Structure-Activity Relationships of 8-Hydroxyquinoline-Derived Mannich Bases with Tertiary Amines Targeting Multidrug-Resistant Cancer.

A recently proposed strategy to overcome multidrug resistance (MDR) in cancer is to target the collateral sensitivity of otherwise resistant cells. We designed a library of 120 compounds to explore the chemical space around previously identified 8-hydroxyquinoline-derived Mannich bases with robust MDR-selective toxicity. We included compounds to study the effect of halogen and alkoxymethyl substitutions in R5 in combination with different Mannich bases in R7, a shift of the Mannich base from R7 to R5, as well as the introduction of an aromatic moiety. Cytotoxicity tests performed on a panel of parental and MDR cells highlight a strong influence of experimentally determined pKa values of the donor atom moieties, indicating that protonation and metal chelation are important factors modulating the MDR-selective anticancer activity of the studied compounds. Our results identify structural requirements increasing MDR-selective anticancer activity, providing guidelines for the development of more effective anticancer chelators targeting MDR cancer.

Ellipsoid Localization Microscopy Infers the Size and Order of Protein Layers in Bacillus Spore Coats.

Multilayered protein coats are crucial to the dormancy, robustness, and germination of bacterial spores. In Bacillus subtilis spores, the coat contains over 70 distinct proteins. Identifying which proteins reside in each layer may provide insight into their distinct functions. We present image analysis methods that determine the order and geometry of concentric protein layers by fitting a model description for a spheroidal fluorescent shell image to optical micrographs of spores incorporating fluorescent fusion proteins. The radius of a spherical protein shell can be determined with <10 nm error by fitting an equation to widefield fluorescence micrographs. Ellipsoidal shell axes can be fitted with comparable precision. The layer orders inferred for B. subtilis and B. megaterium are consistent with measurements in the literature. The aspect ratio of elongated spores and the tendency of some proteins to localize near their poles can be quantified, enabling measurement of structural anisotropy.

A chemocentric approach to the identification of cancer targets.

A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided.

Parallel synthesis of 1,2,4-triazole derivatives using microwave and continuous-flow techniques.

An efficient and convenient solution-phase synthesis of a 1H-1,2,4-triazole library with potential agrochemical activity is reported employing microwave-assisted organic synthesis (MAOS) and continuous-flow microfluidic synthetic methods starting from commercially available 3,5-dibromo-1H-1,2,4-triazole (1). MAOS was used for the synthesis of 5-amino-3-bromo-1,2,4-triazole analogs 3 and for their 3-aryl derivatives 4 via Suzuki-Miyaura coupling with polymer-supported catalyst. A microfluidic hydrogenation reactor integrated into an automated parallel synthesis platform was built and utilized for the reductive dehalogenation reactions providing 5-aminotriazoles (5).

Single-center retrospective study of the technique, safety, and 12-month efficacy of the MiniArc™ single-incision sling: a new minimally invasive procedure for treatment of female SUI.

This study was conducted to report on the technique, safety, and early efficacy of a single-incision mini-sling to treat female stress urinary incontinence (SUI). Women suffering from SUI were offered a single-incision approach to place a suburethral polypropylene mesh tape in a position similar to that of a transobturator sling without passage of needles through the groin. Retrospective data was collected on 61 patients that received the new MiniArc™ single-incision sling at a single center in the United States. Patient selection and concomitant procedures were determined by the senior authors at the center, and the senior authors were the primary surgeons in all cases. Procedures were completed under general, regional, or MAC anesthesia as determined by the surgeon. Average operative time for the sling procedure alone was short and the average blood loss was 29 cc. There were no intraoperative complications. There was one postoperative adverse event secondary to urinary retention that was resolved by loosening of the sling under local anesthesia in an office setting. The overall cure rate at 12 months determined by physician and patient assessment in 58/61 patients was 91.4%. No patients suffered pain or dyspareunia secondary to the sling, and no erosions or extrusions were reported. In this initial study, the MiniArc™ single-incision sling appears to be a safe approach to treat female SUI, and the early clinical results are encouraging.

Copolymerization of ethylene with polar monomers: chain propagation and side reactions. A DFT theoretical study using zwitterionic Ni(II) and Pd(II) catalysts.

Calculations utilizing anionic substituted derivates of the cationic N(wedge)N--Ni(II) and Pd(II) diimine Brookhart complex have been carried out on the barriers of ethylene and acrylonitrile insertion into a M- methyl, propyl and CH(CN)Et bond for M = Ni, Pd. The possibility of side reactions such as chelate formation with the polar functionality and oligomerization of the active species after acrylonitrile insertion are explored. The diimine ring system N--N = -NR' 'CR(1)CR(2)NR' ' with R' ' = 2,6-C(6)H(3)(i-Pr)(2) and R(1),R(2) = Me was functionalized by adding one or two anionic groups (BF(3)(-), etc.) in place of i-Pr on the aryl rings or by replacing one Me diimine backbone group (R(1)) with BH(3)(-). The objective of this investigation is computationally to design catalysts for ethylene/acrylonitrile copolymerization that have activities that are comparable to that of the cationic Ni(II) diimine or at least the Pd(II) diimine Brookhart system for ethylene homopolymerization. Complexes that might meet this objective are discussed.

Dermal graft-augmented rectocele repair.

We describe a new technique in the surgical treatment of rectocele using a dermal allograft to augment site-specific fascial defect repair of the rectovaginal fascia. The posterior vaginal wall is opened and discrete defects in the rectovaginal fascia are repaired in a site-specific fashion using delayed absorbable suture. A second layer of support is created using a rectangular dermal allograft placed over the site-specific repair and secured to the normal anatomic attachments of the rectovaginal fascia using permanent sutures. The vagina is then closed and routine perineorrhaphy performed as indicated. Forty-three women with advanced posterior vaginal wall prolapse underwent dermal graft augmentation of site-specific rectocele repair over a 1-year period. No major intraoperative or postoperative complications were reported. Thirty women were available for follow-up examination at an average of 12.9 months (range 8-17). The average patient age in the follow-up group was 63.6 +/- 10.9 years (range 33-79) and average parity was 2.8 +/- 1.5 (range 0-7). Using the Pelvic Organ Prolapse Quantification score, the average measurement of point A(p) was 0.25 preoperatively and -2.4 postoperatively, whereas point B(p )was 0.9 preoperatively and -2.5 postoperatively. Using a point A(p) measurement of -0.5 or greater to define surgical failure, 28/30 (93%) of women were noted to have surgical cure on follow-up. Site-specific rectocele repair augmented with dermal allograft is associated with high cure rates and minimal complications. It recreates normal anatomic support and is easily adapted into current surgical procedures for rectocele repair.

Tension-free vaginal tape: outcomes among women with primary versus recurrent stress urinary incontinence.

OBJECTIVE: To evaluate the outcomes of tension-free vaginal tape in the treatment of primary versus recurrent genuine stress urinary incontinence. METHODS: A retrospective, multicenter study of 245 consecutive women who were treated with tension-free vaginal tape for genuine stress urinary incontinence (157 for primary and 88 for recurrent genuine stress urinary incontinence) over a 27-month period was performed. Concurrent surgical repairs were performed as required. Subjective and objective outcome data were assessed from routine postoperative visits. Office and hospital records were reviewed to determine patient characteristics, intraoperative findings, and surgical outcomes. RESULTS: Women with recurrent genuine stress urinary incontinence were older (mean age 64.6 versus 59.4 years, P =.004) than those with primary incontinence; they were less likely to have an intact uterus (22.7% versus 66.9%, P <.001), and were more likely to have intrinsic sphincter deficiency (70.5% versus 47.1%, P <.001). The mean duration of follow-up was 38 (+/-16) weeks. Cure rates among patients with recurrent versus primary genuine stress urinary incontinence were similar (85% and 87%, respectively, P =.23). Complication rates were similarly low in both groups (4.5% versus 7.6% for recurrent and primary genuine stress urinary incontinence, respectively, P =.35). Postoperative voiding dysfunction occurred at low rates in both groups. CONCLUSION: Tension-free vaginal tape is a highly effective treatment among patients with recurrent stress incontinence, with outcomes comparable with those among patients with primary incontinence.

Release of tension-free vaginal tape for the treatment of refractory postoperative voiding dysfunction.

OBJECTIVE: To report our experience with surgical release of tension-free vaginal tape (TVT) for the treatment of persistent post-TVT voiding dysfunction. METHODS: A total of 1175 women underwent TVT placement for treatment of genuine stress urinary incontinence and/or intrinsic sphincter deficiency over a 2-year period. Additional procedures and vaginal repairs were performed as indicated. Among these patients, 23 women (1.9%) had persistent voiding dysfunction (urinary retention, incomplete bladder emptying, or severe urgency or urge incontinence) refractory to conservative management. This cohort underwent a simple vaginal TVT release procedure, performed on an outpatient basis. Preoperative characteristics, intraoperative, and postoperative details were assessed by review of operative notes, medical records, and office notes. Continence status was assessed using subjective and objective information. RESULTS: Mean age was 67 years (range 46-86 years), and the mean interval between TVT placement and release was 17.3 weeks (range 2-69 weeks; median 8.6 weeks). For the release procedure, there were no intraoperative complications, and all patients were discharged on the day of surgery. All cases of impaired emptying were completely resolved, and all cases of irritative symptoms were resolved (30%) or improved (70%) by 6 weeks. Fourteen (61%) patients remained continent 6 weeks after the release procedure, six (26%) were improved over baseline, and three patients (13%) had recurrence of stress incontinence. CONCLUSION: Refractory voiding dysfunction after TVT is a relatively uncommon situation and can be successfully managed with a simple midline release procedure. In most cases, the release procedure does not compromise overall improvement in symptoms of stress incontinence.

Repeat tension-free transvaginal tape (TVT) sling for the treatment of recurrent stress urinary incontinence.

The pubovaginal sling is one of the preferred procedures for the treatment of female stress urinary incontinence because of its improved long-term cure rates. Recently a modified technique of the pubovaginal sling, known as the tension-free transvaginal tape (TVT), has gained popularity. We present the first reported cases of repeat TVT pubovaginal sling for the treatment of patients with recurrent stress urinary incontinence. Both patients had repeat TVT slings performed between 6 and 9 months following the initial procedure without revision or removal of the previous TVT sling. Both patients reported surgical cure without significant intraoperative or postoperative complications. It appears that reapplication of the TVT polypropolene sling may be a viable option in the event of initial TVT sling failure.

Levatorplasty release and reconstruction of rectovaginal septum using allogenic dermal graft.

The goal of reconstructive vaginal surgery include: restoration of normal anatomy, as well as maintaining visceral and sexual function. Rectocele repair can be performed utilizing a number of techniques, however some of these techniques severely distort the posterior vaginal wall anatomy and subsequently may result in dyspareunia. We report two patients with postoperative dyspareunia following levatorplasty technique for the treatment of rectocele. The patients elected to have their levatorplasty released and their rectovaginal septum reconstructed utilizing allogenic dermal graft. Postoperatively both patients are sexually active without evidence of dyspareunia or rectocele.

Laparoscopic Burch colposuspension for recurrent stress urinary incontinence.

STUDY OBJECTIVE: To evaluate the effectiveness of laparoscopic Burch colposuspension in the treatment of recurrent stress urinary incontinence in women with previous vaginal or abdominal retropubic continence surgery. DESIGN: Retrospective analysis over 36 months (Canadian Task Force classification III). SETTING: Community hospital. PATIENTS: Thirty-three consecutive patients. INTERVENTION: Laparoscopic Burch colposuspension. MEASUREMENTS AND MAIN RESULTS: Data were obtained by retrospective chart review, telephone interviews, and follow-up physical examinations. Of the 33 patients, 17 (52%) had undergone open retropubic procedures (Burch or Marshall-Marchetti-Krantz), 11 (33%) had had vaginal retropubic needle suspension, and 5 (15%) pubovaginal sling operation. Additional laparoscopic and/or vaginal reconstructive surgery was completed in 32 women (97%) at time of laparoscopic Burch. Average overall operating time was 165 minutes (range 60-287 min), mean estimated blood loss was 178 ml (range 50-600 ml), and hospital stay was 1.1 days. Three intraoperative complications occurred, two cystotomies and one serosal bowel injury. Postoperative objective evaluation over average follow-up of 18.6 months revealed a 90% stress urinary incontinence cure rate. CONCLUSION: Laparoscopic Burch colposuspension is safe and effective treatment of recurrent stress urinary incontinence in women who have undergone previous procedures for retropubic continence.

Repair of a vaginal evisceration following colpocleisis utilizing an allogenic dermal graft.

Vaginal evisceration following colpocleisis is a very rare event and, to our knowledge, there has only been one previous case report. An 86-year-old woman presented to the Emergency Department with acute onset of abdominal pain occurring following a bowel movement. Six months previously, she had undergone a colpocleisis for recurrent vaginal vault prolapse. On presentation to the emergency room, she was noted to have 60 cm of necrotic small bowel protruding through her vaginal introitus. She was taken to the operating room for resection of the small bowel and closure of her colpocleisis. The closure of the vaginal defect was difficult and required a vaginal approach employing an allogenic dermal graft. This was accomplished and the patient had an uneventful recovery and was discharged home. At 18 months followup, she has had no complication or recurrence. Evisceration following colpocleisis is a rare event, but can be very difficult to manage and we suggest consideration of employing a graft to reinforce the repair.

Laparoscopic management of urinary incontinence, ureteric and bladder injuries.

The present review focuses on the most recently published English language literature, and addresses results and complications associated with the laparoscopic approach to urinary incontinence, anterior vaginal wall prolapse, and lower urinary tract injury. Laparoscopic Burch procedures continue to show equal efficacy, but lower morbidity as compared with conventional open techniques. Lower urinary tract injuries may also be managed effectively using the same techniques as those employed in open procedures. Laparoscopy continues to be considered a mode of surgical access, and is effective in treating urinary incontinence, anterior vaginal wall prolapse, and lower urinary tract injuries.

Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study.

OBJECTIVE: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. SUBJECTS AND METHODS: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. RESULTS: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. CONCLUSIONS: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.

Vaginal configuration on MRI after abdominal sacrocolpopexy and sacrospinous ligament suspension.

An MRI study was conducted to compare the vaginal configuration of women who had undergone sacrospinous fixation with transvaginal needle suspension or abdominal sacrocolpopexy with retropubic colposuspension with that of normal controls. MRI examination demonstrated that in normal controls the lower vagina formed an acute angle (mean 53 degrees) with the pubococcygeal line and intersected the upper vagina at a mean angle of 145 degrees. In the abdominal repair group the lower vagina intersected the pubococcygeal line at a mean angle of 57 degrees and joined the upper segment at a mean angle of 137 degrees. In the vaginal repair group the lower vagina intersected the pubococcygeal line at a mean angle of 54 degrees and joined the upper segment at a mean angle of 220 degrees. Our study demonstrated that abdominal sacrocolpopexy with retropubic colposuspension more closely restored the vagina to its normal configuration, whereas sacrospinous fixation with transvaginal needle suspension creates an abnormal vaginal axis.

Use of synthetic mesh and donor grafts in gynecologic surgery.

Traditional surgery for the correction of pelvic organ prolapse continues to result in suboptimal long-term cure rates. In an effort to improve clinical outcomes, various new surgical techniques have been proposed and use of synthetic and donor graft has been advocated. Although the technique of graft placement for the correction of anterior, posterior, and apical vaginal wall reconstruction is easy to perform, controversy exists regarding the optimal choice of material. Synthetic materials have the advantage of being readily available, cost-effective, and consistent in quality, but may present with significant complications, including infection and erosion. In contrast, autologous and heterologous donor grafts provide naturally occurring biomaterials that may undergo desired remodelling, but the in vivo tissue response is still not fully understood. The use of graft materials is still in an early period of evaluation and it is expected that its use will steadily rise with increasing experience and new product development. The following review analyzes our current experience with the use of graft materials in reconstructive pelvic surgery.