We performed a retrospective cohort study using the existing data and specimens at the Shanghai Municipal Center for Disease Control and Prevention (Shanghai CDC), from TB patients who were diagnosed inShanghai during March 2004 through November 2007. Since 1995 inShanghai, all suspected pulmonary TB cases detected in general hospitals or community health centers were referred to a specialized TB hospital or TB clinic for further diagnostic tests, including sputum smear examinations, culture and chest radiography. There were 31 designated district TB hospitals inShanghai; all of the pretreatment positive cultures from patients in each hospital were sent to the Tuberculosis Reference Laboratory (TRL) at Shanghai CDC for drug susceptibility testing and species identification. Shanghai CDC also collected data on the social and demographic characteristics, treatment history, clinical characteristics, drug-susceptibility test results, and clinical outcomes of each patient. All of the investigation protocols in this study were approved by ethics committee of Fudan University. Since this was a retrospective study and all patients’ information was routinely collected by Shanghai CDC for analysis and reports to the government, consent was not obtained from the patients during 2004 through 2006. We started a research project in 2007, and informed consent has been obtained from all patients since then for the information to be used in scientific studies.
The evolutionary origin and nature of the XDR M. tuberculosis strains remain unknown. Two possible explanations have been postulated to describe the occurrence andtransmissionofXDR-TB worldwide. The first explanation involves clonal expansion and spreading of one strain harboring several drug-resistance mutations [10–12]. Alternatively, it appears that drug- resistance mutational events occurred multiple times separately in different strains, proposing repeated selection from a pool of pre-existing strains through the chemotherapeutic usage pat- tern rather than the spread of a single drug-resistant strain . The advent of high throughput Next Generation Sequencing technologies (NGS) provide a step forward in drug-resistant TB research to decipher the biology, adaptation and evolution of these “extreme” strains. Although there are whole genome sequence data for XDRin the international databases [12, 14–18], the whole genome sequences ofXDR strains from Southeast Asia tropical countries are still lack- ing. In 2013, we sequenced the genome of the first XDR M. tuberculosis strain UM 1072388579 with a 500-bp insert-size library . Here, we sequenced the UM 1072388579 genome with a 2-kb insert-size library and combined the genomic sequence data with that from the previous sequencing using the small DNA insert library to improve genome assembly. In Malaysia, only one XDR-TB case has been reported so far. The origin and the genotype ofXDR M. tuberculo- sis in the country are totally unclear. In this study, we demonstrated that the UM 1072388579 strain harbors an ancestral-like spoligotype, which is close to the Beijing clade of East Asia lineage.
Recent global data have shown rising rates of drug-resistant TB in sub-Saharan Africa, the region also suffering from the world’s highest burden of HIV/AIDS . This is the first study of clinical predictors ofMDRandXDR TB in a high HIV prevalence setting and provides important insights into the clinical charac- teristics of patients with drug-resistant TB. We found that three readily available pieces of clinical data – hospitalization history, TB treatment history and HIV status – were strong independent predictors for MDR or XDR TB. Using these data, clinicians practicing in high HIV prevalence settings may be able to cohort high-risk inpatients to reduce transmissionand target drug- susceptibility testing where DST resources are limited. Addition- ally, our findings support the need for strengthening hospital infection control measures, including reducing the duration of hospitalization in high HIV prevalence settings.
Tuberculosis incidence among aborigines is significantly higher than for Han Chinese in Taiwan, but the extent to which Mycobacterium tuberculosis (MTB) strain characteristics contribute to this difference is not well understood. MTB isolates from aborigines and Han Chinese living in eastern and southern Taiwan, the major regions of aborigines, were analyzed by spoligotyping and 24-loci MIRU-VNTR. In eastern Taiwan, 60% of aboriginal patients were #20 years old, significantly younger than the non-aboriginal patients there; aborigines were more likely to have clustered MTB isolates than Han Chinese (odds ratio (OR) = 5.98, p,0.0001). MTB lineages with high clustering were EAI (54.9%) among southern people, and Beijing (62.5%) and Haarlem (52.9%) among eastern aborigines. Resistance to first-line drugs and multidrug resistance (MDR) were significantly higher among eastern aborigines ($15%) than in any other geographic and ethnic group (p,0.05); MDR was detected in 5 of 28 eastern aboriginal patients #20 years old. Among patients from the eastern region, clustered strains (p = 0.01) and aboriginal ethnicity (p = 0.04) were independent risk factors for MDR. The lifestyles of aborigines in eastern Taiwan may explain why the percentage of infected aborigines is much higher than for their Han Chinese counterparts. The significantly higher percentage of the MDR-MTB strains in the aboriginal population warrants close attention to control policy and vaccination strategy.
273,000 of new MDR-TB cases have been accrued worldwide [9,10]; hence, the treatment ofMDR/XDR-MTB due to the limitation of therapeutic choices is difficult . Research studies have made an attempt to find the new antimicrobial agents with herbal origin to develop treatments for TB resistance strains . In many developed countries an interest has been shifted toward utilizing the traditional medicine as their major primary health care requirements, thus a fundamental exploring of alternative anti- TB agents is demanded . For this purpose evaluating plants and herbal agents should be conducted to find their biological properties and also their safety. For example garlic (Allium sativum) is a medicinal plant with variety of biological properties like anti-tumor, anti- hyperlipedemic and anti-mycobacterial activities . Regarding the anti-tuberculosis properties, extracts of Acalypha indica, Adhato davasica, Allium cepa, Allium sativum and Aloe vera have revealed anti-tuberculosis activity . A traditional herbal agent, Dracocephalum kotschyi, a member of Lamiaceae family, which is a wild-growing plant is known for biological activities of its oil . D.kotschyi called “Zarringiah” in Persian is endemic to Iran. It grows in various regions such as Alborz Mountains and North of Khorasan. It was primarily used as anti-spasmodic, analgesic (anti- visceral) and anti- hyperlipidemic , treatment of rheumatoid disorders, and cancer therapy such
The MDR control benefits to India from improving non-MDR TB treatment are shrinking, though there are still important direct benefits for reducing non-MDR TB prevalence and incidence. Because India’s MDR TB epidemic is expected to continue transitioning from a treatment-generated towards a transmission- generated epidemic, the impact on MDR TB of improving non- MDR TB treatment declines over time. In contrast, the impact of improving the rapidity ofMDR TB diagnosis remains constant (see Table 3 and Figure 5). For example, improving non-MDR TB treatment across India to best-observed levels in 2007 would have resulted in a 17% reduction in the prevalence of infectious MDR TB cases over the following 10 years; in contrast, doing so by 2017 results in a 10.8% reduction and a 10.3% reduction by 2027. Figure 3. Projected prevalence and mortality from non-MDRandMDR TB in India with public DOTS treatment programs and counterfactual private treatment expansion in the absence of public treatment. Figure shows model estimations and projections of disease prevalence and deaths after 1996, when public nationwide TB treatment in India began. Private treatment curves (dashed lines) represent outcomes in a scenario where DOTS was never implemented and private clinic population coverage increased to half of the level that DOTS currently covers. Solid lines represent disease prevalence and deaths given observed public treatment levels in India and assume public TB treatment will continue at current levels.
tain families in Czechoslovakia (Van Soolingen et al. 1991), identified sources of infection in a pub and a discotheque (Van Embden et al. 1993b) and demonstrated infection by a neighbor (Godfrey- Faussett et al. 1992a). The importance of trans- mission of TB within shelters for the homeless was also demonstrated in a study with TB patients from Australia (Dwyer et al. 1993) and by means of con- tact investigation by IS6110-RFLP, it was shown that TB was actively transmitted in a neighborhood bar in Minneapolis, where an index case infected 41 of his contacts (Kline et al. 1995). These stud- ies clearly demonstrate the value of RFLP analy- sis in situations where traditional contact tracing alone would not be able to detect clusters of TB; it also shows that single, highly infectious cases can have a severe influence on TB transmission within a community and, as a consequence, on TB pro- grams. Tuberculosis has been known to be en- demic in correctional facilities for many years (Stead 1978) and active transmissionof TB in a New York jail has been confirmed by phage typ- ing and RFLP-analysis (Pelletier et al. 1993). Most outbreaks of TB have been observed in hospitals and patient care settings and many of these involve recent transmissionof TB to patients with immunodepression, as demonstrated in a renal transplant unit (Jereb et al. 1993), in housing fa- cilities or care centers for HIV-infected persons (Daley et al. 1992, Kent et al. 1994) andin hospi- tal facilities (Edlin et al. 1992, Coronado et al. 1993, Beck-Sagué et al. 1992, Wenger et al. 1995). In 1990 through 1992, the Centers for Disease Con- trol (CDC) investigated seven outbreaks ofMDR- TB involving over 200 persons with most cases occurring among persons with HIV infection (CDC unpublished data) and one of these outbreaks in- volved a M. tuberculosis strain resistant to seven drugs causing extremely high mortality rates. Not only HIV-infected patients but also health care workers such as nurses, house keepers and labora-
Tuberculosis infection is a serious human health threat and the early 21st century has seen a remarkable increase in global tuberculosis activity. The pathogen responsible for tuber- culosis is Mycobacterium tuberculosis, which adopts diverse strategies in order to survive in a variety of host lesions. These survival mechanisms make the pathogen resistant to cur- rently available drugs, a major contributing factor in the failure to control the spread oftuberculosis. Multiple drugs are available for clinical use and several potential compounds are being screened, synthesized, or evaluated in preclinical or clinical studies. Lasting and effective achievements in the development of anti-tuberculosis drugs will depend largely on the proper understanding of the complex interactions between the pathogen and its human host. Ample evidence exists to explain the characteristics oftuberculosis. In this study, we highlighted the challenges for the development of novel drugs with potent bacterio- static or bactericidal activity, which reduce the minimum time required to cure tuberculosis infection.
In Brazil, especially in Rio de Janeiro, 30% of the TB cases are diagnosed in hospitals. Public and private hos- pitals differ in their rates of suspicion and isolation of patients who are considered to be at risk for TB. Emer- gency Rooms, in general, do not have any TB control program. In a retrospective study carried out to evaluate indicators of TB risk transmission, where 63.5% of patients were admitted to the hospital through the Emergency Room, in 27.5% of them the interval between admission and sputum collection exceeded 12 h. This delay in isola- tion was correlated with diagnosis of TB at admission and lower bacillary load in the sputum (16). In previous Brazil- ian MDR case studies, there was a significant association with clustering, suggesting that at tertiary care hospitals MDR cases may result from new transmissionof primary resistant organisms (17). According to this information, a patient could be infected with one genetic pattern ofMDR strain transmitted through the health facilities where he was admitted and the variant pattern found was related to an event of microevolution through IS6110 transposition
Methodology/Principal Findings: We performed a retrospective study of all pulmonary tuberculosis patients reported in Songjiang district, Shanghai, to determine the demographic, clinical and microbiological characteristics oftuberculosis cases between urban migrants and local residents. We calculated the odds ratios (OR) and performed multivariate logistic regression to identify the characteristics that were independently associated with tuberculosis among urban migrants. A total of 1,348 pulmonary tuberculosis cases were reported during 2006–2008, among whom 440 (32.6%) were local residents and 908 (67.4%) were urban migrants. Urban migrant (38.9/100,000 population) had higher tuberculosis rates than local residents (27.8/100,000 population), and the rates among persons younger than age 35 years were 3 times higher among urban migrants than among local residents. Younger age (adjusted OR per additional year at risk = 0.92, 95% CI: 0.91–0.94, p,0.001), poor treatment outcome (adjusted OR = 4.12, 95% CI: 2.65–5.72, p,0.001), and lower frequency of any comorbidity at diagnosis (adjusted OR = 0.20, 95% CI: 0.13–0.26, p = 0.013) were significantly associated with tuberculosis patients among urban migrants. There were poor treatment outcomes among urban migrants, mainly from transfers to another jurisdiction (19.3% of all tuberculosis patients among urban migrants).
The threats ofMDR- andXDR- TB, moreover, may prove to be a key element in mobilizing increased funding for all TB drug development; their prevalence will undoubtedly grow if improved therapy is not made widely available. And the ﬁnancial and human costs will be even higher. Furthermore, the activity of a new drug may be more easily observed in the context of the relatively weak companion drugs used inMDR-TB treatment than in the presence of other potent drugs used for drug-susceptible disease. Differences in treatment response, which are more easily detected inMDR-TB therapy, would allow smaller and shorter clinical trials. As in HIV, clinical trials in patients with drug-resistant disease may provide a quicker and less expensive path to licensure than demonstrating that a new drug can substantially improve the treatment for drug- susceptible disease.
The 34 clinical isolates were phenotypically susceptible to RFB as per CC, despite of their resistance to RIF and the presence of SNPs at codon 516 in the rpoB gene (Table 1). However, a shift in the RFB MICs, from #0.03–0.06 mg/ml for wild-type strains to 0.125–0.25 mg/ml for the mutant isolates was observed. The corresponding MIC shift for RIF was from #0.5 mg/ml to 5.0– 15.0 mg/ml. Based on these findings, the relative resistance of the drugs (Table 1) shows that RFB was less affected by the mutations at codon 516 in the rpoB gene as compared to RIF [2,8,9]. The decreased susceptibility to RFB may not predict clinical resistance, but indicate that mutations at codon 516 in the RRDR are associated with incomplete cross-resistance between RIF and RFB. More recently, an epidemiological cut-off (ECOFF) concentration of 0.064 mg/ml was proposed for RFB based on the Middlebrook 7H10 dilution method . The ECOFF is defined as the highest concentration within the MIC distribution of wild-type strains (i.e. isolates lacking resistance mechanisms) . A breakpoint for RFB, based on clinical evidence has not yet been established. According to the CC (0.5 mg/ml) endorsed by the World Health Organization , our results suggest that a substantial proportion M(X)DR TB patients in the ECP may benefit from a treatment regimen that substitute RIF for RFB. This strategy is feasible only if the strains that remain susceptible to RFB are readily detectable. Molecular assays are therefore useful to assist culture-based drug susceptibility testing (DST) in identifying isolates with specific mutations that are associated with RIF-resistance, while they remain susceptible to RFB. The GenoType H MTBDplus assay (Hain LifeScience GmbH, Nehren, Germany) is designed to detect most of the mutations that confer RIF- and INH- resistance and has been suggested to be an important tool to define RFB susceptibility . However, molecular assays with enhanced discriminating capacity are needed for identifying mutations that confer low-level or incomplete cross-resistance to analogue drugs. This information is crucial, particularly for the rifamycins, INH, Table 1. MICs and relative resistance of rifampicin and
In analyses controlling for confounding factors, such as age and gender, we found that more frequent intake of sweet foods reduced VSC concentrations. The presence of carbohydrates, such as glucose and sucrose, has been reported to inhibit the expression and activity of trypsin- like enzyme, which is capable of degrading peptides that may produce malodorous compounds by producing an acidic environment [52–54]. Another study showed that 10 children with moderate to high caries activity who were more likely to consume sugar-containing snacks habitually were free from halitosis . The present study may be the first epidemiological investigation to reveal that the consumption of sweet foods can inhibit VSC production. Fruit consumption was also associated with halitosis in bivariate analysis. As halitosis originates in the oral cavity as a result of proteolytic degradation by anaerobic Gram-negative oral bacteria of various sulfur-containing substrates [2,7], we assume that a greater frequency of fruit intake was accompanied by reduced protein consumption, resulting in less VSC production. Further- more, as most fruits are sweet, the mechanism of halitosis inhibition may be similar to that of sweet food. Further large-scale epidemiological studies are needed to explore associations between diet and halitosis.
In situ measurement of the CO mixing ratio was carried out with a commercial gas filter non-dispersive infrared CO gas analyzer (Thermo Scientific. Model 48C, USA, time res- olution of 1 min; detection limit: 30 ppbv for a 2-min av- erage) equipped with a Nafion dryer to reduce interference by water vapor in the sampled air. The zero point (base- line of the instrumental signal) was routinely checked in the first 10 min of each hour using purified air, and span cal- ibrations were performed in the ambient environment be- fore (May 2006) andin the middle of the field experiments (December 2007) by injecting standard span gas (1.04 parts per million by volume (ppmv), produced by Nissan-Tanaka Corp., Japan). The difference between the span and zero points demonstrated that the measured CO mixing ratio was about 46 ppbv higher than the standard value, and the ratio was adjusted by 95 % afterward. The instrument baseline in the observation period has a stable linear increasing trend with a drift ratio of 0.4 ppb h −1 ; however, this influence was easily removed by zero-point-deduction operations in subse- quent data procedures. The overall uncertainty was estimated to be 5 %. Additional meteorological parameters (wind, RH and temperature) were acquired from the NCEP reanal- ysis dataset (ftp://ftp.cdc.noaa.gov/Datasets/ncep.reanalysis/ surface/) with a time interval of 6 h at the site grid.
discharge into water is reduced by about 60% irrespective of the type of treatment . Pure urine is sterile but there is the likelihood of cross-contamination with the use of urine separating (Ecosan) toilets . According to Jönsson et al. (2000) separated urine contains a greater part of the total nutrients in normal sewage; 80% of N, 55% of P, and 60% of K in just 1.5% of the volume of the sewage. According to Rheiberger (1936), there are comparable levels of creatine, urea and ammonia nitrogens in urine among primates such as man, mangabeys, baboons and chimpanzees. However, he identified sex differences in creatinine nitrogen coefficients of the male mangabeys, baboons and chimpanzees to be higher than those in the female counterparts. In small cases there was reversal of the magnitude seen in the macaques species precluding an assumption as to the validity of the observation. In analysing sex differences in urine with respect to lysine and α - amino nitrogen, the mean excretion of α - amino nitrogen whether ―total,‖ ―free,‖ or ―bound,‖ was higher for females than for males . Thus, it is possible that the higher rate of amino acid excretion observed in females might be correlated with the sexual cycle, although no evidence of this was observed in the case of the four amino acids studied by Thompson and Kirby (1949) when samples from the same subjects were taken at various stages of the menstrual cycle. The influence of sex (gender) on the level of NPK in human urine has received no attention. Therefore, there is a need to study the effect from the Ecological Sanitation (ECOSAN) perspective, especially under local conditions. This is because gender ECOSAN urinals are going to spring up with the advent of industries and ECOSAN concepts, especially in the developing countries. The use of urine in agriculture has been studied in countries such as Sweden, Germany, Switzerland, South Africa, Burkina Faso and Nigeria. In all these studies, the fertilizing ability of human urine was established as being comparable to that of chemical fertilizers, such as 21% N ammonia. However, in Ghana little U
agreement with the predicted for MtCMK (Fig. 2B), and densitometric measurements indicate that MtCMK represents approximately 17% of total protein in the soluble cell extract. In the pET system, target genes are positioned downstream of bacteriophage T7 late promoter. Typically, production hosts contain a prophage ( DE3) encoding the highly processive T7 RNA polymerase under control of the IPTG-inducible lacUV5 promoter that would ensure tight control of recombinant gene basal expression. In agreement with the results presented here, high levels of protein expression in the absence of inducer have been shown to occur in the pET system (26, 27, 30, 33, 39). It has been proposed that leaky protein expression is a property of lac-controlled system when cells approach stationary phase in complex medium and that cyclic AMP, acetate, and low pH are required to achieve high-level expression in the absence of IPTG induction, which may be part of a general cellular response to nutrition limitation (19).
Approximately 10% of the Brazilian indigenous population lives in the state of Mato Grosso do Sul (MS), where a large number of new cases oftuberculosis (TB) are reported. This study was conducted to assess TB occurrence, transmissionand the utility of TB diagnosis based on the Ogawa-Kudoh (O-K) culture method in this remote popu- lation. The incidence of TB was estimated by a retrospective review of the surveillance data maintained by the No- tifiable Diseases Surveillance System for the study region. The TB transmission pattern among indigenous people was assessed by genotyping Mycobacterium tuberculosis isolates using the IS6110 restriction fragment length poly- morphism (RFLP) technique. Of the 3,093 cases identified from 1999-2001, 610 (~20%) were indigenous patients (average incidence: 377/100,000/year). The use of the O-K culture method increased the number of diagnosed cases by 34.1%. Of the genotyped isolates from 52 indigenous patients, 33 (63.5%) belonged to cluster RFLP patterns, indicating recently transmitted TB. These results demonstrate high, on-going TB transmission rates among the in- digenous people of MS and indicate that new efforts are needed to disrupt these current transmissions.
Here, we report the cases of three patients diagnosed with extensively drug-resistant tuberculosisand admitted to a referral hospital in the state of São Paulo, Brazil, showing the clinical and radiological evolution, as well as laboratory test results, over a one- year period. Treatment was based on the World Health Organization guidelines, with the inclusion of a new proposal for the use of a combination of antituberculosis drugs (imipenem and linezolid). In the cases studied, we show the challenge of creating an acceptable, effective treatment regimen including drugs that are more toxic, are more expensive, and are administered for longer periods. We also show that treatment costs are signiicantly higher for such patients, which could have an impact on health care systems, even after hospital discharge. We highlight the fact that in extreme cases, such as those reported here, hospitalization at a referral center seems to be the most effective strategy for providing appropriate treatment and increasing the chance of cure. In conclusion, health professionals and governments must make every effort to prevent cases of multidrug-resistant and extensively drug-resistant tuberculosis.
The cultivating, through different social policies, especially through the ideologization of the values , of the contempt for the real, productive work represents a major problem. Only one country in the world set the objective – within the constitution – to not spend more
No personal identifiable information was used. To en- sure confidentiality, each case was anonymized by the assignment of a random identification number that can only be accessed by authorized public health profes- sionals. This work was carried out in accordance with the recommendations by the Ethics Sub-commission of Life and Health Sciences (SECVS) from the University of Minho (SECVS 135/2015), by the Health Ethics Committee of the ARSN (Northern Region Health Administration) (68/2014) and the Ethics Committee for Health of the São João Hospital Centre (CES-305/15), with written informed consent from all subjects. All pro- cedures were in accordance with the ethical standards of the responsible committees and with the Helsinki Declaration, as revised in 2008. Information collected in- cluded age, place of residence, workplace and commonly frequented places, HIV infection status, whether or not homeless and migratory status. This information is rou- tinely collected by public health teams whenever a case of TB is notified, and electronically recorded in the National Epidemiological Surveillance System. To each case, a specific GPS coordinate was attributed, which was never cross-checked for a concrete address but used solely to determine distances between cases to categorise putative transmission events.