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Wada T.,Japan Institute for Environmental Sciences | Iwamoto T.,Kobe Institute of Health | Hase A.,Japan Institute for Environmental Sciences | Maeda S.,The Research Institute of Tuberculosis
Infection, Genetics and Evolution | Year: 2012

The Beijing family is an endemic lineage of Mycobacterium tuberculosis in eastern Asia. In Japan, five evolutionarily sequential sublineages composing the lineage have predominated. Comparative genomic sequencing based on a microarray technique was conducted for five representative strains of those respective sublineages. Results revealed approximately 200 point mutations specific to each strain. Subsequently, to investigate the genetic diversity of each sublineage, we analysed the phylogenetic divergence of 103 domestic strains belonging to them using genetic markers derived from the mutation information. Results show that the five sublineages have comprised smaller lineages which had diverged at various points. The smaller sub-sublineages have emerged with respective bottlenecks, which are reflected in the excessive monophyletic evolution of the species. Our data provide necessary information to grasp a comprehensive picture of genetic diversity of the lineage constructed in its evolution. © 2012 Elsevier B.V.

PubMed | National Hospital Organization, Fukujuji Hospital and, Keio University, National Center for Global Health and Medicine and 2 more.
Type: Journal Article | Journal: Annals of the American Thoracic Society | Year: 2016

The management of macrolide-resistant Mycobacterium avium complex (MR-MAC) pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB).This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB.The medical records of 102 consecutive cases with MR-MAC pulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014 were reviewed. The data of 311 consecutive cases with MDR-TB were extracted from the medical data at Fukujuji Hospital.Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P=0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P=0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC.Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

Murase Y.,The Research Institute of Tuberculosis
Nihon rinsho. Japanese journal of clinical medicine | Year: 2011

This review summarized recent findings on lineage-specific characteristics of Mycobacterium tuberculosis. M. tuberculosis is more generically diverse than previously assumed, and it is expected that such genetic diversity may influence on both clinical and epidemiological aspects of tuberculosis diseases. In Japan, approximately 75% of clinical isolates belongs to the Beijing family genotype, which is highly prevalent throughout East Asia. Beijing strains have been emerging in some other areas with drug resistance and genetic homogeneity, suggesting their selective advantages over other lineages of M. tuberculosis. More frequent distribution of modern type of Beijing strains among both younger and homeless people in Japan may reflect their recent epidemics. Further studies are needed to reveal the mechanisms underlying the lineage-specific characteristics, and these will offer new insights into future tuberculosis control.

Higuchi K.,The Research Institute of Tuberculosis
Nihon rinsho. Japanese journal of clinical medicine | Year: 2011

At present, there are only two methods to diagnose tuberculosis infection in the world, tuberculin skin test (TST) and interferon gamma release assays (IGRAs). Since TST could show positive responses due to BCG vaccination or infection of non-tuberculous mycobacterium and BCG vaccination is widely done in Japan, TST has a critical problem in its specificity. QuantiFERON-TB Gold (QFT-G/QFT-3G) is one of IGRAs and uses M. tuberculosis-specific antigens (ESAT-6, CFP-10, TB7.7) for stimulation of whole blood to induce IFN-gamma production by antigen-specific T cells. Produced IFN-gamma is measured by ELISA system. IFN-gamma is produced by individuals with TB infection but not by BCG-vaccinated individuals without TB infection. As QFT can detect TB infection among BCG vaccinated individuals more accurately than TST, it is possible to diagnose TB infection efficiently in contact investigation so on. However, as same as TST, QFT cannot discriminate between remote infection and recent infection, nor between progressive infection and controllable recent infection. Since QFT is newly development TB diagnosis test, there are many subjects in the QFT test system. For example, one subject is that accurate QFT results among immunocompromised populations are difficult to obtain because of weak immune responses. After these many research data are accumulated, we will be able to have many solutions in QFT.

Shi R.,Henan Provincial Chest Hospital | Sugawara I.,The Research Institute of Tuberculosis
Tohoku Journal of Experimental Medicine | Year: 2010

Mycobacterium tuberculosis, the causative agent of tuberculosis, is a tenacious and remarkably successfulpathogen that has latently infected one third of the world's population, according to the World Health Organization (WHO) statistics. It is anticipated that 10% of these infected individuals will develop active tuberculosis at some point in their lifetime. The long-term use of the current drug regimen, the emergence of drug-resistant strains, and HIV co-infection have resulted in a resurgence of research efforts to address the urgent need for new anti-tuberculosis drugs. A number of potential candidate drugs with novel modes of action have entered clinical trials in recent years, and these are likely to be effective against antituberculosis drug-resistant strains. They include neuroquinolone derivatives, a modified ethambutol, nitroimidazole groups and so on. This mini-review summarizes the latest information about eight new antituberculosis drug candidates and describes their activities, pharmacokinetics, mechanisms of action, and mechanisms of drug-resistance induced by these drug candidates. © 2010 Tohoku University Medical Press.

Ohmori M.,The Research Institute of Tuberculosis
Kekkaku : [Tuberculosis] | Year: 2012

The nationwide computerized tuberculosis (TB) surveillance system was revised in 2007. It was developed to be user-friendly and to allow the evaluation of current TB problems and control issues in Japan. All public health centers in Japan (518 as of April 2007) have system terminals connected to a central computer, and the data entered at these terminals are sent to the online central computer excluding personal identification data. All the figures and tables in this paper were created using the annual report database which are compiled from this system. The revision in 2007 added many new functions to the system, such as a function for automatically sending data upon transfer. The monitoring information for assisting case management of TB patients by the DOTS was also enhanced. The algorithm for classifying treatment outcomes automatically based on data entered regarding cancellations from registration, bacteriological results and drug usage each month was revised. The proportion of "Failed" and "Defaulted" combined was 4.6% among new sputum smear positive pulmonary TB patients newly registered in 2009, while "Died" accounted for as high as 19.3%, due largely to a high percentage of the elderly. A new system for contact examination management is provided as a subsystem. Feedback of data analyses has been strengthened by various methods. This TB surveillance system is indispensable for implementing the evidence-based TB control program in Japan. An important role of the Research Institute of Tuberculosis is to support the planning and execution of TB control with provision of useful epidemiological information from the system.

Recently, a genome-wide screening identified a functional single-nucleotide polymorphism in dual-specificity phosphatase 14 gene (DUSP14), which was associated with pulmonary tuberculosis (TB) in a West African study. DUSP14 regulates T-cell proliferation and cytokine production in a negative way via dephosphorylation and inactivation of key signaling molecules. The aim of this study is to further explore the possible significance of the DUSP14 polymorphism. Total RNA was extracted from the whole blood of 109 healthcare workers (HCWs) in Vietnam and subjected to quantitative reverse-transcription PCR for DUSP14 and 20 immune-related genes. DUSP14 rs1051838 was genotyped in 502 new pulmonary TB patients and 506 healthy controls. Among disease-free individuals (HCWs), T-helper type-1 (Th1)-related genes, interferon-gamma receptor 2 (IFNGR2) and signal transducer and activator of transcription-1 (STAT1) mRNA levels significantly increased as the number of A alleles of rs1051838 increased, whereas the DUSP14 mRNA level tended to decrease. The AA genotype was associated with protection against active TB in younger patients (⩽45 years old, OR=0.63, 95% CI 0.44–0.90). Our results suggest that a low-expression genotype of DUSP14 accompanied by high transcript levels of Th1 immune-related genes may confer protection against early TB development.Genes and Immunity advance online publication, 3 March 2016; doi:10.1038/gene.2016.11. © 2016 Macmillan Publishers Limited

PubMed | SRL Inc., BML Inc., LSI Corporation, Keio University and 4 more.
Type: | Journal: Annals of the American Thoracic Society | Year: 2016

Since 2010, studies that utilize mycobacterial examination results have been widely used to survey nontuberculous mycobacterial (NTM) lung disease.Our study aims to reveal the clinical and epidemiological status of NTM lung disease in Japan.All data on the isolation and identification of mycobacteria in 2012 and 2013 were obtained from three dominant commercial laboratories in Japan. Pulmonary disease were defined based on the bacteriological diagnostic criteria issued by the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA). The coverage population was estimated using the ratio between national tuberculosis registration data and laboratory results for each of the eight regions.A total of 113,313 mycobacterial specimens from 4,710 institutes were collected, of which specimens from 26,059 patients tested positive for NTM cultures at least once. Among these positive patients, 7,167 (27.5%) satisfied the ATS/IDSA criteria for NTM lung disease, resulting in a 2-year prevalence rate of 24.0 per 100,000. Mycobacterium avium complex (MAC) was the most commonly isolated species (93.3%), and 29.0% of the patients in which MAC was isolated satisfied the criteria for NTM lung disease. Individuals older than 70 years of age accounted for the majority of cases, and 65.5% of cases involved females. After MAC, M. kansasii and M. abscessus exhibited the highest (43.6%) and second-highest (37.1%) incidences per isolation, respectively. The prevalence of M. kansasii was highest in the Kinki region (p < 0.05), and M. abscessus had the greatest prevalence in the Kyushu-Okinawa region (p < 0.005). The proportion of M. intracellulare in MAC cases was higher in the southwestern part of Japan than in other regions. The period prevalence was highest in the southwestern part of Japan, and the standardized prevalence ratio was highest in central regions. Evaluations of clarithromycin susceptibility revealed a clear binomial distribution.This investigation is the first laboratory-based study that assessed a large number of mycobacterial cases in Japan. Although the calculated prevalence might be underestimated, the approach used here could be a useful and relatively timely method for monitoring relative epidemiological data for NTM lung disease.

PubMed | The Research Institute of Tuberculosis, Japan National Institute of Infectious Diseases and Japan BCG Laboratory
Type: Journal Article | Journal: Vaccine | Year: 2016

Enhancement of the T cell-stimulating ability of Mycobacterium bovis BCG (BCG) is necessary to develop an effective tuberculosis vaccine. For this purpose, we introduced the PEST-HSP70-major membrane protein-II (MMPII)-PEST fusion gene into ureC-gene depleted recombinant (r) BCG to produce BCG-PEST. The PEST sequence is involved in the proteasomal processing of antigens. BCG-PEST secreted the PEST-HSP70-MMPII-PEST fusion protein and more efficiently activated human monocyte-derived dendritic cells (DCs) in terms of phenotypic changes and cytokine productions than an empty-vector-introduced BCG or HSP70-MMPII gene-introduced ureC gene-depleted BCG (BCG-DHTM). Autologous human nave CD8

PubMed | A-Life Medical, YARSI University, The University of Tokyo, University of Tokyo and 3 more.
Type: | Journal: Human genome variation | Year: 2016

Tuberculosis (TB) is a complex disease, and both genetic and environmental factors contribute to disease progression. A previous genome-wide linkage study in Thailand determined that chromosome 20p13-12.3 may contain risk factors for young-onset disease. The present study aimed to identify novel susceptibility genes for young-onset TB within a 1-Mbp target region adjacent to the top-ranking risk marker in Chr.20p13-12.3. We performed next-generation sequencing (NGS) of the region in 13 young patients from multi-case families in Thailand. We then selected the functionally interesting single-nucleotide polymorphisms as candidates for subsequent analyses. The detected candidates rs13830 and rs1127354 in ITPA showed an association with young (<45 years old) TB patients. However, there was no association in old (45 years old) patients. These findings confirm that stratifying patients based on age of TB onset can be important for identifying genetic risk factors for TB susceptibility. In addition, in silico expression quantitative trait loci analyses indicated that ITPA expression was associated with rs13830 genotype. This is the first study to use NGS resequencing to gain insight into host genetic factors associated with TB and to report a significant association for ITPA with host susceptibility in young-onset TB. The study also demonstrated the effectiveness of NGS in identifying susceptibility genes in common diseases.

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