bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Hybridization in Plant Speciation
Authors: Soltis Pamela S. , Soltis Douglas E.
Published: January 2009

The importance of hybridization in plant speciation and evolution has been debated for decades, with opposing views of hybridization as either a creative evolutionary force or evolutionary noise. Hybrid speciation may occur at either the homoploid (i.e., between two species of the same ploidy) or the polyploid level, each with its attendant genetic and evolutionary consequences. Whereas allopolyploidy (i.e., resulting from hybridization and genome doubling) has long been recognized as an important mode of plant speciation, the implications of genome duplication have typically not been taken into account in most fields of plant biology. Recent developments in genomics are revolutionizing our views of angiosperm genomes, demonstrating that perhaps all angiosperms have likely undergone at least one round of polyploidization and that hybridization has been an important force in generating angiosperm species diversity. Hybridization and polyploid formation continue to generate species diversity, with several new allopolyploids having originated just within the past century or so. The origins of polyploid species—whether via hybridization between species or between genetically differentiated populations of a single species—and the immediate genetic consequences of polyploid formation are therefore receiving enthusiastic attention. The time is therefore right for a review of the role of hybridization in plant speciation.
Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice
Authors: Zahedi Kamyar , Lentsch Alex B. , Okaya Tomohisa , Barone Sharon , Sakai Nozomu , Witte David P. , Arend Lois J. , Alhonen Leena , Jell Jason , Jänne Juhani , Porter Carl W. , Soleimani Manoocher
Published: January 2009

Expression of spermine/spermidine- N1-acetyltransferase (SSAT), the rate-limiting enzyme of polyamine backconversion cascade, increases after ischemia-reperfusion injuries (IRI). We hypothesized that SSAT plays an important role in the mediation of IRI. To test our hypothesis, wild-type (SSAT-wt) and SSAT-deficient (SSAT-ko) mice were subjected to liver or kidney IRI by ligation of hepatic or renal arteries. The liver and kidney content of putrescine (Put), a downstream by-product of SSAT activity, increased in SSAT-wt animals but not in SSAT-ko animals after IRI, indicating that polyamine backconversion is not functional in SSAT-deficient mice. When subjected to hepatic IRI, SSAT-ko mice were significantly protected against liver damage compared with SSAT-wt mice. Similarly, SSAT-ko animals subjected to renal IRI showed significantly greater protection against damage to kidney tubules than SSAT-wt mice. These studies indicate that SSAT-deficient animals are protected against IRI and suggest that SSAT is an important mediator of the tissue damage in IRI.
Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice
Authors: Bradford Emily M. , Sartor Maureen A. , Gawenis Lara R. , Clarke Lane L. , Shull Gary E.
Published: January 2009

In cystic fibrosis, impaired secretion resulting from loss of activity of the cystic fibrosis transmembrane conductance regulator (CFTR) causes dehydration of intestinal contents and life-threatening obstructions. Conversely, impaired absorption resulting from loss of the NHE3 Na+/H+ exchanger causes increased fluidity of the intestinal contents and diarrhea. To test the hypothesis that reduced NHE3-mediated absorption could increase survival and prevent some of the intestinal pathologies of cystic fibrosis, Cftr/Nhe3 double heterozygous mice were mated and their offspring analyzed. Cftr-null mice lacking one or both copies of the NHE3 gene exhibited increased fluidity of their intestinal contents, which prevented the formation of obstructions and increased survival. Goblet cell hyperplasia was eliminated, but not the accumulation of Paneth cell granules or increased cell proliferation in the crypts. Microarray analysis of small intestine RNA from Cftr-null, NHE3-null, and double-null mice all revealed downregulation of genes involved in xenobiotic metabolism, including a cohort of genes involved in glutathione metabolism. Expression of energy metabolism genes was altered, but there were no changes in genes involved in inflammation. Total intracellular glutathione was increased in the jejunum of all of the mutants and the ratio of reduced to oxidized glutathione was reduced in Cftr-null mutants, indicating that CFTR deficiency affects intestinal glutathione metabolism. The data establish a major role for NHE3 in regulating the fluidity of the intestinal contents and show that reduced NHE3-mediated absorption reverses some of the intestinal pathologies of cystic fibrosis, thus suggesting that it may serve as a potential therapeutic target.
Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3
Authors: Govindarajan Rajgopal , Leung George P. H. , Zhou Mingyan , Tse Chung-Ming , Wang Joanne , Unadkat Jashvant D
Published: January 2009

human equilibrative nucleoside transporter-3 (hENT3) was recently reported as a pH-dependent, intracellular (lysosomal) transporter capable of transporting anti-human immunodeficiency virus (HIV) dideoxynucleosides (ddNs). Because most anti-HIV ddNs (e.g., zidovudine, AZT) exhibit clinical mitochondrial toxicity, we investigated whether hENT3 facilitates transport of anti-HIV ddNs into the mitochondria. Cellular fractionation and immunofluorescence microscopy studies in several human cell lines identified a substantial presence of hENT3 in the mitochondria, with additional presence at the cell surface of two placental cell lines (JAR, JEG3). Mitochondrial or cell surface hENT3 expression was confirmed in human hepatocytes and placental tissues, respectively. Unlike endogenous hENT3, yellow fluorescent protein (YFP)-tagged hENT3 was partially directed to the lysosomes. Xenopus oocytes expressing NH2-terminal-deleted hENT3 (expressed at the cell surface) showed pH-dependent interaction with several classes of nucleosides (anti-HIV ddNs, gemcitabine, fialuridine, ribavirin) that produce mitochondrial toxicity. Transport studies in hENT3 gene-silenced JAR cells showed significant reduction in mitochondrial transport of nucleosides and nucleoside drugs. Our data suggest that cellular localization of hENT3 is cell type dependent and the native transporter is substantially expressed in mitochondria and/or cell surface. hENT3-mediated mitochondrial transport may play an important role in mediating clinically observed mitochondrial toxicity of nucleoside drugs. In addition, our finding that hENT3 is a mitochondrial transporter is consistent with the recent finding that mutations in the hENT3 gene cause an autosomal recessive disorder in humans called the H syndrome.
Suppression of nitrosative and oxidative stress to reduce cardiac allograft vasculopathy
Authors: Hasegawa Tomomi , Iwanaga Koichiro , Hultquist Donald E. , Liao Hui , Visovatti Scott H. , Pinsky David J.
Published: January 2009

Oxidant injury occurs when an organ is severed from its native blood supply and then reperfused and continues during subsequent periods of immune attack. Experiments here test the hypothesis that an antioxidant given only in the peri-reperfusion period protects against not only oxidative but also nitrosative stress, leading to reduced vasculopathy long after cardiac allotransplantation. Experiments were performed using a murine heterotopic cardiac transplantation model. An antioxidant, in the form of intraperitoneal high-dose riboflavin, was given to recipients during the initial 3 days after transplantation. Antioxidant-treated mice showed significantly longer graft survival than control mice. At 4 h after transplantation, antioxidant treatment significantly reduced graft lipid peroxidation and oxidized DNA and preserved antioxidant enzyme activity. At day 6 posttransplantation, the redox-sensitive transcription factor nuclear factor-κB and inducible nitric oxide synthase were significantly reduced following antioxidant treatment, with concomitant reduction of nitrotyrosine. Despite the limited duration of antioxidant treatment, both acute and chronic rejection were significantly suppressed. In vitro experiments confirmed suppression of nitrosative and oxidative stress and cardiomyocyte damage in antioxidant-treated cardiac allografts. Collectively, antioxidant administration during the initial 3 days after transplantation significantly reduces nitrosative and oxidative stress in cardiac allografts, modulates immune responses, and protects against vasculopathy.
Distinct muscle fascicle length changes in feline medial gastrocnemius and soleus muscles during slope walking
Authors: Maas Huub , Gregor Robert J. , Hodson-Tole Emma F. , Farrell Brad J. , Prilutsky Boris I.
Published: January 2009

On the basis of differences in physiology, e.g., histochemical properties and spindle density, and the structural design of the cat soleus (SO) and medial gastrocnemius (MG) muscles, we hypothesized that 1) fascicle length changes during overground walking would be both muscle and slope dependent, which would have implications for the muscles' force output as well as sensory function, and that 2) muscle-tendon unit (MTU) and fascicle length changes would be different, in which case MTU length could not be used as an indicator of muscle spindle strain. To test these hypotheses, we quantified muscle fascicle length changes and compared them with length changes of the whole MTU in the SO and MG during overground walking at various slopes (0, ± 25, ± 50, +75, and +100%). The SO and MG were surgically instrumented with sonomicrometry crystals and fine-wire electromyogram electrodes to measure changes in muscle fascicle length and muscle activity, respectively. MTU lengths were calculated using recorded ankle and knee joint angles and a geometric model of the hindlimb. The resultant joint moments were calculated using inverse dynamics analysis to infer muscle loading. It was found that although MTU length and velocity profiles of the SO and MG appeared similar, length changes and velocities of muscle fascicles were substantially different between the two muscles. Fascicle length changes of both SO and MG were significantly affected by slope intensity acting eccentrically in downslope walking (−25 to −50%) and concentrically in upslope walking (+25 to +100%). The differences in MTU and fascicle behaviors in both the SO and MG muscles during slope walking were explained by the three distinct features of these muscles: 1) the number of joints spanned, 2) the pennation angle, and 3) the in-series elastic component. It was further suggested that the potential role of length feedback from muscle spindles is both task and muscle dependent.
Combination of hormone replacement therapy and high physical activity is associated with differences in Achilles tendon size in monozygotic female twin pairs
Authors: Finni T. , Kovanen V. , Ronkainen P. H. A. , Pöllänen E. , Bashford G. R. , Kaprio J. , Alén M. , Kujala U. M. , Sipilä S.
Published: January 2009

Estrogen concentration has been suggested to play a role in tendon abnormalities and injury. In physically active postmenopausal women, hormone replacement therapy (HRT) has been suggested to decrease tendon diameter. We hypothesized that HRT use and physical activity are associated with Achilles tendon size and tissue structure. The study applied cotwin analysis of fourteen 54- to 62-yr-old identical female twin pairs with current discordance for HRT use for an average of 7 yr. Achilles tendon thickness and cross-sectional areas were determined by ultrasonography, and tendon structural organization was analyzed from the images using linear discriminant analysis (LDA). Maximal voluntary and twitch torques from plantar flexor muscles were measured. Serum levels of estradiol, estrone, testosterone, and sex hormone binding globulin were analyzed. Total daily metabolic equivalent score (MET-h/day) was calculated from physical activity questionnaires. Results showed that, in five physically active (MET > 4) pairs, the cotwins receiving HRT had greater estradiol level ( P = 0.043) and smaller tendon cross-sectional area than their sisters (63 vs. 71 mm2, P = 0.043). Among all pairs, Achilles tendon thickness and cross-sectional area did not significantly differ between HRT using and nonusing twin sisters. Intrapair correlation for Achilles tendon thickness was high, despite HRT use discordance ( r = 0.84, P < 0.001). LDA distinguished different tendon structure only from two of six examined twin pairs who had a similar level of physical activity. In conclusion, the effect of HRT on Achilles tendon characteristics independent of genetic confounding may be present only in the presence of sufficient physical activity. In physically active twin pairs, the higher level of estrogen seems to be associated with smaller tendon size.
Suppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis
Authors: Ortiz-Muñoz Guadalupe , Martin-Ventura Jose Luis , Hernandez-Vargas Purificacion , Mallavia Beñat , Lopez-Parra Virginia , Lopez-Franco Oscar , Muñoz-Garcia Begoña , Fernandez-Vizarra Paula , Ortega Luis , Egido Jesus , Gomez-Guerrero Carmen
Published: January 2009

Objective—

Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction, mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic plaque development.

Methods and Results—

Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared to the fibrous area. SOCS were also increased in aortic lesions from apoE
−/−
mice. In cultured VSMCs, endothelial cells, and monocytes, SOCS1 and SOCS3 were transiently induced by proinflammatory cytokines, proatherogenic lipoproteins, and immune molecules. Furthermore, overexpression of SOCS suppressed STAT activation and reduced inflammatory gene expression and cell growth, whereas SOCS knockdown increased these cell responses. In vivo, antisense oligodeoxynucleotides targeting SOCS3 exacerbated the atherosclerotic process in apoE
−/−
mice by increasing the size, leukocyte content, and chemokine expression in the lesions.

Conclusions—

SOCS expressed in atherosclerotic lesions are key regulators of vascular cell responses. Activation of this endogenous antiinflammatory pathway might be of interest in the treatment of atherosclerosis.
Associations of Pentraxin 3 With Cardiovascular Disease and All-Cause Death
Authors: Jenny Nancy Swords , Arnold Alice M. , Kuller Lewis H. , Tracy Russell P. , Psaty Bruce M.
Published: January 2009

Objective—

We examined associations of pentraxin 3 (PTX3), a vascular inflammation marker, with incident cardiovascular disease (CVD) and all-cause death.

Methods and Results—

1583 Cardiovascular Health Study participants free of prevalent CVD were included. Nonexclusive case groups were angina (n=476), myocardial infarction (MI; n=237), stroke (n=310), CVD death (n=282), and all-cause death (n=772). 535 participants had no events. PTX3 levels were higher in those with subclinical CVD (1.90±1.89 ng/mL) than those without (1.71±1.88 ng/mL;
P
=0.001). Using Cox regression adjusted for age, sex, and ethnicity, a standard deviation increase in PTX3 (1.89 ng/mL) was associated with CVD death (hazard ratio 1.11; 95% confidence interval 1.02 to 1.21) and all-cause death (1.08; 1.02 to 1.15). PTX3 was not associated with angina (1.09; 0.98 to 1.20), MI (0.96; 0.81 to 1.12), or stroke (1.06; 0.95 to 1.18). Adding C-reactive protein (CRP) or CVD risk factors to the models had no significant effects on associations.

Conclusions—

In these older adults, PTX3 was associated with CVD and all-cause death independent of CRP and CVD risk factors. PTX3 likely reflects different aspects of inflammation than CRP and may provide insight into vascular health in aging and chronic diseases of aging that lead to death.
Vascular Endothelial Growth Factor
Authors: Ferrara Napoleone
Published: January 2009

Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. Several VEGF inhibitors have been approved by the FDA for the treatment of advanced cancer and neovascular age-related macular degeneration. This brief review provides a historic account of the challenges associated with the discovery of VEGF and the early steps in elucidating the role of this molecule in the regulation of angiogenesis.
Large Scale Association Analysis of Novel Genetic Loci for Coronary Artery Disease
Authors:   Coronary Artery Disease Consortium
Published: January 2009

Background—

Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined.

Methods and Results—

We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81×10
−21
). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19],
P
=1.44×10
−7
), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17],
P
=1.02×10
−3
), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18],
P
=4.34×10
−4
). The associations with 6q25.1 (rs6922269,
P
=0.020) and 2q36.3 (rs2943634,
P
=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (
P
=0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45],
P
=1.86×10
−5
) but not men (OR=1.03 [0.96 to 1.11],
P
=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele.

Conclusions

The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.
Arginase Promotes Neointima Formation in Rat Injured Carotid Arteries
Authors: Peyton Kelly J. , Ensenat Diana , Azam Mohammed A. , Keswani Amit N. , Kannan Sankaranarayanan , Liu Xiao-ming , Wang Hong , Tulis David A. , Durante William
Published: January 2009

Objective—

Arginase stimulates the proliferation of cultured vascular smooth muscle cells (VSMCs); however, the influence of arginase on VSMC growth in vivo is not known. This study investigated the impact of arginase on cell cycle progression and neointima formation after experimental arterial injury.

Methods and Results—

Balloon injury of rat carotid arteries resulted in a sustained increase in arginase activity in the vessel wall and the induction of arginase I protein in both the media and neointima of injured vessels. Furthermore, local perivascular application of the potent and selective arginase inhibitors
S
-(2-boronoethyl)-
l
-cysteine (BEC) or N
G
-hydroxy-nor-
l
-arginine (L-OHNA) immediately after injury markedly attenuated medial and neointimal DNA synthesis and neointima formation. Substantial arginase I protein and arginase activity was also detected in rat cultured aortic VSMCs. Moreover, treatment of VSMCs with BEC or L-OHNA, or knockdown of arginase I protein, arrested cells in the G
0
/G
1
phase of the cell cycle and induced the expression of the cyclin-dependent protein kinase inhibitor, p21.

Conclusion—

This study demonstrates that arginase is essential for VSMCs to enter the cell cycle and that arginase I contributes to the remodeling response after arterial injury. Arginase I represents a potentially new therapeutic target for the treatment of vasculoproliferative disorders.
Reduced Systolic Torsion in Chronic “Pure” Mitral Regurgitation
Authors: Ennis Daniel B. , Nguyen Tom C. , Itoh Akinobu , Bothe Wolfgang , Liang David H. , Ingels Neil B. , Miller D. Craig
Published: January 2009

Background—

Global left ventricular (LV) torsion declines with chronic ischemic mitral regurgitation (MR), which may accelerate the LV remodeling spiral toward global cardiomyopathy; however, it has not been definitively established whether this torsional decline is attributable to the infarct, the MR, or their combined effect. We tested the hypothesis that chronic “pure” MR alone reduces global LV torsion.

Methods and Results—

Chronic “pure” MR was created in 13 sheep by surgically punching a 3.5- to 4.8-mm hole (HOLE) in the mitral valve posterior leaflet. Nine control (CNTL) sheep were operated on concurrently. At 1 (WK-01) and 12 weeks (WK-12) postoperatively, the 4D motion of implanted radiopaque markers was used to calculate global LV torsion. MR-grade in HOLE was greater than CNTL at WK-01 and WK-12 (2.5�1.1 versus 0.6�0.5,
P
<0.001 at WK-12). HOLE LV mass index was larger at WK-12 compared with CNTL (195�14 versus 170�17 g/m
2
,
P
<0.01), indicating LV remodeling. Global LV systolic torsion decreased in HOLE from WK-01 to WK-12 (4.1�2.8� versus 1.7�1.7�,
P
<0.01), but did not change in CNTL (5.5�1.8� versus 4.2�2.7�,
P
=NS). Global LV torsion was lower in HOLE relative to CNTL at WK-12 (
P
<0.05) but not at WK-01 (
P
=NS).

Conclusions—

Twelve weeks of chronic “pure” MR resulting in mild global LV remodeling is associated with significantly increased LV mass index and reduced global LV systolic torsion, but no other significant changes in hemodynamics. MR alone is a major component of torsional deterioration in “pure” MR and may be an important factor in chronic ischemic mitral regurgitation.
Cdc2-Like Kinases and DNA Topoisomerase I Regulate Alternative Splicing of Tissue Factor in Human Endothelial Cells
Authors: Eisenreich Andreas , Bogdanov Vladimir Y. , Zakrzewicz Andreas , Pries Axel , Antoniak Silvio , Poller Wolfgang , Schultheiss Heinz-Peter , Rauch Ursula
Published: January 2009

Tumor necrosis factor (TNF)-α–stimulated human umbilical vein endothelial cells express 2 naturally occurring forms of tissue factor (TF), the primary initiator of blood coagulation: the soluble alternatively spliced isoform and the full-length TF isoform. The regulatory pathways enabling this phenomenon are completely unknown. Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing via phosphorylation of serine/arginine-rich proteins. In this study, we examined effects of serine/arginine-rich protein kinases on TF splicing following stimulation with TNF-α. Human endothelial cells were pretreated with specific inhibitors or small interfering RNAs against Cdc2-like kinases and DNA topoisomerase I before stimulation with TNF-α. TF levels were determined by semiquantitative RT-PCR, real-time PCR, and Western blotting. Cellular procoagulant activity was analyzed in a chromogenic TF activity assay. All 4 known Cdc2-like kinases forms were expressed in human endothelial cells. Selective inhibition of Cdc2-like kinases and DNA topoisomerase I elicited distinct changes in TF biosynthesis in TNF-α–stimulated endothelial cells, which impacted endothelial procoagulant activity. This study is the first to demonstrate that serine/arginine-rich protein kinases modulate splicing of TF pre-mRNA in human endothelial cells and, consequently, endothelial procoagulant activity under inflammatory conditions.
A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo
Authors: Meder Benjamin , Laufer Christina , Hassel David , Just Steffen , Marquart Sabine , Vogel Britta , Hess Alexander , Fishman Mark C. , Katus Hugo A. , Rottbauer Wolfgang
Published: January 2009

Although it is well known that mutations in the cardiac essential myosin light chain-1 (
cmlc-1
) gene can cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of cMLC-1 in the heart are only poorly understood. We have isolated the zebrafish mutant
lazy susan
(
laz
), which displays severely reduced contractility of both heart chambers. By positional cloning, we identified a nonsense mutation within the zebrafish
cmlc-1
gene to be responsible for the
laz
phenotype, leading to expression of a carboxyl-terminally truncated cMLC-1. Whereas complete loss of cMLC-1 leads to cardiac acontractility attributable to impaired cardiac sarcomerogenesis, expression of a carboxyl-terminally truncated cMLC-1 in
laz
mutant hearts is sufficient for normal cardiac sarcomerogenesis but severely impairs cardiac contractility in a cell-autonomous fashion. Whereas overexpression of wild-type cMLC-1 restores contractility of
laz
mutant cardiomyocytes, overexpression of phosphorylation site serine 195–deficient cMLC-1 (cMLC-1
S195A
) does not reconstitute cardiac contractility in
laz
mutant cardiomyocytes. By contrast, introduction of a phosphomimetic amino acid on position 195 (cMLC-1
S195D
) rescues cardiomyocyte contractility, demonstrating for the first time an essential role of the carboxyl terminus and especially of serine 195 of cMLC-1 in the regulation of cardiac contractility.
CXCL10 Inhibits Viral Replication Through Recruitment of Natural Killer Cells in Coxsackievirus B3-Induced Myocarditis
Authors: Yuan Ji , Liu Zhen , Lim Travis , Zhang Huifang , He Jianqing , Walker Elizabeth , Shier Courtney , Wang Yinjing , Su Yue , Sall Alhousseynou , McManus Bruce , Yang Decheng
Published: January 2009

Coxsackievirus (CV)B3 is the primary cause of viral myocarditis. We previously observed CXC chemokine ligand 10 (CXCL10) upregulation in the myocardium early in infection. However, the impact of CXCL10 in CVB3-induced myocarditis is unknown. Using isolated primary mouse cardiomyocytes we demonstrated for the first time that cardiomyocytes can express CXCL10 on interferon-γ stimulation. To explore the role of CXCL10 in CVB3-induced myocarditis, both CXCL10 transgenic and knockout mice were used. Following CVB3 challenges, the viral titer in the hearts inversely correlated with the levels of CXCL10 at early phase of infection before visible immune infiltration. Furthermore, as compared with the control mice, the decreased virus titers in the CXCL10 transgenic mouse hearts led to less cardiac damage and better cardiac function and vice verse in the knockout mice. This antiviral ability of CXCL10 might be through recruitment of natural killer (NK) cells to the heart and increased interferon-γ expression early in infection. At day 7 postinfection, with massive influx of mononuclear cells the expression of CXCL10 enhanced the infiltration of CXCR3
+
cells, CD4
+
, and CD8
+
T cells, as well as the expression of associated inflammatory cytokines. However, the augmented accumulation of these immune cells and associated cytokines failed to alter the viral clearance and mice survival. These results suggest the protective role of CXCL10 during the early course of CVB3 infection, which is attributed to the recruitment of NK cells. Nonetheless, CXCL10-directed chemoattractant effect is not sufficient for host to clear the virus in the heart.
Which Reported Estimate of the Prevalence of Malnutrition After Stroke Is Valid?
Authors: Foley Norine C. , Salter Katherine L. , Robertson James , Teasell Robert W. , Woodbury M. Gail
Published: January 2009

Background and Purpose—

The reported prevalence of malnutrition after stroke varies widely, whereas it remains unclear which of the estimates is most accurate. The aim of this review was to explore possible sources of this heterogeneity among studies and to evaluate whether the nutritional assessment techniques used were valid.

Methods—

A literature search was conducted to identify all studies in which the nutritional state of patients was assessed after inpatient admission for stroke. The percentages of patients identified as malnourished in each study and method of nutritional assessment are reported. For the purposes of this study, an assessment technique was considered valid if at least one form of validity had been demonstrated previously through psychometric evaluation.

Results—

Eighteen studies meeting inclusion criteria were identified. The reported frequency of malnutrition ranged from 6.1% to 62%. Seventeen different methods of nutritional assessment were used. Four trials used previously validated assessment methods: Subjective Global Assessment, “an informal assessment,” and Mini Nutritional Assessment. The nutritional assessment methods used in the remaining studies used had not been validated previously.

Conclusions—

The use of a wide assortment of nutritional assessment tools, many of which have not been validated, may have contributed to the wide range of estimates of malnutrition. If so, this underscores the need for valid and reliable assessment tools to further our understanding of the relationship between stroke and nutritional status.
Prevalence of Abnormal Glucose Metabolism and Insulin Resistance Among Subtypes of Ischemic Stroke in Japanese Patients
Authors: Urabe Takao , Watada Hirotaka , Okuma Yasuyuki , Tanaka Ryota , Ueno Yuji , Miyamoto Nobukazu , Tanaka Yasutaka , Hattori Nobutaka , Kawamori Ryuzo
Published: January 2009

Background and Purpose—

The purpose was to assess the prevalence of disorders of glucose metabolism and insulin resistance in Japanese ischemic stroke patients with no history of diabetes by performing 75-gram oral glucose tolerance test (OGTT).

Methods—

We recruited 427 ischemic stroke patients (atherothrombotic infarction, n=220; lacunar infarction, n=125; cardioembolic infarction, n=82). OGTT was used to evaluate disorders of glucose metabolism in stroke patients without previously known diabetes (n=113). We investigated the relationships among the prevalence of abnormal glucose metabolism, ischemic stroke subtypes, and the prevalence of insulin resistance using homeostasis model assessment for insulin resistance and immunoreactive insulin at 120 minutes after glucose loading (IRI
120
).

Results—

OGTT identified the presence of disorders of glucose metabolism in 62.8% of ischemic stroke patients without previously known diabetes, including diabetes (24.8%) and impaired glucose tolerance (lone impaired glucose tolerance and impaired fasting glucose plus impaired glucose tolerance, 34.5%). The prevalence of newly diagnosed diabetes and impaired glucose tolerance was the highest in the atherothrombotic infarction group (68.9%). The highest values of homeostasis model assessment for insulin resistance and immunoreactive insulin at 120 minutes after glucose loading were found in atherothrombotic infarction patients with abnormal glucose tolerance.

Conclusions—

In this study, a significantly large percentage of Japanese patients with ischemic stroke and no history of diabetes were found to have disorders of glucose metabolism by OGTT. Impaired glucose tolerance and insulin resistance could play an important pathogenic role in the development of atherothrombotic infarction.
Elevated C-Reactive Protein and Long-Term Mortality After Ischaemic Stroke
Authors: Shantikumar Saran , Grant Peter J. , Catto Andrew J. , Bamford John M. , Carter Angela M.
Published: January 2009

Background and Purpose—

Inflammatory biomarkers predict development of atherothrombotic events. In the present study we examined the relationships between C-reactive protein (CRP), complement C3, and long-term mortality after acute ischemic stroke.

Methods—

CRP and C3 were analyzed by in-house enzyme-linked immunosorbent assay in 394 subjects with acute ischemic stroke who survived for >30 days, followed-up for a median of 7.4 years.

Results—

CRP was higher in subjects who died (10.8 mg/L; 95% CI, 9.1–12.8) compared with survivors (3.8 mg/L; 95% CI, 3.1–4.7), whereas C3 was similar in both groups (
P
=0.26). CRP remained predictive for mortality after adjusting for conventional clinical and demographic risk factors (the adjusted hazard ratio for those with CRP in the highest compared with the lowest quartile was 2.0; 95% CI, 1.3–3.1). However, CRP was no longer independently predictive of mortality after additionally adjusting for β-thromboglobulin or von Willebrand factor.

Conclusions—

Our data suggest that the relationship between CRP and poststroke mortality may in part reflect inflammation-induced endothelial cell dysfunction and platelet activation.
Gender-Related Differences in Diagnostic Evaluation and Outcome of Ischemic Stroke in Poland
Authors: Turaj Wojciech , Słowik Agnieszka , Wnuk Marcin , Szczudlik Andrzej
Published: January 2009

Background and Purpose—

We compared the diagnostic evaluation and outcome of ischemic stroke between men and women in large cohort of Polish patients.

Methods—

Our study included 1488 consecutive patients (755 women and 733 men) with ischemic stroke, treated in a single stroke unit between January 2002 and August 2007. We analyzed demographic factors, major risk factors for stroke, severity of neurological deficit on admission, diagnostic work-up performed during the hospital stay, and outcome on discharge.

Results—

Women were older than men (70.9±13.7 vs 66.2±12.7 years;
P
<0.001) and had greater neurological deficit on admission (median NIHSS score: 7 [3–13] vs 5 [3–10];
P
<0.001). They were also less likely to obtain good recovery on discharge (39.2% vs 49.9%;
P
<0.001). Carotid ultrasound and echocardiography were performed more often in men (77.2% vs 68.7% and 52.4% vs 46.5%, respectively;
P
<0.05). Lesser neurological deficit on admission, younger age, and lack of history of myocardial infarction or previous stroke, but not gender, were independent predictors of full diagnostic work-up.

Conclusions—

Gender does not influence the adequate diagnostic evaluation of ischemic stroke as an independent factor.
Thrombolysis in Stroke Mimics
Authors: Winkler David T. , Fluri Felix , Fuhr Peter , Wetzel Stephan G. , Lyrer Philippe A. , Ruegg Stephan , Engelter Stefan T.
Published: January 2009

Background and Purpose—

Intravenous thrombolysis for acute ischemic stroke is usually based on clinical assessment, blood test results, and CT findings. Intravenous thrombolysis of stroke mimics may occur but has not been studied in detail.

Methods—

We determined frequency, clinical characteristics, and outcome of mimic patients versus patients with stroke treated with intravenous thrombolysis using data of a prospective, single-center thrombolysis data bank.

Results—

Among 250 patients, 243 (97.2%) had strokes and 7 (2.8%) were mimics. Seizure was the most frequent diagnosis among mimics. There was a trend toward lower National Institutes of Health Stroke Scale scores in mimics (9.9±4.2) compared with strokes (13.7±5.4;
P
=0.06). Global aphasia without hemiparesis was the presenting symptom in 3 (42.9%) mimics versus 8 (3.3%) strokes (
P
=0.002). Orolingual angioedema, symptomatic intracranial hemorrhage, and asymptomatic intracranial hemorrhage occurred in 3 (1.2%), 13 (5.3%), and 30 (12.3%) patients with stroke, but were absent in mimics. After 3 months, 6 (85.7%) mimics and 86 (35.4%) strokes had a modified Rankin Scale score of 0 to 1 (
P
=0.01).

Conclusions—

Only few patients receiving intravenous thrombolysis did eventually have a final diagnosis other than stroke, ie, mostly seizures. Their outcome was favorable. Although clinical features differed between the stroke and the mimic groups, the differences were not distinctive enough to allow assigning individual patients to either of the groups. Multimodal neuroimaging or electroencephalographic recordings may be helpful for this assignment. However, their potential benefit has to be weighed against the potential harm of delayed thrombolysis.
Regional White Matter Integrity Differentiates Between Vascular Dementia and Alzheimer Disease
Authors: Zarei Mojtaba , Damoiseaux Jeske S. , Morgese Ciro , Beckmann Christian F. , Smith Steve M. , Matthews Paul M. , Scheltens Philip , Rombouts Serge A.R.B. , Barkhof Frederik
Published: January 2009

Background and Purpose—

Considerable clinical and radiological overlap between vascular dementia (VaD) and Alzheimer disease (AD) often makes the diagnosis difficult. Diffusion-tensor imaging studies showed that fractional anisotropy (FA) could be a useful marker for white matter changes. This study aimed to identify regional FA changes to identify a biomarker that could be used to differentiate VaD from AD.

Methods—

T1-weighted and diffusion-tensor imaging scans were obtained in 13 VaD patients, 16 AD patients, and 22 healthy elderly controls. We used tract-based spatial statistics to study regional changes in fractional anisotropy in AD, VaD, and elderly controls. We then used probabilistic tractography to parcel the corpus callosum in 7 regions according to its connectivity with major cerebral cortices using diffusion-tensor imaging data set. We compared the volume and mean FA in each set of transcallosal fibers between groups using ANOVA and then applied a discriminant analysis based on FA and T2-weighted imaging measures.

Results—

FA reduction in forceps minor was the most significant area of difference between AD and VaD. Segmentation of the corpus callosum using tractography and comparison of FA changes of each segment confirmed the FA changes in transcallosal prefrontal tracts of patients with VaD when compared to AD. The best discriminant model was the combination of transcallosal prefrontal FA and Fazekas score with 87.5% accuracy, 100% specificity, and 93% sensitivity (
P
<0.0001).

Conclusion—

Integrating mean FA in the forceps minor to the Fazekas score provides a useful quantitative marker for differentiating AD from VaD.
Randomized, Double-Blinded, Placebo Controlled Study of Neuroprotection With Lidocaine in Cardiac Surgery
Authors: Mathew Joseph P. , Mackensen G. Burkhard , Phillips-Bute Barbara , Grocott Hilary P. , Glower Donald D. , Laskowitz Daniel T. , Blumenthal James A. , Newman Mark F.
Published: January 2009

Background and Purpose—Cognitive decline after cardiac surgery remains common and diminishes patients’ quality of life. Based on experimental and clinical evidence, this study assessed the potential of intravenously administered lidocaine to reduce postoperative cognitive dysfunction after cardiac surgery using cardiopulmonary bypass.

Methods—After IRB approval, 277 patients undergoing cardiac surgery were enrolled into this prospective, randomized, double-blinded placebo controlled clinical trial. Subjects were randomized to receive: (1) Lidocaine as a 1 mg/kg bolus followed by a continuous infusion through 48 hours postoperatively, or (2) Placebo bolus and infusion. Cognitive function was assessed preoperatively and again at 6 weeks and 1 year postoperatively. The effect of lidocaine on postoperative cognition was tested using multivariable regression modeling;P<0.05 was considered significant.

Results—Among the 241 allocated subjects (Lidocaine: n=114; Placebo: n=127), the incidence of cognitive deficit in the lidocaine group was 45.5% versus 45.7% in the placebo group (P=0.97). Multivariable analysis revealed a significant interaction between treatment group and diabetes, such that diabetic subjects receiving lidocaine were more likely to suffer cognitive decline (P=0.004). Secondary analysis identified total lidocaine dose (mg/kg) as a significant predictor of cognitive decline and also revealed a protective effect of lower dose lidocaine in nondiabetic subjects.

Conclusions—Lidocaine administered during and after cardiac surgery does not reduce the high rate of postoperative cognitive dysfunction. Higher doses of lidocaine and diabetic status were independent predictors of cognitive decline. Protective effects of lower dose lidocaine in nondiabetic subjects need to be further evaluated.
Anoxia-Induced NF-kB-Dependent Upregulation of NCX1 Contributes to Ca
2+
Refilling Into Endoplasmic Reticulum in Cortical Neurons
Authors: Sirabella Rossana , Secondo Agnese , Pannaccione Anna , Scorziello Antonella , Valsecchi Valeria , Adornetto Annagrazia , Bilo Leonilda , Di Renzo Gianfranco , Annunziato Lucio
Published: January 2009

Background and Purpose—

The 3 gene products of the Na
+
/Ca
2+
exchanger (NCX), viz, NCX1, NCX2, and NCX3, may play a pivotal role in the pathophysiology of brain ischemia. The aim of this study was to investigate the transductional and posttranslational mechanisms involved in the expression of these isoforms during oxygen and glucose deprivation and their role in endoplasmic reticulum Ca
2+
refilling in cortical neurons.

Methods—

NCX1, NCX2, and NCX3 transcript and protein expression was evaluated in primary cortical neurons by reverse transcriptase–polymerase chain reaction and Western blot. NCX currents (I
NCX
) and cytosolic Ca
2+
concentrations ([Ca
2+
]
i
) were monitored by means of patch-clamp in whole-cell configuration and Fura-2AM single-cell video imaging, respectively.

Results—

Exposure of cortical neurons to 3 hours of oxygen and glucose deprivation yielded dissimilar effects on the 3 isoforms. First, it induced an upregulation in NCX1 transcript and protein expression. This change was exerted at the transcriptional level because the inhibition of nuclear factor kappa B translocation by small interfering RNA against p65 and SN-50 prevented oxygen and glucose deprivation-induced NCX1 upregulation. Second, it elicited a downregulation of NCX3 protein expression. This change, unlike NCX1, was exerted at the posttranscriptional level because it was prevented by the proteasome inhibitor MG-132. Finally, we found that it significantly increased I
NCX
both in the forward and reverse modes of operation and promoted an increase in ER Ca
2+
accumulation. Interestingly, such accumulation was prevented by the silencing of NCX1 and the NCX inhibitor CB-DMB that triggered caspase-12 activation.

Conclusions—

These results suggest that nuclear factor kappa B-dependent NCX1 upregulation may play a fundamental role in Ca
2+
refilling in the endoplasmic reticulum, thus helping neurons to prevent endoplasmic reticulum stress during oxygen and glucose deprivation.
Treating Visual Speech Perception to Improve Speech Production in Nonfluent Aphasia
Authors: Fridriksson Julius , Baker Julie M. , Whiteside Janet , Eoute David , Moser Dana , Vesselinov Roumen , Rorden Chris
Published: January 2009

Background and Purpose—

Several recent studies have revealed modulation of the left frontal lobe speech areas not only during speech production but also for speech perception. Crucially, the frontal lobe areas highlighted in these studies are the same ones that are involved in nonfluent aphasia. Based on these findings, this study examined the utility of targeting visual speech perception to improve speech production in nonfluent aphasia.

Methods—

Ten patients with chronic nonfluent aphasia underwent computerized language treatment utilizing picture–word matching. To examine the effect of visual speech perception on picture naming, 2 treatment phases were compared—one that included matching pictures to heard words and another in which pictures were matched to heard words accompanied by a video of the speaker’s mouth presented on the computer screen.

Results—

The results revealed significantly improved picture naming of both trained and untrained items after treatment when it included a visual speech component (ie, seeing the speaker’s mouth). In contrast, the treatment phase in which pictures were only matched to heard words did not result in statistically significant improvement of picture naming.

Conclusions—

The findings suggest that focusing on visual speech perception can significantly improve speech production in nonfluent aphasia and may provide an alternative approach to treat a disorder in which speech production seldom improves much in the chronic phase of stroke.
Roles of Glia Limitans Astrocytes and Carbon Monoxide in Adenosine Diphosphate-Induced Pial Arteriolar Dilation in Newborn Pigs
Authors: Kanu Alie , Leffler Charles W.
Published: January 2009

Background and Purpose—Astrocytes, neurons, and microvessels together form a neurovascular unit allowing blood flow to match neuronal activity. Adenosine diphosphate (ADP) is an important signaling molecule in the brain, and dilation in response to ADP is astrocyte-dependent in rats and newborn pigs. Carbon monoxide (CO), produced endogenously by catabolism of heme to CO, iron, and biliverdin via heme oxygenase, is an important cell-signaling molecule in the neonatal cerebral circulation. We hypothesize ADP stimulates CO production by glia limitans astrocytes and that this CO causes pial arteriolar dilation.

Methods—Experiments were performed using anesthetized piglet with closed cranial windows, and freshly isolated piglet astrocytes and microvessels. Astrocyte injury was caused by topical application of L-2-alpha aminoadipic acid (2 mmol/L, 5 hours). Cerebrospinal fluid was collected from under the cranial windows for measurement of ADP-stimulated CO production. CO was measured by gas chromatography-mass spectroscopy analysis.

Results—Before, but not after, astrocyte injury in vivo, topical ADP stimulated both CO production and dilation of pial arterioles. Astrocyte injury did not block dilation to isoproterenol or bradykinin. Chromium mesoporphyrin, an inhibitor of heme oxygenase, also prevented the ADP-induced increase in cerebrospinal fluid CO and pial arteriolar dilation caused by ADP, but not dilation to sodium nitroprusside. ADP also increased CO production by freshly isolated piglet astrocytes and cerebral microvessels, although the increase was smaller in the microvessels.

Conclusions—These data suggest that glia limitans astrocytes use CO as a gasotransmitter to cause pial arteriolar dilation in response to ADP.
Measuring Time
Authors: Vannest Kimberly J. , Parker Richard I.
Published: January 2009

Instructional time use is an intervention without equal. The measure of such has clear and important implications for special education practice and research. Although exhortations to maximize instruction and thereby student engagement exist throughout the literature, few studies discuss how special education teachers use their time, and none address the sampling or measurement issues related to differences of time across the academic calendar, by day or by teacher. This empirical investigation reports the requirements for adequate sampling, discussing variance by teacher and across the calendar year with attention to the standard error of measurement and denoting when stability is achieved. High-quality measurement provides opportunity for a more scientific approach to maximizing time use and thus student achievement. Results suggest that approximately 10 days appear to be sufficient to obtain a reasonably stable measure of teacher time use with a multiple code instrument designed to capture a variety of teacher behaviors.
Exposing the Economic Middle: A Revised Economy Scale for the Study of Early Urban Christianity
Authors: Longenecker Bruce W.
Published: January 2009

In 2004 Steve Friesen proposed a `poverty scale' for Graeco-Roman urbanism as a backdrop against which to assess features of the earliest urban Christian communities. This article offers an assessment of the strengths and weaknesses of Friesen's scale, not least in relation to binary taxonomies of Graeco-Roman economic stratification, rhetorical conventions of the ancient world, and the `middling groups' of Graeco-Roman urbanism. It proposes adjustments to the scale (renamed as the `economic scale') and gives consideration to the significance of those adjustments for the reconstruction of early Christianity relative to ancient poverty.