bluuebunny/crossref_metadata_2025_split huggingface dataset:
Localization of Cyclosporin a Absorption in Rat Small Bowel and the Effect of Bile
Authors: Cakaloglu Yilmaz , Marinos George , Marsden Joanne , Peters Timothy J. , Williams Roger , Tredger J. Michael 
Published: August 2015

1. Cyclosporin A absorption was examined after the instillation of approximately 2 mg/kg into four segments (mean length 15 cm) of rat small bowel, isolated in situ in fed Wistar female rats: SI (duodenum and proximal jejunum distal to the common bile duct); SII (distal jejunum); SIII (proximal ileum) and SIV (distal ileum).
2. Cyclosporin A concentrations in whole blood were assayed by an enzyme-mediated immunoassay for up to 4 h in samples drawn from the femoral vein and used to determine the following pharmacokinetic parameters: the area under the blood cyclosporin A concentration versus time curve (AUC, 0–4 h), the maximum blood concentration of cyclosporin A (Cmax.), the time to reach Cmax. (tmax.), the absorption half-life (t1/2a), the elimination half-life (t1/2λ), and the mean residence time (MRT).
3. Cyclosporin A absorption in SI (AUC, 991 μ l−1 h) was nearly double that in more distal segments and decreased progressively (SII, 533 μg l−1 h; SIII, 470 μg l−1 h; SIV, 419 μg l−1 h). There were corresponding differences in Cmax: 327 μg/l in SI and 201 μg/l, 169 μg/l and 151 μg/l in SII, SIII and SIV, respectively. Tmax. was shorter in SIV (0.9 h) than in other segments (1.3-1.5 h), but there were no significant differences between the segments for t1/2a, t1/2λ or MRT.
4. In the presence of continuous bile flow (diverted via a cannula for SIV), cyclosporin A absorption significantly increased by 23% in SI and by 50% in SIV, but the differential between absorption in SI and SIV was maintained.
5. We conclude that cyclosporin A is absorbed throughout the rat small intestine with the greatest absorption rate in the proximal duodenum and jejunum, and that bile significantly augments cyclosporin A absorption in both the proximal and particularly the distal small bowel.
Ventricular Expression and Circulating Levels of Immunoreactive Dynorphin in Heart Transplant Recipients
Authors: Ationu Art , Sorensen Keld , Whitehead Bruce , Singer Donald , Carter Nicholas 
Published: August 2015

1. Dynorphin, an endogenous opioid peptide, acts on specific κ-opioid receptors in the rat heart for the local regulation of atrial natriuretic peptide release. No known study has examined the expression of dynorphin in the human heart.
2. In the present study a specific radioimmunoassay technique was used to determine ventricular expression of dynorphin at the peptide level in endomyocardial biopsy specimens and in plasma obtained from 13 heart transplant recipients. Ventricular biopsy specimens collected from 10 patients without cardiac complications during necropsy (less than 24 h from time of death) and plasma samples from 10 normal healthy subjects were used as controls.
3. The immunoreactive level of ventricular dynorphin was higher in heart transplant recipients (mean ± SEM 141 ± 32 pg/mg of soluble protein, range 7–573 pg/mg of soluble protein, P &lt;0.001) than in control subjects (16 ± 3 pg/mg of soluble protein, 2–34 pg/mg of soluble protein). The plasma concentration of immunoreactive dynorphin was also higher (P &lt;0.001) in heart transplant recipients (mean ± SEM 14 ± 1 pg/ml, range 5–39 pg/ml) than in normal healthy subjects (7 ± 0.4 pg/ml, 5–10 pg/ml). No relationship was observed between ventricular and plasma levels of dynorphin.
4. These results show that immunoreactive levels of dynorphin in plasma and ventricle are increased after heart transplantation, suggesting a possible pathophysiological role for dynorphin in the heart.
Atrial Natriuretic Peptide-Cyclic Gmp Relationships in Normal Humans: Effects of Dietary Sodium Intake
Authors: Sagnella G. A. , Markandu N. D. , Buckley M. G. , Singer D. R. J. , MacGregor G. A. 
Published: August 2015

1. The present study was designed to investigate the relationships between circulating atrial natriuretic peptide, plasma and urinary cyclic GMP and sodium excretion under basal conditions and in response to changes in dietary sodium intake.
2. Measurements of plasma atrial natriuretic peptide and plasma and urinary (24 h collections) cyclic GMP, sodium and creatinine were made in (i) 30 normotensive subjects on their normal sodium intake and (ii) 12 subjects on the 5th day of a low and on the 5th day of a high sodium intake.
3. Plasma cyclic GMP, urinary cyclic GMP and fractional excretion of cyclic GMP in 30 normotensive subjects on their normal sodium intake were (means ± SEM) 5.4 ± 0.5 pmol/ml, 434.5 ± 31.8 pmol/min and 86.9 ± 8.6%, respectively. There were significant correlations between urinary cyclic GMP and its corresponding filtered load (r = 0.55) and between the renal clearance of cyclic GMP and that of creatinine (r = 0.44), but there were no significant associations between circulating atrial natriuretic peptide and plasma cyclic GMP or the fractional excretion of cyclic GMP or between urinary sodium and the fractional excretion of cyclic GMP.
5. Plasma atrial natriuretic peptide was significantly raised on the 5th day of the high sodium intake compared with the low sodium intake (10.6 ± 1.6 versus 4.2 ± 0.9 pg/ml; P &lt;0.05). Similarly, there were increases in urinary cyclic GMP excretion (692.3 ± 43.4 versus 427.4 ± 41.9 pmol/min, P &lt;0.05), but there were no significant differences in the fractional excretion of cyclic GMP.
6. As neither plasma nor urinary cyclic GMP was strongly associated with circulating levels of atrial natriuretic peptide, the present study suggests that other factors may be more important than circulating atrial natriuretic peptide as determinants of extracellular cyclic GMP.
Early Increase in Glomerular Leucocyte Number after a Reducton in Renal Mass: Implications for the Pathogenesis of Glomerulosclerosis
Authors: Harris K. P. G. , Baker F. , Brown J. , Walls J. 
Published: August 2015

1. Adult female Wistar rats underwent uninephrectomy (n = 8) through a flank incision, or a sham operation (n = 7). One to two weeks later the kidney was perfused in situ and glomeruli were isolated from cortical tissue by sequential sieving, and partially digested. Glomerular leucocytes were labelled with a mouse monoclonal antibody against leucocyte common antigen followed by a fluorescein-labelled anti-mouse immunoglobulin to allow counting.
2. In a further group of animals 24 h albumin excretion and glomerular size were measured 2 weeks after either uninephrectomy (n = 6) or sham operation (n = 6).
3. Glomerular leucocyte number was significantly increased in uninephrectomized animals (15.7 ± 0.9 versus 8.9 ± 0.4, P &lt;0.001), with some glomeruli having leucocyte numbers comparable with those seen in glomerulonephritis.
4. Albuminuria was not increased 2 weeks after uninephrectomy (233 ± 35 versus 170 ± 42 μg/24 h, not significant), and glomerular size was unchanged. Light microscopical appearance was normal.
5. An increase in glomerular leucocyte number is an early response in what was previously considered a non-immunological lesion. It precedes the development of renal scarring and may be important in the pathogenesis of this process.
Separate Effects of Urinary Chondroitin Sulphate and Heparan Sulphate on the Crystallization of Urinary Calcium Oxalate: Differences between Stone Formers and Normal Control Subjects
Authors: Shum D. K. Y. , Gohel M. D. I. 
Published: August 2015

1. Urinary glycosaminoglycans were recovered from the papain digest of polyanions precipitated sequentially by cetylpyridinium chloride and sodium acetate-saturated ethanol. Those from the early morning urine of 48 stone formers and 43 normal control subjects measured 11 and 16 μg of uronic acid/ml of urine, respectively.
2. Preparative agarose gel electrophoresis of the recovered glycosaminoglycans in barium acetate buffer (pH 5.8) yielded fractions containing purely chondroitin sulphate, co-polymeric chondroitin/dermatan sulphates and heparan sulphate. Identification was based on the susceptibility of the fractions to chondroitinase or nitrous acid treatment. Similar compositions of glycosaminoglycan classes were observed in samples from stone formers and normal control subjects.
3. The fractionated glycosaminoglycans were dissolved in urine ultrafiltrate to assay for nucleation-promoting and growth-inhibiting activities towards crystallization of urinary calcium oxalate. When compared at the same uronic acid concentration, both the urinary chondroitin sulphate isomers and heparan sulphates of stone formers demonstrated the capacity to enhance crystal nucleation from calcium oxalate endogenous in urine ultrafiltrates, whereas only urinary heparan sulphates of normal control subjects demonstrated this capacity.
4. Tissue-derived reference chondroitin sulphate, dermatan sulphate and heparin, when similarly tested, showed negligible crystal nucleation-promoting activity. The tissue-derived heparan sulphate was similar to the urinary heparan sulphates in showing marked crystal nucleation-promoting activity.
5. Crystal-growth inhibitory activity was evident in all urinary glycosaminoglycan fractions studied. In particular, urinary heparan sulphate of normal control subjects showed higher activity than that of stone formers or the chondroitin sulphate isomers of both stone formers and normal control subjects (P &lt;0.005).
Renal Functional Response to Ischaemic Renal Failure in Chronic Hypoxic Rats
Authors: Chen C. F. 
Published: August 2015

1. Chronic hypoxic rats are always polycythaemic. It is possible that an increase in packed cell volume may enhance erythrocyte trapping with a consequent increase in renal damage after renal ischaemia. These experiments were designed to assess renal functional changes after renal arterial occlusion in chronic hypoxic rats.
2. Chronic hypoxic rats were prepared by exposure (15h/day) to an altitude chamber (5486 m) for 4 weeks.
3. After 45 min of left renal arterial occlusion, there were significant decreases in the excretion of potassium, p-aminohippurate and inulin and in the p-aminohippurate extraction ratio in 12 sea level ischaemic insulted kidneys. In 12 chronic hypoxic rats, the same parameters were changed after left renal ischaemia but only the p-aminohippurate ratio was significantly altered.
4. Administrations of 1 or 5 mg/kg phosphoramidon did not cause any significant improvement in the measured renal parameters in both kidneys and in both groups of rats after ischaemia.
5. In the second experiment, the rats were challenged by rapid infusion of 10 ml of saline intravenously, and urine was collected for 90 min from each ureter. Four hours after left renal arterial occlusion, the insulted kidney showed increased water and sodium excretion in both sea level and chronic hypoxic rats. However, 24 h after left renal ischaemia, the responses of sea level and chronic hypoxic rats were different. Urinary excretion was significantly reduced in sea level rats, but was almost normal in chronic hypoxic rats.
6. This report suggests that some beneficial factors after chronic hypoxia might play important roles in reducing the damage after renal ischaemia.
Influence of Counter-Regulatory Hormones, Independently of Hypoglycaemia, on Cognitive Function, Warning Symptoms and Glucose Kinetics
Authors: Kerr David , Diamond Michael P. , Tamborlane William V. , Kerr Sara , Sherwin Robert S. 
Published: August 2015

1. To assess the influence of counterregulatory hormones, independently of neuroglycopaenia, on higher cerebral (cognitive) function, ‘hypoglycaemic’ warning symptoms and glucose kinetics, 10 healthy subjects participated in two hyperinsulinaemic (2 m-units min−1 kg−1) glucose clamp studies. After 100 min of euglycaemia (plasma glucose level 5 mmol/l), the plasma glucose level was either (a) maintained at 5 mmol/l for 120 min by glucose infusion with concomitant replacement of counterregulatory hormones (continuous infusions of glucagon, adrenaline, noradrenaline, cortisol and growth hormone) to mimic the hormonal milieu normally associated with hypoglycaemia (hormone infusion study) or (b) lowered to 2.8 mmol/l for 120 min (hypoglycaemia study). Assessments were made of cognitive function (P300 auditory evoked responses), symptoms (visual analogue scales) and glucose kinetics (3-[3H]glucose).
2. Hypoglycaemia was associated with an increase in all symptoms (facial flushing, palpitations, tingling, trembling, sweating, hunger, light-headedness and sleepiness, P &lt;0.01) and all subjects were aware that blood glucose levels had fallen. P300 evoked potential latency increased from 280 ±6 to 312 ±5 ms (mean±SEM, P &lt;0.01). In contrast, P300 latency and several individual symptoms (hunger, facial flushing, sweating and light-headedness) did not change from baseline during the hormone infusion study (P &lt;0.05 versus hypoglycaemia). Hepatic glucose production was lower (1.5±0.4 versus 2.3±0.3mg min−1 kg−1, P &lt;0.05) and peripheral glucose uptake was higher (7.4±1.0 versus 5.6±0.6 mg min−1 kg−1, P &lt;0.01) during infusion of the hormones compared with during hypoglycaemia.
3. In conclusion, the deterioration in cognitive function during hypoglycaemia is a consequence of a low plasma glucose level and is unaffected by the release of counterregulatory hormones. Counterregulatory hormones mediate some but not all of the symptomatic and kinetic responses to hypoglycaemia.
Some Pitfalls in the Measurement of Blood Glutathione
Authors: Schofield D. , Mei G. , Braganza J. M. 
Published: August 2015

1. We report some pitfalls in the measurement of whole blood and plasma glutathione in man.
2. Using a simple tourniquet to the forearm and a 21-gauge needle, blood samples were collected by brachial vein puncture from healthy subjects. Whole blood and plasma were analysed for total glutathione, including the reduced and oxidized forms, by a spectrophotometric recycling method involving the glutathione reductase/NADPH couple.
3. The concentration of oxidized glutathione was determined after treatment of aliquots with either 2-vinylpyridine or N-ethylmaleimide to trap reduced glutathione. Reduced glutathione in the native samples could then be obtained by subtraction.
4. When the reagents were added to separated plasma, 2-vinylpyridine yielded values for oxidized glutathione that were twice as high as with N-ethylmaleimide. In whole blood studies the discrepancy was even greater, and the problem was not resolved by deproteinization of samples with 5-sulphosalicylic acid. Using N-ethylmaleimide, levels of oxidized glutathione were less than 1% of total glutathione in whole blood.
5. Despite attempts to minimize haemolysis, lysed erythrocytes contributed on average 25% to the ‘plasma’ glutathione concentration.
Serum Sialic Acid and Acute-Phase Proteins in Hypertriglyceridaemic Patients Showing the Frederickson's Type IIB Phenotype
Authors: Haq S. , Tutt P. , Haq M. , Crook M. 
Published: August 2015

1. We have shown that serum total sialic acid is elevated in hypertriglyceridaemic patients showing the Frederickson's type IIB phenotype in comparison with normal subjects (2.30 ±0.34 versus 1.92 ± 0.32 mmol/l, P &lt;0.02). Lipid-associated sialic acid was also elevated in the hypertriglyceridaemic group in comparison with the normal subjects (0.60 ±0.09 versus 0.35 ±0.04 mmol/l, P &lt;0.001).
2. We measured five serum acute-phase proteins in the hypertriglyceridaemic patients and the normal subjects, namely α1-antichymotrypsin, α1-acid glycoprotein, α2-macroglobulin, C-reactive protein and haptoglobin. Serum α2-macroglobulin was significantly elevated in the hypertriglyceridaemic patients compared with the normal subjects (2.1 ±1.0 versus 1.5 ± 0.55 g/l, P &lt;0.05) as was serum C-reactive protein (5.9 ±3.5 versus 3.5±1.9mg/l, P &lt;0.05). There were, however, no significant differences in the serum concentrations of α1-antichymotrypsin, α1-acid glycoprotein or haptoglobin between the two groups.
3. There was a significant correlation between serum total sialic acid and serum α1-antichymotrypsin, α1-acid glycoprotein and haptoglobin (Spearman correlation coefficients 0.74, 0.50 and 0.76, respectively) in the normal subjects, and there was a significant correlation between serum total sialic acid and serum α1-antichymotrypsin and α1-acid glycoprotein (Spearman correlation coefficients 0.72 and 0.84, respectively) in the hypertriglyceridaemic patients.
Natriuretic Response to Head-Out Immersion in Humans with Recent Kidney Transplants
Authors: Rabelink Ton J. , van Tilborg Karin A. , Hené Ronald J. , Koomans Hein A. 
Published: August 2015

1. Recently implanted kidneys may have decreased flexibility to adjust sodium excretion to volume challenges, since modulation by renal sympathetic nerve activity is absent. To examine this hypothesis, we studied the natriuretic response to head-out water immersion in eight patients with well-functioning renal allografts of 37 days (range 24–56 days), at a time when renal re-innervation has probably not occurred.
2. By the third hour of head-out water immersion, sodium excretion had increased equally in the patients (from 120 +21 to 204 +37 μmol/min) and in eight healthy control subjects (from 105 +9 to 191+19 μmol/min).
3. Glomerular filtration rate was 60 + 6 ml/min in the patients and 113 +6 ml/min in the control subjects, and did not change upon head-out water immersion. Estimated renal plasma flow increased upon head-out water immersion in the control group but not in the patients. Blood pressure decreased similarly in both groups. The renal vascular resistance, calculated from these data, decreased in response to head-out water immersion in the control subjects but not in the renal transplant patients.
4. Head-out water immersion suppressed plasma renin activity only in the normal group, whereas the plasma aldosterone level was suppressed in both groups. The natriuretic response in patients was associated with about 3-fold elevated plasma levels of atrial natriuretic peptide.
5. Since renal re-innervation at 37 days after transplantation is very unlikely, these data suggest that inact renal innervation is not mandatory for a normal natriuretic response to head-out water immersion in humans. However, sympathetic modulation might be involved in the decrease in renal vascular resistance and plasma renin activity normally observed during immersion.
Relationship between Markers of Endothelial Dysfunction, Oxidant Injury and Tubular Damage in Patients with Insulin-Dependent Diabetes Mellitus
Authors: Yaqoob M. , Patrick A. W. , McClelland P. , Stevenson A. , Mason H. , White M. C. , Bell G. M. 
Published: August 2015

1. Diabetic nephropathy is a serious microvascular complication in patients with insulin-dependent diabetes mellitus, resulting in end-stage renal disease in 30–45% of such patients. Despite intensive investigation, the pathophysiology of diabetic renal disease has not been fully elucidated. However, several clinical and experimental studies have suggested that endothelial dysfunction and free-radical activity may be important factors.
2. Forty normotensive patients with insulin-dependent diabetes mellitus of between 10 and 20 years duration with persistent normoalbuminuria (albumin excretion &lt;30 mg/day) and normal renal function were investigated for markers of endothelial dysfunction (plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity), free oxygen radical generation (erythrocytic superoxide dismutase and glutathione peroxidase) and oxidant injury (serum malondialdehyde). Glomerular proteinuria (albuminuria, transferrinuria), tubular proteinuria (retinol-binding protein) and tubular enzymuria (N-acetyl glucosaminidase and leucine aminopeptidase) were also measured.
3. Patients were divided into two groups. Group 1 comprised 21 patients with elevated markers of endothelial dysfunction, and group 2 comprised 19 patients with normal levels of plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity. Thirty-eight healthy subjects matched for age and sex acted as controls.
4. Groups 1 and 2 were similar in age, sex, body weight, duration of diabetes mellitus and recent glycaemic control. Serum cholesterol, serum creatinine and glomerular proteinuria were similar in the three groups. Group 1 patients had significantly increased oxidant injury, tubular enzymuria and proteinuria compared with group 2 patients and control subjects (P &lt;0.01). Erythrocytic glutathione peroxidase was significantly lower in group 1 compared with the other groups (P &lt;0.01) and erythrocytic superoxide dismutase was lower in both diabetic groups compared with normal control subjects (P &lt;0.01). Serum malondialdehyde, tubular enzymuria and proteinuria were comparable in group 2 patients with control subjects.
5. We conclude that endothelial dysfunction, oxidant injury and renal tubular damage may precede microalbuminuria in diabetic nephropathy. These data support the hypothesis that endothelial dysfunction first affects the postglomerular microvessels. It is associated with oxidant injury and renal tubular damage, which may be factors in the initiation of diabetic nephropathy.
Impact of Treatment with Acetylsalicylic Acid on the Proaggregatory Effects of Adrenaline in vitro in Patients with Stable Angina Pectoris: Influence of the Anticoagulant
Authors: Wallén N. Håkan , Held Claes , Rehnqvist Nina , Hjemdahl Paul 
Published: August 2015

1. The impact of oral acetylsalicylic acid treatment on the enhancing effect of adrenaline on platelet aggregation in vitro was investigated in patients with stable angina pectoris. In addition, the influence of different anticoagulants (i.e. hirudin and citrate) on platelet aggregation in vitro was compared.
2. Eighty-four patients with stable angina pectoris were studied. Sixteen patients were on acetylsalicylic acid treatment (150-250 mg daily), whereas 68 patients were free from acetylsalicylic acid. Platelet-rich-plasma was prepared from citrate- or hirudin-antkoagulated blood. The EC50 (i.e. the concentration of agonist required to produce half-maximal aggregation) for the ADP-induced extent of aggregation was determined. Thereafter the enhancing effect of adrenaline (10 and 50 nmol/l) on ADP-induced aggregation (at EC50) was investigated.
3. In the patients with angina, acetylsalicylic acid caused the expected effects on ADP-induced platelet responses. Adrenaline significantly enhanced both the extent of aggregation and the initial rate of aggregation (primary aggregation), irrespective of the anticoagulant used. In acetylsalicylic acid-treated patients (citrated platelet-rich plasma) the extent of aggregation was partly inhibited, but no significant effect on the rate of aggregation could be observed.
4. A comparative substudy of the anticoagulants in healthy subjects (n = 8) showed that both the aggregating effect of ADP per se and the enhancing effect of adrenaline on ADP-induced aggregation (at EC50) were less influenced by acetylsalicylic acid when evaluated in hirudinized platelet-rich plasma (i.e. with physiological levels of extracellular calcium) as compared with citrated platelet-rich plasma.
5. It is concluded that acetylsalicylic acid treatment slightly attenuates the proaggregatory effect of high physiological concentrations of adrenaline in vitro. The impact of acetylsalicylic acid in vitro is, however, strongly dependent on the anticoagulant used, and is significantly weaker when evaluated in a medium with normal extracellular calcium levels (i.e. hirudin) than in a medium with low levels of extracellular calcium (citrate). Thus, acetylsalicylic acid may be a weak antagonist of catecholamine-induced platelet activation in vivo.