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Aims: To examine the effects of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) on the myogenic differentiation of human urethral rhabdosphincter (RS) satellite cells., Methods: Human RS was obtained from patients undergoing radical prostatectomy for prostate cancer. Selectively cultured RS satellite cells, transfected with temperature sensitive simian virus-40 T antigen (ts-SV40 Tag) to extend their lifespan, were cultured at 33 degrees C, and then incubated at 39 degrees C to induce myogenic differentiation. Varying concentrations of HGF and IGF-1 were added to the differentiation medium. Inactivation of SV40 Tag and evaluations of myogenic differentiation were examined by immunocytochemistry, western blotting and real-time RT-PCR., Results: At 39 degrees C, ts-SV40 Tag-transfected RS satellite cells slowly proliferated, fused to form multinucleated myotubes, and expressed myosin heavy chain (MHC) in association with the temperature-dependent inactivation of SV40 Tag. IGF-1 significantly accelerated the MHC expression in a dose-dependent fashion through activation of the PI3-kinase pathway. Conversely, HGF did not promote MHC expression due a reduction in phosphorylation of both the MAP-kinase and the PI3-kinase pathways, a pattern of response different than the response of proliferating RS satellite cells to HGF., Conclusions: HGF did not induce myogenic differentiation of RS satellite cells. Conversely, IGF-1 promoted myogenic differentiation of RS satellite cells via the PI3-K pathway likewise proliferating RS satellite cells. These findings may be useful for developing novel techniques for regenerating the human RS to treat urinary incontinence., ((c) 2009 Wiley-Liss, Inc.)

Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.

In this paper, we describe a case of ovarian vein syndrome (OVS) successfully treated with retroperitoneoscopic techniques. A 41-year-old woman complained with right flank pain, especially with a recumbent position. OVS was diagnosed and ureterolysis and ovarian vein resection were successfully performed, using retroperitoneoscopic techniques. The patient has been completely pain free for 36 months of follow-up. To our knowledge, no previous reports have described the retroperitoneoscopic treatment of OVS. With the minimally invasive approach, postoperative recovery and patient quality of life were markedly improved.

A novel point mutation in a patient with vascular type Ehlers-Danlos syndrome is herein reported. The patient experienced pneumothorax and multiple arterial troubles during the past 10 years. The patient's hand skin was atrophic, and a paper-like atrophic scar was seen. The collagen microfibrils from the patient's skin demonstrated irregular contour, electron density variegation, and smaller, irregular fibril diameters. The patient's fibroblasts produced apparently much less type III collagen comparing with control. A skipping of exon 24-originated sequences of the patient's mRNA of type III collagen was proved. A single base pair mutation of thymine to guanine at the second position of the intron 24 of COL3A1 was finally found. This is the first report of the mutation of the second position of exon 24 of COL3A1.

Tumor hypoxia is a common feature of several cancers, including prostate cancer, and is associated with tumor progression, acquisition of anti-apoptotic potential and therapeutic resistance. We explored hypoxia-inducible genes and examined the effect of knockdown of a target molecule with small interference RNA (siRNA) on the proliferation of human prostate cancer cells. Human prostate cancer cell lines (LNCaP and PC-3) were cultured in normoxia (21% O2) or hypoxia (0.5% O2). Hypoxia-inducible genes were identified by cDNA microarray analysis. Metallothionein (MT) expression was assessed by real-time RT-PCR, Western blot analysis and immunohistochemical staining. siRNA was transfected to knock down MT expression, and the cell cycle and apoptosis were evaluated by flow cytometry analysis. In cDNA microarray analysis, 22 genes (including MT) were up-regulated under hypoxia. MT-1X and MT-2A were up-regulated in real-time RT-PCR. In particular, MT-2A was increased 3-fold in LNCaP and 8-fold in PC-3. The siRNA-MT-2A treatment resulted in a 20% inhibition of cell growth and induced apoptosis in both LNCaP and PC-3. In human prostate tissue, intense staining of MT was observed in cancer cells and residual cancer cells after androgen ablation therapy, while normal tissue was only stained in patches. In conclusion, MT was up-regulated under hypoxia in prostate cancer cells and overexpressed in prostate cancer tissue and residual cancer cells after androgen ablation therapy. As down-regulation of MT by siRNA inhibited cell growth and induced cell death, MT may be a new molecular target for the treatment of human prostate cancer.

Purpose: We previously reported that the biological functions of beta2-microglobulin include antigen presentation and oncogenic activity. In the current study we investigated the direct role of beta2-microglobulin in the regulation of human renal cell carcinoma cell growth and the possible apoptotic inducing effect of blocking the beta2-microglobulin signaling pathway using an anti-beta2-microglobulin neutralizing antibody., Materials and Methods: We examined the effects of recombinant beta2-microglobulin protein and anti-beta2-microglobulin antibody on renal cell carcinoma cell growth and apoptosis in vitro. To seek a molecular understanding of anti-beta2-microglobulin antibody induced apoptosis we analyzed alterations in the growth and survival signaling components in the phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase and c-jun N-terminal kinase mediated pathways using corresponding kinase inhibitors in SN12C cells., Results: Recombinant beta2-microglobulin protein increased the growth of the 3 human renal cell carcinoma cell lines SN12C, Caki-1 and ACHN in a dose and time dependent manner. Treatment of SN12C, Caki-1 and ACHN cells with an anti-beta2-microglobulin polyclonal antibody strongly suppressed the growth of these cells in vitro, also in a dose and time dependent manner. The addition of recombinant beta2-microglobulin protein or anti-beta2-microglobulin antibody increased or decreased, respectively, the anchorage independent growth of SN12C cells. The recombinant beta2-microglobulin protein accelerated cell growth via activating phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase, and induced the phosphorylation of Bcl-xL/Bcl-2-associated death promoter. However, treatment with anti-beta2-microglobulin antibody induced cell death by inhibiting the phosphorylation of Akt and extracellular signal-regulated kinase, and activating c-jun N-terminal kinase, resulting in the induction of phosphorylation of B-cell lymphoma 2 and decreased phosphorylation of Bcl-xL/Bcl-2-associated death promoter, leading to apoptosis., Conclusions: Our results demonstrate that beta2-microglobulin has an important role in regulating the growth and survival of renal cell carcinoma cells and anti-beta2-microglobulin antibody offers a potential novel therapy for the treatment of human renal cell carcinoma.

Aims: To examine the presence of satellite cells in human urethral rhabdosphincter (RS) and to clarify the growth mechanism of these cells., Methods: Human RS was obtained from patients undergoing radical prostatectomy for prostate cancer. Primary cells were selectively cultured by magnetic affinity cell sorting (MACS) using an anti-neural cell adhesion molecule (NCAM) antibody. Selectively cultured cells, transfected with simian virus-40 T antigen to extend their lifespan, were used for the following experiments: (1) determination of the effects of hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and basic fibroblast growth factor (b-FGF); (2) clarification of the signal transduction pathways used by these growth factors; and (3) examination of the autocrine actions in these cells., Results: Selectively cultured cells expressed striated muscle markers and could differentiate into myotubes. HGF and IGF-1 stimulated the growth of these cells in a dose-dependent fashion. Regarding signal transduction, HGF phosphorylated ERK1/2 for 120 min while only transiently modifying Akt. In contrast, IGF-1 phosphorylated Akt but not ERK1/2. Furthermore, these cells produced transcripts and proteins for both HGF and IGF-1, and anti-HGF and anti-IGF-1 antibodies suppressed cell proliferation., Conclusions: Satellite cells are present in human RS. The proliferation of these cells is primarily enhanced through both the endogenous and exogenous actions of HGF and IGF-I via ERK1/2 and Akt. These findings may be useful in the development of a novel technique for the regeneration of human RS to treat urinary incontinence., (Copyright (c) 2007 Wiley-Liss, Inc.)

Purpose: Beta(2)-microglobulin (beta2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of beta2M has been reported in human renal cell carcinoma, we investigated the effects of beta2M overexpression on cancer cell growth and analyzed its molecular signaling pathway., Experimental Design: We established clonal cell lines that overexpressed beta2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the beta2M-mediated downstream cell signaling pathway., Results: Our results showed that beta2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that beta2M mediates its action through increased phosphorylation of cyclic AMP-responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, beta2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Beta2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the beta2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase., Conclusions: Our results showed for the first time that the beta2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1-/- Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background, spontaneously developed colorectal carcinomas carrying nuclear beta-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)gamma-/- SOCS1-/- mice and SOCS1-/- Tg mice treated with anti-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- SOCS1-/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNgamma/STAT1 pathways.

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), has been implicated in bladder cancer angiogenesis and invasion. However, the molecular basis of its role in invasion remains unclear. We investigated the expression of TP and 10 invasion-related genes in bladder cancers from 72 randomly selected patients by real-time two-step RT-PCR assay. We found that the expression levels of TP, MMP-9, uPA, and MMP-2 were significantly higher in invasive tumors than those in superficial tumors. Also, the expression level of TP significantly correlated with that of uPA, MMP-1, MMP-9, PAI-1 and VEGF. KK47/TP cells, bladder cancer cells that overexpress TP, had a higher expression of MMP-7 and MMP-9 than KK/CV cells that express lower level of TP in hypoxic condition. PC/TP cells, prostate cancer cells that overexpress TP, also had a higher expression of MMP-1 and MMP-7 than PC/CV cells that express no detectable TP. Taken together these data indicate that TP enhances the invasion of tumor cells through the induction of invasion-related genes.

We present a rare case of transitional cell carcinoma of the navicular fossa in an elderly man. We detected the expression of human papillomavirus type 16 specific DNA sequence in the tumor using polymerase chain reaction. Human papillomavirus dissemination into the urethra by urethral instrumentation might cause urethral tumors, such as squamous cell carcinoma or condyloma acuminatum, and also transitional cell carcinoma as seen in the present case.

A 45-year-old man on long-term hemodialysis (HD) was incidentally discovered to have a pheochromocytoma and underwent successful resection. This patient was normotensive, and had no symptoms suggesting pheochromocytoma. The plasma concentrations of total adrenomedullin (AM-T) and mature AM (AM-m) were higher than those in normal controls. To elucidate the source of AM, we measured plasma AM levels by immunoradiometric assay before and 3 weeks after surgery in addition to plasma adrenaline, noradrenaline and dopamine. AM expression was also assessed by immunoblot and immunohistochemical analyses on normal adrenal and tumor tissues. After surgery, elevated plasma adrenaline levels returned to the normal range; however, the levels of AM-T and AM-m remained almost the same as the preoperative values. Furthermore, although AM was expressed in both normal adrenal and tumor tissues, the AM expression level was less in tumor. In this case, it was suggested that elevation in plasma AM level might be a factor associated with normotensive blood pressure; however, adrenal pheochromocytoma was not a major source of circulating AM. To our knowledge, this is the first case of pheochromocytoma in patient with HD associated with AM in the literature.

Purpose: We clarified the contractile properties of human male periurethral striated muscle fibers to better understand how the rhabdosphincter and the levator ani maintain urinary continence., Materials and Methods: Muscle specimens were obtained from 52 male patients who underwent radical prostatectomy or radical cystectomy. The specimens were frozen in liquid nitrogen. Frozen sections (10 microm thick) were stained with myofibrillar ATPase at different pH values (pH 4.2, 4.6 and 10.6), and evaluated for quantitative parameters and fiber type distribution. Myosin heavy chain analysis was performed using SDS-PAGE., Results: Of all 52 cases 37 provided specimens that could be divided into the 2 major fiber types, type 1 (slow twitch) and type 2 (fast twitch). Although type 1 muscle fibers were predominant in RS and LA muscle groups (RS 69.6 +/- 2.7%, LA 67.0 +/- 2.0%), mean muscle fiber size was significantly smaller in RS (mean area 906 +/- 86 microm(2)) than in LA (mean area 2,967 +/- 170 microm(2)) (p <0.0001). In 11 specimens type 2 muscle fibers could be subdivided into types 2A (fast fatigue resistant) and 2B (fast fatigable). Type 2A fibers were significantly more prevalent than type 2B fibers (p <0.05). Likewise, MHC analysis of these 11 specimens found a significantly higher percentage of fiber type 2A expression products (MHC 2A) than of fiber type 2B expression products (MHC 2X) (p <0.05)., Conclusions: RS and LA contribute to urinary continence mechanism by slow contraction. Moreover, the smaller mean size of muscle fibers in RS suggests more fatigue resistance compared with muscle fibers in LA because small fibers have a shorter diffusion distance for metabolic substrates. These results should help contribute to a more detailed understanding of the function of periurethral striated muscles in the human male.

Acquired multi-drug resistance remains a major obstacle in the management of prostate cancer. The objective of this study was to examine whether chemoresistance could be due in part to the expression of the inhibitors of apoptosis proteins (IAPs). We established cisplatin-resistant LNCaP sublines. We examined the effects of cisplatin on cell growth and apoptosis in LNCaP cells and LNCaP sublines by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-1) assay and Hoechst 33258 staining, and analyzed cross-resistance to adriamycin, 5-fluorouracil, taxol, taxotere, and etoposide. In addition, the expression of IAP-1, IAP-2, X-linked IAP (XIAP), neuronal apoptosis inhibitory protein, and survivin was investigated by immunoblot analysis in LNCaP sublines. Although the growth rates were reduced in a dose-dependent manner by cisplatin in LNCaP sublines, the anti-proliferative effects of cisplatin were significantly decreased in LNCaP sublines compared to LNCaP cells. Cisplatin-resistant sublines, LNCaP/C1, LNCaP/ C2, and LNCaP/C3 cells, were 6.3-, 9.1-, and 22.3-fold more resistant to cisplatin than LNCaP cells, respectively, and this resistance was paralleled with reduced induction of apoptosis. LNCaP/C3 cells showed cross-resistance to adriamycin, 5-fluorouracil, and etoposide whereas those cells exhibited no or only weak cross-resistance against taxol and taxotere. With the exception of survivin, all the IAPs were identified in LNCaP cells by immunoblot analysis. Interestingly, the expression of IAP-2, XIAP, and survivin gradually increased with the extent of cisplatin-resistance. Altered expression of IAP-2, XIAP, and survivin was involved in these phenotypes of cisplatin-resistant LNCaP sublines. IAPs may make an important contribution to the resistance to the apoptotic effect of cisplatin in prostate cancer.

A 31-year-old, previously normotensive healthy man developed right flank pain and was admitted to a medical service. Right renal infarction was suspected by enhanced abdominal computed tomography (CT) and arteriography. Fourteen days after the onset, he was transferred to the Oita University Hospital, Oita, Japan. Renal angiography revealed an isolated renal artery dissection causing renal atrophy due to main stem narrowing of the right renal artery. Renogram and renal scintigram with (99m)Tc-diethylene triamine pentaacetic acid revealed a remarkable decline in the glomerular filtration rate and almost no uptake in the right kidney. Four months later, in spite of our belief that functional recovery could not be expected, intravenous pyelography and enhanced abdominal CT scans revealed a functioning right kidney that had spontaneously recovered from the renal artery dissection through conservative management.

The serum level of prostate-specific antigen (PSA) is useful as a clinical marker for diagnosis and assessment of the progression of prostate cancer, and in evaluating the effectiveness of treatment. We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA. Among the four binding sites, a GC box located at nucleotides -53 to -48 was especially critical for basal promoter activity. These results indicate that Sp1 and Sp3 are involved in the basal expression of PSA in prostate cancer cells.

A recto-peritoneal fistula is an extremely rare complication after prostate biopsy. We report herein on a peritonitis arising from a recto-peritoneal fistula 5 days after undergoing prostate biopsy. To our knowledge, this is the first case of recto-peritoneal fistula following transperineal needle biopsy of the prostate in the published literature.

Introduction: Placenta percreta is a rare obstetric complication causing life-threatening hemorrhage., Case Report: The case of a woman with a placenta percreta invading the urinary bladder treated by cesarean hysterectomy and partial bladder resection is presented. Overall estimated blood loss was 11,130 ml, and 59 units of various blood products were transfused., Conclusion: Obstetricians and urologists should be aware of this rare condition.

Introduction: The purpose of the present study was to compare the incidence of inguinal hernias after conventional and minilaparotomy (minilap) radical retropubic prostatectomy (RRP)., Patients and Methods: In this retrospective study, we review our experience with 70 consecutive patients with prostate cancer who underwent prostatectomy from April 1995 through March 2001. Of these, 35 patients had conventional RRP, and 35 patients had minilap RRP., Results: Conventional RRP and minilap RRP groups were similar in body mass index (mean 24.4 and 23.5), operative time (mean 260 and 241 min), previous lower abdominal operation record (mean 37.1 and 25.7%), and post-prostatectomy anastomotic strictures (mean 11.4 and 14.3%). The volume of the estimated blood loss was significantly less for minilap RRP (mean 1,220 ml) than for conventional RRP (mean 1,666 ml; p = 0.0194). The incidence of postoperative inguinal hernias was 17.1% (6 of 35), 2.9% (1 of 35), and 3.2% (1 of 31) in conventional RRP, minilap RRP, and unoperated groups, respectively. The incidence of inguinal hernias after minilap RRP was significantly lower than after conventional RRP (p = 0.0464). Seven patients with postoperative inguinal hernias had a high incidence of postoperative strictures (42.9%), while 63 patients without hernia had a low incidence (9.5%). There was a significant difference in developing postoperative strictures between patients with hernia and those without (p = 0.0124). While postoperative stricture and operative technique were different in the hernia and hernia-free groups on univariate analysis, multivariate logistic analysis revealed that the operative technique was an independent factor for the occurrence of inguinal hernias (p = 0.0419)., Conclusion: Minilap RRP compares favorably with conventional RRP in view of the postoperative inguinal hernia development.

The purpose of the present study is to investigate the role of X-linked inhibitor of apoptosis protein (XIAP) in the regulation of apoptosis induced by cisplatin in human prostate cancer cell line (LNCaP). We examined the effects of cisplatin on cell growth and apoptosis in LNCaP by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-1), flow cytometric analyses, and caspase-3 activity assay. In addition, to clarify the roles of the XIAP, we established clonal cell lines that overexpressed XIAP. The effects of cisplatin on the XIAP expression in the induction of apoptosis in LNCaP were examined by RT-PCR and immunoblot analyses. Although the growth rates were reduced in a dose- and time-dependent manner by cisplatin in LNCaP sublines, the anti-proliferative effects of cisplatin were significantly decreased in XIAP stably overexpressing cell lines. In addition, we found that cisplatin-induced apoptosis following activation of caspase-3, and that the overexpression of XIAP inhibited apoptosis by attenuating caspase-3 activity. Interestingly, treatment of LNCaP cells with 10 and 100 muM cisplatin for 48 h significantly decreased the expression of XIAP at both the protein and mRNA levels in a dose-dependent manner. Furthermore, 10-muM cisplatin treatment of LNCaP decreased XIAP mRNA and protein in a time-dependent manner. These results suggest that cisplatin induces apoptosis by the inhibition of XIAP expression, and that XIAP plays an important role in the regulation of cisplatin-induced apoptosis in LNCaP cells. The ability of cisplatin to down-regulate XIAP may be an important mechanism in chemosensitivity.

A 70-year-old man had undergone urethral dilatation with bougie for 8 months following transurethral resection of the prostate and complained papillary masses at the urethral meatus. Physical and endoscopic examination revealed multiple tumors from the urethral meatus to the bulbous urethra. These tumors were resected transurethrally and 5-FU cream was instilled into urethra. Microscopic examination revealed urethral condyloma acuminata. Human papillomavirus types 6/11 were detected in the condylomas. As high prevalence rate of genital human papillomavirus was reported in penile skin of healthy men, urethral instrumentation including transurethral surgery might cause dissemination of penile skin human papillomavirus into the urethral lumen.

We performed cadaveric renal transplantation on a 46-year-old man on long-term hemodialysis. Methicillin-resistant Staphylococcus aureus (MRSA) enterocolitis occurred on the fifth postoperative day and severe intestinal ulceration and perforation followed. Subtotal abdominal colectomy and the simultaneous removal of the transplant were performed. Postoperatively, disseminated intravascular coagulopathy with pancytopenia and cerebral hemorrhagic infarction developed and the patient died 40 days later.

We repaired a recurrent ileal conduit parastomal hernia, according to Kaufman's technique, by translocating the stoma to the opposite side of the abdominal wall without laparotomy. This procedure is a simple and less invasive treatment for large parastomal hernia.

Suppressor of cytokine signaling-1 (SOCS1/JAB) negatively regulates not only the cytokine-signaling pathway but also lipopolysaccharide (LPS)-induced macrophage activation. We found that SOCS1-deficient dendritic cells (DCs) were also hyperresponsive to interferon-gamma and interleukin-4. To define the role of SOCS1-deficient DCs in vivo, we generated mice in which the SOCS1 expression was restored in T and B cells on a SOCS1(-/-) background. In these mice, DCs were accumulated in the thymus and spleen and produced high levels of BAFF/BLyS and APRIL, resulting in the aberrant expansion of B cells and autoreactive antibody production. SOCS1-deficient DCs efficiently stimulated B cell proliferation in vitro and autoantibody production in vivo. These results indicate that SOCS1 plays an essential role in the normal DC functions and suppression of systemic autoimmunity.

Purpose: Lower pole renal stones are well known to exhibit a poor stone clearance rate following extracorporeal shock wave lithotripsy (ESWL). In the present study, we analyzed several anatomical factors as predictors of lower pole stone clearance that may be used to indicate the usefulness and the universality of ESWL in such patients with two different lithotriptors., Patients and Methods: 93 patients with a unilateral single lower pole stone of 2 cm. or less underwent ESWL using Piezolith 2500 or Medstone STS, were included in the study. An IVP was used to determine the lower infundibulopelvic angle, the caliceal pelvic height, the lower infundibular length, the lower infundibular diameter, the lower infundibular length-to-diameter ratio and the number of lower pole minor calyces. Stone-free status was assessed by a plain film with or without renal ultrasound., Results: The stone clearance rate at the Piezolith 2500 group was 53.1% (34 of 64 patients), while was 51.7% (15 of 29 patients) at the Medstone STS group. In all cases, the overall stone clearance rate was 52.7% (49 of 93 patients). Age, laterality of the stone burden within the kidney and stone size were not different between the stone-free and residual stone groups. Multivariate logistic analysis revealed that length-to-diameter ratio was the most independent predictors of successful stone clearance at each group. The patients exhibited length-to-diameter ratio less than 7 achieved high stone clearance rates, greater than 72%. In contrast, the stone clearance rate was less than one third when length-to-diameter ratio was 7 or greater. Besides length-to-diameter ratio was strong prognostic factor in patients with stones 1 cm. or less and 1 to 2 cm at each group., Conclusion: From this study, it is apparent that successful ESWL is highly sensitive to the anatomy of the lower pole of the kidney. Especially, the lower infundibular length-to-diameter ratio is potentially useful and a universal predictor regardless of the kind of lithotriptors at least in patients with a lower pole radiopaque stone 2 cm. or less treated with ESWL.

To clarify the roles of the X-linked inhibitor of apoptosis protein (XIAP), we investigated the effects of XIAP overexpression on taxol-induced cell growth arrest and apoptosis in the prostate cancer cell line (LNCaP). After the transfection of XIAP cDNA into LNCaP cells, we established clonal cell lines that overexpressed XIAP and examined the taxol effects on growth and apoptosis by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt and flow cytometric analysis. The effects of XIAP overexpression on caspase-3 were examined by immunoblot analysis and activity assay. The interaction between XIAP and caspase-3 in LNCaP cells was examined by cotransfection with myc-XIAP and caspase-3-HA cDNAs followed by immunoprecipitation and immunoblot analysis. Large amounts of XIAP were expressed in the established cell lines. Although the growth rates were reduced in a dose- and time-dependent manner by taxol, these effects were significantly decreased in XIAP stably overexpressing cell lines. In addition, we found that taxol treatment induced the cleavage of pro-caspase-3, followed by apoptosis, and that the overexpression of XIAP inhibited apoptosis by attenuating the cleavage of pro-caspase-3 and caspase-3 activity. Interestingly, XIAP bound to pro-caspase-3 in LNCaP cells transiently cotransfected with myc-XIAP and caspase-3-HA cDNAs, and this interaction was inhibited by taxol treatment. These results suggest that the overexpression of XIAP inhibits taxol-induced apoptosis through the decrease of caspase-3 activity and inhibition of the processing of pro-caspase-3.

Purpose: Lower pole renal stones are well known to show a poor stone clearance rate after extracorporeal shock wave lithotripsy (ESWL) (Dornier Medical Systems, Marietta, Georgia). In the current study we analyzed several anatomical factors as predictors of lower pole stone clearance that may be used to indicate the usefulness of ESWL in such patients., Materials and Methods: Between January 1993 and October 2000, 63 patients with a unilateral single lower pole stone of 2 cm. or less were included in the study. Excretory urography was done to determine the lower infundibulopelvic angle, caliceal pelvic height, lower infundibular length and diameter, lower infundibular length-to-diameter ratio and number of lower pole minor calices. Stone-free status was assessed by x-ray., Results: The overall stone clearance rate was 54% (34 of 63 patients). While caliceal pelvic height, lower infundibular diameter, length, length-to-diameter ratio and number of minor calices were different in the stone-free and residual stone groups on univariate analysis, multivariate logistic analysis revealed that the lower infundibular length-to-diameter ratio, diameter and number of minor calices were independent predictors of successful stone clearance. The 13 patients (20.6%) who showed all 3 favorable anatomical factors (lower infundibular length-to-diameter ratio less than 7, diameter greater than 4 mm. and a single minor calix) achieved an impressive 84.6% stone clearance rate. In patients with only 1 or 2 favorable factors the stone clearance rate was still greater than 60%. In contrast, the stone clearance rate was only 6.7% in the 15 patients who showed none of these factors., Conclusions: From this study it is apparent that successful ESWL is highly sensitive to the anatomy of the lower pole of the kidney. If a patient with a lower pole stone has at least 1 of the favorable factors identified in this study, ESWL may be advocated as first line therapy with a greater than 60% prospect of a successful outcome. Other treatment options should be considered in those without any of these predictive factors.

Background: The purpose of the present paper was to investigate the clinical significance of thymidylate synthase (TS) expression in bladder cancer and its association with proliferation markers, such as p53, Ki-67, and proliferating cell nuclear antigen (PCNA)., Methods: Thymidylate synthase gene expression in 54 patients with bladder cancer was measured by the reverse transcription polymerase chain reaction (RT-PCR) method using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. The TS expression was also examined immunohistochemically. Immunohistochemical studies of p53, Ki-67, and PCNA expression were carried out to examine the correlation between TS expression and the expression of proliferation markers in the tumors. Prognostic and clinical outcome factors such as vascular invasion and distant metastasis were also examined along with TS expression., Results: Twenty-four patients with invasive bladder cancer had TS levels of 5.07 +/- 0.77 (mean +/- SE), while 30 patients with superficial bladder cancer had TS levels of 2.28 +/- 0.38. There was a significant difference in TS levels between invasive and superficial bladder cancer (P = 0.001). There was a positive correlation between TS expression and each proliferation marker of p53 (r = 0.686, P < 0.01), Ki-67 (r = 0.715, P < 0.0001) or PCNA expressions (r = 0.670, P < 0.0001) in these patients. Patients with high TS levels (TS > or = 2.63, the median value) had significantly higher rates of vascular invasion and distant metastasis. Kaplan-Meier analysis demonstrated that patients with high TS levels (TS > or = 2.63) had unfavorable prognosis compared to patients with low TS levels (TS < 2.63; P = 0.034). Furthermore, patients with high TS staining had a significantly poorer prognosis than those with low staining (P = 0.012)., Conclusion: Determination of level of TS expression may help in the selection of an appropriate treatment for bladder cancer because TS expression influences the biological characteristic of bladder tumor.

Background: Adrenomedullin (AM) has pluripotent activities and is involved in the regulation of vasomotor tone, cell differentiation and embryogenesis. However, the expression and pathophysiological role of AM has not been determined in human renal cell carcinoma (RCC)., Methods: Twenty-six RCC specimens and three cultured human RCC cell lines (A498, SN12C and KPK-13) were analyzed. Expression of AM was determined by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. The correlation between AM expression and microvessel count (MVC) in RCC specimens was examined to determine if AM plays a role in tumor angiogenesis. The correlation between the expression of AM and vascular endothelial growth factor (VEGF) was also investigated. Lastly, the effect of hypoxia upon the mRNA expression of AM, VEGF and hypoxia inducible factor-1 (HIF-1) by RCC cell lines was determined., Results: Immunohistochemistry indicated that AM and VEGF were primarily localized in the cytosol of RCC cells. AM and VEGF mRNA were detected in all RCC specimens and cultured RCC cell lines analyzed by RT-PCR. There was a positive correlation between AM mRNA expression and MVC (r = 0.516, P = 0.0062), and between VEGF mRNA expression and MVC (r = 0.485, P = 0.0111). We also observed a positive correlation between AM mRNA expression and VEGF mRNA expression (r = 0.552, P = 0.0029). Hypoxia significantly induced AM and VEGF mRNA expression, although the increase of the AM mRNA level (10.6-26.7 fold) was markedly greater than that of the VEGF mRNA level (1.5-1.9 fold)., Conclusion: These results suggest that hypoxia-induced AM plays a part in tumor angiogenesis in conjunction with VEGF and facilitates human RCC growth under hypoxic conditions.

Taxol is a microtubule-stabilizing agent which induces apoptosis in various cancer cells. In this study, we found that T24 cells derived from high grade human urinary bladder cancer were relatively resistant to taxol and that the IC50 value determined by a colorimetric WST-1 assay was 406.0 nM. Interestingly, cyclosporin A (CsA), an immunosuppressive drug, dramatically enhanced sensitivity to taxol, and the IC50 value was decreased to 47.5 nM in the presence of 1 microM CsA. KK47 cells derived from low grade human urinary bladder cancer showed high sensitivity to taxol with an IC50 value of 78.8 nM which decreased to 14.4 nM in the presence of 1 microM CsA. FK506, another immunosuppressive drug, also enhanced sensitivity to taxol. Furthermore, a concomitant loss of calcineurin activity was observed after the treatment of both cell lines with both CsA and FK506. Taxol induced apoptosis of the cells, as assessed by Hoechst 33258 staining and by the measurement of caspase 3 activity. Immunoblot analysis with an antibody against Bcl-2 phosphorylated at serine 70 demonstrated that taxol induced the phosphorylation of Bcl-2 with its enhancement in the presence of CsA. In addition, treatment of the cells with CsA significantly decreased the expression of Bcl-2 at both the protein and mRNA levels. These results suggest that the enhancement of taxol-induced apoptosis by immunosuppressive drugs is at least partly due to the inhibition of calcineurin activity and the loss of the antiapoptotic function of Bcl-2 via the enhancement of phosphorylation and the reduction of expression.

Background: Currently, alpha-blocker is becoming first-line drug therapy for benign prostatic hyperplasia (BPH). Although highly effective results are obtained with this therapy, a difference between the objective and subjective response rates is reported. To prevent unnecessary medical treatment and to predict the alpha-blocker response, we characterized the clinical features of alpha-blocker responders in men with BPH., Methods: Twenty-two men were consecutively enrolled in this study and received tamsulosin 0.2 mg once daily for 4-6 weeks. The primary measures of efficacy were maximum urinary flow rate (Q(max)) determined from the flow measurements and international prostate symptom score (IPSS). Those with an increase in Q(max) of > or = 30% from baseline and a decrease in IPSS of > or = 25% from baseline were defined as Q(max) responders and IPSS responders, respectively. Clinical findings such as age, pretreatment IPSS and Q(max), serum prostate-specific antigen (PSA), total prostate volume, transition zone (TZ) volume, TZ index and T(2)-weighted magnetic resonance image (MRI) of the prostate TZ were compared between responders and non-responders for both criteria., Results: In 17 of 22 (77.2%) patients IPSS improved by > or = 25%. In 9 of 22 (40.9%) patients Q(max) improved by > or = 30%. There were no differences in clinical findings between IPSS responders and non-responders. On the contrary, Q(max) responders showed smaller total prostate and TZ volumes, a smaller TZ index and a lower intensity of the TZ in MRI than Q(max) non-responders., Conclusions: Determination of the prostate volume and MRI findings of the inner prostate gland were useful in predicting Q(max) responders to the alpha-blocker in men with BPH. In contrast, there were no clinical characteristics of the IPSS responders. IPSS responders without a Q(max) response should be closely followed while continuing the alpha-blocker therapy for a long duration., (Copyright 2002 S. Karger AG, Basel)

Cytokines exert biological functions by activating Janus tyrosine kinases (JAKs), and JAK inhibitors JAB (also referred to as SOCS1 and SSI1) and CIS3 (SOCS3) play an essential role in the negative regulation of cytokine signaling. We have found that transgenic (Tg) mice expressing a mutant JAB (F59D-JAB) exhibited a more potent STAT3 activation and a more severe colitis than did wild-type littermates after treatment with dextran sulfate sodium. We now find that there is a prolonged activation of JAKs and STATs in response to a number of cytokines in T cells from Tg mice with lck promoter-driven F59D-JAB. Overexpression of F59D-JAB also sustained activation of JAK2 in Ba/F3 cells. These data suggested that F59D-JAB up-regulated STAT activity by sustaining JAK activation. To elucidate molecular mechanisms related to F59D-JAB, we analyzed the effects of F59D-JAB on the JAK/STAT pathway using the 293 cell transient expression system. We found that the C-terminal SOCS-box played an essential role in augmenting cytokine signaling by F59D-JAB. The SOCS-box interacted with the Elongin BC complex, and this interaction stabilized JAB. F59D-JAB induced destabilization of wild-type JAB, whereas overexpression of Elongin BC canceled this effect. Levels of endogenous JAB and CIS3 in T cells from F59D-JAB Tg-mouse were lower than in wild-type mice. We propose that F59D-JAB destabilizes wild-type, endogenous JAB and CIS3 by chelating the Elongin BC complex, thereby sustaining JAK activation.

An 82-year old man received total androgen blockade therapy (bilateral orchiectomy and 375 mg/day flutamide) for the treatment of stage C prostate cancer. Serum PSA levels were undetectable for 13 months and thereafter increased gradually. We administered estramustine phosphate sodium (EPS) instead of flutamide under the diagnosis of hormone refractory prostate cancer. EPS therapy was discontinued after 9 months because serum PSA levels increased again. Then, the patient complained of bilateral breast nodules and pain. Bilateral mammectomies were performed due to bilateral breast cancers which had been diagnosed by aspiration biopsies and radiographic examinations, but he died four months after the operations. Final pathological diagnosis was ductal adenocarcinoma of the breasts. Immunohistochemical study revealed expressions of PSA in the breast cancers. We diagnosed double cancers of the prostate and the breast because of the different expression patterns of progesterone receptor between them. We review the literatures and discuss the differential diagnosis of prostate cancer and PSA-producing breast cancer.

Previously, it has been demonstrated that the neurotrophins and their receptors are present in human prostate tissue, but neither their functional role nor localization is clearly understood. We studied the expression of neurotrophins and their receptors in prostate cancer. Between 1990 and 1999, 48 prostate cancer specimens were obtained from patients undergoing radical prostatectomy, of whom 25 received neoadjuvant hormonal therapy (NHT) and 23 were untreated. The specimens were analyzed immunohistochemically for neurotrophins (nerve growth factor, brain derived neurotrophic factor, neurotrophin 3, neurotrophin 4/5) and their receptors (TrkA, TrkB, TrkC, p75NTR). Immunohistochemical studies revealed that both benign and malignant prostate gland epithelial cells expressed the neurotrophins and their receptors to various degrees, but no obvious immunopositive reaction was observed in stromal cells. In benign epithelial cells, the neurotrophins were localized to secretory cells and the receptors were localized to basal cells. The neurotrophins, TrkA and TrkC were expressed to a similar extent in prostate cancer specimens obtained from patients both with and without NHT. In contrast, the expression of TrkB was down-regulated and the expression of p75NTR was up-regulated in prostate cancer after hormonal therapy. These findings suggest that neurotrophins are secreted by prostate cancer cells in an autocrine fashion. Neurotrophins may be involved, through their receptors, in the escape mechanism from cell death after androgen depletion found in prostate cancer.

Emphysematous cystitis is a rare disorder most commonly seen in patients with urinary tract infection and diabetes mellitus. We present a nondiabetic case of a 46-year-old woman with this entity following brain contusion., (Copyright 2000 S. Karger AG, Basel)

Malignant neurofibroma of the urinary bladder is a very rare entity and usually associated with von Recklinghausen's disease. We present the first case of sporadic malignant neurofibroma of the urinary bladder and a review of the literature., (Copyright 2000 S. Karger AG, Basel)

A 45-year-old man with spinal injury and diabetes mellitus who complained high fever and progressive enlargement of left intrascrotal mass visited to our hospital. Preoperative ultrasonography demonstrated epididymitis and abscess formation. Left high orchiectomy was performed because testicular tumor could not be denied. Epididymis was replaces by bright yellow mass associated with abscess and adhered to testis strongly. Histopathologically, the mass diagnosed xanthogranulomatous epididymitis consisted of foamy macrophages and chronic inflammatory cells. This is the first case in Japanese medical literature.

A simple technique for ligation and division of the dorsal vein complex during radical retropubic prostatectomy is described. The dorsal vein complex and anterior wall of the membranous urethra were collectively ligated with a "theta theta" suture using 1-0 catgut and then divided during radical retropubic prostatectomy. This technique prevents dislodgment of the catgut during the procedure, enables maximal preservation of the striated urethral sphincter, and guarantees a lower risk of postoperative urinary incontinence.

A 49-year-old woman had been on hemodialysis for 18 years. She presented with left back pain and macrohematuria. Radiologic studies demonstrated a left renal tumor with acquired cystic disease of the kidney. Her serum erythropoietin (EPO) level was 78.4 U/L despite no history of EPO supplementation. Left radical nephrectomy was performed. Pathologic examination revealed EPO-producing renal cell carcinoma. After surgery, the patient's serum EPO level decreased markedly to 15.1 U/L. The measurement of serum EPO levels may be useful for detecting and monitoring a recurrence of renal cell carcinoma with acquired cystic disease of the kidney in patients on long-term hemodialysis.

We report a rare case of infantile synchronous bilateral testicular teratoma treated by testis sparing surgery. Preoperative ultrasonography, tumor marker status and intraoperative findings were suggestive of benign neoplasia. Under these circumstances we performed high orchiectomy for the left testis and testis sparing surgery for the right. Surgical treatment of teratoma in childhood is controversial, especially when it occurs bilaterally. In this report we discuss testis sparing surgery as the treatment for this disease.

The Biopty-gun is a useful tool in conducting percutaneous renal biopsies, but bleeding is still a significant complication. To reduce the rate of severe bleeding complications, we attempted a new method of renal needle biopsy using a retrograde access technique. Retrograde puncture of the renal calyx was performed using the Lawson nephrostomy kit. The 18-gauge needle of the Bioptygun was inserted along the puncture wire and fired. A 7-french pigtail catheter was retained in the renal pelvis for a few days following the procedure. This biopsy is a promising and safe technique.

Vesicourethral anastomosis during radical retropubic prostatectomy is often difficult. We present a new simple technique using a Nélaton catheter to aid in accurate suture placement for vesicourethral anastomosis.

A 42-year-old man who complained progressive enlargement of an intrascrotal mass visited to our hospital. Preoperative sonography revealed multiple cystic masses adjacent to the left testis. Total surgical excision was performed. The cystic masses were arising from tunica vaginalis testis. Histopathologically, a cystic lymphangioma was diagnosed because of the morphological features and the immunohistochemical stainings of CD34 and Factor VIII related antigen which were observed positive reactions in endothelial cells of the cysts.

Background: The purpose of this study was to evaluate the muscarinic receptor subtypes expressed in rat bladder smooth muscle and characterize the muscarinic receptor-coupled phosphatidylinositol (PI) hydrolysis in order to clarify the first step of bladder smooth muscle contraction., Methods: Expressions of mRNAs of muscarinic receptor subtypes were examined by Northern blot analysis. Changes in the mass of inositol 1,4,5-trisphosphate (IP3) and the inhibitory effects of muscarinic subtype specific antagonists on PI hydrolysis were determined after carbachol stimulation., Results: mRNAs of m2 and m3 genes, encoding M2 and M3 receptors, were expressed in rat bladder smooth muscle. Carbachol produced a rapid increase of IP3, which returned to the basal level within 30 seconds. 4-Diphenylacetoxyl-N-methylpiperidine methiodide (4-DAMP; M1 and M3 antagonist) strongly inhibited the PI hydrolysis, but methoctramine (M2 antagonist) partially inhibited it at 10(-4) mol/L. The IC50 value for atropine was 9.5 x 10(-9) mol/L, for pirenzepine 6.4 x 10(-6) mol/L, and for 4-DAMP 1.5 x 10(-7) mol/L., Conclusion: M2 and M3 receptors are expressed in rat urinary bladder. Only M3 receptor was involved in the production of IP3, which might induce the initial phase of contractile response in rat bladder smooth muscle after carbachol stimulation.

Background: Platelet-activating factor (PAF) is a bioactive phospholipid which is a potent hypotensive agent. To investigate the role of PAF in renovascular hypertension, we determined the PAF concentration and its production level assessed by the activity of cholinephosphotransferase (CPT) in renal tissue and examined the effect of a PAF antagonist on the mean arterial pressure (MAP) in control and two-kidney with one clipped (2K1C) hypertensive rats., Materials and Methods: The concentration of PAF and CPT in the renal medulla and cortex were determined by radioassay. Also, the effect of a PAF antagonist, CV-6209, on MAP was also examined in both 2K1C hypertensive and normal control rats., Results: The PAF concentration and CPT activity were significantly higher in the medulla than in the cortex in both 2K1C hypertensive and normal control rats, and both values in the medulla were also significantly higher in the clipped kidney than in the contralateral unclipped kidney or in control rat kidneys. We also observed a significant negative correlation between the PAF concentration in the medulla, and the medulla weight in the clipped kidney of 2K1C hypertensive rats. Infusion of the PAF antagonist, CV-6209, did not affect MAP in 2K1C hypertensive rats, but was significantly increased (P < 0.05) in control rats., Conclusions: These findings suggest that PAF, whose production is induced by renal ischemia due to renal artery stenosis, plays an important role in the renomedullary vasodepressor system, but the effect of PAF as a vasodilator in the peripheral vessels is limited in 2K1C hypertension.

We report 2 cases of simple renal cysts which were marsupialized with 2 laparoscopic approaches involving either transperitoneal, with reflection of the colon medially or dissection through the mesocolon, and a case of a multilocular renal cyst which was treated by the retroperitoneal approach. Although laparoscopic unroofing of a renal cyst is a safe and effective alternative to open surgical techniques, the transperitoneal approach should only be used for simple renal cysts. The retroperitoneal approach for complicated renal cysts may be indicated if preoperative examinations exclude the possibility of malignancy.