Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial.

LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. METHODS: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. RESULTS: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.

Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses.

BACKGROUND: Chronic Chagas disease presents different clinical manifestations ranging from asymptomatic (namely indeterminate) to severe cardiac and/or digestive. Previous results have shown that the immune response plays an important role, although no all mechanisms are understood. Immunoregulatory mechanisms such as apoptosis are important for the control of Chagas disease, possibly affecting the morbidity in chronic clinical forms. Apoptosis has been suggested to be an important mechanism of cellular response during T. cruzi infection. We aimed to further understand the putative role of apoptosis in Chagas disease and its relation to the clinical forms of the disease. METHODS: Apoptosis of lymphocytes, under antigenic stimuli (soluble T. cruzi antigens - TcAg) where compared to that of non-stimulated cells. Apoptosis was evaluated using the expression of annexin and caspase 3(+) by T cells and the percentage of cells positive evaluated by flow cytometry. In addition activation and T cell markers were used for the identification of TCD4(+) and TCD8(+) subpopulations. The presence of intracellular and plasma cytokines were also evaluated. Analysis of the activation status of the peripheral blood cells showed that patients with Chagas disease presented higher levels of activation determined by the expression of activation markers, after TcAg stimulation. PCR array were used to evaluate the contribution of this mechanism in specific cell populations from patients with different clinical forms of human Chagas disease. RESULTS: Our results showed a reduced proliferative response associated a high expression of T CD4(+)CD62L(-) cells in CARD patients when compared with IND group and NI individuals. We also observed that both groups of patients presented a significant increase of CD4(+) and CD8(+) T cell subsets in undergoing apoptosis after in vitro stimulation with T. cruzi antigens. In CARD patients, both CD4(+) and CD8(+) T cells expressing TNF-α were highly susceptible to undergo apoptosis after in vitro stimulation. Interestingly, the in vitro TcAg stimulation increased considerably the expression of cell death TNF/TNFR superfamily and Caspase family receptors genes in CARD patients. CONCLUSIONS: Taken together, our results suggest that apoptosis may be an important mechanism for the control of morbidity in T. cruzi infection by modulating the expression of apoptosis genes, the cytokine environment and/or killing of effector cells.

The out-of-pocket cost of living with obesity: Results from a survey in Spain, South Korea, Brazil, India, Italy, and Japan.

Objectives: In many countries, obesity treatments are not fully reimbursed by healthcare systems. People living with obesity (PwO) often pay out-of-pocket (OOP) for pharmacological and non-pharmacological interventions, placing them in a position of financial risk to manage their condition. This study sought to understand the OOP expenditures and non-financial costs incurred by PwO to manage weight. Methods: A 25-min cross-sectional online survey was conducted with PwO between ages 18-60 in Italy, Japan, India, Brazil, Spain and South Korea. Respondents were recruited using proprietary vendor panels and non-probability sampling. N = 600 participants completed the survey (n = 100 per country). Results: The mean annual OOP expenditure related to weight loss/management was $7,351, accounting for nearly 17% of annual household income. Costs generally increased by BMI. Half or more of the respondents agreed that obesity affected multiple aspects of their lives (outside activities, running a household, social life, work, family life, traveling). 46% agreed that obesity limited their job prospects. Conclusion: PwO spend a notable amount of their income paying OOP expenditures related to managing their weight. Quantifying the individual economic burden of living with obesity can inform the understanding of the resources required and policy changes needed to treat obesity as a disease.

Matrix metalloproteinases 2 and 9 are differentially expressed in patients with indeterminate and cardiac clinical forms of Chagas disease.

Dilated chronic cardiomyopathy (DCC) from Chagas disease is associated with myocardial remodeling and interstitial fibrosis, resulting in extracellular matrix (ECM) changes. In this study, we characterized for the first time the serum matrix metalloproteinase 2 (MMP-2) and MMP-9 levels, as well as their main cell sources in peripheral blood mononuclear cells from patients presenting with the indeterminate (IND) or cardiac (CARD) clinical form of Chagas disease. Our results showed that serum levels of MMP-9 are associated with the severity of Chagas disease. The analysis of MMP production by T lymphocytes showed that CD8(+) T cells are the main mononuclear leukocyte source of both MMP-2 and MMP-9 molecules. Using a new 3-dimensional model of fibrosis, we observed that sera from patients with Chagas disease induced an increase in the extracellular matrix components in cardiac spheroids. Furthermore, MMP-2 and MMP-9 showed different correlations with matrix proteins and inflammatory cytokines in patients with Chagas disease. Our results suggest that MMP-2 and MMP-9 show distinct activities in Chagas disease pathogenesis. While MMP-9 seems to be involved in the inflammation and cardiac remodeling of Chagas disease, MMP-2 does not correlate with inflammatory molecules.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

Development and validation of a Brazilian version of the short-form McGill pain questionnaire (SF-MPQ).

The aim of this study was to develop and validate a short form of the Brazilian version of McGill Pain Questionnaire (SF-MPQ). Three hundred two patients with chronic pain filled out the validated Brazilian long form of the McGill Pain Questionnaire (LF-MPQ). Words chosen by ≥25% of the patients were selected to comprise the SF-MPQ. The Brazilian SF-MPQ consisted of 15 descriptors (8 sensory, 5 affective, and 2 evaluative) rated on a binary mode (present or absent). Four pain scores were derived by counting the words chosen by the patients for sensory, affective, evaluative, and total descriptors. The SF-MPQ showed poor internal consistency (KR-20 = 0.52) but possibly acceptable because it showed discriminant validity to discriminate patients presenting different levels and mechanisms of pain, and it was strongly correlated with the LF-MPQ. The low KR-20 coefficient could result from the small number of items. The Brazilian version of the SF-MPQ proved to be a useful instrument to evaluate the different qualities of pain. It is a reliable option to the long-form MPQ.

Three Decades of Research on the Development of Ibogaine Treatment of Substance Use Disorders: A Scientometric Analysis.

Ibogaine is a natural psychoactive drug that has been investigated for its potential role in the treatment of substance use disorders since the mid-1960s. To evaluate the interest in ibogaine's use as a therapeutic agent, we performed a scientometric analysis covering the last three decades (1993-2002, 2003-2012, and 2013-2022). A complementary analysis was performed to select and describe published clinical trials and meta-analyses. A total of 1523 references were found. Linear growth of publications in the first and third decades were identified, and the average number of publications from 1993 to 2002 was lower than that in the other two decades. Researchers from five continents were identified. Globally, academic research centers in the United States and Canada were the most productive. Cocaine, tobacco, morphine, and alcohol prevailed as major keywords in the first two decades and opioids and psychedelics were included in the third decade. A few key authors were the most co-referenced. One preclinical meta-analysis and no meta-analysis in humans were found. Research trends for ibogaine are widespread, growing, and consonant with current attentiveness in drug abuse. Our findings support the pressing need for rigorous clinical research on ibogaine to evaluate its efficacy and safety.

Low perforin expression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential.

BACKGROUND & AIMS: Perforin plays a central role in the immunopathogenesis of different viral infections. However, its role in hepatitis C virus (HCV) infection has not been fully understood. Here, we analyzed two closely related questions: first, is CD8+ T cell-mediated killing of HCV-replicating human hepatoma cells mediated by perforin? Second, if so, do HCV-specific CD8+ T cells obtained from chronically HCV infected patients express and upregulate perforin? METHODS: Susceptibility of HCV-replicating human hepatoma cells to the cytotoxic pathway was tested in vitro by addition of perforin substitute streptolysin O and granzyme B and by co-culture experiments with a perforin-expressing HCV-specific CD8+ T cell clone in the presence of perforin or caspase inhibitors. HCV-specific CD8+ T cells were obtained and analyzed for perforin expression and differentiation markers ex vivo from 12 chronically infected patients and 12 patients with resolved HCV infection. RESULTS: HCV-replicating human hepatoma cells were susceptible to cytotoxic killing in vitro and a dominant role of perforin in HCV-specific CD8+ T cell-mediated cytolysis was observed. However, HCV-specific CD8+ T cells obtained ex vivo from chronically HCV infected patients expressed only low levels of perforin and showed an impaired ability to upregulate perforin. This was tightly linked to the distinct differentiation stage of HCV-specific CD8+ T cell differentiation ex vivo since early and intermediate differentiated HCV-specific CD8+ T cells only showed weak perforin expression in contrast to late differentiated CD8+ T cells that displayed strong perforin expression. CONCLUSIONS: Our results suggest that perforin plays a dominant role in CD8+ T cell-mediated lysis of HCV-replicating human hepatoma cells but that lysis may be limited in human chronic viral infection by the low perforin expression of early/intermediate differentiated HCV-specific CD8+ T cells.

Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes.

The TNF-R1 like receptor Fas is highly expressed on the plasma membrane of hepatocytes and plays an essential role in liver homeostasis. We recently showed that in collagen-cultured primary mouse hepatocytes, Fas stimulation triggers apoptosis via the so-called type I extrinsic signaling pathway. Central to this pathway is the direct caspase-8-mediated cleavage and activation of caspase-3 as compared to the type II pathway which first requires caspase-8-mediated Bid cleavage to trigger mitochondrial cytochrome c release for caspase-3 activation. Mathematical modeling can be used to understand complex signaling systems such as crosstalks and feedback or feedforward loops. A previously published model predicted a positive feedback loop between active caspases-3 and -8 in both type I and type II FasL signaling in lymphocytes and Hela cells, respectively. Here we experimentally tested this hypothesis in our hepatocytic type I Fas signaling pathway by using wild-type and XIAP-deficient primary hepatocytes and two recently characterized, selective caspase-3/-7 inhibitors (AB06 and AB13). Caspase-3/-7 activity assays and quantitative western blotting confirmed that fully processed, active p17 caspase-3 feeds back on caspase-8 by cleaving its partially processed p43 form into the fully processed p18 species. Our data do not discriminate if p18 positively or negatively influences FasL-induced apoptosis or is responsible for non-apoptotic aspects of FasL signaling. However, we found that caspase-3 also feeds back on Bid and degrades its own inhibitor XIAP, both events that may enhance caspase-3 activity and apoptosis. Thus, potent, selective caspase-3 inhibitors are useful tools to understand complex signaling circuitries in apoptosis.

Tumor necrosis factor α sensitizes primary murine hepatocytes to Fas/CD95-induced apoptosis in a Bim- and Bid-dependent manner.

UNLABELLED: Fas/CD95 is a critical mediator of cell death in many chronic and acute liver diseases and induces apoptosis in primary hepatocytes in vitro. In contrast, the proinflammatory cytokine tumor necrosis factor α (TNFα) fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Here we report that TNFα sensitizes primary murine hepatocytes cultured on collagen to Fas ligand (FasL)-induced apoptosis. This synergism is time-dependent and is specifically mediated by TNFα. Fas itself is essential for the sensitization, but neither Fas up-regulation nor endogenous FasL is responsible for this effect. Although FasL is shown to induce Bid-independent apoptosis in hepatocytes cultured on collagen, the sensitizing effect of TNFα is clearly dependent on Bid. Moreover, both c-Jun N-terminal kinase activation and Bim, another B cell lymphoma 2 homology domain 3 (BH3)-only protein, are crucial mediators of TNFα-induced apoptosis sensitization. Bim and Bid activate the mitochondrial amplification loop and induce cytochrome c release, a hallmark of type II apoptosis. The mechanism of TNFα-induced sensitization is supported by a mathematical model that correctly reproduces the biological findings. Finally, our results are physiologically relevant because TNFα also induces sensitivity to agonistic anti-Fas-induced liver damage. CONCLUSION: Our data suggest that TNFα can cooperate with FasL to induce hepatocyte apoptosis by activating the BH3-only proteins Bim and Bid.

The impact of the COVID-19 pandemic on unilateral inguinal hernioplasty surgery in Brazil.

OBJECTIVE: to analyze data from patients hospitalized for unilateral inguinal hernioplasty in Brazil in the year before the COVID-19 pandemic, and during the period of the pandemic. METHODS: this is a descriptive study, using data referring to hospitalizations for the surgical procedure of unilateral inguinal hernioplasty in Brazil from March 2019 to February 2020, comparing with data from March 2020 to February 2021. Data were collected from the Hospital Information System (SIH/SUS) and the selected variables were: number of hospitalizations, average hospital stay rate and mortality rate. RESULTS: in all, 119,312 hospitalizations were performed for unilateral inguinal hernioplasty in Brazil from March 2019 to February 2020. During the pandemic period, 53,445 hospitalizations were recorded for this procedure. The average hospital stay increased compared to the previous year. The mortality rate recorded in the year before the pandemic was 0.11, while in the period of the pandemic, it was 0.20. CONCLUSION: It was observed that during the period of the COVID-19 pandemic in Brazil, the number of hospitalizations for unilateral inguinal hernioplasty was reduced by 55,21%. However, there was a significant increase in the mortality rate of this procedure. These results can be explained by the increase in mortality in patients infected with the SARS-CoV-2 virus, and also by the restriction of performing elective surgeries, prioritizing emergency situations, which are more complicated, and consequently, with higher mortality.

Psychometric validation of the Portuguese version of the Neuropathic Pain Symptoms Inventory.

BACKGROUND: It has been shown that different symptoms or symptom combinations of neuropathic pain (NeP) may correspond to different mechanistic backgrounds and respond differently to treatment. The Neuropathic Pain Symptom Inventory (NPSI) is able to detect distinct clusters of symptoms (i.e. dimensions) with a putative common mechanistic background. The present study described the psychometric validation of the Portuguese version (PV) of the NPSI. METHODS: Patients were seen in two consecutive visits, three to four weeks apart. They were asked to: (i) rate their mean pain intensity in the last 24 hours on an 11-point (0-10) numerical scale; (ii) complete the PV-NPSI; (iii) provide the list of pain medications and doses currently in use. VAS and Global Impression of Change (GIC) were filled out in the second visit. RESULTS: PV-NPSI underwent test-retest reliability, factor analysis, analysis of sensitivity to changes between both visits. The PV-NPSI was reliable in this setting, with a good intra-class correlation for all items. The factorial analysis showed that the PV-NPSI inventory assessed different components of neuropathic pain. Five different factors were found. The PV-NPSI was adequate to evaluate patients with neuropathic pain and to detect clusters of NeP symptoms. CONCLUSIONS: The psychometric properties of the PV-NPSI rendered it adequate to evaluate patients with both central and peripheral neuropathic pain syndromes and to detect clusters of NeP symptoms.

Validation of brief pain inventory to Brazilian patients with pain.

PURPOSE: To validate the Brazilian version of the Brief Pain Inventory (BPI-B) scale and to determine the optimal cutpoints for mild, moderate, and severe pain based on patients' rating of their worst pain. METHODS: One hundred forty-three outpatients with cancer were recruited in Hospital das Clinicas-University of Sao Paulo, Brazil. RESULTS: Confirmatory factor analysis confirmed two underlying dimensions, pain severity, and pain interference, with Cronbach's α of 0.91 and 0.87, respectively. Convergent validity was shown by the correlation observed between the BPI dimensions with the EORTC-QLQ-C30 pain scale and the McGill Pain Questionnaire. The BPI-B detected significant differences in the two dimensions by disease and performance status, supporting known-group validity. For the worst pain, the optimal cutpoints were 4 and 7 (1-4 = mild pain, 5-7 = moderate, and 8-10 = severe). CONCLUSIONS: Our data show that BPI-B is a brief, useful, and valid tool for assessing pain and its impact on patient's life.

[The efficacy of three hand asepsis techniques using chlorhexidine gluconate (CHG 2%)]. / Eficácia de três métodos de degermação das mãos utilizando gluconato de clorexidina degermante (GCH 2%).

The scrubbing of hands and forearms using antiseptic agents has been the standard pre-operative procedure to prevent surgical site infection. With the introduction of antiseptic agents, the need to use brushes for pre-operative disinfection has been questioned and it has been recommended that the procedure be abandoned due to the injuries it may cause to the skin. With the purpose to provide the foundations for the efficacy of pre-operative asepsis without using brushes or sponges, the objective of this study was to evaluate three methods of pre-operative asepsis using an antimicrobial agent containing chlorhexidine gluconate - CHG 2%; hand-scrubbing with brush (HSB), hand-scrubbing with sponge (HSS), and hand-rubbing with the antiseptic agent (HRA) only. A comparative crossover study was carried with 29 healthcare providers. Antimicrobial efficacy was measured using the glove-juice method before and after each tested method. Statistical analyses showed there were no significant differences regarding the number of colony-forming units when comparing HRA, HSB, and HSS techniques (p=0.148), which theoretically disregards the need to continue using brushes or sponges for hand asepsis.

[Patient safety in oncology surgery: experience of the São Paulo State Cancer Institute]. / Segurança do paciente em cirurgia oncológica: experiência do Instituto do Câncer do Estado de São Paulo.

Patient safety concerns in surgery are increasing. The frequency of surgery-related adverse events and errors is high, and most could be avoided. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) proposed the Universal Protocol (UP-JCAHO) for preventing wrong site, wrong procedure, and wrong person surgery. In Brazil, very few health-care institutions have adopted this Protocol. Thus, there is a need to improve its dissemination and assess its effectiveness. The aim of the present study was to report the experiences of the Sao Paulo State Cancer Institute (ICESP, acronym in Portuguese) in implementing the UP-JCAHO. The Protocol comprises three steps: pre-operative verification process, marking the operative site and Time out immediately before starting the procedure. The ICESP surgical center (SC) has been functioning since November 2008. The UP-JCAHO is applied to all surgeries. A total 1019 surgeries were performed up to June 2009. No errors or adverse events were registered. The implementation of the UP-JCAHO is simple. It can be a useful tool to prevent error and adverse events in SC.

Land use and cover maps for Mato Grosso State in Brazil from 2001 to 2017.

This paper presents a dataset of yearly land use and land cover classification maps for Mato Grosso State, Brazil, from 2001 to 2017. Mato Grosso is one of the world's fast moving agricultural frontiers. To ensure multi-year compatibility, the work uses MODIS sensor analysis-ready products and an innovative method that applies machine learning techniques to classify satellite image time series. The maps provide information about crop and pasture expansion over natural vegetation, as well as spatially explicit estimates of increases in agricultural productivity and trade-offs between crop and pasture expansion. Therefore, the dataset provides new and relevant information to understand the impact of environmental policies on the expansion of tropical agriculture in Brazil. Using such results, researchers can make informed assessments of the interplay between production and protection within Amazon, Cerrado, and Pantanal biomes.

[Pauliceia 2.0: collaborative mapping of the history of São Paulo, 1870-1940]. / Pauliceia 2.0: mapeamento colaborativo da história de São Paulo, 1870-1940.

This article presents new approaches for investigating the past using digital technologies. "Pauliceia 2.0: collaborative mapping of the history of São Paulo (1870-1920)" is an open-source project intended to broadly engage with the public through collaborative methodologies. This text discusses the concept, current status, and prospects of this project, and presents it as a case study to discuss the relationship between digital technologies and historical methods. The product of this journey (at least the outcome intended by the authors and the other team members listed at the end of the article) is meant to assign new meaning to the project at the juncture between digital humanities, public history, and open science.

O artigo apresenta novas abordagens para investigar o passado usando tecnologias digitais. O projeto "Pauliceia 2.0: mapeamento colaborativo da história de São Paulo (1870-1920)" é de código aberto e visa engajar o público de maneira ampla, usando metodologias colaborativas. O texto discute a concepção do projeto, seu estágio atual e suas perspectivas. Além disso, também se oferece o Pauliceia 2.0 como um estudo de caso para discutir a relação entre tecnologias digitais e métodos históricos. O resultado desse percurso, ao menos essa é a intenção dos autores listados e dos demais integrantes da equipe do projeto, nomeados ao final do artigo, almeja ressignificar o trabalho em questão na confluência entre humanidades digitais, história pública e ciência aberta.

PD1 and PDL1 molecules control suppressor activity of regulatory T cells in chronic Chagas cardiomyopathy patients.

INTRODUCTION: Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the fourth most important tropical disease, which affects approximately 7 million people worldwide. The mechanisms involved in the development of this disease are not completely well understood. An important protective role of regulatory T cells (Treg) in Chagas disease has been observed; however, the specific mechanisms remain unclear. We evaluated apoptosis as a possible mechanism mediated by Treg cells (CD4+CD25HighFOXP3+) to orchestrate the immune response in chronic Chagas disease. METHODS AND RESULTS: Patients with Chagas disease were grouped as the indeterminate (IND; asymptomatic patients with Chagas disease; n = 10) and dilated cardiomyopathy (CARD; n = 10). Healthy T. cruzi-negative individuals (NI; n = 10) were included as a control group. In order to evaluate the apoptotic cell profile, the expression of PD1, PD1L, CD39, CD95, CD95L molecules were investigated. We also evaluated the proportion of CD14+ cells expressing caspase 3. The IND group presented a substantially higher expression of CD39 by Treg cells as compared to the CARD group. On the other hand, the CARD group showed higher expression of PD-1 by Treg cells than both NI and IND groups. Significant positive correlations were observed between Treg CD95L+ cells and CD14 cells expressing caspase 3 as well as between Treg CD39 cells and CD14+ Caspase3+ cells in the IND group. CONCLUSION: Our data indicate that the expressions of different molecules that induce apoptosis are associated with suppressive mechanisms mediated by Treg cells and suggest a possible role for PD1 and PDL1 molecules in the morbidity of chronic Chagas disease.

Correlation between active disease and hypercoagulability state in patients with systemic lupus erythematosus.

OBJECTIVE: This study has investigated whether high levels of Reticulocytes-C4d (R-C4d) and Platelets-C4d (P-C4d) reflecting recent activity in SLE patients are correlated with changes in natural anticoagulation components, coagulation activation and endothelial injury markers. METHODS: This study included three groups: 1) healthy women (control, n = 30); 2) women with low activity of the disease (SLEDAI 2 K ≤ 4, n = 30); 3) women with active disease (moderate or high activity) (SLEDAI 2 K > 4, n = 30). Median fluorescence intensity (MFI) of R-C4d and P-C4d were determined by flow cytometry using double labeling with specific monoclonal antibodies. Endothelial injury and hypercoagulability were evaluated by measuring Thrombomodulin and D-dimer levels. RESULTS: Higher MFI index of R-C4d were related to the recent activity of SLE, and higher expression of P-C4d indicated an elevated risk of thrombotic complications. Increased levels of soluble thrombomodulin and D-dimer were observed in patients with active SLE. CONCLUSION: R-C4d is helpful to monitor early disease activity and PC4-d may be an important tool to detect a prothrombotic phenotype in SLE. Elevated levels of D-dimer and thrombomodulin add value to P-C4d data and corroborate a hypercoagulable profile in women with SLE, contributing to an increased prothrombotic risk associated with inflammation.

Impact of cancer-related symptom synergisms on health-related quality of life and performance status.

To identify the impact of multiple symptoms and their co-occurrence on health-related quality of life (HRQOL) dimensions and performance status (PS), 115 outpatients with cancer, who were not receiving active cancer treatment and were recruited from a university hospital in Sao Paulo, Brazil completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, the Beck Depression Inventory, and the Brief Pain Inventory. Karnofsky Performance Status scores also were completed. Application of TwoStep Cluster analysis resulted in two distinct patient subgroups based on 113 patient experiences with pain, depression, fatigue, insomnia, constipation, lack of appetite, dyspnea, nausea, vomiting, and diarrhea. One group had multiple and severe symptom subgroup and another had less symptoms and with lower severity. Multiple and severe symptoms had worse PS, role functioning, and physical, emotional, cognitive, social, and overall HRQOL. Multiple and severe symptom subgroup was also six times as likely as lower severity to have poor role functioning; five times more likely to have poor emotional; four times more likely to have poor PS, physical, and overall HRQOL; and three times as likely to have poor cognitive and social HRQOL, independent of gender, age, level of education, and economic condition. Classification and Regression Tree analyses were undertaken to identify which co-occurring symptoms would best determine reduction in HRQOL and PS. Pain and fatigue were identified as indicators of reduction on physical HRQOL and PS. Fatigue and insomnia were associated with reduction in cognitive; depression and pain in social; and fatigue and constipation in role functioning. Only depression was associated with reduction in overall HRQOL. These data demonstrate that there is a synergic effect among distinct cancer symptoms that result in reduction in HRQOL dimensions and PS.