Characteristics of inappropriate multiple medication use in older urological outpatients.

OBJECTIVES: To investigate polypharmacy and potentially inappropriate medications (PIMs) in elderly patients visiting the urology department for lower urinary tract symptoms (LUTS). METHODS: We retrospectively analyzed digital medical records of individuals over the age of 65 who visited the urology department for LUTS. This cross-sectional study was conducted in 10 hospitals located in South Korea, between September 2017 and December 2017. All prescribed medications were analyzed using electronic medical records. The updated 2015 Beers criteria were used to identify and assess the appropriateness of the prescribed drugs in elderly patients. RESULTS: We analyzed a total of 2143 patients aged over 65 years from 10 institutions. The mean age was 74.2 ± 6.26 years (65-97), 1634 (76.2%) were men. Patients took a mean of 6.48 ± 2.46 medications (range 0-18), and polypharmacy was found in 1762 patients (82.2%). The number of patients who received PIMs at least once was 1579 (73.7%). The average number of PIMs used per patient was 1.31 ± 1.25 (0-7). PIM use ratio was 18.9 ± 0.15% (0-67%). The number of chronic diseases, and concurrent medication and polypharmacy were predictive factors associated with PIM use. CONCLUSION: Our multi-institutional results show that a substantial proportion of elderly patients took PIMs when visiting the urology department. Factors associated with PIMs were the number of chronic diseases and polypharmacy. Medication use in elderly patients, especially in urology, should be monitored carefully.

Prognostic value of preoperative systemic inflammation markers in localized upper tract urothelial cell carcinoma: a large, multicenter cohort analysis.

BACKGROUND: The aim of this study was to investigate the prognostic value of preoperative systemic inflammation markers in upper tract urothelial carcinoma (UTUC). METHODS: A total of 1137 patients who underwent radical nephroureterectomy with bladder cuff excision at 9 institutions from 2004 to 2015, were retrospectively reviewed. The Glasgow Prognostic Score (GPS), modified GPS (mGPS), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for each patient were calculated. Univariable and multivariable analysis was performed using the Cox proportional hazards regression model. Cut-off values for NLR and PLR were calculated using a receiver operating characteristic curve. RESULTS: The median follow-up period was 39.1 (interquartile range: 18.3-63.8) months. Univariable analysis revealed that GPS, mGPS, PLR, and NLR (all, P=0.001) were significantly associated with both recurrence-free survival (RFS) and cancer-specific survival (CSS). Multivariable analysis revealed that GPS (P=0.001), PLR (hazards ratio [HR] =1.32; 95% CI: 1.08-1.62, P=0.007 and HR =1.87; 95% CI: 1.21-2.92, P=0.005), NLR (HR =1.38; 95% CI: 1.12-1.69, P=0.003 and HR =1.70; 95% CI: 1.10-2.62, P=0.017) were significantly associated with RFS and CSS. CONCLUSIONS: Our results suggest that preoperative systemic inflammation markers such as GPS, PLR, and NLR are independent prognostic factors in patients with UTUC after surgery.

Mild hypothermia protects obese rats from fulminant hepatic necrosis induced by ischemia-reperfusion.

BACKGROUND: Obese Zucker rats demonstrate increased susceptibility to hepatic ischemia-reperfusion injury. This study evaluates the effect of mild systemic hypothermia on ischemia-induced acute fulminant necrosis during warm ischemia and reperfusion, and investigates blood metabolic profiles under normothermic and mildly hypothermic conditions. METHODS: The left and median hepatic lobes of male, obese, Zucker rats were exposed to 75 minutes of ischemia under either normothermic (36.9 +/- 0.3 degrees C) or mildly hypothermic (33.3 +/- 0.1 degrees C) conditions followed by 8 hours of reperfusion. Animals were killed and tissue and blood were harvested for analysis of histology, liver enzymes, and metabolic 1H-NMR spectroscopy. RESULTS: Liver enzyme activities were significantly higher in the normothermic group when compared with mildly hypothermic animals. Histologic analysis showed greater than 75% necrosis in the normothermic group, whereas in the mildly hypothermic group necrosis was less than 25%. Blood from normothermic animals contained greater concentrations of lactate (190%, P = .001) and lower concentrations of glucose (60%, P = .01) than hypothermic animals; hepatic osmolyte betaine was also increased in blood from the normothermic group (220%, P = .0002). In addition, normothermic rats had increased concentrations of circulating fatty acids, triglycerides, glutamate, succinate, and acetate when compared with the hypothermic. CONCLUSION: Mild hypothermia decreased hepatic necrosis in obese rats. NMR blood profiles indicate that hypothermia protects hepatic metabolism.

Warm ischemia-induced alterations in oxidative and inflammatory proteins in hepatic Kupffer cells in rats.

The aim of the study was to investigate the impact of ischemia/reperfusion injury on the proteome of Kupffer cells. Lean Zucker rats (n = 6 each group) were randomized to 75 min of warm ischemia or sham operation. After reperfusion for 8 h, Kupffer cells were isolated by enzymatic perfusion and density gradient centrifugation. Proteins were tryptically digested into peptides and differentially labeled with iTRAQ (isobaric tags for relative and absolute quantitation) reagent. After fractionation by cation exchange chromatography, peptides were identified by mass spectrometry (ESI-LC-MS/MS). Spectra were interrogated against the Swiss-Prot database and quantified using ProteinProspector. The results for heat shock protein 70 and myeloperoxidase were validated by ELISA. Quantitative information for more than 1559 proteins was obtained. In the ischemia group proteins involved in inflammation were significantly up-regulated. The ratio for calgranulin B in the ischemia/sham group was 1.81 +/- 0.97 (p < 0.0001), for complement C3 the ratio was 1.81 +/- 0.49 (p < 0.0001), and for myeloperoxidase the ratio was 1.30 +/- 0.32. Myeloperoxidase was only recently documented in Kupffer cells. The antioxidative proteins Cu,Zn-superoxide dismutase (1.34 +/- 0.19; p < 0.001) and catalase (1.23 +/- 0.43; p < 0.001) were also elevated. In conclusion, ischemia/reperfusion injury induces alterations in the Kupffer cell proteome. Isotope ratio mass spectrometry is a powerful tool to investigate these reactions. The ability to simultaneously monitor several pathways involved in reperfusion stress may result in important mechanistic insight and possibly new treatment options.

Glutamine does not protect against hepatic warm ischemia/reperfusion injury in rats.

The administration of glutamine before experimental ischemia/reperfusion (I/R) has been shown to protect intestinal, pulmonary, and myocardial tissue by inducing heat shock proteins (HSP). However, it is not known whether glutamine is protective for all organs. We therefore tested whether pretreatment with glutamine reduces injury following hepatic I/R in rats. Male lean Zucker rats were pretreated with either glutamine (0.75 g/kg intraperitoneally, n = 6) or saline (n = 6), 24 and 6 hours before ischemia. Seventy percent of the liver was exposed to 75 minutes of warm ischemia followed by 24 hours reperfusion. Liver enzymes, histology, neutrophil accumulation, survival, and heat shock protein (HSP) 70 induction were examined. Glutamine administration did not reduce liver injury. In both groups, 5 of 6 animals survived 24 hours of reperfusion. There was no difference in serum transaminase levels with AST 15113 +/- 4336 U/L (glutamine) vs. 17695 +/- 8531 U/L (control, P > 0.05), and ALT 7763 +/- 2524 (glutamine) U/L vs. 5884 +/- 2063 U/L (control, P > 0.05). The degree of neutrophil accumulation and necrosis was not different between groups at 24 hours of reperfusion. Pretreatment did not result in HSP70 upregulation in any of the groups. Pretreatment with glutamine did not reduce hepatic ischemia/reperfusion injury. The lack of protection was associated with an absence of HSP70 upregulation prior to ischemia.

Mild hypothermia provides significant protection against ischemia/reperfusion injury in livers of obese and lean rats.

OBJECTIVE: To evaluate the effect of anesthesia induced mild systemic hypothermia on hepatic injury in lean and obese rats during warm ischemia. SUMMARY BACKGROUND DATA: Hepatic warm ischemia during surgery remains a significant problem, particularly in organs with presumed baseline dysfunction. METHODS: The left and median lobes of male lean and obese Zucker rats were exposed to 75 minutes of ischemia under either mild hypothermic or normothermic conditions. After 75 minutes of ischemia, the organs were reperfused and animals were observed for 24 hours. Surviving animals were killed and blood and tissue was harvested to determine liver enzymes and examine the histology. RESULTS: Mild hypothermia significantly decreased hepatocellular injury in both lean and obese rats. Biochemical markers of hepatic injury were significantly reduced in hypothermic groups (P < 0.01). Survival in normo- and hypothermic lean groups were not different at 24 hours of reperfusion. However, hypothermia profoundly increased survival in obese rats when compared with normothermic obese rats (100% versus 20%, P < 0.01). Necrosis was more pronounced in both normothermic lean and obese animals who experienced more than >75% necrosis when compared with hypothermic animals. In contrast, mild hypothermia reduced necrosis in lean rats to less than 25% and in obese rats to less than 50%. CONCLUSIONS: We demonstrated in a clinically relevant model that mild hypothermia significantly reduces hepatic injury in a warm ischemia model in lean and obese rats and significantly improved 24-hour survival in obese rats.

Benzo(a)pyrene-induced apoptotic death of mouse hepatoma Hepa1c1c7 cells via activation of intrinsic caspase cascade and mitochondrial dysfunction.

Benzo(a)pyrene (BaP), a potent carcinogen, has been shown to induce apoptosis via activation of caspase-3. However, the upstream of caspase-3 and other apoptosis signaling remain to be elusive. Herein, we demonstrated that treatment of Hepa1c1c7 cells with BaP increased the transcriptional expression of aryl hydrocarbon nuclear transporter and cytochrome p450 1A1 in a time and dose-dependent manner but did not aromatic hydrocarbon receptor. Also, the catalytic activation of caspase-3 and caspase-9 was induced whereas that of caspase-3 and caspase-9 was not by the addition of BaP. BaP also induced the mitochondrial dysfunction, including transition of mitochondria membrane potential and cytosolic release of cytochrome c. Furthermore, a decrease in the expression of Bcl-2 to Bax ratio and phosphorylation of p53(Ser 15) were observed in BaP-treated cells. Taken together, these results demonstrated that BaP-induced apoptosis of Hepa1c1c7 cells via activation of intrinsic caspase pathway including caspase-3, caspase-9, with mitochondrial dysfunction and p53 activation.