bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired Erythropoietin Responsiveness in Anaemic Rheumatoid Arthritis Patients: Potential Relation to Immune Mechanisms
Authors: Stockenhuber Felix , Keil Michaela , Wurnig Christian , Kurz Robert W. , Gottsauner-Wolf Michael , Balcke Peter 
Published: August 2015

1. Serum levels of erythropoietin and the immune parameters tumour necrosis factor-α, soluble interleukin-2 receptor, interleukin-2, interleukin-6 and interferon-γ were measured in patients with rheumatoid arthritis.
2. Out of 69 patients, 44 had anaemia with serum haemoglobin concentrations of 10.8 (SD 1.2) g/dl. In these patients erythropoietin levels were significantly higher than in non-anaemic patients [51.97 (SD 23.9) versus 26.06 (SD 11.9) m-units/ml; P &lt; 0.0001; control patients: 18.1 (SD 13.8) m-units/ml]. Mean soluble interleukin-2 receptor activity was elevated in all patients with rheumatoid arthritis [1324 (SD 715) units/ml; control patients: 480 (SD 75) units/ml; P &lt; 0.001] and was significantly higher in the anaemic group than in the non-anaemic group [1562 (SD 662) versus 696 (SD 402) units/ml; P &lt; 0.0001]. The serum activity of soluble interleukin-2 receptor showed an inverse correlation with haemoglobin (r = 0.79; P &lt; 0.0001) and a positive correlation with erythropoietin (r = 0.70, P &lt; 0.0001).
3. Elevated serum tumour necrosis factor-α levels were found in 19 anaemic patients [20.6 (SD 9.1) pg/ml]. Concentrations of tumour necrosis factor-α in serum showed an inverse correlation with haemoglobin (r = 0.57, P &lt; 0.001) and a positive correlation with erythropoietin (r = 0.46, P &lt; 0.05). Interleukin-6 was detected in seven anaemic patients [21 (SD 14) pg/ml] and interleukin-2 activity in three anaemic patients (12, 16 and 14 units/ml, respectively). Interferon-γ was not detected in any of the patients investigated.
4. The present study supports the concept that in patients with rheumatoid arthritis the responsiveness to erythropoietin is impaired. Immune mechanisms may be operative and point to a pivotal role for tumour necrosis factor-α.
Association of Cerebrospinal Fluid Deficiency of 5-Methyltetrahydrofolate, but Not S-Adenosylmethionine, with Reduced Concentrations of the Acid Metabolites of 5-Hydroxytryptamine and Dopamine
Authors: Surtees Robert , Heales Simon , Bowron ANN 
Published: August 2015

1. Folate deficiency, or inborn errors of folate metabolism, cause reduced turnover of 5-hydroxytryptamine (serotonin), and perhaps dopamine, in the central nervous system. The mechanism by which this occurs are not known. One possibility is that this is mediated by deficiency of the methyl-donor S-adenosylmethionine.
2. To test this in humans, we have measured cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid and homovanillic acid, metabolites of 5-hydroxytryptamine and dopamine, respectively, in children with inborn errors of the methyl-transfer pathway. These children are naturally deficient in 5-methyltetrahydrofolate, S-adenosylmethionine or both before treatment, and replete with S-adenosylmethionine, but not necessarily with 5-methyltetrahydrofolate, during treatment.
3. Children with subnormal cerebrospinal fluid concentrations of 5-methyltetrahydrofolate had significantly reduced concentrations of 5-hydroxyindoleacetic acid and homovanillic acid. Children with subnormal cerebrospinal fluid concentrations of S-adenosylmethionine did not have significantly reduced concentrations of these metabolites.
4. We conclude that the mechanism by which deficiency of 5-methyltetrahydrofolate causes reduced 5-hydroxytryptamine and dopamine turnover is unlikely to be mediated by S-adenosylmethionine.
Reduced Cytosolic Free Sodium Concentration in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats
Authors: Tepel Martin , Holthues JAN , Neusser Marcus , Golinski Petra , Zhu Zhiming , Mehring Norbert , Zidek Walter 
Published: August 2015

1. Cytosolic free sodium concentration and sodium transport systems were measured in intact cultured vascular smooth muscle cells from spontaneously hypertensive rats of the Münster strain and from normotensive Wistar—Kyoto rats using the sodium-sensitive fluorescent dye sodium-binding benzofuran isophthalate.
2. Resting cytosolic free sodium concentration was significantly lower in vascular smooth muscle cells from spontaneously hypertensive rats than from Wistar-Kyoto rats (10.2 ± 1.5 mmol/l, n = 26, versus 19.4 ± 2.5 mmol/l, n = 20, P &lt; 0.01).
3. Inhibition of Na+, K+-ATPase by ouabain caused a dose-dependent increase in cytosolic free sodium concentration in spontaneously hypertensive rats and Wistar—Kyoto rats.
4. Activation of Na+-Ca2+ exchange by ionomycin increased cytosolic free sodium concentration in both strains. However, the ionomycin-induced increase in cytosolic free sodium concentrations was significantly higher in vascular smooth muscle cells from spontaneously hypertensive rats than from Wistar—Kyoto rats (220 ± 35% of the resting cytosolic free sodium concentration versus 148 ± 27%; P &lt; 0.05). The ionomycin-induced increase in cytosolic free sodium concentration was prevented in the absence of external sodium or by inhibition of Na+-Ca2+ exchange by NiCl2.
5. Activation of Na+-H+ exchange by intracellular acidification of vascular smooth muscle cells with propionic acid increased cytosolic free sodium concentration in each strain (19.6 ± 5.7 versus 16.3 ± 3.2 mmol/l).
6. It is concluded that concepts concerning the role of cytosolic free sodium concentration in the pathogenesis of primary hypertension need to be reinvestigated. However, the conclusions from results obtained in cultured vascular smooth muscle cells are limited with respect to conditions in vivo.
Effects of the Neutral Endopeptidase Inhibitor, SCH 42495, on the Cardiovascular Remodelling Secondary to Chronic Hypoxia in Rats
Authors: Thompson J. S. , Sheedy W. , Morice A. H. 
Published: August 2015

1. We have investigated the effects of inhibition of neutral endopeptidase on the cardiovascular remodelling secondary to chronic hypoxia in rats using a novel neutral endopeptidase inhibitor, SCH 42495.
2. Rats were divided into four groups, two of which were maintained in a normobaric, hypoxic chamber (10% O2) and two in room air. Animals received either neutral endopeptidase inhibitor, SCH 42495 (30 mg/kg), or aqueous methyl cellulose vehicle (0.4%) twice daily by oral gavage.
3. At 1, 3, 7, 10 and 14 days, animals (n = 4 per group for days 1, 3, 7 and 14, and n =8 for day 10) were killed. Hearts were dissected and weighed for determination of ventricular ratios, lungs were perfused with formol saline for histological examination of the pulmonary vasculature, and blood was collected for measurement of plasma atrial natriuretic peptide level.
4. Treatment with SCH 42495 caused a significant reduction in the pulmonary vascular remodelling and ventricular hypertrophy in hypoxic rats after 10 days. Plasma atrial natriuretic peptide levels were significantly elevated in both SCH 42495-treated and control hypoxic animals (n = 8) after 10 days when compared with the normoxic groups. However, there was no difference in plasma ANP levels between SCH 42495-treated and control chronic hypoxic groups at day 10.
5. Treatment with SCH 42495 leads to a decrease in cardiovascular remodelling secondary to chronic hypoxia in rats. A local action of atrial natriuretic peptide within the pulmonary vasculature may be responsible for this effect. Modulation of atrial natriuretic peptide may have therapeutic potential in the management of conditions characterized by pulmonary hypertension and pulmonary vascular remodelling.
Physiological and Symptomatic Responses to Postural Change in Non-Diabetic Subjects during Hypoglycaemia
Authors: Maggs D. G. , Macdonald I. A. 
Published: August 2015

1. Insulin-induced hypoglycaemia is characterized by an autonomic disturbance which produces some of the symptoms of hypoglycaemia. How an additional autonomic stress like postural change may alter physiological responses and symptoms of hypoglycaemia is not known. In 10 healthy male subjects (mean age 24 years) we observed physiological and symptomatic responses to postural change during acute (20 min) and prolonged (60 min) hyperinsulinaemic (60 m-units min−1 m−2) hypoglycaemia (2.5 mmol/l) and euglycaemia (4.5 mmol/l), and placebo control (saline).
2. In all studies standing increased plasma catecholamines (adrenaline, P &lt; 0.001; noradrenaline, P &lt; 0.0001), blood pressure (P &lt; 0.0001) and heart rate (P &lt; 0.0001). Catecholamine responses to standing were augmented by acute hypoglycaemia (adrenaline, P &lt; 0.005; noradrenaline, P &lt; 0.01), but less so by prolonged hypoglycaemia (adrenaline, P &lt; 0.05; noradrenaline, P &lt; 0.05). Supine heart rate was higher before standing during prolonged hypoglycaemia (P &lt; 0.05), but did not increase as much on standing when compared with acute hypoglycaemia and prolonged euglycaemia.
3. During acute hypoglycaemia, autonomic symptoms increased on standing, but during prolonged hypoglycaemia, in the presence of generally higher symptom scores, standing had no effect. Autonomic symptoms, with the exception of hunger, tended to decrease with time (P &lt; 0.05) during prolonged hypoglycaemia.
4. To conclude, posture does modify the catecholamine and symptomatic responses to hypoglycaemia, but this effect is dependent on the duration of hypoglycaemia. Hypoglycaemia and hyperinsulinaemia had little or no effect on the cardiovascular responses to changing posture.
Interactions of Body Fat and Muscle Mass with Substrate Concentrations and Fasting Insulin Levels in Adults with Growth Hormone Deficiency
Authors: Salomon F. , Cuneo R. C. , Umpleby A. M. , Sönksen P. H. 
Published: August 2015

1. Adults with growth hormone deficiency have an abnormal body composition. Alterations in body composition are closely related to substrate concentrations and insulin action. The lack of growth hormone has been associated with increased insulin sensitivity.
2. We investigated the correlations of body composition with fasting insulin levels and substrate concentrations in 24 adults with growth hormone deficiency over a wide range of adiposity (body mass index 18.8-42.3 kg/m2).
3. Lean body mass was measured by total body potassium, computer tomography of the thigh and urinary creatinine excretion. Muscle fibre distribution was evaluated from vastus lateralis biopsies. Fat mass was assessed by skinfold thickness measurements, computer tomography of the thigh, and waist and hip girth.
4. Fasting plasma insulin level increased with fat mass (r = 0.67, P = 0.0004) and with waist girth (r = 0.76, P = 0.0001). Fasting plasma insulin level increased with fasting plasma glucose level (r = 0.53, P = 0.01). Fasting plasma glucose level in turn was positively correlated with lean body mass (r = 0.49, P = 0.01) and with total thigh muscle area (r = 0.54, P = 0.01). There was no correlation between lean body mass and fat mass (r = 0.17, not significant) nor between muscle fibre types and fat mass or fat distribution. Fasting plasma insulin level showed no correlation with any measurement of lean body mass or muscle fibre type.
5. These data demonstrate that the presence of obesity is associated with hyperinsulinaemia as the result of insulin resistance in adults with growth hormone deficiency, which could contribute to the increased cardiovascular mortality in adults with growth hormone deficiency.
Hypertension and Cardiac Hypertrophy in Growth Hormone-Deficient Rats
Authors: Harrap Stephen B. , Datodi Shari R. , Crapper Emma K. , Bach Leon A. 
Published: August 2015

1. Growth hormone may influence cardiac growth during post-natal maturation or in response to hypertension, and the growth-hormone deficient dwarf rat model offers an opportunity to study this question.
2. We compared the blood pressure and heart weight of dwarf rats and Fischer (F344) control rats in early adulthood, after two hypertensive stimuli: unilateral renal ischaemia (two-kidney, one-clip) or the administration of deoxycorticosterone acetate and saline drinking fluid.
3. In untreated animals at 13 weeks of age the body weight of dwarf rats was significantly less than that of F344 rats, but the mean arterial pressure was similar. Although the hearts of dwarf rats were smaller than those of F344 rats, the heart weight/body weight ratio was significantly greater in dwarf rats.
4. Both dwarf and F344 rats developed similar hypertensive mean arterial pressures 5 weeks after left renal artery clipping or treatment with deoxycorticosterone acetate salt. The heart weights of hypertensive dwarf and F344 rats were equivalent, indicating a proportionally greater increase in cardiac size in dwarf rats for the same rise in blood pressure.
5. The plasma insulin-like growth factor-I level was markedly lower in dwarf than in F344 rats, and hypertension did not have any significant effects on these levels.
6. These findings indicate that the developmental increase in blood pressure and heart size in growing animals and the adaptive cardiac hypertrophy accompanying hypertension are not affected by growth hormone deficiency.
Effects of Phosphoramidon and Pepstatin a on the Secretion of Endothelin-I and Big Endothelin-I by Human Umbilical Vein Endothelial Cells: Measurement by Two-Site Enzyme-Linked Immunosorbent Assays
Authors: Plumpton C. , Kalinka S. , Martin R. C. , Horton J. K. , Davenport A. P. 
Published: August 2015

1. Two-site enzyme-linked immunosorbent assays have been developed for the rapid, sensitive and non-isotopic measurement of endothelin-1 and big endothelin-1. The sensitivities of detection were 0.5 and 0.3 fmol/well, with ED50 values of 13 and 12 fmol/well for the endothelin-1 and big endothelin-1 assays, respectively. Each assay is highly selective for its corresponding antigen. The ET-1 assay showed no detectable cross-reactivity with ET-1-(1-20), indicating that the assay only recognizes the 21-amino acid biologically active peptide.
2. The two assays were used to measure the effects of two classes of protease inhibitor on the basal release of enothelin-1 and big endothelin-1 from cultured first-passage human umbilical vein endothelial cells.
3. The secretion of both peptides was time-dependent over 12 h. The metalloprotease inhibitor phosphoramidon (1 × 10−4 mol/l) significantly reduced the amount of endothelin-1 secreted into the medium (P &lt; 0.05), with a concomitant increase in the secreted levels of big endothelin-1 (P &lt; 0.01). The aspartyl protease inhibitor, pepstatin A, also caused a significant decrease in the secretion of endothelin (P &lt; 0.05). However, unlike phosphoramidon, there was no increase in the levels of big ET-1 compared with the controls. At these concentrations, neither inhibitor affected the viability of the cells as indicated by Trypan Blue exclusion.
4. The two assays permit the direct measurement of endothelin-1 and its precursor, and will be of use in the elucidation of the putative human endothelin-converting enzyme(s). In addition to a phosphoramidon-sensitive enzyme, the results also suggest the existence of a pepstatin A-sensitive enzyme in human endothelial cells. Furthermore, pepstatin A also appears to limit the generation of big endothelin-1. Thus pepstatin A-sensitive enzymes may be better targets for inhibitors to reduce the harmful vasoconstrictive effects of endothelin-1 in cardiovascular diseases.
Effect of Progestogens and Oestrogens on the Contractile Response of Rat Detrusor Muscle to Electrical Field Stimulation
Authors: Elliott Ruth A. , Castleden C. M. 
Published: August 2015

1. The effect of oestradiol and progesterone pre-treatment on the contractile response of isolated rat detrusor muscle to electrical field stimulation was investigated. The response to direct administration of 2 μmol/l progesterone and 2 μmol/l diethylstilboestrol in the organ bath was also examined.
2. Virgin female Wistar rats were injected sub-cutaneously with oestradiol benzoate (150 μg/kg) for 3 days followed by 1 day of progesterone (160 μg/kg). This cycle was repeated once. Control rats received no injections.
3. In controls, progesterone significantly reduced the maximum contractile response of rat detrusor muscle in vitro by 12% (P &lt; 0.01). The EF50 was significantly increased compared with control. When 2 μmol/l diethylstilboestrol, was added, the maximum contractile response was significantly reduced by 42% (P &lt; 0.01) and the frequency-response curve showed a further increase in EF50.
4. Progesterone had no effect on the atropine-resistant component of electrical field stimulation, but progesterone and diethylstilboestrol reduced the atropine-resistant response by 16% (P &lt; 0.01).
5. Detrusor muscle from pretreated rats showed a non-significant increase in maximum contractile response compared with untreated controls. The addition of 2 μmol/l progesterone to the bath chamber had no effect on this response, but the further addition of 2 μmol/l diethylstilboestrol reduced the maximum contraction.
6. Pretreatment with oestradiol and progesterone had no effect on the atropine- or tetrodotoxin-sensitive response to electrical field stimulation.
7. In conclusion, the direct effect of progesterone and diethylstilboestrol inhibited the contractile response of detrusor muscle to electrical field stimulation and the effects of each summated. Atropine blocked this effect of progesterone, but not that of diethylstilboestrol. Pretreatment with progesterone and oestradiol had no significant effect on rat detrusor contractile response. Since treatment with oestradiol alone has been shown to have a significant inhibitory action on contractile response, the addition of progesterone would appear to alter this effect of oestradiol.
Stable Strontium Absorption as a Measure of Intestinal Calcium Absorption: Comparison with the Double-Radiotracer Calcium Absorption Test
Authors: Blumsohn Aubrey , Morris Brian , Eastell Richard 
Published: August 2015

1. Stable strontium (Sr) has been proposed as an alternative to calcium (Ca) isotopes for the measurement of intestinal Ca absorption. The aim of this study was to compare the time course and fractional absorption of Ca and Sr, when both are measured using dual-tracer techniques.
2. 45Ca and Sr absorption tests were carried out on consecutive days in patients with osteoporosis (n = 10) or chronic renal failure (n = 7). Both tests were repeated in four patients with chronic renal failure after treatment with calcitriol (1 μg daily for 10 days).
3. The time course of Ca absorption was determined using the 85Sr (intravenous)/45Ca (oral) dual-tracer technique, and the time course of Sr absorption using 85Sr (intravenous)/stable Sr (oral). Oral tracers were administered on consecutive days with a test meal containing 5.3 mmol of Ca and 2.5 mmol of either stable Sr or Ca carrier. The fractional absorption of 45Ca and Sr at 6 h (FA360) and the absorption rate as a function of time were calculated by deconvolution.
4. The mean FA360 for Sr (20.2%) was lower than the mean FA360 for 45Ca (37.8%, P &lt; 0.001, paired t-test), but the time course of Sr absorption was similar to that of Ca. There was a significant correlation between the FA360 for 45Ca and Sr, although the relationship was improved by including a quadratic term (R2 = 0.89, P &lt; 0.001, significance of quadratic term, P &lt; 0.05). After 1,25-dihydroxyvitamin D treatment, the FA360 of stable Sr increased 4.29-fold, whereas the FA360 of 45Ca increased only 2.4-fold.
5. Although the fractional absorption of Sr determined by dual-tracer deconvolution was the best predictor of FA360 for 45Ca, little was lost by confining the analysis to a single serum Sr measurement taken 3 h or more after oral administration.
6. We conclude that Sr absorption is qualitatively similar to that of Ca, although absorption of Sr is much lower than that of Ca. Furthermore, the relationship does not appear to be linear. Stable Sr may be useful in place of Ca isotopes in the routine clinical evaluation of Ca absorption.
Effects of Angiotensin II and Aldosterone on Diastolic Function In Vivo in Normal Man
Authors: Clarkson P. B. M. , Wheeldon N. M. , MacLeod C. , Tennent M. , MacDonald T. M. 
Published: August 2015

1. Doppler echocardiographic indices of diastolic function and systemic haemodynamics were studied in response to infusions of angiotensin II (1, 2, 5 and 10 ng min−1 kg−1), D-aldosterone (2, 4, 10 and 20 ng min−1 kg−1) and placebo [0.9% (w/v) NaCl] in ten normal male subjects.
2. Dose-related increases in systolic and diastolic blood pressure were observed with angiotensin II infusion at rates of 2 ng min−1 kg−1 and above, whereas no changes in blood pressure occurred with D-aldosterone. No changes in aortic stroke distance or heart rate were seen with either angiotensin II or aldosterone infusion.
3. Compared with placebo, angiotensin II infusion produced a dose-related prolongation of the isovolumic relaxation time [mean and 95% confidence intervals 12.0 (8.2–15.8) ms, P &lt; 0.001] at 10 ng min−1 kg−1, and a significant reduction in the ratio between early and late transmitral flow velocity integrals at 2 ng min−1 kg−1, [−0.84 (−1.63 to −0.05), P &lt; 0.05] and 5 ng min−1 kg−1 [−0.76 (−1.47 to −0.05), P &lt; 0.05]. No changes in Doppler echocardiographic indices of diastolic function were observed with D-aldosterone infusion.
4. These data suggest that angiotension II, even at a sub-pressor concentration, produces an impairment of left ventricular diastolic filling, which occurs independently of its effect on aldosterone release.
Recovery of 13C in Breath from Infused NaH13CO3 Increases During Euglycaemic Hyperinsulinaemia
Authors: Reaich D. , Graham K. A. , Cooper B. G. , Scrimgeour C. M. , Goodship T. H. J. 
Published: August 2015

1. The effect of euglycaemic hyperinsulinaemia on the recovery of 13C in expired CO2 has been assessed in six normal subjects. Each was studied on three occasions: once with a 6 h primed constant infusion of NaH13CO3 combined with a euglycaemic hyperinsulinaemic clamp for the last 3 h (study 1), once with a 6h primed constant infusion of NaH13CO3 alone (study 2) and once with a 6 h infusion of normal saline combined with a hyperinsulinaemic clamp for the last 3 h (study 3). Measurements of 13C enrichment of expired CO2 were made in the third and sixth hour of each infusion.
2. There was no significant increase in enrichment during study 3 (3 h 0.00047 ± 0.00016 versus 6 h 0.00069 ± 0.00028 atom per cent excess) with potato-starch-derived D-glucose used to maintain eugly-caemia. 13C recovery increased in the sixth hour of both study 1 and 2 (study 1: 3 h 74.4 ± 2.0 versus 6 h 85.5 ± 2.6%, P &lt; 0.01; study 2: 3 h 72.1 ± 2.4 versus 6 h 81.7 ± 1.4%, P &lt; 0.01). There was no significant difference in recovery between studies 1 and 2.
3. These results suggest that increased recovery during a sequential euglycaemic clamp is predominantly time-dependent. Studies which use this technique to examine the effect of insulin on substrate oxidation should take this into account.