Angela Maria da Silva

Clinical and Immunologic Evaluation of 31 Patients with Acute Schistosomiasis mansoni

Thirty-one patients with acute schistosomiasis were evaluated clinically and immunologically. Cytokine levels were determined in peripheral blood mononuclear cell (PBMC) supernatants. Levels of total and antigen-specific IgE, tumor necrosis factor (TNF)-alpha, and immune complexes were measured in serum samples. Clinical findings included general symptoms, liver damage, pulmonary involvement, and pericarditis. All patients had eosinophilia. Immune complexes were detected in 55% of the patients (mean+/-SD, 7.8+/-7.6 microg Eq/mL) and were associated with cough, dyspnea, and abnormal chest radiographic findings. Levels (mean +/- SD) of TNF-alpha (1349.3+/-767.6 pg/mL), interleukin (IL)-1 (2683+/-1270 pg/mL), and IL-6 (382 +/- 52.3 pg/mL) were elevated in PBMC. Serum TNF-alpha levels were elevated in 87% of the patients and were associated with abdominal pain. Higher interferon-gamma levels were detected in PBMC of patients with acute disease than in those of patients with chronic schistosomiasis; IL-5 levels were higher in those with chronic disease. Low IL-5 levels were associated with weight loss. Proinflammatory cytokines and immune complexes with low Th2 responses might explain the immunopathogenesis of acute schistosomiasis.

Association of Type 2 Cytokines with Hepatic Fibrosis in Human Schistosoma mansoni Infection

ABSTRACT The objective of this study was to evaluate the role of cytokines in hepatic fibrosis in the prehepatosplenic and early hepatosplenic stages of schistosomiasis mansoni. Hepatic fibrosis was classified by ultrasonography of 94 patients. Immunological evaluation was performed by the measurement of secreted cytokines (interleukin-5 [IL-5], IL-10, IL-13, gamma interferon, tumor necrosis factor alpha, and transforming growth factor β) in peripheral blood mononuclear cells (PBMC) stimulated by Schistosoma mansoni antigens. Significantly, higher levels of IL-5, IL-10, and IL-13 were found in supernatants of soluble egg antigen-stimulated PBMC from subjects with degree III hepatic fibrosis compared to patients with degree I or II fibrosis. Significant increases in IL-5 and IL-13 levels were also observed in some of the subjects who remained untreated for 1 year following initial assessment and developed more serious fibrosis during this period. The data suggest a role for type 2 cytokines in hepatic fibrosis in human schistosomiasis mansoni.

Heme Oxygenase-1 Promotes the Persistence of Leishmania chagasi Infection

Visceral leishmaniasis (VL) remains a major public health problem worldwide. This disease is highly associated with chronic inflammation and a lack of the cellular immune responses against Leishmania. It is important to identify major factors driving the successful establishment of the Leishmania infection to develop better tools for the disease control. Heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, and its role in VL has not been investigated. In this study, we evaluated the role of HO-1 in the infection by Leishmania infantum chagasi, the causative agent of VL cases in Brazil. We found that L. chagasi infection or lipophosphoglycan isolated from promastigotes triggered HO-1 production by murine macrophages. Interestingly, cobalt protoporphyrin IX, an HO-1 inductor, increased the parasite burden in both mouse and human-derived macrophages. Upon L. chagasi infection, macrophages from Hmox1 knockout mice presented significantly lower parasite loads when compared with those from wild-type mice. Furthermore, upregulation of HO-1 by cobalt protoporphyrin IX diminished the production of TNF-α and reactive oxygen species by infected murine macrophages and increased Cu/Zn superoxide dismutase expression in human monocytes. Finally, patients with VL presented higher systemic concentrations of HO-1 than healthy individuals, and this increase of HO-1 was reduced after antileishmanial treatment, suggesting that HO-1 is associated with disease susceptibility. Our data argue that HO-1 has a critical role in the L. chagasi infection and is strongly associated with the inflammatory imbalance during VL. Manipulation of HO-1 pathways during VL could serve as an adjunctive therapeutic approach.

The Severity of Visceral Leishmaniasis Correlates with Elevated Levels of Serum IL-6, IL-27 and sCD14

Background Visceral leishmaniasis (VL) is a severe disease caused by infection with protozoa of the genus Leishmania. Classic VL is characterized by a systemic infection of phagocytic cells and an intense activation of the inflammatory response. It is unclear why 90% of infected individuals do not develop the disease while a minority develop the classical form. Furthermore, among those that develop disease, a small group progresses to more severe form that is unresponsive to treatment. The presence of inflammatory mediators in serum could theoretically help to control the infection. However, there is also a release of anti-inflammatory mediators that could interfere with the control of parasite multiplication. In this study, we took advantage of the spectrum of outcomes to test the hypothesis that the immune profile of individuals infected with Leishmania (L.) infantum is associated with the development and severity of disease. Methodology/Principal Findings Sera from patients with confirmed diagnosis of VL were evaluated for the presence of numerous molecules, and levels compared with healthy control and asymptomatic infected individuals. Conclusions/Principal Findings Although differences were not observed in LPS levels, higher levels of sCD14 were detected in VL patients. Our data suggest that L. infantum may activate the inflammatory response via CD14, stimulating a generalized inflammatory response with production of several cytokines and soluble molecules, including IFN-γ, IL-27, IL-10, IL-6 and sCD14. These molecules were strongly associated with hepatosplenomegaly, neutropenia and thrombocytopenia. We also observed that IL-6 levels greater than 200 pg/ml were strongly associated with death. Together our data reinforce the close relationship of IFN-γ, IL-10, IL-6, TNF-α and IL-27 in the immune dynamics of VL and suggest the direct participation of sCD14 in the activation of the immune response against L. infantum.

Cytokine profile associated with human chronic schistosomiasis mansoni

This study objective was to evaluate the cytokines associated with early events of hepatic fibrosis in schistosomiasis mansoni. Hepatic fibrosis was classified by ultrasonography in 94 patients. Immunological evaluation was performed by measurement of secreted cytokines (interleukin IL-5, IL-10, IL-13, interferon-gamma, tumor necrosis factor-alpha and transforming growth factors-beta) in peripherl blood mononuclear cells stimulated by Schistosoma mansoni antigens. Significantly, higher levels of IL-5, IL-10 and IL-13 were found in supernatants of SEA-stimulated PBMC from subjects with degree III hepatic fibrosis as compared to patients with degree I or II fibrosis, Significant increases in IL-5 and IL-13 levels were also observed in some of the subjects who remained untreated for one year following initial assessment and developed more serious fibrosis during this period. The data suggests a role for type 2 cytokines in early stages of hepatic fibrosis in human schistosomiasis mansoni.

Infecções em dispositivos neurológicos implantáveis em crianças e adolescentes

OBJECTIVE: To determine frequency, etiology, site and clinical and laboratory findings of ventriculoperitoneal shunt (VPS) infections in children and adolescents with hydrocephalus managed in Hospital Governador Joao Alves Filho, Aracaju SE, Brazil. METHOD: A non-controlled prospective observational study comprising 50 patients that underwent VPS (58 procedures) from January/2003 to October/2004. RESULTS: Infection rate per procedure was 27.6%; surgical risk index (NNISS-CDC) 0 and 1-2 were 25.7% and 30.4% respectively; surgical site infection was the main complication with 50% of the cases. CONCLUSION: Infection rates per procedure, per patient, and per surgical risk index were high. No statistical differences were found related to the following: age, etiology of hydrocephalus, type of procedure, pre-operative length of stay, duration of procedure, antibiotic prophylaxis, previous central nervous system catheter, and surgical risk index.

Impact of visceral leishmaniasis and curative chemotherapy on cytochrome P450 activity in Brazilian patients.

AIMS The aim of the present study was to investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil. METHODS Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2-3 days (phase 2) and 3-6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5-hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9). RESULTS Mean values (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10-1.31), 1.45 (1.32-1.57) and 1.35 (1.26-1.44) ml min(-1)  kg(-1) ; omeprazole/5-hydroxyomeprazole ratio, 0.78 (0.61-0.94), 0.45 (0.27-0.63) and 0.37 (0.20-0.55); losartan/E3174 ratio, 0.66 (0.39-0.92), 0.35 (0.20-0.50) and 0.35 (0.16-0.53). Analysis of variance revealed significant differences in CYP3A (P = 0.018) and CYP2C19 (P = 0.008), but not CYP2C9 (P = 0.11) phenotypic activity, across the three study phases. CONCLUSION The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared with post-chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for the suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on the expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed.

Trends in prostate cancer incidence and mortality in a mid-sized Northeastern Brazilian city

OBJECTIVE International data have reported prostate cancer as the most frequent among men, and the third highest in mortality. A rise in incidence has been observed in the course of recent decades, probably influenced by early detection, mainly in asymptomatic men, through regular screening with prostate-specific antigen (PSA) testing. The purpose of this study was to contribute to information on trends in prostate cancer incidence and mortality using population-based data. METHODS This was an exploratory ecological study of time trends, aiming at describing changes in prostate cancer incidence and mortality in Aracaju, Sergipe, Brazil, from 1996 to 2006. Rates were calculated from data of the Registro de Câncer de Base Populacional de Aracaju. Trends were calculated using the Joinpoint Regression Program. RESULTS For the study period, 1,490 incident cases and 334 deaths were included. Incident cases were more common after 50 years of age, and deaths after 55 years. Age-standardized incidence rates of 46.6 and 50.0/100,000 were observed in the early years of the series, and then progressively increased, with rates higher than 100.0/100,000 in later years. For mortality, age-standardized rates varied from 21.6 and 16.6/100,000 to 24.1 and 28.9/100,000 in later years. Joinpoint analysis identified one joinpoint for the incidence series, resulting in two trends, the first with annual percent change of 34% and the second with 5.8%; for the mortality series no joinpoint was identified, and the annual percent change was 2.1%. CONCLUSION There was a sharp increase in incidence rates during the study period, probably due to screening. Mortality rates had a small upward trend, and did not show major changes during the study period.

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

BackgroundBreast 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.MethodsIncidence 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.ResultsFor 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).ConclusionsIn 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.

Leishmania infantum Induces the Release of sTREM-1 in Visceral Leishmaniasis

Visceral leishmaniasis (VL) is a systemic transmissible disease that remains to be a major global health problem. The inflammatory response during VL is characterized by the release of several cytokines and other pro-inflammatory mediators. Triggering Receptor Expressed on Myeloid Cells (TREM) are a group of evolutionarily conserved membrane-bound surface receptors expressed on neutrophils and monocytes. Engagement of TREM-1 directs intracellular signaling events that drive cytokine production, degranulation, and phagocytosis. In certain inflammatory-associated diseases, TREM-1 can also be found as a soluble form (sTREM-1), which can negatively regulate TREM-1 receptor signaling. In these studies, we now find that high levels of circulating sTREM-1 correlate directly with VL disease severity. In particular, high levels of sTREM-1 were observed in non-survivor VL patients. Furthermore, these levels of sTREM-1 positively correlated with liver size and negatively correlated with leukocyte counts and hemoglobin concentration. Moreover, we found that neutrophils exposure in vitro to Leishmania infantum modulates TREM-1, DAP12, and IL-8 gene expression, while also increasing release of sTREM-1. Finally, results revealed that higher sTREM-1 levels are associated with increasing parasite ratio. Taken together, these studies suggest that L. infantum may modulate TREM-1 in neutrophils and high levels of this molecule is associated with severe VL.