bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent insights into the pathogenesis and therapeutics of pulmonary hypertension
Authors: STRANGE Julian W. , WHARTON John , PHILLIPS Peter G. , WILKINS Martin R.
Published: August 2015

The normal adult pulmonary circulation is a low-pressure, high-capacity circuit. Pulmonary vascular resistance is regulated by alveolar oxygen tension, potassium channels and a variety of locally produced and circulating vasoactive factors. Perturbations of these systems may contribute to the pathogenesis of pulmonary hypertension. Recently, mutations in BMPR2 and ALK-1, genes that encode members of the transforming growth factor-β (TGF-β) receptor superfamily, have been found in patients with primary pulmonary hypertension. These observations provide a novel insight into the pathogenesis of primary pulmonary hypertension, and emphasize the importance of the integrity of the TGF-β receptor family in the maintenance of normal pulmonary vascular structure and function. This review discusses the latest developments in the field of pulmonary vascular biology and the prospects for improving the treatment of pulmonary hypertension.
Effects of indomethacin on energy metabolism in rat jejunal tissue in vivo
Authors: JACOB Molly , BJARNASON Ingvar , SIMPSON Robert J.
Published: August 2015

The non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used group of drugs in clinical medicine. However, their propensity to cause gastrointestinal damage limits their clinical utility. The pathogenesis of this toxicity is not well established. It has been postulated that an early event in the development of damage is an effect of these drugs on mitochondrial function. The present paper sets out to evaluate the effects of indomethacin, a commonly used NSAID, on energy metabolism in vivo. Indomethacin was administered to male Sprague-Dawley rats, either intrajejunally or orally, and indices of mitochondrial function were determined. The parameters chosen for this purpose were oxygen uptake by, lactate levels in and the energy charge of jejunal tissue. Oxygen uptake by and energy charge in jejunal tissue were unaffected at 1 and 3h after dosing by gavage with indomethacin. The drug significantly affected the tissue lactate/pyruvate ratio at 3h (but not at 1h) after oral dosing. Effects of indomethacin on jejunum incubated ex vivo were found to be reversible. The data suggest that indomethacin affects mitochondrial function in vivo, but that compensatory changes in glycolytic rate maintain energy charge.
Adult stem cell plasticity: new pathways of tissue regeneration become visible
Authors: FORBES Stuart J. , VIG Pamela , POULSOM Richard , WRIGHT Nicholas A. , ALISON Malcolm R.
Published: August 2015

There has recently been a significant change in the way we think about organ regeneration. In the adult, organ formation and regeneration was thought to occur through the action of organ-or tissue-restricted stem cells (i.e. haematopoietic stem cells making blood; gut stem cells making gut, etc.). However, there is a large body of recent work that has extended this model. Thanks to lineage tracking techniques, we now believe that stem cells from one organ system, for example the haematopoietic compartment, can develop into the differentiated cells within another organ system, such as liver, brain or kidney. This cellular plasticity not only occurs under experimental conditions, but has also been shown to take place in humans following bone marrow and organ transplants. This trafficking is potentially bi-directional, and even differentiated cells from different organ systems can interchange, with pancreatic cells able to form hepatocytes, for example. In this review we will detail some of these findings and attempt to explain their biological significance.
Determination of age-related increases in large artery stiffness by digital pulse contour analysis
Authors: MILLASSEAU S.C. , KELLY R.P. , RITTER J.M. , CHOWIENCZYK P.J.
Published: August 2015

The stiffness of the aorta can be determined by measuring carotid–femoral pulse wave velocity (PWVcf). PWV may also influence the contour of the peripheral pulse, suggesting that contour analysis might be used to assess large artery stiffness. An index of large artery stiffness (SIDVP) derived from the digital volume pulse (DVP) measured by transmission of IR light (photoplethysmography) was examined. SIDVP was obtained from subject height and from the time delay between direct and reflected waves in the DVP. The timing of these components of the DVP is determined by PWV in the aorta and large arteries. SIDVP was, therefore, expected to provide a measure of stiffness similar to PWV. SIDVP was compared with PWVcf obtained by applanation tonometry in 87 asymptomatic subjects (21–68 years; 29 women). The reproducibility of SIDVP and PWVcf and the response of SIDVP to glyceryl trinitrate were assessed in subsets of subjects. The mean within-subject coefficient of variation of SIDVP, for measurements at weekly intervals, was 9.6%. SIDVP was correlated with PWVcf (r = 0.65, P<0.0001). SIDVP and PWVcf were each independently correlated with age and mean arterial blood pressure (MAP) with similar regression coefficients: SIDVP = 0.63+0.086×age+0.042×MAP (r = 0.69, P<0.0001); PWVcf = 0.76+0.080×age+0.053×MAP (r = 0.71, P<0.0001). Administration of glyceryl trinitrate (3, 30 and 300 μg/min intravenous; each dose for 15 min) in nine healthy men produced similar changes in SIDVP and PWVcf. Thus contour analysis of the DVP provides a simple, reproducible, non-invasive measure of large artery stiffness.
Arsenite inhibits interleukin-6 production in human intestinal epithelial cells by down-regulating nuclear factor-κB activity
Authors: HERSHKO Dan D. , ROBB Bruce W. , HUNGNESS Eric S. , LUO Guangju , GUO Xialing , HASSELGREN Per-Olof
Published: August 2015

Previous studies have suggested that the production of interleukin-6 (IL-6) is increased in the intestinal mucosa during inflammation, and that nuclear factor-κB (NF-κB) is an important regulator of the IL-6 gene in the enterocyte. We tested the hypothesis that sodium arsenite inhibits IL-6 production in stimulated enterocytes and that this effect of arsenite is caused by down-regulation of NF-κB activity. Cultured Caco-2 cells were treated with sodium arsenite and were then stimulated with IL-1β. IL-6 production and gene expression were determined by ELISA and reverse transcriptase–PCR respectively. NF-κB DNA binding activity was determined by electrophoretic mobility shift assay. IL-1β increased NF-κB DNA binding activity, IL-6 mRNA levels and IL-6 production. These effects of IL-1β were inhibited by treatment of the cells with sodium arsenite in a dose- and time-dependent fashion. When cells were transfected with a plasmid expressing the p65 subunit of NF-κB, the inhibitory effect of sodium arsenite on NF-κB activity and IL-6 production was blunted. These results suggest that sodium arsenite inhibits IL-6 production in enterocytes subjected to an inflammatory stimulus, and that this effect, at least in part, reflects down-regulated NF-κB activity.
Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy
Authors: FARQUHARSON Colin A.J. , STRUTHERS Allan D.
Published: August 2015

Experimental studies have suggested a role for aldosterone and glucocorticoids in the pathogenesis of endothelial dysfunction. We therefore set out to characterize the acute effects of these hormones on vascular function in vivo in normal humans. A randomized, placebo-controlled, double-blind crossover study was performed on 16 healthy male volunteers (aged 19–29 years), examining the vascular effects of acute intravenous aldosterone infusion (12pmol·min-1·kg-1 for 4h) and of oral prednisolone (single 50mg dose). Peripheral arterial vascular function was assessed by bilateral forearm venous occlusion plethysmography using two parallel study protocols. In the first protocol, eight subjects received, successively, acetylcholine, sodium nitroprusside, noradrenaline, angiotensin I and angiotensin II. The remaining eight subjects received, successively, acetylcholine, sodium nitroprusside, verapamil and noradrenaline. Aldosterone attenuated endothelium-dependent vasodilatation to acetylcholine as compared with either prednisolone or placebo (maximum vasodilatation: placebo, 357±38%; aldosterone, 257±21%; P<0.05). However, background endothelium-independent vasodilatation was not affected by either aldosterone or prednisolone. There were also no significant changes in vasoconstriction induced by angiotensin or noradrenaline following aldosterone or prednisolone treatment compared with placebo. Blood pressure and baseline blood flow did not differ between any of the study phases. Thus acute short-term systemic administration of aldosterone results in endothelial vasodilator dysfunction in normal men, providing evidence for an aldosterone-induced vasculopathy, which may be particularly relevant not only in heart failure but also in hypertensive patients with high aldosterone/renin ratios.
Tissue-dependent expression of matrix proteins in human endothelin-1 transgenic mice
Authors: SCHWARZ Anja , GODES Michael , THÖNE-REINEKE Christa , THEURING Franz , BAUER Christian , NEUMAYER Hans-Hellmut , HOCHER Berthold
Published: August 2015

Endothelin-1 (ET-1) is a potent pro-fibrotic growth factor. However, little is known about its specific effects on the synthesis of matrix proteins in vivo. We used male 12-month-old ET-1 transgenic mice characterized by transgene expression in the kidney and (to a lesser extent) in the heart. Global cardiac and renal matrix protein synthesis was analysed after Sirius Red and periodate–Schiff staining. Specific expression of collagen types I, III and IV, laminin and fibronectin was examined using immunohistochemistry followed by computer-aided image analysis. Analysis of blood pressure revealed that mean arterial blood pressure was similar in ET-1 transgenic mice and controls. The total cardiac matrix protein content was increased in the myocardium of ET-1 transgenic mice. Analysis of specific cardiac matrix proteins showed increased cardiac expression of collagen type III (+211%; P<0.001) and laminin (+128%; P<0.01) in transgenic mice. The expression of collagen types I and IV and fibronectin was not altered. Global analysis of renal matrix proteins confirmed earlier studies showing pronounced interstitital fibrosis and glomerulosclerosis. Laminin expression was markedly increased in the glomerula (+152%; P<0.01) and even more so in the interstitium (+211%; P<0.001), whereas expression of collagen type III was reduced in glomerula (-48%; P<0.01) and interstitial tissue (-55%; P<0.01) of ET-1 transgenic mice. In conclusion, a primary overexpression of ET-1 does not cause uniformly enhanced synthesis of matrix proteins. In contrast, the effects of ET-1 on the matrix protein pattern is tissue-specific. The major renal and cardiac alterations in matrix proteins induced by ET-1 is a marked enhancement of laminin expression.
Effects of aging and subsequent exercise training on gene expression of endothelin-1 in rat heart
Authors: IEMITSU Motoyuki , MIYAUCHI Takashi , MAEDA Seiji , TANABE Takumi , IRUKAYAMA-TOMOBE Yoko , GOTO Katsutoshi , MATSUDA Mitsuo , YAMAGUCHI Iwao
Published: August 2015

Endothelin-1 (ET-1) is produced by endothelial cells and cardiac myocytes. ET-1 has potent positive inotropic and chronotropic effects on heart and induces myocardial cell hypertrophy. We investigated whether gene expression of ET-1 in rat hearts is altered by aging and subsequent exercise training. We also investigated whether gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which participate in some pathological cardiac conditions, in the rat hearts is altered by aging and subsequent exercise training. We studied mRNA expression of ET-1, ANP and BNP in hearts of sedentary young rats (Sedentary young; 4 months old), sedentary aged rats (Sedentary aged; 23 months old), and swim-trained aged rats (Trained aged; 23 months old, swimming training for 8 weeks). The left ventricle weight mass index for body weight and left ventricular end-diastolic dimension were significantly higher in the Trained aged group compared with the Sedentary aged group. These results showed that Trained aged rats developed cardiac hypertrophy with improvement of cardiac function. The mRNA expression of ET-1 in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The mRNA expression of ANP and BNP in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The present results show that mRNA expression of ET-1 in the heart is increased by aging, and that the mRNA expression is further increased by exercise-induced cardiac hypertrophy, suggesting that ET-1 in the heart may participate in these physiological cardiac adaptations.
ETA receptor antagonists inhibit intimal smooth muscle cell proliferation in human vessels
Authors: MAGUIRE Janet J. , YU Julie C.-M. , DAVENPORT Anthony P.
Published: August 2015

We have determined the ability of the endothelin (ET)A receptor antagonist, PD156707 (CI 1020), to inhibit intimal proliferation in human saphenous veins maintained in organ culture. After 28 days in culture, veins exposed to 1µM PD156707 exhibited a significant reduction in intima to intima-plus-media ratio (I:I+M ratio) (0.14±0.02, n = 15) and an increase in lumen area (3.1±0.8mm2) compared with veins cultured without the antagonist (I:I+M, 0.29±0.02; lumen area, 2.5±0.7mm2; n = 23) but were not significantly different from pre-cultured controls (I:I+M, 0.15±0.02; lumen area, 4.4±1.2mm2; n = 17) (Dunn's test for non-parametric multiple comparisons: α<0.05). In organ bath experiments, ET-1 and 5-hydroxytryptamine constricted pre-cultured control vessels with pD2 values (where pD2 is defined as the negative logarithm of the molar EC50 value of an agonist) of 8.9±0.4 and 7.0±0.4 (n = 3) and Emax (efficacy) values of 86±3% and 71±13% (compared with constriction induced by KCl) respectively. There was no difference in the responsiveness of veins cultured for 14 days to either agonist, indicating that the vessels maintained in organ culture remain viable. Crucially, vein segments cultured with 1µM PD156707 (a concentration that antagonized ET-1 responses in pre-cultured control vessels) contracted to ET-1 with a potency comparable to that obtained in vessels cultured in the absence of the antagonist (pD2 = 8.9±0.4 and 8.0±0.6 respectively, n = 3) confirming that PD156707 was not toxic to the tissue at the concentration used. In conclusion we have shown that the ETA-selective antagonist, PD156707, completely blocked intimal hyperplasia in human saphenous veins in organ culture, suggesting that ETA antagonists may be beneficial in preventing or delaying saphenous vein graft disease in patients receiving bypass grafts for coronary artery disease.
Involvement of endothelin-1 in acute ischaemic arrhythmias in cats and rats
Authors: LIN Li , YUAN Wen-Jun
Published: August 2015

This study aims to investigate the role of endothelin-1 (ET-1) in the genesis of acute ischaemic arrhythmias. In anaesthetized cats and rats receiving continuous monitor of electrocardiogram and arterial blood pressure, the ischaemic arrhythmias during 60-min myocardial ischaemia elicited by the occlusion of the left anterior descending coronary artery (LAD) were analysed. To prevent the putative arrhythmic effects of endogenous ET-1, ETA receptor antagonist BQ610 (1.5–6.0nmol/kg) was intracoronary injected just before LAD occlusion in cats, and preproET-1 mRNA antisense oligodeoxynucleotide (AS-ODN; 30–90nmol/kg) was intravenously injected 2h before LAD occlusion in rats. The results showed that BQ610 dose-dependently decreased the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF), and the numbers of ventricular ectopic beats (VEBs). At the dose of 6.0nmol/kg, the incidence of VT decreased significantly from 33.3% in normal saline (NS) control group to zero (P<0.01), and total VEBs decreased significantly from 831±162 to 158±51 (P<0.05). In rats receiving ET-1 AS-ODN, plasma ET-1 decreased significantly after 2h, and remained stable at 30min of LAD occlusion. However, in rats receiving the control, NS or sense ODN, plasma ET-1 remained unchanged after administration, but increased significantly during LAD occlusion. The ischaemic arrhythmias were dose-dependently suppressed in the presence of ET-1 AS-ODN. At the dose of 90nmol/kg, the incidence of VT decreased significantly from 100% in both the control groups to 30%. The numbers of single VEBs, consecutive VEBs, VT and total VEBs were also significantly decreased, from 60±15 in NS group to 19±12, 11±3 to 2±2, 155±41 to 11±11, and 239±49 to 35±25 respectively. In the present cat and rat models of coronary artery occlusion, antagonism of either ETA receptors or endogenous ET-1 synthesis prevented the ischaemic arrhythmias, indicating that ET-1 is possibly an important promotive factor in the genesis of acute ischaemic arrhythmias.
Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure
Authors: OHNISHI Masato , WADA Atsuyuki , TSUTAMOTO Takayoshi , FUJII Masanori , MATSUMOTO Takehiro , YAMAMOTO Takashi , TAKAYAMA Tomoyuki , WANG Xinwen , KINOSHITA Masahiko
Published: August 2015

Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n = 5; 270beats/min) compared with normal dogs (n = 5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56±0.16 compared with 2.93±0.25litres/min; P<0.01) and systemic vascular resistance had increased (4653±374 compared with 3227±396dyn·s·cm-5; P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95±0.83 compared with 2.12±0.39pg/ml; P<0.05) and ADMA (3.27±0.49 compared with 1.91±0.25nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r = 0.72, P<0.05). Secondly, we chronically administered an ETA receptor antagonist, TA-0201 (0.3mg/kg; n = 5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58±0.24litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36±0.30nmol/ml and 2423±188dyn·s·cm-5 respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ETA receptor antagonist can prevent the inhibition of NO production and the increased peripheral vascular resistance observed in CHF.
Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure
Authors: YAMAMOTO Takashi , WADA Atsuyuki , OHNISHI Masato , TSUTAMOTO Takayoshi , FUJII Masanori , MATSUMOTO Takehiro , TAKAYAMA Tomoyuki , WANG Xinwen , KUROKAWA Kiyoshi , KINOSHITA Masahiko
Published: August 2015

Endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) play important roles in the regulation of body fluid balance in congestive heart failure (CHF). Renal production of ET-1 increases in CHF and it is a significant independent predictor of sodium excretion. ANP inhibits the ET system through cGMP, a second messenger of ANP. However, in severe CHF, plasma cGMP levels reached a plateau despite the activation of ANP secretion. Thus, ANP does not seem to sufficiently oppose exaggerated ET-1 actions in severe CHF, partially due to the accelerated degradation of cGMP, through phosphodiesterase type 5 (PDE5). We examined the chronic effects of a PDE5 inhibitor, T-1032 (1mg/kg per day, n = 5), on renal function and renal production of ET-1 in dogs with CHF induced by rapid ventricular pacing (270beats/min). Vehicle dogs were given a placebo (n = 5) and normal dogs (n = 5) served as normal controls without pacing. In this experimentally produced CHF, plasma levels of ET-1, ANP and cGMP were elevated and renal production of cGMP was increased compared with the normal group, associated with increases in renal expression of preproET-1 mRNA and the number of ET-1-positive cells in glomeruli. In the T-1032 group, systemic and renal production of cGMP were further increased compared with the vehicle group despite no significant difference in plasma ANP levels between the two groups. Subsequently, the agent significantly improved urine flow rate, sodium excretion rate and glomerular filtration rate (GFR) associated with reductions in renal expression of preproET-1 mRNA and the number of ET-1-positive cells compared with the vehicle group. Moreover, there was a significant negative correlation between the number of ET-1-positive cells and GFR (r =-0.802 and P<0.001 respectively). Our results indicate that chronic PDE5 inhibition ameliorates the antagonistic relationship between renal ANP and ET-1 through the cGMP pathway, subsequently preventing renal dysfunction during the progression of CHF.
Endothelin B receptors located on the endothelium provide cardiovascular protection in the hamster
Authors: HONORÉ Jean-Claude , PROTEAU Caroline , D'ORLÉANS-JUSTE Pedro
Published: August 2015

Endothelins (ETs) act through two receptors, namely ETA and ETB. In the cardiovascular system, the activation of both receptors leads to vasoconstriction. However, ETB receptors also mediate endothelium-dependent vasodilatation and clearance of plasma ET-1. With regard to these latter properties, we wanted to assess the contribution of ETB receptors and the effects of selective and mixed ET receptor blockade on vascular tone in control Syrian Golden hamsters and in Bio 14.6 cardiomyopathic hamsters after bolus injection of ET-1 and IRL-1620, a selective ETB agonist. In 12-week-old anaesthetized control hamsters, ET-1 (0.5nmol/kg) induced a sustained pressor response which was only partly reduced by the selective ETA receptor antagonist BQ-123, suggesting a contribution of ETB receptor activation to the vasoconstrictive effects of ET-1. This was confirmed by injection of the selective ETB receptor agonist IRL-1620 (1 nmol/kg). However, the pressor response to this agonist was always preceded by a transient vasodilatation, indicating activation of endothelium-located ETB receptors. When the selective ETB receptor antagonist BQ-788 was administered, the hypotensive phase following IRL-1620 injection was abolished. Interestingly, BQ-788 or a mixture of BQ-788 and BQ-123 significantly potentiated the pressor responses to ET-1. In 12-week-old Bio 14.6 cardiomyopathic hamsters, ET-1 and IRL-1620 induced haemodynamic responses similar to those observed in control hamsters, although the IRL-1620-induced pressor increase was lower. No difference in cardiac prepro ET-1 mRNA expression was observed between the two strains of hamsters. In conclusion, we suggest that endothelium-located ETB receptors are involved in the physiological antagonism of ET-dependent protracted pressor effects, and thus may play a protective role in both normal hamsters and those with cardiomyopathy.
Endothelin receptor blockade inhibits the growth of human papillomavirus-associated cervical carcinoma
Authors: VENUTI Aldo , SALANI Debora , CIRILLI Alessia , SIMEONE Paola , MULLER Antonio , FLAMINI Silvio , PADLEY Robert , BAGNATO Anna
Published: August 2015

Human papillomaviruses (HPVs) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV-transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. HPV-positive cancer cells secrete ET-1 and express mRNA for ET-1 and its receptors, whereas HPV-negative carcinoma cell lines express only the ETB receptor (ETBR) mRNA and do not secrete ET-1. In HPV-positive cancer cells, ETAR mediates the ET-1-induced mitogenic effect and sustains the basal growth rate of unstimulated cervical tumour cells. Therefore, ET-1 may be involved in the neoplastic growth of HPV-associated cervical carcinoma, where the increased ET-1 autocrine loop can be targeted for antitumour therapy. In the present work, the action of specific antagonists of ETAR (BQ-123 and ABT-627), was analysed in CaSki and C33A cells that are derived from human cervical carcinoma. CaSki cells are HPV-16-positive, produce ET-1 and posses ETAR and ETBR, whereas the C33A line is HPV-negative, does not secrete ET-1 and has no ETAR. In HPV-positive cancer cells ABT-627 strongly inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumour cells, whereas the ETBR antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ETAR expression is increased and could be targeted for antitumour therapy. In conclusion, an ET-1 autocrine loop is involved in tumour cell proliferation via ETAR, and ABT-627 is effective in controlling proliferation of cervical carcinoma cells.
Endothelin ETB receptor-mediated mechanisms involved in oleic acid-induced acute lung injury in mice
Authors: GUIMARÃES Cláudio L. , TRENTIN Patricia G. , RAE Giles A.
Published: August 2015

The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1mg·kg-1 intravenously), but not endothelin-1 (up to 1nmol·kg-1 intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8±3.9 to 98.6±10.7µg 1h after injection. Bosentan, the antagonist of endothelin receptors (ETA and ETB) or the selective ETB receptor antagonists Ro 46-8443 or A-192621 (administered 1h before oleic acid at doses of 30, 10 and 30mg·kg-1 respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ETA receptor antagonist A-127722.5 (10mg·kg-1) was inactive. Oleic acid (2mg·kg-1, intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10mg·kg-1 respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ETB receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ETB or mixed ETA/ETB receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.
Contrasting neurovascular findings in chronic orthostatic intolerance and neurocardiogenic syncope
Authors: STEWART Julian M. , WELDON Amy
Published: August 2015

Simple faint (neurocardiogenic syncope) and postural tachycardia syndrome (POTS) characterize acute and chronic orthostatic intolerance respectively. We explored the hypothesis that vascular function is similar in the two conditions. We studied 29 patients with POTS and compared them with 20 patients with neurocardiogenic syncope who were otherwise well, and with 15 healthy control subjects. We measured continuous heart rate, respiration and blood pressure, and used venous occlusion strain gauge plethysmography to measure calf and forearm blood flow, peripheral arterial resistance, peripheral venous resistance and venous pressure (Pv). Upright tilt was performed to 70° for 10min, during which calf blood flow and volume were measured. Calf Pv was increased (to 27.2±2.0mmHg) in a subgroup of POTS patients, who also had increased arterial resistance (57±6mmHg·ml-1·min-1·100ml-1 tissue), increased venous resistance (2.4±0.3mmHg·ml-1·min-1·100ml-1 tissue), and decreased peripheral flow (1.0±0.2ml·min-1·100ml-1 tissue) in the calf; other POTS patients with a normal Pv had decreased arterial resistance (18±2mmHg·ml-1·min-1·100ml-1 tissue) and increased blood flow (3.8±0.3ml·min-1·100ml-1 tissue). Syncope patients were not different from controls (Pv = 11.4±0.5mmHg; calf flow = 3.1±0.2ml·min-1·100ml-1 tissue; arterial resistance = 27±2mmHg·ml-1·min-1·100ml-1 tissue; venous resistance = 1.2±0.3mmHg·ml-1·min-1·100ml-1 tissue). When upright, syncope patients and control subjects had similar increases in heart rate and calf volume, stable blood pressure, and decreases in blood flow. POTS patients had markedly increased heart rate and calf blood flow, unstable blood pressure, and pooling in the lower extremities, regardless of subgroup. We conclude that peripheral vascular physiology in patients with POTS is abnormal, in contrast with normal peripheral vascular physiology in neurocardiogenic syncope.
Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors
Authors: Bosnyak Sanja , Jones Emma S. , Christopoulos Arthur , Aguilar Marie-Isabel , Thomas Walter G. , Widdop Robert E.
Published: August 2015

AT1R (angiotensin type 1 receptor) and AT2R (angiotensin type 2 receptor) are well known to be involved in the complex cardiovascular actions of AngII (angiotensin II). However, shorter peptide fragments of AngII are thought to have biological activity in their own right and elicit effects that oppose those mediated by AngII. In the present study, we have used HEK (human embryonic kidney)-293 cells stably transfected with either AT1R or AT2R to perform a systematic analysis of binding affinities of all the major angiotensin peptides. Additionally, we tested the novel AT2R agonist Compound 21, as well as the MasR (Mas receptor) agonist and antagonist AVE0991 and A-779 respectively, for their ability to bind to AT1R or AT2R. Candesartan, CGP42214 and PD123319 were used as reference compounds. Binding studies using 125I-[Sar1Ile8]AngII on the AT1R-transfected HEK-293 cells revealed only AngII, AngIII [angiotensin III; angiotensin-(2–8)] and candesartan to have high affinity for AT1R. In the AT2R-transfected HEK-293 cells, competition for 125I-[Sar1Ile8]AngII binding was observed for all ligands except candesartan, AVE0991 and A-779, the latter two compounds having negligible affinity at either AT1R or AT2R. The rank order of affinity of ligands at AT2R was CGP42112>AngII≥AngIII>Compound 21≥PD123319≫AngIV [angiotensin IV; angiotensin-(3–8)]>Ang-(1–7) [angiotensin-(1–7)]. Of note, although AngIV and Ang-(1–7) exhibited only modest affinity at AT2R compared with AngII, these two angiotensin peptides, together with AngIII, had substantial AT2R selectivity over AT1R. Collectively, our results suggest that shorter angiotensin peptides can act as endogenous ligands at AT2R.
Distributed model predictive control for consensus of sampled‐data multi‐agent systems with double‐integrator dynamics
Authors: Zhou Lifeng , Li Shaoyuan
Published: August 2015

This study proposes a distributed model predictive control (MPC) strategy to achieve consensus of sampled‐data multi‐agent systems with double‐integrator dynamics. On the basis of the error of state between each agent and the centre of its subsystem, a novel distributed MPC strategy (Algorithm 1) is obtained with the exchange of current states only. Then, a reverse iterative algorithm (Algorithm 2) is specially designed for the receding horizon optimisation of sampled‐data double‐integrator dynamics. Illustrative examples are finally displayed to verify the effectiveness and advantage of the distributed MPC consensus strategy and the impact of sampling period on consensus.
Ancillary services in electric power systems with HVDC grids
Authors: Renner Robert H. , Van Hertem Dirk
Published: August 2015

An electrical power system is intended to transmit power from generation to load. To do so, it needs ancillary services to guarantee a certain level of reliability and quality. With the emergence of DC grids, it becomes necessary to ask what ancillary services they may themselves require, and how DC grids should be required to interact with the remainder of the system. This study defines a first basic set of ancillary services for High Voltage Direct Current (HVDC) grids which did not exist so far, and it shows that this development could affect the ancillary services in AC grids. This study describes how the origin of ancillary services can change if an HVDC grid is added to the existing AC grids and gives an overview of existing definitions for ancillary services.
Heuristic probabilistic power flow algorithm for microgrids operation and planning
Authors: Nikmehr Nima , Najafi Ravadanegh Sajad
Published: August 2015

One of the basic components of future distribution networks is renewable energy resources (RER). The uncertainty in power production of renewable resources such as wind and solar as well as load is another characteristic of such networks. Conventional power flow methods may not be suitable for active distribution networks such as microgrids. In this study, a heuristic load flow method considering the effects of intermittent behaviour of RERs and load is modelled in probabilistic load flow (PLF) algorithm. The method is suitable for both radial and weakly meshed distribution networks with RER for operation and planning of microgrids. Imperialist competitive algorithm (ICA) as heuristic‐based optimisation algorithm is applied to solve the PLF. Based on PLF technique, calculated parameters of the system such as bus voltages and feeders’ current are extracted as random variables. A modified version of IEEE 33‐bus test system with RER is used to evaluate efficiency and capability of the algorithm. Results are compared with Monte Carlo simulation method. The probability density function and cumulative distribution function (CDF) of some network variable are compared. Based on the results, the presented approach can solve the PLF problem regardless of the type of distribution network.
Probabilistic optimal robust multistage feeder routing under load forecasting uncertainty
Authors: Khatami Hamed , Najafi Ravadanegh Sajad
Published: August 2015

One of the main uncertainties in long‐term distribution network planning is load forecasting error. This paper presents a probabilistic multistage expansion planning method to consider the load forecasting error as well as pseudo dynamic behavior of network parameters and geographical constraints. The optimal routes of MV feeders as backbone of distribution networks are obtained for both mid and long‐term case with deterministic and probabilistic modeling. The Imperialist Competitive Algorithm (ICA) is adapted for the optimal expansion planning of MV distribution network. To check and maintain the radial configuration of the MV distribution network during ICA random operators, a novel algorithm is employed. Comparative tabular and graphical results are given for deterministic and probabilistic planning. In probabilistic case the results is also represented by histogram of statistics data, mean and standard deviation of input and output variables using Monte Carlo Simulation (MCS). Based on the results it is possible to design the MV network at the presence of uncertainties more robust and flexible with respect to deterministic planning without reasonable increase in total cost. The efficiency and capability of the method is tested on a relatively large‐scale distribution network.
Hybrid modal‐balanced truncation method based on power system transfer function energy concepts
Authors: Varricchio Sergio Luis , Freitas Francisco Damasceno , Martins Nelson
Published: August 2015

The combined use of modal and balanced truncations methods is proposed for model order reductions. To efficiently combine these methods, a stopping criterion based on spectral energy concepts is also proposed. This criterion was implemented into the code of the widely known subspace accelerated dominant pole algorithm (SADPA), designed to compute a set of dominant poles and associated residues of transfer functions from large‐scale, sparse, linear descriptor systems. The resulting enhanced SADPA code automatically stops once the computed set of dominant poles and associated residues is sufficient to build a modal reduced order model (ROM) whose energy content approaches that of the complete model within a specified tolerance and considering a frequency window of interest. The number of dominant poles in this set is much smaller than the number of poles of the full system model. Hence, their state‐space realisation usually has a small enough dimension for the efficient application of the square root balanced truncation method. This new method, named hybrid modal‐balanced truncation, produces ROMs whose order are much smaller than that of the modal ROMs and, most importantly, can also be applied to unstable models.
Autofocus algorithm using blind homomorphic deconvolution for synthetic aperture radar imaging
Authors: Shao Peng , Xing Mengdao , Xia Xiang‐Gen , Li Yachao , Li Xueshi , Bao Zheng
Published: August 2015

In airborne case, synthetic aperture radar images generally suffer from the deterioration because of the unknown phase error caused by unstable platform and atmosphere perturbation. To obtain the phase error, a novel autofocus algorithm referred to as blind homomorphic deconvolution autofocus algorithm is proposed in this study. In this method, a wavelet scaling function is used to construct a smooth subspace that is orthogonal to noise subspace. Then, the phase error can be separated and reconstructed by the generated smooth subspace based on the differences of the smoothness properties between phase error and image reflectivity. Compared with the traditional autofocus methods, the proposed method does not require an iterative estimation. Thus, the computational complexity can be significantly reduced. Simulation and real data processing results validate the effectiveness of the proposed method.
Mode‐stirred reverberating chamber autocorrelation function: model, multifrequency measurements and applications
Authors: Sorrentino Antonio , Gifuni Angelo , Ferrara Giuseppe , Migliaccio Maurizio
Published: August 2015

In this study, a simple model for the autocorrelation function (ACF) within a reverberating chamber (RC) is developed and verified. In particular, in a well‐stirred RC when n mechanical stirrers operate, the ACF of the total field is given by the product of n ACFs obtained when the n stirrers are singularly operated. Hence, a parameterisation of the ACF is accomplished. Accordingly, it is possible to parameterise the coherence time, TC, of the RC emulated wireless propagation channels. Experiments accomplished at the RC of the Università degli Studi di Napoli Parthenope, formerly Istituto Universitario Navale, confirm the soundness of the proposed model and its operational effectiveness.
Extraction and preconcentration of diclofenac through adsolubilisation process using magnetic nanoparticles adsorbent prior to its spectrophotometric determination
Authors: Ershad Sohrab , Razmara Akbar , Pourghazi Kamyar , Amoli‐Diva Mitra
Published: August 2015

A novel, fast and sensitive method based on cetyltrimethyl ammonium bromide‐coated Fe3O4 nanoparticles as an efficient adsorbent was developed for solid‐phase extraction of diclofenac. The unique properties of magnetic nanoparticles (MNPs) including high surface area and superparamagnetism give the method the advantages of high extraction capacity, fast separation and low consumption of the adsorbent. The main parameters affecting extraction and desorption efficiency, such as the amount of surfactant, pH of the sample solution, desorption conditions, breakthrough volume, amount of MNPs, extraction and desorption times, and ionic strength, were investigated and optimised. Under optimum conditions, the method was successfully applied to determine the analyte and good linearity in the range of 50–1400 ng mL−1 (r2 = 0.9998) was achieved with a low detection limit of 15 ng mL−1. The relative standard deviations of 2.76 and 1.73% (for a concentration of 50 and 500 ng mL−1, respectively) and a high enrichment factor of 98 were obtained. The method was successfully applied for the determination of diclofenac from spiked human plasma and urine samples and good recoveries in the range of 96–101% were obtained.
Application of graphite nanoplatelet‐based and nanoparticle composites to thermal interface materials
Authors: Chang Tien‐Chan , Fuh Yiin‐Kuen , Tu Sheng‐Xun , Lee Yueh‐Mu
Published: August 2015

Thermal interface materials (TIMs) are of crucial importance in improving and enhancing heat transfer in electronic packages, particularly in high‐density electronics at regions of exceedingly high temperatures. Commercial TIMs are generally composed of highly conductive particle fillers such as highly thermally conductive graphite and a matrix so that efficient heat transfer and good compliance of the interface material can be achieved during application. Two types of TIMs are tested based on the hybridisation of graphite nanoplatelets (GNPs) and nanoparticles (NPs). The hybrid materials are fabricated via screen printing process to ensure conformal uniformity of NPs spreading on the GNPs. The performance of fabricated materials such as temperature, applied pressure, heat flux and TIM thickness are concurrently tested in the temperature range 40–80°C and the pressure range 0–5.6 kgf/cm2 using a standard TIM tester. The steady‐state heat flow technique of American Society for Testing and Materials (ASTM) D5470–06 is fully adopted. For a thickness of 160 μm composite with three‐layer GNPs and two‐layer NPs, thermal conductivity is measured at ∼0.2 W/m K. In addition, the measured trend in the change of specific thermal conductivity with pressure corresponds well with the data presented in the literature.
Separated reverse‐conducting insulated‐gate bipolar transistor with snapback‐free characteristics
Authors: Chen Weizhong , Wang Wei , Liu Yong , Liao Pengfei
Published: August 2015

A novel reverse‐conducting insulated‐gate bipolar transistor (RC‐IGBT) featuring separated free‐wheeling diode (FWD) is proposed. The snapbacks of conventional RC‐IGBT are analysed; the electrical characteristics for the proposed RC‐IGBT with four kinds of anti‐paralleled FWDs are discussed. The results show that the new structure achieves snapback‐free characteristics. Moreover, the figures of merit I (FOM I) between VF and Eoff in the forward operation case and FOM II between VR and Qrr in the reverse operation case are superior to conventional RC‐IGBT. Especially for the integrated merged P‐i‐N/Schottky (MPS, FWD‐A), FOM I can be enhanced by 10%, and FOM II can be enhanced by 50%. In addition, the technological ease of fabrication is another attraction of the proposed device.
Teflon coated thread‐shaped contact electrification fibre
Authors: Nguyen Quang , Kim Baek Hyun , Kwon Jae W.
Published: August 2015

The development of the Teflon® coated thread‐shaped contact electrification fibre (CEF) is presented. This fibre has a simple structure, with a thin conductive core and a thin insulating coating. Contact electrification of the fibres has been characterised using both touch mode and drag mode. The output peak voltages generated from contact between the fibre and test rods were ∼6 V for both modes. Owing to a very simple design, the CEF has a wide range of applications. In the future, these CEFs can be directly incorporated into the fabric to harvest energy from the surrounding environment and human activities.
The plasma levitation of droplets
Authors: Poulain Cédric , Dugué Antoine , Durieux Antoine , Sadeghi Nader , Duplat Jérôme
Published: August 2015

We show how to levitate a liquid droplet above a plasma. Submitting a conductive droplet to a voltage larger than 50 V, we get a levitation regime that looks like the one obtained with the well-known thermal Leidenfrost effect, except that light is emitted from beneath the droplet. Spectroscopic analysis shows that this light is emitted by a cold and dense plasma and also that lines coming from the cathode plate material are present revealing a local cathodic sputtering effect. We examine the conditions for the levitation to occur and show that the levitation is essentially of thermal origin. Assuming a stationary heat transfer, we present a model that accounts well for the observed levitation conditions. In particular, stable levitation is shown to be possible for thin cathode plates only.
Photodetachment, electron cooling, and recombination, in a series of neat aliphatic room temperature ionic liquids
Authors: Molins i Domenech Francesc , Healy Andrew T. , Blank David A.
Published: August 2015

Transient absorption following photodetachment of a series of neat methyl-alkyl-pyrrolidinium bis(trifluoromethylsulfonyl)amides at 6.20 eV was measured with sub-picosecond time resolution in the visible and near-IR portions of the spectrum. This series spans the onset of structuring in the liquids in the form of polarity alternation. Excitation promotes the electron into a delocalized state with a very large reactive radius. Strong transient absorption is observed in the visible spectrum with a ∼700 fs lifetime, and much weaker, long-lived absorption is observed in the near-IR spectrum. Absorption in the visible is shown to be consistent with the hole, and absorption in the near-IR is assigned to the free solvated electron. Yield of free electrons is estimated at ∼4%, is insensitive to the size of the cation, and is determined in less than 1 ps. Solvation of free electrons depends strongly on the size of the cation and correlates well with the viscosity of the liquid. In addition to radiolytic stability of the aliphatic cations, ultrafast, efficient recombination of separated charge in NTf2− based ionic liquids following photo-excitation near the band-gap may prevent subsequent reactive damage associated with anions.