Metalloproteinase processing of HBEGF is a proximal event in the response of human aortic endothelial cells to oxidized phospholipids.

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease initiated by monocyte recruitment and retention in the vessel wall. An important mediator of monocyte endothelial interaction is the chemokine interleukin (IL)-8. The oxidation products of phospholipids, including oxidized 1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine (Ox-PAPC), accumulate in atherosclerotic lesions and strongly induce IL-8 in human aortic endothelial cells (HAECs). The goal of this study was to identify the proximal events leading to induction of IL-8 by Ox-PAPC in vascular endothelial cells. METHODS AND RESULTS: In a systems genetics analysis of HAECs isolated from 96 different human donors, we showed that heparin-binding EGF-like growth factor (HBEGF) transcript levels are strongly correlated to IL-8 induction by Ox-PAPC. The silencing and overexpression of HBEGF in HAECs confirmed the role of HBEGF in regulating IL-8 expression. HBEGF has been shown to be stored in an inactive form and activation is dependent on processing by a dysintegrin and metalloproteinases (ADAM) to a form that can activate the epidermal growth factor (EGF) receptor. Ox-PAPC was shown to rapidly induce HBEGF processing and EGF receptor activation in HAECs. Using siRNA we identified 3 ADAMs that regulate IL-8 induction and directly demonstrated that Ox-PAPC increases ADAM activity in the cells using a substrate cleavage assay. We provide evidence for one mechanism of Ox-PAPC activation of ADAM involving covalent binding of Ox-PAPC to cysteine on ADAM. Free thiol cysteine analogs showed inhibition of IL-8 induction by Ox-PAPC, and both a cysteine analog and a cell surface thiol blocker strongly inhibited ADAM activity induction by Ox-PAPC. Using microarray analyses, we determined that this ADAM pathway may regulate at least 30% of genes induced by Ox-PAPC in HAECs. CONCLUSIONS: This study is the first report demonstrating a role for the ADAM-HBEGF-EGF receptor axis in Ox-PAPC induction of IL-8 in HAECs. These studies highlight a role for specific ADAMs as initiators of Ox-PAPC action and provide evidence for a role of covalent interaction of Ox-PAPC in activation of ADAMs.

A Case Series of Preoperative Endovascular Stenting in Patients Undergoing Postchemotherapy Resection of Complex Oncologic Masses.

The incidence of complications for postchemotherapy (PC) resections is high. Severe intraoperative hemorrhage during retroperitoneal lymph node dissection is of significant concern. The safety and efficacy of endovascular technology in vascular surgery have been demonstrated, but no studies have incorporated endovascular stenting in preoperative planning. We present a case series of four patients with nonseminomatous germ cell tumors who underwent preoperative endovascular stenting to identify and protect major vascular structures encased by complex PC tumors. We measured operative time, estimated blood loss, intraoperative transfusion requirement, length of stay, and postoperative complications. In all cases, surgery progressed without full continuous identification of the major vascular structures and their branches because of the assurance that hemorrhage would be controlled should they be breached. PATIENT SUMMARY: Preoperative endovascular stenting may be an effective approach for minimizing intraoperative hemorrhage and operative time in patients undergoing bulky postchemotherapy dissection. Additional studies are needed to better clarify patient selection criteria and quantify the efficacy and adverse consequences.

VesEcho Training System: Suprapubic Catheterization under Ultrasound Guidance.

INTRODUCTION: Suprapubic catheterization is a fundamental skill for urology residents and trainees. Ultrasound guidance for this procedure is effective for minimizing complications and the British Association of Urological Surgeons guideline recommends use of ultrasound for suprapubic catheterization whenever possible. We developed a novel, cost-effective and sonographically accurate training model for suprapubic catheterization and incorporated it into our resident training curriculum. METHODS: The model consists of the 4 components of the bladder (water balloon), a pelvic bone replica and rectus fascia (nonrebreather masks), all housed within an ultrasound compatible gelatin mold. The model was tested during a resident training course to facilitate instruction of suprapubic catheterization. Surveys were administered before and after training to 13 participating urology residents, assessing the model's anatomical and sonographic realism as well as the utility of the curriculum in their education. RESULTS: The simulator model received a mean score of 4.2 out of 5 (SD 0.6, range 3 to 5) for anatomical realism and 4.4 out of 5 for sonographic realism (SD 0.5, range 4 to 5). The value of the simulator as a training tool was rated 4.7 and the overall value of the training course was rated 5 of 5. Regarding change in overall comfort with the procedure, mean total scores (out of 25) significantly increased for all residents after the training course (14.6 to 19.7, 5.1-point increase, p <0.001). CONCLUSIONS: Our novel simulation model and didactic curriculum received positive evaluations from urology residents and increased their comfort with ultrasound guided suprapubic catheterization. It is a sustainable teaching tool and can easily be incorporated into any urology training curriculum.

Fournier's gangrene: a model for early prediction.

Early diagnosis remains the cornerstone of management of Fournier's gangrene. As a result of variable progression of disease, identifying early predictors of necrosis becomes a diagnostic challenge. We present a scoring system based on objective admission criteria, which can help distinguish Fournier's gangrene from nonnecrotizing scrotal infections. Ninety-six patients were identified, 38 diagnosed with Fournier's gangrene and 58 diagnosed with scrotal cellulitis or abscess. Statistical analyses comparing admission vital signs, laboratory values, and imaging studies were performed and Classification and Regression Tree analysis was used to construct a scoring system. Admission heart rate greater than 110 beats/minute, serum sodium less than 135 mmol/L, blood urea nitrogen greater than 15 mg/dL, and white blood cell count greater than 15 × 10(3)/µL were significant predictors of Fournier's gangrene. Using a threshold score of two or greater, our model differentiates patients with Fournier's gangrene from those with nonnecrotizing infections with a sensitivity of 84.2 per cent. Only 34.2 per cent of patients with Fournier's gangrene had hard signs of necrotizing infection on admission, which were not observed in patients with nonnecrotizing infections. Objective admission criteria assist in distinguishing Fournier's gangrene from scrotal cellulitis or abscess. In situations in which results of the physical examination are ambiguous, this scoring system can heighten the index of suspicion for Fournier's gangrene and prompt rapid surgical intervention.

Bone scan overuse in staging of prostate cancer: an analysis of a Veterans Affairs cohort.

OBJECTIVES: To determine the use and subsequent yield of bone scan imaging in a contemporary Veterans Affairs (VA) cohort of men with prostate cancer. With contemporary widespread prostate-specific antigen (PSA) screening, more patients are being diagnosed with low- and intermediate-risk prostate cancer, reducing the need and yield of bone scan imaging. METHODS: We retrospectively reviewed the charts of 1598 men diagnosed with prostate cancer from 1998 to 2004 at the Greater Los Angeles and Long Beach VA Medical Centers. We used univariate and multivariate analyses to measure the association between patient (age, race, and comorbidities) and tumor (PSA, clinical stage, Gleason grade) characteristics with bone scan use and subsequent positivity. We conducted the analysis for scans for the entire cohort and those with low and high risk of metastatic disease. RESULTS: Of 519 men with low-risk disease, 132 (25%) underwent bone scan imaging, none with positive findings. On multivariate analysis for the entire cohort, younger age, Long Beach VA site, increasing PSA level (≥10 ng/mL), clinical stage (cT2 or greater), and Gleason score (≥7) were all positively associated with bone scan use; however, only PSA level ≥20 ng/mL, clinical stage cT3 or greater, and Gleason score ≥4 + 3 corresponded with positivity. A bone scan positivity rate of ≥10% was limited to men with clinical stage cT3 or greater, Gleason score of ≥8, or PSA level of ≥20 ng/mL. CONCLUSIONS: Although decreasing in incidence with time, our results demonstrate extensive overuse of bone scan imaging among VA patients with low-risk prostate cancer. These patterns of overuse for men with low-risk cancer, yielding no positive findings, result in unnecessary patient anxiety and significant economic waste for the VA Healthcare System.

Overtreatment of men with low-risk prostate cancer and significant comorbidity.

BACKGROUND: Men with low-risk prostate cancer and significant comorbidity are susceptible to overtreatment. The authors sought to compare the impact of comorbidity and age on treatment choice in men with low-risk disease. METHODS: The authors sampled 509 men with low-risk prostate cancer diagnosed at the Greater Los Angeles and Long Beach Veterans Affairs Medical Centers between 1997 and 2004. Rates of aggressive treatment (radical prostatectomy, radiation therapy, brachytherapy) were determined among men of different ages and with different Charlson comorbidity scores. Multivariate modeling was used to determine the influence of both variables in predicting nonaggressive treatment, and Cox proportional hazards analysis was used to compare the risk of other-cause mortality among groups according to Charlson score and age. RESULTS: Men with Charlson scores ≥ 3 were treated aggressively in 54% of cases (30 of 56 men), while men aged >75 years at diagnosis were treated aggressively in 16% of cases (7 of 44 men). In multivariate analysis, age >75 years was a much stronger predictor of nonaggressive treatment (relative risk, 12.0; 95% confidence interval [CI], 5.4-28.3) than a Charlson score ≥ 3 (relative risk, 2.0; 95% CI, 1.3-2.9). In survival analysis, men with Charlson scores ≥ 3 had an 8-fold increased risk (hazard ratio, 8.4; 95% CI, 4.2-16.6) and 70% probability of other-cause mortality at 10 years, whereas age >75 years was associated with a 5-fold increased risk (hazard ratio, 4.9; 95%CI, 1.7-13.8) and a 24% probability of other-cause mortality. CONCLUSIONS: Men with significant comorbidity often were overtreated for low-risk prostate cancer. Like advanced age, significant comorbidity should be a strong relative contraindication to aggressive treatment in men with low-risk disease.

Ox-PAPC activation of PMET system increases expression of heme oxygenase-1 in human aortic endothelial cell.

Oxidized-1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine (Ox-PAPC) has been demonstrated to accumulate in atherosclerotic lesions and regulates expression of more than 1,000 genes in human aortic endothelial cell (HAEC). Among the most highly induced is heme oxygenase-1 (HO-1), a cell-protective antioxidant enzyme, which is sensitively induced by oxidative stress. To identify the pathway by which Ox-PAPC induces HO-1, we focused on the plasma membrane electron transport (PMET) complex, which contains ecto-NADH oxidase 1 (eNOX1) and NADPH:quinone oxidoreductase 1 (NQO1) and affects cellular redox status by regulating levels of NAD(P)H. We demonstrated that Ox-PAPC and its active components stimulated electron transfer through the PMET complex in HAECs from inside to outside [as determined by extracellular 2-(4-iodophenyl)-3-(44-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) reduction] and from outside to inside of the cell (as determined by intracellular NBT reduction). Chemical inhibitors of PMET system and siRNAs to PMET components (NQO1 and eNOX1) significantly decreased HO-1 induction by Ox-PAPC. We present evidence that Ox-PAPC activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in HAEC plays an important role in the induction of HO-1 and PMET inhibitors blocked Nrf2 activation by Ox-PAPC. We hypothesized that PMET activation by Ox-PAPC causes intracellular NAD(P)H depletion, which leads to the increased oxidative stress and HO-1 induction. Supporting this hypothesis, cotreatment of cells with exogenous NAD(P)H and Ox-PAPC significantly decreased oxidative stress and HO-1 induction by Ox-PAPC. Taken together, we demonstrated that the PMET system in HAEC plays an important role in the regulation of cellular redox status and HO-1 expression by Ox-PAPC.