Zebrafish models of cerebrovascular disease

Perturbations in cerebral blood flow and abnormalities in blood vessel structure are the hallmarks of cerebrovascular disease. While there are many genetic and environmental factors that affect these entities through a heterogeneous group of disease processes, the ultimate final pathologic insult in humans is defined as a stroke, or damage to brain parenchyma. In the case of ischemic stroke, blood fails to reach its target destination whereas in hemorrhagic stroke, extravasation of blood occurs outside of the blood vessel lumen, resulting in direct damage to brain parenchyma. As these acute events can be neurologically devastating, if not fatal, development of novel therapeutics are urgently needed. The zebrafish (Danio rerio) is an attractive model for the study of cerebrovascular disease because of its morphological and physiological similarity to human cerebral vasculature, its ability to be genetically manipulated, and its fecundity allowing for large-scale, phenotype-based screens

Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity

Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C-terminal, heat shock protein 90 (Hsp90) inhibitor), that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C-terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket. Consistent with these results, a meta-3-fluorophenyl substituted novologue (13b) exhibited a 14-fold lower ED50 compared to 2 for protection against glucose-induced toxicity of primary sensory neurons

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop

Extrasolar Planet Transits Observed at Kitt Peak National Observatory

We obtained J-, H- and JH-band photometry of known extrasolar planet transiting systems at the 2.1-m Kitt Peak National Observatory Telescope using the FLAMINGOS infrared camera between October 2008 and October 2011. From the derived lightcurves we have extracted the mid-transit times, transit depths and transit durations for these events. The precise mid-transit times obtained help improve the orbital periods and also constrain transit-time variations of the systems. For most cases the published system parameters successfully accounted for our observed lightcurves, but in some instances we derive improved planetary radii and orbital periods. We complemented our 2.1-m infrared observations using CCD z'-band and B-band photometry (plus two Hydrogen Alpha filter observations) obtained with the Kitt Peak Visitor's Center telescope, and with four H-band transits observed in October 2007 with the NSO's 1.6-m McMath-Pierce Solar Telescope. The principal highlights of our results are: 1) our ensemble of J-band planetary radii agree with optical radii, with the best-fit relation being: (Rp/R*)J = 0.0017 + 0.979 (Rp/R*)optical, 2) We observe star spot crossings during the transit of WASP-11/HAT-P-10, 3) we detect star spot crossings by HAT-P-11b (Kepler-3b), thus confirming that the magnetic evolution of the stellar active regions can be monitored even after the Kepler mission has ended, and 4) we confirm a grazing transit for HAT-P-27/WASP-40. In total we present 57 individual transits of 32 known exoplanet systems.Comment: 33 pages, 6 figures, accepted in Publications of the Astronomical Society of the Pacifi

Acute Clopidogrel Use and Outcomes in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery

OBJECTIVES We sought to characterize patterns of clopidogrel use before coronary artery bypass grafting (CABG) and examine the drug's impact on risks for postoperative transfusions among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). BACKGROUND Adherence in community practice to American College of Cardiology/American Heart Association guidelines for clopidogrel use among NSTE ACS patients has not been previously characterized. METHODS We evaluated 2,858 NSTE ACS patients undergoing CABG at 264 hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Initiative. We examined the patterns of acute clopidogrel therapy and its association with bleeding risks among those having early CABG ≤5 days and again among those having late surgery >5 days after catheterization. RESULTS Within 24 h of admission, 852 patients (30%) received clopidogrel. In contrast to national guidelines, 87% of clopidogrel-treated patients underwent CABG ≤5 days after treatment. Among those receiving CABG within ≤5 days of last treatment, the use of clopidogrel was associated with a significant increase in blood transfusions (65.0% vs. 56.9%, adjusted odds ratio [OR] 1.36, 95% confidence interval [CI] 1.10 to 1.68) as well as the need for transfusion of ≥4 U of blood (27.7% vs. 18.4%, OR 1.70, 95% CI 1.32 to 2.19). In contrast, acute clopidogrel therapy was not associated with higher bleeding risks if CABG was delayed >5 days (adjusted OR 1.18, 95% CI 0.54 to 2.58). CONCLUSIONS Despite guideline recommendations, the overwhelming majority of NSTE ACS patients treated with acute clopidogrel needing CABG have their surgery within ≤5 days of treatment. A failure to delay surgery is associated with increased blood transfusion requirements that must be weighed against the potential clinical and economic impacts of such delays

Multivariate Models of Adult Pacific Salmon Returns

Most modeling and statistical approaches encourage simplicity, yet ecological processes are often complex, as they are influenced by numerous dynamic environmental and biological factors. Pacific salmon abundance has been highly variable over the last few decades and most forecasting models have proven inadequate, primarily because of a lack of understanding of the processes affecting variability in survival. Better methods and data for predicting the abundance of returning adults are therefore required to effectively manage the species. We combined 31 distinct indicators of the marine environment collected over an 11-year period into a multivariate analysis to summarize and predict adult spring Chinook salmon returns to the Columbia River in 2012. In addition to forecasts, this tool quantifies the strength of the relationship between various ecological indicators and salmon returns, allowing interpretation of ecosystem processes. The relative importance of indicators varied, but a few trends emerged. Adult returns of spring Chinook salmon were best described using indicators of bottom-up ecological processes such as composition and abundance of zooplankton and fish prey as well as measures of individual fish, such as growth and condition. Local indicators of temperature or coastal upwelling did not contribute as much as large-scale indicators of temperature variability, matching the spatial scale over which salmon spend the majority of their ocean residence. Results suggest that effective management of Pacific salmon requires multiple types of data and that no single indicator can represent the complex early-ocean ecology of salmon

Growth and Feed Efficiency of Juvenile Channel Catfish Reared at Different Water Temperatures and Fed Diets Containing Various Levels of Fish Meal

Channel catfish Ictalurus punctatus do not feed well at low temperatures. It is generally thought that a diet containing fish meal enhances feed palatability at low temperatures since fish meal is highly palatable to fish. There is a lack of information on the effects of fish meal levels on the growth performance of channel catfish reared at low temperatures. Therefore, a study was conducted in a recirculating system to examine the effects of fish meal levels on the feed consumption, weight gain, and feed efficiency of juvenile channel catfish reared at various temperatures. Fish with an initial weight of 9.6 ± 0.1 g were stocked in 23-L clear polycarbonate tanks maintained at approximately 17, 21, or 27 °C. The fish were fed with diets containing 0, 4, or 8% menhaden Brevoortia spp. fish meal for 9 weeks. There was a significant interaction between water temperature and fish meal level with respect to weight gain. At 27 °C, fish fed diets containing 4% and 8% fish meal gained significantly more weight than fish fed the all-plantprotein diet. However, the level of fish meal had no significant effect on the weight gain of fish at 17 °C or 21 °C. This suggests that the olfactory and gustatory responses of channel catfish to fish meal (up to 8% in the diet) may not be as sensitive at low temperatures as at optimum temperatures. The results also indicate that more than 4% fish meal in the diet is not beneficial for the optimum growth and feed efficiency of channel catfish fingerlings raised at 27 °C

Applied Fisheries Oceanography: Ecosystem Indicators of Ocean Conditions Inform Fisheries Management in the California Current

Fisheries oceanography is the study of ecological relationships between fishes and the dynamics of their marine environments and aims to characterize the physical, chemical, and biological factors that affect the recruitment and abundance of harvested species. A recent push within the fisheries management community is toward ecosystem-based management. Here, we show how physical and biological oceanography data can be used to generate indicators of ocean conditions in an ecosystem context, and how these indicators relate to the recruitment of salmonids, sablefish, sardines, and rockfish in the California Current

The Impact of For-Profit Hospital Status on the Care and Outcomes of Patients With Non–ST-Segment Elevation Myocardial Infarction Results From the CRUSADE Initiative

ObjectivesWe sought to determine whether for-profit status influenced hospitals’ care or outcomes among non–ST-segment elevation myocardial infarction (NSTEMI) patients.BackgroundWhile for-profit hospitals potentially have financial incentives to selectively care for younger, healthier patients, perform highly reimbursed procedures, reduce costs by limiting access to expensive medications, and encourage shorter in-patient length of stay, there are limited data available to investigate these issues objectively.MethodsUsing data from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines) Initiative, we investigated whether for-profit status influenced hospitals’ patient case mix, care, or outcomes among 145,357 patients with NSTEMI treated between January 1, 2001, and December 31, 2005, at 532 U.S. hospitals. Impact of for-profit status on care and outcomes was analyzed overall and after adjustment for clinical and facility factors using regression modeling.ResultsPatients (n = 11,658) treated at 58 for-profit hospitals were of similar age and gender, but were more likely to be nonwhite (black, Asian, Hispanic, and other) and have health maintenance organization/private insurance, diabetes mellitus, congestive heart failure, hypertension, and renal insufficiency compared with 133,699 patients treated at 474 nonprofit hospitals. For-profit hospitals were less likely to use discharge beta-blockers, but all other treatments were similar including the use of interventional procedures (cardiac catheterization and revascularization procedures) compared with nonprofit centers. In-hospital length of stay and mortality were also similar by hospital type.ConclusionsWe found no evidence that for-profit hospitals selectively treat less sick patients, provide less evidence-based care, limit in-hospital stays, or have patients with worse acute outcomes than nonprofit centers

Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks.

Despite a common understanding that Gli TFs are utilized to convey a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, \u27divergent\u27 Gli-binding motifs (dGBMs). Functional validation revealed these dGBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal