bluuebunny/crossref_metadata_2025 huggingface dataset:
Initial experience with an everolimus-eluting, second-generation drug-eluting stent for treatment of intracranial atherosclerosis
Authors: Natarajan Sabareesh K , Ogilvy Christopher S , Hopkins L Nelson , Siddiqui Adnan H , Levy Elad I
Published: June 2010

Background and purpose

High in-stent restenosis (ISR) rates have been reported after treatment of intracranial atherosclerotic stenosis (ICAS). Balloon-mounted drug-eluting stent (DES) implantation has led to an ISR reduction in coronary vessels and may provide a solution to overcome this obstacle in the intracranial circulation. We present our initial experience with the everolimus-eluting stent (EES; Abbott Vascular, Abbott Park, Illinois, USA), a second-generation balloon-mounted DES, for ICAS treatment.

Methods

A retrospective review of prospectively collected endovascular data at our institution resulted in the identification of six patients with ICAS treated with EES. Data collected included patient demographics, presentation, comorbidities and lesion, intervention and follow-up details.

Results

These six patients had >70% angiographic ICAS and history of stroke or recurrent transient ischemic attacks, despite aspirin therapy and medical management of comorbidities. Lesions were located in the V4-vertebral artery segment (n=2), M1 middle cerebral artery segment (n=1), proximal basilar artery (n=1), supraclinoid internal carotid artery (n=1) and petrous internal carotid artery (n=1). Average stenosis severity was 82.8±6.6% (median, 80%); average lesion length was 10.2±2.2 mm. Stent placement was successful in all cases. Average postintervention stenosis was 5.5±4.4% (median, 7.5%). One patient had postintervention reperfusion hemorrhage that required urgent decompressive craniectomy. None of the five patients with angiographic follow-up (5–6 months) had ISR. The six patients had 4–10 months of clinical follow-up. Only the patient with reperfusion hemorrhage had decreased functional status after treatment (modified Rankin scale score=4) and is making a slow recovery.

Conclusion

This study confirms feasibility of use of a second-generation DES for ICAS and provides short-term follow-up results.
Combined microsurgical and endovascular treatment of a giant left middle cerebral artery aneurysm
Authors: Zomorodi Ali , Bulsara Ketan R , Friedman Allan H , Alexander Michael J
Published: June 2010

Giant fusiform aneurysms of the middle cerebral artery (MCA) bifurcation pose significant treatment challenges. A giant fusiform aneurysm of the left MCA in a pediatric patient, which persisted despite Hunterian ligation of the M1 and double barrel superficial temporal artery (STA) to M2 bypasses, is reported. The aneurysm was trapped by endovascular coiling of the feeding M2 trunk through the STA anastamosis. Hunterian ligation combined with extracranial–intracranial bypass is an effective technique for treating giant fusiform aneurysms of the MCA bifurcation for patients who fail balloon test occlusions. However, in certain cases, flow reversal may not eliminate the aneurysm and continued aneurysm filling may occur through retrograde filling from the bypass recipient vessels. In these cases, endovascular trapping of the aneurysm may be undertaken through the bypass graft. The feasibility of this management scheme is demonstrated.
Attitudes, practices and beliefs towards worksite smoking among administrators of private and public enterprises in Armenia
Authors: Movsisyan Narine K , Thompson Michael E , Petrosyan Varduhi
Published: June 2010

Background

In March 2005, Armenia enacted legislation protecting employees from secondhand smoke. This research was the first attempt to understand the attitudes, beliefs and practices of managers of public and private enterprises regarding smoke-free worksite policies.

Methods

Mixed methods were used. The study team conducted focus group discussions with worksite administrators to explore their beliefs, attitudes and practices related to worksite smoking. These findings guided development of a quantitative instrument to collect more representative data on the same issues. Using stratified random sampling, 243 worksites were interviewed from June-July 2005, representing state/municipal, health, educational, culture and business institutions in three of Armenia's largest cities.

Results/Discussion

Smoking-related practices differed significantly across institutions. More than half of the managers (55.6%) reported having smoking restrictions at worksites, including 37.0% who reported smoke-free workplaces; however, smoking or the presence of ashtrays was observed in 27.8% of workplaces reported to be smoke-free. A substantial proportion of the administrators favored both banning indoor smoking and allowing smoking in special areas. Only 38.0% of managers were aware of employees' existing legal protections from exposure to secondhand smoke. Knowledge of these regulations was not related to adherence to smoke-free worksite policies. The research also revealed widespread confusion between the concepts of worksite smoking restrictions and smoke-free workplaces. Public awareness campaigns that promote promulgation and enforcement of worksite smoking regulations could increase employee demand for smoke-free worksites.

Conclusion

As one of the first studies to investigate smoking-related worksite practices, attitudes and beliefs in former Soviet countries, these findings provide insight into law enforcement processes in economies in transition.
Application of partial cross-section precast system to save the Amazon forest
Authors: Carvalho de Oliveira Dênio Ramam , Ferreira Maurício de Pina , Melo José Guilherme Silva
Published: June 2010

The Brazilian civil construction industry is one of the largest consumers of wood in the country. The majority of wood is used as formwork to build concrete structures and is discarded at the end of the construction process. This study presents an innovative structural system that uses a type of partial cross-section precast system with thin reinforced concrete flat plates, which are transported and assembled at the construction site and act as permanent formwork with structural function. The major advantages of this system include the reduction of transport costs; easier assembly of the structural elements because of its low weight; and the possibility of idealizing and designing rigid connections between structural elements, improvement of the structural behavior and postive impact on the material economy. This paper presents construction details, tests results, and some real cases where partial cross-section beams and columns were successfully applied in Brazil.
Mechanism of antibacterial activity of the white-rot fungusHypholoma fascicularecolonizing wood
Authors: de Boer Wietse , Folman Larissa B. , Klein Gunnewiek Paulien J.A. , Svensson Teresia , Bastviken David , Öberg Gunilla , del Rio José C. , Boddy Lynne
Published: June 2010

In a previous study it was shown that the number of wood-inhabiting bacteria was drastically reduced after colonization of beech ( Fagus sylvatica ) wood blocks by the white-rot fungus Hypholoma fasciculare , or sulfur tuft ( Folman et al. 2008 ). Here we report on the mechanisms of this fungal-induced antibacterial activity. Hypholoma fasciculare was allowed to invade beech and pine ( Pinus sylvestris ) wood blocks that had been precolonized by microorganisms from forest soil. The changes in the number of bacteria, fungal biomass, and fungal-related wood properties were followed for 23 weeks. Colonization by the fungus resulted in a rapid and large reduction in the number of bacteria (colony-forming units), which was already apparent after 4 weeks of incubation. The reduction in the number of bacteria coincided with fungal-induced acidification in both beech and pine wood blocks. No evidence was found for the involvement of toxic secondary metabolites or reactive oxygen species in the reduction of the number of bacteria. Additional experiments showed that the dominant bacteria present in the wood blocks were not able to grow under the acidic conditions (pH 3.5) created by the fungus. Hence our research pointed at rapid acidification as the major factor causing reduction of wood-inhabiting bacteria upon colonization of wood by H. fasciculare.
Seasonal breeding in relation to dietary animal protein in deer mice (Peromyscus maniculatus)
Authors: Tabacaru C. A. , Millar J. S. , Longstaffe F. J. , Ansell A. K.
Published: June 2010

We used stable carbon and nitrogen isotope compositions of hair and liver as a way of examining seasonal diet changes and explaining seasonal breeding in deer mice ( Peromyscus maniculatus (Wagner, 1845)). Summer and winter δ13C values differed, which is attributed to the availability of different plant tissues (C3 plants). The δ15N values of liver showed a decrease in consumed animal protein during winter, but the difference was not large enough to indicate a full trophic level change in diet from summer to winter. The δ15N values of hair remained constant across the seasons, which is attributed to a continuous level of moulting throughout the year. Our data indicate that lowered food quality in the form of reduced dietary animal protein intake may play a role in the cessation of breeding in deer mice in winter.
STATE AND PARAMETER ESTIMATION FOR CANONIC MODELS OF NEURAL OSCILLATORS
Authors: TYUKIN IVAN , STEUR ERIK , NIJMEIJER HENK , FAIRHURST DAVID , SONG INSEON , SEMYANOV ALEXEY , LEEUWEN CEES VAN
Published: June 2010

We consider the problem of how to recover the state and parameter values of typical model neurons, such as Hindmarsh-Rose, FitzHugh-Nagumo, Morris-Lecar, from in-vitro measurements of membrane potentials. In control theory, in terms of observer design, model neurons qualify as locally observable. However, unlike most models traditionally addressed in control theory, no parameter-independent diffeomorphism exists, such that the original model equations can be transformed into adaptive canonic observer form. For a large class of model neurons, however, state and parameter reconstruction is possible nevertheless. We propose a method which, subject to mild conditions on the richness of the measured signal, allows model parameters and state variables to be reconstructed up to an equivalence class.
Binding of nickel(II) tetrakis(dimethylpyrazolium-4-yl)porphyrin to poly(dG-dC)2 and poly(dA-dT)2
Authors: Tjahjono Daryono H. , Suhendar  , Permana Benny , Yoshioka Naoki , Inoue Hidenari
Published: June 2010

The interaction of nickel(II) complex of cationic porphyrins bearing five-membered rings, meso-tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrinatonickel(II) (NiPzP) , with synthetic polynucleotides poly(dG-dC)2 and poly(dA-dT)2 has been characterized by viscometric, visible absorption, CD and MCD spectroscopic, and melting temperature measurements. The nickel(II) complex NiPzP is intercalated into poly(dG-dC)2 but outside bound to the major groove of poly(dA-dT)2. The binding constants of NiPzP to poly(dG-dC)2 and poly(dA-dT)2 are in the order of 106 M-1 and comparable to those of other reported cationic metalloporphyrins. The binding process of NiPzP to poly(dG-dC)2 and poly(dA-dT)2 is endothermic and entropically driven.
Environment and vascular bed origin influence differences in endothelial transcriptional profiles of coronary and iliac arteries
Authors: Burridge Kelley A. , Friedman Morton H.
Published: June 2010

Atherosclerotic plaques tend to form in the major arteries at certain predictable locations. As these arteries vary in atherosusceptibility, interarterial differences in endothelial cell biology are of considerable interest. To explore the origin of differences observed between typical atheroprone and atheroresistant arteries, we used DNA microarrays to compare gene expression profiles of harvested porcine coronary (CECs) and iliac artery endothelial cells (IECs) grown in static culture out to passage 4. Fewer differences were observed between the transcriptional profiles of CECs and IECs in culture compared with in vivo, suggesting that most differences observed in vivo were due to distinct environmental cues in the two arteries. One-class significance of microarrays revealed that most in vivo interarterial differences disappeared in culture, as fold differences after passaging were not significant for 85% of genes identified as differentially expressed in vivo at 5% false discovery rate. However, the three homeobox genes, HOXA9, HOXA10, and HOXD3, remained underexpressed in coronary endothelium for all passages by at least nine-, eight-, and twofold, respectively. Continued differential expression, despite removal from the in vivo environment, suggests that primarily heritable or epigenetic mechanism(s) influences transcription of these three genes. Quantitative real-time polymerase chain reaction confirmed expression ratios for seven genes associated with atherogenesis and over- or underexpressed by threefold in CECs relative to IECs. The present study provides evidence that both local environment and vascular bed origin modulate gene expression in arterial endothelium. The transcriptional differences observed here may provide new insights into pathways responsible for coronary artery susceptibility.
Role of iNOS and peroxynitrite–matrix metalloproteinase-2 signaling in myocardial late preconditioning in rats
Authors: Bencsik Péter , Kupai Krisztina , Giricz Zoltán , Görbe Anikó , Pipis Judit , Murlasits Zsolt , Kocsis Gabriella F. , Varga-Orvos Zoltán , Puskás László G. , Csonka Csaba , Csont Tamás , Ferdinandy Péter
Published: June 2010

We have previously shown that the inhibition of myocardial nitric oxide (NO) and peroxynitrite-matrix metalloproteinase (MMP) signaling by early preconditioning (PC) is involved in its cardioprotective effect. Therefore, in the present study, we investigated the role of NO and peroxynitrite-MMP signaling in the development of late PC. PC was performed by five consecutive cycles of 4-min coronary occlusion and 4-min reperfusion in anesthetized rats in vivo. Twenty-four hours later, hearts were subjected to a 30-min coronary occlusion followed by 180-min reperfusion to measure infarct size. In separate experiments, heart tissue was sampled to measure biochemical parameters before and 3, 6, 12, or 24 h after the PC protocol, respectively. Late PC decreased infarct size, increased cardiac inducible NO synthase (iNOS) activity and gene expression, and decreased SOD activity at 24 h significantly compared with sham-operated controls. Late PC increased cardiac superoxide levels significantly at 24 h; however, it did not change cardiac NO levels. Cardiac peroxynitrite levels were significantly decreased. Downstream cellular targets of peroxynitrite, MMP-2 and MMP-9 activities were decreased in the late PC group at 24 h compared with the sham-operated group. To verify if PC-induced inhibition of MMPs had a causative role in the reduction of infarct size, in separate experiments, we measured infarct size after the pharmacological inhibition of MMPs by ilomastat and found a significant reduction of infarct size compared with the vehicle-treated group. In conclusion, this is the first demonstration that the inhibition of cardiac peroxynitrite-MMP signaling contributes to cardioprotection by late PC and that pharmacological inhibition of MMPs is able to reduce infarct size in vivo. Furthermore, increased expression of iNOS may play a role in the development of late PC; however, increased iNOS activity does not lead to increased NO production in late PC.
Acute AT1-receptor blockade reverses the hemodynamic and baroreflex impairment in adult sheep exposed to antenatal betamethasone
Authors: Shaltout Hossam A. , Rose James C. , Figueroa Jorge P. , Chappell Mark C. , Diz Debra I. , Averill David B.
Published: June 2010

To accelerate lung development and protect neonates from other early developmental problems, synthetic steroids are administered maternally in the third trimester, exposing fetuses that are candidates for premature delivery to them. However, steroid exposure at this point of gestation may lead to elevated blood pressure [mean arterial pressure (MAP)] during adolescence. We hypothesize that fetal exposure to steroids activates the renin-angiotensin system, inducing an elevation in blood pressure and attenuation of baroreflex sensitivity (BRS) that is angiotensin II dependent in early adulthood. To test this hypothesis, fetal sheep were exposed to betamethasone (Beta) or vehicle (control) administered to ewes at day 80 of gestation and delivered at full term. At 1.8 yr of age, male offspring were instrumented for conscious recording of MAP, heart rate, and measurement of BRS [as low-frequency-α, high-frequency-α, sequence (seq) UP, seq DOWN, and seq TOTAL]. Beta-exposed sheep ( n = 6) had higher MAP than control sheep ( n = 5) (93 ± 2 vs. 84 ± 2 mmHg, P < 0.01). Acute blockade of angiotensin type 1 receptors with candesartan (0.3 mg/kg iv) normalized MAP in Beta-exposed sheep (85 ± 4 mmHg), with no effect in control sheep (82 ± 3 mmHg). Before angiotensin type 1 blockade, BRS maximum gain was significantly lower in Beta-exposed vs. control sheep (11 ± 3 vs. 26 ± 3 ms/mmHg, P < 0.0.01). However, 45 min after candesartan injection, BRS was increased in Beta-exposed (21 ± 5 ms/mmHg) and control (35 ± 4 ms/mmHg) sheep. Heart rate variability (HRV) and blood pressure variability (BPV) revealed lower HRV (SD of beat-to-beat interval and root mean square of successive beat-to-beat differences in R-R interval duration) and higher BPV (SD of MAP, systolic arterial pressure in low-frequency range) in Beta-exposed sheep. Candesartan partially restored HRV in Beta-exposed sheep and fully corrected BPV. Thus, in utero exposure to synthetic glucocorticoids causes long-lasting programming of the cardiovascular system via renin-angiotensin system-dependent mechanisms.
Inducible nitric oxide synthase gene deletion exaggerates MAPK-mediated cyclooxygenase-2 induction by inflammatory stimuli
Authors: Lamon Brian D. , Upmacis Rita K. , Deeb Ruba S. , Koyuncu Hilal , Hajjar David P.
Published: June 2010

Cyclooxygenase (COX)-2 and inducible nitric oxide (NO) synthase (iNOS) are responsive to a wide array of inflammatory stimuli, have been localized to vascular smooth muscle cells (SMCs), and are intimately linked to the progression of vascular disease, including atherosclerotic lesion formation. We and others have shown that the production and subsequent impact of COX products appear to be correlative with the status of NO synthesis. This study examined the impact of inflammation-driven NO production on COX-2 expression in SMCs. Concurrent stimulation of quiescent rat aortic SMCs with lipopolysaccharide (LPS) and interferon (IFN)-γ increased COX-2, iNOS, and nitrite production. Pharmacological inhibition of NO synthase ( NG-monomethyl-l-arginine) concentration- and time-dependently magnified LPS + IFN-γ-mediated COX-2 mRNA and protein induction in a cGMP-independent manner. COX-2 induction was associated with activation of the ERK, p38, and JNK mitogen-activated protein kinase (MAPK) pathways. Interestingly, NO synthase inhibition enhanced ERK, p38, and to a lesser extent JNK phosphorylation but suppressed MAPK phosphatase (MKP)-1 induction in response to LPS + IFN-γ. Similarly, the exposure of SMCs from iNOS−/−mice to LPS + IFN-γ produced an enhancement of COX-2 induction, p38, and JNK phosphorylation and an attenuated upregulation of MKP-1 versus their wild-type counterparts. Taken together, our data indicate that NO, in part derived from iNOS, negatively regulates the immediate early induction of COX-2 in response to inflammatory stimuli.
Enhanced basal contractility but reduced excitation-contraction coupling efficiency and β-adrenergic reserve of hearts with increased Cav1.2 activity
Authors: Tang Mingxin , Zhang Xiaoying , Li Yingxin , Guan Yinzheng , Ai Xiaojie , Szeto Christopher , Nakayama Hiroyuki , Zhang Hongyu , Ge Shuping , Molkentin Jeffery D. , Houser Steven R. , Chen Xiongwen
Published: June 2010

Cardiac remodeling during heart failure development induces a significant increase in the activity of the L-type Ca2+ channel (Cav1.2). However, the effects of enhanced Cav1.2 activity on myocyte excitation-contraction (E-C) coupling, cardiac contractility, and its regulation by the β-adrenergic system are not clear. To recapitulate the increased Cav1.2 activity, a double transgenic (DTG) mouse model overexpressing the Cavβ2a subunit in a cardiac-specific and inducible manner was established. We studied cardiac (in vivo) and myocyte (in vitro) contractility at baseline and upon β-adrenergic stimulation. E-C coupling efficiency was evaluated in isolated myocytes as well. The following results were found: 1) in DTG myocytes, L-type Ca2+ current ( ICa,L) density, myocyte fractional shortening (FS), peak Ca2+ transients, and sarcoplasmic reticulum (SR) Ca2+ content (caffeine-induced Ca2+ transient peak) were significantly increased (by 100.8%, 48.8%, 49.8%, and 46.8%, respectively); and 2) cardiac contractility evaluated with echocardiography [ejection fraction (EF) and (FS)] and invasive intra-left ventricular pressure (maximum dP/d t and −dP/d t) measurements were significantly greater in DTG mice than in control mice. However, 1) the cardiac contractility (EF, FS, dP/d t, and −dP/d t)-enhancing effect of the β-adrenergic agonist isoproterenol (2 μg/g body wt ip) was significantly reduced in DTG mice, which could be attributed to the loss of β-adrenergic stimulation on contraction, Ca2+ transients, ICa,L, and SR Ca2+ content in DTG myocytes; and 2) E-C couplng efficiency was significantly lower in DTG myocytes. In conclusion, increasing Cav1.2 activity by promoting its high-activity mode enhances cardiac contractility but decreases E-C coupling efficiency and the adrenergic reserve of the heart.
Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes
Authors: Dabkowski Erinne R. , Baseler Walter A. , Williamson Courtney L. , Powell Matthew , Razunguzwa Trust T. , Frisbee Jefferson C. , Hollander John M.
Published: June 2010

Cardiac complications and heart failure are the leading cause of death in type 2 diabetic patients. Mitochondrial dysfunction is central in the pathogenesis of the type 2 diabetic heart. However, it is unclear whether this dysfunction is specific for a particular subcellular region. The purpose of this study was to determine whether mitochondrial dysfunction in the type 2 diabetic heart is specific to a spatially distinct subset of mitochondria. We investigated mitochondrial morphology, function, and proteomic composition of subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) in 18-wk-old db/ db mice. Oxidative damage was assessed in subpopulations through the measurement of lipid peroxidation byproducts and nitrotyrosine residues. Proteomic profiles and posttranslational modifications were assessed in mitochondrial subpopulations using iTRAQ and multi-dimensional protein identification technologies, respectively. SSM from db/ db hearts had altered morphology, including a decrease in size and internal complexity, whereas db/ db IFM were increased in internal complexity. Db/ db SSM displayed decreased state 3 respiration rates, electron transport chain activities, ATP synthase activities, and mitochondrial membrane potential and increased oxidative damage, with no change in IFM. Proteomic assessment revealed a greater impact on db/ db SSM compared with db/ db IFM. Inner mitochondrial membrane proteins, including electron transport chain, ATP synthesis, and mitochondrial protein import machinery, were predominantly decreased. We provide evidence that mitochondrial dysfunction in the type 2 diabetic heart is associated with a specific subcellular locale. Furthermore, mitochondrial morphological and functional indexes are impacted differently during type 2 diabetic insult and may result from the modulation of spatially distinct mitochondrial proteomes.
Stress signaling by Tec tyrosine kinase in the ischemic myocardium
Authors: Zhang Michael J. , Franklin Sarah , Li Yifeng , Wang Sujing , Ru Xiaochen , Mitchell-Jordan Scherise A. , Mano Hiroyuki , Stefani Enrico , Ping Peipei , Vondriska Thomas M.
Published: June 2010

Nonreceptor tyrosine kinases have an increasingly appreciated role in cardiac injury and protection. To investigate novel tasks for members of the Tec family of nonreceptor tyrosine kinases in cardiac phenotype, we examined the behavior of the Tec isoform in myocardial ischemic injury. Ischemia-reperfusion, but not cardiac protective agents, induced altered intracellular localization of Tec, highlighting distinct actions of this protein compared with other isoforms, such as Bmx, in the same model. Tec is abundantly expressed in cardiac myocytes and assumes a diffuse intracellular localization under basal conditions but is recruited to striated structures upon various stimuli, including ATP. To characterize Tec signaling targets in vivo, we performed an exhaustive proteomic analysis of Tec-binding partners. These experiments expand the role of the Tec family in the heart, identifying the Tec isoform as an ischemic injury-induced isoform, and map the subproteome of its interactors in isolated cells.
Peripheral μ-opioid receptors attenuate the augmented exercise pressor reflex in rats with chronic femoral artery occlusion
Authors: Tsuchimochi Hirotsugu , McCord Jennifer L. , Kaufman Marc P.
Published: June 2010

Recently, opioid receptors have been shown to be expressed on group III and IV afferents, which comprise the sensory arm of the exercise pressor reflex. Although the stimulation of opioid receptors in the central nervous system has been shown to attenuate the exercise pressor reflex, the effect on the reflex of their stimulation in the periphery is unknown. We therefore tested the hypothesis that the activation of peripheral μ-opioid receptors attenuates the exercise pressor reflex. The pressor responses to static contraction were compared before and after the injection of the μ-opioid receptor agonist [d-Ala2, N-MePhe4,Gly-ol5]enkephalin (DAMGO; 1 μg) into the abdominal aorta of decerebrated rats in which one femoral artery had been occluded 72 h previously ( n = 10) and in control rats whose femoral arteries were freely perfused ( n = 8). DAMGO attenuated the peak pressor response to contraction in rats whose femoral arteries had been occluded (before: increase of 34 ± 3 mmHg and after: increase of 22 ± 2 mmHg, P = 0.008); the inhibitory effect of DAMGO was prevented by the injection of naloxone (100 μg) into the abdominal aorta (before: increase of 29 ± 5 mmHg and after: increase of 29 ± 5 mmHg, P = 0.646, n = 7). An intravenous injection of DAMGO (1 μg, n = 6) had no effect on the peak pressor response to contraction in both groups of rats. DAMGO had no effect on the peak pressor response to contraction in rats whose femoral arteries were freely perfused (before: Δ 23 ± 4 mmHg, after: Δ 23 ± 3 mmHg, n = 6) but appeared to have a small effect on topography of the response. DAMGO had no effect on the peak pressor response to tendon stretch in both groups of rats (both P > 0.05). We conclude that the stimulation of peripheral μ-opioid receptors attenuates the exercise pressor reflex in rats whose femoral arteries have been ligated for 72 h.
Mitochondrial aldehyde dehydrogenase mediates vasodilator responses of glyceryl trinitrate and sodium nitrite in the pulmonary vascular bed of the rat
Authors: Badejo Adeleke M. , Hodnette Chris , Dhaliwal Jasdeep S. , Casey David B. , Pankey Edward , Murthy Subramanyam N. , Nossaman Bobby D. , Hyman Albert L. , Kadowitz Philip J.
Published: June 2010

It has been reported that mitochondrial aldehyde dehydrogenase (ALDH2) catalyzes the formation of glyceryl dinitrate and inorganic nitrite from glyceryl trinitrate (GTN), leading to an increase in cGMP and vasodilation in the coronary and systemic vascular beds. However, the role of nitric oxide (NO) formed from nitrite in mediating the response to GTN in the pulmonary vascular bed is uncertain. The purpose of the present study was to determine if nitrite plays a role in mediating vasodilator responses to GTN. In this study, intravenous injections of GTN and sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure under baseline and elevated tone conditions and decreases in systemic arterial pressure in response to GTN and sodium nitrite were attenuated by cyanamide, an ALDH2 inhibitor, whereas responses to the NO donor, sodium nitroprusside (SNP), were not altered. The decreases in pulmonary and systemic arterial pressure in response to GTN and SNP were not altered by allopurinol, an inhibitor of xanthine oxidoreductase, whereas responses to sodium nitrite were attenuated. GTN was ∼1,000-fold more potent than sodium nitrite in decreasing pulmonary and systemic arterial pressures. These results suggest that ALDH2 plays an important role in the bioactivation of GTN and nitrite in the pulmonary and systemic vascular beds and that the reduction of nitrite to vasoactive NO does not play an important role in mediating vasodilator responses to GTN in the intact chest rat.
Short-term type 1 diabetes alters the mechanism of endothelium-dependent relaxation in the rat carotid artery
Authors: Leo C. H. , Joshi A. , Woodman O. L.
Published: June 2010

The aim of the present study was to examine the effect of an early stage of streptozotocin-induced diabetes on the mechanism(s) of endothelium-dependent relaxation. Diabetes was induced by a single injection of streptozotocin (48 mg/kg iv), and the ACh-induced relaxation of rat carotid arteries was examined 6 wk later. A diabetes-induced increase in superoxide levels, determined by L-012-induced chemiluminescence, from carotid arteries was associated with endothelial nitric oxide (NO) synthase (eNOS) uncoupling and increased catalytic subunit of NADPH oxidase expression. The sensitivity and maximum response to ACh were similar in normal and diabetic rats despite a decrease in NO release detected by 4-amino-5-methylamino-2′,7′-difluorofluorescein. In normal rats, N-nitro-l-arginine (100 μM) plus 1 H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (10 μM), to inhibit NOS and soluble guanylate cyclase (sGC), respectively, abolished ACh-induced relaxation, whereas in diabetic rats, the maximum relaxation to ACh was attenuated (maximum relaxation: 25 ± 5%), but not abolished, by that treatment. The remaining ACh-induced relaxation was abolished by NO scavengers, cupric chloride (to degrade nitrosothiols), or blockers of endothelial K+channels. Western blot analysis of the carotid arteries indicated that diabetes significantly increased the expression of eNOS but decreased the proportion of eNOS expressed as the dimer. These findings demonstrate that in early diabetes, ACh-induced relaxation is maintained but is resistant to NOS inhibition. In early diabetes, nitrosothiol-mediated opening of K+channels may act in conjunction with NO stimulation of sGC to maintain endothelium-dependent relaxation despite the increase in vascular superoxide levels.
The Role of Anterior Insula and Anterior Cingulate in Empathy for Pain
Authors: Valentini Elia
Published: June 2010

The understanding of others' feelings and emotional states is commonly defined by the term empathy. Here, I discuss recent findings regarding the differential contribution of anterior insula and anterior cingulate cortices to this function. For the first time, Gu and colleagues (2010) showed no direct involvement of the anterior cingulate during observation of another's pain and proposed the anterior insula as the main neural substrate for the mental representation of empathy.
The Influence of Smoking, Gender, and Family History on Colorectal Adenomas
Authors: Onega Tracy , Goodrich Martha , Dietrich Allen , Butterly Lynn
Published: June 2010

Evidence independently links smoking, family history, and gender with increased risk of adenomatous polyps. Using data from the New Hampshire Colonoscopy Registry (2004–2006), we examined the relation of combined risk factors with adenoma occurrence in 5,395 individuals undergoing screening colonoscopy. Self-reported data on smoking, family history and other factors were linked to pathology reports identifying adenomatous polyps and modeled with multiple logistic regression. In adjusted models a >15 pack-year smoking history increased the likelihood of an adenoma (, 95% CI 1.28–1.86), although ≤15 pack-years did not (, 95% CI 0.87–1.32). Gender-stratified models showed a significantly increased risk of adenoma at lower smoking exposure even for men (; 95% CI:1.00–1.76), but not for women (; 95% CI:0.61–1.14). An ordered logistic regression model of adenoma occurrence showed a smoking history of ≥15 pack-years associated with 61% higher odds of adenoma at successively larger size categories (95% CI 1.34–1.93). For individuals with a family history of colorectal cancer, smoking does not further increase the risk of adenomas. Smoking duration is linked to occurrence and size of adenoma, especially for men.
ADAM17 Regulates Epidermal Growth Factor Receptor Expression through the Activation of Notch1 in Non–Small Cell Lung Cancer
Authors: Baumgart Anja , Seidl Stefan , Vlachou Petros , Michel Lars , Mitova Nadya , Schatz Nicole , Specht Katja , Koch Ina , Schuster Tibor , Grundler Rebekka , Kremer Marcus , Fend Falko , Siveke Jens T. , Peschel Christian , Duyster Justus , Dechow Tobias
Published: June 2010

Epidermal growth factor receptor (EGFR) overexpression and activation are hallmarks of non–small cell lung carcinoma (NSCLC). Although EGFR-targeted therapies are used, the prognosis of NSCLC remains poor. ADAM17 induces activation of the EGFR through ligand cleavage. However, we show that inhibition or knockdown of ADAM17 markedly reduces tumorigenesis and survival to a large part independently from EGFR ligand shedding in NSCLC cells. These findings strongly indicate additional oncogenic mechanisms regulated by ADAM17. We identified Notch1 signaling as an ADAM17-controlled pathway and a critical regulator of anchorage-independent growth by using both Notch1 shRNA and ectopic expression of the active intracellular Notch1 fragment. Strikingly, Notch1 knockdown led to a strong reduction of EGFR expression in all analyzed cell lines. Proliferation, survival, and colony formation of Notch1-deficient cells were insensitive to EGF stimulation. Moreover, targeting Notch1 or ADAM17 resulted in substantial cell death, whereas EGFR inhibition predominantly induced cell cycle arrest. Immunohistochemical analysis of primary human tissue revealed a significant correlation between ADAM17, Notch1 signaling, and high EGFR expression levels. In conclusion, this article describes a novel molecular circuitry in NSCLC, incorporating ADAM17 as a regulator of EGFR expression through the activation of Notch1. Due to their central role in tumorigenesis and survival of NSCLC cells, both ADAM17 and Notch1 constitute promising targets for the treatment of NSCLC. Cancer Res; 70(13); 5368–78. ©2010 AACR.
Socioeconomic Trends in Hospitalization for Multiple Sclerosis
Authors: Lad Shivanand P. , Chapman Christopher H. , Vaninetti Michael , Steinman Lawrence , Green Ari , Boakye Maxwell
Published: June 2010

Objectives: Multiple sclerosis (MS) is a neurological disorder with a high burden on patient quality of life and medical rehabilitation services. Little is known about the acute hospitalization costs and characteristics. We examined the trends in MS hospitalizations from 1993 to 2006. Methods: The Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project was searched using the ICD-9 code 340 (MS). Diagnostic, treatment and administrative data were analyzed using basic statistical software. Results: A total of 288,454 hospital admissions with the primary diagnosis of MS occurred between 1993 and 2006, an average of 20,604 admissions annually. The percentage admitted from the emergency department (ED) increased from 19.4 to 60.0% during 1993–2006. The mean cost for each inpatient increased from USD 7,965 to 20,076. The percentage of discharges to home health care increased from 8.6 to 14.9%, and the percentage of discharges to nursing homes and rehabilitation services increased from 8.3 to 22.6%. In 2006, Medicaid patients were significantly more likely to be admitted from the ED (p < 0.001). Medicare payers were significantly more likely to be discharged to a nursing home/rehabilitation (p < 0.0001). Conclusion: National health insurance policies have made measurable effects on MS disease management. MS is becoming more expensive to treat acutely, and improved treatment modalities geared toward decreasing acute flare-ups may provide substantial cost savings by reducing ED visits, inpatient hospitalizations and the need for rehabilitation.
Validation of a Self-Report Comorbidity Questionnaire for Multiple Sclerosis
Authors: Horton Myles , Rudick Richard A. , Hara-Cleaver Claire , Marrie Ruth Ann
Published: June 2010

Background/Aims: Researchers increasingly recognize the high frequency of comorbidity in multiple sclerosis (MS) and the negative impact on quality of life and disability, but little work has evaluated methods of comorbidity measurement in MS. We aimed to validate a self-report questionnaire for assessing comorbidity in MS. Methods: Patients with MS were recruited from the MS Clinic in Winnipeg, Canada and the Mellen Center (Cleveland Clinic, Cleveland, Ohio, USA) from October 2008 to 2009. Using a questionnaire, participants reported the presence or absence of 36 comorbidities, sociodemographic characteristics, and disability status. Abstractors blinded to questionnaire results collected data regarding the comorbidities of interest and their treatments. Using the medical record as the gold standard, we determined the sensitivity, specificity, positive and negative predictive values of the questionnaire data. To measure agreement we calculated kappa (ĸ) statistics. Results: We enrolled 404 participants. Agreement between self-report and medical records was high (ĸ >0.82) for diabetes and hypertension; substantial (ĸ = 0.62–0.80) for hyperlipidemia, thyroid disease, glaucoma, and lung disease; moderate (ĸ = 0.43–0.56) for osteoporosis, irritable bowel syndrome, migraine, depression, heart disease, and anxiety disorders. Agreement was slight to fair for the remaining comorbidities. Conclusions: Self-report is a valid way to capture comorbidities affecting MS patients.
The Three-Dimensional Structure of Mimivirus
Authors: Klose Thomas , Kuznetsov Yurii G. , Xiao Chuan , Sun Siyang , McPherson Alexander , Rossmann Michael G.
Published: June 2010

Mimivirus, the prototypic member of the new family of Mimiviridae, is the largest virus known to date. Progress has been made recently in determining the three-dimensional structure of the 0.75-µm diameter virion using cryo-electron microscopy and atomic force microscopy. These showed that the virus is composed of an outer layer of dense fibers surrounding an icosahedrally shaped capsid and an internal membrane sac enveloping the genomic material of the virus. Additionally, a unique starfish-like structure at one of the fivefold vertices, required by the virus for infecting its host, has been defined in more detail.
Screening, Diagnosing and Prevention of Fetal Alcohol Syndrome: Is This Syndrome Treatable
Authors: Ismail Sahar , Buckley Stephanie , Budacki Ross , Jabbar Ahmad , Gallicano G. Ian
Published: June 2010

Prenatal alcohol exposure can lead to a wide range of adverse effects on a developing fetus. As a whole, these teratogenic outcomes are generally known as fetal alcohol spectrum disorders, the most severe of which is fetal alcohol syndrome (FAS). Clinically, children diagnosed with FAS vary greatly in their presentation of symptoms, likely due to the amount of alcohol and timing of exposure, as well as maternal and genetic influences. All these factors play a role in determining the mechanisms through which alcohol damages a developing brain, the details of which are still largely unknown. However, continuing research and recent developments have provided promising results that may lead to screening mechanisms and treatment therapies for children with FAS. Here we review the teratogenic effects of alcohol, strategies for detecting maternal alcohol consumption, identification of fetal biological markers, and prevention methods for FAS.
Evaluation of Five Interleukin Genes for Association with End-Stage Renal Disease in White Europeans
Authors: Buckham Theresa A. , McKnight Amy Jayne , Benevente David , Courtney Aisling E. , Patterson Christopher C. , Simmonds Matt , Gough Steven , Middleton Derek , Borrows Richard , Maxwell Alexander P.
Published: June 2010

Background: Genetic variation within interleukin genes has been reported to be associated with end-stage renal disease (ESRD). These findings have not been consistently replicated. No study has yet reported the comprehensive investigation of IL1A, IL1B, IL1RN,IL6 and IL10 genes. Methods: 664 kidney transplant recipients (cases) and 577 kidney donors (controls) were genotyped to establish if common variants in interleukin genes are associated with ESRD. Single nucleotide polymorphism (SNP) genotype data for each gene were downloaded for a northern and western European population from the International HapMap Project. Haploview was used to visualize linkage disequilibrium and select tag SNPs. Thirty SNPs were genotyped using MassARRAY® iPLEX Gold technology and data were analyzed using the χ2 test for trend. Independent replication was conducted in 1,269 individuals with similar phenotypic characteristics. Results: Investigating all common variants in IL1A, IL1B, IL1RN,IL6 and IL10 genes revealed a statistically significant association (rs452204 pempirical = 0.02) with one IL1RN variant and ESRD. This IL1RN SNP tags three other variants, none of which have previously been reported to be associated with renal disease. Independent replication in a separate transplant population of comparable size did not confirm the original observation. Conclusions: Common variants in these five candidate interleukin genes are not major risk factors for ESRD in white Europeans.
Early Brief Treatment with Losartan plus Mycophenolate Mofetil Provides Lasting Renoprotection in a Renal Ablation Model
Authors: Fujihara Clarice Kazue , Vieira, Jr. Jose Mauro , Sena Claudia Ramos , Ventura Bianca Helena , Malheiros Denise Maria , Zatz Roberto
Published: June 2010

Background: Inflammatory events antecede established renal injury in rats with 5/6 renal ablation (Nx), as indicated by the beneficial effects of early, uninterrupted treatment with mycophenolate mofetil (MMF). Angiotensin II also exerts a major pathogenic role at this initial phase. We investigated whether losartan (L) or L+MMF treatment, started early, and L+MMF treatment, started late, would exert lasting renoprotection in Nx even after being discontinued. Methods: Adult male Munich-Wistar rats underwent Nx and were divided into three groups: Nx (untreated), NxL (given L), and NxLMMF (given L and MMF). Protocol 1: treatments began on day 1, and ceased on day 30, after Nx. Protocol 2: L+MMF treatment began on day 30 and ceased on day 60. Results: Protocol 1: on day 30, hypertension, albuminuria and renal injury were strongly attenuated in Groups NxL and NxLMMF. On day 120, these abnormalities were still attenuated in group NxLMMF. Protocol 2: on day 120, all parameters were similar between this late NxLMMF group and untreated Nx. Conclusion: In Nx, temporary suppression of early, transitory hemodynamic/inflammatory phenomena affords relatively durable renoprotection even after treatment discontinuation. This effect is not obtained with similar temporary treatment initiated later in the course of renal disease.
Usefulness of Bezafibrate for Ovulation Induction in Clomiphene Citrate-Resistant Polycystic Ovary Syndrome Patients with Dyslipidemia: A Prospective Pilot Study of Seven Cases
Authors: Hara Shuichiro , Takahashi Toshifumi , Amita Mitsuyoshi , Igarashi Hideki , Kurachi Hirohisa
Published: June 2010

Background: Dyslipidemia is commonly observed in polycystic ovary syndrome (PCOS) patients. Bezafibrate is a drug for dyslipidemia acting through peroxisome proliferator-activated receptors. We investigated the effects of bezafibrate for ovulation induction in patients with PCOS with dyslipidemia who were resistant to clomiphene citrate (CC). Methods: This was a prospective pilot study. Seven infertile, CC-resistant, PCOS patients with dyslipidemia were enrolled in this study. The participants received bezafibrate at 400 mg/day from day 1 of menses and CC at 100 mg/day from day 5 of menses simultaneously until one follicle measuring at least 18 mm in diameter was found by transvaginal ultrasound. The main outcome was ovulation rate. Results: Five of 7 patients successfully ovulated. The mean number of days of menses until the follicle reached 18 mm in diameter was 16 ± 3 (range 13–20). Monofollicular development was observed in all patients that ovulated. One woman became pregnant and delivered a healthy baby. Conclusion: Bezafibrate may be effective for ovulation induction in CC-resistant PCOS patients with dyslipidemia.
Experience of Gemcitabine plus Oxaliplatin Chemotherapy in Patients with Advanced Biliary Tract Carcinoma
Authors: Hollebecque Antoine , Bouché Olivier , Romano Olivier , Scaglia Elodie , Cattan Stéphane , Zerbib Philippe , Heurgue Alexandra , Lagarde Stéphanie , Mariette Christophe , Triboulet Jean-Pierre , Pruvot François-René , Hebbar Mohamed
Published: June 2010

Backgrounds: The combination gemcitabine-oxaliplatin (GEMOX) is frequently used in patients with advanced biliary tract carcinoma (BTC). However, this is only based on phase II studies performed in selected patients.We assessed the efficacy and safety of the GEMOX regimen in non-selected patients with advanced BTC. Methods: All consecutive patients with advanced BTC received the GEMOX regimen in a setting outside a study: gemcitabine 1,000 mg/m2 on day 1, and oxaliplatin 100 mg/m2 on day 2, treatment repeated every 2 weeks until progression or unacceptable toxicity. Results: Forty-four patients were enrolled. Efficacy: 1 complete and 6 partial responses (objective response rate = 16.3%), 18 tumour stabilizations (41.9%, disease control rate = 58.1%), median progression-free survival was 5.0 months and median overall survival was 11.0 months. Toxicity: grade 3 neuropathy in 4 patients, grade 3 asthenia in 5 patients. Conclusion: The GEMOX combination was well tolerated, with a modest activity in non-selected patients with advanced BTC. This regimen should be compared to the new standard gemcitabine-cisplatin combination.