15-Deoxy-Delta-12,14-prostaglandin J2 modulates pro-labour and pro-inflammatory responses in human myocytes, vaginal and amnion epithelial cells.

Background: Prematurity is the leading cause of childhood death under the age of five. The aetiology of preterm birth is multifactorial; however, inflammation and infection are the most common causal factors, supporting a potential role for immunomodulation as a therapeutic strategy. 15-Deoxy-Delta-12,14-prostaglandin J2 (15dPGJ2) is an anti-inflammatory prostaglandin and has been shown to delay lipopolysaccharide (LPS) induced preterm labour in mice and improve pup survival. This study explores the immunomodulatory effect of 15dPGJ2 on the transcription factors NF-κB and AP-1, pro-inflammatory cytokines, and contraction associated proteins in human cultured myocytes, vaginal epithelial cell line (VECs) and primary amnion epithelial cells (AECs). Methods: Cells were pre-incubated with 32µM of 15dPGJ2 and stimulated with 1ng/mL of IL-1ß as an in vitro model of inflammation. Western immunoblotting was used to detect phosphorylated p-65 and phosphorylated c-Jun as markers of NF-κB and AP-1 activation, respectively. mRNA expression of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α was examined, and protein expression of COX-2 and PGE2 were detected by western immunoblotting and ELISA respectively. Myometrial contractility was examined ex-vivo using a myograph. Results: 15dPGJ2 inhibited IL-1ß-induced activation of NF-κB and AP-1, and expression of IL-6, IL-8, TNF-α, COX-2 and PGE2 in myocytes, with no effect on myometrial contractility or cell viability. Despite inhibiting IL-1ß-induced activation of NF-κB, expression of IL-6, TNF-α, and COX-2, 15dPGJ2 led to activation of AP-1, increased production of PGE2 and increased cell death in VECs and AECs. Conclusion: We conclude that 15dPGJ2 has differential effects on inflammatory modulation depending on cell type and is therefore unlikely to be a useful therapeutic agent for the prevention of preterm birth.

A cost-effectiveness analysis of delayed sphincteroplasty for anal sphincter injury.

OBJECTIVE: Anal-sphincter injury may result in faecal incontinence. Sphincteroplasty is usually performed as a primary (immediate) procedure. Delayed sphincteroplasty (DS) can be performed if there is significant trauma or soiling, if the primary procedure has failed, and if the injury was not recognized initially. This study aimed to determine the cost to patient and health service in the event a DS is performed. METHOD: Patients with anal-sphincter-injury who underwent primary sphincteroplasty (PS)/DS were identified from the published literature (primary, n = 103; delayed, n = 777) using Medline, Embase, Ovid and Cochrane databases for studies published between 1976 and 2006. Studies included described at least one of the measured outcomes--probability of functional success/failure and quality of life (QOL). An economic model was constructed and decision analysis performed using a decision tree based on a Markov process. Main outcomes were quality-adjusted-life-years (QALYs) gained from each strategy, costs incurred and incremental cost-effectiveness ratio (ICER) over a 10- and 15-year time horizon. RESULTS: Over 10 years, primary sphincteroplasty (PS) produced a gain of 5.72 QALYs for an estimated 2750 pounds, giving an ICER of 487 pounds per QALY. DS produced a gain of 3.73 QALYs for a cost of 2667 pounds, giving an ICER of 719 pounds per QALY. Both procedures fell below the 10,000 pounds per QALY willingness-to-pay threshold, but PS produced the highest QALYs. Both procedures performed poorly beyond the 10-year mark. CONCLUSION: If DS has to be performed, the resultant cost is greater with concurrently lower QALYs gained. Successful PS substantially improves QOL and reduces overall cost-of-treatment.

Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy.

Complex regulation of T cell functions during pregnancy is required to ensure materno-fetal tolerance. Here we reveal a novel pathway for the temporary suppression of maternal T cell responses in uncomplicated human pregnancies. Our results show that arginase activity is significantly increased in the peripheral blood of pregnant women and remarkably high arginase activities are expressed in term placentae. High enzymatic activity results in high turnover of its substrate L-arginine and concomitant reduction of this amino acid in the microenvironment. Amino acid deprivation is emerging as a regulatory pathway of lymphocyte responses and we assessed the consequences of this enhanced arginase activity on T cell responses. Arginase-mediated L-arginine depletion induces down-regulation of CD3 zeta, the main signalling chain of the TCR, and functional T cell hyporesponsiveness. Importantly, this arginase-mediated T cell suppression was reversible, as inhibition of arginase activity or addition of exogenous L-arginine restored CD3 zeta chain expression and T cell proliferation. Thus, L-arginine metabolism constitutes a novel physiological mechanism contributing to the temporary suppression of the maternal immune response during human pregnancy.