bluuebunny/crossref_metadata_2025 huggingface dataset:
Alternans and spiral breakup in a human ventricular tissue model
Authors: ten Tusscher K. H. W. J. , Panfilov A. V.
Published: March 2006

Ventricular fibrillation (VF) is one of the main causes of death in the Western world. According to one hypothesis, the chaotic excitation dynamics during VF are the result of dynamical instabilities in action potential duration (APD) the occurrence of which requires that the slope of the APD restitution curve exceeds 1. Other factors such as electrotonic coupling and cardiac memory also determine whether these instabilities can develop. In this paper we study the conditions for alternans and spiral breakup in human cardiac tissue. Therefore, we develop a new version of our human ventricular cell model, which is based on recent experimental measurements of human APD restitution and includes a more extensive description of intracellular calcium dynamics. We apply this model to study the conditions for electrical instability in single cells, for reentrant waves in a ring of cells, and for reentry in two-dimensional sheets of ventricular tissue. We show that an important determinant for the onset of instability is the recovery dynamics of the fast sodium current. Slower sodium current recovery leads to longer periods of spiral wave rotation and more gradual conduction velocity restitution, both of which suppress restitution-mediated instability. As a result, maximum restitution slopes considerably exceeding 1 (up to 1.5) may be necessary for electrical instability to occur. Although slopes necessary for the onset of instabilities found in our study exceed 1, they are within the range of experimentally measured slopes. Therefore, we conclude that steep APD restitution-mediated instability is a potential mechanism for VF in the human heart.
Differential effects of postconditioning on myocardial stunning and infarction: a study in conscious dogs and anesthetized rabbits
Authors: Couvreur Nicolas , Lucats Laurence , Tissier Renaud , Bize Alain , Berdeaux Alain , Ghaleh Bijan
Published: March 2006

Postconditioning, i.e., brief intermittent episodes of myocardial ischemia-reperfusion performed at the onset of reperfusion, reduces infarct size after prolonged ischemia. Our goal was to determine whether postconditioning is protective against myocardial stunning. Accordingly, conscious chronically instrumented dogs (sonomicrometry, coronary balloon occluder) were subjected to a control sequence (10 min coronary artery occlusion, CAO, followed by coronary artery reperfusion, CAR) and a week apart to postconditioning with four cycles of brief CAR and CAO performed at completion of the 10 min CAO. Three postconditioning protocols were investigated, i.e., 15 s CAR/15 s CAO ( n = 5), 30 s CAR/30 s CAO ( n = 7), and 1 min CAR/1 min CAO ( n = 6). Left ventricular wall thickening was abolished during CAO and similarly reduced during subsequent stunning in control and postconditioning sequences (e.g., at 1 h CAR, 33 ± 4 vs. 34 ± 4%, 30 ± 4 vs. 30 ± 4%, and 33 ± 4 vs. 32 ± 4% for 15 s postconditioning, 30 s postconditioning, and 1 min postconditioning vs. corresponding control, respectively). We confirmed this result in anesthetized rabbits by demonstrating that shortening of left ventricular segment length was similarly depressed after 10 min CAO in control and postconditioning sequences (4 cycles of 30 s CAR/30 s CAO). In additional rabbits, the same postconditioning protocol significantly reduced infarct size after 30 min CAO and 3 h CAR (39 ± 7%, n = 6 vs. 56 ± 4%, n = 7 of the area at risk in postconditioning vs. control, respectively). Thus, contrasting to its beneficial effects on myocardial infarction, postconditioning does not protect against myocardial stunning in dogs and rabbits. Conversely, additional episodes of ischemia-reperfusion with postconditioning do not worsen myocardial stunning.
Heat shock-induced cardioprotection activates cytoskeletal-based cell survival pathways
Authors: Wei Hongguang , Campbell Wendy , Vander Heide Richard S.
Published: March 2006

To define better the subcellular mechanism of heat shock (HS)-induced cardioprotection, we examined the effect of HS, as well as selective expression of individual HS proteins (HSPs), on cell injury in neonatal rat ventricular myocytes (NRVM). HS was induced in NRVM by a rapid elevation of temperature to 42°C for 20 min followed by 20–24 h of recovery at 37°C. Other NRVM were infected with a replication-deficient adenovirus encoding HSP27 or HSP70. On the same day, all groups were subjected to metabolic inhibition (MI). Cell injury was assayed by measurement of the percentage of total lactate dehydrogenase released, the percentage of cells staining with trypan blue, or TdT-mediated dUTP nick-end labeling, whereas cell signaling was assayed by immunoblot analysis and coimmunoprecipitation. Before MI, the viability of all treated groups did not differ significantly from control NRVM. HS resulted in a significant increase in HSP70 and HSP27 expression. Infection with either virus caused a significant increase in selective HSP content compared with control NRVM. HS protected NRVM from injury. Selective expression of HSP27 or HSP70 alone was not protective in NRVM, but dual infection with both viral vectors (HSP27 + HSP70) was protective. HS and HSP27 + HSP70 expression caused increased paxillin localization in the membrane fraction, which persisted in response to MI, compared with control NRVM. HS increased the integrin-paxillin-focal adhesion kinase interaction, whereas targeted inhibition of focal adhesion kinase activity abolished the integrin-paxillin association and resulted in an increase in cell death. HS and HSP27 + HSP70 expression increased the association of members of the focal adhesion complex and protected NRVM against irreversible injury. Cytoskeletal-based signaling pathways at focal adhesion junctions may represent a unique pathway of cardioprotection.
DNA damage is an early event in doxorubicin-induced cardiac myocyte death
Authors: L'Ecuyer Thomas , Sanjeev Sanjeev , Thomas Ronald , Novak Raymond , Das Lauri , Campbell Wendy , Heide Richard Vander
Published: March 2006

Anthracyclines are antitumor agents the main clinical limitation of which is cardiac toxicity. The mechanism of this cardiotoxicity is thought to be related to generation of oxidative stress, causing lethal injury to cardiac myocytes. Although protein and lipid oxidation have been documented in anthracycline-treated cardiac myocytes, DNA damage has not been directly demonstrated. This study was undertaken to determine whether anthracyclines induce cardiac myocyte DNA damage and whether this damage is linked to a signaling pathway culminating in cell death. H9c2 cardiac myocytes were treated with the anthracycline doxorubicin at clinically relevant concentrations, and DNA damage was assessed using the alkaline comet assay. Doxorubicin induced DNA damage, as shown by a significant increase in the mean tail moment above control, an effect ameliorated by inclusion of a free radical scavenger. Repair of DNA damage was incomplete after doxorubicin treatment in contrast to the complete repair observed in H2O2-treated myocytes after removal of the agent. Immunoblot analysis revealed that p53 activation occurred subsequent in time to DNA damage. By a fluorescent assay, doxorubicin induced loss of mitochondrial membrane potential after p53 activation. Chemical inhibition of p53 prevented doxorubicin-induced cell death and loss of mitochondrial membrane potential without preventing DNA damage, indicating that DNA damage was proximal in the events leading from doxorubicin treatment to cardiac myocyte death. Specific doxorubicin-induced DNA lesions included oxidized pyrimidines and 8-hydroxyguanine. DNA damage therefore appears to play an important early role in anthracycline-induced lethal cardiac myocyte injury through a pathway involving p53 and the mitochondria.
Additive effects of combined blockade of AT1receptor and HMG-CoA reductase on left ventricular remodeling in infarcted rats
Authors: Lee Tsung-Ming , Lin Mei-Shu , Chou Tsai-Fwu , Chang Nen-Chung
Published: March 2006

Both angiotensin receptor antagonists and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to attenuate cardiomyocyte hypertrophy after myocardial infarction. Whether combination treatment may be superior to either drug alone on cardiomyocyte hypertrophy remains unclear. After ligation of the left anterior descending artery, rats were randomized to both, one, or neither of the angiotensin receptor antagonists olmesartan (0.01, 0.1, 1, and 2 mg·kg−1·day−1) and HMG-CoA reductase inhibitor pravastatin (5 mg·kg−1·day−1) for 4 wk. Each drug, when given alone, decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone when compared with vehicles. However, compared with either drug alone, combined olmesartan and pravastatin prevent cardiomyocyte hypertrophy to a larger extent, which was further confirmed by downregulation of the left ventricular atrial natriuretic peptide mRNA. The myocardial endothelin-1 levels at the border zone were 6.5-fold higher ( P <0.0001) in the vehicle group compared with the sham group, which can be inhibited after pravastatin administration. Combination treatment significantly attenuated cardiomyocyte hypertrophy in a dose-dependent manner, although tissue endothelin-1 levels remained stable in combination groups of different olmesartan doses. Measurements of the arrhythmic score mirrored those of cardiomyocyte hypertrophy. Dual therapy with pravastatin and olmesartan, which produced an additive reduction in cardiomyocyte hypertrophy and cardiac fibrosis after myocardial infarction through different mechanisms, decreases the propensity of the heart to arrhythmogenesis. Pravastatin administration provided favorable ventricular remodeling, probably through decreased tissue endothelin-1 level. In contrast, olmesartan-related attenuated cardiomyocyte hypertrophy is independent of endothelin-1 pathway.
Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3β
Authors: Nishihara Masahiro , Miura Tetsuji , Miki Takayuki , Sakamoto Jun , Tanno Masaya , Kobayashi Hironori , Ikeda Yoshihiro , Ohori Katsuhiko , Takahashi Akari , Shimamoto Kazuaki
Published: March 2006

The aim of this study was to determine whether erythropoietin (EPO) affords additional cardioprotection to the preconditioned myocardium by enhanced phosphorylation of Akt, STAT3, or glycogen synthase kinase-3β (GSK-3β). Preconditioning (PC) with 5-min ischemia/5-min reperfusion and EPO (5,000 U/kg iv) reduced infarct size (as % of area at risk, %IS/AR) after 20-min ischemia in rat hearts in situ from 56.5 ± 1.8% to 25.2 ± 2.1% and to 36.2 ± 2.8%, respectively. PC-induced protection was significantly inhibited by a protein kinase C inhibitor, chelerythrine (5 mg/kg), and slightly blunted by a phosphatidylinositol-3-kinase inhibitor, wortmannin (15 μg/kg). The opposite pattern of inhibition was observed for EPO-induced protection. The combination of PC and EPO further reduced %IS/AR to 8.9 ± 1.9%, and this protection was inhibited by chelerythrine and wortmannin. The additive effects of PC and EPO on infarct size were mirrored by their effects on the level of phosphorylated GSK-3β at 5 min after reperfusion but not their effects on the level of phospho-Akt or phospho-STAT3. To mimic phosphorylation-induced inhibition of GSK-3β activity, SB-216763 (SB), a GSK-3β inhibitor, was administered before ischemia or 5 min before reperfusion. Infarct size was significantly reduced by preischemic injection (%IS/AR = 40.4 ± 2.2% by 0.6 mg/kg SB and 34.0 ± 1.8% by 1.2 mg/kg SB) and also by prereperfusion injection (%IS/AR = 32.0 ± 2.0% by 1.2 mg/kg SB). These results suggest that EPO and PC afford additive infarct size-limiting effects by additive phosphorylation of GSK-3β at the time of reperfusion by Akt-dependent and -independent mechanisms.
Calcium channel blockade prevents pressure-dependent inward remodeling in isolated subendocardial resistance vessels
Authors: Sorop Oana , Bakker Erik N. T. P. , Pistea Adrian , Spaan Jos A. E. , VanBavel Ed
Published: March 2006

The capacity for myocardial perfusion depends on the structure of the coronary microvascular bed. Coronary microvessels may adapt their structure to various stimuli. We tested whether the local pressure profile affects tone and remodeling of porcine coronary microvessels. Subendocardial vessels (∼160 μm, n = 53) were cannulated and kept in organoid culture for 3 days under different transvascular pressure profiles: Osc 80: mean 80 mmHg, 60 mmHg peak-peak sine wave pulsation amplitude at 1.5 Hz; St 80: steady 80 mmHg; Osc 40: mean 40 mmHg, 30 mmHg amplitude; St 40: steady 40 mmHg. Under the Osc 80 profile, modest tone developed, reducing the diameter to 81 ± 14% (mean ± SE, n = 6) of the maximal, passive diameter. No inward remodeling was found here, as determined from the passive pressure-diameter relation after 3 days of culture. Under all other profiles, much more tone developed (e.g., Osc 40: to 26 ± 3%, n = 7). In addition, these vessels showed eutrophic (i.e., without a change in wall cross-sectional area) inward remodeling (e.g., Osc 40: passive diameter reduction by 24 ± 3%). The calcium blocker amlodipine induced maintained dilation in St 40 vessels and reversed the 22 ± 3% ( n = 6) inward remodeling to 15 ± 3% ( n = 8) outward remodeling toward day 3. Vessels required a functional endothelium to maintain structural integrity in culture. Our data indicate that reduction of either mean pressure or pulse pressure leads to microvascular constriction followed by inward remodeling. These effects could be reversed by amlodipine. Although microvascular pressure profiles distal to stenoses are poorly defined, these data suggest that vasodilator therapy could improve subendocardial microvascular function and structure in coronary artery disease.
Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways
Authors: Samuelsson Anne-Maj , Bollano Entela , Mobini Reza , Larsson Britt-Mari , Omerovic Elmir , Fu Michael , Waagstein Finn , Holmäng Agneta
Published: March 2006

To investigate the association between hyperinsulinemia and cardiac hypertrophy, we treated rats with insulin for 7 wk and assessed effects on myocardial growth, vascularization, and fibrosis in relation to the expression of angiotensin II receptors (AT-R). We also characterized insulin signaling pathways believed to promote myocyte growth and interact with proliferative responses mediated by G protein-coupled receptors, and we assessed myocardial insulin receptor substrate-1 (IRS-1) and p110α catalytic and p85 regulatory subunits of phospatidylinositol 3 kinase (PI3K), Akt, MEK, ERK1/2, and S6 kinase-1 (S6K1). Left ventricular (LV) geometry and performance were evaluated echocardiographically. Insulin decreased AT1a-R mRNA expression but increased protein levels and increased AT2-R mRNA and protein levels and phosphorylation of IRS-1 (Ser374/Tyr989), MEK1/2 (Ser218/Ser222), ERK1/2 (Thr202/Tyr204), S6K1 (Thr421/Ser424/Thr389), Akt (Thr308/Thr308), and PI3K p110α but not of p85 (Tyr508). Insulin increased LV mass and relative wall thickness and reduced stroke volume and cardiac output. Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Metoprolol plus insulin prevented the increase in relative wall thickness, decreased fibrosis, increased LV mass, and improved function seen with insulin alone. Thus our data demonstrate that chronic hyperinsulinemia decreases AT1a-to-AT2 ratio and increases MEK-ERK1/2 and S6K1 pathway activity related to hypertrophy. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV function.
Central and peripheral renin-angiotensin systems in ouabain-induced hypertension
Authors: Cheung Warren J. , Kent Mary-Anne H. , El-Shahat Esraa , Wang Hongwei , Tan Junhui , White Roselyn , Leenen Frans H. H.
Published: March 2006

Chronic subcutaneous infusion of ouabain causes hypertension via central pathways involving angiotensin type 1 (AT1) receptor stimulation. The present study assessed plasma and tissue ANG I and II levels as well as AT1 receptor and angiotensin-converting enzyme (ACE) mRNA levels and binding densities by real-time PCR and in vitro autoradiography in relevant brain nuclei and peripheral tissues (heart and kidney) in rats at 1 and/or 2 wk after start of ouabain infusion at 50 μg/day. After 2 wk (but not after 1 wk), blood pressures significantly increased (+15 mmHg). At 2 wk, plasma ANG I and II levels were markedly suppressed by ouabain. In contrast, in the heart and kidneys, ANG I levels were not affected, and ANG II levels tended to decrease, whereas in the hypothalamus ANG II content clearly increased. At 1 wk, no changes in ACE and AT1 receptor densities were seen. After 2 wk, there were significant decreases in AT1 receptor mRNA and densities in the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and paraventricular nucleus (PVN). ACE densities decreased only in the OVLT and SFO, but ACE mRNA showed more variable responses (decrease in OVLT vs. increase in PVN). In the kidneys, at 2 wk both AT1 receptor and ACE densities were decreased, but mRNA abundance did not change. The heart showed no significant changes. The increase in hypothalamic ANG II content and associated decreases in central AT1 receptor and ACE densities support the involvement of the brain renin-angiotensin system in the central hypertensive mechanism of action of ouabain.
Postnatal alterations in elastic fiber organization precede resistance artery narrowing in SHR
Authors: González José M. , Briones Ana M. , Somoza Beatriz , Daly Craig J. , Vila Elisabet , Starcher Barry , McGrath John C. , González M. Carmen , Arribas Silvia M.
Published: March 2006

Resistance artery narrowing and stiffening are key elements in the pathogenesis of essential hypertension, but their origin is not completely understood. In mesenteric resistance arteries (MRA) from spontaneously hypertensive rats (SHR), we have shown that inward remodeling is associated with abnormal elastic fiber organization, leading to smaller fenestrae in the internal elastic lamina. Our current aim is to determine whether this alteration is an early event that precedes vessel narrowing, or if elastic fiber reorganization in SHR arteries occurs because of the remodeling process itself. Using MRA from 10-day-old, 30-day-old, and 6-mo-old SHR and normotensive Wistar Kyoto rats, we investigated the time course of the development of structural and mechanical alterations (pressure myography), elastic fiber organization (confocal microscopy), and amount of elastin (radioimmunoassay for desmosine) and collagen (picrosirius red). SHR MRA had an impairment of fenestrae enlargement during the first month of life. In 30-day-old SHR, smaller fenestrae and more packed elastic fibers in the internal elastic lamina were paralleled by increased wall stiffness. Collagen and elastin levels were unaltered at this age. MRA from 6-mo-old SHR also had smaller fenestrae and a denser network of adventitial elastic fibers, accompanied by increased collagen content and vessel narrowing. At this age, elastase digestion was less effective in SHR MRA, suggesting a lower susceptibility of elastic fibers to enzymatic degradation. These data suggest that abnormal elastic fiber deposition in SHR increases resistance artery stiffness at an early age, which might participate in vessel narrowing later in life.
Synergistic activation of salmon cardiac function by endothelin and β-adrenergic stimulation
Authors: Vierimaa Heidi , Ronkainen Jarkko , Ruskoaho Heikki , Vuolteenaho Olli
Published: March 2006

The aim was to find out the effects of endothelin-1 (ET-1) in salmon ( Salmo salar) cardiac contractile and endocrine function and its possible interaction with β-adrenergic regulation. We found that ET-1 has a positive inotropic effect in salmon heart. ET-1 (30 nM) increased the contraction amplitude 17 ± 4.7% compared with the basal level. β-Adrenergic activation (isoprenaline, 100 nM) increased contraction amplitude 30 ± 13.1%, but it did not affect the contractile response to ET-1. ET-1 (10 nM) stimulated the secretion of salmon cardiac natriuretic peptide (sCP) from isolated salmon ventricle (3.3 ± 0.14-fold compared with control) but did not have any effect on ventricular sCP mRNA. Isoprenaline alone (0.1–1,000 nM) did not stimulate sCP release, but ET-1 (10 nM) together with isoprenaline (0.1 nM) caused a significantly greater increase of sCP release than ET-1 alone (5.4 ± 0.07 vs. 3.3 ± 0.14 times increase compared with control). The effects on the contractile and secretory function could be inhibited by a selective ETA-receptor antagonist BQ-610 (1 μM), whereas ETB-receptor blockage (by 100 nM BQ-788) enhanced the secretory response. Thus ET-1 is a phylogenetically conserved regulator of cardiac function, which has synergistic action with β-adrenergic stimulation. The modulatory effects of ET-1 may therefore be especially important in situations with high β-adrenergic tone.
STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium
Authors: Butler Karyn L. , Huffman Lynn C. , Koch Sheryl E. , Hahn Harvey S. , Gwathmey Judith K.
Published: March 2006

The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 ± 58 vs. 1,028 ± 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/d tmax; 4,648 ± 309 vs. 2,737 ± 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum −dP/d t (−dP/d tmin; −2,239 ± 205 vs. −1,215 ± 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/d tmax(4,648 ± 309 vs. 3,241 ± 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and −dP/d tmin(−2,239 ± 205 vs. −1,323 ± 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.
Regional myocardial ischemia-induced activation of MAPKs is associated with subcellular redistribution of caveolin and cholesterol
Authors: Ballard-Croft Cherry , Locklar Adam C. , Kristo Gentian , Lasley Robert D.
Published: March 2006

Ischemia-reperfusion activates ERK and p38 MAPK in cardiac membranes, but the role of caveolae in MAPK signaling during this stress has not been studied. The purpose of this study was to determine the effect of in vivo myocardial ischemia-reperfusion on the level and distribution of caveolin-1 and -3 and cholesterol as well as MAPK activation in caveolin-enriched fractions. Adult male rats were subjected to in vivo regional myocardial ischemia induced by 25 min of coronary artery occlusion and 10 min ( n = 5) or 2 h ( n = 4) of reperfusion. Another group of rats served as appropriate nonischemic time controls ( n = 4). A discontinuous sucrose density gradient was used to isolate caveolae/lipid rafts from ischemic and nonischemic heart tissue. Caveolin-1 and -3, as well as cholesterol, were enriched in the light fractions. A redistribution of caveolin-3 and a reduction in caveolin-1 and cholesterol levels in the light fractions occurred after 10 min of reperfusion. The ERKs were activated in ischemic zone light and heavy fractions by 10 min of reperfusion. p44 ERK was activated after 2 h of reperfusion only in the light fractions, whereas p42 ERK phosphorylation was increased in the light and heavy fractions. Although no p38 MAPK activation occurred after 10 min of reperfusion, 2 h of reperfusion caused significant activation of p38 MAPK in nonischemic zone light and heavy fractions. These results show the importance of caveolar membrane/lipid rafts in MAPK signaling and suggest that subcellular compartmentation of p44/p42 ERKs and p38 MAPK may play distinct roles in the response to myocardial ischemia-reperfusion.
Postural hypocapnic hyperventilation is associated with enhanced peripheral vasoconstriction in postural tachycardia syndrome with normal supine blood flow
Authors: Stewart Julian M. , Medow Marvin S. , Cherniack Neil S. , Natelson Benjamin H.
Published: March 2006

Previous investigations have demonstrated a subset of postural tachycardia syndrome (POTS) patients characterized by normal peripheral resistance and blood volume while supine but thoracic hypovolemia and splanchnic blood pooling while upright secondary to splanchnic hyperemia. Such “normal-flow” POTS patients often demonstrate hypocapnia during orthostatic stress. We studied 20 POTS patients (14–23 yr of age) and compared them with 10 comparably aged healthy volunteers. We measured changes in heart rate, blood pressure, heart rate and blood pressure variability, arm and leg strain-gauge occlusion plethysmography, respiratory impedance plethysmography calibrated against pneumotachography, end-tidal partial pressure of carbon dioxide (PetCO2), and impedance plethysmographic indexes of blood volume and blood flow within the thoracic, splanchnic, pelvic (upper leg), and lower leg regional circulations while supine and during upright tilt to 70°. Ten POTS patients demonstrated significant hyperventilation and hypocapnia (POTSHC) while 10 were normocapnic with minimal increase in postural ventilation, comparable to control. While relative splanchnic hypervolemia and hyperemia occurred in both POTS groups compared with controls, marked enhancement in peripheral vasoconstriction occurred only in POTSHC and was related to thoracic blood flow. Variability indexes suggested enhanced sympathetic activation in POTSHC compared with other subjects. The data suggest enhanced cardiac and peripheral sympathetic excitation in POTSHC.
Low-intensity tensile loading increases intratendinous glucose uptake in the Achilles tendon
Authors: Bojsen-Møller J. , Kalliokoski K. K. , Seppänen M. , Kjaer M. , Magnusson S. P.
Published: March 2006

The metabolic activity of tendinous tissues has traditionally been considered to be of limited magnitude. However, recent studies have suggested that glucose uptake increases in the force-transmitting tissues as a response to contractile loading, which in turn indicates an elevated tissue metabolism. The purpose of the present study was to investigate whether such a mechanism could be observed for the human Achilles tendon following tensile loading. Six subjects participated in the study. Unilateral Achilles tendon loading was applied by 25-min intermittent voluntary plantar flexor contractions. A radioactive tracer ([18F]-2-fluoro-2-deoxy-d-glucose) was administered during muscle action, and glucose uptake was measured by use of PET. Regions of interest were defined on the PET images corresponding to the cross section of Achilles tendon at two longitudinally separated sites (insertion and free tendon). Glucose uptake index was determined within respective regions of interest for the active and resting leg. Tendon force during voluntary contractions was ∼13% of maximal voluntary contraction force. Tendon loading induced an elevated glucose uptake index compared with that of the contralateral resting tendon in the region of tendon insertion (0.13 ± 0.05 vs. 0.09 ± 0.02; P < 0.05) and at the free tendon (0.12 ± 0.01 vs. 0.08 ± 0.02; P < 0.05). The present data suggest that tissue metabolism is elevated in the human Achilles tendon in response to low-intensity loading.
Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise
Authors: Morton James P. , MacLaren Don P. M. , Cable Nigel T. , Bongers Thomas , Griffiths Richard D. , Campbell Iain T. , Evans Louise , Kayani Anna , McArdle Anne , Drust Barry
Published: March 2006

The exercise-induced expression of heat shock proteins (HSPs) in rodent models is relatively well defined. In contrast, comparable data from human studies are limited and the exercise-induced stress response of human skeletal muscle is far from understood. This study has characterized the time course and magnitude of the HSP response in the skeletal muscles of a healthy active, but untrained, young male population following a running exercise protocol. Eight subjects performed 45 min of treadmill running at a speed corresponding to their lactate threshold (11.7 ± 0.5 km/h; 69.8 ± 4.8% maximum O2uptake). Muscle biopsies were obtained from the vastus lateralis muscle immediately before and at 24 h, 48 h, 72 h, and 7 days postexercise. Exercise induced a significant ( P < 0.05) but variable increase in HSP70, heat shock cognate (HSC) 70, and HSP60 expression with peak increases (typically occurring at 48 h postexercise) to 210, 170, and 139% of preexercise levels, respectively. In contrast, exercise did not induce a significant increase in either HSP27, αB-crystallin, SOD 2 (MnSOD) protein content, or the activity of SOD and catalase. When examining baseline protein levels, HSC70, HSP27, and αB-crystallin appeared consistently expressed between subjects, whereas HSP70 and MnSOD displayed marked individual variation of up to 3- and 1.5-fold, respectively. These data are the first to define the time course and extent of HSP production in human skeletal muscle following a moderately demanding and nondamaging running exercise protocol. Data demonstrate a differential effect of aerobic exercise on specific HSPs.
Components and mechanisms of thermal hyperpnea
Authors: White Matthew D.
Published: March 2006

The pattern of breathing during a hyperthermia-induced hyperventilation varies across different species. Thermal tachypnea is a first phase panting response adopted during hyperthermia when tidal volume is minimized and the frequency of breathing is maximized. Blood-gas tensions and pH are maintained during this hyperventilation, and the associated heat loss helps the animal regulate its body temperature. A second pattern of breathing adopted in hyperthermia is thermal hyperpnea; this response is the focus of this review. This form of hyperventilation is evident after an increase in core temperature and it is apparent in humans. Increases of tidal volume as well as frequency of breathing are evident during this response that results in a respiratory alkalosis. The cause of thermal hyperpnea is not resolved; evidence of the potential mechanisms underlying this response support that modulators of the response act in either a multiplicative or additive manner with body temperatures. The details of the designs and methodologies of the studies supporting or refuting these two views are discussed. A physiological rationale for thermal hyperpnea is presented in which it is suggested this response serves a heat-loss role and contributes to selective brain cooling in hyperthermic humans. Ongoing research in this area is focused on resolving the mechanisms underlying thermal hyperpnea and its contribution to cranial thermoregulation. The direct application of this research is for the care of febrile and hyperthermic patients.
Porcine cardiac myocyte power output is increased after chronic exercise training
Authors: Hinken Aaron C. , Korte F. Steven , McDonald Kerry S.
Published: March 2006

Chronic exercise training increases the functional capacity of the heart, perhaps by increased myocyte contractile function, as has been observed in rodent exercise models. We examined whether cardiac myocyte function is enhanced after chronic exercise training in Yucatan miniature swine, whose heart characteristics are similar to humans. Animals were designated as either sedentary (Sed), i.e., cage confined, or exercise trained (Ex), i.e., underwent 16–20 wk of progressive treadmill training. Exercise training efficacy was shown with significantly increased heart weight-to-body weight ratios, skeletal muscle citrate synthase activity, and exercise tolerance. Force-velocity properties were measured by attaching skinned cardiac myocytes between a force transducer and position motor, and shortening velocities were measured over a range of loads during maximal Ca2+activation. Myocytes ( n = 9) from nine Ex pigs had comparable force production but a ∼30% increase in peak power output compared with myocytes ( n = 8) from eight Sed. Interestingly, Ex myofibrillar samples also had higher baseline PKA-induced phosphorylation levels of cardiac troponin I, which may contribute to the increase in power. Overall, these results suggest that enhanced power-generating capacity of porcine cardiac myofibrils contributes to improved cardiac function after chronic exercise training.
Ischemia induces aggravation of baseline repolarization abnormalities in left ventricular hypertrophy: a deleterious interaction
Authors: Rubulis Aigars , Jensen Jens , Lundahl Gunilla , Tapanainen Jari , Bergfeldt Lennart
Published: March 2006

Epidemiological studies show that left ventricular hypertrophy (LVH) and hypertension (HT) in coronary artery disease increases the risk for cardiovascular events including sudden cardiac death (SCD). According to experimental studies, myocardial hypertrophy is associated both with altered electrophysiological properties (including prolonged repolarization) and increased vulnerability to ischemia. However, human data to support a repolarization-related mechanism for the increased SCD risk has not been provided. We therefore studied 187 patients undergoing three-dimensional vectorcardiographic monitoring during coronary angioplasty. Eight parameters reflecting different aspects of ventricular repolarization were used: 1) the ST segment (ST-VM and STC-VM), 2) the T vector (QRS-T angle, Televation, and Tazimuth), and 3) the T vector loop (Tavplan, Teigenv, and Tarea). Data collection was performed at rest and at the time of maximum ischemia during coronary occlusion. The patients were divided into three groups: 33 patients with ECG signs of LVH (18 with HT), 54 with HT but without LVH signs, and 100 patients with neither. Coronary artery disease patients with LVH not only had the most abnormal baseline repolarization (as expected) but also a significantly more pronounced repolarization response during coronary occlusion, whereas HT patients had mean parameter values between LVH patients and those without neither HT nor LVH signs. Because there is a relation between increased SCD risk and repolarization disturbances in various clinical settings, the results of the present study are in agreement with animal data and epidemiological observations, although other factors than disturbed repolarization might be of importance.
The Ins and Outs of Iron Homeostasis
Authors: Donovan Adriana , Roy Cindy N. , Andrews Nancy C.
Published: March 2006

Iron is an essential element that is toxic when it accumulates in excess. Intricate regulatory mechanisms have evolved to maintain iron homeostasis within cells and between different tissues of complex organisms. This review discusses the proteins involved in iron transport and storage and their regulation in health and disease.
Role of the Adventitia in Pulmonary Vascular Remodeling
Authors: Stenmark Kurt R. , Davie Neil , Frid Maria , Gerasimovskaya Evgenia , Das Mita
Published: March 2006

An increasing volume of experimental data indicates that the adventitial fibroblast, in both the pulmonary and systemic circulations, is a critical regulator of vascular wall function in health and disease. A rapidly emerging concept is that the vascular adventitia acts as biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. In response to stress or injury, resident adventitial cells can be activated and reprogrammed to exhibit different functional and structural behaviors. In fact, under certain conditions, the adventitial compartment may be considered the principal injury-sensing tissue of the vessel wall. In response to vascular stresses such as overdistension and hypoxia, the adventitial fibroblast is activated and undergoes phenotypic changes, which include proliferation, differentiation, upregulation of contractile and extracellular matrix proteins, and release of factors that directly affect medial smooth muscle cell tone and growth and that stimulate recruitment of inflammatory and progenitor cells to the vessel wall. Each of these changes in fibroblast phenotype modulates either directly or indirectly changes in overall vascular function and structure. The purpose of this review is to present the current evidence demonstrating that the adventitial fibroblast acts as a key regulator of pulmonary vascular function and structure from the “outside-in.”
From Bacteria to Man: Archaic Proton-Dependent Peptide Transporters at Work
Authors: Daniel Hannelore , Spanier Britta , Kottra Gabor , Weitz Dietmar
Published: March 2006

Uptake of nutrients into cells is essential to life and occurs in all organisms at the expense of energy. Whereas in most prokaryotic and simple eukaryotic cells electrochemical transmembrane proton gradients provide the central driving force for nutrient uptake, in higher eukaryotes it is more frequently coupled to sodium movement along the transmembrane sodium gradient, occurs via uniport mechanisms driven by the substrate gradient only, or is linked to the countertransport of a similar organic solute. With the cloning of a large number of mammalian nutrient transport proteins, it became obvious that a few “archaic” transporters that utilize a transmembrane proton gradient for nutrient transport into cells can still be found in mammals. The present review focuses on the electrogenic peptide transporters as the best studied examples of proton-dependent nutrient transporters in mammals and summarizes the most recent findings on their physiological importance. Taking peptide transport as a general phenomenon found in nature, we also include peptide transport mechanisms in bacteria, yeast, invertebrates, and lower vertebrates, which are not that often addressed in physiology journals.
Monitoring of cAMP Synthesis and Degradation in Living Cells
Authors: Nikolaev Viacheslav O. , Lohse Martin J.
Published: March 2006

cAMP is an important second messenger with a plethora of cellular effects and biological roles. To monitor and visualize cAMP in intact living cells, electrophysiological and fluorescent methods have been developed based on activation of all three types of cAMP effectors: protein kinase A, cyclic nucleotide-gated channels, and exchange protein directly activated by cAMP. In this review, we describe and compare these techniques in terms of their robustness, sensitivity and spatio-temporal resolution.
The continuing quest to comprehend genomic imprinting
Authors: Miyoshi N. , Barton S.C. , Kaneda M. , Hajkova P. , Surani M.A.
Published: March 2006

The discovery of the phenomenon of genomic imprinting in mammals showed that the parental genomes are functionally non-equivalent. Considerable advances have occurred in the field over the past 20 years, which has resulted in the identification and functional analysis of a number of imprinted genes the expression of which is determined by their parental origin. These genes belong to many diverse categories and they have been shown to regulate growth, complex aspects of mammalian physiology and behavior. Many aspects of the mechanism of imprinting have also been elucidated. However, the reasons for the evolution of genomic imprinting remain enigmatic. Further research is needed to determine if there is any relationship between the apparently diverse functions of imprinted genes in mammals, and their role in human diseases. It also remains to be seen what common features exist amongst the diverse imprinting control elements. The mechanisms involved in the erasure and re-establishment of imprints should provide deeper insights into epigenetic mechanisms of wide general interest.
Genomic imprinting in Dicer1-hypomorphic mice
Authors: Fukasawa M. , Morita S. , Kimura M. , Horii T. , Ochiya T. , Hatada I.
Published: March 2006

To address the function of RNA interference (RNAi) in transcriptional silencing in mammals, we analyzed genomic imprinting in Dicer1-hypomorphic mice, in which Dicer1 expression was significantly reduced. We did not observe any abnormality in the allelic expression of imprinted genes in these mice or their offspring, suggesting that reduced expression of Dicer1 did not significantly affect the maintenance and reprogramming of imprinting.
Imprinting in neurons
Authors: Kishino T.
Published: March 2006

Although most imprinted genes display parent-origin-specific gene expression in tissues where they are transcribed, some genes are imprinted in a tissue-specific manner. Genes that show brain-specific imprinting or brain-specific lack of imprinting present a unique opportunity to study the process of imprinting during tissue differentiation. In this review, I introduce the systematic study of brain-cell-lineage-specific imprinting using a primary brain cell culture system, where neurons or glial cells are cultured separately. Two reports using the primary brain cell culture revealed brain-cell-lineage-specific imprinting in Ube3a and Igf2r, which had previously been described to show brain-specific imprinting and brain-specific lack of imprinting, respectively. Such brain-cell-lineage-specific imprinting was associated with cell-specific epigenetic modifications, especially with their reciprocally imprinted antisense non-coding RNAs, Ube3a-ATS and Air. These results emphasize the necessity of imprinting analysis at the cell level rather than in whole brain tissue during brain differentiation. The brain cell culture system provides us with a new powerful tool to understand the molecular mechanism of brain-specific imprinting.
Evolution of mammalian X chromosome-linked imprinting
Authors: Mills W. , Moore T.
Published: March 2006

We analyse the evolution of X chromosome-linked imprinting by modifying our previous model of imprinting of autosomal genes that influence the trade-off between maternal fecundity and offspring viability through alterations in maternal investment (Mills and Moore, 2004). Unlike previous genetic models, we analyse X-linked imprinting in the context of populations at equilibrium for either autosomal or X-linked biallelically expressed alleles at loci that influence the fecundity/viability trade-off. We show that selection under parental conflict over maternal investment in offspring can parsimoniously explain the occurrence of sex-specific gene expression patterns, without a requirement to postulate direct selection for sexual dimorphism mediated through imprinting. We note that sex chromosome imprinting causes a small distortion of the post-weaning sex ratio, providing a possible selection pressure against the evolution of X-linked imprints. We discuss our conclusions in the context of recent reports of imprinting of mouse X-linked Xlr genes.
Multiple Employee Incentive Plans: Too Much of a Good Thing?
Authors: Rubenfeld Stephen , David Jannifer
Published: March 2006

It is becoming increasingly common for employees to have their compensation determined in part by multiple incentive plans. Many employees are covered by merit pay plans as well as individual or group incentive programs such as gainsharing, profit sharing or other bonus plans. From a strategic perspective, these plans are intended to facilitate organizational goal attainment and simultaneously to help employees reap the benefits of their efforts. While targeting specific organizational objectives and reinforcing employee behaviors, the combination of multiple incentive systems may have some unanticipated negative consequences. Careful design and implementation can increase the success of such programs.
Using Continuation Pay to Combat Turnover: An Evaluation
Authors: Wahl Douglas , Singh Gangaram
Published: March 2006

Turnover is a costly problem for the United States military. Continuation pay has become a preferred retention strategy. This article describes the continuation pay strategy that is used by the United States Naval Services with regard to Surface Warfare Officers. Data from 334 officers do not support the retention objectives of the continuation pay strategy. Alternative retention strategies such as retirement benefits and job satisfaction were more salient. Continuation pay is not an effective retention tool. Given the findings of this study, employers may want to take a second look at their retention programs.
Building a Successful Relationship with a Directed Trustee
Authors: Schaeffer Janae L.
Published: March 2006

All plan fiduciaries should be aware of whether their plan trustee is a discretionary trustee or a directed trustee. Directed trustees are generally not liable for the actions they take pursuant to a fiduciary's direction. Trustees can only follow directions, however, if the directions are in accordance with the terms of the plan, prudent and not a prohibited transaction. The issue of whether a direction is prudent often arises in regard to plan investments in employer stock. Trustees have a duty to question directions if they have nonpublic information about the stock that impacts the direction and in certain situations where the company is in extreme financial distress. Even if a directed trustee gives compliance advice or investment input, the fiduciary is still the person with ultimate responsibility and liability. It is the fiduciary, not the directed trustee, who has the legal responsibility to use due diligence in all decisions
Roth 401(k) on the Horizon: Worth the Effort
Authors: Vaughan Terri W.
Published: March 2006

401(k) and 403(b) plans can be amended in 2006 to add a Roth feature giving plan participants the advantage of paying no income tax on the earnings in their Roth account established within the plan. Successfully adding the Roth feature is a joint effort of the plan sponsor and the plan recordkeeper. The plan sponsor and the plan recordkeeper must work together to effectively communicate the complex tax choices to the plan participants. The employer payroll system must accommodate the required separation of this post tax Roth option from the pre-tax salary deferral, and the plan recordkeeping system must provide the appropriate account separation and reporting required under the income tax rules. Even though these tasks will require significant effort, the rewards for plan participants who are shut out of the Roth IRA option because of their family income level or who believe that they will be in a higher tax bracket when they receive payment from their account than when the contributions are made, will appreciate the effort.
Decision Support in the Benefits Consumer Age
Authors: Cohen Alan
Published: March 2006

Benefits consumerism is a reality. Employees may understand why providers and employers are making this move. But the real test for these plans will come at that point where the consumers actually must adopt and use the new plans. Employers are asking a lot of them, and they are going to need help. The most important component of these new plans is an integrated set of decision-support tools to help them with the new decisions they face, not only to elect the new plan, but to make the best decisions about investment, spending, providers and treatments.