bluuebunny/crossref_metadata_2025 huggingface dataset:
Venous duplex scanning of the leg: range, variability and reproducibility
Authors: HAENEN José H. , LANGEN Herman van , JANSSEN Mirian C. H. , WOLLERSHEIM Hub , HOF Martin A. van't , ASTEN Wim N. J. C. van , SKOTNICKI Stefan H. , THIEN Theo
Published: August 2015

Despite the many studies on venous haemodynamics using duplex, only a few evaluated the normal values, variability and reproducibility. Therefore, the range and variability of venous diameter, compressibility, flow and reflux were measured. To obtain normal values, 42 healthy individuals (42 limbs, 714 vein segments) with no history of venous disease were scanned by duplex. To determine the reproducibility the intra-observer variability was measured in 11 healthy individuals (187 vein segments) and the inter-observer variability in 15 healthy individuals (255 vein segments) and 13 patients (169 vein segments) previously diagnosed with deep venous thrombosis. Of the 714 normal vein segments, 708 (99%) were traceable, including the crural veins. Of the traceable vein segments, 675 (95%) were compressible and in 696 (98%) flow was present. Of the 42 common femoral vein segments, in 25 (60%) the reflux duration exceeded 1.0 s, but in the other proximal vein segments the reflux duration was less than 1.0 s (95% confidence interval 3.0–10.0). With the exception of the distal long saphenous vein, in the distal vein segments the reflux duration was less than 0.5 s (95% confidence interval 3.5–8.2). The coefficient of variation of the diameter measurements ranged from 14 to 50% and that of the reflux measurements from 28 to 60%. The κ-coefficient of the inter-observer variability in the classification of compressibility measurements in the patients was 0.77 and that of the reflux measurements was 0.86. This study shows that almost all veins were compressible in healthy individuals, except the distal femoral veins. In healthy individuals the duration of reflux of the proximal veins was less than 1.0 s and in the distal veins it was less than 0.5 s. The inter-observer variability of the reflux and compressibility measurements in the patients was good.
Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats
Authors: DRYDEN Simon , KING Peter , PICKAVANCE Lucy , DOYLE Patrick , WILLIAMS Gareth
Published: August 2015

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P< 0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 μg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P< 0.01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P< 0.01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P< 0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.
The myogenic response: established facts and attractive hypotheses
Authors: SCHUBERT Rudolf , MULVANY Michael J.
Published: August 2015

The myogenic response of small arteries and arterioles has been shown to contribute significantly to autoregulation in different vascular beds. It is characterized by a constriction of the vessel after an increase of transmural pressure and a dilation of the vessel after a decrease of transmural pressure. This review examines the evidence for the mechanisms of the myogenic response, with the aim of distinguishing between facts and hypotheses. It appears to be established that the myogenic response is stimulated by an alteration of vessel wall tension, that it does not require the presence of the endothelium and, for pressure increases, that it is accompanied by a membrane depolarization and an increase of the intracellular Ca2+ concentration, which depends largely on an influx of extracellular calcium via voltage-operated calcium channels. Under in vitro conditions, it may further be considered an established fact that the myogenic response can be modulated by transmitters, like noradrenaline, and factors released from the endothelium upon its activation. In contrast, many other aspects of the myogenic response remain hypothetical. Thus, the mechanism of the depolarization, its importance for the development of the myogenic response, the participation of other pathways for calcium influx, and the role of an intracellular calcium release in the myogenic response are still under debate. Furthermore, the participation of a variety of intracellular second messenger systems in the myogenic response, i.e. inositol trisphosphate, diacylglycerol, phospholipase A2, protein kinase C or 20-hydroxyeicosatetraenoic acid, is still unclear. Additionally, the roles of the pulsatility of the blood pressure and of remote signals from neighbouring vessel segments as well as of different metabolites are not clarified. This review suggests that while the primary mechanisms of the myogenic response are well understood, the details of the signalling pathways are still undefined. The clinical significance of the myogenic response remains to be determined.
Hormone replacement therapy increases isometric muscle strength of adductor pollicis in post-menopausal women
Authors: SKELTON D. A. , PHILLIPS S. K. , BRUCE S. A. , NAYLOR C. H. , WOLEDGE R. C.
Published: August 2015

A randomized open trial of hormone replacement therapy was used to assess changes in adductor pollicis muscle strength during 6–12 months of treatment with Prempak C 0.625® in comparison with an untreated control group. Muscle strength (maximal voluntary force; MVF), muscle cross-sectional area and bone mineral density were measured. Women entering the trial had oestrogen levels below 150 pmolċl-1, confirming their post-menopausal hormonal status. In the treated group, MVF increased by 12.4±1.0% (mean±S.E.M.) of initial MVF over the duration of treatment, while it declined slightly (2.9±0.9%) in the control group. This increase in strength could not be explained by an increase in muscle bulk, there being no significant increase in cross-sectional area during the study. Those subjects who were weakest at enrolment showed the greatest increases in muscle strength after treatment. Bone mineral density in total hip, Ward's triangle and total spine increased in the treated group, in agreement with previous studies. There was no correlation between the individual increases in bone mineral density and those in MVF.
Nitric oxide and penile erection in streptozotocin-diabetic rats
Authors: ARI Gil , VARDI Yoram , FINBERG John P. M.
Published: August 2015

The purpose of this investigation was to study the time course, response to insulin and characteristics of erectile dysfunction in streptozotocin (STZ)-diabetic Sprague–Dawley rats, and the function of the NO-generating system in these animals. Copulation-induced and reflex erection were quantified in conscious Sprague–Dawley rats at different times after injection of STZ. The corporal vasodilatation response to nerve stimulation was studied by measuring the rise in corporal pressure in pithed rats following electrical stimulation of sacral spinal nerve roots. The activity of NO synthase was determined in corporal tissue by measuring the generation of [3H]citrulline from [3H]arginine. Copulation-induced erection was inhibited at 1 and 2 months after STZ treatment, but this could be prevented by a short (2-week) pretreatment with insulin. Reflex erection was inhibited at 1, 4, 6 and 9 months after STZ; at 6 months, this inhibition was also reversible by insulin pretreatment. Following pithing, the basal corporal pressure was elevated in diabetic rats. At 4 months after STZ, this increase was normalized by a 2-week, but not by a 1-week, pretreatment with insulin; however, at 9 months after STZ, insulin pretreatment did not normalize corporal pressure. The increase in corporal pressure caused by stimulation of sacral nerve roots in pithed rats was enhanced in diabetic animals. This enhancement was also normalized at 4 months, but not at 9 months, by 2 weeks of insulin treatment. The inhibition of the stimulation-induced increase in corporal pressure by NG-nitro-L-arginine methyl ester (5 mg/kg) was less following 9 months of diabetes, although NO synthase activity was normal in cavernosal tissue following 6–8 months of diabetes. In conclusion, STZ-induced diabetes caused changes in the erectile system that were initially reversible by a short insulin treatment, but which with time (more than 6 months) became irreversible. NO synthase activity in cavernosal tissue was normal, but the response to NG-nitro-L-arginine methyl ester was inhibited in long-term diabetes (9 months).
An immunoluminometric assay for N-terminal pro-brain natriuretic peptide: development of a test for left ventricular dysfunction
Authors: HUGHES D. , TALWAR S. , SQUIRE I. B. , DAVIES J. E. , NG L. L.
Published: August 2015

Measurement of plasma levels of brain natriuretic peptide (BNP) has been used to assess left ventricular dysfunction and prognosis. Levels of the N-terminus of the precursor of BNP (NT-proBNP) have been reported to be elevated to a greater extent than BNP in left ventricular dysfunction. We have devised a non-radioactive sensitive and specific assay for NT-proBNP based on a competitive ligand binding principle. The chemiluminescent label 4-(2-succinimidyloxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate fluorosulphonate was used to label peptides representing domains in the middle and C-terminal sections of NT-proBNP. Assay of the C-terminal section of NT-proBNP (amino acids 65–76) in patients with proven left ventricular dysfunction [left ventricular wall motion index median 0.9 (range 0.3–1.4)] revealed elevated values [median 639 (386–911) fmol/ml] compared with normal controls [left ventricular wall motion index of 2 in all, NT-proBNP median 159 (120–245) fmol/ml, P< 0.001]. Measurement of the middle section of NT-proBNP (amino acids 37–49) was not a discriminating test. It is thus possible to derivatize small peptides with a methyl acridinium label and preserve immunodetection with specific antibodies. Such methodology may allow non-radioactive immunoluminometric assays to be devised.
Pregnancy decreases immunoreactive parathyroid hormone level in rats with chronic renal failure
Authors: BLUM M. , WEISMAN Y. , TURGEMAN S. , CABILI S. , WOLLMAN Y. , PEER G. , STERN N. , SILVERBERG D. , SCHWARTZ D. , IAINA A.
Published: August 2015

Normal pregnancy is associated with an increase in serum parathyroid hormone and 1,25-dihydroxyvitamin D3 (calcitriol). The effect of pregnancy on these hormones in chronic renal failure (CRF) is unknown. The present work was undertaken to study the changes of serum immunoreactive parathyroid hormone (iPTH) and calcitriol in pregnant rats with CRF. The following experimental groups were studied: CRF1 (5/6 nephrectomized virgin female rats), CRF2 (5/6 nephrectomized pregnant rats at day 20–21 of pregnancy), CRF3 (5/6 nephrectomized rats 2 weeks after delivery) and their respective sham-operated control groups: N1, N2 and N3. The 5/6 nephrectomy (CRF1) resulted in renal failure with very high serum iPTH (100±18 pg/ml) and low calcitriol levels (10.6±4.3 pg/ml) compared with normal rats [N1: 14±2.5 pg/ml (P< 0.001) and 18.2±4.2 pg/ml (P< 0.01) respectively]. The pregnancy in CRF rats (CRF2) resulted in normalization of serum iPTH levels (18.2±5.41 pg/ml), which was associated with a parallel increase in serum calcitriol (29.4±8.0 pg/ml) similar to that in pregnancy of normal rats (N2). Two weeks after delivery the CRF rats (CRF3) once again had high serum iPTH (87±17 pg/ml) and low calcitriol levels (9.3±1.2 pg/ml), similar to those observed in non-pregnant uraemic rats (CRF1). It is concluded that pregnancy decreases serum iPTH in 5/6 nephrectomized CRF rats most probably by the increased level of calcitriol synthesized by the feto-placental unit.
Splanchnic and systemic haemodynamic response to volume changes in patients with cirrhosis and portal hypertension
Authors: VLAVIANOS Panagiotis , MAC MATHUNA Padraik , WILLIAMS Roger , WESTABY David
Published: August 2015

We investigated the haemodynamic response to volume depletion and subsequent repletion in patients with cirrhosis and portal hypertension. Twelve patients with compensated cirrhosis and portal hypertension were included in the study. The haemodynamic changes occurring after removal of approx. 15% of the blood volume, and subsequently after isovolume repletion with colloid, were assessed. Baseline haemodynamic measurements showed increased cardiac output and a systemic vascular resistance at the lower limit of normal. The hepatic venous pressure gradient (HVPG) was increased, at 18 mmHg. After depletion, arterial pressure, cardiac output and all right-heart-sided pressures decreased, and systemic vascular resistance increased. HVPG decreased to 16.0 mmHg. All the above changes were statistically significant. After blood volume restitution, the haemodynamic values returned to baseline. In particular, an increase in HVPG was shown in four out of the twelve patients (two with ascites and two without), which was small in three of them. However, HVPG remained the same as or lower than the baseline in the other eight patients. Patients with cirrhosis and portal hypertension exhibit an abnormal haemodynamic response to blood volume depletion. After volume repletion, no increase in the portal pressure was noted in this group of patients as a whole, although four out of the twelve patients did show an increase, possibly due to extensive collateral circulation.
Glucocorticoids and insulin resistance: old hormones, new targets
Authors: ANDREWS Robert C. , WALKER Brian R.
Published: August 2015

Insulin resistance has been proposed as a mediator of the association between risk factors for cardiovascular disease in the population. The clinical syndrome of glucocorticoid excess (Cushing's syndrome) is associated with glucose intolerance, obesity and hypertension. By opposing the actions of insulin, glucocorticoids could contribute to insulin resistance and its association with other cardiovascular risk factors. In this review, we describe briefly the known mechanisms of insulin resistance and highlight the potential mechanisms for the effect of glucocorticoids. We then discuss factors which modulate the influence of glucocorticoids on insulin sensitivity; this highlights a novel therapeutic strategy to manipulate glucocorticoid action which may prove to be a useful tool in treating subjects with insulin resistance. Finally, we describe evidence from human studies that glucocorticoids make an important contribution to the pathophysiology of insulin resistance in the population.
Pulmonary granulocyte kinetics in relation to endothelial and granulocyte activation
Authors: USSOV W. Yu. , PETERS A. M. , CHAPMAN P. T. , TTOFI A. , MASON J. C. , HASKARD D. O. , HUGHES J. M. B.
Published: August 2015

The aim of the study was to measure the peripheral blood levels of soluble E-selectin in patients with systemic inflammation and compare them with in vivo granulocyte activation, pulmonary intravascular granulocyte pooling, pulmonary extravascular granulocyte migration and 99mTc-diethylenetriaminepenta-acetic acid (DTPA) aerosol clearance, an index of lung injury. The level of soluble E-selectin was measured by capture ELISA. Granulocytes were labelled with 111In and 99mTc for quantification of pulmonary granulocyte kinetics. The pulmonary vascular granulocyte pool (PGP) was expressed as a fraction of the total blood granulocyte pool. Pulmonary granulocyte migration was quantified on 24-h images using the 111In signal. Granulocyte activation was quantified as the percentage of circulating cells showing shape change (‘primed’). Lung injury was assessed from the clearance rate of inhaled 99mTc-DTPA aerosol. Eighteen patients with systemic inflammation were studied: five with inflammatory bowel disease, eight with systemic vasculitis, four with graft versus host disease and one with a recent renal transplant. The peripheral blood levels of soluble E-selectin were significantly elevated in patients with systemic inflammation. The level of soluble E-selectin showed a significant association with granulocyte migration (Spearman rank correlation coefficient, Rs = 0.53; P< 0.05) but not with PGP or with the percentage of cells showing shape change (P> 0.05 for both). Granulocyte migration was bimodal: patients were therefore subdivided into ‘migrators’ and ‘non-migrators’. Soluble E-selectin level, 99mTc-DTPA clearance and PGP, but not the percentage of cells showing shape change, were significantly higher in migrators than in non-migrators. We conclude that pulmonary intravascular granulocyte pooling is increased in the presence of increased numbers of circulating primed granulocytes but increased pooling does not by itself promote granulocyte migration into the lung interstitium. Insofar as an elevated level of E-selectin in peripheral blood reflects vascular endothelial activation, the data are consistent with the notion that pulmonary endothelial activation is required, in addition to granulocyte activation and an expanded PGP, for granulocyte migration into lung parenchyma and, therefore, for lung injury to occur.
Use of herpes simplex virus type 1 for transgene expression within the nervous system*
Authors: LACHMANN Robin H. , EFSTATHIOU Stacey
Published: August 2015

Gene therapy might provide a useful treatment for a number of neurological diseases and a great deal of effort is going into the development of vector systems which will allow the delivery of potentially therapeutic genes to terminally differentiated neurons within the intact mammalian brain. The ability of herpes simplex virus type 1 (HSV-1) to establish a lifelong latent infection within neurons has led to interest in its use as a neuronal gene delivery vector. During HSV latency no viral proteins are produced and transcription from the latent viral genome is limited to a family of nuclear RNAs, the latency-associated transcripts, whose function is not well understood. Obtaining prolonged expression of a transgene in latently infected neurons has proven difficult due to transcriptional silencing of exogenous promoters introduced into the latent viral genome. For this reason there is a great deal of interest in utilizing the HSV latency-associated promoter to drive the expression of therapeutic genes in latently infected neurons of both the peripheral and central nervous systems. In this review we describe a strategy which allows the latency-associated promoter to drive long-term reporter gene expression in the mammalian nervous system. These observations open up the possibility of using similar HSV-based vectors to express therapeutic transgenes within the brain and investigate the potential of gene therapy in a range of neurological disorders.
Circulating stress hormone and insulin concentrations in acute coronary syndromes: identification of insulin resistance on admission
Authors: STUBBS Peter J. , LAYCOCK John , ALAGHBAND-ZADEH J. , CARTER G. , NOBLE Mark I. M.
Published: August 2015

We re-examined, in the context of modern practice, plasma insulin and stress hormone concentrations in patients admitted to hospital with acute coronary syndromes. Venous blood sampling was carried out prior to anti-thrombotic therapy in 148 patients with myocardial infarction (MI); 76 patients with unstable angina (UA) pectoris were also studied, together with 27 patients with non-cardiac chest pain (NCP). There were significant progressive increases in the concentrations of catecholamines, cortisol, glucose and insulin from NCP to UA to MI patients. Hyperglycaemia (glucose > 8 mmol/l) was present in over 50% of MI patients. The plasma cortisol and insulin levels were both significantly positively correlated with the glucose concentration on admission. Only the cortisol concentration was correlated with peak cardiac enzyme levels. The glucose and insulin concentrations on admission in 141 MI and UA patients were related to insulin resistance, as judged from subsequent insulin and glucose concentrations measured while fasting and during a glucose tolerance test. The product of admission insulin×glucose (divided by 25; the admission insulin-resistance index, or AIRI) was significantly correlated with indices of insulin resistance, and was significantly higher (approximately double) in the MI group (7.81±0.76) and the UA group (6.88±1.19) than in the control NCP group (3.59±0.06; Kuskul–Wallis: P = 0.0001), implying that the insulin levels in the first two groups were approximately twice as high as is appropriate for the glucose levels. The ethnic origin of 20% of the patients was the Indian subcontinent; admission insulin and glucose levels in this subgroup were higher than in the non-Asians across all the groups with chest pain. Cortisol was the only stress hormone that was raised in proportion to the size of the infarct, and is a likely partial cause of the elevation in blood glucose. The high insulin levels were related to the prevalence of insulin resistance, and this was particularly important in the Asian subgroup presenting with MI and UA. Thus it appears feasible to identify acute coronary syndrome patients who are insulin-resistant at a time (on admission) when alternative early therapeutic strategies can be instituted.
Effect of adenosine on heart rate variability in humans
Authors: RONGEN Gerard A. , BROOKS Steven C. , POLLARD Michael J. , ANDO Shin-ichi , DAJANI Hilmi R. , NOTARIUS Catherine F. , FLORAS John S.
Published: August 2015

By stimulating afferent nerve endings in skeletal muscle, heart, kidney and the carotid body, adenosine infusion evokes a receptor-specific sympatho-excitatory reflex in humans that overrides its direct negative chronotropic effect. We tested the hypothesis that adenosine increases heart rate by suppressing parasympathetic and augmenting sympathetic components of heart rate variability. High-frequency (PH; 0.15-0.50 Hz) and low-frequency (PL; 0.05-0.15 Hz) components of heart rate variability total power (PT) were determined by spectral analysis. The ratios PH/PT and PL/PH respectively were used to estimate parasympathetic and sympathetic input to the sino-atrial node. Heart rate was recorded before and during a 5 min intravenous infusion of adenosine (140 μg·min-1·kg-1) in seven healthy men. Adenosine did not affect blood pressure, but increased heart rate by 33±6 beats/min, and reduced PT, PH, PL and PH/PT. In contrast, there was an increase in PL/PH. In a second experiment in nine men, brachial artery infusion of adenosine (15 μg·min-1·100 ml-1 forearm tissue) increased heart rate by 3 beats/min, had no effect on PT, PH, PL or PH/PT, yet increased PL/PH. Intra-arterial adenosine exerts a modest effect on heart rate by modulating cardiac sympathetic indices, without affecting parasympathetic indices, of heart rate variability, whereas intravenous infusion of adenosine reduces heart rate variability and raises heart rate by decreasing parasympathetic and increasing cardiac sympathetic tone. These reflex effects may become clinically relevant during adenosine stress testing, or when endogenous adenosine is increased, such as during ischaemia, exercise or vasodepressor reactions, or in heart failure.
Apoptosis and Bcl-xs in the intimal thickening of balloon-injured carotid arteries
Authors: IGASE Michiya , OKURA Takafumi , KITAMI Yutaka , HIWADA Kunio
Published: August 2015

We performed balloon injury in the rat carotid artery and identified intimal thickening after injury. Balloon-injured carotid arteries showed maximum thickness of the neointima on the 14th day before complete endothelial cell regeneration. In this lesion we identified apoptosis of vascular smooth muscle cells (VSMCs) by in situ DNA labelling and electron microscopy in the neointima on the 14th day after injury. mRNA expression levels of bcl-2, bax, bcl-x, p53 and caspase-1 were determined by the reverse transcriptase–polymerase chain reaction method both in injured and uninjured carotid arteries. Neither bcl-2 nor bcl-xl mRNA expression was detected in either injured or uninjured arteries, whereas bax and p53 mRNA expression was identified and their mRNA levels were not altered after balloon injury. In contrast, both bcl-xs and caspase-1 mRNA was detected and was markedly induced only in the injured carotid artery. Positive staining for immunoreactive Bcl-x was observed specifically in the injured arterial wall and co-localized with positive staining of nuclei identified by in situ DNA labelling. We conclude that two opposite cellular responses, VSMC proliferation and apoptosis, exist together in the neointima of the rat carotid artery after balloon injury, and selective induction of Bcl-xs expression is a key regulator of VSMC apoptosis in the process of vascular remodelling.
Short-term variability of blood pressure and heart rate in Guillain-Barreá syndrome without respiratory failure
Authors: ANNANE Djillali , BAUDRIE Véronique , BLANC Anne-Sophie , LAUDE Dominique , RAPHAËL Jean-Claude , ELGHOZI Jean-Luc
Published: August 2015

The effect of Guillain-Barré syndrome (GBS) on the short-term variability of blood pressure and heart rate was evaluated in six patients presenting with a moderate form of the syndrome, i.e. unable to stand up unaided and without respiratory failure, at the height of the disease and during recovery. The patients were compared with six age-matched healthy volunteers. During the acute phase of the syndrome, GBS patients exhibited a significant heart rate elevation (+26 beats/min compared with healthy subjects), but the acceleratory response to atropine, or to 60 ° head-up tilt, was maintained. Resting plasma noradrenaline levels were high in acute GBS, but the secretory response to tilt was preserved. Desensitization to noradrenaline was observed in acute GBS with a reduced pressor action of this α-adrenoceptor agonist. Blood pressure levels were normal and head-up tilt did not induce orthostatic hypotension in this moderate form of GBS. Power spectral analysis demonstrated marked alterations in cardiovascular variability. The overall heart period variability was markedly reduced with the reduction predominantly in the high-frequency (respiratory) range (-73%). The low-frequency component of heart period variability was also reduced (-54%). This cardiovascular profile of moderate GBS at the height of the disease could result from a demyelination of the reflex loop controlling respiratory oscillations in heart rate and from a desensitization of the arterial tree to an elevated plasma noradrenaline. Sympathetic nervous activation may contribute to the high resting heart rate in acute GBS.
Gender differences in the endothelial regulation of α2-adrenoceptor-mediated contraction in the rat aorta
Authors: TEJERA Nuria , BALFAGÓN Gloria , MARÍN Jesús , FERRER Mercedes
Published: August 2015

The aim of this study was to determine the possible influence of sex hormones on the contractile responses induced by clonidine, an agonist of α2-adrenoceptors, as well as the endothelial modulation of these responses. For this purpose, thoracic aorta segments from male (control and castrated) and female (in oestrous phase and ovariectomized) rats were used. In intact segments from the four groups of rats, clonidine (0.01-10 µmol/l) induced concentration-dependent contractions, which were increased by the nitric oxide synthase inhibitor Nω-nitro-⌊-arginine methyl ester (0.1 mmol/l) or by endothelium removal, but were reduced by 1 µmol/l yohimbine (an α2-adrenoceptor antagonist) in all animals and by 1 µmol/l indomethacin (a cyclo-oxygenase inhibitor) in control males only. The rank order of the magnitude of the maximal response was: oestrous females > ovariectomized females > control males > castrated males, whereas the sensitivity to clonidine (EC50 value) was similar in all animals. In endothelium-denuded segments, the rank order was: oestrous females = control males > ovariectomized females = castrated males. These results suggest that: (1) the presence of oestrogen or androgen increases the contraction caused by α2-adrenoceptor activation with clonidine; (2) endothelium negatively modulates the response to this agonist in the four groups of rats, due to endothelial NO release (entirely in females and in part in males); (3) androgen also seems to modulate the response by stimulating the release of an endothelial contracting factor, probably a prostanoid; and (4) the endothelium of males has a greater capacity than that of comparable females for negative regulation of the tension generated by the underlying vascular smooth muscle.
Phagocyte functions in stressed rats: comparison of modulation by glutamine, arginine and ornithine 2-oxoglutarate
Authors: MOINARD Christophe , CHAUVEAU Béatrice , WALRAND Stéphane , FELGINES Catherine , CHASSAGNE Jacques , CALDEFIE Florence , CYNOBER Luc A. , VASSON Marie-Paule
Published: August 2015

The effects of diets supplemented with 6.8 mmol⋅day-1⋅kg-1 glutamine, arginine or ornithine 2-oxoglutarate [ornithine α-ketoglutarate (OKG), a precursor of both glutamine and arginine] on phagocyte functions [i.e. H2O2 production by leucocytes and secretion of tumour necrosis factor α (TNFα) by stimulated macrophages] of stressed rats were studied. The relationship between the immunological effects of these amino acids and their plasma and tissue (muscle and intestine) concentrations was also explored. The catabolic model used consisted of injections of dexamethasone (DEX; 1.5 mg⋅day-1⋅kg-1) for 5 days. As previously described, DEX suppressed TNFα secretion in stimulated macrophages. Supplementation with arginine or OKG, but not glutamine, was able to counteract the DEX effect on TNFα secretion. Glutamine, arginine and OKG supplementation increased H2O2 production by monocytes and polymorphonuclear neutrophils from DEX-treated rats. All DEX-treated rats showed plasma and muscle glutamine depletion and also a decrease in the concentration of arginine in the gastrocnemius. Supplementation with glutamine, arginine or OKG was not able to counteract these depletions. It was concluded that glutamine, arginine and OKG improve phagocyte responses during stress, and that glutamine depletion is not necessarily associated with dysimmunity, since no correlation between glutamine tissue pools and the immune state was observed.
Effects of treatment of rheumatoid arthritis patients with an antibody against tumour necrosis factor α on reticuloendothelial and intrapulmonary granulocyte traffic
Authors: TAYLOR P. C. , PETERS A. M. , GLASS D. M. , MAINI R. N.
Published: August 2015

The therapeutic effects of a monoclonal antibody against tumour necrosis factor α (TNFα) were evaluated objectively in 10 patients with rheumatoid arthritis by 111In-labelled granulocyte imaging before and after treatment, and compared with changes in granulocyte kinetics with respect to the liver, spleen and lungs. Anti-TNFα resulted in a decrease in the size of the whole-body pool of marginating granulocytes, as reflected by a significant increase in the 30 min intravascular recovery of labelled granulocytes from 40% (S.D. 10) to 47% (S.D. 16) of injected activity (P< 0.02). The 111In contents of the spleen, liver and lungs were unchanged, so the origin of the increment in recovery was presumed to be a reduction in granulocyte margination in inflamed synovium, although this was not quantifiable. The sizes of the granulocyte pools in the liver and lungs, expressed as the 111In content of the organ per unit of circulating 111In-labelled cells, were not significantly different after treatment, but the splenic granulocyte pool decreased by 16% (S.D. 19) (P< 0.05). Individual changes in the size of the splenic pool showed no significant correlation with corresponding changes in 30 min recovery or with corresponding indices of inflammation (24 h 111In-granulocyte joint activity and C-reactive protein). We conclude that anti-TNFα produces an obvious resolution in inflammatory joint activity that is accompanied by an increased circulating component of the total blood granulocyte pool, as a result of decreased margination at sites of inflammation. Anti-TNFα may also produce a specific decrease in splenic granulocyte pooling, independent of any anti-inflammatory effects, although a similar decrease in the lungs, which might be anticipated as a result of reduced cytokine-induced granulocyte activation, could not be detected.
Elevated activity of semicarbazide-sensitive amine oxidase in blood from patients with skeletal metastases of prostate cancer
Authors: EKBLOM Jonas , GRÖNVALL Jenny , LENNERNÄST Bo , NILSSON Sten , GARPENSTRAND Håkan , ORELAND Lars
Published: August 2015

The semicarbazide-sensitive amine oxidases constitute a group of copper-containing enzymes whose physiological function is unclear. The enzymes are present in various tissues, including blood plasma. At present, the source of the plasma enzyme in humans is not known. Results of a recent study suggested that semicarbazide-sensitive amine oxidase is expressed in the skeleton, e.g. in the spine. Using an indirect autoradiographic method in mice, we provide evidence that semicarbazide-sensitive amine oxidase is present in high abundance in bone tissue. Specific activities of semicarbazide-sensitive amine oxidase were estimated in blood samples from subjects with femoral bone fractures. Moreover, enzyme activities were also measured in patients suffering from prostate cancer with skeletal metastases. The level of specific semicarbazide-sensitive amine oxidase activity in serum was significantly elevated in patients with skeletal metastases compared with both healthy controls and patients having prostate cancer without signs of skeletal metastases. Based on the results of the present study, we propose that semicarbazide-sensitive amine oxidase in blood plasma may originate, at least in part, from the skeleton.
Broad-band spectral analysis of 24 h continuous finger blood pressure: comparison with intra-arterial recordings
Authors: CASTIGLIONI Paolo , PARATI Gianfranco , OMBONI Stefano , MANCIA Giuseppe , IMHOLZ Ben P. M. , WESSELING Karel H. , DI RIENZO Marco
Published: August 2015

The present study compares the spectral characteristics of 24-h blood pressure variability estimated invasively at the brachial artery level with those estimated by measurement of blood pressure at the finger artery using the non-invasive Portapres device. Broad-band spectra (from 3×10-5 to 0.5 Hz) were derived from both finger and intra-brachial pressures recorded simultaneously for 24 h in eight normotensive and twelve hypertensive ambulant subjects. At frequencies lower than 0.07 Hz, higher spectral estimates were obtained by Portapres than by intra-brachial measurements. The maximum overestimation occurred in systolic pressure at around 10-2 Hz, where the amplitude of the oscillations was two times greater when measured by Portapres. A less pronounced overestimation was found for diastolic pressures. The maximum overestimation was greater during daytime than during night-time. At around 0.1 Hz, invasive and non-invasive spectra were similar. At the respiratory frequencies (0.15-0.50 Hz), the power spectra were overestimated by Portapres during daytime, and underestimated at night. These results provide reference information for the correct interpretation of Portapres data in the estimation of 24-h blood pressure spectral power.
Changes in calcium homoeostasis in patients undergoing liver transplantation: effects of a single infusion of pamidronate administered pre-operatively
Authors: BISHOP N. J. , NINKOVIC M. , ALEXANDER G. J. M. , HOLMES S. D. , MILLIGAN T. , PRICE C. , COMPSTON J. E.
Published: August 2015

Bone turnover, bone loss and fracture risk increase after liver transplantation. It has been postulated that peri-operative administration of a bisphosphonate might prevent bone loss and reduce fracture rate. We studied the effects of a single pre-operative dose of pamidronate on biochemical parameters of skeletal metabolism in the first month after liver transplantation. In a randomized, single-blind study, six of 12 patients with chronic liver disease received 60 mg of pamidronate intravenously on a single occasion 1–30 days before transplantation. Six other patients undergoing transplantation received no pamidronate. We measured serum calcium, phosphate, albumin, bone-specific alkaline phosphatase, plasma parathyroid hormone and tartrate-resistant acid phosphatase before pamidronate infusion and at frequent intervals during the first 30 post-operative days. In treated patients, plasma parathyroid hormone increased 12-fold over baseline values and remained elevated in comparison with baseline at days 26–30; serum calcium and phosphate fell significantly, returning to normal at around day 14 post-operatively. There were no significant changes in any parameter in the untreated group. No changes in bone formation or resorption markers were observed in either group. The large increase in plasma parathyroid hormone concentrations in the treated group is probably secondary to the fall in serum calcium. The magnitude of the increase is much greater than that seen after pamidronate infusion in other patient groups. The lack of change in, or correlation of, serum calcium and plasma parathyroid hormone in the untreated group suggests that additional factors release calcium from bone after liver transplantation, presumably by increasing bone resorption.
Lipoprotein(a), essential fatty acid status and lipoprotein lipids in female Australian vegetarians
Authors: LI Duo , BALL Madeleine , BARTLETT Melinda , SINCLAIR Andrew
Published: August 2015

In the present study we investigated serum lipoprotein(a) [Lp(a)] levels, plasma lipids, the serum phospholipid polyunsaturated fatty acid profile and correlates of serum Lp(a) in healthy free-living female vegetarians (n = 50) and omnivores (n = 24) to assess differences which may have implications for cardiovascular risk. Dietary saturated fat and total plasma cholesterol were significantly lower in the vegetarians compared with omnivores. The mean serum Lp(a) concentration was lower in the vegetarians (171 mg/l) than in the omnivores (247 mg/l). The serum Lp(a) concentration was significantly negatively correlated with carbohydrate intake (as % of energy), and positively correlated with plasma total cholesterol. Compared with the omnivores, the vegetarians had significantly lower concentrations of 20:3,n-6, 20:4,n-6, 22:5,n-6, 20:5,n-3, 22:6,n-3 and total n-6 and n-3 polyunsaturated fatty acids, and a lower n-3/n-6 polyunsaturated fatty acid ratio, in serum phospholipids. Lower concentrations of plasma total cholesterol, serum phospholipid total fatty acids, total saturated fatty acids and arachidonic acid, and a tendency towards a lower serum Lp(a) concentration, in vegetarians may have beneficial effects on cardiovascular disease risk. However, the decreased concentration of serum phospholipid n-3 polyunsaturated fatty acids may potentially promote thrombotic risk. Based on the present data, it would seem appropriate for omnivores to reduce their dietary intake of total fat and saturated fat in order to decrease their plasma cholesterol, and vegetarians should perhaps increase their dietary intake of n-3 polyunsaturated fatty acids, and thus improve the balance of n-3/n-6, in order to reduce any thrombotic tendency that might increase their generally low risk of cardiovascular disease.
Adrenomedullin in monocytes and macrophages: possible involvement of macrophage-derived adrenomedullin in atherogenesis
Authors: NAKAYAMA Masaharu , TAKAHASHI Kazuhiro , MURAKAMI Osamu , MURAKAMI Hiroshi , SASANO Hironobu , SHIRATO Kunio , SHIBAHARA Shigeki
Published: August 2015

Macrophages secrete a variety of growth factors, cytokines and vasoactive peptides, which are related to the progression of atherosclerosis. Adrenomedullin (ADM) is a potent vasodilator peptide and inhibits proliferation and migration of vascular smooth muscle cells. In this study, we investigated the production and secretion of ADM by monocytes and macrophages by Northern blot analysis, RIA and immunocytochemistry. Northern blot analysis showed that ADM mRNA was expressed in human monocytes obtained from peripheral blood and monocyte-derived macrophages. The expression level of ADM mRNA in monocyte-derived macrophages was about five times higher than that in monocytes. Treatment with lipopolysaccharide (100 ng/ml) for 24 h increased ADM mRNA expression levels in both monocytes and monocyte-derived macrophages. The levels of immunoreactive ADM in the media of monocyte-derived macrophages were about three times higher than that of monocytes (0.718±0.046 fmol/24 h/105 cells, n = 8 compared with 0.259±0.018 fmol/24 h/105 cells, n = 8; mean±S.E.M., P < 0.01). The secretion was also increased by treatment with lipopolysaccharide. Immunocytochemistry showed positive ADM immunostaining in macrophages in atherosclerotic lesions of human aorta obtained at autopsy. ADM secreted from activated macrophages may play an inhibitory role in atherogenesis.
Role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis
Authors: WONG Florence , LIU Peter , LILLY Lesley , BOMZON Arieh , BLENDIS Laurence
Published: August 2015

The aim of this study was to assess the relationship between subtle cardiovascular abnormalities and abnormal sodium handling in cirrhosis. A total of 35 biopsy-proven patients with cirrhosis with or without ascites and 14 age-matched controls underwent two-dimensional echocardiography and radionuclide angiography for assessment of cardiac volumes, structural changes and systolic and diastolic functions under strict metabolic conditions of a sodium intake of 22 mmol/day. Cardiac output, systemic vascular resistance and pressure/volume relationship (an index of cardiac contractility) were calculated. Eight controls and 14 patients with non-ascitic cirrhosis underwent repeat volume measurements and the pressure/volume relationship was re-evaluated after consuming a diet containing 200 mmol of sodium/day for 7 days. Ascitic cirrhotic patients had significant reductions in (i) cardiac pre-load (end diastolic volume 106±9 ml; P < 0.05 compared with controls), due to relatively thicker left ventricular wall and septum (P < 0.05); (ii) afterload (systemic vascular resistance 992±84 dyn·s·cm-5; P < 0.05 compared with controls) due to systemic arterial vasodilatation; and (iii) reversal of the pressure/volume relationship, indicating contractility dysfunction. Increased cardiac output (6.12±0.45 litres/min; P < 0.05 compared with controls) was due to a significantly increased heart rate. Pre-ascitic cirrhotic patients had contractile dysfunction, which was accentuated when challenged with a dietary sodium load, associated with renal sodium retention (urinary sodium excretion 162±12 mmol/day, compared with 197±12 mmol/day in controls; P < 0.05). Cardiac output was maintained, since the pre-load was normal or increased, despite a mild degree of ventricular thickening, indicating some diastolic dysfunction. We conclude that: (i) contractile dysfunction is present in cirrhosis and is aggravated by a sodium load; (ii) an increased pre-load in the pre-ascitic patients compensates for the cardiac dysfunction; and (iii) in ascitic patients, a reduced afterload, manifested as systemic arterial vasodilatation, compensates for a reduced pre-load and contractile dysfunction. Cirrhotic cardiomyopathy may well play a pathogenic role in the complications of cirrhosis.
Inter-relationships between small, dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects
Authors: GRIFFIN B. A. , MINIHANE A. M. , FURLONGER N. , CHAPMAN C. , MURPHY M. , WILLIAMS D. , WRIGHT J. J. , WILLIAMS C. M.
Published: August 2015

A predominance of small, dense low-density lipoprotein (LDL) is a major component of an atherogenic lipoprotein phenotype, and a common, but modifiable, source of increased risk for coronary heart disease in the free-living population. While much of the atherogenicity of small, dense LDL is known to arise from its structural properties, the extent to which an increase in the number of small, dense LDL particles (hyper-apoprotein B) contributes to this risk of coronary heart disease is currently unknown. This study reports a method for the recruitment of free-living individuals with an atherogenic lipoprotein phenotype for a fish-oil intervention trial, and critically evaluates the relationship between LDL particle number and the predominance of small, dense LDL. In this group, volunteers were selected through local general practices on the basis of a moderately raised plasma triacylglycerol (triglyceride) level (> 1.5 mmol/l) and a low concentration of high-density-lipoprotein cholesterol (< 1.1 mmol/l). The screening of LDL subclasses revealed a predominance of small, dense LDL (LDL subclass pattern B) in 62% of the cohort. As expected, subjects with LDL subclass pattern B were characterized by higher plasma triacylglycerol and lower high-density lipoprotein cholesterol (< 1.1 mmol/l) levels and, less predictably, by lower LDL cholesterol and apoprotein B levels (P < 0.05; LDL subclass A compared with subclass B). While hyper-apoprotein B was detected in only five subjects, the relative percentage of small, dense LDL-III in subjects with subclass B showed an inverse relationship with LDL apoprotein B (r =-0.57; P < 0.001), identifying a subset of individuals with plasma triacylglycerol above 2.5 mmol/l and a low concentration of LDL almost exclusively in a small and dense form. These findings indicate that a predominance of small, dense LDL and hyper-apoprotein B do not always co-exist in free-living groups. Moreover, if coronary risk increases with increasing LDL particle number, these results imply that the risk arising from a predominance of small, dense LDL may actually be reduced in certain cases when plasma triacylglycerol exceeds 2.5 mmol/l.