Outcomes in the management of appendicitis and cholecystitis in the setting of a new acute care surgery service model: impact on timing and cost.

BACKGROUND: The acute care surgery model is a novel notion in the provision of emergency general surgery. To date, several studies have analyzed the effects on patient health outcomes and timeliness of care for nontrauma patients within the scope of acute general surgery and emergencies, but none have assessed the cost benefits of this model. STUDY DESIGN: A retrospective analysis of patients undergoing appendectomy or cholecystectomy in the setting of acute abdomen was performed to compare data from 2 cohorts, the traditional model from July 2009 to June 2010 and the acute care surgery model from July 2010 to June 2011. Categorical variables and comparison means were examined using chi-square and independent 2-tailed sample t-tests. RESULTS: One hundred and seventy-five patients underwent appendectomy and 113 underwent cholecystectomy. The traditional model team staffed 82 appendectomies and 51 cholecystectomies, and the acute care surgery team staffed 93 and 62, respectively. In the appendectomy group, there was a statistically significant mean reduction of time to surgical evaluation (2.19 hours; p < 0.001) and time to the operating room (5.38 hours, p = 0.006), there were 7 fewer patients with complications (p = 0.06) and a reduced length of stay (1 day, p = 0.002) for the acute care surgery cohort. Similar statistically significant differences were observed in the cholecystectomy group in the acute care surgery cohort: surgical evaluation difference = 5.84 hours (p = 0.03), time to operating room difference = 25.37 hours (p = 0.002), 8 fewer patients with complications (p = 0.01), and length of stay difference was 2 days (p = 0.03) compared with the traditional model cohort. CONCLUSIONS: The newly implemented acute care surgery model in our institution accomplished earlier treatment and shorter length of stay for the 2 most common causes of acute abdomen in our setting. Overall, the new model translated to better outcomes for patients and savings per case for the hospital.

Calmodulin protects androgen receptor from calpain-mediated breakdown in prostate cancer cells.

Although inactivation of the androgen receptor (AR) by androgen-ablation or anti-androgen treatment has been frontline therapy for disseminated prostate cancer for over 60 years, it is not curative because castration-resistant prostate cancer cells retain AR activity. Therefore, curative strategy should include targeted elimination of AR protein. Since AR binds to calmodulin (CaM), and since CaM-binding proteins are targets of calpain (Cpn)-mediated proteolysis, we studied the role of CaM and Cpn in AR breakdown in prostate cancer cells. Whereas the treatment of prostate cancer cells individually with anti-CaM drug or calcimycin, which increases intracellular Ca(++) and activates Cpn, led to minimal AR breakdown, combined treatment led to a precipitous decrease in AR protein levels. This decrease in AR protein occurred without noticeable changes in AR mRNA levels, suggesting an increase in AR protein turnover rather than inhibition of AR mRNA expression. Thus, CaM inactivation seems to sensitize AR to Cpn-mediated breakdown in prostate cancer cells. Consistent with this possibility, purified recombinant human AR (rhAR) underwent proteolysis in the presence of purified Cpn, and the addition of purified CaM to the incubation blocked rhAR proteolysis. Together, these observations demonstrate that AR is a Cpn target and AR-bound CaM plays an important role in protecting AR from Cpn-mediated breakdown in prostate cancer cells. These observations raise an intriguing possibility that anti-CaM drugs in combination with Cpn-activating agents may offer a curative strategy for the treatment of prostate cancer, which relies on AR for growth and survival.

Role of androgen receptor in prostate cancer cell cycle regulation: interaction with cell cycle regulatory proteins and enzymes of DNA synthesis.

The androgen receptor (AR) plays a critical role in proliferation and viability of prostate cancer cells. Therefore, suppressing AR activity by androgen deprivation or anti-androgen treatment has been the frontline therapy for over six decades. However, these treatment strategies are not curative and patients succumb to castration-resistant disease. Although AR is evidently critical for proliferation of prostate cancer cells, very little is known about its mechanism of action in this process. Over the years, the role of AR in prostate cancer cell proliferation and viability has been studied by focusing primarily on its role as a transcription factor. However, recent observations indicate that besides its role as a transcription factor, AR interacts physically with components of the pre-replication complex (pre-RC) and DNA replication machinery (replitase). These interactions may enable AR to exert control over the process of DNA synthesis. In addition, alterations in the proteins that interact with AR in complexes required for DNA synthesis could lead to the development of hormone-refractory prostate cancer. These observations suggest a paradigm shift for the role of AR in proliferation of prostate cancer cells from its role as a transcription factor to a non-transcriptional role as a component of the replication machinery, interacting with cell cycle regulatory proteins and enzymes of DNA synthesis. We propose that a detailed understanding of the structural interactions between AR and the components of pre-RC and replitase may lead to the development of new strategies for the treatment of prostate cancer.

Statistics: The stethoscope of a thinking urologist.

Understanding statistical terminology and the ability to appraise clinical research findings and statistical tests are critical to the practice of evidence-based medicine. Urologists require statistics in their toolbox of skills in order to successfully sift through increasingly complex studies and realize the drawbacks of statistical tests. Currently, the level of evidence in urology literature is low and the majority of research abstracts published for the American Urological Association (AUA) meetings lag behind for full-text publication because of a lack of statistical reporting. Underlying these issues is a distinct deficiency in solid comprehension of statistics in the literature and a discomfort with the application of statistics for clinical decision-making. This review examines the plight of statistics in urology and investigates the reason behind the white-coat aversion to biostatistics. Resources such as evidence-based medicine websites, primers in statistics, and guidelines for statistical reporting exist for quick reference by urologists. Ultimately, educators should take charge of monitoring statistical knowledge among trainees by bolstering competency requirements and creating sustained opportunities for statistics and methodology exposure.

Variance inflation in sequential calculations of body surface area, plasma volume, and prostate-specific antigen mass.

OBJECTIVE: To assess the magnitude of variability among 11 formulae for human body surface area (BSA) and then among eight for plasma volume (PV), as used to represent physiological indices for body metabolism, drug dosages and body fluid management, and to evaluate the potential cumulative effect of variance inflation with prostate-specific antigen (PSA) mass as an endpoint. PATIENTS AND METHODS: In 3020 men undergoing robotic radical prostatectomy (RRP) at the Vattikuti Urology Institute between 2001 and 2008, the variation in BSA and PV formulae was calculated, as well as PSA mass, using analysis of variance (anova), Bland-Altman plots, linear regression, and correlation analyses. RESULTS: For estimating BSA, anova indicated significant variance among the 11 formulae used (P < 0.001) with a between-groups variance of 5.45. Bland-Altman plots reported bias when the Dubois formula was compared to other BSA formulae. Furthermore the anova for PV, with BSA as a predictor, indicated significant variance among the eight formulae used (P < 0.001), with a mean between-group variance of 444.4 and a mean inflation factor of 81.5. Scatter plots between one PV formula (Boer) and others had a good linear fit. For PSA mass, anova indicated significant variance (P < 0.001) using PV as a predictor, with a mean between-group variance of 16 799.6 and a mean variance inflation factor of 37.8. CONCLUSIONS: There is significant variation in the BSA calculated by commonly used formulae. This variation is carried over and further magnified in the sequential calculation of PV and PSA mass. Hence arbitrary selection of BSA and PV formulae is likely to affect inferences.

Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer.

Relapse of prostate cancer after androgen ablation therapy is hormone-refractory, with continued tumor growth being dependent on the androgen receptor (AR). E2F-1, a regulator of cell proliferation and viability, reportedly plays a role in the development of hormone-refractory prostate cancer. Thymoquinone is a component of Nigella sativa, an herb used for thousands of years for culinary and medicinal purposes in Asian and Middle Eastern countries and has been reported to have an antineoplastic effect both in vitro and in vivo. We observed that thymoquinone inhibited DNA synthesis, proliferation, and viability of cancerous (LNCaP, C4-B, DU145, and PC-3) but not noncancerous (BPH-1) prostate epithelial cells by down-regulating AR and E2F-1. In LNCaP cells, this was associated with a dramatic increase in p21(Cip1), p27(Kip1), and Bax. Thymoquinone blunted progression of synchronized LNCaP cells from G1 to S phase, with a concomitant decrease in AR and E2F-1 as well as the E2F-1-regulated proteins necessary for cell cycle progression. In a xenograft prostate tumor model, thymoquinone inhibited growth of C4-2B-derived tumors in nude mice. This in vivo suppression of tumor growth, as with C4-2B cell growth in culture, was associated with a dramatic decrease in AR, E2F-1, and cyclin A as determined by Western blot of tissue extracts. Tissue immunohistochemical staining confirmed a marked reduction in E2F-1 and showed induction of apoptosis on terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. These findings show that thymoquinone suppresses the expression of AR and E2F-1 necessary for proliferation and viability of androgen-sensitive as well as androgen-independent prostate cancer cells both in vitro and in vivo and, moreover, produced no noticeable side effects in mice. We conclude that thymoquinone, a naturally occurring herbal product, may prove to be effective in treating hormone-sensitive as well as hormone-refractory prostate cancer. Furthermore, because of its selective effect on cancer cells, we believe that thymoquinone can also be used safely to help prevent the development of prostate cancer.

Covalent interaction between proform of eosinophil major basic protein (proMBP) and pregnancy-associated plasma protein-A (PAPP-A) is a cell-mediated event and required for proMBP inhibition of the catalytic activity of PAPP-A.

This study was undertaken to determine the mechanism by which proform of eosinophil major basic protein (proMBP) inhibits the IGFBP-4 proteolytic activity of pregnancy-associated plasma protein (PAPP)-A. Co-overexpression of PAPP-A with proMBP in 293T cells, or co-incubation of 293T cells, respectively, overexpressing proMBP and PAPP-A resulted in the formation of a covalent proMBP-PAPP-A complex and inhibition of IGFBP-4 proteolysis. Similar results were obtained when recombinant proMBP and PAPP-A were incubated in the presence of U2 osteosarcoma cells or when recombinant proMBP was added to the U2 cells overexpressing PAPP-A. In contrast, no formation of covalent proMBP-PAPP-A complex or inhibition of IGFBP-4 proteolysis was observed when recombinant proMBP and PAPP-A were incubated under cell-free conditions, although proMBP was able to interact with PAPP-A in a non-covalent manner. These new findings suggest that formation of covalent proMBP-PAPP-A complex is a cell-mediated event and is required for proMBP to inhibit the catalytic activity of PAPP-A.

Studies on regulation of IGF (insulin-like growth factor)-binding protein (IGFBP) 4 proteolysis by pregnancy-associated plasma protein-A (PAPP-A) in cells treated with phorbol ester.

PAPP-A (pregnancy-associated plasma protein-A) is produced by hSFs (human skin fibroblasts) and hOBs (human osteoblasts) and enhances the mitogenic activity of IGFs (insulin-like growth factors) by degradation of IGFBP-4 (insulin-like growth factor-binding protein 4). PKC (protein kinase C) activation in these cells led to reduction in IGFBP-4 proteolysis. This study was undertaken to determine the mechanism by which activation of PKC suppresses IGFBP-4 proteolysis. Treatment of hSFs/hOBs with TPA (PMA; 100 nM) reduced IGFBP-4 proteolysis without significantly decreasing the PAPP-A level in the CM (conditioned medium). Immunodepletion of the proform of eosinophil major basic protein (proMBP), a known PAPP-A inhibitor, from CM of TPA-treated cells (TPA CM) failed to increase IGFBP-4 proteolytic activity. Transduction of hSFs with proMBP retrovirus increased the concentration of proMBP up to 30 ng/ml and led to a moderate reduction in IGFBP-4 proteolysis. In contrast, TPA treatment blocked IGFBP-4 proteolysis but failed to induce a detectable amount of proMBP in the CM. While proMBP overexpression led to the formation of a covalent proMBP-PAPP-A complex and reduced the migration of PAPP-A on SDS/PAGE, TPA treatment dose- and time-dependently increased the conversion of a approximately 470 kDa PAPP-A form (PAPP-A470) to a approximately 400 kDa PAPP-A form (PAPP-A400). Since unreduced PAPP-A400 co-migrated with the 400 kDa recombinant PAPP-A homodimer and since PAPP-A monomers from reduced PAPP-A470 and PAPP-A400 co-migrated on SDS/PAGE, conversion of PAPP-A470 to PAPP-A400 is unlikely to be caused by proteolytic cleavage of PAPP-A. Consistent with the data showing that the increase in the ratio of PAPP-A400/PAPP-A470 is correlated with the extent of reduction in IGFBP-4 proteolysis, partially purified PAPP-A400 exhibited a 4-fold reduction in IGFBP-4 proteolytic activity compared with PAPP-A470. These data suggest that a novel mechanism, namely conversion of PAPP-A470 to the less-active PAPP-A400, could account for the TPA-induced suppression of PAPP-A activity.