Effects of TNF inhibitor on innate inflammatory and Th17 cytokines in stimulated whole blood from rheumatoid arthritis patients

Background

Recent studies point to important roles for IL-17 and Th17 cells in sustaining chronic inflammation and articular destruction in rheumatoid arthritis (RA). We investigated the effects of TNF inhibitor on innate inflammatory and Th17 cytokines production by ex vivo lipopolysaccharide (LPS)-stimulated whole blood in patients with RA and the associations of cytokine levels in whole blood cultures with autoantibodies and markers of disease activity.

Materials and methods

Whole blood cultures from 18 healthy volunteers and 19 RA patients on etanercept therapy were stimulated with LPS and the production of IL-6, TNF-??, IL-23, IL-17A and IL-21 was measured by ELISA.

Results

After stimulation with LPS, the interleukin (IL)-17A (p?=?0.020) and IL-21 (p?=?0.0001) secretions were significantly higher in patients with RA than in controls, while the TNF-?? (p?=?0.002) was significantly lower at baseline. Etanercept significantly decreased IL-21 production (p?=?0.007), while IL-6 production (p?=?0.005) significantly increased after 6?months of therapy. IL-21 significantly correlated with RF (r?=?0.917, p?<?0.01) and antimutated citrullinated vimentin antibodies (r?=?0.770, p?<?0.01) at baseline. Logistic regression analysis revealed that baseline IL-21 levels (p?=?0.004) were significant predictors of DAS28-ESR at 6?months follow-up.

Discussion

Stimulation with LPS increased production of Th17 cytokines in whole blood cultures in patients with RA. Etanercept therapy decreased IL-21 secretion, while the capacity of whole blood cells to produce IL-6 increased. IL-21 production is strongly associated with the levels of autoantibodies. Our findings suggest that IL-21 production in LPS-stimulated whole blood cultures may be predictive of clinical response to etanercept treatment in patients with RA.     

Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]-4-arylpiperazines

Docking of several 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]-4- and 1-benzyl-arylpiperazines to the D(2) dopamine receptor (DAR) was examined. The binding pocket of the D(2) DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF(3), and NO(2)) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D(2) DAR.     

Contrasting behavior of the p18INK4c and p16INK4a tumor suppressors in both replicative and oncogene-induced senescence

The cyclin-dependent kinase (CDK) inhibitors, p18(INK4c) and p16(INK4a), both have the credentials of tumor suppressors in human cancers and mouse models. For p16(INK4a), the underlying rationale is its role in senescence, but the selective force for inactivation of p18(INK4c) in incipient cancer cells is less clear. Here, we show that in human fibroblasts undergoing replicative or oncogene-induced senescence, there is a marked decline in the levels of p18(INK4c) protein and RNA, which mirrors the accumulation of p16(INK4a). Downregulation of INK4c is not dependent on p16(INK4a), and RAS can promote the loss of INK4c without cell-cycle arrest. Downregulation of p18(INK4c) correlates with reduced expression of menin and E2F1 but is unaffected by acute cell-cycle arrest or inactivation of the retinoblastoma protein (pRb). Collectively, our data question the idea that p18(INK4c) acts as a backup for loss of p16(INK4a) and suggest that the apparent activation of p18(INK4c) in some settings represents delayed senescence rather than increased expression. We propose that the contrasting behavior of the two very similar INK4 proteins could reflect their respective roles in senescence versus differentiation.     

Normal subtypes of the posterior part of the cerebral arterial circle in human fetuses

BACKGROUND: Although centuries of the human CAC research are behind us, still there is a stimulus for the authors to describe something new or to add to the "archive" of already known facts about its angioarchitecture. METHODS: With normal configurations of the posterior part of the CAC in early prenatal status, 172 brains of human fetuses from the 13th to the 24th week were used in the purpose of investigation. Brain arteries were injected and microdissected using a surgical microscope. RESULTS: According to diameter values of vascular components in the posterior part of the CAC, 6 basic types and the corresponding number of their subtypes are formed. Incidences of bilateral transitory (18.6%), fetal (9.3%), and adult (33.1%) types, as well bilateral asymmetric types (fetal-transitory in 5.8%, adult-transitory in 14.5%, and adult-fetal in 18.6% of cases), proved that dominant configuration of posterior part had not been present in the period from the fourth to the sixth gestational month. CONCLUSION: The finding of normal subtypes of the posterior part of the CAC, as well as the absence of some subtypes, is a challenge for future studies of the posterior arterial pattern within vascular abnormalities or diseases.     

Lack of genetic association between the phospholipase A2 gene and bipolar mood disorder in a European multicentre case-control study

The possible association between phospholipase A2 gene and bipolar mood disorder was examined in 557 bipolar patients and 725 controls (all personally interviewed), recruited from seven countries (Belgium, Bulgaria, Croatia, Germany, Greece, Italy, and UK). The frequencies of the eight alleles that were identified did not differ between patients and control individuals in the whole population, while the power to detect an association based on our sample was relatively high. Some differences were noted among the various ethnic groups, but no significant trends existed, suggesting that population stratification by country may not be responsible for a type II error. On the basis of these results, mutations of the phospholipase A2 gene, at least in the region close to the polymorphism examined between exons 1 and 2, are not involved in the pathogenesis of bipolar mood disorder.     

Intercostobrachial nerve injury from axillary dissection resulting in necrotizing fasciitis after a burn injury

Abstract:  We present here the successful management of a 50-year-old female patient who developed necrotizing fasciitis after a burn injury to her left arm. The burn injury was sustained in a minimally lymphoedematous arm, in an area of post surgical paresthesia caused by division of the intercostobrachial nerve. This is a common consequence of axillary lymph node dissection. We discuss the diagnosis, management strategies, and the available literature. We conclude that division of the intercostobrachial nerve increases the risk of morbidity significantly and support the view that its preservation at the time of axillary surgery is preferable.