bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of skeletal muscle mass, muscle strength and bone mineral density in adults with cystic fibrosis
Authors: ELKIN Sarah L. , WILLIAMS Lauren , MOORE Margaret , HODSON Margaret E. , RUTHERFORD Olga M.
Published: August 2015

Few studies have investigated peripheral muscle strength and quality in patients with cystic fibrosis (CF). The present study tested the isometric and isokinetic strength of the quadriceps and hamstrings using an isokinetic dynamometer and a strength-testing chair in 25 CF adults and 25 controls. Total body and leg muscle mass were determined by dual-energy X-ray absorptiometry, and bone mineral density (BMD) was also measured. Both muscle strength and muscle mass (total body and leg) were decreased in the CF group. In both groups there was a highly significant relationship between quadriceps strength and leg muscle mass (CF, r = 0.7, P = 0.0002; controls, r = 0.6, P = 0.0013). When strength was normalized for muscle size, there was no significant difference between the two groups. Total body and leg BMD were significantly reduced in CF subjects compared with controls. However, when corrected for height, the differences disappeared. There was a significant relationship found between leg muscle mass and leg BMD. We conclude that CF adults are significantly weaker than controls. This is due to lower muscle mass, and not to a reduced force-generating capacity of the muscle, implying that there is no decrease in the quality of CF muscle. BMD is also reduced in CF subjects, and this appears to be related to shorter stature in this group.
Comparative in vivo effects of irbesartan and losartan on angiotensin II receptor binding in the rat kidney following oral administration
Authors: FABIANI Maurice E. , DINH Diem T. , NASSIS Labrini , CASLEY David J. , JOHNSTON Colin I.
Published: August 2015

We examined the ability of the new non-peptide angiotensin II receptor antagonist irbesartan to inhibit AT1 receptors in vivo in the rat kidney following oral administration, compared with the prototype drug losartan. Male Sprague–Dawley rats (250–300 g) were gavaged with either irbesartan or losartan at doses of 1, 3, 10, 30 or 100 mg/kg, or with corresponding vehicle. Rats were killed at 0, 1, 2, 8, or 24 h after drug administration, trunk blood was collected and the kidneys were removed. The effects of irbesartan and losartan on angiotensin II receptor binding were determined by quantitative in vitro autoradiography using the specific radioligand 125I-[Sar1,Ile8]angiotensin II. High levels of angiotensin II receptor binding in the rat kidney were demonstrated in the glomeruli and inner stripe of the outer medulla, which was attributed to AT1 receptors. At 1 h after dosing, irbesartan (1–100 mg/kg) and losartan (1–30 mg/kg) significantly inhibited AT1 receptor binding in all anatomical areas of the kidney, in a dose-dependent manner, with a maximal effect at 100 mg/kg and 30 mg/kg respectively. For a 10 mg/kg dose, inhibition of AT1 receptor binding was maximal around 1–2 h after oral administration of losartan, whereas maximal binding occurred between 2 and 8 h for irbesartan; both drugs produced persistent tissue blockade at 24h. In radioligand binding studies, irbesartan, losartan and EXP3174 (1×10-10 to 1×10-5 M) displaced 125I-[Sar1,Ile8]angiotensin II binding from renal AT1 receptors in a concentration-dependent manner, with a rank order of potency of irbesartan > EXP3174 > losartan. The concentration required to displace 50% of radioligand binding (IC50) by irbesartan, EXP3174 and losartan was 1.00±0.2 nM, 3.5±0.4 nM and 8.9±1.1 nM respectively. In conclusion, the findings of the present study suggest that irbesartan and losartan produce effective and sustained inhibition of AT1 receptors in vivo in the kidney following oral administration. However, irbesartan appears less potent, with respect to dosage, than losartan in vivo, despite having a higher affinity for AT1 receptors in vitro. The reason for this apparent discrepancy is unclear, but it may reflect the slower onset of action of irbesartan and its rate of tissue accessibility. Inhibition of angiotensin II receptors in target tissues such as the kidney may represent an important action of AT1 receptor antagonists, which may contribute to the beneficial effects of these agents in the clinical setting.
Baroreflex sensitivity in the elderly: influence of age, breathing and spectral methods
Authors: GERRITSEN J. , TENVOORDE B. J. , DEKKER J. M. , KOSTENSE P. J. , BOUTER L. M. , HEETHAAR R. M.
Published: August 2015

Baroreflex sensitivity (BRS) has been proposed as a diagnostic parameter for neurological disorders and as a survival-prognosis parameter in diabetic and cardiac patients. Therefore reference values and the reproducibility of BRS were assessed, taking into account the possible influence of age, gender, test conditions and some analysis variants. Healthy subjects (n = 191) were randomly selected from the 50–75-year-old general population (the Hoorn Study). Variations in blood pressure and heart rate were recorded non-invasively during three breathing modes: spontaneous (3 min), slow metronome (1 min; 6 breaths/min = 0.1 Hz) and fast metronome (1 min; 15 breaths/min = 0.25 Hz), all in a supine position. From these recordings, BRS was assessed as the transfer gain between changes in blood pressure and heart period, and as the α coefficient. BRS values ranged from 5.0 to 8.9 ms·mmHg-1. Slow metronome breathing resulted in higher BRS values than fast breathing, while during spontaneous breathing BRS in the low-frequency band was lower than that in the high-frequency band (respiratory origin). BRS values decreased with lower coherence criteria. BRS-α was significantly higher than BRS-gain. While regression analysis showed no gender differences, BRS decreased with age. Therefore age-specific reference values were calculated. The reproducibility of BRS values was in general moderate, with reliability coefficients ranging from 43 to 81% and coefficients of variation ranging from 34 to 59%. In conclusion, this study shows age, breathing mode, frequency and coherence threshold to affect measures of BRS. Therefore these factors should be considered in clinical studies; appropriate reference values are given.
Dexamethasone and pentastarch produce additive attenuation of ischaemia/reperfusion lung injury
Authors: CHIANG Chi-Huei , WU Chin-Pyng , PERNG Wann-Cherng , YAN Horng-Chin , YU Cheng-Ping
Published: August 2015

The choice of an intravenous solution for the attenuation of ischaemia/reperfusion (I/R) lung injury is still a difficult one. Although 10% (w/v) pentastarch has been used in ICU settings, its use in I/R lung injury has not been well explored. We hypothesized that this synthetic colloid substance, which maintains colloid osmotic pressure and potentially ‘seals’ capillary leaks, in combination with an anti-inflammatory agent (i.e. dexamethasone), would ameliorate I/R lung injury. After 60 min of lung ischaemia in an isolated rat lung model, lungs were reperfused for 60 min in a closed circulating system with one of the following solutions: (1) NS (0.9% normal saline), (2) NS+Dex (dexamethasone), (3) NS+Penta (pentastarch), or (4) NS+Penta+Dex. Haemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (Kfc) and lung pathology were analysed. Results showed significantly lower values of Kfc and LWG in pentastarch- or dexamethasone-perfused groups as compared with those in the NS group. Dexamethasone as an additive to NS+Penta further decreased Kfc and LWG. Histopathological studies showed similar decreases in injury profiles. We conclude that reperfusion with dexamethasone and pentastarch can attenuate I/R lung injury, and that dexamethasone and pentastarch have additive effects. Our data thus suggest that the combination of a colloid substance with ‘sealing effects’ and an anti-inflammatory agent may provide a better reperfusion solution for patients with I/R lung injury or for lungs stored for transplant.
Circulating C-type natriuretic peptide is increased in orthotopic cardiac transplant recipients and associated with cardiac allograft vasculopathy
Authors: BUCKLEY Martin G. , JENKINS Geraint H. , MITCHELL Andrew G. , YACOUB Magdi H. , SINGER Donald R. J.
Published: August 2015

C-type natriuretic peptide (CNP) is a potent, endothelial-derived relaxant and growth-inhibitory factor. Accelerated vascular disease is an important cause of morbidity in cardiac transplant recipients, and endothelial dysfunction is now well recognized in patients with cardiovascular disease. CNP has not previously been investigated following cardiac transplantation. We therefore studied plasma levels of immunoreactive CNP in patients early and late after heart transplantation, compared with levels in healthy subjects. We measured CNP in extracted human plasma using an antibody against human CNP-(1–22). CNP levels were significantly elevated in 13 cardiac recipients 2 weeks post-transplant [2.64±0.26 pmol/l (mean±S.E.M.)] compared with those in the normal healthy subjects (0.62±0.04 pmol/l; n = 20, P < 0.001). Plasma levels of CNP were also significantly elevated in a second group of established cardiac transplant recipients (1.15±0.07 pmol/l; n = 46) studied 1–13 years post-transplant when compared with the healthy subjects (P < 0.001). In the group studied later after transplantation, CNP levels were significantly associated with systolic blood pressure (P < 0.05) and were higher in patients with angiographic post-transplant coronary artery disease (P = 0.032). In conclusion, these findings clearly demonstrate that CNP is elevated soon after cardiac transplantation and remains raised in patients even several years post-transplant. CNP may be important as a circulating or local hormone involved in vascular contractile function and in the pathophysiology of cardiac allograft vasculopathy following heart transplantation.
Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model
Authors: MATERNE Roland , VAN BEERS Bernard E. , SMITH Anne M. , LECONTE Isabelle , JAMART Jacques , DEHOUX Jean-Paul , KEYEUX André , HORSMANS Yves
Published: August 2015

Various liver diseases lead to significant alterations of the hepatic microcirculation. Therefore, quantification of hepatic perfusion has the potential to improve the assessment and management of liver diseases. Most methods used to quantify liver perfusion are invasive or controversial. This paper describes and validates a non-invasive method for the quantification of liver perfusion using computed tomography (CT). Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass iodinated contrast agent. Hepatic, aortic and portal-venous time—density curves were fitted with a dual-input one-compartmental model to calculate liver perfusion. Validation studies consisted of simultaneous measurements of hepatic perfusion with CT and with radiolabelled microspheres in rabbits at rest and after adenosine infusion. The feasibility and reproducibility of the CT method in humans was assessed by three observers in 10 patients without liver disease. In rabbits, significant correlations were observed between perfusion measurements obtained with CT and with microspheres (r = 0.92 for total liver perfusion, r = 0.81 for arterial perfusion and r = 0.85 for portal perfusion). In patients, total liver plasma perfusion measured with CT was 112±28 ml·min-1·100 ml-1, arterial plasma perfusion was 18±12 ml·min-1·100 ml-1 and portal plasma perfusion was 93±31 ml·min-1·100 ml-1. The measurements obtained by the three observers were not significantly different from each other (P > 0.1). Our results indicate that dynamic CT combined with a dual-input one-compartmental model provides a valid and reliable method for the non-invasive quantification of perfusion in the normal liver.
Elevated circulating leptin levels in arterial hypertension: relationship to arteriovenous overflow and extraction of leptin
Authors: HENRIKSEN Jens H. , HOLST Jens J. , MØLLER Søren , ANDERSEN Ulrik B. , BENDTSEN Flemming , JENSEN Gorm
Published: August 2015

Leptin, a peptide hormone produced mainly in fat cells, appears to be important for the regulation of metabolism, insulin secretion/sensitivity and body weight. Recently, elevated plasma leptin levels have been reported in patients with arterial hypertension. Because a change in circulating leptin concentrations in such patients could be caused by altered rates of production or disposal, or both, the aim of the present study was to identify regions of leptin overflow into the bloodstream and of leptin extraction. Patients with arterial hypertension (n = 12) and normotensive controls (n = 20) were studied during catheterization with elective blood sampling from different vascular beds (artery, and renal, hepatic, iliac and cubital veins). Plasma leptin was determined by a radioimmunoassay. Patients with hypertension had significantly elevated levels of circulating leptin (12.8 ng/l, compared with 4.1 ng/l in the controls; P < 0.001), and this was also the case when adjusted for body mass index (BMI) [0.435 and 0.167 ng/l per unit BMI (kg/m2) respectively; P < 0.001]. Circulating leptin was directly related to arterial blood pressure (r = 0.38–0.62, P ⩽ 0.05–0.005) and immunoreactive insulin (r = 0.51, P < 0.62), but not to plasma renin activity. A significant renal extraction ratio for leptin was seen in the hypertensive patients, but this was not significantly lower than that in the controls (0.09 compared with 0.16; P = 0.1). The hypertensive patients had a significantly higher hepatic venous/arterial leptin ratio than the controls (1.02 compared with 0.93; P < 0.02), and this ratio was correlated directly with the BMI (r = 0.38, P = 0.05) and immunoreactive insulin (r = 0.43, P < 0.05). In both hypertensive patients and controls there was a significant spillover of leptin into the iliac vein, but not into the cubital vein. In conclusion, the high concentration of circulating leptin in patients with arterial hypertension is probably caused by increased release of leptin from abdominal (especially mesenteric and omental) and gluteal adipose tissue stores, and renal extraction is slightly reduced. Leptin kinetics in arterial hypertension require further investigation.
Effects of the Ca2+ sensitizer EMD 57033 on intracellular Ca2+ in rat ventricular myocytes: relevance to arrhythmogenesis during positive inotropy
Authors: KAWAI Makoto , LEE John A. , ORCHARD Clive H.
Published: August 2015

We have investigated the effects of the calcium-sensitizing inotropic agent EMD 57033 on Ca2+ handling in intact and skinned rat ventricular myocytes. Intracellular Ca2+ was monitored using fura 2. Myocytes were saponin-skinned, allowing study of sarcoplasmic reticulum (SR) function. In intact myocytes EMD 57033 (1–10 µmol/l) produced a concentration-dependent decrease in the amplitude of the Ca2+ transient and prolonged its declining phase, but had no effect on the rise time. In skinned myocytes, the amplitude of spontaneous Ca2+ release from the SR was decreased by EMD 57033 (5 and 10 µmol/l), although this agent had no significant effect on the frequency of spontaneous Ca2+ release. In the presence of the cross-bridge inhibitor 2,3-butanedione monoxime (5 mmol/l), or in a low bathing Ca2+ concentration (1 mmol/l), EMD 57033 (10 µmol/l) had smaller effects on both the amplitude and time course of the Ca2+ transient in intact cells than in the absence of 2,3-butanedione monoxime or in the presence of 2 and 5 mmol/l Ca2+ respectively. These data suggest that the effects of EMD 57033 on Ca2+ are due to changes in Ca2+ binding to troponin C, secondary to cross-bridge formation. Thus, during positive inotropy, EMD 57033 is unlikely to provoke arrhythmias due to effects on SR Ca2+ handling. In intact cells, its effects on Ca2+ handling would be expected to protect against arrhythmias.
Hyperhomocysteinaemia in young adults is not associated with impaired endothelial function
Authors: HANRATTY Colm G. , MCAULEY Daniel F. , MCGRATH Lawrence T. , YOUNG Ian S. , JOHNSTON G. Dennis
Published: August 2015

A mild to moderate elevation of the total homocysteine concentration (tHcy) is now recognized as a risk factor for vascular disease. It is also associated with endothelial dysfunction in middle-aged and elderly individuals without overt atherosclerotic vascular disease. This is important, as endothelial dysfunction is a well recognized early and potentially reversible marker of the atherosclerotic process. We investigated whether mild hyperhomocysteinaemia was associated with endothelial dysfunction in otherwise healthy young males. We compared endothelial function, by measuring forearm blood flow, in 17 males with mild hyperhomocysteinaemia (defined as tHcy > 10 µmol/l) and 14 controls with low tHcy (defined as < 5 µmol/l). Forearm blood flow was measured in response to the intra-arterial infusion of acetylcholine (endothelial-dependent response) or sodium nitroprusside (endothelial-independent response). Responses to the vasoactive substances were expressed as the area under the curve of the change in forearm blood flow from baseline. Data are given as mean (95% confidence interval). The two groups were well matched for age, body mass index, pulse rate and blood pressure. tHcy was significantly different between the groups [12.3 (10.4–14.2) µmol/l compared with 4.9 (4.6–5.1) µmol/l; P < 0.001]. Concentrations of vitamin B12 and folate were significantly higher in the control group. There was no difference in basal forearm blood flow between the group with mild hyperhomocysteinaemia and the controls, and both the endothelial-dependent [37.5 (26.2–38.8) and 35.3 (26.1–44.4) arbitrary units respectively] and -independent [26.1 (22.2–29.9) and 25.9 (21.0–30.8) units respectively] responses were not significantly different between the groups. Thus the present study demonstrates that, in healthy adults, mild elevation of tHcy was not associated with impaired endothelial-dependent vasodilation. These data suggest an age effect with regard to homocysteine and endothelial dysfunction. The development of vascular disease in individuals with hyperhomocysteinaemia may only result with higher concentrations or after prolonged exposure.
Role of aminothiols as a component of the plasma antioxidant system and relevance to homocysteine-mediated vascular disease
Authors: MOAT Stuart J. , BONHAM James R. , POWERS Hilary J.
Published: August 2015

Hyperhomocysteinaemia is considered to be an independent risk factor for vascular disease. Elevated plasma homocysteine may pose an oxidative stress, leading to the development of vascular damage. A component of this effect may be a disturbance of the extracellular aminothiol redox state. The relative contributions of plasma total homocysteine (tHcy) and plasma total cysteine (tCys) to the total antioxidant capacity (TAOC) of plasma was established in subjects with normal and elevated plasma tHcy. A total of 10 subjects with severe hyperhomocysteinaemia (due to inherited metabolic defects), 13 of their heterozygous parents and 72 normal healthy subjects were recruited to the study. The mean plasma tHcy in the patients was 91.8 µmol/l, compared with 13.2 µmol/l in the parents and 14.7 µmol/l in healthy control subjects. Plasma tCys and plasma TAOC were significantly lower in the subjects with severe hyperhomocysteinaemia compared with the parents and healthy control subjects (P < 0.05). In blood samples from subjects with a normal tHcy, a positive correlation was observed between tCys and tHcy (P = 0.0001). In contrast, in blood samples with tHcy ⩾ 20 µmol/l, plasma tCys was negatively correlated with tHcy (P = 0.0001). In samples with tHcy ⩾ 20 µmol/l, tHcy was inversely correlated with TAOC (P = 0.0001), whereas tCys was positively associated with TAOC (P = 0.0001). Multiple regression analysis revealed that tCys was the most important independent determinant of TAOC in the patient and control groups when the effects of tHcy and several factors known to influence TAOC, such as urate, were taken into account. Thus hyperhomocysteinaemia may pose an oxidative stress not only through the direct cytotoxicity of homocysteine, but also from an associated fall in plasma cysteine.
Effects of acute methionine loading and vitamin Con endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation
Authors: LABINJOH Catherine , NEWBY David E. , WILKINSON Ian B. , MEGSON Ian L. , MACCALLUM Helen , MELVILLE Vanessa , BOON Nicholas A. , WEBB David J.
Published: August 2015

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0±0.1 to 4.7±0.4 ng/ml; P < 0.001) and activity (from 1.2±0.2 to 4.2±0.4 i.u./ml; P < 0.001), which were augmented during acute methionine loading (4.7±0.4 to 5.6±0.5 ng/ml and 4.2±0.4 to 5.5±0.9 i.u./ml respectively; P⩽0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P = 0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.
Acute and long-term effects of low-density lipoprotein (LDL)-apheresis on oxidative damage to LDL and reducing capacity of erythrocytes in patients with severe familial hypercholesterolaemia
Authors: STEFANUTTI C. , GIACOMO S. DI , VIVENZIO A. , ISACCHI G. C. , MASELLA R. , CAPRARI P. , VARÌ R. , TARZIA A. , MOSIELLO A. , CANTAFORA A.
Published: August 2015

Several studies have suggested that the oxidative modification of low-density lipoprotein (LDL) could play a key role in the early stages of atherosclerosis. The susceptibility of LDL to oxidation has been found to be greater in patients with coronary heart disease. Familial hypercholesterolaemia (FH) is a powerful clinical model in which to study the predictive role of LDL in atherogenesis. LDL-apheresis is a treatment that is able to decrease lipid levels in plasma. This study was aimed at investigating the reducing capacity of erythrocytes and the in vitro susceptibility to oxidation of LDL isolated from patients with homozygous, heterozygous and double-heterozygous FH, who were treated fortnightly with LDL-apheresis or left untreated. In 14 FH patients, at baseline and after a cycle of treatment, the susceptibility of LDL to oxidative modification was analysed by studying the kinetics of conjugate diene formation. Plasma hydroperoxides, polyunsaturated fatty acid content, LDL electrophoretic mobility on agarose, the titre of auto-antibodies against oxidized LDL and serum paraoxonase activity were also measured. Furthermore, in order to evaluate a potential relationship between LDL oxidation and redox status, erythrocyte GSH and ATP levels were determined in FH patients treated regularly or never treated previously by LDL-apheresis. Unlike in the control group, the oxidative status of LDL in all FH patients was modified by LDL-apheresis, as revealed by the higher negative charge and the increase in levels of hydroperoxides and antibodies against oxidized LDL in the plasma. Our findings suggest both an acute effect and a long-term effect of LDL-apheresis in FH patients treated with dextran sulphate cellulose apheresis. The acute effect of LDL-apheresis on the susceptibility to oxidation of plasma and LDL was demonstrated by significant decreases in plasma hydroperoxide content, total LDL concentration and polyunsaturated fatty acid content. The increased resistance of LDL to oxidation was shown by prolongation of the lag time (P < 0.05) in samples after a single cycle of treatment. The long-term effect of LDL-apheresis was demonstrated by the comparable values for lag phases (obtained from the kinetics of conjugate diene formation) in patients under active treatment and controls. Compared with healthy controls and untreated patients, the erythrocyte GSH content was significantly higher (P⩽ 0.001) in the treated group, suggesting the activation of reducing mechanisms.
Relationship between migraine and cardiac and pulmonary right-to-left shunts
Authors: WILMSHURST Peter , NIGHTINGALE Simon
Published: August 2015

A relationship between migraine with aura and the presence of right-to-left shunts has been reported in two studies. Right-to-left shunts are also associated with some forms of decompression illness. While conducting research in divers with decompression illness, it was our impression that divers with a large shunt often had a history of migraine with aura in everyday life and after dives. Therefore we routinely asked all divers about migraine symptoms. The medical records of the last 200 individuals referred for investigation of decompression illness were reviewed to determine the association between right-to-left shunts and migraine aura after diving, and migraine in daily life unconnected with diving. Migraine with aura in daily life unconnected with diving occurred significantly more frequently in individuals who had a large shunt which was present at rest (38 of 80; 47.5%) compared with those who had a shunt which was smaller or only seen after a Valsalva manoeuvre (four of 40; 10%) or those with no shunt (11 of 80; 13.8%) (P < 0.001). Hemiplegic migraine occurred in 10 divers, each of whom had a shunt that was present at rest; in eight of these cases the shunt was large. The prevalence of migraine without aura was similar in all groups. Post-dive migraine aura was significantly more frequent in individuals who had a large shunt present at rest (21 of 80; 26.3%) compared with those who had a shunt that was smaller or only seen after a Valsalva manoeuvre (five of 40; 12.5%) or no shunt (one of 80; 1.3%) (P < 0.001). Thus individuals with a large right-to-left shunt have an increased prevalence of migraine with aura in daily life unconnected with diving, and they also have an increased incidence of migraine aura after dives, but only when the dives liberate venous bubbles. These data suggest the possibility that, in some individuals, right-to-left shunts have a role in the aetiology of migraine with aura. The observations suggest that paradoxical gas embolism may precipitate migraine with aura.
Evaluation of pulmonary alveolar epithelial integrity by the detection of restriction to diffusion of hydrophilic solutes of different molecular sizes
Authors: MASON G. R. , PETERS A. M. , BAGDADES E. , MYERS M. J. , SNOOK D. , HUGHES J. M. B.
Published: August 2015

The rate of transfer of a hydrophilic solute from the alveoli to pulmonary blood following inhalation as an aerosol depends on the molecular size of the solute and the permeability of the alveolar epithelium. The value of this measurement for assessing damage to the epithelium in lung disease is compromised by cigarette smoking, which accelerates clearance by unknown mechanisms. The rates of clearance of 99mTc-labelled diethylenetriaminepenta-acetic acid (DTPA) (molecular mass 492 Da) and 113mIn-labelled biotinylated DTPA (B-DTPA) (molecular mass 1215 Da) were monitored simultaneously by dynamic γ-radiation camera imaging following simultaneous inhalation, and compared between eight normal non-smoking subjects and nine habitual cigarette smokers. The clearance rates of DTPA were 0.95 (S.D. 0.39)%/min in non-smokers and 4.13 (1.06) %/min in smokers. These were about twice the clearance rates of B-DTPA, which in the corresponding groups were 0.41 (0.26) and 2.12 (0.72)%/min respectively. The ratio of the B-DTPA/DTPA clearance rates was, in all subjects, less than the ratio (0.74) of the cube roots of the molecular masses of the solutes, assumed to correspond to the ratio of their free diffusion coefficients in water, and was not significantly different between smokers and non-smokers. As alveolar permeability increased, the ratio of clearance rates in the entire population showed a significant trend to increase in a non-linear fashion towards the value corresponding to the ratio of the free diffusion coefficients. We conclude that the diffusion of at least the larger of these two solutes through the pulmonary alveolar epithelium is restricted (i.e. associated with a reflection coefficient greater than zero). Cigarette smoking, however, does not appear to cause a loss of this restriction, and may increase solute clearance by other mechanisms, such as reducing fluid volume within the alveolus, thereby raising the local radiotracer concentration, or increasing the number of pores available for solute exchange without affecting pore size. Conversely, if restriction was lost in lung disease, the ratio of the clearance rates of two solutes of dissimilar sizes could be used to detect disease in smokers as well as non-smokers.
Relationship between C-reactive protein and intima-media thickness in the carotid and femoral arteries and to antibodies against oxidized low-density lipoprotein in healthy men: the Atherosclerosis and Insulin Resistance (AIR) study
Authors: HULTHE Johannes , WIKSTRAND John , FAGERBERG Björn
Published: August 2015

Results from several recent reports have linked high serum C-reactive protein (CRP) levels to atherosclerotic disease and its complications. The aims of the present study were to investigate the relationship between CRP levels and subclinical atherosclerosis, as measured by ultrasound in the carotid and femoral arteries; and also to examine whether CRP levels are associated with antibodies to oxidized low-density lipoprotein (Ox-LDL). The study group (n = 391) consisted of clinically healthy 58-year-old men recruited from the general population. CRP and antibody titres to Ox-LDL were measured by ELISA. The results showed an association between CRP and ultrasound-assessed subclinical atherosclerosis in the femoral artery (r = 0.14, P = 0.010), and also between CRP and systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, high-density lipoprotein, body mass index, waist-to-hip ratio (WHR), blood glucose, cigarette-years and antibody titres to ox-LDL (r = 0.19, P < 0.001). In this clinically healthy population of 58-year-old men, CRP levels were associated with both intima-media thickness and plaque occurrence in the femoral artery. The association between CRP and femoral atherosclerosis was not independent of smoking, serum LDL cholesterol, or systolic blood pressure. CRP levels were independently related to abdominal obesity measured as WHR, smoking and antibody titres to Ox-LDL.
Sodium/lithium countertransport, insulin resistance, insulin peptides and microalbuminuria in clinically healthy 58-year-old men
Authors: HERLITZ Hans , BOKEMARK Lena , ALENHAG Eva-Lena , WIKSTRAND John , FAGERBERG Björn
Published: August 2015

The activity of the erythrocyte transport system, sodium/lithium countertransport (SLC), has been linked to the metabolic syndrome characterized by insulin resistance and compensatory hyperinsulinaemia. We measured SLC and insulin sensitivity with the euglycaemic hyperinsulinaemic clamp method in a patient sample (n = 93) randomly selected from a large clinically healthy group of 58-year-old men (n = 818). The lipid profile, blood pressure, body mass index (BMI) and insulin were also analysed. There was a significant difference (P < 0.001) in SLC between subjects with the metabolic syndrome (n = 19) and subjects without any components of this syndrome (n = 20). There was a highly significant correlation between SLC and BMI, waist/hip ratio, total body fat mass, serum triglycerides, plasma insulin, proinsulin split products and C-peptide in a univariate analysis. There was also a significant correlation between SLC and insulin sensitivity measured as insulin-mediated glucose uptake (P < 0.01). In multiple regression analysis, only two of the variables showing univariate significance were independently correlated to SLC, i.e. serum triglycerides (P < 0.001) and BMI (P < 0.01). The subjects with a SLC value in the highest tertile had a 6-fold higher prevalence of insulin resistance (low-insulin-mediated glucose uptake) as compared with those with a SLC value in the lowest tertile. We conclude that, in clinically healthy 58-year-old men from the general population, erythrocyte SLC is closely linked to metabolic syndrome, in particular to obesity, triglycerides and insulin resistance.
Left ventricular performance during prolonged exercise: absence of systolic dysfunction
Authors: GOODMAN Jack M. , McLAUGHLIN Peter R. , LIU Peter P.
Published: August 2015

We assessed left ventricular systolic and diastolic performance during and after prolonged exercise under controlled conditions in a group of healthy, trained men. Previous studies have examined the effects of prolonged effort on left ventricular function, yet it remains unclear whether or not left ventricular dysfunction (e.g. cardiac fatigue) can be produced under such conditions. We studied 15 healthy men, aged 27±1 years (mean±S.E.M.). Subjects exercised on bicycles at a constant work rate (60% of maximum oxygen uptake per min) for 150 min. Measurements of gas exchange, blood pressure and haematocrit were obtained, concurrent with the assessment of left ventricular function using equilibrium radionuclide angiography, at rest, during exercise (every 30 min) and after 30 min of recovery. Fluid replacement was provided and monitored during the exercise period. The baseline resting and exercise ejection fractions were 66±2% and 78±2% respectively. During exercise, subjects consumed 1816±136 ml of fluid, and the haematocrit had increased at 120 min of exercise (from 47.2%±0.6 to 49.9±0.8%; P < 0.05). There was no change in either systolic or diastolic blood pressure throughout the exercise period, but heart rate drifted upwards from 141±2 beats/min after 30 min to 154±3 beats/min after 150 min (P < 0.05). There was a small decline (8%; P < 0.05) in end-diastolic volume at 150 min. No changes were observed in left ventricular ejection fraction, the pressure/volume ratio or end-systolic volume. After 30 min of sitting in recovery, heart rate was still higher than the pre-exercise value (84±3 compared with 69±2 beats/min; P < 0.05), as were measures of peak filling rate and time to peak filling (P < 0.05). The ejection fraction in the post-exercise recovery period was similar to the pre-exercise value. The results indicate that prolonged exercise of moderate duration may not induce abnormal left ventricular systolic function or cardiac fatigue during exercise.
Relationship between right-to-left shunts and cutaneous decompression illness
Authors: WILMSHURST P. T. , PEARSON M. J. , WALSH K. P. , MORRISON W. L. , BRYSON P.
Published: August 2015

The presence of a large right-to-left shunt is associated with neurological decompression illness after non-provocative dives, as a result of paradoxical gas embolism. A small number of observations suggest that cutaneous decompression illness is also associated with a right-to-left shunt, although an embolic aetiology of a diffuse rash is more difficult to explain. We performed a retrospective case–control comparison of the prevalence and sizes of right-to-left shunts determined by contrast echocardiography performed blind to history in 60 divers and one caisson worker with a history of cutaneous decompression illness, and 123 historical control divers. We found that 47 (77.0%) of the 61 cases with cutaneous decompression illness had a shunt, compared with 34 (27.6%) of 123 control divers (P< 0.001). The size of the shunts in the divers with cutaneous decompression illness was significantly greater than in the controls. Thus 30 (49.2%) of the 61 cases with cutaneous decompression illness had a large shunt at rest, compared with six (4.9%) of the 123 controls (P< 0.001). During closure procedures in 17 divers who had cutaneous decompression illness, the mean diameter of the foramen ovale was 10.9 mm. Cutaneous decompression illness occurred after dives that were provocative or deep in subjects without shunts, but after shallower and non-provocative dives in those with shunts. The latter individuals are at increased risk of neurological decompression illness. We conclude that cutaneous decompression illness has two pathophysiological mechanisms. It is usually associated with a large right-to-left shunt, when the mechanism is likely to be paradoxical gas embolism with peripheral amplification when bubble emboli invade tissues supersaturated with nitrogen. Cutaneous decompression illness can also occur in individuals without a shunt. In these subjects, the mechanism might be bubble emboli passing through an ‘overloaded’ lung filter or autochthonous bubble formation.
Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine
Authors: PODJARNY Eduardo , BURSZTYN Michael , RASHED Gloria , BENCHETRIT Sidney , KATZ Bernard , GREEN Janice , KARMELI Fanny , PELEG Edna , BERNHEIM Jacques
Published: August 2015

Recent studies have shown that maternal hyperinsulinaemia is a risk factor for the development of hypertension in pregnancy. Experimentally, pregnant rats with chronic exogenously induced hyperinsulinaemia (P-INS rats) have increased blood pressure at the end of gestation. This is associated with a blunted elevation of the excretion of the urinary metabolites of nitrate (UNOx). In the present study, we aimed to evaluate the mechanism(s) of the increase in blood pressure in this model. Four groups were studied: normal pregnant rats (P rats), P-INS rats, P-INS rats treated with l-arginine (2 g/l in the drinking water) (l-ARG rats) and hyperinsulinaemic virgin rats (V-INS rats). Systolic blood pressure (SBP), UNOx excretion (on ingestion of a controlled low-nitrate diet), urine noradrenaline (norepinephrine) and plasma endothelin levels were evaluated. Rats were killed on day 22 of pregnancy. Five P-INS rats were not killed at this time, in order to measure SBP 30 and 60 days after delivery. Fetal number and fetal body weight were evaluated. At the end of pregnancy, a 10±3% increase in SBP was found in P-INS rats, contrasting with a fall of -15±4% in P rats (P < 0.01). In the l-ARG group at the end of pregnancy, SBP values had fallen by -14±2%, to values comparable with those of P rats. The increase in UNOx excretion was 175±38% in P rats, 106±12% in l-ARG rats and 41±8% in P-INS rats (P < 0.01 compared with P and l-ARG groups). No differences were found in the urinary excretion of noradrenaline or in the plasma levels of endothelin-1 between the pregnant groups. Fetal number was similar in all groups, but fetal body weight was lower for P-INS rats compared with P and l-ARG rats. Thus the blood pressure response to l-arginine strongly suggests that a decrease in NO availability may be the main pathogenic mechanism involved in the development of hypertension in this model.
Effects of combined oral hormone replacement therapy on tissue factor pathway inhibitor and factor VII
Authors: PEVERILL Roger E. , TEEDE Helena J. , SMOLICH Joseph J. , MALAN Erica , KOTSOPOULOS Dimitra , TIPPING Peter G. , McGRATH Barry P.
Published: August 2015

Oral combined hormone replacement therapy (HRT) with oestradiol and norethisterone increases plasma levels of prothrombin fragment 1+2 (F1+2), indicating an increase in thrombin generation, but the mechanisms underlying this increase are uncertain. The aim of this randomized, placebo-controlled study was to determine whether an increase in factor VII, a factor that combines with tissue factor to activate the extrinsic pathway, or a decrease in tissue factor pathway inhibitor (TFPI), an inhibitor of extrinsic pathway activation, may contribute to increases in thrombin generation occurring with HRT. Healthy postmenopausal women aged 50–75 years received placebo (n = 19) or oral combined HRT (n = 18) and had blood collected for measurement of factor VII coagulation activity (VIIc), activated factor VII (VIIa) and TFPI at baseline and at 6 weeks. Baseline characteristics were similar in the two groups, including age, body mass index and cholesterol levels. As reported previously, HRT increased the F1+2 concentration by 20%. Placebo had no effect on VIIc, VIIa or TFPI, but 6 weeks of combined HRT decreased VIIc [from 1.11±0.06 (mean±S.E.M.) to 1.03±0.06 i.u./ml; P < 0.03], VIIa [from 43.9; 10.8–198.3 (median; range) to 35.0; 6.3–66.8 m-units/ml; P < 0.03] and TFPI [from 81.3±6.5 to 60.4±5.5 ng/ml; P < 0.0001]. The decrease in TPFI with HRT was not correlated with the elevation in F1+2 levels. In conclusion, the increase in thrombin generation seen with HRT is not due to an effect on factor VII; in addition, while a contribution from the decrease in TFPI is possible, increased thrombin generation is not directly related to the decrease in TFPI.
Sympathetic and reflex abnormalities in heart failure secondary to ischaemic or idiopathic dilated cardiomyopathy
Authors: GRASSI Guido , SERAVALLE Gino , BERTINIERI Giovanni , TURRI Carlo , STELLA Maria Luisa , SCOPELLITI Francesco , MANCIA Giuseppe
Published: August 2015

Congestive heart failure (CHF) is characterized by a sympathetic activation and a baroreflex impairment whose degree is directly related to the clinical severity of the disease. However, whether these abnormalities vary according to the ischaemic or idiopathic dilated nature of the CHF state has not been conclusively documented. In patients with a clinically stable, chronic CHF state in New York Heart Association functional class II and III, due either to ischaemic heart disease (IHD; n = 22, age 60.3±2.4 years, means±S.E.M.) or to idiopathic dilated cardiomyopathy (IDC; n = 20, age 58.9±2.8 years), and in 30 age-matched controls, we measured arterial blood pressure (using a Finapres device), heart rate (by electrocardiogram) and postganglionic muscle sympathetic nerve traffic (by microneurography) at rest and during baroreceptor manipulation induced by the vasoactive drug-infusion technique. Blood pressure values were not significantly different in CHF patients and controls. Compared with controls, heart rate was similarly increased and left ventricular ejection fraction (by echocardiography) similarly reduced in CHF patients with IHD or IDC. Muscle sympathetic nerve traffic was significantly greater in CHF patients than in controls, and did not differ between patients with IHD or IDC (67.3±4.2 and 67.8±3.8 bursts/100 heart beats respectively). This was also the case for the degree of baroreflex impairment. These data show that CHF states due to IHD or to IDC are characterized by a similar degree of peripheral sympathetic activation and by a similar impairment of the baroreflex function. Thus the neuroadrenergic and reflex abnormalities characterizing CHF are independent of its aetiology.
Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study
Authors: SIPILÄ Sarianna , TAAFFE Dennis R. , CHENG Sulin , PUOLAKKA Jukka , TOIVANEN Jarmo , SUOMINEN Harri
Published: August 2015

An age-related decline in muscle performance is a known risk factor for falling, fracture and disability. In women, a clear deterioration is observed from early menopause. The effect of hormone replacement therapy (HRT) in preserving muscle performance is, however, unclear. This trial examined the effects of a 12-month HRT and high-impact physical exercise regimen on skeletal muscle in women in early menopause. A total of 80 women aged 50–57 years were assigned randomly to one of four groups: exercise (Ex), HRT, exercise+HRT (ExHRT) and control (Co). The exercise groups participated in a high-impact training programme. The administration of HRT (oestradiol/noretisterone acetate) or placebo was carried out double-blind. Knee extension torque and vertical jumping height were evaluated. Lean tissue cross-sectional area (LCSA) and the relative proportion of fat within the muscle compartment were measured for the quadriceps and lower leg muscles. The ExHRT group showed significant increases in knee extension torque (8.3%) and vertical jumping height (17.2%) when compared with the Co group (-7.2%). Vertical jumping height also increased after HRT alone (6.8%). The LCSA of the quadriceps was increased significantly in the HRT (6.3%) and ExHRT (7.1%) groups when compared with the Ex (2.2%) and Co (0.7%) groups. Lower leg LCSA was also increased in the ExHRT group (9.1%) when compared with the Ex (3.0%) and Co (4.1%) groups. In addition, the increase in the relative proportion of fat in the quadriceps in the Co group (16.6%) was significant compared with those in the HRT (4.9%) and ExHRT (-0.6%) groups. Thus, in post-menopausal women, muscle performance, muscle mass and muscle composition are improved by HRT. The beneficial effects of HRT combined with high-impact physical training may exceed those of HRT alone.
Beneficial effect of β-adrenergic blockade on left ventricular function in haemodialysis patients
Authors: HARA Yuji , HAMADA Mareomi , SHIGEMATSU Yuji , MURAKAMI Bonpei , HIWADA Kunio
Published: August 2015

Congestive heart failure is a common and serious complication in patients undergoing chronic dialysis. However, there have been no studies on preferential medical therapies to improve left ventricular function in haemodialysis patients. β-Blocker treatment is known to improve left ventricular function in patients with dilated cardiomyopathy; moreover, plasma levels of noradrenaline and natriuretic peptides are sensitive markers of left ventricular dysfunction. The present study investigated whether β-blocker treatment could improve left ventricular function in haemodialysis patients with a dilated left ventricle. Our study group comprised 14 haemodialysis patients with a dilated left ventricle, who had undergone maintenance haemodialysis for a mean of 11 years. The following haemodynamic parameters were evaluated before and after 4 months of treatment with the β-blocker metoprolol: left ventricular dimension at end-systole and end-diastole, and fractional shortening. Plasma levels of noradrenaline, atrial natriuretic peptide and brain natriuretic peptide were also determined. Dry body weight and haemoglobin concentration showed no significant change after compared with before treatment with metoprolol. Heart rate decreased significantly, from 79±9 beats/min to 69±9 beats/min, but systolic blood pressure remained unchanged. The left ventricular dimension both at end-systole and at end-diastole was decreased, and fractional shortening increased significantly. Plasma levels of noradrenaline did not change significantly, but those of atrial natriuretic peptide and brain natriuretic peptide decreased markedly [from 100±89 pg/ml to 46±29 pg/ml (P = 0.0051) and from 549±516 pg/ml to 140±128 pg/ml (P = 0.0035) respectively]. In conclusion, β-blocker therapy with metoprolol can markedly attenuate left ventricular remodelling and decrease the plasma levels of natriuretic peptides in haemodialysis patients with a dilated left ventricle.