Systematic Review and Meta-analysis of the Prevalence of Levator Ani Avulsion with Obstetric Anal Sphincter Injury and its Effects on Pelvic Floor Dysfunction.

INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the prevalence of levator ani avulsion (LAA) among primiparous women with obstetric anal sphincter injury (OASI) and how this association could affect future pelvic floor dysfunction. METHODS: Three electronic databases (MEDLINE/PubMed/EMBASE) were searched in December 2018 and again in October 2022. Nine full-text articles were included in the analysis. The exclusion criteria were language other than English, studies not based on primiparous women only, conference abstracts, and evaluation without ultrasound or MRI. RESULTS: The overall prevalence of LAA was 24% (95% CI: 18-30%). Those with OASI, were at a higher risk of LAA, OR 3.49 (95% CI: 1.46 to 8.35). In women with LAA + OASI versus OASI alone, Three of Five studies showed worsened AI symptoms. Three of Five studies assessing urinary incontinence (UI) reported no significant difference in UI, whereas two reported increased UI. All studies that looked at pelvic organ prolapse reported a higher incidence of symptomatic prolapse and reduced pelvic floor muscle strength in women with LAA + OASI compared with those without LAA. CONCLUSION: Levator ani avulsion is prevalent following vaginal birth and is strongly associated with OASI. Incidence of AI does not increase in women with LAA and OASI, but they had greater symptom bother. OASI with LAA appears to increase the incidence of pelvic floor weakness and pelvic organ prolapse. There is no consensus agreement on the effect of LAA + OASI on UI.

International Urogynecology Consultation Chapter 1 Committee 5: relationship of pelvic organ prolapse to associated pelvic floor dysfunction symptoms: lower urinary tract, bowel, sexual dysfunction and abdominopelvic pain.

INTRODUCTION AND HYPOTHESIS: This article from Chapter 1 of the International Urogynecology Consultation (IUC) on Pelvic Organ Prolapse (POP) establishes the prevalence of lower urinary tract disorders, bowel symptoms, vulvo-vaginal/lower abdominal/back pain and sexual dysfunction in women with POP. METHODS: An international group of nine urogynecologists/urologists and one medical student performed a search of the literature using pre-specified search terms in Ovid, MEDLINE, Embase and CINAHL from January 2000 to March 2019. Publications were eliminated if not relevant or they did not include clear definitions of POP or the symptoms associated with POP. Definitions of POP needed to include both a physical examination finding using a validated examination technique and the complaint of a bothersome vaginal bulge. Symptoms were categorized into symptom groups for ease of evaluation. The Specialist Unit for Review Evidence (SURE) was used to evaluate for quality of the included articles. The resulting list of articles was used to determine the prevalence of various symptoms in women with POP. Cohort studies were used to evaluate for possible causation of POP as either causing or worsening the symptom category. RESULTS: The original search yielded over 12,000 references, of which 50 were used. More than 50% of women with POP report lower urinary tract symptoms. Cohort studies suggest that women with POP have more obstructive lower urinary tract symptoms than women without POP. Pain described in various ways is frequently reported in women with POP, with low back pain being the most common pain symptom reported in 45% of women with POP. In cohort studies those with POP had more pain complaints than those without POP. Sexual dysfunction is reported by over half of women with POP and obstructed intercourse in 37-100% of women with POP. Approximately 40% of women have complaints of bowel symptoms. There was no difference in the median prevalence of bowel symptoms in those with and without POP in cohort studies. CONCLUSIONS: The prevalence of lower urinary tract disorders, bowel symptoms, vulvo-vaginal/lower abdominal/back pain and sexual dysfunction in women with POP are common but inconsistently reported. There are few data on incidence of associated symptoms with POP, and cohort studies evaluating causality are rare or inconsistent. Obstructive voiding, lower abdominal and pelvic pain, and sexual dysfunction are most frequently associated with POP.

Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.

PURPOSE: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. MATERIALS AND METHODS: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction. RESULTS: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). CONCLUSIONS: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.

Management of mid-urethral tape complications: a retrospective study.

BACKGROUND/PURPOSE OF THE STUDY: Following mid-urethral tape insertion, for stress urinary incontinence (SUI), a proportion of women experience complications such as voiding dysfunction or tape erosion which fail to respond to conservative management approaches. These women thus require further surgical treatment. Our objective was to describe the outcomes of the surgical management of complications in these women. METHODS: This retrospective study describes the results obtained following the surgical management of mid-urethral tape complications. Twenty-nine consecutive women who required mid-urethral tape lysis, loosening or excision for tape-related complications in the period 2007-2017 were included. Primary outcomes were improvement in voiding dysfunction and resolution of pain, while secondary outcomes were evaluation of the recurrence of stress urinary incontinence and patient satisfaction. Patient outcomes were measured using the Patient Global Impression of Improvement questionnaire. RESULTS: There were 1459 mid-urethral tape procedures performed in the study period. Twenty-nine women (1.99%) who had revision surgery for tape complication were identified. Interventions included tape loosening or lysis in 19 women and tape excision in ten women. Twenty-three of the 29 patients reported a significant improvement in their symptoms postoperatively. Two women had a recurrence of SUI in the tape excision cohort; all patients following tape loosening or lysis remained continent. CONCLUSIONS: Tape revision surgery is a safe and effective treatment for mid-urethral tape complications with the majority of women maintaining continence following revision. Early intervention and proactive management of complications, by the appropriate specialist, will improve outcomes.

Prospective comparative study of the effects of lidocaine on urodynamic and sensory parameters in bladder pain syndrome.

INTRODUCTION AND HYPOTHESIS: Intravesically administered lidocaine is used in patients with bladder pain syndrome (BPS) to test the hypothesis that symptoms have a peripheral versus central mechanism. METHODS: A cross-sectional study of 24 female patients with BPS was performed. The Central Sensitisation Inventory (CSI) and Kings Health Questionnaire (KHQ) were completed. Urodynamic assessment was undertaken. Women were asked to report their pain using a numeric rating scale at cystometric capacity and post void. Participants then received an intravesical instillation of either 20 ml of 2% alkalinised lidocaine (n = 16) or 20 ml of normal saline (n = 8). These solutions were allowed to remain in situ for 20 min and pain score repeated. Urodynamics was repeated. RESULTS: There was a statistically significant volume increase following lidocaine treatment: maximal cystometric capacity (MCC) 192-261 ml post lidocaine (p = 0.005.) In contrast, there was no significant difference in the saline controls: MCC 190-183 ml (p = 0.879.) Individual analysis revealed five of 16 lidocaine participants did not respond to lidocaine. These five reported a significantly worse quality of life (QoL) than lidocaine responders and had a tendency towards central sensitivity syndromes. CONCLUSION: Lidocaine significantly improved MCC in 11/16 participants in this study. These patients appear to have peripherally mediated disease. However, the failure of response to treatment in five participants, as well as their tendency towards central sensitivity syndromes, implies that in this subgroup, a peripheral drive from the bladder is not critical to their pain, suggesting central nervous system (CNS) pathology. This simple and safe test could be used to stratify patients for research or therapeutic trials.

Neuromodulation for Pelvic and Urogenital Pain.

Chronic pain affecting the pelvic and urogenital area is a major clinical problem with heterogeneous etiology, affecting both male and female patients and severely compromising quality of life. In cases where pharmacotherapy is ineffective, neuromodulation is proving to be a potential avenue to enhance analgesic outcomes. However, clinicians who frequently see patients with pelvic pain are not traditionally trained in a range of neuromodulation techniques. The aim of this overview is to describe major types of pelvic and urogenital pain syndromes and the neuromodulation approaches that have been trialed, including peripheral nerve stimulation, dorsal root ganglion stimulation, spinal cord stimulation, and brain stimulation techniques. Our conclusion is that neuromodulation, particularly of the peripheral nerves, may provide benefits for patients with pelvic pain. However, larger prospective randomized studies with carefully selected patient groups are required to establish efficacy and determine which patients are likely to achieve the best outcomes.

Manipulating the extracellular matrix: an animal model of the bladder pain syndrome.

Bladder pain syndrome (BPS) is associated with breakdown of the protective uroepithelial barrier of the urinary bladder allowing urinary constituents access to bladder sensory neurons. Although there are several animal models of cystitis, none specifically relates to BPS. Here, we aimed to create such a model using enzymatic digestion of the barrier proteoglycans (PGs) in the rat. Twenty female Wistar rats were anaesthetized and transurethrally catheterized. Ten animals were treated with 0.25IU of intravesical chondroitinase ABC and heparanase III to digest chondroitin sulphate and heparin sulphate PGs, respectively. Ten animals received saline. Following PG deglycosylation, bladders showed irregular loss of the apical uroplakin and a significant increase in neutrophils, not evident in the control group. Spinal cord sections were also collected for c-fos analysis. A large and significant increase in fos immunoreactivity in the L6/S1 segments in the treatment vs control bladders was observed. Cystometry was performed on 5 treatment and 5 control animals. Analysis revealed a significant increase in micturition reflex excitability postdeglycosylation. On a further group of 10 animals, von Frey mechanical withdrawal thresholds were tested on abdominal skin before and after PG digestions. There was a significant decrease in abdominal mechanical withdrawal threshold postdeglycosylation compared with controls. The results of this animal study suggest that many of the clinical features of BPS are seen after PG digestion from the bladder lumen. This model can be used to further understand mechanisms of pain in patients with BPS and to test new therapeutic strategies.

The Expression of Inflammatory Mediators in Bladder Pain Syndrome.

BACKGROUND: Bladder pain syndrome (BPS) pathology is poorly understood. Treatment strategies are empirical, with limited efficacy, and affected patients have diminished quality of life. OBJECTIVE: We examined the hypothesis that inflammatory mediators within the bladder contribute to BPS pathology. DESIGN, SETTING, AND PARTICIPANTS: Fifteen women with BPS and 15 women with stress urinary incontinence without bladder pain were recruited from Cork University Maternity Hospital from October 2011 to October 2012. During cystoscopy, 5-mm bladder biopsies were taken and processed for gene expression analysis. The effect of the identified genes was tested in laboratory animals. OUTCOME MEASURES AND STATISTICAL ANALYSIS: We studied the expression of 96 inflammation-related genes in diseased and healthy bladders. We measured the correlation between genes and patient clinical profiles using the Pearson correlation coefficient. RESULTS AND LIMITATIONS: Analysis revealed 15 differentially expressed genes, confirmed in a replication study. FGF7 and CCL21 correlated significantly with clinical outcomes. Intravesical CCL21 instillation in rats caused increased bladder excitability and increased c-fos activity in spinal cord neurons. CCL21 atypical receptor knockout mice showed significantly more c-fos upon bladder stimulation with CCL21 than wild-type littermates. There was no change in FGF7-treated animals. The variability in patient samples presented as the main limitation. We used principal component analysis to identify similarities within the patient group. CONCLUSIONS: Our study identified two biologically relevant inflammatory mediators in BPS and demonstrated an increase in nociceptive signalling with CCL21. Manipulation of this ligand is a potential new therapeutic strategy for BPS. PATIENT SUMMARY: We compared gene expression in bladder biopsies of patients with bladder pain syndrome (BPS) and controls without pain and identified two genes that were increased in BPS patients and correlated with clinical profiles. We tested the effect of these genes in laboratory animals, confirming their role in bladder pain. Manipulating these genes in BPS is a potential treatment strategy.

Profibrotic phenotype of conjunctival fibroblasts from mucous membrane pemphigoid.

Ocular mucous membrane pemphigoid is an immunobullous disease in which excessive conjunctival fibrosis causes blindness, and the pathogenesis of scarring is incompletely understood. To establish whether profibrotic fibroblasts with an altered phenotype exist in ocular mucous membrane pemphigoid, we compared the functional characteristics of pemphigoid conjunctival fibroblasts to normal conjunctival fibroblasts with respect to cell division; migration; collagen contraction; matrix metalloproteinase, secretion of collagen and chemokines; and myofibroblast differentiation. We found that pemphigoid fibroblasts showed increased cell division (P = 0.01), increased migration in serum-free medium (72 ± 18 migrated cells versus 33 ± 11, P = 0.04), increased collagen contraction in the presence of 10 ng/ml tumor necrosis factor-α, increased collagen type I secretion (P = 0.03), increased secretion of matrix metalloproteinase-3 (P = 0.03), and increased secretion of eotaxin in response to interleukin-13 (P = 0.04). Differences between pemphigoid and normal conjunctival fibroblasts with respect to collagen contraction and MMP secretion in the presence of interleukin-13 were also observed. Together, these findings indicate that pemphigoid conjunctival fibroblasts have a profibrotic phenotype that is maintained in vitro. No differences between pemphigoid fibroblasts obtained from acutely inflamed versus clinically uninflamed conjunctiva were observed. Developing effective antifibrotic therapies will require understanding of the mechanisms that both induce and maintain the profibrotic phenotype.

Conjunctival interleukin-13 expression in mucous membrane pemphigoid and functional effects of interleukin-13 on conjunctival fibroblasts in vitro.

Interleukin-13 (IL-13) is the dominant effector cytokine of fibrosis in pulmonary and liver disease. Excessive conjunctival fibrosis in the immunobullous disease ocular mucous membrane pemphigoid (MMP) causes blindness; the pathogenesis of scarring in this disease is incompletely understood. To determine whether IL-13 is involved in conjunctival fibrosis in MMP, we studied the expression of IL-13 in ocular MMP patients before and after systemic immunosuppression and examined the effects of IL-13 on normal human conjunctival fibroblasts. We found high stromal cell expression of IL-13 in active ocular MMP by immunohistochemistry; 80% of these cells were CD3-positive T cells. Following immunosuppression, in clinically uninflamed, treated, ocular MMP patients, the number of IL-13 positive cells was significantly reduced, but this was still fourfold greater than in normal conjunctiva. IL-13 stimulated collagen lattice contraction and migration, and decreased production of mmp-3 and mmp-10 by human conjunctival fibroblasts. The addition of T cell culture supernatant to IL-13 synergistically augmented fibroblast migration. IL-13 also up-regulated surface expression of HLA-DR, CD80, CD40, and CD154 by conjunctival fibroblasts, suggesting a potential mechanism for fibroblast-T cell cross talk, via which fibroblasts may actively engage in perpetuating chronic inflammation and continued fibrosis. Together, these findings suggest that IL-13 is involved in conjunctival fibrosis in MMP, and that IL-13 has both profibrotic and pro-inflammatory effects on human conjunctival fibroblasts.

Immune mechanisms in allergic eye diseases: what is new?

PURPOSE OF REVIEW: The purpose of this review will be to focus on new findings that expand our understanding of the immune mechanisms occurring in the various forms of allergic eye disease and in experimental models, and some novel therapeutic approaches. RECENT FINDINGS: The novel data encompass three main areas: effector mechanisms in allergic eye disease; cytokines and chemokines in conjunctival responses; combinations of drugs for improving treatment options for allergic eye disease. SUMMARY: The term 'allergic eye disease' describes a spectrum of clinical conditions, ranging from the common, milder conditions of seasonal and perennial allergic conjunctivitis (SAC, PAC), to the rare and more severe diseases, vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). These latter two diseases can involve the cornea, leading to impaired vision. Although there is an underlying allergic mechanism, each of these ocular surface conditions involves different cellular responses and much effort has been made to identify the molecular pathways, which could be used as potential targets for therapeutic intervention. Currently available drugs, in particular for chronic forms of disease, are inadequate and there is an urgent need for safer, more localized and effective treatment.

Delivery of oligodeoxynucleotides into human saphenous veins and the adjunct effect of ultrasound and microbubbles.

Therapy with naked oligodeoxynucleotides (ODNs, molecular weight: 3000 to 7500) provides an elegant means of modulating gene expression without the problems associated with conventional gene therapy, but the relatively low transfer efficiency on intravascular administration is a limitation to clinical application. Ultrasound, which can be potentiated by microbubbles, shows promise as a method of delivering macromolecules such as plasmid DNA and other transgenes into cells. Since uptake of molecules into cells depends on their molecular weight, it might be expected that the delivery of ODNs, which are relatively small, will be facilitated by ultrasound and microbubbles. In the present study, we delivered ODNs into veins using ultrasound and microbubbles. First, we quantified the uptake of fluorescent-labeled ODNs into intact ex vivo human saphenous veins and isolated smooth muscle cells from the veins, evaluating the effect of ultrasound and microbubbles on uptake. Ultrasound potentiated the delivery of ODN in cells, except at high concentrations. When intact veins were studied, we achieved nuclear localization of fluorescent-labeled ODNs in cells. This increased with increasing concentration and incubation time and was not potentiated by ultrasound, even when microbubbles were used. We then applied a therapeutic ODN (antisense to intercellular adhesion molecule 1, ICAM-1) to vein samples and documented a functional inhibition of gene expression in a sequence-specific manner at the protein level with immunohistochemistry and western blot analysis. Again, no significant difference was seen with adjunct ultrasound. These observations suggest high diffusion of ODNs into human saphenous veins in this ex vivo model, indicating potential applications to inhibition of vascular bypass graft occlusion and other vasculopathies. Although microbubble-ultrasound was of value with cells in culture, it was not beneficial with intact veins.