Durable improvements in urinary incontinence and positive treatment response in patients with idiopathic overactive bladder syndrome following long-term onabotulinumtoxinA treatment: Final results of 3.5-year study.

OBJECTIVES: Here we present the final results from an extension study assessing long-term onabotulinumtoxinA treatment (3.5 years) in patients with idiopathic overactive bladder. METHODS: Patients who completed either of 2 Phase III trials were eligible to enter a 3-year extension study in which they received multiple onabotulinumtoxinA (100 U) treatments. Data were analyzed for the overall population of patients who received 100 U in any treatment cycle (n=829) and within discrete subgroups of patients who received exactly 1 (n=105), 2 (n=118), 3 (n=117), 4 (n=83), 5 (n=46), or 6 (n=33) treatments of the 100 U dose throughout the study (n=502). RESULTS: Of the 829 patients enrolled, 51.7 % completed the study. Discontinuations due to AEs/lack of efficacy were low (5.1/5.7 %); other reasons were not treatment-related. Mean reductions from baseline in urinary incontinence (UI) episodes/day (week 12; co-primary endpoint) were consistent among discrete subgroups who received 1 (-3.1), 2 (-2.9, -3.2), 3 (-4.1 to -4.5), 4 (-3.4 to -3.8), 5 (-3.0 to -3.6), or 6 (-3.1 to -4.1) treatments. A consistently high proportion of patients reported improvement/great improvement on the Treatment Benefit Scale (week 12; co-primary endpoint) in the discrete subgroups across all treatments (70.0-93.5 %). Median time to request retreatment was ≤6 months for 34.2 %, >6-≤12 months for 37.2 %, and >12 months for 28.5 % of patients. Most common AE was UTI, with no changes in safety profile over time. CONCLUSION: Long-term onabotulinumtoxinA treatment resulted in consistent reductions in UI and high proportions of patients reporting improvement after each treatment, with no new safety findings.

Health-related quality of life in preschool children with Type 1 diabetes.

AIMS: To describe health-related quality of life in children aged < 7 years with Type 1 diabetes mellitus compared with healthy children of the same age, and to investigate how health-related quality of life was correlated with aspects of insulin treatment and glycaemic control. METHODS: The participants in this study were 24 children with diabetes (12 girls, mean age 4.5 years) and 27 healthy children (14 girls, mean age 4.6 years). All participants completed the Pediatric Quality of Life Inventory 4.0 Generic Core Scales and the participants with diabetes also completed the Pediatric Quality of Life Inventory 3.0 Type 1 Diabetes Module Scales. HbA1c levels were measured in children with diabetes and the plasma glucose meter memories were uploaded. RESULTS: Children aged <7 years with diabetes had lower parent-rated generic health-related quality of life compared with healthy children (score: 80 vs 91; P = 0.003). The difference was largest in children aged < 5 years (score: 79 vs 93; P = 0.004). Among the parents of children with Type 1 diabetes, 22% rated their child's generic health-related quality of life to be at a level of concern (- 1 sd of a general population). Of the children with Type 1 diabetes aged between 5 and 7 years, 40% rated their own generic health-related quality of life at the same level of concern. CONCLUSION: This study shows a significantly lower level of generic health-related quality of life in very young children with diabetes in comparison with healthy children. We suggest screening for health-related quality of life in children of all ages with Type 1 diabetes mellitus.

A multicenter, prospective trial to evaluate mesh-augmented sacrospinous hysteropexy for uterovaginal prolapse.

INTRODUCTION AND HYPOTHESIS: Hysterectomy is often part of pelvic organ prolapse repair. However, this may offer no benefit when compared to uterine preservation. We aimed to prospectively evaluate a minimally invasive bilateral sacrospinous hysteropexy using polypropylene mesh. We hypothesized that anatomic success and patient satisfaction can be achieved with this technique. METHODS: Women with uterovaginal prolapse desiring surgery who had completed childbearing were enrolled. Preoperative assessment included standardized prolapse examination and validated symptom and pain scale questionnaires. Women with prior pelvic organ prolapse repair or any contraindication to uterine preservation were excluded. Data including demographic, operative and postoperative information was collected on patients for 1 year following surgery. Continuous variables are summarized as means (standard deviation) and categorical variables are summarized as frequencies and percentages. A mixed-effects model was used to evaluate the changes in questionnaire scores and outcomes at 6 months and 12 months after surgery with random effects accounting for the center effect with adjustment for age. RESULTS: The study group comprised 99 women from three female pelvic medicine and reconstructive surgery (urogynecology) centers. The average age of the participants was 67.0 years (11.32 years), BMI 26.04 kg/m(2) (3.56 kg/m(2)), and the majority were multiparous (98.9%) and menopausal (90.9%). Overall success at 12 months, as measured by composite outcome was 97.7% (with the Ba point as the anatomic landmark) and 96.6% (with the C point as the anatomic landmark). The overall exposure rate was 6.52% and reoperation rate was 7.53%. All subjective questionnaire scores and anatomic outcomes had improved at 12 months. CONCLUSIONS: Sacrospinous hysteropexy using a minimally invasive polypropylene mesh kit is an effective and safe technique for addressing uterovaginal prolapse as an alternative to hysterectomy at the time of pelvic reconstructive surgery.

Efficacy of different protocols of transcranial magnetic stimulation for the treatment of tinnitus: Pooled analysis of two randomized controlled studies.

OBJECTIVES: Tinnitus is related to alterations in neuronal activity of auditory and nonauditory brain areas. Targeted modulation of these areas by repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new therapeutic approach for chronic tinnitus. METHODS: Two randomized, double-blind, parallel-group, controlled clinical trials were performed subsequently and pooled for analysis. A total of 192 tinnitus patients were randomly allocated to receive 10 stimulation sessions of either sham rTMS, PET-based neuronavigated 1 Hz rTMS, 1Hz r TMS over the left auditory cortex, or combined 20 Hz rTMS over the left frontal cortex, followed by 1 Hz rTMS over the left auditory cortex. RESULTS: rTMS treatment was well tolerated and no severe side effects were observed. All active rTMS treatments resulted in significant reduction of the TQ as compared to baseline. The comparison between treatment groups failed to reach significant differences. The number of treatment responders was higher for temporal rTMS(38%) and combined frontal and temporal rTMS (43%), as compared to sham (6%). CONCLUSIONS: This large study demonstrates the safety and tolerability of rTMS treatment in patients with chronic tinnitus. While the overall effect did not prove superior to placebo, secondary outcome parameters argue in favour of the active stimulation groups, and specifically the combined frontal and temporal rTMS protocol.

A new measure of sexual function in women with pelvic floor disorders (PFD): the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR).

INTRODUCTION AND HYPOTHESIS: The objective of this study was to create a valid, reliable, and responsive sexual function measure in women with pelvic floor disorders (PFDs) for both sexually active (SA) and inactive (NSA) women. METHODS: Expert review identified concept gaps and generated items evaluated with cognitive interviews. Women underwent Pelvic Organ Prolapse Quantification (POPQ) exams and completed the Incontinence Severity Index (ISI), a prolapse question from the Epidemiology of Prolapse and Incontinence Questionnaire (ISI scores), the Pelvic Floor Distress Inventory-20 (PFDI-20), and the Female Sexual Function Index (FSFI). Principle components and orthogonal varimax rotation and principle factor analysis with oblique rotation identified item grouping. Cronbach's alpha measured internal consistency. Factor correlations evaluated criterion validation. Change scores compared to change scores in other measures evaluated responsiveness among women who underwent surgery. RESULTS: A total of 589 women gave baseline data, 200 returned surveys after treatment, and 147 provided test-retest data. For SA women, 3 subscales each in 2 domains (21 items) and for NSA women 2 subscales in each of 2 domains (12 items) emerged with robust psychometric properties. Cronbach's alpha ranged from .63 to .91. For SA women, correlations were in the anticipated direction with PFDI-20, ISI, and FSFI scores, POPQ, and EPIQ question #35 (all p < .05). PFDI-20, ISI, and FSFI subscale change scores correlated with Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire International Urogynecological Association-revised (PISQ-IR) factor change scores and with mean change scores in women who underwent surgery (all p < .05). For NSA women, PISQ-IR scores correlated with PFDI-20, ISI scores, and with EPIQ question #35 (all p < .05). No items demonstrated differences between test and retest (all p ≥ .05), indicating stability over time. CONCLUSIONS: The PISQ-IR is a valid, reliable, and responsive measure of sexual function.

Transforming growth factor beta1 gene expression during vaginal wound healing in a rabbit menopause model.

OBJECTIVE: Surgical outcome following reconstructive pelvic surgery is largely dependent on the vaginal wound healing process. As peri- and post-menopausal women are the most likely candidates to undergo these surgeries, it is important to understand the effect of estrogen deficiency on this process. Transforming growth factor beta (TGFß) is an important mediator of wound healing. We sought to assess TGFß1 gene expression during the vaginal incisional wound healing process in a rabbit menopause model. DESIGN: Animal study. SETTING: Animal laboratory. SAMPLE: Sixty-three rabbits were used for this study. METHODS: Twenty-one underwent bilateral oophorectomy, 21 underwent a sham surgery, and 21 served as controls. Eight weeks later, standardised full-thickness 6-mm diameter circular segments were excised from the vagina of all rabbits. Animals were killed sequentially, before wounding, and at 0, 4, 7, 14, 21 and 35 days after wounding, and the wounds were harvested. MAIN OUTCOME MEASURES: Wound closure and TGFß1 gene transcription, as measured by real-time polymerase chain reaction (PCR). RESULTS: Wound closure was significantly protracted (P < 0.02), whereas TGFß1 gene expression was significantly increased (P < 0.0001) during the wound healing process in oophorectomised rabbits, as compared with both control and sham groups. CONCLUSION: Oophorectomised rabbits show protracted incisional vaginal wound healing associated with increased TGFß1 gene transcription.

Resequencing of the auxiliary GABA(B) receptor subunit gene KCTD12 in chronic tinnitus.

Tinnitus is a common and often incapacitating hearing disorder marked by the perception of phantom sounds. Susceptibility factors remain largely unknown but GABA(B) receptor signaling has long been implicated in the response to treatment and, putatively, in the etiology of the disorder. We hypothesized that variation in KCTD12, the gene encoding an auxiliary subunit of GABA(B) receptors, could help to predict the risk of developing tinnitus. Ninety-five Caucasian outpatients with a diagnosis of chronic tinnitus were systematically screened for mutations in the KCTD12 open reading frame and the adjacent 3' untranslated region by Sanger sequencing. Allele frequencies were determined for 14 known variants of which three (rs73237446, rs34544607, and rs41287030) were polymorphic. When allele frequencies were compared to data from a large reference population of European ancestry, rs34544607 was associated with tinnitus (p = 0.04). However, KCTD12 genotype did not predict tinnitus severity (p = 0.52) and the association with rs34544607 was weakened after screening 50 additional cases (p = 0.07). Pending replication in a larger cohort, KCTD12 may act as a risk modifier in chronic tinnitus. Issues that are yet to be addressed include the effects of neighboring variants, e.g., in the KCTD12 gene regulatory region, plus interactions with variants of GABA(B1) and GABA(B2).

An examination of TOR1A variants in recurrent major depression.

BACKGROUND: Observations of comorbid depression in subjects with primary dystonia have suggested a dual role for the TOR1A gene in mood disorders and movement disorders. We conducted a systematic search for carriers of the ΔGAG deletion and for other variants in TOR1A exon 5 among 414 Caucasian subjects with recurrent major depression from the Upper Palatinate. FINDINGS: Allele frequencies were determined for 27 TOR1A diallelic markers, including two novel synonymous substitutions (L262L and E310E) in the region encoding the torsinA C-terminus, plus four novel variants in the gene's 3'UTR. No carriers of the ΔGAG deletion were observed. When data were compared to previously examined control populations, no significant allelic associations were noted after corrections for multiple testing. CONCLUSIONS: The present study adds to the spectrum of TOR1A mutations but provides no evidence of a common genetic predisposition to DYT1 dystonia and recurrent major depression.

Thyroid hormone receptor alpha can control action potential duration in mouse ventricular myocytes through the KCNE1 ion channel subunit.

AIMS: The reduced heart rate and prolonged QT(end) duration in mice deficient in thyroid hormone receptor (TR) alpha1 may involve aberrant expression of the K(+) channel alpha-subunit KCNQ1 and its regulatory beta-subunit KCNE1. Here we focus on KCNE1 and study whether increased KCNE1 expression can explain changes in cardiac function observed in TRalpha1-deficient mice. METHODS: TR-deficient, KCNE1-overexpressing and their respective wildtype (wt) mice were used. mRNA and protein expression were assessed with Northern and Western blot respectively. Telemetry was used to record electrocardiogram and temperature in freely moving mice. Patch-clamp was used to measure action potentials (APs) in isolated cardiomyocytes and ion currents in Chinese hamster ovary (CHO) cells. RESULTS: KCNE1 was four to 10-fold overexpressed in mice deficient in TRalpha1. Overexpression of KCNE1 with a heart-specific promoter in transgenic mice resulted in a cardiac phenotype similar to that in TRalpha1-deficient mice, including a lower heart rate and prolonged QT(end) time. Cardiomyocytes from KCNE1-overexpressing mice displayed increased AP duration. CHO cells transfected with expression plasmids for KCNQ1 and KCNE1 showed an outward rectifying current that was maximal at equimolar plasmids for KCNQ1-KCNE1 and decreased at higher KCNE1 levels. CONCLUSION: The bradycardia and prolonged QT(end) time in hypothyroid states can be explained by altered K(+) channel function due to decreased TRalpha1-dependent repression of KCNE1 expression.

Tea catechins' affinity for human cannabinoid receptors.

Among the many known health benefits of tea catechins count anti-inflammatory and neuroprotective activities, as well as effects on the regulation of food intake. Here we address cannabimimetic bioactivity of catechin derivatives occurring in tea leaves as a possible cellular effector of these functionalities. Competitive radioligand binding assays using recombinant human cannabinoid receptors expressed in Chem-1 and CHO cells identified (-)-epigallocatechin-3-O-gallate, EGCG (K(i)=33.6 microM), (-)-epigallocatechin, EGC (K(i)=35.7 microM), and (-)-epicatechin-3-O-gallate, ECG (K(i)=47.3 microM) as ligands with moderate affinity for type 1 cannabinoid receptors, CB1. Binding to CB2 was weaker with inhibition constants exceeding 50 microM for EGC and ECG. The epimers (+)-catechin and (-)-epicatechin exhibited negligible affinities for both CB1 and CB2. It can be concluded that central nervous cannabinoid receptors may be targeted by selected tea catechins but signaling via peripheral type receptors is less likely to play a major role in vivo.

Berry anthocyanins and anthocyanidins exhibit distinct affinities for the efflux transporters BCRP and MDR1.

BACKGROUND AND PURPOSE: Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played by transport mechanisms at the intestinal and blood-brain barriers (BBB) is currently unknown. EXPERIMENTAL APPROACH: In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays. KEY RESULTS: All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside, cyanidin-3-glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyanidin-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside). Malvidin, malvidin-3-galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity. CONCLUSIONS AND IMPLICATIONS: Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain.