Fine mapping and functional analysis of the multiple sclerosis risk gene CD6.

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2(nd) SRCR domain with susceptibility to MS (P max(T) permutation = 1×10(-4)). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. - CD4(+) naïve cells, P = 0.0001; CD8(+) naïve cells, P<0.0001; CD4(+) and CD8(+) central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells.

Monitoring of sedation during neuroaxial blockade.

Abstract Study objective: The arousal state changes during spinal anesthesia. It is not clear if BIS and others devices could monitor the induced neuroaxial blockade sedation. Our objective was evaluate BIS and entropy values when spinal anesthesia is done. Design: We developed a prospective study. Patients: 40 patients were included in this study, ASA I-III, over 60 years old, undergoing spinal anesthesia, without premedication scheduled for orthopedics procedures. Intervention: Spinal anesthesia was performed with the unseated volunteer in the lateral decubitus position with a 25-gauge Whitacre needle at L2-L3 space, andanesthesia was done with 12 mg of 0.5% hyperbaric bupivacaine. Patients were positioned supine for 5 min after spinal anesthesia. Measurements: Observer’s Assessment of Alertness/Sedation OAA/S, response (RE) and state entropy (SE) and BIS, and standard hemodynamic measures. Main results: Statistical analysis were performed by Wilcoxon test or ANOVA, p<0.05 was considered statistically significant.RE and BIS showed a better correlation with the OAA/S scale values (Pk 0.81 and 0.82) than SE (Pk 0.69). The OAA/S, RE and SE showed significative differences from basal values after 30 min of neuroaxial anesthesia (ANOVA p<0.05). BIS showed differences after 40 min (ANOVA p<0.05). There were no differences between BIS and RE values along the study (ANOVA p>0.05). Conclusions: The spinal anesthesia decreased the cortical activity and these were founded by OAA/S scale and depth anesthetics monitors. OAA/S was a more sensitive value of this induced sedation. BIS and RE showed a better correlation with OAA/S scale than SE.