Lycopene in the prevention of renal cell cancer in the TSC2 mutant Eker rat model.

Renal cell carcinoma (RCC) is the most frequent upper urinary tract cancer in humans and accounts for 80-85% of malignant renal tumors. Eker rat represents a unique animal model to study RCC since these rats develop spontaneous renal tumors and leiomyoma, which may be due to tuberous sclerosis 2 (TSC2) mutation resulting in the activation of the mammalian target of rapamycin (mTOR) pathway. This study examines the role of a lycopene-rich diet in the development of RCC in the TSC2 mutant Eker rat model. Ten-week old female Eker rats (n=90) were assigned in equal numbers to receive 0, 100 or 200mg/kg of lycopene as part of their daily diet. After 18 months the rats were sacrificed and the kidneys were removed. Immunohistochemical staining with antibodies against mTOR, phospho-S6 and EGFR were performed, as well as hematoxylin-eosin staining for histologic examination of the tumors. Tumors were counted and measured in individual kidneys. Presence of tumor decreased from 94% in control animals to 65% in the experimental group, but the difference was not statistically significant (P<0.12). However, mean numbers of renal carcinomas were statistically significantly decreased in the lycopene-treated rats (P<0.008) when compared to untreated controls. In the lycopene group, tumor numbers decreased (P<0.002) and the numbers tended to decrease linearly (P<0.003) as supplemental lycopene increased from 0 to 200. Control rats fed only basal diet had a greater length of tumors (23.98 mm) than rats fed lycopene supplement groups (12.90 mm and 11.07 mm) (P<0.05). Moreover tumor length decreased (P<0.02) and tumor length tended to decrease linearly (P<0.03) as supplemental lycopene increased from 0 to 200mg/kg. All tumors showed strong staining with antibodies against mTOR, phospho-S6 and EGFR. In conclusion, dietary supplementation with lycopene attenuates the development of renal cell cancers in the predisposed TSC2 mutant Eker rat model. These results suggest that lycopene may play a role in the prevention of RCC.

Validation of a standardized mapping system of the hip joint for radial MRA sequencing.

OBJECTIVE: Intraarticular gadolinium-enhanced magnetic resonance arthrography (MRA) is commonly applied to characterize morphological disorders of the hip. However, the reproducibility of retrieving anatomic landmarks on MRA scans and their correlation with intraarticular pathologies is unknown. A precise mapping system for the exact localization of hip pathomorphologies with radial MRA sequences is lacking. Therefore, the purpose of the study was the establishment and validation of a reproducible mapping system for radial sequences of hip MRA. MATERIALS AND METHODS: Sixty-nine consecutive intraarticular gadolinium-enhanced hip MRAs were evaluated. Radial sequencing consisted of 14 cuts orientated along the axis of the femoral neck. Three orthopedic surgeons read the radial sequences independently. Each MRI was read twice with a minimum interval of 7 days from the first reading. The intra- and inter-observer reliability of the mapping procedure was determined. RESULTS: A clockwise system for hip MRA was established. The teardrop figure served to determine the 6 o'clock position of the acetabulum; the center of the greater trochanter served to determine the 12 o'clock position of the femoral head-neck junction. The intra- and inter-observer ICCs to retrieve the correct 6/12 o'clock positions were 0.906-0.996 and 0.978-0.988, respectively. CONCLUSIONS: The established mapping system for radial sequences of hip joint MRA is reproducible and easy to perform.

S-adenosyl-L-methionine inhibits collagen secretion in hepatic stellate cells via increased ubiquitination.

BACKGROUND: Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) components that disrupt normal liver microcirculation and lead to organ injury. Hepatic stellate cells (HSCs), following transdifferentiation, are the central mediators of hepatic fibrosis through increased secretion of ECM components, including type I collagen. AIMS: The mechanism(s) by which the antioxidant S-adenosyl-L-methionine (SAMe) acts to modulate type I collagen secretion in activated HSCs was examined. METHODS: Hepatic stellate cells were culture-activated for 13-15 days and treated with SAMe. Type I collagen, proteasomal activity and resident endoplasmic reticulum (ER) protein [78-kDa glucose-regulated protein (Grp78) and protein disulphide isomerase (PDI)] expression were measured. Nuclear factor-κB (NF-κB) activity, and its role in SAMe-mediated collagen inhibition, was determined. Type I collagen polyubiquitination was examined. RESULTS: S-adenosyl-L-methionine significantly inhibited type I collagen secretion without significant changes in type I collagen mRNA expression. SAMe also increased NF-κB activity, and blocking NF-κB activity using a dominant-negative IκBα abolished the SAMe-mediated type I collagen secretion. Examination of the post-transcriptional fate of procollagen demonstrated that SAMe treatment led to intracellular type I collagen polyubiquitination accompanied by diminution of proteasomal activity. Expression of Grp78 and PDI (resident ER proteins) were significantly decreased by SAMe treatment. CONCLUSIONS: S-adenosyl-L-methionine inhibits collagen processing leading to increased ubiquitination and decreased secretion. These findings represent a novel mechanism for modulating type I collagen expression in activated HSCs.

Sudden cardiac death in young athletes and nonathletes.

PURPOSE OF REVIEW: This article will review the incidence and most common causes of sudden cardiac death (SCD) in healthy young adults, including competitive athletes, as well as members of the general population. RECENT FINDINGS: SCD is rare but devastating in a young individual. The incidence of SCD in the young ranges from as low as 0.4 per 100,000 patient-years to as high as 13.4 per 100,000 patient-years. SCD occurs in all populations, not only in athletes. SUMMARY: Whether SCD is more common in athletes is the cause of continued debate stemming from conflicting data. Hypertrophic cardiomyopathy is the most common underlying cause of SCD in young athletes in most series; however, in nonathletic populations, the underlying causes of SCD are more varied.

Physiologic impact of closed-system endotracheal suctioning in spontaneously breathing patients receiving mechanical ventilation.

BACKGROUND: Endotracheal suctioning is required but can have adverse effects, and could affect cardiorespiratory variables that are used to predict whether the patient is ready for extubation. METHODS: In a prospective cohort study in a university hospital's medical intensive care unit, we measured the impact of closed-system suctioning on cardiopulmonary variables in spontaneously breathing patients weaning from mechanical ventilation. All spontaneously breathing, mechanically ventilated patients were screened for enrollment at the initiation of weaning from mechanical ventilation. Before, during, and after standardized closed-system endotracheal suctioning we measured minute volume, heart rate, arterial oxygen saturation, mean arterial pressure, respiratory frequency, oxygen saturation, and tidal volume. RESULTS: Twenty-nine patients were enrolled after a median of 5 (interquartile range [IQR] 3-9) ventilator days. Twenty-five patients (86%) were spontaneously breathing on pressure-support ventilation when suctioned. The median post-suctioning recovery time was > 5 min for minute volume, tidal volume, respiratory rate, and ratio of respiratory rate to tidal volume. The post-suctioning median values of the maximum deviations in the ventilatory variables were clinically important: minute volume -2.4 (IQR 1.6-3.7) L/min, respiratory rate 8 (IQR 2-14) breaths/min, tidal volume -175 (108-220) mL. Heart rate, mean arterial pressure, and oxygen saturation increased after suctioning (P < .05), but the increases were not clinically important. CONCLUSIONS: Post-suctioning changes in the measured variables persisted longer in these spontaneously breathing patients weaning from mechanical ventilation than in patients who are sedated and paralyzed. The effects of suctioning on cardiopulmonary function should be considered in practice and during the design of future studies on weaning and extubation prediction variables.

Conditional Deletion of Eaf1 Induces Murine Prostatic Intraepithelial Neoplasia in Mice.

ELL-associated factor 1 is a transcription elongation factor that shares significant homology and functional similarity to the androgen-responsive prostate tumor suppressor ELL-associated factor 2. EAF2 is frequently down-regulated in advanced prostate cancer and Eaf2 deletion in the mouse induced the development of murine prostatic intraepithelial neoplasia. Here we show that similar to EAF2, EAF1 is frequently down-regulated in advanced prostate cancer. Co-downregulation of EAF1 and EAF2 occurred in 40% of clinical specimens with Gleason score >7. We developed and characterized a murine model of prostate-epithelial specific deletion of Eaf1 in the prostate and crossed it with our previously generated mouse with conventional deletion of Eaf2. The prostates of Eaf1 deletion mice displayed murine prostatic intraepithelial neoplasia lesions with increased proliferation and inflammation. Combined deletion of Eaf1 and Eaf2 in the murine model induced an increased incidence in mPIN lesions characterized by increased proliferation and CD3+ T cells and CD19+ B cells infiltration compared to individual deletion of either Eaf1 or Eaf2 in the murine prostate. These results suggest that EAF1 may play a tumor suppressive role in the prostate. Cooperation between EAF1 and EAF2 may be important for prostate maintaining prostate epithelial homeostasis, and concurrent loss of these two tumor suppressors may promote prostate tumorigenesis and progression.

Concurrent EAF2 and ELL2 loss phenocopies individual EAF2 or ELL2 loss in prostate cancer cells and murine prostate.

Elongation factor for RNA polymerase II 2 (ELL2) and ELL-associated factor 2 (EAF2) are two functionally related androgen responsive gene-encoded proteins with prostate tumor suppressor characteristics. EAF2 and ELL2 have both been shown to be down-regulated in advanced prostate cancer, and mice with either Eaf2 or Ell2 deficiency developed murine prostatic intraepithelial neoplasia (mPIN), increased cellular proliferation and increased vascularity. Functional studies have revealed that EAF2 and ELL2 can bind to each other and have similar roles in regulating cell proliferation, angiogenesis and prostate homeostasis. Here, cell line experiments showed that knockdown of EAF2 or ELL2 induced an increase in proliferation and migration in C4-2 and 22Rv1 prostate cancer cells. Concurrent knockdown of EAF2 and ELL2 increased proliferation and migration similarly to the loss of EAF2 or ELL2 alone. Mice with homozygous deletion of Ell2 or heterozygous deletion of Eaf2 developed mPIN lesions characterized by increased epithelial proliferation, intraductal microvessel density, and infiltrating intraductal CD3-positive T-cells compared to wild-type controls. Mice with combined heterozygous deletion of Eaf2 and Ell2 developed mPIN lesions that were similar to those observed in mice with deficiency in Eaf2 or Ell2 alone. These results suggest that EAF2 and ELL2 have similar functions and are likely to require each other in their regulation of prostate epithelial cell proliferation and migration in prostate cancer cells as well as their tumor suppressive properties in the murine prostate.

Salvage Surgery After Renal Mass Ablation.

Thermal ablative techniques represent treatment options for patients with small renal masses who are not candidates for surgery. The oncologic efficacy of ablation has not been compared in a randomized fashion with nephron-sparing surgery, and the urologist must be knowledgeable regarding the workup and treatment of patients with suspected residual or recurrent tumor following these therapies. Surveillance of patients with tumor recurrence after ablation may be indicated in select circumstances. When patients are deemed appropriate for salvage therapy, most undergo a repeat course of the same ablative modality. Salvage surgery is possible but often complicated by the prior ablative techniques.

Contemporary Trends in the Inpatient Management of Fournier's Gangrene: Predictors of Length of Stay and Mortality Based on Population-based Sample.

OBJECTIVE: To describe clinical management of Fournier's gangrene and to characterize predictive factors associated with inpatient mortality and extended hospital stay. MATERIALS AND METHODS: The National Inpatient Sample was queried from 2004 to 2012 based on the International Classification of Diseases, Ninth Revision, Clinical Modification procedural and diagnosis codes. Patients admitted for Fournier's gangrene who underwent debridement were selected. Multivariate logistic regression analysis was performed to identify predictors of inpatient mortality and extended hospital stay. RESULTS: A total of 9249 patients were identified for a weighted estimate of 43,146 cases. Inpatient mortality was 4.7%. The median length of stay was 9 days (interquartile range 5-17 days). The most common procedure in addition to debridement was a complex closure (8.82%), followed by suprapubic tube placement (5.70%) and fecal diversion (4.68%). Increasing age, yearly hospital volume >10 cases, and Medicaid insurance status were associated with increased risk of mortality. Increasing age, teaching hospital status, increasing number of comorbidities, and Medicaid as a payor were predictive of increased hospital stay. Suprapubic tube placement (odds ratio [OR] 2.8 [95% confidence interval {CI} 1.92-4.07], P ≤ .001), fecal diversion (OR 11.1 [95% CI 6.20-19.7], P ≤ .001), and complex wound closure (OR 4.89 [95% CI 3.97-6.89], P ≤ .001) were also predictive of increased length of stay. CONCLUSION: Identifiable patient and hospital characteristics are predictive of both mortality and length of stay in the management of Fournier's gangrene. Overall inpatient mortality appears lower than what has been reported in the majority of prior reports. The strongest predictor for increased length of stay is the need for complex wound closure, and urinary or fecal diversion.

Minimally Invasive Versus Open Approach for Cystectomy: Trends in the Utilization and Demographic or Clinical Predictors Using the National Cancer Database.

OBJECTIVE: To examine temporal national trends of operative approach for cystectomy and identify demographic or clinical predictive factors that influence choice of approach. METHODS: We performed a retrospective cohort study of patients who underwent cystectomy for bladder cancer between 2010 and 2013 using the National Cancer Database. Approach was stratified by open vs minimally invasive (robotic or laparoscopic). Univariate Pearson chi-square and multivariate logistic regression analysis were used to assess the relationships between demographic and hospital factors and the receipt of minimally invasive or open surgical approach. RESULTS: A total of 9439 patients met our inclusion criteria, of which 34.1% received a minimally invasive approach (MIA). Frequency of MIA increased from 26.3% in 2010 to 39.4% in 2013 (P < .0001). Univariate analysis identified statistically significant associations between year of diagnosis, sex, age, race, clinical T stage, insurance status, income, education, distance from hospital, facility type, geographic location, and facility cystectomy volume, and the choice of approach (all P < .01). On multivariate analysis, independent predictors of MIA included increasing year of diagnosis, male gender, lower clinical T stage, private insurance vs Medicaid, nonacademic vs academic program, northeastern geographic region, receipt of neoadjuvant chemotherapy, and lower cystectomy volume. CONCLUSION: Utilization of MIA for cystectomy has increased nationally over the last several years likely due to increased surgeon familiarity with robotic laparoscopic pelvic surgery. Factors associated with MIA included male sex, locally confined disease, receipt of neoadjuvant chemotherapy, lower cystectomy volume centers, and nonacademic centers.

Extra-articular hip impingement due to heterotopic ossification formation at the anterior inferior iliac spine following previous pelvic external fixation.

Femoroacetabular impingements (FAIs), specifically cam type and pincer type, continue to be accepted as causes of intra-articular hip pathology and sources of hip pain. Reports of other causes of hip impingement including extra-articular causes have surfaced recently. One structure of importance is the anterior inferior iliac spine (AIIS) due to its inconsistent bony morphology and the pull of the rectus femoris muscle putting it at risk for an avulsion fracture. Under certain circumstances, open surgical excision of exostosis formation after an avulsion fracture of the AIIS has been used. The case below represents a clinical scenario in which a medically unstable and multiply injured trauma patient had an external pelvic fixator placed as part of the treatment plan for an unstable pelvic injury. Following this pelvic external fixation treatment, the patient went on to develop clinically significant heterotopic bone formation at the AIIS pin site with extra-articular hip impingement syndrome.

Analysis of an interprofessional home visit assignment: student perceptions of team-based care, home visits, and medication-related problems.

BACKGROUND AND OBJECTIVES: Interprofessional education (IPE) is recommended by many as a means by which to prepare clinicians for collaborative practice and a mechanism by which to improve the overall quality of health care. The objective of this study was to determine the impact of an interprofessional medicine-pharmacy student home visit experience on students' self-assessments of skills and abilities related to team-based care and identification of medication-related problems. METHODS: Third-year medical and fourth-year pharmacy students completed an interprofessional home visit centered on identification of medication-related problems. Students were surveyed before and after the IPE assignment to assess changes in self-assessed skills and abilities. Survey items consisted of Likert-type statements on a 5-point scale (1=strongly disagree, 5=strongly agree) and free-text responses. Students also completed reflection papers regarding their experiences. RESULTS: Twenty-two medical and 20 pharmacy students conducted medication-focused interviews of 22 patients at home as interprofessional teams. Medical and pharmacy student self-assessments of skills and abilities related to team-based care and identification of medication-related problems improved after completion of the assignment. Both groups of students perceived an improvement in confidence regarding communication skills, both with patients and with other health professions students. Changes were reported on 12 survey items. Student feedback on the IPE experience was positive. CONCLUSIONS: Students' self-perception of skills and abilities related to interprofessional team-based care and identification of medication-related problems are improved after IPE medication-focused home visit assignment. Student feedback supports the value of interprofessional patient care clinical experiences.

Scapula fractures: interobserver reliability of classification and treatment.

OBJECTIVES: There is substantial variation in the classification and management of scapula fractures. The first purpose of this study was to analyze the interobserver reliability of the OTA/AO classification and the New International Classification for Scapula Fractures. The second purpose was to assess the proportion of agreement among orthopaedic surgeons on operative or nonoperative treatment. DESIGN: Web-based reliability study. SETTING: Independent orthopaedic surgeons from several countries were invited to classify scapular fractures in an online survey. PARTICIPANTS: One hundred three orthopaedic surgeons evaluated 35 movies of three-dimensional computerized tomography reconstruction of selected scapular fractures, representing a full spectrum of fracture patterns. MAIN OUTCOME MEASUREMENTS: Fleiss kappa (κ) was used to assess the reliability of agreement between the surgeons. RESULTS: The overall agreement on the OTA/AO classification was moderate for the types (A, B, and C, κ = 0.54) with a 71% proportion of rater agreement (PA) and for the 9 groups (A1 to C3, κ = 0.47) with a 57% PA. For the New International Classification, the agreement about the intraarticular extension of the fracture (Fossa (F), κ = 0.79) was substantial and the agreement about a fractured body (Body (B), κ = 0.57) or process was moderate (Process (P), κ = 0.53); however, PAs were more than 81%. The agreement on the treatment recommendation was moderate (κ = 0.57) with a 73% PA. CONCLUSIONS: The New International Classification was more reliable. Body and process fractures generated more disagreement than intraarticular fractures and need further clear definitions.

Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy.

Objectives. To determine the relationship between preoperative erythrocyte sedimentation rate (ESR) and overall survival in localized renal cell carcinoma (RCC) following nephrectomy. Methods. 167 patients undergoing nephrectomy for localized RCC had ESR levels measured preoperatively. Receiver Operating Characteristics curves were used to determine Area Under the Curve and relative sensitivity and specificity of preoperative ESR in predicting overall survival. Cut-offs for low (0.0-20.0 mm/hr), intermediate (20.1-50.0 mm/hr), and high risk (>50.0 mm/hr) groups were created. Kaplan-Meier analysis was conducted to assess the univariate impact of these ESR-based groups on overall survival. Univariate and multivariate Cox regression analysis was conducted to assess the potential of these groups to predict overall survival, adjusting for other patient and tumor characteristics. Results. Overall, 55.2% were low risk, while 27.0% and 17.8% were intermediate and high risk, respectively. Median (95% CI) survival was 44.1 (42.6-45.5) months, 35.5 (32.3-38.8) months, and 32.1 (25.5-38.6) months, respectively. After controlling for other patient and tumor characteristics, intermediate and high risk groups experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735-27.649) and 18.5-fold (HR: 18.531, 95% CI: 2.117-162.228) increased risk of overall mortality, respectively. Conclusion. Preoperative ESR values represent a robust predictor of overall survival following nephrectomy in localized RCC.