IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis.

Ureteral obstruction results in renal fibrosis in part due to inflammatory injury. The role of interleukin-18 (IL-18), an important mediator of inflammation, in the genesis of renal fibrosis was studied using transgenic mice overexpressing human IL-18-binding protein. In addition, HK-2 cells were analyzed following direct exposure to IL-18 compared to control media. Two weeks after ureteral obstruction, the kidneys of wild-type mice had a significant increase in IL-18 production, collagen deposition, alpha-smooth muscle actin and RhoA expression, fibroblast and macrophage accumulation, chemokine expression, and transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) production, whereas E-cadherin expression was simultaneously decreased. The transgenic mice with neutralized IL-18 activity exhibited significant reductions in these indicators of obstruction-induced renal fibrosis and epithelial- mesenchymal transition, without demonstrating alterations in TGF-beta1 or TNF-alpha activity. Similarly, the HK-2 cells exhibited increased alpha-smooth muscle actin expression and collagen production, and decreased E-cadherin expression in response to IL-18 stimulation without alterations in TNF-alpha or TGF-beta1 activity. Our study demonstrates that IL-18 is a significant mediator of obstruction-induced renal fibrosis and epithelial- mesenchymal transition independent of downstream TGF-beta1 or TNF-alpha production.

Tap water irrigation and additives to optimize success with the Malone antegrade continence enema: the Indiana University algorithm.

PURPOSE: We report the long-term effectiveness of standard tap water for Malone antegrade continence enema irrigation as well as our algorithm for managing refractory constipation/fecal incontinence in a large single institution experience. MATERIALS AND METHODS: We retrospectively reviewed the charts of 256 Malone antegrade continence enema procedures performed for chronic constipation and/or incontinence due to neuropathic bowel. Continence, type of fluid used to irrigate the colon, volume of flushes and the need for additives were recorded and a database was created. All patients were initially treated with tap water irrigation. Those in whom tap water irrigation failed underwent complete bowel cleanout with enemas and GoLYTELY via the Malone antegrade continence enema, followed by a gradual increase in irrigation volume. If this was unsuccessful, additives of mineral oil, MiraLAX or glycerin were added to the irrigant daily. RESULTS: A total of 236 patients with at least 6 months of followup were included in this study. Mean age at surgery was 10.2 years (range 2 to 36) and mean followup in the entire cohort was 50 months (range 6 to 115). Mean volume of colonic flushes was 642 ml (range 100 to 1,000). Of the patients 196 (83.1%) achieved total fecal continence with tap water flushes alone. Using additives increased the overall continence rate to 93.6% (p <0.0001). CONCLUSIONS: The Malone antegrade continence enema procedure has proved invaluable for treating children with refractory constipation. When additives are used in conjunction with water flushes, they can significantly improve the overall fecal continence rate in partially continent children.

The Malone antegrade continence enema: single institutional review.

PURPOSE: We report the long-term outcome of the Malone antegrade continence enema procedure in the treatment of chronic constipation and fecal incontinence in children with neuropathic bowel. MATERIALS AND METHODS: We performed a retrospective chart review of 256 Malone antegrade continence enema procedures. Patient age at surgery, bowel segment used, location of stoma, number and type of revisions required, and fecal continence were documented and a database was created. RESULTS: A total of 236 patients with at least 6 months of followup are included in this report. There were 172 in situ appendicocecostomies, 23 split appendix channels, 9 appendicocecostomies with cecal extension, 22 Yang-Monti ileocecostomies and 10 colon flap channels performed. A total of 112 males (47%) and 124 females (53%) were included in the study. Median patient age at surgery was 9 years (range 2 to 36) and median followup for the entire cohort was 50 months (6 to 115). A total of 56 surgical revisions were performed in 39 patients (17%). Median time to first revision was 9.5 months (range 1 to 105). Stomal stenosis occurred in 32 patients (14%). Overall, surgical revisions were required in 14% of in situ appendix channels (24 of 172), 22% of split appendix channels (5 of 23), 33% of appendix channels with cecal extension (3 of 9), 18% of Yang-Monti Malone antegrade continence enema channels (4 of 22) and 30% of colon flap channels (3 of 10). Independent of channel technique, surgical revisions were required in 15% of umbilical stomas and 18% of lower quadrant stomas (p = 0.516). Two patients had minimal stomal leakage, and 94% (221 of 236) achieved fecal continence with irrigations. CONCLUSIONS: The long-term results of the Malone antegrade continence enema channel in a large cohort of patients with neuropathic bowel and chronic constipation are encouraging. Of the patients 17% will require revision surgery, and patients/parents should be counseled accordingly. In our series in situ appendicocecostomy had the lowest revision rate on long-term followup, although the difference was not statistically significant (p = 0.226).

The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX.

BACKGROUND/AIMS: The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. METHODS: Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. RESULTS: Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. CONCLUSIONS: WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.

Cytokines in epithelial-mesenchymal transition: a new insight into obstructive nephropathy.

PURPOSE: Tubulointerstitial fibrosis is the final common pathway to end stage renal disease. The pathophysiology of renal fibrosis involves fibroblast proliferation, macrophage infiltration, the elaboration of cytokines and other proinflammatory mediators, and an imbalance in extracellular matrix deposition and degradation. Although the exact origin of activated fibroblasts remains uncertain, emerging evidence indicates that mature tubular epithelial cells are capable of transforming into myofibroblasts under pathological conditions, a process that is called epithelial-mesenchymal transition. MATERIALS AND METHODS: We reviewed the pertinent literature from January 1980 through June 2007 with regard to the contribution of epithelial-mesenchymal transition to renal fibrogenesis. RESULTS: Epithelial-mesenchymal transition is an orchestrated, highly regulated process that proceeds in stepwise fashion and appears to contribute significantly to renal fibrosis and the progression of chronic renal disease. Several cytokines and growth factors regulate epithelial-mesenchymal transition, of which transforming growth factor-beta1 is the most studied. CONCLUSIONS: Epithelial-mesenchymal transition is a cellular mechanism that has long been recognized as a central feature of normal development. However, increasing evidence implicates epithelial-mesenchymal transition in the pathophysiology of tubulointerstitial fibrosis and chronic renal disease. Recent insights into the molecular events and intrinsic signaling pathways that are active during epithelial-mesenchymal transition have evoked novel therapeutic strategies aimed at halting the onset and progression of chronic renal fibrosis.

Specimen extraction with a surgical glove during laparoscopic radical prostatectomy.

INTRODUCTION AND OBJECTIVE: Cost containment during techniques of laparoscopic radical prostatectomy remains an ongoing concern. We present a cost-effective alternative technique of specimen extraction using a surgical glove. MATERIALS AND METHODS: We describe an alternative technique of prostate removal using a surgical glove in seven patients who underwent laparoscopic radical prostatectomy using a robotic-assisted technique. RESULTS: The glove extraction technique was successful in all seven patients for which the method was attempted without complication. CONCLUSION: Similar to commercially available devices, a surgical glove provides a reliable straightforward means of specimen extraction during laparoscopic radical prostatectomy.

Associations with contralateral recurrence following nephrectomy for renal cell carcinoma using a cohort of 2,352 patients.

PURPOSE: We determined the incidence of and factors associated with the development of renal cell carcinoma (RCC) in the contralateral kidney after nephrectomy for localized RCC. MATERIALS AND METHODS: Between 1970 and 2000, 2,352 patients with sporadic, localized unilateral RCC and a normal contralateral kidney underwent nephrectomy for RCC. Cancer specific survival rates were estimated using the Kaplan-Meier method. Univariate Cox proportional hazards models were used to determine associations with outcome. RESULTS: Of the 2,352 patients studied 28 (1.2%) had RCC in the contralateral kidney, including 20 with clear cell and 8 with papillary RCC. Mean time from primary surgery to contralateral recurrence was 5.2 years (median 4.8, range 0 to 18) for clear cell RCC compared with 5.6 years (median 1.3, range 0 to 21) for papillary cell RCC. Positive surgical margins (risk ratio 14.23, p = 0.010) and multifocality (risk ratio 5.74, p = 0.019) were significantly associated with contralateral recurrence following nephrectomy for clear cell RCC, while nuclear grade (risk ratio for grades 3/4 vs 1/2, 4.78, p = 0.040) was significantly associated with contralateral recurrence following nephrectomy for papillary RCC. In patients with clear cell RCC estimated cancer specific survival rates 1, 3, and 5 years following contralateral recurrence were 93.8%, 80.2% and 72.9%, respectively. CONCLUSIONS: In patients with localized RCC and a normal contralateral kidney who underwent nephrectomy for RCC positive surgical margins and multifocality were significant predictors of contralateral recurrence for clear cell RCC, while nuclear grade was a significant predictor of contralateral recurrence for papillary RCC.

Urinary matrix calculi: our experience at a single institution.

PURPOSE: Matrix stones are an uncommon form of urinary calculi and may be mistaken for tumors involving the renal collecting system, thereby presenting a diagnostic and therapeutic dilemma to the practicing urologist. MATERIALS AND METHODS: From 1980 to 2003 we identified 5 patients with urinary matrix stones referred to our tertiary medical center for evaluation and treatment. RESULTS: All 5 cases had complex clinical and radiographic features at presentation. We outline the clinical presentations, imaging findings and management, and review the literature of matrix stone disease. CONCLUSIONS: A high index of suspicion is required in diagnosing matrix calculi in addition to carefully selected radiographic imaging. Due to their variable appearance in standard radiological studies, the evaluation of matrix stones may require invasive techniques such as ureteroscopy for accurate diagnosis. Percutaneous removal is the primary treatment modality to render patients stone-free.