723 research outputs found
ELEVATED SERUM LEVELS OF TNF SOLUBLE RECEPTORS IN PATIENTS WITH POSITIVE ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODIES
ANCA are found in various systemic vasculitis and are supposed to play a role in the pathogenesis of the disease, in cooperation with other factors such as cytokines. A total of 36 ANCA-positive and 10 ANCA-negative serum samples were analysed for the presence of TNF soluble receptors (TNF-sR), which are shed from the surface of activated cells and may act as TNF inhibitors. Of the ANCA-positive samples, 67% had elevated TNF-sR75 and 72% had elevated TNF-sR55 compared to ANCA-negative specimens (mean [S.E.] 18.7 [17.3] vs 3.6 [1.5] and 10.5 [9.7] vs 1.9 [0.7] ng/ml, P<0.01). Elevation of TNF-sR in patients with ANCA suggests that cytokines and their inhibitors are involved in the pathogenesis of ANCA-associated autoimmune disease
Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers.
The new anti-aggregating agent prasugrel is bioactivated by cytochromes P450 (CYP) 3A and 2B6. Ritonavir is a potent CYP3A inhibitor and was shown in vitro as a CYP2B6 inhibitor. The aim of this open-label cross-over study was to assess the effect of ritonavir on prasugrel active metabolite (prasugrel AM) pharmacokinetics in healthy volunteers. Ten healthy male volunteers received 10 mg prasugrel. After at least a week washout, they received 100 mg ritonavir, followed by 10 mg prasugrel 2 hr later. We used dried blood spot sampling method to monitor prasugrel AM pharmacokinetics (C(max) , t(1/2) , t(max) , AUC(0-6 hr) ) at 0, 0.25, 0.5, 1, 1.5, 2, 4 and 6 hr after prasugrel administration. A 'cocktail' approach was used to measure CYP2B6, 2C9, 2C19 and 3A activities. In the presence of ritonavir, prasugrel AM C(max) and AUC were decreased by 45% (mean ratio: 0.55, CI 90%: 0.40-0.7, p = 0.007) and 38% (mean ratio: 0.62, CI 90%: 0.54-0.7, p = 0.005), respectively, while t(1/2) and t(max) were not affected. Midazolam metabolic ratio (MR) dramatically decreased in presence of ritonavir (6.7 ± 2.6 versus 0.13 ± 0.07) reflecting an almost complete inhibition of CYP3A4, whereas omeprazole, flurbiprofen and bupropion MR were not affected. These data demonstrate that ritonavir is able to block prasugrel CYP3A4 bioactivation. This CYP-mediated drug-drug interaction might lead to a significant reduction of prasugrel efficacy in HIV-infected patients with acute coronary syndrome
Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly pathway
<p>Abstract</p> <p>Background</p> <p>Protein kinase CK2 is a pleiotropic serine/threonine protein kinase with hundreds of reported substrates, and plays an important role in a number of cellular processes. The cellular functions of <it>Plasmodium falciparum </it>CK2 (PfCK2) are unknown. The parasite's genome encodes one catalytic subunit, PfCK2α, which we have previously shown to be essential for completion of the asexual erythrocytic cycle, and two putative regulatory subunits, PfCK2β1 and PfCK2β2.</p> <p>Results</p> <p>We now show that the genes encoding both regulatory PfCK2 subunits (PfCK2β1 and PfCK2β2) cannot be disrupted. Using immunofluorescence and electron microscopy, we examined the intra-erythrocytic stages of transgenic parasite lines expressing hemagglutinin (HA)-tagged catalytic and regulatory subunits (HA-CK2α, HA-PfCK2β1 or HA-PfCK2β2), and localized all three subunits to both cytoplasmic and nuclear compartments of the parasite. The same transgenic parasite lines were used to purify PfCK2β1- and PfCK2β2-containing complexes, which were analyzed by mass spectrometry. The recovered proteins were unevenly distributed between various pathways, with a large proportion of components of the chromatin assembly pathway being present in both PfCK2β1 and PfCK2β2 precipitates, implicating PfCK2 in chromatin dynamics. We also found that chromatin-related substrates such as nucleosome assembly proteins (Naps), histones, and two members of the Alba family are phosphorylated by PfCK2α <it>in vitro</it>.</p> <p>Conclusions</p> <p>Our reverse-genetics data show that each of the two regulatory PfCK2 subunits is required for completion of the asexual erythrocytic cycle. Our interactome study points to an implication of PfCK2 in many cellular pathways, with chromatin dynamics being identified as a major process regulated by PfCK2. This study paves the way for a kinome-wide interactomics-based approach to elucidate protein kinase function in malaria parasites.</p
Prenatal Exposure to DEHP Affects Spermatogenesis and Sperm DNA Methylation in a Strain-Dependent Manner.
Di-(2-ethylhexyl)phtalate (DEHP) is a plasticizer with endocrine disrupting properties found ubiquitously in the environment and altering reproduction in rodents. Here we investigated the impact of prenatal exposure to DEHP on spermatogenesis and DNA sperm methylation in two distinct, selected, and sequenced mice strains. FVB/N and C57BL/6J mice were orally exposed to 300 mg/kg/day of DEHP from gestation day 9 to 19. Prenatal DEHP exposure significantly decreased spermatogenesis in C57BL/6J (fold-change = 0.6, p-value = 8.7*10-4), but not in FVB/N (fold-change = 1, p-value = 0.9). The number of differentially methylated regions (DMRs) by DEHP-exposure across the entire genome showed increased hyper- and decreased hypo-methylation in C57BL/6J compared to FVB/N. At the promoter level, three important subsets of genes were massively affected. Promoters of vomeronasal and olfactory receptors coding genes globally followed the same trend, more pronounced in the C57BL/6J strain, of being hyper-methylated in DEHP related conditions. In contrast, a large set of micro-RNAs were hypo-methylated, with a trend more pronounced in the FVB/N strain. We additionally analyze both the presence of functional genetic variations within genes that were associated with the detected DMRs and that could be involved in spermatogenesis, and DMRs related with the DEHP exposure that affected both strains in an opposite manner. The major finding in this study indicates that prenatal exposure to DEHP can decrease spermatogenesis in a strain-dependent manner and affects sperm DNA methylation in promoters of large sets of genes putatively involved in both sperm chemotaxis and post-transcriptional regulatory mechanisms
Anti-fibroblast antibodies detected by cell-based ELISA in systemic sclerosis enhance the collagenolytic activity and matrix metalloproteinase-1 production in dermal fibroblasts
Objectives. Antibodies binding to the surface of fibroblasts (anti-fibroblast antibodies: AFA) have been described in systemic sclerosis (SSc). We aimed to assess the effect of AFA on extracellular matrix (ECM) turnover and whether AFA were associated with anti-topoisomerase-I antibody. Methods. IgG were purified from AFA-positive and AFA-negative sera selected within 20 SSc and 20 healthy individuals, and tested on normal dermal fibroblasts, at protein and mRNA level, for their capacity to induce collagen deposition or degradation. Results. Fibroblasts stimulated with AFA-positive but not with AFA-negative and control IgG showed an increased capacity to digest collagen matrix and produce metalloproteinase-1 (MMP-1) while their production of total collagen, type I collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) was unaffected. The steady-state mRNA levels of MMP-1, COL1A1 and TIMP-1 paralleled the protein levels. AFA-positive IgG did not induce Smad 2/3 phosphorylation, indicating that this transforming growth factor-β signalling pathway was not involved. IL-1 and tumour necrosis factor (TNF) neutralization did not reverse the enhanced production of MMP-1, suggesting a direct effect of AFA on fibroblasts. Finally, anti-topoisomerase-I antibodies were present in 11 of 12 AFA-negative IgG, and an anti-topoisomerase-I monoclonal antibody failed to enhance MMP-1 production, thus indicating a lack of correlation between AFA and anti-topoisomerase-I antibody. Conclusions. These results indicate that SSc antibodies binding to fibroblasts enhance matrix degradation and MMP production events that may favour inflammation but do not directly impact on fibrosis developmen
Identification and weighting of the most critical "real-life” drug-drug interactions with acenocoumarol in a tertiary care hospital
Purpose: The objective of this study was to identify the most clinically relevant drug-drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution. Methods: We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system (n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994-2007) (n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding. Results: One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs. Conclusion: Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drug
Identification and weighting of the most critical "real-life” drug-drug interactions with acenocoumarol in a tertiary care hospital
Purpose: The objective of this study was to identify the most clinically relevant drug-drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution. Methods: We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system (n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994-2007) (n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding. Results: One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs. Conclusion: Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drug
Drain Versus No Drain in Open Mesh Repair for Incisional Hernia, Results of a Prospective Randomized Controlled Trial.
Open mesh repair of incisional hernia is associated with different local complications, particularly bleeding and seroma formation. Traditionally, drains have been placed perioperatively to prevent these complications, despite the lack of scientific evidence or expert consensus. We formulated the hypothesis that the absence of drainage would reduce number of patients presenting collections or complications. The present study aimed to compare postoperative complication rates after open mesh repair for incisional hernia with or without prophylactic wound drainage.
Prospective randomized study using standardized surgical technique and drain placement. The primary endpoint was the evaluation of residual fluid collection with ultrasound on postoperative day 30. Other complications, subdivided into medical and surgical, were analyzed as secondary endpoints.
There were 144 patients randomized (70 with drain, 74 without drain). No difference was identified between both groups for fluid collection at 30 days (60.3% vs. 62%, p = 0.844). However, less surgical complications were identified in the drain group (21.7% vs. 42.7%, p = 0.007), with a lower wound dehiscence rate (1.5% vs. 9.3%, p = 0.041).
Prophylactic drainage in open incisional hernia repair does not objectively reduce the rate of postoperative fluid collections. Therefore, our results do not support the use of routine drainage in incisional hernia repair.
Trial registration on clinicaltrials.gov (NCT00478348)
- …