Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

Long-term outcomes after sacrocolpopexy with or without transobturator tape.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to report the long-term outcomes after sacrocolpopexy (SCP) with or without transobturator tape (TOT). METHODS: We conducted a planned secondary analysis of a prospective, observational study comparing urinary outcomes in women who underwent SCP with or without TOT based on the results of a prolapse-reduction stress test. Patients were enrolled between November 2008 and December 2011 and were followed up 5 years after surgery. The primary outcomes were 5-year success rates for stress urinary incontinence (SUI) and pelvic organ prolapse (POP) estimated using the Kaplan-Meier method. SUI success was defined as a negative cough stress test, no bothersome SUI symptoms, and no additional anti-incontinence surgery. POP success was defined as no vaginal bulge symptoms, no apical descent greater than one-third of the total vaginal length or anterior or posterior vaginal wall prolapse beyond the hymen, and no retreatment for prolapse. RESULTS: Of 240 women enrolled, 175 (73%) completed 5 years of follow-up. The estimated SUI success rate was 91.1% in the TOT group and 56.5% in the no TOT group (difference, 34.6%; 95% confidence interval, 24.1 to 45.1). The estimated POP success rate was 90.0% in the TOT group and 92.9% in the no TOT group (difference, -2.9%; 95% confidence interval, -10.7 to 4.9). CONCLUSIONS: The advantage of concomitant TOT for SUI after SCP that was seen at 2 years remained at 5 years. Long-term POP failure rates after SCP are low and not affected by concomitant TOT.

Assessment of the effect of transobturator tape surgery on women's sexual function using a validated questionnaire.

OBJECTIVE: Women with pelvic floor disorders and urinary incontinence (UI) are at an increased risk of sexual dysfunction. The purpose of this study was to investigate the effect of surgery for UI on sexual function. METHODS: We retrospectively reviewed the charts of 82 women who underwent mid-urethral transobturator tape (TOT) surgery between March 2010 and December 2014. The Pelvic Floor Distress Inventory-20 (PFDI-20) and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-12 (PISQ-12) were administered pre- and postoperatively. RESULTS: We observed a significant increase in the total postoperative PISQ-12 scores compared to the preoperative scores (from 27.1±7.3 to 30.5±6.8, P<0.001). Improved sexual function was confirmed in the physical (13.3±4.5 vs. 15.8±3.5, P<0.001) and partner-related domains (6.7±2.6 vs. 7.4±2.4, P=0.001). Coital incontinence and preoperative urinary distress inventory score were significant factors influencing postoperative sexual function in women undergoing TOT surgery for UI after adjusting for age, body mass index, menopause, and preoperative PISQ-12 score in multivariate regression analysis. CONCLUSION: TOT surgery for UI correction resulted in significant improvement in sexual function.

Risk factors and factors affecting the severity of overactive bladder symptoms in Korean women who use public health centers.

OBJECTIVE: To investigate the prevalence, risk factors of overactive bladder (OAB) and the factors affecting the severity of OAB symptoms. METHODS: A total 822 interviews with women aged 18-80 years who visited public health centers were conducted between April 2014 and April 2015. The questionnaire was composed of 16 questions about urinary symptoms, 14 questions about self-treatment and the use of complementary and alternative medicine, and 21 questions about socio-demographic characteristics. The diagnostic criterion for OAB is a total OAB symptom score of 3 and more, with an urgency score of 2 or more. To know the risk factors and factors affecting the severity of OAB, the multivariate logistic regression analysis was performed. RESULTS: One hundred fifty-seven participants (19.3%) were diagnosed with OAB, of whom 10.7%, 8.1%, and 0.7% had mild, moderate, and severe OAB symptoms, respectively. In addition, the prevalence of OAB increased with age. Among all the participants, 39.1% had stress incontinence, among them 32.7% had OAB as well. The significant risk factors of OAB were identified as age, current smoking, hyperlipidemia, cardiovascular and renal disease, whereas, the factors affecting the severity of OAB were age, current smoking, and hyperlipidemia. CONCLUSION: Those who have risk factors and factors affecting severity of OAB should be educated to increase OAB awareness and act of urinary health promotion.

Predictors of Acute Postoperative Urinary Retention after Transvaginal Uterosacral Suspension Surgery.

OBJECTIVES: To investigate the rate of postoperative urinary retention (POUR) and identify the risk factors for this complication in women who underwent transvaginal uterosacral suspension surgery. METHODS: A retrospective chart review was conducted for 75 women who underwent transvaginal uterosacral suspension surgery with vaginal hysterectomy, repair of cystocele, and levator myorrhaphy with/without transobturator anti-incontinence surgery. POUR was defined as a need for continuous intermittent catheterization on the third day subsequent to removal of the urethral indwelling catheter. RESULTS: Acute POUR was reported in 18 women (24.0%). Thirty-six of the 75 patients (48.0%) had undergone anti-incontinence surgery. Crude analysis revealed significant association between the following variables and the risk of POUR: hypertension, the lower average flow rate in the pressure-flow study (PFS), greater post-void residual (PVR) urine volume in PFS, and PVR >30% of the total bladder capacity (TBC) in PFS. In the logistic regression analysis, PVR >30% of the TBC in PFS was identified as the only significant predictor of POUR (odds ratio, 15.4; 95% confidence interval, 2.5-90.9; P = 0.003). CONCLUSIONS: The PVR >30% of the TBC in PFS was identified as the only predictive factor of acute POUR in women who underwent transvaginal uterosacral suspension surgery.

Comparison of sexual function between sacrocolpopexy and sacrocervicopexy.

OBJECTIVE: To compare sexual function before and 12 months after between sacrocolpopexy and sacrocervicopexy. METHODS: This retrospective study examined a cohort of 55 sexually active women who underwent either supracervical hysterectomy with sacrocervicopexy (n=28) or total abdominal hysterectomy with sacrocolpopexy (n=27) for stage II to IV pelvic organ prolapse. Pelvic floor support was measured with Pelvic Organ Prolapse-Quantification examination. Pelvic floor function was measured with the Pelvic Floor Distress Inventory-Short Form 20 and sexual function was measured with Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-Short Form 12 (PISQ-12). RESULTS: Baseline pelvic floor symptoms, demographics and PISQ-12 questionnaire scores were similar between the two groups. Overall improvements in sexual function were seen based on PISQ-12 scores in both groups, but were not statistically significant. No differences were seen in PISQ-12 scores regardless of sparing the cervix or surgical route. Responses to the PISQ-12 question of avoiding sexual intercourse because of vaginal bulging showed significant improvement in both group. No recurrences of prolapse occurred. CONCLUSION: In women with pelvic organ prolapse, sexual function after either sacrocolpopexy or sacrocervicopexy was not different. Sexual dysfunction in terms of avoidance of sexual activity because of vaginal bulging was greatly improved in both groups with statistical significance.

Factors affecting medication discontinuation in patients with overactive bladder symptoms.

OBJECTIVE: To find out the factors affecting medication discontinuation in patients with overactive bladder (OAB) symptoms. METHODS: The clinical data of 125 patients with OAB symptoms who had taken antimuscarinics and behavioral therapy were retrospectively reviewed. Antimuscarinics related outcomes were evaluated by an independent observer with telephone interview. All patients were asked about duration of medication and reason of continuation or discontinuation of antimuscarinics. To determine pre-treatment factors predicting self-report discontinuation of antimuscarinics, variables of only those with P-values <0.25 on the univariate analysis were included in the Cox proportional hazard modeling. RESULTS: Mean follow-up was 39.6 months and the proportion of discontinuation of antimuscarinics was 60.0% (75/125). The mean duration of medication was 21.2 months in the continuation group and 3.3 months in the discontinuation group. The reasons of discontinuation of antimuscarinics were improved OAB symptoms (46.7%), tolerable OAB symptoms (33.3%), no change of OAB symptoms (1.3%), side-effects (8.0%) and no desire to take long-term medication (10.7%). The variables affecting remaining cumulative probability of antimuscarinics were age, history of anti-incontinence surgery or vaginal surgery, and having stress predominant urinary incontinence on urodynamic study. CONCLUSION: The lower rate of cumulative continuation of antimuscarinics encourages us to give a more detailed counseling and education to the patients with OAB symptoms before prescription. And explorations about newer agent and non-pharmacologic treatment with good efficacy and lower side-effects are needed.

Two-year urinary outcomes of sacrocolpopexy with or without transobturator tape: results of a prolapse-reduction stress test-based approach.

INTRODUCTION AND HYPOTHESIS: Women undergoing sacrocolpopexy (SCP) are at risk for postoperative stress urinary incontinence (SUI). However, the optimal management for this condition remains debatable. The aim of this study was to evaluate urinary outcomes 2 years after SCP with or without transobturator tape (TOT) based on the results of a prolapse-reduction stress test. METHODS: A prospective, observational study was conducted assessing a cohort of women undergoing SCP. Patients were assigned to the TOT or non-TOT group based on results of a prolapse-reduction stress test. The primary outcome was SUI (defined as a positive cough stress test or bothersome symptoms) or additional surgery for this condition. RESULTS: Among the 247 women enrolled, 223 (90 %) received surgery per assignment and completed the follow-up. Two years after surgery, 5.4 % of women in the TOT group and 28.6 % in the non-TOT group had SUI or received additional anti-incontinence surgery (p < 0.01). In the non-TOT group, more women with symptoms of SUI prior to surgery had postoperative SUI or received additional anti-incontinence surgery than those without symptoms (42.9 % vs. 20.0 %, p = 0.01). CONCLUSIONS: A preoperative prolapse-reduction stress test alone is not sufficient to determine the need for anti-incontinence surgery at the time of SCP. In particular, women with symptoms of SUI despite a negative prolapse-reduction stress test are more likely to experience postoperative SUI or additional anti-incontinence surgery.

Translation and linguistic validation of Korean version of short form of pelvic floor distress inventory-20, pelvic floor impact questionnaire-7.

The short forms of pelvic floor distress inventory (PFDI) and pelvic floor impact questionnaire (PFIQ) are useful disease specific questionnaires evaluating symptoms, quality of life for pelvic floor disorders. The purpose is to develop linguistic validation of the PFDI-20 and PFIQ-7 questionnaires. Three types of Korean version of questionnaires have been used in four locations of University Hospitals in Korea. Each version of questionnaires was developed by forward translation and back-translation by bilingual translators and was verified by the patients with pelvic floor disorder and healthy persons. For harmonization of 3 types of questionnaires, four authors reviewed, discussed all discrepancies, incorporated and produced a new version. The multi-step processes of translation and linguistic validation of the Korean version of PFDI-20 and PFIQ-7 questionnaire were completed. Further process of validation of Korean version of these questionnaires is required.

Single-port access compared with three-port laparoscopic adnexal surgery in a randomized controlled trial.

OBJECTIVE: Scar-related cosmetic outcomes were compared prospectively between conventional three-port and single-port access laparoscopic adnexal gynaecological surgery. METHODS: Enrolled patients were randomly assigned to a single- or three-port surgery group. Scar-related outcomes were evaluated at 1 month, 6 months and 1 year. Scars were assessed by an independent observer using the modified Vancouver Scar Scale (mVSS). All patients were asked about pain related to the scar and scar satisfaction; results were recorded using a numerical rating scale. RESULTS: Seventy-three patients were enrolled between June 2010 and June 2011. Demographic and surgical outcomes did not differ between the groups. mVSS results were similar in the two groups at each follow-up point. The scar satisfaction profile measured at 1 month showed no significant difference between the groups, but the single-port access group had better results than the conventional group at all other follow-up timepoints. CONCLUSION: Cosmetic outcome was better for single-port than for three-port adnexal gynaecological surgery at 6-month and 1-year follow-up.

Predictors of postoperative antimuscarinics in women with mixed urinary incontinence after transobturator surgery.

INTRODUCTION AND HYPOTHESIS: The study sought to identify the risk factors of postoperative use of antimuscarinics after transobturator surgery in women with mixed urinary incontinence (MUI) displaying both urodynamic stress urinary incontinence (SUI) and involuntary detrusor contraction (IDC) with leakage in urodynamic study. METHODS: The clinical data of 103 patients with MUI who underwent transobturator tape (TOT) sling surgery were retrospectively reviewed. The patients were followed at least a year. To determine risk factors for postoperative use of antimuscarinics, variables of only those with P values < 0.05 on univariate analysis were included in the multivariate logistic regression analysis with forward stepwise building. RESULTS: Eight-four (81.6 %) of 103 patients were included in this study. The cure rate of urge urinary incontinence (UUI) was 69.0 % (58/84). Antimuscarinics were prescribed postoperatively in 22 (26.2 %) of 84 patients. Variables affecting postoperative use of antimuscarinics were age, parity, episode of any UUI, preoperative use of antimuscarinics, predominant urgency incontinence type, detrusor pressure at maximum flow, and Urogenital Distress Inventory 6. Increasing age and preoperative use of antimuscarinics increased the odds of postoperative use of antimuscarinics following TOT surgery. CONCLUSION: Patients who were older and had taken antimuscarinics preoperatively were significantly associated with postoperative use of antimuscarinics.

Factors predicting the response to biofeedback-assisted pelvic floor muscle training for urinary incontinence.

OBJECTIVE: To evaluate the efficacy of biofeedback-assisted pelvic floor muscle training (PFMT) for urinary incontinence and to determine the patient characteristics predictive of success. METHODS: Clinical and physiologic data of 86 patients with urinary incontinence who had received biofeedback-assisted PFMT were analyzed retrospectively. The clinical response was determined to be a success (requiring no more therapy) or a failure (requiring surgery or other medical therapy) at 3 months after completion of treatment. RESULTS: The success group included 57% of the enrolled patients. In the univariate analysis, the following factors had P values of less than 0.20: alcohol consumption, detrusor overactivity, type of urinary incontinence, and the change in the average amplitude of tonic contraction before treatment and after the 8th session of biofeedback-assisted PFMT. In the multiple logistic regression analysis, the only independent predictive factor of a successful response was a significant change in the average tonic contraction before treatment and after the 8th session (odds ratio, 1.661; 95% confidence interval, 1.015- 2.721). CONCLUSION: After biofeedback-assisted PFMT, 57% of patients with urinary incontinence required no further therapy. Increased pelvic floor muscle activity after the 8th session of PFMT predicted a successful response to treatment.

Predictors of leiomyoma recurrence after laparoscopic myomectomy.

STUDY OBJECTIVE: To evaluate recurrence and reoperation rate after laparoscopic myomectomy in relation to risk factors and identify suitable candidates for laparoscopic myomectomy to decrease recurrence. DESIGN: Multicenter retrospective cohort study (Canadian Task Force classification II-2). SETTING: Five university hospitals and a university-affiliated teaching hospital. PATIENTS: Five hundred and twelve women who underwent laparoscopic myomectomy between 1995 and 2004. All patients had a follow-up with clinical examination and transvaginal sonography for a median 13 months after surgery. INTERVENTION: Laparoscopic myomectomy. MEASUREMENTS AND MAIN RESULTS: Recurrence was defined as the appearance of a leiomyoma on ultrasound examination or identification of leiomyoma during subsequent surgery after the initial surgery. Cox regression (full model) analysis of the possible risk factors for recurrence followed by a stepwise variable selection was performed to eliminate confounding factors. The cumulative probability of leiomyoma recurrence increased steadily during the follow-up period, 11.7% after 1 year, 36.1% after 3 years, 52.9% at 5 years, and reached 84.4% at 8 years. The cumulative probability of reoperation for recurrent leiomyoma was much lower: 6.7% at 5 years and 16% at 8 years. Significant risk factors that were independently associated with cumulative recurrence were age, preoperative number of myoma, preoperative uterine size by pelvic examination, presence of associated pelvic disease, and delivery after laparoscopic myomectomy. The operative time and change of hematocrit were associated with the reoperation. Those who had fewer than 2 myomas before surgery, uterus size less than 13 gestational weeks measured by pelvic examination, no childbirth after laparoscopic myomectomy, and age at index surgery less than 35.5 years showed the lowest recurrence after laparoscopic myomectomy from Classification and Regression trees analysis. CONCLUSION: The risk of recurrence of leiomyoma after laparoscopic myomectomy is linked with the age, preoperative number of leiomyoma, preoperative uterine size, presence of associated pelvic disease, and childbirth after surgery.

Adapting a cognitive behavioral program in treating alcohol dependence in South Korea.

PURPOSE: This paper aims to evaluate the effects of the traditional Korean moral behavioral-cognitive approach treatment for promoting insight in patients with alcohol dependence. METHOD: Data were collected from 22 participants and 22 nonparticipants. The program consisted of daily practices of self-control and reflection, and weekly feedback sessions. The data were analyzed using the Mann-Whitney and Wilcoxon tests, among others. RESULT: There was statistically significant promotion of insight, especially in control/dependence insight, after treatment. CONCLUSION: The therapeutic intervention, considering the sociocultural factors, could be more effective in promoting insight in clients with alcohol dependence.

The incidence of ureteral obstruction and the value of intraoperative cystoscopy during vaginal surgery for pelvic organ prolapse.

OBJECTIVE: The objective of the study was to determine the incidence of ureteral obstruction during vaginal surgery for pelvic organ prolapse and the accuracy and efficacy of intraoperative cystoscopy. STUDY DESIGN: The study was a retrospective review of 700 consecutive patients who underwent vaginal surgery for anterior and/or apical pelvic organ prolapse with universal intraoperative cystoscopy. RESULTS: Thirty-seven patients (5.3%) had no spillage of dye from 1 or both ureters intraoperatively. The false-positive and negative cystoscopy rates were 0.4% and 0.3%, respectively. Thus, the true incidence of intraoperative ureteral obstruction was 5.1%. Intraoperative cystoscopy was accurate in 99.3% of cases, with a sensitivity and specificity of 94.4% and 99.5%, respectively. Suture removal relieved ureteral obstruction in 88% of cases. Six subjects (0.9%) had true ureteral injuries. CONCLUSION: Vaginal surgery for anterior and/or apical pelvic organ prolapse is associated with an intraoperative ureteral obstruction rate of 5.1%. Intraoperative cystoscopy accurately detects ureteral obstruction and allows for relief of obstruction in the majority of cases.

Incidence of perioperative complications of urogynecologic surgery in elderly women.

OBJECTIVE: The purpose of this study was to determine the incidence of and risk factors for perioperative complications in elderly women who undergo urogynecologic surgery. STUDY DESIGN: A retrospective chart review of patients > or = 75 years old who underwent urogynecologic surgery between January 1999 and December 2003 was performed. Demographics, comorbidities, and significant perioperative complications were recorded. The Charlson Comorbidity Index and American Society of Anesthesiologists classification were calculated to summarize the patients' overall perioperative risk. Logistic regression was used to identify independent risk factors for perioperative complications. RESULTS: Two hundred sixty-seven patients who were > or = 75 years old met the inclusion criteria; 25.8% of the patients had a significant perioperative complication. The most common perioperative complication was blood transfusion or significant blood loss, pulmonary edema, and postoperative congestive heart failure. Independent risk factors that were predictive of a patient having a perioperative complication were the length of surgery, coronary artery disease, and peripheral vascular disease. The Charlson Comorbidity Index and American Society of Anesthesiologists classification did not predict perioperative complications in this population. CONCLUSION: Pre-existing cardiovascular disease increases the risk of a significant perioperative complication in elderly women who undergo urogynecologic surgery. However, the overall perioperative morbidity rate in elderly women who undergo urogynecologic surgery is low.

Adherent cells generated during long-term culture of human umbilical cord blood CD34+ cells have characteristics of endothelial cells and beneficial effect on cord blood ex vivo expansion.

Hematopoiesis depends on the association of hematopoietic stem cells with stromal cells that constitute the hematopoietic microenvironment. The in vitro development of the endothelial cell from umbilical cord blood (UCB) is not well established and has met very limited success. In this study, UCB CD34(+) cells were cultured for 5 weeks in a stroma-free liquid culture system using thrombopoietin, flt3 ligand, and granulocyte-colony stimulating factor. By week 4-5, we found that firmly adherent fibroblast-like cells were established. These cells showed characteristics of endothelial cells expressing von Willebrand factor, human vascular cell adhesion molecule-1, human intracellular adhesion molecule-1, human CD31, E-selectin, and human macrophage. Furthermore, when comparing an ex vivo system without an established endothelial monolayer to an ex vivo system with an established endothelial monolayer, better expansion of total nucleated cells, CD34(+) cells, and colony-forming units (CFUs)-granulocyte-macrophage and CFUs-granulocyte-erythroid-megakaryocyte-macrophage were found during culture. This phenomenon was in part due to the fact that a significant reduction of apoptotic fractions was found in the CD34(+) cells, which were cultured on the adherent monolayer for up to 5 weeks. To gather quantitative data on the number of endothelial cells derived from a given number of CD34 cells, we performed limiting dilution assay by using Poisson distribution: the number of tested cells (linear scale) producing a 37% negative culture (logarithmic scale) is the number of cells containing one endothelial cell. By this method, one endothelial cell may be found from 314 CD34(+) cells after 5 weeks of culture. These results suggest that the UCB CD34(+) cell fraction contains endothelial cell precursors, establishing the hematopoietic microenvironment and providing the beneficial effects through downregulating apoptosis on UCB expansion protocols. These observations may provide insight for future cellular therapy or graft engineering.