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ObjectiveTo investigate a selection of renal injury biomarkers in fetal congenital lower urinary tract obstruction (LUTO) and their potential to identify renal damage in significant obstructive patterns, eventually to benefit fetal intervention and predict the outcome in terms of survival.Study DesignTen fetuses with congenital LUTO were submitted to fetal urine analysis that included six renal injury biomarkers: Neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), transforming growth factor beta-1 (TGF-β1), retinol-binding protein (RBP), cystatin C (uCyC), and microalbuminuria (µALB). The results were compared with urinary parameters of patients born with LUTO and healthy newborns.ResultThe majority of fetal biomarker levels showed significantly higher values when compared to all groups at birth with exception of KIM-1 and μALB. RBP and uCyC performed with 100% accuracy to identify severe renal damage in fetal LUTO.ConclusionUrine CyC, NGAL, RBP, and TGF-ß1 demonstrated high capability of identifying significant renal impairment due to severe LUTO and may contribute to currently used fetal medicine diagnostic parameters.

Autoantibodies are biomarkers for autoimmune disease diagnosis, monitoring, and prediction. Therefore, this study established the frequency of latent and overt polyautoimmunity in children and adolescents with >6 months of diagnosis of immune thrombocytopenia (ITP). Forty-seven patients with chronic or persistent disease had non-organ-specific and organ-specific autoantibodies assessed. Frequency of latent polyautoimmunity was 36.2%, and, of overt polyautoimmunity, it was 4.3%. Of ITP patients with latent polyautoimmunity, 52.9% were positive for antinuclear antibody (ANA), 47.1% for autoantibodies other than ANA, and 64.7% for multiple autoantibodies. In addition, patients with latent polyautoimmunity and those positive for ANA were significantly older at disease onset. Both ITP patients positive and negative for autoantibodies reported family members with autoimmune diseases. The autoantibodies observed were as follows: ANA, anti-dsDNA, anti-SSA/Ro, IgM aCL, anti-GAD, anti-IA2, anti-IAA, anti-TG, anti-TPO, anti-LKM1, and SMA. Of ITP patients with overt polyautoimmunity, 1 was diagnosed with type 1 diabetes mellitus and the other with thyroiditis. In conclusion, children and adolescents with ITP present high frequency of latent and overt polyautoimmunity even for autoantibodies other than ANA. Therefore, ANA and other non-organ-specific and organ-specific autoantibodies should be considered for assessment during ITP patients' follow-up.

Tyro3, Axl, and Mer (TAM) receptors and ligands mediate apoptotic bodies engulfment which alteration has been related with juvenile systemic lupus erythematosus (JSLE) pathogenesis. Thus, the aim was to determine their soluble levels.Serum sTyro3, sAxl, sMer, and Gas6 levels were measured using ELISA in 67 JSLE patients, 12 juvenile idiopathic arthritis (JIA) inflammatory and 20 healthy controls and related with SLEDAI-2K score, anti-dsDNA antibody, ESR, CRP, C3, C4 levels, and nephritis.JSLE patients with active disease (SLEDAI-2K4) had significantly increased sMer levels compared with healthy controls (median 8.4 vs. 6.0 ng/mL, p = 0.009) and inactive disease patients (5.2 ng/mL, p = 0.0003). sMer levels correlated with SLEDAI-2K (r = 0.44; p = 0.0004) and ESR (r = 0.24; p = 0.04), while sAxl correlated with SLEDAI-2K (r = 0.33; p = 0.008) and C4 levels (r = - 0.24; p = 0.04). JSLE patients taking glucocorticoid had increased sAxl and sMer levels. Moreover, sAxl correlated with sMer and sTyro3 levels. Patients with nephritis and those with focal or diffuse proliferative glomerulonephritis had these protein levels similar to healthy controls and patients without renal involvement. sTyro3 levels of JSLE patients taking glucocorticoid were decreased, and correlated with Gas6 and sAxl, while Gas6 levels correlated with age upon enrollment. JIA controls had protein levels similar to healthy controls and JSLE patients.This study reinforces that sMer is increased in active JSLE patients, yet sMer and sAxl correlates with disease activity parameters, and their alterations are disease-specific. However, further studies are needed to determine exact roles of sTyro3 and Gas6 in disease pathogenesis. Key Points • sMer and sAxl serum levels are related with active disease in JSLE patients • sMer correlated with SLEDAI-2K score in JSLE • sTyro3, sAxl, sMer and Gas6 levels did not related with nephritis in JSLE patients • sTyro3 and Gas6 exact roles in JSLE are not established and further studies are needed.

Maternal immunization with pertussis acellular vaccine (Tdap) is an intervention that provides protection to newborns. However, it has been reported that high maternal antibody levels may adversely affect the immune response of infants after active immunization. In this study, we evaluated neonatal passive acquisition of pertussis-specific antibodies and their influence on the neonatal cell-mediated immune response. Pregnant women were either vaccinated with Tdap vaccine (case group, n = 66) or received no vaccine (control group, n = 101). Whole-cell Bordetella pertussis (Bp), pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)-specific serum IgG were quantified in paired maternal-cord sera, and Bp- and PT-specific IgA were evaluated in colostrum by ELISA. Ex vivo neonatal blood lymphocyte responsiveness after Bp stimulation was assessed in case (n = 17) and control (n = 15) groups using flow cytometry to detect proliferation, cytokine production and activation phenotype of lymphocytes in the context of high specific IgG acquired after maternal vaccination. Anti-Bp, PT, FHA and PRN IgG concentrations in maternal and cord sera from case group were higher than those in control group with positive correlation indexes in both groups for all pertussis antigens. The control group presented higher placental transfer ratios of specific antibodies and, in the case group, vaccination between 26 and 31 gestation weeks was associated with the best placental transfer ratios. Specific IgA concentrations in colostrum were not affected by vaccine status. Whole blood assays revealed that newborns responded to Bp stimulation with higher expression of CD40L, CD69 and CD4+ T cell proliferation compared to unstimulated cells, and a lower Th1 response, while a preserved Th2 response compared to adults, but there were no differences between the neonatal groups for any of the studied parameters. Our results indicate that higher pertussis-specific IgG levels in newborn sera after maternal vaccination do not affect the neonatal ex vivo cell-mediated immune response.

The objective was to investigate whether phagocytes from healthy and septic newborns have a developmental deficiency in their capacity to recognize, phagocytize and generate hydrogen peroxide (H2O2) in response to Escherichia coli and Staphylococcus aureus. TLR expression and phagocytic ability of neutrophils and monocytes from 44 healthy preterm and term neonates, from 13 newborns with late-onset sepsis and from 24 healthy adults were determined using flow cytometry, and H2O2 production was measured by dihydrorhodamine test. TLR-2 and TLR-4 expressions were similar among the groups. The phagocytic ability of monocytes and neutrophils exposed to E. coli and S. aureus in healthy and septic neonates was significantly reduced compared to that of adults. Monocytes from septic newborns exposed to E. coli had higher H2O2 production than those of the other groups. The oxidative burst of monocytes exposed to S. aureus was reduced in preterm newborns compared with term ones and those with sepsis, and no differences were found in the oxidative burst of neutrophils. Even with the ability to recognize bacteria, a decreased clearance of pathogens can cause an imbalance in the immune response, which could lead to a predisposition to sepsis. Once established, the increased production of cytokines and ROS in an attempt to control the infection as well as the lack of full phagocytic activity leads to persistence of the pathogen and a state of constant inflammation.

Summary Introduction The diagnosis of renal function impairment and deterioration in congenital urinary tract obstruction (UTO) continues to be extremely challenging. The use of new renal biomarkers in this setting may favor early renal injury detection, allowing for a reliable choice of optimal therapeutic options and the prevention or minimization of definitive renal damage. Objective The aim of the study was to investigate a selection of promising biomarkers of renal injury with the intention of evaluating and comparing their profile with clinically based decisions for surgical intervention of infants with congenital obstructive uropathies. Study design The first-year profile of renal biomarkers, serum creatinine (sCr), serum and urine cystatin C (CyC), neutrophil gelatinase–associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), transforming growth factor beta-1 (TGF-β1), retinol-binding protein (RBP), and microalbuminuria (μALB), was analyzed in a cohort of 37 infants with congenital UTO, divided into three subgroups, 14 cases with grade III unilateral hydro(uretero)nephrosis, 13 cases with grade III bilateral hydro(uretero)nephrosis, and 10 cases with low urinary tract obstruction (LUTO), compared with 24 healthy infants matched by gestational age and birth weight. Serum and urine samples were stored at −70 °C and thereafter analyzed by quantitative enzymatic immunoassay. Results Compared with the control group (Figure), all renal biomarker values were significantly increased in patients (P ≤ 0.02). In the unilateral hydronephrosis and LUTO group, RBP (P ≤ 0.043), NGAL (P ≤ 0.043), KIM-1 (P ≤ 0.03), and TGF-β1 (P ≤ 0.034) values dropped significantly after surgery. Neutrophil gelatinase–associated lipocalin alone and in combination with urine and serum CyC demonstrated the best performance in determining the need for surgery (area under the curve, 0.801 and 0.881, respectively). Biomarker profile analysis was suggestive of surgical intervention in 55.4% (7/13) of non-operated cases, and most of the biomarker values were above the cutoff levels within at least 3 months before the clinically based surgical decision in 58% (14/24) of all operated patients. Discussion To the best of the authors' knowledge, this is the first study to present the clinical use of selected group of serum and urinary biomarkers in the setting of UTO to distinguish between patients who would benefit from surgery intervention. The most promising results were obtained using NGAL, RBP, TGF-β1, and KIM-1, especially in the unilateral hydro(uretero)nephrosis and LUTO subgroups when compared with the control group. Conclusions Urine biomarkers, alone and in combination, demonstrated high potential as a non-invasive diagnostic tool for identifying infants who may benefit from earlier surgical intervention. Download : Download high-res image (117KB) Download : Download full-size image Figure . Comparative analysis of pre-operative values of the urine biomarkers in operated patients and control participants at the age of 12 months. The significance of all values was verified by the Student t-test for paired data and by the ¶) Wilcoxon signed-rank test for paired data. The median for urine biomarker sampling was 7 (3–59) days before surgery, in operated patients. KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase–associated lipocalin; RBP, retinol-binding protein; TGF-β1, transforming growth factor beta-1; uCyC, urine cystatin C; μALB, microalbuminuria; uCr, urine creatinine.

A imunização materna com a vacina acelular para pertussis (dTpa) é uma intervenção adicional que visa fornecer proteção aos recém-nascidos (RN). No entanto, tem sido relatado que altos níveis de anticorpos adquiridos por transferência placentária podem afetar adversamente a resposta imune desses RN após a imunização ativa, devido ao mascaramento antigênico. Neste estudo, avaliamos a aquisição passiva neonatal de anticorpos específicos para pertussis e sua influência na resposta imune celular dos neonatos. A casuística foi composta por gestantes vacinadas com a vacina dTpa (grupo caso, n=66) ou por gestantes que não receberam a vacina (grupo controle, n=101). As concentrações de anticorpos IgG séricos específicos para Bordetella pertussis total (Bp), toxina pertussis (PT), hemaglutinina filamentosa (FHA) e pertactina (PRN) foram quantificadas em soro materno e de cordão umbilical de seu respectivo RN, e as concentrações de anticorpos IgA específicos para Bp e PT foram dosadas nas amostras de colostro por meio de ensaio imunoenzimático. A responsividade dos linfócitos do sangue neonatal foi avaliada após estimulação ex vivo com Bp inativada por citometria de fluxo com o intuito de detectar a proliferação, produção de citocinas e fenótipo de ativação dos linfócitos T em um contexto de altas concentrações de IgG específicas adquiridas após a vacinação materna. As concentrações de anticorpos IgG anti-Bp, PT, FHA e PRN foram maiores nas amostras de soro materno e de cordão umbilical do grupo caso quando comparadas ao grupo controle (p < 0,0001), com índices de correlação positivos em ambos os grupos para todos os antígenos estudados (p < 0,0001). As vacinações realizadas entre 26 e 31 semanas de gestação foram associadas com as melhores taxas de transferência placentária, embora índices significativamente menores foram detectados no grupo caso (p < 0,01). As concentrações de anticorpos IgA anti-Bp e anti-PT no colostro não foram afetadas pelo estado vacinal da parturiente. Os ensaios de cultura celular revelaram que os RN responderam ao estímulo com Bp, com maior expressão de CD40L, CD69 e proliferação de células T CD4, em comparação com células não estimuladas. Também foi observada uma menor resposta Th1, enquanto a resposta Th2 foi preservada, em comparação com os adultos, mas sem diferenças entre os grupos de neonatos em nenhum dos parâmetros estudados. Nossos resultados indicam que níveis mais altos de anticorpos IgG específicos para B. pertussis no soro dos RN após a vacinação materna não afetam a resposta imune neonatal mediada por células Maternal immunization with pertussis acellular vaccine (Tdap) is an additional intervention that provides protection to newborns. However, it has been reported that high antibody levels acquired via placental transfer may adversely affect the immune response of newborns after active immunization due to epitope masking. In this study, we evaluated neonatal passive acquisition of pertussis-specific antibodies and their influence on the neonatal cell-mediated immune response. The sample consisted of pregnant women vaccinated with the Tdap vaccine (case group, n=66) or pregnant women who received no vaccine (control group n=101). Whole-cell Bordetella pertussis (Bp), pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)-specific serum IgG concentrations were quantified in paired maternal-cord sera, and Bp- and PT-specific IgA concentrations were evaluated in colostrum samples by immunoenzymatic assay. Ex vivo neonatal blood lymphocyte responsiveness after inactivated Bp stimulation was assessed using flow cytometry to detect the proliferation, cytokine production and activation phenotype of T lymphocytes in the context of high specific IgG concentrations acquired after maternal vaccination. Anti-Bp, PT, FHA and PRN IgG antibody concentrations in maternal and cord serum samples from case group were higher than those in control group (p < 0.0001), with positive correlation indexes in both groups for all pertussis antigens (p < 0.0001). Vaccinations performed between 26 and 31 gestation weeks were associated with the best placental transfer ratios, although significantly lower ratios were detected in case group (p < 0.01). Anti-Bp and anti-PT IgA concentrations in colostrum were not affected by vaccine status. Cell culture assays revealed that newborns responded to Bp stimulation with higher expression of CD40L CD69 and CD4+ T cell proliferation compared to unstimulated cells. It was also observed a lower Th1 response, while a preserved Th2 response compared to adults, but there were no differences between neonatal groups for any of the studied parameters. Our results indicate that higher pertussis-specific IgG levels in newborn sera after maternal vaccination do not affect the neonatal cell-mediated immune response

Objective.To evaluate soluble Fas antigen (sFas), sFas ligand (sFasL), soluble tumor necrosis factor-related apoptosis-inducing ligand, and soluble cytoplasmic Bcl-2 protein (sBcl-2) serum levels, Fas and Bcl-2 expressions in T and B lymphocytes and monocytes and relations with erythrocyte sedimentation rate, C-reactive protein (CRP), Childhood Myositis Assessment Scale, and manual muscle testing in juvenile dermatomyositis (JDM).Methods.Serum levels were determined by ELISA and peripheral cell expressions by flow cytometry for patients with JDM or juvenile idiopathic arthritis (JIA), and healthy controls.Results.Patients with JDM had increased sBcl-2, which correlated with CRP. Expression of Bcl-2 was increased and expression of Fas was decreased in CD3+, CD4+, and CD8+ T lymphocytes compared with JIA and/or healthy controls.Conclusion.Patients with JDM presented a unique apoptosis-related proteins profile, which may contribute to disease development.

OBJECTIVE: To investigate the transmission of anti-Staphylococcus aureus (Sa) IgG, IgG1 and IgG2 via placental transfer and the transfer of IgA via the colostrum according to maternal Sa carrier status at delivery. METHODS: We evaluated anti-Sa IgG, IgG1 and IgG2 in maternal and cord sera and IgA in colostrum from a case (n=49, Sa+) and a control group (n=98, Sa-). RESULTS: Of the 250 parturients analyzed for this study, 49 were nasally colonized with S. aureus (prevalence of 19.6%). Ninety-eight non-colonized subjects were selected for the control group. The anti-Sa IgG, IgG1 and IgG2 levels and the IgG avidity indexes in the maternal and cord sera did not differ between the groups, with a low transfer ratio of anti-Sa IgG to the newborns in both groups. The anti-Sa IgG2 titers were significantly higher than the IgG1 titers in the maternal and cord sera. Inversely, the transfer ratios were higher for anti-Sa IgG1 compared with IgG2; however, no differences between the groups were detected. The Sa-specific IgA levels and avidity indexes in the colostrum were equivalent between groups. CONCLUSIONS: Maternal Sa nasal colonization at delivery is not associated with higher antibody levels in the mother or newborns. The high titers of anti-Sa IgG2 found in the cord serum indicate a greater reactivity with non-protein antigens, which may further contribute to the susceptibility to staphylococcal infections at birth. The presence of IgA in the colostrum with avidity to S. aureus reinforces the importance of breastfeeding shortly after birth.

Type 2 Diabetes mellitus (DM2) is a metabolic disease Type 2 Diabetes mellitus (DM2) is a metabolic disease characterized by hyperglycemia and cardiovascular dysfunctions that can be controlled with physical exercise, dietary control and pharmacological treatment. Recent research has demonstrated associations between DM2 and some genetic polymorphisms, especially alterations to the gene that codes for Angiotensin Converting Enzyme (ACE). The purpose of this study was to discuss the pathophysiology of DM2 and the use of physical exercise as a non-pharmacological method for controlling these patients’ glycemia and blood pressure. The relationship between DM2 and polymorphisms of the ACE gene was also covered. The literature search included textbooks in the healthcare field in addition to review articles and original articles found on the databases Pubmed, Scielo and Portal Capes. Keywords used were “blood glucose”, “type 2 diabetes”, “exercise”, “blood pressure” and “ACE gene polymorphism” and their translations in Portuguese. The main subject of this article is the practice of daily exercise, the types and intensities that have proven effective for glycemic and haemodinamic control and possible relationships with the ACE polymorphism, which are currently still tentative, since the evidence of associations can be strongly influenced by the population studied. The benefits of exercise are unquestionable and the recommended forms are discussed in this review. However the literature is still lacking studies that analyze the effects of physical exercise on diabetics and take into account the relationship with genetic aspects. This area is evidently an appropriate subject for further research. Diabetes Mellitus tipo 2 (DM2) é uma doença metabólica caracterizada por hiperglicemia e disfunções cardiovasculares, as quais podem ser controladas com exercícios físicos, controle dietético e tratamento farmacológico. Pesquisas recentes têm demonstrado associações entre DM2 e alguns polimorfismos genéticos, em especial do gene da Enzima Conversora de Angiotensina (ECA). A proposta desse estudo foi abordar a fisiopatologia do DM2 e a prática de exercício físico como forma de controle não farmacológico da glicemia e pressão arterial destes pacientes, bem como a associação entre o DM2 e polimorfismos do gene da ECA. A pesquisa incluiu livros da área de saúde, bem como artigos de revisão e originais referentes ao tema abordado, pesquisados nos bancos de dados disponíveis na internet: Pubmed, Scielo e Portal Capes. As palavras chave utilizadas foram “blood glucose”, “type 2 diabetes”, “exercise”, “blood pressure” e “ACE gene polymorphism”, e suas traduções para a língua portuguesa. Os principais assuntos do presente artigo referem-se à prática diária de exercícios, tipo e intensidades adequadas que têm se mostrado eficazes no controle glicêmico e hemodinâmico, assim como as possíveis relações com os polimorfismos da ECA, que ainda se apresentam incipientes, pois a constatação de associações entre estes podem ser fortemente influenciadas pelo tipo de população estudada. Os benefícios do exercício são indiscutíveis e suas recomendações apresentadas nesta revisão. Porém a literatura ainda é carente de estudos analisando os efeitos do exercício físico para diabéticos, considerando sua relação com aspectos genéticos, o que coloca este assunto em evidência como objeto de estudo na atualidade.

Background TAM (Tyro3, Axl, Mer) kinases receptors and Gas6 ligand are pivotal regulators of innate immunity and responsible for the clearance of apoptotic cells. TAM receptors and Gas6 ligand were individually tested in adult onset lupus with different results. 1-5 Objectives To quantify simultaneously soluble TAM receptors and Gas6 ligand in JSLE patients and evaluated the relation with disease activity parameters. Methods sTyro3, sAxl, sMer and Gas6 ligand were measured in sera from 44 JSLE patients (39 girls, mean age 14.2 yrs, ACR criteria), 14 gender and age-matched healthy individuals (11 girls, mean age 13.9 yrs) and 9 JIA patients as disease controls (4 girls, mean age 10.5, ACR criteria). Soluble TAM receptors and Gas6 ligand were quantified by commercial ELISA Kits following manufacturer9s instructions. Disease activity parameters included SLEDAI score, anti-dsDNA (ELISA), C3 and C4 (nephelometry), ERS (Westergreen) and CRP (nephelometry). Fifteen JSLE patients had active disease (SLEDAI score >4) and 34 had nephritis. Statistical analysis used Mann-Whitney U test and Spearman9s rank. A p Results sTyro3, sAxl, sMer and Gas6 ligand were detected in all patients and controls with results similar to that described in literature. JSLE patients presented sTyro3, sAxl, sMer and Gas6 ligand levels similar to healthy controls and patients with active disease and with nephritis had the higher levels, but without statistical significance. TAM receptors and Gas6 ligand levels did not correlated with disease activity parameters. JIA patients had soluble levels similar to healthy controls. (Table) Conclusions To our knowledge this is the first study to quantify soluble TAM (Tyro3, Axl, Mer) receptors and Gas6 ligand in JSLE patients. Although most studies with adult onset LES have reported increased concentrations this was not observed in JSLE patients even when we considered patients with active disease and with nephritis. Further studies with exclusively JSLE patients are needed to confirm these results. References Zhu H, et al. Lupus 2014;23:624-34. Recarte-Perlz P, et al. Arthritis Res Ther 2013;15:R41. Gheita TA, et al. J Clin Immunol. 2012;32:1279-86. Wu J, et al. Arthritis Res Ther 2011;13:R62. Suh CH, et al. Arthritis Res Ther. 2010;12:R146. Acknowledgements We thank FAPESP (grants 2012/22997-4 and 2008/58238-4) for supporting this study. Disclosure of Interest None declared