Probenecid induces the recovery of renal ischemia/reperfusion injury via the blockade of Pannexin 1/P2X7 receptor axis.

Renal ischemia/reperfusion injury (RI/RI) is one of the main driving causes of acute kidney injury. However, effective treatment to limit injury and promote recovery and/or survival is still unavailable. Probenecid (PBN), a drug indicated for refractory gout, exhibits protective activities against several preclinical diseases including cerebral and myocardial I/RI via Pannexin 1 (Panx1) and P2X7 receptors' (P2X7R) inhibition. However, its protective role against RI/RI has not been previously addressed. Accordingly, we subjected rats to bilateral RI/RI with/or without PBN treatment. Twenty-four hours post-reperfusion, PBN showed mild tubular injury and reduced serum nephrotoxicity indices, gene and protein expression levels of Panx 1 and P2X7R, and ATP and pro-inflammatory cytokines' levels. The nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome signaling was also downregulated, as demonstrated by reduced gene and protein expression of NLRP3 and caspase-1, along with suppressed IL-1ß maturation. Furthermore, PBN enhanced Tregs activity as indicated by elevated FoxP3 gene expression, IL-10, and TGF-ß renal levels. On day 5 post-reperfusion, PBN noticeably enhanced renal recovery, as demonstrated by intact tubular epithelium and restored nephrotoxicity indices, Panx 1 and P2X7R gene and protein expression levels, ATP and pro-inflammatory cytokine levels, and NLRP3 inflammasome signaling. Besides, renal Tregs activity was also significantly increased. Our study elaborates for the first time the effectiveness of PBN in recovering post-ischemic renal injury through synergistic inhibition in Panx1/P2X7R axis leading to inactivation of NLRP3 inflammasome signaling and activation of Tregs in ischemic renal tissues. Therefore, PBN can be considered a promising drug for RI/RI treatment.

Development of a New Dislodgeable Foliar Residue Analytical Laboratory Method for Pesticides.

The dislodgeable foliar residue (DFR) is the amount of pesticide that exists on foliage after the pesticide has dried and which could dislodge to the skin or clothes of workers and is a key parameter for non-dietary risk assessments required to demonstrate safe use for pesticide registration. DFR data in the literature are described as insufficiently reliable, limited, and encompasses considerable statistical uncertainties. The purpose of this article is to describe a newly developed laboratory method for the quantification of DFR with an illustrative example. The laboratory method reflected available field DFR methodology but involved controlled application of droplets to leaves and validation of the wash-off process used to remove the residue from the leaf surface before the analytical quantification. A very high level of accuracy (99.7-102.1%) and precision (±1.5%) was achieved. Residue data generated from the illustrated application of the method showed a robust normal distribution, unlike field studies. The method is deemed to be controllable, cost-efficient, and time-saving, taking hours rather than days. This enables the generation of more data to allow extrapolation between the generated data by investigating multiple factors that may influence DFR. An improved understanding of DFR could save time, money, and resources.

Co-treatment with Esculin and erythropoietin protects against renal ischemia-reperfusion injury via P2X7 receptor inhibition and PI3K/Akt activation.

Renal ischemia/reperfusion (RI/R) is a critical clinical outcome with slightly reported improvement in mortality and morbidity. Effective therapies are still crucially required. Accordingly, the therapeutic effects of esculin (ESC, LCESI-MS/MS-isolated compound from Vachellia farnesiana flowers extract, with reported P2X7 receptor inhibitor activity) alone and in combination with erythropoietin (EPO) were investigated against RI/R injury and the possible underlying mechanisms were delineated. ESC and EPO were administered for 7 days and 30 min prior to RI, respectively. Twenty-four hour following reperfusion, blood and kidney samples were collected. Results revealed that pretreatment with either ESC or EPO reduced serum nephrotoxicity indices, renal oxidative stress, inflammatory, and apoptosis markers. They also ameliorated the renal histopathological injury on both endothelial and tubular epithelial levels. Notably, ESC markedly inhibited P2X7 receptors and NLRP3 inflammasome signaling (downregulated NLRP3 and Caspase-1 gene expressions), whereas EPO significantly upregulated PI3K and Akt gene expressions, also p-PI3K and p-Akt levels in renal tissues. ESC, for the first time, demonstrated effective protection against RI/R-injury and its combination with EPO exerted maximal renoprotection when compared to each monotherapy, thereby representing an effective therapeutic approach via inhibiting oxidative stress, inflammation, renal tubular and endothelial injury, apoptosis, and P2X7 receptors expression, and activating PI3K/Akt pathway.

Holmium Laser Enucleation vs Bipolar Plasmakinetic Enucleation of a Large Volume Benign Prostatic Hyperplasia: A Randomized Controlled Trial.

Objectives: To compare safety and efficacy of bipolar plasmakinetic enucleation of prostate (BPEP) vs holmium laser enucleation of prostate (HoLEP) for management of large benign prostatic hyperplasia (BPH) (>80 g). Patients and Methods: Patients with failed medical treatment, International Prostate Symptom Score (IPSS) >13, peak urinary flow rate (Qmax)<15 mL/s and prostate size ≥80 g were enrolled in this randomized controlled trial from November 2016 to February 2018 and managed by HoLEP (Group A; 33 patients) or BPEP (Group B; 31 patients). Patients on anticoagulants (AC) were not excluded. Patients were followed up for 12 months. Perioperative data were compared between both groups using Student's-t, Mann-Whitney, Paired-t, Wilcoxon signed rank, chi-square, or Fisher-exact tests as appropriate. Results: There was no significant difference between both groups in age, rate of presentation with urinary retention, recurrent hematuria, frequency of patients on ACs/antiplatelets, prostate size, prostate specific antigen (PSA), Qmax, IPSS, quality of life (QoL), and post-void residual urine (PVRU). Operative time was significantly longer in BPEP (p = 0.003) and catheterization duration (p = 0.019). Other perioperative parameters including level of Na+ and hemoglobin, resected tissue weight, hospital stay, and complications were not significantly different between both groups. There was no need for blood transfusion in all patients. There was significant postoperative improvement in IPSS, PVRU, QoL, PSA, and Qmax in each group. However, there was no significant difference between both groups in these parameters. Conclusion: HoLEP and BPEP are comparable regarding safety and efficacy for treatment of BPH (>80 g) including patients on ACs. However, BPEP required a longer catheterization duration and operative time. ClinicalTrials.gov Identifier: NCT03998150.

Upregulation of Twist2 in Non-Muscle Invasive Urothelial Carcinoma of the Bladder Correlate with Response to Treatment and Progression.

BACKGROUND: Twist2 is a transcription factor and an epithelial-to-mesenchymal transition that plays an important role in cell polarity, cell adhesion, and has a role in tumour invasion and metastases. AIM: In this study, we examined the expression of Twist2 in non-muscle invasive bladder carcinoma (NMIBC) and correlated the expression with response to treatment and tumour progression. METHODS: Data of 305 patients with NMIBC of Ta, T1 were retrieved from hospitals archives. Twist2 expression was examined in tissue samples by immunohistochemistry at initial diagnosis and final follow-up, normal control was 10 normal urothelium, 10 patients with muscle-invasive bladder cancer (MIBC) were a positive control. Treatment of NMIBC was implemented according to the European Association of Urology guidelines on NMIBC. The descriptive statistical analysis included means, standard deviation, p-value; Univariate and multivariate Cox regression analyses. RESULTS: Twist2 expression score was identified as negative, low (1-15%); medium (15-40%); and high (40-100%). Patients who had low or low medium scores at the initial diagnosis had a good response and a favourable prognosis. Expression of a high score of Twist2 in patients having high-grade T1 tumours showed non-responsiveness to repeated courses of intravesical bacillus Calmette Guerin (BCG) therapy and was upstaged to MIBC. CONCLUSION: Twist2 expression in tissue samples of NMIBC would indicate the tumour response to therapy, upgrading and upstaging in the follow up after intravesical BCG therapy.

Clinical versus Pathologic staging of Renal Tumors: Role of Multi-Detector CT Urography.

INTRODUCTION: Our ability to diagnose renal cell carcinoma (RCC) has increased in the past 30 years as a result of the extensive application of imaging techniques, such as ultrasonography, computed tomography, and magnetic resonance imaging. Multi-detector computed tomography (MDCT) remains the most appropriate imaging modality for the diagnosis and staging of RCC. The aim of this work was to compare the findings of MDCT with surgical pathology to determine the accuracy of delineating tumor size, localization, organ confinement, lymph node metastases, and the extent of tumor thrombus in the renal vein and inferior vena cava. METHODS: The clinical, surgical, and anatomo-pathologic records of 99 patients treated by nephrectomy (radical or partial) for solid renal tumors at Theodor Bilharz Research Institute and Nasser Institute from 2005 to 2011 were reviewed retrospectively. All cases were staged pre-operatively with abdominal MDCT (pre- and post-contrast enhancement) in addition to the routine biochemical, hematological, and radiological work-up. The tumors' histologic types were determined according to the WHO classification of renal tumors in adults in 2004, and staging was updated to the TNM 2010 system. Data were analyzed using the t-test. RESULTS: The mean age was 52 (range 21-73). Seventy-eight patients were males, and 21 patients were females (Male/Female ratio: 3.7:1). There were no significant differences in the mean tumor size between radiographic and pathologic assessments in different tumor stages. The overall incidence of lymph node invasion in surgical specimens was 76%, whereas MDCT showed a positive incidence in 68.4% of cases (false negative result in 7 cases, 7.6%). CONCLUSION: Our findings indicated that MDCT urography is an accurate method to estimate renal tumor size, lymph node, vascular and visceral metastases preoperatively. Also, preoperative staging of renal tumors with MDCT represents a valuable and accurate tool.