Tuberculosis in older adults: case studies from four countries with rapidly ageing populations in the western pacific region.

BACKGROUND: The Western Pacific Region has one of the fastest-growing populations of older adults (≥ 65 years) globally, among whom tuberculosis (TB) poses a particular concern. This study reports country case studies from China, Japan, the Republic of Korea, and Singapore reflecting on their experiences in managing TB among older adults. FINDINGS: Across all four countries, TB case notification and incidence rates were highest among older adults, but clinical and public health guidance focused on this population was limited. Individual country reports illustrated a range of practices and challenges. Passive case finding remains the norm, with limited active case finding (ACF) programs implemented in China, Japan, and the Republic of Korea. Different approaches have been trialled to assist older adults in securing an early diagnosis, as well as adhering to their TB treatment. All countries emphasised the need for person-centred approaches that include the creative application of new technology and tailored incentive programs, as well as reconceptualisation of how we provide treatment support. The use of traditional medicines was found to be culturally entrenched among older adults, with a need for careful consideration of their complementary use. TB infection testing and the provision of TB preventive treatment (TPT) were underutilised with highly variable practice. CONCLUSION: Older adults require specific consideration in TB response policies, given the burgeoning aging population and their high TB risk. Policymakers, TB programs and funders must invest in and develop locally contextualised practice guidelines to inform evidence-based TB prevention and care practices for older adults.

Predicting the risk of pulmonary tuberculosis based on the neutrophil-to-lymphocyte ratio at TB screening in HIV-infected individuals.

BACKGROUND: The neutrophil to lymphocyte ratio (NL ratio) has been reported to be a predictive biomarker of tuberculosis (TB). We assessed the association between the NL ratio and the incidence of active TB cases within 1 year after TB screening among HIV-infected individuals in Thailand. METHODS: A day care center that supports HIV-infected individuals in northernmost Thailand performed TB screening and follow-up visits. We compared the baseline characteristics between the TB screening positive group and the TB screening negative group. The threshold value of NL ratio was determined by cubic-spline curves and NL ratios were categorized as high or low NL ratio. We assessed the association between NL ratio and progression to active TB within 1-year using the Cox-proportional hazard model. RESULTS: Of the 1064 HIV-infected individuals who screened negative for TB at baseline, 5.6% (N = 60) eventually developed TB and 26 died after TB diagnosis. A high NL ratio was associated with a higher risk of TB (adjusted hazard ratio (aHR) 2.19, 95% CI: 1.23-3.90), after adjusting for age, sex, ethnicity, CD4 counts, and other risk factors. A high NL ratio in HIV-infected individuals with normal chest X-ray predicted TB development risk. In particular, a high NL ratio with TB symptoms could predict the highest risk of TB development (aHR 2.58, 95%CI: 1.07-6.23). CONCLUSIONS: Our results showed that high NL ratio increased the risk of TB. NL ratio combined with TB symptoms could increase the accuracy of TB screening among HIV-infected individuals.

Cross-sectional studies of tuberculosis prevalence in Cambodia between 2002 and 2011.

OBJECTIVE: To measure trends in the pulmonary tuberculosis burden between 2002 and 2011 and to assess the impact of the DOTS (directly observed treatment, short-course) strategy in Cambodia. METHODS: Cambodia's first population-based nationwide tuberculosis survey, based on multistage cluster sampling, was conducted in 2002. The second tuberculosis survey, encompassing 62 clusters, followed in 2011. Participants aged 15 years or older were screened for active pulmonary tuberculosis with chest radiography and/or for tuberculosis symptoms. For diagnostic confirmation, sputum smear and culture were conducted on those whose screening results were positive. FINDINGS: Of the 40,423 eligible subjects, 37,417 (92.6%) participated in the survey; 103 smear-positive cases and 211 smear-negative, culture-positive cases were identified. The weighted prevalences of smear-positive tuberculosis and bacteriologically-positive tuberculosis were 271 (95% confidence interval, CI: 212-348) and 831 (95% CI: 707-977) per 100,000 population, respectively. Tuberculosis prevalence was higher in men than women and increased with age. A 38% decline in smear-positive tuberculosis (P = 0.0085) was observed with respect to the 2002 survey, after participants were matched by demographic and geographical characteristics. The prevalence of symptomatic, smear-positive tuberculosis decreased by 56% (P = 0.001), whereas the prevalence of asymptomatic, smear-positive tuberculosis decreased by only 7% (P = 0.7249). CONCLUSION: The tuberculosis burden in Cambodia has declined significantly, most probably because of the decentralization of DOTS to health centres. To further reduce the tuberculosis burden in Cambodia, tuberculosis control should be strengthened and should focus on identifying cases without symptoms and in the middle-aged and elderly population.

Applicability of artificial intelligence-based computer-aided detection (AI-CAD) for pulmonary tuberculosis to community-based active case finding.

BACKGROUND: Artificial intelligence-based computer-aided detection (AI-CAD) for tuberculosis (TB) has become commercially available and several studies have been conducted to evaluate the performance of AI-CAD for pulmonary tuberculosis (TB) in clinical settings. However, little is known about its applicability to community-based active case-finding (ACF) for TB. METHODS: We analysed an anonymized data set obtained from a community-based ACF in Cambodia, targeting persons aged 55 years or over, persons with any TB symptoms, such as chronic cough, and persons at risk of TB, including household contacts. All of the participants in the ACF were screened by chest radiography (CXR) by Cambodian doctors, followed by Xpert test when they were eligible for sputum examination. Interpretation by an experienced chest physician and abnormality scoring by a newly developed AI-CAD were retrospectively conducted for the CXR images. With a reference of Xpert-positive TB or human interpretations, receiver operating characteristic (ROC) curves were drawn to evaluate the AI-CAD performance by area under the ROC curve (AUROC). In addition, its applicability to community-based ACFs in Cambodia was examined. RESULTS: TB scores of the AI-CAD were significantly associated with the CXR classifications as indicated by the severity of TB disease, and its AUROC as the bacteriological reference was 0.86 (95% confidence interval 0.83-0.89). Using a threshold for triage purposes, the human reading and bacteriological examination needed fell to 21% and 15%, respectively, detecting 95% of Xpert-positive TB in ACF. For screening purposes, we could detect 98% of Xpert-positive TB cases. CONCLUSIONS: AI-CAD is applicable to community-based ACF in high TB burden settings, where experienced human readers for CXR images are scarce. The use of AI-CAD in developing countries has the potential to expand CXR screening in community-based ACFs, with a substantial decrease in the workload on human readers and laboratory labour. Further studies are needed to generalize the results to other countries by increasing the sample size and comparing the AI-CAD performance with that of more human readers.

Analysis of tuberculosis prevalence surveys: new guidance on best-practice methods.

BACKGROUND: An unprecedented number of nationwide tuberculosis (TB) prevalence surveys will be implemented between 2010 and 2015, to better estimate the burden of disease caused by TB and assess whether global targets for TB control set for 2015 are achieved. It is crucial that results are analysed using best-practice methods. OBJECTIVE: To provide new theoretical and practical guidance on best-practice methods for the analysis of TB prevalence surveys, including analyses at the individual as well as cluster level and correction for biases arising from missing data. ANALYTIC METHODS: TB prevalence surveys have a cluster sample survey design; typically 50-100 clusters are selected, with 400-1000 eligible individuals in each cluster. The strategy recommended by the World Health Organization (WHO) for diagnosing pulmonary TB in a nationwide survey is symptom and chest X-ray screening, followed by smear microscopy and culture examinations for those with an abnormal X-ray and/or TB symptoms. Three possible methods of analysis are described and explained. Method 1 is restricted to participants, and individuals with missing data on smear and/or culture results are excluded. Method 2 includes all eligible individuals irrespective of participation, through multiple missing value imputation. Method 3 is restricted to participants, with multiple missing value imputation for individuals with missing smear and/or culture results, and inverse probability weighting to represent all eligible individuals. The results for each method are then compared and illustrated using data from the 2007 national TB prevalence survey in the Philippines. Simulation studies are used to investigate the performance of each method. KEY FINDINGS: A cluster-level analysis, and Methods 1 and 2, gave similar prevalence estimates (660 per 100,000 aged ≥ 10 years old), with a higher estimate using Method 3 (680 per 100,000). Simulation studies for each of 4 plausible scenarios show that Method 3 performs best, with Method 1 systematically underestimating TB prevalence by around 10%. CONCLUSION: Both cluster-level and individual-level analyses should be conducted, and individual-level analyses should be conducted both with and without multiple missing value imputation. Method 3 is the safest approach to correct the bias introduced by missing data and provides the single best estimate of TB prevalence at the population level.

Drug resistance and IS6110-RFLP patterns of Mycobacterium tuberculosis in patients with recurrent tuberculosis in northern Thailand.

The emergence of drug resistant Mycobacterium tuberculosis has become a global threat to tuberculosis (TB) prevention and control efforts. This study aimed to determine the drug resistance profiles and DNA fingerprints of M. tuberculosis strains isolated from patients with relapsed or retreatment pulmonary TB in Chiang Rai province in northern Thailand. Significant differences in multidrug resistance (MDR) (P = 0.025) and resistance to isoniazid (P = 0.025) and rifampin (P = 0.046) between first and second registrations of patients with retreatment TB were found. However, there were no significant differences in resistance to any drugs in patients with relapsed TB. The rate of MDR-TB strains was 12.2% among new patients at first registration, 22.5% among patients with recurrence who had previously undergone treatment at second registration and 12.5% at third registration. Two retreatment patients whose initial treatment had failed had developed MDR-TB with resistance to all TB drugs tested, including rifampin, isoniazid, streptomycin and ethambutol. IS6110-RFLP analysis revealed that 66.7% (10/15 isolates) of MDR-TB belonged to the Beijing family. In most cases, IS6110-RFLP patterns of isolates from the same patients were identical in relapse and retreatment groups. However, some pairs of isolates from retreatment patients after treatment failure had non-identical IS6110-RFLP patterns. These results suggest that, after failure and default treatment, patients with retreatment tuberculosis have a significantly greater risk of MDR-TB, isoniazid and rifampin resistance than do other patients.

Potential function of granulysin, other related effector molecules and lymphocyte subsets in patients with TB and HIV/TB coinfection.

BACKGROUND: Host effector mechanism against Mycobacterium tuberculosis (Mtb) infection is dependent on innate immune response by macrophages and neutrophils and the alterations in balanced adaptive immunity. Coordinated release of cytolytic effector molecules from NK cells and effector T cells and the subsequent granule-associated killing of infected cells have been documented; however, their role in clinical tuberculosis (TB) is still controversy. OBJECTIVE: To investigate whether circulating granulysin and other effector molecules are associated with the number of NK cells, iNKT cells, Vγ9(+)Vδ2(+) T cells, CD4(+) T cells and CD8(+) T cells, and such association influences the clinical outcome of the disease in patients with pulmonary TB and HIV/TB coinfection. METHODS: Circulating granulysin, perforin, granzyme-B and IFN-γ levels were determined by ELISA. The isoforms of granulysin were analyzed by Western blot analysis. The effector cells were analyzed by flow cytometry. RESULTS: Circulating granulysin and perforin levels in TB patients were lower than healthy controls, whereas the granulysin levels in HIV/TB coinfection were much higher than in any other groups, TB and HIV with or without receiving HAART, which corresponded to the number of CD8(+) T cells which kept high, but not with NK cells and other possible cellular sources of granulysin. In addition, the 17kDa, 15kDa and 9kDa isoforms of granulysin were recognized in plasma of HIV/TB coinfection. Increased granulysin and decreased IFN-γ levels in HIV/TB coinfection and TB after completion of anti-TB therapy were observed. CONCLUSION: The results suggested that the alteration of circulating granulysin has potential function in host immune response against TB and HIV/TB coinfection. This is the first demonstration so far of granulysin in HIV/TB coinfection.

Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis.

Tuberculosis (TB) is one of the most devastating chronic infectious diseases, but the role of host genetics in disease development after infection in this disease remains unidentified. Genome-wide association studies (GWASs) in Thais and Japanese were carried out and separately analyzed, attempted replication, then, combined by meta-analysis were not yielding any convincing association evidences; these results suggested that moderate to high effect-size genetic risks are not existed for TB per se. Because of failure in replication attempt of the top 50 single-nucleotide polymorphisms (SNPs) identified form meta-analysis data, we empirically split TB cases into young TB case/control data sets (GWAS-T(young)=137/295 and GWAS-J(young)=60/249) and old TB case/control data sets (GWAS-T(old)=300/295 and GWAS-J(old)=123/685), re-analyzed GWAS based on age-stratified data and replicated the significant findings in two independent replication samples (young TB; Rep-T(young)=155/249, Rep-J(young)=41/462 and old TB; Rep-T(old)=212/187, Rep-J(old)=71/619). GWAS and replication studies conducted in young TB identified at-risk locus in 20q12. Although the locus is located in inter-genic region, the nearest genes (HSPEP1-MAFB) from this locus are promising candidates for TB susceptibility. This locus was also associated with anti-TNF responsiveness, drug with increased susceptibility for TB. Moreover, eight SNPs in an old TB meta-analysis and six SNPs in young TB meta-analysis provided replication evidences but did not survive genome-wide significance.These findings suggest that host genetic risks for TB are affected by age at onset of TB, and this approach may accelerate the identification of the major host factors that affect TB in human populations.

Social factors affecting ART adherence in rural settings in Zambia.

The purpose of this study was to assess the factors that influence ART adherence arising in rural settings in Zambia. A survey was conducted with face-to-face interviews using a semi-structured questionnaire and written informed consent was obtained at ART sites in Mumbwa District in rural Zambia. The questionnaire included items such as the socio-demographic characteristics of respondents, support for adherence, ways to remember when to take ARVs at scheduled times, and the current status of adherence. Valid responses were obtained from 518 research participants. The mean age of the respondents was 38.3 years and the average treatment period was 12.5 months. More than half of the respondents (51%) were farmers, about half (49%) did not own a watch, and 10% of them used the position of the sun to remember when to take ARVs. Sixteen percent of respondents experienced fear of stigma resulting from taking ARVs at work or home, and 10% felt pressured to share ARVs with someone. Eighty-eight percent of the participants reported that they had never missed ARVs in the past four days. Multivariable logistic regression analysis identified age (38 years old or less, odds ratio (OR) = 2.5, 95% confidence interval (CI): 1.3-4.8, p=0.005), "remembering when to take ARVs based on the position of the sun" (OR = 3.3, 95% CI: 1.3-8.8, p=0.016), and "feeling pressured to share ARVs with someone" (OR = 4.4, 95% CI: 1.6-12.0, p=0.004) as independent factors for low adherence. As ART services expand to rural areas, program implementers should pay more attention to more specific factors arising in rural settings since they may differ from those in urban settings.

Decreased plasma granulysin and increased interferon-gamma concentrations in patients with newly diagnosed and relapsed tuberculosis.

Granulysin and interferon-gamma (IFN-γ) have broad antimicrobial activity which controls Mycobacterium tuberculosis (M. tuberculosis) infection. Circulating granulysin and IFN-γ concentrations were measured and correlated with clinical disease in Thai patients with newly diagnosed, relapsed and chronic tuberculosis (TB). Compared to controls, patients with newly diagnosed, relapsed and chronic TB had lower circulating granulysin concentrations, these differences being significant only in newly diagnosed and relapsed TB (P < 0.001 and 0.004, respectively). Granulysin concentrations in patients with newly diagnosed and relapsed TB were significantly lower than in those with chronic TB (P= 0.003 and P= 0.022, respectively). In contrast, significantly higher circulating IFN-γ concentrations were found in patients with newly diagnosed and relapsed TB compared to controls (P < 0.001). The IFN-γ concentrations in newly diagnosed and relapsed patients were not significantly different from those of patients with chronic TB. However, in vitro stimulation of peripheral blood mononuclear cells (PBMCs) from patients with newly diagnosed, relapsed and chronic TB with purified protein derivative (PPD) or heat killed M. tuberculosis (H37Ra) enhanced production of granulysin by PBMCs. In vitro, stimulation of PBMCs of newly diagnosed TB patients with PPD produced greater amounts of IFN-γ than did controls, while those stimulated with H37Ra did not. The results demonstrate that patients with active pulmonary TB have low circulating granulysin but high IFN-γ concentrations, suggesting possible roles in host defense against M. tuberculosis for these agents.

Association between circulating full-length osteopontin and IFN-gamma with disease status of tuberculosis and response to successful treatment.

The T helper type 1 (Th1) immune response plays an important role in protective immunity, pathophysiology and development of tuberculosis (TB). To investigate whether osteopontin (OPN) and other Th1 response-related molecules are associated withTB disease status, including co-infection with HIV, and response to anti-TB treatment, circulating levels of full-length OPN (F-OPN), thrombin-cleaved N-terminal fragment of OPN (N-half OPN), IFN-gamma, IP-10, IL-18, IL-12/ IL-23 (p40), IL-10, IL-15 and C-reactive protein (CRP) were measured before and after anti-TB treatment. Patients with newly active pulmonary TB had significantly higher plasma levels of F-OPN, IFN-gamma and CRP than healthy controls (HC). F-OPN, N-half OPN, IFN-gamma, IP-10, IL-18 and IL-10 levels were higher in patients with extensive TB/HIV co-infection than in patients with a single disease of TB or HIV. Plasma levels of F-OPN correlated well with those of IP-10, IL-18 and N-half OPN among patients with active TB. The F-OPN, IFN-gamma, IP-10 and CRP levels decreased significantly after effective anti-TB treatment. These data suggest that circulating OPN and Th1 response-related molecules, including IFN-gamma, may be regulated in response to expansion of active TB and could serve as markers of disease activity before and during treatment.

Expansion of antiretroviral treatment to rural health centre level by a mobile service in Mumbwa district, Zambia.

PROBLEM: Despite the Government's effort to expand services to district level, it is still hard for people living with HIV to access antiretroviral treatment (ART) in rural Zambia. Strong demands for expanding ART services at the rural health centre level face challenges of resource shortages. APPROACH: The Mumbwa district health management team introduced mobile ART services using human resources and technical support from district hospitals, and community involvement at four rural health centres in the first quarter of 2007. This paper discusses the uptake of the mobile ART services in rural Mumbwa. LOCAL SETTING: Mumbwa is a rural district with an area of 23 000 km² and a population of 167 000. Before the introduction of mobile services, ART services were provided only at Mumbwa District Hospital. RELEVANT CHANGES: The mobile services improved accessibility to ART, especially for clients in better functional status, i.e. still able to work. In addition, these mobile services may reduce the number of cases "lost to follow-up". This might be due to the closer involvement of the community and the better support offered by these services to rural clients. LESSONS LEARNT: These mobile ART services helped expand services to rural health facilities where resources are limited, bringing them as close as possible to where clients live.

High tuberculosis burden among HIV-infected populations in Thailand due to a low-sensitivity tuberculin skin test.

The current Thai guideline recommends that among people living with HIV, isoniazid preventive therapy (IPT) should be given to those with a positive tuberculin skin test (TST). We conducted a case-control study, nested within a cohort study, in Chiang Rai Province in Thailand to determine the role of TST in predicting the development of active tuberculosis (TB) within the following 2 years. Comparison between participants with CD4+ counts <50cells/mm3 to those with CD4+ ≥200cells/mm3 revealed that TST results were less sensitive (7.7% vs 50.0%) and had a lower negative predictive value (73.1% vs 97.3%) in those with a CD4+ count <50cells/mm3. In people with HIV, using a positive TST result as a criterion for initiating IPT inadvertently decreases the benefits of IPT, especially among those with low CD4+ counts.

Transmission of specific genotype streptomycin resistant strains of Mycobacterium tuberculosis in the Tokyo Metropolitan Area in Japan.

BACKGROUND: From 2003 through to 2004, an outbreak of tuberculosis was identified at a university campus in Yokohama City, located in the southern part of the Tokyo Metropolitan Area (TMA). All Mycobacterium tuberculosis (M. tuberculosis) strains detected with regards to this outbreak turned out to be Streptomycin resistant with matched patterns of 14 IS6110 bands of Restriction Fragment Length Polymorphism (RFLP). The M. tuberculosis bacilli, which had the matched IS6110 band patterns with resistance to Streptomycin to those of bacilli isolated in the outbreak, were also concurrently detected through either the population-based or the hospital-based DNA fingerprinting surveillance of M. tuberculosis either in Shinjuku City or in Kawasaki City respectively. The aim of the present study is to describe the spread of the specific genotype strains of M. tuberculosis in the TMA as observed in the above incident, and to identify the possible transmission routes of the strains among people living in urban settings in Japan. METHODS: We applied Variable Numbers of Tandem Repeats (VNTR) analysis to all M. tuberculosis isolates which were resistant to Streptomycin with a matched IS6110-RFLP band pattern (M-strains). They were isolated either from cases related to the tuberculosis outbreak that happened at a university, or through DNA fingerprinting surveillance of M. tuberculosis both in Shinjuku City and in Kawasaki City. For VNTR analysis, 12MIRU loci, 4ETR loci, seven loci by Supply, four loci by Murase (QUB15, Mtub24, VNTR2372, VNTR3336) were selected. RESULTS: Out of a total of 664 isolates collected during the study period, 46 isolates (6.9%) were identified as M-strains. There was a tendency that there was a higher proportion of those patients whose isolates belonged to M4-substrains, with four copies of tandem repeat at the ETR-C locus, to have visited some of the internet-cafés in the TMA than those whose isolates belonged to M5-substrains, with five copies at the ETR-C locus, although statistically not significant (38.1% vs. 10.0%, Exact p = 0.150). CONCLUSION: Although firm conclusions could not be reached through the present study, it suggested that we have to take into consideration that tuberculosis can be transmitted in congregated facilities like internet cafés where tuberculosis high-risk people and general people share common spaces.

Multidrug-resistant TB and HIV in Thailand: overlapping, but not independently associated, risk factors.

The HIV and multi-drug resistant tuberculosis (MDR-TB) epidemics are closely linked. In Thailand as part of a sentinel surveillance system, we collected data prospectively about pulmonary TB cases treated in public clinics. A subset of HIV-infected TB patients identified through this system had additional data collected for a research study. We conducted multivariate analysis to identify factors associated with MDR-TB. Of 10,428 TB patients, 2,376 (23%) were HIV-infected; 145 (1%) had MDR-TB. Of the MDR-TB cases, 52 (37%) were HIV-infected. Independent risk factors for MDR-TB included age 18-29 years old, male sex, and previous TB treatment, but not HIV infection. Among new patients, having an injection drug use history was a risk factor for MDR-TB. Of 539 HIV-infected TB patients in the research study, MDR-TB was diagnosed in 19 (4%); the only significant risk factors were previous TB treatment and previous hepatitis. In Thailand, HIV is common among MDR-TB patients, but is not an independent risk factor for MDR-TB. Populations at high risk for HIV-young adults, men, injection drug users - should be prioritized for drug susceptibility testing.

Multi-drug resistant TB and HIV in Thailand: overlapping, but not independently associated risk factors.

The HIV and multi-drug resistant tuberculosis (MDR-TB) epidemics are closely linked. In Thailand as part of a sentinel surveillance system, we collected data prospectively about pulmonary TB cases treated in public clinics. A subset of HIV-infected TB patients identified through this system had additional data collected for a research study. We conducted multivariate analysis to identify factors associated with MDR-TB. Of 10,428 TB patients, 2,376 (23%) were HIV-infected; 145 (1%) had MDR-TB. Of the MDR-TB cases, 52 (37%) were HIV-infected. Independent risk factors for MDR-TB included age 18-29 years old, male sex, and previous TB treatment, but not HIV infection. Among new patients, having an injection drug use history was a risk factor for MDR-TB. Of 539 HIV-infected TB patients in the research study, MDR-TB was diagnosed in 19 (4%); the only significant risk factors were previous TB treatment and previous hepatitis. In Thailand, HIV is common among MDR-TB patients, but is not an independent risk factor for MDR-TB. Populations at high risk for HIV-young adults, men, injection drug users - should be prioritized for drug susceptibility testing.

[The current and future situations of TB/HIV (co-infection of tuberculosis and HIV) in Japan].

While HIV epidemic is still low in Japan, reported HIV infected persons and AIDS cases have been increasing and the tuberculosis epidemiologic situation in Japan is categorized as a intermediate level. Therefore it is necessary to understand the current situations of TB/HIV and identify issues to be addressed for better understanding of the epidemiologic situation of TB/HIV co-infection and improvement of disease control programmes and clinical practice to prevent and treat the TB/HIV. In the symposium, four panelists presented the current situations of TB/HIV in Japan from the views of epidemiology, clinical characteristic, treatment, prognosis and prevention and discussed the issues of them. 2. Clinical charcteristics of patients with HIV and tuberculosis: Hideaki NAGAI (Department of Pulmonary Medicine, National Hospital Organization Tokyo National Hospital). The number of cases with HIV and tuberculosis will increase because of the increment of HIV-infected patients and high morbidity rate of tuberculosis in Japan. It is difficult to diagnose tuberculosis in HIV-infected patients because of atypical chest X-ray, atypical clinical characteristics, extrapulmonary tuberculosis. Side effects, drug-drug interaction, and immune reconstruction syndrome must be considered when the concurrent treatment to HIV and tuberculosis is administered. It is unclear when to start antiretroviral therapy after the initiation of tuberculosis treatment. Careful consideration is needed to initiate antiretroviral therapy. 3. The situation of early detection, the prevention, the treatment and the problem of tuberculosis patients with Human Immunodeficiency Virus infection: Yuka SASAKI (Department of Thoracic Disease, National Hospital Organization Chiba-East National Hospital). We investigated the situation of early detection, the prevention, the treatment and the problem of tuberculosis patients with Human Immunodeficiency Virus infection by the questionnaires. In Japan, many of national organization hospitals with division of thoracic disease did the examination for the patients who were contacted with infectious tuberculosis. Many of physicians expected in the QFT-2G to detect the latent tuberculosis infection in HIV/AIDS patients. The prognosis of the patients with tuberculosis and AIDS has been improving gradually. In future, the specialists of tuberculosis treatment would detected HIV infected patients in tuberculosis patients as possibly early, would do the treatment for the latent tuberculosis infection, and most hospitals would be able to do the AIDS and tuberculosis treatment. 4. Issues in estimating current and future TB/HIV situation in Japan: Norio YAMADA (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association). The information on HIV seroprevalence of newly diagnosed tuberculosis cases is limited. We carried out cross-sectional seroprevalence survey of hospitalized TB cases. Thirty-three out of 282 hospitals returned the results by the end of March 2008. There are 222 eligible patients at the 33 hospitals. Only one of them is HIV-infected. The prevalence of HIV coinfection adjusted for distribution of notified tuberculosis cases is 0.13%. Taking into account other estimates based on the previously reported studies and AIDS surveillance, it is thought that recent prevalence of HIV co-infection among newly diagnosed tuberculosis cases is at least 0.1% in Japan. Considering low participation rate in the seroprevalence survey and the low epidemic level of HIV in Japan, it might be sensible to establish sentinel surveillance as well as improve the reporting of HIV status included in the tuberculosis surveillance to monitor TB/HIV situation in Japan.

A novel Ancestral Beijing sublineage of Mycobacterium tuberculosis suggests the transition site to Modern Beijing sublineages.

Global Mycobacterium tuberculosis population comprises 7 major lineages. The Beijing strains, particularly the ones classified as Modern groups, have been found worldwide, frequently associated with drug resistance, younger ages, outbreaks and appear to be expanding. Here, we report analysis of whole genome sequences of 1170 M. tuberculosis isolates together with their patient profiles. Our samples belonged to Lineage 1-4 (L1-L4) with those of L1 and L2 being equally dominant. Phylogenetic analysis revealed several new or rare sublineages. Differential associations between sublineages of M. tuberculosis and patient profiles, including ages, ethnicity, HIV (human immunodeficiency virus) infection and drug resistance were demonstrated. The Ancestral Beijing strains and some sublineages of L4 were associated with ethnic minorities while L1 was more common in Thais. L2.2.1.Ancestral 4 surprisingly had a mutation that is typical of the Modern Beijing sublineages and was common in Akha and Lahu tribes who have migrated from Southern China in the last century. This may indicate that the evolutionary transition from the Ancestral to Modern Beijing sublineages might be gradual and occur in Southern China, where the presence of multiple ethnic groups might have allowed for the circulations of various co-evolving sublineages which ultimately lead to the emergence of the Modern Beijing strains.

The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation.

In diabetic nephropathy decreased activities of matrix metalloproteinase (MMP)-2, MMP-9 and plasmin contribute to mesangial matrix accumulation. Megsin, a novel member of the serine protease inhibitor superfamily, is predominantly expressed in mesangial cells and is up-regulated in diabetic nephropathy and its overexpression spontaneously induces progressive mesangial expansion in mice. High-glucose stimulated megsin mRNA expression in an in vivo model of type II diabetic nephropathy as well as in vitro in cultured mesangial cells. Megsin potentially inhibits total enzymatic activities of MMP-2 and -9 and plasmin, indicating decreased degradation of mesangial matrix. A specific monoclonal anti-megsin neutralizing antibody restored MMP activity in a transforming growth factor-beta independent manner. Our study suggests that the mesangial matrix accumulation caused by hyperglycemia in diabetes might be due at least in part to up-regulation of megsin which can inhibit plasmin and MMP activities.