B-cell subsets imbalance and reduced expression of CD40 in ataxia-telangiectasia patients.

BACKGROUND: Ataxia-telangiectasia (AT) is a well-known primary immunodeficiency with recurrent sinopulmonary infections and variable abnormalities in both the humoral and cellular immune system. Dysfunctions in immunoglobulin production, reduced number of B cells, and B-cell receptor excision circles copies have been reported. We aimed to understand the immunological mechanisms involving the humoral compartment in AT patients by analysing peripheral blood B cells subsets, B-T lymphocyte cooperation through the expression of CD40 and CD40 ligand (CD40L), and cytokines involved in class-switch recombination production. METHODS: We compared the proportion of B-cell subsets, the expression of CD40/CD40L, and the plasma levels of IL-6 and IFN-γ of 18 AT patients and 15 healthy age-sex-matched controls using flow cytometry. RESULTS: We found that some steps in peripheral B cell development were altered in AT with a pronounced reduction of cell-surface CD40 expression. The proportions of transitional and naïve-mature B cells were reduced, whereas CD21-low, natural effector memory, IgM-only memory, and IgG atypical memory B cells were present in a higher proportion. CONCLUSIONS: These findings revealed a disturbed B-cell homeostasis with unconventional maturation of B lymphocyte memory cells, which can explain the consequent impairment of humoral immunity.

Inflammasome gene profile is modulated in septic patients, with a greater magnitude in non-survivors.

Inflammasome signalling induces the processing and secretion of interleukin (IL)-1ß and IL-18 which, coupled with pyroptosis, activate further the inflammatory response. In the present study we evaluated the expression of genes involved in inflammasome signalling pathways in septic patients, their interaction networks and the predicted functions modulated in survivors and non-survivors. Twenty-seven patients with sepsis secondary to community-acquired pneumonia admitted to intensive care units from three general hospitals in São Paulo were included into the study. We performed a polymerase chain reaction (PCR) array encompassing 35 genes related to the nucleotide-binding oligomerization domain and leucine-rich repeat-containing (NLR)-inflammasome in peripheral blood mononuclear cells obtained at admission and after 7 days of follow-up. Eleven healthy volunteers were used as the reference group. Increased NLRC4 and NLRP3 and decreased nucleotide-binding oligomerization domain (NOD1), and NLRP1 expression was observed in septic patients compared to healthy individuals; the IL-1ß and IL-18 expression levels were also high in the patients. The gene expression changes followed the same patterns in surviving and non-surviving patients, with higher magnitudes observed in non-survivors. Functional analyses revealed, however, that activation and inhibition intensity for representing functions were different in survivors and non-survivors, as for production of reactive oxygen species, synthesis of nitric oxide and for the control of bacterial infections. Our results showed that the genes involved in the activation of the NLR-inflammasome cascades were altered substantially in septic patients, with a higher number of altered genes and a higher intensity in the disturbance of gene expression found among patients dying of sepsis.

The combined effects of binder addition and different sintering methods on the mechanical properties of bovine hydroxyapatite.

Hydroxyapatite (HA) from bovine bones has been used as a biomaterial in dentistry due to its biocompatibility and bioactivity. However, dense HA bioceramics still present inadequate properties for applications that require high mechanical performance, such as infrastructure. Microstructural reinforcements and control of ceramic processing steps are methods to improve these shortcomings. The present study assessed the effects of polyvinyl butyral (PVB) addition in combination with two sintering methodologies (2-step and conventional), on the mechanical properties of polycrystalline bovine HA bioceramics. The samples were divided into four groups (with 15 samples per group): conventional sintering with binder (HBC) and without binder (HWC) and 2-step sintering with (HB2) and without binder (HW2). HA was extracted from bovine bones, turned into nanoparticles in a ball mill, and subjected to uniaxial and isostatic pressing into discs, according to ISO 6872 standards. All groups were characterized by x-ray diffractometry (XRD), differential thermal analysis (DTA) and Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and relative density. Besides, mechanical analyses (biaxial flexural strength (BFS) and modulus of elasticity) were also performed. The characterization results demonstrated that adding agglutinants or the sintering method did not affect HA's chemical and structural characteristics. Even so, the HWC group showed the highest mechanical values for BFS and modulus of elasticity being 109.0 (98.0; 117.0) MPa and 105.17 ± 14.65 GPa, respectively. The HA ceramics submitted to conventional sintering and without the addition of binders achieved better mechanical properties than the other groups. The impacts of each variable were discussed and correlated to the final microstructures and mechanical properties.

Increased neutrophil oxidative burst metabolism in systemic lupus erythematosus.

INTRODUCTION: There is increased frequency of discoid lesions (2.7%) and SLE (0.5%) in patients with chronic granulomatosus disease, but the literature is still controversial about phagocyte oxidative burst in SLE patients. MATERIALS AND METHODS: 300 SLE patients and 301 blood donors were evaluated for quantitation of the oxidative burst in phagocytes by flow cytometry based on the oxidation of 2,7-dichlorofluorescein-diacetate after stimuli with Staphylococcus aureus and Pseudomonas aeruginosa. RESULTS: Neutrophils from SLE patients displayed higher basal reactive oxygen species (ROS) production than healthy controls [Mean of fluorescence intensity (MFI) = 53.77 ± 11.38 vs 15.08 ± 2.63, p < 0.001] and after stimulation with S. aureus (MFI = 355.46 ± 58.55 vs 151.92 ± 28.25, p < 0.001) or P. aeruginosa (MFI = 82.53 ± 10.1 vs 48.99 ± 6.74, p < 0.001). There was stronger neutrophil response after bacterial stimuli (ΔMFI) in SLE patients than in healthy controls (S. aureus = 301.69 ± 54.42 vs 118.38 ± 26.03, p < 0.001; P. aeruginosa = 28.76 ± 12.3 vs 15.45 ± 5.15, p < 0.001), but no difference with respect to the oxidative burst profile according to disease activity (SLEDAI ≥ 6) or severity (SLICC-DI ≥2). Patients with kidney involvement presented higher basal and stimulated ROS production in neutrophils. DISCUSSION: The present findings corroborate the important role of innate immunity in SLE and implicate neutrophils in the pathophysiology of the disease.

Impact of a multidimensional infection control strategy on catheter-associated urinary tract infection rates in the adult intensive care units of 15 developing countries: findings of the International Nosocomial Infection Control Consortium (INICC).

PURPOSE: We aimed to evaluate the impact of a multidimensional infection control strategy for the reduction of the incidence of catheter-associated urinary tract infection (CAUTI) in patients hospitalized in adult intensive care units (AICUs) of hospitals which are members of the International Nosocomial Infection Control Consortium (INICC), from 40 cities of 15 developing countries: Argentina, Brazil, China, Colombia, Costa Rica, Cuba, India, Lebanon, Macedonia, Mexico, Morocco, Panama, Peru, Philippines, and Turkey. METHODS: We conducted a prospective before-after surveillance study of CAUTI rates on 56,429 patients hospitalized in 57 AICUs, during 360,667 bed-days. The study was divided into the baseline period (Phase 1) and the intervention period (Phase 2). In Phase 1, active surveillance was performed. In Phase 2, we implemented a multidimensional infection control approach that included: (1) a bundle of preventive measures, (2) education, (3) outcome surveillance, (4) process surveillance, (5) feedback of CAUTI rates, and (6) feedback of performance. The rates of CAUTI obtained in Phase 1 were compared with the rates obtained in Phase 2, after interventions were implemented. RESULTS: We recorded 253,122 urinary catheter (UC)-days: 30,390 in Phase 1 and 222,732 in Phase 2. In Phase 1, before the intervention, the CAUTI rate was 7.86 per 1,000 UC-days, and in Phase 2, after intervention, the rate of CAUTI decreased to 4.95 per 1,000 UC-days [relative risk (RR) 0.63 (95% confidence interval [CI] 0.55-0.72)], showing a 37% rate reduction. CONCLUSIONS: Our study showed that the implementation of a multidimensional infection control strategy is associated with a significant reduction in the CAUTI rate in AICUs from developing countries.

Vaccine antibodies and T- and B-cell interaction in juvenile systemic lupus erythematosus.

Both systemic lupus erythematosus (SLE) and its treatment can cause immunosuppression and a decreased response to vaccination. We evaluated 30 children and adolescents with SLE, and 14 age-matched healthy subjects (control group) regarding immunophenotyping and lymphocyte apoptosis by flow cytometry, while measles and tetanus antibodies were measured by enzyme-linked immunosorbent assay (ELISA). The SLE group was divided according to disease activity into inactive SLE and active SLE. Individuals with active SLE had lower CD4+ T and natural killer (NK) cells/mm(3) than the control group. Active and inactive SLE individuals had more CD38 molecules/CD8+ T cells and more CD4+ T, CD8+ T and B cells in apoptosis (as assessed by caspase-3 expression) than the control group. Patients with active SLE had a diminished CD28 expression on both CD4+ T and on CD8+ T cells and a higher CD86 expression on B cells than the control group. Measles antibody levels in the SLE groups were similar to the control group. In contrast, tetanus antibody levels were lower in the SLE groups than in the control group. The latter also directly correlated with the CD4+ T-cell and NK-cell counts from SLE patients (regression coefficient, 2.686 and 1.782; p = 0.010 and p = 0.039, respectively). We concluded that despite being up-to-date for tetanus vaccine, SLE patients presented with a poor immune response to tetanus vaccine.

Cytokine and hormonal profile in serum samples of patients undergoing controlled ovarian stimulation: interleukin-1beta predicts ongoing pregnancy.

BACKGROUND: Changes in the endometrium are not regulated exclusively by ovarian hormones; the immune system has also been implicated in normal endometrial function, similar to processes taking place during inflammatory and reparative path. Many cytokines are crucially important for reproductive processes, and the role of cytokines in the female reproductive system function has been broadly investigated during controlled ovarian stimulation (COS) for IVF attempts. The aim of this study was to evaluate the levels of serum cytokines and hormones, and the clinical outcomes of women who underwent COS and ICSI procedures. METHODS: The study prospectively included 96 patients (aged 22-43 years, unexplained or male infertility, n = 61; female infertility factors, n = 35) who underwent ICSI cycles. Serum levels of interleukin (IL-8, IL-6, IL-1beta, IL-10, IL-12), tumour necrosis factor and leukaemia-inhibitory factor (LIF) and the hormones FSH, estradiol, progesterone, anti-Mullerian hormone and Inhibin-B were measured on the day of oocyte retrieval. RESULTS: The ongoing pregnancy rate was 25.3%. The presence of serum IL-1beta positively affected the implantation rate (P = 0.004) and increased the chance of becoming pregnant by 15 fold. Furthermore, the percentage of patients with detectable serum IL-1beta levels who conceived (62.5%) was higher than those who failed to conceive (37.5%; P = 0.019). The LIF was undetectable in all serum samples, and no other factors influenced the clinical outcomes of patients undergoing ICSI cycles. CONCLUSIONS: Our findings revealed that detectable serum levels of IL-1beta on the day of oocyte retrieval in patients undergoing COS and ICSI are predictive of successful implantation and ongoing pregnancy.

Contrasting Relationship of True Weevils (Curculionidae) and Woody Plants Diversity in Semi-arid Landscape Units.

In general, insect herbivore diversity is positively correlated to plant diversity since plant assemblages structure different microhabitats and provide food resources for such insects. Although poorly studied, insect herbivores in tropical dry forests are positively affected by tree species richness and the structural architecture of vegetation. In this study, we analyzed whether true weevil and woody plants present similar patterns of diversity across different landscape units in a Neotropical tropical dry forests located in Brazil, and if there is a correlation among their assemblages. We used Hill numbers according to species richness and the inverse of Simpson to compare the taxonomic diversity of true weevils and plants in nine landscape units located at the São Francisco river basin in the states of Sergipe and Alagoas, north-eastern Brazil. All trees and shrubs with diameter at breast height (1.3 m) ≥ 5 cm were sampled, and true weevils were collected using a modified Malaise trap. We used co-correspondence analysis to test if plants and true weevil species tend to co-occur. A total of 538 true weevils from 60 species was collected, and a total of 1419 plants belonging to 49 species was recorded. There is no general pattern of co-occurrence and diversity among true weevils and plants, indicating that the plant community is not structuring true weevil assemblage in the Caatinga. However, there was positive relationship between Sibinia sp4 and Fabaceae-Mimosoideae. These results suggest true weevil-plant relationships in the Caatinga differ from that of more mesic ecosystems. Therefore, we observed that the mechanisms that regulate herbivore-plant diversity relationships do not always follow a positive relationship, as observed in previous studies.

Sepsis: evolving concepts and challenges.

Sepsis remains a major cause of morbidity and mortality worldwide, with increased burden in low- and middle-resource settings. The role of the inflammatory response in the pathogenesis of the syndrome has supported the modern concept of sepsis. Nevertheless, a definition of sepsis and the criteria for its recognition is a continuous process, which reflects the growing knowledge of its mechanisms and the success and failure of diagnostic and therapeutic interventions. Here we review the evolving concepts of sepsis, from the "systemic inflammatory response syndrome triggered by infection" (Sepsis-1) to "a severe, potentially fatal, organic dysfunction caused by an inadequate or dysregulated host response to infection" (Sepsis-3). We focused in the pathophysiology behind the concept and the criteria for recognition and diagnosis of sepsis. A major challenge in evaluating the host response in sepsis is to characterize what is protective and what is harmful, and we discuss that, at least in part, the apparent dysregulated host response may be an effort to adapt to a hostile environment. The new criteria for recognition and diagnosis of sepsis were derived from robust databases, restricted, however, to developed countries. Since then, the criteria have been supported in different clinical settings and in different economic and epidemiological contexts, but still raise discussion regarding their use for the identification versus the prognostication of the septic patient. Clinicians should not be restricted to definition criteria when evaluating patients with infection and should wisely use the broad array of information obtained by rigorous clinical observation.

Attractiveness of Different Food Resources to Dung Beetles (Coleoptera: Scarabaeidae) of a Dry Tropical Area.

Excrement scarcity is one of the main historical factors leading dung beetles to adapt to other food resources. In the Caatinga, a seasonally tropical dry forest, harsh environmental conditions seem to restrict the availability of food resources. In this scenario, the aim of our study was to experimentally investigate the attractiveness of different potential food resources to these insects in the Caatinga. Field samplings were performed, and we tested five resources in pitfall baited traps: excrement, carrion, fruits of two species of columnar cacti, and seeds of one species of Euphorbiaceae (Jatropha mollissima (Pohl)). In a controlled setting, we tested dietary preferences of Deltochilum verruciferum Felsche by offering one or two resources simultaneously. In the field experiments, 297 dung beetles (9 species) were recovered from the traps, and D. verruciferum was the most abundant species. Carrion and excrement were the most attractive resources. Controlled dietary preference tests with D. verruciferum evidenced that these beetles used all tested food resources, excrement and carrion most pronouncedly. Our findings support copro-necrophagy as the main feeding habit of D. verruciferum, but also suggest that alternative resources might be utilized if preferred resources are scarce.

Persistent effects of pre-Columbian plant domestication on Amazonian forest composition.

The extent to which pre-Columbian societies altered Amazonian landscapes is hotly debated. We performed a basin-wide analysis of pre-Columbian impacts on Amazonian forests by overlaying known archaeological sites in Amazonia with the distributions and abundances of 85 woody species domesticated by pre-Columbian peoples. Domesticated species are five times more likely than nondomesticated species to be hyperdominant. Across the basin, the relative abundance and richness of domesticated species increase in forests on and around archaeological sites. In southwestern and eastern Amazonia, distance to archaeological sites strongly influences the relative abundance and richness of domesticated species. Our analyses indicate that modern tree communities in Amazonia are structured to an important extent by a long history of plant domestication by Amazonian peoples.

Effect of pentoxifylline on lung inflammation and gas exchange in a sepsis-induced acute lung injury model.

Experimental models of sepsis-induced pulmonary alterations are important for the study of pathogenesis and for potential intervention therapies. The objective of the present study was to characterize lung dysfunction (low PaO2 and high PaCO2, and increased cellular infiltration, protein extravasation, and malondialdehyde (MDA) production assessed in bronchoalveolar lavage) in a sepsis model consisting of intraperitoneal (ip) injection of Escherichia coli and the protective effects of pentoxifylline (PTX). Male Wistar rats (weighing between 270 and 350 g) were injected ip with 10(7) or 10(9) CFU/100 g body weight or saline and samples were collected 2, 6, 12, and 24 h later (N = 5 each group). PaO2, PaCO2 and pH were measured in blood, and cellular influx, protein extravasation and MDA concentration were measured in bronchoalveolar lavage. In a second set of experiments either PTX or saline was administered 1 h prior to E. coli ip injection (N = 5 each group) and the animals were observed for 6 h. Injection of 10(7) or 10(9) CFU/100 g body weight of E. coli induced acidosis, hypoxemia, and hypercapnia. An increased (P < 0.05) cell influx was observed in bronchoalveolar lavage, with a predominance of neutrophils. Total protein and MDA concentrations were also higher (P < 0.05) in the septic groups compared to control. A higher tumor necrosis factor-alpha (P < 0.05) concentration was also found in these animals. Changes in all parameters were more pronounced with the higher bacterial inoculum. PTX administered prior to sepsis reduced (P < 0.05) most functional alterations. These data show that an E. coli ip inoculum is a good model for the induction of lung dysfunction in sepsis, and suitable for studies of therapeutic interventions.

Leptospira interrogans activation of peripheral blood monocyte glycolipoprotein demonstrated in whole blood by the release of IL-6.

Glycolipoprotein (GLP) from pathogenic serovars of Leptospira has been implicated in the pathogenesis of leptospirosis by its presence in tissues of experimental animals with leptospirosis, the inhibition of the Na,K-ATPase pump activity, and induced production of cytokines. The aims of the present study were to investigate the induction of IL-6 by GLP in peripheral blood mononuclear cells (PBMC) and to demonstrate monocyte stimulation at the cellular level in whole blood from healthy volunteers. PBMC were stimulated with increasing concentrations (5 to 2500 ng/ml) of GLP extracted from the pathogenic L. interrogans serovar Copenhageni, lipopolysaccharide (positive control) or medium (negative control), and supernatants were collected after 6, 20/24, and 48 h, and kept at -80 degrees C until use. Whole blood was diluted 1:1 in RPMI medium and cultivated for 6 h, with medium, GLP and lipopolysaccharide as described above. Monensin was added after the first hour of culture. Supernatant cytokine levels from PBMC were measured by ELISA and intracellular IL-6 was detected in monocytes in whole blood cultures by flow-cytometry. Monocytes were identified in whole blood on the basis of forward versus side scatter parameters and positive reactions with CD45 and CD14 antibodies. GLP ( > or = 50 ng/ml)-induced IL-6 levels in supernatants were detected after 6-h incubation, reaching a peak after 20/24 h. The percentage of monocytes staining for IL-6 increased with increasing GLP concentration. Thus, our findings show a GLP-induced cellular activation by demonstrating the ability of GLP to induce IL-6 and the occurrence of monocyte activation in whole blood at the cellular level.

Risk factors for death in patients with candidemia.

OBJECTIVE: To analyze possible risk factors for death among patients with nosocomial candidemia. To identify risk factors for death in patients with candidemia, we analyzed demographic, clinical, and microbiological data. SETTING: Six tertiary hospitals in Brazil. PATIENTS: A cohort of 145 patients with candidemia. DESIGN: 26 possible risk factors for death, including age, underlying disease, signs of deep-seated infection, neutropenia, number of positive blood cultures, removal of a central venous catheter, etiologic agent of the candidemia, susceptibility pattern of the isolate to amphotericin B, and antifungal treatment were evaluated by univariate stepwise logistic regression analysis. RESULTS: Non-albicans species accounted for 63.4% of the candidemias. Risk factors for death in univariate analysis were older age, catheter retention, poor performance status, candidemia due to species other than Candida parapsilosis, hypotension, candidemia due to species other than Candida parapsilosis, and no antifungal treatment. In multivariate analysis, older age and nonremoval of a central venous catheter were the only factors associated with an increased risk for death. CONCLUSIONS: These data suggest that patients with candidemia and a central venous catheter should have the catheter removed.

Pathogenetic aspects of sepsis and possible targets for adjunctive therapy.

The outcome of patients with sepsis arises from multiple factors affecting both the host and the invading microorganisms. Age, presence of underlying disease, source of infection and some specific etiological agents have been related to prognosis. Appropriateness of antimicrobial therapy, considering the in vitro susceptibility tests for the infecting bacteria, has been strongly associated with the outcome. Therefore even after the cascade of sepsis has been triggered, the control of bacteria growth is still fundamental for the outcome of the infection. This is a major distinction point from experimental studies in which whole killed bacteria and their products are used as model of sepsis. However, even within the setting of adequate antimicrobial use, patients still die of sepsis. Thus, strategies focusing on further therapy targets are an important area of interest for basic and clinical research. Although such adjunctive sepsis therapy has failed to achieve consistent better survival rates so far, nevertheless, it improved our understanding of the pathophysiological events seen in sepsis that the possibility that a new and effective treatment may arise has been warmly considered. In this paper we aim to review some aspects of the pathogenesis of sepsis, focusing on recent advances and on possible targets for adjunctive therapy. Published clinical trials and experimental data supporting such trials are commented on.

High rate of non-albicans candidemia in Brazilian tertiary care hospitals.

In order to evaluate the epidemiology of candidemia in Brazil, we performed a prospective multicenter study conducted in six general hospitals from São Paulo and Rio de Janeiro, We enrolled a total of 145 candidemic patients (85 males) with a median age of 32 years. Non-albicans species accounted for 63% of all episodes and the species most frequently causing candidemia were C. albicans (37%), C. parapsilosis (25%), C. tropicalis (24%), C. rugosa (5%), and C. glabrata (4%). Systemic azoles were used before the onset of candidemia in only six patients. There were no differences in the coexisting exposures or underlying diseases associated with the species most frequently causing candidemia. The overall crude mortality rate was 50%. Nosocomial candidemias in our tertiary hospitals are caused predominantly by non-albicans species, which are rarely fluconazole resistant. This predominance of non-albicans species could not be related to the previous use of azoles.

Inflammatory response after myocardial revascularization with or without cardiopulmonary bypass.

BACKGROUND: Tumor necrosis factor-alpha has been implicated in complications seen after cardiac operations with cardiopulmonary bypass. The release of tumor necrosis factor-alpha and its possible effects were studied in patients undergoing coronary artery bypass grafting with and without cardiopulmonary bypass. METHODS: Twenty patients were studied, 10 with (group 1) and 10 without cardiopulmonary bypass (group 2). Serial blood samples were obtained before, during, and up to 48 hours after operation. Circulating tumor necrosis factor-alpha levels, leukocyte counts, and erythrocyte sedimentation rates were measured. Hemodynamic variables (blood pressure and heart rate), temperature, orotracheal intubation time, postoperative bleeding, and inotropic drug requirements were compared. RESULTS: Serum levels of tumor necrosis factor-alpha were detected in 6 patients (60%) in group 1 and none in group 2. The patients in group 1 had more hypotension than those in group 2 (7.4 +/- 1.0 mm Hg versus 8.5 +/- 0.7 mm Hg), required more inotropic drugs (8 patients versus 1 patient), and had a higher heart rate (114 +/- 8 beats per minute versus 98 +/- 10 beats per minute), a higher temperature (37.1 degrees +/- 0.5 degrees C versus 36.6 degrees +/- 0.3 degrees C), increased postoperative bleeding (820 +/- 120 mL versus 360 +/- 84 mL), a longer orotracheal intubation time (13.6 +/- 2.2 hours versus 9.3 +/- 1.4 hours), and a more pronounced leukocytosis. CONCLUSIONS: Cardiopulmonary bypass induces the whole-body inflammatory response through the release of tumor necrosis factor alpha, resulting in adverse systemic effects.

Circulating levels of sTNFR and discrepancy between cytotoxicity and immunoreactivity of TNF-alpha in patients with visceral leishmaniasis.

OBJECTIVES: To study the influence of soluble tumour necrosis factor (TNF) receptors (sTNFR) on bioactivity and immunoreactivity of TNF-alpha in patients with visceral leishmaniasis (Kala-azar) and to examine the association between circulating levels of sTNFR type I and type II with clinical manifestations of the disease. METHODS: Ten patients with Kala-azar were enrolled. Plasma samples for TNF-alpha and sTNFR were obtained on days 0, 7 and 21-28 of antimonial therapy. Bioactivity of TNF-alpha was measured by cytotoxicity to L-929 cells and immunoreactivity by enzyme-linked immunosorbent assay (ELISA). sTNFR-I and sTNFR-II were measured by ELISA. RESULTS: Measured by ELISA, TNF-alpha was detected at baseline in all patients (range from 22.3 to 163 pg/mL) and showed a linear decline over time on therapy (r = -0.49, P = 0.007). In contrast, when measured by cytotoxicity assay, TNF-alpha was detected in only one patient at baseline (193 pg/mL) and in four patients at the end of therapy (38.7, 95, 133 and 232 pg/mL) and there was no linear association between TNF-alpha and duration of therapy (r = -0.18, P = 0.45). sTNFR-I and sTNFR-II were detected in all patients before therapy. There was a strong positive correlation between plasma concentrations of sTNFR-I and sTNFR-II (r = 0.8, P = 0.006). Levels of sTNFR-I and sTNFR-II declined exponentially with time on therapy. CONCLUSIONS: We concluded that sTNFR-I and sTNFR-II are related to disease activity in patients with Kala-azar and that these circulating receptors may interfere with the biological activity of TNF-alpha in patients with Kala-azar.

Pentoxifylline decreases tumor necrosis factor and interleukin-1 during high tidal volume.

Tumor necrosis factor-alpha (TNF-alpha) is one of the most important proinflammatory cytokines which plays a central role in host defense and in the acute inflammatory response related to tissue injury. The major source of TNF-alpha are immune cells such as neutrophils and macrophages. We tested the hypothesis that pentoxifylline, a methylxanthine derivative, down-regulates proinflammatory cytokine expression during acute lung injury in rats. Male Wistar rats weighing 250 to 450 g were anesthetized ip with 50 mg/kg sodium thiopental and randomly divided into three groups: group 1 (N = 7): tidal volume (V T) = 7 ml/kg, respiratory rate (RR) = 50 breaths/min and normal saline infusion; group 2 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and normal saline infusion; group 3 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and pentoxifylline infusion. The animals were ventilated with an inspired oxygen fraction of 1.0, a positive end-expiratory pressure of 3 cmH2O, and normal saline or pentoxifylline injected into the left femoral vein. The mRNA of TNF-alpha rapidly increased in the lung tissue within 180 min of ventilation with a higher V T with normal saline infusion. The concentrations of inflammatory mediators were decreased in plasma and bronchoalveolar lavage (BAL) in the presence of higher V T with pentoxifylline infusion (TNF-alpha: plasma, 102.2+/-90.9 and BAL, 118.2+/-82.1; IL-1 : plasma, 45.2+/-42.7 and BAL, 50.2+/-34.9, P < 0.05). We conclude that TNF-alpha produced by neutrophil influx may function as an alert signal in host defense to induce production of other inflammatory mediators.

Induction of interleukin-10 by HIV antigens in peripheral mononuclear cells of health care workers after occupational exposure to HIV-1-positive blood.

Evaluation of HIV-induced IL-2 production by peripheral blood mononuclear cells (PBMC) and HIV-specific T helper and cytotoxic T lymphocyte (CTL) responses in health care workers (HCW) occupationally exposed to HIV reveals a high rate of response to HIV among non-seroconverters. IL-10 is also known to interfere with HIV infection in vitro. To evaluate the induction of IL-10 by HIV antigens in HCW occupationally exposed to HIV, 18 HCW with percutaneous injury were enrolled in this study, 9 of them exposed to HIV-contaminated blood, and 9 exposed to HIV-negative blood. PBMC were incubated on plates coated with HIV-1 antigens, and IL-10 was measured in supernatants by ELISA. Five of nine HCW exposed to HIV-contaminated blood presented HIV-induced IL-10. Two of nine HCW exposed to HIV-negative source patients also had detectable levels of HIV-induced IL-10, one of them in the sample obtained on the day of accidental exposure. There was a relationship between the type of device involved in injury and IL-10 production. Individuals exposed to hollow needles or scalpels presented HIV-induced IL-10, whereas those exposed to solid needles and to digital puncture did not, suggesting a relationship between infectious load and IL-10. Although occupational exposure to HIV leads to a low rate of seroconversion, these individuals can develop an antigen-specific immune response characterized in our study by induction of IL-10 in PBMC in vitro.