The application of bicyclo1.1.1pentanes (BCPs) as phenyl bioisosteres has garnered significant attention, as these structural motifs can improve the physiochemical profiles of drug candidates. ...Despite the potential of using 1-bicyclo1.1.1pentylpyrazoles (BCPPs) as 1-phenylpyrazole bioisosteres, this area remains underexplored because of the relative lack of reliable synthetic methods for the preparation of BCPPs. Herein we address this synthetic gap and report the development of novel and scalable routes to generate a host of BCPPs.
Objective To analyze the process of urethral healing, which is the basis of urethral reconstructive surgery but remains poorly understood, we have developed a rat model of urethroplasty. ...Understanding this process may provide strategies to prevent aberrant urethral healing and improve the healing process. Methods We performed urethroplasties on 36 male Sprague-Dawley rats. On postoperative days 2, 4, 6, 8, 10, and 12, animals were sacrificed. The number of neutrophils, macrophages, fibroblasts, blood vessels, and Ki67 proliferative index was evaluated with immunostaining and collagen I and III contents with picrosirius staining. Expression of VEGF , PDGF , TNFα , TGFβ , and FGF was analyzed with quantitative real-time PCR. Results Urethral healing occurs in phases of inflammation, proliferation, maturation, and remodeling analogous to dermal healing, however, with extended duration of each phase. The inflammatory phase reached to postoperative day 4 being characterized by neutrophil and macrophage predominance and high levels of VEGF, PDGF, TGFβ , TNFα , and IL-10 . The proliferative phase extended until day 10 characterized by myofibroblast proliferation and angiogenesis. Maturation and remodeling started on day 10 with decreasing proliferation and angiogenesis, increasing collagen I formation, and periurethral alignment of connective tissue. The healing process involved >50% of the periurethral/spongiosum area in the inflammatory and >80% in the maturation and remodeling phase. Conclusion Urethral healing occurs in phases similar to those observed in dermal healing, however, with extension of each phase. The healing process is not limited to the site of injury but involves the vast majority of periurethral tissue and corpus spongiosum. This appears to be the result of the unique anatomical features of the urethra.
Objective To describe the effects of androgens on urethral wound healing, we compared the urethral healing process in castrated Sprague-Dawley rats with and without testosterone supplementation. ...Methods Of 30 castrated male Sprague-Dawley rats, 15 received testosterone cypionate (3 mg/kg; T+ rats). All rats underwent an urethroplasty procedure and were sacrificed at postoperative days 5, 10, and 20. Neutrophils, macrophages, vessels, myofibroblasts, Ki67+ cells, collagen, and cytokines were quantified with immunofluorescence and real-time polymerase chain reaction. Results Penile length was significantly increased in T+ rats (21.8 vs 13.25 mm; P <.001) and operative time decreased (20.8 vs 23.3 minutes; P <.017). On day 5, T+ rats showed elevated neutrophil (727.4 vs 30.75 per high power field; P = .051) and macrophage counts (1295.8 vs 481.5 per high power field; P = .051) compared with those of T− rats. This elevation persisted throughout day 10 (291.7 vs 34; P = .002 and 1283.7 vs 110.2; P = .005) and day 20 (252.7 vs 12.2; P <.001 and 1672.7 vs 115.2; P <.001) reflecting increased and prolonged inflammation. Myofibroblasts were decreased in T+ rats on day 5 (215.7 vs 808.3; P <.001) and increased by day 10 (1490.1 vs 263.0; P = .001) and day 20 (1964.0 vs 210.0; P <.001) consistent with a delayed onset but with prolongation of the proliferative phase. Limitations include the use of castrated rats, which may have been exposed to androgens before castration. Conclusion Testosterone supplementation leads to an increased inflammatory response and myofibroblast proliferation accompanied by prolonged inflammatory and proliferative phases. These novel findings suggest a delayed and possibly impaired urethral healing in the presence of excessive androgens.
Objective To examine the association between decreased serum testosterone levels and artificial urinary sphincter (AUS) cuff erosion. Materials and Methods We evaluated serum testosterone levels in ...53 consecutive patients. Low testosterone was defined as <280 ng/dL and found in 30/53 patients (56.6%). Chi-square and Student t tests, Kaplan-Meier analysis, binary logistic regression, and Cox regression analysis were used to determine statistical significance. Results Nearly all men with AUS cuff erosions had low serum testosterone (18/20, 90.0%) compared to those without erosions (12/33, 36.4%, P < .001). Mean time to erosion was 1.70 years (0.83-6.86); mean follow-up was 2.76 years (0.34-7.92). Low testosterone had a hazard ratio of 7.15 for erosion in a Cox regression analysis (95% confidence interval 1.64-31.17, P = .009) and Kaplan-Meier analysis demonstrated decreased erosion-free follow-up (log-rank P = .002). Low testosterone was the sole independent risk factor for erosion in a multivariable model including coronary artery disease and radiation (odds ratio 15.78; 95% confidence interval 2.77-89.92, P = .002). Notably, history of prior AUS, radiation, androgen ablation therapy, or concomitant penile implant did not confound risk of cuff erosion in men with low testosterone levels. Conclusion Men with low testosterone levels are at a significantly higher risk to experience AUS cuff erosion. Appropriate counseling before AUS implantation is warranted and it is unclear whether testosterone resupplementation will mitigate this risk.
Hospital quality-of-care measures are publicly reported to inform consumer choice and stimulate quality improvement. The number of hospitals and states with enough pediatric hospital discharges to ...detect worse-than-average inpatient care remains unknown.
This study was a retrospective analysis of hospital discharges for children aged 0 to 17 years from 3974 hospitals in 44 states in the 2009 Kids' Inpatient Database. For 11 measures of all-condition or condition-specific quality, we assessed the number of hospitals and states that met a "power standard" of 80% power for a 5% level significance test to detect when care is 20% worse than average over a 3-year period. For this assessment, we approximated volume as 3 times actual 2009 admission volumes.
For all-condition quality, 1380 hospitals (87% of all pediatric discharges) and all states met the power standard for the family experience-of-care measure; 1958 hospitals (95% of discharges) and all states met the standard for adverse drug events. For condition-specific quality measures of asthma, birth, and mental health, 203 to 482 hospitals (52%-90% of condition-specific discharges) met the power standard and 40 to 44 states met the standard. One hospital and 16 states met the standard for sickle cell disease. No hospital and ≤27 states met the standard for the remaining measures studied (appendectomy, cerebrospinal fluid shunt surgery, gastroenteritis, heart surgery, and seizure).
Most children are admitted to hospitals in which all-condition measures of quality have adequate power to show modest differences in performance from average, but most condition-specific measures do not. Policies regarding incentives for pediatric inpatient quality should take these findings into account.
Use of prophylactic antibiotics after stented hypospadias repair is very common, but most research has not identified any clinical benefits of this practice. Only one study has found that ...postoperative prophylaxis reduces symptomatic urinary tract infections (UTIs). Data from the same trial suggested that prophylaxis may also reduce urethroplasty complications. No studies on this subject have been placebo-controlled.
We performed a randomized, double-blind, placebo-controlled study to evaluate the effect of postoperative prophylactic antibiotics on the incidence of infection or urethroplasty complications after stented repair of midshaft-to-distal hypospadias.
Boys were eligible for this multicenter trial if they had a primary, single-stage repair of mid-to-distal hypospadias with placement of an open-drainage urethral stent for an intended duration of 5–10 days. Participants were randomized in a double-blind fashion to receive oral trimethoprim-sulfamethoxazole or placebo twice daily for 10 days postoperatively. The primary outcome was a composite of symptomatic UTI, surgical site infection (SSI), and urethroplasty complications, including urethrocutaneous fistula, meatal stenosis, and dehiscence. Secondary outcomes included each component of the primary outcome as well as acute adverse drug reactions (ADRs) and C. difficile colitis.
Infection or urethroplasty complications occurred in 10 of 45 boys (22%) assigned to receive antibiotic prophylaxis as compared with 5 of 48 (10%) who received placebo (relative risk RR, 2.1; 95% confidence interval CI, 0.8 to 5.8; p = 0.16). There were no significant differences between groups in symptomatic UTIs, SSIs, or any urethroplasty complications. Mild ADRs occurred in 3 of 45 boys (7%) assigned to antibiotics as compared with 5 of 48 (10%) given placebo (RR, 0.6; 95% CI, 0.2 to 2.5; p = 0.72). There were no moderate-to-severe ADRs, and no patients developed C. difficile colitis.
In this placebo-controlled trial of 93 patients, prophylactic antibiotics were not found to reduce infection or urethroplasty complications after stented mid-to-distal hypospadias repair. The study did not reach its desired sample size and was therefore underpowered to independently support a conclusion that prophylaxis is not beneficial. However, the result is consistent with most prior research on this subject.
NCT02096159Summary TableClinical outcomes of patients assigned to receive prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) vs. placebo for 10 days after hypospadias repair.Summary TableTMP-SMX (n = 45)Placebo (n = 48)Relative risk (95% CI)p valueInfection or urethroplasty complications10 (22%)5 (10%)2.1 (0.8–5.8)0.16Symptomatic urinary tract infection2 (4%)3 (6%)0.7 (0.1–4.1)0.99Surgical site infection1 (2%)1 (2%)1.1 (0.1–16.6)0.99Urethrocutaneous fistula5 (11%)1 (2%)5.3 (0.7–43.9)0.10Meatal stenosis1 (2%)0–0.48Urethral stricture00––Dehiscence1 (2%)0–0.48Urethral diverticulum00––Mild adverse drug reaction3 (7%)5 (10%)0.6 (0.2–2.5)0.72Moderate-to-severe adverse drug reaction00––C. difficile colitis00––
Hemiscrotal Agenesis: New Variation in a Rare Anomaly Flum, Andrew S; Chaviano, Antonio H; Kaplan, William E
Urology (Ridgewood, N.J.),
2012, 2012-Jan, 2012-1-00, 20120101, Letnik:
79, Številka:
1
Journal Article
Recenzirano
Scrotal agenesis is a rarely encountered developmental anomaly of the scrotum, with only 6 cases of complete agenesis reported in published studies. We report, to our knowledge, the first case of ...hemiscrotal agenesis. The specific embryologic basis of scrotal agenesis is unknown but is likely multifactorial, involving localized androgen insensitivity, localized 5α-reductase deficiency, and/or failure of labioscrotal fold formation.
In Canadian Maverick , bestselling author William Kaplan critically examines the life and times of lawyer, politician, academic, and Supreme Court Justice Ivan C. Rand. Born to a working-class New ...Brunswick family, Rand's hard work and impressive intellect led to an extraordinary career that redefined Canada's legal landscape.
Rand's 1943 appointment to the Supreme Court of Canada invigorated what was then a pedestrian institution. His work in labour law, including his development of the Rand Formula, and his key judgments in civil liberties cases inspired a generation of Canadian judges, lawyers, and law students.
Kaplan's rigorous study encompasses Rand's legal contributions, his pivotal role in the creation of the State of Israel, and his position as founding dean of the University of Western Ontario's Faculty of Law. An absorbing account of a complex and sometimes contradictory figure, Canadian Maverick draws a compelling portrait of one of Canada's most influential legal minds.
Purpose Abnormal bladder function following posterior urethral valve ablation can lead to deleterious effects on renal function and urinary continence. We performed a pilot study to determine if ...bladder dysfunction could be ameliorated by the early administration of oxybutynin. Materials and Methods We enrolled infants who underwent primary posterior urethral valve ablation by the age of 12 months. On initial urodynamics patients demonstrating high voiding pressures (greater than 60 cm H2 O) and/or small bladder capacity (less than 70% expected) were started on oxybutynin. Urodynamics and ultrasound were performed every 6 months until completion of toilet training, at which time oxybutynin was discontinued. Results Oxybutynin was started in 18 patients at a mean age of 3.4 months and was continued for a mean of 2.2 years. Urodynamics revealed that initial high voiding pressures improved from a mean of 148.5 to 49.9 cm H2 O in 15 of 17 patients. All 8 patients with initially poor bladder compliance demonstrated improvement on oxybutynin. All 7 patients with initially low bladder capacity (mean 47.7% expected bladder capacity) demonstrated improvement while on oxybutynin (mean 216% expected bladder capacity). Conclusions This pilot study demonstrates that early use of anticholinergic therapy in infants with high voiding pressures and/or small bladder capacity after primary posterior urethral valve ablation has beneficial effects on bladder function.
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