Suprarenal aortic clamping and reperfusion decreases medullary and cortical blood flow by decreased endogenous renal nitric oxide and PGE2 synthesis

ObjectiveThis study examined the hypothesis that clamping the aorta above the superior mesenteric artery (SMA) followed by suprarenal aortic clamping and reperfusion (SRACR) decreases microvascular blood flow by loss of endogenous medullary and cortical nitric oxide (NO) and prostaglandin (PG) E2 synthesis.Study DesignAnesthetized male Sprague-Dawley rats (350 g) had either microdialysis probes or laser Doppler fibers inserted into the renal cortex to a depth of 2 mm and into the renal medulla at 4 mm. Laser Doppler blood flow was continuously monitored (data reported as percentage of change compared to basal), and the microdialysis probes were connected to a syringe pump and perfused in vivo at 3 μL/min with lactated Ringer solution. Dialysate fluid was collected at basal time zero, following 30 minutes of suprarenal aortic clamping (ischemia) followed by 60 minutes of reperfusion and compared to a sham operation. Both groups were treated with saline carrier, indomethacin (INDO) (10 mg/kg, a cyclooxygenase [COX] inhibitor), NG-nitro-l-arginine methyl ester (l-NAME) (20 mg/kg, a NO synthase [NOS] inhibitor), or l-arginine (200 mg/kg, an NO precursor). Dialysate was analyzed for total NO (μM) and PGE2 (pg/mL) synthesis. The renal cortex and medulla were analyzed for inducible NOS (iNOS) and COX-2 content by Western blot. All data are reported as mean ± SEM, N > 5 and analyzed by analysis of variance.ResultsSRACR caused a marked decrease in medullary and cortical blood flow with a concomitant decrease in endogenous medullary and cortical NO synthesis. Treatment with l-NAME further decreased blood flow and NO synthesis in the medulla and cortex. l-Arginine restored medullary and cortical NO synthesis and blood flow in the cortex but not the medulla. SRACR did not alter renal medullary or cortical PGE2; however, addition of INDO, COX inhibitor, caused a concomitant decrease in medullary and cortical PGE2 synthesis and blood flow.ConclusionsNO is an important endogenous renal vasodilator that, when maintained can help preserve cortical blood flow following SRACR. These data also suggest that avoidance of COX-2 inhibitors can help maintain endogenous renal cortical and medullary PGE2 synthesis and thus contribute to maintaining normal blood flow.Clinical RelevanceThis study is the first to combine in vivo physiologic assays to simultaneously identify clinically relevant intrarenal vasodilators (cortical and medullary) that are required to maintain microvascular blood flow. Identification of endogenous renal cortical and medullary vasodilators responsible for maintaining renal microvascular blood flow will allow development of treatment strategies to preserve these vasodilators following SRACR. Successful preservation of endogenous intrarenal vasodilators will help maintain renal microvascular blood flow and renal function in the treatment of complex aortic pathology that requires SRACR

Health-related quality of life in patients with melanoma brain metastases treated with immunotherapy.

Aims: To describe the health-related quality of life (HRQoL) of melanoma brain metastasis (MBM) patients throughout the first 18 weeks of ipilimumab-nivolumab or nivolumab treatment. Materials & methods: HRQoL data (European Organisation for Research and Treatment of Cancer's Core Quality of Life Questionnaire, additional Brain Neoplasm Module, and EuroQol 5-Dimension 5-Level Questionnaire) were collected as a secondary outcome of the Anti-PD1 Brain Collaboration phase II trial. Mixed linear modeling assessed changes over time, whereas the Kaplan-Meier method was used to determine median time to first deterioration. Results: Asymptomatic MBM patients treated with ipilimumab-nivolumab (n = 33) or nivolumab (n = 24) maintained baseline HRQoL. MBM patients with symptoms or leptomeningeal/progressive disease treated with nivolumab (n = 14) reported a statistically significant trend toward improvement. Conclusion: MBM patients treated with either ipilimumab-nivolumab or nivolumab did not report a significant deterioration in HRQoL within 18 weeks of treatment initiation. Clinical trial registration: NCT02374242 (ClinicalTrials.gov).Jake R Thompson, Julia Lai-Kwon, Rachael L Morton, Alexander D Guminski, Maria Gonzalez, Victoria Atkinson, Shahneen Sandhu, Michael P Brown, Alexander M Menzies, Grant A McArthur, Serigne N Lo, Georgina V Long, Iris Bartul

To be mortal is human: Professional consensus around the need for more psychology in palliative care

LetterUrsula M. Sansom-Daly, Elizabeth A. Lobb, Holly E. Evans, Lauren J. Breen, Anna Ugalde, Megan Best, Nienke Zomerdijk, Elizabeth A. Beasley, Keryn L. Taylor, Josephine Clayton, Louise Sharpe, Iris Bartula, and Ian Olver, PoCoG End of Life Care Special Interest Grou