Effect of Protease Inhibitors in Healing of the Vaginal Wall.

Impaired elastogenesis and increased degradation of elastic fibers has been implicated in the pathogenesis of pelvic organ prolapse. Loss of the elastogenic organizer, fibulin-5 (FBLN5), leads to pelvic organ prolapse in mice. The objective of this study was to investigate the regulation of FBLN5 after surgical injury of the vaginal wall using the rat as a preclinical animal model. Both endogenous and recombinant FBLN5 were degraded after surgical injury. Estrogen did not alter the dramatic loss of vaginal FBLN5 in the acute phase after injury (12-48 h), but resulted in rescue of the poor recovery of FBLN5 levels in the late phase (7 d) of healing in ovariectomized animals. In contrast with estrogen, the general MMP inhibitor, actinonin, abrogated injury-induced degradation of FBLN5 significantly. Further, actinonin rescued the negative effects of injury on biomechanics, histomorphology, and elastic fibers. Control of excessive matrix degradation by local application of actinonin at the time of surgery may lead to improved elastic fiber regeneration and wound healing, thereby potentially enhancing pelvic floor recovery after reconstructive surgery for prolapse.

Safety of Manual Morcellation After Vaginal or Laparoscopic-assisted Vaginal Hysterectomy.

UNLABELLED: STUDY OBJECTIVE: To determine the safety of manual vaginal morcellation by evaluating the rates of incidental uterine malignancy and manual vaginal morcellation after vaginal or laparoscopic-assisted vaginal hysterectomy. DESIGN: Retrospective analysis (Canadian Task Force classification II-2). SETTING: University of Texas Southwestern Medical Center, Dallas, TX. PATIENTS: Women (n = 1,629) undergoing vaginal or laparoscopic-assisted vaginal hysterectomy. INTERVENTIONS: Vaginal hysterectomy (n = 1,091) or laparoscopic-assisted vaginal hysterectomy (n = 538) with and without scalpel morcellation. MEASUREMENTS AND MAIN RESULTS: The number of uterine malignancies, rate of vaginal morcellation, surgical indications, pathology diagnoses, and uterine weights were evaluated. Chi-square analysis was used to compare categoric data, and analysis of variance was used to compare uterine weights. There were no cases of leiomyosarcomas. There were 2 other sarcomas, 4 smooth muscle tumors of uncertain malignant potential, and 8 endometrial adenocarcinomas. The vaginal morcellation rate was 19.4%, but no malignancy was morcellated. Myomas were more common preoperatively and histologically in morcellated specimens. Mean (± standard deviation) uterine weights for morcellated versus nonmorcellated laparoscopic-assisted vaginal hysterectomy specimens were 285.5 ± 159.3 versus 140.1 ± 83.6 g (p < .001), respectively, and 199.9 ± 92.8 versus 111.9 ± 61.4 (p < .001), respectively, for vaginal hysterectomy. CONCLUSION: Vaginal manual morcellation is safe with a low risk of incidental malignancy. Variables that influence the decision for the vaginal approach may also affect malignancy risk and morcellation decisions. Thus, all patients undergoing vaginal or laparoscopic-assisted vaginal hysterectomy should be counseled regarding incidental malignancy, risk of morcellation, and alternatives for intact specimen removal.

Deletion of macrophage Vitamin D receptor promotes insulin resistance and monocyte cholesterol transport to accelerate atherosclerosis in mice.

Intense effort has been devoted to understanding predisposition to chronic systemic inflammation because it contributes to cardiometabolic disease. We demonstrate that deletion of the macrophage vitamin D receptor (VDR) in mice (KODMAC) is sufficient to induce insulin resistance by promoting M2 macrophage accumulation in the liver as well as increasing cytokine secretion and hepatic glucose production. Moreover, VDR deletion increases atherosclerosis by enabling lipid-laden M2 monocytes to adhere, migrate, and carry cholesterol into the atherosclerotic plaque and by increasing macrophage cholesterol uptake and esterification. Increased foam cell formation results from lack of VDR-SERCA2b interaction, causing SERCA dysfunction, activation of ER stress-CaMKII-JNKp-PPARγ signaling, and induction of the scavenger receptors CD36 and SR-A1. Bone marrow transplant of VDR-expressing cells into KODMAC mice improved insulin sensitivity, suppressed atherosclerosis, and decreased foam cell formation. The immunomodulatory effects of vitamin D in macrophages are thus critical in diet-induced insulin resistance and atherosclerosis in mice.

Obstetrics and fecal incontinence.

Anal incontinence (AI) can be a debilitating condition for women following vaginal delivery. Operative vaginal delivery and anal sphincter laceration are important risk factors for the development of postpartum AI. Obtaining a comprehensive delivery history, along with a thorough physical examination of the perineum, vagina and rectum may aid the clinician in the diagnosis of an anal sphincter defect. Sonographic imaging can also assist in identifying sphincter defects. The treatment of AI may include a combination of dietary modification, medications that promote constipation, pelvic floor physical therapy, biofeedback, anal sphincteroplasty, and/or sacral neuromodulation.

Cystolith formation complicating single-incision sling.

Single-incision slings are the newest midurethral slings developed for the surgical treatment of stress urinary incontinence. We report the case of a patient who underwent single-incision sling placement who presented with recurrent stress incontinence 3 years after the procedure. She was found to have a 1.7-cm bladder stone that formed around the single-incision sling polypropylene barb.

Vitamin D deficiency induces high blood pressure and accelerates atherosclerosis in mice.

Multiple epidemiological studies link vitamin D deficiency to increased cardiovascular disease (CVD), but causality and possible mechanisms underlying these associations are not established. To clarify the role of vitamin D-deficiency in CVD in vivo, we generated mouse models of diet-induced vitamin D deficiency in two backgrounds (LDL receptor- and ApoE-null mice) that resemble humans with diet-induced hypertension and atherosclerosis. Mice were fed vitamin D-deficient or -sufficient chow for 6 weeks and then switched to high fat (HF) vitamin D-deficient or -sufficient diet for 8-10 weeks. Mice with diet-induced vitamin D deficiency showed increased systolic and diastolic blood pressure, high plasma renin, and decreased urinary sodium excretion. Hypertension was reversed and renin was suppressed by returning chow-fed vitamin D-deficient mice to vitamin D-sufficient chow diet for 6 weeks. On a HF diet, vitamin D-deficient mice had ~2-fold greater atherosclerosis in the aortic arch and ~2-8-fold greater atherosclerosis in the thoracic and abdominal aorta compared to vitamin D-sufficient mice. In the aortic root, HF-fed vitamin D-deficient mice had increased macrophage infiltration with increased fat accumulation and endoplasmic reticulum (ER) stress activation, but a lower prevalence of the M1 macrophage phenotype within atherosclerotic plaques. Similarly, peritoneal macrophages from vitamin D-deficient mice displayed an M2-predominant phenotype with increased foam cell formation and ER stress. Treatment of vitamin D-deficient mice with the ER stress reliever PBA during HF feeding suppressed atherosclerosis, decreased peritoneal macrophage foam cell formation, and downregulated ER stress proteins without changing blood pressure. Thus, we suggest that vitamin D deficiency activates both the renin angiotensin system and macrophage ER stress to contribute to the development of hypertension and accelerated atherosclerosis, highlighting vitamin D replacement as a potential therapy to reduce blood pressure and atherosclerosis.