α2C-Adrenoceptor polymorphism is associated with improved event-free survival in patients with dilated cardiomyopathy

Aims The sympathetic nervous system plays a central role in cardiac growth but its overstimulation is associated with increased mortality in patients with chronic heart failure. Pre-synaptic α2-adrenoceptors are essential feedback regulators to control the release of norepinephrine from sympathetic nerves. In this study we tested whether a deletion polymorphism in the human α2C-adrenoceptor gene (α2CDel322-325) affects progression of heart failure in patients with dilated cardiomyopathy (DCM). Methods and results We genotyped and phenotyped 345 patients presenting with DCM in the heart transplant unit of the German Heart Institute, starting in 1994. Patients were treated according to guidelines (99% ACEI, 76% β-blockers) and were followed until December 2002 or until a first event [death, heart transplantation, or implantation of a left ventricular assist device (LVAD) for a life-threatening condition] occurred. Mean follow-up time was 249 weeks (4.9 years) in event-free patients and 104 weeks (2 years) in patients with events. During follow-up, 51% of the patients exhibited an event: death (18%), implantation of LVAD as bridging for transplantation (7%), or heart transplantation (25%). By Kaplan-Meier analysis, DCM patients with the deletion variant Del322-325 in the α2C-adrenoceptor showed significantly decreased event rates (P=0.0043). Cox regression analysis revealed that the presence of the deletion was associated with reduced death rate (relative risk: 0.129, 95% CI: 0.18-0.9441, P=0.044) and event rates (relative risk: 0.167, 95% CI: 0.041-0.685, P=0.012). Conclusion α2C-Adrenoceptor deletion may be a novel, strong, and independent predictor of reduced event rates in DCM patients treated according to guideline

Extended Cave Drip Water Time Series Captures the 2015–2016 El Niño in Northern Borneo

Time series of cave drip water oxygen isotopes (δ18O) provide site‐specific assessments of the contributions of climate and karst processes to stalagmite δ18O records employed for hydroclimate reconstructions. We present ~12‐year‐long time series of biweekly cave drip water δ18O variations from three sites as well as a daily resolved local rainfall δ18O record from Gunung Mulu National Park in northern Borneo. Drip water δ18O variations closely match rainfall δ18O variations averaged over the preceding 3–18 months. We observe coherent interannual drip water δ18O variability of ~3‰ to 5‰ related to the El Niño–Southern Oscillation (ENSO), with sustained positive rainfall and drip water δ18O anomalies observed during the 2015/2016 El Niño. Evidence of nonlinear behavior at one of three drip water monitoring sites implies a time‐varying contribution from a longer‐term reservoir. Our results suggest that well‐replicated, high‐resolution stalagmite δ18O reconstructions from Mulu could characterize past ENSO‐related variability in regional hydroclimate.Plain Language SummaryCave stalagmites allow for the reconstruction of past regional rainfall variability over the last hundreds of thousands of years with robust age control. Such reconstructions rely on the fact that differences in the isotopic composition of rainwater set by regional rainfall patterns is preserved as the rainwater travels through cave bedrock to feed the cave drip waters forming stalagmites. Long‐term monitoring of rainwater and cave drip water isotopes ground truth the climate to stalagmite relationship across modern‐day changes in regional rainfall. Twelve years of monitoring data presented in this study identify individual El Niño–Southern Oscillation events in rainfall and cave drip water isotopic composition, providing a strong foundation for stalagmite‐based climate reconstructions from this site.Key PointsThree 12‐year‐long cave drip water δ18O time series capture El Niño and La Niña events in northern BorneoEstimates of karst residence times range from 3 to 18 months, with a secondary contribution from a longer‐term reservoir at one drip siteDrip water nonstationarity implies multiple stalagmites are required to reconstruct El Niño–Southern Oscillation variability over timePeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/1/grl60264-sup-0002-2019GL086363-SI.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/2/grl60264_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/3/grl60264.pd

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape

The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies