Low-pressure hydrodistension induces bladder glomerulations in female patients with interstitial cystitis/bladder pain syndrome.

AIMS: The role of hydrodistension in the diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS) is controversial. This study evaluated the effect of low-pressure hydrodistension on glomerulation formation in female patients diagnosed with the disease. METHODS: Sixty female patients with the clinical diagnosis of IC/BPS and 30 female controls without the disease underwent cystoscopy and hydrodistension. Cold-cup biopsy was taken from bladder posterior wall at sites with normal cystoscopic appearance before hydrodistension in the IC/BPS group. The tissue samples were processed for histology study. Low-pressure (40 cmH2 O) hydrodistension for 2 min was performed and the appearance of glomerulations was compared between the two groups. High-pressure (80 cmH2 O) hydrodistension for 8 min was then performed as a therapeutic measure for the IC/BPS patients. Further changes to the degree of glomerulations were recorded. RESULTS: Histology showed pathological changes in the normal-appearing IC/BPS bladder mucosa including urothelium denudation, inflammatory cell infiltration, stromal edema, fibrosis, and vascular congestion. Low-pressure hydrodistension induced significant glomerulation formation in the patient group (percentage of patients with Grades 0-4: 0%, 8.3%, 40%, 35%, 10%, respectively) while none in the controls. High-pressure hydrodistension further increased the glomerulation grading in the IC/BPS patients. CONCLUSIONS: Structural changes are present in prehydrodistension IC/BPS bladder wall, which may not be macroscopically detectable. Hydrodistension at low pressure is adequate to disrupt the integrity of such diseased mucosa and offers a more discriminative test in the diagnosis of IC/BPS.

Risks of interstitial cystitis among patients with systemic lupus erythematosus: A population-based cohort study.

OBJECTIVE: To investigate whether the risk of interstitial cystitis increases among the patients with systemic lupus erythematosus. METHODS: This was a nationwide population-based cohort study. Data were obtained from the National Health Insurance Research Database in Taiwan. Women aged >18 years newly diagnosed as systemic lupus erythematosus during 2001-2008 were identified as the control group. The comparison included individuals randomly selected from the National Health Insurance Research Database in the year of 2000, by matching one systemic lupus erythematosus participant with eight non-systemic lupus erythematosus participants with sex and age. These participants were followed up until being diagnosed as interstitial cystitis, or the end of 2011. Women diagnosed with lupus cystitis were excluded from this study. RESULTS: This study included 7240 women with systemic lupus erythematosus and 57 920 women without systemic lupus erythematosus as controls. The incidence rate of interstitial cystitis was significantly higher in the systemic lupus erythematosus group, with an incidence rate ratio of 2.26 (95% confidence interval 1.57-3.27, P < 0.0001). After adjustment, the risk increased by 2.45-fold (adjusted hazard ratio 2.45, 95% confidence interval 1.57-3.27, P < 0.05). Age as a factor increases incidence rate ratios among all age groups, 2.12-, 3.32- and 4.65-fold. Age ≥45 years had an increased adjusted hazard ratio (2.07, 95% confidence interval 1.37-3.13, P < 0.05). Comorbidities, for example, hypertension, diabetes mellitus, dyslipidemia and renal disease, were insignificant. CONCLUSIONS: This is the first population-based cohort study showing a higher incidence of interstitial cystitis among patients with systemic lupus erythematosus. These findings support the concordance of interstitial cystitis with autoimmune diseases, and the temporal relationship to develop interstitial cystitis in patients with systemic lupus erythematosus.

Incorporating Simplified Fournier's Gangrene Severity Index with early surgical intervention can maximize survival in high-risk Fournier's gangrene patients.

OBJECTIVES: To determine the optimal surgical timing in high-risk patients with Fournier's gangrene by the Simplified Fournier's Gangrene Severity Index. METHODS: From 1989 to 2018, 118 male patients diagnosed with Fournier's gangrene with complete medical records were retrospectively reviewed. Patients' demographics, laboratory parameters at initial diagnosis, Fournier's Gangrene Severity Index and Simplified Fournier's Gangrene Severity Index, and the time interval from emergency room arrival to surgical intervention were collected. The Fournier's gangrene patients were categorized into low-risk (Simplified Fournier's Gangrene Severity Index ≤2) and high-risk groups (Simplified Fournier's Gangrene Severity Index >2). Differences between the variables within the two groups were analyzed. The optimal surgical timing was analyzed with the receiver operating characteristic curve in high-risk Fournier's gangrene patients. RESULTS: The overall mortality of 118 Fournier's gangrene patients was 14.4%. After risk stratification with the Simplified Fournier's Gangrene Severity Index scoring system, the mortality of low-risk and high-risk Fournier's gangrene patients was 1.3% and 41.0%, respectively. In the high-risk group, the time interval from emergency room arrival to surgical intervention was the only variable with a significant difference between survivors and non-survivors (P = 0.039). The optimal surgical timing was determined at 14.35 h, which allowed the highest sensitivity (0.688) and specificity (0.762) to affect mortality. The mortality was significantly lower in high-risk Fournier's gangrene patients with early surgical intervention compared with late intervention (23.8% vs 68.8%, P = 0.007). CONCLUSIONS: The Simplified Fournier's Gangrene Severity Index is a quick and reliable screening tool for first-line physicians to identify high-risk patients with Fournier's gangrene (Simplified Fournier's Gangrene Severity Index >2) who have poor survival outcomes. We recommended early surgical intervention within 14.35 h to maximize the survival of high-risk Fournier's gangrene patients.

Association of Prostate Blood Flow with Male Lower Urinary Tract Symptoms.

PURPOSE: To investigate the association of prostate blood flow (PBF) with lower urinary tract symptoms (LUTS) in aged males using Doppler spectral waveform (DSW) analysis. PATIENTS AND METHODS: We performed a prospective analysis involving 133 aged males with clinical diagnosis of LUTS. DSW parameters (peak-systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI)) were measured at bilateral neurovascular bundles (NVB), periurethral, and capsular branches by Doppler transrectal ultrasound with the patient in the right lateral decubitus position. The associations of PBF parameters and the International Prostate Symptom Score (IPSS) were analyzed. RESULTS: Overall, total IPSS scores were significantly correlated with the RI of bilateral NVB vessels (r2 = 0.03, 0.04; p = 0.04, 0.02, respectively), and PSV of left NVB vessels. PSV of bilateral NVB vessels were associated with the storage score (p = 0.022 and p = 0.016), but not with the voiding score. The sum of the frequency and urgency score was also associated with EDV of both capsular and urethral branches (p = 0.043 and p = 0.009, respectively), and PSV of NVB vessels on both sides (p = 0.045 and p = 0.019, respectively). CONCLUSIONS: There is an association between PBF and LUTS, especially with storage symptoms. The findings may provide some insights in understanding the underlying pathophysiology of lower urinary tract dysfunction.

Trends in reoperation for female stress urinary incontinence: A nationwide study.

AIMS: Using the National Health Insurance (NHI) database in Taiwan, the study aimed to evaluate the rates and associated factors for reoperation of female stress incontinence. METHODS: Records of female patients who had received a primary surgical treatment for stress incontinence from January 2000 to December 2006 were retrieved. Among these, patients who had reoperations during follow-up till December 2010 were identified. The data were analyzed for reoperation rates, surgery methods, patient demography, surgeon, and hospital attributes. RESULTS: Among 14,613 patients with a mean follow-up of 86.28 ± 26.76 months, 563 (3.85%) had reoperations, an incidence rate of 54.37 per 10,000 person year (PY). Injection procedures had the highest reoperation rate of 893.30/10,000 PY. The adjusted hazard ratio (HR) of reoperation was higher for mid-urethral sling when compared to pubovaginal sling (HR 1.54, 95% CI 1.16-2.05) or retropubic urethropexy including Burch operation (HR 1.30, 95% CI 1.04-1.61). Surgeons with high service volumes tended to have fewer reoperations. No correlations were noted between the reoperation rate with patient age, surgeon age/gender, year of operation and hospital status. However, urologists had higher reoperation rates than gynecologists. For repeat surgery, the majority of patients chose the same specialty but different surgical types. Mid-urethral sling was used most commonly in 48.85% of reoperations. CONCLUSIONS: Substantial number of patients need reoperation for stress incontinence. The choice of primary surgery type and surgeon specialty may affect the reoperation rates. Mid-urethral sling is the most common reoperation choice.

In vitro extracellular matrix model to evaluate stroma cell response to transvaginal mesh.

AIMS: The use of surgical mesh for female pelvic floor reconstruction has increased in recent years. However, there is paucity of information about the biological responses of host stroma cells to different meshes. This study was aimed to establish an in vitro experimental model to study the micro-environment of extracellular matrix (ECM) with embedded mesh and the stroma cell behaviors to different synthetic meshes. METHODS: Matrigel multi-cellular co-culture system with embedded mesh was used to evaluate the interaction of stroma cells and synthetic mesh in a simulated ECM environment. Human umbilical vein endothelial cells (HUVEC) and NIH3T3 fibroblasts were inoculated in the system. The established multi-cellular Matrigel co-culture system was used to detect stroma cell recruitment and tube formation ability for different synthetic meshes. RESULTS: HUVEC and NIH3T3 cells were recruited into the mesh interstices and organized into tube-like structures in type I mesh material from Perigee, Marlex and Prolift 24 hr after cell inoculation. On the contrary, there was little recruitment of HUVEC and NIH3T3 cells into the type III mesh of intra-vaginal sling (IVS). CONCLUSIONS: The Matrigel multi-cellular co-culture system with embedded mesh offers a useful in vitro model to study the biological behaviors of stroma cells in response to different types of synthetic meshes. The system can help to select ideal mesh candidates before actual implantation into the human body.

The surgical trends and time-frame comparison of primary surgery for stress urinary incontinence, 2006-2010 vs 1997-2005: a population-based nation-wide follow-up descriptive study.

INTRODUCTION AND HYPOTHESIS: The purpose of our study was to describe the surgical trends for female stress urinary incontinence (SUI) during 2006-2010, and a time-frame comparison with 1997-2005, based upon the National Health Insurance (NHI) claims data in Taiwan. METHODS: Women who underwent various primary surgeries for SUI during 2006-2010 were identified, with a total of 15,099 inpatients. The variables included surgical types, patient age, surgeon age and gender, specialty, and hospital accreditation levels. Chi-squared tests and SAS version 9.3.1 were used for statistical analysis. RESULTS: During the follow-up study, midurethral sling (MUS) application increased significantly from 53.09 % in 2006 to 78.74 % in 2010. It was associated concomitantly with a decrease in retropubic urethropexy (RPU) from 29.68 % to 12.99 %, and pubovaginal sling treatment (PVS) from 9.33 % to 3.46 %. MUS was most commonly used among all patients' and surgeons' age groups, and different accreditation hospital levels. MUS was more commonly used by gynecologists (71.38 %) than urologists (57.91 %); while PVS and periurethral injection were more commonly performed by urologists than gynecologists. Similar surgical trends were found during time-frame comparison, 2006-2010 vs 1997-2005. SUI surgeries increased in patients aged ≥60, surgeons aged ≥ 50, and in regional hospitals. CONCLUSION: This follow-up study depicts the increase in popularity of MUS and offers evidence of surgical trends and a paradigm shift for female SUI surgery. More older women were willing to seek healthcare and undergo surgery. The surgical skills and knowledge spread from medical centers into regional hospitals. The time-frame shift may have a profound impact on patients, as well as the healthcare providers.

Changes of urinary bladder contractility in high-fat diet-fed mice: the role of tumor necrosis factor-α.

OBJECTIVES: To study the role of tumor necrosis factor-α in bladder dysfunction associated with obesity. METHODS: Male 8-week-old C57BL/6J mice were divided into three groups: (i) control mice; (ii) vehicle-treated high-fat diet-fed mice; and (iii) etanercept-treated high-fat diet-fed mice. High-fat diet feeding lasted for 12 weeks, vehicle or etanercept (0.8 mg/kg/day, a tumor necrosis factor-α antagonist) treatment was given during the last 4 weeks. At the end of the treatment period, serum tumor necrosis factor-α, total cholesterol, triglyceride and blood glucose were measured. Bladder strip contractile responses to 1 µmol/L acetylcholine or 50 mmol/L KCl were studied in an organ bath. Bladder protein kinase Cζ, nuclear factor-κB and intercellular adhesion molecule-1 expressions were analyzed using western blots. RESULTS: Serum levels of tumor necrosis factor-α total cholesterol, triglyceride and glucose were significantly elevated in high-fat diet-fed mice; and the levels were not ameliorated by etanercept treatment. High-fat diet-fed mouse bladder showed reduced contractile responses to acetylcholine and KCl stimulation accompanied by high expression levels of phospho-protein kinase Cζ, nuclear nuclear factor-κB and intercellular adhesion molecule-1. Etanercept restored normal bladder contractile responses, as well as protein kinase Cζ nuclear factor-κB and intercellular adhesion molecule-1 expressions. CONCLUSIONS: A high-fat diet induces bodyweight gain, hyperlipidemia and hyperglycemia in mice. Elevated serum tumor necrosis factor-α level associated with increased protein kinase Cζ phosphorylation, nuclear factor-κB nuclear migration, intercellular adhesion molecule-1 expression and impaired muscle contractility are shown in the high-fat diet-fed mouse bladder. Tumor necrosis factor-α antagonist treatment restores normal bladder contractility, and protein kinase Cζ nuclear factor-κB and intercellular adhesion molecule-1 levels.

Validation and simplification of Fournier's gangrene severity index.

OBJECTIVES: To validate the predictive value of Fournier's Gangrene Severity Index in patients with Fournier gangrene and to facilitate patient mortality risk-stratification by simplifying the Fournier's Gangrene Severity Index. METHODS: From January 1989 to December 2011, 85 male patients with clinically-documented Fournier's gangrene undergoing intensive treatment and with complete medical records were recruited. The demographic information and nine parameters of Fournier's Gangrene Severity Index were compared between survivors and non-survivors. The parameters that showed a significant difference between the two groups were selected to generate a simplified scoring index. RESULTS: Of the 85 patients recruited, 16 patients died of the disease with mortality rate of 18.8%. The Fournier's Gangrene Severity Index score at initial diagnosis was significantly higher in non-survivors than in survivors. Of the nine parameters of Fournier's Gangrene Severity Index, the scores of serum creatinine level, hematocrit level and serum potassium level were significantly different between the two groups. However, the mean body temperatures, heart rate, respiration rate, white blood cell count, serum sodium and bicarbonate levels were non-significantly different. Of the 12 patients with chronic kidney disease or end-stage renal disease, 10 died of severe sepsis. A simplified scoring index including parameters of creatinine, hematocrit and potassium was generated, which provided sensitivity and specificity of 87% and 77% in predicting patient mortality, respectively. The predictive values of this simplified Fournier's Gangrene Severity Index were shown to be non-inferior to Fournier's Gangrene Severity Index in our patients. CONCLUSIONS: The simplified Fournier's Gangrene Severity Index is easy to use at initial diagnosis, and offers a way to compare outcomes in different clinical populations.

Alteration of loperamide-induced prostate relaxation in high-fat diet-fed rats.

OBJECTIVE: To investigate the change of loperamide-induced prostate relaxation in rats fed with high-fat diet (HFD). MATERIALS AND METHODS: Adult male Wistar rats were divided into 2 groups: (1) control rats fed with normal chow and (2) rats fed with HFD for 6 months. The prostate was removed for histology study. Isolated prostate strips were hung in organ bath and precontracted with 1 µmol/L phenylephrine or 50 mmol/L KCl. The relaxation responses to loperamide 0.1 to 10 µmol/L were recorded. Western blotting analyses were performed for prostate µ-opioid receptors (MOR) and ATP-sensitive potassium (K(ATP)) channel proteins: sulfonylurea receptor (SUR) and inwardly rectifying potassium channel (Kir) 6.2 subunits. RESULTS: Body weight, prostate weight, plasma levels of glucose, insulin, triglyceride, and cholesterol, as well as systolic blood pressure, were significantly increased in the HFD rats. Histology showed prostatic hyperplasia in the HFD rat prostate. Prostatic relaxation induced by loperamide was markedly reduced in HFD when compared to the control. Protein expressions of MOR, SUR, and Kir 6.2 were decreased in HFD-fed rats. CONCLUSION: Loperamide-induced prostate relaxation is decreased in HFD rats due to reduced MOR and K(ATP) channel expressions.

In vitro study of the revised ultrasound based real-time tracking of renal stones for shock wave lithotripsy: Part 1.

PURPOSE: Extracorporeal shock wave lithotripsy has been popular since the 1980s. Only 30% to 50% of the shock waves of all conventional lithotripters are focused on stones. We developed an ultrasound based, real-time stone tracking system (version 1) to improve accuracy and treatment efficiency. However, some problems remained. We revised the existing system (version 2) and tested its reliability and performance. MATERIALS AND METHODS: We revised the system by adding more algorithms to decrease renal stone misidentification. We verified the advanced system by 2 tests using no tracking and tracking with 13 stone trajectories for versions 1 and 2. We performed the coincidence test to evaluate the accuracy of targeting the stone within the effective focal area and the stone fragmentation efficiency test to clarify the decrease in the number of shocks needed for stone fragmentation. RESULTS: In the coincidence test the mean ± SD results of the nontracking system, and tracking versions 1 and 2 were 68.8% ± 18.8%, 89.9% ± 5.2% and 94.3% ± 4.5%, respectively. Version 2 was statistically significantly better than version 1 (p = 1.5 × 10(-4)). In the stone fragmentation efficiency test the mean results of the nontracking system, and versions 1 and 2 were 49.5% ± 14.2%, 85.1% ± 4.5% and 89.5% ± 4.2%, respectively. Version 2 was statistically significantly better than version 1 (p = 1.9 × 10(-8)). CONCLUSIONS: The revised tracking system is better than version 1. It improves treatment efficiency, decreases stone misidentification and can shorten treatment time.

Prostatic relaxation induced by agmatine is decreased in spontaneously hypertensive rats.

UNLABELLED: What's known on the subject? and What does the study add? Neurotransmitters are known to control prostate contractility. Agmatine is one of them and induces relaxation through imidazoline receptors. The paper shows that the action of agmatine is reduced in hypertensive rats, and that this change is related to the decrease of ATP-sensitive potassium channels in the prostate. The findings can increase our understanding of the possible underlying mechanism for the development of clinical benign prostatic hyperplasia. OBJECTIVES: To compare agmatine-induced prostatic relaxation in hypertensive and control rats. To investigate the responsible mechanism(s) and the role of the ATP-sensitive potassium channel. METHODS: Prostate strips were isolated from male spontaneously hypertensive (SH) rats and normal Wistar-Kyoto (WKY) rats for measurement of isometric tension. The strips were precontracted with 1 µmol/L phenylephrine or 50 mmol/L KCl. Dose-dependent relaxation of the prostatic strips was studied by cumulative administration of agmatine, 1 to 100 µmol/L, into the organ bath. Effects of specific antagonists on agmatine-induced relaxation were studied. Western blotting analysis was used to measure the gene expression of the ATP-sensitive potassium channel in the rat prostate. RESULTS: Prostatic relaxation induced by agmatine was markedly reduced in SH rats compared with WKY rats. The relaxation caused by agmatine was abolished by BU224, a selective imidazoline I(2)-receptor antagonist, but was not modified by efaroxan at a dose sufficient to block imidazoline I(1)-receptors. The relaxation induced by diazoxide at a concentration sufficient to activate ATP-sensitive potassium channels was markedly reduced in the SH rat prostate. Expressions of ATP-sensitive potassium channel sulphonylurea receptor and inwardly rectifying potassium channel (Kir) 6.2 subunits were both decreased in the prostate of SH rats. CONCLUSION: The decrease of agmatine-induced prostatic relaxation in SH rats is related to the change in ATP-sensitive potassium channels.

Metabolic syndrome decreases tissue perfusion and induces glandular hyperplasia in the fructose-fed rat prostate.

AIMS: The effects of metabolic syndrome on the prostate blood perfusion and histological structure were studied using fructose-fed rats (FR). METHODS: Age-matched male Wistar rats were divided into two groups: group I, normal control rats and group II, 9-week FR. Animal body weight, blood pressure, and serum metabolic parameters were monitored. With the rats under anesthesia, prostatic blood flow volume and flow velocity were measured by laser Doppler flowmetry. The prostate was then removed for histological examination and morphometric study. RESULTS: The 9-week FR showed significant increases in body weight, blood pressure, plasma glucose, insulin, and triglyceride levels. The blood flow volume (345.8 ± 20.57 ml/min/100 g vs. 440.4 ± 35.57 ml/min/100 g of tissue, P < 0.05 for n = 8) and flow rate (29.4 ± 1.25 units vs. 40.9 ± 2.65 units, P < 0.05 for n = 8) in the FR ventral prostate were significantly decreased when compared to controls. Structurally, the FR prostate weight was significantly higher than that of the controls (612.4 ± 16.9 mg vs. 427.3 ± 6.5 mg, P < 0.05 for n = 8). Prostate histology showed glandular hyperplasia while morphometry showed increased stromal component in the FR. CONCLUSIONS: Metabolic syndrome in the FR decreases prostatic perfusion and induces prostatic glandular hyperplasia. The findings suggest that chronic ischemia may be a link between metabolic syndrome and prostatic enlargement.

Loperamide-induced rat prostate relaxation through activation of peripheral µ-opioid receptors.

AIMS: The effect of µ-opioid receptor (MOR) agonist, loperamide on prostate relaxation and the role of potassium channel in this action were studied in isolated Wistar rat prostate. METHODS: Tissue strips from rat prostate ventral lobe were hung in organ bath containing: group 1: standard Tyrode's solution (TS); group 2: TS with 1 µM naloxone; group 3: TS with 0.1 µM naloxonazine; and group 4: TS with 0.01-1 µM glybenclamide. The strips were pre-contracted with either 50 mM KCl or 1 µM phenylephrine. Dose-response study on the prostate strip was performed by cumulative administration of loperamide 0.1-10 µM into the organ bath. Western blot study was performed to detect the presence of MOR protein and adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP) ) subunit Kir6.2 protein expressions in the prostate tissue. RESULTS: Loperamide induced relaxation of the pre-contracted prostate strips in a dose-dependent fashion. Pre-treatment with 1 µM naloxone significantly inhibited the relaxation, thus suggesting activation of MOR in the loperamide effect. Pre-treatment with 0.1 µM naloxonazine inhibited relaxation only in the phenylephrine-contracted strips. The K(ATP) channel blocker glybenclamide significantly inhibited the loperamide-induced relaxation, indicating involvement of K(ATP) channels in mediating the prostate relaxation. Western blots showed the expression of MOR and Kir6.2 protein in the rat prostate. CONCLUSIONS: MOR and Kir6.2 are expressed in the rat prostate and loperamide induces rat prostate relaxation through activation of peripheral MOR. K(ATP) channels are involved in mediating the effect of loperamide on the relaxation of prostate.

Study on the pathophysiological mechanism responsible for lower urinary tract symptoms associated with prostate cancer using an animal model.

OBJECTIVES: To investigate the pathophysiological mechanism leading to lower urinary tract symptoms in prostate cancer (PCa) by using an animal model. METHODS: An orthotopic PCa model in mice was established by injection of human DU145 cells into the prostate gland lateral lobe of NOD.CB17-Prkdcscid /NcrCrlBltw (NOD-SCID) mice. Cancer growth was quantified by a luciferase-based in vivo imaging system (IVIS) serially every 7 days. Comparisons were made for urodynamic parameters, bladder histology, and biological markers until the sixth week. Bladder wall structural changes were assessed by the bladder wall thickness and degree of fibrosis. Biomarker expressions in bladder tissue including muscarinic acetylcholine receptor 2 (M2 ), transient receptor potential cation channel subfamily V member 4 (TRPV4), BCL2-associated X protein (Bax), and caspase3 were evaluated by immunohistochemical staining and immunofluorescence confocal laser scanning microscopy. RESULTS: DU145 cell growth in the prostate was successfully monitored by a luciferase-based IVIS. after orthotopic injection. Using our injection technique, no anatomical obstruction of the bladder outlet and urethra was noted up to 6 weeks after injection. The presence of PCa induced changes in urinary bladder histology, biomarkers, and urodynamic parameters. Cystometry showed features of detrusor overactivity with increased voiding frequency and high-amplitude voiding contractions from the fourth week onward. Histological analyses 4 weeks after DU145 injection demonstrated detrusor thickening and bladder wall fibrosis. Immunohistochemistry showed increased expressions of bladder M2 , TRPV4, Bax, and caspase3 in the PCa mice as early as in the first or second week. CONCLUSIONS: PCa can induce bladder microenvironment changes involving neural receptors and biological mediators leading to histological and functional alterations even in the absence of overt anatomical obstruction.

Role of hyperglycaemia in the pathogenesis of hypotension observed in type-1 diabetic rats.

The role of hyperglycaemia in the pathogenesis of hypotension in diabetic disorders was investigated using the changes in cardiac M(2)-muscarinic receptor (M(2)-mAChR) gene expression in type-1-like diabetic rats and cultured cardiomyocytes. Blood pressure was markedly decreased in diabetic rats following the intravenous injection of streptozotocin (STZ) for 8 weeks. Also, the baroreflex sensitivity (Delta HR/Delta BP), as measured by the changes in heart rate (Delta HR) and mean blood pressure (Delta BP) 1 min after the intravenous injection of phenylephrine (10 microg/kg), was significantly increased. Arecaidine propargyl ester (APE), a M(2)-mAChR agonist produced a marked reduction in heart rate in these diabetic rats. Normalization of plasma glucose in diabetic rats using insulin (0.5 IU) or phlorizin (1 mg/kg) injection attenuated the blood pressure reduction and reversed the mRNA and protein levels of cardiac M(2)-mAChR. A high concentration of glucose (20 mmol/l) directly influenced the increase in gene expression of M(2)-mAChR in the H9c2 cardiac cell line. Hyperglycaemia induced an increase in cardiac M(2)-mAChR gene expression, suggesting a role in the pathogenesis of hypotension in diabetic disorders.

Alterations of nerve-growth factor and p75(NTR) expressions in urinary bladder of fructose-fed obese rats.

The study investigated the effects of metabolic syndrome on urinary bladder nerve-growth factor (NGF) and p75(NTR) expression in fructose-fed obese rats. Age-matched male Wistar rats were divided into four groups; group I: normal control rats; group II: 6-week fructose-fed rats (FR); group III: 9-week FR; and group IV: 12-week FR. In vivo cystometry under anesthesia was performed. In vitro bladder NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). Expressions of the mRNAs that encoded NGF and NGF receptor p75(NTR) in control and 9-week FR bladder were studied using the method of reverse transcription combined with polymerase chain reaction (RT-PCR). The three groups of FR showed significant increases in body weight, blood pressure, plasma glucose, insulin and triglyceride levels when compared to control rats. The bladder NGF levels in the 9-week and 12-week FR were significantly lower than the control (66.8+/-5.4, 49.4+/-7.1 and 95.2+/-6.5 pg/microg protein; p<0.05 and p<0.01 respectively, for n=8 in each group). The bladder emptying function was deteriorated in these two groups of FR as shown by the significantly increased residual volume and decreased emptying fraction. The mRNA expressions of bladder NGF and p75(NTR) in the 9-week FR were significantly decreased when compared to the control group (p<0.05 and p<0.001 respectively, n=8 in each group). In conclusion, long-term metabolic syndrome in FR significantly decreases bladder NGF and p75(NTR) expression. These alterations are associated with deterioration in bladder emptying function.

Metabolic Syndrome Induced Bladder Cannabinoid Receptor Changes in the Fructose-Fed Rats.

OBJECTIVES: To investigate the effect of metabolic syndrome on the bladder cannabinoid receptors 1 and 2 (CB1/CB2) expression and function in the fructose-fed rats (FR). METHODS: Adult male Sprague-Dawley rats were divided into two groups: (i) Control rats fed with normal chow; and (ii) Rats fed with high-fructose diet (FR) for 9 weeks. The body weight, blood pressure, plasma sugar, insulin, triglyceride and cholesterol were measured. Bladder muscle strips were prepared in organ bath and pre-contracted with 1 µM/L acetylcholine (ACh) or 50 mM/L KCl. The relaxation responses to CB1/CB2 agonist Bay59-3047 (0.01-1 µM/L) were recorded. The effects of CB1 antagonist AM251, CB2 antagonist AM630, protein kinase A (PKA) inhibitor H-89 and ATP-sensitive potassium channel (KATP) inhibitor glibenclamide on the Bay59-3047-induced response were tested. Western blotting and real-time polymerase chain reaction (RT-PCR) analyses were performed for bladder CB1/CB2 receptors. RESULTS: Significant increases of body weight, blood pressure, plasma glucose, insulin, cholesterol and triglyceride levels were found in the FR. Bay59-3047 reduced ACh and KCl pre-contracted bladder strip tension in a dose-dependent fashion. The relaxation responses were significantly decreased in the FR. The Bay59-3047-induced relaxation was attenuated by AM251, glibenclamide and H-89. Western blotting and RT-PCR showed decreased expressions of FR bladder CB1 and CB2 receptor protein and mRNA. CONCLUSION: CB1/CB2 receptors mediate rat bladder relaxation through the PKA and KATP pathway. The CB1 receptor may play a more prominent role. The response is decreased in the FR bladder due to reduced expressions of the cannabinoid receptors.

Induction of apoptosis in prostate cancer by ginsenoside Rh2.

The therapeutic action of ginsenoside Rh2 on several cancer models has been reported. This study aimed to evaluate its apoptotic effect on prostate cancer and the underlying mechanism. Cultured DU145 cells were treated with Rh2 (5 × 10-5 to 1 × 10-4 M), peroxisome proliferator-activated receptor-delta (PPAR-delta) antagonist GSK0660 (1 × 10-6 to 5 × 10-6 M); or small interfering RNA (siRNA) of PPAR-delta. The treatment effects were evaluated with cell viability assay, life/death staining and flow cytometry for apoptosis. Immunostaining was used for reactive oxygen species (ROS) and superoxide detection. Western blot analysis for PPAR-delta and signal transducer and activator of transcription 3 (STAT3) protein expression were performed. The results showed that Rh2 significantly decreased DU145 cell survival and increased cell apoptosis. ROS and superoxide induction, PPAR-delta up-regulation and phosphorylated STAT3 (p-STAT3) down-regulation by Rh2 were demonstrated. GSK0660 partially but significantly inhibited the Rh2-induced apoptosis and restored cell viability. Treatment with siRNA reversed the Rh2-induced apoptosis as well as changes in PPAR-delta and p-STAT3 expression. In conclusion, our findings have demonstrated that ginsenoside Rh2 induces prostate cancer DU145 cells apoptosis through up-regulation of PPAR-delta expression which is associated with p-STAT3 up-regulation and ROS/superoxide induction. Rh2 may be potentially useful in the treatment of prostate cancer.