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

Do schistosome vaccine trials in mice have an intrinsic flaw that generates spurious protection data?

The laboratory mouse has been widely used to test the efficacy of schistosome vaccines and a long list of candidates has emerged from this work, many of them abundant internal proteins. These antigens do not have an additive effect when co-administered, or delivered as SWAP homogenate, a quarter of which comprises multiple candidates; the observed protection has an apparent ceiling of 40–50 %. We contend that the low level of maturation of penetrating cercariae (~32 % for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes. The pulmonary capillary bed is the obstacle encountered by schistosomula en route to the portal system. The fragility of pulmonary capillaries and their susceptibility to a cytokine-induced vascular leak syndrome have been documented. During lung transit schistosomula burst into the alveolar spaces, and possess only a limited capacity to re-enter tissues. The acquired immunity elicited by the radiation attenuated (RA) cercarial vaccine relies on a pulmonary inflammatory response, involving cytokines such as IFNγ and TNFα, to deflect additional parasites into the alveoli. A principal difference between antigen vaccine protocols and the RA vaccine is the short interval between the last antigen boost and cercarial challenge of mice (often two weeks). Thus, after antigen vaccination, challenge parasites will reach the lungs when both activated T cells and cytokine levels are maximal in the circulation. We propose that “protection” in this situation is the result of physiological effects on the pulmonary blood vessels, increasing the proportion of parasites that enter the alveoli. This hypothesis will explain why internal antigens, which are unlikely to interact with the immune response in a living schistosomulum, plus a variety of heterologous proteins, can reduce the level of maturation in a non-antigen-specific way. These proteins are “successful” precisely because they have not been selected for immunological silence. The same arguments apply to vaccine experiments with S. japonicum in the mouse model; this schistosome species seems a more robust parasite, even harder to eliminate by acquired immune responses. We propose a number of ways in which our conclusions may be tested

economic costs and spatial distribution analysis in an Endemic Northeastern City, Brazil

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Exercise-induced intra-ventricular gradients as a frequent potential cause of myocardial ischemia in cardiac syndrome X patients

<p>Abstract</p> <p>Background</p> <p>The development of intra-ventricular gradients (IVG) during dobutamine or exercise stress is not infrequent, and can be associated to symptoms during stress.</p> <p>The purpose of this study was to assess the occurrence of IVG during exercise stress echocardiography in cardiac syndrome X patients.</p> <p>Methods</p> <p>We prospectively evaluated 91 patients (pts) mean aged 51 ± 12 years (age ranged 20 to 75 years old), 44 of whom were women. All pts had angina, positive exercise ECG treadmill testing, normal rest echocardiogram and no coronary artery disease on coronary angiogram (cardiac X syndrome). After complete Doppler echocardiographic evaluation with determination of left ventricular outflow tract index (LVOTi), relative left ventricular wall thickness (RLVWT) and left ventricular end-diastolic volume index (LVDVi), all patients underwent stress echocardiography with two-dimensional and Doppler echographic evaluation during and after treadmill exercise.</p> <p>Results</p> <p>For analysis purpose patients were divided in 2 groups, according to the development of IVG. Doppler evidence of IVG was found in 33 (36%) of the patients (Group A), with mean age 47 ± 14 years old (age ranged 20 to 72 years) and with a mean end-systolic peak gradient of 86 ± 34 mmHg (ranging from 30 to 165 mmHg). The IVG development was accompanied by SAM of the mitral valve in 23 pts. Three of these pts experienced symptomatic hypotension. Ten were women (30% pts). 58 pts in group B, 34 of whom were women (59%) (p = 0,01 vs group A), mean aged 53,5 ± 10,9 years old (age ranged 34 to 75 years) (p = 0,03 vs group A), did not develop IVG. LVOTi was 10,29 ± 0,9 mm/m²in group A and 11,4 ± 1 mm/m²in group B (p < 0,000); RLVWT was 0,36 ± 0,068 in group A and 0,33 ± 0,046 in group B (p < 0,01); LVDVi was 44,8 ± 10 ml/m²in group A and 56 ± 11,6 ml/m²in group B (p = 0,000).</p> <p>Conclusion</p> <p>1. A significant number of patients with cardiac X syndrome developed IVG during upright exercise in treadmill. These pts (group A) are mainly males and younger than those who did not develop IVG.</p> <p>2. The development of IVG and mitral valve SAM on exertion seems to be associated with ST segment downsloping during stress testing in patients without epicardial coronary disease.</p> <p>3. The development of IVG and mitral valve SAM seems to be associated with lower LVOTi, lower LVDVi and higher RLVWT.</p

Determinants of the exclusive breastfeeding abandonment: psychosocial factors

OBJECTIVE To assess the determinants of exclusive breastfeeding abandonment. METHODS Longitudinal study based on a birth cohort in Viçosa, MG, Southeastern Brazil. In 2011/2012, 168 new mothers accessing the public health network were followed. Three interviews, at 30, 60, and 120 days postpartum, with the new mothers were conducted. Exclusive breastfeeding abandonment was analyzed in the first, second, and fourth months after childbirth. The Edinburgh Postnatal Depression Scale was applied to identify depressive symptoms in the first and second meetings, with a score of ≥ 12 considered as the cutoff point. Socioeconomic, demographic, and obstetric variables were investigated, along with emotional conditions and the new mothers’ social network during pregnancy and the postpartum period. RESULTS The prevalence of exclusive breastfeeding abandonment at 30, 60, and 120 days postpartum was 53.6% (n = 90), 47.6% (n = 80), and 69.6% (n = 117), respectively, and its incidence in the fourth month compared with the first was 48.7%. Depressive symptoms and traumatic delivery were associated with exclusive breastfeeding abandonment in the second month after childbirth. In the fourth month, the following variables were significant: lower maternal education levels, lack of homeownership, returning to work, not receiving guidance on breastfeeding in the postpartum period, mother’s negative reaction to the news of pregnancy, and not receiving assistance from their partners for infant care. CONCLUSIONS Psychosocial and sociodemographic factors were strong predictors of early exclusive breastfeeding abandonment. Therefore, it is necessary to identify and provide early treatment to nursing mothers with depressive symptoms, decreasing the associated morbidity and promoting greater duration of exclusive breastfeeding. Support from health professionals, as well as that received at home and at work, can assist in this process

Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the <it>CYBA </it>gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O₂^•-(-675 T → A in <it>CYBA</it>, unregistered) and in glutathione metabolism (-129 C → T in <it>GCLC </it>[rs17883901] and -65 T → C in <it>GPX3 </it>[rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients.</p> <p>Methods</p> <p>401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: ≥ 60 mL (n = 265) or < 60 mL/min/1.73 m²(n = 136) and were genotyped.</p> <p>Results</p> <p>No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying <it>CYBA </it>genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying <it>GCLC </it>genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (<it>p </it>= 0.0082). Logistic regression analysis identified the presence of at least one A allele of the <it>CYBA </it>SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, <it>p </it>= 0.0354) and the presence of at least one T allele of the <it>GCLC </it>rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, <it>p </it>= 0.0068).</p> <p>Conclusions</p> <p>The functional SNPs <it>CYBA </it>-675 T → A and <it>GCLC </it>rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.</p

Population level determinants of acute mountain sickness among young men: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Many visitors, including military troops, who enter highland regions from low altitude areas may suffer from acute mountain sickness (AMS), which negatively impacts workable man-hours and increases healthcare costs. The aim of this study was to evaluate the population level risk factors and build a multivariate model, which might be applicable to reduce the effects of AMS on Chinese young men traveling to this region.</p> <p>Methods</p> <p>Chinese highland military medical records were used to obtain data of young men (n = 3727) who entered the Tibet plateau between the years of 2006-2009. The relationship between AMS and travel profile, demographic characteristics, and health behaviors were evaluated by logistic regression. Univariate logistic models estimated the crude odds ratio. The variables that showed significance in the univariate model were included in a multivariate model to derive adjusted odds ratios and build the final model. Data corresponding to odd and even years (2 subsets) were analyzed separately and used in a simple cross-validation.</p> <p>Results</p> <p>Univariate analysis indicated that travel profile, prophylactic use, ethnicity, and province of birth were all associated with AMS in both subsets. In multivariate analysis, young men who traveled from lower altitude (600-800 m <it>vs</it>. 1300-1500 m, adjusted odds ratio (AOR) = 1.32-1.44) to higher altitudes (4100-4300 m <it>vs</it>. 2900-3100 m, AOR = 3.94-4.12; 3600-3700 m <it>vs</it>. 2900-3100 m, AOR = 2.71-2.74) by air or rapid land transport for emergency mission deployment (emergency land deployment <it>vs</it>. normal land deployment, AOR = 2.08-2.11; normal air deployment <it>vs</it>. normal land deployment, AOR = 2.00-2.20; emergency air deployment <it>vs</it>. normal land deployment, AOR = 2.40-3.34) during the cold season (cold <it>vs</it>. warm, AOR = 1.25-1.28) are at great risk for developing AMS. Non-Tibetan male soldiers (Tibetan <it>vs</it>. Han, AOR = 0.03-0.08), born and raised in lower provinces (eastern <it>vs</it>. northwestern, AOR = 1.32-1.39), and deployed without prophylaxis (prophylactic drug <it>vs</it>. none, AOR = 0.75-0.76), also represented a population at significantly increased risk for AMS. The predicted model was built; the area under receiver operating characteristic curve was 0.703.</p> <p>Conclusion</p> <p>Before a group of young men first enter a high altitude area, it is important that a health service plan should be made referring to the group's travel profile and with respect to young men's ethnicity and province of birth. Low-cost Chinese traditional prophylactic drugs might have some effect on decreasing the risk of AMS, although this needs further verification.</p

Mercury exposure, malaria, and serum antinuclear/antinucleolar antibodies in amazon populations in Brazil: a cross-sectional study

BACKGROUND: Mercury is an immunotoxic metal that induces autoimmune disease in rodents. Highly susceptible mouse strains such as SJL/N, A.SW, B10.S (H-2(s)) develop multiple autoimmune manifestations after exposure to inorganic mercury, including lymphoproliferation, elevated levels of autoantibodies, overproduction of IgG and IgE, and circulating immune complexes in kidney and vasculature. A few studies have examined relationships between mercury exposures and adverse immunological reactions in humans, but there is little evidence of mercury-associated autoimmunity in humans. METHODS: To test the immunotoxic effects of mercury in humans, we studied communities in Amazonian Brazil with well-characterized exposures to mercury. Information was collected on diet, mercury exposures, demographic data, and medical history. Antinuclear and antinucleolar autoantibodies (ANA and ANoA) were measured by indirect immunofluorescence. Anti-fibrillarin autoantibodies (AFA) were measured by immunoblotting. RESULTS: In a gold mining site, there was a high prevalence of ANA and ANoA: 40.8% with detectable ANoA at ≥1:10 serum dilution, and 54.1% with detectable ANA (of which 15% had also detectable ANoA). In a riverine town, where the population is exposed to methylmercury by fish consumption, both prevalence and levels of autoantibodies were lower: 18% with detectable ANoA and 10.7% with detectable ANA. In a reference site with lower mercury exposures, both prevalence and levels of autoantibodies were much lower: only 2.0% detectable ANoA, and only 7.1% with detectable ANA. In the gold mining population, we also examined serum for AFA in those subjects with detectable ANoA (≥1:10). There was no evidence for mercury induction of this autoantibody. CONCLUSIONS: This is the first study to report immunologic changes, indicative of autoimmune dysfunction in persons exposed to mercury, which may also reflect interactions with infectious disease and other factors