Recently, we showed that manual stimulation (MS) of denervated vibrissal muscles enhanced functional recovery following facial nerve cut and suture (FFA) by reducing poly-innervation at the ...neuro-muscular junctions (NMJ). Although the cellular correlates of poly-innervation are established, with terminal Schwann cells (TSC) processes attracting axon sprouts to “bridge” adjacent NMJ, molecular correlates are poorly understood. Since quantitative RT-PCR revealed a rapid increase of IGF-1 mRNA in denervated muscles, we examined the effect of daily MS for 2 months after FFA in IGF-1
+/− heterozygous mice; controls were wild-type (WT) littermates including intact animals. We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive TSC. There were no differences between intact WT and IGF-1
+/− mice for vibrissal whisking amplitude (48° and 49°) or the percentage of bridged NMJ (0%). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (42% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (12% more than intact). After FFA and handling in IGF-1
+/− mice, the pattern was similar (whisking amplitude 57% lower than intact; proportion of bridged NMJ 42% more than intact). However, MS did not improve outcome (whisking amplitude 47% lower than intact; proportion of bridged NMJ 40% more than intact). We conclude that IGF-I is required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.
Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in ...CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home.
A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER® and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs.
Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life.
Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.
Abstract Functional recovery following facial nerve injury is poor. Neuromuscular junctions (NMJs) are “bridged” by terminal Schwann cells and numerous regenerating axonal sprouts. We have shown that ...this poly-innervation of NMJs can be reduced by manual stimulation (MS) with restoration of whisking function. In addition, we have recently reported that insulin-like growth factor-1 (IGF-1) is required to mediate the beneficial effects of MS. Here we extend our findings to brain derived neurotrophic factor (BDNF). We then examined the effect of MS after facial-facial anastomosis (FFA) in heterozygous mice deficient in BDNF (BDNF+/− ) or in its receptor TrkB (TrkB+/− ). We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive terminal Schwann cells. In intact BDNF+/− or TrkB+/− mice and their wild type (WT) littermates, there were no differences in vibrissal whisking nor in the percentage of bridged NMJ (0% in each genotype). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (27% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (11% more than intact). After FFA and handling in BDNF+/− or TrkB+/− mice, whisking amplitude was again reduced (53% and 60% lower than intact) and proportion of bridged NMJ increased (24% and 29% more than intact). However, MS failed to improve outcome in both heterozygous strains (whisking amplitude 55% and 58% lower than intact; proportion of bridged NMJ 27% and 18% more than intact). We conclude that BDNF and TRkB are required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.
Aims Moderate wine consumption is associated with a significant reduction of cardiovascular mortality. The molecular basis of this phenomenon remains unknown. Platelet-derived growth factor (PDGF) is ...an important contributor to atherogenesis. We investigated the effects of selected red and white wines on PDGF receptor (PDGFR) signalling in rat and human vascular smooth muscle cells (VSMCs). Methods and results All red wines concentration dependently inhibited the ligand-induced tyrosine phosphorylation of the PDGFR, downstream signalling events such as mitogen activated protein (MAP) kinase activation (Erk 1/2) and induction of immediate early genes (Egr-1, c-fos), and PDGF-induced cellular responses, whereas all white wines had no effect. At concentrations achieved after wine consumption in humans, all red wines completely abolished PDGF-dependent VSMC proliferation and migration. Red wines also inhibited PDGFR phosphorylation in vascular tissue, and in human coronary smooth muscle cells. Quantitative analyses of all tested wines and of samples collected at various time points (Days 0–16) of the ‘mash fermentation’, which is only performed for red wine, revealed that flavonoids of the catechin family, which potently inhibit PDGFR signalling, are extracted from grape seeds and skins during this process and therefore accumulate specifically in red wine. The accumulation of flavonoids correlated with the inhibitory potency of red wines on PDGFR signalling. Furthermore, this procedure could be imitated by incubation of wines with shredded grape seeds, and flavonoid-enriched white wine inhibited the PDGFR as potently as red wines. Conclusion Only red wines abrogate a critical pathogenic mechanism during atherogenesis, PDGFR signalling, in VSMCs. This effect is mediated by non-alcoholic constituents, which accumulate during the mash fermentation. Our findings offer a molecular explanation for the vasoprotective effects particularly of red wine. Therefore, future epidemiological studies should consider differential protective effects of red and white wine in vivo.
Activating transcription factor-2 (ATF-2) is a basic region leucine zipper protein whose DNA target sequence is the widely distributed cAMP response element (CRE). We report here that mice carrying a ...germline mutation in ATF-2 demonstrated unique actions of ATF-2 not duplicated by other ATF/CREB family members. Mutant mice had decreased postnatal viability and growth, with a defect in endochondral ossification at epiphyseal plates similar to human hypochondroplasia. The animals had ataxic gait, hyperactivity and decreased hearing. In the brain, there were reduced numbers of cerebellar Purkinje cells, atrophic vestibular sense organs and enlarged ventricles. Unlike CREB alpha/delta-deficient mice whose main defect is in long-term potentiation, the widespread abnormalities in ATF-2 mutant mice demonstrate its absolute requirement for skeletal and central nervous system development, and for maximal induction of select genes with CRE sites, such as E-selectin.
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