Demographic, socioeconomic, and health structure factors associated with the use of HIV pre-exposure prophylaxis in Brazil: A nationwide ecological study.

Aims: To assess the cumulative rate of HIV Pre-Exposure Prophylaxis (PrEP) users in Brazil since its 2018 implementation and to analyze the association between PrEP usage and state-level structural factors. Methods: A nationwide ecological study from 2018 to 2022 was conducted, examining the 5-year cumulative rate of PrEP users in relation to demographic, socioeconomic, and healthcare infrastructure variables. Multiple linear regression analysis identified significant predictors of PrEP utilization. Results: Between 2018 and 2022, 124,796 individuals used PrEP, with a cumulative rate of 61.5 per 100,000 population. The highest usage was in Minas Gerais, São Paulo, and Santa Catarina, while the lowest was in Distrito Federal, Maranhão, and Alagoas. Regression analysis showed that higher PrEP usage was associated with lower population density, a younger median age, a lower male to female ratio, and reduced social vulnerability. Additionally, PrEP usage was positively associated with the density of medical doctors and the number of dispensing units. Conclusions: The study reveals significant regional disparities in PrEP usage across Brazil, influenced by socioeconomic and healthcare factors. It highlights the need for targeted public health strategies to enhance PrEP access and uptake, especially in socially vulnerable regions.

CD4+ Th1 and Th17 responses and multifunctional CD8 T lymphocytes associated with cure or disease worsening in human visceral leishmaniasis.

Introduction: In VL, a proinflammatory phenotype is typically associated with enhanced phagocytosis and a Th1 mediated immune response resulting in infection control. In contrast, an anti-inflammatory phenotype, associated with a predominant regulatory response, typically enables intracellular multiplication of Leishmania parasites and disease progression. Methods: To investigate the impact of chemotherapy on Th2 and Th17 immune responses in patients with visceral leishmaniasis (VL), we assessed all combinations of intracellular expression of IFN-γ, IL-10, IL-4 and IL-17 in the CD4+ and CD8+ T cell populations of peripheral blood mononuclear cell (PBMC) samples from patients, after antigenic stimulation with Leishmania lysate, throughout treatment and follow-up. As increases in spleen and liver sizes and decreases in hematocrit, hemogloblin, erythrocytes, monocytes, leukocytes and platelets levels are strongly related to the disease, we studied the correlations between the frequencies of T cells producing the afore mentioned cytokines, individually and in combination, and these variables, as markers of disease or cure. Results: We found that the frequency of IFN-γ-producingCD4+ T cells increased until the end of chemotherapy with Glucantime® or AmBisome ®, while IL-10, IL-4 and IL-17-producing CD4+ T cells peaked on day 7 following the start of treatment. Although the frequency of CD4+IL-17+ cells decreased during treatment an increase was observed after clinical cure. The frequency of CD4+ T cells producing only IFN-γ or IL-17 correlated with blood monocytes levels. Frequencies of double-producers of IFN-γ and IL-10 or IL-4 correlated positively with eosinophils and platelets levels. Together, this suggest that IFN-γ drives the immune response towards Th1 at cure. In contrast, and associated with disease or Th2 response, the frequency of CD4+ IL-10+ cells correlated positively with spleen sizes and negatively with circulating monocyte levels, while the frequency of CD4+ producing both IL-4 and IL-10 correlated negatively with platelets levels. The frequency of CD8+ single-producers of IFN-γ increased from day 21 to 90 while that of single-producers of IL-10 peaked on day 7, of IL-4 on day 30 and of IL-17, on day 180. IFN-γ expression in CD8+ single- and double-producers of cytokines was indicative of an immune response associated with cure. In contrast, frequencies of CD8+ double-producers of IL-4 and IL-10, IL-4 and IL-17 and IL-10 and IL-17 and producers of three and four cytokines, were associated with disease and were low after the cure. Frequencies of CD8+ T cells producing IFN-γ alone or with IL-17 were positively correlated with platelets levels. In contrast, as markers of disease: 1) frequencies of single producers of IL-10 correlated negatively with leukocytes levels, 2) frequencies of double producers of IL-4 and IL-10 correlated negatively with platelet, leukocyte, lymphocyte and circulating monocyte levels, 3) frequencies of triple-producers of IFN-γ, IL-4 and IL-10 correlated negatively with platelet, leukocyte and neutrophil levels and 4) frequencies of producers of IFN-γ, IL-4, IL-10 and IL-17 simultaneously correlated positively with spleen size, and negatively with leukocyte and neutrophil levels. Discussion: Our results confirmed that the clinical improvement of VL patients correlates with the decrease of an IL-4 and IL-10 CD4+Th2 response, the recovery of CD4+ Th1 and Th17 responses and the frequency of CD8+ single-producers of IFN-γ and double producers of IFN-γ and IL-17.

COVID-19 recurrence is related to disease-early profile T cells while detection of anti-S1 IgG is related to multifunctional T cells.

COVID-19 is caused by SARS-CoV-2 infection and leads from asymptomatic to severe outcomes. The recurrence of the COVID-19 has been described, however, mechanisms involved remains unclear. Thus, the work aimed to investigate the role of multifunctional T cells in patients with recurrent COVID-19. We evaluated clinical characteristics, presence of anti-S1 and anti-Nucleocapsid IgG in patients' sera, and multifunctional T cells (for IFN-γ, IL-2, and TNF-α) in patients with multiple episodes of COVID-19 and controls. Data demonstrate that patients with recurrent COVID-19 have a T cell pattern predominantly related to IFN-γ production. Also, patients with COVID-19 history and absence of anti-S1 IgG had lower levels of CD4+ IFN + IL-2 + TNF + T cells independently of number of disease episodes. Complementary, vaccination changed the patterns of T cells phenotypes and induced IgG seroconversion, despite not induce higher levels of multifunctional T cells in all patients. In conclusion, the data suggest that recurrent disease is related to early-disease T cell profile and absence of anti-S1 IgG is related to lower multifunctional CD4 T cell response, what suggests possibility of new episodes of COVID-19 in these patients.

Association between genetic variants in TREM1, CXCL10, IL4, CXCL8 and TLR7 genes with the occurrence of congenital Zika syndrome and severe microcephaly.

Congenital Zika syndrome (CZS) is a cluster of malformations induced by Zika virus (ZIKV) infection and the underline mechanisms involved in its occurrence are yet not fully understood. Along with epidemiological and environmental factors, the genetic host factors are suggested as important to the CZS occurrence and development, however, few studies have evaluated this. This study enrolled a total of 245 individuals in a case-control association study compound a cohort of high specific interest constituted by 75 mothers who had delivered CZS infants, their 76 infants, and 47 mothers that had delivered healthy infants, and their 47 infants. Sixteen single-nucleotide polymorphisms on TREM1, CXCL10, IL4, CXCL8, TLR3, TLR7, IFNR1, CXCR1, IL10, CCR2 and CCR5 genes were genotyped to investigate their association as risk factors to CZS. The results show an association between C allele at TREM1 rs2234246 and C allele at IL4 rs224325 in mothers infected with ZIKV during pregnancy, with the increased susceptibility to CZS occurrence in their infants and the SNP CXCL8 rs4073 and the G allele at CXCL10 rs4508917 with presence of CZS microcephaly in the infants. Furthermore, the T allele at CXCL8 rs4073 and TRL7 rs179008 SNPs were associated with the severity of microcephaly in children with CZS. These results suggest that these polymorphisms in genes of innate immune responses addressed here are associated to increased risk of occurrence and severity of CZS in pregnant mothers infected with ZIKV and their CZS infants.

Use of N-acetylcysteine as treatment adjuvant regulates immune response in visceral leishmaniasis: Pilot clinical trial and in vitro experiments.

This investigation aimed to assess the effect of N-acetylcysteine (NAC) as an adjuvant treatment to alleviate visceral leishmaniasis (VL). The present work includes both blinded randomized clinical intervention and experimental in vitro studies. The clinical trial included 60 patients with VL randomly allocated into two groups: a test group (n = 30) treated with meglumine antimoniate plus NAC (SbV + NAC) and a control group (n = 30) treated with meglumine antimoniate only (SbV). The primary outcome was clinical cure (absence of fever, spleen and liver sizes reduction, and hematological improvement) in 180 days. The cure rate did not differ between the groups; both groups had similar results in all readout indices. The immunological parameters of the patients treated with SbV + NAC showed higher sCD40L in sera during treatment, and the levels of sCD40L were negatively correlated with Interleukin-10 (IL-10) serum levels. In addition, data estimation showed a negative correlation between the sCD40L levels and the spleen size in patients with VL. For the in vitro experiments, peripheral blood mononuclear cells (PBMCs) or PBMC-derived macrophages from healthy donors were exposed to soluble Leishmania antigen (SLA) or infected with stationary promastigotes of Leishmania infantum in the presence or absence of NAC. Results revealed that NAC treatment of SLA-stimulated PBMCs reduces the frequency of monocytes producing IL-10 and lowers the frequency of CD4+ and CD8+ T cells expressing (pro-)inflammatory cytokines. Together, these results suggest that NAC treatment may modulate the immune response in patients with VL, thus warranting additional investigations to support its case use as an adjuvant to antimony therapy for VL.

Insight Into the Long Noncoding RNA and mRNA Coexpression Profile in the Human Blood Transcriptome Upon Leishmania infantum Infection.

Visceral leishmaniasis (VL) is a vector-borne infectious disease that can be potentially fatal if left untreated. In Brazil, it is caused by Leishmania infantum parasites. Blood transcriptomics allows us to assess the molecular mechanisms involved in the immunopathological processes of several clinical conditions, namely, parasitic diseases. Here, we performed mRNA sequencing of peripheral blood from patients with visceral leishmaniasis during the active phase of the disease and six months after successful treatment, when the patients were considered clinically cured. To strengthen the study, the RNA-seq data analysis included two other non-diseased groups composed of healthy uninfected volunteers and asymptomatic individuals. We identified thousands of differentially expressed genes between VL patients and non-diseased groups. Overall, pathway analysis corroborated the importance of signaling involving interferons, chemokines, Toll-like receptors and the neutrophil response. Cellular deconvolution of gene expression profiles was able to discriminate cellular subtypes, highlighting the contribution of plasma cells and NK cells in the course of the disease. Beyond the biological processes involved in the immunopathology of VL revealed by the expression of protein coding genes (PCGs), we observed a significant participation of long noncoding RNAs (lncRNAs) in our blood transcriptome dataset. Genome-wide analysis of lncRNAs expression in VL has never been performed. lncRNAs have been considered key regulators of disease progression, mainly in cancers; however, their pattern regulation may also help to understand the complexity and heterogeneity of host immune responses elicited by L. infantum infections in humans. Among our findings, we identified lncRNAs such as IL21-AS1, MIR4435-2HG and LINC01501 and coexpressed lncRNA/mRNA pairs such as CA3-AS1/CA1, GASAL1/IFNG and LINC01127/IL1R1-IL1R2. Thus, for the first time, we present an integrated analysis of PCGs and lncRNAs by exploring the lncRNA-mRNA coexpression profile of VL to provide insights into the regulatory gene network involved in the development of this inflammatory and infectious disease.

TREM-1 Expression on the Surface of Neutrophils in Patients With Visceral Leishmaniasis Is Associated With Immunopathogenesis.

Visceral leishmaniasis (VL) is a systemic chronic and potentially fatal disease for humans. Mechanisms related to the dysregulation of the inflammatory response may be involved in both the pathogenesis and prognosis of VL. Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) is a receptor constitutively expressed on neutrophils and monocyte subsets. The protein serves to regulate and amplify inflammatory responses. This study aimed to evaluate the expression profile of TREM-1 on the surface of neutrophils from patients with VL at varying time points during leishmanicidal treatment. For this purpose, neutrophils were isolated from the peripheral blood of patients with VL at different stages of treatment, which include 0, 7, and 30 days after treatment. Surface TREM-1 expression was assessed by immunophenotyping neutrophil populations. In addition, the association of TREM-1 expression on the surface of neutrophils with clinical and laboratory parameters and serum levels of inflammatory mediators was also evaluated. Results demonstrate a lower surface expression of TREM-1 in VL patients in the absence of treatment. However, increased levels of TREM-1 expression were observed 7 and 30 days after the start of treatment, with levels similar to those of healthy controls. TREM-1 expression was directly correlated with lymphocyte and erythrocyte count and indirectly correlated with spleen and liver size. Furthermore, elevated levels of TREM-1 expression were also correlated with lower serum levels of interleukin (IL)-22. Taken together, these results suggest that infection by Leishmania infantum leads to depressed TREM-1 expression on the neutrophil surface and may contribute to the inflammatory imbalance that characterizes active VL disease.

Analysis of breast cancer survival in a northeastern Brazilian state based on prognostic factors: A retrospective cohort study.

Breast cancer is a major health problem worldwide. Analysis of breast cancer epidemiology in emerging countries enables assessment of prognostic factors, cancer care quality, and the equity of resource distribution. We aimed to estimate the overall (OS) and cancer-specific survival (SS) of breast cancer patients in the northeastern Brazilian state of Sergipe to identify independent prognostic factors. We analyzed a cohort for the factors age at diagnosis, place of residence, time to treatment, staging, and molecular classification, using the Kaplan-Meier method, log-rank test, Pearson's chi-squared test and Cox regression model. The outcome was the vital status at the end of the study. Our analysis showed an OS probability of 0.72 and an SS probability of 0.75. In multivariate analysis, time to treatment within 60 days, stage IV, and triple-negative classification remained independent prognostic factors for both OS [unadjusted hazard ratio (HRp) 1.50 (1.21; 1.86), HRp 16.56 (8.35; 32.85), and HRp 2.73 (1.73; 4.29), respectively] and SS [HRp 1.43 (1.13; 1.81), HRp 20.53 (9.45; 44.56), and HRp 3.14 (1.88; 5.26), respectively]. Better survival was demonstrated for the following patients: those receiving their first treatment after 60 days, with an OS of 52.5 months (51.2; 53.8) and SS of 53.5 months (52.3; 54.7); stage I patients, with an OS of 58.8 months (57.7; 60.0) and SS of 59.2 months (58.1; 60.3); patients without nodal metastasis, with an OS of 54.2 months (53.0; 55.4) and SS of 55.6 months (54.5; 56.7); and patients with luminal A classification, with an OS of 56.8 months (55.0; 58.5) and SS of 57.8 months (56.2; 59.4). This study identified independent prognostic factors and that OS and SS were lower for patients from Sergipe than for patients in high-income areas. Therefore, determining the profiles of breast cancer patients in this population will inform specific cancer care.

Association of IL-9, IL-10, and IL-17 Cytokines With Hepatic Fibrosis in Human Schistosoma mansoni Infection.

This is a case series study to evaluate immunological markers associated with schistosomiasis advanced fibrosis, including 69 patients from an endemic area from the State of Sergipe and from the Hepatology Service of the University Hospital in Sergipe, Brazil. Hepatic fibrosis was classified based on Niamey protocol for ultrasonography (US). Immune response to Schistosoma mansoni antigens was evaluated by stimulating peripheral blood mononuclear cells (PBMCs) from these patients with either adult worm (SWAP-10 µg/ml) or egg (SEA-10 µg/ml) antigens or purified protein derivative of turberculin (PPD-10 µg/ml) or phytohemagglutinin (PHA-1 µg/ml) for 72 h. The levels of IFN-γ, TNF-α, IL-5, IL-10, and IL-17 were measured in these supernatants by ELISA and IL-9 by Luminex. Single nucleotide polymorphisms in IL-17, IL10, and CD209 genes were genotyped using TaqMan probe by qPCR. Higher levels of IL-9, IL-10, and IL-17 were found in PBMC supernatants of patients with advanced hepatic fibrosis. Direct correlations were detected between IL-9 and IL-17 levels with US spleen sizes, portal vein diameters, and periportal thickening. The CD209 rs2287886 AG polymorphism patients produce higher IL-17 levels. Together, these data suggest a role of these cytokines in the immunopathogenesis of advanced fibrosis in human schistosomiasis.

Trends in prostate cancer incidence and mortality to monitor control policies in a northeastern Brazilian state.

Prostate cancer differently affects different regions of the world, displaying higher rates in more developed areas. After the implementation of prostate-specific antigen (PSA) testing, several studies described rising rates globally, but it is possible that indolent lesions are being detected given the lack of changes in mortality data. The Brazilian government recommends against PSA screening in the male population regardless of age, but the Urology Society issued a report recommending that screening should start at 50 years old for certain men and for those aged ≥75 years with a life expectancy exceeding 10 years. In this study, we examined the incidence and mortality rates of invasive prostate cancer over time in the Sergipe state of Brazil. The databases of the Aracaju Cancer Registry and Mortality Information System were used to calculate age-standardized rates for all prostate tumors (International Classification of Diseases 10th edition: C61 and D07.5) in the following age ranges: 20-44, 45-54, and ≥65 years. We identified 3595 cases of cancer, 30 glandular intraepithelial high-grade lesions, and 3269 deaths. Using the Joinpoint Regression Program, we found that the incidence of prostate cancer dramatically increased over time until the mid-2000s for all age groups, after which the rates declined. Prostate cancer mortality rates increased until 2005, followed by a non-significant annual percent change of 22.0 in 2001-2005 and a stable rate thereafter. We noticed that the increases and decreases of the incidence rates of prostate cancer were associated with the screening recommendations. Meanwhile, the increased mortality rates did not appear to be associated with decreased PSA testing; instead, they were linked to the effects of age and improvements in identification of the cause of death. Thus, we do not believe a PSA screening program would benefit the population of this study.

Trends in the incidence and mortality of colorectal cancer in a brazilian city.

OBJECTIVES: This study was conducted to analyze the trends in colorectal cancer (CRC) incidence and mortality in the city of Aracaju, Sergipe State, Brazil, between 1996 and 2015 with Joinpoint Regression Program 4.7.0.0 and to identify the geographical distribution of CRC in the municipality. RESULTS: A total of 1322 cases of CRC and 467 CRC-related deaths during the study period were included. In total, 40% of the incident cases and 43% of the deaths occurred in men, while 60% of the incident cases and 57% of the deaths occurred in women. Males who were 20 to 44 years old had the most significant trend in growth. Among women, those in the group aged 45 to 64 years had the highest observed annual percent change (APC). In both sexes, mortality was stable. Regarding the geographic distribution, there were constant hotspots in the northeast region of the municipality. This study showed a significant increase in incidence, mainly in young men between 20 and 44 years of age, but stable mortality in Aracaju.

Trends in cervical cancer and its precursor forms to evaluate screening policies in a mid-sized Northeastern Brazilian city.

Cervical cancer is a health issue that disproportionately affects developing countries, where the Papanicolaou test (Pap smear) remains an important screening tool. Brazilian government recommendations have focused screening on the female population aged from 25 to 64 years old. In this study, we examined the incidence and mortality rates of invasive cervical cancer lesions and the incidence rates of in situ precancerous cervical lesions, aiming to calculate their respective statistics over time in a mid-sized Brazilian city, Aracaju. The 1996-2015 database from the Aracaju Cancer Registry and Mortality Information System was used to calculate age standardized rates for all invasive cervical tumors (International code of diseases, ICD-10: C53) and preinvasive cervical lesions (ICD-10: D06) in the following patient age ranges; ≤ 24, 25-34, 35-44, 45-54, 55-64 and ≥ 65 years old. We identified 1,030 cancer cases, 1,871 in situ lesions and 334 deaths. Using the Joinpoint Regression Program, we calculated the annual percentage incidence changes and our analyses show that cervical cancer incidence decreased up to 2008, increased up to 2012 and decreased again thereafter, a significant trend in all age groups from 25 years. The incidence of precursor lesions increased from 1996 to 2005 and has since decreased, a result significant in all age groups until 64 years. Cervical cancer mortality has decreased by 3.8% annually and trend analysis indicates that Pap smears have been effective in decreasing cancer incidence and mortality. However, recent trends shown here show a decreasing incidence of in situ lesions and may indicate either a real decrease or incomplete catchment. Thus, we suggest health policies should be re-considered and include sufficient screening and HPV vaccination strategies to avoid cervical cancer resurgence in the population.

Ocular Findings in Infants with Microcephaly Caused by Presumed Congenital Infection by Zika Virus in Sergipe.

This study aims at identifying ocular findings in infants with microcephaly associated with presumed intrauterine infection by ZIKV. A cross-sectional study included 62 outpatient infants with congenital microcephaly, presumably secondary to maternal ZIKV infection. The included infants had head circumference below -2 standard deviations, with negative maternal serology for toxoplasmosis, rubella, cytomegalovirus, syphilis, and HIV. Assessment of ocular alterations was performed through review of their medical records. Forty two (67.7%) of the children analyzed presented some degree of ocular alteration. Findings in the posterior segment occurred in 29 (46.8%) patients, including atrophy of the retinal pigmentary epithelium in 15 (24.2%) patients, chorioretinal scars in 14 (22.6%) patients, retinal coloboma in 6 (9.7%) patients, and punctate retinal hemorrhage in 1 (1.6%) patient. Other ocular alterations were seen in 15 (24.2%) patients, including pathological strabismus in 11 (17.7%) patients, congenital cataracts in 2 (3.2%) patients, and nystagmus in 2 (3.2%) patients. Functional alterations were seen in four (6.5%) children. More than one change occurred in 11 (17.7%) children, eight of whom had head circumferences below -3 standard deviations. Changes in both the eyes occurred in 22 (35.5%) children, while 20 (32.3%) children had unilateral involvement. Among the 42 children with any ocular alteration, 27 (64.3%) children presented with severe microcephaly (head circumference with standard deviation lower than -3). The majority of children with microcephaly, presumably secondary to maternal ZIKV infection, present ocular alterations, with a higher frequency of involvement in the fundus. Severe ocular alterations are related to severe microcephaly.

Assessing trends of breast cancer and carcinoma in situ to monitor screening policies in developing settings.

There have been arguments about the role of breast cancer screening at the population level, and some points of controversy have arisen, such the establishment of organized screening policies and the age at which to begin screening. The real benefit of screening has been questioned because the results of this practice may increase the diagnosis of indolent lesions without decreasing mortality due to breast cancer. The authors have proposed a study of incidence and mortality trends for breast cancer in a developing setting in Brazil to monitor the effectiveness of the official recommendations that prioritize the age group from 50 to 69 years. The database of the Cancer Registry and the Mortality Information System was used to calculate age-standardized and age-specific rates, which were then used to calculate incidence and mortality trends using the Joinpoint Regression Program. The results showed stability in trends across all ages and age-specific groups in both incidence and mortality. In conclusion, we found that incidence and mortality rates are compatible with those in regions with similar human development indexes, and trends have demonstrated stabilization. Thus, we do not endorse changes in the official recommendations to conduct screening for ages other than 50 to 69 years, nor should policy makers implement organized screening strategies.

Mortality Trends for Neglected Tropical Diseases in the State of Sergipe, Brazil, 1980-2013.

BACKGROUND: Neglected Tropical Diseases are a set of communicable diseases that affect the population so low socioeconomic status, particularly 1.4 billion people who are living below the poverty level. This study has investigated the magnitude and mortality time trends for these diseases in the state of Sergipe, Northeast Region of Brazil. METHODS: We conducted an ecological study of time series, based on secondary data derived from the Mortality Information System of the Ministry of Health. The mortality rates (crude, age-standardized rates and proportional ratio) were calculated from the deaths due to Neglected Tropical Diseases in the state of Sergipe, from 1980 to 2013. The time trends were obtained using the Joinpoint regression model. RESULTS: Three hundred six thousand and eight hundred seventy-two deaths were certified in the state and Neglected Tropical Diseases were mentioned as the underlying cause in 1,203 certificates (0.39%). Mean number of deaths was 35.38 per year, and crude and age-standardized mortality rates were, respectively: 2.16 per 100 000 inhabitants (95% CI: 1.45-2.87) and 2.87 per 100 000 inhabitants (95% CI: 1.93-3.82); the proportional mortality ratio was 0.41% (95% CI: 0.27-0.54). In that period, Schistosomiasis caused 654 deaths (54.36%), followed by Chagas disease, with 211 (17.54%), and by Leishmaniases, with 142 (11.80%) deaths. The other diseases totalized 196 deaths (16.30%). There were increasing mortality trends for Neglected Tropical Diseases, Schistosomiasis and Chagas disease in the last 15 years, according to the age-standardized rates, and stability of the mortality trends for Leishmaniases. CONCLUSIONS: The Neglected Tropical Diseases show increasing trends and are a real public health problem in the state of Sergipe, since they are responsible for significant mortality rates. The following diseases call attention for showing greater number of deaths in the period of study: Schistosomiasis, Chagas disease and Leishmaniases. We finally suggest that public managers take appropriate actions to develop new strategies in epidemiological and therapeutic surveillance, and in the follow-up of these patients.

Cross-resistance of Leishmania infantum isolates to nitric oxide from patients refractory to antimony treatment, and greater tolerance to antileishmanial responses by macrophages.

Visceral leishmaniasis is a life-threatening disease characterized by intense parasitism of the spleen, liver, and bone marrow. Antimonials have served as front-line antileishmanial therapeutics for decades, but the increasing failure rates under antimonial treatment have challenged the continued use of these drugs. Pentavalent antimonials are known to reinforce the killing mechanisms of macrophages, although the associated mechanism remains unclear. Here, for the first time, we determined whether Leishmania infantum strains isolated from patients refractory to antimony treatment (relapse cases) were cross-resistant to antimonials, liposomal amphotericin B, and/or nitric oxide, and also whether these strains modulate macrophage infection. We selected four clinical isolates from relapse cases and two clinical isolates from antimony-responsive patients (control group) for the present study. The L. infantum promastigotes from all four relapse cases were resistant to trivalent antimonial treatment and nitric oxide, while only one isolate was resistant to liposomal amphotericin B. We evaluated whether the resistant strains from relapse cases showed enhanced infectivity and amastigote survival in macrophages, or macrophage-killing mechanisms in macrophages activated by lipopolysaccharide plus interferon gamma. Infection indexes calculated using macrophages infected with isolates from relapse were higher than those observed with control strains that were stimulated independently. Macrophage infection was higher with L. infantum isolates from relapse cases and correlated with enhanced interleukin 1-ß production but showed similar nitrite production. Our results demonstrate that L. infantum field isolates from relapse cases were resistant to antimonials and nitric oxide and that these parasites stimulated inflammatory cytokines and were resistant to macrophage-killing mechanisms, factors that may contribute to disease severity.

Soluble CD40 Ligand in Sera of Subjects Exposed to Leishmania infantum Infection Reduces the Parasite Load in Macrophages.

BACKGROUND: While CD40L is typically a membrane glycoprotein expressed on activated T cells and platelets that binds and activates CD40 on the surface on antigen presenting cells, a soluble derivative (sCD40L) that appears to retain its biological activity after cleavage from cell membrane also exists. We recently reported that sCD40L is associated with clinical resolution of visceral leishmaniasis and protection against the disease. In the present study we investigated if this sCD40L is functional and exerts anti-parasitic effect in L. infantum-infected macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Macrophages from normal human donors were infected with L. infantum promastigotes and incubated with either sera from subjects exposed to L. infantum infection, monoclonal antibodies against human CD40L, or an isotype control antibody. We then evaluated infection by counting the number of infected cells and the number of parasites in each cell. We also measured a variety of immune modulatory cytokines in these macrophage culture supernatants by Luminex assay. The addition of sCD40L, either recombinant or from infected individuals' serum, decreased both the number of infected macrophages and number of intracellular parasites. Moreover, this treatment increased the production of IL-12, IL-23, IL-27, IL-15, and IL1ß such that negative correlations between the levels of these cytokines with both the infection ratio and number of intracellular parasites were observed. CONCLUSIONS/SIGNIFICANCE: sCD40L from sera of subjects exposed to L. infantum is functional and improves both the control of parasite and production of inflamatory cytokines of infected macrophages. Although the mechanisms involved in parasite killing are still unclear and require further exploration, these findings indicate a protective role of sCD40L in visceral leishmaniasis.

Time trends in breast cancer incidence and mortality in a mid-sized northeastern Brazilian city.

BACKGROUND: Breast cancer incidence within an area is usually proportional to the area's income level. High-income areas have shown the highest incidence rates and since 2003, negative trends. As for mortality, rates are often higher in low-income regions. The purpose of this study was to analyze trends in incidence and mortality in a capital city of a northeastern Brazilian state with an intermediate human development index. METHODS: Incidence data from the Population-Based Cancer Registry of Aracaju and mortality data from the Official State Database for the period 1996-2006 were used. Incidence and mortality crude and age-standardized rates were calculated. Time trends were obtained using the Joinpoint Regression Model. RESULTS: For the period studied, invasive breast cancer age-standardized incidence rates increased annually with an annual percentage change (APC) of 2.9 (95% CI: 1.2-4.6). Significant increasing trends were observed in groups aged 45-54 years (APC: 3.9, 95% CI: 1.4 to 6.6), and 55-64 years (APC: 5.6, 95% CI: 1.8 to 9.6). Age-standardized mortality rates did not show an increasing trend (APC: 3.0, (95% CI: -2.8 to9.1), except for the group aged 55-64 years (APC: 11.3, 95% CI: 1.1 to 22.4). CONCLUSIONS: In the study community, breast cancer showed increasing incidence among women in the peri- and postmenopausal periods. However, mortality did not present increasing overall trends, except for among the group aged 55-64 years. For better outcomes, screening policies should focus on the peri- and postmenopausal periods of women's lives to diagnose disease.

[Self-efficacy as a mediator for improvement in oral health clinical indices]. / A auto-eficácia como mediadora da melhora em índices clínicos de saúde oral.

The concept of self-efficacy (SE) was developed by BANDURA, in 1977. SE has been widely utilized in health care and has shown to be a powerful predictor in various domains of behavior such as in smoking cessation, weight control and participation in programs of disease prevention. This study investigated if a psychosocial intervention fosters improvements in clinical indices in patients who are about to receive dental treatment. It was predicted that the experimental group (EG) would show a greater progress as to plaque and bleeding clinical indices than the control group (CG), and SE would mediate that improvement. Besides the standardized dental procedures, the 30 participants from the EG received a psychosocial intervention based on the PROCHASKA; DiCLEMENTE'S model (1983). The 30 participants in the CG received only standardized dental procedures. The results revealed that the prevalence of scores 2 and 3 of the plaque and bleeding indices underwent a significant decrease in the EG, in relation to the CG (U = 97.00, p = 0.0001 and U = 179.00, p = 0.0001, respectively). Only the subjects from the EG presented a relevant increase of SE, considering the pre- and post-treatment periods (Z = -3.58, p < 0.0001). Yet, there was no difference between both groups as to the increase of SE between the pre- and post-testing periods. In short, the results showed that psychosocial intervention was effective and suggest that other factors besides SE may mediate a relevant improvement of clinical indices in the EG.