bluuebunny/crossref_metadata_2025 huggingface dataset:
ETA receptor blockade improves post-ischaemic functional recovery in ‘hibernating’ rat myocardium
Authors: BEYER Martin E. , FISCHER Marcus , HÖVELBORN Tobias , HOFFMEISTER Hans Martin
Published: August 2015

Endothelin-1 (ET-1) is a potent vasoconstrictor, and ETA receptors mainly mediate this effect. Elevated plasma levels of ET-1 are observed in patients with coronary heart disease. The release of this peptide from the damaged endothelium may play a role in the initiation and maintenance of myocardial ischaemia. This study examines the ETA receptor-mediated role of endogenous ET-1 in post-ischaemic myocardial function after prolonged hypoperfusion in normal non-failing hearts. In an isolated rat heart model for short-term myocardial hibernation, left ventricular functional recovery after 3h of hypoperfusion (15% of pre-ischaemic flow) followed by 2h of reperfusion was determined. Under steady-state conditions, coronary flow, left ventricular pressure (LVP) and dP/dtmax were measured in the isovolumically beating heart. Additionally, the maximal inotropic response (LVP and dP/dtmax) to calcium stimulation was determined. To study the role of ETA receptors under these pathophysiological conditions, one group was treated with the ETA antagonist BQ 610 (0.8µmol/l) during hypoperfusion, and compared with a control group which received a saline infusion during hypoperfusion. Reperfusion for 2h after 3h of hypoperfusion resulted in partial functional recovery in both groups. Post-ischaemic recovery was significantly better in the hearts that were treated with the ETA antagonist BQ 610 during hypoperfusion (LVP, +19.5% compared with control; dP/dtmax, +13.7% compared with control). The inotropic response to calcium was nearly normalized after ETA blockade. Thus the normal non-failing myocardium profits from ETA receptor blockade during a prolonged period of hypoperfusion, resulting in significantly better post-ischaemic recovery of myocardial function.
Effects of implantable cardioverter defibrillator implantation and shock application on serum endothelin-1 and big-endothelin levels
Authors: SZÜCS Andrea , KELTAI Katalin , ZIMA Endre , VÁGÓ Hajnalka , SOÓS Pál , RÓKA Attila , SZABOLCS Zoltán , GELLÉR László , MERKELY Béla
Published: August 2015

The incidence of ventricular tachyarrhythmias in the early post-operative period following implantable cardioverter-defibrillator (ICD) implantation is relatively high compared with that in control periods. Since endothelin-1 (ET-1) has been proven to be an endogenous arrhythmogenic substance, we investigated the changes in serum ET-1 and big-ET levels in patients undergoing ICD implantation. Serum concentrations of ET-1 and big-ET were measured in 14 patients with various heart diseases before the operation, as well as 1min and 1h after the last shock therapy. Big-ET levels and the sum of ET-1 and big-ET levels were unchanged immediately after the operation, but had increased significantly by 1h after implantation (before, 1.57±0.61pmol/l; 1min, 1.86±0.87pmol/l; 1h, 4.29±1.65pmol/l for big-ET; before, 3.44±1.07pmol/l; 1min, 3.79±1.29pmol/l; 1h, 6.36±2.03pmol/l for big-ET+ET-1). There was a significant correlation between left ventricular ejection fraction and big-ET level measured 1h after the last shock delivery (r =-0.542, P<0.05). We conclude that the increased big-ET level observed 1h after the last induction and shock therapy of ventricular fibrillation might have a pathophysiological role in the increased incidence of post-operative spontaneous ventricular arrhythmias.
Effects of periodontopathic bacteria on the expression of endothelin-1 in gingival epithelial cells in adult periodontitis
Authors: ANSAI Toshihiro , YAMAMOTO Eri , AWANO Shuji , YU Weixian , TURNER Anthony J. , TAKEHARA Tadamichi
Published: August 2015

Adult periodontitis, which is the major cause of adult tooth loss, is commonly characterized by chronic inflammatory disease caused by infection with periodontopathic bacteria such as Porphyromonas gingivalis. Our aims in the present study were to examine the expression of endothelin-1 (ET-1) in cultured HEp-2 epithelial cells after infection with P. gingivalis, and in gingival tissue from adult periodontitis patients. The cell lines were infected with the strains P. gingivalis 33277 and 381 for assessment of bacterial invasion using an antibiotic protection assay, and the expression of ET-1, inflammatory cytokines and cell adhesion molecules was examined by ELISA and reverse transcription–PCR. The expression of ET-1, as well as that of interleukin-1β, interleukin-8 and ICAM-1 (intercellular cell adhesion molecule 1), was induced significantly in a time-dependent manner, whereas the expression of MCP-1 (monocyte chemotactic protein-1), RANTES (regulated upon activation, normal T-cell expressed and secreted) and VCAM-1 (vascular cell adhesion molecule 1) was not. Furthermore, in gingival tissues from adult periodontitis patients, we also observed increased expression of ET-1 mRNA compared with tissue from normal healthy donors. These results suggest that infection by periodontopathic bacteria up-regulates the expression of ET-1, together with that of inflammatory cytokines and ICAM-1, in gingival epithelial cells, and that ET-1 expression may be closely involved in the regulation of cytokine responses and cell–cell adhesion in adult periodontitis lesions.
Endothelin receptor A blockade reduces proteinuria and vascular hypertrophy in spontaneously hypertensive rats on high-salt diet in a blood-pressure-independent manner
Authors: TRENKNER Jörg , PRIEM Friedrich , BAUER Christian , NEUMAYER Hans-Hellmut , RASCHAK Manfred , HOCHER Berthold
Published: August 2015

The renal endothelin (ET) system is involved in the pathogenesis of kidney fibrosis as well as blood pressure control by regulating tubular sodium excretion. Long-term effects of ETA receptor blockade on blood pressure and kidney function in spontaneously hypertensive rats (SHRs) on a high-salt diet are unknown. We treated SHRs on a 6% (w/v) NaCl sodium diet (SHR-S) for 48 weeks with the ETA antagonist LU 135252 (whose selectivity for ETA is 150 times greater than for ETB) with 10, 30 and 100mg·kg-1·day-1 or placebo. The ETA antagonist had at no time-point any effect on blood pressure. Glomerular filtration rate was normal in SHR-S and not altered by LU 135252. However, urinary albumin excretion was markedly reduced by the ETA antagonist (SHR-S, 145±50mg/day; SHR-S+10mg·kg-1·day-1 LU 135252, 33±11mg/day, P<0.05 versus SHR-S; SHR-S+30mg·kg-1·day-1 LU 135252, 55±16mg/day and SHR-S+100mg·kg-1·day-1 LU 135252, 32±11mg/day, P<0.05 versus SHR-S at both concentrations). Total urinary protein excretion was likewise significantly reduced by treatment with 10mg·kg-1·day-1 LU 135252 (SHR-S, 0.25±0.06g/day; SHR-S+10mg·kg-1·day-1 LU 135252, 0.089±0.01g/day, P<0.05 versus SHR-S). The higher dosages of LU 135252 showed only a trend towards reduction of total urinary protein excretion. Computer-aided image analysis after haematoxylin/eosin and periodic acid-Schiff staining revealed that treatment with 10mg·kg-1·day-1 LU 135252 significantly reduces the media/lumen ratio of intrarenal arteries. Higher dosages of LU 135252 were less effective. Renal matrix protein synthesis in SHR-S was not altered by LU 135252. In conclusion, the renal ET system contributes in a blood-pressure-independent manner to the regulation of urinary protein excretion and renal vascular hypertrophy in SHR-S. Lower doses of the ETA antagonist were more effective, indicating that a potential additional blockade of the ETB receptor using higher doses of LU 135252 seems to oppose the beneficial effects of a sole ETA blockade. Urinary protein excretion is an independent risk factor of chronic renal failure, thus ETA antagonists might be a therapeutic tool to prevent proteinuria-induced chronic renal failure.
Activity of the endothelin system in kidney allograft recipients is not associated with progression of chronic graft dysfunction
Authors: SLOWINSKI Torsten , SUBKOWSKI Thomas , DIEHR Petra , BACHERT Daniela , FRITSCHE Lutz , NEUMAYER Hans.-H. , HOCHER Berthold
Published: August 2015

Endothelin (ET) A receptor antagonists have been shown to be beneficial in rat models of chronic kidney allograft dysfunction. We investigated urinary and plasma ET-1 (uET-1, pET-1) and BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble ET-converting enzyme (ECE) concentration in 310 adult Caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. All patients were on cyclosporine A- or FK506-based immunosuppression protocols. From all available measurements since transplantation, we calculated the slope of serum creatinine-1/year (slopeCrea) as a parameter for progression of chronic graft dysfunction, as well as the mean of serum creatinine (meanCrea) from most recent year before measurements as a parameter for actual graft function. The slope of urinary protein excretion/year (slopeProt) and mean of urinary protein concentration (meanProt) from most recent year was calculated analogue. uET-1 and uBigET-1 were adjusted for protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Blood and urine probes for measurements were always drawn immediately before morning dosage of immunosuppressants. There was no significant correlation of any measured component of the ET system with slopeCrea or slopeProt. MeanCrea (mg/dl) was significantly correlated with pBigET-1 (fmol/ml) and pET-1 (fmol/ml) (pBigET-1: r = 0.179, P = 0.001; pET-1: r = 0.161, P = 0.009). The other measured components of the ET systems were not significant correlated with meanCrea. In conclusion, the actual graft function is associated with elevated pET-1 and BigET-1 concentrations as it is well known from other forms of impaired kidney function. However, the actual concentration of ET-1, soluble ECE, and BigET-1 in urine and plasma in our study is not associated with parameters for progression of chronic graft dysfunction.
Arteriojugular endothelin-1 gradients in aneurysmal subarachnoid haemorrhage
Authors: MENON David K. , DAY Diana , KUC Rhoda E. , DOWNIE Andrew J. , CHATFIELD Doris A. , DAVENPORT Anthony P.
Published: August 2015

Plasma endothelin (ET) is elevated in patients with vasospasm following subarachnoid haemorrhage (SAH). However, systemic levels provide no indication regarding local production in the brain, and late elevation may be a consequence rather than a cause of vasospasm. We measured arteriojugular (AJ) gradients of ET-1 in 17 patients over the first week after SAH, and related these to the subsequent development of vasospasm. Daily, paired arterial and jugular bulb blood samples were obtained up to seven days post SAH, and assayed for ET-1 using radioimmunoassay. Systemic levels and AJ gradients were compared in patients with and without vasospasm. Significant AJ gradients were observed for ET-1 (P<0.01). These differences remained significant in the subgroup of patients who developed vasospasm (0.12±0.05pmol/l; P<0.05), in whom AJ gradients represented 25±7% of systemic levels (0.84±0.05pmol/l). AJ gradients did not reach significance in patients who did not develop vasospasm (0.09±0.07pmol/l; P = 0.2). Systemic ET-1 levels and AJ gradients were unrelated to SAH grade, surgical or endovascular interventions, or extracranial complications. AJ gradients in the first week following SAH suggest early production of ET-1 in the cerebrovascular bed. However, early systemic ET-1 levels did not discriminate between patients with and without vasospasm. Larger AJ differences may predict vasospasm, but further work is needed to confirm this observation. AJ gradient measurement may provide a useful technique for investigating the role of other peptides in acute brain injury.
Endothelin-stimulated glucose uptake: effects of intracellular Ca2+, cAMP and glucosamine
Authors: WU-WONG Jinshyun R. , BERG Cathleen E. , DAYTON Brian D.
Published: August 2015

Endothelin-1 (ET-1) is a 21-amino-acid peptide that binds to G-protein-coupled receptors to evoke biological responses. Previously we have shown that ET-1 stimulates glucose uptake in 3T3-L1 adipocytes and neonatal rat cardiomyocytes, but the mechanism is not completely understood. ET-1 is known to modulate intracellular Ca2+ and cAMP levels. Depletion of intracellular Ca2+ by treating 3T3-L1 adipocytes with EDTA and 1,2-bis(2-amino-5-methylphenoxy)ethane-N,N,N´,N´-tetra-acetic acid tetra-acetoxymethyl ester (MAPTAM) did not have a significant effect on ET-1-induced glucose uptake. Forskolin, a potent stimulator which stimulates adenylate cyclase and increases the intracellular cAMP level, partially inhibited insulin-stimulated glucose uptake in 3T3-L1 cells, but had no significant impact on the effect of ET-1. Forskolin also did not show an effect on the tyrosine phosphorylation of a 75kDa protein induced by ET-1. Glucosamine treatment causes insulin resistance in cells, possibly by entering the hexosamine biosynthetic pathway. In neonatal rat cardiomyocytes, glucosamine treatment blocked both insulin and ET-1-stimulated glucose uptake and also eliminated the translocation of IRAP, an aminopeptidase in GLUT4-containing vesicles, from the cytoplasm to the plasma membrane. These results suggest that ET-1-induced glucose uptake is independent of its effects on modulating intracellular Ca2+ and cAMP levels, but is likely linked to the hexosamine biosynthetic pathway.
Acute effects of 17 β-oestradiol on functional activity of endothelin-converting enzymes in human arteries and veins
Authors: HEIGL Andres , LACHAT Mario , LATTMANN Thomas , LÜSCHER Thomas , BARTON Matthias
Published: August 2015

In this study, we investigated the short-term effect of 17β-oestradiol on functional enzyme activity (FEA) of endothelin-converting enzymes in vitro using human internal mammary arteries (n = 7–8) and human saphenous veins (n = 16–17) obtained from patients undergoing coronary artery bypass graft surgery. Vascular rings were preincubated with either solvent control (0.2% ethanol) or 17β-oestradiol (1µM) for 30min and concentration–response curves to big ET-1 (0.1–100nM) or ET-1 (0.1–100nM) were performed. FEA for each concentration was calculated as the percentage activity [(contraction to big ET-1/contraction to ET-1)×100] normalized to KCl (100mM). In control experiments, at low concentrations FEA was lower in internal mammary arteries than in saphenous veins (P<0.05). While FEA was suppressed in saphenous veins by 10nM (4±1 versus 22±5%, P<0.01) and 30nM (26±4 versus 48±7%, P<0.05) 17β-oestradiol, FEA was markedly enhanced in internal mammary arteries by 10nM (33±12 versus 1±1%, P<0.001) and 30nM (44±12 versus 8±3%, P<0.01) 17β-oestradiol . FEA was not affected by 100nM 17β-oestradiol. These results demonstrate for the first time that short-term exposure to 17β-oestradiol affects FEA in vitro. Human internal mammary arteries have lower FEA than the saphenous veins, but FEA is differentially affected by acute exposure to 17β-oestradiol in human arteries and veins. Whether changes in FEA play a role in the vascular effects of 17β-oestradiol in vivo remains to be determined.
Roles of angiogenic factors and endothelin-1 in gastric ulcer healing
Authors: AKIMOTO Masumi , HASHIMOTO Hiroshi , MAEDA Atsushi , SHIGEMOTO Mutsuo , YAMASHITA Katsuko
Published: August 2015

Endothelins (ETs) participate directly and indirectly in angiogenesis via ET receptors. During early fetal angiogenesis, vascular endothelial growth factor (VEGF) and its receptors kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase-1 (Flt-1) are required for the development of the systemic vasculature. In late angiogenesis, stromal-cell-derived factor (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) act in an organ-specific manner to promote the formation and development of large blood vessels supplying the gastrointestinal tract. We studied the roles of these ligand receptors in angiogenesis during healing of gastric ulcers. We studied the following five groups, each consisting of ten cases of endoscopically confirmed gastric ulcer: active stage (GA), healing stage (GH) and scar stage (GS) of gastric ulcers located in the angulus; Helicobacter pylori (Hp)-positive gastritis (gast+); and Hp-negative gastritis (gast-). All cases in the ulcer groups were Hp-positive. The study materials consisted of frozen biopsy specimens of lesions arising in the angulus. ET-1 was measured by enzyme immunoassay. The other factors were assayed by reverse-transcription–PCR. The distributions of ET-1, ETA receptor (ETAR), SDF-1 and CXCR4 in the gastric mucosa were evaluated by enzyme immunoassay. ET-1 and ETAR reached peak levels during the GH (ET: P<0.05, ETAR: P<0.01). VEGF mRNA increased slightly during the GA, but did not differ significantly among the groups. KDR and Flt-1 levels were high during the GA, the level being significantly higher than those during the GH and GS (P<0.05). SDF-1 levels significantly decreased during the GH and GS compared with levels during the GA, and CXCR4 significantly increased during the GH and GS (P<0.01). On immunostaining, ET-1-positive cells and ETAR-positive cells were found in the endothelium, vascular smooth muscle and gastric epithelium, and CXCR4-positive cells were found in the endothelium and gastric epithelium during the GH and GS. Our results suggest that VEGF receptors are mainly expressed early in ulcer development and participate in the initial stage of angiogenesis. SDF-1 receptors and ETAR are primarily expressed during the GH and GS and are involved in vascular maturation and gastric mucosal regeneration during late angiogenesis.
The inflammatory macrophage: a story of Jekyll and Hyde
Authors: DUFFIELD Jeremy S.
Published: August 2015

Recent investigations have highlighted new roles for the macrophage (Mϕ) in the biology of inflammation. Selective depletion of Mϕs from inflamed sites has confirmed their predominant role in immune-mediated damage. The components of this injury have been dissected. Mϕs mediate death of stromal, parenchymal and other immune cells by engaging the death programme, resulting in apoptosis. In addition, Mϕs induce destruction of matrix and extracellular structures both directly and indirectly by inducing stromal cells to release matrix metalloproteinases. However, there is another side to the inflammatory Mϕ. Evidence is provided that Mϕs at the same sites possess the ability to aid cell proliferation, secrete and stabilize new matrix components and induce resident cells to secrete matrix components themselves. Mϕ phagocytosis of apoptotic cells brings about a change from the cell-killing matrix-degrading cell to the matrix-generating cell-proliferating tissue-healing cell. Just as both Mϕ types are necessary at the inflamed site, the right balance of these two populations is required for healing and resolution. Evidence of excessive inflammation as a manifestation of impaired phagocytosis of apoptotic cells emphasizes that defects in the transition from one Mϕ type to another may account for the uncontrolled excessive inflammation seen in disease. Recent insights into the mechanisms by which apoptotic cells signal the change of function to the Mϕ offer the prospect of novel targets for manipulation of Mϕs in the inflamed tissue.
Effects of inhibition of ATP-sensitive potassium channels on metabolic vasodilation in the human forearm
Authors: FAROUQUE H.M. Omar , MEREDITH Ian T.
Published: August 2015

Experimental data suggest that vascular ATP-sensitive potassium (KATP) channels may be an important determinant of functional hyperaemia, but the contribution of KATP channels to exercise-induced hyperaemia in humans is unknown. Forearm blood flow was assessed in 39 healthy subjects (23 males/16 females; age 22±4 years) using the technique of venous occlusion plethysmography. Resting forearm blood flow and functional hyperaemic blood flow (FHBF) were measured before and after brachial artery infusion of the KATP channel inhibitors glibenclamide (at two different doses: 15 and 100µg/min) and gliclazide (at 300µg/min). FHBF was induced by 2min of non-ischaemic wrist flexion–extension exercise at 45 cycles/min. Compared with vehicle (isotonic saline), glibenclamide at either 15µg/min or 100µg/min did not significantly alter resting forearm blood flow or peak FHBF. The blood volume repaid at 1 and 5min after exercise was not diminished by glibenclamide. Serum glucose was unchanged after glibenclamide, but plasma insulin rose by 36% (from 7.2±0.8 to 9.8±1.3m-units/l; P = 0.02) and 150% (from 9.1±1.3 to 22.9±3.5m-units/l; P = 0.002) after the 15 and 100µg/min infusions respectively. Gliclazide also did not affect resting forearm blood flow, peak FHBF, or the blood volume repaid at 1 and 5min after exercise, compared with vehicle (isotonic glucose). Gliclazide induced a 12% fall in serum glucose (P = 0.009) and a 38% increase in plasma insulin (P = 0.001). Thus inhibition of vascular KATP channels with glibenclamide or gliclazide does not appear to affect resting forearm blood flow or FHBF in healthy humans. These findings suggest that vascular KATP channels may not play an important role in regulating basal vascular tone or skeletal muscle metabolic vasodilation in the forearm of healthy human subjects.
Effects of angiotensin II receptor blockade versus angiotensin-converting-enzyme inhibition on ventricular remodelling following myocardial infarction in the mouse
Authors: PATTEN Richard D. , ARONOVITZ Mark J. , EINSTEIN Michael , LAMBERT Matthew , PANDIAN Natesa G. , MENDELSOHN Michael E. , KONSTAM Marvin A.
Published: August 2015

Left ventricular (LV) remodelling following myocardial infarction (MI) is associated with increased morbidity and mortality. Previous data suggest that angiotensin II (Ang II) plays a central role in the molecular events contributing to LV remodelling. We explored the effects of angiotensin-converting-enzyme (ACE) inhibition versus Ang II (AT1) receptor blockade on LV remodelling in mice post-MI. Mice underwent sham procedure or left coronary artery ligation, and received placebo, the AT1 receptor antagonist, losartan or the ACE inhibitor, enalapril. At 6 weeks, echocardiography and haemodynamic studies were performed. Infarct size and interstitial collagen content were determined. Expression of genes encoding atrial natriuretic peptide (ANP), collagen type I, AT1a and AT1b receptors were measured. The placebo MI group showed increased LV end-diastolic diameter, LV end-systolic diameter with depressed fractional shortening (P<0.01 versus shams), increased LV mass and volume (both P<0.01 versus shams). The placebo MI group also exhibited increased non-infarct zone collagen content (P<0.01), ANP (P<0.01) and collagen type 1 (P<0.01) gene expression, with a non-significant rise in AT1a receptor gene expression. Neither losartan or enalapril prevented LV dilation or improved fractional shortening. Both similarly lowered systolic blood pressure (P<0.01 for each versus placebo). Losartan and enalapril inhibited LV hypertrophy (P<0.01), and decreased ANP (P<0.01) and collagen type 1 gene expression (P<0.05). Levels of AT1a receptor gene expression were higher than shams (P<0.05 for both), but similar to placebo. AT1b receptor gene expression was much lower than that for AT1a receptor and similar in all groups. Thus, in this model, AT1 receptor antagonism and ACE inhibition have equivalent inhibitory effects on myocardial hypertrophy and fibrosis. These results serve as an important basis for planned investigations to evaluate the anti-remodelling effects of these agents on mice in which genetic manipulations are used to disrupt components of the Ang II signalling system.
Heart rate variability and baroreflex sensitivity are reduced in chronically undernourished, but otherwise healthy, human subjects
Authors: VAZ Mario , BHARATHI A.V. , SUCHARITA S. , NAZARETH D.
Published: August 2015

Alterations in autonomic nerve activity in subjects in a chronically undernourished state have been proposed, but have been inadequately documented. The present study evaluated heart rate and systolic blood pressure variability in the frequency domain in two underweight groups, one of which was undernourished and recruited from the lower socio-economic strata [underweight, undernourished (UW/UN); n = 15], while the other was from a high class of socio-economic background [underweight, well nourished (UW/WN); n = 17], as well as in normal-weight controls [normal weight, well nourished (NW/WN); n = 27]. Baroreflex sensitivity, which is a determinant of heart rate variability, was also assessed. The data indicate that total power (0–0.4Hz), low-frequency power (0.04–0.15Hz) and high-frequency power (0.15–0.4Hz) of RR interval variability were significantly lower in the UW/UN subjects (P<0.05) than in the NW/WN controls when expressed in absolute units, but not when the low- and high-frequency components were normalized for total power. Baroreflex sensitivity was similarly lower in the UW/UN group (P<0.05). Heart rate variability parameters in the UW/WN group were generally between those of the UW/UN and NW/WN groups, but were not statistically different from either. The mechanisms that contribute to the observed differences between undernourished and normal-weight groups, and the implications of these differences, remain to be elucidated.
P-selectin blockade fails to improve acute lung injury in sheep
Authors: CHANDRA Abhijit , KATAHIRA Jiro , SCHMALSTIEG Frank C. , MURAKAMI Kazunori , ENKHBAATAR Perenlei , COX Robert A. , HAWKINS Hal K. , TRABER Lillian D. , HERNDON David N. , TRABER Daniel L.
Published: August 2015

Accumulation of neutrophils in the lung contributes to the endothelial damage in the tissue associated with acute respiratory distress syndrome. This initial recruitment of neutrophils within the pulmonary microvasculature may involve P-selectin. Thus we hypothesized that an antibody against P-selectin would reduce pulmonary damage. Sheep were chronically instrumented and prepared. The first group received 40% body surface area third-degree burns with 48 breaths of cotton smoke and 1 mg/kg of anti-(P-selectin) antibody (termed 3D4) 1h post injury (n = 5). The second group (non-treated) received the same injury but no antibody treatment (n = 6). The third group comprised of sham animals without any injury or antibody treatment (n = 6). Sheep were studied for 48h during which they were uniformly resuscitated with Ringer's lactate solution by following the Parkland formula. All the animals were mechanically ventilated. In the non-treated injured group, the arterial partial pressure of O2 (‘PaO2’)/inspired fraction of O2 (‘FiO2’) ratio dropped to 168±30 at 48h, whereas the lung lymph flow increased to an average of 46±9ml/h (10-fold of baseline). These changes were not prevented by an anti-(P-selectin) antibody. The plasma and lymph nitrate/nitrite levels were lower in the antibody-treated group than in the non-treated group. The lymph conjugated dienes were significantly lower in the treated animals. However, lung myeloperoxidase activity and lung tissue conjugated dienes were significantly increased in the treated animals compared with the non-treated injured controls. In conclusion, although the anti-(P-selectin) antibody did not protect against lung injury during the initial 48h of burn and smoke, it decreased some aspects of injury in the peripheral microcirculation.
Cardiovascular hypertrophy in diabetic spontaneously hypertensive rats: optimizing blockade of the renin–angiotensin system
Authors: LASSILA Markus , DAVIS Belinda J. , ALLEN Terri J. , BURRELL Louise M. , COOPER Mark E. , CAO Zemin
Published: August 2015

The aim of the present study was to compare the antihypertrophic effects of blockade of the renin–angiotensin system (RAS), vasopeptidase inhibition and calcium channel antagonism on cardiac and vascular hypertrophy in diabetic spontaneously hypertensive rats (SHR). SHR with streptozotocin-induced diabetes were treated with one of the following therapies for 32 weeks: the angiotensin-converting enzyme (ACE) inhibitor captopril (100mg/kg); the angiotensin AT1 receptor antagonist valsartan (30mg/kg); a combination of captopril with valsartan; the vasopeptidase inhibitor mixanpril (100mg/kg); or the calcium channel antagonist amlodipine (6mg/kg). Systolic blood pressure and cardiac and mesenteric artery hypertrophy were assessed. Mean systolic blood pressure in diabetic SHR (200±5mmHg) was reduced by captopril (162±5mmHg), valsartan (173±5mmHg), mixanpril (176±2mmHg) and amlodipine (159±4mmHg), and was further reduced by the combination of captopril with valsartan (131±5mmHg). Captopril, valsartan and mixanpril reduced heart and left ventricle weights by approx. 10%. The combination of captopril and valsartan further reduced heart weight (-24%) and left ventricular weight (-29%). Amlodipine did not affect cardiac hypertrophy. Only mixanpril and the combination of captopril and valsartan significantly reduced mesenteric weight. The mesenteric wall/lumen ratio was reduced by all drugs, and to a greater extent by the combination of captopril and valsartan. We conclude that optimizing the blockade of vasoconstrictive pathways such as the RAS, particularly with the combination of ACE inhibition and AT1 receptor antagonism, is associated with antitrophic effects in the context of diabetes and hypertension. In contrast, calcium channel blockade, despite similar effects on blood pressure, confers less antitrophic effects in the diabetic heart and blood vessels.
Natriuretic peptides maintain sodium homoeostasis during chronic volume loading post-myocardial infarction in sheep
Authors: CHARLES Christopher J. , ELLIOTT John M. , NICHOLLS M. Gary , RADEMAKER Miriam T. , RICHARDS A. Mark
Published: August 2015

The impaired ability to excrete sodium is a key feature of established congestive heart failure and is also apparent in asymptomatic left ventricular (LV) impairment. However, few studies have examined responses to chronic volume loading immediately post-myocardial infarction (MI). Experimental MI was induced in six sheep by thrombogenic coil coronary artery occlusion, and resulted in significant LV dysfunction with reduced LV ejection fraction (P = 0.001) and subsequent remodelling (increased LV volumes, P = 0.015). Chronic volume loading with 2, 3 and 4litres/day intravenous saline (each for 7 days) showed no evidence of renal sodium or volume retention in sheep with experimental MI compared with six normal control sheep. Plasma levels of brain natriuretic peptide (BNP), N-terminal pro-BNP and cGMP (all P<0.05) were higher in the MI group compared with normal control sheep. There were no differences in haemodynamics, body mass or renin–aldosterone levels between groups. This study provides evidence that natriuretic peptides play a pivotal role in preserving volume/electrolyte balance in the early stages of post-MI cardiac dysfunction.
Association between serum values of C-reactive protein and cytokine production in whole blood of patients with Type 2 diabetes
Authors: Castoldi Giovanna , Galimberti Stefania , Riva Chiara , Papagna Ruggero , Querci Federico , Casati Marco , Zerbini Gianpaolo , Caccianiga Gianluigi , Ferrarese Carlo , Baldoni Marco , Valsecchi Maria Grazia , Stella Andrea
Published: August 2015

Diabetes mellitus accelerates atherosclerotic processes, and it is known that inflammation plays a key role in atherosclerosis. The aim of the present study was to evaluate in patients with Type 2 diabetes whether serum levels of CRP (C-reactive protein) are associated with cytokine production in whole blood. A total of 89 outpatients with Type 2 diabetes were enrolled, and blood pressure, body mass index, fasting blood glucose, glycated haemoglobin, cholesterol, triacylglycerols (triglycerides) and hs-CRP (high-sensitivity CRP) were measured. IL-6 (interleukin-6), IL-1β (interleukin-1β) and TNF-α (tumour necrosis factor-α) were measured before and after 24 h of incubation of whole blood with LPS (lipopolysaccharide) or saline. The basal values of IL-1β, IL-6 and TNF-α were low and were not significantly related to hs-CRP levels. A univariate analysis showed that the level of IL-1β and IL-6, obtained after 24 h of incubation of whole blood with LPS, increased significantly with increasing levels of hs-CRP and, after adjusting for potential confounders, IL-1β still remained statistically significant. In our sample of patients with Type 2 diabetes, there was no association between serum hs-CRP levels and basal levels of IL-6, IL-1β and TNF-α. Conversely, a significant association was observed between serum hs-CRP levels and IL-1β and IL-6 production after 24 h of incubation of whole blood with LPS. In conclusion, our data suggest that patients with Type 2 diabetes and high hs-CRP levels may have an enhanced reactivity in response to specific stimuli that produce different interleukins, with possible implications in inflammatory atherosclerotic processes.
Urinary cortisol is inversely associated with capillary recruitment in women: a potential explanation for the cortisol–blood pressure relationship
Authors: de Jongh Renate T. , Ijzerman Richard G. , Serné Erik H. , van Weissenbruch Mirjam M. , Voordouw Jasper J. , Delemarre-van de Waal Henriette A. , Stehouwer Coen D. A.
Published: August 2015

The relationships of cortisol with elevated blood pressure and insulin resistance are likely to be the result of a complex interplay of different mechanisms. We hypothesize that cortisol is associated with impaired microvascular function and that this contributes to cortisol-associated high blood pressure and insulin resistance. We examined 24 h urinary free cortisol excretion in 56 healthy adults (26 women). Blood pressure was assessed by 24 h ambulatory measurements. Insulin sensitivity was determined using the hyperinsulinaemic euglycaemic clamp technique. Skin capillary recruitment after arterial occlusion was visualized with videomicroscopy and endothelium-(in)dependent vasodilation was evaluated with iontophoresis of acetylcholine and sodium nitroprusside combined with laser Doppler fluxmetry. Men were characterized by higher urinary cortisol excretion [median (interquartile range), 162 (130–194) compared with 118 (99–156) nmol/24 h, P<0.05]. In women, but not in men, urinary cortisol excretion was associated with impaired capillary recruitment (r=−0.66, P<0.001), higher systolic blood pressure (r=0.64, P<0.001) and lower insulin sensitivity (r=−0.43, P<0.05). Urinary cortisol excretion was not associated with endothelium-(in)dependent vasodilation in men or women. Regression analysis demonstrated that capillary recruitment statistically explained 37% of the association between urinary cortisol and blood pressure in women. Capillary recruitment did not explain part of the association between urinary cortisol and insulin sensitivity. In conclusion, urinary cortisol excretion is inversely associated with capillary recruitment in women, but not in men, and capillary recruitment explains part of the cortisol–blood pressure relationship. These data suggest that, in women, impairment of capillary function mediates some of the adverse effects of cortisol and thus may provide a target to prevent such adverse effects.
Mechanisms by which fatty acids regulate leucocyte function
Authors: Martins de Lima Thais , Gorjão Renata , Hatanaka Elaine , Cury-Boaventura Maria Fernanda , Portioli Silva Erica Paula , Procopio Joaquim , Curi Rui
Published: August 2015

Fatty acids (FAs) have been shown to alter leucocyte function and thus to modulate inflammatory and immune responses. In this review, the effects of FAs on several aspects of lymphocyte, neutrophil and macrophage function are discussed. The mechanisms by which FAs modulate the production of lipid mediators, activity of intracellular signalling pathways, activity of lipid-raft-associated proteins, binding to TLRs (Toll-like receptors), control of gene expression, activation of transcription factors, induction of cell death and production of reactive oxygen and nitrogen species are described in this review. The rationale for the use of specific FAs to treat patients with impaired immune function is explained. Substantial improvement in the therapeutic usage of FAs or FA derivatives may be possible based on an improvement in the understanding of the precise molecular mechanisms of action with respect to the different leucocyte types and outcome with respect to the inflammatory responses.
Hydrothermal synthesis and tribological properties of MoSe2 nanoflowers
Authors: Zhang Xianghua , Xue Maoquan , Yang Xinghua , Luo Guangsi , Yang Feng
Published: August 2015

Molybdenum selenide (MoSe2) nanoflowers have been favourably synthesised by a mild hydrothermal route using sodium molybdate and selenium powder at low temperatures. The gained crystallographic products were analysed by powder X‐ray powder diffraction (XRD), energy‐dispersive spectroscopy, scanning electron microscopy (SEM) and high‐resolution transmission electron microscopy. The XRD pattern of the product can be easily indexed to hexagonal MoSe2. SEM and transmission electron microscopy graphics of the products reveal that the MoSe2 nanoflowers with diameters of about 100 nm consist of nanosheets. The tribological behaviours of MoSe2 as oil additives were evaluated on a ball‐on‐disc tribometer. Under the given experimental conditions, the oil containing MoSe2 gave lower friction coefficients than that of the base oil. A smooth triboﬁlm formed on worn surfaces is believed to be responsible for the good lubricating effects of MoSe2 as additives.
The importance of understanding: Model space moderates goal specificity effects
Authors: Kistner Saskia , Burns Bruce D. , Vollmeyer Regina , Kortenkamp Ulrich
Published: August 2015

The three-space theory of problem solving predicts that the quality of a learner's model and the goal specificity of a task interact on knowledge acquisition. In Experiment 1 participants used a computer simulation of a lever system to learn about torques. They either had to test hypotheses (nonspecific goal), or to produce given values for variables (specific goal). In the good- but not in the poor-model condition they saw torque depicted as an area. Results revealed the predicted interaction. A nonspecific goal only resulted in better learning when a good model of torques was provided. In Experiment 2 participants learned to manipulate the inputs of a system to control its outputs. A nonspecific goal to explore the system helped performance when compared to a specific goal to reach certain values when participants were given a good model, but not when given a poor model that suggested the wrong hypothesis space. Our findings support the three-space theory. They emphasize the importance of understanding for problem solving and stress the need to study underlying processes.
Inference and analysis of population structure using genetic data and network theory
Authors: Greenbaum Gili , Templeton Alan R. , Bar-David Shirli
Published: August 2015

Clustering individuals to subpopulations based on genetic data has become commonplace in many genetic studies. Inference of population structure is most often done by applying model-based approaches, aided by visualization using distance-based approaches such as multidimensional scaling. While existing distance-based approaches suffer from lack of statistical rigor, model-based approaches entail assumptions of prior conditions such as that the subpopulations are at Hardy-Weinberg equilibria. Here we present a distance-based approach for inference of population structure using genetic data by defining population structure using network theory terminology and methods. A network is constructed from a pairwise genetic-similarity matrix of all sampled individuals. Thecommunity partition, a partition of a network to dense subgraphs, is equated with population structure, a partition of the population to genetically related groups. Community detection algorithms are used to partition the network into communities, interpreted as a partition of the population to subpopulations. The statistical significance of the structure can be estimated by using permutation tests to evaluate the significance of the partition’smodularity, a network theory measure indicating the quality of community partitions. In order to further characterize population structure, a new measure of the Strength of Association (SA) for an individual to its assigned community is presented. The Strength of Association Distribution (SAD) of the communities is analyzed to provide additional population structure characteristics, such as the relative amount of gene flow experienced by the different subpopulations and identification of hybrid individuals. Human genetic data and simulations are used to demonstrate the applicability of the analyses. The approach presented here provides a novel, computationally efficient, model-free method for inference of population structure which does not entail assumption of prior conditions. The method is implemented in the software NetStruct, available athttps://github.com/GiliG/NetStruct.
Change of mind
Authors: Ogawa Rodney T
Published: August 2015

Purpose

– The purpose of this paper is for the author to recount how his use of organizational theory to understand educational reform in the USA led to a change of mind.

Design/methodology/approach

– My shift resulted from my conclusion, derived from the new institutionalism, that only marginal changes can be made in schools and, thus, fundamental change requires the design and construction of new systems.

Findings

– I moved from applying organization theory to find ways in which schools could improve academic outcomes for students, generally, and students from underserved communities, specifically to using organization theory to develop conditions that support efforts to design new systems to support learning.

Originality/value

– This paper’s contribution is that it encourages students of school organization to consider applying their theoretical perspectives to designing innovative social arrangements to foster learning and teaching.
Crisis management policy. How discourses shape academic-political actors
Authors: Maesse Jens
Published: August 2015

Purpose

– The purpose of this paper is to contribute to a discourse analytical understanding of the political economy. The term “crisis” is an important label in recent discussion in political economy. Yet the genuine discursive dimension of “the crisis” and the multiple linguistic layers of the crisis discourse remains an open issue.

Design/methodology/approach

– Realist perspectives usually believe in an external reality of crises independent of the language construction; in contrast, constructivist perspectives argue that a crisis is always the result of a socio-linguistic construction process. This contribution follows a critical-constructivist perspective, thereby taking into account powerful discursive actors which are able to “declare” a state in the world as a “crisis”.

Findings

– From a discourse analytical point of view, this paper examines the rules and logics of crisis management policy, arguing that a new politico-academic elite has appeared which is beyond the classical distinction between “Keynesians” and “neo-liberals”. By taking a position in the discourse of the recent debate on financial regulation, these new elite might be able to manage the crisis for a particular time, as they are constructed as “moderating actors” through academic and political discourses.

Research limitations/implications

– From a practical point of view, this analysis cannot offer economic solutions; from an analytical viewpoint, it will not give insights into discursive contexts.

Practical implications

– This analysis helps to understand current debates on economic policy and to improve the communicative efficiency of the participants.

Originality/value

– This paper combines a discourse analysis with a governmentality perspective and applies this analytical tool onto a political and economic topic currently prevailing in the global political economy.
Two sides of the same coin: matter and embodiment in metaphors of money
Authors: Sifaki Evi , Mooney Annabelle
Published: August 2015

Purpose

– The purpose of this paper is to document the conceptual metaphors (Lakoff and Johnson, 2003) found in the talk of Greek and Australian adults to describe how people think about money. As money becomes increasingly abstract, understanding money, dealing with debt and encouraging financial literacy become more problematic.

Design/methodology/approach

– Semi-structured interviews of a small sample (n = 7) are analysed using Lakoff and Johnson’s model of metaphor to map the underlying conceptual structures of money.

Findings

– This paper argues that the abstraction of money has led people to search for a conceptual object. The forms and features of this object are recovered by tracing the metaphors, their presuppositions and entailments. This shows that people think about money as a physical object that needs to be carefully managed to avoid bodily harm and personal physical discomfort. Specifically, money is an object with weight that physically constrains the body, a substance that can be addictive albeit with the agentive capacity of sentient beings.

Social implications

– While the physical and corporeal nature of money implicitly underpins existing money management techniques (e.g. “jam jar” accounts), a detailed understanding of money as a (conceptual) object provides detailed discursive, lexical and persuasive resources for promoting sound financial behaviour and perhaps informing both economic and social policies.

Originality/value

– While metaphor has been studied in economics texts, very little attention has been paid to the language that ordinary people use to talk about money. This research gives a clear picture of money as a metaphorically physical object.
Law enforcement officers
'
risk perceptions toward on-duty motor-vehicle events
Authors: Tiesman Hope M. , Heick Rebecca J. , Konda Srinivas , Hendricks Scott
Published: August 2015

Purpose

– Motor-vehicle-related events (MVEs) are the leading cause of on-duty death for law enforcement officers, yet little is known about how officers view this significant job hazard. The purpose of this paper is to explore officers’ motor-vehicle risk perception and examine how prior on-duty MVEs and the death or injury of a fellow officer influences this perception.

Design/methodology/approach

– A state-wide random sample of 136 law enforcement agencies was drawn using publically accessible databases, stratified on type and size of agency. In total, 60 agencies agreed to participate and a cross-sectional questionnaire was distributed to 1,466 officers. Using six-point Likert scales, composite scores for motor-vehicle and intentional violence risk perception were derived. A linear regression multivariable model was used to examine factors affecting motor-vehicle risk perception.

Findings

– Motor-vehicle risk perception scores were significantly higher than intentional violence scores. A prior on-duty motor-vehicle crash, prior roadside incident, or knowledge of fellow officer’s injury or death from a MVE significantly increased motor-vehicle risk perception scores. After controlling for potential confounders though, only prior on-duty crashes and roadside incidents impacted motor-vehicle risk perception.

Research limitations/implications

– The study comprised primarily small, rural agencies and generalizability may be limited. Also, although the data were collected anonymously, reporting and response biases may affect these findings.

Originality/value

– This study involved a large and diverse cohort of officers and explored motor-vehicle risk perception. A better understanding of officers’ risk perceptions will assist in the development and implementation of occupational injury prevention programs, training, and policy.