Continence Is Not Affected after Sling Revision with Transvaginal Tape Elongation for Post-Sling Voiding Dysfunction.

Voiding dysfunction (VD) after sling operation is not uncommon. Sling revisions by incision/excision are usually effective; however, they may result in recurrent stress urinary incontinence (SUI). We aimed to evaluate continence status after an innovative sling revision procedure that preserves the integrity of the sling. Patients who underwent either a single-incision (AJUST) or a trans-obturator (TVT-O) mid-urethral sling were studied. Transvaginal tape elongation (i.e., sling midline incision and mesh interposition) was performed on patients with post-sling VD. Factors that may affect recurrent SUI were investigated by statistical analyses. Of 119 patients, 90 (75.6%) (45 AJUST and 45 TVT-O) were available for long-term (median 9; 8-10 years) follow-up. A significantly higher rate (17.2% vs. 3.3%, p = 0.014) of VD was noted after AJUST (N = 10) than after TVT-O (N = 2). After sling revision, four (33%) of the 12 cases reported recurrent SUI, which was not significantly different (p = 1.000) from the rate (37%, 29/78) of patients who did not undergo sling revision. Further statistical analyses revealed no significant predisposing factors affecting the recurrence of SUI. Surgical continence did not seem to be affected by having had sling revision with transvaginal tape elongation for post-sling VD.

Spontaneous abdominal wall endometriosis: A Case Report and review of the literature.

OBJECTIVE: We present a case of spontaneous abdominal wall endometriosis presenting as a painless nodular mass in a woman with no prior history of abdominal surgery. CASE REPORT: Abdominal wall endometriosis (AWE) is an uncommon form of endometriosis, usually arising due to a past history of cesarean section or abdominal hysterectomy. However, in rare cases, abdominal wall endometriosis can arise in women with no prior history of abdominal surgery. A 48-year-old woman presented to our obstetrics and gynecology clinic with a painless nodular mass in the right lower quadrant of the abdomen. Abdominal wall ultrasound showed a hypoechoic heterogenous mass under the skin. Wide surgical resection of the mass was conducted and post-operative histopathological report revealed abdominal wall endometriosis. CONCLUSION: Spontaneous abdominal wall endometriosis is an uncommon pathologic condition in which accurate diagnosis is difficult. As an increasing number of obstetrical and gynecological procedures are conducted worldwide, surgeons should keep this clinical entity in the differential diagnosis of any abdominal mass in reproductive-aged females regardless of their past surgical history.

Association of Baseline Pelvic Floor Muscle Activities With Sexual and Urinary Functions In Female Stress Urinary Incontinence.

BACKGROUND: The presence of reactive and strong pelvic floor muscle (PFM) activities is supposed to be associated with better urinary and sexual functions in female stress urinary incontinence (SUI). AIM: This study was to explore the association of baseline PFM activities, both volitional and reflex, with urinary and sexual functions in women with SUI but who had no experience of PFM training programs before. METHODS: Secondary analysis of a prospectively maintained database identified 125 sexually active women with SUI who had met the eligibility criteria. All patients had undergone intravaginal digital examination and pelvic ultrasound to detect volitional and reflex PFM activities, respectively, and responded to questionnaire surveys, including short forms of the urogenital distress inventory, incontinence impact questionnaire-7, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire. On pelvic ultrasound, an inward clitoral motion and an anorectal lift preceding or during coughing were regarded as the presence of reflex activities of the PFM. OUTCOMES: The relationship of volitional and reflex PFM activities with pelvic floor dysfunction relating questionnaires and urethral function on urodynamic studies was analyzed. RESULT: Of the 125 women studied, 30 (24.0%) had volitional PFM contraction strength less than grade 2, 74 (59.2%) grade 2 to 3, and 21 (16.8%) greater than grade 3 based on the modified Oxford grading scale. During or preceding coughing, an inward clitoral motion was not observed on ultrasound in 9 (7.2%) women and an anorectal lift was not observed in 8 (6.4%) women. The strength of volitional PFM contraction and the presence or absence of anorectal lift reflex was not associated with urethral and sexual function. In contrast, the absence of reflex inward clitoral motion was significantly associated with lower maximum urethral closure pressure (P = .042) and higher scores of urogenital distress inventory-6 (P = .006) and incontinence impact questionnaire-7 (P = .029). CLINICAL IMPLICATIONS: Higher volitional PFM contraction strength was not associated with better sexual and urinary functions; however, loss of one reflex PFM activity was associated with poorer urinary function. STRENGTHS & LIMITATION: To our knowledge, this is the first study that evaluates the association of baseline PFM activities with sexual and urinary functions in female SUI. Nevertheless, the cross-sectional design of this study cannot well support the cause-effect relationship CONCLUSION: Besides PFM physiotherapy for enhancing sexual and urinary functions in female SUI, additional treatment strategies such as neuromodulation should take into consideration for those who had absent reflex PFM activities. Yang E, Yang SH, Huang WC, et al. Association of Baseline Pelvic Floor Muscle Activities With Sexual and Urinary Functions In Female Stress Urinary Incontinence. J Sex Med 2021;18:1698-1704.

A 3-year longitudinal survey of overactive bladder in community-dwelling male residents aged 40 years and above.

OBJECTIVES: To evaluate the short-term evolution and risk factors of overactive bladder (OAB) in community-dwelling male residents aged 40 years and above in central Taiwan. METHODS: This was a 3-year longitudinal cohort study. From January 2012 to December 2012, community residents aged 40 years and above, living in central Taiwan, were invited to participate in this study. A yearly Overactive Bladder Symptom Score (OABSS) questionnaire was used to assess the prevalence, incidence, remission, persistence, and relapse of OAB for three consecutive years. OAB was defined as total OABSS ≧4 and urgency score ≧2. RESULTS: Nine hundred forty-one male residents aged ≧40 years were recruited. The prevalence of OAB was 15%. The male residents with OAB were older, had a history of urological surgery, were unemployed, had lower educational levels, and lower yearly incomes compared with male residents without OAB. The prevalence increased with age when stratified into different age cohorts (40-49, 7%; 50-59, 12.7%; 60-69, 18.2%; ≧70, 32%; P < .001). Age ≧60 (odds ratio [OR] 2.58; 95% CI, 1.62-4.11) and history of urological surgery (OR 2.85; 95% CI, 1.29-6.30) were the major risk factors after multivariable logistic regression analysis. Eight hundred participants completed all the 3 years' questionnaires. The second- and third-year incidence rates of OAB were 10% (69/691) and 6.2% (42/674), respectively. The remission rates were 47.7% (52/109) and 46% (58/126), respectively. The two-year OAB persistence rate was 30.3% (33/109). CONCLUSIONS: The prevalence and yearly incidence of OAB are high in community-dwelling male residents aged ≧40 years in central Taiwan. Age is an important risk factor.

Development and Clinical Evaluation of a High-Throughput LC-MS/MS Assay for Vitamin B6 in Human Plasma and Serum.

BACKGROUND: Pyridoxal 5'-phosphate (PLP) is the primary circulatory form of vitamin B6, an essential cofactor for numerous biochemical enzymatic reactions. Conventional PLP analysis using high-performance liquid chromatography (HPLC) with fluorescence requires derivatization and long injection-to-injection time. Development of high-throughput LC-MS/MS assays is desirable. METHODS: Stable isotope labeled internal standard was added to aliquots of samples, proteins were precipitated using trichloroacetic acid, and supernatants were analyzed by multiple reaction monitoring using LC-MS/MS in positive ion mode. Analysis time for PLP was 3.0 min using single column HPLC separation and 2.4 min using alternating column regeneration (ACR). Clinical evaluation of the method included review of results (n = 102 386) from routine performance of the assay. RESULTS: The assay was linear to 500 nmol/L; limit of quantification was 5 nmol/L. Imprecision (CV) of the assay was <5%. Equivalent performance was observed for single HPLC column and ACR. In 62% of routinely analyzed patient samples, PLP concentrations were within the reference interval; higher PLP concentrations were observed in samples from males than from females. Vitamin B6 deficiency was lowest in children and highest in elderly adults. Lower PLP concentrations were observed in samples collected during winter/spring than during summer/fall. We observed lower concentrations in plasma collected in lithium heparin tubes, suggesting PLP degradation caused by the anticoagulant. CONCLUSIONS: This LC-MS/MS method allows PLP determination using simple sample preparation and short analysis time. We observed association of PLP concentrations with age, sex, and season of sample collection. Our data indicate that lithium heparin anticoagulant tubes reduce measured PLP concentration.

Associations of Waist Circumference, Socioeconomic, Environmental, and Behavioral Factors with Chronic Kidney Disease in Normal Weight, Overweight, and Obese People.

Background: Chronic kidney disease (CKD) places a heavy burden on the healthcare system worldwide. The risk factors may vary by body adiposity. We aimed to investigate the associations of socioeconomic, environmental, and behavioral factors with CKD in different groups of body mass indexes (BMI). Methods: A case-control study was conducted in 3280 participants (1048 CKD and 2232 non-CKD) from seven hospitals and nearby communities from May 2012 to August 2015. Personal characteristics, anthropometrics, environmental exposures, and health-related behaviors were assessed using a structured questionnaire. The logistic regression models were utilized for analysis. Results: Older age (odd ratio, OR = 2.85; p < 0.001), being men (OR = 4.23; p < 0.001), smoking (OR = 3.36; p < 0.001), stable income (OR = 0.33; p < 0.001), higher education (OR = 0.37~0.38; p < 0.001), and daily adequate water intake (OR = 0.64; p = 0.010) were associated with CKD in normal weight people. Older age (OR = 2.49; p < 0.001), being men (OR = 3.36; p < 0.001), education (OR = 0.44, p = 0.004), hypertension (OR = 2.93; p<0.001), diabetes (OR = 1.83; p = 0.004), and using traditional Chinese medicine (OR = 2.03, p = 0.014) were associated with CKD in overweight people. Older age (OR = 2.71; p < 0.001), being men (OR = 2.69; p < 0.001), hypertension (OR = 2.93; p < 0.001), diabetes (OR = 1.94; p = 0.001) were associated with CKD in obese people. Conclusions: The associated factors of CKD varied by different groups of BMI. These findings may help to develop potential interventions to manage CKD.

Education and Protein Supplementation Improve Nutritional Biomarkers among Hypoalbuminemic Peritoneal Dialysis Patients: A Quasi-Experimental Design.

Protein-energy wasting is prevalent in peritoneal dialysis patients, which causes a heavy burden for individuals and healthcare systems. We aimed to investigate the effect of nutritional education, and/or protein supplementation on nutritional biomarkers in hypoalbuminemic peritoneal dialysis patients. A quasi-experimental study was conducted in two dialysis centers at Taipei Tzu Chi Hospital and Shin Kong Wu Ho-Su Memorial Hospital. Patients were allocated in three groups including control (n = 12), milk protein (n = 21) and soy protein (n = 20). All patients received dietary guidelines from dietitians and completed 3-day dietary records during monthly visits for consecutive three months. Nutrients were analyzed using Nutritionist Professional software. Blood urea nitrogen (BUN), creatinine, albumin, total protein, hemoglobin, serum calcium, phosphorus, sodium, and potassium were assessed monthly. Total cholesterol and triglycerides were measured every three months. After three-month intervention, protein intake (percent of total calories), and serum albumin were significantly increased in three groups. Protein, phosphorus intake, and BUN were increased in two intervention groups. Total serum protein increased in control and milk protein groups, and creatinine increased the control group. Serum phosphorus was not significantly changed. Nutritional education alone, or combined with protein supplementation, significantly improve protein intake, and nutritional status by increasing serum albumin, but not serum phosphorus in hypoalbuminemic peritoneal dialysis patients.

Coproduction of Research Questions and Research Evidence in Public Health: The Study to Prevent Teen Drinking Parties.

Community-based participatory research (CBPR) provides a set of principles and practices intended to foster coproduction of knowledge. However, CBPR often has shortcomings when applied to population-level policy and practice interventions, including a focus on single communities and a lack of focus on policy change. At the same time, community trials focused on policy have shortcomings, including lack of stakeholder involvement in framing research questions and modest engagement in study implementation and interpretation and dissemination of results. We describe an attempt to hybridize CBPR and community trials by creating a partnership that included a national membership organization, a coalition advisory board, intervention and delayed intervention communities, and an academic study team, which collaborated on a study of community strategies to prevent underage drinking parties. We use qualitative and quantitative data to critically assess the partnership. Areas where the partnership was effective included (1) identifying a research question with high public health significance, (2) enhancing the intervention, and (3) improving research methods. Challenges included community coalition representatives' greater focus on their own communities rather than the production of broader scientific knowledge. This model can be applied in future attempts to narrow the gap between research, policy, and practice.

The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance.

Panitumumab and cetuximab target the epidermal growth factor receptor for the treatment of metastatic colorectal cancer. These therapies provide a significant survival benefit to patients with metastatic colorectal cancer with wild-type RAS. A single point mutation in the ectodomain of EGFR (S468R) confers acquired or secondary resistance in cetuximab treated patients, which is not observed in panitumumab-treated patients. Structural and biophysical studies presented here show this mutation directly blocks cetuximab binding to EGFR domain III and describes a unique mechanism by which panitumumab uses a central cavity to accommodate this mutation.

Using public health and community partnerships to reduce density of alcohol outlets.

Excessive alcohol use causes approximately 80,000 deaths in the United States each year. The Guide to Community Preventive Services recommends reducing the density of alcohol outlets - the number of physical locations in which alcoholic beverages are available for purchase either per area or per population - through the use of regulatory authority as an effective strategy for reducing excessive alcohol consumption and related harms. We briefly review the research on density of alcohol outlets and public health and describe the powers localities have to influence alcohol outlet density. We summarize Regulating Alcohol Outlet Density: An Action Guide, which describes steps that local communities can take to reduce outlet density and the key competencies and resources of state and local health departments. These include expertise in public health surveillance and evaluation methods, identification and tracking of outcome measures, geographic information systems (GIS) mapping, community planning and development of multisector efforts, and education of community leaders and policy makers. We illustrate the potential for partnerships between public health agencies and local communities by presenting a contemporary case study from Omaha, Nebraska. Public health agencies have a vital and necessary role to play in efforts to reduce alcohol outlet density. They are often unaware of the potential of this strategy and have strong potential partners in the thousands of community coalitions nationwide that are focused on reducing alcohol-related problems.

Ordering of the N-terminus of human MDM2 by small molecule inhibitors.

Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel ß-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.

Identification of substrates of SMURF1 ubiquitin ligase activity utilizing protein microarrays.

The ubiquitin proteasome pathway (UPP) has been implicated in a number of pathogenic diseases: cancer, inflammation, metabolic disorders, and viral infection. The human genome contains well over 500 genes encoding proteins involved in the UPP. Ubiquitin ligases (E3s) comprise the largest subset of these genes, and together with an E2 partner, provide the substrate selectivity required for regulating cellular proteins through the covalent attachment of ubiquitin. Many ligases that have been identified in critical cellular pathways have no known substrates. Even those E3s with known substrates may have a yet unidentified role in the pathways on which they lie and as such may have additional substrates. It is critical to identify these substrates for discovery of selective small molecule inhibitors aimed at therapeutic intervention. Other methods, such as mass spectrometry, have been utilized for identifying ligase substrates, but these are labor-intensive and require a significant investment. In this study, we utilized protein microarrays for the identification of substrates of the HECT domain E3, Smurf1. Smurf1 is a critical regulator of TGF-beta and bone morphogenic protein signaling, and has been demonstrated to play a role in regulating cell polarity through the degradation of RhoA. We set out to identify novel Smurf1 substrates involved in the regulation of the aforementioned pathways. Proof-of-principle experiments with known Smurf1 substrates demonstrated efficient ubiquitination thereby validating this approach. Assaying a human protein microarray for ubiquitination with Smurf1 and the partner E2 ubiquitin ligase Ubch5 or Ubch7 identified 89 potential substrates of the Smurf1 E3 activity, which spanned a number of different biological pathways. Substrates identified utilizing protein microarray technology have been validated in vitro. Here we demonstrate the utility of this approach for identifying substrates of particular E2/E3 complexes.

Clinical and pathophysiological correlates of the symptom severity of stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: The pathophysiology of stress urinary incontinence (SUI) is multifactorial. The aim of this study was to explore the factor determining the symptom severity of SUI. METHODS: One hundred twenty-four women with SUI were retrospectively investigated. Clinical data for analyses included demographics, pelvic organ prolapse quantification, SUI severity using a 4-point Likert scale, ultrasound, 1-h pad tests, and urodynamic studies. Data were analyzed using the Spearman's rho test and Kruskal-Wallis test. RESULTS: The symptom severity was not correlated with risk factors of SUI or the morphologic manifestations representing urethral support defect, but was significantly correlated with urine loss on 1-h pad test, Valsalva leak point pressure (VLPP) grading, and maximum urethral closure pressure (MUCP). Women with higher SUI severity had greater urine loss on 1-h pad tests, worse VLPP grading, and lower MUCP. CONCLUSIONS: Urethral sphincter function appears to be an important determinant for the symptom severity of SUI.

The correlations of incontinence-related quality of life measures with symptom severity and pathophysiology in women with primary stress urinary incontinence.

PURPOSE: We sought to explore the correlations of incontinence-related quality of life (QoL) measures with the symptom severity and pathophysiological factors for female stress urinary incontinence (SUI). METHODS: We retrospectively reviewed the records of 707 women who had primary SUI. Clinical data for analysis included Ingelman-Sundberg scales, 1-h pad tests, incontinence-related QoL questionnaires comprising short forms of the Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7), ultrasound assessment of urethral support and urethral sphincter function determined by maximum urethral closure pressure and Valsalva leak point pressure. The correlations of incontinence-related QoL, measured by UDI-6 and IIQ-7 questionnaires, with the independent variables such as Ingelman-Sundberg scales, 1-h pad tests, urethral support and urethral sphincter function were investigated. RESULTS: The scores of item 3 of UDI-6 as well as the sum scores of UDI-6 and IIQ-7 had significant correlation with incontinence severity assessed by Ingelman-Sundberg scales and 1-h pad tests. However, only the scores of item 3 of UDI-6 were significantly correlated with the presence of bladder neck funneling on ultrasound and maximum urethral closure pressure. No correlations exist between sum scores of UDI-6 or IIQ-7 and the pathophysiological factors of SUI. CONCLUSIONS: Urogenital Distress Inventory-6 and IIQ-7 play important and complementary roles in comprehensive assessment for SUI, but are not identical to the pathophysiological factors.

Different modes of inhibitor binding to prolyl hydroxylase by combined use of X-ray crystallography and NMR spectroscopy of paramagnetic complexes.

In aqueous solution, azaquinolone inhibitors bind to prolyl 4-hydroxylase in two different orientations, as first detected by (19)F spectroscopy. This contrasts with the crystallographic structure where only one orientation has been determined. Dissection of the metal binding properties of the enzyme allowed structures of both complexes to be obtained in solution from (19)F and (13)C dipolar shifts in a labeled ligand.

Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction.

Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that is frequently disabled in human tumors. In many tumor types, p53 is deleted or mutated, but in others p53 is inactivated by overexpression or amplification of its negative regulator mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as a potent inhibitor of the MDM2-p53 protein-protein interaction. This screening hit was found to be chemically unstable and difficult to handle due to poor DMSO solubility. Co-crystallization with the target protein helped to direct further optimization and provided a tractable lead series of novel MDM2-p53 inhibitors. In cellular assays, these compounds were shown to upregulate p53 protein levels and p53 signaling and to cause p53-dependent inhibition of proliferation and apoptosis.

Reliability of real-time ultrasound to detect pelvic floor muscle contraction in urinary incontinent women.

PURPOSE: We determined the reliability of real-time ultrasound for detecting involuntary or reflex pelvic floor muscle contraction. MATERIALS AND METHODS: A total of 118 women with the symptomatic and urodynamic evidence of stress urinary incontinence were recruited in a 3-year period from tertiary referral urogynecology clinics. Under the oral instruction of strong coughing involuntary pelvic floor muscle contraction was detected using introital ultrasound in real-time and cine loop modes. Two dynamic imaging features were considered involuntary pelvic floor muscle contraction, including an inward clitoral motion and a superior-anterior anorectal lift before or during coughing. RESULTS: Real-time ultrasound had good reliability to detect involuntary pelvic floor muscle contraction. For interobserver and intra-observer reliability Cohen's kappa was 0.645 to 0.679. Of the 118 women real-time ultrasound before or during coughing showed an inward clitoral motion in 100 (93%) and an anorectal lift in 108 (92%). Neither type of contraction during coughing was identified in 2 women. Although the 2 contraction patterns were synchronized in 88% of women, for this synchronization kappa was only 0.159, indicating poor coordination between these 2 involuntary activities. CONCLUSIONS: Real-time ultrasound is a reliable tool for detecting involuntary pelvic floor muscle contraction.

A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels approximately 2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR(-/-) mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.

Function of the extrinsic hindlimb muscles in trotting dogs.

The extrinsic appendicular muscles of mammals have been suggested to impose parasagittal torques on the trunk that require recruitment of the oblique hypaxial muscles for stabilization. To determine if the recruitment of the protractors and retractors of the hindlimb are compatible with this hypothesis, we monitored changes in the recruitment of eleven muscles that span the hip joint to controlled manipulations of locomotor forces in trotting dogs. The results indicate that the primary retractor muscles of the hindlimb produce a small retraction moment at the hip joint early in the support phase during trotting at constant speed on a level surface. Thus, although the forelimb of dogs appears to function as a compliant strut, the hindlimb functions as a lever early in stance phase. Nevertheless, our results indicate that when dogs run at constant speed on a level surface a primary function of both the retractor and protractor muscles of the hindlimb is to produce swing phase of the limb. When the trotting dogs did net work in the fore-aft direction, by running uphill or downhill or by resisting a horizontally directed force, recruitment of the protractor and retractor muscles of the hip joint increased or decreased in the anticipated fashion. These observations are consistent with the hypothesis that recruitment of the oblique hypaxial muscles in trotting dogs function to stabilize the trunk against torques produced by protractor and retractor muscles of the hindlimb.