A comparison of native vaginal and ligament surgery for cure of pelvic organ prolapse and overactive bladder.

The key messages from the Shkarupa et al. native cardinal/uterosacral ligament (CL/USL) study, was that, in premenopausal women, ligament repair alone is sufficient for cure of pelvic organ prolapse (POP) and urgency, achieving cure rates of 85.7% for POP and 81.6% for urgency at 12 months. However, in postmenopausal women, the cure rates were 20.5% for POP and 33.3% for urge at 12 months. The Lancet Prospect Trial recorded 21% for native vaginal repair at 12 months. The poor POP cure rate in the Prospect Trial, and the rapid deterioration in the post-menopausal CL/USL repair group, can be explained by known biomechanics. The vagina has little structural strength. Ligaments, with a much higher breaking strain, are the main structural support of pelvic organs. Yet, even native ligament repair reported very low cure rates at 12 months. The poor results in postmenopausal women with native ligament repair can be explained by collagen breakdown after the menopause, as collagen is the key structural component of ligaments. An important question posed in the ligament repair study was, "What happens to women cured by ligament repair after the menopause when the collagen leaches out of the ligaments?". One recommendation was that collagen creating tapes be routinely applied in prolapse surgery and OAB, at least in postmenopausal women. The recommendation for routine collagen-creating ligament repair methods, especially in older women, are supported by high 5-year surgical cure rates in 70-year-old Japanese women, 91.2% for POP, at 12 months, falling to 79.0 at 60 months, using collagen creating Tissue Fixation System (TFS) minislings.

Chronic pelvic pain of "unknown origin" in the female.

The remit of this review is confined to the experimental scientific works and surgeries based on the Integral Theory Paradigm (ITP). Chronic pelvic pain (CPP) is a major societal problem which is said to occur in up to 20% of women. The pathogenesis of CPP of "unknown origin" is said to be unknown and CPP is said to be incurable. According to the ITP, however, CPP is said to be mainly caused by the inability of loose or weak uterosacral ligaments (USLs) to mechanically support visceral nerve plexuses (VPs), T11-L2 and S2-4. These fire off de novo impulses, interpreted by the cortex as pain coming from the end organs. CPP, when it occurs simultaneously in multiple pelvic sites, is associated with uterine/apical prolapse (often minimal) and bladder symptoms such as overactive bladder (OAB), nocturia, retention. This combination of symptoms was described in 1993 as the "posterior fornix syndrome" (PFS). As such, CPP when associated with the PFS, is potentially curable by surgical repair of USLs. However, patients with CPP generally complain only of one symptom, CPP. This is known as the "Pescatori iceberg" effect. Other PFS symptoms are "under the surface" and must be sought out by direct questioning. The diagnostic algorithm is helpful in locating other associated symptoms. Definitive diagnosis of CPP, caused by USL laxity, is immediate alleviation of pain by mechanical support of USLs by using the speculum test or by tampons in the posterior fornix. Treatment of CPP can be non-surgical, by strengthening USLs by squatting exercises, supporting USLs mechanically with tampons or USL surgery. Coexisting bladder symptoms are (variously) improved or cured. URL for CPP https://www.pelviperineology.org/volume/36/issue/3.

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates.

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces δ-catenin mRNA levels in cultured human neurons. δ-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was partially reversed by elevating δ-catenin expression. Prenatal VPA exposure significantly reduced synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals' USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of δ-catenin functions.

Ketamine's rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors.

Ketamine is shown to enhance excitatory synaptic drive in multiple brain areas, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine's therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment in cultured mouse hippocampal neurons significantly reduces Ca2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). The ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and glutamate receptor plasticity in cultured hippocampal neurons. Moreover, when a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within 1 hr after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamine's effects on animals' behaviors. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity, which in turn enhances synaptic strength to induce rapid antidepressant actions.

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates.

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces δ-catenin mRNA levels in cultured human neurons. δ-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was reversed by elevating δ-catenin expression. Prenatal VPA exposure significantly reduced synaptic AMPA receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals' USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of δ-catenin functions. Highlights: Prenatal exposure of valproic acid (VPA) in mice significantly reduces synaptic δ-catenin protein and AMPA receptor levels in the pups' brains.VPA treatment significantly impairs dendritic branching in cultured cortical neurons, which is reversed by increased δ-catenin expression.VPA exposed pups exhibit impaired communication such as ultrasonic vocalization.Neuronal activation linked to ultrasonic vocalization is absent in VPA-exposed pups.The loss of δ-catenin functions underlies VPA-induced autism spectrum disorder (ASD) in early childhood.

Native tissue repair of cardinal/uterosacral ligaments cures overactive bladder and prolapse, but only in pre-menopausal women.

INTRODUCTION: The aim of this article was to study the effect of native tissue cardinal/uterosacral ligament repair on overactive bladder (OAB) and pelvic organ prolapse (POP). MATERIAL AND METHODS: Inclusion criteria included decrease of urge symptoms following insertion of a gauze tampon in the posterior fornix of vagina ('simulated operation'). Exclusion criteria included SUI, POP grades 3-4. The surgery consisted of plication of cardinal/uterosacral ligaments. Post-operative assessment was performed at3, 6, 12 and 18 months after surgery and included evaluation by stage of prolapse, Urinary Distress Inventory Short Form 6 (UDI-6), Overactive Bladder Questionnaire (OAB-q), Pelvic Floor Impact Questionnaire- Short Form 7 (PFIQ-7), and International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-SF) questionnaires and voiding diary. RESULTS: At 3 months, cure rates for frequency, urgency, nocturia and prolapse were comparable. By the 6-month review, catastrophic failure commenced in the postmenopausal group, parallel for all pa-rameters, starkly contrasting with premenopausal group. At 18 months, % cure rates for pre-menopausal (post-menopausal in brackets) were 79.6 (15.4) for POP, 67.3 (20.5) for urgency, 87.7 (20.5) for nocturia and 59.2 (15.4) for frequency. CONCLUSIONS: We hypothesize the stepwise parallel recurrence of POP and symptoms in the menopausal group was a consequence of collagen deficiency in the plicated ligaments. Nevertheless, plication of uterosacral-cardinal ligament complex is simple, inexpensive, effective, especially applicable pre-menopausally for POP and as an alternative treatment option in that difficult group of pre-menopausal women who have major OAB/nocturia symptoms but only minimal prolapse.

Phosphorylation of the AMPA receptor subunit GluA1 regulates clathrin-mediated receptor internalization.

Synaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. During long-term potentiation and synaptic upscaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to phosphorylation of AMPAR subunit GluA1 (also known as GRIA1) and subsequent elevation of GluA1 surface expression, either by an increase in receptor forward trafficking to the synaptic membrane or a decrease in receptor internalization. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 serine 845 (S845) predominantly plays a role in receptor internalization, rather than forward trafficking, during synaptic plasticity. Notably, internalization of AMPARs depends upon the clathrin adaptor AP2, which recruits cargo proteins into endocytic clathrin-coated pits. In fact, we further reveal that an increase in GluA1 S845 phosphorylation upon two distinct forms of synaptic plasticity diminishes the binding of the AP2 adaptor, reducing internalization and resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated internalization of AMPARs.

The novel technique of post-hysterectomy vaginal vault prolapse repair: Apical sling and "neocervix" formation.

OBJECTIVE: We primarily aimed to evaluate the effectiveness of the novel technique: bilateral sacrospinous fixation by monofilament polypropylene apical sling combined with "neocervix" formation in surgical treatment of post - hysterectomy vaginal vault prolapse. The secondary objective was to estimate the impact of the surgery on voiding function and quality of life. STUDY DESIGN: This prospective study involved 61 women suffering from post-hysterectomy prolapse. We used the following criteria to evaluate the results of surgical treatment: results of vaginal examination (POP-Q system), uroflowmetry, bladder ultrasound, validated questionnaires were used. All listed parameters were determined before the surgery and at control examinations in 1, 6, 12 months after the treatment. RESULTS: Mean operation time was 35min. No cases of intraoperative damage to the bladder/rectum, as well as clinically significant bleeding were noted.At 12-month follow-up anatomical cure rate (≤stage I, POP-Q) was 100%, 94,4% and 100% for vaginal apex, anterior and posterior vaginal walls, respectively. The following long-term complications were noted stress urinary incontinence de novo and urgency de novo were noted in 6.5% and 4,9%, respectively. Statistically significant (P<0.05) improvement in peak flow rate was observed according to uroflowmetry. Comparison of the scores by the questionnaires revealed a significant improvement in the quality of life in the postoperative period. CONCLUSION: The novel technique: combination of the apical sling and purse-string "neocervix" formation appears to be effective and safe method for treatment patients with vaginal vault prolapse. The technique improves voiding function and quality of life.

The hybrid technique of pelvic organ prolapse treatment: apical sling and subfascial colporrhaphy.

INTRODUCTION AND HYPOTHESIS: The majority of patients with cystocele undergoing reconstructive surgery have combined defects of pubocervical fascia and uterosacral/cardinal ligament complex. In this regard, the simultaneous correction of both defects is rational. Furthermore, decreasing the use of synthetic materials in pelvic floor surgery is an important goal. The aim was to evaluate the objective and subjective cure rate of a hybrid technique: bilateral sacrospinous fixation using modern monofilament synthetic tape (apical sling) combined with the original technique of subfascial colporrhaphy. MATERIALS AND METHODS: This prospective study involved 148 women suffering from cystocele combined with apical prolapse. We used the following criteria to evaluate the results of surgical treatment: results of the vaginal examination (POP-Q system), urodynamic tests, bladder ultrasound, special questionnaires (Pelvic Floor Distress Inventory [PFDI-20], Pelvic Floor Impact Questionnaire [PFIQ-7], Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire [PISQ-12], International Consultation on Incontinence Modular Questionnaire Short Form [ICIQ-SF]). All listed parameters were determined before the surgery and at control examinations at 1, 6, and 12 months after the treatment. RESULTS: At the 1-year follow-up, the objective cure rate for prolapse was 97.8%. The rate of anatomical recurrence was 2.2% (3 out of 138). The following long-term complications were noted: de novo urgency and stress urinary incontinence de novo in 2 (1.4%) and 4 (2.9%) patients, respectively. Comparison of the scores by the questionnaires also revealed a significant improvement in the quality of life in the postoperative period. Patient satisfaction rate was 97.1%. CONCLUSION: The hybrid technique is an effective and safe uterus-sparing method for patients with advanced forms of cystocele combined with apical prolapse. This technique improves voiding function, quality of life, and provides a high satisfaction rate.