bluuebunny/crossref_metadata_2025 huggingface dataset:
IL-6 Deficiency Protects Against Angiotensin II–Induced Endothelial Dysfunction and Hypertrophy
Authors: Schrader Laura I. , Kinzenbaw Dale A. , Johnson Andrew W. , Faraci Frank M. , Didion Sean P.
Published: October 2007

Objective—

The goal of this study was to test the hypothesis that IL-6 mediates the increases in superoxide, vascular hypertrophy, and endothelial dysfunction in response to angiotensin II (Ang II).

Methods and Results—

Responses of carotid arteries from control and IL-6–deficient mice were examined after acute (22-hour) incubation with Ang II (10 nmol/L) or chronic infusion of Ang II (1.4 mg/kg/d for 14 days). The hypertrophic response and endothelial dysfunction produced by Ang II infusion was markedly less in carotid arteries from IL-6–deficient mice than that in control mice. IL-6 deficiency also protected against endothelial dysfunction in response to acute (local) Ang II treatment (eg, 100 μmol/L acetylcholine produced 100±4 and 98±4% relaxation in vehicle-treated and 51±4 and 99±4% relaxation in Ang II–treated, control, and IL-6–deficient vessels, respectively). Endothelial dysfunction could be reproduced in vessels from IL-6–deficient mice with combined Ang II plus IL-6 (0.1 nmol/L) treatment. Increases in vascular superoxide and IL-6, as well as reductions in endothelial nitric oxide synthase mRNA expression, produced by Ang II were absent in IL-6–deficient mice.

Conclusions—

These data demonstrate that IL-6 is essential for Ang II–induced increases in superoxide, endothelial dysfunction, and vascular hypertrophy.
Notch Signaling Contributes to the Expression of Cardiac Markers in Human Circulating Progenitor Cells
Authors: Koyanagi Masamichi , Bushoven Philipp , Iwasaki Masayoshi , Urbich Carmen , Zeiher Andreas M. , Dimmeler Stefanie
Published: October 2007

It has been demonstrated that adult human circulating endothelial progenitor cells (EPCs) can differentiate to a cardiomyogenic phenotype. Notch signaling promotes epithelial-to-mesenchymal transformation and plays a role in heart and vessel development. Here, we investigated the role of Notch activation for cardiac differentiation of EPCs in a coculture system with neonatal cardiomyocyte. After coculture, Notch activation was transiently detected in EPCs, as determined by immunhistochemical detection of NICD (the intracellular cleavage fragment of Notch-1) and expression of human Notch target genes. Inhibition of γ-secretase blocked Notch cleavage and NICD translocation. Furthermore, the expression of the cardiac marker protein α-sarcomeric actinin and troponin T was significantly suppressed by γ-secretase inhibition or addition of soluble recombinant Jagged-1, indicating that Notch activation facilitates cardiac marker gene expression. Because noncanonical Wnts have previously been shown to promote cardiac differentiation, we additionally determined the influence of Notch activation on the expression of Wnt5a and Wnt11. Wnt5a and Wnt11 expression in the human cells was induced by the coculture and was blocked by γ-secretase inhibition. Likewise, stimulation of Notch signaling by immobilized Jagged-1 promoted Wnt5a expression in EPCs. These data suggest that Notch is activated upon coculture of EPCs with neonatal rat cardiac myocytes. γ-Secretase–dependent Notch activation is required for cardiac gene expression in human cells and induces the expression of noncanonical Wnt proteins, which may act in a paracrine manner to further amplify cardiac differentiation.
Hemin Upregulates Egr-1 Expression in Vascular Smooth Muscle Cells via Reactive Oxygen Species ERK-1/2–Elk-1 and NF-κB
Authors: Hasan Rukhsana N. , Schafer Andrew I.
Published: October 2007

Reactive oxygen species (ROS) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis. One source of ROS in the vasculature is free heme released from hemoglobin. Because Egr-1, the regulator of cell proliferation and apoptosis, is also induced by oxidant stress and is likewise implicated in atherosclerosis, we examined the regulation of Egr-1 by heme in vascular smooth muscle cells (SMCs). Hemin increased Egr-1 expression (mRNA, protein) within 30 minutes and ERK-1/2 phosphorylation and nuclear translocation within 5 minutes. Inhibiting hemin-induced ERK-1/2 activation by U0126 (MAPK-inhibitor), the antioxidant
N
-acetyl cysteine, the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride, the superoxide scavenger tiron, or tricarbonyldichlororuthenium(II)-dimer (carbon-monoxide donor; CORM-2) blocked hemin-induced Egr-1 expression. Hemin activated Elk-1, SRF, and NF-κB and promoted their interaction with the Egr-1 promoter. Downregulating Elk-1 (via siRNA) or blocking NF-κB activation (via BAY-11-7082) abolished hemin induction of Egr-1. Finally, hemin-induced Egr-1 bound the promoters of tissue factor (TF), Plasminogen Activator Inhibitor (PAI)-1, and NGF-1A Binding (NAB)-2, upregulating their expression, and increased the biochemical activity of TF and PAI-1. Upregulation of Egr-1 and its target genes by heme-induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis.
A Population of Multipotent CD34-Positive Adipose Stromal Cells Share Pericyte and Mesenchymal Surface Markers, Reside in a Periendothelial Location, and Stabilize Endothelial Networks
Authors: Traktuev Dmitry O. , Merfeld-Clauss Stephanie , Li Jingling , Kolonin Mikhail , Arap Wadih , Pasqualini Renata , Johnstone Brian H. , March Keith L.
Published: October 2007

It has been shown that stromal–vascular fraction isolated from adipose tissues contains an abundance of CD34
+
cells. Histological analysis of adipose tissue revealed that CD34
+
cells are widely distributed among adipocytes and are predominantly associated with vascular structures. The majority of CD34
+
cells from freshly isolated stromal–vascular fraction were CD31
−
/CD144
−
and could be separated from a distinct population of CD34
+
/CD31
+
/CD144
+
(endothelial) cells by differential attachment on uncoated plastic. The localization of CD34
+
cells within adipose tissue suggested that the nonendothelial population of these cells occupied a pericytic position. Analysis of surface and intracellular markers of the freshly isolated CD34
+
/CD31
−
/CD144
−
adipose-derived stromal cells (ASCs) showed that >90% coexpress mesenchymal (CD10, CD13, and CD90), pericytic (chondroitin sulfate proteoglycan, CD140a, and CD140b), and smooth muscle (α-actin, caldesmon, and calponin) markers. ASCs demonstrated polygonal self-assembly on Matrigel, as did human microvascular endothelial cells. Coculture of ASCs with human microvascular endothelial cells on Matrigel led to cooperative network assembly, with enhanced stability of endothelial networks and preferential localization of ASCs on the abluminal side of cords. Bidirectional paracrine interaction between these cells was supported by identification of angiogenic factors (vascular endothelial growth factor, hepatocyte growth factor, basic fibroblast growth factor), inflammatory factors (interleukin-6 and -8 and monocyte chemoattractant protein-1 and -2), and mobilization factors (macrophage colony-stimulating factor and granulocyte/macrophage colony-stimulating factor) in media conditioned by CD34
+
ASCs, as well a robust mitogenic response of ASCs to basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor-BB, factors produced by endothelial cells. These results demonstrate for the first time that the majority of adipose-derived adherent CD34
+
cells are resident pericytes that play a role in vascular stabilization by mutual structural and functional interaction with endothelial cells.
Coexistence of Foam Cells and Hypocholesterolemia in Mice Lacking the ABC Transporters A1 and G1
Authors: Out Ruud , Jessup Wendy , Le Goff Wilfried , Hoekstra Menno , Gelissen Ingrid C. , Zhao Ying , Kritharides Leonard , Chimini Giovanna , Kuiper Johan , Chapman M. John , Huby Thierry , Van Berkel Theo J.C. , Van Eck Miranda
Published: October 2007

The concept that macrophages can become foam cells as a result of a disturbed balance between the uptake of cholesterol from lipoproteins and cholesterol efflux is generally accepted. ABCA1 and ABCG1 are two cholesterol transporters that may act sequentially to remove cellular cholesterol, but currently their combined role in vivo is unknown. We report here that targeted disruption of both ABCA1 and ABCG1 in mice, despite severe plasma hypocholesterolemia, leads to massive lipid accumulation and foam cell formation of tissue macrophages. A complete ablation of cellular cholesterol efflux in vitro is observed, whereas in vivo macrophage-specific reverse cholesterol transport to the feces is markedly decreased. Despite the massive foam cell formation of tissue macrophages, no lipid accumulation was observed in the vascular wall, even in mice of 1 year old, indicating that the double knockout mice, possibly because of their hypocholesterolemia, lack the trigger to attract macrophages to the vessel wall. In conclusion, even under hypocholesterolemic conditions macrophages can be converted into foam cells, and ABCA1 and ABCG1 play an essential role in the prevention of foam cell formation.
Magnetization Transfer Imaging Shows Tissue Abnormalities in the Reversible Penumbra
Authors: Tourdias Thomas , Dousset Vincent , Sibon Igor , Pele Eric , Menegon Patrice , Asselineau Julien , Pachai Chahin , Rouanet François , Robinson Philip , Chene Geneviève , Orgogozo Jean Marc
Published: October 2007

Background and Purpose—

In the concept of ischemic penumbra, the volume of salvaged penumbra is considered as the volume of FLAIR normalization on follow-up MRI compared with early diffusion and perfusion abnormalities. Using magnetization transfer imaging, very sensitive to macromolecular disruption, we investigated whether FLAIR normalization was a good marker for tissue full recovery.

Methods—

We prospectively included 30 patients with acute middle cerebral artery stroke. Diffusion-weighted imaging (DWI) and perfusion-weighted imaging were performed within 12 hours after onset (MRI.1), and the final infarct was documented by MRI with FLAIR and magnetization transfer at 1-month follow-up (MRI.2). We compared magnetic transfer ratio of a normal region with values measured at 1 month (MRI.2) in 4 regions of interest: (1) the initial DWI hypersignal (CORE=DWI_MRI.1); (2) the infarct growth area (infarct growth=FLAIR_MRI.2−DWI_MRI.1); (3) the hypoperfused area that normalized (reversible perfusion abnormalities=perfusion-weighted imaging_MRI.1−FLAIR_ MRI.2); and (4) the early DWI abnormalities that normalized (reversible diffusion abnormalities=DWI_MRI.1− FLAIR_MRI.2).

Results—

In comparison with values obtained in normal tissue (magnetic transfer ratio=49.8%, SD=1.9), magnetic transfer ratio at 1 month was significantly decreased in reversible perfusion abnormalities (45.2%, SD=2.5;
P
<0.0001) and reversible diffusion abnormalities (43.2%, SD=2.8;
P
=0.0156). It was also markedly reduced, as expected, in the CORE (40.9%, SD=5.2) and infarct growth regions (43.1%, SD=2.0).

Conclusions—

Magnetic transfer ratio assessed presence of microstructural damages in the MRI-defined salvaged penumbra. This may imply cellular loss and partial infarction. Evaluation of the efficacy of therapies that promote reperfusion or neuroprotection may benefit from this additional information.
Incidence of Visual Extinction After Left Versus Right Hemisphere Stroke
Authors: Becker Elisabeth , Karnath Hans-Otto
Published: October 2007

Background and Purpose—

Generally it is accepted that spatial neglect occurs predominantly after stroke of the human right hemisphere. In contrast, it remained controversial whether extinction follows the same hemispheric asymmetry. The opinion prevails that the laterality of visual extinction is not as pronounced as it is for spatial neglect.

Methods—

To directly compare the incidence of the 2 disorders within the same sample, spatial neglect and visual extinction were investigated during a 1-year period in 83 consecutively admitted patients with unilateral right or left hemisphere stroke.

Results—

The incidence of visual extinction and of spatial neglect was not significantly different, neither after left hemisphere (2.4% neglect; 4.9% extinction) nor after right hemisphere (26.2% neglect; 24.3% extinction) stroke.

Conclusions—

Visual extinction seems to be as asymmetrically associated with the human right hemisphere as is spatial neglect.
Intercellular Adhesion Molecule 1 (ICAM1) Lys56Met and Gly241Arg Gene Variants, Plasma-Soluble ICAM1 Concentrations, and Risk of Incident Cardiovascular Events in 23 014 Initially Healthy White Women
Authors: Zee Robert Y.L. , Cheng Suzanne , Erlich Henry A. , Lindpaintner Klaus , Rifai Nader , Buring Julie E. , Ridker Paul M
Published: October 2007

Background and Purpose—

The objective of this study was to examine the association of 2 nonsynonymous intercellular adhesion molecule 1 (ICAM1) gene variants (Lys56Met and Gly241Arg) with baseline plasma soluble ICAM1 concentrations and with risk of total and selected cardiovascular disease (CVD) events in a prospective cohort of 23 014 apparently healthy white American women followed for 10 years. ICAM1 variations have been associated with plasma soluble ICAM1 concentrations and inflammatory conditions, including atherosclerosis. However, to date, no large prospective, genetic–epidemiological data set is available that would allow evaluation of the degree of association of these gene variants with risk of CVD.

Methods—

ICAM1 genotypes and baseline plasma soluble ICAM1 concentrations were determined. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction, or death due to ischemic CVD); other measures were incident ischemic stroke, myocardial infarction, and coronary revascularization. During follow-up, 751 total incident CVD events, 187 incident myocardial infarction cases, 203 incident ischemic stroke cases, and 433 coronary revascularization events occurred.

Results—

All observed genotype frequencies were in Hardy-Weinberg equilibrium across the whole sample population. We found baseline plasma soluble ICAM1 concentrations to be significantly reduced among carriers of Met56 allele (
P
<0.0001) and Arg241 allele (
P
<0.0001) as compared with the respective noncarriers of these variants. However, the polymorphisms tested and the respective haplotypes were neither associated with overall risk nor with risk with risk for selected CVD events regardless of whether analyses were adjusted for traditional CVD risk factors/confounders (all
P
values >0.10).

Conclusions—

In this large prospective study, we found an association of the nonsynonymous gene variants tested with reduced baseline plasma soluble ICAM1 concentrations. However, no evidence was found for an association of the gene variants tested with the overall or selected CVD end points examined, suggesting that these variants may not add useful aids to current risk predictors for early assessment of cardiovascular events.
Vascular Permeability Precedes Spontaneous Intracerebral Hemorrhage in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Lee Jin-Moo , Zhai Guihua , Liu Qingwei , Gonzales Ernesto R. , Yin Kejie , Yan Ping , Hsu Chung Y. , Vo Katie D. , Lin Weili
Published: October 2007

Background and Purpose—

Stroke-prone spontaneous hypertensive rats (SHRsp) fed a high-salt diet develop malignant hypertension, blood–brain barrier breakdown, and spontaneous intracerebral hemorrhage (ICH). The precise spatial and temporal relationship between these events has not been well-delineated.

Methods—

Ten SHRsp male rats, fed a high-salt diet, were imaged weekly using MRI, starting at 12 weeks of age. T1-weighted (with and without Gd), T2-weighted, and T2* sequences were acquired. Permeability maps were calculated.

Results—

Seven SHRsp rats had spontaneous ICH develop before death. Five of the 7 rats had focally increased vascular permeability at the site of the ICH; 3 of these rats had vascular permeability 1 to 2 weeks before spontaneous ICH.

Conclusions—

Salt-loaded SHRsp rats have increased vascular permeability up to 2 weeks before ICH, predicting hemorrhage both in space and time. These results suggest that hypertensive ICH is preceded by focal vasculopathy detectable by Gd leak.
Influence of Galantamine on Vasomotor Reactivity in Alzheimer’s Disease and Vascular Dementia Due to Cerebral Microangiopathy
Authors: Bär Karl-Jürgen , Boettger Michael Karl , Seidler Nicole , Mentzel Hans Joachim , Terborg Christoph , Sauer Heinrich
Published: October 2007

Background and Purpose—

Recent reports suggest that vascular factors play a crucial role in the development and progression of Alzheimer’s disease. We aimed to assess vasomotor reactivity in patients with Alzheimer’s disease and vascular dementia due to microangiopathy using transcranial Doppler sonography and near-infrared spectroscopy during a CO
2
exposition task.

Methods—

The normalized CO
2
reactivity assessed at the middle cerebral artery and the oxygenated and deoxygenated hemoglobin of the frontal cortex were obtained. To investigate the impact of cholinergic deficiency known for Alzheimer’s disease on vasomotor reactivity, both groups were reinvestigated during treatment with the acetylcholine esterase inhibitor galantamine.

Results—

Transcranial Doppler analysis revealed significantly reduced normalized CO
2
reactivity for Alzheimer’s disease and vascular dementia. Vasomotor reactivity assessed by near-infrared spectroscopy was decreased in patients with vascular dementia, but not in Alzheimer’s disease. Galantamine treatment showed a beneficial effect, normalizing these parameters close to age-matched control levels.

Conclusions—

Our results suggest that Alzheimer’s disease is associated with a lack of vasomotor reactivity, which might be associated with disturbed autoregulation indicating a potential risk for a decreased protection of brain tissue against blood pressure changes. Additionally, a diminished increase of cortical oxygenated hemoglobin during the CO
2
test was apparent in patients with vascular dementia. Galantamine treatment influenced vascular reactivity in the CO
2
test, thus providing evidence for the cholinergic deficiency, thereby adding to vascular dysregulation in Alzheimer’s disease, but also indicating an important role of cholinergic system dysfunction for vascular dementia.
Progressive Increase in Infarct Size, Neuroinflammation, and Cognitive Deficits in the Presence of High Levels of Amyloid
Authors: Whitehead Shawn N. , Cheng Guanliang , Hachinski Vladimir C. , Cechetto David F.
Published: October 2007

Background and Purpose—

In the elderly, cerebral ischemia (CI) occurs in the presence of high levels of amyloid. Neuroinflammation plays a critical role in the pathophysiology of Alzheimer’s disease and CI. This study examined infarct size, neuroinflammation, and cognitive deficits over time in rat models of Alzheimer’s disease and CI.

Methods—

β-amyloid toxicity was modeled using bilateral intracerebroventricular injections of β-amyloid 25 to 35 peptides. CI was modeled using unilateral injections of the potent vasoconstrictor, endothelin-1, into the striatum.

Results—

Infarct volumes were higher in the presence of amyloid and compared with the CI model alone. In the CI model alone, the infarct volume was significantly smaller 28 days after surgery compared with 7 days after surgery. However, when Alzheimer’s disease and CI models were combined, the infarct volume was significantly larger 28 days after surgery compared with 7 days after surgery. The neuroinflammation in the region of the infarct was also significantly increased. The Barnes circular platform test showed time-dependent increases in memory and learning deficits in the β-amyloid-treated rats that were even greater when β-amyloid treatment was combined with CI.

Conclusions—

CI in the presence of high levels of amyloid results in progressive increases in infarct size, neuroinflammation, and cognitive deficits.
Vascular Disease
Authors: Hakim Antoine M.
Published: October 2007

The gap between existing knowledge and the patient care provided in stroke has become more apparent. The translational gap is evidence of our scientific progress, but the sheer magnitude of our implementation gap is astounding. For instance, almost 5 decades ago we recognized the risk factors for stroke, yet in Canada until recently fewer than 20% of cases of hypertension were effectively controlled. We recognize that continued exposure to risk factors will not only lead to clinically evident strokes, but far more frequently to silent strokes resulting in cognitive decline. In addition, the same risk factors cause damage to other organs. This growing gap between existing knowledge and its translational delivery is leading our politicians to demand more practical returns. As scientific and clinical opinion leaders in stroke, we have a huge opportunity now to lead the process of narrowing the translational gap. We need to keep our emphasis on individual research excellence but temper it with a social mission to improve stroke prevention, care and rehabilitation. Toward this end, the Canadian Stroke Network partnered with the Heart and Stroke Foundation of Canada to develop the ‘Canadian Stroke Strategy’, an approach to focus research, increase training of stroke specialists, coordinate the care of patients, and bring ‘systems change’ to respond to the growing gap in all facets of stroke care. Lessons learned from both successes and failures can inform our translational efficiency in the future and facilitate collective progress in stroke care.
Chronic Kidney Disease Is Associated With White Matter Hyperintensity Volume
Authors: Khatri Minesh , Wright Clinton B. , Nickolas Thomas L. , Yoshita Mitsuhiro , Paik Myunghee C. , Kranwinkel Grace , Sacco Ralph L. , DeCarli Charles
Published: October 2007

Background and Purpose—

White matter hyperintensities have been associated with increased risk of stroke, cognitive decline, and dementia. Chronic kidney disease is a risk factor for vascular disease and has been associated with inflammation and endothelial dysfunction, which have been implicated in the pathogenesis of white matter hyperintensities. Few studies have explored the relationship between chronic kidney disease and white matter hyperintensities.

Methods—

The Northern Manhattan Study is a prospective, community-based cohort of which a subset of stroke-free participants underwent MRIs. MRIs were analyzed quantitatively for white matter hyperintensities volume, which was log-transformed to yield a normal distribution (log-white matter hyperintensity volume). Kidney function was modeled using serum creatinine, the Cockcroft-Gault formula for creatinine clearance, and the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate. Creatinine clearance and estimated glomerular filtration rate were trichotomized to 15 to 60 mL/min, 60 to 90 mL/min, and >90 mL/min (reference). Linear regression was used to measure the association between kidney function and log-white matter hyperintensity volume adjusting for age, gender, race–ethnicity, education, cardiac disease, diabetes, homocysteine, and hypertension.

Results—

Baseline data were available on 615 subjects (mean age 70 years, 60% women, 18% whites, 21% blacks, 62% Hispanics). In multivariate analysis, creatinine clearance 15 to 60 mL/min was associated with increased log-white matter hyperintensity volume (β 0.322; 95% CI, 0.095 to 0.550) as was estimated glomerular filtration rate 15 to 60 mL/min (β 0.322; 95% CI, 0.080 to 0.564). Serum creatinine, per 1-mg/dL increase, was also positively associated with log-white matter hyperintensity volume (β 1.479; 95% CI, 1.067 to 2.050).

Conclusions—

The association between moderate–severe chronic kidney disease and white matter hyperintensity volume highlights the growing importance of kidney disease as a possible determinant of cerebrovascular disease and/or as a marker of microangiopathy.
fMRI Activity Patterns in Human LOC Carry Information about Object Exemplars within Category
Authors: Eger Evelyn , Ashburner John , Haynes John-Dylan , Dolan Raymond J. , Rees Geraint
Published: October 2007

The lateral occipital complex (LOC) is a set of areas in the human occipito-temporal cortex responding to objects as opposed to low-level control stimuli. Conventional functional magnetic resonance imaging (fMRI) analysis methods based on regional averages could not detect signals discriminative of different types of objects in this region. Here, we examined fMRI signals using multivariate pattern recognition (support vector classification) to systematically explore the nature of object-related information available in fine-grained activity patterns in the LOC. Distributed fMRI signals from the LOC allowed for above-chance discrimination not only of the category but also of within-category exemplars of everyday man-made objects, and such exemplar-specific information generalized across changes in stimulus size and viewpoint, particularly in posterior subregions. Object identity could also be predicted from responses of the early visual cortex, even significantly across the changes in size and viewpoint used here. However, a dissociation was observed between these two regions of interest in the degree of discrimination for objects relative to size: In the early visual cortex, two different sizes of the same object were even better discriminated than two different objects (in accordance with measures of pixelwise stimulus similarity), whereas the opposite was true in the LOC. These findings provide the first evidence that direct evoked fMRI activity patterns in the LOC can be different for individual object exemplars (within a single category). We propose that pattern recognition methods as used here may provide an alternative approach to study mechanisms of neuronal representation based on aspects of the fMRI response independent of those assessed in adaptation paradigms.
A Supposed Contradiction about Emotion-Arousal in Aristotle's Rhetoric
Authors: Dow Jamie
Published: October 2007

Aristotle, in the Rhetoric, appears to claim both that emotion-arousal has no place in the essential core of rhetorical expertise and that it has an extremely important place as one of three technical kinds of proof. This paper offers an account of how this apparent contradiction can be resolved. The resolution stems from a new understanding of what Rhetoric I.1 refers to – not emotions, but set-piece rhetorical devices aimed at manipulating emotions, which do not depend on the facts of the case in which they are deployed. This understanding is supported by showing how it fits with evidence for how rhetoric was actually taught in the fifth and fourth centuries BCE, in particular by rasymachus and Gorgias. The proposed interpretation fits well with Aristotle's overall view of the nature of rhetoric, the structure of rhetorical speeches, and what is and is not relevant to the pragma, the issue of the case at hand.
Minorities Within Minority: The Contribution of Lutheranism to the Richness of Inter-Ethnic Living Together in Transylvania (Romania)
Authors: Nagy Dorottya
Published: October 2007

This paper is a follow-up to a presentation given at the study-day 'Religion and Ethnicity in Transylvania' on the 17th of October 2006, organized by the section Kerkinactie of the Protestant Church in the Netherlands and Centrum IIMO (University of Utrecht). The article aims to present the positions and the functions of Lutheranism in the contemporary Transylvanian society. It formulates the thesis that Lutheranism in Transylvania has the potential for offering a major theological forum where inter-ethnic living together could be evaluated and explored with a responsibility and mission for the people of Transylvania which considers ethnic diversity not as maius malum but as maius bonum.
Food Affects Zidovudine Concentration Independent of Effects on Gastrointestinal Absorption
Authors: Ndovi Themba T. , Cao Ying‐Jun , Fuchs Edward , Fletcher Courtney V. , Guidos Anita , Hendrix Craig W.
Published: October 2007

Food can change drug concentrations by several mechanisms, including some that are independent of absorption effects. This study tests the hypothesis that a meal decreases zidovudine (ZDV) concentration in blood plasma independent of an effect on drug absorption. The study was conducted as a substudy nested in a larger protocol in which ZDV was given to 7 healthy men by continuous infusion for 5 days starting on day 1. The subjects received only a standardized breakfast meal on day 2 and were fasted on day 3 until the 8‐hour sampling period each day was finished. Blood samples were collected through an indwelling cannula in the arm contralateral to the ZDV infusion at the same time of day on both days. It was found that food decreased the blood plasma ZDV concentration at 1 hour postprandial by 14% (5.0%–22%; geometric mean change with 95% confidence interval). This decrease recovered by 6 hours postprandial. Similar changes were seen with the ZDV primary metabolite, zidovudine glucuronide. The authors conclude that food decreases blood plasma ZDV concentrations independent of any absorption effects. This effect may be due to the increased hepatic metabolism because feeding increases hepatic blood flow and because ZDV has a high hepatic extraction ratio with low affinity to blood plasma proteins.
Ethanol Does Not Alter the Pharmacokinetic Profile of the Controlled‐release Formulation of Carvedilol
Authors: Henderson Linda S. , Tenero David M. , Campanile Andrea M. , Baidoo Charlotte A. , Danoff Theodore M.
Published: October 2007

The concomitant ingestion of alcohol may alter the release of a drug from a modified‐release dosage form, posing a potential risk to patients. In a randomized, open‐label, 4‐period cross‐over study, the pharmacokinetic profiles of R(+) and S(−) carvedilol were compared after a single oral dose of carvedilol controlled‐release formulation (administered following a standard meal) was given alone or concomitantly with ethanol. Thirty‐nine healthy subjects participated in this study. Following coadministration of carvedilol controlled‐release 40 mg with ethanol (approximately 38 g), ethanol ingestion 2 hours before or 2 hours after carvedilol controlled‐release administration, area under the curve for the R(+) and S(−) carvedilol enantiomers was similar compared with carvedilol controlled‐release given alone. Carvedilol exposure was not affected by the concomitant administration of ethanol and carvedilol controlled‐release. Maximum plasma concentrations for the R(+) and S(−) carvedilol enantiomers were similar except when ethanol was ingested 2 hours after carvedilol controlled‐release administration, where there was a modest decrease in maximum plasma concentration for R(+) and S(−) carvedilol (16% and 17%, respectively). Carvedilol controlled‐release given alone or concomitantly with ethanol ingestion was generally well tolerated, and no serious or severe adverse events were reported. Ethanol did not alter the pharmacokinetic profile of carvedilol controlled‐release.
Lack of Pharmacokinetic and Pharmacodynamic Interactions Between a Smoking Cessation Therapy, Varenicline, and Warfarin: An In Vivo and In Vitro Study1
Authors: Burstein Aaron H. , Clark David J. , O'Gorman Melissa , Willavize Susan A. , Brayman Timothy G. , Grover G. Scott , Walsky Robert L. , Obach R. Scott , Faessel Hélène M.
Published: October 2007

This study investigated the effect of varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in 24 adult smokers and compared these findings with data generated using human in vitro systems. Subjects were randomized to receive varenicline 1 mg twice a day or placebo for 13 days and then switched to the alternative treatment after a 1‐week washout period. A single dose of warfarin 25 mg was given on day 8 of each treatment period, and serial blood samples were collected over 144 hours postdose. Pharmacokinetic parameters for both (R)‐ and (S)‐warfarin and international normalized ratio (INR) values were determined. Varenicline was assessed as an inhibitor and inducer of human cytochrome P450 activities using liver microsomes and hepatocytes, respectively. Consistent with the in vitro data, no alteration in human pharmacokinetics of warfarin enantiomers was observed with varenicline treatment. The 90% confidence intervals for the ratios of area under the concentration–time curve from zero hours to infinity and peak plasma concentrations were completely contained within 80% to 125%. Warfarin pharmacodynamic parameters, maximum INR, and the area under the prothrombin (INR)–time curve, were also unaffected by steady‐state varenicline. Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment.
Estimating genealogies from linked marker data: a Bayesian approach
Authors: Gasbarra Dario , Pirinen Matti , Sillanpää Mikko J , Arjas Elja
Published: October 2007

Background

Answers to several fundamental questions in statistical genetics would ideally require knowledge of the ancestral pedigree and of the gene flow therein. A few examples of such questions are haplotype estimation, relatedness and relationship estimation, gene mapping by combining pedigree and linkage disequilibrium information, and estimation of population structure.

Results

We present a probabilistic method for genealogy reconstruction. Starting with a group of genotyped individuals from some population isolate, we explore the state space of their possible ancestral histories under our Bayesian model by using Markov chain Monte Carlo (MCMC) sampling techniques. The main contribution of our work is the development of sampling algorithms in the resulting vast state space with highly dependent variables. The main drawback is the computational complexity that limits the time horizon within which explicit reconstructions can be carried out in practice.

Conclusion

The estimates for IBD (identity-by-descent) and haplotype distributions are tested in several settings using simulated data. The results appear to be promising for a further development of the method.
Wee1 kinase alters cyclin E/Cdk2 and promotes apoptosis during the early embryonic development of Xenopus laevis
Authors: Wroble Brian N , Finkielstein Carla V , Sible Jill C
Published: October 2007

Background

The cell cycles of the Xenopus laevis embryo undergo extensive remodeling beginning at the midblastula transition (MBT) of early development. Cell divisions 2–12 consist of rapid cleavages without gap phases or cell cycle checkpoints. Some remodeling events depend upon a critical nucleo-cytoplasmic ratio, whereas others rely on a maternal timer controlled by cyclin E/Cdk2 activity. One key event that occurs at the MBT is the degradation of maternal Wee1, a negative regulator of cyclin-dependent kinase (Cdk) activity.

Results

In order to assess the effect of Wee1 on embryonic cell cycle remodeling, Wee1 mRNA was injected into one-cell stage embryos. Overexpression of Wee1 caused cell cycle delay and tyrosine phosphorylation of Cdks prior to the MBT. Furthermore, overexpression of Wee1 disrupted key developmental events that normally occur at the MBT such as the degradation of Cdc25A, cyclin E, and Wee1. Overexpression of Wee1 also resulted in post-MBT apoptosis, tyrosine phosphorylation of Cdks and persistence of cyclin E/Cdk2 activity. To determine whether Cdk2 was required specifically for the survival of the embryo, the cyclin E/Cdk2 inhibitor, Δ34-Xic1, was injected in embryos and also shown to induce apoptosis.

Conclusion

Taken together, these data suggest that Wee1 triggers apoptosis through the disruption of the cyclin E/Cdk2 timer. In contrast to Wee1 and Δ34-Xic1, altering Cdks by expression of Chk1 and Chk2 kinases blocks rather than promotes apoptosis and causes premature degradation of Cdc25A. Collectively, these data implicate Cdc25A as a key player in the developmentally regulated program of apoptosis in X. laevis embryos.
Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia
Authors: Kaur Pavinder , Feldhahn Niklas , Zhang Bin , Trageser Daniel , Müschen Markus , Pertz Veerle , Groffen John , Heisterkamp Nora
Published: October 2007

Background

Ph-positive leukemias are caused by the aberrant fusion of the BCR and ABL genes. Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor related to imatinib, which is widely used to treat chronic myelogenous leukemia. Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl.

Results

After transplant of 10,000 highly malignant leukemic cells into compatible recipients, untreated mice succumbed to leukemia within 21 days, whereas mice treated with 75 mg/kg nilotinib survived significantly longer. We examined cells from mice that developed leukemia while under treatment for Bcr/Abl kinase domain point mutations but these were not detected. In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out. Nilotinib also exhibited impressive anti-leukemia activity in P190 Bcr/Abl transgenic mice that had developed overt leukemia/lymphoma masses and that otherwise would have been expected to die within 7 days. Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced. Treated mice survived more than 30 days.

Conclusion

These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.
Dissociation of neural correlates of verbal and non-verbal visual working memory with different delays
Authors: Rothmayr Christoph , Baumann Oliver , Endestad Tor , Rutschmann Roland M , Magnussen Svein , Greenlee Mark W
Published: October 2007

Background

Dorsolateral prefrontal cortex (DLPFC), posterior parietal cortex, and regions in the occipital cortex have been identified as neural sites for visual working memory (WM). The exact involvement of the DLPFC in verbal and non-verbal working memory processes, and how these processes depend on the time-span for retention, remains disputed.

Methods

We used functional MRI to explore the neural correlates of the delayed discrimination of Gabor stimuli differing in orientation. Twelve subjects were instructed to code the relative orientation either verbally or non-verbally with memory delays of short (2 s) or long (8 s) duration.

Results

Blood-oxygen level dependent (BOLD) 3-Tesla fMRI revealed significantly more activity for the short verbal condition compared to the short non-verbal condition in bilateral superior temporal gyrus, insula and supramarginal gyrus. Activity in the long verbal condition was greater than in the long non-verbal condition in left language-associated areas (STG) and bilateral posterior parietal areas, including precuneus. Interestingly, right DLPFC and bilateral superior frontal gyrus was more active in the non-verbal long delay condition than in the long verbal condition.

Conclusion

The results point to a dissociation between the cortical sites involved in verbal and non-verbal WM for long and short delays. Right DLPFC seems to be engaged in non-verbal WM tasks especially for long delays. Furthermore, the results indicate that even slightly different memory maintenance intervals engage largely differing networks and that this novel finding may explain differing results in previous verbal/non-verbal WM studies.
Food Restriction Alters Neuronal Morphology in the Hypothalamic Ventromedial Nucleus of Male Rats
Authors: Flanagan-Cato Loretta M. , Fluharty Steven J. , Weinreb Elena B. , LaBelle Denise R.
Published: October 2007

Several lines of evidence have implicated the hypothalamic ventromedial nucleus (VMH) in the control of caloric homeostasis. For example, the activity of VMH neurons depends on energy availability. We tested the hypothesis that energy balance may involve the remodeling of the dendritic arbor of VMH neurons. We compared two groups of animals: one group had ad libitum access to food, and the other experienced 10-d restricted access to food. As expected, the food-deprived group lost body weight and had reduced levels of glucose, insulin, and leptin. VMH neurons were visualized after Golgi impregnation, and dendrite length was measured. Food deprivation had differential effects on VMH neurons. In particular, within the ventrolateral VMH, for neurons with long primary dendrites (LPDs) that extended in the lateral, but not medial, direction, the LPDs were 31% shorter. These same neurons exhibited a 32% reduction in the number of other dendrites without a change in soma size. In contrast, within the dorsomedial VMH, for neurons with medially, but not laterally, extended LPDs, the soma area was reduced by 28%. However, neurons in the dorsomedial VMH did not display a change in the length or number of dendrites, regardless of LPD direction. Thus, although structural changes during calorie depletion occur in both the dorsomedial and ventrolateral VMH, only the latter exhibits a remodeled dendritic arbor. These results also suggest that the direction of the LPD may be an important marker of neuronal function in the VMH.
Estradiol-17β-Induced Human Neural Progenitor Cell Proliferation Is Mediated by an Estrogen Receptor β-Phosphorylated Extracellularly Regulated Kinase Pathway
Authors: Wang Jun Ming , Liu Lifei , Brinton Roberta Diaz
Published: October 2007

Estradiol-17β (E2) induces rodent hippocampal neural progenitor cell (NPC) proliferation in vitro, in vivo, and after brain injury. The purpose of the present investigation was to determine whether E2-induced proliferation observed in rodent model systems generalized to cells of human neural origin and the signaling pathway by which E2 promotes mitosis of human NPCs (hNPCs). Results of these analyses indicate that E2 induced a significant increase in hNPC proliferation in a time- and dose-dependent manner. E2-induced hNPC DNA replication was paralleled by elevated cell cycle protein expression and centrosome amplification, which was associated with augmentation of total cell number. To determine whether estrogen receptor (ER) and which ER subtype were required for E2-induced hNPC proliferation, ER expression was first determined by real-time RT-PCR, followed by Western blot analysis, and subsequently verified pharmacologically using ERα or β-selective ligands. Results of these analyses indicated that ERβ expression was predominant relative to ERα, which was barely detectable in hNPCs. Activation of ERβ by the ERβ-selective ligand, diarylpropionitrile, led to an increase in phosphorylated extracellular signal-regulated kinase, and subsequent centrosome amplification and hNPC proliferation, which were blocked by the MEKK antagonist, UO126, but not its inactive analog, UO124. These findings, for the first time, demonstrate the molecular cascade and related cell biology events involved in E2-induced hNPC proliferation in vitro. Therapeutic implications of these findings relevant to hormone therapy and prevention of neurodegenerative disease are discussed.
MyResearch.com: speculations on bridging research and teaching in the arts
Authors: Manghani Sunil
Published: October 2007

The article takes the phrase MyResearch.com as an opening metaphor to explore underlying issues in linking research with teaching in the areas of art, design and media. In part, MyResearch.com is suggestive of a culture of scholarship becoming something like the social networks of Second
Life, MySpace and YouTube, all of which have set new trends in promoting and sharing various media output. However, the phrase also captures a more critical point about the reification of ideas, warning against research becoming some kind of commodity or tool we might neatly apply to our teaching.
Drawing connections between the intellectual fashions of the early twentieth century flneurs and bohemians and our own twenty-first century digital culture, the article speculates upon what research really means in the arts and seeks to reclaim what is distinctive about the arts and art education's
ethical commitment to the world in which we live.
Pulmonary Hypertension in the Neonate
Authors: Steinhorn Robin H , Farrow Kathryn N
Published: October 2007

Persistent pulmonary hypertensin of the newborn (PPHN), a major clinical problem in the neonatal intensive care unit, can contribute significantly to morbidity and mortality in both term and preterm infants. Hypoxemic respiratory failure or PPHN can place newborns at risk for death, neurologic injury, and other morbidities. PPHN is categorized into parenchymal lung disease (meconium aspiration syndrome, respiratory distress syndrome, sepsis), idiopathic (or “black-lung”), and pulmonary hypoplasia (as seen in congenital diaphragmatic hernia). Treatment involves correction of factors that may promote vasoconstriction, mechanical ventilation to achieve optimal lung volume that may include high-frequency oscillatory ventilation, medical optimization of cardiac output and left ventricular function, and inhaled nitric oxide. A number of alternative and emerging pulmonary vasodilators are being investigated.
Pharmacology Review
Authors: Wong Ronald J. , Bhutani Vinod K. , Vreman Hendrik J. , Stevenson David K.
Published: October 2007

Competitive inhibitors of heme oxygenase (HO) have been studied as interventional agents for neonatal hyperbilirubinemia. Several naturally occurring and synthetic metalloporphyrins have been shown to be potent inhibitors of HO activity and effective in reducing bilirubin concentrations in vitro and in vivo. Targeting HO may aid in preventing hyperbilirubinemia in newborns. Tin mesoporphyrin (SnMP) has emerged as a potential agent for reducing total bilirubin concentrations in preterm newborns. Adverse effects associated with SnMP use include photosensitization (which complicates its use in conjunction with phototherapy), and potential inhibition of several other enzymes that have essential roles in metabolism. Clinical studies of SnMP have shown that it prevents excessive neonatal hyperbilirubinemia and reduces the need for neonatal phototherapy in term and near-term infants. Because further research, specifically safety investigations, are complicated, use of SnMP should be reserved for neonates who are at especially high risk for developing bilirubin-induced neurologic dysfunction or participating in clinical trials.
Assisted Reproductive Technology and Preimplantation Genetic Diagnosis
Authors: Cowan Janet M. , Demmer Laurie A.
Published: October 2007

Assisted reproductive technology (ART) techniques have enabled couples with low fertility to conceive, and approximately 1% of births in the United States result from such procedures. ART combined with preimplantation genetic diagnosis (PGD) has provided a method for couples at risk for genetic conditions to deliver a baby free from the condition. ART presents many perinatal risks and may be associated with long-term health effects for the offspring. PGD, which can screen for known conditions, at present cannot screen for all genetic conditions.