Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex: Design, synthesis, radioligand binding assay, and pharmacological evaluation.

Agonists of Benzodiazepine (BZD) receptor are exhaustively used in the control of muscle spasms, seizure, anxiety, and insomnia. BZDs have some unwanted effects; therefore, the development of new BZD receptor agonists with better efficacy and fewer unwanted effects is one of the subjects of interest. In this study, based on the pharmacophore/receptor model of the BZD binding site of GABAA receptors, a series of new 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives (6a-f) were designed. Energy minima conformers of the designed compounds and diazepam were well matched in conformational analysis and showed proper interaction with the BZD-binding site of the GABAA receptor model (α1ß2ϒ2) in docking studies. The designed compounds were synthesized in acceptable yield and evaluated for their in vitro affinity to the benzodiazepine receptor of rat brains by radioligand receptor binding assay. The results demonstrated that the affinities of most of the novel compounds were even higher than diazepam. The novel compound 6a with the best affinity in radioligand receptor binding assay (Ki=0.44 nM and IC50= 0.73±0.17 nM) had considerable hypnotic activity and weak anticonvulsant and anxiolytic effects with no negative effect on memory in animal models. Flumazenil as a selective benzodiazepine receptor antagonist was able to prevent hypnotic and anticonvulsant effects of 6a indicating the role of BZD receptors in these effects.

Complete Penile Disassembly for Repair of Epispadias Causes Erectile Tissue Alteration Through Transforming Growth Factor Beta 1 Overexpression in a Rabbit Model.

OBJECTIVE: To investigate corporal tissue viability and changes in endothelial content following current techniques used for epispadias repair in an animal model. MATERIALS AND METHODS: Sixty rabbits were allocated into 3 groups: sham operation (penile degloving), complete disassembly model, and Cantwell-Ransley model. On weeks 2, 4, 12, and 24 postoperation, the penile tissue was harvested and processed for (1) Masson's trichrome staining for smooth muscle cell (SMC)-to-collagen ratios, (2) immunohistochemical staining for endothelial factor (CD31), and transforming growth factor beta 1 (TGF-ß1) (3) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling (TUNEL) assay to detect apoptosis. RESULTS: Masson trichrome staining of corporal tissue showed significant decrease in SMC-to-collagen ratio in complete disassembly group compared with sham operation group. The expression of CD31 was significantly lower (P <.05) in complete disassembly group compared with the other groups at all time points, whereas no significant difference was observed between the Cantwell-Ransley group and the sham operation group. Moreover, apoptotic index was markedly higher in the complete disassembly group compared with the 2 other operation groups (P <.05). Immunohistochemistry also showed a significantly higher expression of TGF-ß1 in the penile tissue after complete disassembly than Cantwell-Ransley or sham operation. CONCLUSION: Complete detachment of the urethra from the corpus cavernosa may result in endothelial dysfunction, alteration of SMC content of erectile tissue, and replacement of the native cavernosal tissue with fibrotic tissue. An increased expression of TGF-ß1, following the complete disassembly technique, might be one of the important factors causing the abovementioned alterations.

Autophagy, Apoptosis, and Cell Proliferation in Exstrophy-Epispadias Complex.

OBJECTIVE: To investigate the state of autophagy and its interactions with apoptosis and cell proliferation in patients who underwent successful early closure or delayed closure of exstrophy. They compared those outcomes with cell culture samples from patients with vesicoureteral reflux as control. PATIENTS AND METHODS: Primary cultures of bladder smooth muscle cells (SMCs) were established from patients with successful neonatal bladder closure (group 1, N = 5), delayed closure because of small bladder template (group 2, N = 5), and vesicoureteral reflux as control (group 3, N = 5). The myogenicity of the cultures was determined using anti-Desmin antibody. Immunostainings for LC3 to assess autophagy and Ki67 to assess cell proliferation were applied. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick-end labeling assay. RESULTS: Autophagy marker (LC3) expression was significantly higher in the delayed closure group than in the other groups, whereas no significant difference was noted between the neonatal closure and the control groups. Apoptotic indices of the SMCs were remarkably higher in SMC cultures from the delayed closures than in the neonatal closure and the control groups. A significantly lower expression of proliferation marker (Ki67) in the delayed closure group compared with the control and the neonatal closure group was also of note. CONCLUSION: Patients with small bladder template and delayed closure showed upregulated autophagic process and increased apoptotic indices while experiencing a dramatic decrease in the proliferation of their bladder SMCs. Finally, the concept of manipulating autophagy may lead to promising outcomes for patients with bladder exstrophy in the future.

The Surgical Management of Bladder Polyps in the Setting of Exstrophy Epispadias Complex.

OBJECTIVE: To investigate the surgical course for treating bladder polyps in patients with exstrophy epispadias complex (EEC). EEC bladder polyps are unique pathologic entities, with a distinct difference between polyps discovered at birth and polyps developed after failed exstrophy closure. METHODS: A prospectively maintained database of 1300 patients with EEC was reviewed for bladder exstrophy patients with bladder polyps. The following data were obtained: patient demographics, polyp type, past medical and surgical history, and continence outcomes. Polyps were categorized as (1) primary, bladder polyps at birth or during neonatal period; and (2) secondary, bladder polyps following a failed exstrophy closure. RESULTS: Of 1300 EEC patients, 43 patients with polyps met the inclusion criteria. All closures for primary polyp patients were successful, and continence outcomes remained similar in early and delayed closures (P = .689). Secondary polyp patients were more likely to require augmentation to increase bladder capacity (P = .033). Bladder neck reconstruction (n = 8) was successful in 83.0% of patients with primary polyps, and none were successful for those with secondary polyps (P = .035). CONCLUSION: Delaying primary bladder closure for patients with small polypoid bladder templates did not affect closure or continence outcomes. However, primary and secondary polyps may require different surgical interventions. Bladder neck reconstruction was markedly less successful in secondary polyp patients, and secondary polyp patients were more likely to need augmentation to increase bladder capacity. This study emphasizes the importance of a successful primary closure and suggests that secondary polyps are an indicator of decreasing potential for bladder growth.

Disseminated tuberculosis after extracorporeal shock-wave lithotripsy in an AIDS patient presenting with urosepsis.

Haematogenous dissemination of undiagnosed urinary tuberculosis after performing extracorporeal shock-wave lithotripsy (ESWL) is extremely rare. Herein, we report a 41-year-old male who presented with urosepsis to the emergency room; catheterization was performed and retention resolved. He had a tattoo on his left arm and a five-year history of intravenous drug use. Blood tests indicated anaemia, leukocytosis, elevated CRP and ESR and mild hyponatraemia; haematuria, moderate bacteriuria and 2+ proteinuria on urinanalysis were observed. Chest X-ray revealed lesions suggestive of miliary tuberculosis, which was confirmed by chest CT scan. Brain CT and MRI suggested brain involvement in the setting of tuberculosis. On further investigations, HIV infection and hepatitis C seropositivity were detected and the patient remained in a coma for five days with a Glasgow Coma Scale of 6/15. Finally, the diagnosis of haematogenous dissemination of tuberculosis following lithotripsy was established. Anti-tuberculosis and anti-retroviral therapy were prescribed and monthly follow-up visits were scheduled. In conclusion, in a patient diagnosed with ureterolithiasis, a thorough history and physical examination, with specific attention to HIV and tuberculosis predisposing factors, should be carried out and preoperative screening tests considering the possibility of urinary tuberculosis are required. Finally, if urinary tuberculosis is detected, ESWL must be postponed until after appropriate treatment of tuberculosis.