bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of insulin on the cardiac autonomic nervous system in insulin-resistant states
Authors: PAOLISSO Giuseppe , MANZELLA Daniela , RIZZO Maria Rosaria , BARBIERI Michelangela , VARRICCHIO Gina , GAMBARDELLA Antonio , VARRICCHIO Michele
Published: August 2015

The effects of insulin infusion on cardiac autonomic nervous system (ANS) activity were investigated in healthy subjects (n = 15) and in patients with various types of insulin-resistance, such as obese subjects (n = 20) and those with hypertension (n = 15) or type II (non-insulin-dependent) diabetes (n = 22). Healthy subjects and patients underwent euglycaemic hyperinsulinaemic glucose clamp, and cardiac ANS and haemodynamic changes were investigated by continuous recording of heart rate variability by the Holter technique and by venous occlusion plethysmography respectively. At baseline, healthy subjects had the highest values for total spectral power and the low-frequency (LF) component, and the lowest value for the high-frequency (HF) component. In the pooled data (n = 72), the fasting plasma insulin concentration was correlated with baseline total spectral power (r = -0.37; P< 0.001) and the LF/HF ratio (r = -0.35; P< 0.003). Such correlations were still significant (P< 0.01 for both) after adjustment for body fat and mean arterial blood pressure. In a multivariate linear stepwise analysis (n = 72), a model including body fat, waist/hip ratio, fasting plasma glucose concentration and insulin-mediated glucose uptake explained 47% of the variability of the change in the LF/HF ratio, with body fat (t = -3.11; P< 0.01) and insulin-mediated glucose uptake (t = -3.48; P< 0.008) being significantly and independently associated with insulin-mediated changes in the LF/HF ratio. Insulin infusion reduced the total spectral power and increased the LF/HF ratio in healthy subjects, but not in insulin-resistant patients. In conclusion, our study demonstrates that insulin fails to stimulate cardiac ANS activity in insulin-resistant patients, independently of the causes of insulin resistance.
Venous reflux has a limited effect on calf muscle pump dysfunction in post-thrombotic patients
Authors: HAENEN José H. , JANSSEN Mirian C. H. , BRAKKEE Alphonsus J. M. , LANGEN Herman VAN , WOLLERSHEIM Hub , DE BOO Theo. M. , SKOTNICKI Stefan H. , THIEN Theo
Published: August 2015

The purpose of the present study was to evaluate the relationship between calf muscle pump dysfunction (CMD) and the presence and location of valvular incompetence. Deep vein obstruction might influence CMD, and so venous outflow resistance (VOR) was measured. VOR and calf muscle pump function were measured in 81 patients, 7–13 years after venographically confirmed lower-extremity deep venous thrombosis. The supine venous pump function test (SVPT) measures CMD, and the VOR measures the presence of venous outflow obstructions, both with the use of strain-gauge plethysmography. Valvular incompetence was measured using duplex scanning in 16 vein segments of one leg. Venous reflux was measured in proximal veins using the Valsalva manoeuvre, and in the distal veins by distal manual compression with sudden release. Abnormal proximal venous reflux was defined as a reflux time of more than 1 s, and abnormal distal venous reflux as a reflux time of more than 0.5 s. No statistically significant relationship was found between the SVPT and either the location or the number of vein segments with reflux. Of the 81 patients, only nine still had an abnormally high VOR, and this VOR showed no relationship with the SVPT. In conclusion, venous reflux has a limited effect on CMD, as measured by the SVPT. The presence of a venous outflow obstruction did not significantly influence the SVPT. Duplex scanning and the SVPT are independent complementary tests for evaluating chronic venous insufficiency.
Determinants of the acetate recovery factor: implications for estimation of [13C]substrate oxidation
Authors: SCHRAUWEN Patrick , BLAAK Ellen E. , AGGEL-LEIJSSEN Dorien P. C. van , BORGHOUTS Lars B. , WAGENMAKERS Anton J. M.
Published: August 2015

When using 13C or 14C tracers to study substrate metabolism, an acetate correction factor should be applied to correct for loss of label in the exchange pathways of the tricarboxylic acid cycle. We have shown recently that the [13C]acetate recovery factor has a high inter-individual variability and should therefore be determined in every subject. In the present study we examined the factors that might explain some of the variability between subjects in acetate recovery factor. Data were pooled from four different studies with identical protocols, in which the acetate recovery factor was measured, prior to an intervention, to correct plasma fatty acid oxidation rates. Acetate recovery was measured after 2 h of [1,2-13C]acetate infusion at rest followed by 1 h of cycling exercise at 40–50% of maximal oxygen uptake. Inter-individual variance in acetate recovery was 12.0% at rest and 16.1% during exercise. Stepwise regression revealed that, at rest, 37.1% of the acetate recovery could be accounted for by basal metabolic rate adjusted for fat-free mass, percentage body fat and respiratory quotient (RQ). During exercise, 69.1% of the variance in acetate recovery could be accounted for by energy expenditure adjusted for fat-free mass, % body fat and RQ. In conclusion, we show that the acetate recovery factor has a high inter-individual variability, both at rest and during exercise, which can partly be accounted for by metabolic rate, RQ and % body fat. These data indicate that the acetate recovery factor needs to be determined in every subject, under similar conditions as used for the tracer-derived determination of substrate oxidation. Failure to do this might result in large under- or over-estimation of plasma substrate oxidation, and hence to artificial differences between groups.
Influence of age and dietary fish oil on plasma soluble adhesion molecule concentrations
Authors: MILES Elizabeth A. , THIES Frank , WALLACE Fiona A. , POWELL Jonathan R. , HURST Tina L. , NEWSHOLME Eric A. , CALDER Philip C.
Published: August 2015

Soluble forms of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin (termed sICAM-1, sVCAM-1 and sE-selectin respectively) are found in the plasma, and are elevated during inflammatory conditions in which there is increased expression of the cellular forms of the molecules on endothelial and other cells. sICAM-1, sVCAM-1 and sE-selectin concentrations were measured in the plasma of 140 healthy Caucasian subjects aged between 18 and 75 years (100 males/40 females). sICAM-1 concentrations varied between 59.9 and 299.7 ng/ml (median 150 ng/ml), sVCAM-1 concentrations varied between 222.8 and 1672.9 ng/ml (median 662 ng/ml) and sE-selectin concentrations varied between 12.4 and 90.3 ng/ml (median 45.5 ng/ml). There were significant positive linear correlations between age and the plasma concentrations of sICAM-1 (r = 0.580; P < 0.001) and sVCAM-1 (r = 0.392; P < 0.001), which were retained when the effects of gender, body mass index and fasting plasma triacylglycerol and total cholesterol concentrations were controlled for. The significant positive linear correlation between age and the plasma concentration of sE-selectin (r = 0.234; P = 0.027) was lost when other variables were controlled for. Male subjects < 40 years of age had significantly lower plasma concentrations of both sICAM-1 and sVCAM-1 than males > 55 years of age (both P < 0.001), but the difference in plasma sE-selectin concentrations between the age groups did not reach significance (P = 0.073). Subgroups of 16 males aged < 40 years and 12 elderly subjects (> 55 years of age) participated in a doubled-blind, placebo-controlled study of fish oil supplementation over 12 weeks. The level of eicosapentaenoic acid in plasma phospholipids did not change with placebo supplementation, but was significantly increased with fish oil supplementation in both young male and elderly subjects (median increase 200%). sICAM-1, sVCAM-1 and sE-selectin concentrations were unaffected by supplementation with placebo in either young male or elderly subjects. sICAM-1 concentrations were unaffected by fish oil supplementation. sE-selectin concentrations were significantly increased by fish oil supplementation in young males (P = 0.043; median increase 38%), but fish oil tended to decrease plasma sE-selectin concentrations in the elderly subjects (P = 0.075), with a median decrease of 11%. sVCAM-1 concentrations were unaffected by fish oil supplementation in young males. Fish oil supplementation significantly decreased plasma sVCAM-1 concentrations in the elderly subjects (P = 0.043), with a median decrease of 20% (range 16–60%). These observations suggest that fish oil decreases endothelial activation in elderly subjects.
Protein and energy metabolism in chronic bacterial infection: studies in melioidosis
Authors: PATON Nicholas I. , ANGUS Brian , CHAOWAGUL Wipada , SIMPSON Andrew J. , SUPUTTAMONGKOL Yupin , ELIA Marinos , CALDER Graham , MILNE Eric , WHITE Nicholas J. , GRIFFIN George E.
Published: August 2015

Chronic infection is often accompanied by a wasting process, the metabolic basis of which is not fully understood. The aims of the present study were to measure protein and energy metabolism in patients with melioidosis (a serious and antibiotic-refractory Gram-negative bacterial infection which is endemic in South-East Asia) in order to define the metabolic abnormalities that might contribute to wasting. Whole-body protein turnover was measured using the [13C]leucine technique, both in the fasted state and while consuming a high-energy meal. Resting energy expenditure was measured by indirect calorimetry, and total energy expenditure by the bicarbonate/urea method. Results were normalized for fat-free mass, as estimated from skinfold thickness. Protein turnover was increased in melioidosis patients compared with healthy controls during fasting (170.9 compared with 124.1 µmol·kg-1·h-1; P = 0.04), but the net rate of catabolism (22.2 compared with 20.5 µmol·kg-1·h-1; P = 0.77) and the anabolic response to feeding were similar in the two groups. Resting energy expenditure was higher in melioidosis patients compared with controls (191.4 and 157.3 kJ·kg-1·day-1 respectively; P = 0.04), but total energy expenditure (measured in a separate group of eight patients with melioidosis) was low (192.1 kJ·kg-1·day-1). In conclusion, this study found no evidence of metabolic causative factors, such as accelerated net protein catabolism during fasting, a blunted anabolic response to feeding or increased daily energy expenditure, and therefore suggests that reduced energy intake is the prime cause of wasting. The observed normal response to feeding should encourage nutritional approaches to prevent wasting.
Post-transcriptional effects of extracellular pH on tumour necrosis factor-α production in RAW 246.7 and J774 A.1 cells
Authors: HEMING Thomas A. , TUAZON Divina M. , DAVÉ Sanat K. , CHOPRA Ashok K. , PETERSON Johnny W. , BIDANI Akhil
Published: August 2015

The present studies determined the effects of extracellular pH (pHo) on the production of tumour necrosis factor-α (TNF-α) in the macrophage-like cell lines RAW 246.7 and J774 A.1. The cells were activated with lipopolysaccharide (LPS) at pHo 5.5, 6.5 or 7.4. TNF-α gene transcription was monitored by Northern blot analysis. Synthesis of the cytokine was monitored by ELISA measurements of the TNF-α content of cell-conditioned media (extracellularly released TNF-α) and cell lysates (cytosolic TNF-α). The magnitude of the TNF-α response differed markedly between the two cell lines. RAW cells were more responsive to LPS than were J774 cells. However, the effects of pHo on TNF-α production were similar in the two cell lines. TNF-α gene transcription was insensitive to experimental pHo. The pHo had no effect on the abundance of TNF-α mRNA at 2, 4 or 18 h. Nonetheless, synthesis of TNF-α was affected significantly by pHo. The TNF-α contents of cell-conditioned medium and cell lysate at 18 h were reduced progressively at lower pHo values. The data indicate that pHo alters TNF-α production in RAW and J774 cells at a post-transcriptional level. These findings suggest that pHo influences the phenotypic responses of macrophages to activating stimuli and modifies the role that macrophages play in inflammatory and immune actions.
Additive hypotensive and anti-albuminuric effects of angiotensin-converting enzyme inhibition and angiotensin receptor antagonism in diabetic spontaneously hypertensive rats
Authors: CAO Zemin , BONNET Fabrice , DAVIS Belinda , ALLEN Terri J. , COOPER Mark E.
Published: August 2015

Angiotensin II plays a pivotal role in the development of diabetic nephropathy, but it remains controversial as to the best approach to effectively block the actions of this hormone in the kidney. The aim of the present study was to explore the effects of long-term treatment (8 months) with a combination of an angiotensin type 1 (AT1) receptor antagonist, irbesartan (15 mg/kg per day), and an angiotensin-converting enzyme (ACE) inhibitor, captopril (100 mg/kg per day), in diabetic spontaneously hypertensive rats. Captopril treatment reduced blood pressure (163±3 mmHg versus diabetic 201±3 mmHg), but not albumin excretion rate (43.8×/÷1.3 mg/day versus diabetic 46.8×/÷1.4 mg/day). Irbesartan treatment was associated with a similar reduction in blood pressure (173±3 mmHg) to captopril, and albumin excretion rate was reduced (14×/÷1.5 mg/day). The combination of irbesartan and captopril induced further reductions in blood pressure (140±3 mmHg) and albumin excretion rates (4.0×/÷1.5 mg/day). Gene expression of transforming growth factor β-1 was reduced by all treatments to a similar level as assessed by in situ hybridization. These results demonstrate the additive hypotensive and anti-albuminuric effects of an ACE inhibitor and an AT1 receptor, suggesting that combination therapy is an approach not only more effective at reducing blood pressure, but also at retarding the development of diabetic nephropathy.
Counteracting sarcopenia in post-menopausal women: do hormones and strength training accomplish the task?
Authors: KJÆR MICHAEL
Published: August 2015

Accelerated loss of muscle mass and strength with aging, termed sarcopenia, represents both an individual problem of decreased mobility as well as a socio-economic burden by increasing risk of falls and subsequent injuries, especially if combined with decreased bone density and mass. The causes of sarcopenia are multifactorial, and include: age-related decline in physical activity, anabolic steroid hormones and growth factors, decreased energy intake and reduced muscle protein synthesis, nervous system degeneration, oxidative stress, and alterations in the immune system. However, the relative role of these factors remains largely unknown. The fact that the rate of muscle loss increases rapidly after transition into menopause suggests a strong coupling to changes in ovarian hormone status [1]. Similarly, it has been shown that menopause transition is also strongly accompanied by a reduction in leisure time physical activity.
Dilution and redistribution effects of rapid 2-litre infusions of 0.9% (w/v) saline and 5% (w/v) dextrose on haematological parameters and serum biochemistry in normal subjects: a double-blind crossover study
Authors: LOBO Dileep N. , STANGA Zeno , SIMPSON J.Alastair D , ANDERSON John A. , ROWLANDS Brian J. , ALLISON Simon P.
Published: August 2015

Although hypoalbuminaemia after injury may result from increased vascular permeability, dilution secondary to crystalloid infusions may contribute significantly. In this double-blind crossover study, the effects of bolus infusions of crystalloids on serum albumin, haematocrit, serum and urinary biochemistry and bioelectrical impedance analysis were measured in healthy subjects. Ten male volunteers received 2-litre infusions of 0.9% (w/v) saline or 5% (w/v) dextrose over 1 h; infusions were carried out on separate occasions, in random order. Weight, haemoglobin, serum albumin, serum and urinary biochemistry and bioelectrical impedance were measured pre-infusion and hourly for 6 h. The serum albumin concentration fell in all subjects (20% after saline; 16% after dextrose) by more than could be explained by dilution alone. This fall lasted more than 6 h after saline infusion, but values had returned to baseline 1 h after the end of the dextrose infusion. Changes in haematocrit and haemoglobin were less pronounced (7.5% after saline; 6.5% after dextrose). Whereas all the water from dextrose was excreted by 2 h after completion of the infusion, only one-third of the sodium and water from the saline had been excreted by 6 h, explaining its persistent diluting effect. Impedances rose after dextrose and fell after saline (P < 0.001). Subjects voided more urine (means 1663 and 563 ml respectively) of lower osmolality (means 129 and 630 mOsm/kg respectively) and sodium content (means 26 and 95 mmol respectively) after dextrose than after saline (P < 0.001). While an excess water load is excreted rapidly, an excess sodium load is excreted very slowly, even in normal subjects, and causes persistent dilution of haematocrit and serum albumin. The greater than expected change in serum albumin concentration when compared with that of haemoglobin suggests that, while dilution is responsible for the latter, redistribution also has a role in the former. Changes in bioelectrical impedance may reflect the electrolyte content rather than the volume of the infusate, and may be unreliable for clinical purposes.
Lipid synthesis in macrophages derived from the human cell line THP-1: modulation of the effects of native and oxidized chylomicron-remnant-like particles by oestrogen
Authors: NAPOLITANO Mariarosaria , BATT Kelly V. , AVELLA Michael , BRAVO Elena , BOTHAM Kathleen M.
Published: August 2015

The effects of native and oxidized chylomicron remnants on the synthesis of cholesteryl ester and triacylglycerol in macrophages, and the way that this is influenced by exposure of the cells to oestrogen, was investigated using the human monocyte cell line THP-1 and chylomicron-remnant-like particles containing human apolipoprotein E (CRLPs). Synthesis of the lipids was measured by the incorporation of [3H]oleate into cholesteryl ester and triacylglycerol. CRLPs (5-40μg of cholesterol/ml) containing either trilinolein or triolein as the triacylglycerol component caused a dose-dependent decrease in cholesteryl ester formation, while triacylglycerol production was unchanged. After oxidation of the CRLPs, the level of thiobarbituric acid-reactive substances was increased by 6.3-fold and 2.2-fold in particles containing trilinolein and triolein respectively. Furthermore, CRLPs containing oxidized trilinolein lost their ability to down-regulate cholesterol esterification, while CRLPs containing oxidized triolein did not. Both types of oxidized CRLPs decreased triacylglycerol synthesis. Treatment of the macrophages with 17β-oestradiol caused increases of approx. 94% and 34% in the synthesis of cholesteryl ester and triacylglycerol respectively in the absence of CRLPs. The differences between control and oestrogen-treated cells were abolished, however, when CRLPs (40μg of cholesterol/ml) were added to the incubations. In addition, in contrast with their lack of effect in control cells, CRLPs containing oxidized trilinolein decreased cholesterol esterification in oestrogen-treated cells by approx. 48%. These findings with CRLPs suggest that chylomicron remnants have significant effects on cholesteryl ester and triacylglycerol synthesis in macrophages, which may be modulated both by the oxidation state of the particles and by oestrogen.
Expression of neuropilin-1 by human glomerular epithelial cells in vitro and in vivo
Authors: HARPER Steven J. , XING Chang Ying , WHITTLE Cathy , PARRY Robin , GILLATT David , PEAT Danielle , MATHIESON Peter W.
Published: August 2015

Vascular endothelial growth factor (VEGF) is a potent promoter of endothelial mitogenesis and of endothelial permeability. Within the kidney it is synthesized primarily in the visceral glomerular epithelial cells (vGECs); however, the role of VEGF in the glomerulus remains unknown, as does the target cell upon which it acts. Although the target cells may be those of the glomerular endothelium, there are micro-anatomical reasons why this might not be the case. This, therefore, led us to consider the possibility that glomerular VEGF may bind to the vGECs themselves. Since it has been shown that vGECs do not express the main tyrosine kinase VEGF receptors, we chose to study vGEC expression of the more recently described VEGF isoform-specific receptors, the neuropilins. The expression of mRNAs for neuropilin-1, neuropilin-2 and soluble neuropilin was studied in whole kidney, sieved glomeruli and cultured podocytes by reverse transcription-PCR, and neuropilin-1 mRNA expression in isolated single glomeruli was analysed by nested reverse transcription-PCR. The expression of neuropilin-1 protein was investigated in cultured vGECs by Western blotting and immunocytochemistry, and in normal kidney sections by immunohistochemistry. Neuropilin-1 mRNA was detected in whole kidney, single and sieved glomeruli and cultured vGECs. Neuropilin-1 protein was detected in cultured vGECs and in vGECs in normal kidney sections by immunohistochemistry. Thus the present study suggests that vGECs may have the potential to bind the VEGF that they secrete. Functional studies will be required to address the potential significance of this finding in terms of an autocrine loop or VEGF sequestration.
Dietary obesity in the rat induces endothelial dysfunction without causing insulin resistance: a possible role for triacylglycerols
Authors: NADERALI Ebrahim K. , BROWN Michael J. , PICKAVANCE Lucy C. , WILDING John P.H. , DOYLE Patrick J. , WILLIAMS Gareth
Published: August 2015

Impaired arterial vasorelaxation, due primarily to endothelial dysfunction, is associated with obesity. To clarify the relationship with insulin resistance and other metabolic disturbances, we studied endothelial-dependent and -independent vascular responses in rats with dietary-induced obesity. Dietary-obese rats had significantly higher body weights (10-32%; P < 0.001) and fat-pad masses (220-280%; P < 0.001) than lean controls, together with raised plasma levels of triacylglycerols (15-80%; P < 0.001), non-esterified fatty acids (13-38%; P < 0.05) and leptin (85-180%; P < 0.001). However, measures of insulin sensitivity (including the hyperinsulinaemic-euglycaemic clamp in a parallel experiment) were comparable with those in controls. Contractions induced in mesenteric arteries by noradrenaline (0.5-8μmol/l) were comparable in lean and obese groups, but vasorelaxation in noradrenaline-preconstricted arteries was markedly reduced in dietary-obese rats of both sexes. Concentration-response curves to endothelium-dependent vasorelaxants (acetylcholine, A23187 and insulin) showed significant reductions in maximal relaxation (20-95% less than in leans; P < 0.001) and significant rightward shifts in EC40 (concentration giving 40% of maximal response) (P < 0.01). Relaxation in response to the direct NO donor, sodium nitroprusside, showed a lesser impairment (12%; P < 0.01) in dietary-obese rats. Maximal relaxation to acetylcholine was correlated inversely in both sexes with fat-pad mass (r2 = 0.37, P < 0.05) and plasma triacylglycerols (r2 = 0.51, P < 0.01), and with leptin in males only (r2 = 0.35, P < 0.05). Independent determinants of acetylcholine-induced relaxation were fat mass and plasma triacylglycerols; plasma insulin and insulin sensitivity had no effect. Dietary-induced obesity severely impaired arterial relaxation in both sexes, particularly at the endothelial level. This is not attributable to insulin resistance, but may be related to moderate hypertriglyceridaemia.
Mechanisms underlying the impairment in orthostatic tolerance after nocturnal recumbency in patients with autonomic failure
Authors: OMBONI Stefano , SMIT Adrianus A.J. , VAN LIESHOUT Johannes J. , SETTELS Jos J. , LANGEWOUTERS Gerard J. , WIELING Wouter
Published: August 2015

In the present study, we have assessed in patients with neurogenic orthostatic hypotension the haemodynamics underlying the reduced tolerance to standing after prolonged recumbency at night. In 10 patients with neurogenic orthostatic hypotension (age 33-68 years), of which seven were being treated with fludrocortisone and/or sleeping in the 12° head-up tilt position, 24h continuous non-invasive finger blood pressure was recorded by a Portapres device. Beat-to-beat blood pressure, heart rate, stroke volume, cardiac output and total peripheral vascular resistance obtained by pulse contour analysis were assessed during 5min of standing in the evening (at 22.30 hours) and in the morning (at 06.30hours). On average, the inverse of the normal 24h blood pressure profile was found, with a large diversity in blood pressure profiles among patients. Supine blood pressure values were similar, but standing blood pressure values were lower in the morning than in the evening (P < 0.01). This resulted from larger falls in stroke volume and cardiac output upon standing in the morning compared with the evening, while total peripheral resistance did not change. There was no relationship between the decrease in body weight during the night (mean 0.9kg; range 0.2-1.6kg) and the evening-morning difference in standing blood pressure. We conclude that, in patients with neurogenic orthostatic hypotension, the impaired tolerance to standing in the morning is due to larger falls in stroke volume and cardiac output. Not only nocturnal polyuria, but also a redistribution of body fluid, are likely mechanisms underlying the pronounced decreases in stroke volume and cardiac output after prolonged recumbency at night.
Exhaled nitric oxide after inhalation of isotonic and hypotonic solutions in healthy subjects
Authors: MANISCALCO Mauro , VATRELLA Alessandro , CREMONA George , CARRATÙ Luigi , SOFIA Matteo
Published: August 2015

Airway nitric oxide (NO) homoeostasis is influenced by chemical and mechanical stimuli in humans; airway epithelium, which is an important site of NO production, is sensitive to osmotic challenge. The effect of inhaled hypotonic solutions on exhaled NO (eNO) is not known. In this study we evaluated the effect of ultrasonically nebulized distilled water (UNDW), a hypotonic indirect stimulus, on eNO levels. A total of 10 non-smoking healthy subjects were enrolled in the study. eNO was detected by chemiluminescence, and specific airway conductance (sGaw) was measured by plethysmography. Bronchial challenges with UNDW and with an isotonic solution were performed according to a double-blind experimental design. Baseline levels of eNO were 28.1±14.7p.p.b. UNDW did not cause any significant change in sGaw (from 0.190±0.029 to 0.181±0.036cmH2Oċs-1). With respect to baseline values, the eNO concentration decreased significantly after inhalation of 8 or 16ml of UNDW (from 26.0±13.1 to 17.2±8.5 and 16.6±7.7p.p.b. respectively; P < 0.001, n = 10). After bronchial challenge with UNDW, eNO was significantly reduced in comparison with after inhalation of the isotonic solution. In five subjects, pretreatment with NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor NO synthesis, decreased NO levels from 21.7±8.5 to 10.0±3.3p.p.b. Subsequent inhalation of 16ml of UNDW did not cause any further decrease in NO levels (10.1±3.7p.p.b.; not significant compared with l-NAME). We conclude that inhalation of aqueous solutions decreases eNO levels in healthy subjects, and that this effect is not associated with any significant change in airway calibre. The UNDW-induced decrease in eNO is not enhanced by pretreatment with the NO synthase inhibitor l-NAME, suggesting that inhaled solutions may interfere with the airway NO pathway in humans.
Plasma cardiotrophin-1 following acute myocardial infarction: relationship with left ventricular systolic dysfunction
Authors: TALWAR Suneel , SQUIRE Iain B. , O'BRIEN Russell J. , DOWNIE Paul F. , DAVIES Joan E. , NG Leong L.
Published: August 2015

The glycoprotein 130 (gp130) signalling pathway is important in the development of heart failure. Cardiotrophin-1 (CT-1), a cytokine acting via the gp130 pathway, is involved in the process of ventricular remodelling following acute myocardial infarction (AMI) in animals. The aims of the present study were to examine the profile of plasma CT-1 following AMI in humans, and its relationship with echocardiographic parameters of left ventricular (LV) systolic function. Serial measurements of plasma CT-1 levels were made in 60 patients at 14-48h, 49-72h, 73-120h and 121-192h following AMI and at a later clinic visit. LV function was assessed using a LV wall motion index (WMI) score on admission (WMI-1) and at the clinic visit (WMI-2). Compared with values in control subjects (29.5±3.6fmol/ml), the plasma CT-1 concentration was elevated in AMI patients at 14-48h (108.1±15.1fmol/ml), 49-72h (105.2±19.7fmol/ml), 73-120h (91.2±14.9fmol/ml) and 121-192h (118.8±22.6fmol/ml), and at the clinic visit (174.9±30.9 fmol/ml) (P < 0.0001). Levels were higher following anterior compared with inferior AMI. For patients with anterior AMI, CT-1 levels were higher at the clinic visit than at earlier times. WMI-1 correlated with CT-1 at all times prior to hospital discharge (P < 0.05). On best subsets analysis, the strongest correlate with WMI-1 was CT-1 level at 49-72h (R2 = 20%, P < 0.05). In conclusion, plasma levels of CT-1 are elevated soon after AMI in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after AMI is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after AMI.
Prostaglandin F2α metabolite and F2-isoprostane excretion rates in migraine
Authors: HELMERSSON Johanna , MATTSSON Peter , BASU Samar
Published: August 2015

The pathophysiology theory of migraine postulates a local, neurogenic inflammation and the possible involvement of oxidative stress. We analysed the levels of 15-oxo-dihydro-prostaglandin F2α (a metabolite of prostaglandin F2α) and 8-iso-prostaglandin F2α (a major isoprostane), which are biomarkers for inflammation and oxidative stress respectively, in urine from 21 patients with migraine, with and without aura. Urine samples from migraine patients were collected during a migraine attack, and control samples were collected from the same subjects on a migraine-free morning. The mean basal levels of 15-oxo-dihydro-prostaglandin F2α and 8-iso-prostaglandin F2α in the morning control urine samples were 0.54±0.11 and 0.31±0.13nmol/mmol of creatinine respectively. The mean levels of 15-oxo-dihydro-prostaglandin F2α and 8-iso-prostaglandin F2α in the urine samples collected during the migraine attack in the 21 patients were 0.53±0.13 and 0.32±0.11nmol/mmol of creatinine respectively. Thus there were no differences in the 15-oxo-dihydro-prostaglandin F2α and 8-iso-prostaglandin F2α excretion rates during the migraine attack compared with on the migraine-free day. However, the basal 8-iso-prostaglandin F2α excretion levels on the migraine-free day were significantly lower in pre-menopausal women (0.24±0.08nmol/mmol of creatinine, n = 11) compared with post-menopausal women (0.39±0.14nmol/mmol of creatinine; n = 7; P = 0.009). In conclusion, in this study we found no support for the involvement of inflammation and oxidative stress in migraine pathophysiology. Our results indicate, however, a lower level of oxidative stress in pre-menopausal compared with post-menopausal women.
Insulin-mediated vasodilatation, but not glucose uptake or endothelium-mediated vasodilatation, is enhanced in young females compared with males
Authors: LIND Lars , FUGMANN Andreas , MILLGÅRD Jonas , BERNE Christian , LITHELL Hans
Published: August 2015

In order to evaluate possible differences between men and women with regard to the ability of insulin to induce vasodilatation, promote glucose uptake and enhance endothelium-dependent vasodilatation, 12 young (22-28 years), non-obese women and 15 corresponding males were subjected to 2h of euglycaemic hyperinsulinaemia (insulin infusion rate of 56m-unitsċmin-1ċm-2). Forearm blood flow was measured by venous occlusion plethysmography. Endothelium-dependent vasodilatation was evaluated by the local intra-arterial infusion of methacholine into the brachial artery (2-4μg/min). The cardiac index was measured by thoracic bioimpedance. A 2h period of hyperinsulinaemia increased the plasma insulin concentration to a similar degree in both sexes (females, 84±8.8m-units/l; males, 87±7.5m-units/l), but induced a more marked increase in forearm blood flow in females than in males (+104±67% and +52±30% respectively; P < 0.01; 95% confidence interval for difference 11-94%). Furthermore, a significant decrease in total peripheral resistance (-20±6.9%; P < 0.01) and an increase in cardiac index (+23±13%; P < 0.01) were seen in women only (P < 0.05 compared with men). Blood pressure and heart rate were not altered in either sex. Whole-body insulin-mediated glucose uptake and forearm glucose uptake did not differ between the sexes, and the ability of insulin to enhance endothelium-dependent vasodilatation (+19%; P < 0.01) was similar in men and women. In conclusion, the present study shows that the ability of insulin to cause vasodilatation was greater in non-obese young women compared with men. However, no differences between the sexes were seen with regard to insulin-mediated glucose uptake and the ability of insulin to enhance endothelium-dependent vasodilatation.
Cystatin C of pleural effusion as a novel diagnostic aid in pleural diseases of different aetiologies
Authors: DOMEJ Wolfgang , TILZ Gernot Peter , FÖLDES-PAPP Zeno , DEMEL Ulrike , RABOLD Thomas , HOLZER Herwig
Published: August 2015

There has been considerable recent interest in the potential use of serum cystatin C as a diagnostic tool. Here we examined the hypothesis that the cystatin C level in the pleural effusion can differ from the corresponding serum level. We evacuated pleural effusion fluids from 47 patients by thoracentesis. Cystatin C, β2-microglobulin, inorganic phosphate, creatinine and total protein were quantified in both pleural effusion fluids and corresponding sera. We determined cystatin C levels in pleural effusions and calculated the ratio of cystatin C levels in serum and effusion, to discriminate between effusions caused by severe renal impairment and other types of effusion. Extremely high concentrations of cystatin C in serum/effusion pairs were only measured in patients with renal failure (6.0±0.8/6.0±0.8mg/l, means±S.D., n = 11). A clearly defined region was found to correspond to pleural effusion caused by renal failure (r = 0.954). The quantification of cystatin C in the effusion was justified by the discovery that there were some patients with a high serum cystatin C level but a low effusion concentration, or a low serum cystatin C but a high effusion concentration, indicating causes other than renal failure. In conclusion, the pilot data indicate a relationship between the cystatin C concentration in pleural fluid and the underlying disease. Thus cystatin C levels in pleural effusion and serum may be a valuable criterion for the differential diagnosis of pleural diseases of different aetiologies.
Disruption of the elastin gene in adult Williams syndrome is accompanied by a paradoxical reduction in arterial stiffness
Authors: LACOLLEY Patrick , BOUTOUYRIE Pierre , GLUKHOVA Marina , DANIEL LAMAZIERE Jean-Marie , PLOUIN Pierre-François , BRUNEVAL Patrick , VUONG Phat , CORVOL Pierre , LAURENT Stéphane
Published: August 2015

Although the aetiology of Williams syndrome (WS) is related to elastin gene disruption, its pathogenesis remains unknown, particularly that of vascular lesions. The aim of the present study was to compare the elastic properties of three WS patients with age- and gender-matched normotensive and hypertensive controls. Common carotid arteries of WS patients had a higher distensibility, a thicker intima-media and a lower elastic modulus. Electron microscopy studies of one WS renal artery showed major abnormalities of the elastic fibres, which displayed a reticular structure and a thickening of the internal elastic lamina, whereas the ultrastructure of elastic fibres was normal in a control subadventitial muscular fibrodysplasia. In this WS arterial stenosis, we studied the expression patterns of several major smooth muscle (SM) phenotypic markers using immunofluorescence and used a normal renal artery as a control. In WS, SM-α-actin- and myosin-heavy-chain-positive cells contained low amounts of heavy caldesmon, and laminin-β1 chain was expressed into the basement membranes, indicating a less differentiated phenotype. In conclusion, in WS patients, the carotid artery wall was abnormally distensible and thick, and major ultrastructural abnormalities of elastic fibres were observed in association with smooth muscle cell de-differentiation. These results indicate that the haplo-insufficiency of the elastin gene in WS patients leads to abnormal elastic fibre assembly within the media. Arterial wall hypertrophy found with a primary defect in elastin may represent a major factor responsible for increased distensibility. We suggest that, in WS, the increased proliferative response and the associated de-differentiation process represent two important mechanisms underlying the matrix accumulation and the development of arterial stenosis.
Plasma brain natriuretic peptide as a predictor of haemodynamically significant patent ductus arteriosus in preterm infants
Authors: PUDDY V.F. , AMIRMANSOUR C. , WILLIAMS A.F. , SINGER D.R.J.
Published: August 2015

Patent ductus arteriosus (PDA) is an important cause of morbidity in extremely preterm infants. As increased plasma brain natriuretic peptide (BNP) is a common feature of adult cardiac disease, we investigated the value of plasma BNP concentration as a predictor of haemodynamically significant PDA in very preterm infants. We studied 18 preterm infants (12 male) of median gestational age 30 weeks (range 24-34), median birth weight 1.46kg (0.54-2.13) and 11 healthy term controls. Plasma BNP levels were measured by double-antibody radioimmunoassay on days 3, 5 and 7 of life, and an echocardiogram was performed on day 7. Six infants of median gestation 26 weeks (26-30), median birth weight 0.92kg (0.54-1.04) had PDA proven by echocardiography on day 7. BNP concentrations (pg/ml) on day 3 were significantly higher in these infants than in the remaining twelve [median 2012 (786-2759) versus 42 (7-704), P<0.001]. In four infants PDA was treated successfully (one surgically, three with non-steroidal anti-inflammatory drugs). Two had haemodynamically insignificant closing ducts. In these infants with therapeutic or spontaneous resolution of a PDA, plasma BNP fell to normal values [median after treatment 9pg/ml (8-27)]. Early measurement of plasma BNP in the first few days of life is a useful method for predicting those preterm infants who may require intervention for PDA.
Measurement of apolipoprotein B-48 in the Svedberg flotation rate (Sf)>400, Sf 60–400 and Sf 20–60 lipoprotein fractions reveals novel findings with respect to the effects of dietary fatty acids on triacylglycerol-rich lipoproteins in postmenopausal women
Authors: JACKSON Kim G. , ROBERTSON M. Denise , FIELDING Barbara A. , FRAYN Keith N. , WILLIAMS Christine M.
Published: August 2015

The present study was designed to examine whether the type of fat ingested in an initial test meal influences the response and density distribution of dietary-derived lipoproteins in the Svedberg flotation rate (Sf)>400, Sf 60 - 400 and Sf 20 - 60 lipoprotein fractions. A single-blind randomized within-subject crossover design was used to study the effects of palm oil, safflower oil, a mixture of fish and safflower oil, and olive oil on postprandial apolipoprotein (apo) B-48, retinyl ester and triacylglycerol responses in each lipoprotein fraction following an initial test meal containing one of the oils and a second standardized test meal. For all dietary oils, late postprandial (300min) concentrations of triacylglycerol and apo B-48 were significantly higher in the Sf 60 - 400 fraction than in the Sf>400 fraction (P<0.02). Significantly greater apo B-48 incremental areas under the curve (IAUCs) were also observed in the Sf 60 - 400 fraction than in the Sf>400 fraction following palm oil, safflower oil and olive oil (P<0.04), with a similar non-significant trend for fish/safflower oil. Olive oil resulted in a significantly greater apo B-48 IAUC in the Sf>400 fraction (P<0.02) than did any of the other dietary oils, as well as a tendency for a higher IAUC in the Sf 60 - 400 fraction compared with the palm, safflower and fish/safflower oils. In conclusion, we have found that the majority of intestinally derived lipoproteins present in the circulation following meals enriched with saturated, polyunsaturated or monounsaturated fatty acids are of the density and size of small chylomicrons and chylomicron remnants. Olive oil resulted in a greater apo B-48 response compared with the other dietary oils following sequential test meals, suggesting the formation of a greater number of small (Sf 60 - 400) and large (Sf>400) apo B-48-containing lipoproteins in response to this dietary oil.
Role of female sex hormones in neuronal nitric oxide release and metabolism in rat mesenteric arteries
Authors: MINOVES Nuria , BALFAGÓN Gloria , FERRER Mercedes
Published: August 2015

This study examines the effects of female sex hormones on the vasoconstrictor response to electrical field stimulation (EFS), as well as the modulation of this response by neuronal NO. For this purpose, segments of denuded superior mesenteric artery from ovariectomized (OvX) female Sprague–Dawley rats and from control rats (in oestrus phase) were used. EFS induced frequency-dependent contractions, which were greater in segments from OvX rats than in those from control rats. The NO synthase inhibitor NG-nitro-l-arginine methyl ester strengthened EFS-elicited contractions to a greater extent in arteries from OvX rats than in those from control rats. Similar results were observed with the preferential neuronal NO synthase inhibitor 7-nitroindazole. The sensorial neurotoxin capsaicin did not modify EFS-induced contractions in segments from either group. In noradrenaline-precontracted segments, sodium nitroprusside (SNP) induced concentration-dependent relaxation, which was greater in segments from control rats than in those from OvX rats. 8-Bromo-cGMP induced similar concentration-dependent relaxation in noradrenaline-precontracted segments from both OvX and control rats. Diethyldithiocarbamate, a superoxide dismutase (SOD) inhibitor, reduced the relaxation induced by SNP in segments from both groups of rats. SOD, a superoxide anion scavenger, enhanced the relaxation induced by SNP in segments from OvX rats, but did not modify it in segments from control rats. EFS induced NO−2 formation, which was greater in segments from OvX than in those from control rats, and pretreatment with tetrodotoxin, a blocker of nerve impulse propagation, abolished release in both cases. These results suggest that EFS induces greater neuronal NO release in mesenteric segments from OvX rats than in those from control rats and, although NO metabolism is also higher, the contribution of net neuronal NO in the vasomotor response to EFS is greater in segments from OvX rats than in those from control rats.
Independent contribution of psychological factors to fibrin turnover in subjects with sleep apnoea and/or systemic hypertension
Authors: VON KÄNEL Roland , BARDWELL Wayne A. , BERRY Charles C. , DIMSDALE Joel E.
Published: August 2015

By promoting atherosclerosis and thrombosis, a blood-clotting diathesis could contribute to excess cardiovascular morbidity and mortality in patients with systemic hypertension and/or obstructive sleep apnoea. Since psychological states affect haemostatic activity, we wondered about the contribution of behavioural factors to a hypercoagulable state in subjects with increased risk of cardiovascular disease. To tease apart the potential additive nature of cardiovascular disease risk, we examined four patient groups–hypertensives and normotensives, with and without sleep apnoea. The procoagulant molecules thrombin–antithrombin III complex, fibrin D-dimer and von Willebrand factor antigen were measured in 88 subjects (mean age 47 years; range 32–64 years) who underwent full polysomnography. Subjects completed the Center for Epidemiological Studies–Depression (CES-D) Scale, the Cook–Medley (CM) Hostility Scale, and the Profile of Mood States (POMS). Sleep apnoea, hypertension status, age, body mass index and psychological variables (CES-D, CM Stress, and POMS Vigour–Activity) together explained 29% of the variance in D-dimer, a marker of fibrin turnover (r2 = 0.29, P = 0.001). CES-D, CM Stress and POMS Vigour–Activity explained 17% of this variance even after controlling for sleep apnoea, hypertension status, age and body mass index (Δr2 = 0.17, P = 0.001). Thrombin–antithrombin III complex and von Willebrand factor were not significantly related to psychological variables, but this may reflect limited statistical power. Thus psychological factors are independently associated with D-dimer and explain as much of its variance as do traditional correlates (hypertension, sleep apnoea, age and body mass index). These results may provide a rationale for linking behavioural aspects with cardiovascular events.
Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in Type II diabetes
Authors: DARKO D. , DORNHORST A. , KELLY F.J. , RITTER J.M. , CHOWIENCZYK P.J.
Published: August 2015

Type II diabetes is characterized by increased oxidative stress, endothelial dysfunction and hypertension. We investigated whether short-term treatment with oral vitamin C reduces oxidative stress and improves endothelial function and blood pressure in subjects with Type II diabetes. Subjects (n = 35) received vitamin C (1.5g daily in three doses) or matching placebo for 3 weeks in a randomized, double-blind, parallel-group design. Plasma concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α), a non-enzymically derived oxidation product of arachidonic acid, were used as a marker of oxidative stress. Endothelial function was assessed by measuring forearm blood flow responses to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine (with nitroprusside as an endothelium-independent control) and by the pulse wave responses to systemic albuterol (endothelium-dependent vasodilator) and glyceryl trinitrate (endothelium-independent vasodilator). Plasma concentrations of vitamin C increased from 58±6 to 122±10μmol/l after vitamin C, but 8-epi-PGF2α levels (baseline, 95±4pg/l; after treatment, 99±5pg/l), blood pressure (baseline, 141±5/80±2mmHg; after treatment, 141±5/81±3mmHg) and endothelial function, as assessed by the systemic vasodilator response to albuterol and by the forearm blood flow response to acetylcholine, were not significantly different from baseline or placebo. Thus treatment with vitamin C (1.5 g daily) for 3 weeks does not significantly improve oxidative stress, blood pressure or endothelial function in patients with Type II diabetes.