bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent
Authors: Ford Rebecca J. , Rush James W. E.
Published: October 2010

Activation of AMP-activated protein kinase (AMPK) induces vasorelaxation in arteries from healthy animals, but the mechanisms coordinating this effect are unclear and the integrity of this response has not been investigated in dysfunctional arteries of hypertensive animals. Here we investigate the mechanisms of relaxation to the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) in isolated thoracic aorta rings from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Although AICAR generated dose-dependent (10−6-10−2 M) relaxation in precontracted WKY and SHR aortic rings with (E+) or without (E−) endothelium, relaxation was enhanced in E+ rings. Relaxation in SHR E+ rings was also enhanced at low [AICAR] (10−6 M) compared with that of WKY (57 ± 8% vs. 3 ± 2% relaxation in SHR vs. WKY E+), but was similar and near 100% in both groups at high [AICAR]. Pharmacological dissection showed that the mechanisms responsible for the endothelium-dependent component of relaxation across the dose range of AICAR are exclusively nitric oxide (NO) mediated in WKY rings, but partly NO dependent and partly cyclooxygenase (COX) dependent in SHR vessels. Further investigation revealed that ACh-stimulated COX-endothelium-derived contracting factors (EDCF)-mediated contractions were suppressed by AICAR, and this effect was reversed in the presence of the AMPK inhibitor Compound C in quiescent E+ SHR aortic rings. Western blots demonstrated that P(Thr172)-AMPK and P(Ser79)-acetyl-CoA carboxylase (indexes of AMPK activation) were elevated in SHR versus WKY E+ rings at low AICAR (∼2-fold). Together these findings suggest that AMPK-mediated inhibition of EDCF-dependent contraction and elevated AMPK activation may contribute to the enhanced sensitivity of SHR E+ rings to AICAR. These results demonstrate AMPK-mediated vasorelaxation is present and enhanced in arteries of SHR and suggest that activation of AMPK may be a potential strategy to improve vasomotor dysfunction by suppressing enhanced endoperoxide-mediated contraction and enhancing NO-mediated relaxation.
Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research
Authors: Beard Richard S. , Bearden Shawn E.
Published: October 2010

Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H2S) through the transsulfuration pathway. H2S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine β-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H2S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (−/−) and heterozygous (+/−), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H2S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease.
Phosphorescence quenching microrespirometry of skeletal muscle in situ
Authors: Golub Aleksander S. , Tevald Michael A. , Pittman Roland N.
Published: October 2010

We have developed an optical method for the evaluation of the oxygen consumption (V̇o2) in microscopic volumes of spinotrapezius muscle. Using phosphorescence quenching microscopy (PQM) for the measurement of interstitial Po2, together with rapid pneumatic compression of the organ, we recorded the oxygen disappearance curve (ODC) in the muscle of the anesthetized rats. A 0.6-mm diameter area in the tissue, preloaded with the phosphorescent oxygen probe, was excited once a second by a 532-nm Q-switched laser with pulse duration of 15 ns. Each of the evoked phosphorescence decays was analyzed to obtain a sequence of Po2values that constituted the ODC. Following flow arrest and tissue compression, the interstitial Po2decreased rapidly and the initial slope of the ODC was used to calculate the V̇o2. Special analysis of instrumental factors affecting the ODC was performed, and the resulting model was used for evaluation of V̇o2. The calculation was based on the observation of only a small amount of residual blood in the tissue after compression. The contribution of oxygen photoconsumption by PQM and oxygen inflow from external sources was evaluated in specially designed tests. The average oxygen consumption of the rat spinotrapezius muscle was V̇o2= 123.4 ± 13.4 (SE) nl O2/cm3·s ( N = 38, within 6 muscles) at a baseline interstitial Po2of 50.8 ± 2.9 mmHg. This technique has opened the opportunity for monitoring respiration rates in microscopic volumes of functioning skeletal muscle.
The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension
Authors: Capone Carmen , Faraco Giuseppe , Park Laibaik , Cao Xian , Davisson Robin L. , Iadecola Costantino
Published: October 2010

Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by “slow pressor” angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice ( n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng·kg−1·min−1), AP started to rise after 9 days ( P < 0.05 vs. saline), remained elevated at 11–17 days, and returned to baseline at 21 days ( P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng·kg−1·min−1) induced cerebrovascular dysfunction and oxidative stress without elevating AP ( P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng·kg−1·min−1) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.
Colocalization of voltage-gated Na+channels with the Na+/Ca2+exchanger in rabbit cardiomyocytes during development
Authors: Gershome Cynthia , Lin Eric , Kashihara Haruyo , Hove-Madsen Leif , Tibbits Glen F.
Published: October 2010

Reverse-mode activity of the Na+/Ca2+exchanger (NCX) has been previously shown to play a prominent role in excitation-contraction coupling in the neonatal rabbit heart, where we have proposed that a restricted subsarcolemmal domain allows a Na+current to cause an elevation in the Na+concentration sufficiently large to bring Ca2+into the myocyte through reverse-mode NCX. In the present study, we tested the hypothesis that there is an overlapping expression and distribution of voltage-gated Na+(Nav) channel isoforms and the NCX in the neonatal heart. For this purpose, Western blot analysis, immunocytochemistry, confocal microscopy, and image analyses were used. Here, we report the robust expression of skeletal Nav1.4 and cardiac Nav1.5 in neonatal myocytes. Both isoforms colocalized with the NCX, and Nav1.5-NCX colocalization was not statistically different from Nav1.4-NCX colocalization in the neonatal group. Western blot analysis also showed that Nav1.4 expression decreased by sixfold in the adult ( P < 0.01) and Nav1.1 expression decreased by ninefold ( P < 0.01), whereas Nav1.5 expression did not change. Although Nav1.4 underwent large changes in expression levels, the Nav1.4-NCX colocalization relationship did not change with age. In contrast, Nav1.5-NCX colocalization decreased ∼50% with development. Distance analysis indicated that the decrease in Nav1.5-NCX colocalization occurs due to a statistically significant increase in separation distances between Nav1.5 and NCX objects. Taken together, the robust expression of both Nav1.4 and Nav1.5 isoforms and their colocalization with the NCX in the neonatal heart provides structural support for Na+current-induced Ca2+entry through reverse-mode NCX. In contrast, this mechanism is likely less efficient in the adult heart because the expression of Nav1.4 and NCX is lower and the separation distance between Nav1.5 and NCX is larger.
p120 regulates endothelial permeability independently of its NH2terminus and Rho binding
Authors: Herron Crystal R. , Lowery Anthony M. , Hollister Patricia R. , Reynolds Albert B. , Vincent Peter A.
Published: October 2010

The association of p120-catenin (p120) with the juxtamembrane domain (JMD) of vascular endothelial (VE)-cadherin is required to maintain VE-cadherin levels and transendothelial resistance (TEER) of endothelial cell monolayers. To distinguish whether decreased TEER was due to a loss of p120 and not to the decrease in VE-cadherin, we established a system in which p120 was depleted by short hairpin RNA delivered by lentivirus and VE-cadherin was restored via expression of VE-cadherin fused to green fluorescent protein (GFP). Loss of p120 resulted in decreased TEER, which was associated with decreased expression of VE-cadherin, β-catenin, plakoglobin, and α-catenin. Decreased TEER was rescued by restoration of p120 but not by the expression of VE-cadherin-GFP, despite localization of VE-cadherin-GFP at cell-cell borders. Expression of VE-cadherin-GFP restored levels of β-catenin and α-catenin but not plakoglobin, indicating that p120 may be important for recruitment of plakoglobin to the VE-cadherin complex. To evaluate the role of p120 interaction with Rho GTPase in regulating endothelial permeability, we expressed a recombinant form of p120, lacking the NH2terminus and containing alanine substitutions, that eliminates binding of Rho to p120. Expression of this isoform restored expression of the adherens junction complex and rescued permeability as measured by TEER. These results demonstrate that p120 is required for maintaining VE-cadherin expression and TEER independently of its NH2terminus and its role in regulating Rho.
Endosomal KATPchannels as a reservoir after myocardial ischemia: a role for SUR2 subunits
Authors: Bao Li , Hadjiolova Krassimira , Coetzee William A. , Rindler Michael J.
Published: October 2010

ATP-sensitive K+(KATP) channels, composed of inward rectifier K+(Kir)6.x and sulfonylurea receptor (SUR)x subunits, are expressed on cellular plasma membranes. We demonstrate an essential role for SUR2 subunits in trafficking KATPchannels to an intracellular vesicular compartment. Transfection of Kir6.x/SUR2 subunits into a variety of cell lines (including h9c2 cardiac cells and human coronary artery smooth muscle cells) resulted in trafficking to endosomal/lysosomal compartments, as assessed by immunofluorescence microscopy. By contrast, SUR1/Kir6.x channels efficiently localized to the plasmalemma. The channel turnover rate was similar with SUR1 or SUR2, suggesting that the expression of Kir6/SUR2 proteins in lysosomes is not associated with increased degradation. Surface labeling of hemagglutinin-tagged channels demonstrated that SUR2-containing channels dynamically cycle between endosomal and plasmalemmal compartments. In addition, Kir6.2 and SUR2 subunits were found in both endosomal and sarcolemmal membrane fractions isolated from rat hearts. The balance of these KATPchannel subunits shifted to the sarcolemmal membrane fraction after the induction of ischemia. The KATPchannel current density was also increased in rat ventricular myocytes isolated from hearts rendered ischemic before cell isolation without corresponding changes in subunit mRNA expression. We conclude that an intracellular pool of SUR2-containing KATPchannels exists that is derived by endocytosis from the plasma membrane. In cardiac myocytes, this pool can potentially play a cardioprotective role by serving as a reservoir for modulating surface KATPchannel density under stress conditions, such as myocardial ischemia.
Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury
Authors: Demchenko Ivan T. , Zhilyaev S. Yu , Moskvin A. N. , Piantadosi Claude A. , Allen Barry W.
Published: October 2010

Breathing hyperbaric oxygen (HBO2), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO2, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO2at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted pharmacologically or surgically. Our findings indicate that pulmonary damage in HBO2is caused by an abrupt and significant increase in pulmonary vascular pressure, sufficient to produce barotrauma in capillaries. Specifically, extreme HBO2exposures produce massive sympathetic outflow from the central nervous system that depresses left ventricular function, resulting in acute left atrial and pulmonary hypertension. We attribute these effects on the heart and on the pulmonary vasculature to HBO2-mediated central sympathetic excitation and catecholamine release that disturbs the normal equilibrium between excitatory and inhibitory activity in the autonomic nervous system.
Cold exposure reveals two populations of microtubules in pulmonary endothelia
Authors: Ochoa Cristhiaan D. , Stevens Troy , Balczon Ron
Published: October 2010

Microtubules are composed of α-tubulin and β-tubulin dimers. Microtubules yield tubulin dimers when exposed to cold, which reassemble spontaneously to form microtubule fibers at 37°C. However, mammalian neurons, glial cells, and fibroblasts have cold-stable microtubules. While studying the microtubule toxicity mechanisms of the exotoxin Y from Pseudomonas aeruginosa in pulmonary microvascular endothelial cells, we observed that some endothelial microtubules were very difficult to disassemble in the cold. As a consequence, we designed studies to test the hypothesis that microvascular endothelium has a population of cold-stable microtubules. Pulmonary microvascular endothelial cells and HeLa cells (control) were grown under regular cell culture conditions, followed by exposure to an ice-cold water bath and a microtubule extraction protocol. Polymerized microtubules were detected by immunofluorescence confocal microscopy and Western blot analyses. After cold exposure, immunofluorescence revealed that the majority of HeLa cell microtubules disassembled, whereas a smaller population of endothelial cell microtubules disassembled. Immunoblot analyses showed that microvascular endothelial cells express the microtubule cold-stabilizing protein N-STOP (neuronal stable tubule-only polypeptides), and that N-STOP binds to endothelial microtubules after cold exposure, but not if microtubules are disassembled with nocodazole before cold exposure. Hence, pulmonary endothelia have a population of cold-stable microtubules.
The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia
Authors: Pezzulo Alejandro A. , Starner Timothy D. , Scheetz Todd E. , Traver Geri L. , Tilley Ann E. , Harvey Ben-Gary , Crystal Ronald G. , McCray Paul B. , Zabner Joseph
Published: October 2010

Organotypic cultures of primary human airway epithelial cells have been used to investigate the morphology, ion and fluid transport, innate immunity, transcytosis, infection, inflammation, signaling, cilia, and repair functions of this complex tissue. However, we do not know how closely these cultures resemble the airway surface epithelium in vivo. In this study, we examined the genome-wide expression profile of tracheal and bronchial human airway epithelia in vivo and compared it with the expression profile of primary cultures of human airway epithelia grown at the air-liquid interface. For comparison, we also investigated the expression profile of Calu-3 cells grown at the air-liquid interface and primary cultures of human airway epithelia submerged in nutrient media. We found that the transcriptional profile of differentiated primary cultures grown at the air-liquid interface most closely resembles that of in vivo airway epithelia, suggesting that the use of primary cultures and the presence of an air-liquid interface are important to recapitulate airway epithelia biology. We describe a high level of similarity between cells of tracheal and bronchial origin within and between different human donors, which suggests a very robust expression profile that is specific to airway cells.
Zoledronic Acid Potentiates mTOR Inhibition and Abolishes the Resistance of Osteosarcoma Cells to RAD001 (Everolimus): Pivotal Role of the Prenylation Process
Authors: Moriceau Gatien , Ory Benjamin , Mitrofan Laura , Riganti Chiara , Blanchard Frédéric , Brion Régis , Charrier Céline , Battaglia Séverine , Pilet Paul , Denis Marc G. , Shultz Leonard D. , Mönkkönen Jukka , Rédini Françoise , Heymann Dominique
Published: October 2010

Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways. Cancer Res; 70(24); 10329–39. ©2010 AACR.
CEBPD Reverses RB/E2F1-Mediated Gene Repression and Participates in HMDB-Induced Apoptosis of Cancer Cells
Authors: Pan Yen-Chun , Li Chien-Feng , Ko Chiung-Yuan , Pan Min-Hsiung , Chen Pei-Jung , Tseng Joseph T. , Wu Wen-Chun , Chang Wen-Chang , Huang A-Mei , Sterneck Esta , Wang Ju-Ming
Published: October 2010

Purpose: Recent evidence indicates that a tumor suppressor gene CEBPD (CCAAT/enhancer-binding protein delta) is downregulated in many cancers including cervical cancer, which provides a therapeutic potential associated with its reactivation. However, little is known for CEBPD activators and the effect of reactivation of CEBPD transcription upon anticancer drug treatment. In this study, we identified a novel CEBPD activator, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB). The purpose of this study is to characterize the mechanism of HMDB-induced CEBPD activation and its potential effect in cancer therapy.

Experimental Design: Methylation-specific PCR assay, reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to dissect the signaling pathway of HMDB-induced CEBPD transcription. Furthermore, a consequence of HMDB-induced CEBPD expression was linked with E2F1 and retinoblastoma (RB), which discloses the scenario of CEBPD, E2F1, and RB bindings and transcriptional regulation on the promoters of proapoptotic genes, PPARG2 and GADD153. Finally, the anticancer effect of HMDB was examined in xenograft mice.

Results: We demonstrate that CEBPD plays an essential role in HMDB-mediated apoptosis of cancer cells. HMDB up-regulates CEBPD transcription through the p38/CREB pathway, thus leading to transcriptional activation of PPARG2 and GADD153. Furthermore, increased level of CEBPD attenuates E2F1-induced cancer cell proliferation and partially rescues RB/E2F1-mediated repression of PPARG2 and GADD153 transcription. Moreover, HMDB treatment attenuates the growth of A431 xenografts in severe combined immunodeficient mice mice.

Conclusions: These results clearly demonstrate that HMDB kills cancer cells through activation of CEBPD pathways and suggest that HMDB can serve as a superior chemotherapeutic agent with limited potential for adverse side effects. Clin Cancer Res; 16(23); 5770–80. ©2010 AACR.
Modulation of 4E-BP1 Function as a Critical Determinant of Enzastaurin-Induced Apoptosis
Authors: Dumstorf Chad A. , Konicek Bruce W. , McNulty Ann M. , Parsons Stephen H. , Furic Luc , Sonenberg Nahum , Graff Jeremy R.
Published: October 2010

Enzastaurin (LY317615.HCl) is currently in a phase III registration trial for diffuse large B-Cell lymphoma and numerous phase II clinical trials. Enzastaurin suppresses angiogenesis and induces apoptosis in multiple human tumor cell lines by inhibiting protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathway signaling. PI3K/AKT pathway signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding proteins (4E-BP). When hypophosphorylated, 4E-BPs associate with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex. Herein, we show that enzastaurin treatment impacts signaling throughout the AKT/mTOR pathway leading to hypophosphorylation of 4E-BP1 in cancer cells of diverse lineages (glioblastoma, colon carcinoma, and B-cell lymphoma). Accordingly, enzastaurin treatment increases the amount of eIF4E bound to 4E-BP1 and decreases association of eIF4E with eIF4G, thereby reducing eIF4F translation initiation complex levels. We therefore chose to evaluate whether this effect on 4E-BP1 was involved in enzastaurin-induced apoptosis. Remarkably, enzastaurin-induced apoptosis was blocked in cancer cells depleted of 4E-BP1 by siRNAs, or in 4EBP1/2 knockout murine embryonic fibroblasts cells. Furthermore, eIF4E expression was increased and 4E-BP1 expression was decreased in cancer cells selected for reduced sensitivity to enzastaurin-induced apoptosis. These data highlight the importance of modulating 4E-BP1 function, and eIF4F complex levels, in the direct antitumor effect of enzastaurin and suggest that 4E-BP1 function may serve as a promising determinant of enzastaurin activity. Mol Cancer Ther; 9(12); 3158–63. ©2010 AACR.
Notch Signaling Pathway as a Therapeutic Target in Breast Cancer
Authors: Al-Hussaini Hamed , Subramanyam Deepa , Reedijk Michael , Sridhar Srikala S.
Published: October 2010

The highly conserved Notch signaling pathway is involved in regulating a number of key cellular processes. This pathway has been implicated in both the development and progression of breast cancer and has emerged as a possible therapeutic target. Several clinical trials are currently underway to determine if targeting the Notch pathway with drugs such as the γ-secretase inhibitors may be an effective therapeutic strategy that improves outcomes in this disease. Mol Cancer Ther; 10(1); 9–15. ©2010 AACR.
New Criteria During Right Ventricular Pacing to Determine the Mechanism of Supraventricular Tachycardia
Authors: AlMahameed Soufian T. , Buxton Alfred E. , Michaud Gregory F.
Published: October 2010

Background—

Right ventricular pacing (RVP) during supraventricular tachycardia produces progressive QRS fusion before the QRS morphology becomes stable. This transition zone (TZ) may provide useful information for differentiating orthodromic reciprocating tachycardia (ORT) from atrioventricular nodal reentrant tachycardia and atrial tachycardia independent of entrainment success.

Methods and Results—

We studied the effect of properly timed RVP on atrial timing during the TZ in 92 patients with supraventricular tachycardia who had RVP within 40 ms of the tachycardia cycle length. The TZ during RVP includes progressively fused QRS complexes and the first paced complex with a stable QRS morphology based on analysis of the 12-lead ECG. We also measured the stimulus-atrial interval from the end of the TZ and with each QRS complex thereafter until pacing was terminated or ventriculo-atrial block occurred. A fixed stimulus-atrial interval was defined as variation <10 ms during RVP. Atrial preexcitation, postexcitation, or supraventricular tachycardia termination with abrupt ventriculo-atrial block was observed within the TZ in 32 of 34 patients with ORT. A fixed stimulus-atrial interval was established within the TZ in 33 of 34 patients with ORT. At least 1 of these 2 responses was observed in all patients with ORT. None of the patients with atrioventricular nodal reentrant tachycardia or atrial tachycardia had atrial timing perturbed or a fixed stimulus-atrial interval established within the TZ.

Conclusions—

During RVP within 40 ms of the tachycardia cycle length, ORT is the likely mechanism when atrial timing is perturbed or a fixed stimulus-atrial interval is established within the TZ.
Temporal Effects of Catalase Overexpression on Healing After Myocardial Infarction
Authors: Pendergrass Karl D. , Varghese Susan T. , Maiellaro-Rafferty Kathryn , Brown Milton E. , Taylor W. Robert , Davis Michael E.
Published: October 2010

Background—

Reactive oxygen species, such as hydrogen peroxide (H
2
O
2
), contribute to progression of dysfunction after myocardial infarction (MI). However, chronic overexpression studies do not agree with acute protein delivery studies. The purpose of the present study was to assess the temporal role of cardiomyocyte-derived H
2
O
2
scavenging on cardiac function after infarction using an inducible system.

Methods and Results—

We developed a tamoxifen-inducible, cardiomyocyte-specific, catalase-overexpressing mouse. Catalase overexpression was induced either 5 days before or after MI. Mice exhibited a 3-fold increase in cardiac catalase activity that was associated with a significant decrease in H
2
O
2
levels at both 7 and 21 days. However, cardiac function improved only at the later time point. Proinflammatory and fibrotic genes were acutely upregulated after MI, but catalase overexpression abolished the increase despite no acute change in function. This led to reduced overall scar formation, with lower levels of Collagen 1A and increased contractile Collagen 3A expression at 21 days.

Conclusions—

In contrast to prior studies, there were no acute functional improvements with physiological catalase overexpression before MI. Scavenging of H
2
O
2
, however, reduced proinflammatory cytokines and altered cardiac collagen isoforms, associated with an improvement in cardiac function after 21 days. Our results suggest that sustained H
2
O
2
levels rather than acute levels immediately after MI may be critical in directing remodeling and cardiac function at later time points.
Ginseng Inhibits Cardiomyocyte Hypertrophy and Heart Failure via NHE-1 Inhibition and Attenuation of Calcineurin Activation
Authors: Guo Juan , Gan Xiaohong Tracey , Haist James V , Rajapurohitam Venkatesh , Zeidan Asad , Faruq Nazo Said , Karmazyn Morris
Published: October 2010

Background—

Ginseng is a medicinal plant used widely in Asia that has gained popularity in the West during the past decade. Increasing evidence suggests a therapeutic role for ginseng in the cardiovascular system. The pharmacological properties of ginseng are mainly attributed to ginsenosides, the principal bioactive constituents in ginseng. The present study was carried out to determine whether ginseng exerts a direct antihypertrophic effect in cultured cardiomyocytes and whether it modifies the heart failure process in vivo. Moreover, we determined the potential underlying mechanisms for these actions.

Methods and Results—

Experiments were performed on cultured neonatal rat ventricular myocytes as well as adult rats subjected to coronary artery ligation (CAL). Treatment of cardiomyocytes with the α
1
adrenoceptor agonist phenylephrine (PE) for 24 hours produced a marked hypertrophic effect as evidenced by significantly increased cell surface area and ANP gene expression. These effects were attenuated by ginseng in a concentration-dependent manner with a complete inhibition of hypertrophy at a concentration of 10 μg/mL. Phenylephrine-induced hypertrophy was associated with increased gene and protein expression of the Na
+
-H
+
exchanger 1 (NHE-1), increased NHE-1 activity, increased intracellular concentrations of Na
+
and Ca
2+
, enhanced calcineurin activity, increased translocation of NFAT3 into nuclei, and GATA-4 activation, all of which were significantly inhibited by ginseng. Upregulation of these systems was also evident in rats subjected to 4 weeks of CAL. However, animals treated with ginseng demonstrated markedly reduced hemodynamic and hypertrophic responses, which were accompanied by attenuation of upregulation of NHE-1 and calcineurin activity.

Conclusions—

Taken together, our results demonstrate a robust antihypertrophic and antiremodeling effect of ginseng, which is mediated by inhibition of NHE-1–dependent calcineurin activation.
Nutrition Status and Risk Factors Associated With Length of Hospital Stay for Surgical Patients
Authors: Leandro‐Merhi Vânia Aparecida , de Aquino José Luiz Braga , Sales Chagas José Francisco
Published: October 2010

Objective: To diagnose the nutrition status of hospitalized patients and identify the risk factors associated with hospital length of stay (LOS). Methods: The subjective approach and the body mass index (BMI) were used to classify the nutrition status, and other indicators (anthropometry, biochemistry, and energy intake) were analyzed regarding their association with length of hospital stay of 350 patients. The chi‐square test was used to compare proportions, and the Mann‐Whitney or Kruskal‐Wallis test was used to compare continuous measures. Linear association was verified using Spearman's rank correlation coefficient. Cox's regression model was used to investigate factors associated with LOS. Results: Disease was the factor that influenced LOS the most in the studied population. Longer LOS prevailed in males (P < .0001), patients aged ≥60 years (P = .0008), patients with neoplasms (P < .0001), patients who lost weight during their hospital stay (P < .0001), and malnourished patients (P = .0034). There was a negative and significant, but weak, correlation between LOS and nutrition indicators (calf circumference, arm circumference, triceps skinfold thickness, subscapular skinfold thickness, arm fat area, lymphocyte count, and hemoglobin). Among adults, well‐nourished patients were 3 times more likely to be discharged sooner (P = .0002, RR = 3.3 [1.7–6.2]) than those who had some degree of malnutrition. Well‐nourished patients with digestive tract diseases (DTD) were also discharged sooner than malnourished patients with the same condition (P = .02, RR = 2.5 [1.1–5.8]). In patients with neoplasms, arm circumference was an independent risk factor to assess LOS (P = .009, RR = 1.1 [1.0–1.1]). Conclusions: LOS was associated with disease and nutrition status. Among the more common diseases, nutrition status according to the subjective approach determined the LOS for patients with DTD and nutrition status according to arm circumference determined the LOS for patients with neoplasms.
Blind outcome assessment: the development and use of procedures to maintain and describe blinding in a pragmatic physiotherapy rehabilitation trial
Authors: Lowe CJ Minns , Wilson MS , Sackley CM , Barker KL
Published: October 2010

Objectives: (1) To develop trial protocols which promote the achievement of blind outcome assessment. (2) To report outcome assessor beliefs regarding group allocation at follow-up assessments. (3) To document and describe instances of unblinding occurring during the trial to assist and inform rehabilitation researchers and clinicians.

Design: Prospective longitudinal observational study.

Setting: An NHS Hospital Trust specializing in orthopaedic surgery.

Subjects: One hundred and seven patients participating in a prospective pragmatic randomized controlled trial investigating physiotherapy rehabilitation following total knee arthroplasty, plus three outcome assessors.

Interventions: A protocol was developed using available research and designed to minimize instances of unblinding during a physiotherapy rehabilitation trial. Administrative, office, patient and research staff procedures were included.

Main measures: Trial questionnaires measured blind outcome assessment responses at 3 and 12 months post surgery. The outcome assessor kept a field diary recording the events surrounding instances of unblinding. Data underwent descriptive and content analysis.

Results: Blind outcome assessment was believed successful for n = 74 (81.32%) assessments at 3-month follow-up, and n = 83 (91.21%) at 12 months. Forty instances ( n = 28 participants) of unblinding were described in the field diary. While the main cause of unblinding was participants telling the outcome assessor, in 12.5% of events the assessor drew the wrong conclusion regarding group allocation. Not all unblinding events were remembered at subsequent assessments, even in this relatively small trial.

Conclusions: Blind outcome assessment was considered achievable in this trial. Specific trial protocols enabled blinding beliefs to be reported and instances of unblinding to be described.
Cardiac Hamartoma in a Young Squirrel Monkey Who Died Suddenly
Authors: Golbar H. M. , Izawa T. , Kuwamura M. , Fujita D. , Okamura K. , Yamazaki R. , Tagami Y. , Sasai H. , Yamate J.
Published: October 2010

A case of cardiac hamartoma in a 2-month-old squirrel monkey is reported. The monkey showed a loss of appetite and died suddenly. Microscopically, an encapsulated nodular lesion was found at the right atrial wall. The lesion consisted of irregularly shaped, slender myocytes intermingled with a few fibroblasts and collagen fibers. Neither nuclear atypia nor inflammatory cell infiltrate was seen. The constituting cells had stratified striations in the cytoplasm and reacted immunohistochemically for desmin, indicating the nature of myocytes. Based on the above findings, a diagnosis of cardiac hamartoma was made. This is the first case of cardiac hamartoma in this species.
Review Paper: Absorbable Polymeric Surgical Sutures: Chemistry, Production, Properties, Biodegradability, and Performance
Authors: Pillai Chennakkattu Krishna Sadasivan , Sharma Chandra P.
Published: October 2010

Among biomaterials used as implants in human body, sutures constitute the largest groups of materials having a huge market exceeding $1.3 billion annually. Sutures are the most widely used materials in wound closure and have been in use for many centuries. With the development of the synthetic absorbable polymer, poly(glycolic acid) (PGA) in the early 1970s, a new chapter has opened on absorbable polymeric sutures that got unprecedented commercial successes. Although several comparative evaluations of suture materials have been published, there were no serious attempts of late on a comprehensive review of production, properties, biodegradability, and performance of suture materials. This review proposes to bring to focus scattered data on chemistry, properties, biodegradability, and performance of absorbable polymeric sutures.
The Development and Psychometric Assessment of the Adolescent Sexual Coercion Risk Scale
Authors: Bramsen Rikke Holm , Lasgaard Mathias , Elklit Ask , Koss Mary P.
Published: October 2010

The objective of this study was to develop a psychometric measure of risk for sexual victimization from adolescent peers. Items were generated on the basis of the literature and on consultations with a multidisciplinary group of key informants. The items were administered to a sample of 327 female Grade-9 students and examined using exploratory factor analysis. The Adolescent Sexual Coercion Risk Scale items formed two lower-order factors composed of items regarding signaling sexual boundaries and displaying risk behaviors, respectively. Subsequent confirmatory factor analysis supported the two factors, and preliminary psychometric analyses demonstrated that the factors have satisfactory internal consistency. In addition, low scores on the ability to signal sexual boundaries and high scores on risk behaviors were associated with self-reported peer sexual victimization, supporting the validity of the factors as measures of risk. Future validation and potential usage of the measure are discussed.
Volunteering and Hypertension Risk in Later Life
Authors: Burr Jeffrey A. , Tavares Jane , Mutchler Jan E.
Published: October 2010

Objective: This study examined the relationship between volunteer activity and hypertension, a risk factor for cardiovascular disease, renal failure, and cognitive impairment. Method: Employing data from the Health and Retirement Study, we estimated regression models of hypertension status that include volunteer activity and psychosocial and health behavior risk factors for middle-aged and older persons. Results: Multivariate analyses showed volunteers had lower hypertension risk and lower systolic and diastolic blood pressure than nonvolunteers and that a threshold effect was present, whereby a modest amount of volunteer time commitment (but not a high amount) was associated with lower risk of hypertension. We did neither find support that psychosocial and health behaviors mediated this relationship nor find support for a moderating effect of volunteering for the relationships among health behaviors and hypertension. Discussion: The results of this study indicate that research is needed to determine what mediates the relationship between volunteering and hypertension.
Exploring How Symptoms of Attention-Deficit/Hyperactivity Disorder Are Related to Reading and Mathematics Performance
Authors: Hart Sara A. , Petrill Stephen A. , Willcutt Erik , Thompson Lee A. , Schatschneider Christopher , Deater-Deckard Kirby , Cutting Laurie E.
Published: October 2010

Children with attention-deficit/hyperactivity disorder (ADHD) tend to perform more poorly on tests of reading and mathematical performance than their typical peers. Quantitative genetic analyses allow for a better understanding of the etiology of ADHD and reading and mathematics outcomes, by examining their common and unique genetic and environmental influences. Analyses were conducted on a sample 271 pairs of 10-year-old monozygotic and dizygotic twins drawn from the Western Reserve Reading and Mathematics Project. In general, the results suggested that the associations among ADHD symptoms, reading outcomes, and math outcomes were influenced by both general genetic and general shared-environment factors. The analyses also suggested significant independent genetic effects for ADHD symptoms. The results imply that differing etiological factors underlie the relationships among ADHD and reading and mathematics performance. It appears that both genetic and common family or school environments link ADHD with academic performance.
Local hegemonic blocs: The case of tourism in Rhodes
Authors: Avdikos Vasilis
Published: October 2010

The paper explores the ways that a powerful local industry can be regarded as a local ideological hegemonic bloc. The concept of the local hegemonic bloc is deployed in a case study of the Rhodes tourist industry to provide a way of analysing how a specific spatial industrial concentration creates and sustains an ideological atmosphere locally, which supports the industry’s status while simultaneously legitimating exploitative actions.
Progressive Micromechanical Modeling for Pullout Energy of Hooked-end Steel Fiber in Cement-based Composites
Authors: Xu B.W. , Ju J.W. , Shi H.S.
Published: October 2010

A progressive micromechanical damage-plasticity formulation is proposed to analyze the single hooked-end steel fiber pullout energy from the surrounding cement-based matrix within the context of hooked-end steel fiber-reinforced cementitious composites (HSFRCC). As the hooked-end steel fiber has a unique fiber geometry, its fiber pullout energy from the cement-based matrix consists of the interfacial fiber-matrix debonding, the frictional sliding and pullout energy, and the elastoplastic deformation energy of the steel fiber hooked end. The aforementioned energy components are analytically derived first, and the superposition principle is subsequently employed to obtain the total energy dissipation during the fiber pullout process. Good agreement is obtained for comparisons between the experimental results of single hooked-end steel fiber pullout tests and the proposed analytical predictions. This satisfactory verification supports the validity and applicability of the proposed damage-plasticity energy prediction formulation, and suggests the applicability of this methodology to further investigation on micromechanical fracture energy prediction of HSFRCC during flexural macro-cracking.
Obesity Prevention Practices of Elementary School Nurses in Minnesota
Authors: Morrison-Sandberg Leslie F. , Kubik Martha Y. , Johnson Karen E.
Published: October 2010

Elementary schools are an optimal setting to provide obesity prevention interventions, yet little is known about the obesity prevention practices of elementary school nurses. The purpose of this study was to gain insight into current obesity-related school nursing practice in elementary schools in Minnesota, opinions regarding school nurse-led obesity prevention programs, and school nurses' interest in implementing obesity prevention programs. Semistructured interviews were conducted with key informants from 21 Minnesota school districts (urban = 7; suburban = 8; and rural = 6), who were licensed school nurses (LSNs). Findings indicated that LSNs provided some primary and secondary obesity prevention services. Key informants felt school nurses, administrators, and parents would be supportive of school-based, LSN-led obesity prevention efforts. Interest in increasing efforts was limited by time constraints, staffing, and resources. School nurses are well positioned to provide prevention services that will contribute to reducing childhood obesity.
Investigation of the combined effects of intentional mistuning, damping and coupling on the forced response of bladed disks
Authors: Yu CB , Wang JJ , Li QH
Published: October 2010

Blade-to-blade mistuning is always inevitable in bladed disk assemblies due to imperfections in the manufacturing progress as well as wear during operation. As a result, the forced response of a mistuned bladed disk may be drastically larger than that of the nominal or tuned design. The attendant increase in stress can lead to premature high cycle fatigue (HCF) of the blades. Therefore, it is of great importance to predict and, ultimately, to reduce the blade forced response levels caused by mistuning. In this paper, intentional and random mistuning is introduced into a simplified 12-bladed disk model by varying the stiffness of the blades. The combined effects of intentional mistuning, damping and coupling are examined. The numerical results indicate that there is some threshold value of intentional mistuning and coupling that leads to maximum mistuning effects and certain relations among intentional mistuning strength, integer harmonics, damping and coupling can suppress the response levels of bladed disks with random mistuning, which provides useful guidelines for safe and reliable designs of bladed disk systems.
Free Vibration Behavior of Exponential Functionally Graded Beams with Varying Cross-section
Authors: Ait Atmane Hassen , Tounsi Abdelouahed , Meftah Sid Ahmed , Belhadj Hichem Abdesselem
Published: October 2010

This paper presents a theoretical investigation in free vibration of a functionally graded beam (FGB) which has a variable cross-section. It is assumed that material properties vary along the beam thickness only according to exponential distributions (it is simply called E-FGB). The governing equation is reduced to an ordinary differential equation in spatial coordinate for a family of cross-section geometries with exponentially varying width. Analytical solutions of the natural frequencies are obtained for E-FG beams with clamped-free, hinged-hinged, and clamped-clamped end supports. Results show that the non-uniformity in the cross-section and the inhomogeneity in material properties influence the natural frequencies. It is also shown that, all other parameters remaining the same, the natural frequencies of E-FG beams are always proportional to those of homogeneous isotropic beams. Therefore, one can predict the behaviour of E-FG beams knowing that of similar homogeneous beams.