Functional Inflammatory Genotypes in Ischemic Stroke: Could We Use Them to Predict Age of Onset and Long-Term Outcome?

Functional single-nucleotide polymorphisms (SNPs) of inflammatory cytokines have been previously related to the occurrence of an ischemic stroke (IS). We investigated whether five functional SNPs (i.e., TNF-α-308G>A, IL6-174G>C, IL12B 1188A>C, IL4-589C>T, and IL10-1082G>A) might be associated with the age of onset and 6-month outcome of an acute IS. A probe-free real-time PCR methodology was used to genotype 145 consecutively admitted cases with a first-ever IS. Simple Kaplan-Mayer and adjusted Cox regression analyses showed no association between inflammatory genotypes and the age of IS onset. IL6-174G>C, IL12B 1188A>C, IL4-589C>T, and IL10-1082G>A were not found to significantly contribute to the long-term outcome of the disease. However, carriage of the TNF-α-308 GG genotype was significantly associated with reduced odds for an adverse outcome. Larger studies are needed to confirm our results

Remitting–relapsing multiple sclerosis patient refractory to conventional treatments and bone marrow transplantation who responded to natalizumab

Bone marrow transplantation (BMT) was introduced as a treatment option 15 years ago for severe, drug-resistant multiple sclerosis (MS). Up until now, BMT has been undertaken in relatively few patients worldwide, with moderate success, and recent studies suggest that patients with early, highly aggressive MS benefit most from this treatment. In this work, we determined peripheral blood lymphocyte populations in a patient (patient A) with remitting–relapsing multiple sclerosis (RR-MS), refractory to conventional treatments, and who underwent BMT, relapsed, and has been treated with natalizumab for the last 22 months. Eleven other RR-MS patients in the acute phase of the disease, untreated or treated with interferon-beta, and 20 healthy subjects served as controls. Natalizumab treatment in patient A resulted in lymphocytosis and increased levels of CD20+/CD20+CD5+ B cells and T regulatory cells (Tregs). The patient maintained relatively low levels of T cells, T helper cells, memory T helper cells, and naive cytotoxic T cells, and very low levels of naive T helper cells and natural killer cells throughout. The Tregs of patient A post-treatment with natalizumab responded well in culture to a peptide mapping to a myelin basic protein antigenic epitope (mean 42% increase) compared with Tregs of healthy controls (mean 15% increase) whereas Tregs of the RR-MS controls or patient A prenatalizumab treatment either did not respond or responded adversely to the peptide (mean 3% and 21% decreases, respectively). Since the beginning of natalizumab treatment, patient A has had no relapses, and his Expanded Disability Status Score has improved. From the parameters studied, Treg responsiveness to autoantigens seems to be an important differentiating factor in RR-MS progression

Cytokines as Biomarkers of Treatment Response to IFN in Relapsing-Remitting Multiple Sclerosis

Background. MS patients show a remarkable heterogeneity in their response to disease modifying treatments. Given the need for early treatment initiation and the diversity of available options, a predictive marker that indicates good or poor response to treatment is highly desirable. Objective. To find a biomarker for treatment response to IFN among pro-and anti-inflammatory cytokines. Materials and Methods. IFN-, TNF-, IL-2, IL-4, IL-6, IL-10, IL-17A, and TGF-1 levels were measured in serum and CSF of 43 patients with RR-MS who were followed up for a mean period of 5.3 years. Thirty-five patients received IFN treatment and were divided into good responders (GR, n = 19) and poor responders (PR, n = 16). The remaining 8 patients showed a very favorable outcome and remained untreated (noRx). Results. GR had significantly higher serum baseline levels of IL-17A than PR and significantly higher serum levels of IL-17A, IFN-, TNF-, and IL-2 than noRx. PR had significantly higher IFN-serum levels than noRx. No significant differences were observed in serum levels of IL-6, IL-4, IL-10, and TGF-1 or the levels of all cytokines measured in CSF between the 3 groups of patients. Conclusions. Baseline serum levels of IL-17A can be used as a biomarker of IFN treatment response

Beneficial effect of the oxygen free radical scavenger amifostine (WR-2721) on spinal cord ischemia/reperfusion injury in rabbits

<p>Abstract</p> <p>Background</p> <p>Paraplegia is the most devastating complication of thoracic or thoraco-abdominal aortic surgery. During these operations, an ischemia-reperfusion process is inevitable and the produced radical oxygen species cause severe oxidative stress for the spinal cord. In this study we examined the influence of Amifostine, a triphosphate free oxygen scavenger, on oxidative stress of spinal cord ischemia-reperfusion in rabbits.</p> <p>Methods</p> <p>Eighteen male, New Zealand white rabbits were anesthetized and spinal cord ischemia was induced by temporary occlusion of the descending thoracic aorta by a coronary artery balloon catheter, advanced through the femoral artery. The animals were randomly divided in 3 groups. Group I functioned as control. In group II the descending aorta was occluded for 30 minutes and then reperfused for 75 min. In group III, 500 mg Amifostine was infused into the distal aorta during the second half-time of ischemia period. At the end of reperfusion all animals were sacrificed and spinal cord specimens were examined for superoxide radicals by an ultra sensitive fluorescent assay.</p> <p>Results</p> <p>Superoxide radical levels ranged, in group I between 1.52 and 1.76 (1.64 ± 0.10), in group II between 1.96 and 2.50 (2.10 ± 0.23), and in group III (amifostine) between 1.21 and 1.60 (1.40 ± 0.19) (p = 0.00), showing a decrease of 43% in the Group of Amifostine. A lipid peroxidation marker measurement ranged, in group I between 0.278 and 0.305 (0.296 ± 0.013), in group II between 0.427 and 0.497 (0.463 ± 0.025), and in group III (amifostine) between 0.343 and 0.357 (0.350 ± 0.007) (p < 0.00), showing a decrease of 38% after Amifostine administration.</p> <p>Conclusion</p> <p>By direct and indirect methods of measuring the oxidative stress of spinal cord after ischemia/reperfusion, it is suggested that intra-aortic Amifostine infusion during spinal cord ischemia phase, significantly attenuated the spinal cord oxidative injury in rabbits.</p

Repetitive Transcranial Magnetic Stimulation, Cognition, and Multiple Sclerosis: An Overview

Multiple sclerosis (MS) affects cognition in the majority of patients. A major aspect of the disease is brain volume loss (BVL), present in all phases and types (relapsing and progressive) of the disease and linked to both motor and cognitive disabilities. Due to the lack of effective pharmacological treatments for cognition, cognitive rehabilitation and other nonpharmacological interventions such as repetitive transcranial magnetic stimulation (rTMS) have recently emerged and their potential role in functional connectivity is studied. With recently developed advanced neuroimaging and neurophysiological techniques, changes related to alterations of the brain’s functional connectivity can be detected. In this overview, we focus on the brain’s functional reorganization in MS, theoretical and practical aspects of rTMS utilization in humans, and its potential therapeutic role in treating cognitively impaired MS patients

Alpha2-adrenergic receptors activate cyclic AMP-response element-binding protein through arachidonic acid metabolism and protein kinase A in a subtype-specific manner.

International audienceOn incubation with epinephrine, PC12 cells stably expressing alpha2-adrenergic receptor (alpha2-AR) undergo morphological and biochemical changes characteristic of neuron-like differentiation. The present study shows that alpha2-AR stimulation increases the phosphorylation of the transcription factor cAMP-response element-binding protein (CREB), the activity of a CRE-reporter plasmid and the expression of cyclin D1 with subtype-dependent efficiency (alpha2A approximately alpha2C >> alpha2B). The effects of epinephrine were mimicked by cell exposure to forskolin or to exogenous arachidonic acid (AA) and they were abrogated by prior treatment with the inhibitor of phospholipase C (PLC) (U73122) or the inhibitor of cytochrome P450-dependent epoxygenase, ketoconazole. On the other hand, treatment of the cells with epinephrine caused activation of protein kinase A (PKA), which was fully abolished by ketoconazole. Inhibition of PKA activity with H89 or ketoconazole abolished the effects of epinephrine on CREB, suggesting that activation of the cAMP/PKA pathway by AA epoxy-derivatives is responsible for CREB activation by alpha2-ARs. The effects of epinephrine were unaffected by LY294002. Furthermore, treatment with staurosporine, tyrphostin AG1478, PP1 or PD98059 did not change the extent of CREB phosphorylation but enhanced its transcriptional activity. Altogether, our results demonstrate that, in PC12 cells, the alpha2-AR subtypes cause phosphorylation and activation of CREB through a pathway involving stimulation of PLC, AA release, generation of epoxygenase derivative and increase of PKA activity. They also suggest attenuation of CREB transcriptional activity by mitogen-activated protein kinase, protein kinase C and Src kinases