bluuebunny/crossref_metadata_2025 huggingface dataset:
Forearm vasoconstriction in response to noradrenaline and NG-monomethyl-L-arginine in essential hypertension
Authors: KNEALE Barry J. , CHOWIENCZYK Philip J. , BRETT Sally E. , COCKCROFT JohnR. , RITTER James M.
Published: August 2015

A role for abnormal NO production in essential hypertension remains controversial. Blunted vasoconstriction of forearm resistance vasculature in response to NG-monomethyl-⌊-arginine (⌊-NMMA; an inhibitor of NO biosynthesis), relative to the response to noradrenaline, has been reported in hypertensive patients and interpreted as evidence of reduced basal NO biosynthesis. We sought to determine whether reduced sensitivity of forearm vasculature to the vasoconstrictor action of l-NMMA relative to that of noradrenaline is a consistent finding in essential hypertension. We studied a group of patients (n = 32; blood pressure 176±4/102±2 mmHg; means±S.E.M.) and a group of healthy normotensive controls (n = 32; blood pressure 130±2/75±1 mmHg). Noradrenaline (60–240 pmol·min-1) and ⌊-NMMA (1–4 μmol·min-1) were infused into the brachial artery, and forearm blood flow was measured by venous occlusion plethysmography. The effects of each vasoconstrictor were similar in hypertensive and control subjects. The highest dose of l-NMMA reduced forearm blood flow by 0.75±0.12 ml·min-1·dl-1 in the control group and by 0.89±0.10 ml·min-1·dl-1 in the hypertensive group. The study had 90% power (with P = 0.05) to detect a 10% difference in forearm blood flow response between the hypertensive and control groups. We conclude that reduced sensitivity of forearm resistance vasculature to the vasoconstrictor action of l-NMMA is not a universal feature of essential hypertension. This argues against a primary role for reduced basal NO biosynthesis in skeletal muscle resistance vessels in the pathogenesis of essential hypertension.
Effect of aging on CD11b and CD69 surface expression by vesicular insertion in human polymorphonuclear leucocytes
Authors: NOBLE J. M. , FORD G. A. , THOMAS T. H.
Published: August 2015

The exocytosis of intracellular vesicles is an important function of the plasma membrane, which is responsible for hormone secretion, cell surface expression of antigens, ion transporters and receptors, and intracellular and intercellular signalling. Human aging is associated with many physiological and cellular changes, many of which are due to alterations in plasma membrane functioning. Alterations in vesicle externalization with age could account for many of these changes. We investigated whether alterations in vesicle exocytosis occur with increasing age by flow-cytometric determination of CD11b and CD69 expression on the surface of human polymorphonuclear leucocytes (PMN) stimulated with phorbol myristate acetate (PMA), a tumour promoter which binds to and activates protein kinase C (PKC) directly, or with formyl-Met-Leu-Phe (fMLP), which activates PKC indirectly via interactions with a cell surface receptor and G-protein, and subsequent inositol phosphate hydrolysis. Following stimulation with PMA, a decrease in the proportion of PMN expressing CD69 at high levels was observed in elderly compared with young subjects (young, 55.3%; elderly, 43.9%; P = 0.01). No aging-related differences in the proportion of PMN expressing CD11b (young, 73.7%; elderly, 68.4%; P = 0.15), or in the number of molecules of CD69 or CD11b expressed per cell, were observed. Stimulation with fMLP or low PMA concentrations resulted in full CD11b expression but minimal CD69 expression in both young and elderly subjects. Cells which expressed CD69 had no CD11b expression, while those cells expressing CD11b had minimal CD69 expression. Thus the PMA-induced expression of CD11b and CD69 in human PMN represents two separate processes, only one of which is affected in aging. CD11b expression appears to require a lesser degree of PKC stimulation compared with that required for CD69 expression. The age-associated reduction in PMA-stimulated CD69 expression may occur either at or distal to PKC activation. Such a decrease may contribute to the age-associated impairments in PMN function that contribute, in turn, to immunosenescence.
Neither endogenous nor inhaled nitric oxide influences the function of circulating platelets in healthy volunteers
Authors: ALBERT Johanna , WALLÉN N. Håkan , LI Nailin , FROSTELL Claes , HJEMDAHL Paul
Published: August 2015

Experimental models have indicated prothrombotic effects of inhibition of nitric oxide (NO) production, and anti-thrombotic effects of inhaled NO, but the influence of NO on platelet function in vivo in humans is not well established. We therefore investigated the effects of systemic inhibition of NO synthesis by NG-monomethyl-⌊-arginine (⌊-NMMA) and of NO inhalation on platelet function in vivo. On two occasions, ⌊-NMMA (13.5 mg/kg) or saline infusion was administered to 14 healthy volunteers in a double-blind cross-over study. After a 30 min infusion of ⌊-NMMA or placebo, NO inhalation (30 p.p.m) was added during the remaining 30 min of infusion, on both occasions. Measurements included filtragometry ex vivo (reflecting platelet aggregability), flow-cytometric evaluation of platelets in whole blood (fibrinogen binding and P-selectin expression), plasma β-thromboglobulin (reflecting platelet secretion), cGMP in platelets and plasma, thrombin generation markers (thrombin fragment 1+2 and thrombin–antithrombin complexes) in plasma, and bleeding time. l-NMMA increased blood pressure and decreased heart rate. NO inhalation did not influence blood pressure or heart rate, but caused a 3-fold elevation in plasma cGMP levels (P < 0.001). Neither ⌊-NMMA nor NO influenced filtragometry readings or flow-cytometric determinations of platelet fibrinogen binding and P-selectin expression. Furthermore, plasma β-thromboglobulin, platelet cGMP and thrombin generation markers were not influenced by either treatment. Bleeding time was not influenced by ⌊-NMMA compared with placebo, but was increased by ≈ 25% during NO inhalation (P < 0.01), whether NO synthesis had been inhibited or not. The prolongation of bleeding time by inhaled NO was not accompanied by any effect on the platelet variables assessed. The present results indicate that circulating platelets are not influenced by endogenous or inhaled NO, presumably due to the rapid inactivation of NO in the blood. This does not exclude possible effects of endothelial NO in the interface between the blood and the vessel wall.
Pulse rate variability is not a surrogate for heart rate variability
Authors: CONSTANT Isabelle , LAUDE Dominique , MURAT Isabelle , ELGHOZI Jean-Luc
Published: August 2015

To investigate the differences between heart rate (HR) variability and pulse rate (PR) variability, short-term variability of finger pulse wave and ECG signals were studied in 10 children with a fixed ventricular pacemaker rhythm (80 beats/min). Ten healthy children in sinus rhythm served as a reference population. Distal PR and HR were measured continuously using a Finapres device and an ECG respectively. Power spectra for HR and PR were calculated in both the supine and orthostatic positions. In paced subjects, PR spectra exhibited the characteristic respiratory peak, although the HR spectra were flat. Similarly, in healthy children the respiratory fluctuations were more pronounced when calculated from the finger pulse wave signal compared with the ECG signal. The overestimation of HR respiratory fluctuation resulting from distal PR measurement was more pronounced in the standing position; however, this postural effect was demonstrated only in healthy subjects. We observed mechanical respiratory modulation of distal PR independent of classical HR modulations. Our results suggest a mechanical respiratory influence via cardiac output and aortic transmural pressure changes on pulse wave velocity. We conclude that respiratory PR variability does not precisely reflect respiratory HR variability in standing healthy subjects and in patients with low HR variability. Consequently, HR modulation should be studied using the ECG signal rather than the distal pulse wave signal. However, when ECG recording is not available, the distal pulse wave is an acceptable alternative.
Relationship between erythropoietin and nitric oxide in the contraction of rat renal arcuate arteries and human umbilical vein endothelial cells
Authors: WU Xiao Chun , JOHNS Edward J. , RICHARDS Nicholas T.
Published: August 2015

We have investigated the effects of recombinant human erythropoietin (EPO) on the responses of rat renal arcuate arteries to dopamine, noradrenaline and acetylcholine and on the release of NO from human umbilical vein endothelial cells (HUVEC) in culture. Noradrenaline induced a concentration-dependent constriction and acetylcholine a concentration-dependent relaxation of the vessels. The effects of dopamine were concentration-dependent, leading to relaxation of the vessels at low concentrations and contraction of the vessels at high concentrations. NG-Nitro-L-arginine methyl ester (L-NAME; 0.1 mM) did not change the vasoconstrictor responses to noradrenaline and dopamine, but inhibited the acetylcholine- and dopamine-induced vasorelaxation. Neither 0.1 nor 20 units·ml-1 EPO affected noradrenaline-induced constriction, or dopamine- or acetylcholine-induced relaxation, of the vessels. EPO at 20 units·ml-1 attenuated dopamine-induced constriction of the vessels. This effect was blunted by application of L-NAME, suggesting that EPO may stimulate dopamine-mediated NO release from these vessels. EPO stimulated NO release from the resting HUVEC in a concentration- and time-dependent manner, an effect that was inhibited by the presence of NG-nitro-L-arginine. These data suggest that, in vitro, EPO is able to stimulate NO release from rat renal arcuate arteries and HUVEC in culture. Whether these acute short-term actions can be related to the longer-term actions of EPO remains to be resolved.
Splanchnic and extrasplanchnic extraction of insulin following oral and intravenous glucose loads
Authors: BRUNDIN Tomas
Published: August 2015

In the basal state, approx. 60–70% of the insulin released from the pancreas is extracted by the liver; the remaining 30–40% is extracted by extrasplanchnic organs. Carbohydrate ingestion is known to stimulate pancreatic insulin release and to inhibit whole-body insulin extraction. The present study was undertaken to obtain a quantitative assessment of the degree to which early postprandial insulinaemia in peripheral blood is due to the inhibition of splanchnic as opposed to extrasplanchnic insulin extraction. By means of catheterization, which allowed frequent analyses of insulin and C-peptide in arterial and hepatic venous blood and estimates of splanchnic plasma flow (indocyanine), insulin extraction by splanchnic and extrasplanchnic tissues was studied in 16 healthy volunteers at timed intervals before and after or during oral (n = 8) and intravenous (n = 8) isoglycaemic glucose loads. Splanchnic insulin extraction (66±2% in the basal state) fell significantly during the 10 min after oral glucose to a minimum of 45±8%; during 5–20 min of intravenous glucose administration it rose significantly to a maximum of 72±2%. Extrasplanchnic extraction of insulin fell from 90–100% in the basal state to a minimum of 3±6% (P< 0.001) after oral glucose; during the first 5 min of intravenous glucose infusion it fell in relative but not in absolute terms. It is concluded that the early postprandial increase in peripheral insulinaemia largely (> 85% during the first 30 min) reflects a marked inhibition of insulin extraction. It is suggested that intestinal hormones and/or splanchnic blood flow may be involved in the mechanisms governing the postprandial inhibition of insulin extraction.
Serum carnitine concentrations in patients with idiopathic hypertrophic cardiomyopathy: relationship with impaired myocardial fatty acid metabolism
Authors: NAKAMURA Tomoki , SUGIHARA Hiroki , KINOSHITA Noriyuki , ITO Kazuki , ADACHI Yoshihiko , HIRASAKI Satoshi , MATSUO Akiko , AZUMA Akihiro , KODO Naoki , NAKAGAWA Masao
Published: August 2015

We evaluated the clinical significance of serum carnitine concentrations in determining the severity of impaired myocardial fatty acid metabolism in idiopathic hypertrophic cardiomyopathy (HCM). We studied 56 asymptomatic or mildly symptomatic patients with HCM. Serum levels of free carnitine and acylcarnitine were measured by the enzymic cycling method. Myocardial scintigraphy with 123I-labelled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) was performed, and the images were analysed quantitatively and semi-quantitatively. Serum free carnitine levels were significantly higher in HCM patients than in normal subjects (52.5±9.5 and 42.3±5.5 nmol/ml respectively; P< 0.0001). On the other hand, serum acylcarnitine levels and acyl/free carnitine ratios were lower in HCM patients than in normal subjects (10.2±4.0 nmol/ml and 0.19±0.08, compared with 13.2±3.9 nmol/ml and 0.32±0.11 respectively; P< 0.0001). Clinical characteristics were not significantly different between the patients showing high and normal free carnitine levels, although female patients with high free carnitine levels were few (P = 0.02). Both quantitative and semi-quantitative analyses revealed that the severity of decreased myocardial BMIPP uptake was significantly correlated with serum free carnitine levels (quantitative analysis: r = -0.422, P< 0.0012; semi-quantitative analysis: r = 0.633, P< 0.0001). In the presence of reduced carnitine uptake into the myocardium in HCM, there may also be reduced transport of acylcarnitines out of the myocardium into the plasma. Although inborn errors of fatty acid metabolism and carnitine deficiencies are reported to provoke secondary HCM and are associated with low serum carnitine concentrations, this study has revealed that the levels of carnitine are, in contrast, increased in idiopathic HCM. Moreover, serum carnitine concentrations are a sensitive indicator of the severity of impaired myocardial fatty acid metabolism even in asymptomatic patients with HCM.
Effects of arm dominance and brachial artery cannulation on forearm blood flow measured by strain-gauge plethysmography
Authors: KAMPER Adriaan M. , CHANG Peter C.
Published: August 2015

The human forearm model is used extensively in physiological, pharmacological and clinical investigations. Effects of arm dominance or arterial cannulation on forearm flow measurements have never been tested formally. In the present study we tested the hypotheses that left or right arm dominance or cannulation of the brachial artery do not affect forearm haemodynamic responses to physiological or pharmacological stimuli. Results obtained in 16 volunteers showed that forearm blood flow responses to physiological stimuli are comparable before and after intra-arterial cannulation in either the dominant or the non-dominant forearm. Cannulation of a forearm brachial artery has a small effect on baseline blood flow. Responses to intra-arterially infused noradrenaline (norepinephrine) were not influenced by left or right arm dominance. Intravenous infusion of noradrenaline in eight subjects resulted in small responses in forearm blood flow that were slightly asymmetrical. During the intravenous infusion of noradrenaline, forearm blood flow or the forearm blood flow ratio did not reflect the marked increase in FVR that occurred. These results support our hypotheses (a) that either arm can be used as the control or intervention arm, and (b) that intra-arterial cannulation does not affect the results of intra-arterial infusion studies.
Muscle protein degradation and amino acid metabolism during prolonged knee-extensor exercise in humans
Authors: VAN HALL G. , SALTIN B. , WAGENMAKERS A. J. M.
Published: August 2015

The aim of this study was to investigate whether prolonged one-leg knee-extensor exercise enhances net protein degradation in muscle with a normal or low glycogen content. Net amino acid production, as a measure of net protein degradation, was estimated from leg exchange and from changes in the concentrations of amino acids that are not metabolized in skeletal muscle. Experiments were performed at rest and during one-leg knee-extensor exercise in six subjects having one leg with a normal glycogen content and the other with a low glycogen content. Exercise was performed for 90 min at a workload of 60–65% of maximal one-leg power output, starting either with the normal-glycogen or the low-glycogen leg, at random. The net production of threonine, lysine and tyrosine and the sum of the non-metabolized amino acids were 9–20-fold higher (P< 0.05) during exercise of the normal-glycogen leg than at rest. Total amino acid production was also 10-fold higher during exercise compared with that at rest (difference not significant). The net production rates of threonine, glycine and tyrosine and of the sum of the non-metabolized amino acids were about 1.5–2.5-fold higher during exercise with the leg with a low glycogen content compared with the leg with a normal glycogen content (P< 0.05). Total amino acid production was 1.5-fold higher during exercise for the low-glycogen leg compared with the normal-glycogen leg (difference not significant). These data indicate that prolonged one-leg knee-extensor exercise leads to a substantial increase in net muscle protein degradation, and that a lowering of the starting muscle glycogen content leads to a further increase. The carbon atoms of the branched-chain amino acids (BCAA), glutamate, aspartate and asparagine, liberated by protein degradation, and the BCAA and glutamate extracted in increased amounts from the blood during exercise, are used for the synthesis of glutamine and for tricarboxylic-acid cycle anaplerosis.
Use of opposing reflex stimuli and heart rate variability to examine the effects of lipophilic and hydrophilic β-blockers on human cardiac vagal control
Authors: VAILE Julian C. , FLETCHER Janine , AL-ANI Muzahim , ROSS Hamish F. , LITTLER William A. , COOTE John H. , TOWNEND Jonathan N.
Published: August 2015

Evidence from animal studies suggests that β-blockers can act within the central nervous system to increase cardiac vagal motoneuron activity. We have attempted to determine whether such an effect is evident in healthy humans, by examining the effects of lipophilic and hydrophilic agents on heart rate variability and cardiac vagal reflexes. A total of 20 healthy volunteers took part in the study. Autonomic studies were performed after 72 h of treatment with placebo, atenolol or metoprolol in a blinded cross-over design. ECG recordings were taken at rest and during mental and orthostatic stress. Heart rate variability was measured in the time and frequency domains. The effects on heart rate of two opposing cardiac vagal reflexes were examined. Trigeminal stimulation causing vagal stimulation, and isometric forearm muscle contraction (‘muscle heart reflex’) causing vagal inhibition, were performed alone and simultaneously. At rest, during mental stress and during trigeminal stimulation, β-blocker therapy was associated with significantly increased high-frequency beat-to-beat heart rate variability when compared with placebo. There were no significant differences in effects on heart rate or heart rate variability between atenolol and metoprolol. Analysis of the muscle heart reflex, alone and with simultaneous trigeminal stimulation, showed that the magnitude of the R–R interval response was significantly greater after β-blocker therapy compared with placebo, but the effects of atenolol and metoprolol were equivalent. β-Blocker therapy increased cardiac vagal activity, as shown by measures of high-frequency heart rate variability and reflex studies. Lipophilic and hydrophilic β-blockers appeared to be equally efficacious in increasing the cardiac vagal modulation of heart rate.
Impaired oxygen delivery to muscle in chronic fatigue syndrome
Authors: MCCULLY Kevin K. , NATELSON Benjamin H.
Published: August 2015

The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced oxygen delivery to muscles. Patients with CFS according to CDC (Center for Disease Control) criteria (n = 20) were compared with normal sedentary subjects (n = 12). Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemia oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous-wavelength near-IR spectroscopy. Phosphocreatine resynthesis was measured simultaneously using 31P magnetic resonance spectroscopy. The time constant of oxygen delivery was significantly reduced in CFS patients after exercise (46.5±16 s; mean±S.D.) compared with that in controls (29.4±6.9 s). The time constant of oxygen delivery was also reduced (20.0±12 s) compared with controls (12.0±2.8 s) after cuff ischaemia. Oxidative metabolism was also reduced by 20% in CFS patients, and a significant correlation was found between oxidative metabolism and recovery of oxygen delivery. In conclusion, oxygen delivery was reduced in CFS patients compared with that in sedentary controls. This result is consistent with previous studies showing abnormal autonomic control of blood flow. Reduced oxidative delivery in CFS patients could be specifically related to CFS, or could be a non-specific effect of reduced activity levels in these patients. While these results suggest that reduced oxygen delivery could result in reduced oxidative metabolism and muscle fatigue, further studies will be needed to address this issue.
Detection of presymptomatic atherosclerosis: a current perspective
Authors: ADAMS Mark R. , CELERMAJER David S.
Published: August 2015

Atherosclerosis, the pathological process underlying myocardial infarction, stroke and other occlusive vascular disease, is the major cause of death in the Western world. The development of techniques to accurately and reproducibly detect and measure the early changes of atherosclerosis and/or to identify subjects at highest cardiovascular risk may aid in the development of prevention strategies and facilitate a decrease in morbidity and mortality from atherosclerosis. Increasing understanding of the pathophysiology of early atherosclerosis has allowed the development of a number of potential methods for the assessment of the early stages of atherosclerosis in humans. These include techniques for assessing early structural changes in the coronary arteries with electron-beam computed tomography and magnetic resonance imaging. External vascular ultrasound has also been used to image other circulations as a surrogate marker for coronary atherosclerosis, e.g. the measurement of carotid artery intima-media thickness. Early functional changes of atherosclerosis have also been described many years before the development of structural changes. A number of techniques have been developed to measure endothelial dysfunction, one of the earliest changes of atherosclerosis, including non-invasive measurement of endothelial function using external vascular ultrasound. A variety of serum markers have also been described, and may be useful markers of atherosclerosis. We discuss some of the more promising techniques for the detection of early, presymptomatic atherosclerosis.
Structural and functional assessment of small arteries in patients with chronic heart failure
Authors: HILLIER C. , COWBURN P. J. , MORTON J. J. , DARGIE H. J. , CLELAND J. G. F. , MCMURRAY J. J. V. , McGRATH J. C.
Published: August 2015

The physiological response to a chronically failing heart is the implementation of compensatory mechanisms intended to support blood pressure. These mechanisms, which are not fully understood, increase peripheral vascular tone, thus increasing the strain on the weakened myocardium. This study investigated the structure and function of small arteries from heart failure patients and controls without heart failure in an attempt to identify abnormalities associated with heart failure which may be related to these mechanisms. Small arteries were dissected from gluteal biopsies and studied using wire myography. Arterial morphological parameters were measured and concentration–response curves constructed for a number of vasoconstrictor and vasodilator agonists. Plasma concentrations of neuroendocrine hormones were also measured. There were no morphological differences between small arteries from control subjects and those from patients with chronic heart failure. In heart failure patients, vasoconstrictor responses to endothelin-1 were significantly reduced, although plasma endothelin-1 levels were increased. Arteries from heart failure patients also showed evidence of an impaired neuronal uptake mechanism, since blockade by cocaine had no effect on noradrenaline-induced vasoconstriction in these vessels. These results suggest that small-artery structure is not altered in chronic heart failure and so cannot account for the heightened vascular resistance in this syndrome. However, abnormal neuronal uptake and impaired vasoconstriction in response to endothelin-1 may be associated with the complex compensatory phenomenon involved in heart failure.
Cytotoxic T lymphocytes and viral evolution in primary HIV-1 infection
Authors: PRICE David A. , O'CALLAGHAN Chris A. , WHELAN Joseph A. , EASTERBROOK Philippa J. , PHILLIPS Rodney E.
Published: August 2015

Efforts to develop immune-based therapies for HIV infection have been impeded by incomplete definition of the immunological correlates of protection. Despite many precedents demonstrating that CD8+ cytotoxic T lymphocytes are key mediators of protective anti-viral immunity in non-human animal models, direct evidence that these effector cells control viral replication in HIV-1 infection has remained elusive. The first part of this paper describes a detailed immunological and genetic study founded on evolutionary considerations. Following infection with HIV-1, virus variants which escaped recognition by autologous cytotoxic T lymphocytes were shown to possess a selection advantage within the host environment. Cytotoxic T lymphocytes therefore exert anti-viral pressure in vivo. This observation provides compelling evidence that cytotoxic T lymphocytes comprise a significant element of anti-retroviral immunity. Subsequently, the quantification of peripheral cytotoxic T lymphocyte frequencies utilizing peptide–(human leucocyte antigen class I) tetrameric complexes is described. Five patients with qualitatively similar immunodominant cytotoxic T lymphocyte responses during symptomatic primary HIV-1 infection were studied longitudinally. Expansions of virus-specific CD8+ lymphocytes comprising up to 2% of the total CD8+ T cell population were observed in the acute phase of infection. Antigenic load was identified as an important determinant of circulating HIV-1-specific CD8+ lymphocyte levels; however, significant numbers of such cells were also found to persist following prolonged therapeutic suppression of plasma viraemia. In addition, an analysis of antigenic sequence variation with time in this case series suggests that the early administration of combination anti-retroviral therapy may limit HIV-1 mutational escape from host cytolytic specificities. The implications of these preliminary data are discussed. The data presented suggest that vaccination protocols should aim to elicit vigorous cytotoxic T lymphocyte responses to HIV-1. Attempts to stimulate polyvalent responses to mutationally intolerant epitopes are likely to be most effective. Optimal management of HIV-1 infection requires an understanding of dynamic host–virus interactions, and may involve strategies designed to enhance cytotoxic T lymphocyte activity following periods of anti-retroviral drug therapy.
Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men
Authors: JEUKENDRUP A. E. , VET-JOOP K. , STURK A. , STEGEN J. H. J. C. , SENDEN J. , SARIS W. H. M. , WAGENMAKERS A. J. M.
Published: August 2015

The aim of the present study was to establish whether gastro-intestinal (GI) complaints observed during and after ultra-endurance exercise are related to gut ischaemia-associated leakage of endotoxins [lipopolysaccharide (LPS)] into the circulation and associated cytokine production. Therefore we collected blood samples from 29 athletes before, immediately after, and 1, 2 and 16 h after a long-distance triathlon for measurement of LPS, tumour necrosis factor-α and interleukin-6 (IL-6). As the cytokine response would trigger an acute-phase response, characteristic variables of these responses were also measured, along with creatine kinase (CK) to obtain an indicator of muscle damage. There was a high incidence (93% of all participants) of GI symptoms; 45% reported severe complaints and 7% of the participants abandoned the race because of severe GI distress. Mild endotoxaemia (5–15 pg/ml) was evident in 68% of the athletes immediately after the race, as also indicated by a reduction in IgG anti-LPS levels. In addition, we observed production of IL-6 (27–fold increase immediately after the race), leading to an acute-phase response (20-fold increase in C-reactive protein and 12% decrease in pre-albumin 16 h after the race). The extent of endotoxaemia was not correlated with the GI complaints or the IL-6 response, but did show a correlation with the elevation in C-reactive protein (rs 0.389; P = 0.037). Creatine kinase levels were increased significantly immediately post-race, and increased further in the follow-up period. Creatine kinase levels did not correlate with those of either IL-6 or C-reactive protein. It is therefore concluded that LPS does enter the circulation after ultra-endurance exercise and may, together with muscle damage, be responsible for the increased cytokine response and hence GI complaints in these athletes.
Hip and knee arthroplasty: a comparison and the endocrine, metabolic and inflammatory responses
Authors: HALL G. M. , PEERBHOY D. , SHENKIN A. , PARKER C. J. R. , SALMON P.
Published: August 2015

Changes in circulating levels of catecholamines, cortisol, glucose, interleukin-6 and C-reactive protein and in the leucocyte count were investigated for 7 days after surgery in 158 patients undergoing hip or knee arthroplasty. We compared the responses to the two operations, and also examined the effects of pathology (osteoarthritis and rheumatoid arthritis) on the changes associated with knee arthroplasty. Exploratory factor analysis was applied to the data to identify the variables and sampling times that could be used in future to provide a concise description of the response. Patients undergoing knee arthroplasty showed significantly greater changes in noradrenaline, adrenaline and glucose levels, but not in cortisol levels, compared with those undergoing hip arthroplasty. Interleukin-6 and C-reactive protein concentrations were also significantly greater in knee patients than hip patients; however, when corrected for pathology, many of these differences were not significant. Minimal effects of pathology (chronic inflammation with rheumatoid arthritis) were found on the hormonal changes in knee patients. In particular, there was little evidence to support the inference from animal data that the hypothalamic–pituitary–adrenal axis is impaired. The expected increases in interleukin-6 and C-reactive protein concentrations were found in the rheumatoid arthritis patients. Exploratory factor analysis showed that the response could be separated into six components, accounting for 60% of the total variance, and identified the variables and sampling times indicative of each. In conclusion, there are differences in the hormonal, but not inflammatory, responses to hip and knee arthroplasty. Little evidence was found for an important effect of pathology on the changes associated with knee surgery. Factor analysis provided a useful summary of the data.
5-Hydroxytryptamine- and U46619-mediated vasoconstriction in bovine pulmonary conventional and supernumerary arteries: effect of endogenous nitric oxide
Authors: BUNTON D. , MACDONALD A. , BROWN T. , TRACEY A. , MCGRATH J. C. , SHAW A. M.
Published: August 2015

We compared 5-hydroxytryptamine (5-HT)- and U46619-mediated contractions in bovine pulmonary conventional arteries (CA) and supernumerary arteries (SA). The effects of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) (100 μM) and the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 μM) on the responses of CA and SA to 5-HT and U46619 were also examined. In addition, the effects of the 5-HT2B receptor antagonist SB 200646 (1 nM–1 μM) on the responses to 5-HT in SA and CA were studied. Tissue cGMP levels were measured in the absence and presence of l-NAME, ODQ, 5-HT and U46619. 5-HT was approximately 30 times more potent in SA {-log [EC50 (M)] (pEC50) 6.32±0.13} than in CA (5.05±0.14). U46619 displayed a similar potency in both CA (pEC50 7.80±0.07) and SA (7.75±0.12). l-NAME did not significantly alter the resting tone of CA or SA. In contrast, ODQ produced a transient increase in the tone of both CA and SA. Neither l-NAME nor ODQ altered the responses to 5-HT or U46619 in CA. In addition, neither l-NAME nor ODQ altered the responses to U46619 in SA, but both l-NAME and ODQ increased the magnitude of the response to 5-HT in SA without changing the sensitivity. Inhibition of the 5-HT2B receptor with SB 200646 did not alter the response to 5-HT in SA or CA. Basal levels of cGMP (pmol/mg of protein) were similar in CA (1.16±0.33) and SA (0.8±0.51), and were not significantly changed in the presence of 5-HT or U46619. l-NAME and ODQ reduced the basal levels of cGMP in both SA and CA. The results suggest that endogenous NO selectively attenuates the vasoconstrictor response to 5-HT in SA, but not in CA. These results also suggest that the NO/cGMP pathway may have a role in maintaining low vascular tone, but that other mechanisms are able to compensate for the absence of this pathway.
Volume acceleration as an index of respiratory drive during exercise
Authors: URUMA Takahiro , KIMURA Hiroshi , KOJIMA Akira , HASAKO Kiyoshi , MASUYAMA Shigeru , TATSUMI Koichiro , KURIYAMA Takayuki
Published: August 2015

In order to evaluate the applicability of volume acceleration (AI) at the onset of inspiration as an index of neuromuscular output, CO2 rebreathing in six healthy subjects and incremental-load exercise in eight healthy subjects was performed while measuring AI and mouth occlusion pressure (P0.1). During CO2 rebreathing, AI increased linearly with end-tidal CO2 partial pressure and P0.1. During incremental-load exercise, P0.1 and AI increased exponentially with minute ventilation and mean inspiratory flow, and AI increased linearly with P0.1. Dyspnoea sensation at rest and exercise with or without the circuit system in eight healthy subjects was examined. Dyspnoea sensation increased markedly with the circuit system in some subjects. Incremental-load exercise was carried out by 13 healthy subjects and 21 patients with chronic obstructive pulmonary disease (COPD) to evaluate the difference in AI as respiratory drive between the two groups in the absence of a respiratory circuit. In patients with COPD, AI responses to minute ventilation, mean inspiratory flow and carbon dioxide output (co2) were greater than those in healthy subjects. In patients with COPD, the AI response to co2 was greater in those with a lower FEV1.0 (forced expiratory volume in 1.0 s), but the ventilatory response to co2 was lower in those with a lower FEV1.0. These data suggest that AI reflects neuromuscular output during CO2 rebreathing and incremental-load exercise under conditions where mechanical properties of the respiratory system are expected to be involved. During exercise, flow increased markedly, and the influence of the resistance of the respiratory circuit also increased. Therefore the use of AI has the advantage of less resistance (no respiratory circuit) and less additional respiratory effort, in comparison with the use of P0.1, especially in patients with COPD.
Hepatic sugar phosphate levels reflect gluconeogenesis in lung cancer: simultaneous turnover measurements and 31P magnetic resonance spectroscopy in vivo
Authors: LEIJ-HALFWERK Susanne , DAGNELIE Pieter C. , VAN DEN BERG J. Willem O. , WILSON J. H. Paul , SIJENS Paul E.
Published: August 2015

Stable-isotope tracers were used to assess whether levels of phosphomonoesters (PME) and phosphodiesters (PDE) in the livers of lung cancer patients, as observed by 31P magnetic resonance (MR) spectroscopy, reflect elevated whole-body glucose turnover and gluconeogenesis from alanine. Patients with advanced non-small-cell lung cancer without liver metastases (n = 24; weight loss 0–24%) and healthy control subjects (n = 13) were studied after an overnight fast. 31P MR spectra of the liver in vivo were obtained, and glucose turnover and gluconeogenesis from alanine were determined simultaneously using primed-constant infusions of [6,6-2H2]glucose and [3-13C]alanine. Liver PME concentrations were 6% higher in lung cancer patients compared with controls (not significant); PME levels in patients with ⩾ 5% weight loss were significantly higher than in patients with < 5% weight loss (P < 0.01). PDE levels did not differ between the groups. In lung cancer patients, whole-body glucose production was 19% higher (not significant) and gluconeogenesis from alanine was 42% higher (P < 0.05) compared with healthy subjects; turnover rates in lung cancer patients with ⩾ 5% weight loss were significantly elevated compared with both patients with < 5% weight loss and healthy subjects (P < 0.05). PME levels were significantly correlated with glucose turnover and gluconeogenesis from alanine in lung cancer patients (r = 0.48 and r = 0.48 respectively; P < 0.05). In conclusion, elevated PME levels in lung cancer patients appear to reflect increased glucose flux and gluconeogenesis from alanine. These results are consistent with the hypothesis that elevated PME levels are due to contributions from gluconeogenic intermediates.
Abnormal magnesium status in patients with cardiovascular diseases
Authors: SASAKI Shota , OSHIMA Tetsuya , MATSUURA Hideo , OZONO Ryoji , HIGASHI Yukihito , SASAKI Nobuo , MATSUMOTO Toshiyuki , NAKANO Yukiko , UEDA Atsushi , YOSHIMIZU Atsunori , KURISU Satoshi , KAMBE Masayuki , KAJIYAMA Goro
Published: August 2015

To investigate magnesium status in patients with cardiovascular diseases and in those presenting high factors for these diseases, we measured the concentrations of serum total Mg, serum ionized Mg and intra-erythrocyte Mg. Mg is an important cofactor for many enzymes, especially those involved in phosphate transfer reactions. Mg deficiency has been shown to be associated with fatal cardiovascular diseases, as well as with risk factors for these diseases. Only measurement of the serum concentration of total Mg is routinely available, but ionized Mg is the physiologically active component. Furthermore, most of the body's Mg is present in the intracellular space. Subjects included patients with ischaemic heart disease (n = 80), cardiac arrhythmia (n = 60), diabetes mellitus (n = 36), essential hypertension (n = 194) and hypercholesterolaemia (n = 60). The same measurements were made in healthy controls (30 men and 26 women; mean age 58±11 years). The serum ionized Mg concentration was measured with a selective ion electrode. The intra-erythrocyte Mg concentration was measured by atomic absorption. No gender difference was found for any Mg parameter, nor was age related to any Mg parameter. The serum albumin concentration was positively correlated only with the serum total Mg concentration. Although the serum total Mg concentration was similar in all groups, patients with diabetes mellitus and arrhythmia had lower serum levels of ionized Mg. Patients with essential hypertension exhibited higher intra-erythrocyte Mg concentrations than the healthy controls. Thus the measurement of serum total Mg concentration may obscure the presence of extracellular Mg deficiency in patients with arrhythmia and diabetes mellitus. Furthermore, the intracellular accumulation of Mg does not support the hypothesis of Mg deficiency in patients with essential hypertension.
Reproducible assessment of vaginal and rectal mucosal and skin blood flow: laser doppler fluximetry of the pelvic microcirculation
Authors: EMMANUEL A. V. , KAMM M. A. , BEARD R. W.
Published: August 2015

Pelvic venous congestion is a common cause of chronic pelvic pain in women of reproductive age. Although this condition represents a functional disturbance of the pelvic circulation which is related to the menstrual cycle, its aetiology remains unknown. Indirect techniques demonstrate that the vasoconstrictive reflex response of the microcirculation of the foot to a rise in venous pressure is attenuated throughout the menstrual cycle. We wished to develop a simple and non-invasive direct measure of pelvic blood flow to aid diagnosis of this condition. Laser doppler blood flux measurements of the skin of the big toe and of the vaginal and rectal mucosa in the follicular and luteal phases of the menstrual cycle in 12 healthy asymptomatic premenopausal women (mean age 30 years) with regular cycles and in four healthy asymptomatic postmenopausal women (mean age 59 years) were carried out both in the supine position and in response to 40° head-up tilt. The coefficient of variation of resting vaginal flux was lower for measurements in postmenopausal women (0.04) and in premenopausal women in the follicular phase (0.07) compared with those in the luteal phase (0.16). At rest, vaginal blood flow was higher than rectal and skin flux in both premenopausal and postmenopausal women. In the follicular phase a decrease in flow was observed in response to head-up tilt in the skin (-32.0%), vagina (-34.3%) and rectum (-9.4%). In the luteal phase this reflex was attenuated at these three sites (-8.6%, +6.7% and +7.4% respectively). There were no significant reflex changes in postmenopausal women. Thus laser doppler fluximetry is a reproducible method for comparing the flux of blood in the microcirculation of the skin and of the vaginal and rectal mucosa. The skin is the least sensitive site for testing vascular reactivity in response to cyclical changes. The vaginal and rectal microcirculations are the most sensitive sites for testing visceral cyclical reactivity, and have the advantage of direct anatomical relevance. The follicular phase of the menstrual cycle is associated with greatest vascular reactivity and is the most appropriate phase during which to test for abnormal vascular responses.
Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat
Authors: SHERMAN Rachel C. , LANGLEY-EVANS Simon C.
Published: August 2015

Epidemiological evidence from diverse human populations, supported by experimental evidence from animal models, suggests that maternal nutrition during pregnancy is an important fetal programming influence upon cardiovascular disease. Experiments with a low-protein-diet model of rat pregnancy suggest a role for the renin–angiotensin system in the programming mechanism, since fetal undernutrition permanently elevates pulmonary and plasma angiotensin-converting enzyme activity. Long-term beneficial effects of captopril on blood pressure in this model require further investigation in order to clarify the role of angiotensin II. Pregnant rats were fed a control diet containing 18% (w/w) casein as the protein source or a low-protein diet containing 9% (w/w) casein. Between the ages of 2 and 4 weeks postnatally, mothers and their pups were treated with losartan or nifedipine. All pups in the study had blood pressure determined at 4 and 12 weeks of age using a tail cuff. Animals exposed to the low-protein diet in utero and not subjected to drug treatment had elevated blood pressure relative to control rats (mean increase of 27 mmHg; P < 0.001). Treatment of rats exposed to the control diet in utero with either nifedipine or losartan between 2 and 4 weeks of age did not alter their blood pressure. Nifedipine had no effect upon the blood pressure of low-protein-exposed pups, but losartan prevented the blood pressure elevation in these animals. Between 4 and 12 weeks of age, blood pressure increased significantly in all groups (P < 0.001). The pattern of blood pressure among the groups was identical to that observed at 4 weeks, suggesting that the observed early effects of losartan would be maintained into adult life. The data are consistent with the hypothesis that angiotensin II plays a major role in the prenatal programming of hypertension. The action of angiotensin II at the AT1 receptor between 2 and 4 weeks of age may be critically up-regulated by fetal factors, including exposure to glucocorticoids of maternal origin.
Effects of proinsulin C-peptide on nitric oxide, microvascular blood flow and erythrocyte Na+,K+-ATPase activity in diabetes mellitus type I
Authors: FORST T. , DUFAYET DE LA TOUR D. , KUNT T. , PFÜTZNER A. , GOITOM K. , POHLMANN T. , SCHNEIDER S. , JOHANSSON B. L. , WAHREN J. , LÖBIG M. , ENGELBACH M. , BEYER J. , VAGUE P.
Published: August 2015

This study was conducted to evaluate the influence of proinsulin C-peptide on erythrocyte Na+,K+-ATPase and endothelial nitric oxide synthase activities in patients with type I diabetes. In a randomized double-blind study design, ten patients with type I diabetes received intravenous infusions of either human C-peptide or physiological saline on two different occasions. C-peptide was infused at a rate of 3 pmol·min-1·kg-1 for 60 min, and thereafter at 10 pmol·min-1·kg-1 for 60 min. At baseline and after 60 and 120 min, laser Doppler flow (LDF) was measured following acetylcholine iontophoresis or mild thermal stimulation (44 °C), and venous blood samples were collected to determine plasma cGMP levels and erythrocyte membrane Na+,K+-ATPase activity. The LDF response to acetylcholine increased during C-peptide infusion and decreased during saline infusion [18.6±19.2 and -13.2±9.4 arbitrary units respectively; mean±S.E.M.; P < 0.05). No significant change in LDF was observed after thermal stimulation. The baseline plasma concentration of cGMP was 5.5±0.6 nmol·l-1; this rose to 6.8±0.9 nmol·l-1 during C-peptide infusion (P < 0.05). Erythrocyte Na+,K+-ATPase activity increased from 140±29 nmol of Pi·h-1·mg-1 in the basal state to 287±5 nmol of Pi·h-1·mg-1 during C-peptide infusion (P < 0.01). There was a significant linear relationship between plasma C-peptide levels and erythrocyte Na+,K+-ATPase activity during the C-peptide infusion (r = 0.46, P < 0.01). No significant changes in plasma cGMP levels or Na+,K+-ATPase activity were observed during saline infusion. This study demonstrates an effect of human proinsulin C-peptide on microvascular function, which might be mediated by an increase in NO production and an activation of the erythrocyte Na+,K+-ATPase. These mechanisms are compatible with the previous observed microvascular effects of C-peptide in patients with type I diabetes.