Antinociceptive effect of resveratrol in carrageenan-evoked hyperalgesia in rats: prolonged effect related to COX-2 expression impairment

Resveratrol is a natural polyphenol that protects from cancer and cardiovascular diseases. Resveratrol is able to induce apoptotic cell death and it inhibits the cyclooxygenase (COX) cascade. We measured the antinociceptive effect of resveratrol on carrageenan-induced hyperalgesia, prostaglandin-E2 (PGE2) concentration in CSF and COX-1/COX-2 gene expression in the spinal cord and dorsal root ganglion (DRG) in rats. Resveratrol induced a prolonged antinociceptive effect, which was correlated to the inhibition of COX-2 mRNA increase in DRG and cord elicited by carrageenan. An increase in the basal threshold of mechanical nociception was also observed with resveratrol in the absence of any inflammatory insult. A rapid bilateralisation of COX-2 mRNA production, not accompanied by a parallel increase in c-Fos expression, was observed in spinal cord three hours after the inflammatory insult. This increase in COX-2 mRNA concentration in the spinal cord on the opposite side of the inflammatory insult was abolished by resveratrol. In conclusion, the antinociceptive effect exhibited by resveratrol was related to the prevention of COX-2 mRNA increase induced by carrageenan. Resveratrol also prevented the bilateralisation of COX-2 expression. The later effect, together with the prolonged analgesia induced by a single injection, may be of great benefit for preventing chronic pain states often seen after inflammatory insults.     

Anti-neuropeptide Y plasma immunoglobulins in relation to mood and appetite in depressive disorder

Depression and eating disorders are frequently associated, but the molecular pathways responsible for co-occurrence of altered mood, appetite and body weight are not yet fully understood. Neuropeptide Y (NPY) has potent antidepressant and orexigenic properties and low central NPY levels have been reported in major depression. In the present study, we hypothesized that in patients with major depression alteration of mood, appetite and body weight may be related to NPY-reactive autoantibodies (autoAbs). To test this hypothesis, we compared plasma levels and affinities of NPY-reactive autoAbs between patients with major depression and healthy controls. Then, to evaluate if changes of NPY autoAb properties can be causally related to altered mood and appetite, we developed central and peripheral passive transfer models of human autoAbs in mice and studied depressive-like behavior in forced-swim test and food intake. We found that plasma levels of NPY IgG autoAbs were lower in patients with moderate but not with mild depression correlating negatively with the Montgomery-?sberg Depression Rating Scale scores and with immobility time of the forced-swim test in mice after peripheral injection of autoAbs. No significant differences in NPY IgG autoAb affinities between patients with depression and controls were found, but higher affinity of IgG autoAbs for NPY was associated with lower body mass index and prevented NPY-induced orexigenic response in mice after their central injection. These data suggest that changes of plasma levels of anti-NPY autoAbs are relevant to altered mood, while changes of their affinity may participate in altered appetite and body weight in patients with depressive disorder.     

Novel C2orf71 mutations account for ∼1% of cases in a large French arRP cohort

Autosomal-recessive retinitis pigmentosa (arRP) is a genetically heterogeneous group of disorders to which a novel gene, C2orf71, was recently associated. The purpose of our study was to establish the prevalence and nature of C2orf71 mutations in a clinically well-characterized cohort of 345 sporadic and arRP French cases. Direct sequencing of C2orf71 was performed in 209 subjects for whom mutations had previously been excluded by microarray technology and direct sequencing of EYS. Putative pathogenicity of the identified variants was evaluated through co-segregation analysis, screening of more than 188 control chromosomes and prediction programs. We identified two patients compound heterozygous for mutations predicted to lead to a premature stop codon, 3 of which are novel. In addition, 3 patients carried a single variant of likely pathogenicity. Furthermore a large number of novel putative non-disease causing variants were identified, highlighting the extremely polymorphic nature of C2orf71. To our knowledge, our study provides the first large scale screening of C2orf71 in a French arRP cohort through direct sequencing and suggests that it would account for approximately 1% of arRP cases.     

Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features

In metazoans, thousands of DNA replication origins (Oris) are activated at each cell cycle. Their genomic organization and their genetic nature remain elusive. Here, we characterized Oris by nascent strand (NS) purification and a genome-wide analysis in Drosophila and mouse cells. We show that in both species most CpG islands (CGI) contain Oris, although methylation is nearly absent in Drosophila, indicating that this epigenetic mark is not crucial for defining the activated origin. Initiation of DNA synthesis starts at the borders of CGI, resulting in a striking bimodal distribution of NS, suggestive of a dual initiation event. Oris contain a unique nucleotide skew around NS peaks, characterized by G/T and C/A overrepresentation at the 5' and 3' of Ori sites, respectively. Repeated GC-rich elements were detected, which are good predictors of Oris, suggesting that common sequence features are part of metazoan Oris. In the heterochromatic chromosome 4 of Drosophila, Oris correlated with HP1 binding sites. At the chromosome level, regions rich in Oris are early replicating, whereas Ori-poor regions are late replicating. The genome-wide analysis was coupled with a DNA combing analysis to unravel the organization of Oris. The results indicate that Oris are in a large excess, but their activation does not occur at random. They are organized in groups of site-specific but flexible origins that define replicons, where a single origin is activated in each replicon. This organization provides both site specificity and Ori firing flexibility in each replicon, allowing possible adaptation to environmental cues and cell fates.     

Increased tumor necrosis factor-alpha mRNA expression in whole blood from patients with rheumatoid arthritis: reduction after infliximab treatment does not predict response

OBJECTIVE: It has been suggested that patients with rheumatoid arthritis (RA) with abundant tumor necrosis factor-alpha (TNF-alpha) are more likely to respond to TNF-alpha inhibitors. We measured expression of TNF-alpha mRNA in peripheral blood of RA patients undergoing infliximab treatment in order to test its predictive value for treatment response. METHODS: Forty-four RA patients showing persistent disease activity and 27 healthy controls were studied. Peripheral blood TNF-alpha mRNA levels were measured before and 4 hours after the first infliximab infusion and at Week 22 using quantitative RT-PCR. Results were correlated to the treatment response at Week 22 in the whole RA cohort and a subset of patients showing high TNF-alpha mRNA levels at baseline. RESULTS: At baseline and at Week 22, TNF-alpha mRNA expression in RA patients was significantly increased compared to healthy controls. At both timepoints, no significant difference was observed between responders and nonresponders. Compared to baseline, infliximab treatment induced a decrease in TNF-alpha mRNA level at 4 hours and at Week 22, although this effect was significant only in patients with high TNF-alpha mRNA expression at baseline. Such variation compared to baseline was similar in responders and nonresponders. CONCLUSION: Peripheral blood TNF-alpha mRNA expression is increased in RA, but its reduction with anti-TNF treatment is not associated with treatment response.     

Proximal tibial epiphyseal intraosseous schwannoma: a rare entity

Schwannoma is a benign nerve sheath tumor most commonly located in the soft tissue. Occasionally, schwannomas involve osseous structures. The rarity of osseous involvement leads to omission of schwannoma from the initial differential diagnosis in the majority of cases. Intraosseous schwannomas arising in children have not been reported. We present the case of a schwannoma affecting the proximal tibial epiphysis in a growing child. Intraosseous schwannomas should be included in the differential diagnosis of lytic epiphyseal benign-appearing bone lesions in children. Its radiographic characteristics mimic those of benign chondroblastoma.     

Effects of anti‐TNF‐α agents on circulating endothelial‐derived and platelet‐derived microparticles in psoriasis

Psoriasis involves TNF‐α secretion leading to release of microparticles into the bloodstream. We investigated the effect of TNF blockers on microparticles levels before and after treatment in patients (twenty treated by anti‐TNF‐α agents and 6 by methotrexate) with severe psoriasis. Plasmatic microparticles were labelled using fluorescent monoclonal antibodies and were analysed using cytometry. Three months later, 70% of patients treated with anti‐TNF‐α agents achieved a reduction in PASI score of at least 75%. The clinical improvement in patients treated with anti‐TNF‐α agents was associated with a significant reduction of the mean number of platelet microparticles (2837/μl vs 1849/μl, P = 0.02) and of endothelial microparticles (64/μl vs 22/μl, P = 0.001). Microparticles are significantly decreased in psoriatic patients successfully treated by anti‐TNF‐α. Microparticles levels as circulating endothelial cells represent signs of endothelial dysfunction and are elevated in psoriasis. Then, TNF blockade may be effective to reduce cardiovascular risk through the reduction of circulating microparticles.