High rates of advanced disease,complications, and decline of renal function after radical nephroureterectomy

ObjectivesRecurrences remain common following radical nephroureterectomy (RNU) for locally advanced upper-tract urothelial carcinoma (UTUC). We review a cohort of RNU patients to identify the incidence of locally advanced disease, decline in renal function, complications, and utilization of adjuvant chemotherapy (AC).MethodsInstitutional databases from 7 academic medical centers identified 414 RNU patients treated between 2003 and 2012 who had not received neoadjuvant chemotherapy. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation. Complications were classified according to the modified Clavien system. Cox proportional hazard modeling and Kaplan-Meier analysis determined factors associated with cancer-specific survival.ResultsOf 414 patients, 177 (43%) had locally advanced disease, including 118 pT3N0/Nx, 13 pT4N0/Nx, and 46 pTanyN+. Estimated 3- and 5-year cancer-specific survival was 47% and 34%, respectively. Only 31% of patients with locally advanced UTUC received AC. Mean estimated glomerular filtration rate declined from 59 to 51 ml/min/1.73 m² following RNU, including a new-onset decline below 60 and 45 ml/min/1.73 m² in 25% and 15% of patients, respectively (P<0.001 for both). Complications occurred in 46 of 177 (26%) patients, of which one-quarter were grade III or IV. Increasing age (Hazard Ratio (HR) 1.4, P = 0.03), positive surgical margins (HR 2.1, P = 0.01), and positive lymph nodes (HR 4.3, P<0.001) were associated with an increased risk of death from UTUC, whereas receipt of AC (HR 0.85, P = 0.05) was associated with a decrease in UTUC mortality.ConclusionsUnder one-third of RNU patients with locally advanced UTUC cancers received AC. Perioperative complications and decline in renal function may have contributed to this low rate. Such data further underscore the need for continued discussion regarding the use of chemotherapy in a neoadjuvant setting for appropriately selected patients with UTUC.     

Measurement of Human Cytochrome P450 Enzyme Induction Based on Mesalazine and Mosapride Citrate Treatments Using a Luminescent Assay

Drug metabolism mostly occurs in the liver. Cytochrome P450 (CYP) is a drug-metabolizing enzyme that is responsible for many important drug metabolism reactions. Recently, the US FDA and EU EMA have suggested that CYP enzyme induction can be measured by both enzymatic activity and mRNA expression. However, these experiments are time-consuming and their inter-assay variability can lead to misinterpretations of the results. To resolve these problems and establish a more powerful method to measure CYP induction, we determined CYP induction by using luminescent assay. Luminescent CYP assays link CYP enzyme activity to firefly luciferase luminescence technology. In this study, we measured the induction of CYP isozymes (1A2, 2B6, 2C9, and 3A4) in cryopreserved human hepatocytes (HMC424, 478, and 493) using a luminometer. We then examined the potential induction abilities (unknown so far) of mesalazine, a drug for colitis, and mosapride citrate, which is used as an antispasmodic drug. The results showed that mesalazine promotes CYP2B6 and 3A4 activities, while mosapride citrate promotes CYP1A2, 2B6, and 3A4 activities. Luminescent CYP assays offer rapid and safe advantages over LC-MS/MS and qRT-PCR methods. Furthermore, luminescent CYP assays decrease the interference between the optical properties of the test compound and the CYP substrates. Therefore, luminescent CYP assays are less labor intensive, rapid, and can be used as robust tools for high-throughput CYP screening during early drug discovery.     

Cardiovascular Safety Pharmacology of Sibutramine

Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC₅₀ of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD₅₀, and 9% and 17% decreases in APD₉₀, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.     

The effect of electron density in furan pendant group on thermal-reversible Diels–Alder reaction based self-healing properties of polymethacrylate derivatives

Herein, we discuss the effect of electron density in a furan pendant group on the thermally reversible Diels–Alder (DA) reaction based self-healing efficiency in polymethacrylate derivatives. First, the furan-functionalized polymethacrylates (rPFMA and dPFMA) having different electron density in the furan pendant groups were prepared through free-radical polymerization. The healing efficiency of rPFMA, which was expected to have high healing efficiency due to the high reactivity of DA reaction originating from the electron density in the furan moiety, was shown to be 95.89% in the first and 69.86% in the second healing process, respectively, where it is higher than that of dPFMA having relatively low electron density in the furan moiety. To illustrate these results, kinetic tests of the DA reaction for rPFMA64 and dPFMA64 were performed, where the reactivity of the DA reaction for rPFMA64 was much higher than that for dPFMA64. This could be explained by the electron density in the furan pendant groups which controls the reactivity of DA reaction having a major effect on the efficiency of self-healing performance in furan-functionalized polymethacrylates.

Herein, we discuss the effect of electron density in a furan pendant group on the thermally reversible Diels–Alder (DA) reaction based self-healing efficiency in polymethacrylate derivatives.     

Agricultural Pesticide Usage and Prioritization in South Korea

This study aims to review agricultural pesticide usage and trends and to identify hazardous pesticides for regulation, in terms of public health, in South Korea. The authors collected data on usage and trends of agricultural pesticides through agriculture-related databases. Criteria from the US Environmental Protection Agency classification for carcinogenicity, World Health Organization classification for acute toxicity, and European Union prioritization list for endocrine-disrupting chemicals were used for the hazard categorization of identified individual active ingredients. Pesticides to be prioritized among all pesticides used in South Korea between 2007 and 2011 were selected by taking into account the volume of usage, toxicity, and epidemiological evidence. Annual agricultural use of pesticides has increased rapidly from the 1970s to 1990s in South Korea, but has declined since 2001. The quantity of pesticides used in 2011 was reported as 19,131 tons, and was comprised of 34.7% insecticides, 28.0% fungicides, and 27.1% herbicides. The 50 pesticides with the greatest volume of usage accounted for 82.6% of the total volume of pesticides used between 2007 and 2011, with the most-used active ingredient being machine oil, followed by mancozeb and then paraquat. Organophosphates were the most used among the top 50 pesticides. A total of 24 pesticides were selected for recommendation of intensive regulation in South Korea. In conclusion, the authors described the usage and trends of overall agricultural pesticides, which would serve as a fundamental step forward in managing pesticide in terms of public health. Intensive efforts are required for the prevention of potential health effects from the 24 identified pesticides.     

Diabetes Mellitus and Disturbances in Brain Connectivity: A Bidirectional Relationship?

Diabetes mellitus (DM) is associated with deficits across multiple cognitive domains. The observed impairments in cognitive function are hypothesized to be subserved by alterations in brain structure and function. Several lines of evidence indicate that alterations in glial integrity and function, as well as abnormal synchrony within brain circuits and associated networks, are observed in adults with DM. Microangiopathy and alterations in insulin homeostasis appear to be principal effector systems, although a unitary explanation subsuming the complex etiopathology of white matter in DM is unavailable. A contemporary model of disease pathophysiology for several mental disorders, including but not limited to mood disorders, posits abnormalities in the synchronization of cellular systems in circuits. The observation that similar abnormalities occur in diabetic populations provides the basis for hypothesizing the convergence of pathoetiological factors. Herein, we propose that abnormal structure, function and chemical composition as well as synchrony within and between circuits is an accompaniment of DM and is shared in common with several mental disorders.