Polymorphisms and gene expression of metalloproteinases and their inhibitors associated with cerebral ischemic stroke in young patients with sickle cell anemia.

BACKGROUND: Sickle cell anemia (SCA) is a genetic disease with great clinical heterogeneity and few viable strategies for treatment; hydroxyurea (HU) is the only widely used drug. Thus, the study of single nucleotide polymorphisms (SNPs) and the gene expression of MMPs 1, 2, 9, 7 and TIMPs 1 and 2, which are involved in the regulation of extracellular matrix, inflammation, and neuropathies, may provide further insights into the pathophysiology of the disease and elucidate biomarkers and molecules as potential therapeutic targets for patients with SCA. METHODS AND RESULTS: We evaluated 251 young individuals with SCA from northeastern Brazil. The groups were divided according to vaso-occlusive crisis (VOC) and cerebrovascular disease (CVD), compared to control individuals. SNP detection and gene expression assays were performed by real-time PCR, TaqMan system®. Both the expression levels of MMP1 gene, and the SNP MMP1-1607 1G/2G were associated with the risk of cerebral ischemic stroke (IS), and the expression of MMP1 was also associated with a higher frequency of VOC/year. Expression levels of MMP7, TIMP1, and TIMP2 were increased in patients conditioned to IS. The SNP 372T>C (rs4898) TIMP1 T alleles were more frequent in patients with > 5 VOC events/year. The SNP rs17576 of MMP9 showed differences in gene expression levels; it was increased in the genotypes AG, and AG+GG. CONCLUSION: The findings of this study, the SNPs, and expression provide initial support for understanding the role of MMPs-TIMPs in the pathophysiology of SCA in young patients.

Aspects of cognitive assessments and spectroscopic magnetic resonance imaging in people with chronic hepatitis C: a systematic review.

Extrahepatic manifestations are common in people with hepatitis C virus (HCV). Cognitive changes are pointed out, but the mechanisms are still uncertain. The aim of this systematic review was to analyze studies involving spectroscopic magnetic resonance in people infected with HCV, which also included cognitive tests. The research occurred in six databases (Directory of Open Access Journals, Lilacs, Medcaribe, Medline, Scielo and ScienceDirect) and the selection of studies was carried out in two stages: search for titles and abstracts, then reading of the full articles, excluding those that did not meet the eligibility criteria. 12,888 titles and abstracts were selected, but only 6 articles were included in the review. Impairments in attention, concentration, speed of information processing, memory, verbal fluency and executive functions were identified as well as an increase in the Cho/Cr and mI/Cr ratios and a reduction in the NAA/Cr ratio in some included studies. Longitudinal studies, with more homogeneous samples and methods, as well as with better controlled confounding factors, are necessary to adequately identify the effect of HCV on the brain.

A time series analysis of detection and mortality of hepatitis C in Brazil, 2008-2018.

BACKGROUND: The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030. In Brazil, efforts have been undertaken to achieve this goal; there are, however, great challenges. It is important to understand the disease profile in different regions of the country in order to design strategies to fight the disease nationwide. The objective of this study was to analyse the time trend of the incidence and mortality of hepatitis C in Brazil during the period from 2008 to 2018 according to sociodemographic and clinical characteristics. METHODS: All newly diagnosed cases of hepatitis C reported between 2008 and 2018, in all regions of Brazil, were included. The indicators were obtained from the databases of the Brazilian Ministry of Health. For the time series analysis, a joinpoint regression model was used. RESULTS: Between 2008 and 2018, 136,759 newly diagnosed cases of hepatitis C were reported considering anti-HCV and HCV RNA positivity, and 271,624 newly diagnosed cases were reported considering one or another positive test. The majority of the records were concentrated in the Southeast (61%) and South (26.2%) Regions. The joinpoint regression model indicated an increasing trend in the detection rate of hepatitis C in Brazil, but there was a decreasing trend in the mortality rate during the period analysed. CONCLUSIONS: Differences were observed in the time trend of hepatitis C and in the sociodemographic and clinical characteristics in different regions of Brazil. These data can provide support to design strategies for the elimination of hepatitis C in Brazil, according to regional particularities.

Liver expression of IL-22, IL-22R1 and IL-22BP in patients with chronic hepatitis C with different fibrosis stages.

AIMS: Liver fibrosis is the result of an exacerbated wound-healing response associated with chronic liver injury. Interleukin-22 (IL-22) plays a key role in liver disease, through either a protective or an adverse role, depending on the context. The relationship between IL-22 and its receptors IL-22R1 and IL-22BP (soluble inhibitor) in liver fibrosis is unknown. In this study, we assessed the presence and quantity of IL-22, IL-22R1, and IL-22BP-producing cells in liver tissues of patients with chronic hepatitis C. METHODS AND RESULTS: The number of IL-22-producing cells was significantly higher in stages F1, F2, and F3 when compared to F0 or F4 (p < 0.05). The immunostaining of IL-22R1 decreased as liver fibrosis increased from F1 to F4. On the other hand, the concentration of IL-22BP-producing cells was higher in patients with cirrhosis (F4). Furthermore, the IL-22BP:IL-22 ratio was highest in patients with cirrhosis. CONCLUSIONS: Our results suggest that IL-22, IL-22R1 and IL-22BP may be involved in the mechanisms of liver fibrosis in patients with chronic hepatitis C.

Reduced Expression of IL-1ß and IL-18 Proinflammatory Interleukins Increases the Risk of Developing Cervical Cancer.

Background: The objective of this study was to analyze the gene expression profile of the proinflammatory interleukins, (IL-1ß and IL-18) in patients with premalignant lesions and cervical cancer. Methods: Total IL-1ß and IL-18 mRNA was quantified by qPCR to obtain the expression data in cervical tissues. A total of 74 cervical biopsies were obtained from women undergoing a colposcopy. The samples were divided into: normal (19), low level lesions (LSIL) or NIC I (17), high level lesions (HSIL) or CIN II and CIN III (29) and cancer (9). The normal cervical tissue samples were included as controls. The OR and 95% CI were calculated for the determination of the risk of progression between each type of lesion and cancer using logistic regression. Results: The results showed that an increase in the risk of progression of pre-neoplastic lesions to cancer was between 2.5 and 2.08 times higher in women with lower IL-1ß and IL-18 expression, respectively. Conclusions: This study provided evidence that IL-1ß and IL-18 are potential biomarkers that can be explored in further studies for monitoring the evolution of pre-neoplastic lesions and avoiding overtreatment or undertreatment of the patients.

Association of the SOD2 Polymorphism (Val16Ala) and SOD Activity with Vaso-occlusive Crisis and Acute Splenic Sequestration in Children with Sickle Cell Anemia.

The SOD2 polymorphism Val16Ala T→C influences the antioxidative response. This study investigated the association of the SOD2 polymorphism and superoxide dismutase (SOD) activity with the vaso-occlusive crisis (VOC) and acute splenic sequestration (ASS) in children with sickle cell anemia (SCA). One hundred ninety-five children with SCA aged 1-9 years old were analyzed. The TC and CC genotypes were associated with lower SOD activity compared with the TT genotype (p=0.0321; p=0.0253, respectively). Furthermore, TC and CC were more frequent in patients with VOC or ASS (p=0.0285; p=0.0090, respectively). These results suggest that the SOD2 polymorphism associated with low SOD activity could be a susceptibility factor for the occurrence of VOC and ASS.

Cognitive Dysfunction and Single Nucleotide Polymorphisms in Hepatitis C Virus-Infected Persons: A Systematic Review.

The aim of this study was to realize a systematic review to identify data reported in the literature involving people infected by hepatitis C virus (HCV) with cognitive dysfunctions and single nucleotide polymorphisms (SNPs). The research was realized in six databases and the selection of studies was performed in two stages. Initially, we searched indexed articles from the following electronic databases: SciELO, MEDLINE, PubMed, HighWire, LILACS, and ScienceDirect. Then the articles were completely read and those that did not meet the eligibility criteria were excluded. Therefore, 5,669 articles were obtained and, of these, 25 were selected. Finally, one article involving people with HCV and cognitive impairment was included in the review. The frequency of the APOE-ɛ4 allele in people with HCV and mild liver disease was significantly lower in those with work memory impairment (p = 0.003) and attention (p = 0.008). This situation differs from other studies that showed an association between ɛ4 allele high frequency and cognitive decline. Thus, studies with larger samples involving people with HCV, cognitive alterations, and SNPs are necessary, in view of the lack of this theme in the literature and the divergences in the findings.

Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects.

Outbreaks of the Zika, dengue, and chikungunya viruses, especially in the Americas, pose a global threat due to their rapid spread and difficulty controlling the vector. Extreme phenotypes are often observed, from asymptomatic to severe clinical manifestations, which are well-studied in dengue. Host variations are also important contributors to disease outcomes, and many case-control studies have associated single nucleotide polymorphisms (SNPs) with severe dengue. Here, we found that the TC genotype and T-carriers for SNP rs1285933 in the C-type lectin superfamily member 5 (CLEC5A) gene was associated with severe dengue in a Northern Brazilian population (OR=2.75 and p-value=0.01, OR=2.11 and p-value=0.04, respectively). We also tested the functional effect of the CLEC5A protein and found that it is upregulated on the surface of human monocytes after in vitro dengue infection. CLEC5A was correlated with viral load inside the monocytes (Spearman r=0.55, p=0.008) and TNF production in culture supernatants (Spearman r=0.72, p=0.03). Analysis of mRNA in blood samples from DENV4-infected patients exhibiting mild symptoms showed that CLEC5A mRNA expression is correlated with TNF (r=0.67, p=0.0001) and other immune mediators. Monocytes from rs1285933 TT/TC individuals showed lower CLEC5A expression compared to CC genotypes. However, in these cells, CLEC5A was not correlated with TNF production. In summary, we confirmed that CLEC5A is genetically associated with dengue severity outcome, playing a central role during the immune response triggered by a dengue viral infection, and rs1285933 is a relevant SNP that is able to regulate signaling pathways after interactions between the dengue virus and CLEC5A receptors.

Mediators Go Together: High Production of CXCL9, CXCL10, IFN-γ, and TNF-α in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic demyelinating and disabling syndrome caused by human T lymphotropic virus 1 (HTLV-1). Although the pathogenic mechanisms that lead to HAM/TSP outcome have not been elucidated, genetic and immunological factors may be involved in the myelopathy occurrence. This study aimed to compare cytokines, chemokines, and nitric oxide (NO) levels in asymptomatic and HAM/TSP HTLV-1-infected patients. The study group consisted of 21 HAM/TSP and 48 asymptomatic HTLV-1 patients. Chemokines (CCL5, CCL2, CXCL8, CXCL9, and CXCL10) and cytokines [IL-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-4, IL-6, and IL-10] were measured using cytometric bead array, whereas NO production was measured after reaction of supernatants with nitrate reduction solution. CXCL9 and CXCL10 chemokines levels were found to be higher in the HAM/TSP group. CXCL9 was also strongly correlated with CXCL10 and both CXCL9 and CXCL10 were moderately correlated with CCL2 and CCL5 levels, in both HAM/TSP and asymptomatic groups. There was no significant difference related to NO, IL-4, IL-6, and IL-10 levels between the clinical groups but TNF-α and IFN-γ levels were increased in HAM/TSP patients. Thus, factors such as CXCL9, CXCL10, TNF-α, and IFN-γ could be good prognostic biomarker candidates, and further studies may help to clarify their association with HAM/TSP immunopathogenesis.

Serum cytokine/chemokine profiles in patients with dengue fever (DF) and dengue hemorrhagic fever (FHD) by using protein array.

BACKGROUND: DENV infection can induce different clinical manifestations varying from mild forms to dengue fever (DF) or the severe hemorrhagic fever (DHF). Several factors are involved in the progression from DF to DHF. No marker is available to predict this progression. Such biomarker could allow a suitable medical care at the beginning of the infection, improving patient prognosis. OBJECTIVES: The aim of this study was to compare the serum expression levels of acute phase proteins in a well-established cohort of dengue fever (DF) and dengue hemorrhagic fever (DHF) patients, in order to individuate a prognostic marker of diseases severity. STUDY DESIGN: The serum levels of 36 cytokines, chemokines and acute phase proteins were determined in DF and DHF patients and compared to healthy volunteers using a multiplex protein array and near-infrared (NIR) fluorescence detection. Serum levels of IL-1ra, IL-23, MIF, sCD40 ligand, IP-10 and GRO-α were also determined by ELISA. RESULTS: At the early stages of infection, GRO-α and IP-10 expression levels were different in DF compared to DHF patients. Besides, GRO-α was positively correlated with platelet counts and IP-10 was negatively correlated with total protein levels. CONCLUSIONS: These findings suggest that high levels of GRO-α during acute DENV infection may be associated with a good prognosis, while high levels of IP-10 may be a warning sign of infection severity.

Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-β during acute phase

Dengue is an acute febrile disease caused by the mosquito-borne dengue virus (DENV) that according to clinical manifestations can be classified as asymptomatic, mild or severe dengue. Severe dengue cases have been associated with an unbalanced immune response characterised by an over secretion of inflammatory cytokines. In the present study we measured type I interferon (IFN-I) transcript and circulating levels in primary and secondary DENV infected patients. We observed that dengue fever (DF) and dengue haemorrhagic fever (DHF) patients express IFN-I differently. While DF and DHF patients express interferon-α similarly (52,71 ± 7,40 and 49,05 ± 7,70, respectively), IFN- β were associated with primary DHF patients. On the other hand, secondary DHF patients were not able to secrete large amounts of IFN- β which in turn may have influenced the high-level of viraemia. Our results suggest that, in patients from our cohort, infection by DENV serotype 3 elicits an innate response characterised by higher levels of IFN- β in the DHF patients with primary infection, which could contribute to control infection evidenced by the low-level of viraemia in these patients. The present findings may contribute to shed light in the role of innate immune response in dengue pathogenesis.

Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-ß during acute phase.

Dengue is an acute febrile disease caused by the mosquito-borne dengue virus (DENV) that according to clinical manifestations can be classified as asymptomatic, mild or severe dengue. Severe dengue cases have been associated with an unbalanced immune response characterised by an over secretion of inflammatory cytokines. In the present study we measured type I interferon (IFN-I) transcript and circulating levels in primary and secondary DENV infected patients. We observed that dengue fever (DF) and dengue haemorrhagic fever (DHF) patients express IFN-I differently. While DF and DHF patients express interferon-α similarly (52,71 ± 7,40 and 49,05 ± 7,70, respectively), IFN- ß were associated with primary DHF patients. On the other hand, secondary DHF patients were not able to secrete large amounts of IFN- ß which in turn may have influenced the high-level of viraemia. Our results suggest that, in patients from our cohort, infection by DENV serotype 3 elicits an innate response characterised by higher levels of IFN- ß in the DHF patients with primary infection, which could contribute to control infection evidenced by the low-level of viraemia in these patients. The present findings may contribute to shed light in the role of innate immune response in dengue pathogenesis.

Relation between leukocyte count, adiposity, and cardiorespiratory fitness in pubertal adolescents / Relação entre contagem de leucócitos, adiposidade e aptidão cardiorrespiratória em adolescentes púberes

Objective To compare the total and differential leukocyte count in obese and normal-weight adolescents, and to verify their possible relations with cardiorespiratory fitness and adiposity indicators. Methods A cross-sectional study conducted with 139 adolescents (107 obese and 32 normal weight) aged between 13 and 18 years. Cardiorespiratory fitness was determined by direct gas analysis during an incremental treadmill test. Total leukocytes and subsets were estimated by flow cytometry. Body composition was assessed by dual-energy X-ray absorptiometry. The t-test for independent samples was used for comparison between groups. The relation between leukocytes, cardiorespiratory fitness and adiposity indicators was verified by Pearson’s correlation and multiple linear regression (adjusted for age and body mass index) tests. Results Obese adolescents had higher leukocyte (8.12±2.36u/L x 103; p=0.001), neutrophil (4.33±1.86u/L x 103; p=0.002), and monocyte (0.70±0.22u/L x 103; p=0.002) counts compared to the levels of normal weight subjects. After the necessary adjustments, cardiorespiratory fitness had a negative association with leukocytes, neutrophils, and monocytes in boys. Conclusion Obese adolescents had higher total and differential leucocyte count when compared to normal weight individuals. We also observed a weak positive association between adiposity and total leukocyte, monocyte, and neutrophil counts, and in boys, a negative association between cardiorespiratory fitness and total count of leukocytes, monocytes, and neutrophils. .

Objetivo Comparar a contagem total e diferencial de leucócitos de adolescentes obesos e eutróficos, e verificar suas possíveis relações com a aptidão cardiorrespiratória e indicadores de adiposidade. Métodos Estudo transversal realizado com 139 adolescentes (107 obesos e 32 eutróficos), com idades entre 13 e 18 anos. A aptidão cardiorrespiratória foi determinada por análise direta de gases durante um teste incremental em esteira rolante. As contagens de leucócitos totais e subconjuntos foram estimadas por citometria de fluxo. A composição corporal foi avaliada pelo método de dupla energia de raios X. O teste t para amostras independentes foi utilizado para comparação entre os grupos. A relação entre leucócitos, aptidão cardiorrespiratória e indicadores de adiposidade foi verificada por meio dos testes de correlação de Pearson e regressão linear múltipla (ajustado para idade e índice de massa corporal). Resultados Os adolescentes obesos apresentaram leucócitos (8,12±2,36u/L x 103; p=0,001), neutrófilos (4,33±1,86u/L x 103; p=0,002) e monócitos (0,70±0,22u/L x 103; p=0,002) mais elevados em comparação com os níveis dos eutróficos. Após os ajustes necessários, a aptidão cardiorrespiratória foi negativamente associada com leucócitos, neutrófilos e monócitos em meninos. Conclusão Adolescentes obesos apresentaram maior contagem de leucócitos totais e subpopulações, quando comparados aos eutróficos. Observou-se também uma fraca relação positiva entre adiposidade e leucócitos totais, monócitos ...

Relation between leukocyte count, adiposity, and cardiorespiratory fitness in pubertal adolescents.

OBJECTIVE: To compare the total and differential leukocyte count in obese and normal-weight adolescents, and to verify their possible relations with cardiorespiratory fitness and adiposity indicators. METHODS: A cross-sectional study conducted with 139 adolescents (107 obese and 32 normal weight) aged between 13 and 18 years. Cardiorespiratory fitness was determined by direct gas analysis during an incremental treadmill test. Total leukocytes and subsets were estimated by flow cytometry. Body composition was assessed by dual-energy X-ray absorptiometry. The t-test for independent samples was used for comparison between groups. The relation between leukocytes, cardiorespiratory fitness and adiposity indicators was verified by Pearson's correlation and multiple linear regression (adjusted for age and body mass index) tests. RESULTS: Obese adolescents had higher leukocyte (8.12±2.36u/L x 103; p=0.001), neutrophil (4.33±1.86u/L x 103; p=0.002), and monocyte (0.70±0.22u/L x 103; p=0.002) counts compared to the levels of normal weight subjects. After the necessary adjustments, cardiorespiratory fitness had a negative association with leukocytes, neutrophils, and monocytes in boys. CONCLUSION: Obese adolescents had higher total and differential leucocyte count when compared to normal weight individuals. We also observed a weak positive association between adiposity and total leukocyte, monocyte, and neutrophil counts, and in boys, a negative association between cardiorespiratory fitness and total count of leukocytes, monocytes, and neutrophils.

Influence of fatty acids in maternal diet on atherogenesis in offspring of LDL receptor-deficient mice.

AIMS: The present study investigated the effect of a maternal diet rich in omega-6 (E6D) or omega-9 (E9D) on atherogenesis in the offspring of mice. MAIN METHODS: LDL receptor-deficient mice were fed a diet rich in either omega-6 (E6D) or omega-9 (E9D) for 45 days prior to mating and until the birth of the offspring, evaluating the effect on the offspring aorta in comparison to a standard diet (STD), by immunohistochemical analysis, morphometric analysis and electron microscopy. KEY FINDINGS: Hypercholesterolemic female mice fed E6D generated offspring with high levels of total cholesterol, triglycerides (TG) and CC-chemokine ligand 2/monocyte chemoattractant protein 1 (CCL2/ MCP-1) as well as a reduction in high-density lipoprotein. The ascending aorta of these animals exhibited an increase in arterial wall thickness as well as increased expression of CCL2/MCP-1 and vascular cell adhesion molecule 1. The ultrastructural analysis revealed severe alterations in endothelial cells. The offspring from mothers fed E9D exhibited a reduction in TG and an increase in low-density lipoprotein. The ultrastructural analysis revealed a well-preserved aortic endothelium in these animals. SIGNIFICANCE: The results suggest that hypercholesterolemic mothers feed a diet rich in omega-6 predispose their offspring to endothelial dysfunction.

Prevalencia de la co-infección con hepatitis B y C en pacientes HIV positivos y factores de riesgo asociados / Prevalence of co-infection with hepatitis B and C in HIV-positive patients and associated risk factors

Los virus de la hepatitis B (HBV) y C (HCV) son, frecuentemente, causa de enfermedad hepática crónica en pacientes infectados por el HIV (HIV +), ya que tienen las mismas rutas de transmisión. Se ha informado de prevalencias variables de co-infección, dependiendo de la población bajo estudio. El objetivo de este estudio fue determinar la prevalencia y los factores de riesgo asociados a la infección por HBV y HCV en pacientes HIV+ en el Hospital Universitario Oswaldo Cruz (HUOC) de Recife, Brasil, entre julio y spetiembre de 2004.

Hepatitis B and C are highly prevalent among HIV infected patients, resulting of shared transmission routes. Prevalences of HIV and hepatitis co-infections vary depending on the population studied. The main goal was to assess the prevalence and associated risk factors for HBV and HCV among HIV-infected patients. HIV infected patients at the Hospital Universitário Oswaldo Cruz (HUOC), Recife, Brazil, were studiend from July through September 2004.