Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n = 35) and PB from SLE patients (n = 34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p = 0.006 and p = 0.05) and lower amount of IL-17 per cell (p = 0.03 and p = 0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p < 0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group

Chronic hemolytic anemia is associated with a new glucose-6-phosphate dehydrogenase in-frame deletion in an older woman

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is usually observed in hemizygote males and very rarely in females. The G6PD class 1 variants, very uncommon, are associated with chronic hemolytic anemia. Here we report a Portuguese woman who suffered in her sixties from a chronic hemolytic anemia due to G6PD deficiency. Molecular studies revealed heterozygosity for an in-frame 18-bp deletion, mapping to exon 10 leading to a deletion of 6 residues, 362-367 (LNERKA), which is a novel G6PD class 1 variant, G6PD Tondela. Two of her three daughters, asymptomatic, with G6PD activity within the normal range, are heterozygous for the same deletion. The patient's leukocyte and reticulocyte mRNA studies revealed an almost exclusive expression of the mutant allele, explaining the chronic hemolytic anemia. Patient whole blood genomic DNA HUMARA assay showed a balanced pattern of X chromosome inactivation (XCI), but granulocyte DNA showed extensive skewing, harboring the mutated allele, implying that in whole blood, lymphocyte DNA, with a very long lifetime, may cover up the current high XCI skewing. This observation indicates that HUMARA assay in women should be assessed in granulocytes and not in total leukocytes

Reduced salivary flow and colonization by mutans streptococci in children with Down syndrome

OBJECTIVES: Although individuals with Down syndrome have considerable oral disease, the prevalence of dental caries in this group is low. The present study aimed to compare known risk factors for dental caries development in children with Down syndrome and a matched population (siblings). In both populations, the number of acidogenic microorganisms, such as mutans streptococci, lactobacilli and Candida species, and the paraffin-stimulated pH, flow rate and IgA concentration in whole saliva were evaluated and compared. METHOD: Saliva was collected, and the caries index was evaluated in 45 sibling pairs aged between 6 and 18 years old. The salivary IgA concentration was determined by immunoturbidimetry. Salivary mutans streptococci, lactobacilli and Candida species were quantified on mitis salivarius agar containing bacitracin and 20% sucrose, rogosa agar supplemented with glacial acetic acid and sabouraud agar supplemented with chloramphenicol, respectively. RESULTS: Down syndrome children had a higher caries-free rate (p<0.05) and lower salivary mutans streptococci counts (p<0.03) compared to their siblings. Similar numbers of lactobacilli and Candida species were found in both groups. Salivary flow rates were 36% lower in Down syndrome children compared to their siblings (p<0.05). The salivary pH did not differ between Down syndrome children and controls. The Down syndrome children had an IgA secretion rate 29% lower than that of their siblings, but this difference was not statistically significant. CONCLUSIONS: In conclusion, the lower number of mutans streptococci in the saliva may be one of the factors contributing to the lower caries rate observed in Down syndrome children, despite evidence of hyposalivation

Parenteral Nutrition-Associated Cholestasis and Triglyceridemia in Surgical Term and Near-Term Neonates: A Pilot Randomized Controlled Trial of Two Mixed Intravenous Lipid Emulsions

BACKGROUND: Cholestasis is a common complication in infants receiving prolonged parenteral nutrition (PN). We studied the effects of two intravenous lipid emulsions composed with either 30% soybean oil, 30% medium-chain triglycerides (MCT), 25% olive oil, and 15% fish oil (SMOF) or with 50% MCT and 50% soybean oil n-6 (MCT/SOY) on the incidence of cholestasis in surgical term and near-term neonates. METHODS: A single-center, double-blinded, randomized controlled trial compared the incidence of cholestasis using either SMOF or MCT/SOY in neonates born at gestational age ≥34 weeks undergoing major surgery. The primary outcome was the incidence of conjugated serum bilirubin >1 mg/dL. Other liver enzymes were assessed as secondary outcomes. A post-hoc analysis assessed serum triglycerides levels. Odds ratios were estimated by mixed-effects regression models. RESULTS: Enrollment was prematurely interrupted because the MCT/SOY became unavailable, thus 49 infants (SMOF 22, MCT/SOY 27) completed the study. The exposure (time on PN, cumulative dose of lipids) was similar in both groups. Similar cumulative incidence rates were found for elevated conjugated bilirubinemia and other liver enzymes. Hypertriglyceridemia >250 mg/dL (12/49) was more frequent in MCT/SOY (37.0%, 95% CI 21.53-55.77) than in SMOF (9.1%, 95% CI 2.53-27.81, p = 0.024). Triglyceridemia at the first assessment (median 8 postnatal days) was significantly higher with MCT/SOY than with SMOF (181 vs. 134 mg/dL, p = 0.006). Over the whole study period, mean triglyceride concentration was 36.5 mg/dL higher with MCT/SOY compared with SMOF (p = 0.013). CONCLUSION: Both emulsions had similar effects on the incidence of cholestasis and markers of liver integrity, but MCT/SOY induced higher serum triglyceride concentrations.info:eu-repo/semantics/publishedVersio

Effective computational methods for hybrid stochastic gene networks

At the scale of the individual cell, protein production is a stochastic process with multiple time scales, combining quick and slow random steps with discontinuous and smooth variation. Hybrid stochastic processes, in particular piecewise-deterministic Markov processes (PDMP), are well adapted for describing such situations. PDMPs approximate the jump Markov processes traditionally used as models for stochastic chemical reaction networks. Although hybrid modelling is now well established in biology, these models remain computationally challenging. We propose several improved methods for computing time dependent multivariate probability distributions (MPD) of PDMP models of gene networks. In these models, the promoter dynamics is described by a finite state, continuous time Markov process, whereas the mRNA and protein levels follow ordinary differential equations (ODEs). The Monte-Carlo method combines direct simulation of the PDMP with analytic solutions of the ODEs. The push-forward method numerically computes the probability measure advected by the deterministic ODE flow, through the use of analytic expressions of the corresponding semigroup. Compared to earlier versions of this method, the probability of the promoter states sequence is computed beyond the naive mean field theory and adapted for non-linear regulation functions

Condições socioeconômicas e padrões alimentares de crianças de 4 a 11 anos: estudo SCAALA - Salvador/ Bahia

OBJETIVOS: identificar os padrões alimentares de crianças e sua associação com o nível socioeconômico das famílias. MÉTODOS: estudo transversal com 1260 crianças de 4 a 11 anos, residentes em Salvador-Bahia que incluiu aplicação de um Questionário de Frequência Alimentar semi-quantitativo. Os padrões alimentares foram identificados, empregando-se análise fatorial por componentes principais. O nível socioeconômico foi avaliado por meio de um indicador socioeconômico composto. Regressão logística multivariada foi empregada. RESULTADOS: identificaram-se quatro padrões que explicaram 45,9% da variabilidade dos dados de frequência alimentar. Crianças que pertencem ao nível socioeconômico mais alto têm 1,60 vezes mais chance (p&lt;0,001) de apresentarem maior frequência de consumo de alimentos do padrão 1 (frutas, verduras, leguminosas, cereais e pescados) e 3,09 vezes mais chance (p&lt;0,001) de apresentarem maior frequência de consumo dos alimentos do padrão 2 (leite/ derivados, catchup/ maionese/ mostarda e frango), quando se compara com aquele de crianças de nível socioeconômico mais baixo. Resultado inverso foi observado no padrão 4 (embutidos, ovos e carnes vermelhas); isto é, quanto maior o nível socioeconômico menor a chance da adoção desse padrão. Tendência similar foi notada para o padrão 3 (frituras, doces, salgadinhos, refrigerante/ suco artificial). CONCLUSÕES: padrões alimentares de crianças são dependentes das condições socioeconômicas das famílias e a adoção de itens alimentares mais saudáveis associa-se aos grupos de mais altos níveis socioeconômicos

Tolerogenic versus Inflammatory Activity of Peripheral Blood Monocytes and Dendritic Cells Subpopulations in Systemic Lupus Erythematosus

Abnormalities in monocytes and in peripheral blood dendritic cells (DC) subsets have been reported in systemic lupus erythematosus (SLE). We aim to clarify the tolerogenic or inflammatory role of these cells based on ICOSL or IFN-α and chemokine mRNA expression, respectively, after cell purification. The study included 18 SLE patients with active disease (ASLE), 25 with inactive disease (ISLE), and 30 healthy controls (HG). In purified plasmacytoid DC (pDC) was observed a lower ICOSL mRNA expression in ASLE and an increase in ISLE; similarly, a lower ICOSL mRNA expression in monocytes of ALSE patients was found. However, a higher ICOSL mRNA expression was observed in ASLE compared to HG in myeloid DCs. Interestingly, clinical parameters seem to be related with ICOSL mRNA expression. Regarding the inflammatory activity it was observed in purified monocytes and CD14(-/low) CD16(+) DCs an increase of CCL2, CXCL9, and CXCL10 mRNA expression in ASLE compared to HG. In myeloid DC no differences were observed regarding chemokines, and IFN-α mRNA expression. In pDC, a higher IFN-α mRNA expression was observed in ASLE. Deviations in ICOSL, chemokine, and IFN-α mRNA expression in peripheral blood monocytes and dendritic cells subpopulations in SLE appear to be related to disease activity

Dietary soy and meat proteins induce distinct physiological and gene expression changes in rats

This study reports on a comprehensive comparison of the effects of soy and meat proteins given at the recommended level on physiological markers of metabolic syndrome and the hepatic transcriptome. Male rats were fed semi-synthetic diets for 1 wk that differed only regarding protein source, with casein serving as reference. Body weight gain and adipose tissue mass were significantly reduced by soy but not meat proteins. The insulin resistance index was improved by soy, and to a lesser extent by meat proteins. Liver triacylglycerol contents were reduced by both protein sources, which coincided with increased plasma triacylglycerol concentrations. Both soy and meat proteins changed plasma amino acid patterns. The expression of 1571 and 1369 genes were altered by soy and meat proteins respectively. Functional classification revealed that lipid, energy and amino acid metabolic pathways, as well as insulin signaling pathways were regulated differently by soy and meat proteins. Several transcriptional regulators, including NFE2L2, ATF4, Srebf1 and Rictor were identified as potential key upstream regulators. These results suggest that soy and meat proteins induce distinct physiological and gene expression responses in rats and provide novel evidence and suggestions for the health effects of different protein sources in human diets

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Perfeccionismo no transtorno obsessivo-compulsivo e nos transtornos alimentares

OBJETIVO: Este estudo tem dois objetivos principais. Primeiro, avaliar as dimensões do perfeccionismo no transtorno obsessivo-compulsivo e nos transtornos alimentares em comparação com duas amostras controle: psiquiátrica (depressão/ansiedade) e não clínica. Segundo, avaliar se o perfeccionismo é um traço de personalidade especificamente relacionado com estas diferentes condições clínicas. MÉTODO: 39 pacientes com transtorno obsessivo-compulsivo, 24 com transtornos alimentares, 65 com um diagnóstico de depressão e/ou ansiedade (todos estes pacientes encontravam-se em regime de ambulatório) e 70 controles não clínicos completaram a versão portuguesa da Multidimensional Perfectionism Scale. RESULTADOS: Comparativamente à amostra não clínica, todas as amostras clínicas apresentaram níveis significativamente mais elevados na Multidimensional Perfectionism Scale total, no Perfeccionismo Auto-Orientado e no Perfeccionismo-Socialmente-Prescrito. Não houve diferenças estatisticamente significativas no Perfeccionismo-Auto-Orientado e na Multidimensional Perfectionism Scale total nas três amostras clínicas. No entanto, a amostra com transtornos alimentares apresentou níveis significativamente mais elevados de Perfeccionismo-Socialmente-Prescrito, comparativamente à transtornos alimentares e à amostra psiquiátrica (depressão/ansiedade). CONCLUSÃO: O perfeccionismo revelou estar associado a uma grande variedade de condições psicopatológicas. Contudo, as diferenças encontradas entre a amostra de transtornos alimentares, de transtorno obsessivo-compulsivo e a psiquiátrica no Perfeccionismo-Socialmente-Prescrito necessitam de investigação subsequente no sentido de clarificar a especificidade desta dimensão com os transtornos alimentares