bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of 'The Complete Guide to Simulations & Serious Games' by Clark Aldrich
Authors: Shea Peter
Published: April 2010

The Complete Guide to Simulations & Serious Games is described as an "encyclopedic overview and complete lexicon for those who care about the next generation of educational media." This book differs from Learning by Doing in that it doesn't seek to distinguish the wide and various categories of simulationshow simulations differ based on their structure and content and why those differences matter. Rather, it seeks to "present and distinguish between the different mechanisms" related to simulations, so that people who create simulations have a shared understanding of the concepts they use in conversation with one another.
Online Educators, Come Out of Your Caves!
Authors: Welch Mark
Published: April 2010

Mark Welch explains why he and other online educators really (really) love networking and attending conferences.
What I Learned from Teaching Adult Learners Online
Authors: Blake Denise A.
Published: April 2010

Being asked to teach an online course when you are inexperienced with distance education can be daunting. Denise A. Blake of Shenandoah University reflects on her personal experience with e-learning, which started just in this way. She shares what she learned about online learners, particularly adult students, and what instructors should be doing to meet their needs.
Using Digital Comics for Language Learning
Authors: Zimmerman Bill
Published: April 2010

Telling stories by building comic strips is a way to strengthen struggling students' emerging English-language skills and make the difficult job of language learning a much more enjoyable experience. Comic strips are a perfect vehicle for learning a language. Each strip's three or four panels provide a finite, accessible world in which funny or compelling characters live and go about their lives. And readers with limited reading skills are not as overwhelmed in dealing with the size of a comic strip as they can be with a book of many pages.
3 e-Learning Technologies to Watch
Authors: Little Bob
Published: April 2010

In his recent predictions for the development of learning technologies in 2010, Clark Quinna U.S.-based independent consultant with a PhD in applied cognitive science, and (full disclosure) on the advisory board of this web sitesuggests that "several technologies are poised to cross the chasm: social tools, mobile technologies and virtual worlds...
An Interview with Howard Rheingold
Authors: Rowell Laurie , Rheingold Howard
Published: April 2010

Howard Rheingold, writer, educator, and thinker, is renowned for tracking not just what is going on now in the digital world, but where the digital world will be going next. His books, such as Tools for Thought (1985), Virtual Reality (1991), The Virtual Community (1994) and Smart Mobs in (2002), usher in the next adventure in computer-human interaction. Here, he talks about skills that matter, such as locating and verifying the accuracy of information in a digital age.
An Interview With Reggie Smith III, President of the United States Distance Learning Association
Authors: Gualtieri Lisa , Smith Reggie
Published: April 2010

Public policy is what will make distance learning truly mainstream, increasing access to education and training opportunities. Reggie Smith III, president of the United States Distance Learning Association (USDLA), believes that these transformative changes are just around the bend, and he is working to make them a reality. The USDLA is a non-profit association that advocates for the development and application of distance learning across the board, from children's schooling to employee training.
Teaching the Librarians of the Future Without Online Instruction
Authors: Cocciolo Anthony
Published: April 2010

I teach at the only School of Information and Library Science (SILS) on the east coast of the United States that does not offer a single online coursenot a program or a blended option either. (I discovered this through a search of the American Library Association accredited programs, which maintains a list of LIS programs with online course options.) Are were a bunch of luddites, teaching our students the way of the past, when libraries were the primary sources of high-quality information, and librarians were the gatekeepers to that world of knowledge? Certainly not.
An Interview With Anthony J. Cernera, President of Sacred Heart University
Authors: Gualtieri Lisa , Cernera Anthony J.
Published: April 2010

Dr. Anthony J. Cernera has been the president of Sacred Heart University in Fairfield, Connecticut, since 1988. Beginning in 1997, the university started to add online degree programs and coursesmore than a dozen in all, including a doctorate in physical therapy and one in nursing practice, set to launch this fall. Enrollment has more than doubled. eLearn Magazine interviewed Cernera, who is also president of the International Federation of Catholic Universities, about how and why SHU has committed to online students.
Effect of daikenchuto (TU-100) on gastrointestinal and colonic transit in humans
Authors: Manabe Noriaki , Camilleri Michael , Rao Archana , Wong Banny S. , Burton Duane , Busciglio Irene , Zinsmeister Alan R. , Haruma Ken
Published: April 2010

Daikenchuto (TU-100) is a traditional Japanese (Kampo) medicine used to treat postoperative ileus. TU-100 dose dependently increases gastrointestinal (GI) motility by modulating cholinergic and serotonergic mechanisms in animal studies. The aim of this study was to evaluate the effects of orally administered TU-100 on GI and colonic transit and bowel function in healthy humans. In a randomized, parallel-group, double-blind, placebo-controlled, dose-response study, 60 healthy subjects were randomly assigned to placebo or TU-100 2.5 g or 5 g tid ingested immediately before meals for 5 consecutive days. We measured GI and colonic transit by validated scintigraphy and stool frequency and consistency by daily diaries of bowel function. There were overall treatment effects on colonic filling at 6 h without any significant differences between each dose of TU-100 and placebo. There tended to be overall treatment effects on ascending colon (AC) emptying half-time; the TU-100 (7.5 g/day) treatment significantly accelerated AC emptying compared with placebo. There were numerically higher values of GC24 (which reflect overall colonic transit) with both doses of TU-100, but these changes were not statistically significant. There were no significant overall treatment effects on gastric emptying or stool frequency and consistency. One subject, who received 7.5 g/day of TU-100, had elevated creatine phosphokinase following the study. TU-100 (7.5 g/day) significantly accelerated AC emptying. Further randomized controlled trials in patients with functional constipation or irritable bowel syndrome with constipation are warranted to evaluate the clinical efficacy of TU-100 in these disorders.
Cross-organ sensitization of thoracic spinal neurons receiving noxious cardiac input in rats with gastroesophageal reflux
Authors: Qin Chao , Malykhina Anna P. , Thompson Ann M. , Farber Jay P. , Foreman Robert D.
Published: April 2010

Gastroesophageal reflux (GER) frequently triggers or worsens cardiac pain or symptoms in patients with coronary heart disease. This study aimed to determine whether GER enhances the activity of upper thoracic spinal neurons receiving noxious cardiac input. Gastric fundus and pyloric ligations as well as a longitudinal myelotomy at the gastroesophageal junction induced acute GER in pentobarbital-anesthetized, paralyzed, and ventilated male Sprague-Dawley rats. Manual manipulations of the stomach and lower esophagus were used as surgical controls in another group. At 4–9 h after GER surgery, extracellular potentials of single neurons were recorded from the T3 spinal segment. Intrapericardial bradykinin (IB) (10 μg/ml, 0.2 ml, 1 min) injections were used to activate cardiac nociceptors, and esophageal distensions were used to activate esophageal afferent fibers. Significantly more spinal neurons in the GER group responded to IB compared with the control group (69.1 vs. 38%, P < 0.01). The proportion of IB-responsive neurons in the superficial laminae of GER animals was significantly different from those in deeper layers (1/8 vs. 46/60, P < 0.01); no difference was found in control animals (7/25 vs. 20/46, P > 0.05). Excitatory responses of spinal neurons to IB in the GER group were greater than in the control group [32.4 ± 3.5 impulses (imp)/s vs. 13.3 ± 2.3 imp/s, P < 0.01]. Forty-five of 47 (95.7%) neurons responded to cardiac input and ED, which was higher than the control group (61.5%, P < 0.01). These results indicate that acute GER enhanced the excitatory responses of thoracic spinal neurons in deeper laminae of the dorsal horn to noxious cardiac stimulus.
Hydrogen peroxide activates focal adhesion kinase and c-Src by a phosphatidylinositol 3 kinase-dependent mechanism and promotes cell migration in Caco-2 cell monolayers
Authors: Basuroy Shyamali , Dunagan Mitzi , Sheth Parimal , Seth Ankur , Rao R. K.
Published: April 2010

Recent studies showed that c-Src and phosphatidylinositol 3 (PI3) kinase mediate the oxidative stress-induced disruption of tight junctions in Caco-2 cell monolayers. The present study evaluated the roles of PI3 kinase and Src kinase in the oxidative stress-induced activation of focal adhesion kinase (FAK) and acceleration of cell migration. Oxidative stress, induced by xanthine and xanthine oxidase system, rapidly increased phosphorylation of FAK on Y397, Y925, and Y577 in the detergent-insoluble and soluble fractions and increased its tyrosine kinase activity. The PI3 kinase inhibitors, wortmannin and LY294002, and the Src kinase inhibitor, 4-amino-5[chlorophyll]-7-[t-butyl]pyrazolo[3–4-d]pyrimidine, attenuated tyrosine phosphorylation of FAK. Oxidative stress induced phosphorylation of c-Src on Y418 by a PI3 kinase-dependent mechanism, whereas oxidative stress-induced activation of PI3 kinase was independent of Src kinase activity. Hydrogen peroxide accelerated Caco-2 cell migration in a concentration-dependent manner. Promotion of cell migration by hydrogen peroxide was attenuated by LY294002 and PP2. Reduced expression of FAK by siRNA attenuated hydrogen peroxide-induced acceleration of cell migration. The expression of constitutively active c-SrcY527Fenhanced cell migration, whereas the expression of dominant negative c-SrcK296R/Y528Fattenuated hydrogen peroxide-induced stimulation of cell migration. Oxidative stress-induced activation of c-Src and FAK was associated with a rapid increase in the tyrosine phosphorylation and the levels of paxillin and p130CASin actin-rich, detergent-insoluble fractions. This study shows that oxidative stress activates FAK and accelerates cell migration in an intestinal epithelium by a PI3 kinase- and Src kinase-dependent mechanism.
Fasting-induced intestinal apoptosis is mediated by inducible nitric oxide synthase and interferon-γ in rat
Authors: Ito Junta , Uchida Hiroyuki , Yokote Takayuki , Ohtake Kazuo , Kobayashi Jun
Published: April 2010

Nitric oxide (NO) is associated with intestinal apoptosis in health and disease. This study aimed to investigate the role of intestinal NO in the regulation of apoptosis during fasting in rats. Male Wistar rats were divided into two groups and subcutaneously injected with saline (SA) or aminoguanidine (AG), followed by fasting for 24, 48, 60, and 72 h. At each time point, the jejunum was subjected to histological evaluation for enterocyte apoptosis by histomorphometric assessment and TUNEL analysis. We performed immunohistochemistry for inducible NO synthase (iNOS) expression in the jejunum and measured tissue nitrite levels using HPLC and 8-hydroxydeoxyguanosine adduct using ELISA, indicative of endogenous NO production and reactive oxygen species (ROS) production, respectively. Jejunal transcriptional levels of iNOS, neuronal NO synthase (nNOS), and interferon-γ (IFN-γ) were also determined by RT-PCR. Fasting caused significant jejunal mucosal atrophy due to attenuated cell proliferation and enhanced apoptosis with increase in iNOS transcription, its protein expression in intestinal epithelial cells (IEC), and jejunal nitrite levels. However, AG treatment histologically reduced apoptosis with inhibition of fasting-induced iNOS transcription, protein expression, and nitrite production. We also observed fasting-induced ROS production and subsequent IFN-γ transcription, which were all inhibited by AG treatment. Furthermore, we observed reduced transcriptional levels of nNOS, known to suppress iNOS activation physiologically. These results suggest that fasting-induced iNOS activation in IEC may induce apoptosis mediators such as IFN-γ via a ROS-mediated mechanism and also a possible role of nNOS in the regulation of iNOS activity in fasting-induced apoptosis.
Regulation of NF-κB responses by epigenetic suppression of IκBα expression in HCT116 intestinal epithelial cells
Authors: O'Gorman Angela , Colleran Amy , Ryan Aideen , Mann Jelena , Egan Laurence John
Published: April 2010

Intestinal epithelial cells play critical roles in regulating mucosal immunity. Since epigenetic factors such as DNA methylation and histone modifications are implicated in aging, carcinogenesis, and immunity, we set out to assess any role for epigenetic factors in the regulation of intestinal epithelial cell immune responses. Experiments were conducted using the HCT116 cell line, and a subclone was genetically engineered to lack DNA methyltransferases (DNMT). The induction of the chemokine interleukin-8 and the antiapoptotic protein cFLIP by tumor necrosis factor-α were markedly less in HCT116 cells lacking DNMT than in parental cells. These effects were accompanied by lower monocyte chemotaxis and higher caspase signaling in HCT116 cells lacking DNMT than parental cells. Tumor necrosis factor-α-induced NF-κB activation was blocked and IκBα expression was higher in HCT116 cells lacking DNMT than in parental cells. A CpG island in the IκBα gene promoter region was found to contain variable levels of methylation in parental HCT116 cells. Chromatin immunoprecipitation analysis of histone proteins bound to the IκBα gene promoter revealed that higher levels of IκBα expression in HCT116 cells lacking DNMT compared with parental cells were accompanied by more chromatin marks permissive to gene transcription. These findings show that epigenetic factors influence the NF-κB system in intestinal epithelial cells, resulting in a previously unrecognized mechanism of innate immune regulation.
Matrix metalloproteinases cleave the β2-adrenergic receptor in spontaneously hypertensive rats
Authors: Rodrigues Stephen F. , Tran Edward D. , Fortes Zuleica B. , Schmid-Schönbein Geert W.
Published: April 2010

We recently observed the enhanced serine and matrix metalloproteinase (MMP) activity in the spontaneously hypertensive rat (SHR) compared with its normotensive Wistar-Kyoto (WKY) rat and the cleavage of membrane receptors in the SHR by MMPs. We demonstrate in vivo that MMP-7 and MMP-9 injection leads to a vasoconstrictor response in microvessels of rats that is blocked by a specific MMP inhibitor (GM-6001, 1 μM). Multiple pathways may be responsible. Since the β2-adrenergic receptor (β2-AR) is susceptible to the action of endogenous MMPs, we hypothesize that MMPs in the plasma of SHRs are able to cleave the extracellular domain of the β2-AR. SHR arterioles respond in an attenuated fashion to β2-AR agonists and antagonists. Aorta and heart muscle of control Wistar rats were exposed for 24 h (37°C) to fresh plasma of male Wistar and WKY rats and SHRs with and without doxycycline (30 μM) and EDTA (10 mM) to reduce MMP activity. The density of extracellular and intracellular domains of β2-AR was determined by immunohistochemistry. The density of the extracellular domain of β2-AR is reduced in aortic endothelial cells and cardiac microvessels of SHRs compared with that of WKY or Wistar rats. Treatment of the aorta and the heart of control Wistar rats with plasma from SHRs, but not from WKY rats, reduced the number of extracellular domains, but not intracellular domains, of β2-AR in aortic endothelial cells and cardiac microvessels. MMP inhibitors (EDTA and doxycycline) prevented the cleavage of the extracellular domain. Thus MMPs may contribute to the reduced density of the extracellular domain of β2-AR in blood vessels and to the increased arteriolar tone of SHRs compared with normotensive rats.
Skin temperature modifies the impact of hypohydration on aerobic performance
Authors: Kenefick R. W. , Cheuvront S. N. , Palombo L. J. , Ely B. R. , Sawka M. N.
Published: April 2010

This study determined the effects of hypohydration on aerobic performance in compensable [evaporative cooling requirement (Ereq) < maximal evaporative cooling (Emax)] conditions of 10°C [7°C wet bulb globe temperature (WBGT)], 20°C (16°C WBGT), 30°C (22°C WBGT), and 40°C (27°C WBGT) ambient temperature (Ta). Our hypothesis was that 4% hypohydration would impair aerobic performance to a greater extent with increasing heat stress. Thirty-two men [22 ± 4 yr old, 45 ± 8 ml·kg−1·min−1 peak O2 uptake (V̇o2peak)] were divided into four matched cohorts ( n = 8) and tested at one of four Ta in euhydrated (EU) and hypohydrated (HYPO, −4% body mass) conditions. Subjects completed 30 min of preload exercise (cycle ergometer, 50% V̇o2peak) followed by a 15 min self-paced time trial. Time-trial performance (total work, change from EU) was −3% ( P = 0.1), −5% ( P = 0.06), −12% ( P < 0.05), and −23% ( P < 0.05) in 10°C, 20°C, 30°C, and 40°C Ta, respectively. During preload exercise, skin temperature (Tsk) increased by ∼4°C per 10°C Ta, while core (rectal) temperature (Tre) values were similar within EU and HYPO conditions across all Ta. A significant relationship ( P < 0.05, r = 0.61) was found between Tsk and the percent decrement in time-trial performance. During preload exercise, hypohydration generally blunted the increases in cardiac output and blood pressure while reducing blood volume over time in 30°C and 40°C Ta. Our conclusions are as follows: 1) hypohydration degrades aerobic performance to a greater extent with increasing heat stress; 2) when Tsk is >29°C, 4% hypohydration degrades aerobic performance by ∼1.6% for each additional 1°C Tsk; and 3) cardiovascular strain from high skin blood flow requirements combined with blood volume reductions induced by hypohydration is an important contributor to impaired performance.
Dithranol Therapy in Childhood Psoriasis: Unjustifiably on the Verge of Falling into Oblivion
Authors: de Jager M.E.A. , van de Kerkhof P.C.M. , de Jong E.M.G.J. , Seyger M.M.B.
Published: April 2010

Background: In childhood psoriasis, physicians aim for an effective and safe treatment such as with dithranol. This study presents the largest study of dithranol-treated patients described in the literature. Objective: The aim of the study was to determine the position of dithranol in the treatment strategy for psoriasis. Methods: All juvenile patients receiving dithranol treatment at our center were evaluated retrospectively. Results: Sixty patients (with 82 treatment episodes in total) were included. The mean age at the start of dithranol treatment was 11.1 years (range: 3.7–17.9 years). The result of the treatment was: excellent (3.7%), good (69.5%), moderate (8.5%), reasonable (13.4%) or disappointing (4.9%). Mild irritation was seen in 39%, and severe irritation in 63% of the patients. Conclusions: Dithranol can be regarded as an efficacious and safe topical therapy for the treatment of childhood psoriasis. It is a valuable alternative topical treatment which should not be disregarded in the treatment regimen for childhood psoriasis and should be commenced before ultraviolet or systemic treatments are initiated.
Donor Dominance Cures CHILD Nevus
Authors: König Arne , Skrzypek Jan , Löffler Harald , Oeffner Frank , Grzeschik Karl-Heinz , Happle Rudolf
Published: April 2010

Background: Congenital hemidysplasia with ichthyosiform nevus and limb defects (MIM 308050, CHILD) syndrome is an X-linked dominant, male-lethal, multisystem birth defect. Patients suffer from an inflammatory nevus that covers large areas, predominantly of one side of the body, with a sharp midline demarcation. Treatment of CHILD nevus is notoriously difficult. Objective: The aim of this study was to develop a novel surgical approach for this disorder. Methods: In 2 patients, the CHILD nevus was dermabraded, and the area was covered with split skin grafts obtained from a contralateral unaffected donor region. In a third patient, papillomatous, strawberry-like lesions on fingers and toes were excised, and the defects were covered with full-thickness grafts obtained from the unaffected left, gluteal area. Results: Highly satisfying functional and cosmetic results were documented during a follow-up period ranging from 3 to 8 years. Conclusion: The favorable outcome, superior to that obtained by simple dermabrasion or extensive plastic surgery, can best be explained by the donor dominance of the grafted skin samples that carried, in all or most cells, the mutant X chromosome in an inactivated form.
Low-Density Lipoproteins Induce Heat Shock Protein 27 Dephosphorylation, Oligomerization, and Subcellular Relocalization in Human Vascular Smooth Muscle Cells
Authors: García-Arguinzonis Maísa , Padró Teresa , Lugano Roberta , Llorente-Cortes Vicenta , Badimon Lina
Published: April 2010

Objective—

High levels of circulating low-density lipoproteins (LDL) are a major atherosclerotic risk factor. The effects of intimal LDL on vascular smooth muscle cell (VSMC) phenotype and function during plaque remodeling and vascular repair are not fully understood. We have investigated whether exposure of VSMC to LDL induces changes on the proteomic profile of the heat shock protein (HSP) family–molecular chaperones involved in atherosclerosis.

Methods & Results—

2D electrophoresis demonstrates that LDL modifies the proteomic profile of HSP27 (HSPB1). Western blot analysis evidenced a significant HSP27 dephosphorylation after exposure of cells to native LDL (nLDL) and aggregated-LDL (agLDL) for 24 hours (
P
<0.05). Dephosphorylation of HSP27 was not related to changes in p38
MAPK
phosphorylation. Both nLDL and agLDL induced relocalization of unphosphorylated HSP27 to the tip of actin stress fibers and focal adhesion structures in VSMC. During cell adhesion, phospho-HSP27 was located at the cell surface contact region in LDL-treated cells, whereas it remained cytosolic in control cells. Immunohistochemistry studies showed that phosphorylated HSP27 is rarely found in lipid-rich areas of atherosclerotic plaques in human coronary arteries.

Conclusion—

Our results indicate that in VSMC, LDL modulate HSP27 phosphorylation and subcellular localization, affecting actin polymerization and cytoskeleton dynamics.
MicroRNAs Are Necessary for Vascular Smooth Muscle Growth, Differentiation, and Function
Authors: Albinsson Sebastian , Suarez Yajaira , Skoura Athanasia , Offermanns Stefan , Miano Joseph M. , Sessa William C.
Published: April 2010

Objective—Regulation of vascular smooth muscle (VSM) proliferation and contractile differentiation is an important factor in vascular development and subsequent cardiovascular diseases. Recently, microRNAs (miRNAs) have been shown to regulate fundamental cellular processes in a number of cell types, but the integrated role of miRNAs in VSM in blood vessels is unknown. Here, we investigated the role of miRNAs in VSM by deleting the rate-limiting enzyme in miRNA synthesis, Dicer.

Methods and Results—Deletion of Dicer in VSM results in late embryonic lethality at embryonic day 16 to 17, associated with extensive internal hemorrhage. The loss of VSM Dicer results in dilated, thin-walled blood vessels caused by a reduction in cellular proliferation. In addition, blood vessels from VSM-deleted Dicer mice exhibited impaired contractility because of a loss of contractile protein markers. We found this effect to be associated with a loss of actin stress fibers and partly rescued by overexpression of microRNA (miR)-145 or myocardin.

Conclusion—Dicer-dependent miRNAs are important for VSM development and function by regulating proliferation and contractile differentiation.
Junctional Adhesion Molecule A Expressed on Human CD34
+
Cells Promotes Adhesion on Vascular Wall and Differentiation Into Endothelial Progenitor Cells
Authors: Stellos Konstantinos , Langer Harald , Gnerlich Stephan , Panagiota Victoria , Paul Angela , Schönberger Tanja , Ninci Elena , Menzel Dagmar , Mueller Iris , Bigalke Boris , Geisler Tobias , Bültmann Andreas , Lindemann Stephan , Gawaz Meinrad
Published: April 2010

Objective—

To investigate the role of junctional adhesion molecule A (JAM-A) on adhesion and differentiation of human CD34
+
cells into endothelial progenitor cells.

Methods and Results—

Tissue healing and vascular regeneration is a multistep process requiring firm adhesion of circulating progenitor cells to the vascular wall and their further differentiation into endothelial cells. The role of JAM-A in platelet-mediated adhesion of progenitor cells was investigated by adhesion assays in vitro and with the help of intravital fluorescence microscopy in mice. Preincubation of human CD34
+
progenitor cells with soluble JAM-A-Fc (sJAM-A-Fc) resulted in significantly decreased adhesion over immobilized platelets or inflammatory endothelium under high shear stress in vitro and after carotid ligation in vivo or ischemia/reperfusion injury in the microcirculation of mice. Human CD34
+
cells express JAM-A, as defined by flow cytometry and Western blot analysis. JAM-A mediates differentiation of CD34
+
cells to endothelial progenitor cells and facilitates CD34
+
cell-induced reendothelialization in vitro. Pretreatment of human CD34
+
cells with sJAM-A-Fc resulted in increased neointima formation 3 weeks after endothelial denudation in the carotid arteries of nonobese diabetic/severe combined immunodeficient mice.

Conclusion—

These results indicate that the expression of JAM-A on CD34
+
cells mediates adhesion to the vascular wall after injury and differentiation into endothelial progenitor cells, a mechanism potentially involved in vascular regeneration. Human CD34
+
cells express JAM-A, mediating their interaction with platelets and endothelial cells. Specifically, JAM-A expressed on human CD34
+
progenitor cells regulates their adhesion over immobilized platelets or inflammatory endothelium under high shear stress in vitro and after carotid ligation in vivo or ischemia/reperfusion injury in the microcirculation of mice. Moreover, it mediates differentiation of CD34
+
cells to endothelial progenitor cells and facilitates reendothelialization.
Red Cells, Hemoglobin, Heme, Iron, and Atherogenesis
Authors: Nagy Emőke , Eaton John W. , Jeney Viktória , Soares Miguel P. , Varga Zsuzsa , Galajda Zoltán , Szentmiklósi József , Méhes Gábor , Csonka Tamás , Smith Ann , Vercellotti Gregory M. , Balla György , Balla József
Published: April 2010

Objective—

We investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis.

Methods and Results—

We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIV=O). The protein oxidation marker dityrosine accumulates in complicated lesions, accompanied by the formation of cross-linked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity.

Conclusion—

The interior of advanced atheromatous lesions is a prooxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. These events amplify the endothelial cell cytotoxicity of plaque components.
Genetic Modification of Mesenchymal Stem Cells Overexpressing CCR1 Increases Cell Viability, Migration, Engraftment, and Capillary Density in the Injured Myocardium
Authors: Huang Jing , Zhang Zhiping , Guo Jian , Ni Aiguo , Deb Arjun , Zhang Lunan , Mirotsou Maria , Pratt Richard E. , Dzau Victor J.
Published: April 2010

Rationale
:

Although mesenchymal stem cell (MSC) transplantation has been shown to promote cardiac repair in acute myocardial injury in vivo, its overall restorative capacity appears to be restricted mainly because of poor cell viability and low engraftment in the ischemic myocardium. Specific chemokines are upregulated in the infarcted myocardium. However the expression levels of the corresponding chemokine receptors (eg, CCR1, CXCR2) in MSCs are very low. We hypothesized that this discordance may account for the poor MSC engraftment and survival.

Objective
:

To determine whether overexpression of CCR1 or CXCR2 chemokine receptors in MSCs augments their cell survival, migration and engraftment after injection in the infarcted myocardium.

Methods and Results
:

Overexpression of CCR1, but not CXCR2, dramatically increased chemokine-induced murine MSC migration and protected MSC from apoptosis in vitro. Moreover, when MSCs were injected intramyocardially one hour after coronary artery ligation, CCR1-MSCs accumulated in the infarcted myocardium at significantly higher levels than control-MSCs or CXCR2-MSCs 3 days postmyocardial infarction (MI). CCR1-MSC–injected hearts exhibited a significant reduction in infarct size, reduced cardiomyocytes apoptosis and increased capillary density in injured myocardium 3 days after MI. Furthermore, intramyocardial injection of CCR1-MSCs prevented cardiac remodeling and restored cardiac function 4 weeks after MI.

Conclusions
:

Our results demonstrate the in vitro and in vivo salutary effects of genetic modification of stem cells. Specifically, overexpression of chemokine receptor enhances the migration, survival and engraftment of MSCs, and may provide a new therapeutic strategy for the injured myocardium.
Magnetic Targeting Enhances Engraftment and Functional Benefit of Iron-Labeled Cardiosphere-Derived Cells in Myocardial Infarction
Authors: Cheng Ke , Li Tao-Sheng , Malliaras Konstantinos , Davis Darryl R. , Zhang Yiqiang , Marbán Eduardo
Published: April 2010

Rationale
:

The success of cardiac stem cell therapies is limited by low cell retention, due at least in part to washout via coronary veins.

Objective
:

We sought to counter the efflux of transplanted cells by rendering them magnetically responsive and imposing an external magnetic field on the heart during and immediately after injection.

Methods and Results
:

Cardiosphere-derived cells (CDCs) were labeled with superparamagnetic microspheres (SPMs). In vitro studies revealed that cell viability and function were minimally affected by SPM labeling. SPM-labeled rat CDCs were injected intramyocardially, with and without a superimposed magnet. With magnetic targeting, cells were visibly attracted toward the magnet and accumulated around the ischemic zone. In contrast, the majority of nontargeted cells washed out immediately after injection. Fluorescence imaging revealed more retention of transplanted cells in the heart, and less migration into other organs, in the magnetically targeted group. Quantitative PCR confirmed that magnetic targeting enhanced cell retention (at 24 hours) and engraftment (at 3 weeks) in the recipient hearts by ≈3-fold compared to nontargeted cells. Morphometric analysis revealed maximal attenuation of left ventricular remodeling, and echocardiography showed the greatest functional improvement, in the magnetic targeting group. Histologically, more engrafted cells were evident with magnetic targeting, but there was no incremental inflammation.

Conclusions
:

Magnetic targeting enhances cell retention, engraftment and functional benefit. This novel method to improve cell therapy outcomes offers the potential for rapid translation into clinical applications.
Interleukin-17A Is Dispensable for Myocarditis but Essential for the Progression to Dilated Cardiomyopathy
Authors: Baldeviano G. Christian , Barin Jobert G. , Talor Monica V. , Srinivasan Sachin , Bedja Djahida , Zheng Dongfeng , Gabrielson Kathleen , Iwakura Yoichiro , Rose Noel R. , Cihakova Daniela
Published: April 2010

Rationale
:

One-third of myocarditis cases progresses to dilated cardiomyopathy (DCM), but the mechanisms controlling this process are largely unknown. CD4
+
T helper (Th)17 cells have been implicated in the pathogenesis of autoimmune diseases, but the role of Th17-produced cytokines during inflammation-induced cardiac remodeling has not been previously studied.

Objective
:

We examined the importance of interleukin (IL)-17A in the progression of myocarditis to DCM using a mouse model.

Methods and Results
:

Immunization of mice with myocarditogenic peptide in complete Freund’s adjuvant induced the infiltration of IL-17A–producing Th17 cells into the inflamed heart. Unexpectedly, IL-17A–deficient mice developed myocarditis with similar incidence and severity compared to wild-type mice. Additionally, IL-17A deficiency did not ameliorate the severe myocarditis of interferon (IFN)γ-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, IL-17A–deficient mice were protected from postmyocarditis remodeling and did not develop DCM. Flow cytometric and cytokine analysis revealed an important role for IL-17A in heart-specific upregulation of IL-6, TNFα, and IL-1β and the recruitment of CD11b
+
monocyte and Gr1
+
granulocyte populations into the heart. Furthermore, IL-17A–deficient mice had reduced interstitial myocardial fibrosis, downregulated expression of matrix metalloproteinase-2 and -9 and decreased gelatinase activity. Treatment of BALB/c mice with anti–IL-17A monoclonal antibody administered after the onset of myocarditis abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function.

Conclusions
:

Our findings reveal a critical role for IL-17A in postmyocarditis cardiac remodeling and the progression to DCM. Targeting IL-17A may be an attractive therapy for patients with inflammatory dilated cardiomyopathy.
Cyclic Mechanical Stretch Induces Cardiomyocyte Orientation and Polarization of the Gap Junction Protein Connexin43
Authors: Salameh Aida , Wustmann Anne , Karl Sebastian , Blanke Katja , Apel Daniel , Rojas-Gomez Diana , Franke Heike , Mohr Friedrich W. , Janousek Jan , Dhein Stefan
Published: April 2010

Rationale
:

Cyclic mechanical stretch (CMS) is an important physiological and pathological factor in the heart.

Objective
:

We examined whether CMS can affect localization of gap junctions with regard to the cell axis.

Methods and Results
:

Neonatal rat cardiomyocytes were cultured (7 days) on flexible 6-well plates. Thereafter, cells were kept static or stimulated with CMS (1 Hz; 0, 10, 20% elongation) for 0, 24, or 48 hours (with or without 10 μmol/L PD98059, 5 μmol/L BIM I (bisindolylmaleimide I), 2 μmol/L H8 [
N
-(2-methlyamino-ethyl)-5-isoquinoline-sulfonamid], or 0.1 μmol/L angiotensin II. Additionally, cells were exposed to 24 hours of CMS followed by 24 hours of static recovery. CMS (24 hour, 10%) induced elongation of the cardiomyocytes and orientation 79±8° toward the stretch direction. Moreover, the distribution of connexin (Cx)43 together with N-cadherin changed, so that both proteins were accentuated at the cell poles, whereas in nonstretched cells, they were distributed around the cell without preferential localization. Additional angiotensin II reduced polar Cx43 accentuation. The CMS-induced changes in Cx43 were reversible within 24 hours after end of stretch, and could be completely prevented by the MEK1/2 inhibitor PD98059 but not by BIM I or H8. Moreover, stretch resulted in Cx43 protein and Cx43-mRNA upregulation and in a significant upregulation of the phosphorylated forms of ERK1/2, glycogen synthase kinase 3β and AKT. Furthermore, CMS resulted in a significant increase of the transcription factors activator protein 1 and CREB (cAMP response element–binding protein) in the nucleus.

Conclusions
:

CMS results in self-organization of cardiomyocytes leading to elongated cells orientated transverse to the stretch axis, enhanced Cx43 expression and Cx43 accentuation at the cell poles. The Cx43-changes seem to depend on the ERK1/2 signaling cascade.
Isoform-Selective Physical Coupling of TRPC3 Channels to IP
3
Receptors in Smooth Muscle Cells Regulates Arterial Contractility
Authors: Adebiyi Adebowale , Zhao Guiling , Narayanan Damodaran , Thomas-Gatewood Candice M. , Bannister John P. , Jaggar Jonathan H.
Published: April 2010

Rationale
:

Inositol 1,4,5-trisphosphate (IP
3
)-induced vasoconstriction can occur independently of intracellular Ca
2+
release and via IP
3
receptor (IP
3
R) and canonical transient receptor potential (TRPC) channel activation, but functional signaling mechanisms mediating this effect are unclear.

Objectives
:

Study mechanisms by which IP
3
Rs stimulate TRPC channels in myocytes of resistance-size cerebral arteries.

Methods and Results
:

Immunofluorescence resonance energy transfer (immuno-FRET) microscopy using isoform-selective antibodies indicated that endogenous type 1 IP
3
Rs (IP
3
R1) are in close spatial proximity to TRPC3, but distant from TRPC6 or TRPM4 channels in arterial myocytes. Endothelin-1 (ET-1), a phospholipase C–coupled receptor agonist, elevated immuno-FRET between IP
3
R1 and TRPC3, but not between IP
3
R1 and TRPC6 or TRPM4. TRPC3, but not TRPC6, coimmunoprecipitated with IP
3
R1. TRPC3 and TRPC6 antibodies selectively inhibited recombinant channels, but only the TRPC3 antibody blocked IP
3
-induced nonselective cation current (
I
Cat
) in myocytes. TRPC3 knockdown attenuated immuno-FRET between IP
3
R1 and TRPC3, IP
3
-induced
I
Cat
activation, and ET-1 and IP
3
-induced vasoconstriction, whereas TRPC6 channel knockdown had no effect. ET-1 did not alter total or plasma membrane-localized TRPC3, as determined using surface biotinylation. RT-PCR demonstrated that C-terminal calmodulin and IP
3
R binding (CIRB) domains are present in myocyte TRPC3 and TRPC6 channels. A peptide corresponding to the IP
3
R N-terminal region that can interact with TRPC channels activated
I
Cat
. A TRPC3 CIRB domain peptide attenuated IP
3
- and ET-1–induced
I
Cat
activation and vasoconstriction.

Conclusions
:

IP
3
stimulates direct coupling between IP
3
R1 and membrane-resident TRPC3 channels in arterial myocytes, leading to
I
Cat
activation and vasoconstriction. Close spatial proximity between IP
3
R1 and TRPC3 establishes this isoform-selective functional interaction.
Induction of Cardiac Angptl4 by Dietary Fatty Acids Is Mediated by Peroxisome Proliferator-Activated Receptor β/δ and Protects Against Fatty Acid–Induced Oxidative Stress
Authors: Georgiadi Anastasia , Lichtenstein Laeticia , Degenhardt Tatjana , Boekschoten Mark V. , van Bilsen Marc , Desvergne Beatrice , Müller Michael , Kersten Sander
Published: April 2010

Rationale
:

Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart.

Objective
:

To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences.

Methods and Results
:

Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response. The gene most significantly and consistently upregulated by dietary fatty acids encoded Angiopoietin-like protein (Angptl)4, a circulating inhibitor of lipoprotein lipase expressed by cardiomyocytes. Induction of Angptl4 by the fatty acid linolenic acid was specifically abolished in peroxisome proliferator-activated receptor (PPAR)β/δ
−/−
and not PPARα
−/−
mice and was blunted on siRNA-mediated PPARβ/δ knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPARβ/δ but not PPARα to the Angptl4 gene. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma triglyceride-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. In contrast, Angptl4 deletion led to enhanced oxidative stress in the heart, both after an acute oral fat load and after prolonged high fat feeding.

Conclusions
:

Stimulation of cardiac Angptl4 gene expression by dietary fatty acids and via PPARβ/δ is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid–induced oxidative stress.
Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage (IMASH)
Authors: Wong George Kwok Chu , Poon Wai S. , Chan Matthew T.V. , Boet Ronald , Gin Tony , Ng Stephanie C.P. , Zee Beny C.Y.
Published: April 2010

Background and Purpose—

Pilot clinical trials using magnesium sulfate in patients with acute aneurysmal subarachnoid hemorrhage have reported trends toward improvement in clinical outcomes. This Phase III study aimed to compare intravenous magnesium sulfate infusion with saline placebo among such patients.

Methods—

We recruited patients with aneurysmal subarachnoid hemorrhage within 48 hours of onset from 10 participating centers. The patients were randomly assigned to magnesium sulfate infusion titrated to a serum magnesium concentration twice the baseline concentration or saline placebo for 10 to 14 days. Patients and assessors were blinded to treatment allocation. The study is registered at www.strokecenter.org/trials (as Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage [IMASH]) and www.ClinicalTrials.gov (NCT00124150).

Results—

Of the 327 patients recruited, 169 were randomized to receive treatment with intravenous magnesium sulfate and 158 to receive saline (placebo). The proportions of patients with a favorable outcome at 6 months (Extended Glasgow Outcome Scale 5 to 8) were similar, 64% in the magnesium sulfate group and 63% in the saline group (OR, 1.0; 95% CI, 0.7 to 1.6). Secondary outcome analyses (modified Rankin Scale, Barthel Index, Short Form 36, and clinical vasospasm) also showed no significant differences between the 2 groups. Predefined subgroups included age, admission World Federation of Neurological Surgeons grade, pre-existing hypertension, intracerebral hematoma, intraventricular hemorrhage, location of aneurysm, size of aneurysm, and mode of aneurysm treatment. In none of the subgroups did the magnesium sulfate group show a better outcome at 6 months.

Conclusions—

The results do not support a clinical benefit of intravenous magnesium sulfate infusion over placebo infusion in patients with acute aneurysmal subarachnoid hemorrhage.
Size Ratio Correlates With Intracranial Aneurysm Rupture Status
Authors: Rahman Maryam , Smietana Janel , Hauck Erik , Hoh Brian , Hopkins Nick , Siddiqui Adnan , Levy Elad I. , Meng Hui , Mocco J.
Published: April 2010

Background and Purpose—

The prediction of intracranial aneurysm (IA) rupture risk has generated significant controversy. The findings of the International Study of Unruptured Intracranial Aneurysms (ISUIA) that small anterior circulation aneurysms (<7 mm) have a 0% risk of subarachnoid hemorrhage in 5 years is difficult to reconcile with other studies that reported a significant portion of ruptured IAs are small. These discrepancies have led to the search for better aneurysm parameters to predict rupture. We previously reported that size ratio (SR), IA size divided by parent vessel diameter, correlated strongly with IA rupture status (ruptured versus unruptured). These data were all collected retrospectively off 3-dimensional angiographic images. Therefore, we performed a blinded prospective collection and evaluation of SR data from 2-dimensional angiographic images for a consecutive series of patients with ruptured and unruptured IAs.

Methods—

We prospectively enrolled 40 consecutive patients presenting to a single institution with either ruptured IA or for first-time evaluation of an incidental IA. Blinded technologists acquired all measurements from 2-dimensional angiographic images. Aneurysm rupture status, location, IA maximum size, and parent vessel diameter were documented. The SR was calculated by dividing the aneurysm size (mm) by the average parent vessel size (mm). A 2-tailed Mann-Whitney test was performed to assess statistical significance between ruptured and unruptured groups. Fisher exact test was used to compare medical comorbidities between the ruptured and unruptured groups. Significant differences between the 2 groups were subsequently tested with logistic regression. SE and probability values are reported.

Results—

Forty consecutive patients with 24 unruptured and 16 ruptured aneurysms met the inclusion criteria. No significant differences were found in age, gender, smoking status, or medical comorbidities between ruptured and unruptured groups. The average maximum size of the unruptured IAs (6.18±0.60 mm) was significantly smaller compared with the ruptured IAs (7.91±0.47 mm;
P
=0.03), and the unruptured group had significantly smaller SRs (2.57±0.24 mm) compared with the ruptured group (4.08±0.54 mm;
P
<0.01). Logistic regression was used to evaluate the independent predictive value of those variables that achieved significance in univariate analysis (IA maximum size and SR). Using stepwise selection, only SR remained in the final predictive model (OR, 2.12; 95% CI, 1.09 to 4.13).

Conclusion—

SR, the ratio between aneurysm size and parent artery diameter, can be easily calculated from 2-dimensional angiograms and correlates with IA rupture status on presentation in a blinded analysis. SR should be further studied in a large prospective observational cohort to predict true IA risk of rupture.
Speaking in Tongues, Dancing with Ghosts: Redescription, Translation, and the Language of Resurrection
Authors: Parrish John W.
Published: April 2010

This essay provides a constructive critique and extension of Jonathan Z. Smith’s writings on Paul and 1 Corinthians. Beginning with a demonstration of the problems with applying Smith’s locative/utopian dichotomy to Paul and the Corinthians, I argue that this theoretical scheme renders the Corinthians’ acceptance of Paul’s message incomprehensible. Smith’s later scheme of ‘‘here, there, and anywhere’’ provides a more useful heuristic. Following an analysis of the social and religious setting of 1 Corinthians, I explore the analogous case of the 1870 Ghost Dance as it developed among the Paiute of Western Nevada. After briefly discussing the implications of this analogy for our understanding of the Corinthian Christ group (and early Christianities generally), I conclude that both the Corinthians and the Paiute are displaced religions of ‘‘here’’ that have experimented with features characteristic of the religions of ‘‘anywhere.’’ This cross-cultural description provides our models of Paul and the Corinthians with a sounder anthropological footing than they might previously have had.