The Role of Fatty Acids and Cigarette Smoke Toxicants in Cigarette Smoke-Induced Cardiovascular Disease

Young, healthy smokers have an increased risk of developing cardiovascular disease (CVD), but early identification of these individuals can prevent progression to more severe cardiovascular diseases like atherosclerosis, stroke, and heart attacks. However, methods developed to detect cardiovascular disease in its early stages are limited and very costly. The goal of this project is to identify biomarkers that can be tested in a single blood draw from smokers in order to both assess their risk of developing cardiovascular disease and identify possible therapeutic targets to prevent disease progression. The long term goals of this project are to investigate the association between CVD risk, aryl hydrocarbon receptor (AHR) activity, and polyunsaturated fatty acids (PUFAs) in smokers, and to elucidate the mechanisms of their contribution to cigarette smoke (CS)-induced vascular dysfunction. We have shown that AHR activity and α-linolenic acid (ALA, an n-3 PUFA) are potential biomarkers for CVD risk in young, healthy smokers. It is possible that the biomarkers identified in young, healthy smokers may serve not only as early identification of individuals most at risk of developing CVD, but also as biomarkers for future CVD risk in smokers with early stage CVD. As expected, the biomarkers identified in young, healthy smokers are different from biomarkers identified in older smokers with hypertension, a risk factor for development of CVD. In a second study conducted in subjects between 40 and 70 yrs old with physician-diagnosed hypertension. We found that ALA, which we previously demonstrated to predict flow-mediated dilation (FMD) in young, healthy smokers, is not associated with atherosclerotic cardiovascular disease (ASCVD) risk in smokers with preexisting hypertension. Nonetheless, we found that 13,14-dihydroxydocosapentaenoic acid (DiHDPA), along with 11- and 20-hydroxyeicosatetraenoic acid (HETE), predict ASCVD risk in smokers, whereas 14,15-epoxyeicosatetraenoic acid (EEQ), 13,14- and 16,17-epoxyeicosatetraenoic acid (EDP), and 16,17-DiHDPA predict ASCVD risk in non-smokers. These results suggest that the fatty acids identified in this study may be used to predict CVD risk in subjects with pre-existing CVD risk factors. In order to investigate the specific mechanisms through which n-3 PUFAs protect against CS-induced vascular dysfunction in humans, we generated a mouse model of CS-exposure that resembles what is seen in young, healthy smokers. We made the novel observation that although CS impairs nitric oxide (NO)-dependent flow-mediated dilation (FMD), an n-3 PUFA diet restores FMD by increasing NO-independent dilation. We also found that the vasoprotective properties of n-3 PUFAs may be, at least in part, due to its antioxidant properties and reduction of Cyp1a1 expression. These studies will contribute to the understanding of CVD progression in smokers and the mechanisms of how n-3 PUFAs protect against CS-induced CVD. In addition, these findings will continue to contribute to the development of biomarkers to detect patients at high CVD risk while they are at early stages of the disease

Remodeling of brain morphology in temporal lobe epilepsy.

Mesial temporal lobe epilepsy (TLE) is one of the most widespread neurological network disorders. Computational anatomy MRI studies demonstrate a robust pattern of cortical volume loss. Most statistical analyses provide information about localization of significant focal differences in a segregationist way. Multivariate Bayesian modeling provides a framework allowing inferences about inter-regional dependencies. We adopt this approach to answer following questions: Which structures within a pattern of dynamic epilepsy-associated brain anatomy reorganization best predict TLE pathology. Do these structures differ between TLE subtypes? We acquire clinical and MRI data from TLE patients with and without hippocampus sclerosis (n = 128) additional to healthy volunteers (n = 120). MRI data were analyzed in the computational anatomy framework of SPM12 using classical mass-univariate analysis followed by multivariate Bayesian modeling. After obtaining TLE-associated brain anatomy pattern, we estimate predictive power for disease and TLE subtypes using Bayesian model selection and comparison. We show that ipsilateral para-/hippocampal regions contribute most to disease-related differences between TLE and healthy controls independent of TLE laterality and subtype. Prefrontal cortical changes are more discriminative for left-sided TLE, whereas thalamus and temporal pole for right-sided TLE. The presence of hippocampus sclerosis was linked to stronger involvement of thalamus and temporal lobe regions; frontoparietal involvement was predominant in absence of sclerosis. Our topology inferences on brain anatomy demonstrate a differential contribution of structures within limbic and extralimbic circuits linked to main effects of TLE and hippocampal sclerosis. We interpret our results as evidence for TLE-related spatial modulation of anatomical networks

A finite-volume scheme for modeling compressible magnetohydrodynamic flows at low Mach numbers in stellar interiors

Fully compressible magnetohydrodynamic (MHD) simulations are a fundamental tool for investigating the role of dynamo amplification in the generation of magnetic fields in deep convective layers of stars. The flows that arise in such environments are characterized by low (sonic) Mach numbers (M_son < 0.01 ). In these regimes, conventional MHD codes typically show excessive dissipation and tend to be inefficient as the Courant-Friedrichs-Lewy (CFL) constraint on the time step becomes too strict. In this work we present a new method for efficiently simulating MHD flows at low Mach numbers in a space-dependent gravitational potential while still retaining all effects of compressibility. The proposed scheme is implemented in the finite-volume Seven-League Hydro (SLH) code, and it makes use of a low-Mach version of the five-wave Harten-Lax-van Leer discontinuities (HLLD) solver to reduce numerical dissipation, an implicit-explicit time discretization technique based on Strang splitting to overcome the overly strict CFL constraint, and a well-balancing method that dramatically reduces the magnitude of spatial discretization errors in strongly stratified setups. The solenoidal constraint on the magnetic field is enforced by using a constrained transport method on a staggered grid. We carry out five verification tests, including the simulation of a small-scale dynamo in a star-like environment at M_son ~ 0.001 . We demonstrate that the proposed scheme can be used to accurately simulate compressible MHD flows in regimes of low Mach numbers and strongly stratified setups even with moderately coarse grids

Cognitive improvement in patients with carotid stenosis is independent of treatment type

Treatment of carotid artery stenosis decreases the long-term risk of stroke and may enhance cerebral blood flow. It is therefore expected to have the potential to prevent cognitive decline or even improve cognition over the long-term. However, intervention itself can cause peri-interventional cerebral infarcts, possibly resulting in a decline of cognitive performance, at least for a short time. We investigated the long-term effects of three treatment methods on cognition and the emotional state one year after intervention. In this prospective observational cohort study, 58 patients with extracranial carotid artery stenosis (≥ 70%) underwent magnetic resonance imaging and assessment of cognition, mood and motor speed before carotid endarterectomy (n = 20), carotid stenting (n = 10) or best medical treatment (n = 28) (i.e., time-point 1 [TP1]), and at one-year follow-up (TP2). Gain scores, reflecting cognitive change after treatment, were built according to performance as (TP2 -TP1)/TP1. Independent of the treatment type, significant improvement in frontal lobe functions, visual memory and motor speed was found. Performance level, motor speed and mood at TP1 were negatively correlated with gain scores, with greater improvement in patients with low performance before treatment. Active therapy, whether conservative or interventional, produces significant improvement of frontal lobe functions and memory in patients with carotid artery disease, independent of treatment type. This effect was particularly pronounced in patients with low cognitive performance prior to treatment

Local field potential activity dynamics in response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Local field potentials (LFPs) may afford insight into the mechanisms of action of deep brain stimulation (DBS) and potential feedback signals for adaptive DBS. In Parkinson's disease (PD) DBS of the subthalamic nucleus (STN) suppresses spontaneous activity in the beta band and drives evoked resonant neural activity (ERNA). Here, we investigate how STN LFP activities change over time following the onset and offset of DBS. To this end we recorded LFPs from the STN in 14 PD patients during long (mean: 181.2 s) and short (14.2 s) blocks of continuous stimulation at 130 Hz. LFP activities were evaluated in the temporal and spectral domains. During long stimulation blocks, the frequency and amplitude of the ERNA decreased before reaching a steady state after ~70 s. Maximal ERNA amplitudes diminished over repeated stimulation blocks. Upon DBS cessation, the ERNA was revealed as an under-damped oscillation, and was more marked and lasted longer after short duration stimulation blocks. In contrast, activity in the beta band suppressed within 0.5 s of continuous DBS onset and drifted less over time. Spontaneous activity was also suppressed in the low gamma band, suggesting that the effects of high frequency stimulation on spontaneous oscillations may not be selective for pathological beta activity. High frequency oscillations were present in only six STN recordings before stimulation onset and their frequency was depressed by stimulation. The different dynamics of the ERNA and beta activity with stimulation imply different DBS mechanisms and may impact how these activities may be used in adaptive feedback

Immunohistochemical localization of fibronectin as a tool for the age determination of human skin wounds

We analyzed the distribution of fibronectin in routinely embedded tissue specimens from 53 skin wounds and 6 postmortem wounds. In postmortem wounds a faint but focal positive staining was exclusively found at the margin of the specimens which dit not extend into the adjacent stroma. Vital wounds were classified into 3 groups. The first comprising lesions with wound ages ranging from a few seconds to 30 min, the second comprising those with wound ages upt to 3 weeks, and the third group with lesions more than 3 weeks old. Ten out of 17 lesions with a wound age up to 30 min showed a clear positive reaction within the wound area. Three specimens in this group were completely negative, while in 4 additional cases the result was not significantly different from postmortem lesions. These 7 cases were characterized by acute death with extremely short survival times (only seconds). In wounds up to 3 weeks old fibronectin formed a distinct network containing an increasing number of inflammatory cells corresponding to the wound age. In 2 cases with a survival time of 17 days and in all wounds older than 3 weeks fibronectin was restricted to the surface of fibroblasts and to parallel arranged fibers in the granulation tissue without any network structures. We present evidence that fibronectin is a useful marker for vital wounds with a survival time of more than a few minutes. Fibronectin appears before neutrophilic granulocytes migrate into the wound area. Since a faint positive fibronectin staining is seen in postmortem lesions and bleedings, we propose that only those wounds which show strong positive fibronectin staining also extending into the adjacent stroma should be regarded as vital

Explaining participation in regional transnational social movement organizations

Since the late 1980s, governments have focused intensely on formalizing political and economic relationships within regions. There has also been a concurrent rise in transnational, regional level organizing among social movement activists globally, suggesting the regionalization of 'global civil society.' However, opportunities for participation in transnational associations vary widely across countries. In this article, we examine the influence of international (both global and regional) institutional contexts, citizen participation in international society, and national level factors on varying levels of participation in regional transnational social movement organizations (TSMOs). We use negative binomial regression to examine relationships among these factors at three time points: 1980, 1990, and 2000. We find that in the early time period, citizen network connections to international society facilitated the formation of and participation in regionally organized TSMOs. Over time, however, regional and global institutional contexts were more predictive of participation in regional TSMOs than were international network ties. Our analysis also uncovered how qualitatively different forms of regionalism translated into significantly different levels of TSMO regionalization. In Europe, where the regional institutional structure is more elaborated than elsewhere in the world, the number of regional TSMOs in which citizens participated greatly outpaced that found elsewhere. Irrespective of international, institutional factors, however, state-level features remained crucial to explaining the development of regional TSMO sectors and the variable levels of participation in them. Citizens in states with restrictions on political rights and civil liberties had significantly lower participation in these organizations in 1990 and 2000. Even so, over time, citizens in states with more ties to global and regional multilateral processes found more ways to overcome this disadvantage and strengthen their participation in regional, transnational civil society. © 2007 SAGE Publications

First direct detection of an exoplanet by optical interferometry; Astrometry and K-band spectroscopy of HR8799 e

To date, infrared interferometry at best achieved contrast ratios of a few times $10^{-4}$ on bright targets. GRAVITY, with its dual-field mode, is now capable of high contrast observations, enabling the direct observation of exoplanets. We demonstrate the technique on HR8799, a young planetary system composed of four known giant exoplanets. We used the GRAVITY fringe tracker to lock the fringes on the central star, and integrated off-axis on the HR8799e planet situated at 390 mas from the star. Data reduction included post-processing to remove the flux leaking from the central star and to extract the coherent flux of the planet. The inferred K band spectrum of the planet has a spectral resolution of 500. We also derive the astrometric position of the planet relative to the star with a precision on the order of 100$\,\mu$as. The GRAVITY astrometric measurement disfavors perfectly coplanar stable orbital solutions. A small adjustment of a few degrees to the orbital inclination of HR 8799 e can resolve the tension, implying that the orbits are close to, but not strictly coplanar. The spectrum, with a signal-to-noise ratio of $\approx 5$ per spectral channel, is compatible with a late-type L brown dwarf. Using Exo-REM synthetic spectra, we derive a temperature of $1150\pm50$\,K and a surface gravity of $10^{4.3\pm0.3}\,$cm/s$^{2}$. This corresponds to a radius of $1.17^{+0.13}_{-0.11}\,R_{\rm Jup}$ and a mass of $10^{+7}_{-4}\,M_{\rm Jup}$, which is an independent confirmation of mass estimates from evolutionary models. Our results demonstrate the power of interferometry for the direct detection and spectroscopic study of exoplanets at close angular separations from their stars.Comment: published in A&