Trimodal therapy versus radical cystectomy for cT2N0M0 urothelial muscle-invasive bladder cancer: Single-center experience.

Background: Bladder cancer is ranked the ninth most common cancer in the world. Locally, the incidence of bladder cancer has increased tenfold over the past 26 years. Radical cystectomy (RC) is considered a gold standard management option for muscle-invasive bladder cancer (MIBC), but trimodal therapy (TMT) has shown comparable oncological outcomes in selected patients. Materials and Methods: This is a retrospective study in which we reviewed medical records of patients diagnosed with MIBC without nodal disease or distant metastasis (cT2N0M0) who underwent either RC or TMT. Demographic data, comorbidities, histopathological and clinical staging, neoadjuvant/adjuvant therapy, and follow-up were analyzed. Results: We included a total of 31 patients in the study, with 10 patients in the TMT group and 21 patients in the RC group. There was no significant difference in recurrence between the TMT and RC groups (P = 0.58). The TMT group had a higher percentage of local recurrence (40% vs. RC 5.2%, P = 0.018) but no significant difference in metastasis (0% vs. 10%, P = 0.420). The difference in overall survival between the TMT and RC groups was not significant (P = 0.25). Conclusion: TMT may be considered an alternative option for patients unwilling to undergo RC due to related complications and prioritize a better quality of life. However, the decision should be made after considering the cost of extensive follow-ups and patient compliance with surveillance.

Cordycepin- melittin nanoconjugate intensifies wound healing efficacy in diabetic rats.

The current study was designed to develop a nanoconjugate of cordycepin-melittin (COR-MEL) and assess its healing property in wounded diabetic rats. The prepared nanoconjugate has a particle size of 253.5 ± 17.4 nm with a polydispersity index (PDI) of 0.35 ± 0.04 and zeta potential of 17.2 ± 0.3 mV. To establish the wound healing property of the COR-MEL nanoconjugate, animal studies were pursued, where the animals with diabetes were exposed to excision and treated with COR hydrogel, MEL hydrogel, or COR-MEL nanoconjugate topically. The study demonstrated an accelerated wound contraction in COR-MEL nanoconjugate -treated diabetic rats, which was further validated by histological analysis. The nanoconjugate further exhibited antioxidant activities by inhibiting the accumulation of malondialdehyde (MDA) and exhaustion of superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic activities. The nanoconjugate further demonstrated an enhanced anti-inflammatory activity by retarding the expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Additionally, the nanoconjugate exhibits a strong expression of transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF)-A, and platelet-derived growth factor (PDGFR)-ß, indicating enrichment of proliferation. Likewise, nanoconjugate increased the concentration of hydroxyproline as well as the mRNA expression of collagen, type I, alpha 1 (Col 1A1). Thus, it is concluded that the nanoconjugate possesses a potent wound-healing activity in diabetic rats via antioxidant, anti-inflammatory, and pro-angiogenetic mechanisms.

Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats.

Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg) for 4 weeks. Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.

A Pediatric Case of Spinal Intradural Epidermoid Cyst: A Rare Encounter.

Intradural epidermoid cysts of the spine are rare congenital lesions. Their etiology is thought to stem from ectodermal remnants during embryonic development. They result in a diverse clinical presentation, often marked by an insidious onset and variable neurological deficits. Timely diagnosis is crucial for optimizing patient outcomes. We present the case of a 10-year-old male child presenting a six-month history of worsening back pain, intermittent leg weakness, and urinary incontinence. The physical examination revealed tenderness over the lower thoracic and lumbar spine, lower limb weakness, hyperreflexia, and sensory deficits. The diagnostic work-up, including cerebrospinal fluid analysis and magnetic resonance imaging, confirmed the presence of an intradural epidermoid cyst in the lumbosacral region. Surgical excision resulted in complete resection, with subsequent improvement in neurological deficits. This pediatric case underscores the importance of maintaining a high index of suspicion for unexplained neurological deficits. Characteristic imaging findings played a pivotal role in the diagnosis, guiding successful surgical intervention and achieving favorable outcomes.

Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4/NF-κB, JAK1/STAT3, and Nrf2/HO-1 Signaling.

Cisplatin (CIS) is an effective chemotherapeutic agent against different cancers. The use of CIS is associated with acute lung injury (ALI) and other adverse effects, and oxidative stress and inflammation were implicated in its toxic effects. Candesartan (CAN), an angiotensin II (Ang II) receptor blocker, showed beneficial effects against oxidative stress and inflammation. Therefore, this study investigated the potential of CAN to prevent CIS-induced oxidative stress, inflammation, and lung injury in rats, pointing to the involvement of TLR4/NF-κB, JAK1/STAT3, PPARγ, and Nrf2/HO-1 signaling. The rats received CAN (5 mg/kg) for 10 days and were challenged with a single dose of CIS (7 mg/kg) on day 7. CIS caused injury to the alveoli and the bronchial tree, increased lipid peroxidation, nitric oxide, myeloperoxidase, TLR-4, NF-κB p65, iNOS, TNF-α, IL-6, IL-1ß, and caspase-3, and decreased cellular antioxidants and IL-6 in the lungs of rats. CAN effectively prevented tissue injury, suppressed TLR-4/ NF-κB signaling, and ameliorated oxidative stress, inflammatory markers, and caspase-3 in CIS-administered rats. CAN enhanced antioxidants and IL-10, decreased Ang II, increased Ang (1-7), suppressed the phosphorylation of JAK1 and STAT3, and upregulated SOCS3 in CIS-administered rats. These effects were associated with the downregulation of Keap1 and enhanced Nrf2, GCLC, HO-1, and PPARγ. In conclusion, CAN prevented CIS-induced lung injury by attenuating oxidative stress, suppressing TLR-4/NF-κB and JAK1/STAT3 signaling, Ang II, and pro-inflammatory mediators, and upregulating PPARγ, and Nrf2/HO-1 signaling.

Saudi Urological Association consensus guidelines on the use of robotic surgery in urology.

Over the past three decades, minimally invasive robotic technology has evolved substantially in urological practice, replacing many open procedures and becoming part of routine clinical practice. The Health Sector Transformation Program for the Kingdom's Vision 2030 aims to restructure the health sector and optimize its status and prospects as an effective and integrated ecosystem centered on the patient's health. Therefore, this consensus seeks to endorse the clinical practice guidelines for robotic surgery (RS) in the KSA, highlighting its effectiveness, safety, and favorable outcomes compared to open and laparoscopic surgeries in certain procedures when used by trained surgeons in well-structured RS programs.

A flavonoid-rich fraction of Monolluma quadrangula inhibits xanthine oxidase and ameliorates potassium oxonate-induced hyperuricemia in rats.

Hyperuricemia represents a risk factor for the progression of chronic kidney disease. Oxidative stress and inflammation are implicated in the mechanisms underlying hyperuricemia-mediated kidney injury. Monolluma quadrangula possesses several beneficial effects; however, its effect on hyperuricemia has not been investigated. This study evaluated the renoprotective and xanthine oxidase (XO) inhibitory activity of M. quadrangula in hyperuricemic rats. Phytochemical investigation revealed the presence of six known flavonoid isolated for the first time from this species. The rats received M. quadrangula extract (MQE) and potassium oxonate (PO) for 7 days. In vitro assays showed the radical scavenging and XO inhibitory activities of MQE, and in silico molecular docking revealed the inhibitory activity of the isolated flavonoids towards XO. Hyperuricemic rats showed elevated serum uric acid, creatinine, urea, and XO activity, and renal pro-inflammatory cytokines, MDA and NO, and decreased GSH, SOD, and catalase. MQE ameliorated serum uric acid, urea, creatinine, and XO activity, and renal pro-inflammatory cytokines. In addition, MQE attenuated renal oxidative stress, enhanced antioxidants, downregulated URAT-1, and GLUT-9 and upregulated OAT-1 in PO-induced rats. In conclusion, M. quadrangula attenuated hyperuricemia and kidney impairment by suppressing XO activity, oxidative stress and inflammation, and modulating urate transporters.

Robot-Assisted Radical Prostatectomy in Low-Volume Regions: Should It Be Abandoned or Adopted? A Multi-Institutional Outcome Study.

Purpose: To present multinational experience in robot-assisted radical prostatectomy (RARP) by fellowship-trained expertise in low-volume regions in Gulf Cooperation Council (GCC) countries and to compare the current results with global outcomes reported in recent meta-analyses. Methods: A retrospective review of prospectively collected data was performed for patients undergoing RARP for localized prostate cancer (PCa). Three fellowship-trained surgeons at four academic and referral centers in Saudi Arabia and Kuwait performed all procedures between February 2014 and December 2019. Data on demographics, perioperative characteristics, pathology, and adverse events were collected. Results: A total of 207 patients were included with a median (IQR) follow-up duration of 28 (15-38) months. The median prostate volume and prostate-specific antigen were 42 (32-53) g and 9.1 (5.8-14.1) ng/mL, respectively. While 65.2% of patients had a Gleason score ≥7, 20% had grade group 4 disease, and 7.8% had ≥cT3 disease. The mean ± SD operative time was 203 ± 52 minutes, and the mean estimated blood loss was 158 ± 107 mL. Only 4 (1.9%) patients received perioperative blood transfusions. Positive surgical margins were observed in 21.7% of patients, all of whom had ≥pT3 disease. There were 23 complications in 18 (8.7%) patients, including Clavien-Dindo grade III complications in 2.4%. At the 12-month follow-up, 35.8% of patients were potent, 94.6% were continent, and 9.2% had biochemical recurrence. Conclusions: The safety and efficacy of RARP by fellowship-trained expertise in GCC countries were well established. The outcomes seem promising and comparable to international centers and should improve with increasing case volume and fellowship-trained expertise.

Umbelliferone Inhibits Spermatogenic Defects and Testicular Injury in Lead-Intoxicated Rats by Suppressing Oxidative Stress and Inflammation, and Improving Nrf2/HO-1 Signaling.

INTRODUCTION: Lead (Pb) is an environmental toxic metal that threatens human health. Umbelliferone (UMB) is a coumarin with known medicinal and protective properties against cytotoxicity. This study explored the ameliorative effect of UMB against Pb-induced testicular toxicity in rats, focusing on steroidogenesis, oxidative stress and inflammation. MATERIALS AND METHODS: Rats received lead acetate (50 mg/kg) and UMB (25, 50 or 100 mg/kg) via oral gavage for 4 weeks. RESULTS: Pb-intoxicated rats exhibited testicular tissue injury and decreased serum levels of LH, FSH and testosterone. The count, viability, motility and normal morphology of the sperms were decreased accompanied with downregulated steroidogenesis markers in Pb-induced group. UMB prevented testicular injury, increased serum levels of LH, FSH and testosterone, upregulated steroidogenesis markers and improved the semen quality. In addition, UMB attenuated oxidative stress and oxidative DNA damage, downregulated the expression of pro-inflammatory mediators and Bax, boosted antioxidant defenses and Bcl-2, and upregulated Nrf2/HO-1 signaling in Pb-intoxicated rats. CONCLUSION: UMB prevents Pb-induced testicular injury by suppressing oxidative damage, inflammation and cell death, and boosting antioxidant defenses, Nrf2/HO-1 signaling and pituitary-gonadal axis. Thus, UMB may represent a protective and cost-effective agent against Pb testicular toxicity, pending further investigations to elucidate other underlying mechanisms.

Pimpinella anisum extract attenuates spontaneous and agonist-induced uterine contraction in term-pregnant rats.

ETHNOPHARMACOLOGY RELEVANCE: Pimpinella anisum is a well-known traditional medicinal herb which has been used in folk medicine as an antiulcer, anticancer, antibacterial and as a muscle relaxant. AIM OF THE STUDY: This study was performed to explore the modulatory effects of Pimpinella anisum on term-pregnant rat uterine contractility and to investigate its possible underlying mechanisms. MATERIAL AND METHODS: Intact uterine strips without endometrial layer were isolated from female term-pregnant Wistar rats (22 days of gestation) and mounted in a tissue bath apparatus for in vitro isometric force recording. The effects of different concentrations of Pimpinella anisum extract (PAE) (1, 3, 5, and 7 mg/mL) were examined on uterine contractions generated spontaneously or induced with oxytocin (5 nmol/L), Bay K8644 (1 µmol/L), and carbachol (10 µmol/L). In some experiments, PAE was applied on depolarized myometrium in the presence of high-KCl solution (60 mmol/L). The effect on Ca2+ release was also examined. RESULTS: Application of PAE significantly reduced uterine contractions generated spontaneously or induced with oxytocin, Bay K8644, and carbachol in a concentration-dependent manner (n = 7; P < 0.01). In depolarized myometrium, PAE significantly reduced the tonic force induced by high-KCl solution (n = 7; P < 0.01). PAE prevented oxytocin-induced transient contraction in the entire absence of external calcium (n = 7; P < 0.01). CONCLUSION: The present findings demonstrate the potentials of PAE to relax pregnant uterine contractions possibly by blocking Ca2+ entry via L-type calcium channels and inhibiting Ca2+ release from the internal store. The tocolytic effects of PAE may be a potential adjuvant against strong premature uterine contractions which threaten early pregnancy although clinical studies are required.

Effects of Intermittent and Continuous Oxytocin Exposure on Myometrial Contractile Activity in Term-Pregnant Rats In Vitro.

Continuous oxytocin exposure to augment labor contractions may cause receptor desensitization and further reduce the uterine response to oxytocin, resulting in an increased risk of uterine atony. This study aimed to investigate and compare the uterine response to continuous and intermittent oxytocin stimulation. We hypothesized that intermittent brief episodes of oxytocin separated by recovery periods rather than continuous oxytocin application improves subsequent uterine contractions. Myometrial strips were isolated from term-pregnant rats (22 days of gestation; n = 11), mounted in tissue bath chambers, and exposed to continuous oxytocin (5 nM) for 2 h or 6 repeated episodes of 10-min oxytocin exposure (5 nM) separated by 10 min of recovery period in Krebs solution. Contractile parameters (force amplitude, frequency, and integral force) significantly decreased during continuous oxytocin exposure compared with control (n = 11; P < 0.01). Interestingly, myometrial contractility significantly increased during subsequent short intermittent oxytocin exposure which was sustained for 6 h compared with control or continuous exposure (n = 11; P < 0.01). Brief intermittent oxytocin stimulations resulted in better uterine response and improved contractile force than continuous exposure, which may be attributed to attenuation of receptor desensitization or recovery of oxytocin receptor function following intermittent exposure. These findings would help maintain adequate strong contractions to avoid postpartum bleeding.

Surgical and oncological outcome after laparoscopic versus open nephroureterectomy for non-metastatic, upper-tract urothelial carcinoma. A single-centre experience.

OBJECTIVES: We determined the surgical and oncological outcomes of laparoscopic nephroureterectomy (LNU) in comparison to open nephroureterectomy (ONU) and factors predicting bladder recurrence after nephroureterectomy. Methods: We retrospectively reviewed and compared the data of patients who underwent ONU or LNU for non-metastatic, upper-tract urothelial carcinoma from 2000 to 2016. The primary endpoint was to determine bladder cancer recurrence-free survival (BCRFS), cancer-specific survival (CSS), and overall survival (OS). The data were analysed using Student's t-test, Chi-square test, and Kaplan-Meier curve. Results: Total of 50 patients, of which 24 had LNU and 26 had ONU, met the inclusion criteria. Median durations of follow-up were 4.2 and 6.5 years (p=0.1070) in LNU and ONU, respectively. Operative time, blood loss and hospital stay were significantly lower in the LNU group than in the ONU group (p=0.0001, p=0.0001, p=0.0018). Cancer-specific survival rate in the LNU was 75% and ONU was 73.3% (p=0.1902), whereas BCRFS and CSS were not significantly different in both groups (log-rank test; BCRFS: p=0.809 and CSS: p=0.802). Patients who underwent ureteroscopy with biopsy (p=0.001), had multifocality (p=0.001) and previous history of (H/O) bladder cancer (p=0.020) were at significant risk for developing bladder cancer recurrence after nephroureterectomy.  Conclusion: Laparoscopic nephroureterectomy can benefit patients because of its minimal invasiveness, and oncologic outcomes are comparable to ONU. Preoperative ureteroscopy with biopsy, multifocality and previous H/O bladder cancer might be risk factors for bladder cancer recurrence.

Physiology of puberty in boys and girls and pathological disorders affecting its onset.

Puberty is a physiological event involving the attainment of reproductive capability and complete development of sexual and physical organs. Changing from childhood to adulthood is a complex process and is tightly controlled by interconnection pathways at the level of the hypothalamus which can be influenced by environmental, psychosocial, and endocrine factors. Although various mechanisms underlying the onset of normal puberty have been investigated in humans and animals, the exact molecular mechanisms thereof remain unclear. The aim of this review is to summarize the current state of knowledge and provide a synoptic overview about the physiology of puberty in adolescent boys and girls, and describe pathological disorders affecting its onset.

Olea europaea leaf extract up-regulates Nrf2/ARE/HO-1 signaling and attenuates cyclophosphamide-induced oxidative stress, inflammation and apoptosis in rat kidney.

Olive leaf extract (OLE) has potential health benefits and protects against cytotoxicity in different organs. However, nothing has yet been reported on its potential to prevent cyclophosphamide (CP)-induced nephrotoxicity. This study investigated the possible protective effect of OLE on CP-induced kidney injury in rats, focusing on oxidative stress, inflammation, apoptosis and Nrf2/ARE/HO-1 signaling. Rats received 100 or 200 mg/kg body weight OLE for 15 days and a single injection of 150 mg/kg CP at day 16. CP induced kidney injury evidenced by the significantly increased serum creatinine and urea, and histopathological alterations, including glomerular atrophy, interstitial hemorrhage, dilated urinary space and necrosis. CP-induced rats exhibited increased kidney lipid peroxidation, protein carbonyl, nitric oxide (NO) and pro-inflammatory cytokines, and up-regulated NF-κB, Bax, cytochrome c and caspase-3. OLE ameliorated kidney function markers and prevented CP-induced tissue damage. In addition, OLE significantly prevented oxidative stress, inflammation and apoptosis by enhancing the antioxidant defenses and Bcl-2 expression, and suppressing the pro-inflammatory and pro-apoptotic markers NF-κB, Bax, cytochrome c and caspase-3. OLE up-regulated Nrf2, HO-1 and NQO-1 expression in the kidney of CP-induced rats. In conclusion, OLE has a substantial protective role against CP-induced nephrotoxicity in rats by up-regulating the Nrf2/ARE/HO-1 signaling, enhancing the antioxidant activity and attenuating inflammation and apoptosis.

Operative outcomes of robotic partial nephrectomy. A report of the first 101 cases from a single center in Saudi Arabia.

OBJECTIVES: To report robotic partial nephrectomy (RPN) outcomes from a single tertiary hospital in Saudi Arabia. Methods: We retrospectively reviewed consecutive cases of patients undergoing RPN at King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of  Saudi Arabia, between January 2008 and January 2018. The study reports patient's demographics, tumor characteristics, operative details, and perioperative outcomes, using descriptive statistics of median and range values. Results: One hundred and one patients underwent RPN during the study period. Average tumor size was 3 (1.3-6.4) cm and average radius exophytic nearness anterior/posterior location (RENAL) score was 6 (4-10). Perioperative parameters were blood loss 200 (5-1500) ml and warm ischemia time 17 (8-40) minutes, excluding off-clamp surgery in 12 (11.9%); operative time was 166 (66-381) minutes. Conversion to open partial nephrectomy occurred in 9 (8.9%) patients, major complications in 3 (3%) patients, positive surgical margins in 5 (5%) patients, and the hospital stay was 4 (2-14) days. A total of 73 (73%) patients achieved a trifecta of freedom from any complication, negative surgical margins, and ischemia time ≤25 minutes. Study limitations included the retrospective design and small cohort size. Conclusions: The initial experience of robotic partial nephrectomy was associated with a surgical outcome comparable to that reported by higher-volume centers.

Umbelliferone prevents oxidative stress, inflammation and hematological alterations, and modulates glutamate-nitric oxide-cGMP signaling in hyperammonemic rats.

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that occurs as a result of liver failure. Umbelliferone (UMB; 7-hydroxycoumarin) is a natural product with proven hepatoprotective activity; however, nothing has yet been reported on its protective effect against hyperammonemia, the main culprit behind the symptoms of HE. Here, we evaluated the effect of UMB against ammonium chloride (NH4Cl)-induced hyperammonemia, oxidative stress, inflammation and hematological alterations in rats. We demonstrated the modulatory role of UMB on the glutamate-nitric oxide (NO)-cGMP pathways in the cerebrum of rats. Rats received intraperitoneal injections of NH4Cl (3 times/week) for 8 weeks and concomitantly received 50 mg/kg UMB. NH4Cl-induced rats showed significantly elevated blood ammonia and liver function markers. Lipid peroxidation and NO were increased in the liver and cerebrum of rats while the antioxidant defenses were declined. UMB significantly reduced blood ammonia, liver function markers, lipid peroxidation and NO, and enhanced the antioxidant defenses in NH4Cl-induced rats. UMB significantly prevented anemia, leukocytosis, thrombocytopenia and prolongation of PT and aPTT. Hyperammonemic rats showed elevated levels of cerebral TNF-α, IL-1ß and glutamine as well as increased activity and expression of Na+/K+-ATPase, effects that were significantly reversed by UMB. In addition, UMB down-regulated nitric oxide synthase and soluble guanylate cyclase in the cerebrum of hyperammonemic rats. In conclusion, this study provides evidence that UMB protects against hyperammonemia via attenuation of oxidative stress and inflammation. UMB prevents hyperammonemia associated hematological alterations and therefore represents a promising protective agent against the deleterious effects of excess ammonia.

The effect of extracellular ATP on rat uterine contraction from different gestational stages and its possible mechanisms of action.

BACKGROUND: The mechanisms underlying the onset of labor are not fully understood. Extracellular adenosine 5'-triphosphate (ATP) is known to cause uterine contractions in different species but the exact underlying mechanisms are poorly investigated to date. The aims of this study were to investigate the effect of extracellular ATP on spontaneous uterine contractions from different gestational stages and to elucidate its possible underlying mechanisms. METHODS: Longitudinal uterine strips were obtained from rats in different gestational stages (nonpregnant, late-pregnant, and term-pregnant). The effects of 1 mM ATP were examined on uterine contractions generated spontaneously, depolarized by high-KCl (60 mM), induced by oxytocin (5 nM), in the presence of high external Ca2+, or in the absence of external Ca2+. RESULTS: Application of 1 mM extracellular ATP significantly increased the force of spontaneous contraction in uterine strips obtained from all gestational stages with prominent increase in term-pregnant rats compared to other gestations. ATP significantly increased the force induced by depolarization (122%, p=0.010, n=6), oxytocin (129%, p=0.001, n=7), high-Ca2+ (145%, p=0.005, n=6) and it was able to cause transient contraction in the absence of external Ca2+ (33%, p<0.01). CONCLUSIONS: Extracellular ATP is able to increase the force and frequency of uterine contractions and its effect increases with the progression of pregnancy and it involves Ca2+ influx and release. These findings open a new window for clinicians to consider ATP as a therapeutic target to control the uterine activity during difficult labors.

The response of rat and human uterus to oxytocin from different gestational stages in vitro.

Oxytocin (OT) and oxytocin receptors (OTRs) play essential roles in parturition and the effect of OT on uterine contractility is greatly influenced by the expression of OTRs in myometrium. We investigated the effect of OT on uterine strips isolated from non-pregnant, late-pregnant, term-pregnant, and labouring rats and from labouring and non-labouring women. Longitudinal uterine strips (from each gestational stage) were dissected and mounted vertically in an organ bath setup system and challenged with 5 nM OT and the effect was investigated on uterine contractility. In other experiments, phospholipase C (PLC), prostaglandin H synthase-2 (PGHS-2), and calcium-activated chloride channels (CaCCs) were blocked and the effect of OT was tested in labouring rats. OT stimulated the labouring uterus with greater force compared to other gestations in rats and also augmented the uterine force in labouring women compared to the non-labouring. However, blocking the PLC, PGHS-2, and CaCCs significantly reduced the OT-induced force increase in labouring rats. These data suggest that as labour approaches, the sensitivity of the uterine tissues to OT is greatly enhanced concomitant with the increased expression of OTR to ensure strong and adequate uterine contractions essential for the normal delivery and to prevent the postpartum haemorrhage.

Possible involvement of Nrf2 and PPARγ up-regulation in the protective effect of umbelliferone against cyclophosphamide-induced hepatotoxicity.

Umbelliferone (UMB) is a coumarin derivative with promising hepatoprotective effects. In this study, we examined the possible protective effects of UMB against cyclophosphamide (CP)-induced hepatotoxicity, addressing the question of the possible role of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator activated receptor gamma (PPARγ). Wistar rats were orally administered UMB at doses 50 and 100mg/kg two weeks prior to CP injection. Five days after CP administration, the rats were sacrificed and samples were collected for analyses. CP induced a significant increase in circulating liver marker enzymes and pro-inflammatory cytokines. Hepatic lipid peroxidation and nitric oxide levels, and nuclear factor-kappaB (NF-κB) and inducible nitric oxide synthase (iNOS) expression were significantly increased following CP administration. UMB supplementation attenuated CP-induced inflammation and oxidative stress as assessed by restoration of the activity and expression of the antioxidant defenses, and suppression of pro-inflammatory cytokines. Histological examination also showed that UMB could significantly reduce CP-induced alterations. CP-induced rats showed significant down-regulation of Nrf2, HO-1 and PPARγ, an effect that was markedly reversed by UMB. In conclusion, the hepatoprotective effects of UMB appear to depend on co-activation of PPARγ and Nrf2, and subsequent suppression of oxidative stress and inflammation.

Recurrence and progression in nonmuscle invasive transitional cell carcinoma of urinary bladder treated with intravesical Bacillus Calmette-Guerin: A single center experience and analysis of prognostic factors.

BACKGROUND: Intravesical Bacillus Calmette-Guerin (BCG) has been the standard of care for the prevention of nonmuscle invasive bladder cancer (NMIBC) recurrence following resection. Attempts to improve on the result by combining it with other agents have largely failed. This study addresses the result of BCG therapy in our patient population and compares the result with our combination BCG and interferon therapy published earlier. MATERIALS AND METHODS: The medical records of patients diagnosed with NMIBC and treated with transurethral resection and intravesical BCG were reviewed. Univariate analysis was performed on most known prognostic factors. Results were compared to published data on the use of BCG and interferon from the same institution. RESULTS: Thirty-one patients were identified. Median age was 66 (range 33-109), 80.6% were males. Fourteen patients (45%) had ≤ 3 tumors and 18 (58.1%) had T1 lesions. Four patients (12.9%) had Grade 3 tumors and 25 (80.6%) had Grade 2 tumors. One patient (3.2) had concurrent carcinoma in situ and 11 (35.5%) were treated upon initial diagnosis. At 5 years, the relapse-free survival was 61.3% (95% confidence interval (CI) 44.2-78.4%), progression-free survival was 85.6% (95% CI 73.3-97.9%), and overall survival was 93% (95% CI 84.1-100%). Comparison with the BCG and interferon data showed no significant difference. CONCLUSION: The result of BCG therapy in our patient population is similar to western reported data. Efficacy of BCG alone is equal to BCG and interferon within our institution.