Preoperative Optimization of Promotility in Robotic Prostatectomy and Minimally Invasive Kidney Surgery.

INTRODUCTION: Patients are routinely discharged postoperative day 1 following minimally invasive surgery (MIS) for prostate cancer and kidney cancer. Delays in discharge are often related to gastrointestinal symptoms such as nausea, abdominal pain and vomiting; however, the role of baseline constipation in these symptoms and resultant delays in discharge is unclear. We conducted a prospective observational study to describe the incidence of baseline constipation among patients undergoing MIS prostate and kidney surgery, and its relationship to length of stay (LOS). METHODS: Consenting adult patients undergoing MIS procedures for kidney and prostate cancer completed constipation symptom questionnaires perioperatively. Clinicopathological data were collected prospectively. Delay in discharge, defined as LOS >2 days, was the primary outcome. Patients were stratified by the primary outcome and preoperative Patient Assessment of Constipation Symptoms (PAC-SYM) scores were compared. RESULTS: A total of 97 patients enrolled, of whom 29 underwent radical nephrectomy, 34 underwent robotic partial nephrectomy and 34 underwent robotic prostatectomy. Constipation symptoms were reported in 67/97 patients (69%). A total of 17/97 patients (18%) had a delay in discharge. Patients who discharged on time had a median PAC-SYM score of 2 (IQR 2-9) compared to 4 (IQR 0-7.5) for those with a delay (p=0.021). Patients who had a delay with gastrointestinal symptoms had a median PAC-SYM score of 5 (IQR 1.5-11.5, p=0.032). CONCLUSIONS: Seven out of 10 patients undergoing routine MIS procedures report constipation symptoms, which may represent a target for preoperative interventions to reduce LOS after surgery.

The July Effect in Radical Cystectomy: Mortality, Morbidity, and Efficiency.

Background: The "July effect" is the potential effect that new and recently promoted residents have on patient care during the first months of the academic year. Literature suggests that the July effect may worsen patient outcomes and lead to systemic inefficiencies. Objective: We evaluate the July effect on mortality, morbidity, and efficiency outcomes in patients undergoing radical cystectomy. Methods: A chart review was performed in patients who underwent radical cystectomy between January 2008 and April 2012. Demographic information was abstracted from patient charts and outcomes compared between operations performed in July, September, and November (first month of each resident's university rotation) to the remainder of the year. Outcomes of interest included mortality, complications, and markers of efficiency (operative time, length of hospital stay, and estimated blood loss). Results: Two hundred and fifty one patients were included in the analysis. There were no major differences in mortality or morbidity between the July, September, November group and the rest of the year. Multivariable analysis demonstrates a trend for operations performed in the months of July, September, and November to be associated with longer OR times 2.06 (0.99-4.27), p = 0.053. Length of hospital stay and estimated blood loss were no different between the two groups. Conclusions: These data demonstrate no increase in mortality or morbidity during the early academic period. Additionally, while there is a trend for OR time to be longer in the early group, length of hospital stay and estimated blood loss were no different. These data may be used as an impetus to continue to investigate technical/clinical teaching practices, strategies to assess resident progression, and to initiate protocols to support residents early in the academic year in efforts to prevent inefficiencies.

Estimation of alkane-water logP for neutral, acidic, and basic compounds using an alkylated polystyrene-divinylbenzene high-performance liquid chromatography column.

Reliable HPLC methods are available to estimate octanol-water partition coefficients, but there is no comparable method for alkane-water partition coefficients that is accurate and applicable across a broad span of logP(alk). This study describes a high-throughput method for determining HPLC-logP(alk), a chromatographic parameter closely related to logP(alk), using an alkylated polystyrene-divinylbenzene column and fast acetonitrile gradient. A structurally diverse set of neutral, acidic, and basic compounds was analyzed under ionization-suppressing pH conditions. In this chromatographic system, the relationship between gradient retention time and isocratic logk was essentially linear. Thus, gradient retention time could be used as the sole input needed to determine an apparent logP(alk)by HPLC. HPLC-logP(alk) showed linear correlation (R(2)>0.96, n=59) with reference logP(alk) values from shake-flask measurements over 8 orders of magnitude, ranging from -2.3 to +5.7. Linear solvation energy relationship (LSER) analysis revealed that the relative contributions of intermolecular forces effecting retention in the fast gradient system or its corresponding isocratic variant were highly similar to those governing partition in bulk alkane-water.

Human cancer xenografts in outbred nude mice can be confounded by polymorphisms in a modifier of tumorigenesis.

Tumorigenicity studies often employ outbred nude mice, in the absence of direct evidence that this mixed genetic background will negatively affect experimental outcome. Here we show that outbred nude mice carry two different alleles of Pla2g2a, a genetic modifier of intestinal tumorigenesis in mice. Here, we identify previous unreported linked polymorphisms in the promoter, noncoding and coding sequences of Pla2g2a and show that outbred nude mice from different commercial providers are heterogeneous for this polymorphic Pla2g2a allele. This heterogeneity even extends to mice obtained from a single commercial provider, which display mixed Pla2g2a genotypes. Notably, we demonstrated that the polymorphic Pla2g2a allele affects orthotopic xenograft establishment of human colon cancer cells in outbred nude mice. This finding establishes a non-cell-autonomous role for Pla2g2a in suppressing intestinal tumorigenesis. Using in vitro reporter assays and pharmacological inhibitors, we show promoter polymorphisms and nonsense-mediated RNA decay (NMD) as underlying mechanisms that lead to low Pla2g2a mRNA levels in tumor-sensitive mice. Together, this study provides mechanistic insight regarding Pla2g2a polymorphisms and demonstrates a non-cell-autonomous role for Pla2g2a in suppressing tumors. Moreover, our direct demonstration that mixed genetic backgrounds of outbred nude mice can significantly affect baseline tumorigenicity cautions against future use of outbred mice for tumor xenograft studies.

Signal transduction for Schistocerca gregaria ion transport peptide is mediated via both cyclic AMP and cyclic GMP.

The second messengers involved in the signal transduction for Schistocerca gregaria, ion transport peptide (Schgr-ITP) that regulates ion and fluid transport across the ileum of the desert locust S. gregaria, were measured using competitive enzyme-linked immunosorbent assays (ELISAs). Synthetic Schgr-ITP elevates intracellular levels of both cyclic AMP and cyclic GMP, measured over a 15 min period in the presence of 3-isobutyl-1-methylxanthine, in a dose-dependent manner. Furthermore, crude corpora cardiaca (CC) extracts elevate intracellular cyclic AMP levels 2-fold greater than Schgr-ITP, suggesting that factors present in the CC, other than Schgr-ITP, also act via this second messenger. These results suggest that the interaction of Schgr-ITP with two separate receptors, most likely a G-protein coupled receptor and a membrane bound guanylate cyclase, elevates intracellular levels of cyclic AMP and cyclic GMP to regulate ion and fluid transport across the locust ileum. Cyclic AMP stimulates Cl(-), K(+) and Na(+) reabsorption, whereas secretion of H(+) into the lumen of the ileum is most likely mediated via cyclic GMP. Cyclic GMP also stimulates Cl(-) uptake in a similar manner to cyclic AMP. The measurement of tissue (central nervous system) levels of Schgr-ITP using an indirect ELISA confirms that the peptide is only present in the locust brain and the CC. The amounts present are greatest in the CC, where the peptide is presumably stored for release into the hemolymph when locusts feed.

The p53 inhibitor pifithrin-alpha forms a sparingly soluble derivative via intramolecular cyclization under physiological conditions.

The transcription factor p53 coordinates cell cycle arrest and apoptosis in response to DNA damage. Pifithrin-alpha (PFT-alpha) is a small molecule inhibitor of p53 activity that is frequently used in cell culture studies of p53 function. Here we report an investigation of the stability of this compound. PFT-alpha rapidly converts to a planar tricyclic derivative, with a half-life of 4.2 h under physiological conditions. This spontaneous conversion greatly alters the structural and physicochemical properties of the drug. PFT-alpha has a pKa of 9.11 and is an ionic species in physiological medium, whereas the tricyclic derivative has a pKa of 4.36 and exists as the neutral free base at pH 7. The tricyclic derivative is very hydrophobic, with a log P of 4.26. Although PFT-alpha is generally used at 10-30 microM concentration, the aqueous solubility of its derivative is only 0.2 microM, and it can form a visible precipitate under conditions of typical use. The conversion of PFT-alpha proceeds via an intramolecular cyclization reaction involving the imine and carbonyl groups. Modification of the carbonyl function creates a stable analogue of PFT-alpha that remains soluble indefinitely. These results provide a strategy for the rational design of PFT-alpha analogues that exhibit predictable stability, hydrophobicity, and aqueous solubility.