Incidental Prostate Cancer Diagnosis Is Common After Holmium Laser Enucleation of the Prostate.

OBJECTIVE: To determine the incidence of incidental prostate cancer detection (iPCa) after holmium laser enucleation of the prostate (HoLEP). The published rate of iPCa after HoLEP is widely variable from 7% to 23% and we aim to define preoperative risk factors for iPCa to inform risk-adjusted preoperative evaluation for PCa. METHODS: Consecutive patients undergoing HoLEP from 2018 to 2022 were included and comprehensive clinical data abstracted from a prospectively maintained database. iPCa was defined as a diagnosis of PCa on pathologic examination of the HoLEP specimen. Patients with and without iPCa were compared with respect to preoperative clinical variables. RESULTS: Of 913 HoLEP patients, 183 (20%) were diagnosed with iPCa. Most patients (95%) had a preoperative prostate-specific antigen (PSA), 9% had negative MRI, and 30% had negative prostate biopsy. On multivariable analysis, PSA density (OR 1.06; 95% CI 1.03, 1.10; P < .001), preoperative biopsy status (OR 0.47, CI 0.30, 0.75; P = .002), and current 5-alpha reductase inhibitor use (OR 0.64, CI 0.43, 0.97; P = .034), were associated with iPCa diagnosis. CONCLUSION: In a significantly prescreened population, we identified a 20% rate of iPCa after HoLEP. Preoperative characteristics associated with iPCa diagnosis included increasing age, increasing PSA density, and current 5-alpha reductase inhibitor use. However, these factors alone may be of limited clinical utility to prospectively identify patients at high risk of iPCa diagnosis. We suggest and advocate for development of a standardized, risk-adapted evaluation focused on expanded use of imaging and selective biopsy to prioritize identification of clinically significant PCa prior to nononcologic surgery.

Modified Frailty Index predicts postoperative complications following adult-acquired buried penis surgery: A retrospective cohort study.

BACKGROUND: Given that patients with morbid obesity are predisposed to frailty, we sought to determine whether the 5-Factor Modified Frailty Index (mFI-5) predicts postoperative complications following surgery for adult-acquired buried penis, and secondarily, to compare the mFI-5 to body mass index (BMI) and American Society of Anesthesiologists (ASA) status as preoperative risk stratification measures. METHODS: We included all patients who underwent surgical management for adult-acquired buried penis at an academic Level I trauma center between 2015 and 2023. A manual chart review was performed to collect data on patient demographics, modified frailty index variables, intraoperative data, postoperative outcomes, and complications. RESULTS: A total of 55 patients underwent surgical repair of adult-acquired buried penis, with 26 experiencing postoperative complications (47.3%). Univariable regression analyses revealed that the mFI-5 was a significant predictor of postoperative complications (odds ratio [OR] 3.40, 95% confidence interval [CI]: 1.56-7.42, p = .002), ongoing postoperative urinary problems (OR 2.03, 95% CI: 1.02-4.05, p = .045), patient dissatisfaction with outcomes (OR 3.29, 95% CI: 1.35-8.02, p = .009), and persistent postoperative symptoms (OR 2.42, 95% CI: 1.10-5.35, p = .029). There was no significant association between ASA classification and postoperative complications (OR 1.59, 95% CI:.544-4.63, p = .398). Multivariable analysis demonstrated that the mFI-5 was an independent predictor of postoperative complications (OR 5.34, 95% CI: 1.80-15.9, p = .003) when controlling for BMI and age. CONCLUSION: The mFI-5 is an independent predictor of postoperative complications in patients undergoing surgical repair of adult-acquired buried penis. The simplicity of the index permits efficient preoperative risk stratification of adult-acquired buried penis patients and provides important counseling information that may not be reflected by age or BMI alone.

Histologic inflammation and collagen content are not positively correlated in human BPH.

INTRODUCTION: Recent clinical studies have implicated prostate inflammation and fibrosis in the development of bladder outlet obstruction and lower urinary tract symptoms (LUTS). Studies utilizing rodent models, including work in our laboratory, have shown prostate fibrosis to occur as a consequence of inflammation. However, the relationship between collagen content and inflammation in human tissue samples obtained from surgical treatment of benign prostatic hypererplasia (BPH)/LUTS has not to our knowledge been previously examined. METHODS: Prostate tissue specimens from 53 patients (ages 47-88, mean 65.1) treated by open simple prostatectomy or transurethral resection of the prostate for BPH/LUTS were stained to quantitatively assess prostate inflammation and collagen content. Patients with prostate cancer present in greater than 5% of the surgical specimen were excluded. Prostate volume was determined from pelvic CT scan obtained within 2 years of surgery. RESULTS: Analysis of the data showed that inflammation was inversely correlated with collagen content (r = -0.28, p = 0.04). In men with prostates less than 75 cm3 inflammation increases and collagen content decreases with prostate volume (p = 0.002 and p = 0.03, respectively) while in men with prostate volume over 75 cm3 inflammation decreases and collagen content increases with prostate volume (p = 0.30 and p = 0.005, respectively). CONCLUSIONS: Our data do not support the assumed positive association of prostate inflammation with collagen content. Coordinated analysis of scatter plots of inflammation and collagen content with prostate volume revealed a subset of prostates with volumes >50 cm3 prostate characterized by intense inflammation and low collagen content and it is this subgroup that appears most responsible for the inverse correlation of inflammation and collagen.

"Postoperative Outcomes Following Buried Penis Reconstruction: A Single-Institution Experience Using the Wisconsin Classification System".

BACKGROUND: Adult acquired buried penis (AABP) is a complex condition often necessitating surgical intervention. This study seeks to examine the validity of the Wisconsin Classification System (WCS) in guiding the surgical management of AABP. Additionally, we aimed to identify which factors contribute to postoperative complications and persistent symptoms following AABP repair. METHODS: We retrospectively reviewed all patients who underwent surgical repair of AABP from 2015-2021 by the senior author at our institution. Patients were categorized according to anatomic characteristics using the WCS. Preoperative symptoms, postoperative symptoms, and postoperative complications were evaluated. RESULTS: Fifty-two patients underwent AABP repair. The mean age was 56.5±14.8 years, and the mean duration of follow-up was 350.0±517.4 days. The assigned preoperative WCS score was congruent with operative management in most patients (86.0%). Morbid obesity (BMI>40.0kg/m2) and postoperative complications were associated with persistent symptoms following AABP repair (p=0.026 and p=0.021, respectively). Increased WCS score was not associated with persistent postoperative symptoms (p=0.314). Morbid obesity (p=0.003), diabetes (p=0.029) and having a panniculectomy during AABP repair (p=0.046) increased the odds for developing postoperative complications. Patients with Type I AABP had significantly fewer complications than those with Type II, III, or IV (p=0.032). CONCLUSIONS: The Wisconsin Classification System serves as a preoperative guide, an educational tool for patients, and provides a framework for the discussion of intraoperative maneuvers and the likelihood of complications. It is imperative to counsel patients on the surgical management of AABP and the postoperative course, as this may permit realistic patient expectations and optimize outcomes.

Collagen is More Abundant and Structurally Altered in Lichen Sclerosus.

OBJECTIVE: To test the hypothesis that genital skin and male urethra affected by lichen sclerosus (LS) has increased collagen content and altered collagen structure. METHODS: We used picrosirius red to stain and image collagen in human urethral, vulvar, and foreskin specimens with and without LS. Using Image J software, we quantified and compared (1) collagen content (using 2o metrics: collagen proportionate area [CPA] and collagen fiber count), (2) collagen fiber length and width, and (3) collagen structure using the texture analysis technique gray level co-localization matrix (GLCM) with respect to LS status and tissue type. RESULTS: We analyzed 23 LS specimens (vulva n=9, urethra n=7, foreskin n=7) and 29 non-LS specimens (vulva n=9, urethra n=7, foreskin n=13). Fiber count and CPA were significantly higher in all LS specimens compared to non-LS specimens (CPA: mean±SD 0.971±0.03 vs 0.948±0.02, P < .007; fiber count: mean±SD = 2906±127 vs 2509±78 fibers; P = .003). Collagen fiber width and length were similar with respect to LS status. GLCM analysis showed decreased inverse difference moment and increased entropy in LS tissues indicative of less homogeneous and more disorganized tissue structure (P<.001). CONCLUSION: LS tissues have greater collagen content compared to non-LS tissues. Quantitative assessment of collagen organization, using GLCM, revealed less homogeneity and more disorganization of collagen in LS compared to non-LS tissues. Taken together, our findings suggest that alterations in physical tissue properties seen in LS may be due to both increased collagen abundance and altered structure.

A systematic approach for successful repair of radiated and non-radiated ureteral injuries.

BACKGROUND: Successful ureteral reconstruction is challenging, particularly in radiated fields. We characterize and directly compare surgical outcomes in modern cohorts of radiated and non-radiated patients undergoing ureteral reconstruction utilizing a systematic approach to pre-operative assessment. We hypothesize that radiated patients will undergo more complex ureteral reconstructions and experience higher rates of surgical failure and complications compared to nonradiated patients. METHODS: Consecutive cases of ureteral reconstruction for acquired ureteral injury performed by a single surgeon from 2010-2018 were retrospectively reviewed. Clinical data were collected including pre-operative bladder capacity, ureteral injury characteristics, and surgical technique. Ileal ureter and autotransplantation were classified as "complex" ureteral repairs, and surgical success was defined as freedom from surgical revision of the ureteral anastomosis and/or ureteral stenting. RESULTS: There were 47 ureteral reconstructions performed including 17 (36%) radiated patients. Radiated patients had lower pre-operative bladder capacity and were more likely to undergo complex repairs compared to non-radiated patients (35% vs. 7%, P=0.01). Overall surgical success was high (98%) and similar between radiated (94%) and non-radiated groups (100%) at median follow up of 30 months. Clavien grade 3-4 complications occurred in 18% of radiated and 10% of non-radiated patients (P=0.48). CONCLUSIONS: Careful pre-operative evaluation and appropriate selection of surgical technique facilitates high and similar success of ureteral reconstruction in radiated and non-radiated patients. Complex ureteral repairs were more common in radiated patients, however the majority of radiated ureteral injuries (65%) were reconstructed without tissue transfer. Radiated patients had lower pre-operative bladder capacities, but similar surgical morbidity, renal function, and persistent urge incontinence compared to non-radiated patients.

Effect of Metabolic Syndrome on Anatomy and Function of the Lower Urinary Tract Assessed on MRI.

OBJECTIVE: To investigate the relationship between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) with functional and anatomic changes of the lower urinary tract with MRI. MATERIALS AND METHODS: The bladder and prostate of 95 subjects (56M, 39F) were segmented on T2-weighted pelvic MRI using Materialize Mimics 3D software. Bladder wall volume (BWV), post-void residual (PVR) and prostate volume (PV) were quantified from the 3D renderings. LUTS were quantified using validated questionnaires administered at the time of MRI. Wilcoxin rank sum, win ratio and chi-square tests were used to correlate symptom scores, BWV, PVR and PV in patients 1) without vs with MetS, 2) with mild (IPSS or UDI-6: 0-7) vs moderate-severe (IPSS: 8-35 or UDI-6: ≥8) and 3) normal vs enlarged prostates (>40cm3). Multivariate linear regression was used to determine predictors for BWV, PVR and PV. RESULTS: Men with MetS had increased BWV (66.8 vs 51.1cm3, P = .003), higher PVR (69.1 vs 50.5cc, P= .05) and increased PV (67.2 vs 40.1cm3, P= .01). Women without and with MetS had similar BWV, PVR and LUTS (P= .3-.78). There was no difference in prevalence of MetS, BWV, PVR or PV in men or women with mild vs moderate-severe LUTS (P = .26-.97). Men with enlarged prostates were more likely to have MetS (P = .003). There was no difference in BWV, PVR and LUTS for men with normal vs enlarged prostates (P= .44-.94). In men, BWV was highly correlated with MetS (P = .005) on regression analysis. CONCLUSION: MetS leads to detrusor hypertrophy and may contribute to impaired bladder function, likely related to the effect on the prostate.

A mechanism linking perinatal 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure to lower urinary tract dysfunction in adulthood.

Benign prostatic hyperplasia/lower urinary tract dysfunction (LUTD) affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging paradigms about when this disease process begins. We delivered a single dose of a widespread environmental contaminant present in the serum of most Americans [2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 1 µg/kg], and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues, and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood.

The influence of intermittent hypoxia, obesity, and diabetes on male genitourinary anatomy and voiding physiology.

We used male BTBR mice carrying the Lepob mutation, which are subject to severe and progressive obesity and diabetes beginning at 6 wk of age, to examine the influence of one specific manifestation of sleep apnea, intermittent hypoxia (IH), on male urinary voiding physiology and genitourinary anatomy. A custom device was used to deliver continuous normoxia (control) or IH to wild-type and Lepob/ob (mutant) mice for 2 wk. IH was delivered during the 12-h inactive (light) period in the form of 90 s of 6% O2 followed by 90 s of room air. Continuous room air was delivered during the 12-h active (dark) period. We then evaluated genitourinary anatomy and physiology. As expected for the type 2 diabetes phenotype, mutant mice consumed more food and water, weighed more, and voided more frequently and in larger urine volumes. They also had larger bladder volumes but smaller prostates, seminal vesicles, and urethras than wild-type mice. IH decreased food consumption and increased bladder relative weight independent of genotype and increased urine glucose concentration in mutant mice. When evaluated based on genotype (normoxia + IH), the incidence of pathogenic bacteriuria was greater in mutant mice than in wild-type mice, and among mice exposed to IH, bacteriuria incidence was greater in mutant mice than in wild-type mice. We conclude that IH exposure and type 2 diabetes can act independently and together to modify male mouse urinary function. NEW & NOTEWORTHY Metabolic syndrome and obstructive sleep apnea are common in aging men, and both have been linked to urinary voiding dysfunction. Here, we show that metabolic syndrome and intermittent hypoxia (a manifestation of sleep apnea) have individual and combined influences on voiding function and urogenital anatomy in male mice.

Cluster analysis of men undergoing surgery for BPH/LUTS reveals prominent roles of both bladder outlet obstruction and diminished bladder contractility.

Lower urinary tract symptoms (LUTS) in aging men are commonly attributed to bladder outlet obstruction from benign prostatic hyperplasia (BPH) but BPH/LUTS often reflects a confluence of many factors. We performed a hierarchical cluster analysis using four objective patient characteristics (age, HTN, DM, and BMI), and five pre-operative urodynamic variables (volume at first uninhibited detrusor contraction, number of uninhibited contractions, Bladder Outlet Obstruction Index (BOOI), Bladder Contractility Index (BCI) and Bladder Power at Qmax) to identify meaningful subgroups within a cohort of 94 men undergoing surgery for BPH/LUTS. Two meaningful subgroups (clusters) were identified. Significant differences between the two clusters included Prostate Volume (95 vs 53 cc; p-value = 0.001), BOOI (mean 70 vs 49; p-value = 0.001), BCI (mean 129 vs 83; p-value <0.001), Power (689 vs 236; p-value <0.001), Qmax (8.3 vs 4.9 cc/sec; p-value <0.001) and post-void residual (106 vs 250 cc; p-value = 0.001). One cluster is distinguished by larger prostate volume, greater outlet resistance and better bladder contractility. The other is distinguished by smaller prostate volume, lower outlet resistance and worse bladder contractility. Remarkably, the second cluster exhibited greater impairment of urine flow and bladder emptying. Surgery improved flow and emptying for patients in both clusters. These findings reveal important roles for both outlet obstruction and diminished detrusor function in development of diminished urine flow and impaired bladder emptying in patients with BPH/LUTS.

Histopathology of Anterior Urethral Strictures: Toward a Better Understanding of Stricture Pathophysiology.

PURPOSE: Histopathology can provide insights into disease mechanisms but to date it has been poorly described for urethral stricture. The purpose of this study was to comprehensively describe histopathological findings of stricture specimens obtained at the time of anterior urethroplasty. MATERIALS AND METHODS: All pathological specimens of men who underwent anterior urethroplasty of urethral stricture disease from 2010 to 2017 at a single institution were rereviewed by a single blinded pathologist directed to rule out lichen sclerosus and then describe inflammatory cell type and severity when present. Cohorts comprising strictures with no inflammation, minimal to mild inflammation or moderate to severe inflammation were developed and stricture, patient and surgical outcome characteristics were compared. RESULTS: Histopathology slides from 100 anterior urethroplasty cases were reviewed. Two or more lichen sclerosus characteristics were present in 21% of specimens and 44% of specimens showed chronic inflammation, which was minimal in 20%, mild in 39%, moderate in 39% and severe in 2%. Lymphocytes in 86% of specimens and plasma cells in 12% were the predominant cell types. Patients with inflammatory stricture reported worse overall health. Inflammation was largely absent from isolated bulbomembranous strictures (9%) and more common in lichen sclerosus strictures (100%). The 11% overall failure rate was not affected by the presence (7%) or absence (14%) of inflammation. CONCLUSIONS: Chronic inflammation is prevalent in a significant percent of urethral stricture disease specimens. Associations with worse overall health suggest systemic mediators. Absent inflammation in bulbomembranous strictures suggests a unique pathophysiology in this region. The presence of inflammation did not affect surgical outcomes at mid-term followup.

Impact of droplet evaporation rate on resulting in vitro performance parameters of pressurized metered dose inhalers.

Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of pulmonary diseases. The overall efficiency of pMDI drug delivery may be defined by in vitro parameters such as the amount of drug that deposits on the model throat and the proportion of the emitted dose that has particles that are sufficiently small to deposit in the lung (i.e., fine particle fraction, FPF). The study presented examines product performance of ten solution pMDI formulations containing a variety of cosolvents with diverse chemical characteristics by cascade impaction with three inlets (USP induction port, Alberta Idealized Throat, and a large volume chamber). Through the data generated in support of this study, it was demonstrated that throat deposition, cascade impactor deposition, FPF, and mass median aerodynamic diameter of solution pMDIs depend on the concentration and vapor pressure of the cosolvent, and the selection of model throat. Theoretical droplet lifetimes were calculated for each formulation using a discrete two-stage evaporation process model and it was determined that the droplet lifetime is highly correlated to throat deposition and FPF indicating that evaporation kinetics significantly influences pMDI drug delivery.

Metastatic Tumor Burden Does Not Predict Overall Survival Following Cytoreductive Nephrectomy for Renal Cell Carcinoma: a Novel 3-Dimensional Volumetric Analysis.

OBJECTIVE: To compare 1-dimensional (1D) and 3-dimensional (3D) volume measurements and determine whether primary tumor (PT) burden is predictive of overall survival (OS) following cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Records and imaging studies of patients with mRCC treated with CN from 2006 to 2015 were included, with tumor volumes measured by a faculty radiologist blinded to clinical outcomes using Advantage Workstation Volume Share (Ver 4.6, GE, Waukesha, WI). RESULTS: Complete PT and metastatic tumor volumes were measured for 67 patients. For 15 (22.3%) patients, 1D volume was within ±10% of the measured 3D volume. In 40 (59.7%) patients, the 1D calculated PT volume was >10% of the actual 3D volume. Fractional percentage of tumor volume (FPTV) removed during CN was calculated using the formula PT volume/(PT + met volume). FPTV was not associated with OS when analyzed as a continuous variable. Patients were divided into 2 groups based on previously published cut point of 90% FPTV. No differences between cohorts in age, gender, grade, subtype, number of metastatic sites, performance status, Memorial Sloan Kettering Cancer Center risk group, or International Metastatic Renal Cell Carcinoma Database Consortium risk group were identified. OS was not different between cohorts (P = .38). CONCLUSION: 1D measurements of PT diameter frequently overestimate mRCC PT volume. In patients with mRCC selected for CN, the ratio of primary to metastatic tumor does not predict OS.

A Critical Analysis of Perioperative Outcomes in Morbidly Obese Patients Following Renal Mass Surgery.

OBJECTIVE: To evaluate if body mass index (BMI) ≥ 40 is associated with risk of postoperative complications, receipt of perioperative blood transfusion (PBT), length of hospital stay (LOS), perioperative death, or hospital readmission rate following renal mass surgery. MATERIALS AND METHODS: After Institutional Review Board approval, comprehensive information was collected for patients treated with surgery for renal mass from 2000 to 2015 at one institution. Univariable and multivariable analyses were used to evaluate the association of BMI ≥ 40 among other putative risk factors for perioperative outcomes. RESULTS: A total of 1048 patients were treated surgically, including 115 (11%) with BMI > 40. Minimally invasive and open surgical approaches were used for 480 (45.8%) and 568 (54.2%) patients, respectively. Morbid obesity was not associated with risk of major complications, overall complications, receipt of PBT, LOS, hospital readmission rate, or perioperative death. Charlson comorbidity index was the only independent predictor of major complications following renal mass surgery, P = .0006, per point odds ratio 1.2 (95%C.I. 1.08-1.32). Surgical site infections (SSIs) were more common in patients with BMI ≥ 40 vs BMI < 40 (10.5% vs 4.8%, P = .01). Following multivariable analysis, BMI ≥ 40 was the only independent predictor of SSIs, odds ratio 2.6, 95% confidence interval 1.32-5.13; P = .006. CONCLUSION: Morbid obesity (BMI ≥ 40) is an independent predictor of developing SSIs following renal mass surgery. Morbid obesity is not predictive of risk for major complications, receipt of PBT, hospital readmission, perioperative death, or LOS.

Extreme obesity does not predict poor cancer outcomes after surgery for renal cell cancer.

OBJECTIVE: To assess whether extreme obesity (body mass index [BMI] ≥ 40 kg/m(2) ) is associated with peri-operative outcomes, overall survival (OS), cancer-specific survival (CSS), or recurrence-free survival (RFS) after surgical treatment for renal cell carcinoma (RCC). PATIENTS AND METHODS: After institutional review board approval, we used an institutional database to identify patients treated surgically between January 2000 and December 2014 with a pathological diagnosis of RCC. Comprehensive clinical and pathological data were reviewed. Kaplan-Meier analyses were used to estimate OS, RFS and CSS. Univariate and multivariate Cox proportional hazards analysis was used to evaluate associations with OS, CSS and RFS in patients with extreme obesity, among other known predictive variables. RESULTS: In all, 100 patients (11.9%) with a BMI ≥ 40 kg/m(2) and 743 patients (88.1%) with a BMI < 40 kg/m(2) who were treated surgically for RCC were identified. Morbid obesity was not associated with an increased risk of blood transfusion (odds ratio [OR] 1, 95% confidence interval [CI] 0.587-1.70; P = 1.0). The median (interquartile range) length of hospital stay (LOS) was 4 (3-6) days. Morbid obesity was not associated with longer LOS (P = 0.26) or 30-day hospital readmission rates (P = 1.0). Major complications (Clavien ≥ 3a) were recorded in 67 patients (7.95%). BMI ≥ 40 kg/m(2) was not a predictor of major complications (OR 0.58, 95% CI 0.227-1.47; P = 0.251) or 90-day mortality (P = 0.4067). BMI ≥ 40 kg/m(2) was not associated with worse OS (P = 0.7), CSS (P = 0.2) or RFS (P = 0.5). BMI ≥ 35 kg/m(2) was also not associated with worse OS, CSS or RFS (P = 0.3, 0.1, 0.5, respectively). The 5-year OS rate was 68.9% for the entire cohort, including 69 and 70% for patients with BMI < 40 kg/m(2) and BMI ≥ 40 kg/m(2) , respectively (P = 0.69). The 5-year CSS was 79.5% for the entire cohort, including 78.4 and 87.9% (P = 0.16) for patients with BMI < 40 kg/m(2) and BMI ≥ 40 kg/m(2) , respectively. The 5-year RFS rates for BMI < 40 kg/m(2) and BMI ≥ 40 kg/m(2) were 84.1 and 90.6%, respectively (P = 0.48). CONCLUSIONS: Extreme obesity is not associated with worse peri-operative or cancer outcomes after surgery for RCC. Surgery should remain a standard treatment option in well selected morbidly obese patients.

Epac activation initiates associative odor preference memories in the rat pup.

Here we examine the role of the exchange protein directly activated by cAMP (Epac) in ß-adrenergic-dependent associative odor preference learning in rat pups. Bulbar Epac agonist (8-pCPT-2-O-Me-cAMP, or 8-pCPT) infusions, paired with odor, initiated preference learning, which was selective for the paired odor. Interestingly, pairing odor with Epac activation produced both short-term (STM) and long-term (LTM) odor preference memories. Training using ß-adrenergic-activation paired with odor recruited rapid and transient ERK phosphorylation consistent with a role for Epac activation in normal learning. An ERK antagonist prevented intermediate-term memory (ITM) and LTM, but not STM. Epac agonist infusions induced ERK phosphorylation in the mitral cell layer, in the inner half of the dendritic external plexiform layer, in the glomeruli and, patchily, among granule cells. Increased CREB phosphorylation in the mitral and granule cell layers was also seen. Simultaneous blockade of both ERK and CREB pathways prevented any long-term ß-adrenergic activated odor preference memory, while LTM deficits associated with blocking only one pathway were prevented by stronger ß-adrenergic activation. These results suggest that Epac and PKA play parallel and independent, as well as likely synergistic, roles in creating cAMP-dependent associative memory in rat pups. They further implicate a novel ERK-independent pathway in the mediation of STM by Epac.

Two mutations associated with macrolide resistance in Treponema pallidum: increasing prevalence and correlation with molecular strain type in Seattle, Washington.

BACKGROUND: Although azithromycin promised to be a safe and effective single-dose oral treatment of early syphilis, azithromycin treatment failure has been documented and is associated with mutations in the 23S rDNA of corresponding Treponema pallidum strains. The prevalence of strains harboring these mutations varies throughout the United States and the world. We examined T. pallidum strains circulating in Seattle, Washington, from 2001 to 2010 to determine the prevalence of 2 mutations associated with macrolide resistance and to determine whether these mutations were associated with certain T. pallidum strain types. METHODS: Subjects were enrolled in a separate ongoing study of cerebrospinal fluid abnormalities in patients with syphilis. T. pallidum DNA purified from blood and T. pallidum strains isolated from blood or cerebrospinal fluid were analyzed for two 23S rDNA mutations and for the molecular targets used in an enhanced molecular stain typing system. RESULTS: Nine molecular strain types of T. pallidum were identified in Seattle from 2001 to 2010. Both macrolide resistance mutations were identified in Seattle strains, and the prevalence of resistant T. pallidum exceeded 80% in 2005 and increased through 2010. Resistance mutations were associated with discrete molecular strain types of T. pallidum. CONCLUSIONS: Macrolide-resistant T. pallidum strains are highly prevalent in Seattle, and each mutation is associated with discrete strain types. Macrolides should not be considered for treatment of syphilis in regions where prevalence of the mutations is high. Combining the resistance mutations with molecular strain typing permits a finer analysis of the epidemiology of syphilis in a community.

Ginger stimulates hematopoiesis via Bmp pathway in zebrafish.

BACKGROUND: Anemia is a hematologic disorder with decreased number of erythrocytes. Erythropoiesis, the process by which red blood cells differentiate, are conserved in humans, mice and zebrafish. The only known agents available to treat pathological anemia are erythropoietin and its biologic derivatives. However, erythropoietin therapy elicits unwanted side-effects, high cost and intravenous or subcutaneous injection, warranting the development of a more cost effective and non-peptide alternative. Ginger (Zingiber officinale) has been widely used in traditional medicine; however, to date there is no scientific research documenting the potential of ginger to stimulate hematopoiesis. METHODOLOGY/PRINCIPAL FINDINGS: Here, we utilized gata1:dsRed transgenic zebrafish embryos to investigate the effect of ginger extract on hematopoiesis in vivo and we identified its bioactive component, 10-gingerol. We confirmed that ginger and 10-gingerol promote the expression of gata1 in erythroid cells and increase the expression of hematopoietic progenitor markers cmyb and scl. We also demonstrated that ginger and 10-gingerol can promote the hematopoietic recovery from acute hemolytic anemia in zebrafish, by quantifying the number of circulating erythroid cells in the dorsal aorta using video microscopy. We found that ginger and 10-gingerol treatment during gastrulation results in an increase of bmp2b and bmp7a expression, and their downstream effectors, gata2 and eve1. At later stages ginger and 10-gingerol can induce bmp2b/7a, cmyb, scl and lmo2 expression in the caudal hematopoietic tissue area. We further confirmed that Bmp/Smad pathway mediates this hematopoiesis promoting effect of ginger by using the Bmp-activated Bmp type I receptor kinase inhibitors dorsomorphin, LND193189 and DMH1. CONCLUSIONS/SIGNIFICANCE: Our study provides a strong foundation to further evaluate the molecular mechanism of ginger and its bioactive components during hematopoiesis and to investigate their effects in adults. Our results will provide the basis for future research into the effect of ginger during mammalian hematopoiesis to develop novel erythropoiesis promoting agents.