Preoperative portal vein or portal and hepatic vein embolization: DRAGON collaborative group analysis.

BACKGROUND: The extent of liver resection for tumours is limited by the expected functional reserve of the future liver remnant (FRL), so hypertrophy may be induced by portal vein embolization (PVE), taking 6 weeks or longer for growth. This study assessed the hypothesis that simultaneous embolization of portal and hepatic veins (PVE/HVE) accelerates hypertrophy and improves resectability. METHODS: All centres of the international DRAGON trials study collaborative were asked to provide data on patients who had PVE/HVE or PVE on 2016-2019 (more than 5 PVE/HVE procedures was a requirement). Liver volumetry was performed using OsiriX MD software. Multivariable analysis was performed for the endpoints of resectability rate, FLR hypertrophy and major complications using receiver operating characteristic (ROC) statistics, regression, and Kaplan-Meier analysis. RESULTS: In total, 39 patients had undergone PVE/HVE and 160 had PVE alone. The PVE/HVE group had better hypertrophy than the PVE group (59 versus 48 per cent respectively; P = 0.020) and resectability (90 versus 68 per cent; P = 0.007). Major complications (26 versus 34 per cent; P = 0.550) and 90-day mortality (3 versus 16 per cent respectively, P = 0.065) were comparable. Multivariable analysis confirmed that these effects were independent of confounders. CONCLUSION: PVE/HVE achieved better FLR hypertrophy and resectability than PVE in this collaborative experience.

HCV viremia drives an increment of CD86 expression by myeloid dendritic cells.

The host immune response, including innate and adaptive immunity, plays a critical role in determining the outcome of viral infection. Nevertheless, little is known about the exact reasons for the failure of the host immune system in controlling hepatitis C virus (HCV) infection. Impairment of dendritic cells (DCs) function is probably one of the mechanisms responsible for immune evasion of HCV. In this study, the frequency and phenotype of DCs subsets were analyzed in three groups: HCV-infected individuals who developed viral persistence (1), HCV-infected individuals who spontaneously cleared the virus (2) and HCV-seronegative uninfected subjects (3). The results showed that the frequency of DCs subsets was not statistically significant between groups. Plasmacytoid DCs circulating exhibited an immature phenotype characterized by low expression of CD86. On the other hand, CD86 expression in myeloid DCs was significantly higher in chronic infected individuals compared to healthy controls (P=0.037). A positive correlation was observed between CD86(+) myeloid DC (mDC) and HCV viral load (r=0.4121, P=0.0263). These results suggest that HCV did not have an inhibitory effect on mDC maturation and the HCV viremia drives the increase of CD86 expression in mDC. The regulation of DCs maturation and migration lies at the level of intracellular signaling. HCV can activate or block intracellular signaling pathways and alter DC function. In conclusion, the present study suggests that imbalance of DC maturation by the virus represents a mechanism of evasion of the immune system despite the fact that HCV viremia appears to exert a "stimulatory" effect on cell-surface immune phenotype.

Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.

Three hundred million individuals are at risk of infection by schistosomes and around 200,000 die each year of this disease. Severe clinical disease in schistosomiasis is often the consequence of heavy infection which, in several endemic areas, are determined largely by the susceptibility/resistance of individuals. Previously, we reported evidence, based on a segregation analysis in Brazilian pedigrees, that intensity of infection by Schistosoma mansoni was influenced by a major gene, indicating that host genetic factors are probably critical in controlling schistosome infection and disease development. To localize this gene, referred to as SM1, we performed a genome-wide study on 142 Brazilian subjects belonging to 11 informative families Our results show a linkage to only one region, on chromosome 5q31-q33, with maximum two-point lod scores of +4.74 and +4.52 for D5S636 and the colony stimulating factor-1 receptor marker (CSF1R), respectively. This was corroborated by multipoint analysis, indicating a close proximity to CSF1R as the most likely location of SM1. This region contains several candidate genes encoding immunological molecules that were shown to play important roles in human protection against schistosomes.

Spirometric values in elderly asthmatic patients are not influenced by obesity.

BACKGROUND: Studies have suggested that asthma in obese individuals differs from the classic asthma phenotype, presenting as a disease that is more difficult to control. OBJECTIVE: The objective of the present study was to determine whether obesity, age or a combination of the two are associated with worse spirometry parameters in patients with asthma. METHODS: This was an observational cross-sectional study involving patients over 18 years of age who had been diagnosed with asthma (allergic or nonallergic). We evaluated the results of their spirometric tests. The patients were classified in accordance with two criteria: body mass index (BMI) and age. Based on their BMIs, the patients were divided into three groups: normal weight, overweight and obese. Patients were also separated into two categories by age: 18-59 years of age; and ≥ 60 years of age. RESULTS: We evaluated 451 patients with asthma and their spirometry tests. In the present study, the pulmonary function parameters were negatively correlated with BMI and age (P < 0.05). We found that there was a statistically significant correlation between spirometric values and BMI among patients 18-59 years of age (P < 0.001), however, among patients over 60, we did not observe this negative association. CONCLUSIONS AND CLINICAL RELEVANCE: The spirometric values decreased significantly in proportion to the increase of BMI and age in patients with asthma, especially among young adults. There was no negative correlation between BMI and FEV(1) in the group ≥ 60 years of age, suggesting that perhaps the time of disease is a major factor in the loss of lung function than weight gain in the elderly.

CD4+ T cells from HIV-1-infected patients recognize wild-type and mutant human immunodeficiency virus-1 protease epitopes.

Human immunodeficiency virus (HIV)-1 protease is a known target of CD8+ T cell responses, but it is the only HIV-1 protein in which no fully characterized HIV-1 protease CD4 epitopes have been identified to date. We investigated the recognition of HIV-1 protease by CD4+ T cells from 75 HIV-1-infected, protease inhibitor (PI)-treated patients, using the 5,6-carboxyfluorescein diacetate succinimidyl ester-based proliferation assay. In order to identify putative promiscuous CD4+ T cell epitopes, we used the TEPITOPE algorithm to scan the sequence of the HXB2 HIV-1 protease. Protease regions 4-23, 45-64 and 73-95 were identified; 32 sequence variants of the mentioned regions, encoding frequent PI-induced mutations and polymorphisms, were also tested. On average, each peptide bound to five of 15 tested common human leucocyte antigen D-related (HLA-DR) molecules. More than 80% of the patients displayed CD4+ as well as CD8+ T cell recognition of at least one of the protease peptides. All 35 peptides were recognized. The response was not associated with particular HLA-DR or -DQ alleles. Our results thus indicate that protease is a frequent target of CD4+ along with CD8+ proliferative T cell responses by the majority of HIV-1-infected patients under PI therapy. The frequent finding of matching CD4(+) and CD8+ T cell responses to the same peptides may indicate that CD4+ T cells provide cognate T cell help for the maintenance of long-living protease-specific functional CD8+ T cells.

Allergic asthma in patients with common variable immunodeficiency.

BACKGROUND: Many patients with common variable immunodeficiency (CVID) have a clinical history suggestive of allergic respiratory disease. However, in such individuals, the prevalence of asthma and the role of atopy have not been well established. The objective of this study was to evaluate pulmonary function and identify asthma in patients with CVID. We also investigated the role of IgE as a trigger of asthma in these patients. METHODS: Sixty-two patients diagnosed with CVID underwent spirometry, as well as skin prick testing and in vitro determination of serum-specific IgE levels for aeroallergens, together with bronchial provocation with histamine and allergen. RESULTS: The most common alteration identified through spirometry was obstructive lung disease, which was observed in 29 (47.5%) of the 62 patients evaluated. Eighteen (29.0%) of the 62 patients had a clinical history suggestive of allergic asthma. By the end of the study, asthma had been diagnosed in nine (14.5%) patients and atopy had been identified in six (9.7%). In addition, allergic asthma had been diagnosed in four patients (6.5% of the sample as a whole; 22.2% of the 18 patients with a clinical history suggestive of the diagnosis). CONCLUSION: In this study, CVID patients testing negative for specific IgE antibodies and suspected of having allergic asthma presented a positive response to bronchial provocation tests with allergens. To our knowledge, this is the first such study. When CVID patients with a history suggestive of allergic asthma test negative on traditional tests, additional tests designed to identify allergic asthma might be conducted.

A vaccine against S. pyogenes: design and experimental immune response.

Streptococcus pyogenes causes severe invasive infections: the post-streptococcal sequelae of acute rheumatic fever (RF) and rheumatic heart disease (RHD), acute glomerulonephritis, and uncomplicated pharyngitis and pyoderma. Efforts to produce a vaccine against S. pyogenes began several decades ago, and different models have been proposed. Here, we describe the methodology used in the development of a new vaccine model, consisting of both T and B protective epitopes constructed as synthetic peptides and recombinant proteins. Two adjuvants were tested in an experimental inbred mouse model: a classical Freund's adjuvant and a new adjuvant (AFCo1) that induces mucosal immune responses and is obtained by calcium precipitation of a proteoliposome derived from the outer membrane of Neisseria meningitides B. The StreptInCor vaccine epitope co-administrated with AFCo1 adjuvant induced mucosal (IgA) and systemic (IgG) antibodies as preferential Th1-mediated immune responses. No autoimmune reactions were observed, suggesting that the vaccine epitope is safe.

Influence of single-nucleotide polymorphisms on C-reactive protein levels in chronic kidney disease before and after kidney transplantation.

INTRODUCTION: We sought to evaluate 2 single-nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP) gene promoter region for their effects on CRP levels in chronic kidney disease (CKD) patients before and after a successful kidney transplantation. METHODS: Fifty CKD patients were evaluated before and at the first and second years after the graft. Two SNPs were studied, a bi-allelic (G-->A) at the -409 and a tri-allelic (C-->T-->A) variation at the -390 position in the CRP gene. RESULTS: All patients presented the -409GG genotype. At the -390 position, the "A" allele was not found; there were 15 "CC" patients, 11 "TT" patients, and 24 "CT" patients. CRP levels were different among patients with various genotypes (P < .019). Also the presence of the allele "T" was sufficient to determine differences in CRP levels both in pretransplantation (P = .045) and at 1 year posttransplantation (P = .011), but not at the second year (P = .448). CONCLUSION: SNPs at the -390 position of the CRP gene promoter region influence CRP basal levels in such a way that the "C" allele correlated with the lowest and the "T" with the highest. We did not observe this influence in our patients at the second year posttransplantation.

Rheumatic Heart Disease: Pathogenesis and Vaccine.

Rheumatic fever (RF) and rheumatic heart disease (RHD) follow untreated S. pyogenes throat infections in children who present susceptible genes that favor the development of autoimmune reactions. In this review, we focus on the genes that confer susceptibility and on the autoimmune reactions that occur due to molecular mimicry between human-tissue proteins and streptococcal M protein. Polyarthritis is the initial manifestation, which can evolve to carditis and severe valve damage; these culminate in rheumatic heart disease (RHD) or Sydenham's chorea, which affects the central nervous system. A perspective on vaccine development to prevent the disease is also discussed.

Autoimmunity in Chagas' disease. Identification of cardiac myosin-B13 Trypanosoma cruzi protein crossreactive T cell clones in heart lesions of a chronic Chagas' cardiomyopathy patient.

Heart tissue destruction in chronic Chagas' disease cardiomyopathy (CCC) may be caused by autoimmune recognition of heart tissue by a mononuclear cell infiltrate decades after Trypanosoma cruzi infection. Indirect evidence suggests there is molecular mimicry between T. cruzi and heart tissue. In murine models of CCC, antibodies and CD4+ T cells recognize myosin, the major heart protein. We recently identified a heart-specific epitope of cardiac myosin heavy chain (residues 1442-1447, AAALDK) that is crossreactive with a homologous sequence (AAAGDK) of the immunodominant T. cruzi antigen B13. Furthermore, cardiac myosin-B13 crossreactive antibodies are present in 100% CCC patients vs 14% asymptomatic T. cruzi-seropositive individuals (P = 2.3 x 10(-6)), suggesting a role for molecular mimicry between cardiac myosin and B13 in CCC pathogenesis. In this paper, we obtained heart-infiltrating T cell clones from CCC patients to assess whether molecular mimicry between cardiac myosin and B13 is directly involved in the genesis of heart lesions. We identified T cell clones derived from CCC heart lesions simultaneously responsive to cardiac myosin heavy chain (but not skeletal myosin heavy chain) and B13 T. cruzi protein, but could not find T cell clones primarily reactive to any T. cruzi antigen. Together with the association of myosin-B13 crossreactive antibodies with CCC, the present data strongly suggest the relevance of molecular mimicry between cardiac myosin and the T. cruzi protein B13 in the pathogenesis of heart lesions in chronic Chagas' disease cardiomyopathy.

Rheumatic fever: from innate to acquired immune response.

Rheumatic fever (RF) is triggered by S. pyogenes and affects 3-4% of untreated susceptible children. The immune response against streptococcal antigens can lead cross-recognition of heart tissue proteins resulting in rheumatic heart disease (RHD). HLA class II alleles have been associated with the development of RF/RHD. Tumor necrosis factor (TNF)-alpha is also located in the same chromosomal region of HLA genes and has been investigated in RHD patients from Mexico, Turkey, and Brazil. Associations with the TNFA-308 allele were found and probably are related to the development of valvular lesions. A deficient mannose-binding lectin (MBL) allele was found in Brazilian patients. MBL is a protein important for the first line of host defense against the bacteria. The association with diverse genes probably indicates a role of certain molecules in both the innate and adaptive immune response. Antigen-presenting cells bearing the HLA-DR7 molecule from RHD patients preferentially recognized a heart-tissue protein cross-reactive M5 (81-96) peptide. The same peptide was also recognized by heart tissue T cell clones. Cardiac myosin peptides were recognized by high numbers of intralesional T cell clones. The cytokine pattern of infiltrating mononuclear cells in both myocardium and valvular tissue showed a predominance of proinflammatory cytokines (TNF-alpha and IFN-gamma) and scarce production of regulatory cytokines, such as IL-4, in the valve tissue. IL-10, a predominant regulatory cytokine, was also secreted by large numbers of cells in both valve and myocardium tissue. Data here indicate the complexity of immune reactions leading to autoimmune lesions in RF/RHD.

Proteomic inventory of myocardial proteins from patients with chronic Chagas' cardiomyopathy.

Chronic Chagas' disease cardiomyopathy (CCC) is an often fatal outcome of Trypanosoma cruzi infection, with a poorer prognosis than other cardiomyopathies. CCC is refractory to heart failure treatments, and is the major indication of heart transplantation in Latin America. A diffuse myocarditis, plus intense myocardial hypertrophy, damage and fibrosis, in the presence of very few T. cruzi forms, are the histopathological hallmarks of CCC. To gain a better understanding of the pathophysiology of CCC, we analyzed the protein profile in the affected CCC myocardium. Homogenates from left ventricular myocardial samples of end-stage CCC hearts explanted during heart transplantation were subjected to two-dimensional electrophoresis with Coomassie blue staining; protein identification was performed by MALDI-ToF mass spectrometry and peptide mass fingerprinting. The identification of selected proteins was confirmed by immunoblotting. We demonstrated that 246 proteins matched in gels from two CCC patients. They corresponded to 112 distinct proteins. Along with structural/contractile and metabolism proteins, we also identified proteins involved in apoptosis (caspase 8, caspase 2), immune system (T cell receptor ss chain, granzyme A, HLA class I) and stress processes (heat shock proteins, superoxide dismutases, and other oxidative stress proteins). Proteins involved in cell signaling and transcriptional factors were also identified. The identification of caspases and oxidative stress proteins suggests the occurrence of active apoptosis and significant oxidative stress in CCC myocardium. These results generated an inventory of myocardial proteins in CCC that should contribute to the generation of hypothesis-driven experiments designed on the basis of the classes of proteins identified here.

Rheumatic fever: how S. pyogenes-primed peripheral T cells trigger heart valve lesions.

The pathogenesis of rheumatic fever (RF) is related to autoimmune humoral and cellular responses against human tissues triggered by Streptococcus pyogenes. CD4(+) T cells are the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). Heart-infiltrating CD4(+) T cell clones are able to recognize heart tissue and streptococcal antigens by molecular mimicry. The streptococcal M5(81-103) region, an immunodominant region, was recognized by both intralesional and peripheral T cell clones (62% and 38%, respectively). Peripheral T lymphocytes from Brazilian patients with severe RHD preferentially recognized the M5(81-96) peptide, in the context of HLA-DR7(+) and DR53(+) molecules. HLA-DR7 seems to be related to the development of multiple valvular lesions in RHD patients from different countries. In addition, the fact that peripheral and intralesional T cells recognized the M5(81-103) region points to this region as one of the streptococcal triggers of autoimmune reactions in RHD. T cell repertoire analysis from peripheral and intralesional T cell lines derived from RHD patients showed several oligoclonal expansions of BV families. Major expansions were found in the heart lesions, suggesting that such T cell populations preferentially migrate from the periphery to the heart. Some cross-reactive intralesional T cell clones displayed the same T cell receptor (TCR) BVBJ and CDR3 sequences, showing a degenerate pattern of antigen recognition. Heart tissue-infiltrating cells from myocardium and valvular tissue produced TNF-alpha, IFN-gamma, IL-10, and IL-4, whereas few cells from valvular tissue produced IL-4, showing that the lack of regulation in the valves could be responsible for the permanent and progressive valvular lesions.

Experiencing release: sex environments and escapism for HIV-positive men who have sex with men.

There are nonsexual reasons that may motivate people to seek out sexual activity with others. Some men who have sex with men may seek out sex environments to engage in sexual behavior. Among the nonsexual reasons that exist for men who have sex with men is a desire to escape from distressing thoughts and feelings. The amplified sexuality and other unique characteristics of sex environments allow men to have more intense emotional experiences around sex. Using the cognitive escape model as a theoretical foundation, this analysis focuses on the emotional vulnerability that some of the men who visit these venues may be avoiding and how their experiences at these venues might act as releasing mechanisms to alleviate dissonant thoughts and feelings. Implications for public health services and future research are discussed.

Heart infiltrating T cell clones from a rheumatic heart disease patient display a common TCR usage and a degenerate antigen recognition pattern.

CD4+ T cells are most likely the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). We have demonstrated that infiltrating CD4+ T cell clones were able to recognize several heart tissue and streptococcal antigens by molecular mimicry. Clonality analysis of the mitral valve and myocardium infiltrating T cell lines showed several oligoclonal expansions, some of which were found in both sites of the lesions. The results presented in this study showed a degenerate pattern of reactivity of intralesional T cell clones from one RHD patient. Four mitral valve and one papillar muscle-derived T cell clones, presenting the same TCR-BV13 BJ2S7 with same sequences of the CDR3 region recognized different antigens. They expressed two alpha chains at the RNA level and the AV AJ segments were the same for mitral valve T cell clones, but not for the papillar muscle-derived T cell clone. Two other intralesional T cell clones using the same TCR-BV3 JB2S1 segments with identical CDR3 sequences also recognized different antigens. These results indicate that intralesional T cell clones with common TCR usage can recognize several epitopes that probably amplify the deleterious immune reaction. These data, allow us to hypothesize that degenerate T cell recognition may lead to intramolecular degenerate reactivity against epitopes with low homology. This can be a novel mechanism of epitope spreading, of relevance in the increase of epitopes targets that can activate cross-reactive autoimmune T cells.

Microbiome and Asthma: What Have Experimental Models Already Taught Us?

Asthma is a chronic inflammatory disease that imposes a substantial burden on patients, their families, and the community. Although many aspects of the pathogenesis of classical allergic asthma are well known by the scientific community, other points are not yet understood. Experimental asthma models, particularly murine models, have been used for over 100 years in order to better understand the immunopathology of asthma. It has been shown that human microbiome is an important component in the development of the immune system. Furthermore, the occurrence of many inflammatory diseases is influenced by the presence of microbes. Again, experimental models of asthma have helped researchers to understand the relationship between the microbiome and respiratory inflammation. In this review, we discuss the evolution of murine models of asthma and approach the major studies involving the microbiome and asthma.