Inflammation, lipid dysregulation, and transient receptor potential cation channel subfamily V member 4 signaling perpetuate chronic vulvar pain.

ABSTRACT: Localized provoked vulvodynia is characterized by chronic vulvar pain that disrupts every aspect of the patient's life. Pain is localized to the vulvar vestibule, a specialized ring of tissue immediately surrounding the vaginal opening involved in immune defense. In this article, we show inflammation is the critical first step necessary for the generation of pain signals in the vulva. Inflammatory stimuli alone or combined with the transient receptor potential cation channel subfamily V member 4 (TRPV4) agonist 4α-phorbol 12,13-didecanoate stimulate calcium flux into vulvar fibroblast cells. Activity is blocked by the TRPV4 antagonist HC067047, denoting specificity to TRPV4. Using lipidomics, we found pro-resolving lipids in the vulvar vestibule were dysregulated, characterized by a reduction in pro-resolving mediators and heightened production of inflammatory mediators. We demonstrate specialized pro-resolving mediators represent a potential new therapy for vulvar pain, acting on 2 key parts of the disease mechanism by limiting inflammation and acutely inhibiting TRPV4 signaling.

Human papillomavirus anogenital screening in solid organ transplant recipients: a narrative review.

PURPOSE: To provide a narrative review of anogenital screening for human papillomavirus in solid organ transplant recipients. METHODS: Keyword searches of PubMed and Ovid MEDLINE databases were performed. Keywords included human papillomavirus, malignancy, cervical cancer, Pap smear, solid organ transplant, and immunosuppression. Manual searches were also conducted of other relevant journals and reference lists of primary articles. RESULTS: Forty-one studies, articles, or clinical practice guidelines across 25 years of literature were included. Eligible literature was written in English or offered an English translation. CONCLUSION: Human papillomavirus-related anogenital malignancies disproportionately affect transplant recipients compared to the general population. Evidence-based guidelines for cervical cancer screening and prevention in transplant patients are lacking. Current practice guidelines generally agree on increased Pap screening for transplant recipients compared to the general population. However, recommended screening frequency differs between organizations and amongst medical specialties. Vaccination against HPV remains the most effective strategy to prevent HPV-driven pre-malignant and malignant lesions.

Specialized Pro-resolving Mediators Reduce Pro-nociceptive Inflammatory Mediator Production in Models of Localized Provoked Vulvodynia.

Localized provoked vulvodynia (LPV) is the most common cause of chronic dyspareunia in premenopausal women, characterized by pain with light touch to the vulvar vestibule surrounding the vaginal opening. The devastating impact of LPV includes sexual dysfunction, infertility, depression, and even suicide. Yet, its etiology is unclear. No effective medical therapy exists; surgical removal of the painful vestibule is the last resort. In LPV, the vestibule expresses a unique inflammatory profile with elevated levels of pro-nociceptive proinflammatory mediators prostaglandin E2 (PGE2) and interleukin-6 (IL-6), which are linked to lower mechanical sensitivity thresholds. Specialized pro-resolving mediators (SPMs), lipids produced endogenously within the body, hold promise as an LPV treatment by resolving inflammation without impairing host defense. Ten of 13 commercially available SPMs reduced IL-6 and PGE2 production by vulvar fibroblasts, administered either before or after inflammatory stimulation. Using a murine vulvar pain model, coupling proinflammatory mediator quantification with mechanical sensitivity threshold determination, topical treatment with the SPM, maresin 1, decreased sensitivity and suppressed PGE2 levels. Docosahexaenoic acid, a precursor of maresin 1, was also effective in reducing PGE2 in vulvar fibroblasts and rapidly restored mouse sensitivity thresholds. Overall, SPMs and their precursors may be a safe and efficacious for LPV. Perspective: Vulvodynia, like many pain conditions, is difficult to treat because disease origins are incompletely understood. Here, we applied our knowledge of more recently discovered vulvodynia disease mechanisms to screen novel therapeutics. We identified several specialized pro-resolving mediators as likely potent and safe for treating LPV with potential for broader application.

Risk factors for wound complications in morbidly obese women undergoing primary cesarean delivery.

OBJECTIVE: To determine factors influencing separation and infectious type wound complications (WCs) in morbidly obese women undergoing primary cesarean delivery (CD). METHODS: Retrospective cohort study evaluating infectious and separation WC in morbidly obese (body mass index [BMI] > 35 kg/m(2)) women undergoing primary CD between January 1994 and December 2008. Chi-square, Fisher's exact and Student's t tests used to assess associated factors; backward logistic regression to determine unadjusted and adjusted odds ratios. RESULTS: Of 623 women, low transverse skin incisions were performed in 588 (94.4%), vertical in 35 (7%). Overall WC rate was 13.5%, which varied by incision type (vertical 45.7% vs. 11.6% transverse; p < 0.01), but not BMI class. Incision type and unscheduled CD were associated with infection risk, while incision type, BMI, race and drain use were associated with wound separation. CONCLUSION: In morbidly obese women both infectious and separation type WC are more common in vertical than low transverse incisions; therefore transverse should be preferred.

M2 mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors.

AIMS: Previous studies have shown increased density of M2 receptors in hypertrophied rat bladders that possess an M2 contractile phenotype. The aim of the current study is to determine whether human bladders with an M2 contractile phenotype also have a greater density of bladder M2 receptors. MATERIALS AND METHODS: Human bladders were obtained from 24 different organ transplant donors. Darifenacin and methoctramine affinity was determined by the rightward shift of cumulative carbachol concentration contractile response curves for each bladder. Radioligand binding and immunoprecipitation was used to quantify M2 and M3 subtypes in isolated detrusor muscle and urothelium. In addition, pig bladder muscle and urothelial receptors were quantified for comparison. RESULTS: In the human urothelium total, M2 and M3 muscarinic receptor density is significantly negatively correlated with the affinity of darifenacin for inhibition of contraction of the detrusor muscle. In the detrusor muscle there is no correlation between receptor density and darifenacin affinity for inhibition of contraction. Muscarinic receptor density is greater in the muscle than in the urothelium in human bladders whereas in the pig bladder the density is greater in the urothelium than in the muscle. CONCLUSIONS: The greater density of urothelial muscarinic receptors in human bladders with lower darifenacin affinity, indicative of a greater contribution of M2 receptors to the contractile response, points towards a possible role of the urothelium in controlling M2 mediated contractile phenotype. In comparison between human and pig bladders, the distribution of muscarinic receptor subtypes in the muscle and urothelium are quite different.