Hydrologic responses to forest management and climate change vary with topography and climatic zone. Long-term hydrologic characteristics of three southern U.S. watersheds representing three types of ...forest ecosystems are examined. Inland upland watersheds of the east coast had significantly higher water yields than the warm, flat, shallow groundwater-dominated pine flatwoods on the Atlantic coast, as shown by a comparison of the potential evapotranspiration ratio and the runoff/precipitation ratio. Streamflow from flatwood watersheds tends to be discontinuous in most years, while that in upland watersheds usually is continuous. Stormflow peaks in the flatwood watersheds were lower than those in upland watersheds, with some exceptions during very wet conditions. Climate appears to be the main factor determining watershed balance in these forests, while topography is the main factor influencing wetland development. Some implications of these findings for forest management are discussed.
The 170 National Forests and Grasslands (NFs) in the conterminous United States are public lands that provide important ecosystem services such as clean water and timber supply to the American ...people. This study investigates the potential impacts of climate change on two key ecosystem functions (i.e., water yield and ecosystem productivity) using the most recent climate projections derived from 20 Global Climate Models (GCMs) of the Coupled Model Intercomparison Project phase 5 (CMIP5). We find that future climate change may result in a significant reduction in water yield but an increase in ecosystem productivity in NFs. On average, gross ecosystem productivity is projected to increase by 76 ~ 229 g C m(-2) yr(-1) (8% ~ 24%) while water yield is projected to decrease by 18 ~ 31 mm yr(-1) (4% ~ 7%) by 2100 as a result of the combination of increased air temperature (+1.8 ~ +5.2 °C) and precipitation (+17 ~ +51 mm yr(-1)). The notable divergence in ecosystem services of water supply and carbon sequestration is expected to intensify under higher greenhouse gas emission and associated climate change in the future, posing greater challenges to managing NFs for both ecosystem services.
Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of ...spironolactone.
The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial randomized 360 acute HF patients with reduced or preserved ejection fraction to spironolactone 100 mg daily or usual care for 96 hours. The current analysis assessed the effects of study therapy within tertiles of baseline estimated glomerular filtration rate (eGFR) and subgroups at heightened risk for diuretic resistance.
Across eGFR tertiles, there was no incremental benefit of high-dose spironolactone on any efficacy endpoint, including changes in log N-terminal pro-B-type natriuretic peptide and signs and symptoms of congestion (all P for interaction ≥ 0.06). High-dose spironolactone had no significant effect on N-terminal pro-B-type natriuretic peptide reduction regardless of blood pressure, diabetes mellitus status, and loop diuretic dose (all P for interaction ≥ 0.38). In-hospital changes in serum potassium and creatinine were similar between treatment groups for all GFR tertiles (all P for interaction ≥ 0.18). Rates of inpatient worsening HF, 30-day worsening HF, and 60-day all-cause mortality were numerically higher among patients with lower baseline eGFR, but relative effects of study treatment did not differ with renal function (all P for interaction ≥ 0.27).
High-dose spironolactone did not improve congestion over usual care among patients with acute HF, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe during the inpatient stay, even when administered at high doses to patients with moderate renal dysfunction.
Les patients présentant une insuffisance cardiaque (IC) aiguë accompagnée d’une insuffisance rénale et de facteurs de risque de résistance aux diurétiques pourraient être plus susceptibles d’obtenir une réduction significative de la congestion grâce à l’ajout de spironolactone.
L’essai ATHENA-HF (AldosteroneTargeted Neurohormonal Combined withNatriuresis Therapy inHeartFailure) a été mené auprès de 360 patients présentant une IC aiguë et une fraction d’éjection réduite ou préservée, répartis aléatoirement pour recevoir pendant 96 heures soit de la spironolactone à raison de 100 mg par jour, soit les soins usuels. La présente analyse visait à évaluer les effets du traitement à l’étude en fonction des tertiles du taux de filtration glomérulaire estimé (TFGe) au début de l’étude et des sous-groupes de sujets présentant un risque accru de résistance aux diurétiques.
Dans tous les tertiles du TFGe, l’administration d’une forte dose de spironolactone n’a procuré aucun bienfait supplémentaire à l’égard des paramètres d’efficacité, y compris les variations logarithmiques du fragment N-terminal du propeptide du peptide natriurétique de type B N-Terminal et les signes et symptômes de congestion (toutes les valeurs de p pour l’interaction ≥ 0,06). L’administration d’une forte dose de spironolactone n’a pas eu d’effet significatif quant à la réduction du propeptide natriurétique de type B N-terminal, sans égard à la pression artérielle, à la présence ou à l’absence de diabète et à la dose du diurétique de l’anse (toutes les valeurs de p pour l’interaction ≥ 0,38). Les variations des taux sériques de potassium et de créatinine durant l’hospitalisation étaient comparables dans les deux groupes de traitement, et ce, dans tous les tertiles du TFGe (toutes les valeurs de p pour l’interaction ≥ 0,18). Le taux de patients dont l’IC s’est aggravée durant l’hospitalisation et après 30 jours, ainsi que le taux de mortalité toutes causes confondues à 60 jours, étaient numériquement supérieurs chez les patients présentant un TFGe inférieur au départ, mais les effets relatifs du traitement à l’étude ne variaient pas selon l’état de la fonction rénale (toutes les valeurs de p pour l’interaction ≥ 0,27).
L’administration d’une forte dose de spironolactone ne s’est pas révélée supérieure aux soins usuels pour réduire la congestion chez les patients présentant une IC aiguë, indépendamment de l’état de leur fonction rénale et des facteurs de risque de résistance aux diurétiques présents. La mise en route ou la poursuite du traitement par la spironolactone chez les patients hospitalisés s’est révélée sans danger durant le séjour à l’hôpital, même lorsque le médicament était administré à de fortes doses à des patients présentant une dysfonction rénale modérée.
Results are reported from a search for the rare decays Bs0→τ±μ∓ and B0→τ±μ∓, where the τ lepton is reconstructed in the channel τ−→π−π+π−ντ. These processes are effectively forbidden in the standard ...model, but they can potentially occur at detectable rates in models of new physics that can induce lepton-flavor-violating decays. The search is based on a data sample corresponding to 3 fb−1 of proton-proton collisions recorded by the LHCb experiment in 2011 and 2012. The event yields observed in the signal regions for both processes are consistent with the expected standard model backgrounds. Because of the limited mass resolution arising from the undetected τ neutrino, the Bs0 and B0 signal regions are highly overlapping. Assuming no contribution from B0→τ±μ∓, the upper limit B(Bs0→τ±μ∓)<4.2×10−5 is obtained at 95% confidence level. If no contribution from Bs0→τ±μ∓ is assumed, a limit of B(B0→τ±μ∓)<1.4×10−5 is obtained at 95% confidence level. These results represent the first limit on B(Bs0→τ±μ∓) and the most stringent limit on B(B0→τ±μ∓).
Purpose
Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, ...particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a “liquid biopsy” for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations.
Methods
Blood and biopsies of 1–3 tumors were obtained from 4 evaluable patients with advanced breast cancer. One patient provided samples from an additional 7 tumors post-mortem. DNA extracted from plasma, tumor tissues, and buffy coat of blood were used for probe-directed capture of all exons in 149 cancer-related genes and massively parallel sequencing. Somatic mutations in DNA from plasma and tumors were identified by comparison to buffy coat DNA.
Results
Sequencing of plasma DNA identified 27.94 ± 11.81% (mean ± SD) of mutations detected in a tumor(s) from the same patient; such mutations tended to be present at high allelic frequency. The majority of mutations found in plasma DNA were not found in tumor samples. Mutations were also found in plasma that matched clinically undetectable tumors found post-mortem.
Conclusions
The incomplete overlap of genetic alteration profiles of plasma and tumors warrants caution in the sole reliance of plasma DNA to identify therapeutically targetable alterations in patients and indicates that analysis of plasma DNA complements, but does not replace, tumor DNA profiling.
Trial Registration
: Subjects were prospectively enrolled in trial NCT01836640 (registered April 22, 2013).
Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity ...with sildenafil treatment in subjects with HF and preserved ejection fraction.
A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus -0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV -52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus -6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure.
In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.
Phosphaturic mesenchymal tumors (PMT) are rare neoplasms characterized by secretion of FGF23, resulting in renal phosphate wasting and osteomalacia. This tumor-induced osteomalacia (TIO) is cured by ...complete resection; thus, diagnosis is important, particularly on biopsy. Although PMT have a classic histologic appearance of bland spindled cells with conspicuous vascular network and characteristic smudgy basophilic matrix, there is a broad histologic spectrum and variant histologic patterns can make recognition difficult. Recent studies have demonstrated
FN1-FGFR1
and
FN1-FGF1
gene fusions in PMT; however, approximately 50% of cases are negative for these fusions. We sought to characterize 6 cases of PMT in-depth, compare fusion detection methods, and determine whether alternative fusions could be uncovered by targeted RNA sequencing. Of the 6 cases of PMT in our institutional archive, 3 were not given diagnoses of PMT at the time of initial pathologic examination. We characterized the immunoprofile (SMA, D2-40, CD56, S100 protein, desmin, SATB2, and ERG) and gene fusion status (
FN1
and
FGFR1
rearrangements by fluorescent in situ hybridization (FISH) and two targeted RNA sequencing approaches) in these cases. Tumors were consistently positive for SATB2 and negative for desmin, with 5/6 cases expressing ERG and CD56. One specimen was acid-decalcified and failed FISH and RNA sequencing. We found
FN1
gene rearrangements by FISH in 2/5 cases, and a
FN1-FGFR1
fusion by targeted RNA sequencing. No alternative gene fusions were identified by RNA sequencing. Our findings suggest that IHC and molecular analysis can aid in the diagnosis of PMT, guiding excision of the tumor and resolution of osteomalacia.
Mibefradil is a T-type Ca2+ channel antagonist with reported cross-reactivity with other classes of ion channels, including K+, Cl-, and Na+ channels. Using whole-cell voltage clamp, we examined ...mibefradil block of four Na+ channel isoforms expressed in human embryonic kidney cells: Nav1.5 (cardiac), Nav1.4 (skeletal muscle), Nav1.2 (brain), and Nav1.7 (peripheral nerve). Mibefradil blocked Nav1.5 in a use/frequency-dependent manner, indicating preferential binding to states visited during depolarization. Mibefradil blocked currents of all Na+ channel isoforms with similar affinity and a dependence on holding potential, and drug off-rate was slowed at depolarized potentials (k(off) was 0.024/s at -130 mV and 0.007/s at -100 mV for Nav1.5). We further probed the interaction of mibefradil with inactivated Nav1.5 channels. Neither the degree nor the time course of block was dependent on the stimulus duration, which dramatically changed the residency time of channels in the fast-inactivated state. In addition, inhibiting the binding of the fast inactivation lid (Nav1.5 ICM + MTSET) did not alter mibefradil block, confirming that the drug does not preferentially interact with the fast-inactivated state. We also tested whether mibefradil interacted with slow-inactivated state(s). When selectively applied to channels after inducing slow inactivation with a 60-s pulse to -10 mV, mibefradil (1 microM) produced 45% fractional block in Nav1.5 and greater block (88%) in an isoform (Nav1.4) that slow-inactivates more completely. Our results suggest that mibefradil blocks Na+ channels in a state-dependent manner that does not depend on fast inactivation but probably involves interaction with one or more slow-inactivated state(s).
Drell-Yan lepton pairs produced in the process pp¯→ℓ+ℓ−+X through an intermediate γ*/Z boson have an asymmetry in their angular distribution related to the spontaneous symmetry breaking of the ...electroweak force and the associated mixing of its neutral gauge bosons. The CDF and D0 experiments have measured the effective-leptonic electroweak mixing parameter sin2θefflept using electron and muon pairs selected from the full Tevatron proton-antiproton data sets collected in 2001-2011, corresponding to 9–10 fb−1 of integrated luminosity. The combination of these measurements yields the most precise result from hadron colliders, sin2θefflept=0.23148±0.00033. This result is consistent with, and approaches in precision, the best measurements from electron-positron colliders. The standard model inference of the on-shell electroweak mixing parameter sin2θW, or equivalently the W-boson mass MW, using the zfitter software package yields sin2θW=0.22324±0.00033 or equivalently, MW=80.367±0.017 GeV/c2.
Novel urinary kidney safety biomarkers have been identified recently that may outperform or add value to the conventional renal function biomarkers, blood urea nitrogen (BUN) and serum creatinine ...(SCr). To assess the relative performance of the growing list of novel biomarkers, a comprehensive evaluation was conducted for 12 urinary biomarkers in 22 rat studies including 12 kidney toxicants and 10 compounds with toxicities observed in organs other than kidney. The kidney toxicity studies included kidney tubular toxicants and glomerular toxicants. The 12 urinary biomarkers evaluated included Kim-1, clusterin, osteopontin, osteoactivin, albumin, lipocalin-2, GST-α, β2-microglobulin, cystatin C, retinol binding protein 4, total protein, and N-acetyl-β-D-glucosaminidase. Receiver operator characteristic (ROC) curves were generated for each biomarker and for BUN and SCr to compare the relative performance of the 12 biomarkers in individual animals against the microscopic histomorphologic changes observed in the kidney. Among the kidney toxicity biomarkers analyzed, Kim-1, clusterin, and albumin showed the highest overall performance for detecting drug-induced renal tubular injury in the rat in a sensitive and specific manner, whereas albumin showed the highest performance in detecting drug-induced glomerular injury. Although most of the evaluated kidney biomarkers were more sensitive in detecting kidney toxicity compared with BUN and SCr, all biomarkers demonstrated some lack of specificity, most notably NGAL and osteopontin, illustrating the need for caution when interpreting urinary biomarker increases in rat samples when organ toxicity is unknown.
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