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author:("cdoda, Julio")
1.  Prisons as Reservoir for Community Transmission of Tuberculosis, Brazil 
Emerging Infectious Diseases  2015;21(3):452-455.
We conducted a population-based study of tuberculosis (TB) cases in Dourados, Brazil, to assess the relationship between incarceration and TB in the general population. Incarceration was associated with TB in an urban population; 54% of Mycobacterium tuberculosis strains were related to strains from persons in prisons. TB control in prisons is critical for reducing disease prevalence.
PMCID: PMC4344267  PMID: 25642998
tuberculosis and other mycobacteria; Mycobacterium tuberculosis; bacteria; prisoners; reservoir; community transmission; genotyping; case–control study; epidemiology; Brazil
2.  Active and latent tuberculosis in Brazilian correctional facilities: a cross-sectional study 
Tuberculosis (TB) rates among prisoners are more than 20 times that of the general population in Brazil, yet there are limited data available to facilitate the development of effective interventions in this high-transmission setting. We aimed to assess risk factors for TB infection and evaluate the yield of mass screening for active disease among inmates.
We administered a questionnaire and tuberculin skin test (TST) to a population-based sample of inmates from 12 prisons in Central-West Brazil and collected sera for HIV testing and two sputum samples for smear microscopy and culture from participants reporting a cough of any duration. Hierarchical Poisson regression models were used to evaluate factors associated with latent tuberculosis infection (LTBI).
We recruited 3,380 inmates, of which 2,861 (84.6%) were males from 8 prisons, and 519 (15.4%) were females from 4 prisons. Among the 1,020 (30%) subjects who reported a cough, we obtained sputum from 691 (68%) and identified 31 cases of active TB for a point prevalence of 917 (95% CI, 623–1302) per 100,000 prisoners. Evaluation of the two sputum smear samples failed to identify 74% of the TB cases, and 29% of the cases reported less than 2 weeks of symptoms. Obtaining a second culture identified an additional 7 (24%) cases. The prevalences of LTBI were 22.5% and 11.7% for male and female prisoners, respectively and duration of incarceration (in years) was associated with LTBI in male and female in the multivariable model (1.04, 95% CI, 1.01-1.07 and 1.34, 95% CI, 1.06-1.70, respectively). The prevalence of LTBI is 8.6% among newly incarcerated inmates, among whom LTBI prevalence significantly increased by 5% with each year of incarceration.
Although the overall LTBI prevalence among inmates in Central-West Brazil is low, tuberculosis incidence is high (>1,800/100,00), likely due to the high force of infection among a largely susceptible inmate population. Efforts to reduce transmission in prisons may require mass screening for active TB, utilizing sputum culture in case-detection protocols.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0764-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4307675  PMID: 25608746
Tuberculosis; Prisoners; TST; Infection; Active case detection; Screening cross-sectional study; Brazil; Epidemiology
4.  Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit 
Critical care medicine  2009;37(5):1605-1611.
To evaluate the impact of antiretroviral therapy (ART) and the prognostic factors for in-intensive care unit (ICU) and 6-month mortality in human immunodeficiency virus (HIV)-infected patients.
A retrospective cohort study was conducted in patients admitted to the ICU from 1996 through 2006. The follow-up period extended for 6 months after ICU admission.
The ICU of a tertiary-care teaching hospital at the Universidade de São Paulo, Brazil.
A total of 278 HIV-infected patients admitted to the ICU were selected. We excluded ICU readmissions (37), ICU admissions who stayed less than 24 hours (44), and patients with unavailable medical charts (36).
Outcome Measure
In-ICU and 6-month mortality.
Main Results
Multivariate logistic regression analysis and Cox proportional hazards models demonstrated that the variables associated with in-ICU and 6-month mortality were sepsis as the cause of admission (odds ratio [OR] = 3.16 [95% confidence interval [CI] 1.65– 6.06]); hazards ratio [HR] = 1.37 [95% CI 1.01–1.88]), an Acute Physiology and Chronic Health Evaluation II score > 19 [OR = 2.81 (95% CI 1.57–5.04); HR = 2.18 (95% CI 1.62–2.94)], mechanical ventilation during the first 24 hours [OR = 3.92 (95% CI 2.20–6.96); HR = 2.25 (95% CI 1.65–3.07)], and year of ICU admission [OR = 0.90 (95% CI 0.81– 0.99); HR = 0.92 [95% CI 0.87– 0.97)]. CD4 T-cell count <50 cells/mm3 was only associated with ICU mortality [OR = 2.10 (95% CI 1.17– 3.76)]. The use of ART in the ICU was negatively predictive of 6-month mortality in the Cox model [HR = 0.50 (95% CI 0.35– 0.71)], especially if this therapy was introduced during the first 4 days of admission to the ICU [HR = 0.58 (95% CI 0.41– 0.83)]. Regarding HIV-infected patients admitted to ICU without using ART, those who have started this treatment during ICU stay presented a better prognosis when time and potential confounding factors were adjusted for [HR 0.55 (95% CI 0.31– 0.98)].
The ICU outcome of HIV-infected patients seems to be dependent not only on acute illness severity, but also on the administration of antiretroviral treatment. (Crit Care Med 2009; 37: 000–000)
PMCID: PMC4143892  PMID: 19325488
intensive care; human immunodeficiency virus; acquired immunodeficiency syndrome; antiretroviral therapy; prognostic factors; critical care; mortality
5.  Evaluation of the anti-mycobacterium tuberculosis activity and in vivo acute toxicity of Annona sylvatic 
The recent emergence of extensively multidrug-resistant Mycobacterium tuberculosis strains has further complicated the control of tuberculosis. There is an urgent need for the development of new molecular candidates antitubercular drugs. Medicinal plants have been an excellent source of leads for the development of drugs. The aim of this study was to evaluate the in vitro activity of 28 alcoholic extracts and essential oils of native and exotic Brazilian plants against Mycobacterium tuberculosis and to further study these extracts through chemical fractionation, the isolation of their constituents, and an evaluation of the in vivo acute toxicity of the active extracts. To the best of our knowledge this is the first chemical characterization, antituberculosis activity and acute toxicity evaluation of Annona sylvatica.
The anti-mycobacterial activity of these extracts and their constituent compounds was evaluated using the resazurin reduction microtiter assay (REMA). To investigate the acute toxicity of these extracts in vivo, female Swiss mice were treated with the extracts at doses of 500, 1000 and 2000 mg · kg-1 of body weight. The extracts were characterized by LC-MS, and the constituents were isolated and identified by chromatographic analysis of spectroscopic data.
Of the 28 extracts, the methanol extract obtained from the leaves of Annona sylvatica showed anti-mycobacterial activity with an minimal inhibitory concentration (MIC) of 184.33 μg/mL, and the ethyl acetate fraction (EAF) resulting from liquid-liquid partitioning of the A. sylvatica extract showed an MIC of 115.2 μg/mL. The characterization of this extract by LC-MS identified flavonoids and acetogenins as its main constituents. The phytochemical study of the A. sylvatica EAF resulted in the isolation of quercetin, luteolin, and almunequin.
Among the compounds isolated from the EAF, luteolin and almunequin were the most promising, with MICs of 236.8 μg/mL (827.28 μM) and 209.9 μg/mL (328.48 μM), respectively. The acute administration of the EAF fraction in doses of 500, 1000, and 2000 mg · kg-1 of body weight did not cause signs of toxicity in the treated animals.
PMCID: PMC4082671  PMID: 24974069
Mycobacterium tuberculosis; Annona sylvatica; Resazurin reduction toxicity; Luteolin; Almunequin
6.  Health-service performance of TB treatment for indigenous and non-indigenous populations in Brazil: a cross-sectional study 
Health-service evaluation studies are fundamental for proposing interventions and ensuring improvements in healthcare quality. The present study assesses the performance of health services for indigenous and non-indigenous populations with regard to tuberculosis (TB) control.
Interviews with TB patients who underwent treatment between 2009 and 2011 were conducted using the Primary Care Assessment Tool adapted for TB care in Brazil.
Primary healthcare (PHC) was the first treatment for most patients at symptom onset, and the diagnoses were typically performed by specialized services. Many patients experienced delayed TB diagnoses that required more than three medical appointments (51% and 47% for indigenous and non-indigenous populations, respectively). Indigenous people received social support, such as basic-needs grocery packages (2.19 ± 1.63 vs. 1.13 ± 0.49 for non-indigenous people, p < 0.01) and home visits from health professionals, with an emphasis on the performance of directly observed treatment strategies (DOT; 4.57 ± 0.89 vs. 1.68 ± 1.04 for non-indigenous people, p < 0.01).
Regardless of the differences between indigenous and non-indigenous populations, the time needed to receive a TB diagnosis was unsatisfactory for both groups. Furthermore, DOT must be performed with better coverage among non-indigenous patients.
PMCID: PMC4049501  PMID: 24885134
Tuberculosis; Indigenous; Prevention; Control; Health services
7.  Evaluation of the traditional and revised world health organization classifications of dengue cases in Brazil 
Clinics  2013;68(10):1299-1304.
Dengue is a worldwide public health problem with approximately 50 million cases reported annually. The World Health Organization proposed a revised classification system in 2008 to more effectively identify the patients who are at increased risk of complications from dengue. Few studies have validated this new classification system in clinical practice. We conducted a cross-sectional study of patients hospitalized for dengue in Dourados, Mato Grosso do Sul, Brazil, to evaluate the capacity of the two classification systems for detecting severe cases of dengue.
We conducted a cross-sectional study of survey data from the medical records of patients admitted to the University Hospital of the Federal University of Grande Dourados under clinical suspicion of dengue during an epidemic from September 2009 to April 2010.
The distribution of patients according to the traditional classification system was as follows: dengue fever, 150/181 (82.9%); dengue hemorrhagic fever, 27/181 (14.9%); and dengue hemorrhagic shock, 4/181 (2.2%). Using the revised classification system, the distribution was as follows: dengue without warning signs, 45/181 (24.3%); dengue with warning signs, 107/181 (59.1%); and severe dengue, 29/181 (15.6%). Of the 150 patients classified as having dengue fever, 105 (70%) were reclassified as having dengue with warning signs or severe dengue.
These data demonstrate that the revised classification system has greater discriminatory power for detecting patients at risk of progression to severe disease and those needing hospitalization.
PMCID: PMC3798712  PMID: 24212835
Dengue; Dengue Hemorrhagic Fever; Dengue Shock; Severe Dengue; Case Classification
8.  Impact of Latent Infection Treatment in Indigenous Populations 
PLoS ONE  2013;8(7):e71201.
The aims of the present study were to identify risk factors associated with latent tuberculosis (TB), examine the development of active disease among contacts, and assess the effectiveness of treating latent infection in indigenous Brazilians from January 2006 to December 2011. This was a retrospective study consisting of 1,371 tuberculosis contacts, 392 of whom underwent treatment for latent infection. Morbidity-from-TB data were obtained from the Information System for Disease Notification (SINAN) database, and the contacts’ data were collected from the clinical records using forms employed by Special Department of Indigenous Health (SESAI) multidisciplinary teams, according to SESAI’s instructions. The variables that were associated with latent infection among the contacts were age (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.02–1.04) and close contact with a smear-positive index case (OR: 2.26, 95% CI: 1.59–3.22). The variables associated with the development of active TB among the contacts were a tuberculin skin test (TST) ≥10 mm (relative risk [RR]: 1.12, 95% CI: 1.07–1.17), age (RR: 1.01, 95% CI: 1.00–1.03), and treatment of latent infection (RR: 0.03, 95% CI: 0.01–0.27). The estimated number of latent infection treatments needed to prevent one case of active TB among the contacts was 51 treatments (95% CI: 33–182). In contacts with TST ≥10 mm, 10 (95% CI: 6–19) latent infection treatments were necessary to prevent one case of active TB. Age and close contact with a smear-positive index case were associated with latent TB. Screening with TST is a high priority among individuals contacting smear-positive index cases. Age and TST are associated with the development of active TB among contacts, and treatment of latent infection is an effective measure to control TB in indigenous communities.
PMCID: PMC3729554  PMID: 23936264
9.  Heterologous expression of pathogen-specific genes ligA and ligB in the saprophyte Leptospira biflexa confers enhanced adhesion to cultured cells and fibronectin 
BMC Microbiology  2011;11:129.
In comparison to other bacterial pathogens, our knowledge of the molecular basis of the pathogenesis of leptospirosis is extremely limited. An improved understanding of leptospiral pathogenetic mechanisms requires reliable tools for functional genetic analysis. Leptospiral immunoglobulin-like (Lig) proteins are surface proteins found in pathogenic Leptospira, but not in saprophytes. Here, we describe a system for heterologous expression of the Leptospira interrogans genes ligA and ligB in the saprophyte Leptospira biflexa serovar Patoc.
The genes encoding LigA and LigB under the control of a constitutive spirochaetal promoter were inserted into the L. biflexa replicative plasmid. We were able to demonstrate expression and surface localization of LigA and LigB in L. biflexa. We found that the expression of the lig genes significantly enhanced the ability of transformed L. biflexa to adhere in vitro to extracellular matrix components and cultured cells, suggesting the involvement of Lig proteins in cell adhesion.
This work reports a complete description of the system we have developed for heterologous expression of pathogen-specific proteins in the saprophytic L. biflexa. We show that expression of LigA and LigB proteins from the pathogen confers a virulence-associated phenotype on L. biflexa, namely adhesion to eukaryotic cells and fibronectin in vitro. This study indicates that L. biflexa can serve as a surrogate host to characterize the role of key virulence factors of the causative agent of leptospirosis.
PMCID: PMC3133549  PMID: 21658265
10.  The Multifunctional LigB Adhesin Binds Homeostatic Proteins with Potential Roles in Cutaneous Infection by Pathogenic Leptospira interrogans 
PLoS ONE  2011;6(2):e16879.
Leptospirosis is a potentially fatal zoonotic disease in humans and animals caused by pathogenic spirochetes, such as Leptospira interrogans. The mode of transmission is commonly limited to the exposure of mucous membrane or damaged skin to water contaminated by leptospires shed in the urine of carriers, such as rats. Infection occurs during seasonal flooding of impoverished tropical urban habitats with large rat populations, but also during recreational activity in open water, suggesting it is very efficient. LigA and LigB are surface localized proteins in pathogenic Leptospira strains with properties that could facilitate the infection of damaged skin. Their expression is rapidly induced by the increase in osmolarity encountered by leptospires upon transition from water to host. In addition, the immunoglobulin-like repeats of the Lig proteins bind proteins that mediate attachment to host tissue, such as fibronectin, fibrinogen, collagens, laminin, and elastin, some of which are important in cutaneous wound healing and repair. Hemostasis is critical in a fresh injury, where fibrinogen from damaged vasculature mediates coagulation. We show that fibrinogen binding by recombinant LigB inhibits fibrin formation, which could aid leptospiral entry into the circulation, dissemination, and further infection by impairing healing. LigB also binds fibroblast fibronectin and type III collagen, two proteins prevalent in wound repair, thus potentially enhancing leptospiral adhesion to skin openings. LigA or LigB expression by transformation of a nonpathogenic saprophyte, L. biflexa, enhances bacterial adhesion to fibrinogen. Our results suggest that by binding homeostatic proteins found in cutaneous wounds, LigB could facilitate leptospirosis transmission. Both fibronectin and fibrinogen binding have been mapped to an overlapping domain in LigB comprising repeats 9–11, with repeat 11 possibly enhancing binding by a conformational effect. Leptospirosis patient antibodies react with the LigB domain, suggesting applications in diagnosis and vaccines that are currently limited by the strain-specific leptospiral lipopolysaccharide coats.
PMCID: PMC3036719  PMID: 21347378
11.  Genome-Wide Transposon Mutagenesis in Pathogenic Leptospira Species▿ ‡  
Infection and Immunity  2008;77(2):810-816.
Leptospira interrogans is the most common cause of leptospirosis in humans and animals. Genetic analysis of L. interrogans has been severely hindered by a lack of tools for genetic manipulation. Recently we developed the mariner-based transposon Himar1 to generate the first defined mutants in L. interrogans. In this study, a total of 929 independent transposon mutants were obtained and the location of insertion determined. Of these mutants, 721 were located in the protein coding regions of 551 different genes. While sequence analysis of transposon insertion sites indicated that transposition occurred in an essentially random fashion in the genome, 25 unique transposon mutants were found to exhibit insertions into genes encoding 16S or 23S rRNAs, suggesting these genes are insertional hot spots in the L. interrogans genome. In contrast, loci containing notionally essential genes involved in lipopolysaccharide and heme biosynthesis showed few transposon insertions. The effect of gene disruption on the virulence of a selected set of defined mutants was investigated using the hamster model of leptospirosis. Two attenuated mutants with disruptions in hypothetical genes were identified, thus validating the use of transposon mutagenesis for the identification of novel virulence factors in L. interrogans. This library provides a valuable resource for the study of gene function in L. interrogans. Combined with the genome sequences of L. interrogans, this provides an opportunity to investigate genes that contribute to pathogenesis and will provide a better understanding of the biology of L. interrogans.
PMCID: PMC2632054  PMID: 19047402
12.  Targeted Mutagenesis in Pathogenic Leptospira Species: Disruption of the LigB Gene Does Not Affect Virulence in Animal Models of Leptospirosis▿  
Infection and Immunity  2008;76(12):5826-5833.
The pathogenic mechanisms of Leptospira interrogans, the causal agent of leptospirosis, remain largely unknown. This is mainly due to the lack of tools for genetically manipulating pathogenic Leptospira species. Thus, homologous recombination between introduced DNA and the corresponding chromosomal locus has never been demonstrated for this pathogen. Leptospiral immunoglobulin-like repeat (Lig) proteins were previously identified as putative Leptospira virulence factors. In this study, a ligB mutant was constructed by allelic exchange in L. interrogans; in this mutant a spectinomycin resistance (Spcr) gene replaced a portion of the ligB coding sequence. Gene disruption was confirmed by PCR, immunoblot analysis, and immunofluorescence studies. The ligB mutant did not show decrease virulence compared to the wild-type strain in the hamster model of leptospirosis. In addition, inoculation of rats with the ligB mutant induced persistent colonization of the kidneys. Finally, LigB was not required to mediate bacterial adherence to cultured cells. Taken together, our data provide the first evidence of site-directed homologous recombination in pathogenic Leptospira species. Furthermore, our data suggest that LigB does not play a major role in dissemination of the pathogen in the host and in the development of acute disease manifestations or persistent renal colonization.
PMCID: PMC2583567  PMID: 18809657
13.  Pathogenic Leptospira species express surface-exposed proteins belonging to the bacterial immunoglobulin superfamily 
Molecular microbiology  2003;49(4):929-945.
Proteins with bacterial immunoglobulin-like (Big) domains, such as the Yersinia pseudotuberculosis invasin and Escherichia coli intimin, are surface-expressed proteins that mediate host mammalian cell invasion or attachment. Here, we report the identification and characterization of a new family of Big domain proteins, referred to as Lig (leptospiral Ig-like) proteins, in pathogenic Leptospira. Screening of L. interrogans and L. kirschneri expression libraries with sera from leptospirosis patients identified 13 lambda phage clones that encode tandem repeats of the 90 amino acid Big domain. Two lig genes, designated ligA and ligB, and one pseudo-gene, ligC, were identified. The ligA and ligB genes encode amino-terminal lipoprotein signal peptides followed by 10 or 11 Big domain repeats and, in the case of ligB, a unique carboxy-terminal non-repeat domain. The organization of ligC is similar to that of ligB but contains mutations that disrupt the reading frame. The lig sequences are present in pathogenic but not saprophytic Leptospira species. LigA and LigB are expressed by a variety of virulent leptospiral strains. Loss of Lig protein and RNA transcript expression is correlated with the observed loss of virulence during culture attenuation of pathogenic strains. High-pressure freeze substitution followed by immunocytochemical electron microscopy confirmed that the Lig proteins were localized to the bacterial surface. Immunoblot studies with patient sera found that the Lig proteins are a major antigen recognized during the acute host infection. These observations demonstrate that the Lig proteins are a newly identified surface protein of pathogenic Leptospira, which by analogy to other bacterial immunoglobulin superfamily virulence factors, may play a role in host cell attachment and invasion during leptospiral pathogenesis.
PMCID: PMC1237129  PMID: 12890019
14.  Leptospira Immunoglobulin-Like Proteins as a Serodiagnostic Marker for Acute Leptospirosis▿  
Journal of Clinical Microbiology  2007;45(5):1528-1534.
There is an urgent need for improved diagnosis of leptospirosis, an emerging infectious disease which imparts a large disease burden in developing countries. We evaluated the use of Leptospira immunoglobulin (Ig)-like (Lig) proteins as a serodiagnostic marker for leptospirosis. Lig proteins have bacterial immunoglobulin-like (Big) tandem repeat domains, a moiety found in virulence factors in other pathogens. Sera from patients identified during urban outbreaks in Brazil reacted strongly with immunoblots of a recombinant fragment comprised of the second to sixth Big domains of LigB from L. interrogans serovar Copenhageni, the principal agent for transmission in this setting. Furthermore, the sera recognized an analogous LigB fragment derived from L. kirschneri serovar Grippotyphosa, a pathogenic serovar which is not endemic to the study area. The immunoblot assay detected anti-LigB IgM antibodies in sera from 92% (95% confidence interval, 85 to 96%) of patients during acute-phase leptospirosis. The assay had a sensitivity of 81% for sera from patients with less than 7 days of illness. Anti-LigB antibodies were found in sera from 57% of the patients who did not have detectable anti-whole-Leptospira responses as detected by IgM enzyme-linked immunosorbent assay and microagglutination test. The specificities of the assay were 93 to 100% and 90 to 97% among sera from healthy individuals and patients with diseases that have clinical presentations that overlap with those of leptospirosis, respectively. These findings indicate that the antibody response to this putative virulence determinant is a sensitive and specific marker for acute infection. The use of this marker may aid the prompt and timely diagnosis required to reduce the high mortality associated with severe forms of the disease.
PMCID: PMC1865864  PMID: 17360842

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