Protective effect of vasoactive intestinal peptide on bone destruction in the collagen-induced arthritis model of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by the presence of inflammatory synovitis accompanied by destruction of joint cartilage and bone. Treatment with vasoactive intestinal peptide (VIP) prevents experimental arthritis in animal models by downregulation of both autoimmune and inflammatory components of the disease. The aim of this study was to characterize the protective effect of VIP on bone erosion in collagen-induced arthritis (CIA) in mice. We have studied the expression of different mediators implicated in bone homeostasis, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), receptor activator of nuclear factor-κB (RANK), receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), IL-1, IL-4, IL-6, IL-10, IL-11 and IL-17. Circulating cytokine levels were assessed by ELISA and the local expression of mediators were determined by RT-PCR in mRNA extracts from joints. VIP treatment resulted in decreased levels of circulating IL-6, IL-1β and TNFα, and increased levels of IL-4 and IL-10. CIA-mice treated with VIP presented a decrease in mRNA expression of IL-17, IL-11 in the joints. The ratio of RANKL to OPG decreased drastically in the joint after VIP treatment, which correlated with an increase in levels of circulating OPG in CIA mice treated with VIP. In addition, VIP treatment decreased the expression of mRNA for RANK, iNOS and COX-2. To investigate the molecular mechanisms involved, we tested the activity of NFκB and AP-1, two transcriptional factors closely related to joint erosion, by EMSA in synovial cells from CIA mice. VIP treatment in vivo was able to affect the transcriptional activity of both factors. Our data indicate that VIP is a viable candidate for the development of treatments for RA

Deep Chandra Observations of A2495: A Possible Sloshing-regulated Feedback Cycle in a Triple-offset Galaxy Cluster

We present the analysis of new, deep Chandra observations (130 ks) of the galaxy cluster A2495. This object is known for the presence of a triple offset between the peaks of the intracluster medium (ICM), the brightest cluster galaxy (BCG), and the warm gas glowing in Hα line. The new Chandra data confirm that the X-ray emission peak is located at a distance of ∼6.2 kpc from the BCG, and at ∼3.9 kpc from the Hα emission peak. Moreover, we identify two generations of X-ray cavities in the ICM, likely inflated by the central radio galaxy activity. Through a detailed morphological and spectral analysis, we determine that the power of the active galactic nucleus (AGN) outbursts (P cav = 4.7 ± 1.3 × 1043 erg s−1) is enough to counterbalance the radiative losses from ICM cooling (L cool = 5.7 ± 0.1 × 1043 erg s−1). This indicates that, despite a fragmented cooling core, A2495 still harbors an effective feedback cycle. We argue that the offsets are most likely caused by sloshing of the ICM, supported by the presence of spiral structures and a probable cold front in the gas at ∼58 kpc east of the center. Ultimately, we find that the outburst interval between the two generations of X-ray cavities is of the order of the dynamical sloshing timescale, as already hinted from the previous Chandra snapshot. We thus speculate that sloshing may be able to regulate the timescales of AGN feedback in A2495, by periodically fueling the central AGN

Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: Study protocol for a randomized control trial

Background: Patent ductus arteriosus (PDA) is one of most common complications in preterm infants. Although ibuprofen represents the first choice for the closure of PDA, this treatment can cause severe gastrointestinal and adverse renal effects and worsen platelet function. The successful closure of the PDA with paracetamol has been recently reported in several preterm infants, and the safety of paracetamol for this use has been suggested by the available data. Methods/design: We present the design of a randomized, multicenter, controlled study, whose aim is to assess the effectiveness and safety of intravenous paracetamol in comparison to intravenous ibuprofen for the treatment of PDA in preterm infants. A total of 110 infants born at 25 +0 to 31 +6 weeks of gestational age will be enrolled and randomized to receive paracetamol or ibuprofen (55 patients per group) starting at 24-72h of life. The primary endpoint of the study is the comparison of the PDA closing rate observed after a 3-day course with paracetamol or ibuprofen. The secondary endpoints include the closure rate of PDA after the second course of treatment with ibuprofen, the re-opening rate of the PDA, the incidence of surgical ligation, and the occurrence of adverse effects. Discussion: The results of this study will provide new information about the possible use of paracetamol in the treatment of PDA. Paracetamol could offer several important therapeutic advantages over current treatment options, and it could become the treatment of choice for the management of PDA, mainly due to its more favorable side effect profile. Trial registration: Clinicaltrials.gov NCT02422966. Eudract no. 2013-003883-30

Do novel European Headache Federation criteria identify differences in migraine burden?: baseline data of an international real-life study on resistant and refractory migraine (REFINE)

Question. We evaluated if EHF criteria for resistant (RES) and refractory (REF) migraine identify patients with more severe migraine burden. Methods. We performed an observational, multi center, international study to compare baseline characteristics, comorbidities, and PROMs of non-resistant and non-refractory (NRNR) migraine, RES and REF individuals in the REFINE study. Results. We included 175 individuals with NRNR migraine, 133 (39.7%) with RES and 27 (8.0%) with REF. Individuals with RES and REF migraine as compared to those with NRNR reported higher monthly migraine days (median=8, IQR=5-14 vs. median=13, IQR=10- 17 and median=15, IQR=10-20; p≤0.001), months of chronification (median=24, IQR=12-72 vs. median=40, IQR=12-108 and median=60, IQR=18-96; p=0.044), monthly days of symptomatic drugs assumption (median=8, IQR=5-15 vs. median=12, IQR=9-20 and median=15, IQR=10-20; p≤0.001), medication overuse (19.4% vs. 45.9% and 40.7%; p≤0.001). They also had more comorbidities such as depression (18.3% vs. 31.1% and 44.4%; p=0.002) and anxiety (13.7% vs. 21.1% and 37%; p=0.009). In these groups, PROMs also revealed a higher presence of anxiety (p≤0.001) and depression (p≤0.001) symptoms and poorer sleep quality (p=0.006). Regarding specific perceptions about migraine, RES and REF individuals reported higher impact of migraine on daily life (p≤0.001) and work, household work, and social life (p≤0.001), along with a lower perception of the effectiveness of their ongoing treatment for migraine (p≤0.001), when compared to NRNR subjects (Table 1). Conclusion. RES and REF migraine is associated with relevant migraine burden considering migraine features, comorbidities and scores at several scales; the severe burdensome condition of RES and REF is confirmed by the median number of monthly migraine days and PROMs.info:eu-repo/semantics/publishedVersio

Genotoxic effect induced by hydrogen peroxide in human hepatoma cells using comet assay

Background: Hydrogen peroxide is a common reactive oxygen intermediate generated by variousforms of oxidative stress. Aims: The aim of this study was to investigate the DNA damage capacity ofH2O2 in HepG2 cells. Methods: Cells were treated with H2O2 at concentrations of 25 μM or 50 μM for5 min, 30 min, 40 min, 1 h or 24 h in parallel. The extent of DNA damage was assessed by the cometassay. Results: Compared to the control, DNA damage by 25 μM and 50 μM H2O2 increasedsignificantly with increasing incubation time up to 1 h, but it was not increased at 24 h. Conclusions:Our Findings confirm that H2O2 is a typical DNA damage inducing agent and thus is a good modelsystem to study the effects of oxidative stress. DNA damage in HepG2 cells increased significantlywith H2O2 concentration and time of incubation but later decreased likely due to DNA repairmechanisms and antioxidant enzyme

Treatment with Idelalisib in Patients with Relapsed or Refractory Follicular Lymphoma: The Observational Italian Multicenter FolIdela Study

Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years—mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)—were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice

A lineage-specific Exo70 is required for receptor kinase-mediated immunity in barley

In the evolution of land plants, the plant immune system has experienced expansion in immune receptor and signaling pathways. Lineage-specific expansions have been observed in diverse gene families that are potentially involved in immunity but lack causal association. Here, we show that Rps8-mediated resistance in barley to the pathogen Puccinia striiformis f. sp. tritici (wheat stripe rust) is conferred by a genetic module: Pur1 and Exo70FX12, which are together necessary and sufficient. Pur1 encodes a leucine-rich repeat receptor kinase and is the ortho-log of rice Xa21, and Exo70FX12 belongs to the Poales-specific Exo70FX clade. The Exo70FX clade emerged after the divergence of the Bromeliaceae and Poaceae and comprises from 2 to 75 members in sequenced grasses. These results demonstrate the requirement of a lineage-specific Exo70FX12 in Pur1-mediated immunity and sug-gest that the Exo70FX clade may have evolved a specialized role in receptor kinase signalin

Avaliação da ocorrencia de secas no município de Viçosa-MG, utilizando o índice de precipitação padronizada (SPI).

A metodologia do Índice de Precipitação Padronizada (SPI) foi testada e avaliada a ocorrência de eventos de seca no município de Viçosa-MG, nas escalas de tempo 3, 6 e 12 meses

APC Activation Restores Functional CD4+CD25+ Regulatory T Cells in NOD Mice that Can Prevent Diabetes Development

BACKGROUND: Defects in APC and regulatory cells are associated with diabetes development in NOD mice. We have shown previously that NOD APC are not effective at stimulating CD4(+)CD25(+) regulatory cell function in vitro. We hypothesize that failure of NOD APC to properly activate CD4(+)CD25(+) regulatory cells in vivo could compromise their ability to control pathogenic cells, and activation of NOD APC could restore this defect, thereby preventing disease. METHODOLOGY/PRINCIPAL FINDINGS: To test these hypotheses, we used the well-documented ability of complete Freund's adjuvant (CFA), an APC activator, to prevent disease in NOD mice. Phenotype and function of CD4(+)CD25(+) regulatory cells from untreated and CFA-treated NOD mice were determined by FACS, and in vitro and in vivo assays. APC from these mice were also evaluated for their ability to activate regulatory cells in vitro. We have found that sick NOD CD4(+)CD25(+) cells expressed Foxp3 at the same percentages, but decreased levels per cell, compared to young NOD or non-NOD controls. Treatment with CFA increased Foxp3 expression in NOD cells, and also increased the percentages of CD4(+)CD25(+)Foxp3(+) cells infiltrating the pancreas compared to untreated NOD mice. Moreover, CD4(+)CD25(+) cells from pancreatic LN of CFA-treated, but not untreated, NOD mice transferred protection from diabetes. Finally, APC isolated from CFA-treated mice increased Foxp3 and granzyme B expression as well as regulatory function by NOD CD4(+)CD25(+) cells in vitro compared to APC from untreated NOD mice. CONCLUSIONS/SIGNIFICANCE: These data suggest that regulatory T cell function and ability to control pathogenic cells can be enhanced in NOD mice by activating NOD APC