypertrophic wall. Contrast-enhanced CT, with the peripheral layer enhanced homogeneously by contrast medium, indicated air in the gallbladder with a thickened wall. Furthermore, MRI and colonoscopy revealed a fistula between the gallbladder and transverse colon strongly suggested. Those findings suggested cholecystocolic fistula associated with XGC. The patient was treated initially by administration of antibiotics, while fasting. Unfortunately, surgical specimens did not show the fistula, thus it was decided that the existence of cholecystocolic fistula with spontaneous resolution were highly suspected by the clinical course and imaging in this patient.

The track records of the use of anti-methicillin-resistant Staphylococcus aureus agents (anti-MRSA agents) in a 5-year period (2001.4-2006.3) were collected, and cases in which anti-MRSA agents were used for >4 days were selected. In each case, the results of laboratory data and bacterial examination before and after administering the anti-MRSA agents were investigated retrospectively. In addition, it was also investigated in each case whether therapeutic drug monitoring (TDM) was carried out. It was observed that the number of patients treated with anti-MRSA agents and the total dose of anti-MRSA agents used tended to increase over time, except for arbekacin sulfate. It was, however, shown that treatment with anti-MRSA agents resulted in significant decreases in body temperature, C-reactive protein, and white blood cell counts. Bacterial examination was conducted in 75.6% of the patients treated with anti-MRSA agents, with MRSA being detected in 72.4% of the cases examined. On the other hand, TDM was also conducted in 60% of the cases, but this was at a lower percentage than that of the other examinations. Quantitative bacterial examination after treatment with anti-MRSA agents indicates that TDM can be considered important for the appropriate use of anti-MRSA agents.

Setting: University medical school in Japan., Objective: To clarify the influence of prior intradermal purified protein derivative (PPD) injection on QuantiFERON-TB Gold (QFT-G)., Design: Ninety-seven sixth-year university medical students aged 20-29 years concurrently underwent QFT-G and tuberculin skin test (TST). The first negative QFT-G and the first TST <15 mm were followed by a second QFT-G one month later., Results: Five of the 97 (5%) subjects tested positive for the first QFT-G. Thirty-three underwent a second QFT-G, five of whom (15%) turned positive, demonstrating the booster phenomenon of QFT-G., Conclusions: Prior intradermal PPD injection may boost QFT-G. Further studies of the diagnostic significance and immunological mechanisms of this phenomenon are needed. For clinical application, especially during contact screening, QFT-G should be evaluated while keeping in mind the possible influence of prior PPD intradermal injection.

Pathogens of the Aspergillus species are frequently seen in deep-seated mycoses. We previously demonstrated that the culture filtrate of Aspergillus fumigatus (CF) has immunosuppressive effects on polymorphonuclear leukocytes (PMNs), which act as the main phagocytes to hyphae of Aspergillus fumigatus (A. fumigatus). But little is known about the gene expression profiles involved in it. Therefore we investigated the changes in gene expression in human PMNs treated with CF or gliotoxin at two time points, using microarray analysis. CF and gliotoxin changed the expression of 548 and 381 genes, respectively. Only 51 genes showed the same expression patterns with the two stimulants, and CF-induced changes in gene expression occurred comparatively earlier than those induced by gliotoxin. Among 31 genes encoding apoptosis, which were up- or down-regulated in this assay, only 3 genes were similarly changed by both kinds of stimulation. Apoptosis was detected and quantified using two apoptosis assays. CF and gliotoxin changed the expessions of only 3 out of 19 regulated genes related to inflammatory mediators and receptors similarly. The up-regulation of the gene encoding annexin 1 (ANXA1), which is known to be involved in extravasation and apoptosis of neutrophils, may play a role in the immunosuppressive effect of A. fumigatus. The difference in expression changes between CF and gliotoxin is presumed to be caused by the interaction among the components of CF and therefore the interaction is an area of interest for further investigation.

Patients with toxic epidermal necrolysis (TEN) have been known to have various complications. Though pulmonary complications are often observed, they usually show an acute form; however, chronic complications are quite rare and little is known about either their incidences or clinical manifestations. We herein report a 33-year-old man who presented with chronic pulmonary complications after a recovery from TEN. At the onset of TEN, he had severe respiratory failure and artificial ventilation was instituted. Despite being extubated successfully, respiratory failure reappeared 1 month later. A diagnosis of chronic bronchitis with severe obstructive ventilatory impairment and bronchiectasis was made and he was treated with steroids, bronchodilators and antibiotics, however, he died 1.5 years after the onset of TEN. There have been 13 reported cases of chronic pulmonary complications with TEN or Stevens-Johnson syndrome (SJS) in the English published work. Such cases are usually classified into chronic bronchitis/bronchiolitis with obstructive change (including bronchiolitis obliterans and bronchiolitis obliterans organizing pneumonia), respiratory tract obstruction and bronchiectasis. Approximately 40% of all such patients die while the surviving continue to suffer from these complications because no curative therapy yet exists. As a result, the prognosis seems to be poor. The relationship between TEN and these chronic pulmonary complications remains to be elucidated. Interestingly, our patient was asymptomatically anti-Ro/SS-A positive at the onset of TEN. In addition, eccrine gland involvement and an extremely high level of serum salivary amylase were observed at the onset of TEN, furthermore, Sjögren-like symptoms occurred after recovery from TEN. These findings suggested that the Sjögren-like autoimmune abnormalities induced by anti-Ro/SS-A correlated with the development of chronic pulmonary complications in our patient.

Study Objectives: Vascular endothelial growth factor (VEGF) signaling may be required for maintenance of the alveolar structures, and alveolar septal cell apoptosis could contribute to the pathogenesis of COPD presenting emphysematous changes; however, the common mutation at position 936 in the 3' untranslated region of the VEGF gene, a C to T substitution (the C allele was denoted as 1, and the T allele as 2), VEGF936*2, has been reported to be associated with significantly lower VEGF plasma levels. Based on these concepts, we hypothesized that VEGF936*1/2 polymorphism may be linked to the development of COPD., Design: The differences in VEGF936*1/2 allele frequency were examined in 113 patients with smoking-related COPD and two control groups (101 smoker/ex-smoker control subjects and 102 population control subjects) using the polymerase chain reaction-restriction fragment length polymorphism technique., Results: VEGF936*1/2 allele frequencies did not differ among the groups: 0.792/0.208 in COPD patients, 0.822/0.178 in smoker/ex-smoker control subjects, and 0.842/0.152 in population control subjects., Conclusion: The 936 C/T polymorphism of the VEGF gene (including both homozygous and heterozygous) was not associated with the development of COPD (odds ratio, 1.23; 95% confidence interval, 0.760 to 1.995).

Since people have very limited access to informations on TB, Chiba Anti-TB Association started "Chiba Kekkaku Dial 110", free TB consultation service through telephone, fax and e-mail, since October 1997. We received 1453 consultations during three years by September 2000. The most frequent consultations was about tuberculin skin test (TST) that amounted to 383, 26.4% of the all consultations. We reviewed the consultations on TST to know why consultations on TST are so frequent and what are problems clients want to know. We categorized the consultations according to the professions of clients and three periods of TST, that is, before testing, during testing and reading, and post reading. There were 178 (46.5%) consultations from health professionals, 134 (35.0%) from general citizens and the rest of them were from those unknown job. The health professionals were 94 physicians, 34 public health nurses, 23 school nurses, 19 nurses, 2 medical technicians, 2 radiographers and 4 others. Consultation after tuberculin reading was the most frequent: 93 out of 178 consultations from health professionals and 97 out of 134 from general citizens. Especially, difficulty in the interpretation of the reading result was common reason of the consultations in both health professionals (69/93) and general citizens (89/97). They feel difficulties in TST result because of widely practiced BCG revaccination and booster phenomenon due to the repetition of TST. Furthermore, TST reading results vary very much between readers especially in double redness (erythema), and it sometimes affects the diagnosis of tuberculosis infection. Therefore, if repeated TST and BCG revaccination practices in children are abolished, most of those consultations might be solved. When induration measurement is used in TST according to the international standard, the complexity of the classifications of the result seems to be dissolved. Considering the current practices in Japan, we recommend that the size of TST induration should be measured and recorded as we measure and record erythema. And induration should be referred in interpretation when they diagnose TB infection with TST.

Construction workers living in temporal quarters, HANBA, rarely have opportunity to receive the routine health screening program such as that for general inhabitants organized by the local government or that for permanent employees by the employer. Long delay in detecting TB and high drop-out rate from TB treatment among them have been reported. We carried out the following interventions to cope with the problems: In 1999 and 2000, we organized TB screening with X-ray and further examination in the same day when necessary among workers in 6 HANBA in Chiba City. A total of 382 workers were screened, and they also received structured interviews to assess their health-related behaviors and conditions. Four active pulmonary TB cases were detected, and the incidence of 1,047/1,000,000 was forty times higher than that of Chiba City. All four patients were treated and cured. According to the experiences through our intervention, we developed the following recommendations on TB control of construction workers living in HANBA: 1) A system carry out the health examination routinely in the HANBA should be provided, and its implementation be supervised by the public health center and the Labor Standards Inspection Office. 2) It is necessary to guarantee worker's minimum living conditions and medical treatment, and for this regular purpose, close cooperation should be established between clinical service providers and public health, social welfare, and work management authorities. 3) We should start "DOTS" (Directly Observed Treatment Short-Course) not only to the patients in the hospital but also to the outpatients and in the HANBA. To control TB among those workers, further effort is necessary to motivate them to receive basic regular health screening program that is provided in free of charge in Japan.

A case of lung adenocarcinoma and extensive deep vein thrombosis in a patient with Peutz-Jeghers syndrome (PJS) is presented. A 31-year-old Chinese man complained of shoulder pain and swelling of the right arm. A series of diagnostic procedures revealed a primary adenocarcinoma in the left upper lobe with cervical and supraclavicular lymph node metastases accompanied by deep vein thrombosis in the superior vena cava and right jugular vein. In addition, typical pigmentation of the lips and oral mucosa and multiple hamartomas in the stomach, duodenum and colon led to the diagnosis of PJS. PJS is known to be associated with increased risk of malignancies, especially in the gastrointestinal tract, breast, genitals and pancreas. As bronchoscopic examination showed no hamartomatous lesions in the bronchi, the development of primary lung cancer in this young patient might be independent of any hamartomatous lesion and might be associated with some genetic factors relating to PJS.

Study Objectives: Alveolar septal cell apoptosis may contribute to the pathogenesis of emphysema. Because tumor necrosis factor (TNF)-alpha is assumed to play an important role in the induction of apoptosis, and allele 2 of the polymorphism at position--308 in the promoter of the TNF-alpha gene has been associated with alteration of TNF-alpha secretion in vitro, we hypothesized that genotypes containing this allele would show more destructive emphysematous changes of the lung., Design: The percentage ratio of the low attenuation area to the corresponding lung area was evaluated using a visual scoring system for CT findings in patients with COPD (n = 84), and these patients were classified into two groups: those with a visual score < 11 and those with a visual score > or = 11. A polymerase chain reaction-based assay was developed to determine the TNF-alpha genotype (TNF-alpha-308*1/2) between subjects with high and low visual scores on chest CT scans., Results: The TNF-alpha-308*1/2 allele frequency tended to differ between patients with a visual score < 11 (0.90/0.10) and those with a visual score > or = 11 (0.81/0.19) [odds ratio, 2.15; 95% confidence interval, 0.87 to 5.30; p = 0.09]., Conclusion: These results indicate that the TNF-alpha-308 allele 2 may be partly associated with the extent of emphysematous changes in patients with COPD.

Tumor necrosis factor alpha (TNF-alpha), a potent proinflammatory cytokine, may be involved in the development of chronic obstructive pulmonary disease (COPD). The production of TNF-alpha is elevated in the airways of these patients. A polymorphism at position -308 of the TNF-alpha gene promoter (TNF-alpha-308*1/2) is known to be associated with alteration of TNF-alpha secretion in vitro. In this study we examined the differences in TNF-alpha-308*1/2 allele frequency to investigate the association of this polymorphism with the presence of smoking-related COPD. TNF-alpha-308*1/2 allele frequency in 106 patients (73 men and 33 women) was compared with 110 asymptomatic smoker/ex-smoker control subjects matched for sex and age and population control subjects consisting of 129 blood donors. Genotype was analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique on genomic DNA isolated from peripheral blood lymphocytes. TNF-alpha-308*1/2 allele frequencies were significantly different among the groups: 0.835/0.165 in patients with COPD, 0.918/0.082 in smoker/ex-smoker control subjects, and 0.922/0.078 in population control subjects. These results indicate that TNF-alpha-308*1/2 alleles are significantly associated with the presence of smoking-related COPD.

Arborcandins A, B, C, D, E and F, which possess potent 1,3-beta-glucan synthase inhibitory activity, were isolated from the culture broth of a filamentous fungus, strain SANK 17397. Arborcandins are novel cyclic peptides, that are structurally different from known glucan synthase inhibitors such as echinocandins. The 1,3-beta-glucan synthases of Candida albicans and Aspergillus fumigatus were inhibited by arborcandins with IC50 ranging from 0.012 to 3 microg/ml. The apparent Ki value of arborcandin C for C. albicans and A. fumigatus were 0.12 microM and 0.016 microM, respectively. The inhibition against these two 1,3-beta-glucan synthases by arborcandin C was noncompetitive. These compounds exhibited potent fungicidal activity against Candida spp. with MIC ranging from 0.25 to 8 microg/ml. The growth of A. fumigatus was suppressed by arborcandins with concentrations ranging from 0.063 to 4 microg/ml.

Endothelin-1 (ET-1) is a potent vasoactive peptide, and is thought to play an important role in the regulation of pulmonary vascular tone. Previous studies suggested that ET-1 can act as a vasoconstrictor via the endothelin-A and -B 2 receptors located on smooth muscle cells, and also act as a vasodilator through the endothelin-B 1 receptor situated on endothelial cells in the pulmonary circulation. To determine the role of endothelin-B receptors in hypoxic pulmonary hypertension, we examined the hemodynamic effects of a selective endothelin-B receptor agonist (IRL 1620) in chronic hypoxic pulmonary hypertensive rats. In rat lungs perfused with a half-blood solution, vasoconstriction by KCl administration was gradually reversed by IRL 1620 in normoxic rats, but not in chronic hypoxic rats. In in vivo studies, small doses of IRL 1620 induced transient vasodilation in normoxic rats, but had no obvious effects in chronic hypoxic rats. A high dose of IRL 1620 mediated vasoconstriction only in chronic hypoxic rats. Endothelin-B receptor messenger-RNA expression was lower in the lungs of chronic hypoxic rats than in normoxic rats. These results suggested that although the vasodilatory response mediated by endothelin-B receptor can be expected to play a protective role in the development of pulmonary hypertension, that response is diminished in hypoxic pulmonary hypertension.

CDDP/5'-DFUR combination chemotherapy was performed on 17 patients with non-resected and recurrent gastric cancer (clinical stage were IVb in all patients). They were treated with 1,400 mg/m2 of 5'-DFUR on days 1-4 orally following by withdrawal 10 days, every 2 weeks repeatedly and 80 mg/m2 of CDDP (c. i. v., on day 5, every 4 weeks). This chemotherapy was performed for at least 2 courses on all patients. Eight of 17 patients achieved a partial response and the overall response rate was 47.1% (differentiated type 57.1%, undifferentiated type 45.5%). Response rates of each lesion were as follows: primary foci 42.9%, abdominal lymph nodes 57.1%, hepatic metastasis 60.0% and ascites 33.3%, respectively. Improvement of performance status was seen in 12 of 17 patients (70.6%). The overall median survival time was 227 days. The median outpatient period was 113 days. There was no high-grade toxicity over grade 2. Therapeutic toxicity of grade 2 was manifested as renal dysfunction (23.5%), nausea/vomiting (17.6%), leukopenia (5.9%) and anemia (5.9%). We evaluated the therapeutic effect by visual examination after completion of the second course. However, poor effect and high incidence of renal dysfunction were found in patients treated with this therapy over four times. Therefore, the maximum effect seemed to be revealed after completion of the fourth course. From the present study, CDDP/5'-DFUR combination chemotherapy seems to be effective for patients with high-grade advanced gastric cancer and improved their quality of life.

In Japan, BCG vaccination, which covers more than 90% of infants, has been given according to the national immunization policy. Moreover, first-grade children in elementary school are screened with tuberculin skin test, and those who show negative reaction in the Japanese standard, i.e. size of erythema less than 10 mm, are re-vaccinated with BCG according to the Tuberculosis Prevention Law. However, since the incidence of tuberculosis among children below age 14 is as low as 1.5/100,000 in Japan, it is time to reconsider the BCG vaccination policy. As the first step to assess the efficiency of the present program, we observed the occurrence of Koch's phenomenon after BCG vaccination in elementary school children in Chiba City in 1995 and 1996, and we introduced the two-step tuberculin test to elementary school children in 1997. Among 180 BCG vaccinated children in 1995 and 1996, 168 (93.3%) had been vaccinated by 4-year of age. We could follow local reaction of BCG re-vaccination and observed Koch's phenomenon in 117 (69.6%, 95% C.I. of 62.7-76.6%). Among 92 tuberculin negative children in 1997, 85 (92.4%) had been vaccinated by 4-year of age. In the two-step tuberculin test program of 85 initial negative-reactors, 63 (74.1%, 95% C.I. of 64.8-83.4%) turned to positive by the second test. Those results suggest that more than 69% of tuberculin-negative school children who were vaccinated previously maintained immunity with BCG. Our studies raised a problem of the current BCG re-vaccination policy that depends on the result of tuberculin test. Due to the discrepancy between tuberculin allergy and immunity in tuberculosis, many school children may be given BCG vaccination unnecessarily. Taking into consideration the incidence of tuberculosis in children, discontinuation of BCG re-vaccination policy at elementary school entrance should be considered.

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

Endothelin-1 (ET-1) is a potent vasoactive peptide and is thought to play an important role in the regulation of vascular tone. ET-1 can both constrict blood vessels, via endothelin-A (ET-A) receptors in vascular smooth muscle cells, and dilate then via endothelin-B (ET-B) receptors in endothelial cells in the systemic circulation. To determine the role of ET-B receptors in the pulmonary circulation, we examined the hemodynamic effects of a selective ET-B receptor agonist (IRL 1620) in rats. In rat lungs perfused with a salt solution, IRL 1620 caused pulmonary vasoconstriction in a dose-dependent manner. In lungs perfused with a hypoxic half-blood solution (10% O2), doses of IRL 1620 less than 10 nM caused pulmonary vasodilation, but higher doses caused pulmonary vasoconstriction. IRL 1620 caused transient vasodilation of the systemic circulation at every dose used (0.1, 1, and 5 nmol/kg) in anesthetized rats. In contrast, the effects of IRL 1620 on the pulmonary circulation varied with the dose. Small doses (0.1 or 1 nmol/kg) caused pulmonary vasodilation, but a higher dose (5 nmol/kg) caused pulmonary vasoconstriction. These results show tachyphylaxis in the pulmonary vasodilator response to IRL 1620, but not in the systemic vasodilator response. The present data show the dual action (vasoconstriction and vasodilation) of ET-B receptors.

Chronic hypoxia (10% O2 for 2-3 weeks) causes pulmonary hypertension and vascular remodeling in the rat. To study the role of thromboxase A2 in chronic hypoxic pulmonary hypertension, the hemodynamic effects of intravenous administration of a thromboxane analogue (STA2) were measured in chronic hypoxic (H) and normoxic (N) Sprague-Dawley rats. During anesthesia baseline pulmonary arterial pressure (PAP) was higher in H rats (34.6 +/- 1.0 mmHg) than in N rats (18.4 +/- 1.2 mmHg). Intravenous STA2 (0.3 microgram) acutely increased pulmonary artery pressure by 74% +/- 11% (25 +/- 4 mmHg) in H rats and by 47% +/- 2% (9 +/- 1 mmHg) in N rats, which indicates that both the absolute and relative acute pulmonary vasoconstriction caused by STA2 were greater in H rats. The changes in systemic arterial pressure caused by STA2 were smaller than the changes in pulmonary arterial pressure both in H rats (11% +/- 3%) and in N rats (17% +/- 3%). Lungs were isolated and perfused with saline, and the vasoconstrictive response to 0.05 microgram of STA2 in lungs (14.5 +/- 2.4 mmHg) from H rats was greater than the response to 0.1 microgram of STA2 (5.6 +/- 1.3 mmHg) in lungs from N rats. To examine whether blockade of calcium channels could suppress the vasoconstrictor response to STA2, the effects of the calcium channel blocker nicardipine hydrochloride on vasoconstriction caused by STA2 were measured in H and N rats. In vivo, the blockade of calcium channels suppressed the increase in pulmonary artery pressure caused by STA2. This suppression was greater in H rats (56% +/- 11%) than in N rats (25% +/- 4%). Similar results were obtained with isolated perfused lungs. Blockade of calcium channels suppressed the vasoconstriction caused by STA2 and this suppression was greater in H rats than in N rats. The finding that thromboxane A2 induced greater vasoconstriction in H rats than in N rats indicates that thromboxane A2 may play an important role in pulmonary hypertension, and suggests that blockade thromboxane A2 may benefit some patients with primary and secondary pulmonary hypertension. Furthermore, the finding that suppression of thromboxane-induced vasoconstriction by blockade of calcium channels was greater in H rats than in N rats indicates that such treatment may also benefit some patients.

In the past eight years, we experienced 94 cases of nontuberculous mycobacteria (NTM) isolation from the specimens of sputum, gastric juice, pleural fluid and fiberoptic bronchoscopic procedure at Chiba Kaihin Municipal Hospital. The species of NTM were M. avium complex (MAC) in 23, M. gordonae in 15, M. kansasii in 12, M. fortuitum in 8, M. chelonae in 7, etc.. The number of isolation of NTM has increased, and it is worthwhile to mention that it had exceeded the number of isolation of M. tuberculosis since 1991. We experienced 28 cases of pulmonary infections caused by NTM during the same period. Thirteen cases were by M. avium complex, 11 cases by M. kansasii, one case by MAC and M. kansasii, one case by M. chelonae and two cases by unidentified NTM. Pulmonary infections by NTM also gradually increased. Thirteen cases (46.4%) had underlying diseases in the respiratory system. Most of them were progressive diseases with cavities and were easily diagnosed by mycobacterial examinations of the specimens such as sputum or gastric juice. We were unable to diagnose 12 cases (42.9%) by mycobacterial examinations. Most of them had no underlying diseases and showed small lesions without cavitation on the chest X-ray. Eight cases were diagnosed by the histopathological examination of TBLB (transbronchial lung biopsy) specimens. In such cases, these procedures were also useful for the early diagnosis. This study indicated the increase of the isolation of NTM and the pulmonary infections by NTM. Once the infections are established, they are progressive, and the early diagnosis of these infections are thought to be important.

A 28 year-old man was admitted to our hospital because of fever, cough and chest pain. A chest X-ray film taken on admission showed infiltrate in the left upper lung field with ipsilateral pleural effusion. Microscopical examinations of stained specimens of sputa and pleural effusions disclosed no acid-fast bacilli. The level of adenosine deaminase (ADA) in pleural effusion was 46.4 IU/l. A tuberculin skin test was moderately positive. The most probable diagnosis was pulmonary tuberculosis with pleural effusion. Isoniazid (INH) and rifampicin (RFP) were administered on the 5th hospital day and continued to lower the fever and reduce the pleural effusion. The cultured specimens of sputa and pleural effusions yielded Mycobacterium kansasii. After six months of treatment, chest X-ray film showed improvement and the administration of INH, RFP was discontinued without recurrence.

We conducted a study on the diagnosis of pulmonary tuberculosis at Chiba Kaihin Municipal Hospital. Examinations were performed to determine the presence of active Mycobacterium tuberculosis in sputum and gastric aspirate. For the sputum smear-negative cases, fiberoptic bronchoscopy was further used as a means for detecting the tuberculosis. The results obtained were as follows: 1. A total of 114 cases in the past six years diagnosed as active pulmonary tuberculosis (including 88 primary treatment cases) were analysed. 2. The 114 cases consisted of 74 males and 40 females, the mean age was 49.3 years old. Categorically, the main age groups were: 60s, 24 cases; 30s, 21 cases; and 40s, 20 cases. 3. Chest X-ray findings: Cavitary cases were 28.9% GAKKAI classification of the sizes of the affected areas being Type 1 (mostly limited cases), 58.9% of all total cases, and 68.4% in the cases under the age of 50 years old. The number of cases having infection in a solitary nodule was 19, and the ages of 15 out of the 19 patients were under 50 years old. 4. Sputum or gastric aspirate smear-positive cases totalled 37 (32.5%), and culture-positive cases totalled 77 (67.5%). Sputum or gastric aspirate cultures were positive in 52 out of 56 cases (92.9%) with extended shadows, GAKKAI classification Types 2 and 3, but were positive in 25 out of 58 cases (43.1%) with Type 1. 5. Fiberoptic bronchoscopy was performed on 49 out of the 77 smear-negative cases. 6. Definite diagnosis was obtained in 90 (78.8%) out of total 114 cases. The results of this study suggest that examination for active mycobacterium in sputum and gastric aspirate are very useful for the diagnosis of active pulmonary tuberculosis, especially in extended cases.

In an open, multicenter trial, we investigated the clinical efficacy of a combination therapy of ceftazidime (CAZ) and tobramycin (TOB) for intractable pulmonary infections mainly caused by Pseudomonas aeruginosa. Evaluated for the utility of the combination therapy were 33 cases with pneumonia (Group I: pneumonia caused by P. aeruginosa 15, Group II: pneumonia caused by other Gram-negative bacilli 4 and pneumonia which causative organism was not determined 14) and 23 cases with chronic respiratory tract infection caused by P. aeruginosa. The results obtained are summarized as follows. 1. In Group I pneumonia, included 11 severe cases and 4 moderate cases, with a mean age of 69.3 years. Significant underlying diseases were present in 14 out of the 15 (93.3%): they included 10 cases of pulmonary diseases and 4 cerebrovascular diseases. The overall efficacy rate in these cases was 60.0%: but the efficacy rate in moderate cases was 100% and that in severe cases was 45.5%. 2. In Group II pneumonia included 16 severe cases and 2 moderate cases with a mean age of 68.2 years. Significant underlying diseases were present in 15 out of 18 (83.3%, all of the underlying diseases were pulmonary diseases) and the overall efficacy rate was 72.2% with 100% efficacy rate among moderate cases and 68.8% among severe cases. 3. In the cases with chronic respiratory tract infections caused by P. aeruginosa, the efficacy rate was 82.6% and the eradication rate was 65.2%. We consider the combination therapy of CAZ and TOB is useful for intractable pulmonary infections caused by P. aeruginosa.

Correct assessment of lymph node metastasis in the head-neck region is very important for management of head and neck cancer. 233 lymph nodes were removed by radical neck dissection from 12 cases with cancer in the head and neck region, who did not undergo any preoperative treatment, and the materials were histopathologically examined. The histopathological findings were compared with preoperative US and CT findings. Histopathologically, 26 lymph nodes were found positive for metastasis and the remaining 207 lymph nodes, negative. US detected 45 (19%) of 233 lymph nodes before operation, and 40 of the 45 lymph nodes (89% : 40/45) were qualitatively correctly diagnosed. CT detected 21 lymph nodes (19%), 16 of which were qualitatively correctly diagnosed (76% : 16/21). Of 26 lymph nodes which were histopathologically involved, 19 lymph nodes were correctly diagnosed by US and 11 by CT. Possible reasons explaining the superiority of US to CT in terms of diagnostic reliability are the following: 1) US demonstrates more clearly the existence of lymph nodes than CT. 2) US is more reliable for measuring sizes of lymph nodes than CT. In literature, CT has been often reported to be useful to diagnose cervical lymph node involvement in individual cases. However, we insist that it is necessary to diagnose individual lymph nodes strictly for correct assessment of the reliability of image diagnosis.