Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

B beta(15-42) (FX06) reduces pulmonary, myocardial, liver, and small intestine damage in a pig model of hemorrhagic shock and reperfusion

Objective:  The fibrin-derived peptide B beta(15-42) (also called FX06) has been shown to reduce myocardial infarct size following ischemia/reperfusion. Hemorrhagic shock (HS) followed by volume resuscitation represents a similar scenario, whereby a whole organism is vulnerable to reperfusion injury. Design: We subjected male farm-bred landrace pigs (similar to 30 kg) to HS by withdrawing blood to a mean arterial pressure of 40 mm Hg for 60 minutes. Pigs were then resuscitated with shed blood and crystalloids for 60 minutes, and at this time, FX06 (2.4 mg/kg, n = 8) or vehicle control (phosphate buffered saline; 2.4 mg/kg, n = 7) was injected as an intravenous bolus. Setting:  University hospital laboratory. Subjects:  Anesthetized male farm-bred landrace pigs. Measurements and Main Results:  Data are presented as mean +/- So. Five hours after resuscitation, controls presented acute lung injury (Pao(2)/Fio(2)-ratio *400 mm Hg; extra-vascular lung water index: *5.2 +/- 2.1 mL/kg, cardiac index: *6.3 +/- 1.4 L/min/m(2); stroke volume index: *51 +/- 11 mL/m(2); cardiac TnT levels: *0.11 +/- 0.09 ng/mL; *p <0.05). Also, tissue oxygenation (tp0(2); mm Hg) was significantly improved during reperfusion in FX06-treated pigs when compared with controls (liver 51 +/- 4 vs. *65 +/- 4; serosa 44 +/- 5 vs. *55 +/- 7; mucosa 14 +/- 4 vs. *26 4). Finally, FX06 reduced accumulation of mye loperoxidase- positive cells (mainly neutrophils) in myocardium, liver, and small intestine and reduced interleukin-6 plasma levels (*p <0.05; compared with controls). Conclusion:  We conclude that in a pig model of HS and reperfusion, administration of FX06 during reperfusion protects shock-susceptible organs such as heart, lung, liver, and small intestine. (Crit Care Med 2009; 37:598-605

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Summary: Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with high mortality and poor neurological outcome. We compared the effects of pravastatin and simvastatin on survival and neurofunction in a murine model of CA/CPR. Pravastatin, a hydrophilic statin, increased survival and neurofunction during a 28-day follow-up period. This therapy was associated with improved pulmonary function, reduced pulmonary edema, and increased endothelial cell function in vitro. In contrast, lipophilic simvastatin did not modulate survival but increased pulmonary edema and impaired endothelial cell function. Although pravastatin may display a therapeutic option for post-CA syndrome, the application of simvastatin may require re-evaluation. Key Words: cardiac arrest, endothelial cell function, ischemia and reperfusion injury, pravastatin, resuscitation, simvastati

Impact of Toll-Like Receptor 2 Deficiency on Survival and Neurological Function after Cardiac Arrest: A Murine Model of Cardiopulmonary Resuscitation

<div><p>Background</p><p>Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with poor survival rate and neurofunctional outcome. Toll-like receptor 2 (TLR2) plays an important role in conditions of sterile inflammation such as reperfusion injury. Recent data demonstrated beneficial effects of the administration of TLR2-blocking antibodies in ischemia/reperfusion injury. In this study we investigated the role of TLR2 for survival and neurofunctional outcome after CA/CPR in mice.</p> <p>Methods</p><p>Female TLR2-deficient (TLR2^-/-) and wild type (WT) mice were subjected to CA for eight min induced by intravenous injection of potassium chloride and CPR by external chest compression. Upon the beginning of CPR, n = 15 WT mice received 5 µg/g T2.5 TLR2 inhibiting antibody intravenously while n = 30 TLR2^-/- and n = 31 WT controls were subjected to injection of normal saline. Survival and neurological outcome were evaluated during a 28-day follow up period. Basic neurological function, balance, coordination and overall motor function as well as spatial learning and memory were investigated, respectively. In a separate set of experiments, six mice per group were analysed for cytokine and corticosterone serum levels eight hours after CA/CPR.</p> <p>Results</p><p>TLR2 deficiency and treatment with a TLR2 blocking antibody were associated with increased survival (77% and 80% vs. 51% of WT control; both <i>P < 0.05</i>). Neurofunctional performance was less compromised in TLR2^-/- and antibody treated mice. Compared to WT and antibody treated mice, TLR2^-/- mice exhibited reduced IL-6 (both <i>P < 0.05</i>) but not IL-1β levels and increased corticosterone plasma concentrations (both <i>P < 0.05</i>).</p> <p>Conclusion</p><p>Deficiency or functional blockade of TLR2 is associated with increased survival and improved neurofunctional outcome in a mouse model of CA/CPR. Thus, TLR2 inhibition could provide a novel therapeutic approach for reducing mortality and morbidity after cardiac arrest and cardiopulmonary resuscitation.</p> </div

Survival after successful resuscitation in an observation period of 28 days.

<p>Survival of mice following eight min of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) within the 28-day observation period. Black line (1): wildtype (WT) controls (n = 31), gray line (2): TLR2-deficient (TLR2^-/-, n = 30), dotted line (3): antibody (T2.5)-treated WT mice (n = 15). Data was analysed by Kaplan-Meier log-rank survival analysis and pairwise multiple comparison procedures (Holm-Sidak method). *<i>P < 0.05</i> WT vs. TLR2^-/-; #<i>P < 0.05</i> WT vs. WT+T2.5.</p