Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens.

Multiple sclerosis affects more women than men. The reasons for this are unknown. Previously, we have shown significant differences in women versus men in inflammatory cytokine responses to the major protein component of myelin, proteolipid protein (PLP), which is thought to be a target in MS patients. Here, using the ELISPOT assay, we examined sex differences in single-cell secretion of Th1 and Th2 cytokines from freshly isolated PBMC between relapsing remitting (RR) MS patients and healthy individuals. Cells were stimulated with MS-associated antigens including proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and non-disease related antigens. Our data show a sex bias in the cytokine responses to multiple MS-relevant myelin antigens: Women with MS show IFNgamma-skewed responses and men with MS show IL-5-skewed responses. These data extend our previous findings [Pelfrey, C.M., Cotleur, A.C., Lee, J.C., Rudick, R.A. 2002. Sex differences in cytokine responses to myelin peptides in multiple sclerosis. J. Neuroimmunol. 130, 211-223.]: (1) by demonstrating gender skewing in cytokine responses to an expanded myelin antigen repertoire, which includes MBP, MOG and PLP; (2) by showing TNFalpha and IL-10 do not display comparable gender skewing compared to IFNgamma and IL5; (3) by defining the patient population as early, untreated RRMS patients to avoid confounding factors, such as different disease stages/disability and immunomodulatory therapy; and (4) by showing HLA type does not appear to underlie the gender differences. These findings may explain increased susceptibility to MS in women and could contribute to the differences in disease severity between men and women.

Randomised, double-blind, parallel group, placebo-controlled study to evaluate the analgesic efficacy and safety of VVZ-149 injections for postoperative pain following laparoscopic colorectal surgery.

INTRODUCTION: In spite of advances in understanding and technology, postoperative pain remains poorly treated for a significant number of patients. In colorectal surgery, the need for developing novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids worsen ileus, nausea and constipation. We describe a prospective, double-blind, parallel group, placebo-controlled randomised controlled trial testing the hypothesis that a novel analgesic drug, VVZ -149, is safe and effective in improving pain compared with providing opioid analgesia alone among adults undergoing laparoscopic colorectal surgery. METHODS AND ANALYSIS: Based on sample size calculations for primary outcome, we plan to enrol 120 participants. Adult patients without significant medical comorbidities or ongoing opioid use and who are undergoing laparoscopic colorectal surgery will be enrolled. Participants are randomly assigned to receive either VVZ-149 with intravenous (IV) hydromorphone patient-controlled analgesia (PCA) or the control intervention (IV PCA alone) in the postoperative period. The primary outcome is the Sum of Pain Intensity Difference over 8 hours (SPID-8 postdose). Participants receive VVZ-149 for 8 hours postoperatively to the primary study end point, after which they continue to be assessed for up to 24 hours. We measure opioid consumption, record pain intensity and pain relief, and evaluate the number of rescue doses and requests for opioid. To assess safety, we record sedation, nausea and vomiting, respiratory depression, laboratory tests and ECG readings after study drug administration. We evaluate for possible confounders of analgesic response, such as anxiety, depression and catastrophising behaviours. The study will also collect blood sample data and evaluate for pharmacokinetic and pharmacodynamic relationships. ETHICS AND DISSEMINATION: Ethical approval of the study protocol has been obtained from Institutional Review Boards at the participating institutions. Trial results will be disseminated through scientific conference presentations and by publication in scientific journals. TRIAL REGISTRATION NUMBER: NCT02489526; pre-results.

Immunological studies of mitoxantrone in primary progressive MS.

Mitoxantrone (MX) has demonstrated efficacy in multiple sclerosis (MS), but its immunologic mechanisms of action are poorly understood. Furthermore, no study has examined the immunological effects of MX in primary progressive MS (PPMS). This study investigated the immunological effects of MX therapy in PPMS patients. Lymphocyte phenotypes and chemokine receptor (CCR) expression were evaluated by flow cytometry on fresh PBMC from 20 PPMS patients enrolled in a placebo (PLC)-controlled trial of MX. Longitudinal data were collected at weeks 0, 12, 24, 36 and short-term data (pre-/post-infusion) were collected at weeks 0 and 36. CXCR3, CCR1, CCR2 and CCR5 on CD4 and CD8 T cells and CD14 monocytes were evaluated. MX therapy induced a significant increase in the proportion of CD8 T cells (CD45RO(-)) over 9 months. Expression of several CCR increased following MX treatment. Two of the eight MX-treated patients demonstrated dramatic upregulation (70-76%) of CCR2 on monocytes. These two patients were the only MX-treated patients to demonstrate active inflammation by magnetic resonance imaging (MRI). PLC patients did not show significant changes in CCR expression. MX therapy was not associated with selective loss of CD4, CD8 or CD14 cells 1 month after treatment or over 9 months. These results suggest that MX therapy leads to a longitudinal increase in CD8 T cells and may increase CCR in patients with inflammation on MRI. Overall, MX did not show extensive immune changes in PPMS, although patients with active disease (gadolinium enhancing lesions) may identify a subset of PPMS subjects who respond immunologically to MX therapy. An improved understanding of MX may help identify markers of disease activity and response to therapy.

Effects of sex hormones on costimulatory molecule expression in multiple sclerosis.

Sex hormones play a central role as modulators of immune responses and autoimmune diseases. We hypothesized that suppression of MS disease during pregnancy may be mediated by sex steroid hormones via regulation of costimulatory molecules such as CD40L or CD80/CD86 (B7-1/B7-2). We tested two sex hormones that are implicated in immune suppression during pregnancy: estriol and progesterone. We also examined whether this regulation is gender-specific or disease-related. PBMC from untreated relapsing remitting multiple sclerosis (RR MS) patients and controls were examined for expression of T cell and monocyte costimulatory molecules following mitogen stimulation in the presence or absence of sex hormones. In the absence of hormones, we confirmed that mitogen stimulation induced significantly more CD40L on the surface of CD4(+)T cells in MS patients compared to controls, and we extend these findings by showing there were no gender differences in induction of CD40L. Although supra-physiologic doses of hormones mildly suppressed CD40L expression on activated T cells, in vitro exposure to typical pregnancy-related physiologic doses of estriol or progesterone showed very little or no suppression of CD40L. On monocytes, neither estriol nor progesterone significantly altered the expression of CD80/CD86. These results suggest that physiologic doses of estriol or progesterone cannot alter CD40L on T cells or CD80/CD86 on monocytes sufficiently to explain the improvement observed in MS during pregnancy. Thus, although amelioration of MS and other autoimmune diseases during pregnancy is thought to be due to increased sex hormones, the present results do not support a role for suppression of costimulation via estriol or progesterone.

Endocarditic sinus of valsalva fistulae to right ventricular outflow tract in adult ventricular septal defects.

Surgical repair of congenital ventricular septal defects (VSDs) in adults is quite rare. Most congenital VSDs are repaired in children. Of those adult patients diagnosed as having VSDs, many are not repaired due to irreversible pulmonary vascular disease. Repair in a patient with a VSD and fistula is even more uncommon. From a review of the literature, we found no other case reports with our unique combination of echocardiographic and surgical findings: a supracristal VSD, right and left sinus of Valsalva fistulas into the right ventricular outflow tract, and a pulmonary artery to pulmonary vein fistula in the context of an aseptic endocarditis lesion. We review the important aspects of anesthetic management in an adult with an intracardiac shunt. An adult patient with unrepaired congenital VSD may develop multiple fistulas as a consequence of endocarditis. This patient refused surgery until the progressive dyspnea was worsened by the endocarditis and the fistulas. At the time of surgery, his ventricular ejection fraction measured 47%, the ventricular chambers were enlarged, and the pulmonary to systemic flow ratio measured 2:1. He did well clinically after the VSD and fistulae repair.