INFLAMMATORY IMMUNOPATHOLOGY OF COVID-19 AND ITS CORRELATION WITH THE SEVERITY OF THE DISEASE / IMUNOPATOLOGIA INFLAMATÓRIA DA COVID-19 E SUA CORRELAÇÃO COM A GRAVIDADE DA DOENÇA

SARS-CoV-2, which caused the coronavirus pandemic in 2019 (COVID-19), is a beta-coronavirus, and its infection in host cells can activate innate and adaptive immune responses through the activation of several pro-inflammatory cytokines. Thus, in this study we established the relationship between the severity and immunopathology of COVID-19 through the main inflammatory cytokines. Results show that tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) and interleukins (IL), such as IL-6, are stimulated by the activation of T cell subsets, which results in immune-mediated cellular destruction. Several cytokines reduce the immune response and predispose to a pro-inflammatory and auto-reactive state, including IL-1ß, IL-1RA, IL-7, IL-8, IL-9, IL-10, and associated inflammatory markers (LDH, GM-CSF and VEGF). These higher cytokine levels end up favoring tissue damage in multiple systems, including lungs, heart, gastrointestinal, brain, kidneys and other organs. Increasingly, a greater impact of the markers IL-6, ferritin, pro-calcitonin, lactic dehydrogenase, D-dimer and hypoalbuminemia was observed in patients with severe infection of the disease. In general, the data analyzed confirmed that COVID-19 severity is not caused simply by the viral infection, but rather by immune response and aberrant inflammation. In this way, this study allows a contribution to clinical practice, and it shows that it is essential to carry out in-depth studies about the immunopathology of COVID-19, in order to determine the severity markers involved in the pathogenesis of the viral infection.

O SARS-CoV-2, causador da doença coronavírus 2019 (COVID-19), é um beta-coronavírus, e sua infecção nas células do hospedeiro pode ativar respostas imunes inata e adaptativa, por meio da secreção de várias citocinas pró-inflamatórias. Assim, estabelecemos neste estudo a correlação da gravidade e imunopatologia da COVID-19 com as principais citocinas inflamatórias. Resultados mostram que o fator de necrose tumoral alfa (TNF-α), interferon-gama (IFN-γ) e interleucinas (IL), como a IL-6, são estimulados pela ativação de subconjuntos de células T, o que resulta em destruição celular imunomediada. Sendo que, diversas citocinas deprimem a resposta imune sadia, e predispõem a um estado pró-inflamatório e auto-reativo, dentre elas, IL-1ß, IL-1RA, IL-7, IL-8, IL-9, IL-10, e os marcadores inflamatórios associados (LDH, GM-CSF e VEGF). Isso acaba por favorecer danos teciduais em múltiplos sistemas, como no pulmonar, cardíaco, gastrointestinal, cerebral, renal, dentre outros. Acrescenta-se que foi observado um impacto maior dos marcadores IL-6, ferritina, pró-calcitonina, desidrogenase láctica, D-dímero e hipoalbuminemia em pacientes com infecção grave da doença. De forma geral, pela análise de dados, verificou-se que a gravidade da doença COVID-19 parece ser modulada não apenas pela infecção viral, mas também por respostas imunes e inflamatórias aberrantes no hospedeiro. Dessa forma, este estudo permite contribuir para o auxílio da prática clínica, sendo imprescindível a realização de estudos aprofundados acerca da imunopatologia da COVID-19, a fim de que se determine os marcadores de gravidade envolvidos na patogênese da infecção viral.

Quality of life in Brazilian medical students: a systematic review and meta-analysis

Abstract Objectives Medical training negatively impacts the quality of life of students. Assessing the well-being of medical students could guide academic policies and future research for improving the mental and physical health status of the population at risk. This study aimed to identify the influence of medical training on the quality of life of Brazilian medical students. Methods A systematic review and meta-analysis was conducted according to the Cochrane criteria and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol (PRISMA). The search was performed by two independent investigators using a predefined protocol registered on the PROSPERO database (CRD42021237926). Data were extracted from PubMed, Embase, and Biblioteca Virtual de Saúde (BVS). For quantitative synthesis, a meta-analysis was conducted to assess the mean difference in the quality of life between medical students at different stages in the academic cycle, stratified by sex. All data were analyzed using the random-effects model, with a confidence interval of 95% (95%CI). Results After evaluating the eligibility criteria, five studies were included in the meta-analysis. The data revealed that students in the pre-clinical cycle of the course exhibited higher quality of life scores in the physical (3.05 [1.48-4.62], p < 0.0001) and psychological (3.05 [0.80-5.30], p < 0.0001) domains than students in the clerkship cycle. No statistically significant differences were observed in the environmental (0.78 [-2.92-4.49], p = 0.68) or social domains (1.41 [-0.52-3.34], p = 0.15). Conclusion Our analysis revealed that the medical course is associated with decreased quality of life of medical students in the physical and psychological domains. This finding was observed in both men and women. However, these findings should be interpreted with caution given the study limitations. Registration number PROSPERO, CRD42021237926.

Age, gender, and 11 comorbidities as risk factors associated with COVID-19 mortality: A retrospective cohort including 1.8 million individuals.

The aim of this study was to investigate the risk factors age, gender, and 11 comorbidities for mortality attributed to COVID-19 among Brazilians. An observational, retrospective cohort study with 1,804,151 individuals was performed using the São Paulo State Statistics Portal database for COVID-19 monitoring. Multivariate binary logistic regression was conducted to estimate the influence of odds ratio (OR) for asthma, diabetes, obesity, Down's syndrome, puerperal, hematological, hepatic, neurological, pulmonary, immunological, kidney, and other diseases contributing to mortality attributed to COVID-19. An additional analysis was undertaken using age-stratified data including children, adults, and seniors. Our findings demonstrated that cardiac diseases (9.37%) and diabetes (6.26%) were the most prevalent disorders in therapeutically managed and deceased patients. Multivariate regression model found that male individuals (OR = 1.819, CI 1.783 to 1.856, p < 0.001), older age (OR per year = 1.081, CI 1.081 to 1.082, p < 0.001) and presenting comorbidities (OR varying from 1.84-5.47) were at a higher risk of death. The age-stratified analysis also indicates disparities in the impact of the comorbidities between children, adults, and seniors. Our comprehensive findings indicate the primary risk factors for mortality attributed to COVID-19 in the entire population examined, provide a broader perspective than investigations focused solely on hospitalized patients. This study may be utilized as a valuable tool for decision-making during the COVID-19 outbreak.

Plasma Levels of Matrix Metalloproteinases 2 and 9 in Patients with Chronic Chagas Heart Disease and Systemic Arterial Hypertension: Correlation with TGF-Beta Plasma Levels.

Background: Chronic Chagas heart disease (CCHD) and systemic arterial hypertension (SAH) frequently coexists in areas where Chagas disease is endemic. The effects of the association of both conditions (CCHD-SAH) on the extracellular matrix (ECM) remodeling are unknown. Matrix metalloproteinases (MMP) 2 and 9 are involved in ECM remodeling. The aim of this study was to evaluate MMP 2 and MMP9 in CCHD-SAH patients and to correlate their levels with those of the profibrogenic cytokine TGF-beta. Methods: We included 19 patients with CCHD-SAH, 14 patients with CCHD alone, and 19 controls matched by sex and age. MMP-2 and MMP-9 plasma levels were studied by gel zymography and showed as optical densities (OD). TGF-beta plasma levels were measured by double-ligand ELISA and expressed as pg/mL. Results: Median (5th, 95th) MMP-2 plasma levels were 1224.7 OD (1160, 1433.5) in patients with CCHD alone, 1424.1 OD (1267.5, 1561) in patients with CCHD-SAH, and 940 OD (898.1, 1000.8) in controls (p=0.001). MMP-9 plasma levels were 1870 OD (1740, 1904.1) in patients with CCHD alone, 1754.6 OD (1650, 2049) in those with CCHD-SAH and 89.7 OD (80, 96) in controls (p=0.0003). MMP-9 plasma levels were higher than those of MMP 2 in patients with CCHD-SAH (p=0.01). No correlation was found between TGF-beta plasma levels with MMP-2 serum levels (r = 0.12; p=0.7), but a moderate negative correlation (r = -0.46; p=0.048) was observed between TGF-beta and MMP-9 plasma levels. Conclusions: MMP-2 and especially MMP-9 may play a role in the ECM remodeling process in patients with CCHD-SAH. TGF-Beta may counteract the MMP effect on the ECM remodeling process in patients with CCHD-SAH.

Quality of life in Brazilian medical students: A systematic review and meta-analysis.

INTRODUCTION: Medical training negatively impacts the quality of life of students. Assessing the well-being of medical students might guide academic policies and future research for improving mental and physical health status of the population at risk. OBJECTIVES: This study aimed to identify the influence of medical training on the quality of life of Brazilian medical students. METHOD: A systematic review and meta-analysis was conducted according to the Cochrane criteria and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. The search was performed by two independent investigators using a predefined protocol registered in PROSPERO (CRD42021237926). Data were extracted from PubMed, EMBASE, and Biblioteca Virtual de Saúde. For quantitative synthesis, a meta-analysis was conducted to assess the mean difference in the quality of life between medical students of different academic cycles stratified by sex. All data were analyzed using the random-effects model, with a confidence interval of 95%. RESULTS: After evaluating the eligibility criteria, five studies were included in the meta-analysis. The data revealed that students in the pre-clinical cyclee of the course exhibited higher quality of life scores in the physical (3.05 [1.48, 4.62], p< 0.0001) and psychological (3.05 [0.80, 5.30], p< 0.0001) domains than students in the clerkship cycle. No statistically significant difference was observed in the environmental (0.78 [-2.92, 4.49], p= 0.68]) and social domains (1.41 [-0.52, 3.34], p= 0.15). CONCLUSION: Our analysis revealed that the medical course is associated with a decreased quality of life in the physical and psychological domains of medical students. This finding was observed in both men and women. However, these findings should be interpreted with caution given the limitations of this study.

Kinins and nitric oxide in patients with chronic chagas disease and systemic arterial hypertension.

BACKGROUND: Chronic Chagas disease (CCHD) associated with Systemic Arterial Hypertension (SAH) is frequently found in areas where the disease is endemic. The pathogenesis of patients with both pathologies (CCHD-SAH) is unsettled. Nitric Oxide (NO) and Kinins are important players in the myocardial inflammation process in experimental CCHD. No previous study has addressed this question in patients with CCHD, particularly in those with CCHD-SAH. Accordingly, this study was undertaken in an attempt to contribute to the understanding of the pathogenesis of patients with CCHD-SAH. METHODS: Thirty-seven patients with a positive serology for Chagas disease were enrolled; 15 had CCHD alone, 22 had CCHD-SAH (abnormal ECG/Doppler echocardiogram plus a systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on admission), and 11 had SAH alone. Thirty healthy individuals matched by age and sex served as controls. Plasma High-molecular (Hkg) and low-molecular weight (LKg) kininogens, plasma kallikrein levels (Pkal and Tcal), Kininase II, and plasma NO were measured. RESULTS: HKg and LKg were lower in CCHD-SAH patients in comparison with other groups (P < .0001). Pkal and Tcal were higher in CCHD-SAH patients in comparison with the other groups (P< .0001). Kininase II levels were similar in SAH, CCHD, and CCHD-SAH patients, but lower in comparison with controls (P< .0001). NO levels were similar in CCHD and CCHD-SAH patients, but higher in comparison with SAH patients and controls (P > .0001). CONCLUSION: Such findings suggest increased Kinin and NO activity in patients with CCHD-SAH, thus contributing to the understanding of the pathogenesis of this condition.

Carbon-Coated Stent and the Role of the Kallikrein-Kinin System in Peripheral Angioplasty.

OBJECTIVE: The purpose of this study was to investigate the clinical evolution of patients treated with carbon-coated stent, as well as its patency and the inflammatory response triggered by this process through the quantification of serum elements of the kallikrein-kinin system (KKS). METHODS: This was a single-center prospective study with 27 patients with peripheral artery disease (PAD) who required percutaneous transluminal angioplasty and stenting of the iliacofemoropopliteal segment using carbon-coated stent grafts (carbostents). The blood concentrations of the total and kininogen fractions were evaluated using immunoenzymatic methods. Plasma kallikrein levels were assessed by the colorimetric method and tissue kallikrein levels were evaluated by the spectrophotometric method. The activity of kininase II was measured by -fluorometric analysis. RESULTS: Of the 27 patients who completed the 6 months of the study (11 iliac territory, 16 femoropopliteal territory), only one experienced restenosis (3.7%) (femoropopliteal segment) and no patient had occlusion (96.3% of patency). In 1 year, four patients were lost to follow-up and all 23 patients evaluated maintained stent patency, except for the patient who had restenosis throughout the first 6 months. We report complete (100%) member salvage in 12 months of follow-up. The activity levels of high- and low-molecular-weight kininogens decreased significantly over time (before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.001, and before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.001; 24 h vs. 6 months, p < 0.001, respectively). Patients also had significantly lower levels of plasma and tissue kallikrein (before vs. 24 h, p < 0.001; before vs. 6 months, p < 0.001, and before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.05, respectively). There was a significant increase in the enzymatic activity of kininase II at 24 h and after 6 months compared to the pre-treatment control (p < 0.001). CONCLUSION: Our early experience shows that the use of carbon-coated stents in PAD appears to be safe, with low rates of early restenosis (3.7% in the first 6 months and 5% in the 12 months of follow-up). We concluded that KKS was involved in the inflammatory response caused by the placement of carbon-coated stents.

Determination of the Th1, Th2, Th17, and Treg cytokine profile in patients with chronic Chagas heart disease and systemic arterial hypertension.

Chronic Chagas heart disease (CCHD affects about 30% of patients with chronic Chagas disease (CCD). Systemic arterial hypertension (SAH) afflicts about 25% of patients with CCD. The association of CCHD with SAH (CCHD-SAH) predisposes patients to develop chronic heart failure. The role of cytokines in disease progression in patients with CCHD-SAH is unknown. Accordingly, the aim of this study was to evaluate the plasma levels of cytokines expressing the Th1, Th2, Th17 pattern, as well as Treg cytokines, TNF-alpha, IL-1ß, IL-8, IL-7 in patients with SAH-CCHD to get insight into the immunomodulation process in patients with this condition. Fifteen patients with CCHD, 22 patients with CCHD-SAH, and 28 controls were studied. All patients underwent history-taking, physical examination, 12-lead resting ECG, chest X-ray, and Doppler-echocardiogram. Ten of 15 (66%) patients with CCHD, and 16 of 22 (73%) patients with CCHD-SAH had decreased left ventricular ejection fraction (p > 0.05). Cytokines levels were performed on plasma samples using the ELISA method. Overall, proinflammatory, anti-inflammatory, and regulatory cytokine levels were increased in patients with CCHD-SAH in comparison to patients with CCHD and controls. However, such a difference was higher regarding IL-2, IL-5, IL-17, IL-12, and TNF-alpha cytokine levels, respectively. Cytokine levels were higher in CCHD patients in comparison to controls. Patients with CCHD-SAH have increased plasma levels of pro-inflammatory, anti-inflammatory, and regulatory cytokines in comparison with CCHD patients, thus suggesting a higher level of immunomodulation in patients with CCHD-SAH.

Interleukins and inflammatory markers in in-stent restenosis after femoral percutaneous transluminal angioplasty.

BACKGROUND: Inflammatory activity may influence results of percutaneous transluminal angioplasty (PTA). The purpose of this study was to evaluate the relationship between (1) proinflammatory markers (interleukin [IL]-6, IL-8, tumor necrosis factor α (TNF-α), and highly sensitive C-reactive protein [CRP]); (2) type 1 T helper cell marker (IL-12); and (3) Type 2 T helper cell marker (transforming growth factor-ß [TGF-ß]) and in-stent restenosis, 6 months after femoral PTA with stent implantation. METHODS: We performed a single-center prospective study with 26 patients with peripheral artery disease requiring PTA and stenting. As control, we studied 26 patients who were submitted to diagnostic angiography. Serum samples were collected before stent implantation, 24 hr and 6 months after the procedure. To detect restenosis, a new angiography was obtained at 6 months. RESULTS: Restenosis was observed in 10 (38.5%) patients who underwent PTA and stenting. There was a trend to increased levels of IL-6, TNF-α, TGF-ß, and IL-12 24 hr after PTA and stenting compared with pretreatment. IL-8 levels showed a statistically significant reduction 24 hours after versus pretreatment (P < 0.05), 6 months vs. pretreatment, and 6 months vs. 24 hr (P < 0.01). There was no statistical difference between cytokine levels when comparing restenosis and no restenosis groups. CRP levels were already high at pretreatment. CONCLUSIONS: No inflammatory marker was independently identified as risk factor for in-stent restenosis, 6 months after femoral PTA with stent implantation. The question that remains is whether acute phase reactants will be clinically useful to predict the individual risk for in-stent restenosis.

Human leucocyte antigen-G (HLA-G) and its murine functional homolog Qa2 in the Trypanosoma cruzi Infection.

Genetic susceptibility factors, parasite strain, and an adequate modulation of the immune system seem to be crucial for disease progression after Trypanosoma cruzi infection. HLA-G and its murine functional homolog Qa2 have well-recognized immunomodulatory properties. We evaluated the HLA-G 3' untranslated region (3'UTR) polymorphic sites (associated with mRNA stability and target for microRNA binding) and HLA-G tissue expression (heart, colon, and esophagus) in patients presenting Chagas disease, stratified according to the major clinical variants. Further, we investigated the transcriptional levels of Qa2 and other pro- and anti-inflammatory genes in affected mouse tissues during T. cruzi experimental acute and early chronic infection induced by the CL strain. Chagas disease patients exhibited differential HLA-G 3'UTR susceptibility allele/genotype/haplotype patterns, according to the major clinical variant (digestive/cardiac/mixed/indeterminate). HLA-G constitutive expression on cardiac muscle and colonic cells was decreased in Chagasic tissues; however, no difference was observed for Chagasic and non-Chagasic esophagus tissues. The transcriptional levels of Qa2 and other anti and proinflammatory (CTLA-4, PDCD1, IL-10, INF-γ, and NOS-2) genes were induced only during the acute T. cruzi infection in BALB/c and C57BL/6 mice. We present several lines of evidence indicating the role of immunomodulatory genes and molecules in human and experimental T. cruzi infection.

Characterization of the kallikrein-kinin system, metalloproteinases, and their tissue inhibitors in the in-stent restenosis after peripheral percutaneous angioplasty.

BACKGROUND: The kallikrein-kinin system (KKS) has several direct and indirect effects on cells and cellular mediators involved in the inflammatory process. Studies about inflammation on percutaneous transluminal angioplasty with stent (PTA/stent) to treat peripheral arterial disease (PAD) in humans are scarce. The matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases expressed in various cells and tissues such as fibroblasts, inflammatory cells, and, smooth muscle cells. Changes in the extracellular matrix (ECM) take place in the pathogenesis of many cardiovascular pathologies. MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are crucial in ECM remodeling in both physiologic and pathologic conditions. The aim of this study was to evaluate the role of the KKS and the MMP metabolism, which are important mediators that may contribute to tissue repair, in the process of arterial restenosis due to intimal hyperplasia in the femoropopliteal segment with the aim of developing new interventions. METHODS: Thirty-nine consecutive patients were selected (regardless of ethnic group, age, or sex) for revascularization, who underwent PTA/stent of the femoropopliteal segment. Twenty-five patients with the same clinical characteristics who were scheduled for diagnostic angiography but not subjected to PTA/nitinol stent were also selected. The concentrations in blood of total and kininogen fractions were evaluated using immunoenzymatic methods. Plasma kallikrein was evaluated by the colorimetric method. Tissue kallikrein was evaluated by the spectrophotometric method. The activity of kininase II was measured by fluorometric analysis. Quantification of MMPs was performed by zymography, which is an electrophoresis technique, and TIMPs were measured by enzyme-linked immunosorbent assay. RESULTS: Among the 31 patients who completed the survey, there were 10 cases of angiographically defined restenosis of >50%, and 21 cases without restenosis. There was an increase in the concentrations of the substrates (high-molecular-weight kininogens and lower molecular weight kininogens) and enzymes (plasma and tissue kallikrein) in patients with restenosis, indicating activation of this inflammatory pathway in these patients. The activity of kininase II was not significantly different between the groups of patients studied. There were no statistical differences between restenosis and no restenosis patients for both MMPs and TIMPs dosage, but there is an upward trend of MMPs in time 6 months in patients with restenosis. CONCLUSIONS: With the aim of identifying factors contributing to restenosis after endovascular intervention, this study showed evidence of high activation of the KKS in the pathologic inflammatory process of PTA/stent restenosis. In the other hand, it could not show participation of metalloproteinase metabolism in PTA/stent restenosis.

Polymorphic sites at the immunoregulatory CTLA-4 gene are associated with chronic chagas disease and its clinical manifestations.

BACKGROUND: Chagas disease affects approximately 10 million people mainly in Latin America. The immune regulation by the host seems to be an essential factor for disease evolution, and immune system inhibitory molecules such as CTLA-4 and PD-1 favor the maintenance of peripheral tolerance. Considering that polymorphisms at the immunoregulatory CTLA-4 and PDCD1 genes may alter their inhibitory function, we investigated the association of alleles, genotypes and haplotypes of polymorphic sites observed at the CTLA-4 and PDCD1 genes with different clinical manifestations of chronic Chagas disease (indeterminate, cardiac, digestive and mixed). METHODS: The polymorphisms at the CTLA-4 (-1722T/C, -318C/T and +49A/G) and PDCD1 (PD-1.3G/A) genes were typed using TaqMan methodology in 277 chronic Chagas disease patients classified into four groups, according to clinical characteristics, and 326 non-infected controls. RESULTS: Our results showed that CTLA-4 -1722CC genotype (22%), -1722C allele (27%) and CTLA-4 TCG (8.6%), TCA (26%) and CCA (15%) haplotypes were strongly associated with the indeterminate form, while the CTLA-4-318CT genotype (82%) and CTLA-4-318T allele (47%) were found mainly in patients with the mixed form of the disease. The CTLA-4 TCG haplotype (10.2%) was associated with the digestive form. On the other hand, the PD-1.3G/A polymorphism was not associated with chronic Chagas disease and its clinical manifestations. CONCLUSIONS: Here, we showed that alleles, genotypes and haplotypes reported to increase the expression of the regulatory molecule CTLA-4 were associated with the indeterminate form of the disease. Taken together, our data support the idea that polymorphic sites at immunoregulatory genes may influence the development of Chagas disease variants.

Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease.

BACKGROUND: Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease. METHODOLOGY/PRINCIPAL FINDINGS: First, we observed CD4(+)IL-17(+) T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+)IL-17(+) cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+)CD25(+) regulatory T cells. However, CD4(+)CD25(+) T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500). CONCLUSION/SIGNIFICANCE: These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF-α is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.

Imbalanced matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 activities in patients with thromboangiitis obliterans.

The pathogenic mechanisms of thromboangiitis obliterans (TAO) are not entirely known and the imbalance of matrix metalloproteinases (MMPs) plays a role in vascular diseases. We evaluated the MMP-2 and MMP-9 circulating levels and their endogenous tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in TAO patients with clinical manifestations. The study included 20 TAO patients (n = 10 female, n = 10 male) aged 38-59 years under clinical follow-up. The patients were classified into two groups: (1) TAO former smokers (n = 11) and (2) TAO active smokers (n = 9); the control group included normal volunteer non-smokers (n = 10) and active smokers without peripheral artery disease (n = 10). Patient plasma samples were used to analyze MMP-2 and MMP-9 levels using zymography, and TIMP-1 and TIMP-2 concentrations were determined by enzyme-linked immunosorbent assays. The analysis of MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios (which were used as indices of net MMP-2 and MMP-9 activity, respectively) showed significantly higher MMP-9/TIMP-1 ratios in TAO patients (p < 0.05). We found no significant differences in MMP-2/TIMP-2 ratios (p > 0.05). We found higher MMP-9 levels and decreased levels of TIMP-1 in the TAO groups (active smokers and former smokers), especially in active smokers compared with the other groups (all p < 0.05). MMP-2 and TIMP-2 were not significantly different in patients with TAO as compared to the control group (p > 0.05). In conclusion, our results showed increased MMP-9 and reduced TIMP-1 activity in TAO patients, especially in active smokers compared with non-TAO patients. These data suggest that smoke compounds could activate MMP-9 production or inhibit TIMP-1 activity.

Inflammatory markers and restenosis in peripheral percutaneous angioplasty with intravascular stenting: current concepts.

In this article, we review the current status of inflammation linked to percutaneous transluminal angioplasty with stent implantation, especially as it relates to restenosis and its clinical implications. Common to multiple vascular diseases, including atherosclerosis, interventional restenosis is a localized inflammatory reaction. Activated smooth muscle cells respond to local inflammation and migrate from the media into the lumen of the vessel, where they proliferate and synthesize cytokines which they respond to in an autocrine manner, sustaining the progression of the lesion. The deleterious effects of proinflammatory cytokines, particularly immunomodulatory interleukins, on vascular pathophysiology and development of these maladaptive processes have been the subject of intense study. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are important in many physiologic and pathologic processes and their expression is related with the classic cardiovascular risk factors as well as with inflammation. They seem to play a central role in atherosclerosis and restenosis. The primary use of drug-eluting stents has become routine clinical practice for coronary artery disease, but the use in peripheral arteries remains to be further studied, like that demonstrated in sirolimus-coated Cordis trials. New studies to understand this complex process in peripheral arteries are warranted.

Pharmacology of the human saphenous vein.

Nowadays, the great saphenous vein is the vascular conduit that is most frequently employed in coronary and peripheral revascularization surgery. It is known that saphenous vein bypass grafts have shorter patency than arterial ones, partly because the wall of the normal saphenous vein has different structural and functional characteristics. The features of this vein can be affected by the large distention pressures it is submitted to during its preparation and insertion into the arterial system. Indeed, a vein graft is subjected to considerable changes in hemodynamic forces upon implantation into the arterial circulation, since it is transplanted from a non-pulsatile, low-pressure, low-flow environment with minimal shear stress to a highpressure system with pulsatile flow, where it undergoes cyclic strain and elevated shear. These changes can be responsible for functional and morphological alterations in the vessel wall, culminating in intima hyperproliferation and atherosclerotic degeneration, which contribute to early graft thrombosis. This review has followed a predetermined strategy for updating information on the human saphenous vein (HSV). Besides presenting the aspects relative to the basic pharmacology, this text also includes surgical aspects concerning HSV harvesting, the possible effects of the major groups of cardiovascular drugs on the HSV, and finally the interference of major cardiovascular diseases in the vascular reactivity of the HSV.

Etiopathogenesis, clinical diagnosis and treatment of thromboangiitis obliterans - current practices.

Thromboangiitis obliterans (TAO) is a segmental inflammatory occlusive disorder that affects small- and medium-sized arteries, and arm and leg veins of young smokers. Several different diagnostic criteria have been offered for the diagnosis of TAO. Clinically, it manifests as migratory thrombophlebitis or signs of arterial insufficiency in the extremities. It is characterized by highly cellular and inflammatory occlusive thrombi, primarily of the distal extremities. Thromboses are often occlusive and sometimes display moderate, nonspecific inflammatory infiltrate, consisting mostly of polymorphonuclear leukocytes, mononuclear cells and rare multinuclear giant cells. The immune system appears to play a critical role in the etiology of TAO. However, knowledge about immunological aspects involved in the progression of vascular tissue inflammation, and consequently, the evolution of this disease, is still limited. There are several studies that suggest the involvement of genetic factors and results have shown increasing levels of antiendothelial cell antibodies in patients with active disease. Vasodilation is impaired in patients with TAO. TAO disorder may actually be an autoimmune disorder, probably initiated by an unknown antigen in the vascular endothelium, possibly a component of nicotine. There are various therapies available for treatment of TAO, but the major and indispensable measure is smoking cessation. Except for discontinuation of tobacco use, no forms of therapy are definitive. Sympathectomy, cilostazol and prostaglandin analogues (prostacyclin or prostaglandin E) have been used in specific conditions. Recently, therapeutic angiogenesis with autologous transplantation of bone marrow mononuclear cells has been studied in patients with critical limb ischemia.

Kinins and cytokines in plasma and cerebrospinal fluid of patients with neuropsychiatric lupus.

OBJECTIVE: To evaluate the kinin system components and selected cytokines in plasma and cerebrospinal fluid (CSF) of patients with neuropsychiatric lupus (NPL). METHODS: We studied 29 women with active NPL and 29 healthy women matched to patients for age. Low (LKg) and high molecular weight kininogen (HKg) and cytokine concentrations [interleukin 1beta (IL-1beta), IL-6, IL-8, IL-10, and tumor necrosis factor-a (TNF-a)] were determined by ELISA. The activities of tissue kallikrein, plasma prekallikrein, and kininase II were assayed by their action on selective substrates. RESULTS: Compared to controls, patients with NPL presented increased plasma and CSF levels of LKg, HKg, and prekallikrein, increased activity of tissue kallikrein and kininase II, and increased levels of IL-6, IL-10, and TNF-a (p < 0.001 each comparison). IL-1beta levels were increased in patient plasma (p < 0.001), whereas plasma IL-8 levels did not differ from controls. IL-1beta and IL-8 were not detected in CSF of patients or controls. CONCLUSION: The increased levels of kininogen fractions, kallikreins, and kininase II in patient plasma and CSF indicate overactivity of the kinin system, suggesting intense kinin production. Since kinins may induce the production of proinflammatory cytokines including IL-1beta, IL-6, and TNF-a, these findings support the participation of kinins and cytokines in the acute manifestations of NPL. Most of the variables evaluated in patients' CSF increased proportionally in relation to plasma levels. In contrast, the activity of tissue kallikrein in patient CSF increased out of proportion to plasma levels, appearing to be locally synthesized in response to brain involvement.