1,432 research outputs found
A RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL COMPARING THE 22 VERSUS 26 GAUGE NEEDLE IN THE PRODUCTION OF THE POST-LUMBAR PUNCTURE SYNDROME IN NORMAL INDIVIDUALS
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73449/1/j.1526-4610.1972.hed1202073.x.pd
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Platelet endothelial cell adhesion molecule-1 inhibits platelet response to thrombin and von Willebrand factor by regulating the internalization of glycoprotein Ib via AKT/glycogen synthase kinase-3/dynamin and integrin Ī±IIbĪ²3
OBJECTIVE:
Platelet endothelial cell adhesion molecule-1 (PECAM-1) regulates platelet response to multiple agonists. How this immunoreceptor tyrosine-based inhibitory motif-containing receptor inhibits G protein-coupled receptor-mediated thrombin-induced activation of platelets is unknown.
APPROACH AND RESULTS:
Here, we show that the activation of PECAM-1 inhibits fibrinogen binding to integrin Ī±IIbĪ²3 and P-selectin surface expression in response to thrombin (0.1-3 U/mL) but not thrombin receptor-activating peptides SFLLRN (3Ć10(-7)-1Ć10(-5) mol/L) and GYPGQV (3Ć10(-6)-1Ć10(-4) mol/L). We hypothesized a role for PECAM-1 in reducing the tethering of thrombin to glycoprotein IbĪ± (GPIbĪ±) on the platelet surface. We show that PECAM-1 signaling regulates the binding of fluorescein isothiocyanate-labeled thrombin to the platelet surface and reduces the levels of cell surface GPIbĪ± by promoting its internalization, while concomitantly reducing the binding of platelets to von Willebrand factor under flow in vitro. PECAM-1-mediated internalization of GPIbĪ± was reduced in the presence of both EGTA and cytochalasin D or latrunculin, but not either individually, and was reduced in mice in which tyrosines 747 and 759 of the cytoplasmic tail of Ī²3 integrin were mutated to phenylalanine. Furthermore, PECAM-1 cross-linking led to a significant reduction in the phosphorylation of glycogen synthase kinase-3Ī² Ser(9), but interestingly an increase in glycogen synthase kinase-3Ī± pSer(21). PECAM-1-mediated internalization of GPIbĪ± was reduced by inhibitors of dynamin (Dynasore) and glycogen synthase kinase-3 (CHIR99021), an effect that was enhanced in the presence of EGTA.
CONCLUSIONS:
PECAM-1 mediates internalization of GPIbĪ± in platelets through dual AKT/protein kinase B/glycogen synthase kinase-3/dynamin-dependent and Ī±IIbĪ²3-dependent mechanisms. These findings expand our understanding of how PECAM-1 regulates nonimmunoreceptor signaling pathways and helps to explains how PECAM-1 regulates thrombosis
"Antiscepticism and Easy Justification" - Ch 5 of Seemings and Epistemic Justification
In this chapter I investigate epistemological consequences of the fact that seeming-based justification is elusive, in the sense that the subject can lose this justification simply by reflecting on her seemings. I argue that since seeming-based justification is elusive, the antisceptical bite of phenomenal conservatism is importantly limited. I also contend that since seeming-based justification has this feature, phenomenal conservatism isnāt actually afflicted by easy justification problems
Post-mortem culture of Balamuthia mandrillaris from the brain and cerebrospinal fluid of a case of granulomatous amoebic meningoencephalitis, using human brain microvascular endothelial cells
The first isolation in the UK of Balamuthia mandrillaris amoebae from a fatal case of granulomatous amoebic meningoencephalitis is reported. Using primary cultures of human brain microvascular endothelial cells (HBMECs), amoebae were isolated from the brain and cerebrospinal fluid (CSF). The cultures showed a cytopathic effect at 20ā28 days, but morphologically identifiable B. mandrillaris amoebae were seen in cleared plaques in subcultures at 45 days. The identification of the organism was later confirmed using PCR on Chelex-treated extracts. Serum taken while the patient was still alive reacted strongly with slide antigen prepared from cultures of the post-mortem isolate, and also with those from a baboon B. mandrillaris strain at 1 : 10 000 in indirect immunofluorescence, but with Acanthamoeba castellanii (Neff) at 1 : 160, supporting B. mandrillaris to be the causative agent. If the presence of amoebae in the post-mortem CSF reflects the condition in life, PCR studies on CSF and on biopsies of cutaneous lesions may also be a valuable tool. The role of HBMECs in understanding the interactions of B. mandrillaris with the bloodābrain barrier is discussed
Using Genetic Technologies To Reduce, Rather Than Widen, Health Disparities
Evidence shows that both biological and nonbiological factors contribute to health disparities. Genetics, in particular, plays a part in how common diseases manifest themselves. Today, unprecedented advances in genetically based diagnoses and treatments provide opportunities for personalized medicine. However, disadvantaged groups may lack access to these advances, and treatments based on research on non-Hispanic whites might not be generalizable to members of minority groups. Unless genetic technologies become universally accessible, existing disparities could be widened. Addressing this issue will require integrated strategies, including expanding genetic research, improving genetic literacy, and enhancing access to genetic technologies among minority populations in a way that avoids harms such as stigmatization
On the Relationship Between Phylogenetic Diversity and Trait Diversity
Niche differences are key to understanding the distribution and structure of biodiversity. To examine niche differences, we must first characterize how species occupy niche space, and two approaches are commonly used in the ecological literature. The first uses species traits to estimate multivariate trait space (soācalled functional trait diversity, FD); the second quantifies the amount of time or evolutionary history captured by a group of species (phylogenetic diversity, PD). It is oftenābut controversiallyāassumed that these putative measures of niche space are at a minimum correlated and perhaps redundant, since more evolutionary time allows for greater accumulation of trait changes. This theoretical expectation remains surprisingly poorly evaluated, particularly in the context of multivariate measures of trait diversity. We evaluated the relationship between phylogenetic diversity and trait diversity using analytical and simulationābased methods across common models of trait evolution. We show that PD correlates with FD increasingly strongly as more traits are included in the FD measure. Our results indicate that phylogenetic diversity can be a useful surrogate for highādimensional trait diversity, but we also show that the correlation weakens when the underlying process of trait evolution includes variation in rate and optima
General dimensions of human brain morphometry inferred from genome-wide association data
Understanding the neurodegenerative mechanisms underlying cognitive decline in the general population may facilitate early detection of adverse health outcomes in late life. This study investigates genetic links between brain morphometry, ageing and cognitive ability. We develop Genomic Principal Components Analysis (Genomic PCA) to model general dimensions of brain-wide morphometry at the level of their underlying genetic architecture. Genomic PCA is applied to genome-wide association data for 83 brain-wide volumes (36,778 UK Biobank participants) and we extract genomic principal components (PCs) to capture global dimensions of genetic covariance across brain regions (unlike ancestral PCs that index genetic similarity between participants). Using linkage disequilibrium score regression, we estimate genetic overlap between those general brain dimensions and cognitive ageing. The first genetic PCs underlying the morphometric organisation of 83 brain-wide regions accounted for substantial genetic variance (R2 Ā =Ā 40%) with the pattern of component loadings corresponding closely to those obtained from phenotypic analyses. Genetically more central regions to overall brain structure - specifically frontal and parietal volumes thought to be part of the central executive network - tended to be somewhat more susceptible towards age (rĀ =Ā -0.27). We demonstrate the moderate genetic overlap between the first PC underlying each of several structural brain networks and general cognitive ability (rg Ā =Ā 0.17-0.21), which was not specific to a particular subset of the canonical networks examined. We provide a multivariate framework integrating covariance across multiple brain regions and the genome, revealing moderate shared genetic etiology between brain-wide morphometry and cognitive ageing
Perfluorinated alkyl acids and fecundity assessment in striped mullet (\u3ci\u3eMugil cephalus\u3c/i\u3e) at Merritt Island national wildlife refuge
This study investigated wild caught striped mullet (Mugil cephalus) at Merritt Island National Wildlife Refuge (MINWR) for levels of 15 perfluoroalkyl acids (PFAA) in tandem with individual fecundity measurements (Oocyte sub-stage 2 late, n=42) and oocyte reproductive stages (Stages 1ā5, n=128). PFAAmeasurementswere quantified in stripedmullet liver (n=128),muscle (n=49), and gonad (n=10). No significant negative impacts of liver PFAA burden on wild-caught,mullet fecundity endpoints were observed in this study; however, changes in PFAAwere observed in the liver asmullet progressed through different sub-stages of oocyte development. Of the PFAA with significant changes by sub-stage of oocyte development, the carboxylic acids (perfluorooctanoic acid, perfluorononanoic acid, and perfluorotridecanoic acid) increased in the liver with increasing sub-stage while the sulfonic acid and its precursor (perfluorooctanesulfonic acid (PFOS) and perfluorooctanesulfonamide, respectively) decreased in the liver with increasing sub-stage of oocyte development. This is a unique find and suggests PFAA change location of compartmentalization as mullet progress towards spawning. Investigations also revealed higher than expected median muscle and gonad levels of PFOS in striped mullet collected at MINWR (9.01 ng/g and 80.2 ng/g, respectively)
Transiting Exoplanet Studies and Community Targets for JWST's Early Release Science Program
The James Webb Space Telescope will revolutionize transiting exoplanet
atmospheric science due to its capability for continuous, long-duration
observations and its larger collecting area, spectral coverage, and spectral
resolution compared to existing space-based facilities. However, it is unclear
precisely how well JWST will perform and which of its myriad instruments and
observing modes will be best suited for transiting exoplanet studies. In this
article, we describe a prefatory JWST Early Release Science (ERS) program that
focuses on testing specific observing modes to quickly give the community the
data and experience it needs to plan more efficient and successful future
transiting exoplanet characterization programs. We propose a multi-pronged
approach wherein one aspect of the program focuses on observing transits of a
single target with all of the recommended observing modes to identify and
understand potential systematics, compare transmission spectra at overlapping
and neighboring wavelength regions, confirm throughputs, and determine overall
performances. In our search for transiting exoplanets that are well suited to
achieving these goals, we identify 12 objects (dubbed "community targets") that
meet our defined criteria. Currently, the most favorable target is WASP-62b
because of its large predicted signal size, relatively bright host star, and
location in JWST's continuous viewing zone. Since most of the community targets
do not have well-characterized atmospheres, we recommend initiating preparatory
observing programs to determine the presence of obscuring clouds/hazes within
their atmospheres. Measurable spectroscopic features are needed to establish
the optimal resolution and wavelength regions for exoplanet characterization.
Other initiatives from our proposed ERS program include testing the instrument
brightness limits and performing phase-curve observations.(Abridged)Comment: This is a white paper that originated from an open discussion at the
Enabling Transiting Exoplanet Science with JWST workshop held November 16 -
18, 2015 at STScI (http://www.stsci.edu/jwst/science/exoplanets). Accepted
for publication in PAS
Calvarium Thinning in Patients with Spontaneous Cerebrospinal Fluid Leaks of the Anterior Skull Base
Objectives/Hypothesis
Patients with spontaneous cerebrospinal fluid leaks (sCSF-L) of the temporal bone have isolated calvarial and skull base thinning that is independent of obesity. This study determines if anterior skull base (ASB) sCSF-L patients also have calvarial thinning.
Study Design
Retrospective Cohort Study.
Methods
This was a retrospective cohort study of ASB sCSF-L patients compared to nonobese (body mass index [BMI]ā<ā30ākg/m2) and obese (BMIāā„ā30) control groups. Twenty-one patients in the ASB sCSF-L group and 25 patients in each control group were included. Calvarium and extracranial zygoma thicknesses were measured bilaterally with blinded, standardized, volumetric analysis.
Results
ASB sCSF-L patients had a mean (SD) age of 50.43 (10.19) years, an average (SD) BMI of 38.81 (8.92) kg/m2, and most were female (85.71%). The calvarium in patients with ASB sCSF-L was significantly thinner than the nonobese (2.55āmm [0.77] vs. 2.97 [0.67] mm; P =ā.006; 95% confidence intervals [CI], 0.12ā0.30; Cohen d, 0.58) and obese control groups (2.55 [0.77] vs. 2.92 [0.76] mm; P =ā.02; 95% CI, 0.05ā0.34; Cohen d, 0.66). The calvarium thickness of the nonobese patients was not significantly different from the obese patient controls (2.97 [0.67] vs. 2.92 [0.76] mm, P =ā.9). The extracranial zygoma was not significantly different among the groups (analysis of variance, P =ā.33).
Conclusions
ASB sCSF-L patients have isolated calvarial thinning that is independent of obesity. Like lateral skull base sCSF-L patients, these data suggest that the additional obesity-associated intracranial process contributes to skull thinning
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