bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized clinical trial comparing the effectiveness of two dietary interventions for patients with hyperlipidaemia
Authors: MHURCHÚ Cliona NÍ , MARGETTS Barrie M. , SPELLER Viv
Published: August 2015

1.Intervention trials in free-living populations have shown relatively small reductions in risk factors for cardiovascular disease, including lipid levels, and have led some to question whether diet is an effective treatment for hyperlipidaemia. However, behaviour change is a complex process and it is possible that standard intervention methods fail to motivate people sufficiently to comply with dietary advice.

2.This study applied motivational interviewing, a style of behaviour change counselling, to dietary education for people with hyperlipidaemia. One-hundred and twenty-one patients with hyperlipidaemia who had been referred to a hospital dietetic department for dietary advice were randomized to receive either standard or motivational dietary interventions for a period of 3 months. Outcomes assessed included dietary knowledge, stage of change, dietary intakes, lipid levels and body mass indices.

3.From baseline, both methods of dietary intervention resulted in self-reported changes in dietary habits and knowledge, statistically significant reductions in intake of total fat (from 32.8% to 28.4%), saturated fat (from 11.4% to 9.2%) and energy intakes [-239 ;kcal (-999.98 ;kJ)/day], and in body mass indices (-0.45 ;kg/m2). Serum cholesterol did not change significantly in either intervention group.

4.Motivational and standard dietary interventions achieved statistically significant changes in reported dietary knowledge and behaviour, and led to a reduction in body weight, but not serum cholesterol. Whether this lack of effect is real or due to subjects overestimating true dietary change cannot be determined. Change in body weight was associated with a reported change in energy intake; this provides some support for there having been a real change in intake.
Contractile response of isolated human hepatic arteries to α-adrenoceptor agonists is not impaired in patients with cirrhosis
Authors: HADOKE Patrick W. F. , DILLON John F. , JOHN Timothy G. , WALKER Simon W. , HAYES Peter C. , WILLIAMS Brent C.
Published: August 2015

1.Impaired vasoconstriction in animals with cirrhosis is maintained in isolated vessels in vitro, indicating an intrinsic alteration in function or structure of the cells in the vascular wall. This may be due to receptor down-regulation, a defect in post-receptor signal transduction or overproduction of vasodilator compounds. This investigation examined the role of these mechanisms in modulating α-adrenoceptor-mediated contraction in hepatic arteries from patients with advanced cirrhosis.

2.Hepatic arteries were obtained from subjects with and without cirrhosis for functional investigation in vitro. Endothelial cell function was assessed using endothelium-dependent (acetylcholine) and independent (3′-morpholinosydnonimine) vasodilators. α-Adrenoceptor-mediated contraction was assessed by constructing cumulative concentration–response curves to the α1-selective agonist phenylephrine, the non-selective adrenoceptor agonist noradrenaline and the receptor-independent vasoconstrictor potassium chloride.

3.None of the vessels used in this study had an intact endothelium but endothelium-independent relaxation was not different in arteries from subject with (79.5±10.16%; n = 23) and without (84.45±18%; n = 20) cirrhosis. Phenylephrine, noradrenaline and potassium chloride produced contractions that were of similar size (P> 0.05) in arteries from subjects with (10.10±0.97 ;g, 8.85±1.03 ;g and 8.56±0.65 ;g respectively) and without (10.42±1.23 ;g, 9.58±1.39 ;g and 8.62±0.98 ;g respectively) cirrhosis. The sensitivities (pD2) of the responses to these agonists were also similar (P< 0.05) in arteries from patients with cirrhosis (5.45±0.10, 5.60±0.12 and 1.57±0.03 respectively) and those from non-cirrhotic donors (5.58±0.11, 5.67±0.11 and 1.54±0.05 respectively).

4.Contraction of the denuded hepatic artery was unaffected by cirrhosis indicating that vascular abnormalities in this condition in man are not due to an intrinsic alteration of smooth muscle cell function in hepatic conduit arteries.
Measurement and significance of circulating natriuretic peptides in cardiovascular disease
Authors: SAGNELLA G. A.
Published: August 2015

1.The major cardiovascular and renal actions of α-atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and the fact that the heart is strategically located to sense changes in intravascular volume indicate the importance of these peptides in the overall control of the extracellular fluid volume under normal and pathophysiological conditions.

2.This review examines the clinical and diagnostic significance of the measurement of plasma natriuretic peptides in diseases of the cardiovascular system with particular emphasis on the assessment of patients with heart failure.

3.Raised plasma levels of ANP and BNP have repeatedly been found in patients with heart disease originating from diverse causes including tachycardias, valvular stenosis or ventricular dysfunction. The raised circulating levels of natriuretic peptide (ANP, N-terminal proANP and BNP in particular) are associated with (i) raised atrial and pulmonary wedge pressures; (ii) reduced ventricular systolic and diastolic function; (iii) presence (and possibly geometric form) of left ventricular hypertrophy; and (iv) severe myocardial infarction. Although both plasma ANP and BNP are raised in the presence of left ventricular hypertrophy, BNP appears to be a better index of left ventricular hypertrophy.

4.Several situations where the measurement of natriuretic peptides may be of benefit in the overall assessment of heart disease are discussed. However, it is emphasized that the measurement of plasma natriuretic peptides alone appears to be of limited value as a specific diagnostic tool, given that raised levels are a consequence of haemodynamic and structural abnormalities arising from diverse pathological processes. Despite these limitations, the major value of plasma natriuretic peptides in the examination of patients with suspected heart disease rests on the premise that: (i) a normal value would not be consistent with cardiac disease; (ii) the presence of markedly raised levels may help to target those for subsequent detailed assessment of underlying cardiac dysfunction; and (iii) markedly raised levels of plasma natriuretic peptides after myocardial infarction can identify those at high risk of death.
Regional plasma levels of cardiac peptides and their response to acute neutral endopeptidase inhibition in man
Authors: LAINCHBURY J. G. , NICHOLLS M. G. , ESPINER E. A. , IKRAM H. , YANDLE T. G. , RICHARDS A. M.
Published: August 2015

1.The cardiac natriuretic peptides, atrial natriuretic peptide and brain natriuretic peptide, are degraded via clearance receptors and the enzyme neutral endopeptidase (EC 3.4.24.11). We studied the regional plasma concentrations of these peptides and their response to acute neutral endopeptidase inhibition in a consecutive series of patients with a broad spectrum of severity of cardiac dysfunction who were undergoing diagnostic right and left heart catheterization (24 patients, mean age 62.6 years).

2.Baseline blood samples were obtained for hormone analysis from femoral artery, femoral vein, renal vein, hepatic vein, superior vena cava, coronary sinus and pulmonary artery, and initial haemodynamic measurements were made. Twelve patients then received a neutral endopeptidase inhibitor (SCH 32615, 200 ;mg intravenously) and 12 received vehicle alone. The cardiac catheterization procedure was then completed and haemodynamic and hormone measurements were repeated.

3.Haemodynamic status was similar at baseline in both groups, and at repeated measurement (post-procedure after placebo or active drugs) haemodynamic variables were not significantly different from baseline values. Plasma levels of atrial and brain natriuretic peptides exhibited an arteriovenous increment (344% and 124% respectively) across the heart (femoral artery to coronary sinus) and decrement (by 28–54% and 9–16% respectively) across all other tissue beds (P< 0.05 for all) except the lung (no change). Final levels of atrial natriuretic peptide rose above initial levels at all sites in both groups (P< 0.05) except coronary sinus levels in the vehicle group (no change). The increase was consistently greater in the inhibitor group at all sites (P< 0.05 versus placebo). Levels of brain natriuretic peptide rose at all sites in the inhibitor group only (P< 0.05). The transcardiac step-up in atrial natriuretic peptide was markedly augmented after the administration of neutral endopeptidase inhibitor. Other tissue gradients were not significantly altered by neutral endopeptidase inhibitor.

4.Atrial and brain natriuretic peptides in plasma are degraded by a number of tissues, and respond differently to cardiac catheterization. Neutral endopeptidase has a significant role in determining plasma levels of natriuretic peptides, in part perhaps by influencing the amount of intact peptide reaching the circulation after secretion from the heart.
Increased Na+ and decreased Mg2+ intracellular concentrations in vascular smooth muscle cells from spontaneously hypertensive rats
Authors: KISTERS Klaus , KREFTING Ernst-Rudolf , SPIEKER Claus , ZIDEK Walter , DIETL Karl Heinz , BARENBROCK Michael , RAHN Karl Heinz
Published: August 2015

1.Although in blood cells decreased magnesium concentrations and increased sodium concentrations in essential hypertension have often been described, only sparse data exist on cellular magnesium or sodium content and exchange in vascular smooth muscle cells.

2.Therefore in aortic smooth muscle cells from 10 spontaneously hypertensive rats (SHR) of the Münster strain and 10 normotensive Wistar–Kyoto rats (WKY) aged 3 and 8–10 months, the intracellular magnesium and sodium content was measured.

3.Electron-probe X-ray microanalysis was used to determine intracellular Mg2+ and Na+ concentrations in aortic cryosections 3 ;μm thick. The Mg2+ content was 47±13 ;mmol/kg dry weight in SHR versus 48±19 ;mmol/kg dry weight in WKY aged 3 months, and 37±6 ;mmol/kg dry weight in SHR versus 47±4 ;mmol/kg dry weight in WKY aged 8–10 months (P< 0.05). Vascular smooth muscle Na+ content was 283±59 ;mmol/kg dry weight in WKY and 402±123 ;mmol/kg dry weight in SHR aged 3 months (P< 0.05), and 289±17 ;mmol/kg dry weight in WKY versus 548±39 ;mmol/kg dry weight in SHR aged 8–10 months (P< 0.05).

4.Aortic smooth muscle cells from SHR are characterized by a markedly lower intracellular Mg2+ content in 8–10-month-old animals and increased Na+ concentrations compared with normotensive cells in 3- and 8–10-month-old rats. The results may be due to genetically determined disturbances in transmembrane Mg2+ and Na+ transport. Cellular magnesium and sodium handling may be disturbed in SHR aortic smooth muscle as it is in hypertensive blood cells. In addition, it is concluded that vascular smooth muscle cell Mg2+–Na+ exchanger can be altered in a subgroup of SHR.
Different effects of atrial and C-type natriuretic peptide on the urinary excretion of endothelin-1 in man
Authors: VILLA Giorgio LA , MANNELLI Massimo , LAZZERI Chiara , VECCHIARINO Sabrina , FEO Maria Laura DE , GUERRA Cristina TOSTI , BANDINELLI Renzo , FOSCHI Marco , FRANCHI Franco
Published: August 2015

1.Following the observation that brain natriuretic peptide enhances the urinary excretion rate of endothelin-1, the relationship between natriuretic peptides and urinary endothelin-1 was further investigated. Six healthy volunteers received, on three different occasions, increasing doses of atrial or C-type natriuretic peptide (0, 2 and 4 ;pmol·min-1·kg-1 for 1 ;h each), or placebo.

2.Atrial natriuretic peptide caused significant increases in the urinary excretion of cGMP, sodium and endothelin-1, without affecting plasma endothelin-1, renal plasma flow, glomerular filtration rate and urine flow rate. C-type natriuretic peptide did not modify any of these parameters. During atrial natriuretic peptide infusion, urinary endothelin-1 directly correlated with plasma atrial natriuretic peptide, urinary cGMP and sodium excretion.

3.These results indicate that enhancement of the urinary excretion of endothelin-1 by natriuretic peptides is dose-dependent and somewhat related to their ability to bind to natriuretic peptide receptors A, activate guanylate cyclase and induce a natriuretic response.
Renal targeting of a non-steroidal anti-inflammatory drug: effects on renal prostaglandin synthesis in the rat
Authors: HAAS Marijke , MOOLENAAR Frits , MEIJER Dirk K. F. , JONG Paul E. DE , ZEEUW Dick DE
Published: August 2015

1.Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal release of the active metabolite naproxen–lysine.

2.In the present study we questioned whether naproxen–lysozyme is active in the rat kidney, inhibiting the urinary excretion of prostaglandin E2 and renal sodium and water excretion in salt-restricted baseline conditions as well as during frusemide treatment.

3.A high dose of free naproxen (10 ;mg·day-1·kg-1) did not affect prostaglandin E2 excretion in baseline conditions (naproxen, 11±1 ;ng/8 ;h; vehicle, 13±4 ;ng/8 ;h), whereas sodium and water excretion were, respectively, 3.0 and 1.6 times lower in the naproxen group (P< 0.05). Naproxen completely prevented the frusemide-induced increase (3-fold) in prostaglandin E2 excretion (naproxen 6.6±1.1 ;ng/8 ;h, vehicle 40±12 ;ng/8 ;h, P< 0.005). Frusemide-stimulated natriuresis and diuresis were, respectively, 1.6 (P< 0.05) and 1.8 times (P< 0.005) lower in the naproxen group.

4.A dose of 2 ;mg·day-1·kg-1 lysozyme-conjugated naproxen did not affect prostaglandin E2 excretion in baseline conditions (conjugate, 18±2 ;ng/8 ;h; vehicle, 24±5 ;ng/8 ;h). The conjugate also had no effect on sodium and water excretion. However, the naproxen conjugate completely prevented the frusemide-induced increase (2-fold) in prostaglandin E2 excretion (conjugate, 16±3 ;ng/8 ;h; vehicle, 48±13 ;ng/8 ;h, P< 0.05). Surprisingly, frusemide-induced natriuresis and diuresis were not affected by the conjugate.

5.In conclusion, a renal specific delivery of the non-steroidal anti-inflammatory drug naproxen using lysozyme results in an inhibitory effect on renal prostaglandin E2 synthesis but does not affect the excretion of sodium and water, in contrast to free naproxen.
Pulmonary response of normal human subjects to inhaled vasodilator substances
Authors: BRETT S. J. , CHAMBERS J. , BUSH A. , ROSENTHAL M. , EVANS T. W.
Published: August 2015

1.Inhaled vasodilators such as nitric oxide and epoprostenol (prostaglandin I2) are now widely employed as supportive therapies to improve oxygenation and reduce pulmonary vascular resistance in patients with acute and chronic pulmonary hypertension. However, few data exist concerning their effects in normal individuals. The aim of this study was to characterize the response of the pulmonary circulation in normal individuals to inhaled nitric oxide and nebulized prostaglandin I2.

2.Eight healthy volunteers were exposed to inhaled nitric oxide (0, 20 and 40 ;p.p.m.) and nebulized prostaglandin I2 (10 ;μg/ml). Changes in effective pulmonary blood flow and diffusing capacity of the lung for carbon monoxide (TLCO) were measured using respiratory mass spectrometry. Bicycle ergometry was used to increase effective pulmonary blood flow as a positive control.

3.Exercise produced significant increases in both effective pulmonary blood flow and TLCO, but neither nitric oxide nor prostaglandin I2 produced significant changes in either parameter.

4.No significant change in pulmonary haemodynamics was demonstrated in response to inhaled nitric oxide or nebulized prostaglandin I2, using doses known to be effective in patients with acute and chronic pulmonary hypertension. These data suggest that the normal pulmonary vascular bed is not amenable to vasodilatation by inhaled drugs. The study further suggests that the normal pulmonary vasodilatation seen on exercise is not mediated pharmacologically, but is a secondary consequence to the mechanical effects of a rise in pulmonary blood flow. This study thus supports the view that there is no resting vasoconstrictor tone in the pulmonary vascular bed.
Transforming growth factor-β1 gene polymorphisms and coronary artery disease
Authors: SYRRIS Petros , CARTER Nicholas D. , METCALFE James C. , KEMP Paul R. , GRAINGER David J. , KASKI Juan C. , CROSSMAN David C. , FRANCIS Sheila E. , GUNN Julian , JEFFERY Steve , HEATHCOTE Kirsten
Published: August 2015

1. A meta-analysis of 17 years of literature on erythrocyte Na+/Li+ countertransport (NLCT) and Na+/K+ co-transport (COT) measurements in relation to essential hypertension is presented. The analysis aimed to answer two questions: (i) Which clinical or laboratory variables influence NLCT and COT flux values? (ii) How useful are NLCT and COT measurements as a diagnostic aid in essential hypertension?

2. Regression analysis was performed on the mean flux values and relevant clinical and laboratory values. Studies in both normotensive and hypertensive subjects were stratified for variables which showed a significant association with the measured flux. For hypertensive subjects the studies were also stratified for medication. Means of strata were calculated after weighing the mean of a study by the inverse of its own variance and were compared in normotensive as well as hypertensive subjects using a t-test.

3. The analysis did not demonstrate systematic effects of laboratory variables for either NLCT or COT. It was found that essential hypertension, family history of hypertension, gender and antihypertensive medication are main determinants for the flux values of both transport systems. After stratification for these determinants, significant differences in weighed mean flux values between normotensive and hypertensive subjects were demonstrated. However, these differences are much smaller than the variance in the weighed mean flux values, suggesting the existence of other unknown variables that strongly affect the flux rates.

4. In conclusion, NLCT and COT measurements cannot be of diagnostic use in essential hypertension.
Increased myogenic tone precedes structural changes in mild experimental uraemia in the absence of hypertension in rats
Authors: SAVAGE Tessa , MCMAHON Aisling C. , MULLEN Adrian M. , NOTT Cathy A. , DODD Susan M. , TRIBE Rachel M. , YAQOOB Magdi M.
Published: August 2015

1. Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodelling and the localization of atherosclerotic plaque. Uraemia is a proatherogenic process and is expected to be associated with impaired vascular reactivity.

2. To study this, 12 male Wistar rats were rendered uraemic by five-sixths nephrectomy and 12 control rats were sham operated simultaneously. After 8 weeks a tail-cuff systolic blood pressure was recorded, blood samples were taken and the animals killed. Isolated femoral arteries were dissected and mounted on a pressure myograph and myogenic tone was assessed over a range of intravascular pressures from 40 to 160 mmHg. Histologically the arteries were comparatively examined for gross morphology, calcification and deposition of collagen.

3. Biochemically the serum urea and creatinine were greater in the uraemic compared with the control rats (urea: 23.5±6 mmol/l and 6.8±01 mmol/l respectively, P not significant; creatinine: 130.7±13 mmol/l and 70.3±5 mmol/l respectively, P < 0.01) but systolic blood pressure was the same in both groups (control, 97±1 mmHg; uraemic, 98±2 mmHg), compatible with mild uraemia.

4. Myogenic tone was significantly greater in uraemic vessels (7.3±1.8% versus 2.3±0.4% in control, P = 0.01). The actual vessel lumen diameter was also smaller in pressurized uraemic vessels compared with control vessels (471±30 μm versus 604±33 μm, P< 0.01) after equilibration in physiological salt solution. However, when incubated in calcium-free physiological salt solution, the passive internal diameter was similar in uraemic vessels (538±25 μm compared with 595±31 μm in control). Histologically, there were no differences between the two groups.

5. We conclude that some aspects of vascular reactivity are altered in mild experimental uraemia as shown by a reduced internal lumen diameter and increased myogenic tone. Furthermore, these changes are apparent in the absence of hypertension and precede structural changes.
Chronic infusions of brain natriuretic peptide in conscious sheep: bioactivity at low physiological levels
Authors: CHARLES Christopher J. , ESPINER Eric A. , NICHOLLS M. Gary , RADEMAKER Miriam T. , RICHARDS A. Mark
Published: August 2015

1. The circulating cardiac hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have similar bioactivity, as judged by comparative short-term studies. However, no study has reported the effects of longer-term administration of BNP. Accordingly, we have compared the haemodynamic, hormonal and renal actions of chronic (4-day) administration of BNP and ANP (0.5 pmol·min-1·kg-1) in a vehicle-controlled study in normal conscious sheep.

2. BNP infusions raised plasma BNP levels within the physiological range (4 pmol/l increment, P< 0.001) and increased cyclic GMP levels (P = 0.01). BNP infusions induced significant falls in right atrial pressure (P = 0.048), stroke volume (P = 0.014) and cardiac output (P = 0.003) associated with a rise in haematocrit (P = 0.001). There were no significant renal effects or changes in renin–aldosterone. By comparison, equimolar infusion of ANP induced a smaller increment in plasma ANP levels (2 pmol/l, P = 0.03) with qualitatively similar but statistically non-significant changes in plasma cyclic GMP and haemodynamic indices.

3. In conclusion, chronic low-dose infusions of BNP elevate plasma cyclic GMP levels and induce significant haemodynamic actions. This study provides evidence that subtle variations in circulating BNP levels, well within the physiological range, may be important in long-term cardiovascular control.
Gastrectomy osteopenia in the rat: the role of vitamin B12 deficiency and the type of reconstruction of the digestive tract
Authors: WOJTYCZKA A. , BERGÉ B. , RÜMENAPF G. , SCHWILLE P. O. , BALLANTI P. , SCHREIBER M. , FRIES W. , HOHENBERGER W.
Published: August 2015

1. The mechanisms underlying gastrectomy osteopenia are not yet clear. The gastrectomy-associated cobalamin (vitamin B12) deficiency may favour osteopenia and skeletal fractures. Also, the exclusion of the duodenum from the food passage may contribute to gastrectomy osteopenia. To investigate this, rats were gastrectomized and the passage of nutrients restored either with the duodenum excluded (Roux Y) or included (Longmire). Sham-operated rats served as controls. In half of the rats in each gastrectomy group the serum B12 levels were normalized by parenteral administration of B12.

2. Four months post operation, both gastrectomy groups showed a similar degree of osteopenia. There was normal bone mineralization; serum levels of parathyroid hormone were normal, but decreased for 25-hydroxyvitamin D, and elevated for 1,25-dihydroxyvitamin D; in urine there was decreased pH and excessive hyperphosphaturia.

3 B12 therapy had no influence on any of the essential bone and mineral metabolic parameters.

4. We conclude that osteopenia in the gastrectomized rat (i) is not due to B12 or folic acid deficiency, calcium deficiency or secondary hyperparathyroidism; (ii) is independent of the type of anatomic reconstruction of the digestive tract; (iii) appears to be related to disturbed vitamin D, phosphorus and acid–base metabolism.
Angiotensin-converting enzyme inhibition restores the diffusing capacity for carbon monoxide in patients with chronic heart failure by improving the molecular diffusion across the alveolar capillary membrane
Authors: GUAZZI Marco , AGOSTONI Piergiuseppe
Published: August 2015

Conductance of alveolar capillary membrane (DM) and capillary blood volume (VC) are the subcomponents of the pulmonary diffusing capacity for carbon monoxide (DLco). In chronic heart failure, stress failure of the membrane provides a mechanism for reduced DM and subsequent impairment of DLco. Angiotensin-converting enzyme inhibition improves DLco in patients with chronic heart failure. This study was aimed at investigating which of the two subcomponents of DLco is affected by angiotensin-converting enzyme inhibitors. Twenty-seven patients with NYHA class II to III chronic heart failure (group 1) and 13 age- and sex-matched normal subjects underwent pulmonary function testing with determination of DM and VC, while receiving placebo and 48 ;h and 1 and 2 months after starting enalapril treatment (10 ;mg twice daily). Nine similar patients (group 2) received isosorbide dinitrate (40 ;mg thrice daily) for a month then enalapril for another month, and underwent pulmonary function testing at 48 ;h and 1 month after starting treatments. Effects of angiotensin-converting enzyme inhibition in normal controls were not significant in the short- or mid-term. In group 1 patients, the only change observed at 48 ;h was a reduction in VC (probably due to a decrease in capillary pulmonary pressure). There was a marked increase in DM to a similar extent at 1 and 2 months, resulting in a significant improvement in DLco despite a decrease in VC. In group 2 patients, nitrates failed to improve DLco and DM, whereas enalapril was as effective as in group 1. These observations suggest a modulatory effect of angiotensin-converting enzyme inhibition on the membrane function which emerges gradually and persists over time and is probably dissociated from changes in pulmonary capillary pressure and VC. Chronic heart failure disturbs the alveolar capillary interface and increases gas diffusion resistance; angiotensin-converting enzyme inhibition restores the diffusive properties of the membrane and gas transfer, and protects the lung when the heart is failing.
Impaired sympathetic response before intradialytic hypotension: a study based on spectral analysis of heart rate and pressure variability
Authors: PELOSI Gualtiero , EMDIN Michele , CARPEGGIANI Clara , MORALES Maria Aurora , PIACENTI Marcello , DATTOLO Pietro , CERRAI Tiziano , MACERATA Alberto , L'ABBATE Antonio , MAGGIORE Quirino
Published: August 2015

The purpose of this study was to evaluate the autonomic response to standard haemodialysis and the changes associated with the onset of intradialytic hypotension in 12 normotensive patients with uraemia. Power spectra of R–R interval and of blood pressure fluctuations were obtained during a standard dialysis session and estimated in the low-frequency (LF, 30–150 ;mHz) and high-frequency (HF, 150–400 ;mHz) range. The absolute power of the LF component of blood pressure variations and the LF/HF ratio of R–R interval were assumed as indexes of sympathetic activity. Standard haemodialysis induced hypotension in six patients (unstable) while a minor pressure decline was present in the other six (stable). Normalized blood volume before dialysis and percentage volume reduction were similar in the two groups. Tachycardia in response to pressure and volume decrease was more pronounced in stable than in unstable patients, as evidenced by a higher slope of the relation between R–R interval and systolic blood pressure (7.9 versus 0.9 ;ms/mmHg, P< 0.01). Sympathetic tone was enhanced during early dialysis in all patients (+2±1 for R–R LF/HF ratio, +2.4±0.6 ;mmHg2 and +7.2±2 ;mmHg2 for absolute LF power of diastolic and of systolic blood pressure respectively, P< 0.05), compared with baseline predialysis values. During late dialysis, unstable patients showed an impairment of sympathetic activation which preceded hypotension and was maximal during the crisis (-2.9±1.4 for R–R LF/HF ratio, -2.7±1.4 ;mmHg2 and -8.6±4.0 ;mmHg2 for absolute LF power of diastolic and of systolic blood pressure respectively, P< 0.05). On the contrary, stable patients showed constantly elevated indexes (+3.7±1.4 for R–R LF/HF ratio, +5.9±2.7 ;mmHg2 and +13.3±6.2 ;mmHg2 for LF of diastolic and of systolic blood pressure, P< 0.05). Values returned to predialysis levels after the end of the dialysis session in all patients. We conclude that standard haemodialysis activates a marked and reversible sympathetic response in both stable and unstable uraemic patients. However, in unstable patients, such activation is impaired in late dialysis, therefore contributing to the onset of the hypotensive crisis.
Autonomic nervous system dysfunction in sclerodermic and primary Raynaud's phenomenon
Authors: PANCERA Paolo , SANSONE Stefano , PRESCIUTTINI Barbara , MONTAGNA Luciano , CERÙ Silvia , LUNARDI Claudio , LECHI Alessandro
Published: August 2015

Our aim was to investigate the sympathetic hyperactivity of systemic sclerosis that may lead to greater morbidity and mortality from cardiovascular events. We analysed the sympathetic (low-frequency) and vagal (high-frequency) components of heart rate variability, in supine and upright positions, in 10 patients with systemic sclerosis, 12 patients with primary Raynaud's phenomenon and 14 controls. We also analysed lung function in order to evaluate a possible link between heart rate variability and ventilation parameters. Heart rate variability was reduced in the supine position in subjects with systemic sclerosis both in comparison with primary Raynaud's phenomenon (total power: 1103±156 versus 3302±486 ;ms2, P< 0.004) and control subjects (3148±422 ;ms2, P< 0.002). Low-frequency power was higher in patients with systemic sclerosis than in the controls (54.5±4.5 versus 42.5±3.5 normalized units, P< 0.01). During tilt, the change in heart rate was +44% in controls, +24% in subjects with primary Raynaud's phenomenon, and only +17% in the patients with systemic sclerosis (P< 0.01 versus controls). In patients with systemic sclerosis we found a significant correlation between high-frequency power and the indices of lung function (residual volume: r2 = 0.5143, P< 0.01; total lung capacity: r2 = 0.5142, P< 0.01, vital capacity: r2 = 0.3789, P< 0.05). Heart rate variability was reduced and sympathetic output increased in patients with systemic sclerosis. Subjects with primary Raynaud's phenomenon were characterized by normal heart rate variability and by some degree of sympathetic hyperactivity. During tilting, subjects with systemic sclerosis maintained an unmodified heart rate variability, thus suggesting an impaired baroceptor modulation of the autonomic control. The negative correlation between high-frequency power and indices of respiratory insufficiency in patients with systemic sclerosis suggests that the pulmonary structure plays an important role in the modulation of heart rate variability.
Sustained elevation of plasma brain natriuretic peptide levels associated with progressive ventricular remodelling after acute myocardial infarction
Authors: NAGAYA Noritoshi , GOTO Yoichi , NISHIKIMI Toshio , UEMATSU Masaaki , MIYAO Yuji , KOBAYASHI Yoshio , MIYAZAKI Shunichi , HAMADA Seiki , KURIBAYASHI Sachio , TAKAMIYA Makoto , MATSUO Hisayuki , KANGAWA Kenji , NONOGI Hiroshi
Published: August 2015

Previous studies have shown that levels of plasma brain natriuretic peptide (BNP) increase in an early phase of acute myocardial infarction. However, the relations between plasma BNP levels and left ventricular remodelling, which occurs long after acute myocardial infarction, are not fully understood. Venous plasma BNP levels were measured 2, 7, 14, 30, 90 and 180 days after the onset of acute myocardial infarction in 21 patients. Left ventricular end-diastolic volume index (EDVI, ml/m2) in acute (5 days) and chronic (6 months) phases were assessed by electron-beam computed tomography using Simpson'S method. The remodelling group (n = 9) was defined by an increase in EDVI ⩾ 5 ml/m2 relative to the baseline value. Plasma BNP levels on days 2, 7, 14, 30 and 90 were significantly higher in the remodelling group than in the non-remodelling group (n = 12, P< 0.05). Sustained elevation of plasma BNP levels was noted from day 2 (61±12 pmol/l) to day 90 (55±12 pmol/l) and significantly decreased on day 180 (24±3 pmol/l) in the remodelling group. In contrast, plasma BNP levels significantly decreased from day 2 (25±4 pmol/l) to day 90 (9±1 pmol/l) and reached a steady level thereafter in the non-remodelling group. Plasma BNP levels on day 7 correlated positively with an increase in EDVI (r = 0.70, P< 0.001) from the acute to chronic phase. More importantly, the sustained elevation of plasma BNP (percentage decrease smaller than 25%) from day 30 to day 90 identified patients in the remodelling group with a sensitivity of 100% and a specificity of 83%. In conclusion, not only the high levels of plasma BNP in an acute phase, but also the sustained elevation of plasma BNP in a chronic phase, may be associated with progressive ventricular remodelling occurring long after acute myocardial infarction.
Heart rate variability in 1-day-old infants born at 4330 m altitude
Authors: MORTOLA Jacopo P. , LEÓN-VELARDE Fabiola , AGUERO Lourdes , FRAPPELL Peter B.
Published: August 2015

In fetuses and newborn infants heart rate variability changes in conditions of acute and chronic hypoxia; we therefore asked whether heart rate variability of infants born at high altitude differed from that of low-altitude infants. Short-term recordings (4–5 min) of inter-beat intervals were obtained in 19 infants in Lima (50 m altitude) and in 15 infants in Cerro de Pasco (4330 m, barometric pressure ∼ 450 mmHg, inspired oxygen pressure ∼ 94 mmHg) during quiet rest in warm conditions (ambient temperature, Ta, ∼ 35 °C). In 12 infants from each group recordings were also obtained during cooling (Ta ∼ 26 °C). Heart rate variability was evaluated from 512 consecutive inter-beat intervals, with analysis based on time-domain and frequency-domain methods. At warm Ta, heart rate variability did not differ between the two groups. During cooling, heart rate increased only in the low-altitude group. As in the warm, during cooling most parameters of heart rate variability did not differ between the two groups. The only exception was the inter-beat interval power of the high-frequency range of the spectrum (0.15–0.4 Hz), which, at least in adults, is believed to be a reflection of vagal activity, and was greater in the high-altitude group. It is concluded that gestation at high altitude, despite its blunting effects on fetal growth, does not have a major impact on heart rate variability of the newborn. Nevertheless, the possibility that differences in response to cooling may reflect some limitation in heart rate control needs to be examined further.
Altered small artery morphology and reactivity in critical limb ischaemia
Authors: HILLIER C. , SAYERS R. D. , WATT P. A. C. , NAYLOR R. , BELL P. R. F. , THURSTON H.
Published: August 2015

Although the pathophysiology of critical limb ischaemia is poorly understood, there is evidence that the condition of the small arteries may determine the outcome of revascularization procedures. This study was designed to investigate the effects of critical limb ischaemia on the structure and function of the small arteries in the leg. Small arteries (< 500 μm) from proximal (non-ischaemic) and distal (ischaemic) sites were obtained from patients undergoing bypass surgery for critical limb ischaemia and mounted in a myograph. Reactivity and morphological measurements were carried out and compared with controls. Control vessels from the thigh and calf showed no difference in media to lumen ratio. However, a comparison of ischaemic and non-ischaemic vessels from the patients with critical limb ischaemia showed significant thinning of the ischaemic vessel wall. Contraction studies using noradrenaline and angiotensin II revealed a significant decrease in the response of ischaemic vessels compared with the non-ischaemic vessels from the same patient. Moreover, these differences in reactivity were still apparent after the responses were corrected for wall thickness. Endothelial function assessed using the endothelium-dependent agonists acetylcholine and bradykinin showed a significantly impaired relaxation response to acetylcholine but not to bradykinin in the ischaemic vessels, and acetylcholine-induced relaxation was not improved after incubation with indomethacin. There was no change in the response to the endothelium-independent cAMP-mediated vasodilator iloprost but a significant impairment to sodium nitroprusside which acts via cGMP. These results suggest that small arteries in critical limb ischaemia are altered in both structure and function, with vessel wall thinning and impaired responses to acetylcholine and sodium nitroprusside.
Increased splanchnic blood flow after hypoglycaemia in diabetic and normal man: evidence against glucagon as a mediator
Authors: PARKER D. R. , BARGIOTA A. , BRAATVEDT G. D. , HALLIWELL M. , CORRALL R. J. M.
Published: August 2015

Superior mesenteric artery blood flow increases significantly after hypoglycaemia in healthy humans. Glucagon has vasoactive properties but its role in hypoglycaemic hyperaemia is unclear. To assess this role, we studied the superior mesenteric artery blood flow response to hypoglycaemia of patients with uncomplicated Type 1 (insulin-dependent) diabetes mellitus of at least 10 years duration; a group known to have defective glucagon response to hypoglycaemia. Hypoglycaemia was induced using an intravenous infusion of soluble human insulin (2.5 m-unitsċmin-1ċkg-1) discontinued at a plasma glucose of 2.5 mmol/l. Superior mesenteric artery blood flow was measured using transcutaneous duplex Doppler ultrasound. Plasma samples were assayed for glucose, insulin, glucagon, catecholamines, growth hormone and cortisol. Plasma glucose concentration fell to a nadir of 1.8 (0.3) mmol/l in patients and 1.4 (0.1) mmol/l in controls. Plasma glucagon concentration was unchanged in patients from a baseline level of 111.7 (13.1) ng/l but rose in controls from 105 (8.5) to a peak of 239 (3.1) ng/l (P< 0.001). Superior mesenteric artery blood flow increased in both groups: from 385 (29) to 921 (100) ml/min (140% increase; P< 0.05) in patients and from 517 (50) to 790 (67) (53% increase; P< 0.001) in controls. This study shows that patients with Type 1 diabetes have a normal splanchnic vascular hyperaemic response to hypoglycaemia despite defective glucagon counter-regulation. These results support our previous work suggesting that glucagon is not a major mediator of this response; it seems likely that circulating adrenaline is the major regulatory mechanism.
Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover
Authors: LAMBERT Gavin W. , VAZ Mario , COX Helen S. , TURNER Andrea G. , KAYE David M. , JENNINGS Garry L. , ESLER Murray D.
Published: August 2015

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.
Angiotensin II increases the release of endothelin-I from human cultured endothelial cells but does not regulate its circulating levels
Authors: FERRI Claudio , DESIDERI Giovambattista , BALDONCINI Roberta , BELLINI Cesare , VALENTI Marco , SANTUCCI Anna , MATTIA Giancarlo DE
Published: August 2015

We investigated the effect of angiotensin II on endothelin-1 secretion in vitro and in vivo. In vivo, angiotensin II was given intravenously to 23 essential hypertensive and 8 control subjects according to different protocols: Study A, 1.0 ngċmin-1ċkg-1 and 3.0 ngċmin-1ċkg-1 angiotensin II for 30 min each; Study B, 1.0 ngċmin-1ċkg-1 and 3.0 ngċmin-1ċkg-1 angiotensin II for 120 min each; Study C, 3.0 ngċmin-1ċkg-1 angiotensin II for 30 min followed by a dose increment of 3.0 ngċmin-1ċkg-1 every 30 min until mean blood pressure levels increased by 25 mmHg; Study D, 1.0 ngċmin-1ċkg-1 followed by 3.0 ngċmin-1ċkg-1 angiotensin II for 60 min each on two different NaCl diets (either 20 mmol NaCl/day or 220 mmol NaCl/day, both for 1 week). In all in vivo studies neither plasma nor urine endothelin-1 levels changed with angiotensin II infusion. In contrast, angiotensin II (10-9, 10-8, 10-7 mol/l) stimulated endothelin-1 secretion from cultured human vascular endothelial cells derived from umbilical cord veins in a time- and dose-dependent manner. The in vitro angiotensin II effects were abolished by candesartan cilexetil, an inhibitor of the membrane-bound AT1 receptor, and also by actinomycin D, an RNA synthesis inhibitor, and cycloheximide, a protein synthesis inhibitor, indicating that endothelin-1 release depended on AT1 receptor subtype and de novo protein synthesis. Our findings indicate that angiotensin II regulates endothelin-1 release by cultured endothelial cells through an AT1 receptor-dependent pathway, but does not influence circulating endothelin-1 levels in vivo.
Increased phosphoglycerate kinase in the brains of patients with Down's syndrome but not with Alzheimer's disease
Authors: LABUDOVA Olga , KITZMUELLER Erwin , RINK Hermann , CAIRNS Nigel , LUBEC Gert
Published: August 2015

Impaired glucose metabolism in Down's syndrome (DS) has been well-documented in vivo, although information on the underlying biochemical defect is limited and no biochemical studies on glucose handling enzymes have been carried out in the brain. Through gene hunting in fetal DS brain we found an overexpressed sequence homologous to the phosphoglycerate kinase (PGK) gene. This finding was studied further by investigating the activity levels of this key enzyme of carbohydrate metabolism in the brains of patients with DS. PGK activity was determined in five brain regions of nine patients with DS, nine patients with Alzheimer's disease and 14 controls. PGK activity was significantly elevated in the frontal, occipital and temporal lobe and in the cerebellum of patients with DS. PGK activity in corresponding brain regions of patients with Alzheimer's disease was comparable with controls. We conclude that our findings complement previously published data on impaired brain glucose metabolism in DS evaluated by positron emission tomography in clinical studies. Furthermore, we show that in DS, impaired glucose metabolism, represented by increased PGK activity, is a specific finding rather than a secondary phenomenon simply due to neurodegeneration or atrophy. These observations are also supported by data from subtractive hybridization, showing overexpressed PGK in DS brains at the transcriptional level early in life.
Systemic inflammatory response syndrome without systemic inflammation in acutely ill patients admitted to hospital in a medical emergency
Authors: TAKALA Annika , JOUSELA Irma , OLKKOLA Klaus T. , JANSSON Sten-Erik , LEIRISALO-REPO Marjatta , TAKKUNEN Olli , REPO Heikki
Published: August 2015

Criteria of the systemic inflammatory response syndrome (SIRS) are known to include patients without systemic inflammation. Our aim was to explore additional markers of inflammation that would distinguish SIRS patients with systemic inflammation from patients without inflammation. The study included 100 acutely ill patients with SIRS. Peripheral blood neutrophil and monocyte CD11b expression, serum interleukin-6, interleukin-1β, tumour necrosis factor-α and C-reactive protein were determined, and severity of inflammation was evaluated by systemic inflammation composite score based on CD11b expression, C-reactive protein and cytokine levels. Levels of CD11b expression, C-reactive protein and interleukin-6 were higher in sepsis patients than in SIRS patients who met two criteria (SIRS2 group) or three criteria of SIRS (SIRS3 group). The systemic inflammation composite score of SIRS2 patients (median 1.5; range 0–8, n = 56) was lower than that of SIRS3 patients (3.5; range 0–9, n = 14, P = 0.013) and that of sepsis patients (5.0; range 3–10, n = 19, P< 0.001). The systemic inflammation composite score was 0 in 13/94 patients. In 81 patients in whom systemic inflammation composite scores exceeded 1, interleukin-6 was increased in 64 (79.0%), C-reactive protein in 59 (72.8%) and CD11b in 50 (61.7%). None of these markers, when used alone, identified all patients but at least one marker was positive in each patient. Quantifying phagocyte CD11b expression and serum interleukin-6 and C-reactive protein concurrently provides a means to discriminate SIRS patients with systemic inflammation from patients without systemic inflammation.
Effects of acute prolonged exposure to high-altitude hypoxia on exercise-induced breathlessness
Authors: BURKI Nausherwan K. , MCCONNELL J. Wesley , AYUB Mohammad , LILES Richard M.
Published: August 2015

The direct effects of hypoxia on exercise-induced breathlessness are unclear. Increased breathlessness on exercise is known to occur at high altitude, but it is not known whether this is related to the hypoxia per se, or to other ventilatory parameters. To examine the role of high-altitude hypoxia in exercise-induced breathlessness, studies were performed in 10 healthy, normal subjects at sea level and after acute exposure to an altitude of 4450 ;m. Although the perception of hand weights did not alter between sea level and high altitude, the intensity of exercise-induced breathlessness increased significantly at high altitude. This was associated with a higher minute ventilation and respiratory frequency for any given exercise level, whereas tidal volume was not significantly altered from sea level values. The increased intensity of breathlessness with exercise did not change significantly over the 5 days at high altitude. These results suggest that the increased intensity of exercise-induced breathlessness at high altitude is not related to peripheral mechanisms or the pattern of ventilation, or to the level of hypoxia per se, but to the level of reflexly increased ventilation.