Overexpression of O-GlcNAc by prostate cancer cells is significantly associated with poor prognosis of patients.

BACKGROUND: O-linked ß-N-acetylglucosamine (O-GlcNAc) is a glycan essential for fundamental cellular processes such as transcription/translation, nuclear transport, protein stability and protein-protein interactions. However, the role of O-GlcNAc in prostate cancer progression of patients remains poorly unknown. Here we investigated the clinicopathological significance of O-GlcNAc expression level in prostate cancer. METHODS: O-GlcNAc expression level in prostate cancer cells was determined by immunohistochemistry of prostate biopsy specimens obtained from 56 patients later treated with hormone deprivation therapy comparing with adjacent normal prostate glands in the same sections. Overall survival was determined by the Kaplan-Meier and Cox proportional hazards methods with univariate and multivariate models. The effects of reduced O-GlcNAc expression level on proliferation and invasion of prostate cancer LNCaP cells were examined using small interfering RNA (siRNA) targeting O-GlcNAc transferase (OGT), the enzyme responsible for O-GlcNAc biosynthesis. RESULTS: Defining cancer cells showing stronger cytoplasmic staining than normal prostate glands as overexpression of O-GlcNAc, 39% of prostate cancer patients were categorized as overexpression. The Kaplan-Meier and Cox proportional hazards methods with univariate model analysis revealed that O-GlcNAc overexpression was associated with overall survival (P=0.0012 for the Kaplan-Meier and P=0.0021 for Cox univariate hazard model analysis). Furthermore, O-GlcNAc was the only item in which a significant difference was observed at overall survival by multivariate analysis (P=0.0475). Finally, siRNA-mediated OGT knockdown in LNCaP cells resulted in decreased expression of O-GlcNAc and promoted decreased proliferation and tumor cell invasion compared with control siRNA-transfected LNCaP cells. CONCLUSIONS: These results indicate that O-GlcNAc expression level in prostate cancer cells is associated with poor prognosis of prostate cancer patients and likely enhances tumor cell proliferation and invasion.

Effect of herpes simplex virus vector-mediated interleukin-4 gene therapy on bladder overactivity and nociception.

We investigated the effects of replication-defective herpes simplex virus (HSV) vector expression of interleukin-4 (IL-4) on bladder overactivity and nociception. HSV vector expressing murine interleukin-4 (S4IL4) or the control vector expressing ß-galactosidase (SHZ) were injected to the rat bladder wall. At 1 week after viral injection, in cystometry performed under urethane anesthesia, the S4IL4-treated group did not show the intercontraction intervals reduction during intravesical administration of 10 nM resiniferatoxin (RTx). At 2 weeks after viral injection, behavioral studies were performed on vector-injected animals in an awakened state. Freezing behavior induced by 3 µM RTx, administered for 1 min into the bladder, was significantly suppressed in the S4IL4 group compared with the SHZ group. Murine IL-4 levels examined by ELISA were significantly increased in bladder and bladder afferent dorsal root ganglia at 2 weeks after viral injection. The expression of IL-1ß and IL-2 and bladder inflammatory responses were significantly suppressed in the RTx-irritated bladder of S4IL4-injected rats. These results indicate that HSV vector-mediated interleukin-4 expression in the bladder and bladder afferent pathways reduces the inflammatory response, bladder overactivity and nociceptive behavior induced by bladder irritation in the rat model. Therefore, IL-4 gene therapy could be a new strategy for treating urinary frequency and/or bladder pain.

Importance of transition zone prostate biopsies in patients with gray-zone PSA levels undergoing the ultrasound-guided systematic ten-biopsy regimen for the first time.

INTRODUCTION: We analyzed the efficacy of routine transition zone biopsies for patients undergoing ultrasound-guided systematic prostate biopsies for the first time because of an elevated serum prostate-specific antigen (PSA) level. PATIENTS AND METHODS: Using the systematic ten-biopsy regime, four additional transition zone biopsies were performed in 236 consecutive patients, because they showed an elevated PSA level (range 4.0- 9.9 ng/ml). RESULTS: The overall prostate cancer detection rate was 21.2% (50/236). In 24 patients (48.0%), cancers were detected only in the peripheral zone, in 4 (8.0%) only in the transition zone, and in 22 (44.0%) in both zones. No distinguishing characteristics could be determined for the cancers detected in the transition zone only. CONCLUSIONS: Although the cancer detection rate for the transition zone was significantly lower than for the peripheral zone, it was higher than that reported in most other studies which may have included biopsy specimens from patients with advanced prostate cancers. The usefulness of transition zone biopsies for the detection of early-stage prostate cancer, especially in patients with a PSA gray zone, can, therefore, not be denied.

A retroperitoneal bronchogenic cyst: laparoscopic treatment.

Subdiaphragmatic bronchogenic cysts are rare, and those located retroperitoneally are exceptional. We describe a retroperitoneal cyst presenting as an asymptomatic adrenal mass which was treated with laparoscopic surgery with three trocars.

The role of capsaicin-sensitive afferents in autonomic dysreflexia in patients with spinal cord injury.

OBJECTIVES: To determine whether capsaicin-sensitive nerves in the bladder form the afferent limb involved in autonomic dysreflexia (AD) in patients with spinal cord injury (SCI). PATIENTS AND METHODS: Seven men with SCI (five cervical cord, two thoracic cord) with AD and detrusor hyper-reflexia (DH) were enrolled. Under general anaesthesia, capsaicin solution (100 mL of 2 mmol/L in 10% ethanol) was instilled in the bladder and retained for 30 min. The patients were assessed by medium-fill cystometry (CMG) just before and 50 min after the capsaicin treatment. Intra-arterial blood pressure (BP) and heart rate were monitored continuously throughout the procedure; 10% ethanol was instilled before capsaicin treatment in four patients as a control. Serum catecholamines were measured during bladder filling and capsaicin treatment, and the blood ethanol concentration also measured after instillation in all patients. The CMG with concomitant monitoring of BP and heart rate was repeated 1 week, 1, 3, 6, 12 and 24 months after instillation. In two patients the instillations were repeated 5 and 12 months after the first because of recurrence of DH. Urodynamic variables assessed were maximum cystometric capacity (MCC), maximum amplitude of uninhibited detrusor contraction (UICmax), the bladder capacity at 40 cmH2O detrusor pressure (Cdp40) and a systolic BP of> 140 mmHg or diastolic BP of> 90 mmHg (C(HT)). RESULTS: There was an increase in BP and a decrease in heart rate in all patients during bladder filling before capsaicin treatment. Instillation of capsaicin produced a significant increase in both systolic and diastolic BP and a significant decrease in heart rate. The maximum cardiovascular effects were at 5-10 min after instillation and gradually returned to baseline within 40 min. The vehicle had negligible effects on either BP or heart rate. After capsaicin treatment, the responses of BP and heart rate to bladder distension were significantly reduced. Both serum catecholamine values and the blood ethanol concentration remained within normal limits. The mean (range) follow-up after the first treatment was 15 (6-30) months. One month after treatment all seven patients became continent and their episodes of AD became negligible and well tolerable between catheterizations (for 3-4 h); the effects lasted for >or= 3 months in all. MCC was significantly increased at 4 weeks and 3 months, and UICmax significantly decreased at 4 weeks after treatment. Both mean Cdp40 and C(HT) increased 1 week, 1 and 3 months after treatment. Two patients received a second instillation, and have been continent with no symptomatic AD for 6 and 24 months. The remaining five patients have been continent with no symptomatic AD for 6-12 months. CONCLUSION: These results indicate that intravesical capsaicin, but not the vehicle, acutely triggers AD in patients with SCI, suggesting involvement of bladder capsaicin- sensitive afferents in AD in these patients. The results also suggest that intravesical capsaicin may be a promising therapy for both AD and DH in such patients. Further long-term follow-up studies are needed to evaluate the duration of its effect.

Importance of transition zone biopsies in patients undergoing ultrasound-guided prostate systemic biopsies for the first time.

INTRODUCTION: We analyze the efficacy of routine transition zone biopsies in patients undergoing ultrasound-guided systemic prostate biopsies for the first time because of a suspicious digital rectal examination or an elevated serum prostate-specific antigen (PSA) level. PATIENTS AND METHODS: During systemic prostate biopsy two or four additional transition zone biopsies were performed in 192 consecutive patients: in 182 because of a serum PSA concentration >4.1 ng/ml and in 10 because of a suspicious digital rectal examination and a serum PSA level <4.0 ng/ml. RESULTS: The overall prostate cancer detection rate was 37.5% (72/192). In 24 patients (33.3%), cancer was only detected in the peripheral zone, in 3 (4.2%) only in the transition zone, and in 45 (62.5%) in both zones. CONCLUSION: Transition zone biopsies performed at the first time of systemic prostate biopsy seem to have a low efficacy.

Effect of apomorphine on intracavernous pressure and blood pressure in conscious, spinalized rats.

Apomorphine, given subcutaneously (s.c.), induces erection and bladder overactivity in rats through stimulation of dopamine (D1- and D2-like) receptors in the central nervous system. In paraplegic patients, apomorphine was reported to cause bladder overactivity. This suggests that apomorphine may have a spinal site of action also for stimulation of erection. The present study was initiated to evaluate the effect of apomorphine on erectile function in spinalized rats. Apomorphine (100 microg/kg, s.c.) was given to awake, unrestrained male Sprague-Dawley rats (300 g) with or without spinal cord injury, made at the Th 8 level 2 weeks before the experiment. Intracavernous pressure changes from baseline were evaluated as time to first response to apomorphine (TFR; sec), number of phasic pressure changes in the first 30 min (PP30), duration (D; sec) of the phasic pressure changes, the amount of increase in tonic peak pressure (TPP; cmH2O), and burst peak pressure (BPP; cmH2O). Blood pressure (cmH2O) was recorded via an intra-arterial catheter. Apomorphine, 100 microg/kg, caused no significant differences in TFR (217.8 vs 271.2), PP30 (6.4 vs 6.5), D (38.9 vs 37.6.), TPP (51.0 vs 54.0) and BPP (128.9 vs 160.4) between normal (n=8) and spinalized rats (n=6). However, blood pressure decreased significantly more in spinalized than in normal animals (17.7 vs 43.3; P<0.05). The results suggest that both in normal rats, and in rats with spinal cord injury, apomorphine given s.c., can produce erection. This finding supports the use of apomorphine for treatment of erectile dysfunction in paraplegia patients. However, due consideration should be given to possible decreases in blood pressure.

Adenocarcinoma of female paraurethral duct showing neuroendocrine differentiation.

Two cases are presented in which a female urethral adenocarcinoma took the form of a diverticular cancer. The pathologic examination of each tumor revealed a columnar/mucinous type of adenocarcinoma with evidence of abundant mucous secretion. Some of the cancer cells were positive on immunohistochemical staining with the conventional neuroendocrine marker chromogranin A, indicating focal neuroendocrine differentiation. The present cases may indicate a possible site of origin for female paraurethral adenocarcinomas.

[Significance of PSA-density: analysis in PSA gray zone cases].

We studied the sensitivity and specificity of digital examination and prostate specific antigen (PSA) density to detect prostatic cancer in those patients whose PSA values are in a range of 4 to 10 ng/ml or in a gray zone. Sextant prostate biopsy revealed 14 cases (17.2%) of prostatic cancer out of 81 PSA gray zone cases. The sensitivity of digital examination was 38.5%, and the specificity was 73.0%. If we use 0.29 as a PSA density cut-off value, the sensitivity was 70.0%, and the specificity was 70.0%. At a PSA density cut off value of 0.22, we could obtain 90% sensitivity, which was considered applicable for detection of cancer in PSA gray zone cases.

Micturition in thoracic spinal cord injured cats with autografting of the adrenal medulla to the sacral spinal cord.

PURPOSE: The role of noradrenergic projection from the pontine micturition center to the sacral spinal cord during micturition was examined in thoracic spinal cord injured cats after autografting the adrenal medulla to the sacral spinal cord. MATERIALS AND METHODS: In 13 female cats the lower thoracic cord was transected and the right adrenal gland was removed under halothane anesthesia. The resected adrenal medulla was divided into several small pieces, which were subsequently autografted to the sacral spinal cord in 7 cats. Another 6 cats underwent sham operation and served as controls. Continuous cystometry and electromyography of the external urethral sphincter were performed every 2 weeks postoperatively without anesthesia. At week 8 the sacral spinal cord was removed and immunohistochemical testing was done to assess tyrosine hydroxylase immunoreactivity. RESULTS: At week 6 the relative mean duration of detrusor-external sphincter coordination plus or minus standard error during bladder contraction was 62.4% +/- 4.9% in adrenal grafted cats, which was significantly (p = 0.0485) longer than in controls (34.2% +/- 12.6%). However, maximum bladder contraction pressure, bladder contraction duration and post-void residual urine volume were not significantly different in the 2 groups. Tyrosine hydroxylase immunoreactive cells were observed in and on the sacral spinal cord in adrenal grafted animals but not in controls. CONCLUSIONS: Autografting the adrenal medulla to the sacral spinal cord prolonged detrusor-external sphincter coordination during bladder contraction in thoracic spinal cord injured cats, although other urodynamic parameters did not change. Therefore, noradrenergic projections to the sacral spinal cord may relax the external urethral sphincter during bladder contraction.

[Partial nephrectomy using a microwave tissue coagulator for bilateral renal cell carcinomas: a case report].

We report a case of bilateral renal cell carcinomas in a 56-year-old male treated by partial nephrectomy at the same time using a microwave tissue coagulator technique. The patient did not need dialysis after the operation because we did not need to sacrifice the artery feeding to normal renal tissue during the operation. This technique has advantages of nephron sparing without occlusion of the renal artery, and decreased operation time and blood loss.

Supracostal approach--an excellent exposure for renal and adrenal surgery.

The supracostal extraperitoneal and extrapleural approach provides wide exposure during renal and adrenal operations without damaging the neurovascular bundles and spares the partial resection of rib. We performed renal and adrenal operations on 33 patients by this approach. The procedures were accomplished smoothly obtaining a broad surgical field without costal resection. Complications were rare and postoperative pain seemed to be mild. Hence, the supracostal approach is considered as a better method with excellent exposure to the kidney and adrenal and is anatomically comprehensive.

Prostatic adenocarcinoma with marked neuroendocrine differentiation.

A case is presented of prostatic cancer with marked neuroendocrine differentiation. Double-labeled immunohistochemical staining was performed with prostate-specific antigen and Chromogranin A. Both antibodies were localized to some of the cancer cells with Paneth cell-like features. Furthermore, most of the cancer cells were positively stained with luminal cell marker CAM 5.2, suggesting that neuroendocrine cells originated from the prostatic luminal cells.

The serous-lined tunnel principle for urinary reconstruction: a more rational method.

OBJECTIVE: To examine the feasibility of using the serous-lined-tunnel principle for orthotopic neobladder, continent cutaneous diversion and ureteric replacement by an intestinal segment. Patients and methods We created: (i) an orthotopic ileal neobladder using the serous-lined technique for antirefluxing ureteric implantation in 16 patients; (ii) a continent ileal pouch, adopting the principle for continent-valve construction and for ureteric implantation, in 10 patients (another patient with a failed continent valve underwent revision using an adaptation of this principle; and (iii) by applying the same principle an ileal ureter with a proximal antirefluxing mechanism was constructed in two patients (with lower ureteric cancer), and total replacement of the ureter by a tubular segment of the colon in association with a continent transverse colon pouch in one irradiated patient. RESULTS: In all, 52 ureters implanted into ileal neobladders or continent pouches functioned well, with neither obstruction nor reflux; 11 continent valves functioned well with no incontinence. Two patients with ileal ureters showed no ileo-ureteric reflux and had less hydronephrosis than before surgery. The tubularized ureter provided a unidirectional flow into the pouch. Conclusion Ureteric reimplantation and continent valve formation achieved by adopting the serous-lined tunnel principle provided satisfactory results. The versatility of the principle is apparent in the present experience and the creative application of the serous-lined tunnel principle should be possible in urinary reconstruction.

[Laparoscopic adrenalectomy at Shinshu University School of Medicine].

We report our experience with transperitoneal laparoscopic adrenalectomy in 26 cases (mean age 45 years). We experienced primary aldosteronism in 19 cases, Cushing syndrome in 6 cases and non-functioning tumor in one case. There was no significant difference in the operation time between right and left, men and women, primary aldosteronism and Cushing syndrome. The blood loss decreased with training. There were no severe complications during and after the operation. The weight of the resected adrenal glands increased. The blood loss decreased significantly compared with the open surgery. Transperitoneal laparoscopic adrenalectomy is becoming the safe and standard surgery for the adrenal gland tumor, and the number of suitable cases for this procedure is expected to increase in the future.

Effect of KMD-3213, an alpha1A-adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs.

BACKGROUND: KMD-3213 is an alpha1A-adrenoceptor-selective antagonist currently being developed for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia. In the present study, the uroselectivity of KMD-3213 was evaluated and compared with that of prazosin and tamsulosin in a decerebrate dog model. METHODS: Intercollicular decerebration was carried out in male mongrel dogs under anesthesia. The inhibitory effects of intravenously and intraduodenally administered compounds on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve were estimated. Systemic blood pressure was measured simultaneously. RESULTS: The alpha1-antagonists tested produced a dose-dependent inhibition of the induced IUP response and decreased mean blood pressure (MBP). The ID50 of KMD-3213, tamsulosin and prazosin for IUP (dose required to inhibit the increase in IUP by 50%) was 3.15, 1.73 and 11.8 microg/kg i.v., respectively, and the ED20 for the hypotensive effect (dose required to reduce MBP by 20%) was 8.03, 0.59 and 2.46 microg/kg i.v., respectively. The data indicate that uroselectivity (ED20/ID50) of KMD-3213 is 12- and 7.5-fold higher than that of prazosin and tamsulosin, respectively. When the drugs were administered intraduodenally, KMD-3213 was sufficiently absorbed from the digestive tract and continued to demonstrate at least 3.8-fold higher uroselectivity than tamsulosin. CONCLUSION: Based on these findings, KMD-3213 appears to be an effective orally active compound for decreasing urethral resistance during micturition that does not induce any negative cardiovascular effects in patients with benign prostatic hyperplasia.

Symptomatic and urodynamic improvement by oral distigmine bromide in poor voiders after transurethral resection of the prostate.

UNLABELLED: OBJECTIVESz: To study the clinical and urodynamic effects of oral distigmine bromide (distigmine) by using pressure-flow studies in patients who were persistently poor voiders after transurethral resection of the prostate. METHODS: The study included 14 poor voiders after transurethral resection of the prostate who were 50 years old or older. Their poor voiding conditions were characterized by a mean International Prostate Symptom Score of 18.9 or a mean quality-of-life index of 4.6 and a mean maximum flow rate of 8.9 mL/s. All patients underwent symptomatic and urodynamic investigations before and after 4 weeks of daily treatment with 15 mg oral distigmine. RESULTS: In the baseline pressure-flow studies, all patients had weak detrusor contractility as demonstrated by Schäfer's diagram and the maximum Watts factor but did not have bladder outlet obstruction. They had symptomatic improvements after oral distigmine treatment, with the International Prostate Symptom Score reduced to a mean of less than 10 and the quality-of-life index reduced to a mean of less than 3. In the urodynamic investigations, the maximum flow rate improved significantly to a mean of more than 12 mL/s in parallel with a significant increase in the maximum Watts factor. Detrusor contractility according to Schäfer's diagram also tended to improve after oral distigmine treatment. However, no significant changes were found in any of the parameters of bladder outlet obstruction. CONCLUSIONS: Poor voiders after transurethral resection of the prostate who have weak detrusor contractility without bladder outlet obstruction may benefit clinically from treatment with distigmine because of its efficacy in increasing detrusor contractility without enhancing bladder outlet obstruction.

Role of dopamine D1 and D2 receptors in the micturition reflex in conscious rats.

To clarify the role of dopamine D1 and D2 receptors in the volume-induced micturition reflex, conscious, female rats were investigated cystometrically before and after intravenous administration of SKF 38393 (a selective D1 receptor agonist), SCH 23390 (a selective D1 receptor antagonist), quinpirole (a selective D2 receptor agonist), and remoxipride (a selective D2 receptor antagonist). The effect of quinpirole was also investigated in the presence of remoxipride. Intravenous administration of SKF 38393 (0.01-3.0 mg/kg) did not affect any cystometric parameters investigated. On the other hand, SCH 23390 (0.1-1.0 mg/kg i.v.) reduced bladder capacity and micturition volumes and increased the micturition pressure in a dose-dependent manner. Quinpirole (0.01-0.1 mg/kg) given intravenously, dose-dependently decreased bladder capacity and micturition volumes. Pre-treatment with remoxipride (1.0 mg/kg i.v.) significantly attenuated the effect of quinpirole (0.1 mg/kg i.v.). Remoxipride (0.1-1.0 mg i.v.) itself did not cause any significant changes in the cystometric parameters. These results suggest that in conscious rats, D1 receptors tonically inhibit the micturition reflex and that D2 receptors are involved in facilitation of the micturition reflex. It may be speculated that detrusor hyperreflexia associated with Parkinson's disease results from activation failure of D1 receptors and that administration of D2 receptor agonists might worsen the condition.