bluuebunny/crossref_metadata_2025 huggingface dataset:
Concomitant antagonism of endothelial and vascular smooth muscle cell ETBreceptors for endothelin induces hypertension in the hamster
Authors: Honoré Jean-Claude , Fecteau Marie-Hélène , Brochu Isabelle , Labonté Julie , Bkaily Ghassan , D’Orleans-Juste Pedro
Published: May 2005

In the vascular system, endothelin (ET) type B (ETB) receptors for ET-1 are located on endothelial and on venous and arterial smooth muscle cells. In the present study, we investigated the hemodynamic effects of chronic ETBreceptor blockade at low and high doses in the Syrian Golden hamster. After 16 days of gavage with A-192621 (0.5 or 30 mg·kg−1·day−1), a selective ETBreceptor antagonist, hamsters were anesthetized with a mixture of ketamine and xylazine (87 and 13 mg/kg im, respectively), and basal mean arterial blood pressure (MAP) and pressor responses to exogenous ET-1 were evaluated. The lower dose of A-192621 (0.5 mg·kg−1·day−1) did not modify basal MAP, whereas the higher dose (30 mg·kg−1·day−1) increased MAP and plasma ET levels. Radio-telemetry recordings confirmed the increase in MAP induced by the higher dose of A-192621 in conscious hamsters. On the other hand, although the lower dose of A-192621 was devoid of intrinsic pressor effects, it markedly reduced the transient hypotensive phase induced by intravenously injected IRL-1620, a selective ETBreceptor agonist. Finally, A-192621 (0.5 mg·kg−1·day−1) alone or A-192621 (30 mg·kg−1·day−1) + atrasentan (6 mg·kg−1·day−1), a selective ETAreceptor antagonist, potentiated the pressor response to exogenous ET-1. Our results suggest that, in the hamster, ETBreceptors on vascular smooth muscle cells are importantly involved in the clearance of endogenous ET-1, whereas the same receptor type on the endothelium is solely involved in the vasodilatory responses to the pressor peptide. Blockade of endothelial and vascular smooth muscle cell ETBreceptors triggers a marked potentiation of ETA-dependent increases in systemic resistance.
Measurement of total pulmonary arterial compliance using invasive pressure monitoring and MR flow quantification during MR-guided cardiac catheterization
Authors: Muthurangu Vivek , Atkinson David , Sermesant Maxime , Miquel Marc E. , Hegde Sanjeet , Johnson Robert , Andriantsimiavona Rado , Taylor Andrew M. , Baker Edward , Tulloh Robert , Hill Derek , Razavi Reza S.
Published: May 2005

Pulmonary hypertensive disease is assessed by quantification of pulmonary vascular resistance. Pulmonary total arterial compliance is also an indicator of pulmonary hypertensive disease. However, because of difficulties in measuring compliance, it is rarely used. We describe a method of measuring pulmonary arterial compliance utilizing magnetic resonance (MR) flow data and invasive pressure measurements. Seventeen patients with suspected pulmonary hypertension or congenital heart disease requiring preoperative assessment underwent MR-guided cardiac catheterization. Invasive manometry was used to measure pulmonary arterial pressure, and phase-contrast MR was used to measure flow at baseline and at 20 ppm nitric oxide (NO). Total arterial compliance was calculated using the pulse pressure method (parameter optimization of the 2-element windkessel model) and the ratio of stroke volume to pulse pressure. There was good agreement between the two estimates of compliance ( r = 0.98, P < 0.001). However, there was a systematic bias between the ratio of stroke volume to pulse pressure and the pulse pressure method (bias = 61%, upper level of agreement = 84%, lower level of agreement = 38%). In response to 20 ppm NO, there was a statistically significant fall in resistance, systolic pressure, and pulse pressure. In seven patients, total arterial compliance increased >10% in response to 20 ppm NO. As a population, the increase did not reach statistical significance. There was an inverse relation between compliance and resistance ( r = 0.89, P < 0.001) and between compliance and mean pulmonary arterial pressure ( r = 0.72, P < 0.001). We have demonstrated the feasibility of quantifying total arterial compliance using an MR method.
Calcitonin gene-related peptide and substance P contribute to reduced blood pressure in sympathectomized rats
Authors: Supowit S. C. , Ethridge R. T. , Zhao H. , Katki K. A. , DiPette D. J.
Published: May 2005

CGRP and substance P (SP) are produced in dorsal root ganglia (DRG) sensory neurons and modulate vascular tone. Sympathetic and sensory nerves compete for NGF, a potent stimulator of CGRP and SP, and it has been suggested that sympathetic hyperinnervation in spontaneously hypertensive rats may reduce the availability of NGF to sensory nerves, thus reducing CGRP and SP. The purpose of this study was to determine whether destruction of peripheral sympathetic nerves in normal rats would increase the availability of NGF for sensory neurons and enhance expression of CGRP and SP. Sympathectomy was produced in rats by guanethidine sulfate administration. Control rats received saline. Sympathectomized rats displayed reductions in blood pressure (BP) and atria norepinephrine levels, whereas NGF levels in the DRG, spleen, and ventricles were increased. Sympathectomy also enhanced CGRP and SP mRNA and peptide content in DRG. Administration of CGRP and SP receptor antagonists increased the BP in sympathectomized rats but not in the controls. Thus sympathectomy enhances sensory neuron CGRP and SP expression that contributes to the BP reduction.
Reduced functional expression of K+channels in vascular smooth muscle cells from rats made hypertensive withNω-nitro-l-arginine
Authors: Bratz Ian N. , Swafford Albert N. , Kanagy Nancy L. , Dick Gregory M.
Published: May 2005

Smooth muscle membrane potential is determined, in part, by K+channels. In the companion paper to this article (Bratz IN, Dick GM, Partridge LD, and Kanagy NL. Am J Physiol Heart Circ Physiol 289: H1277–H1283, 2005), we demonstrated that superior mesenteric arteries from rats made hypertensive with Nω-nitro-l-arginine (l-NNA) are depolarized and express less K+channel protein compared with those from normotensive rats. In the present study, we used patch-clamp techniques to test the hypothesis that l-NNA-induced hypertension reduces the functional expression of K+channels in smooth muscle. In whole cell experiments using a Ca2+-free pipette solution, current at 0 mV, largely due to voltage-dependent K+(KV) channels, was reduced ∼60% by hypertension (2.7 ± 0.4 vs. 1.1 ± 0.2 pA/pF). Current at +100 mV with 300 nM free Ca2+, largely due to large-conductance Ca2+-activated K+(BKCa) channels, was reduced ∼40% by hypertension (181 ± 24 vs. 101 ± 28 pA/pF). Current blocked by 3 mM 4-aminopyridine, an inhibitor of many KVchannel types, was reduced ∼50% by hypertension (1.0 ± 0.4 vs. 0.5 ± 0.2 pA/pF). Current blocked by 1 mM tetraethylammonium, an inhibitor of BKCachannels, was reduced ∼40% by hypertension (86 ± 14 vs. 53 ± 19 pA/pF). Differences in BKCacurrent magnitude are not attributable to changes in single-channel conductance or Ca2+/voltage sensitivity. The data support the hypothesis that l-NNA-induced hypertension reduces K+current in vascular smooth muscle. Reduced molecular and functional expression of K+channels may partly explain the depolarization and augmented contractile sensitivity of smooth muscle from l-NNA-treated rats.
Mechanisms of enhanced shock-induced arrhythmogenesis in the rabbit heart with healed myocardial infarction
Authors: Li Li , Nikolski Vladimir , Wallick Don W. , Efimov Igor R. , Cheng Yuanna
Published: May 2005

Shock-induced vulnerability and defibrillation have been mostly studied in structurally normal hearts. However, defibrillation therapy is normally applied to patients with diseased hearts, frequently those with prior myocardial infarction (MI). Shock-induced vulnerability and defibrillation have not been well studied under this condition. We sought to examine the mechanisms of shock-induced arrhythmogenesis and arrhythmia maintenance in a rabbit model of healed MI (4 wk or more postinfarction). Ligation of the lateral division or posterolateral division of the left coronary artery at a level of 40–70% from the apex was performed 53 ± 21 days before acute experiments. Shock-induced vulnerability was assessed in infarcted ( n = 8) and structurally normal ( n = 8) hearts by delivering internal monophasic shocks at different shock strengths and delivery phases. Electrical activities from the anterior epicardium during shock application and during shock-induced arrhythmias were optically recorded and quantitatively analyzed. Ligation resulted in a transmural left ventricular free wall infarction mainly located at the apical region with a consistent endocardial border zone (BZ) as confirmed by histological studies. There were significant increases in the incidence, severity, and duration of shock-induced arrhythmias in the infarcted hearts versus controls due to 1) postshock break-excitation wavefronts that frequently originated near the infarction BZ and 2) the existence of an infarction BZ that created an anatomic reentry pathway and facilitated arrhythmia maintenance. In conclusion, the infarction BZ contributes to both increased shock-induced arrhythmogenesis and arrhythmia maintenance in the rabbit model of healed MI.
Temporal and spatial distribution of ciliogenesis in the tracheobronchial airways of mice
Authors: Toskala Elina , Smiley-Jewell Suzette M. , Wong Viviana J. , King Dustin , Plopper Charles G.
Published: May 2005

Little is known about ciliogenesis as it proceeds through the entire airway tree, from the trachea to the terminal bronchioles, especially during the postnatal period. The purpose of this study was to define the spatial and temporal (prenatal and postnatal) pattern of normal cilia development in the mouse. Three airway generations representing the entire airway tree were examined: trachea, lobar bronchi, and terminal bronchiole. Ciliated cells in lung lobe whole mounts were labeled with a fluorescent dye for confocal microscopy, and ciliated cell surface density was measured for each airway generation and age. The same samples were examined by scanning electron microscopy to verify the appearance of ciliated cells among the differentiating epithelium of the airways. Ciliated cells were first detected in the trachea and lobar bronchi at 16 days gestational age (DGA) and in the terminal bronchioles at 18 DGA. Ciliated cell surface density increased with prenatal and postnatal age at all airway levels. However, the ciliated cell surface density of the trachea and lobar bronchi was always greater compared with the terminal bronchiole. In conclusion, the study revealed that in developing tracheobronchial airways of the mouse: 1) Ciliogenesis differs temporally and spatially by airway generation; 2) Ciliated cell surface density increases with age in all airway generations, but density decreases in a proximal to distal direction; and 3) A significant portion of ciliogenesis continues after birth. This study provides a healthy basis for investigations of neonatal pulmonary disease or pollutant toxicity affecting cilia and its functions.
Pressure-induced leukocyte margination in lung postcapillary venules
Authors: Ichimura Hideo , Parthasarathi Kaushik , Issekutz Andrew C. , Bhattacharya Jahar
Published: May 2005

Although pressure elevation in lung postcapillary venules increases endothelial P-selectin expression, the extent to which P-selectin causes lung leukocyte margination remains controversial. To address this issue, we optically viewed postcapillary venules of the isolated blood-perfused rat lung by real-time fluorescence imaging. To determine leukocyte margination in single postcapillary venules, we quantified the fluorescence of leukocytes labeled in situ with rhodamine 6G (R6G). Although baseline fluorescence was sparse, a 10-min pressure elevation by 10 cmH2O markedly increased R6G fluorescence. Both stopping blood flow during pressure elevation and eliminating leukocytes from the perfusion blocked the fluorescence increase, affirming that these fluorescence responses were attributable to pressure-induced leukocyte margination. A P-selectin-blocking MAb and the L- and P-selectin blocker fucoidin each inhibited the fluorescence increase, indicating that P-selectin was critical for inducing margination. Time-dependent imaging of blood-borne fluorescent beads revealed reduction of plasma velocity during pressure elevation. After pressure returned to baseline, a similar reduction of plasma velocity, established by manually decreasing the perfusion rate, prolonged margination. Our findings show that in lung postcapillary venules, the decrease in plasma velocity critically determines pressure-induced leukocyte margination.
Hyperglycemia after protein ingestion concurrent with injection of a GLP-1 receptor agonist in rats: a possible role for dietary peptides
Authors: Aziz Alfred , Anderson G. Harvey , Giacca Adria , Cho France
Published: May 2005

Protein ingestion after injection of the glucagon-like peptide-1 receptor agonist Exendin-4 (Ex-4) causes hyperglycemia in rats. The objectives of this study were to determine the components of protein digestion responsible for this effect and to associate it with changes in the concentrations of other metabolites and hormones. Two experiments were conducted. In the first experiment, food-deprived rats were gavaged with intact whey (WP) or albumin protein, their hydrolysates, amino acid mixtures (1 g/2.5 ml), or water 5 min after injection of either PBS or Ex-4 (0.5 μg/rat). Tail vein blood was analyzed for glucose over 2 h. In the second experiment, food-deprived rats were gavaged with WP with or without Ex-4. Groups of conscious rats were killed by decapitation either before, or at selected times after gavage. Plasma concentrations of glucose, amino acids, free fatty acids (FFA), glycerol, insulin, glucagon, and leptin were measured. In experiment 1, blood glucose was higher when intact proteins and protein hydrolysates, but not amino acid mixtures, were given with than without Ex-4 ( P < 0.05). In experiment 2, concentrations of glucose, FFA, and the ratio of tyrosine to branched-chain amino acid were higher ( P < 0.01), but leptin and essential amino acid concentrations were lower ( P < 0.05), and insulin, glucagon, and glycerol were similar when WP was given with or without Ex-4. We conclude that the hyperglycemia caused by the administration of Ex-4 concurrently with dietary protein arises from the action of peptides released during digestion and their interaction with Ex-4 in the regulation of glucose, fatty acid, and amino acid metabolism.
Heat extraction through the palm of one hand improves aerobic exercise endurance in a hot environment
Authors: Grahn Dennis A. , Cao Vinh H. , Heller H. Craig
Published: May 2005

In situations where the accumulation of internal heat limits physical performance, enhanced heat extraction from the body should improve performance capacity. The combined application of local subatmospheric pressure (35–45 mmHg) to an entire hand (to increase blood volume) and a heat sink (18–22°C) to the palmar surface were used to draw heat out of the circulating blood. Subjects walked uphill (5.63 km/h) on a treadmill in a 40°C environment. Slopes of the treadmill were held constant during paired experimental trials (with and without the device). Heat extraction attenuated the rate of esophageal temperature rise during exercise (2.1 ± 0.4° and 2.9 ± 0.5°C/h, mean ± SE, with and without the device, respectively; n = 8) and increased exercise duration (46.1 ± 3.4 and 32.3 ± 1.7 min with and without the device, respectively; n = 18). Hand cooling alone had little effect on exercise duration (34.1 ± 3.0, 38.0 ± 3.5, and 57.0 ± 6.4 min, for control, cooling only, and cooling, and subatmospheric pressure, respectively; n = 6). In a longer term study, nine subjects participated in two or four trials per week for 8 wk. The individual workloads (treadmill slope) were varied weekly. Use of the device had a beneficial effect on exercise endurance at all workloads, but the benefit proportionally decreased at higher workloads. It is concluded that heat can be efficiently removed from the body by using the described technology and that such treatment can provide a substantial performance benefit in thermally stressful conditions.
Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemic-reperfused rat hearts
Authors: Takeda Satoshi , Mochizuki Seibu , Saini Harjot K. , Elimban Vijayan , Dhalla Naranjan S.
Published: May 2005

To study the cardioprotective effects of vanadate on ischemia-reperfusion (I/R) injury, isolated rat hearts perfused at constant flow were subjected to global ischemia for 30 min followed by reperfusion for 30 min. In this experimental model, I/R markedly decreased ventricular developed pressure and increased end-diastolic pressure. Pretreatment of hearts with 4 μM vanadate attenuated I/R-induced cardiac dysfunction. The reduction in sarcoplasmic reticulum (SR) Ca2+uptake and Ca2+release, as well as SR protein contents for Ca2+-pump ATPase and Ca2+-release channel, was also prevented by vanadate. Pretreatment of hearts with an antioxidant mixture containing superoxide dismutase + catalase exerted effects similar to those of vanadate in I/R hearts. Postischemic treatment of hearts with vanadate or superoxide dismutase + catalase also had beneficial effects on I/R-induced changes in cardiac performance and SR function. Alterations in cardiac function and SR Ca2+transport due to an oxyradical-generating system (xanthine + xanthine oxidase) or an oxidant (H2O2) were attenuated by treatment with vanadate. These results suggest that vanadate may exert beneficial effects on cardiac performance and SR function in I/R hearts because of its antioxidant action.
Muscle endurance is greater for old men compared with strength-matched young men
Authors: Hunter Sandra K. , Critchlow Ashley , Enoka Roger M.
Published: May 2005

The purpose was to compare the time to task failure for a sustained isometric contraction performed at a submaximal intensity with the elbow flexor muscles by young and old men who were matched for strength. Eight young men (18–31 yr) and eight old men (67–76 yr) sustained an isometric contraction at 20% of maximal voluntary contraction (MVC) torque until the target torque could no longer be achieved for at least 5 s. The maximal torque exerted at the wrist was similar for the young and old men before the fatiguing task (65.9 ± 8.0 vs. 65.4 ± 8.7 N·m; P > 0.05), and they experienced similar reductions in MVC torque after the fatiguing contraction (31.4 ± 10.6%; P < 0.05). The time to task failure was longer for the old men (22.6 ± 7.4 min) compared with the strength-matched young men (13.0 ± 5.2 min; P < 0.05), despite each group sustaining a similar torque during the fatiguing contraction ( P > 0.05). The increases in torque fluctuations, electromyographic (EMG) bursting activity, and heart rate were greater for young men compared with the old men, and they were less at task failure for the old men ( P < 0.05). Mean arterial pressure increased at a similar rate for both groups of men ( P > 0.05), whereas the averaged EMG activity and rating of perceived exertion reached similar values at task failure for the young and old men ( P > 0.05). These findings indicate that the longer time to task failure for the old men when performing the submaximal contraction was not due the absolute target torque exerted during the contraction.
The effect of dynamic knee-extension exercise on patellar tendon and quadriceps femoris muscle glucose uptake in humans studied by positron emission tomography
Authors: Kalliokoski Kari K. , Langberg Henning , Ryberg Ann Kathrine , Scheede-Bergdahl Celena , Doessing Simon , Kjaer Andreas , Boushel Robert , Kjaer Michael
Published: May 2005

Both tendon and peritendinous tissue show evidence of metabolic activity, but the effect of acute exercise on substrate turnover is unknown. We therefore examined the influence of acute exercise on glucose uptake in the patellar and quadriceps tendons during dynamic exercise in humans. Glucose uptake was measured in five healthy men in the patellar and quadriceps tendons and the quadriceps femoris muscle at rest and during dynamic knee-extension exercise (25 W) using positron emission tomography and [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG). Glucose uptake index was calculated by dividing the tissue activity with blood activity of [18F]FDG. Exercise increased glucose uptake index by 77% in the patellar tendon (from 0.30 ± 0.09 to 0.51 ± 0.16, P = 0.03), by 106% in the quadriceps tendon (from 0.37 ± 0.15 to 0.75 ± 0.36, P = 0.02), and by 15-fold in the quadriceps femoris muscle (from 0.31 ± 0.11 to 4.5 ± 1.7, P = 0.005). The exercise-induced increase in the glucose uptake in neither tendon correlated with the increase in glucose uptake in the quadriceps muscle ( r = −0.10, P = 0.87 for the patellar tendon and r = −0.30, P = 0.62 for the quadriceps tendon). These results show that tendon glucose uptake is increased during exercise. However, the increase in tendon glucose uptake is less pronounced than in muscle and the increases are uncorrelated. Thus tendon glucose uptake is likely to be regulated by mechanisms independently of those regulating skeletal muscle glucose uptake.
Caffeine increases time to fatigue by maintaining force and not by altering firing rates during submaximal isometric contractions
Authors: Meyers B.M. , Cafarelli E.
Published: May 2005

Caffeine increases time to fatigue [limit of endurance (Tlim)] during submaximal isometric contractions without altering whole muscle activation or neuromuscular junction transmission. We used 10 male volunteers in a randomized, double-blind, repeated-measures experiment to examine single motor unit firing rates during intermittent submaximal contractions and to determine whether administering caffeine increased Tlim by maintaining higher firing rates. On 2 separate days, subjects performed intermittent 50% maximal voluntary contractions of the quadriceps to Tlim, 1 h after ingesting a caffeine (6 mg/kg) or placebo capsule. Average motor unit firing rates recorded with tungsten microelectrodes were constant for the duration of contractions. Caffeine increased average Tlim by 20.5 ± 8.1% ( P < 0.05) compared with placebo conditions. This increase was due to seven subjects, termed responders, who increased Tlim significantly. Two other subjects showed no response, and a third had a shorter Tlim. Neither the increased Tlim nor the responders' performance could be explained by alterations in firing rates or other neuromuscular variables. However, the amplitude of the evoked twitch and its maximal instantaneous rate of relaxation did not decline to the same degree in the caffeine trial of the responders; this resulted in values 20 and 30% higher at the time point matching the end of the placebo trial ( P < 0.05). The amplitude of the evoked twitch and the maximal instantaneous rate of relaxation were linearly correlated (caffeine r = 0.72, placebo r = 0.80, both P < 0.001), suggesting that the increase in Tlim may be partially explained by caffeine's effects on calcium reuptake and twitch force.
Genetic Determinants of Cardiovascular Disease Risk in Familial Hypercholesterolemia
Authors: Jansen Angelique C.M. , van Aalst-Cohen Emily S. , Tanck Michael W.T. , Cheng Suzanne , Fontecha Marcel R. , Li Jia , Defesche Joep C. , Kastelein John J.P.
Published: May 2005

Objective—

To investigate the contribution of polymorphisms in multiple candidate genes to cardiovascular disease (CVD) risk in a large cohort of patients with heterozygous familial hypercholesterolemia (FH).

Methods and Results—

We genotyped 1940 FH patients for 65 polymorphisms in 36 candidate genes. During 91.451 person-years, 643 (33.1%) patients had at least 1 cardiovascular event. Multifactorial Cox survival analysis revealed that the G20210A polymorphism in the prothrombin gene was strongly associated with a significantly increased CVD risk (GA versus GG;
P
<0.001).

Conclusions—

In a large cohort of FH patients, we found that the G20210A polymorphism in the prothrombin gene is strongly associated with CVD risk. Our results constitute a step forward in the unraveling of the hereditary propensity toward CVD in FH and might lead to better risk stratification and hence to more tailored therapy for CVD prevention.
Sphingomyelinase Induces Aggregation and Fusion of Small Very Low–Density Lipoprotein and Intermediate-Density Lipoprotein Particles and Increases Their Retention to Human Arterial Proteoglycans
Authors: Öörni Katariina , Posio Pirjo , Ala-Korpela Mika , Jauhiainen Matti , Kovanen Petri T.
Published: May 2005

Objectives—

Infiltration of low-density lipoprotein (LDL) into subendothelial space is an early step in atherosclerosis. In addition to LDL particles, small very low–density lipoprotein (sVLDL) and intermediate-density lipoprotein (IDL) particles are also able to enter the arterial intima and be retained within the subendothelial extracellular matrix. Here we compared how proteolysis with α-chymotrypsin and phospholipid hydrolysis with phospholipase A
2
or sphingomyelinase (SMase) of sVLDL, IDL, and LDL particles can influence their aggregation, fusion, and binding to human arterial proteoglycans in vitro.

Methods and Results—

In each of the 3 lipoprotein classes, the particles became only slightly aggregated with α-chymotrypsin or phospholipase A
2
. However, the particles strongly aggregated when treated with SMase. The aggregated/fused particles were found to bind to proteoglycans in proteoglycan affinity chromatography more tightly than the native-sized counterparts. In addition, in a microtiter well assay, the binding of SMase-treated lipoproteins was enhanced: the amounts of proteoglycan-bound SMase-treated LDL, IDL, and sVLDL were 4-, 5-, and 20-fold higher, respectively, than the amounts of proteoglycan-bound native lipoproteins.

Conclusion—

These results imply a specific role for SMase as an sVLDL- and IDL-modifying enzyme and also suggest a novel mechanism of lipid accumulation in atherogenesis, namely enhanced retention of atherogenic triglyceride-rich lipoprotein particles in intimal areas expressing extracellular SMase activity.
Functional Characterization of Connexin43 Mutations Found in Patients With Oculodentodigital Dysplasia
Authors: Shibayama Junko , Paznekas William , Seki Akiko , Taffet Steven , Jabs Ethylin Wang , Delmar Mario , Musa Hassan
Published: May 2005

Specific mutations in
GJA1
, the gene encoding the gap junction protein connexin43 (Cx43), cause an autosomal dominant disorder called oculodentodigital dysplasia (ODDD). Here, we characterize the effects of 8 of these mutations on Cx43 function. Immunochemical studies have shown that most of the mutant proteins formed gap junction plaques at the sites of cell-cell apposition. However, 2 of the mutations (a codon duplication in the first extracellular loop, F52dup, and a missense mutation in the second extracellular loop, R202H, produced full-length connexins that failed to properly form gap junction plaques. Cx43 proteins containing ODDD mutations found in the N-terminus (Y17S), first transmembrane domain (G21R, A40V), second transmembrane domain (L90V), and cytoplasmic loop (I130T, K134E) do form gap junction plaques but show compromised channel function. L90V, I130T, and K134E demonstrated a significant decrease in junctional conductance relative to Cx43WT. Mutations Y17S, G21R, and A40V demonstrated a complete lack of functional electrical coupling even in the presence of significant plaque formation between paired cells. Heterologous channels formed by coexpression of Cx43WT and mutation R202H resulted in electrically functional gap junctions that were not permeable to Lucifer yellow. Therefore, the mutations found in ODDD not only cause phenotypic variability, but also result in various functional consequences. Overall, our data show an extensive range of molecular phenotypes, consistent with the pleiotropic nature of the clinical syndrome as a whole.
Cell-to-Cell Connection of Endothelial Progenitor Cells With Cardiac Myocytes by Nanotubes
Authors: Koyanagi Masamichi , Brandes Ralf P. , Haendeler Judith , Zeiher Andreas M. , Dimmeler Stefanie
Published: May 2005

The regeneration of new myocardium by stem or progenitor cells is an important therapeutic option. Cellular or nuclear fusion is considered as an alternative to cell reprogramming by transdifferentiation. However, the generation of hybrid cells may also be a consequence of a transient transmembrane exchange of proteins and organelles between cells. Therefore, we investigated the formation of intercellular connections, which may allow the transport of macromolecular structures between labeled adult human endothelial progenitor cells (EPC) and GFP-expressing neonatal rat cardiomyocytes (CM) in a coculture system. FACS analysis revealed that, 6 days after initiation of coculture, 2.1±0.4% of the cells stained positive for GFP and Dil-ac-LDL. 6 hours after initiation of the coculture, ultrafine intercellular structures between Dil-ac-LDL-labeled EPC and GFP-expressing CM were observed. The number of EPC, which established nanotubular connections with CM increased from 0.5±0.2% after 6 hours to 2.6±0.3% after 24 hours of coculture. The intercellular connections had a diameter from 50 to 800 nm, a length of 5 to 120 μm, and were only transiently established. To determine whether the nanotubular structures allowed the transport of organelles, we labeled CM with a mitochondrial live tracker (MitoTracker). Using time-lapse video microscopy, we observed the transport of stained complexes between CM and EPC resulting in up-take of MitoTracker-positive structures in EPC. Thus, the present study shows a novel type of cell-to-cell communication between progenitor cells and CM in vitro, which may contribute to the acquisition of a cardiomyogenic phenotype independent of permanent cellular or nuclear fusion.
p38 Mitogen-Activated Protein Kinase Activates eNOS in Endothelial Cells by an Estrogen Receptor α-Dependent Pathway in Response to Black Tea Polyphenols
Authors: Anter Elad , Chen Kai , Shapira Oz M. , Karas Richard H. , Keaney John F.
Published: May 2005

Black tea has been shown to improve endothelial function in patients with coronary artery disease and recent data indicate the polyphenol fraction of black tea enhances endothelial nitric oxide synthase (eNOS) activity through p38 MAP kinase (p38 MAPK) activation. Because the mechanisms for this phenomenon are not yet clear, we sought to elucidate the signaling events in response to black tea polyphenols. Bovine aortic endothelial cells (BAECs) exposed to black tea polyphenols demonstrated eNOS activation that was inhibited by the estrogen receptor (ER) antagonist ICI 182,780, and siRNA-mediated silencing of ER expression. Consistent with this observation, black tea polyphenols induced time-dependent phosphorylation of ERα on Ser-118 that was inhibited by ICI 182,780. Phosphorylation of ERα on Ser-118 was due to p38 MAP kinase (p38 MAPK) as, it was inhibited by SB203580 and overexpression of dominant-negative p38α MAPK. Conversely, constitutively active MKK6 induced p38 MAPK activation that recapitulated the effects of polyphenols by inducing ERα phosphorylation and downstream activation of Akt, and eNOS. The key role of ERα Ser-118 phosphorylation was confirmed in eNOS-transfected COS-7 cells, as polyphenol-induced eNOS activation required cotransfection with ERα subject to phosphorylation at Ser-118. This residue appeared critical for functional association of ERα with p38 MAPK as ERα with Ser-118 mutated to alanine could not form a complex with p38 MAPK. These findings suggest p38 MAP kinase-mediated eNOS activation requires ERα and these data uncover a new mechanism of ERα activation that has broad implications for NO bioactivity and endothelial cell phenotype.
Functional Properties of Mouse Connexin30.2 Expressed in the Conduction System of the Heart
Authors: Kreuzberg Maria M. , Söhl Goran , Kim Jung-Sun , Verselis Vytas K. , Willecke Klaus , Bukauskas Feliksas F.
Published: May 2005

Gap junction channels composed of connexin (Cx) 40, Cx43, and Cx45 proteins are known to be necessary for impulse propagation through the heart. Here, we report mouse connexin30.2 (mCx30.2) to be a new cardiac connexin that is expressed mainly in the conduction system of the heart. Antibodies raised to the cytoplasmic loop or the C-terminal regions of mCx30.2 recognized this protein in mouse heart as well as in HeLa cells transfected with wild-type mCx30.2 or mCx30.2 fused with enhanced green fluorescent protein (mCx30.2-EGFP). Immunofluorescence analyses of adult hearts yielded positive signals within the sinoatrial node, atrioventricular node, and A-V bundle of the cardiac conduction system. Dye transfer studies demonstrated that mCx30.2 and mCx30.2-EGFP channels discriminate poorly on the basis of charge, but do not allow permeation of tracers >400 Da. Both mCx30.2 and mCx30.2-EGFP gap junctional channels exhibited weak sensitivity to transjunctional voltage (V
j
) and a single channel conductance of ≈9 pS, which is the lowest among all members of the connexin family measured in HeLa cell transfectants. HeLa mCx30.2-EGFP transfectants when paired with cells expressing Cx40, Cx43, or Cx45 formed functional heterotypic gap junction channels that exhibited low unitary conductances (15 to 18 pS), rectifying open channel I-V relations and asymmetric V
j
dependence. The electrical properties of homo- and hetero-typic junctions involving mCx30.2 may contribute to slow propagation velocity in nodal tissues and directional asymmetry of excitation spread in the AV nodal region.
HMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome
Authors: Moonis Majaz , Kane Kevin , Schwiderski Ute , Sandage Bobby W. , Fisher Marc
Published: May 2005

Background and Purpose—

Statins reduce the risk of stroke recurrence, but the benefits of statins in improving outcome of acute stroke patients have not been well explored.

Methods—

We assessed potential effects of statins initiated before or within 4 weeks of stroke on 90-day outcome. Favorable outcomes were National Institutes of Health Stroke Scale (NIHSS) score ≤2 at 12 weeks and modified Rankin Scale (mRS) ≤2.

Results—

Before stroke, 129 patients were receiving statins, 123 initiated statins within 4 weeks, and 600 patients were not on statins. Multivariate logistic regression analysis demonstrated that poststroke statins were associated with a significant probability of a favorable outcome at 12 weeks [NIHSS (
P
=0.002; OR, 1.92; CI, 1.27 to 2.91) and mRS (
P
=0.033; OR, 1.57; CI, 1.04 to 2.38)], whereas prestroke statins demonstrated a trend toward significance.

Conclusions—

These preliminary results suggest that statin use may improve outcome of acute ischemic stroke.
Total Homocysteine Is Associated With White Matter Hyperintensity Volume
Authors: Wright Clinton B. , Paik Myunghee C. , Brown Truman R. , Stabler Sally P. , Allen Robert H. , Sacco Ralph L. , DeCarli Charles
Published: May 2005

Background—

Total homocysteine (tHcy) has been implicated as a risk factor for stroke and dementia, but the mechanism is unclear. White matter hyperintensities may be a risk factor for both, but studies of the relationship between tHcy and quantitative measures of white matter hyperintensity volume (WMHV) are lacking, especially in minority populations.

Methods—

A community-based sample of 259 subjects with baseline tHcy levels underwent pixel-based quantitative measurement of WMHV. We examined the relationship between tHcy and WMHV adjusting for age, sociodemographics, vascular risk factors, and B
12
deficiency.

Results—

Higher levels of tHcy were associated with WMHV adjusting for sociodemographics and vascular risk factors.

Conclusions—

These cross-sectional data provide evidence that tHcy is a risk factor for white matter damage.
Recurrent Stroke Risk Is Higher Than Cardiac Event Risk After Initial Stroke/Transient Ischemic Attack
Authors: Brown Devin L. , Lisabeth Lynda D. , Roychoudhury Canopy , Ye Yining , Morgenstern Lewis B.
Published: May 2005

Background and Purpose—

Patients with ischemic stroke and transient ischemic attack (TIA) are at risk for recurrent cerebrovascular and cardiac events. Understanding which of these adverse events is more likely to occur next is instructive for preventive therapy planning.

Methods—

Subjects (n=1923) were identified from a sample of hospital discharges from administrative claims for the Michigan Medicare population from January 2001 to June 2001 using
International Classification of Diseases
, 9th Revision codes for ischemic stroke/TIA. Outcomes (cardiac events, myocardial infarction [MI], percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass grafting [CABG] and ischemic strokes) were identified for 2001 to 2003. Comparison between cardiac and stroke as secondary events were made using cumulative incidence estimates.

Results—

Over the follow-up period, 172 patients had a cardiac event (62.8% MI, 7.6% CABG, 14.5% PTCA, 9.3% MI and PTCA, and 5.8% MI and CABG) and 239 had a stroke as their first event. Cardiac event at 2 years had occurred in 7.7%, and stroke occurred in 11.8%.

Conclusion—

The risk of stroke after initial stroke/TIA is higher than the risk of cardiac events. The propensity after stroke/TIA to have the first recurrent ischemic event in the brain, rather than in the heart, has implications for prophylactic therapy selection.
Frequency of Depression After Stroke
Authors: Hackett Maree L. , Yapa Chaturangi , Parag Varsha , Anderson Craig S.
Published: May 2005

Background and Purpose—

Although depression is an important sequelae of stroke, there is uncertainty regarding its frequency and outcome.

Methods—

We undertook a systematic review of all published nonexperimental studies (to June 2004) with prospective consecutive patient recruitment and quantification of depressive symptoms/illness after stroke.

Results—

Data were available from 51 studies (reported in 96 publications) conducted between 1977 and 2002. Although frequencies varied considerably across studies, the pooled estimate was 33% (95% confidence interval, 29% to 36%) of all stroke survivors experiencing depression. Differences in case mix and method of mood assessment could explain some of the variation in estimates across studies. The data also suggest that depression resolves spontaneously within several months of onset in the majority of stroke survivors, with few receiving any specific antidepressant therapy or active management.

Conclusions—

Depression is common among stroke patients, with the risks of occurrence being similar for the early, medium, and late stages of stroke recovery. There is a pressing need for further research to improve clinical practice in this area of stroke care.
Evaluation of C-Reactive Protein Measurement for Assessing the Risk and Prognosis in Ischemic Stroke
Authors: Di Napoli Mario , Schwaninger Markus , Cappelli Roberto , Ceccarelli Elena , Di Gianfilippo Giacinto , Donati Cristina , Emsley Hedley C.A. , Forconi Sandro , Hopkins Stephen J. , Masotti Luca , Muir Keith W. , Paciucci Anna , Papa Francesca , Roncacci Sabina , Sander Dirk , Sander Kerstin , Smith Craig J. , Stefanini Alessandro , Weber Daniela
Published: May 2005

Background and Purpose—

Several studies have shown, in different populations, that modest elevation of plasma C-reactive protein (CRP) in the range seen in apparently healthy individuals is a strong predictor of future vascular events. Elevated plasma CRP concentrations are also associated with an increased risk of cerebrovascular events and an increased risk of fatal and nonfatal cardiovascular events in ischemic stroke patients. These epidemiological and clinical observations suggest that determination of plasma CRP concentrations could be used as an adjunct for risk assessment in primary and secondary prevention of cerebrovascular disease and be of prognostic value. The aim of this review is to summarize the evidence for CRP as an independent predictor of cerebrovascular events in at-risk individuals and ischemic stroke patients and to consider its usefulness in evaluating prognosis after stroke.

Summary of Review—

CRP fulfils most of the requirements of a new risk and prognostic predictor, but several issues await further confirmation and clarification before this marker can be included in the routine evaluation of stroke patients and subjects at risk for cerebrovascular disease. Potentially important associations have been established between elevated plasma CRP concentrations and increased efficacy of established therapies, particularly lipid-lowering therapy with statins.

Conclusion—

At present, there is not sufficient evidence to recommend measurement of CRP in the routine evaluation of cerebrovascular disease risk in primary prevention, because there is insufficient evidence as to whether early detection, or intervention based on detection, improves health outcomes, although shared risk of cardiovascular disease indicates this may be of value. In secondary prevention of stroke, elevated CRP adds to existing prognostic markers, but it remains to be established whether specific therapeutic options can be derived from this.
Increased Extracellular K
+
Concentration Reduces the Efficacy of
N
-methyl-
d
-aspartate Receptor Antagonists to Block Spreading Depression-Like Depolarizations and Spreading Ischemia
Authors: Petzold Gabor C. , Windmüller Olaf , Haack Stephan , Major Sebastian , Buchheim Katharina , Megow Dirk , Gabriel Siegrun , Lehmann Thomas-Nicolas , Drenckhahn Christoph , Peters Oliver , Meierkord Hartmut , Heinemann Uwe , Dirnagl Ulrich , Dreier Jens P.
Published: May 2005

Background and Purpose—

Spreading depression (SD)-like depolarizations may augment neuronal damage in neurovascular disorders such as stroke and traumatic brain injury. Spreading ischemia (SI), a particularly malignant variant of SD-like depolarization, is characterized by inverse coupling between the spreading depolarization wave and cerebral blood flow. SI has been implicated in particular in the pathophysiology of subarachnoid hemorrhage. Under physiological conditions, SD is blocked by
N
-methyl-
d
-aspartate receptor (NMDAR) antagonists. However, because both SD-like depolarizations and SI occur in presence of an increased extracellular K
+
concentration ([K
+
]
o
), we tested whether this increase in baseline [K
+
]
o
would reduce the efficacy of NMDAR antagonists.

Methods—

Cranial window preparations, laser Doppler flowmetry, and K
+
-sensitive/reference microelectrodes were used to record SD, SD-like depolarizations, and SI in rats in vivo; microelectrodes and intrinsic optical signal measurements were used to record SD and SD-like depolarizations in human and rat brain slices.

Results—

In vivo, the noncompetitive NMDAR antagonist dizocilpine (MK-801) blocked SD propagation under physiological conditions, but did not block SD-like depolarizations or SI under high baseline [K
+
]
o
. Similar results were found in human and rat neocortical slices with both MK-801 and the competitive NMDAR antagonist D-2-amino-5-phosphonovaleric acid.

Conclusions—

Our data suggest that elevated baseline [K
+
]
o
reduces the efficacy of NMDAR antagonists on SD-like depolarizations and SI. In conditions of moderate energy depletion, as in the ischemic penumbra, or after subarachnoid hemorrhage, NMDAR inhibition may not be sufficient to block these depolarizations.
Improved Quality of Stroke Care for Hospitalized Medicare Beneficiaries in Michigan
Authors: Jacobs Bradley S. , Baker Patricia L. , Roychoudhury Canopy , Mehta Rajendra H. , Levine Steven R.
Published: May 2005

Background and Purpose—

We reported previously that acute ischemic stroke patients encountered delays in obtaining neuroimaging and receiving thrombolysis, and that deep venous thrombosis prophylaxis was used only in a minority of eligible patients. We investigated whether these and other measures improved after a quality improvement initiative.

Methods—

Medicare fee-for-service ischemic stroke and transient ischemic attack discharges in 136 acute care hospitals in Michigan were identified by
International Classification of Diseases
, 9th Revision, Clinical Modification codes. Only patients with stroke symptoms persisting for >1 hour and present on arrival were included in the analysis. Seven quality indicators were abstracted from chart review at baseline (discharges between July 1, 1998, and June 30, 1999) and at remeasurement (discharges between January 1, 2001, and June 30, 2001) after an intensive quality improvement initiative throughout Michigan hospitals. Quality indicators were compared at baseline and remeasurement.

Results—

Indicators of care were determined in 5146 patients at baseline and 4980 patients on remeasurement. Four quality-of-care indicators showed significant improvement on remeasurement: antithrombotic prescribed at discharge (81.9 baseline versus 83.7% remeasurement;
P
=0.026), avoidance of sublingual nifedipine in patients with acute ischemic stroke (97.1 versus 99.7%;
P
<0.0001), documentation of a computed tomography (CT)/MRI during hospitalization (98.0 versus 99.1%;
P
=0.024), and appropriate deep venous thrombosis prophylaxis (13.8 versus 26.9%;
P
<0.0001). Time to CT/MRI did not significantly change, but time to thrombolysis improved (113 versus 88.5 minutes;
P
=0.045).

Conclusions—

Improvement occurred in several indicators of quality of care in Michigan Medicare beneficiaries presenting with acute stroke symptoms.
AutoCITE
Authors: Taub Edward , Lum Peter S. , Hardin Phillip , Mark Victor W. , Uswatte Gitendra
Published: May 2005

Background and Purpose—

To evaluate the effectiveness of a device that automates Constraint-Induced Movement therapy (CI therapy), termed AutoCITE, when only partially supervised by therapists.

Methods—

Twenty-seven participants with chronic stroke trained with AutoCITE for 3 hours per day for 10 consecutive weekdays. Participants were assigned to 1 of 3 groups in a fixed irregular order (ie, in alternating blocks): supervision from a therapist for 100%, 50%, or 25% of training time.

Results—

The effect sizes of the treatment gains for the 3 groups on the Motor Activity Log (MAL) were very large and for the Wolf Motor Function Test they were large (all
P
<0.001) but were not significantly different from one another. Gains were comparable to those previously reported for participants who received an equal amount of standard one-on-one CI therapy without the device. At 1-month and long-term follow-up, gains from pretreatment on the MAL were also significant (
P
<0.001).

Conclusion—

These results demonstrate that AutoCITE training with greatly reduced supervision from a therapist is as effective as standard one-on-one CI therapy.