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1.  Mycobacterium tuberculosis DNA fingerprint clusters and its relationship with RDRio genotype in Brazil 
SUMMARY
Mycobacterium tuberculosis (Mtb) strains designated as RDRio are responsible for a large cluster of new cases of tuberculosis (TB) in Rio de Janeiro. They were previously shown to be associated with severe manifestations of TB. Here, we used three genotyping methods (IS6110 RFLP, spoligotyping, and multiplex PCR) to characterize RDRio and non-RDRio strains from the metropolitan area of Vitória, State of Espirito Santo in southeast Brazil to determine strain diversity and transmission patterns. Strains with identical IS6110 RFLP patterns were considered to belong to a cluster indicative of recent transmission. Between 2000 and 2010, we identified 5470 new TB patients and genotyped 981 Mtb strains. Of these, 376 (38%) were RDRio. By RFLP, 180 (48%) of 376 RDRio strains and 235 (40%) of 593 non-RDRio strains belonged to RFLP cluster pattern groups (p = 0.023). Simpson’s diversity index based on RFLP patterns was 0.96 for RDRio and 0.98 for non-RDRio strains. Thus, although RDRio strains appear to be comprised of a fewer number of RFLP genotypes, they represent a heterogeneous group. While TB cases caused by RDRio appear more likely to be due to recent transmission than cases caused by non-RDRio strains, the difference is small. These observations suggest that factors other than inherent biological characteristic of RDRio lineages are more important in determining recent transmission, and that public health measures to interrupt new transmissions need to be emphasized for TB control in Vitória.
doi:10.1016/j.tube.2012.09.001
PMCID: PMC3734852  PMID: 23232111
Tuberculosis; DNA fingerprinting; Mycobacterium tuberculosis; Epidemiologic surveillance; RDRio
2.  Dissemination of Acinetobacter nosocomialis Clone among Critically Ill Patients and the Environment 
Journal of Clinical Microbiology  2013;51(8):2707-2709.
We examined the environmental dissemination of Acinetobacter nosocomialis multilocus sequence typing clonal complex 260/71 in Rio de Janeiro, Brazil, including water from a dam and food samples. The increasing use of sequence based methods has demonstrated a large, previously unpredicted, dissemination of bacteria that may serve as opportunistic pathogens.
doi:10.1128/JCM.00915-13
PMCID: PMC3719634  PMID: 23698521
3.  Epidemiology of extrapulmonary tuberculosis in Brazil: a hierarchical model 
Background
Although extrapulmonary tuberculosis (EPTB) is less frequent than Pulmonary Tuberculosis (PTB) and is a secondary target for national TB control programs, its significance has increased worldwide during the HIV epidemic. The objective of this study was to examine the epidemiology of EPTB in Brazil between 2007 and 2011.
Methods
Cross-sectional study involving all cases of TB reported to the Brazilian Notifiable Diseases Surveillance System (Sistema de Informações de Agravo de Notificação - SINAN) in Brazil between 2007 and 2011. Sociodemographic and clinical characteristics of patients with exclusively PTB and exclusively EPTB were compared. Following analysis with Pearson’s chi-square test, variables with p < 0.05 were included in a hierarchical regression model. Variables with p < 0.05 in the corresponding level were kept in the model.
Results
A total of 427,548 cases of TB were included. Of these, 356,342 cases (83.35%; 95% confidence interval (CI) 83.23% - 83.45%) were PTB, 57,217 (13.37%; 95% CI 13.28% - 13.48%) were EPTB, 13,989 (3.27%; 95% CI 3.21% - 3.32%) were concurrent pulmonary and extrapulmonary TB. Patients with EPTB were mainly white (16.7%), and most (29.1%) patients had five to eight years of education. Among comorbidities, HIV infection was prominent (OR 2.15; 95% CI 2.09 – 2.21), although the proportion of cases awaiting test results or untested was high (39%). Ethanol use (OR 0.45; 95% CI 0.43 – 0.46), diabetes mellitus (OR 0.54; 95% CI 0.51 – 0.57) and mental illness (OR 0.88; 95% CI 0.82 – 0.95) were associated with PTB.
Conclusions
Thirteen percent of patients diagnosed with TB in Brazil have only EPTB. More effective diagnostic strategies and control measures are needed to reduce the number of cases of extrapulmonary TB in Brazil.
doi:10.1186/1471-2334-14-9
PMCID: PMC3893400  PMID: 24400848
4.  Obesity in the United States – Dysbiosis from Exposure to Low-Dose Antibiotics? 
The rapid increase in obesity prevalence in the United States in the last 20 years is unprecedented and not well explained. Here, we explore a hypothesis that the obesity epidemic may be driven by population-wide chronic exposures to low-residue antibiotics that have increasingly entered the American food chain over the same time period. We propose this hypothesis based on two recent bodies of published reports – (1) those that provide evidence for the spread of antibiotics into the American food chain, and (2) those that examine the relationship between the gut microbiota and body physiology. The livestock use of antimicrobial agents has sharply increased in the US over the same 20-year period of the obesity epidemic, especially with the expansion of intensified livestock production, such as the concentrated animal feeding operations. Observational and experimental studies support the idea that changes in the intestinal microbiota exert a profound effect on body physiology. We propose that chronic exposures to low-residue antimicrobial drugs in food could disrupt the equilibrium state of intestinal microbiota and cause dysbiosis that can contribute to changes in body physiology. The obesity epidemic in the United States may be partly driven by the mass exposure of Americans to food containing low-residue antimicrobial agents. While this hypothesis cannot discount the impact of diet and other factors associated with obesity, we believe studies are warranted to consider this possible driver of the epidemic.
doi:10.3389/fpubh.2013.00069
PMCID: PMC3867737  PMID: 24392444
obesity; antibiotic residues; intestinal microbiota; food chain; CAFOs; animal husbandry; polysaccharide diet
5.  Inhibition of TGF–β signaling in subchondral bone mesenchymal stem cells attenuates osteoarthritis 
Nature medicine  2013;19(6):704-712.
Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for osteoarthritis due to limited understanding of osteoarthritis pathogenesis. We show that TGF–β1 is activated in the subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) osteoarthritis mouse model. TGF–β1 concentrations also increased in human osteoarthritis subchondral bone. High concentrations of TGF–β1 induced formation of nestin+ mesenchymal stem cell (MSC) clusters leading to aberrant bone formation accompanied by increased angiogenesis. Transgenic expression of active TGF–β1 in osteoblastic cells induced osteoarthritis. Inhibition of TGF–β activity in subchondral bone attenuated degeneration of osteoarthritis articular cartilage. Notably, knockout of the TGF–β type II receptor (TβRII) in nestin+ MSCs reduced development of osteoarthritis in ACLT mice. Thus, high concentrations of active TGF–β1 in the subchondral bone initiated the pathological changes of osteoarthritis, inhibition of which could be a potential therapeutic approach.
doi:10.1038/nm.3143
PMCID: PMC3676689  PMID: 23685840
6.  Identification of novel antimicrobial resistance genes from microbiota on retail spinach 
BMC Microbiology  2013;13:272.
Background
Drug resistance genes and their mobile genetic elements are frequently identified from environmental saprophytic organisms. It is widely accepted that the use of antibiotics in animal husbandry selects for drug resistant microorganisms, which are then spread from the farm environment to humans through the consumption of contaminated food products. We wished to identify novel drug resistance genes from microbial communities on retail food products. Here, we chose to study the microbial communities on retail spinach because it is commonly eaten raw and has previously been associated with outbreaks of bacterial infections.
Results
We created metagenomic plasmid libraries from microbiota isolated from retail spinach samples. We identified five unique plasmids that increased resistance to antimicrobial drugs in the E. coli host. These plasmids were identified in E. coli that grew on plates that contained ampicillin (pAMP), aztreonam (pAZT), ciprofloxacin (pCIP), trimethoprim (pTRM), and trimethoprim-sulfamethoxazole (pSXT). We identified open reading frames with similarity to known classes of drug resistance genes in the DNA inserts of all 5 plasmids. These drug resistance genes conferred resistance to fluoroquinolones, cephalosporins, and trimethoprim, which are classes of antimicrobial drugs frequently used to treat human Gram negative bacterial infections. These results show that novel drug resistance genes are found in microbiota on retail produce items.
Conclusions
Here we show that microbiota of retail spinach contains DNA sequences previously unidentified as conferring antibiotic resistance. Many of these novel sequences show similarity to genes found in species of bacteria, which have previously been identified as commensal or saprophytic bacteria found on plants. We showed that these resistance genes are capable of conferring clinically relevant levels of resistance to antimicrobial agents. Food saprophytes may serve as an important reservoir for new drug-resistance determinants in human pathogens.
doi:10.1186/1471-2180-13-272
PMCID: PMC3890574  PMID: 24289541
Antibiotic resistance; Gram negative bacteria; Metagenomic library
7.  Extrapulmonary Tuberculosis: Mycobacterium tuberculosis Strains and Host Risk Factors in a Large Urban Setting in Brazil 
PLoS ONE  2013;8(10):e74517.
Background
Factors related to the development of extrapulmonary forms of tuberculosis (EPTB) are still poorly understood, particularly in high-endemic countries like Brazil. The objective of the paper is to determine host and Mycobacterium tuberculosis (MTB) strain-related factors associated with the development of EPTB in Espírito Santo state, Brazil.
Methods and Findings
We conducted a retrospective laboratory-based surveillance study of new tuberculosis (TB) cases diagnosed in Espírito Santo state, Brazil between 1998 and 2007. We genotyped 612 isolates of MTB from 606 TB patients using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) typing and compared sociodemographic and clinical characteristics of patients with pulmonary TB (PTB) and EPTB. Among 606 patients, 464 (77%) had PTB, 79 (13%) had EPTB, 51 (8%) had both, and 12 (2%) had miliary TB. The IS6110 RFLP analysis demonstrated that 250 (41%) isolates belonged to clustered RFLP patterns, 27 (11%) of which were from EPTB. We identified 73 clusters including 35 (48%) composed of 2 isolates each. By spoligotyping, 506 (83%) MTB isolates fell into known patterns and 106 (17%) fell into patterns with no family assignment; 297 (48%) isolates belonged to the Latin-American Mediterranean family. Higher school level (4-7 years OR: 0.16 95% CI 0.34-0.73 and > 8 years of education, OR 0.06 95% CI 0.009-0.50) white ethnicity (OR: 2.54 95% CI 1.03-6.25) and HIV infection (OR: 16.83 95% CI 5.23-54.18) were associated with EPTB. No specific strain lineage or percentage of clustering was associated with EPTB.
Conclusions
These results demonstrate that risk factors for EPTB are related more to host than to MTB strain lineage characteristics.
doi:10.1371/journal.pone.0074517
PMCID: PMC3788772  PMID: 24098337
8.  Blood Cells and Interferon-Gamma Levels Correlation in Latent Tuberculosis Infection 
ISRN pulmonology  2013;2013:256148.
The Mycobacterium tuberculosis (M. tb) infection is largely spread in world’s population. Most infected individuals develop latent tuberculosis infection (LTBI). Tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are the available tests to detect the infection. It has been reported that some individuals take a longer period of time to develop the infection than others with the same exposure level. It is suggested that the innate immunity, in which neutrophils have an important protective role, is responsible for this. Many hematologic abnormalities have been described as common findings during severe disease. To investigate if these changes are related to LTBI development and if they interfere in TST and IFN-γ production, we recruited 88 household contacts of tuberculosis (TB) pulmonary patients and compared blood cell counts with these tests’ results. There were no statistically significant changes in hemoglobin, hematocrit, platelets, global leukocyte, neutrophils, basophils, eosinophils, typical lymphocytes, atypical lymphocytes, and monocytes counts between infected and noninfected individuals. Also, there was no correlation between TST or IGRA and blood cell counts. These results suggest that blood cell counts are not LTBI markers and do not interfere in TST results or IFN-γ levels obtained by IGRA.
doi:10.1155/2013/256148
PMCID: PMC3769793  PMID: 24040564
9.  Prevalence and patterns of multimorbidity among tuberculosis patients in Brazil: a cross-sectional study 
Introduction
The number of subjects with tuberculosis (TB) presenting with co-occurrence of multiple chronic medical conditions, or multimorbidity (MM) is increasing in Brazil. This manuscript aimed to characterize subjects with TB, according to their MM status and to analyse factors associated with TB treatment outcomes.
Methods
This is a cross-sectional study that included 39,881 TB subjects reported in Brazil, in 2011. MM were defined as any (two or more) occurrence of chronic medical conditions in a TB patient (TB–MM). Data analysis was performed by hierarchical logistic regression models comparing TBMM with those with only TB.
Results
Of the reported TB cases in 2011, 454 (1.14%) had MM. The subjects in the age group 40–59 years (OR: 17.89; 95% CI, 5.71-56.03) and those ≥ 60 years (OR: 44.11; 95% CI, 14.09-138.06) were more likely to develop TB–MM. The TB–MM subjects were less likely to be male (OR: 0.63; 95% CI, 0.52-0.76), institutionalized (OR: 0.59; 95% CI, 0.23-0.80) and live in rural areas (OR: 0.63; 95% CI, 0.42-0.95). Death from causes other than TB was higher among TB–MM subjects (OR: 1.76; 95% CI, 1.36-2.28). Of 454 TB–MM subjects 302 (66.5%) were cured and 152 (33.5%) were not cured. The odds of not being cured was 1.55 (95% CI, 1.04-2.32) among males, 2.85 (95% CI, 1.12-7.28) among institutionalized subjects, and 3.93 (IC 95%, 1.86-8.30) among those who were infected with HIV. TB retreatment after previous abandonment (OR: 7.53; 95% CI, 2.58-21.97) and transfer from a treatment site (OR: 2.76; 95% CI, 1.20-6.38) were higher for subjects not cured compared to those who were cured.
Conclusions
While TB is well recognized to be a disease engendered by social inequity, we found that even among TB patients, those who have MM have greater inequity in terms of socioeconomic status and adverse clinical outcomes. Addressing the problem of TB and TB–MM requires a multisectorial approach that includes health and social service organizations.
doi:10.1186/1475-9276-12-61
PMCID: PMC3765118  PMID: 23962018
Tuberculosis; Multimorbidities; Inequity; Social determinants; Hierarchical models
10.  Clonal Composition and Community Clustering of Drug-Susceptible and -Resistant Escherichia coli Isolates from Bloodstream Infections 
Multidrug-resistant Escherichia coli strains belonging to a single lineage frequently account for a large proportion of extraintestinal E. coli infections in many parts of the world. However, limited information exists on the community prevalence and clonal composition of drug-susceptible E. coli strains. Between July 2007 and September 2010, we analyzed all consecutively collected Gram-negative bacterial isolates from patients with bloodstream infection (BSI) admitted to a public hospital in San Francisco for drug susceptibility and associated drug resistance genes. The E. coli isolates were genotyped for fimH single nucleotide polymorphisms (SNPs) and multilocus sequence types (MLSTs). Among 539 isolates, E. coli accounted for 249 (46%); 74 (30%) of them were susceptible to all tested drugs, and 129 (52%) were multidrug resistant (MDR). Only five MLST genotypes accounted for two-thirds of the E. coli isolates; the most common were ST131 (23%) and ST95 (18%). Forty-seven (92%) of 51 ST131 isolates, as opposed to only 8 (20%) of 40 ST95 isolates, were MDR (P < 0.0001). The Simpson's diversity index for drug-susceptible ST genotypes was 87%, while the index for MDR ST genotypes was 81%. ST95 strains were comprised of four fimH types, and one of these (f-6) accounted for 67% of the 21 susceptible isolates (P < 0.003). A large proportion (>70%) of both MDR and susceptible E. coli BSI isolates represented community-onset infections. These observations show that factors other than the selective pressures of antimicrobial agents used in hospitals contribute to community-onset extraintestinal infections caused by clonal groups of E. coli regardless of their drug resistance.
doi:10.1128/AAC.01025-12
PMCID: PMC3535975  PMID: 23147723
11.  Association between an Emerging Disseminated form of Leishmaniasis and Leishmania (Viannia) braziliensis Strain Polymorphisms 
Journal of Clinical Microbiology  2012;50(12):4028-4034.
Leishmania (Viannia) braziliensis causes three main types of American tegumentary leishmaniasis (ATL), localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL). All forms are observed among individuals of Corte de Pedra, Brazil. We previously used random amplified markers to identify a multiclonal population among L. (V.) braziliensis isolates from ATL patients, defining parasite clades associated with different clinical syndromes. Herein we compared sequences of random amplified markers to identify genotypes of L. (V.) braziliensis recovered from lesions of CL, ML, and DL patients. Six polymorphic genomic loci were sequenced from 35 parasite isolates. Single-nucleotide polymorphisms (SNPs) and insertions-deletions (indels) at each locus allowed us to segregate the L. (V.) braziliensis population according to haplotypes. Several SNPs, indels, and haplotypes were significantly associated with an increased risk of DL. Molecular genotyping may provide markers to identify L. (V.) braziliensis strains likely to cause this emerging, hard-to-treat form of ATL.
doi:10.1128/JCM.02064-12
PMCID: PMC3503016  PMID: 23035200
12.  Socio-Demographic and Clinical Differences in Subjects with Tuberculosis with and without Diabetes Mellitus in Brazil – A Multivariate Analysis 
PLoS ONE  2013;8(4):e62604.
Background
Several studies have evaluated the relationship between diabetes mellitus (DM) and tuberculosis (TB), but the nature of this relationship is not fully understood. TB incidence may be influenced by immunosuppression from DM, but this association may be confounded by other clinical and socioeconomic factors. We aimed to assess socio-demographic and clinical differences in TB patients with and without DM.
Methods
Using the Brazilian national surveillance system (SINAN), we compared 1,797 subjects with TB and DM with 29,275 subjects diagnosed with TB only in 2009. We performed multivariate analysis to identify factors associated with the presence of DM among TB patients.
Results
Subjects with TB – DM were older; have initial positive sputum smear test (OR = 1.42, 95% CI 1.26–1.60), and were more likely to die from TB (OR = 1.44, 95% CI 1.03–2.01). They were less likely to have been institutionalized [in prison, shelter, orphanage, psychiatric hospital (OR = 0.74, 95% CI 0.60–0.93)]; developed extra pulmonary TB (OR = 0.62, 95% CI 0.51–0.75) and to return to TB treatment after abandonment (OR = 0.66, 95% CI 0.51–0.86).
Conclusions
Prevalence of NCD continues to rise in developing countries, especially with the rise of elderly population, the prevention and treatment of infectious diseases will be urgent. DM and TB represent a critical intersection between communicable and non-communicable diseases in these countries and the effect of DM on TB incidence and outcomes provide numerous opportunities for collaboration and management of these complex diseases in the national public health programs.
doi:10.1371/journal.pone.0062604
PMCID: PMC3634755  PMID: 23638123
13.  Psychometric Properties of the Patient Activation Measure among Individuals Presenting for Elective Lumbar Spine Surgery 
Background
An individual’s propensity to engage in adaptive health and rehabilitation behaviors may account for variation in postsurgical outcome.
Purpose
To determine the psychometric properties and construct validity of the recently developed Patient Activation Measure (PAM) (previously unused in spine research) in persons undergoing elective lumbar spine surgery.
Methods
We prospectively used the PAM to assess activation in 283 patients undergoing elective lumbar spine surgery. Reliability statistics were computed using repeated assessment (baseline and 1-week follow-up) before surgery. Additional psychological attributes were assessed at baseline and correlated with patient activation. Factor analysis was used to confirm the theoretical structure of patient activation.
Results
Repeat PAM administrations had an intraclass correlation coefficient of 0.85. The PAM showed positive correlation with optimism (r = 0.75), hope (r = 0.73), self-efficacy (r = 0.65), and internal locus of control (r = 0.65) but no correlation with comorbidity (r = 0.01). Confirmatory factor analysis of the PAM items indicated reasonable fit between observed data and a three-factor patient activation model.
Conclusions
The PAM is a reliable, valid measure of patient activation for individuals undergoing elective lumbar spine surgery and may have clinical utility in identify those at risk for poor engagement in postsurgical rehabilitation.
doi:10.1007/s11136-009-9549-0
PMCID: PMC3561629  PMID: 19916057
Patient Activation Measure; Validation; Positive psychology; Lumbar spine surgery
14.  An adjunctive therapeutic vaccine against reactivation and post-treatment relapse tuberculosis 
Vaccine  2011;30(2):459-465.
Preventing latently infected or inadequately treated individuals from progressing to active disease could make a major impact on tuberculosis (TB) control worldwide. The purpose of this study was to evaluate a new approach to prevent reactivation and TB relapse that combines drug treatment and vaccination. Mycobacterium tuberculosis harbors a gene called mce1R that, in vivo, negatively regulates a 13-gene cluster called the mce1 operon. In a Cornell mouse model, BALB/c mice infected with M. tuberculosis H37Rv disrupted in mce1R consistently develop latent infection and reactivation disease. We used this new mouse model to test a recombinant M. tuberculosis cell wall protein (Mce1A), encoded by a gene in the mce1 operon, for its ability to prevent post-treatment TB. At 32 weeks of follow-up, a complete sterilizing protection was observed in lungs of the vaccinated mice. Mce1A but not phosphate-buffered saline administered intraperitoneally during the period of latent infection prevented disease progression and proliferation of M. tuberculosis mce1R mutant. The only visible lung lesions in vaccinated mice included small clusters of lymphocytes, while the unvaccinated mice showed progressively enlarging granulomas comprised of foamy macrophages surrounded by lymphocytes. The combination of anti-TB drugs and a vaccine may serve as a powerful treatment modality against TB reactivation and relapse.
doi:10.1016/j.vaccine.2011.10.052
PMCID: PMC3246084  PMID: 22079078
tuberculosis; latent TB infection; adjunctive TB vaccine; therapeutic TB vaccine; mce1 operon; mce1R
15.  Levels of Interferon-Gamma Increase after Treatment for Latent Tuberculosis Infection in a High-Transmission Setting 
Pulmonary Medicine  2012;2012:757152.
Objectives. We investigated IFN-γ levels before and after a six month course of isoniazid among individuals with latent tuberculosis infection (LTBI) in a high-transmission setting. Design. A total of 26 household contacts of pulmonary tuberculosis patients who were positive for LTBI by tuberculin skin test completed six months of treatment and submitted a blood sample for a follow-up examination. The IFN-γ response to Mycobacterium tuberculosis-specific antigens was measured, and the results before and after the completion of LTBI treatment were compared. Results. Of the 26 study participants, 25 (96%) showed an IFN-γ level higher than their baseline level before treatment (P ≤ 0.001). Only one individual had a decreased IFN-γ level after treatment but remained positive for LTBI. Conclusion. In a high-transmission setting, the IFN-γ level has increased after LTBI treatment. Further studies must be undertaken to understand if this elevation is transient.
doi:10.1155/2012/757152
PMCID: PMC3539439  PMID: 23320165
16.  gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma 
The New England journal of medicine  2011;364(22):2119-2127.
Background
Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209–217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone.
Methods
We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA⋆A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209–217(210M) plus incomplete Freund’s adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival.
Results
The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine–interleukin-2 group, as compared with the interleukin-2–only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P = 0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P = 0.008). The median overall survival was also longer in the vaccine–interleukin-2 group than in the interleukin-2–only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P = 0.06).
Conclusions
In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.)
doi:10.1056/NEJMoa1012863
PMCID: PMC3517182  PMID: 21631324
17.  Influence of HTLV-1 on the clinical, microbiologic and immunologic presentation of tuberculosis 
BMC Infectious Diseases  2012;12:199.
Background
HTLV-1 is associated with increased susceptibility to Mycobacterium tuberculosis infection and severity of tuberculosis. Although previous studies have shown that HTLV-1 infected individuals have a low frequency of positive tuberculin skin test (TST) and decreasing in lymphoproliferative responses compared to HTLV-1 uninfected persons, these studies were not performed in individuals with history of tuberculosis or evidence of M. tuberculosis infection. Therefore the reasons why HTLV-1 infection increases susceptibility to infection and severity of tuberculosis are not understood.The aim of this study was to evaluate how HTLV-1 may influence the clinical, bacteriologic and immunologic presentation of tuberculosis.
Methods
The study prospectively enrolled and followed 13 new cases of tuberculosis associated with HTLV-1 (cases) and 25 patients with tuberculosis without HTLV-1 infection (controls). Clinical findings, bacterial load in the sputum, x-rays, immunological response and death were compared in the two groups.
Results
There were no differences in the demographic, clinical and TST response between the two study groups. IFN-γ and TNF-α production was higher in unstimulated cultures of mononuclear cells of case than in control patients (p < 0.01). While there was no difference in IFN-γ production in PPD stimulated cultures, TNF-α levels were lower in cases than in controls (p = 0.01). There was no difference in the bacterial load among the groups but sputum smear microscopy results became negative faster in cases than in controls. Death only occurred in two co-infected patients.
Conclusion
While the increased susceptibility for tuberculosis infection in HTLV-1 infected subjects may be related to impairment in TNF-α production, the severity of tuberculosis in co-infected patients may be due to the enhancement of the Th1 inflammatory response, rather than in their decreased ability to control bacterial growth.
doi:10.1186/1471-2334-12-199
PMCID: PMC3449207  PMID: 22925731
HTLV-1; Tuberculosis; Mycobacterium tuberculosis
18.  Surgery for Valvular Heart Disease: A Population-Based Study in a Brazilian Urban Center 
PLoS ONE  2012;7(5):e37855.
Background
In middle income countries, the burden of rheumatic heart disease (RHD) remains high, but the prevalence of other heart valve diseases may rise as the population life expectancy increases. Here, we compared population-based data on surgical procedures to assess the relative importance of causes of heart valve disease in Salvador, Brazil.
Methodology/Principal Findings
Medical charts of patients who underwent surgery for valvular heart disease from January 2002–December 2005 were reviewed. Incidence of surgery for valvular heart disease was calculated. Logistic regression was used to identify factors associated with in-hospital death following surgery. The most common etiologies for valvular dysfunction in 491 valvular heart surgery patients were RHD (60.3%), degenerative valve disease (15.3%), and endocarditis (4.5%). Mean annual incidence for surgeries due to any valvular heart diseases, RHD, and degenerative valvular disease were 5.02, 3.03, and 0.77 per 100,000 population, respectively. Incidence of surgery due to RHD was highest in young adults; procedures were predominantly paid by the public health sector. In contrast, the incidence of surgery due to degenerative valvular disease was highest among those older than 60 years of age; procedures were mostly paid by the private sector. The overall in-hospital case-fatality ratio was 11.9%. Independent factors associated with death included increase in age (odds ratio: 1.04 per year of age; 95% confidence interval: 1.02–1.06), endocarditis (6.35; 1.92–21.04), multiple valve operative procedures (4.35; 2.12–8.95), and prior heart valve surgery (2.49; 1.05–5.87).
Conclusions/Significance
RHD remains the main cause for valvular heart surgery in Salvador, which primarily affects young adults without private health insurance. In contrast, surgery due to degenerative valvular disease primarily impacts the elderly with private health insurance. Strategies to reduce the burden of valvular heart disease will need to address the disparate factors that contribute to RHD as well as degenerative valve disease.
doi:10.1371/journal.pone.0037855
PMCID: PMC3362603  PMID: 22666401
19.  Acinetobacter soli as a Cause of Bloodstream Infection in a Neonatal Intensive Care Unit▿ 
Journal of Clinical Microbiology  2011;49(6):2283-2285.
Acinetobacter soli is a new bacterial species described from forest soil. Five cases of bloodstream infection caused by A. soli clonal isolates are reported here for the first time. The patients were neonates admitted to an intensive care unit. This is a new neonatal pathogen with the potential to cause outbreaks.
doi:10.1128/JCM.00326-11
PMCID: PMC3122775  PMID: 21525230
20.  Mce2 operon mutant strain of Mycobacterium tuberculosis is attenuated in C57BL/6 mice 
Summary
Mycobacterium tuberculosis genome contains four related sets of an operon called mce (mce1-4). The disruption of one of these operons, mce1, causes M. tuberculosis to become hypervirulent, whereas the mce3 and mce4 operon mutants are attenuated in mice. This study examined the phenotype of the mce2 operon mutant. The deletion of mce2 operon in M. tuberculosis H37Rv had no effect on bacterial growth in 7H9 liquid broth or survival within macrophages. However, RAW macrophage-like cells infected with the mutant strain were reduced in their ability to produce TNF-α, IL-6 and MCP-1. In C57BL/6 mouse lungs, the mce2 operon mutant and wild type H37Rv replicated similarly up to 20 weeks of infection. However, by 56 weeks of infection, all mice infected with the wild type H37Rv had died, while 80% of those infected with the mutant remained alive (P< 0.0001). The proportion of affected lung parenchyma in mice infected with the mutant was substantially less than that of mice infected with the wild type for the same time periods of infection. These observations suggest that the mce2 operon mutant is attenuated, and that this attenuation is related not to the bacterial burden but to the mutant’s decreased ability to elicit a type of immune response and lung pathology detrimental to the survival of the animal.
doi:10.1016/j.tube.2009.10.004
PMCID: PMC3228843  PMID: 19963438
Mycobacterium tuberculosis; mce operons; mce2 operon mutant
21.  Attenuation of Mycobacterium tuberculosis functionally disrupted in a fatty acyl-CoA synthetase gene fadD5 
The Journal of infectious diseases  2010;201(8):1232-1239.
One key adaptation that Mycobacterium tuberculosis established to survive long term in vivo is a reliance on lipids as an energy source. M. tuberculosis H37Rv has 36 fadD genes annotated as putative fatty acyl-CoA synthetase genes, which encode enzymes that activate fatty acids for metabolism. One such gene, fadD5 (Rv0166), is located within the mce1 operon, a cluster of genes associated with M. tuberculosis persistence. We disrupted the putative fatty acid binding site of fadD5 in H37Rv M. tuberculosis. No significant differences were found in the growth of the mutant and wild-type strains in vitro in nutrient-rich broth or in activated RAW264.7 cells. However, the fadD5 mutant was diminished in growth in minimal medium containing mycolic acid, but not other long-chain fatty acids. C57BL/6 mice infected with the fadD5 mutant survived significantly longer than those infected with wild-type, and the mutant never attained the plateau phase of infection in the mouse lungs. The steady-state infection phase was maintained for up to 168 days at a level one to two logs less than that shown by wild-type. These observations raise a rather intriguing possibility that FadD5 may serve to recycle mycolic acids for the long-term survival of the tubercle bacilli.
doi:10.1086/651452
PMCID: PMC3225055  PMID: 20214478
Mycobacterium tuberculosis; fatty acyl-CoA synthetase; fadD; mce1 operon; fatty acid metabolism
23.  A cluster of Listeria monocytogenes infections in hospitalized adults 
Background
Listeriosis occurs mainly in persons at extremes of age and with immunocompromising conditions. It is believed that most cases of listeriosis are acquired in the community. A cluster of listeriosis in hospitalized patients prompted the present investigation.
Methods
Case series of listeriosis, from 21 August 2006 to 01 June 2007, in a hospital in the city of Rio de Janeiro, Brazil.
Results
Six patients with Listeria monocytogenes infection were identified: 5 during hospitalization and one at a day-clinic. By the time the infection was diagnosed, five patients had been in the hospital for a mean of 9 days. All patients were elderly (median age: 80 years) and had immunocompromising conditions. Five (83%) patients died. Four patients developed bloodstream infections, 3 caused by serotype 1/2b. Two had peritonitis, one caused by serotype 3b and another by serotype 1/2b. Four L. monocytogenes isolates belonged to a single PFGE genotype, suggesting a common source. An epidemiological investigation pointed to the hospital kitchen as the possible contamination.
Conclusions
Data suggest a healthcare associated outbreak of listeriosis and highlight the importance of developing guidelines for prevention and treatment of healthcare associated foodborne diseases, especially in hospitals with immunocompromised adult patients.
doi:10.1016/j.ajic.2010.02.014
PMCID: PMC2952061  PMID: 20570397
24.  Modulation of Transcriptional and Inflammatory Responses in Murine Macrophages by the Mycobacterium tuberculosis Mammalian Cell Entry (Mce) 1 Complex 
PLoS ONE  2011;6(10):e26295.
The outcome of many infections depends on the initial interactions between agent and host. Aiming at elucidating the effect of the M. tuberculosis Mce1 protein complex on host transcriptional and immunological responses to infection with M. tuberculosis, RNA from murine macrophages at 15, 30, 60 min, 4 and 10 hrs post-infection with M. tuberculosis H37Rv or Δ-mce1 H37Rv was analyzed by whole-genome microarrays and RT-QPCR. Immunological responses were measured using a 23-plex cytokine assay. Compared to uninfected controls, 524 versus 64 genes were up-regulated by 15 min post H37Rv- and Δ-mce1 H37Rv-infection, respectively. By 15 min post-H37Rv infection, a decline of 17 cytokines combined with up-regulation of Ccl24 (26.5-fold), Clec4a2 (23.2-fold) and Pparγ (10.5-fold) indicated an anti-inflammatory response initiated by IL-13. Down-regulation of Il13ra1 combined with up-regulation of Il12b (30.2-fold), suggested switch to a pro-inflammatory response by 4 hrs post H37Rv-infection. Whereas no significant change in cytokine concentration or transcription was observed during the first hour post Δ-mce1 H37Rv-infection, a significant decline of IL-1b, IL-9, IL-13, Eotaxin and GM-CSF combined with increased transcription of Il12b (25.1-fold) and Inb1 (17.9-fold) by 4 hrs, indicated a pro-inflammatory response. The balance between pro-and anti-inflammatory responses during the early stages of infection may have significant bearing on outcome.
doi:10.1371/journal.pone.0026295
PMCID: PMC3200323  PMID: 22039457
25.  Post-treatment reactivation tuberculosis in mice caused by Mycobacterium tuberculosis disrupted in mce1R 
The Journal of infectious diseases  2010;202(5):752-759.
Background
Reactivation tuberculosis (TB) arises from those who are latently infected or from those who have been previously treated. The mechanism of reactivation TB in either situation is not well understood. A 13-gene mce1 operon of M. tuberculosis was previously shown to be associated with latent infection in mice, and may also play a role in reactivation.
Methods
We tested mce1 operon Mycobacterium tuberculosis mutants in a Cornell mouse model to examine disease progression and reactivation.
Results
In BALB/c mice, the wild type, mce1 operon mutant, and mce1R (negative transcriptional regulator of the mce1 operon) mutant M. tuberculosis strains were equally susceptible to orally administered isoniazid and pyrazinamide. However, after cessation of the treatment, the mce1R mutant rapidly and progressively proliferated in mouse lungs and spleen, while the other strains remained latent. The reactivation of the mce1R mutant was associated with disease progression in the mouse lungs.
Conclusions
This observation demonstrates that the constitutive expression of the mce1 genes by M. tuberculosis in latent state can cause reactivation TB. The constitutive expression of the mce1 genes in the mce1R mutant may allow this mutant to maintain its lipid metabolism, enabling it to survive long term and proliferate inside granulomas.
doi:10.1086/655224
PMCID: PMC2916974  PMID: 20629532
Reactivation tuberculosis; mce1 operon; Mycobacterium tuberculosis; Cornell mouse model

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