Establishing a peripartum perineal trauma clinic: a narrative review.

INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injury (OASI) is not rare, and its consequences are multiple and potentially severe, especially for young women. Some dedicated perineal clinics have been established to improve the management of OASI. Despite their obvious importance, these specific clinics are underrepresented and underdeveloped. The objectives of this review are to explore various options for developing a peripartum perineal clinic and to compare the different practices regarding the mode of delivery for subsequent pregnancies after an OASI. METHODS: This narrative review covers information from patients' questionnaires specific to anal incontinence, anal physiology assessment, pelvic floor and anal sphincter imaging, and the arguments for choosing the mode of delivery after an OASI. RESULTS: This review highlights the extensive range of practices regarding the delivery mode after an OASI throughout national professional organizations and experienced perineal clinics. CONCLUSION: This review summarizes the different choices in developing a perineal clinic to facilitate their development in promoting health care and education specific for peripartum women concerning the perineal consequences of delivery for obstetrician-gynaecologists, family doctors, and residents.

Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia.

BACKGROUND: Pelvic floor muscle (PFM) dysfunctions are reported to be involved in provoked vestibulodynia (PVD). Although heightened PFM tone has been suggested, the relative contribution of active and passive components of tone remains misunderstood. Likewise, alterations in PFM contractility have been scarcely studied. AIMS: To compare PFM tone, including the relative contribution of its active and passive components, and muscular contractility in women with PVD and asymptomatic controls. METHODS: Fifty-six asymptomatic women and 56 women with PVD participated in the study. The PVD diagnosis was confirmed by a gynecologist based on a standardized examination. OUTCOMES: PFM function was evaluated using a dynamometric speculum combined with surface electromyography (EMG). PFM general tone was evaluated in static conditions at different vaginal apertures and during repeated dynamic cyclic stretching. The active contribution of tone was characterized using the ratio between EMG in a static position and during stretching and the proportion of women presenting PFM activation during stretching. Contribution of the passive component was evaluated using resting forces, stiffness, and hysteresis in women sustaining a negligible EMG signal during stretching. PFM contractility, such as strength, speed of contraction, coordination, and endurance, also was assessed during voluntary isometric efforts. RESULTS: Greater PFM resting forces and stiffness were found in women with PVD compared with controls, indicating an increased general tone. An increased active component also was found in women with PVD because they presented a superior EMG ratio, and a larger proportion of them presented PFM activation during stretching. Higher passive properties also were found in women with PVD. Women with PVD also showed decreased strength, speed of contraction, coordination, and endurance compared with controls. CLINICAL IMPLICATIONS: Findings provide further evidence of the contribution of PFM alterations in the etiology of PVD. These alterations should be assessed to provide patient-centered targeted treatment options. STRENGTHS AND LIMITATIONS: The use of a validated tool investigating PFM alterations constitutes a strength of this study. However, the study design does not allow the determination of the sequence of events in which these muscle alterations occurred-before or after the onset of PVD. CONCLUSION: Findings support the involvement of active and passive components of PFM tone and an altered PFM contractility in women with PVD. Morin M, Binik YM, Bourbonnais D, et al. Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia. J Sex Med 2017;14:592-600.

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series.

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.

Preparative scale synthesis of the biaryl core of anacetrapib via a ruthenium-catalyzed direct arylation reaction: unexpected effect of solvent impurity on the arylation reaction.

In this report, we disclose our findings regarding the remarkable effect of a low-level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described.

Application of a new method in the study of pelvic floor muscle passive properties in continent women.

The aim of this study was to present a new methodology for evaluating the pelvic floor muscle (PFM) passive properties. The properties were assessed in 13 continent women using an intra-vaginal dynamometric speculum and EMG (to ensure the subjects were relaxed) in four different conditions: (1) forces recorded at minimal aperture (initial passive resistance); (2) passive resistance at maximal aperture; (3) forces and passive elastic stiffness (PES) evaluated during five lengthening and shortening cycles; and (4) percentage loss of resistance after 1min of sustained stretch. The PFMs and surrounding tissues were stretched, at constant speed, by increasing the vaginal antero-posterior diameter; different apertures were considered. Hysteresis was also calculated. The procedure was deemed acceptable by all participants. The median passive forces recorded ranged from 0.54N (interquartile range 1.52) for minimal aperture to 8.45N (interquartile range 7.10) for maximal aperture while the corresponding median PES values were 0.17N/mm (interquartile range 0.28) and 0.67N/mm (interquartile range 0.60). Median hysteresis was 17.24N *mm (interquartile range 35.60) and the median percentage of force losses was 11.17% (interquartile range 13.33). This original approach to evaluating the PFM passive properties is very promising for providing better insight into the patho-physiology of stress urinary incontinence and pinpointing conservative treatment mechanisms.

Accuracy of recall in quality-of-life assessment among women operated on for stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: The purpose of this study is to assess the validity and reliability of a retrospective quality-of-life (QOL) assessment. METHODS: The Incontinence Impact Questionnaire (IIQ-30) and the Short-Form Health Survey (SF-12) were self-administered pre-operatively. At 3 months post-op, the IIQ-30 and SF-12 surveys were mailed to patients to reassess their pre-operative QOL status. Pearson's correlation coefficient (r) and the intraclass correlation coefficient (ICC) were used to test the validity and reliability of the recalled IIQ and SF-12 scores. RESULTS: Recall validity was excellent for the IIQ-30 (r = 0.64) and moderate for the SF-12 (r = 0.46 (physical component summary or PCS) and 0.42 (mental component summary or MCS)). Recall reliability was moderate with the IIQ-30 (ICC = 0.62) and poor with the SF-12 (ICC = 0.44 (PCS) and 0.49 (MCS)). CONCLUSIONS: The IIQ-30 can be reliably used in a retrospective manner among women who have undergone surgery for SUI 3 months earlier.

Responsiveness and clinical utility of the geriatric self-efficacy index for urinary incontinence.

OBJECTIVES: To report on the responsiveness testing and clinical utility of the 12-item Geriatric Self-Efficacy Index for Urinary Incontinence (GSE-UI). DESIGN: Prospective cohort study. SETTING: Six urinary incontinence (UI) outpatient clinics in Quebec, Canada. PARTICIPANTS: Community-dwelling incontinent adults aged 65 and older. MEASUREMENTS: The abridged 12-item GSE-UI, measuring older adults' level of confidence for preventing urine loss, was administered to all new consecutive incontinent patients 1 week before their initial clinic visit, at baseline, and 3 months posttreatment. At follow-up, a positive rating of improvement in UI was ascertained from patients and their physicians using the Patient's and Clinician's Global Impression of Improvement scales, respectively. Responsiveness of the GSE-UI was calculated using Guyatt's change index. Its clinical utility was determined using receiver operating curves. RESULTS: Eighty-nine of 228 eligible patients (39.0%) participated (mean age 72.6+5.8, range 65-90). At 3-month follow-up, 22.5% of patients were very much better, and 41.6% were a little or much better. Guyatt's change index was 2.6 for patients who changed by a clinically meaningful amount and 1.5 for patients having experienced any level of improvement. An improvement of 14 points on the 12-item GSE-UI had a sensitivity of 75.1% and a specificity of 78.2% for detecting clinically meaningful changes in UI status. Mean GSE-UI scores varied according to improvement status (P<.001) and correlated with changes in quality-of-life scores (r=0.7, P<.001) and reductions in UI episodes (r=0.4, P=.004). CONCLUSION: The GSE-UI is responsive and clinically useful.

Synthesis of 3-aminoisoxazoles via the addition-elimination of amines on 3-bromoisoxazolines.

A novel two-step procedure for the synthesis of 3-amino-5-substituted-isoxazoles is described. In the presence of a base, readily available 3-bromoisoxazolines react with amines to afford 3-aminoisoxazolines. An oxidation protocol was developed for these heterocycles to provide 3-aminoisoxazoles in consistently high yield.

Reliability of dynamometric passive properties of the pelvic floor muscles in postmenopausal women with stress urinary incontinence.

UNLABELLED: The passive properties of the pelvic floor muscles (PFM) might play a role in stress urinary incontinence (SUI) pathophysiology. AIM: To investigate the test-retest reliability of the dynamometric passive properties of the PFM in postmenopausal SUI women. METHODS: Thirty-two SUI postmenopausal women were convened to two sessions 2 weeks apart. In each session, the measurements were repeated twice. The pelvic floor musculature was evaluated in four different conditions: (1) forces recorded at minimal aperture (initial passive resistance); (2) passive resistance at maximal aperture; (3) five lengthening and shortening cycles (Forces and passive elastic stiffness (PES) were evaluated at different vaginal apertures. Hysteresis was also calculated.); (4) Percentage of passive resistance loss after 1 min of sustained stretching was computed. The generalizability theory was used to calculate two reliability estimates, the dependability indices (Phi) and the standard error of measurement (SEM), for one session involving one measurement or the mean of two measurements. RESULTS: Overall, the reliability of the passive properties was good with indices of dependability of 0.75-0.93. The SEMs for forces and PES were 0.24-0.67 N and 0.03-0.10 N/mm, respectively, for mean, maximal and 20-mm apertures, representing an error between 13% and 23%. Passive forces at minimal aperture showed lower reliability (Phi = 0.51-0.57) compared with other vaginal openings. The aperture at a common force of 0.5 N was the only parameter demonstrating a poor reliability (Phi = 0.35). CONCLUSION: This new approach for assessing PFM passive properties showed enough reliability for highly recommending its inclusion in the PFM assessment of SUI postmenopausal women.

Creation and testing of the Geriatric Self-Efficacy Index for Urinary Incontinence.

OBJECTIVES: To report on the content development, construct validity, and reliability testing of the Geriatric Self-Efficacy Index for Urinary Incontinence (GSE-UI). DESIGN: Prospective cohort study. SETTING: Six UI outpatient clinics in Quebec, Canada. PARTICIPANTS: Community-dwelling incontinent men and women aged 65 and older. MEASUREMENTS: Thirty-eight items were generated using a literature search and interdisciplinary panel of experts. Item reduction was achieved through field-testing with 75 older men and women with UI attending an information session. The final 20-item draft, measuring older adults' level of confidence in preventing urine loss, was administered to a new group of consecutive patients 1 week before and at the time of their first visit to the UI clinic to enable evaluation of test-retest reliability. A 3-day voiding diary, quantifying the frequency of UI, and the Incontinence Quality of Life questionnaire were used to test construct validity. RESULTS: One hundred sixteen of 300 eligible patients (39%) participated (mean age+/-standard deviation 74+/-6, range 65-87). The GSE-UI items showed normal distributions and no ceiling effects. Self-efficacy scores ranged from 16 to 193 (mean 104+/-41, possible range 0-200) and correlated positively with quality of life scores (r=0.7, P<.001) and negatively with UI severity (r=-0.4, P<.001). Internal consistency for the GSE-UI was 0.94 (Cronbach alpha). Initial test-retest reliability of the 20 items using intraclass correlations ranged from 0.50 to 0.86. CONCLUSION: The GSE-UI will enable measurement of whether a person's confidence in their ability to prevent urine loss is an important mechanism contributing to improvements in UI.

Enantioselective organocatalytic transfer hydrogenation reactions using Hantzsch esters.

Within the realm of catalytic asymmetric hydrogenation, the focus continues to be on the use of chiral metal complexes in conjunction with a hydrogen source. Recently, the widespread development of organocatalysis, including the invention of iminium activation, has led to the discovery of many new enantioselective transformations. Based on this strategy, a number of bioinspired processes for the enantioselective organocatalytic transfer hydrogenation of alpha,beta-unsaturated carbonyl compounds and imines have been discovered. These topics will be the focus of this Account.

In vivo footprinting analysis of the Glypican 3 (GPC3) promoter region in neuroblastoma cells.

Glypican 3 (GPC3) is an X-linked gene that has its peak expression during development and is down-regulated in all studied tissues after birth. We have shown that GPC3 was expressed in neuroblastoma and Wilms' tumor. To understand the mechanisms regulating the transcription of this gene in neuroblastoma cells, we have focused our study on the identification of putative transcription factors binding the promoter. In this report we performed in vivo dimethylsulfate, UV type C irradiation and DNaseI footprinting analyses coupled with ligation-mediated PCR on nearly 1000 bp of promoter in two neuroblastoma cell lines, SJNB-7 (expressing GPC3) and SK-N-FI (not expressing GPC3). Nucleosome signature footprints were observed in the most distal part of the studied region in both cell lines. We detected eight large differentially protected regions, suggesting the presence of binding proteins in both cell lines but more DNA-protein interactions in GPC3-expressing cells. Sp1 was previously shown to be able to bind some of these regions. Here by combining electromobility shift assays and chromatin immunoprecipitations we showed that the transcription factor NFY was part of the DNA-protein complex found in footprinted regions upstream of the described minimal promoter. These studies performed on chromatin in situ suggest that NFY and yet unknown cell type-specific factors may play an important role in the regulation of GPC3.

Transcriptional regulation of the cyclin-dependent kinase inhibitor 1A (p21) gene by NFI in proliferating human cells.

The cyclin-dependent kinase inhibitor 1A (CDKN1A), also known as p21 (WAF1/CIP1) modulates cell cycle, apoptosis, senescence and differentiation via specific protein-protein interactions with the cyclins, cyclin-dependent kinase (Cdk), and many others. Expression of the p21 gene is mainly regulated at the transcriptional level. By conducting both ligation-mediated PCR (LMPCR) and chromatin immunoprecipitation (ChIP) in vivo, we identified a functional target site for the transcription factor, nuclear factor I (NFI), in the basal promoter from the p21 gene. Transfection of recombinant constructs bearing mutations in the p21 NFI site demonstrated that NFI acts as a repressor of p21 gene expression in various types of cultured cells. Inhibition of NFI in human skin fibroblasts through RNAi considerably increased p21 promoter activity suggesting that NFI is a key repressor of p21 transcription. Over-expression of each of the four NFI isoforms in HCT116 cells established that each of them contribute to various extend to the repression of the p21 gene. Most of all, over-expression of NFI-B in doxorubicin, growth-arrested HCT116 increased the proportion of cells in the S-phase of the cell cycle whereas NFI-A and NFI-X reduced it, thereby establishing a role for NFI in the cell cycle dependent expression of p21.

Organocatalytic transfer hydrogenation of cyclic enones.

The first enantioselective organocatalytic transfer hydrogenation of cyclic enones has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated cycloalkenones, to generate beta-stereogenic cyclic ketones. The use of imidazolidinone 4 as the asymmetric catalyst has been found to mediate the hydrogenation of a large class of enone substrates with tert-butyl Hantzsch ester serving as an inexpensive source of hydrogen. The capacity of catalyst 4 to enable enantioselective transfer hydrogenation of cycloalkenones has been extended to five-, six-, and seven-membered ring systems. The sense of asymmetric induction is in complete accord with the stereochemical model first reported in conjunction with the use of catalyst 4 for enantioselective ketone Diels-Alder reactions.

Enantioselective organocatalytic hydride reduction.

The first enantioselective organocatalytic hydride reduction has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated aldehydes to generate beta-stereogenic aldehydes. The use of imidazolidinone 2 as the asymmetric catalyst has been found to mediate the transfer of hydrogen to a large class of enal substrates from ethyl Hantzsch ester. The capacity of catalyst 2 to accelerate E-Z isomerization prior to selective E-olefin reduction allows the implementation of geometrically impure enals in this operationally simple protocol.

Enantioselective allylation of beta,gamma-unsaturated aldehydes generated via Lewis acid induced rearrangement of 2-vinyloxiranes.

[reaction: see text] 2-Vinyloxiranes have been found to be excellent surrogates to beta,gamma-unsaturated aldehydes. These valuable electrophiles, generated in situ by treatment of a 2-vinyloxirane with a catalytic amount of Sc(OTf)(3), are effectively trapped by the chiral allylating agents based on alpha-pinene, affording bishomoallylic alcohols in high yield and excellent selectivity.