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Introduction Despite being an occupational hazard, environmental exposure to lead (Pb) has been and will continue to be a major public health concern, because this metal is widely present in [...], BACKGROUND: The role of environmental factors in Alzheimer's disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain [beta]-amyloid (A[beta]) deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. OBJECTIVES: This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. METHODS: Female APP/PS1 mice at 8 wk of age were administered either 50 mg/kg Pb-acetate (PbAc) (i.e., 27 mg Pb/kg) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immuno-staining. In addition, A[beta] perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed in vivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. RESULTS: APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to A[beta]40, higher A[beta]40/A[beta]42 ratios, strikingly lower A[beta]40 levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. DISCUSSION: Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders. https://doi.org/10.1289/EHP14384

Purpose: To describe the technique as well as the oncological and functional outcomes of partial salvage prostatic cryoablation (SCAP) in the treatment of local recurrent prostate cancer after primary radiotherapy. Materials and methods: The indications for partial SCAP were: PSA10 years and PSA doubling time >12 months. Cryoablation was performed with the Precise© device (Galil MedicalⓇ, Arden Hills, Minnesota, USA). Results: Fourteen patients underwent partial SCAP from 09/2010 to 09/2018. Primary treatment consisted of: 29% brachytherapy and 71% EBRT with concomitant androgen deprivation therapy (ADT) in 50%. Median time to recurrence was 8.5 years [3.2–19.3]. At the time of cryotherapy, median age was 72 years [58–84], Charlson was 3 [1–6] and serum PSA was 4.2 [2.2–9.0]. Mean procedure time was 90 min [60–120]. Median hospital stay and catheter duration were respectively 2 days [2–6] and 8 days [3–14]. Median biochemical disease-free survival was 4.4 years and 71% of the patients were free of third-line treatment at the time of evaluation. No patient developed metastasis, and all were alive at the time of the last evaluation. De novo urinary incontinence was reported in one patient and de novo erectile dysfunction in one patient. Conclusions: Partial SCAP was an alternative to salvage prostatectomy and whole gland ablation for highly selected patients with locally recurrent PCa after radiotherapy. It significantly avoided or at least delayed the need for ADT.

Loris Cacciatore,1 Angelo Territo,2 Antonio Minore,1 Antonio Testa,1 Guglielmo Mantica,3 Francesco Esperto1 1Department of Urology, Fondazione Policlinico Universitario Campus Bio-Medico Di Roma, Rome, Italy; 2Department of Urology, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain; 3Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genova, Genoa, ItalyCorrespondence: Loris Cacciatore, Department of Urology, Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy, Email loris.cacciatore@unicampus.itAbstract: Bladder pain Syndrome presents a multifaceted challenge in contemporary urological practice, marked by LUTS, negative behavioural, sexual, or emotional experiences, and the potential for sexual dysfunction. We meticulously explored the existing literature of conservative, non-invasive and invasive interventions, aiming to provide clinicians with a nuanced understanding of available options for comprehensive BPS management. We delve into the effectiveness and safety profiles from behavioural approaches through lifestyle changes and physical therapy, to oral or intravesical medications, until the definitive surgical treatment. The best option evaluated is the involvement of a multidisciplinary team, including urologists, urotherapists, gynaecologists, pain specialists, primary care physicians and psychologists, educating those patients regarding the condition and its chronic course and tailoring the perfect treatment for each person. Despite this, BPS remains a challenge for urologists. Indeed, our objective is to contribute to the evolving landscape of BPS management, fostering informed decision-making and personalized care for individuals grappling with this challenging condition.Keywords: bladder pain syndrome, interstitial cystitis, lower urinary tract symptoms, females, continence, therapy, conservative treatment

Objective: To present the surgical technique and outcomes of robotic ureteral reimplantation in ileal conduit (IC) and neobladder (NB) in patients with prior minimally-invasive radical cystectomy and intracorporeal urinary diversion, who developed benign uretero-ileal anastomotic strictures. Patients and surgical procedure: We report on a multiinstitutional cohort of 10 patients (7 IC, 3 NB) who had 12 uretero-ileal strictures (8 unilateral, 2 bilateral) causing hydronephrosis and renal function deterioration, who underwent robotic uretero-ileal reimplantation in referral centers for robotic surgery between 2016 and 2022. Median age was 67.5 years (Interquartile range [IQR]: 66–69). The stricture was diagnosed at a median of 6 months (IQR 5–10) from the initial surgery. All unilateral strictures were on the left side. Two patients received unsuccessful endoscopic dilatation before the reconstructive surgery. All patients underwent nephrostomy placement prior to the reconstructive procedure. Robotic uretero-ileal reanastomosis started with adhesiolysis, followed by the identification of the ureters and urinary diversion, facilitated by the use of intracavitary saline or ICG. When dissecting the ureters, a „no touch” technique was used, in order to minimize devascularization and ischemia. Localization of the ureteral stricture was critical. The excision of the entire ischemic segment was performed until signs indicative of adequate tissue trophism were found. At the same time, consideration was given to spare sufficient length of the ureteral stumps to allow for a tension-free anastomosis. Direct anastomosis using monofilament resorbable suture, with insertion of mono J or double J stent was performed with both ileal conduit and neobladder. Bricker technique was used in case of unilateral stricture. Results: The median operative time for robotic uretero-ileal reanastomosis was 152 min (IQR 120–180) and the median blood loss was 50 ml (IQR 40–70). No intraoperative complications occurred according to the ICARUS criteria. Median length of hospital stay was 4.5 days (IQR 3–6). Two Clavien-DIndo II (20 %) postoperative complications were registered (urinary tract infection and acute kidney injury). No patients required readmission or reoperation. The mean length of ureteral catheterization for reimplantation in IC was 20.7 days (± 4.29). For patients with NB, the mean ureteral and urethral catheterization times were 54.3 days (± 22.8) and 19.3 days (± 11.08), respectively. The ureteral stents were removed in all patients. At a median of 16 months follow-up (range 6–36 months), 2 patients (one IC and one NB, respectively) had persistent hydronephrosis. Conclusion: In patients requiring surgery for benign ureteral strictures following cystectomy, robotic surgery allows for safe and efficient ureteral reimplantation in urinary diversion.

IntroductionThe 5xFAD mouse is a popular model of familial Alzheimer's disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan.MethodsMale and female 5xFAD and wild type (WT) littermates underwent in vivo 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter.ResultsWith increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan.DiscussionWhile the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

Abstract The laparoscopic approach represents the standard of treatment for renal and adrenal diseases, and its use is increasing even outside referral centres. Although most procedures are routinely performed, intraoperative complications do not occur, and the rate and predictive factors of these complications have not been established. The aim of this study was to evaluate the incidence and type of intraoperative complications and to identify predictive factors in patients undergoing laparoscopic renal and adrenal surgery. This was a cohort, multicentre, international retrospective study. Patients who underwent laparoscopic renal and adrenal surgeries between April 2017 and March 2022 were included in the study. Bivariate analysis was performed using contingency tables and the χ2 test for independent samples to compare qualitative variables and the T test and Mood test for continuous variables. Multivariate analysis was performed using a logistic regression model to obtain adjusted odds ratios. A total of 2374 patients were included in the study. Intraoperative complications were reported for 8.09% of patients who underwent renal surgery, with the most common complications reported being hollow viscus and vascular complications, and for 6.75% of patients who underwent adrenal surgery, with the most common complication reported being parenchymatous viscous complications. Multivariate analysis revealed that both adrenal and renal surgery radiological preoperative factors, such as invasive features during adrenalectomy and the RENAL score during nephrectomy, are predictive factors of intraoperative complications. In contrast to existing data, surgeon experience was not associated with a reduction in the incidence of perioperative complications.

Abstract Background 68Ga-PSMA-11 positron emission tomography enables the detection of primary, recurrent, and metastatic prostate cancer. Regional radiopharmaceutical uptake is generally evaluated in static images and quantified as standard uptake values (SUVs) for clinical decision-making. However, analysis of dynamic images characterizing both tracer uptake and pharmacokinetics may offer added insights into the underlying tissue pathophysiology. This study was undertaken to evaluate the suitability of various kinetic models for 68Ga-PSMA-11 PET analysis. Twenty-three lesions in 18 patients were included in a retrospective kinetic evaluation of 55-min dynamic 68Ga-PSMA-11 pre-prostatectomy PET scans from patients with biopsy-demonstrated intermediate- to high-risk prostate cancer. Three kinetic models—a reversible one-tissue compartment model, an irreversible two-tissue compartment model, and a reversible two-tissue compartment model, were evaluated for their goodness of fit to lesion and normal reference prostate time-activity curves. Kinetic parameters obtained through graphical analysis and tracer kinetic modeling techniques were compared for reference prostate tissue and lesion regions of interest. Results Supported by goodness of fit and information loss criteria, the irreversible two-tissue compartment model optimally fit the time-activity curves. Lesions exhibited significant differences in kinetic rate constants (K 1, k 2, k 3, K i) and semiquantitative measures (SUV and %ID/kg) when compared with reference prostatic tissue. The two-tissue irreversible tracer kinetic model was consistently appropriate across prostatic zones. Conclusions An irreversible tracer kinetic model is appropriate for dynamic analysis of 68Ga-PSMA-11 PET images. Kinetic parameters estimated by Patlak graphical analysis or full compartmental analysis can distinguish tumor from normal prostate tissue.

Objective: To report the outcomes of intra- and extra-peritoneal robot-assisted radical prostatectomy (RARP) and robot-assisted radical cystectomy (RARC) with Hugo™ robot-assisted surgery (RAS) system (Medtronic, Minneapolis, MN, USA). Methods: Data of twenty patients who underwent RARP and one RARC at our institution between February 2022 and January 2023 were reported. The primary endpoint of the study was to report the surgical setting of Hugo™ RAS system to perform RARP and RARC. The secondary endpoint was to assess the feasibility of RARP and RARC with this novel robotic platform and report the outcomes. Results: Seventeen patients underwent RARP with a transperitoneal approach, and three with an extraperitoneal approach; and one patient underwent RARC with intracorporeal ileal conduit. No intraoperative complications occurred. Median docking and console time were 12 (interquartile range [IQR] 7–16) min and 185 (IQR 177–192) min for transperitoneal RARP, 15 (IQR 12–17) min and 170 (IQR 162–185) min for extraperitoneal RARP. No intraoperative complications occurred. One patient submitted to extraperitoneal RARP had a urinary tract infection in the postoperative period that required an antibiotic treatment (Clavien-Dindo Grade 2). In case of transperitoneal RARP, two minor complications occurred (one pelvic hematoma and one urinary tract infection; both Clavien-Dindo Grade 2). Conclusion: Hugo™ RAS system is a novel promising robotic platform that allows to perform major oncological pelvic surgery. We showed the feasibility of RARP both intra- and extra-peritoneally and RARC with intracorporeal ileal conduit with this novel platform.

IntroductionAlzheimer's disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer's Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline.Methods5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data.ResultsProphylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake.DiscussionProphylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD.