Ultrastructural and immunohistochemical analysis of rat uroepithelial cell junctions after partial bladder outlet obstruction and selective COX-2 inhibitor treatment

The present study was undertaken to evaluate alterations in uroepithelial cell junctional complexes in partial bladder outlet obstruction (PBOO) of rat bladders using ultrastructural morphometry and immunohistochemistry, and to determine whether selective COX-2 inhibitors have any effects on these structures. A total of 18 male rats were separated into three groups of six rats each: (1) sham-operated animals served as controls; (2) a PBOO group, without further treatment (3) and a group that immediately after PBOO, received treatment for 4 weeks with oral Celecoxib, a selective COX-2 inhibitor. Uroepithelial cell junctions were evaluated using transmission electron microscopy combined with morphometry. Results were also assessed by E-cadherin and -catenin immunohistochemistry. Morphometrical analysis of ultrastructural evaluations revealed that 4 weeks of PBOO caused a significant reduction in the electron density of zonula adherens and zonula occludens junctional complexes. Moreover, some desmosomes located between the deeper cells of the uroepithelium showed signs of disintegration. Selective COX-2 inhibitor treatment during 4 weeks of PBOO showed protective effects on adherens and occludens junctions, as well as on desmosomes. Immunohistochemical analysis of E-cadherin confirmed that the decreased E-cadherin immunolabelling in 4 weeks of PBOO was prevented by selective COX-2 inhibitor treatment. Based on ultrastructural morphometrical analysis, we conclude that PBOO alone and in combination with selective COX-2 inhibitors can have considerable effects on uroepithelial cellular junctions. Our findings provide a novel area of investigation regarding the selective use of COX-2 inhibitors following PBOO.     

Non-invasive Parameters Predicting Bladder Outlet Obstruction in Korean Men with Lower Urinary Tract Symptoms

The goal of this study was to evaluate the clinical and urodynamic features in Korean men with lower urinary tract symptoms (LUTS) and to determine non-invasive parameters for predicting bladder outlet obstruction (BOO). Four hundred twenty nine Korean men with LUTS over 50 yr of age underwent clinical evaluations for LUTS including urodynamic study. The patients were divided into two groups according to the presence of BOO. These two groups were compared with regard to age, the results of the uroflowmetry, serum prostate-specific antigen (PSA) level, prostate volume, International Prostate Symptom Score (I-PSS), and the results of the urodynamic study. Patients with BOO had a lower maximal flow rate (Q_max), lower voided volume, higher serum PSA level and larger prostate volume (P<0.05). BOO group had a significantly higher rate of involuntary detrusor contraction and poor compliance compared to the patients without BOO (P<0.05). The multivariate analysis showed that Q_max and poor compliance were significant factors for predicting BOO. Our results show that Q_max plays a significant role in predicting BOO in Korean men with LUTS. In addition, BOO is significantly associated with detrusor dysfunction, therefore, secondary bladder dysfunction must be emphasized in the management of male patients with LUTS.     

良性前列腺增生合并膀胱出口梗阻非侵入性诊断方法的研究进展

目的：探讨良性前列腺增生（ BPH)合并膀胱出口梗阻（ BOO)的非侵入性诊断方法的研究进展。方法在Pubmed、EMBASE、万方数据库,以“良性前列腺增生”、“膀胱出口梗阻”、“非侵入性诊断方法”为关键词,检索2008年1月—2014年1月有关BPH合并BOO的非侵入性诊断方法的相关文献,结合国内外最新的研究进展,进行归纳总结。结果压力－流率测定是诊断膀胱出口梗阻的金标准,但此方法具有侵入性,而且价格昂贵、过程复杂。近年来,临床上使用的非侵入性诊断BPH合并BOO的方法有无尿动力学测量方法和非侵入性的尿动力学方法。无尿动力学测量方法包括国际前列腺症状评分、残余尿量、前列腺特异性抗原、超声测量等,非侵入性的尿动力学方法包括最大尿流率、阴茎袖套试验、近红外光谱、多普勒阻力指数测定等。这两种非侵入性诊断方法具有无创、简单、重复性好等优点。结论新的非侵入性诊断BPH合并BOO的方法较传统的压力－尿流动力学检测有着无创、简单、重复性好等优点,但尚未有充分证据证明能够取代压力－尿流动力学方法,成为新的诊断BPH合并BOO的金标准,其临床应用价值还需要进一步的研究验证。     

膀胱出口梗阻对膀胱逼尿肌损害的研究进展

膀胱出口梗阻(bladder outlet obstruction,BOO),是指膀胱出口至尿道外口之间任何部位出现梗阻,它对膀胱逼尿肌功能的影响包括逼尿肌不稳定(DI)、逼尿肌收缩功能受损和逼尿肌顺应性改变。BOO致膀胱逼尿肌损害的患者在临床上极为常见,但由于这种损害的具体机理还不明确,故疗效欠佳。多年来研究发现其损害机理涉及膀胱的神经支配、基因表达和转录、超微机构等的变化,机理十分复杂。     

Time dependent bladder apoptosis induced by acute bladder outlet obstruction and subsequent emptying is associated with decreased MnSOD expression and Bcl-2/Bax ratio

Ischemia/reperfusion (I/R) injury-induced oxidative stress plays an important role in the functional impairment of the bladder following acute bladder outlet obstruction (BOO) via induction of apoptosis. The purpose of this study was to investigate the time course of the bladder apoptosis, and apoptosis related molecular changes in the early stage of acute BOO. Twelve-week-old male Sprague Dawley rats were divided into control, acute BOO only (I), and acute BOO plus subsequent emptying (I/R) for 30, 60, 120 min, 3 days and 2 weeks. We examined the extent of bladder apoptosis, expression of Mn-superoxide dismutase (Mn-SOD), Bcl-2, Bax, caspase 3 and poly (ADP-ribose) (PAR) in the bladder. Bladder apoptosis was significantly increased in the I/R group at 30, 60, and 120 min following bladder emptying. BOO plus subsequent emptying for 30, 60, 120 min showed significant decrease in MnSOD and Bcl-2 expression, and significant increase in caspase 3, Bax expression, and amounts of PAR. These results indicate that bladder apoptosis, induced by acute BOO and subsequent emptying, is associated with decreased MnSOD expression, increased PARP activity and imbalance in apoptosis pathways.     

Urodynamics and bladder muscarinic receptors in rats with cerebral infarction and bladder outlet obstruction

We characterized muscarinic receptor binding and urodynamic parameters in rats with cerebral infarction and chronic bladder outlet obstruction as models of detrusor overactivity. Bladder weight showed little significant difference between the cerebral-infarcted and sham rats, but the bladder weight was about three times greater in the bladder outlet-obstructed rats. Bladder capacity and voided volume were significantly lower (36.7 and 55.1%, respectively) in the cerebral-infarcted than in the sham rats. Involuntary contractions before micturition were seen in the bladder outlet-obstructed rats but not in sham rats. The bladder outlet-obstructed rats showed significant increases (2.65 and 2.57 times, respectively) in bladder capacity and voided volume, compared with those in sham rats. Bmax values for specific [N-methyl-3H]scopolamine ([3H]NMS) binding in the bladder were significantly (34%) increased in the cerebral-infarcted rats compared with sham rats, whereas Kd was unaffected by infarction. On the other hand, there was little significant change in Kd and Bmax for specific [3H]NMS binding in the bladder-obstructed rats compared with sham rats. In conclusion, the present study shows that cerebral infarction but not bladder outlet obstruction in rats causes up-regulation of bladder muscarinic receptors, and that such regulation of bladder muscarinic receptors may be at least partly associated with the symptoms of detrusor overactivity subsequent to cerebral infarction.     

Pathophysiological effect of bladder outlet obstruction on the urothelium

Bladder outlet obstruction (BOO) and associated lower urinary tract symptoms are major urological issues that significantly affect patient’s quality of life and may lead to severe complications. The prevalence of both is increasing each year, raising the burden to health system. Therefore, casual and symptomatic treatment should be of great importance. However, management of symptoms is often difficult as their pathophysiology is multifactorial and not well elucidated. Recently urothelium has gathered much attention as one of the potential causal agents. It has been suggested that in addition to its barrier function, urothelium regulates transport through blood-urine barrier and is a part of “sensory web” by which it modulates afferent input. In this review we focus on adjustment of urothelium related to BOO in terms of its ultrastructure, barrier and transport function, and impact on “sensory web.”     

Smooth muscle hypertrophy following partial bladder outlet obstruction is associated with overexpression of non-muscle caldesmon

Partial bladder outlet obstruction (PBOO) induces remodeling of urinary bladder smooth muscle (detrusor). We demonstrate an increase in bladder wall mass, muscle bundle size, and a threefold increase in the cross-sectional area of detrusor myocytes following PBOO in male New Zealand White rabbits compared to that of controls. Some bladders with detrusor hypertrophy function close to normal (compensated), whereas others were dysfunctional (decompensated), showing high intravesical pressure, large residual urine volume, and voiding difficulty. We analyzed the expression of smooth muscle-specific caldesmon (h-CaD) and non-muscle (l-CaD) by Western blotting, RT-PCR, and real-time PCR. The expression of l-CaD is increased significantly at the mRNA and protein levels in the decompensated bladders compared to that of normal and compensated bladders. The CaD was also co-localized with myosin containing cytoplasmic fibrils in cells dissociated from obstructed bladders and cultured overnight. Our data show that the inability of decompensated bladders to empty, despite detrusor hypertrophy, is associated with an overexpression of l-CaD. The level of l-CaD overexpression might be a useful marker to estimate the degree of detrusor remodeling and contractile dysfunction in PBOO.     

Pheochromocytoma of the urinary bladder

The case of a 65-year-old male with pheochromocytoma arising in the urinary bladder is presented. Clinical evaluation included ultrasonography, intravenous pyelography and computerized tomography (CT) scan. Transurethral resection of an exophytic tumor 1 cm in diameter was performed. The histological diagnosis was pheochromocytoma of the bladder. The evaluation and management of this type of tumor is discussed.     

Ultrastructure of tumors induced in the rat urinary bladder by nitrosomethyldodecylamine

Summary N-Nitroso-N-methyl-n-dodecylamine (NMDA) is a powerful carcinogen in the rat and the Syrian golden hamster. In both species the urinary bladder is the main target organ. We studied the ultrastructure of these bladder tumors in the Fischer rat in some detail, since this compound provides an interesting model for carcinogenesis in the urinary bladder. We found that the proliferating basal layers of the transitional cell carcinomas were undergoing squamous metaplasia, which indicates that squamous carcinomas in the organ may arise from pre-existing transitional cell tumors.The author gratefully acknowledges the excellent technical assistance of Mark ShermanThis work was supported by Contract No. N01-CO-75380 with the National Cancer Institute, NIH, Bethesda, Maryland 20205, USABy acceptance of this article, the publisher or recipient acknowledges the right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article     

SGK1抑制剂EMD638683对膀胱出口梗阻小鼠肾组织细胞焦亡的作用及机制研究

目的:确定小鼠膀胱出口梗阻(bladder outlet obstruction,BOO)模型引起下尿路梗阻介导的肾脏炎性损伤;研究血清和糖皮质激素调节激酶1(serum and glucocorticoid-regulated kinase 1, SGK1)抑制剂EMD638683抗梗阻性肾病炎症的作用机制,探讨SGK1与NLRP3-caspase-1-IL-1β/细胞焦亡(pyroptosis)通路诱导细胞损伤的关系。方法:构建小鼠BOO模型,HE染色观察肾组织病理变化及炎症细胞浸润,PAS染色观察肾脏的组织病变,Masson染色法检测肾小管的胶原沉积,免疫组化法和Western blot法检测NLRP3、caspase-1、F4/80、gasdermin D-N末端片段(GSDMD-N)、IL-1β和SGK1的表达。醛固酮(aldosterone, ALD)处理小鼠肾小管上皮细胞(mouse renal tubular epithelial cells, mRTECs),EMD638683进行干预,Western blot法检测NLRP3、caspase-1、IL-1β、SGK1...     

Neural mechanisms of impaired micturition reflex in rats with acute partial bladder outlet obstruction

To determine the contribution of neural elements to micturition, we evaluated, in intact rats, the cystometrogram, pelvic afferent nervous activity, pelvic efferent nervous activity and external urethral sphincter-electromyogram activity in the normal and acute partial bladder outlet obstruction states. In the normal state, in response to saline filling, mechanoreceptor-dependent pelvic afferent nervous activity gradually activated and finally triggered a voiding reflex, including four phases of detrusor contractions. Phase 1 was characterized by an initial rising intravesical pressure, Phase 2 was characterized by a series of high-frequency oscillations in intravesical pressure, Phase 3 contraction was characterized by a rebound intravesical pressure and Phase 4 contraction was characterized by a rapid fall in intravesical pressure. In the acute partial bladder outlet obstruction state, Phase 1 contraction rose and high-frequency oscillations fell in Phase 2. This voiding dysfunction is ascribed to the bursting extraurethral sphincter activity being converted to tonic extraurethral sphincter activity. In summary, the suppressed high-frequency oscillations in Phase 2 of the detrusor muscle contraction could be detrimental to efficient voidings in the acute partial bladder outlet obstructed rat.     

Lymphoepithelioma-like carcinoma of the urinary bladder

A 78-yr-old woman presented with gross hematuria for 2 weeks. On cystoscopy, a frond-like mass was observed at the bladder trigone. Transurethral resection of bladder tumor was performed for the mass. Histopathological findings showed that 90% of lesions were lymphoepithelioma-like carcinoma (LELCA) and a few lesions were non-invasive transitional cell carcinoma. On microscopy, syncytial growth pattern and indistinct cytoplasmic borders were observed with the severe infiltration of lymphoid cells. The case was followed-up for 8 months without recurrence. This is the first report of a LELCA case in Korea.     

The effect of testosterone replacement therapy on bladder functions,histology, apoptosis,and Rho-kinase expression in bladder outlet obstruction and hypogonadism rat model

Background/aimThe effect of testosterone replacement therapy was investigated on bladder functions, histology, apoptosis as well as Rho-kinase expression in the rat bladder outlet obstruction (BOO) and hypogonadism models. Materials and methods30 mature male rats divided into 4 groups: sham group (n = 8), BOO group (n = 8), BOO + orchiectomy group (n = 7), BOO + orchiectomy + testosterone (T) treatment group (n = 7). Cystometric findings, apoptosis index, Rho-kinase (ROCK-2) expression, and smooth muscle/collagen ratio were compared. Results BOO did not change ROCK-2 expression level, compared to sham group (P > 0.05). However, when compared to BOO group (P < 0.01), BOO + orchiectomy led ROCK-2 increase. The testosterone treatment failed to reverse the up-regulation of ROCK-2 induced by orchiectomy although it tended to lower ROCK-2 level. Compared to sham group (P = 0.002), changes in maximal bladder capacity and leak point pressure were higher (P = 0.026, P = 0.001), and bladder compliance was lower in BOO group. Also, the apoptosis index was different between the two groups (P = 0.380). Smooth muscle/collagen ratio was higher in BOO + orchiectomy + T group than in BOO + orchiectomy group (P = 0.010).ConclusionsThe research draws attention to alternating treatment approaches in case of the presence of hypogonadism and BOO.     

Prostatic involvement by transitional cell carcinoma in patients with bladder cancer and its prognostic significance

To study the importance of prostatic involvement by transitional cell carcinoma (TCC) in patients with bladder cancer, we examined the entire prostates by whole-mount sections from 214 radical cystoprostatectomy specimens for detailed patterns of involvement by TCC and correlated the results with lymph node metastasis and patients' survival. Prostatic involvement by TCC was detected in 69 (32%) of 214 cases. Among them, 30 (43%) patients had carcinoma in situ (CIS) and the other 39 (57%) were invasive TCC. Carcinoma in situ occurred in either prostatic urethra (n = 6, 20%) or, more commonly, in prostatic ducts/acini (n = 14, 47%), and in a combination of prostatic urethra and ducts (n = 10, 33%). Ten (26%) of the invasive TCC resulted from direct penetration from the primary tumor in the bladder, and the remaining 29 (72%) cases arose from prostatic urethra/ducts, of which 11, 13, and 5 invaded the lamina propria, prostatic stroma, and periprostatic or seminal vesical tissue, respectively. Both prostatic TCC involvement and nodal metastasis were highly significant prognostic factors for patients' survival and the survival significance of prostatic TCC involvement still existed regardless of lymph node status. Furthermore, the presence of prostatic CIS and degrees of prostatic invasion are associated with nodal metastasis and survival. Patients with prostatic CIS or urethral lamina propria invasion had a similar, but higher incidence of lymph node metastasis and lower long-term and 5-year survival than those patients without prostatic involvement. Similarly, prostatic stromal invasion and periprostatic/seminal vesical invasion had a similar, but much higher nodal metastasis and worse survival than patients with only prostatic CIS or urethral lamina propria invasion. In summary, presence of prostatic TCC involvement and levels of involvement are significant prognostic factors in patients with bladder cancer.     

Recommendations for the reporting of urinary bladder specimens containing bladder neoplasms

The Association of Directors of Anatomic and Surgical Pathology have developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for carcinomas of the urinary bladder are reported herein.This report was prepared by an ad hoc committee composed of William M. Murphy (Chair), John D. Crissman, Sonny L. Johansson, and Alberto G. Ayala.     

Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats

This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).