A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload

BACKGROUND: It has been recently demonstrated that CD8+ T-lymphocyte numbers are genetically transmitted in association with the MHC class I region. The present study was designed with the objective of narrowing the region associated with the setting of CD8+ T-lymphocyte numbers in a population of C282Y homozygous hemochromatosis subjects, in whom a high prevalence of abnormally low CD8+ T-lymphocyte counts has been described. METHODS: The study includes 43 C282Y homozygous subjects fully characterized both phenotypically and genotypically. Clinical characterization includes measurements of iron parameters at diagnosis (transferrin saturation and serum ferritin), total body iron stores and T-cell immunophenotyping determined by flow cytometry. Genetic characterization includes HLA class I alleles (A, B and C) and four additional microsatellite markers (D6S265, D6S2222, D6S105 and D6S2239) spanning 5 Megabases in the 6p21.3 region. RESULTS: Eighty-two extended C282Y carrying haplotypes were defined. Single-locus analysis revealed that the HLA-A region was associated with CD8+ T-cell numbers. Multivariate analysis showed that the combinations of the most common HLA-A alleles (HLA-A*03, -A*02 and -A*01) were associated with significantly lower numbers of CD8+ T-lymphocytes (0.30 ± 0.14 × 10(6)/ml), in comparison with subjects carrying only one copy of those alleles (0.46 ± 0.19 × 10(6)/ml) and subjects without any copy of those alleles (0.79 ± 0.15 × 10(6)/ml;p = 0.0001). No differences were observed in CD8+ T-cell counts among control subjects carrying the same combinations of HLA-A alleles (0.47 ± 0.14; 0.45 ± 0.21 and 0.41 ± 0.17 × 10(6)/ml, respectively), therefore not supporting a direct effect of HLA specificity but rather an indirect association with a locus close to HLA-A. Multivariate analysis showed that the combination of the most common HLA-A alleles also have an impact on the clinical expression of HH in terms of iron stores, in males(p = 0.0009). CONCLUSION: The present study provides evidence supporting an inextricable link between extended HLA haplotypes, CD8+ T-lymphocyte numbers and severity of iron overload in hereditary hemochromatosis(HH). It gives additional information to better define a candidate region involved in the regulation of CD8+ T-lymphocyte numbers. A new evolutionary hypothesis concerning the inheritance of the phenotype of low CD8+ T-lymphocyte numbers associated with particular ancestral HLA haplotypes carrying the C282Y mutation and its implication on the clinical heterogeneity of HH is discussed

Evaluation of Depression, Anxiety and Sleep Quality in the Brazilian Population During Social Isolation Due to the New Coronavirus (SARS-CoV-2) pandemic: the DEGAS-CoV Study/ Avaliação da Depressão, Ansiedade e Qualidade do Sono na População Brasileira Durante o Isolamento Social Devido à Nova Pandemia do Coronavírus (SARS-CoV-2): o Estudo DEGAS-CoV

Introduction: The new coronavirus infection (COVID-19) has caused distress and repercussions in mental and physical health of individuals. Depression, anxiety and worsening of sleep quality have been reported in several recent articles that surveyed populations all over the globe. Our work meant to access, through a cross-sectional study, these disorders in the Brazilian population, through the application of an online questionnaire conducted on the second trimester of 2020. Materials and Methods: We applied an online questionnaire, filled with questions regarding social, economic, financial, educational and health status, as well as questions from the Hospital Anxiety and Depression Scale (HAD), and from the Pittsburgh Sleep Quality Index (PSQI).Results: We collected 2,695 valid answers, from April 24th to May 31st, 2020. Age ranged from 18 to 79 years, mean of 31.3. Women were 76.3%, men 23.7%. Symptoms of Anxiety were found in 56.5%, of depression in 46.1%, and of bad sleep in 49.2%. Some groups were more prone than others to one or more of those conditions, such as: younger people, women, mestizos, people with lesser years of education, of lower income or whose income dropped significantly during the pandemic, caregivers, students, sedentary or people practicing less physical activity, people who followed more hours of news of COVID-19 and those less engaged in social and instrumental activities.Conclusion: anxiety, depression and bad sleep quality were significantly high in our survey. Mental and sleep health is heterogeneously affected among individuals, depending on social, economic, financial, educational and health status

Percepção do enfermeiro sobre promoção da saúde na Unidade de Terapia Intensiva

Objetivou-se relatar a percepção dos enfermeiros sobre a promoção da saúde, descrever ações de promoção da saúde e identificar dificuldades na realização de atividades de promoção da saúde na Unidade de Terapia Intensiva (UTI). Trata-se de um estudo descritivo, exploratório, qualitativo realizado com 31 enfermeiros de duas UTIs adulto e uma UTI neonatal de hospital de referência em Fortaleza, Ceará, Brasil, entre julho e agosto de 2009, mediante questionário. Os dados foram analisados e categorizados a partir da análise de conteúdo de Bardin. Emergiram as seguintes categorias e subcategorias: Conceito de promoção da saúde: visão biomédica x visão holística de promoção da saúde; Ações de promoção da saúde; Comunicação e apoio emocional ao paciente/família; Promoção da saúde na UTI; Promoção da saúde com enfoque na educação em saúde; e Dificuldades para o desenvolvimento de ações de promoção da saúde

The Glycosylphosphatidylinositol-PLC in Trypanosoma brucei Forms a Linear Array on the Exterior of the Flagellar Membrane Before and After Activation

Bloodstream forms of Trypanosoma brucei contain a glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC) that cleaves the GPI-anchor of the variable surface glycoprotein (VSG). Its location in trypanosomes has been controversial. Here, using confocal microscopy and surface labelling techniques, we show that the GPI-PLC is located exclusively in a linear array on the outside of the flagellar membrane, close to the flagellar attachment zone, but does not co-localize with the flagellar attachment zone protein, FAZ1. Consequently, the GPI-PLC and the VSG occupy the same plasma membrane leaflet, which resolves the topological problem associated with the cleavage reaction if the VSG and the GPI-PLC were on opposite sides of the membrane. The exterior location requires the enzyme to be tightly regulated to prevent VSG release under basal conditions. During stimulated VSG release in intact cells, the GPI-PLC did not change location, suggesting that the release mechanism involves lateral diffusion of the VSG in the plane of the membrane to the fixed position of the GPI-PLC

Transthyretin Protects against A-Beta Peptide Toxicity by Proteolytic Cleavage of the Peptide: A Mechanism Sensitive to the Kunitz Protease Inhibitor

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (A-Beta) in the brain. Transthyretin (TTR) is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1–14) and (15–42) showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an αAPP peptide containing the Kunitz Protease Inhibitor (KPI) domain but not in the presence of the secreted αAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology