Background: Acute renal angiotensin type 2 receptor (AT 2 R) activation promotes natriuresis, and chronic renal and systemic AT 2 R stimulation blunts angiotensin II-induced hypertension. AT 2 Rs are expressed in renal proximal and distal tubules as well as the renal vasculature. To test the hypothesis that the renal proximal tubule AT 2 R plays a key role in natriuresis and blood pressure control, we generated renal proximal tubule-specific AT 2 R knockout (PT-AT 2 R-/-) mice. Methods and Results: Mice with the AT 2 R exon 3 flanked by loxP sites were crossed with mice overexpressing cre recombinase under the control of the renal proximal tubule cell (RPTC)-specific sodium and glucose cotransporter 2 (Sglt2) promotor. The resulting male and female PT-AT 2 R-/- mice showed a selective deletion of the AT 2 R in proximal tubules with a 79% and 66% (p<0.0001) decrease, respectively, in AT 2 R protein levels. Initial experiments documented the unique role for the RPTC AT 2 R in promoting natriuresis; in PT-AT 2 R-/- mice the natriuretic response was abolished in response to renal interstitial (RI) infusion of the selective AT 2 R agonist C21. Pressure natriuresis is a key mechanism by which sodium excretion and consequently blood pressure is controlled. It is defective in hypertensive humans and animal models of hypertension. To test whether the PT-AT 2 R plays a role in pressure natriuresis, we determined the natriuretic response to an acute increase in renal perfusion pressure (RPP) in PT-AT 2 R-/- and control mice. We found that urinary sodium excretion (UNaV) was reduced by 67% and 59% (p<0.0001), respectively, in male and female PT-AT 2 R -/- mice, when compared to control. Elevated RPP, consistent with earlier results in rats, increased RI cGMP more than 2-fold (p=0.007) in control mice, but no change in cGMP was found in PT-AT 2 R-/- mice. Using confocal immunofluorescence microscopy, we observed that concomitant with reduced sodium excretion, sodium hydrogen exchanger-3 (NHE3) retrieval from brush border microvilli of RPTC was defective in PT-AT 2 R -/- mice in response to increased RPP. Also, while elevated RPP increased phosphorylation of the kinase src in the renal cortex of control mice, this response was abolished in PT-AT 2 R-/- mice. Conclusion: Our results with PT-AT 2 R-/- mice suggest that the RPTC AT 2 R is a key mediator of pressure natriuresis. Targeting the AT 2 R may thus provide a novel approach to improve pressure natriuresis and better control blood pressure in hypertension.

We report that environmental context can have a major impact on morphine locomotor behavior and ERK effects. We manipulated environmental context in terms of an environmental novelty/ familiarity dimension and measured morphine behavioral effects in both acute and chronic morphine treatment protocols. Wistar rats (n=7 per group) were injected with morphine 10mg/kg or vehicle (s.c.), and immediately placed into an arena for 5min, and locomotor activity was measured after one or 5 days. The morphine treatments were initiated either when the environment was novel or began after the rats had been familiarized with the arena by being given 5 daily nondrug tests in the arena. The results showed that acute and chronic morphine effects were strongly modified by whether the environment was novel or familiar. Acute morphine administered in a novel environment increased ERK activity more substantially in several brain areas, particularly in reward-associated areas such as the VTA in comparison to when morphine was given in a familiar environment. Repeated morphine treatments initiated in a novel environment induced a strong locomotor sensitization, whereas repeated morphine treatments initiated in a familiar environment did not induce a locomotor stimulant effect but rather a drug discriminative stimulus dis-habituation effect. The marked differential effects of environmental novelty/familiarity and ongoing dopamine activity on acute and chronic morphine treatments may be of potential clinical relevance for opioid drug addiction.

Mesotheliomas of the tunica vaginalis testis are rare malignant tumors that can present as a scrotal mass or hydrocele. These tumors are typically aggressive with high rates of recurrence and metastasis. Suspected risk factors for malignant mesothelioma include asbestos exposure, chronic inflammation, trauma, and persistent hydrocele. We report the case of a malignant epithelioid mesothelioma of the tunica vaginalis testis that presented as a finding at hydrocelectomy and was ultimately treated with radical inguinal orchiectomy. This patient was on chronic immunosuppression therapy with tacrolimus and mycophenolate mofetil secondary to a kidney transplant but had none of the common risk factors for mesothelioma formation. To our knowledge, this is the first case describing a possible connection between chronic immunosuppression and mesothelioma of the tunica vaginalis. However, future studies are needed to investigate this association and discern whether this could have played a role in our patient or if his mesothelioma formation was coincidental.

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy IV (MP56)1 May 2024MP56-07 PROPENSITY SCORE ADJUSTED COMPARISON AND 15-YEAR FOLLOW-UP OF ONCOLOGIC AND RENAL FUNCTION OUTCOMES: RADIOFREQUENCY ABLATION VERSUS PARTIAL NEPHRECTOMY Robert I. Carey, Genesis G. Dolgetta, Tonya S. King, Spencer Kortum, Benjamin J. Behers, Pedro Briceno, and Karim Ghazli Robert I. CareyRobert I. Carey , Genesis G. DolgettaGenesis G. Dolgetta , Tonya S. KingTonya S. King , Spencer KortumSpencer Kortum , Benjamin J. BehersBenjamin J. Behers , Pedro BricenoPedro Briceno , and Karim GhazliKarim Ghazli View All Author Informationhttps://doi.org/10.1097/01.JU.0001008940.44711.d4.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We describe the 15-year follow-up of oncologic and renal function outcomes for a cohort of patients who underwent either laparoscopic radiofrequency ablation (LRFA) or partial nephrectomy (PN) for solid-enhancing renal masses between 3-7 cm. This study is unique due to the large tumor size, follow-up length, and use of RENAL nephrometry scoring for all tumors. METHODS: LRFA was performed with a Covidien Cooltip probe system using multiple probes and multi-pass technique. Direct real-time, fiberoptic temperature monitoring was performed for each case with temperature goals of greater than 60 degrees C achieved at the deep and peripheral margins. PN was performed with standard arterial and venous clamping and sliding clip renorrhaphy closure. Renal function was assessed at 3 months and annually thereafter. Oncologic and renal function outcomes for both cohorts were compared using a propensity-score based analysis with adjustment for age, baseline renal function, tumor volume, RENAL score, and histologic stage. RESULTS: Patients undergoing LRFA (n=50) were older (median age 73 vs. 68 years, p<0.001), with similar BMI (median 26.6 vs. 28.5) and gender (66% vs. 70% male, p=0.71) compared to PN (n=117). For LRFA and PN, median tumor volume was 14.9 vs. 36.1 (p<0.001), median pre-surgery GFR was 61.4 vs. 50.9 (p=0.002), and median RENAL score was 6.5 vs. 9.0 (p<0.001). LRFA had more T1a patients (72% vs. 36.8%, p<0.001). With propensity score adjustment, patients undergoing PN had 95% lower odds of metastasis (p=0.002), and 85% lower odds of radical nephrectomy (p=0.031), compared to LRFA. PN had lower rates of both overall mortality (HR=0.44, 95%CI 0.14-1.39, p=0.16) and disease-specific mortality (HR=0.14, 95%CI 0.01-1.89, p=0.14), however neither were statistically significant. Disease-specific survival was 91% for LRFA. 3/50 (6%) of patients undergoing LRFA required salvage PN. Propensity adjusted mean % change in GFR at one year was significantly greater for PN vs. LRFA (24% vs. -14%, p<0.001). CONCLUSIONS: PN patients showed better renal function preservation and required fewer salvage surgeries than LRFA. At one-year, renal function declines 14% for LRFA, while improving 24% for PN, with adjustment for propensity score. Local tumor bed recurrence and metastasis occur more frequently with LRFA over 15-year follow-up with these tumors despite the independent temperature monitoring. Source of Funding: The Burzik Foundation © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e928 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Robert I. Carey More articles by this author Genesis G. Dolgetta More articles by this author Tonya S. King More articles by this author Spencer Kortum More articles by this author Benjamin J. Behers More articles by this author Pedro Briceno More articles by this author Karim Ghazli More articles by this author Expand All Advertisement PDF downloadLoading ...

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose positron emission tomography in vivo in 9‐, 12‐, and 18‐month‐old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9‐month‐old SHR decreasing) 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12‐month‐old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

The disinhibition of dopamine neurons in the VTA by morphine is considered an important contributor to the reward potency of morphine. In this report, three experiments were conducted in which a low dose of apomorphine (0.05 mg/kg) was used as a pretreatment to reduce dopamine activity. Locomotor hyperactivity was used as the behavioral response to morphine (10.0 mg/kg). In the first experiment, five treatments with morphine induced the development of locomotor and conditioned hyperactivity that were prevented by apomorphine given 10 min prior to morphine. Apomorphine before either vehicle or morphine induced equiv-alent reductions in locomotion. In the second experiment, the apomorphine pretreatment was initiated after induction of a conditioned hyperactivity and apomorphine prevented the expression of the conditioning. To assess the effects of apomorphine on VTA and the nucleus accumbens, ERK measurements were carried out after the induction of locomotor and conditioned hyperactivity. Increased ERK activation was found and these effects were prevented by the apomorphine in both experiments. A third experiment was conducted to assess the effects of acute morphine on ERK before locomotor stimulation was induced by morphine. Acute morphine did not increase locomotion, but a robust ERK response was produced indicating that the morphine-induced ERK acti-vation was not secondary to locomotor stimulation. ERK activation was again prevented by the apomorphine pretreatment. We suggest that contiguity between the ongoing behavioral activity and the morphine activation of the dopamine reward system incentivizes and potentiates the ongoing behavior generating equivalent behavioral sensitization and conditioned effects.

Cystic teratomas are a common ovarian neoplasm that are rarely found in other locations of the body, namely the sacrococcygeal region and anterior mediastinum. Localization to the urinary bladder is exceedingly rare, with only a few cases documented in the literature. Cystic teratomas are usually asymptomatic and found incidentally, but localization to the bladder can present as irritative lower urinary tract symptoms and/or mimic urinary tract calculi. We report the rare case of a mature cystic teratoma of the urinary bladder, presenting as foul-smelling urine with recurrent urinary tract infections and microhematuria, that was originally misdiagnosed as a bladder calculus.

Background The renin‐angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G‐protein–coupled receptors, the angiotensin type‐1 and type‐2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type‐1 and type‐2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non–antibody‐based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type‐1 and type‐2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type‐1 and type‐2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin‐angiotensin system activation, including oxidative stress, inflammation, amyloid‐β load, and paired helical filament‐tau tangle burden. Conclusions These robust high‐throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.

You have accessJournal of UrologyCME1 Apr 2023PD27-12 CORRELATION OF POST-PROSTATECTOMY DECIPHER GENOMIC CLASSIFICATION TO CLINICAL OUTCOMES IN PROSTATE CANCER OVER 8 YEAR FOLLOW-UP Benjamin Behers, Spencer Kortum, Genesis Dolgetta, Karim Ghazli, Tonya King, Victoria Bird, and Robert Carey Benjamin BehersBenjamin Behers More articles by this author , Spencer KortumSpencer Kortum More articles by this author , Genesis DolgettaGenesis Dolgetta More articles by this author , Karim GhazliKarim Ghazli More articles by this author , Tonya KingTonya King More articles by this author , Victoria BirdVictoria Bird More articles by this author , and Robert CareyRobert Carey More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003305.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Decipher genomic classification (DGC) has been developed to predict disease severity in prostate cancer. This study seeks to evaluate how well Decipher scores predicted actual clinical outcome in 192 patients that underwent robotic prostatectomy (RALRP) with 8-year follow-up of survival outcomes. METHODS: Data is collected from an IRB-approved, prospectively-maintained database of 192 patients who underwent RALRP with DGC testing of the post prostatectomy specimens with mean 8 year follow-up outcomes. The Decipher prediction signatures were Metastasis Risk, Androgen Deprivation Therapy (ADT) Response, Post-Operative Radiation Response, Docetaxel Sensitivity, Seminal Vesicle Invasion, Genomic Gleason Score of Primary 4 or 5, Genomic CAPRA-S Score of High (>5), Pathology Stage T3 (pT3 Disease), Tumor Cell Proliferation, and Androgen Receptor (AR) Signaling Activity. A logistic regression analysis test evaluated these signatures with the actual clinical outcomes of metastatic castration-resistant prostate cancer (mCRPC), metastasis, ADT use, overall mortality (OM), and disease-specific mortality (DSM). RESULTS: Higher Decipher scores for pT3 Disease was the most significant predictor of requiring ADT. The odds of ADT were 1.8 times greater for every 25-unit increase in pT3 Disease (95% CI 1.84-4.96, p<0.001). A negative relationship was seen between the Decipher prediction of Genomic Gleason Score of Primary 4 or 5 and no disease progression. The odds of no progression was 0.6 times lower for every 25-unit increase in Genomic Gleason Score of Primary 4 or 5 (95% CI 0.41-0.82, p=0.002). Higher Decipher scores for Post-Operative Radiation Response had a positive relationship with overall mortality. For every 25-unit increase in Post-Operative Radiation Response, OM was 1.9 times greater (95% CI 1.32-2.87, p<0.001). Finally, AR Signaling Activity had a negative relationship with disease-specific mortality. DSM was 0.21 times lower for every 25-unit increase in AR Signaling Activity (95% CI 0.05-0.85, p=0.028). CONCLUSIONS: This paper finds correlation between Decipher genomic predictions with actual clinical outcomes at 8 year post prostatectomy follow-up. Decipher scores for pT3 Disease and Genomic Gleason Score of Primary 4 or 5 signature were the best predictors of requiring ADT treatment and of no disease progression, respectively. AR Signaling Activity signature was the best predictor of disease-specific mortality, whereas Post-Operative Radiation Response was the best predictor of overall mortality. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e746 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Benjamin Behers More articles by this author Spencer Kortum More articles by this author Genesis Dolgetta More articles by this author Karim Ghazli More articles by this author Tonya King More articles by this author Victoria Bird More articles by this author Robert Carey More articles by this author Expand All Advertisement PDF downloadLoading ...

Kidney function is influenced by salt intake and may adapt rapidly to dietary salt variations by modulating pressure-natriuresis. In particular, salt-sensitive (SS) individuals respond to a high-salt diet with a large rise in blood pressure (BP), indicative of a blunted pressure-natriuresis relationship, while 7-12% of the normotensive population have reduced BP with Na + loading, a condition termed inverse salt sensitivity. We compared effects of acute intravenous Na + loading on renal function in normotensive salt-resistant (SR) (11) and SS (5) individuals, as described below. After subjects were prepared in metabolic balance at 100 mmol Na + /d, they underwent Phase I renal function studies (0700h-1100h); Phase II oral sodium citrate load (1100h) followed by a continuous intravenous infusion of 0.9% saline (1100h-1300h); Phase III post-control monitoring period (1300h-1500h). During the entire protocol, BP and heart rate were monitored every 10 min. Blood and urine samples were obtained every hour and analyzed for Na + , K + , creatinine, osmolality and pH. Renal function tests included GFR, filtered Na + load (F Na ), urinary Na + exretion (U Na V), fractional Na + reabsorption (FR Na ), and fractional Na + excretion (FE Na ). Mean BP was calculated using 6 measurements/hour. SS systolic (SBP) and diastolic BP (DBP) were significantly higher than in subjects with SR throughout the procedure (at 1100h SS 137±6.3 vs SR 114±2.6 mmHg, p<0.001 two-way ANOVA). Phase II changes in BP were calculated by subtracting BP at 1100h; there were no significant changes for SR BP. With Na + infusion, SS SBP and DBP increased and remained elevated through the end of the procedure. The increase of SS DBP at 1500h was significantly higher than that of SR (85.8±5.5 vs 65.9±1.6 mmHg, p<0.05 t-test). Both GFR and F Na were increased in SR, while there were no changes in SS after Na + infusion (GFR SR Y=2.9*X-28.37; SS Y=0.61*X-11.45). FR Na was increased in SR, but decreased in SS. The difference between slopes was significant (SS Y=-1.92*X+21.56; SR Y=0.64*X-6.8, P<0.01). After 1 h of Na + loading, FE Na decreased to 1.3 in SS but increased to 1.6 in SR (P=0.089 t-test). The results indicate that renal function of individuals with SS responds differently to acute intravenous Na + loading than those with SR.

You have accessJournal of UrologyCME1 Apr 2023MP07-05 RISK FACTORS ASSOCIATED WITH POST-OPERATIVE SMALL BOWEL OBSTRUCTION FOLLOWING ROBOTIC SACROCOLPOPEXY WITH 12-YEAR EXPERIENCE Cassandra Schuster, Benjamin Behers, Spencer Kortum, Genesis Dolgetta, Karim Ghazli, Victoria Bird, and Robert Carey Cassandra SchusterCassandra Schuster More articles by this author , Benjamin BehersBenjamin Behers More articles by this author , Spencer KortumSpencer Kortum More articles by this author , Genesis DolgettaGenesis Dolgetta More articles by this author , Karim GhazliKarim Ghazli More articles by this author , Victoria BirdVictoria Bird More articles by this author , and Robert CareyRobert Carey More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003222.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Robotic sacrocolpopexy (RASCP) is a transabdominal approach for repair of pelvic organ prolapse (POP) that avoids placement of transvaginal mesh and provides durable repair of high grade prolapse. Given that the procedure has a trans-peritoneal component, there is a risk of reoperation due to small bowel obstruction (SBO). METHODS: Data was collected from an IRB-approved prospectively maintained database of RASCP in a tertiary care hospital. The surgery is performed with a da Vinci Si or Xi system with 4 robotic ports and 1 assistant port by a single surgeon. Commercially available 4×24 cm Y-shaped wide pore polypropylene mesh is modified to accommodate the anterior and posterior dissections of the vaginal walls and are attached with running barbed suture with 16-20 sites of fixation. The long Y-arm of the mesh is trimmed to size for attachment to the anterior longitudinal ligament with GoreTex sutures. Posterior peritoneal flaps are created and the entirety of the mesh and repair is completely covered by peritoneum. No mesh or suture is left exposed. Mid-urethral slings were placed at the time of sacrocolpopexy to prevent de novo stress incontinence. All patients for RASCP had stage 4 prolapse. There were no conversions from robotic to open. RESULTS: Between 2010 and 2022, 450 patients underwent RASCP at the same institution. 80 (17.8%) involved extensive lysis of adhesions (ELOS) and 370 did not code for ELOS. At mean 78-month (12–140 month) follow-up, there were 8 (1.8%) reoperations for SBO. 6/80 (7.5%) patients with ELOS had reoperations for SBO had ELOS. Age, BMI, procedure time, suture type, and brand of mesh were not associated with SBO. Only ELOS was found to be associated with SBO on multivariate analysis. Mean age was 66.1 years and mean BMI 28.2. Robotic console time between 59 and 123 min. All 8 reoperations for SBO had previous abdominal procedures, and 6 were coded as ELOS. There were no reoperations for SBO in patients with no previous abdominal surgery. CONCLUSIONS: RASCP is a safe and durable surgery for repair of POP. Risk of reoperation for SBO is associated with concomitant ELOS. In ELOS patients the risk of SBO is 7.5% and in patients without ELOS the risk is 0.5%. Although many patients presenting for RASCP have had previous abdominal operations, not all such patients require ELOS. For patients with histories of numerous prior bowel or abdominal surgeries who are at increased risk for ELOS at time of RASCP, careful patient selection is recommended and appropriate preoperative counseling suggested. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e86 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cassandra Schuster More articles by this author Benjamin Behers More articles by this author Spencer Kortum More articles by this author Genesis Dolgetta More articles by this author Karim Ghazli More articles by this author Victoria Bird More articles by this author Robert Carey More articles by this author Expand All Advertisement PDF downloadLoading ...