One-year follow-up after standardized perineal reconstruction in women with deficient perineum after vaginal delivery.

INTRODUCTION: Perineal tears are common after childbirth and, if not surgically repaired, they may result in a deficient perineum that can cause symptoms of pelvic floor dysfunction. Perineal reconstruction aims to restore the perineal body and increase the support of the pelvic floor. The objective of the present study was to estimate symptom reduction after perineal reconstruction in patients with deficient perineum after vaginal delivery and to compare outcomes between participants with or without concomitant levator ani muscle deficiency. MATERIAL AND METHODS: Participants presenting at the Karolinska Pelvic Floor Center with symptoms of deficient perineum at least 1 year after vaginal birth were invited to the study. Inclusion criteria were a visible perineal scar and confirmed anatomic defect. Levator ani defects were assessed using the Levator Ani Deficiency score. A perineal reconstruction was performed in a standardized way. Subjective symptoms were evaluated using the validated "Karolinska Symptoms After Perineal Tear Inventory" at baseline and 1-year follow-up. A score difference in the symptom of an acquired sensation of a wide vagina was the primary outcome. Results were stratified by the presence or absence of a levator ani deficiency. RESULTS: A perineal reconstruction was performed in 131 patients and 128 patients completed the Karolinska Symptoms After Perineal Tear Inventory at baseline and 119 at follow-up. Median age was 36.1 (interquartile range [IQR] 7.9), median body mass index 22.3 (IQR 5.1) and a median of two vaginal deliveries. Fifty-four women (41.2%) had a levator ani deficiency. The mean score reduction for the item "Do you feel that your vagina is too wide/loose?" was -1.56 (SD 0.96; P < 0.001) from a mean score of 2.75 (maximum 3) at baseline. The mean total score reduction was -9.1 points (SD 5.3; P < 0.001) from a mean score of 18.4 (maximum 33) points at baseline. There were no significant differences between groups when stratifying by levator ani deficiency. CONCLUSIONS: Our results show that perineal reconstructive surgery significantly decreases symptoms of deficient perineum after vaginal delivery. A concomitant levator ani defect does not affect the symptom reduction of an acquired sensation of a wide vagina or the total score reduction after surgery.

Identification of amino acid residues of nerve growth factor important for neurite outgrowth in human dorsal root ganglion neurons.

Nerve growth factor (NGF) is an essential neurotrophic factor for the development and maintenance of the central and the peripheral nervous system. NGF deficiency in the basal forebrain precedes degeneration of basal forebrain cholinergic neurons in Alzheimer's disease, contributing to memory decline. NGF mediates neurotrophic support via its high-affinity receptor, the tropomyosin-related kinase A (TrkA) receptor, and mediates mitogenic and differentiation signals via the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). However, the molecular mechanisms underlying the different NGF/TrkA/ERK signalling pathways are far from clear. In this study, we have investigated the role of human NGF and three NGF mutants, R100E, W99A and K95A/Q96A, their ability to activate TrkA or ERK1/2, and their ability to induce proliferation or differentiation in human foetal dorsal root ganglion (DRG) neurons or in PC12 cells. We show that the R100E mutant was significantly more potent than NGF itself to induce proliferation and differentiation, and significantly more potent in activation of ERK1/2 in DRG neurons. The W99A and K95A/Q96A mutants, on the other hand, were less effective than the wild-type protein. An unexpected finding was the high efficacy of the K95A/Q96A mutant to activate TrkA and to induce differentiation of DRG neurons at elevated concentrations. These data demonstrate an NGF mutant with improved neurotrophic properties in primary human neuronal cells. The R100E mutant represents an interesting candidate for further drug development in Alzheimer's disease and other neurodegenerative disorders.

Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid.

Amniotic fluid (AF) surrounds the growing fetus, and cells derived from AF are commonly used for diagnosis of genetic diseases. Intra-amniotic infections are strongly linked to preterm birth, which is the leading cause of perinatal mortality worldwide. Surprisingly little is known, however, about mature hematopoietic cells in AF, which could potentially be involved in immune responses during pregnancy. In this study, we show that the dominating population of viable CD45+ cells in AF is represented by a subset of fetal CD103+ group 3 innate lymphoid cells (ILCs) producing high levels of IL-17 and TNF. Fetal CD103+ ILC3s could also be detected at high frequency in second-trimester mucosal tissues (e.g., the intestine and lung). Taken together, our data indicate that CD103+ ILC3s accumulate with gestation in the fetal intestine and subsequently egress to the AF. The dominance of ILC3s producing IL-17 and TNF in AF suggests that they could be involved in controlling intra-amniotic infections and inflammation and as such could be important players in regulating subsequent premature birth.

Ascl1 Is Required for the Development of Specific Neuronal Subtypes in the Enteric Nervous System.

The enteric nervous system (ENS) is organized into neural circuits within the gastrointestinal wall where it controls the peristaltic movements, secretion, and blood flow. Although proper gut function relies on the complex neuronal composition of the ENS, little is known about the transcriptional networks that regulate the diversification into different classes of enteric neurons and glia during development. Here we redefine the role of Ascl1 (Mash1), one of the few regulatory transcription factors described during ENS development. We show that enteric glia and all enteric neuronal subtypes appear to be derived from Ascl1-expressing progenitor cells. In the gut of Ascl1(-/-) mutant mice, neurogenesis is delayed and reduced, and posterior gliogenesis impaired. The ratio of neurons expressing Calbindin, TH, and VIP is selectively decreased while, for instance, 5-HT(+) neurons, which previously were believed to be Ascl1-dependent, are formed in normal numbers. Essentially the same differentiation defects are observed in Ascl1(KINgn2) transgenic mutants, where the proneural activity of Ngn2 replaces Ascl1, demonstrating that Ascl1 is required for the acquisition of specific enteric neuronal subtype features independent of its role in neurogenesis. In this study, we provide novel insights into the expression and function of Ascl1 in the differentiation process of specific neuronal subtypes during ENS development. SIGNIFICANCE STATEMENT: The molecular mechanisms underlying the generation of different neuronal subtypes during development of the enteric nervous system are poorly understood despite its pivotal function in gut motility and involvement in gastrointestinal pathology. This report identifies novel roles for the transcription factor Ascl1 in enteric gliogenesis and neurogenesis. Moreover, independent of its proneurogenic activity, Ascl1 is required for the normal expression of specific enteric neuronal subtype characteristics. Distinct enteric neuronal subtypes are formed in a temporally defined order, and we observe that the early-born 5-HT(+) neurons are generated in Ascl1(-/-) mutants, despite the delayed neurogenesis. Enteric nervous system progenitor cells may therefore possess strong intrinsic control over their specification at the initial waves of neurogenesis.

Clinical efficacy of a trocar-guided mesh kit for repairing lateral defects.

INTRODUCTION AND HYPOTHESIS: The optimal surgery for lateral defects is not well defined. Our objective was to assess the effects of anterior trocar-guided transvaginal mesh repair versus anterior colporrhaphy in women with lateral defects. METHODS: This subanalysis from a randomized controlled trial of mesh kit versus anterior colporrhaphy assessed 99 patient diagnosed at baseline with lateral defects in the anterior vaginal wall. Thirty-nine patients underwent anterior colporrhaphy and 60 anterior trocar-guided transvaginal mesh surgery. RESULTS: One year after surgery, a persistent lateral defect was significantly more common after colporrhaphy compared with transvaginal mesh [11/32 (34.4 %) vs 1/42 (2.4 %), risk ratio (RR) 14.4, 95 % confidence interval (CI) 2.0-106.1; P < 0.001)] However, there were no significant differences between treatment groups with regard to subjective symptoms as reflected by the overall Urogenital Distress Inventory scores, with mean difference from baseline 37.3 ± 50.6 in the colporrhaphy group vs 39.0 ± 45.8 in the mesh group (p = 0.61). CONCLUSIONS: Use of a transvaginal mesh kit increases the odds for anatomical correction of lateral defects compared with anterior colporrhaphy but does not necessarily improve lower urinary tract symptoms.

Effects of anterior trocar guided transvaginal mesh surgery on lower urinary tract symptoms.

AIMS: To assess the effects of trocar guided transvaginal mesh on lower urinary tract symptoms after anterior vaginal wall prolapse repair. METHODS: One hundred twenty-one patients undergoing anterior transvaginal mesh surgery was prospectively evaluated at baseline and 1 year after surgery using the urogenital distress inventory (UDI). RESULTS: Overall UDI scores declined from 91 before surgery to 31 one year after surgery (P < 0.001). UDI subscales for obstructive and irritative symptoms improved 1 year after surgery (P < 0.001 for both) while stress symptoms did not (P = 0.11). CONCLUSION: Trocar guided transvaginal mesh surgery for anterior vaginal wall prolapse was associated with an overall resolution of most symptoms associated with overactive bladder syndrome and bladder outlet obstruction. These beneficial effects should be weighed against an increased risk for stress urinary incontinence related to the procedure.

Urodynamic assessment of anterior vaginal wall surgery: a randomized comparison between colporraphy and transvaginal mesh.

AIMS: To investigate the urodynamic effects of anterior vaginal wall prolapse surgery using either trocar guided transvaginal mesh or colporraphy. METHODS: A prospective, randomized multicenter trial enrolling 50 patients: 27 underwent anterior colporrhaphy and 23 anterior trocar guided transvaginal mesh. Urodynamic assessment was performed pre- and two months postoperatively. RESULTS: De novo stress urinary incontinence was significantly more common after trocar guided transvaginal mesh surgery compared to colporraphy. In comparison to baseline urodynamics, transvaginal mesh surgery resulted in a significant decrease in maximal urethral closing pressures (MUCP) whereas conventional anterior colporraphy had no significant effect on urodynamic parameters. CONCLUSION: Trocar guided transvaginal mesh of anterior vaginal wall prolapse results in a lowering of MUCPs and increases the risk for de novo stress urinary incontinence compared to colporraphy.

Nonobstetric risk factors for symptomatic pelvic organ prolapse.

OBJECTIVE: To identify possible nonobstetric risk factors for symptomatic pelvic organ prolapse in the general female population. METHODS: This was a population-based, cross-sectional study derived from a sample of 5,489 Stockholm women, 30 to 79 years old, who answered a validated questionnaire for the identification of symptomatic prolapse. The 454 women whose answers indicated the presence of such prolapse and the 405 randomly selected control participants with answers that gave no indication of prolapse received a 72-item questionnaire, which probed into a priori suspected risk factors. Only those women with intact uteri and no prior surgery for incontinence or prolapse were included. Multivariable logistic regression models estimated prevalence odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In addition to age and parity, overweight (prevalence OR for body mass index [kg/m] 26-30 compared with 19-25 was 1.9, 95% CI 1.2-3.1), history of conditions suggestive of deficient connective tissue (varicose veins/hernia/hemorrhoids, prevalence OR for positive history compared with no history 1.8, 95% CI 1.2-2.8), family history of prolapse (prevalence OR for positive history compared with no history 3.3, 95% CI 1.7-6.4), heavy lifting at work (prevalence OR for 10 kg or more compared with no heavy lifting 2.0, 95% CI 1.1-3.6), and presence of constipation, hard stools, or difficult evacuation (prevalence OR relative to normal bowel habits 2.1, 95% CI 1.4-3.3) all were linked independently, significantly, and positively to the presence of symptomatic prolapse. CONCLUSION: In this nonconsulting population, age and parity were the dominating risk factors, but significant independent associations with markers suggestive of congenital susceptibility (family history and conditions signaling weak connective tissue) and nonobstetric strain on the pelvic floor (overweight/obesity, heavy lifting, and constipation) imply that individual predisposition and lifestyle/environment also may play an important role. The causal direction of the association with bowel habits remains uncertain, and the link to family history could be partly because of information bias.

Sexual dysfunction after trocar-guided transvaginal mesh repair of pelvic organ prolapse.

OBJECTIVE: To estimate sexual dysfunction before and after trocar-guided transvaginal mesh surgery for pelvic organ prolapse. METHODS: Sexually active women participating in a prospective multicenter study were recruited at 26 centers. All participants underwent a standardized surgical procedure and were evaluated before (n=105) and 1 year after (n=84) surgery using the short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). Nonparametric statistics were used for comparisons. RESULTS: Mean age at surgery was 61.5 years (standard deviation [SD] 7.6), median parity was 2 (range, 1-6), and mean body mass index was 26.8 (SD 4.3) (body mass index is calculated as weight (kg)/[height m]). Anterior transvaginal mesh repair was performed in 46 patients (44%), posterior in 26 patients (25%), and combined anterior and posterior in 33 patients (31%). Overall sexual function scores worsened from 15.5 (SD 8.0) at baseline to 11.7 (SD 6.9) 1 year after surgery (P<.001). The trend toward deteriorating sexual function scores was similar for all three surgical procedures. There was an overall worsening of all symptoms in the behavioral-emotive and partner-related items, whereas improvements were observed in physical function. Overall rates and severity of dyspareunia in specific neither improved nor worsened. CONCLUSION: Sexual function scores deteriorate 1 year after trocar-guided transvaginal mesh surgery. The worsening was attributed primarily to a worsening in behavioral-emotive and partner-related items. Anatomical cure after surgery was not associated with improved PISQ scores. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00402844 LEVEL OF EVIDENCE: II.

A 5-year prospective follow-up study of vaginal surgery for pelvic organ prolapse.

The objective of this study was to evaluate anatomic, functional, short- and long-term outcome of vaginal surgery for pelvic organ prolapse. This was a prospective observational study of 185 consecutive women planned for vaginal prolapse reconstructive surgery. Stage of prolapse, urinary incontinence (UI), bowel and mechanical symptoms were assessed preoperatively and at 1, 3 and 5 years postoperatively. The mean follow-up time was 53 months. The anatomic recurrence rate was 41.1% but less than half of them were symptomatic. Anterior compartment was most prone for recurrence and the majority of the recurrences took place within the first year. UI remained at the same level at 1-year follow-up. De novo urge occurred in 22.6% and de novo stress incontinence in 6.0%. An improvement was seen in difficulty in emptying bowel 1 year after surgery (54%). Patients were primarily cured from mechanical symptoms. Re-operation rate was 9.7%; if additional operation for incontinence was included, it was13.5%.

Operation for pelvic organ prolapse: a follow-up study.

OBJECTIVE: Long-term results of surgery for pelvic organ prolapse in terms of objective and subjective cure rates, postoperative complications and side-effects were studied retrospectively. METHODS: Two hundred and sixty-nine women underwent surgery between 1986 and 1988 and were invited to a follow-up visit in 1998-99. One hundred and twenty-eight (47%) women attended the follow-up. In the time between surgery and follow-up, 67 (25%) women had died. The medical records were reviewed for women not attending follow-up (n = 131), revealing a higher age and a more severe prolapse in the lost to follow-up group. RESULTS: The subjective cure rate, with cure of all symptoms of pelvic organ prolapse, was 46% (n = 59). The objective cure rate, with satisfactory anatomic outcome, was 56% (n = 72). If perfect results had been attained in the women who did not undergo follow-up examination, the subjective and objective cure rates would be 73% and 79%, respectively. Previous prolapse surgery, a traumatic delivery, urinary incontinence and a prolapse stage III or more seemed to be risk factors for an adverse outcome. CONCLUSIONS: In evaluating the cure rate of pelvic floor surgery not only the anatomic outcome should be studied but also the outcome in terms of side-effects and/or symptoms as resolved, persistent or new onset. An unsatisfactory anatomic outcome was not necessarily associated with symptoms. The modest cure rate after surgery may be due to the aggravation with time of pelvic floor disorder, this confounding the results of surgery.