bluuebunny/crossref_metadata_2025 huggingface dataset:
Olfactory Learning in Drosophila
Authors: Busto Germain U. , Cervantes-Sandoval Isaac , Davis Ronald L.
Published: December 2010

Studies of olfactory learning in Drosophila have provided key insights into the brain mechanisms underlying learning and memory. One type of olfactory learning, olfactory classical conditioning, consists of learning the contingency between an odor with an aversive or appetitive stimulus. This conditioning requires the activity of molecules that can integrate the two types of sensory information, the odorant as the conditioned stimulus and the aversive or appetitive stimulus as the unconditioned stimulus, in brain regions where the neural pathways for the two stimuli intersect. Compelling data indicate that a particular form of adenylyl cyclase functions as a molecular integrator of the sensory information in the mushroom body neurons. The neuronal pathway carrying the olfactory information from the antennal lobes to the mushroom body is well described. Accumulating data now show that some dopaminergic neurons provide information about aversive stimuli and octopaminergic neurons about appetitive stimuli to the mushroom body neurons. Inhibitory inputs from the GABAergic system appear to gate olfactory information to the mushroom bodies and thus control the ability to learn about odors. Emerging data obtained by functional imaging procedures indicate that distinct memory traces form in different brain regions and correlate with different phases of memory. The results from these and other experiments also indicate that cross talk between mushroom bodies and several other brain regions is critical for memory formation.
Hijacking Solute Carriers for Proton-Coupled Drug Transport
Authors: Anderson Catriona M. H. , Thwaites David T.
Published: December 2010

The physiological role of mammalian solute carrier (SLC) proteins is to mediate transmembrane movement of electrolytes, nutrients, micronutrients, vitamins, and endogenous metabolites from one cellular compartment to another. Many transporters in the small intestine, kidney, and solid tumors are H+-coupled, driven by local H+-electrochemical gradients, and transport numerous drugs. These transporters include PepT1 and PepT2 (SLC15A1/2), PCFT (SLC46A1), PAT1 (SLC36A1), OAT10 (SLC22A13), OATP2B1 (SLCO2B1), MCT1 (SLC16A1), and MATE1 and MATE2-K (SLC47A1/2).
Serum Hepcidin and Macrophage Iron Correlate With MCP-1 Release and Vascular Damage in Patients With Metabolic Syndrome Alterations
Authors: Valenti Luca , Dongiovanni Paola , Motta Benedetta Maria , Swinkels Dorine W. , Bonara Paola , Rametta Raffaela , Burdick Larry , Frugoni Cecelia , Fracanzani Anna Ludovica , Fargion Silvia
Published: December 2010

Objective—

Increased body iron stores and hepcidin have been hypothesized to promote atherosclerosis by inducing macrophage iron accumulation and release of cytokines, but direct demonstration in human cells is lacking. The aim of this study was to evaluate the effect of iron on cytokine release in monocytes ex vivo and the correlation with vascular damage and to evaluate the relationship among serum levels of hepcidin, cytokines, and vascular damage in patients with metabolic syndrome alterations.

Methods and Results—

Manipulation of iron status with ferric ammonium citrate and hepcidin-25 induced monocyte chemoattractant protein (MCP)-1 and interleukin-6 in human differentiating monocytes of patients with hyperferritinemia associated with the metabolic syndrome (n=11), but not in subjects with hemochromatosis or
HFE
mutations impairing iron accumulation (n=15), and the degree of induction correlated with the presence of carotid plaques, detected by echocolor–Doppler. In monocytes of healthy subjects (n=7), iron and hepcidin increased the mRNA levels and release of MCP-1, but not of interleukin-6. In 130 patients with metabolic alterations, MCP-1 levels, as detected by ELISA, were correlated with hepcidin-25 measured by time-of-flight mass spectrometry (
P
=0.005) and were an independent predictor of the presence of carotid plaques (
P
=0.05).

Conclusion—

Hepcidin and macrophage iron correlate with MCP-1 release and vascular damage in high-risk individuals with metabolic alterations.
Platelet-Endothelial Cell Adhesion Molecule-1 Regulates Endothelial NO Synthase Activity and Localization Through Signal Transducers and Activators of Transcription 3–Dependent NOSTRIN Expression
Authors: McCormick Margaret E. , Goel Reema , Fulton David , Oess Stefanie , Newman Debra , Tzima Ellie
Published: December 2010

Background—

NO produced by the endothelial NO synthase (eNOS) is an important regulator of cardiovascular physiological and pathological features. eNOS is activated by numerous stimuli, and its activity is tightly regulated. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) has been implicated in regulating eNOS activity in response to shear stress. The current study was conducted to determine the role of PECAM-1 in the regulation of basal eNOS activity.

Methods and Results—

We demonstrate that PECAM-1–knockout ECs have increased basal eNOS activity and NO production. Mechanistically, increased eNOS activity is associated with a decrease in the inhibitory interaction of eNOS with caveolin-1, impaired subcellular localization of eNOS, and decreased eNOS traffic inducer (NOSTRIN) expression in the absence of PECAM-1. Furthermore, we demonstrate that activation of blunted signal transducers and activators of transcription 3 (STAT3) in the absence of PECAM-1 results in decreased NOSTRIN expression via direct binding of the signal transducers and activators of transcription 3 to the NOSTRIN promoter.

Conclusion—

Our results reveal an elegant mechanism of eNOS regulation by PECAM-1 through signal transducers and activators of transcription 3–mediated transcriptional control of NOSTRIN.
Systemic Markers of Interferon-γ–Mediated Immune Activation and Long-Term Prognosis in Patients With Stable Coronary Artery Disease
Authors: Pedersen Eva Ringdal , Midttun Øivind , Ueland Per Magne , Schartum-Hansen Hall , Seifert Reinhard , Igland Jannicke , Nordrehaug Jan Erik , Ebbing Marta , Svingen Gard , Bleie Øyvind , Berge Rolf , Nygård Ottar
Published: December 2010

Objective—

Interferon γ (IFN-γ) is centrally involved in atherosclerosis-related inflammation, but its activity cannot be reliably assessed by systemic measurements. In activated macrophages, IFN-γ stimulates production of neopterin and conversion of tryptophan to kynurenine. We evaluated the relationships of plasma neopterin and plasma kyunernine:tryptophan ratio (KTR) to long-term prognosis in patients with stable angina pectoris and angiographically verified significant coronary artery disease.

Methods and Results—

Samples were obtained from 2380 patients with a mean age of 63.7 years; 77.3% were men. During a median follow-up of 56 months, 10.8% of patients experienced a major coronary event (MCE), and 9.5% died. For MCE, each SD increment of neopterin and KTR (logarithmically transformed) was associated with multivariable adjusted hazard ratios and 95% CIs of 1.28 (1.10 to 1.48) and 1.28 (1.12 to 1.48), respectively. The corresponding hazard ratios (95% CIs) for all-cause mortality were 1.40 (1.21 to 1.62) (neopterin) and 1.23 (1.06 to 1.43) (KTR).

Conclusion—

In patients with stable angina pectoris, systemic markers of IFN-γ activity, plasma neopterin, and plasma KTR provide similar risk estimates for MCE and mortality. Our results support experimental data linking IFN-γ to acute atherosclerotic complications.
Phase I/IIa Clinical Trial of Therapeutic Angiogenesis Using Hepatocyte Growth Factor Gene Transfer to Treat Critical Limb Ischemia
Authors: Morishita Ryuichi , Makino Hirofumi , Aoki Motokuni , Hashiya Naotaka , Yamasaki Keita , Azuma Junya , Taniyama Yoshiaki , Sawa Yoshiki , Kaneda Yasufumi , Ogihara Toshio
Published: December 2010

Objective—

To evaluate the safety and feasibility of intramuscular gene transfer using naked plasmid DNA-encoding hepatocyte growth factor (HGF) and to assess its potential therapeutic benefit in patients with critical limb ischemia.

Methods and Results—

Gene transfer was performed in 22 patients with critical limb ischemia by intramuscular injection of HGF plasmid, either 2 or 4 mg, 2 times. Safety, ankle-brachial index, resting pain on a 10-cm visual analog scale, wound healing, and walking distance were evaluated before treatment and at 2 months after injection. No serious adverse event caused by gene transfer was detected over a follow-up of 6 months. Of particular importance, no peripheral edema, in contrast to that seen after treatment with vascular endothelial growth factor, was observed. In addition, the systemic HGF protein level did not increase during the study. At 2 months after gene transfer, the mean±SD ankle-brachial index increased from 0.46±0.08 to 0.59±0.13 (
P
<0.001), the mean±SD size of the largest ischemic ulcers decreased from 3.08±1.54 to 2.32±1.88 cm (
P
=0.007), and the mean±SD visual analog scale score decreased from 5.92±1.67 to 3.04±2.50 cm (
P
=0.001). An increase in ankle-brachial index by >0.1, a reduction in ulcer size by >25%, and a reduction in visual analog scale score by >2 cm at 2 months after gene transfer were observed in 11 (64.7%) of 17 limbs, 18 (72%) of 25 ulcers, and 8 (61.5%) of 13 limbs, respectively.

Conclusion—

Intramuscular injection of naked HGF plasmid is safe and feasible and can achieve successful improvement of ischemic limbs as sole therapy.
Transcriptional Activation of Apolipoprotein CIII Expression by Glucose May Contribute to Diabetic Dyslipidemia
Authors: Caron Sandrine , Verrijken An , Mertens Ilse , Samanez Carolina Huaman , Mautino Gisèle , Haas Joel T. , Duran-Sandoval Daniel , Prawitt Janne , Francque Sven , Vallez Emmanuelle , Muhr-Tailleux Anne , Berard Isabelle , Kuipers Folkert , Kuivenhoven Jan A. , Biddinger Sudha B. , Taskinen Marja-Riitta , Van Gaal Luc , Staels Bart
Published: December 2010

Objective—

Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism.

Methods and Results—

Liver-specific insulin receptor–deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces
apoCIII
transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element–binding protein and hepatocyte nuclear factor-4α. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-α but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin.

Conclusion—

Glucose induces
apoCIII
transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.
Reciprocal Control of hERG Stability by Hsp70 and Hsc70 With Implication for Restoration of LQT2 Mutant Stability
Authors: Li Peili , Ninomiya Haruaki , Kurata Yasutaka , Kato Masaru , Miake Junichiro , Yamamoto Yasutaka , Igawa Osamu , Nakai Akira , Higaki Katsumi , Toyoda Futoshi , Wu Jie , Horie Minoru , Matsuura Hiroshi , Yoshida Akio , Shirayoshi Yasuaki , Hiraoka Masayasu , Hisatome Ichiro
Published: December 2010

Rationale:

The human ether-a-go-go–related gene (hERG) encodes the α subunit of the potassium current
I
Kr
. It is highly expressed in cardiomyocytes and its mutations cause long QT syndrome type 2. Heat shock protein (Hsp)70 is known to promote maturation of hERG. Hsp70 and heat shock cognate (Hsc70) 70 has been suggested to play a similar function. However, Hsc70 has recently been reported to counteract Hsp70.

Objective:

We investigated whether Hsc70 counteracts Hsp70 in the control of wild-type and mutant hERG stability.

Methods and Results:

Coexpression of Hsp70 with hERG in HEK293 cells suppressed hERG ubiquitination and increased the levels of both immature and mature forms of hERG. Immunocytochemistry revealed increased levels of hERG in the endoplasmic reticulum and on the cell surface. Electrophysiological studies showed increased
I
Kr
. All these effects of Hsp70 were abolished by Hsc70 coexpression. Heat shock treatment of HL-1 mouse cardiomyocytes induced endogenous Hsp70, switched mouse ERG associated with Hsc70 to Hsp70, increased
I
Kr
, and shortened action potential duration. Channels with disease-causing missense mutations in intracellular domains had a higher binding capacity to Hsc70 than wild-type channels and channels with mutations in the pore region. Knockdown of Hsc70 by small interfering RNA or heat shock prevented degradation of mutant hERG proteins with mutations in intracellular domains.

Conclusions:

These results indicate reciprocal control of hERG stability by Hsp70 and Hsc70. Hsc70 is a potential target in the treatment of LQT2 resulting from missense hERG mutations.
Thioredoxin 1 Negatively Regulates Angiotensin II–Induced Cardiac Hypertrophy Through Upregulation of miR-98/let-7
Authors: Yang Yanfei , Ago Tetsuro , Zhai Peiyong , Abdellatif Maha , Sadoshima Junichi
Published: December 2010

Rationale:

Thioredoxin (Trx)1 inhibits pathological cardiac hypertrophy. MicroRNAs (miRNAs) are small noncoding RNAs that downregulate posttranscriptional expression of target molecules.

Objectives:

We investigated the role of miRNAs in mediating the antihypertrophic effect of Trx1 on angiotensin II (Ang II)–induced cardiac hypertrophy.

Methods and Results:

Microarray analyses of mature rodent microRNAs and quantitative RT-PCR/Northern blot analyses showed that Trx1 upregulates members of the let-7 family, including miR-98, in the heart and the cardiomyocytes therein. Adenovirus-mediated expression of miR-98 in cardiomyocytes reduced cell size both at baseline and in response to Ang II. Knockdown of miR-98, and of other members of the let-7 family, augmented Ang II–induced cardiac hypertrophy, and attenuated Trx1-mediated inhibition of Ang II–induced cardiac hypertrophy, suggesting that endogenous miR-98/let-7 mediates the antihypertrophic effect of Trx1. Cyclin D2 is one of the predicted targets of miR-98. Ang II significantly upregulated cyclin D2, which in turn plays an essential role in mediating Ang II–induced cardiac hypertrophy, whereas overexpression of Trx1 inhibited Ang II–induced upregulation of cyclin D2. miR-98 decreased both expression of cyclin D2 and the activity of a cyclin D2 3′UTR luciferase reporter, suggesting that both Trx1 and miR-98 negatively regulate cyclin D2. Overexpression of cyclin D2 attenuated the suppression of Ang II–induced cardiac hypertrophy by miR-98, suggesting that the antihypertrophic actions of miR-98 are mediated in part by downregulation of cyclin D2.

Conclusions:

These results suggest that Trx1 upregulates expression of the let-7 family, including miR-98, which in turn inhibits cardiac hypertrophy, in part through downregulation of cyclin D2.
Circulating Platelet-Activating Factor Is Primarily Cleared by Transport, Not Intravascular Hydrolysis by Lipoprotein-Associated Phospholipase A
2
/ PAF Acetylhydrolase
Authors: Liu Jinbo , Chen Rui , Marathe Gopal K. , Febbraio Maria , Zou Weilin , McIntyre Thomas M.
Published: December 2010

Rationale:

The phospholipid platelet-activating factor (PAF) stimulates all cells of the innate immune system and numerous cardiovascular cells. A single enzyme (plasma PAF acetylhydrolase [PAF-AH] or lipoprotein-associated phospholipase [Lp-PL]A
2
) in plasma hydrolyzes PAF, but significant controversy exists whether its action is pro- or antiinflammatory and accordingly whether its inhibition will slow cardiovascular disease.

Objective:

We sought to define how PAF and related short-chain oxidized phospholipids turnover in vivo and the role of PAF acetylhydrolase/Lp-PLA
2
in this process.

Methods and Results:

[
3
H-acetyl]PAF was hydrolyzed by murine or human plasma (t
1/2
, 3 and 7 minutes, respectively), but injected [
3
H-acetyl]PAF disappeared from murine circulation more quickly (t
1/2
, <30 seconds). [
3
H]PAF clearance was unchanged in PAF receptor
−/−
animals, or over the first 2 half-lives in PAF-AH
−/−
animals. [
3
H]PAF turnover was reduced by coinjecting excess unlabeled PAF or an oxidatively truncated phospholipid, and [
3
H]PAF clearance was slowed in hyperlipidemic apolipoprotein (apo)E
−/−
mice with excess circulating oxidatively truncated phospholipids. [
3
H]PAF, fluorescent NBD-PAF, or fluorescent oxidatively truncated phospholipid were primarily accumulated by liver and lung, and were transported into endothelium as intact phospholipids through a common mechanism involving TMEM30a.

Conclusions:

Circulating PAF and oxidized phospholipids are continually and rapidly cleared, and hence continually and rapidly produced. Saturable PAF receptor–independent transport, rather than just intravascular hydrolysis, controls circulating inflammatory and proapoptotic oxidized phospholipid mediators. Intravascular PAF has access to intracellular compartments. Inflammatory and proapoptotic phospholipids may accumulate in the circulation as transport is overwhelmed by substrates in hyperlipidemia.
Vasoconstrictor Potential of Coronary Aspirate From Patients Undergoing Stenting of Saphenous Vein Aortocoronary Bypass Grafts and Its Pharmacological Attenuation
Authors: Kleinbongard Petra , Böse Dirk , Baars Theodor , Möhlenkamp Stefan , Konorza Thomas , Schöner Sandra , Elter-Schulz Miriam , Eggebrecht Holger , Degen Hubertus , Haude Michael , Levkau Bodo , Schulz Rainer , Erbel Raimund , Heusch Gerd
Published: December 2010

Rationale:

Stent implantation into atherosclerotic plaques releases, apart from particulate debris, soluble substances that contribute to impaired microvascular perfusion.

Objective:

To quantify the release of vasoconstrictors and to determine the efficacy of coronary dilators to attenuate their action.

Methods and Results:

Using a distal protection/aspiration device, coronary arterial blood was retrieved before and during stenting in 22 patients with severe saphenous vein aorto-coronary bypass stenoses. The release of catecholamines, endothelin, serotonin, thromboxane B
2
, and tumor necrosis factor (TNF)α was measured. The response of rat mesenteric arteries with intact (+E) and denuded (−E) endothelium to aspirate plasma was normalized to that by KCl. Responses to selective receptor blockade, adenosine, nitroprusside, and verapamil against the aspirate-induced constriction were determined. The coronary arterial plasma withdrawn before stenting induced 21±5% and the aspirate plasma after stenting induced 95±8% of maximum KCl-induced vasoconstriction. Serotonin, thromboxane B
2
, and TNFα release into aspirate plasma increased by 1.9±0.2 μmol/L, 25.6±3.1 pg/mL, and 19.7±6.1 pg/mL, respectively, during stenting. The aspirate-induced vasoconstriction was largely antagonized by selective serotonin receptor blockade, with little further antagonism by additional thromboxane receptor blockade. TNFα did not induce constriction per se but potentiated the constriction with serotonin and the thromboxane-analog U-46619 in arteries +E. The concentrations to induce half-maximal vasodilation were comparable for nitroprusside (+E, 3.3×10
−8
; −E, 1.9×10
−8
mol/L) and verapamil (+E, 8.3×10
−8
; −E, 7.8×10
−8
mol/L), and the vasoconstriction was eventually eliminated. The vasodilator response to adenosine was dependent on functional endothelium and weaker.

Conclusion:

Serotonin is the main coronary vasoconstrictor after stenting, and thromboxane and TNFα somewhat potentiate the serotonin response. Nitroprusside and verapamil are more potent than adenosine to attenuate the aspirate plasma-induced vasoconstriction, and they are not dependent on functional endothelium.
Anatomical and Technical Factors Associated With Stroke or Death During Carotid Angioplasty and Stenting
Authors: Naggara Olivier , Touzé Emmanuel , Beyssen Bernard , Trinquart Ludovic , Chatellier Gilles , Meder Jean-François , Mas Jean-Louis
Published: December 2010

Background and Purpose—

The purposes of this study were to assess the relationships between anatomic and technical factors and the 30-day risk of stroke or death after carotid angioplasty and stenting in the Endarterectomy versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial and to perform a systematic review of the literature.

Methods—

We included patients from EVA-3S in whom carotid stenting was attempted irrespective of allocated treatment. Two radiologists blinded to clinical data independently assessed the aortic arch and carotid arteries on procedural angiograms. In addition, we performed a systematic review of studies that reported 30-day risk of stroke or death in relation with arterial anatomy and technique. Outcomes were stroke or death and stroke occurring within 30 days of the carotid angioplasty and stenting procedure.

Results—

Two hundred sixty-two patients from EVA-3S fulfilled the inclusion criteria (including 1 initially allocated to surgery and 13 in whom stent insertion failed).Within 30 days after the procedure, 25 (9.5%) patients had a stroke or had died. The risk of stroke or death was higher in patients with internal carotid artery–common carotid artery angulation ≥60° (relative risk, 4.96; 2.29 to 10.74) and lower in those treated with cerebral protection devices (relative risk [RR], 0.38; 0.17 to 0.85). In the systematic review (56 studies; 34 398 patients), the risk of stroke or death was higher in patients with left-sided carotid angioplasty and stenting (RR, 1.29; 1.05 to 1.58), increased internal carotid artery–common carotid artery angulation (RR, 3.41; 1.52 to 7.63), and when the target internal carotid artery stenosis was >10 mm (RR, 2.36; 1.28 to 3.38). There was no significant increase in risk of stroke or death in patients with Type III aortic arch, aortic arch calcification, or with ostial involvement, calcification, ulceration or degree of stenosis of the target internal carotid artery stenosis. The use of a cerebral protection device was associated with a lower risk of stroke or death (RR, 0.55; 0.41 to 0.73). Risk was not related with stent or cerebral protection device type.

Conclusions—

Our results strongly suggest that some technical and anatomic factors, especially extreme angulation of the carotid artery, have an impact on the risks of carotid angioplasty and stenting.
Remote Limb Ischemic Postconditioning Protects Against Neonatal Hypoxic–Ischemic Brain Injury in Rat Pups by the Opioid Receptor/Akt Pathway
Authors: Zhou Yilin , Fathali Nancy , Lekic Tim , Ostrowski Robert P. , Chen Chunhua , Martin Robert D. , Tang Jiping , Zhang John H.
Published: December 2010

Background and Purpose—

Remote ischemic postconditoning, a phenomenon in which brief ischemic stimuli of 1 organ protect another organ against an ischemic insult, has been demonstrated to protect the myocardium and adult brain in animal models. However, mediators of the protection and underlying mechanisms remain to be elucidated. In the present study, we tested the hypothesis that remote limb ischemic postconditioning applied immediately after hypoxia provides neuroprotection in a rat model of neonatal hypoxia–ischemia (HI) by mechanisms involving activation of the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.

Methods—

HI was induced in postnatal Day 10 rat pups by unilateral carotid ligation and 2 hours of hypoxia. Limb ischemic postconditioning was induced by 4 conditioning cycles of 10 minutes of ischemia and reperfusion on both hind limbs immediately after HI. The opioid antagonist naloxone, phosphatidylinositol-3-kinase inhibitor wortmannin, or opioid agonist morphine was administered to determine underlying mechanisms. Infarct volume, brain atrophy, and neurological outcomes after HI were evaluated. Expression of phosphorylated Akt, Bax, and phosphorylated ERK1/2 was determined by Western blotting.

Results—

Limb ischemic postconditioning significantly reduced infarct volume at 48 hours and improved functional outcomes at 4 weeks after HI. Naloxone and wortmannin abrogated the postconditioning-mediated infarct-limiting effect. Morphine given immediately after hypoxia also decreased infarct volume. Furthermore, limb ischemic postconditioning recovered Akt activity and decreased Bax expression, whereas no differences in phosphorylated ERK1/2expression were observed.

Conclusions—

Limb ischemic postconditioning protects against neonatal HI brain injury in rats by activating the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.
Pharmacogenetic Effect of the Stromelysin (MMP3) Polymorphism on Stroke Risk in Relation to Antihypertensive Treatment
Authors: Sherva Richard , Ford Charles E. , Eckfeldt John H. , Davis Barry R. , Boerwinkle Eric , Arnett Donna K.
Published: December 2010

Background and Purpose—

Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (matrix metalloproteinase-3 [MMP3]) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the Genetics of Hypertension Associated Treatment study, ancillary to the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine whether it modifies clinical outcome response to blood pressure–lowering drugs.

Methods—

The effect of the MMP3 5A/6A polymorphism on stroke rates was examined by using multivariate-adjusted Cox regression models, including a test for interactions between genotype and antihypertensive drug class.

Results—

Compared with participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (hazard ratio=1.32; 95% CI, 1.08 to 1.61;
P
=0.007) and 5A/6A individuals taking lisinopril had lower stroke rates (hazard ratio
interaction
=0.74; 95% CI, 0.53 to 1.04;
P
interaction
=0.08), whereas 5A/5A individuals taking lisinopril had the lowest stroke rate (hazard ratio
interaction
=0.51; 95% CI, 0.31 to 0.85;
P
interaction
=0.009). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin vs chlorthalidone.

Conclusions—

The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared with patients treated with chlorthalidone, whereas a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00563901.
Increased Risk of Stroke in the Year After a Hip Fracture
Authors: Kang Jiunn-Horng , Chung Shiu-Dong , Xirasagar Sudha , Jaw Fu-Shan , Lin Herng-Ching
Published: December 2010

Background and Purpose—

Stroke is a documented risk factor for hip fracture. However, no documented studies are available on the risk of stroke among patients with hip fracture. This study investigated the frequency and risk of stroke after hip fracture using a nationwide population-based study.

Methods—

The study cohort included 2101 patients hospitalized with a principal diagnosis of hip fracture from 2001 to 2004. The comparison cohort consisted of 6303 randomly selected subjects matched on sex, age, and year of index healthcare use as controls. We tracked patients for a 1-year period from their index healthcare encounter to identify those who had a stroke. Stratified Cox proportional hazard regression was performed to evaluate the association of hip fracture with subsequent stroke during 1-year follow-up.

Results—

Of a total of 8404 patients, 86 (4.1%) from the study group and 170 (2.7%) from the comparison group had strokes during the follow-up period (
P
<0.001). The stratified Cox proportional analysis shows that the 1-year crude hazard of stroke among patients with hip fracture was 1.55 times (95% CI, 1.19 to 2.03;
P
=0.001) that of the comparison group. Furthermore, after adjusting for the major cardiovascular risk factors, the increased stroke risk of patients with hip fracture persisted at about the same level as in the unadjusted analysis (hazard ratio, 1.53; 95% CI, 1.17 to 2.01;
P
=0.002).

Conclusion—

Hip fracture is associated with increased risk of stroke in the next year.
Relationship Between Baseline Blood Pressure Parameters (Including Mean Pressure, Pulse Pressure, and Variability) and Early Outcome After Stroke
Authors: Geeganage Chamila , Tracy Michael , England Timothy , Sare Gillian , Moulin Thierry , Woimant France , Christensen Hanne , De Deyn Peter Paul , Leys Didier , O'Neill Desmond , Ringelstein E. Bernd , Bath Philip M.W. ,   for TAIST Investigators
Published: December 2010

Background and Purpose—

High blood pressure (BP) in acute stroke is associated independently with a poor outcome. Recent evidence suggests that other hemodynamic parameters may also be associated with outcomes following stroke.

Methods—

The relationship between baseline BP, heart rate, and other hemodynamic parameters, and early outcomes were assessed using data from TAIST trial.

Results—

Death or neurological deterioration at day 10 was associated, both in unadjusted and adjusted analyses, with systolic BP (adjusted OR, 1.02; 95% CI, 1.01–1.03), mean arterial pressure (OR, 1.02; 95% CI, 1.01–1.04), pulse pressure (OR, 1.02; 95% CI, 1.01–1.03), and BP variability (OR, 1.03; 95% CI, 1.01–1.05). Similar relationships were noted for deterioration alone, and recurrent stroke.

Conclusions—

Early death or neurologic deterioration, deterioration, and recurrent stroke are associated independently with high systolic BP, mean arterial pressure, pulse pressure, and BP variability. These measures offer potential therapeutic targets for improving early outcome after acute ischemic stroke.
Determinants of Quality of Life After Stroke in China
Authors: Delcourt Candice , Hackett Maree , Wu Yanfeng , Huang Yining , Wang Jiguang , Heeley Emma , Wong Lawrence , Sun Jian , Li Qiang , Wei Jade Wei , Liu Ming , Li Zhengyi , Wu Li , Cheng Yan , Huang Qifang , Xu En , Yang Qidong , Lu Chuanzhen , Anderson Craig S. ,   for the ChinaQUEST Investigators
Published: December 2010

Background and Purpose—

Limited information exists on the long-term consequences of stroke in China. We aimed to describe the profile and determinants of health-related quality of life among 12-month survivors of stroke.

Methods—

The ChinaQUEST (QUality Evaluation of Stroke care and Treatment) study was a prospective 62-hospital registry study of patients with acute stroke (ischemic stroke and intracerebral hemorrhage). Health-related quality of life was determined in 12-month survivors using a 35-item quality-of-life questionnaire (QOL-35) designed specifically for use in Chinese people. Proxy responses were used in those who were unable to personally complete the QOL-35.

Results—

A total of 4283 12-month stroke survivors completed assessments directly (1730 [40.4%]) or by a proxy (2553 [59.6%]). Mean (SD) health-related quality of life scores were higher in self-responders (70 [0.3] out of a best possible 100 score) than in proxy responders (60 [0.3];
P
<0.001). The strongest baseline variables that predicted “low” (below median) health-related quality of life scores in self-responders were having a lower income (income <10 000 Chinese Yuan Renminbi [CNY, approximately US $1428] versus >19 000 CNY [approximately US $2714]; OR, 2.06; 95% CI, 1.37 to 3.10) and being disabled at discharge (OR, 3.65; 95% CI, 2.72 to 4.91). Proxy responders had similar predictive factors, including being disabled at discharge (OR, 4.99; 95% CI, 4.00 to 6.21), but income was not significant.

Conclusions—

In China, the strongest predictor of 12-month health-related quality of life after stroke is level of disability at hospital discharge. Level of income was another important factor. Health insurance schemes that offset the economic impact of stroke could help improve the health and well-being of Chinese people affected by stroke.
Discriminating Carotid Atherosclerotic Lesion Severity by Luminal Stenosis and Plaque Burden
Authors: Zhao Xihai , Underhill Hunter R. , Zhao Qian , Cai Jianming , Li Feiyu , Oikawa Minako , Dong Li , Ota Hideki , Hatsukami Thomas S. , Chu Baocheng , Yuan Chun
Published: December 2010

Background and Purpose—

To determine associations between stenosis, measures of plaque burden, and compositional features of carotid atherosclerosis, including high-risk features of intraplaque hemorrhage (IPH) and surface disruption.

Methods—

Institutional Review Board approval and informed consent for all participants were obtained before study initiation. Patients with either carotid stenosis >50% by duplex ultrasound or suspected coronary artery disease underwent multi-contrast carotid MRI at 3.0 T. For each artery, stenosis, percent wall volume (PWV=100%×wall volume/total vessel volume), and mean wall thickness (MWT) were measured. Presence or absence of a lipid-rich necrotic core, calcification, IPH, and surface disruption were recorded.

Results—

One hundred eighty-one patients were included in the final analysis. The area under the curve (AUC) calculated from receiver-operating-characteristics analysis found the presence of IPH was similarly classified by stenosis (AUC=0.82), PWV (AUC=0.88), and MWT (AUC=0.88). Notably, IPH was present in the lowest category of each parameter. Prevalence of IPH in arteries with 0% stenosis was 4.4%. In arteries with PWV <40%, prevalence was 3.2%; in arteries with MWT <1.0 mm, prevalence was 2.3%. Strength of classification for surface disruption was similarly classified by stenosis (AUC=0.87), PWV (AUC=0.93), and MWT (AUC=0.94).

Conclusions—

Measures of plaque burden do not substantially improve disease assessment compared to stenosis. The finding of IPH in all categories of stenosis and plaque burden suggests that direct characterization of plaque composition and surface status is necessary to fully discriminate disease severity.
Activation of Epsilon Protein Kinase C-Mediated Anti-Apoptosis Is Involved in Rapid Tolerance Induced by Electroacupuncture Pretreatment Through Cannabinoid Receptor Type 1
Authors: Wang Qiang , Li Xuying , Chen Yanke , Wang Feng , Yang Qianzi , Chen Shaoyang , Min Yuyuan , Li Xin , Xiong Lize
Published: December 2010

Background and Purpose—

Our previous study has demonstrated that the rapid tolerance to cerebral ischemia by electroacupuncture (EA) pretreatment was possibly mediated through an endocannabinoid system-related mechanism. The purpose of this study was to investigate whether activation of epsilon protein kinase C (εPKC) was involved in EA pretreatment-induced neuroprotection via cannabinoid receptor type 1 in a rat model of transient focal cerebral ischemia.

Methods—

The activation of εPKC in the ipsilateral brain tissues after EA pretreatment was investigated in the presence or absence of cannabinoid receptor antagonists. At 2 hours after the end of EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion for 120 minutes in rats. The neurobehavioral scores, infarction volumes, neuronal apoptosis, and the expression of
Bcl-2
and
Bax
were evaluated after reperfusion in the presence or absence of εPKC-selective peptide inhibitor (TAT-εV1–2) or activator (TAT–ψεRACK).

Results—

EA pretreatment enhanced εPKC activation. Systemic delivery of TAT–ψεRACK conferred neuroprotection against a subsequent cerebral ischemic event when delivered 2 hours before ischemia. Pretreatment with EA reduced infarct volumes, improved neurological outcome, inhibited neuronal apoptosis, and increased the
Bcl-2
-to-
Bax
ratio after reperfusion, and the beneficial effects were attenuated by TAT-εV1–2. In addition, the blockade of cannabinoid receptor type 1, but not cannabinoid receptor type 2 receptor, reversed the increase in εPKC activation and neuroprotection induced by EA pretreatment.

Conclusion—

EA pretreatment may activate endogenous εPKC-mediated anti-apoptosis to protect against ischemic damage after focal cerebral ischemia via cannabinoid receptor type 1, which represents a new mechanism of EA pretreatment-induced rapid tolerance to focal cerebral ischemia in rats.
Association Between Carotid Artery Plaque Ulceration and Plaque Composition Evaluated With Multidetector CT Angiography
Authors: Homburg Philip J. , Rozie Sietske , van Gils Marjon J. , van den Bouwhuijsen Quirijn J.A. , Niessen Wiro J. , Dippel Diederik W.J. , van der Lugt Aad
Published: December 2010

Background and Purpose—

Symptomatic carotid artery plaque ulceration is associated with distinct plaque components such as a large lipid-rich necrotic core (LR-NC) in ischemic stroke patients with a ≥50% carotid stenosis. We evaluated the associations between carotid artery plaque ulceration and plaque characteristics in ischemic stroke patients with ≥50% stenosis, as well as in those with a low degree of stenosis (0% to 49%).

Methods—

Consecutive patients (n=346) with symptoms in the anterior circulation were evaluated with multidetector CT angiography (MDCTA) for the presence of atherosclerotic plaque, degree of stenosis, and plaque ulceration in the symptomatic carotid artery. Plaque volume and plaque component proportions of LR-NC, fibrous tissue, and calcification were measured. The associations between plaque ulceration and plaque characteristics were analyzed using logistic regression.

Results—

Atherosclerotic plaque was present in 185 patients. Plaque ulcerations were present in 38 (21%) patients, of which half had a low degree stenosis (0% to 49%). Plaque volume was significantly larger in ulcerated plaques. After adjustment for age, sex, and degree of stenosis, LR-NC proportion was strongly associated with plaque ulceration (odds ratio, 2.21; 95% CI, 1.49 to 3.27), whereas calcification proportion was inversely associated with plaque ulceration (odds ratio, 0.60; 95% CI, 0.40 to 0.89). These associations remained significant in patients with a low degree stenosis (0% to 49%).

Conclusion—

Plaque volume, degree of stenosis, and LR-NC proportion evaluated noninvasively with MDCTA are associated with carotid artery plaque ulceration, even in patients with a low degree stenosis (0% to 49%). Plaque volume and composition analysis with MDCTA may identify rupture prone plaques and improve risk stratification in ischemic stroke patients.
Decreased Kidney Function
Authors: van Lammeren Guus W. , Moll Frans L. , Blankestijn Peter J. , de Kleijn Dominique P.V. , Bots Michiel L. , Verhaar Marianne C. , de Vries Jean-Paul P.M. , Pasterkamp Gerard
Published: December 2010

Background and Purpose—

Chronic kidney disease is an important risk factor for development and progression of atherosclerosis. The objective of the current study was to investigate the contribution of moderate kidney failure to cardiovascular (CV) mortality and morbidity after carotid endarterectomy (CEA). In addition, we investigated which proportion received optimal medical treatment or underwent diagnostic workup of the kidneys prior to CEA.

Methods—

Between 2002 and 2009, 1085 patients undergoing CEA were included in this study. Estimated glomerular filtration rate (eGFR) was assessed at baseline. Moderate kidney failure was defined as an eGFR 30–59 and compared with normal or mildly reduced kidney function (eGFR ≥60). Primary endpoint was CV death, composed of fatal myocardial infarction, fatal stroke, and ruptured abdominal aneurysm. Secondary endpoints were CV morbidity.

Results—

Moderate kidney failure (eGFR 30–59) was observed in 26.5% (288/1085) of the patients. During a median follow-up of 2.95 years (0.0 to 3.0 years), the adjusted hazard ratio for CV death with an eGFR 30–59 was 2.22 (1.27 to 3.89). Adjusted hazard ratio for MI with an eGFR 30–59 was 1.90 (1.04 to 3.47). No higher risk for stroke and peripheral interventions was observed. Of all patients with an eGFR 30–59, 38.3% (105/274) received angiotensin-converting enzyme inhibitors, 74.5% (204/274) received statins, and 34.4% (99/288) visited a nephrologist.

Conclusions—

Patients with an eGFR 30–59 have a 2.2-fold increased risk for CV death and 1.9-fold increased risk for myocardial infarction the 3 three years after CEA compared with patients with an eGFR ≥60, independent of other CV risk factors. A minority of these patients receive optimal medical treatment, which might explain the increased risk for progression of chronic kidney disease and CV morbidity and mortality.
Diagnostic Accuracy of the Barthel Index for Measuring Activities of Daily Living Outcome After Ischemic Hemispheric Stroke
Authors: Kwakkel Gert , Veerbeek Janne M. , Harmeling-van der Wel Barbara C. , van Wegen Erwin , Kollen Boudewijn J.
Published: December 2010

Background and Purpose—

This study investigated the diagnostic accuracy of the Barthel Index (BI) in 206 stroke patients, measured within 72 hours, for activities of daily living at 6 months and determined whether the timing of BI assessment during the first days affects the accuracy of predicting activities of daily living outcome at 6 months.

Methods—

Receiver operating characteristic curves were constructed to determine the area under the curve and optimal cutoff points for BI at Days 2, 5, and 9. OR, sensitivity, specificity, positive predictive value, and negative predictive value were calculated to predict BI ≥19.

Results—

The area under the curve ranged from 0.785 on Day 2 to 0.837 and 0.848 on Days 5 and 9. Comparison of the receiver operating characteristic curves showed that the area under the curve was significantly different between Days 2 and 5 (
P
<0.001) and between Days 2 and 9 (
P
<0.001). No significant difference was found between Days 5 and 9 (
P
=0.08). Using a BI cutoff score of 7, the positive predictive value gradually increased from 0.696 on Day 2 to 0.817 on Day 2 to 0.864 on Day 9, whereas negative predictive value declined from 0.778 on Day 2 to 0.613 on Day 9.

Conclusions—

Assessment of the BI early poststroke showed good discriminative properties for final outcome of BI at 6 months. However, Day 5 proved to be the earliest time for making an optimal prediction of final outcome of activities of daily living. The BI should be measured at the end of the first week in hospital-based stroke units for early rehabilitation management.
Recurrent Stroke Due to a Novel Voltage Sensor Mutation in Ca
v
2.1 Responds to Verapamil
Authors: Knierim Ellen , Leisle Lilia , Wagner Christiane , Weschke Bernhard , Lucke Barbara , Bohner Georg , Dreier Jens P. , Schuelke Markus
Published: December 2010

Background and Purpose—

Familial hemiplegic migraine is characterized by recurrent migraine, hemiparesis, and ataxia. Causes may be mutations in calcium and sodium channels or in a subunit of the Na/K-ATPse. Migraine treatment with calcium channel blockers was only successful in some patients.

Summary of Case—

We describe a 6-year-old girl with recurrent ischemic strokes after minor head trauma associated with seizures, hemiparesis, fever, and altered consciousness. Genetic analysis revealed a spontaneous, novel dominant
CACNA1A
mutation (c.4046G→A, p.R1349Q) that removed a highly conserved arginine of the voltage sensing region of the P/Q-type Ca
v
2.1 channel. Because a homologous mutation in the
tottering-5J
mouse increased open probability of the channel as well as calcium influx, we treated the patient with the calcium channel blocker verapamil during characteristic prodromi after head trauma. Treatment was instantly effective and prevented a new stroke.

Conclusion—

CACNA1A
mutations should be considered in the diagnostic workup of childhood stroke, especially if associated with ataxia and migraine.
Do the Individual, Social, and Environmental Correlates of Physical Activity Differ Between Urban and Rural Women?
Authors: Cleland Verity J. , Ball Kylie , King Abby C. , Crawford David
Published: December 2010

In this article, associations between individual, social, and environmental factors and physical activity among 3,669 women (18-45 years) living in socioeconomically disadvantaged urban and rural areas were compared. In 2007-2008, participants reported levels of leisure-time physical activity (LTPA) and transport-related physical activity (TRPA) as well as five individual, four social, and three environmental factors. Physical activity self- efficacy demonstrated stronger associations with LTPA among urban relative to rural women; child care was associated with LTPA and intentions with TRPA among urban women only, and enjoyment was associated with TRPA among rural women only. Correlates of physical activity among urban and rural women were generally similar, although some tailoring of physical activity promotion strategies may be warranted.
Cross-cultural perception and power dynamics across changing organizational and national contexts: Curaçao and the Netherlands
Authors: Heijes Coen
Published: December 2010

In this article we study the role of power and power differences in cross-cultural perception. We do so by way of exploratory case studies in the Internal Revenue Service (IRS) and the police in the Netherlands and Curaçao. We demonstrate how cross-cultural perception between two specific ethnic groups, European Dutch and African Curaçaoans, changes depending on the amount of power imbalance in the various organizational and national contexts. With this article, we follow the call for research on the impact of power dynamics on cross-cultural perception, an approach that goes beyond the traditional, dimensional approach that is prevalent in organization literature.
Identification of dependency patterns in research collaboration environments through cluster analysis
Authors: Lee Bangrae , Kwon Ohjin , Kim Han-joon
Published: December 2010

In this paper, we present a new way of detecting dependency patterns in research collaboration environments. We use co-authorship data at the organization level to measure the degree of research collaboration. Thus we adopt a special clustering technique, called ‘cross-associations clustering’, to extract the dependency patterns among research groups. To assist in evaluating the dependency patterns, we suggest a collaboration dependency index to indicate whether a research group is dependent on other groups. In our work, as target research environments, we choose four significant areas: alternative energy, water shortage, food shortage and global warming. Through extensive cluster analysis, we have found that dependency patterns exist in the areas of alternative energy, water shortage and global warming, but not in the food shortage area.