bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of human breast cancers by dietary l-arginine
Authors: Park Kenneth G. M. , Heys Steven D. , Blessing Karen , Kelly Peter , McNurlan Margaret A. , Eremin Oleg , Garlick Peter J.
Published: August 2015

1. The amino acid L-arginine has been shown to enhance immune mechanisms and inhibit tumour growth in experimental animals, but although many of the immunological effects of arginine have been reproduced in man there have been few studies of its effects on human tumours. In this study the effects of arginine on human breast cancers were determined by measuring tumour protein synthesis and comparing this with immunohistochemical assessments of cell proliferation.

2. Patients with breast cancer were randomized to receive either a standard diet or arginine supplementation. At the time of surgery, the rate of tumour protein synthesis was measured by the incorporation of the stable isotope [1-13C]leucine into tumour protein. Tumours were also assessed histologically and by staining for the presence of the activation antigen Ki67.

3. The median rate of tumour protein synthesis was 10%/ day (range 5.5–15.8%/day) in the control patients and 25.6%/day (range 9-37%/day) in the patients receiving arginine supplements (P < 0.005, Wilcoxon rank sum test). The rates of protein synthesis correlated with Ki67 expression within these tumours (r=0.78, P < 0.001). A double-staining technique confirmed that tumour cells, rather than tumour-infiltrating lymphoreticular cells, expressed Ki67.

4. This study demonstrates that, in contrast to animal studies, L-arginine stimulates human tumours in vivo. This represents the first direct evidence that a single amino acid can modulate the behaviour of a human cancer.
Effect of acute and chronic administration of ethanol on the pancreatic exocrine response to cholecystokinin in rats fed different diets
Authors: Manso M. A. , Gallego H. A. , de Dios I.
Published: August 2015

1. The effects of a diet rich in protein and fat, compared with a control diet, with or without chronic ingestion of ethanol on the pancreatic response to cholecystokinin were studied in rats after a 7-month treatment period. The acute effects of intraduodenal administration of 20% (v/v) ethanol were also analysed under these experimental conditions.

2. Animals receiving a diet rich in protein and fat showed a greater percentage increase in pancreatic output in response to cholecystokinin.

3. Chronic ethanol consumption reduced the basal secretion of protein and amylase; and even though the response capacity to cholecystokinin (considered as the percentage secretion on cholecystokinin stimulation with respect to basal secretion) was maintained, this led to hormone-stimulated secretion being decreased in comparison with the animals receiving water. In contrast, a lack of inhibition of basal volume flow and flow after cholecystokinin stimulation was seen after long-term ingestion of ethanol.

4. Acute administration of ethanol generally depressed cholecystokinin-stimulated pancreatic secretion.

5. On stimulation with cholecystokinin, the diet rich in protein and fat combined with long-term ingestion of ethanol led to non-parallel changes in the release of pancreatic enzymes, since an increase in trypsin secretion and a decrease in amylase secretion occurred concomitantly.
Perforin gene expression in T lymphocytes correlates with disease activity in immunoglobulin A nephropathy
Authors: Nakamura Tsukasa , Ebihara Isao , Osada Shiori , Okumura Ko , Tomino Yasuhiko , Koide Hikaru
Published: August 2015

1. We studied perforin gene expression in T lymphocytes obtained from 26 patients with IgA nephropathy and from 15 healthy age-matched control subjects.

2. The majority of patients with IgA nephropathy (96%) had elevated perforin mRNA expression, whereas no perforin mRNA expression was detected in the T lymphocytes of normal control subjects.

3. A positive correlation was noted between perforin mRNA expression and urinary protein excretion.

4. Perforin mRNA expression correlated also with the histopathology in the renal tissue of patients with IgA nephropathy.

5. Sixty per cent of patients with grade III or IV histopathology had high perforin mRNA expression in T lymphocytes [more than (++)].

6. These studies suggest that disregulation of perforin gene expression in T lymphocytes may be associated with the progression of IgA nephropathy and could be used as an indicator of disease activity.
Platelet cytosolic free calcium concentration, total plasma calcium concentration and blood pressure in human twins: a genetic analysis
Authors: Williams P. D. , Puddey I. B. , Martin N. G. , Beilin L. J.
Published: August 2015

1. We used path analysis and maximum-likelihood model fitting to evaluate the relative contributions of genetic and environmental factors to the relationships observed between level of blood pressure and both total plasma calcium concentration and platelet cytosolic free calcium concentration in 109 twin pairs.

2. Total plasma calcium concentration was positively associated with systolic (r = 0.26, P < 0.001) but not diastolic blood pressure, a relationship which remained significant after adjustment for albumin, age and body mass index. A relationship between platelet cytosolic free calcium concentration and both systolic and diastolic blood pressure (r=0.17 and r=0.13, respectively, P ≤ 0.05) was no longer significant after adjustment for age and body mass index.

3. Additive genetic influences, unique environmental effects and age contributed to 60%, 30% and 10% of the variance in systolic blood pressure, respectively. Additive genetic effects explained 78% of the variance in plasma total calcium concentration and at least 48% of the variance in platelet cytosolic free calcium concentration in females and 37% in males.

4. Bivariate factor models provided evidence of genetic, but not environmental, co-variation of total plasma calcium concentration and systolic blood pressure, suggesting that a common genetic factor (or factors) contributes to their univariate relationship. In contrast, there was evidence of environmental, but not genetic, covariation of platelet cytosolic free calcium concentration and systolic blood pressure, suggesting that some of the individual experiences specific to each twin may be causing these two traits to vary together.

5. The possible confounding effects of adiposity and environmental factors should be considered in future studies investigating the role of intracellular calcium levels in the pathogenesis of hypertension.
Growth regulatory peptides in gastric mucosa
Authors: Jankowski J. , Al-Rawi H. J. , Johnston D. A. , Hopwood D. , Filipe M. I. , Coghill G. , Wormsley K. G.
Published: August 2015

1. Epidermal growth factor and the related peptide transforming growth factor α have been implicated in the stimulation of gastric mucosal proliferation. We assessed the immunohistochemical distribution of these peptides and their receptor, epidermal growth factor receptor, in mucosa from the antrum and body of the stomach from 28 patients. Twenty-three of the 56 biopsies were histologically normal (12 antrum and 11 body), whereas the other 33 showed varying degrees of inflammation.

2. Epidermal growth factor, transforming growth factor α and epidermal growth factor receptor had maximal density of distribution on the apical surfaces of the superficial epithelial cells, but were also expressed to a lesser extent on neck and body cells of the glandular tissue (P < 0.05). We also demonstrated that epidermal growth factor expression was greater in the epithelial cells of inflamed mucosa than in those of normal mucosa (P < 0.05).

3. We assessed mucosal proliferation by the Ki-67 labelling index. Ki-67-positive cells were found predominantly in the neck area of the glands and were more frequent in glandular antral tissue than in body glandular tissue (P < 0.05). Expression of epidermal growth factor receptor in the neck and isthmus cells had a significant correlation with the Ki-67 labelling index (P < 0.05).

4. We conclude that epidermal growth factor and epidermal growth factor receptor may be important in the adaptation of gastric mucosa to inflammation.
Absorption of human calcitonin across the rat colon in vivo
Authors: Hastewell J. , Lynch S. , Williamson I. , Fox R. , Mackay M.
Published: August 2015

1. We studied the absorption of human calcitonin across the colon of juvenile female rats in vivo. Both pharmacokinetic and pharmacodynamic parameters were monitored to measure absorption.

2. Intracolonically administered human calcitonin at doses of 0.1–5.0 mg/kg resulted in a dose-dependent reduction in plasma calcium levels.

3. The bioavailability of intracolonically administered human calcitonin at doses of 5.0, 1.0 and 0.1 mg/kg was 0.5%, 0.9% and 0.2%, respectively.

4. Immunohistochemistry showed that human calcitonin transport across the rat colon was rapid and that a significant amount was via a transcellular pathway.

5. We conclude that human calcitonin crosses the gastrointestinal tract of rats in significant amounts and that this demonstrates the feasibility of an oral form for clinical use.
Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism
Authors: Lang Chim C. , Motwani Joseph G. , Coutie Wendy J. R. , Struthers Allan D.
Published: August 2015

1. Brain natriuretic peptide is a new natriuretic hormone with striking similarity to atrial natriuretic peptide, but there are no previous data concerning its clearance in man. Two pathways of clearance for atrial natriuretic peptide are recognized: degradation by neutral endopeptidase and binding to atrial natriuretic peptide clearance receptors. We have examined the effect of candoxatril, an inhibitor of neutral endopeptidase (dose range 10–200 mg), and the effect of an infusion of a pharmacological dose [45 μg (90 μg in two patients)] of synthetic human atrial natriuretic peptide on plasma human brain natriuretic peptide-like immunoreactivity levels in seven patients with mild to moderate chronic heart failure.

2. Plasma human brain natriuretic peptide-like immunoreactivity levels were elevated in all patients (mean ± sem 22.0 ± 6.2 pmol/l) compared with healthy control subjects (1.3 ± 0.2 pmol/l, n = 11).

3. In all patients, candoxatril increased both plasma atrial natriuretic peptide (P < 0.05) and plasma human brain natriuretic peptide-like immunoreactivity (P < 0.05) levels.

4. By contrast, an exogenous infusion of atrial natriuretic peptide had no effect on plasma human brain natriuretic peptide-like immunoreactivity levels despite increasing the plasma atrial natriuretic peptide concentration to 424 ± 74 pmol/l, which is a level of atrial natriuretic peptide which would have ‘swamped’ all atrial natriuretic peptide clearance receptors.

5. We have therefore shown that plasma human brain natriuretic peptide-like immunoreactivity levels in chronic heart failure are increased by a neutral endopeptidase inhibitor, but are unchanged by an exogenous infusion of atrial natriuretic peptide. Our results suggest that in patients with chronic heart failure, degradation by neutral endopeptidase is an important pathway for clearance of brain natriuretic peptide. By an indirect approach, we did not find any evidence of a role for atrial natriuretic peptide clearance receptors in the metabolism of brain natriuretic peptide in these patients. Although this is in agreement with work in vitro, there could be alternative explanations for the lack of a change in circulating human brain natriuretic peptide-like immunoreactivity during exogenous administration of atrial natriuretic peptide.
Isolation of an ultrafilterable Ca2+−ATPase inhibitor from the plasma of uraemic patients
Authors: Zidek W. , Rustemeyer T. , Schlüter W. , Karas M. , Kisters K. , Graefe U.
Published: August 2015

1. Calcium concentration and Ca2+ -ATPase activity under basal conditions and after maximal stimulation with calmodulin were measured in erythrocytes from 32 patients with end-stage renal failure on haemodialysis and from 27 healthy subjects.

2. In patients with renal failure the Ca2+ concentration in erythrocytes was elevated compared with healthy subjects (4.27 ± 1.02 versus 2.86 ± 0.57 μmol/l, P < 0.05).

3. Basal Ca2+ -ATPase activity was lower in the patients with renal failure than in healthy subjects (4.62 ± 1.34 versus 5.43 ± 1.23 pmol of phosphate min−1 10−6 erythrocytes). After maximal stimulation, Ca2+−ATPase activity reached 6.93 ± 2.81 pmol of phosphate min−1 10−6 erythrocytes in the patients with renal failure, whereas in healthy subjects stimulation yielded a Ca2+−ATPase activity of 32.54 ± 8.48 pmol of phosphate min−1 10−6 erythrocytes.

4. Incubation of erythrocytes from healthy subjects with plasma from uraemic patients caused inhibition of Ca2+−ATPase. Likewise, the ultrafiltrate from plasma obtained by haemofiltration treatment inhibited Ca2+−ATPase.

5. Gel chromatography of the ultrafiltrate and laser desorption/ionization mass spectroscopy revealed that a fraction containing substances with a molecular mass of about 300 Da inhibited Ca2+−ATPase.

6. It is concluded that, in uraemia, a Ca2+−ATPase inhibitor accumulates in the plasma, and this could contribute to the toxicity of uraemia by inhibiting cellular Ca2+ transport in erythrocytes and possibly other tissues.
Relationship between spontaneous dyspnoea and lability of airway obstruction in asthma
Authors: Peiffer C. , Toumi M. , Razzouk H. , Marsac J. , Lockhart A.
Published: August 2015

1. As marked lability of bronchial obstruction is a risk factor for asthma severity, it may influence dyspnoea, the most common subjective complaint in asthma. We therefore studied the relationship between spontaneous dyspnoea and the degree of bronchial lability, as assessed by the daily variability in peak expiratory flow rate and the bronchial responsiveness to either carbachol or salbutamol, in 33 stable symptomatic asthmatic patients.

2. Three times daily, for 10 consecutive days, the patients rated the intensity of their dyspnoea on a visual analogue scale and immediately afterwards recorded their peak expiratory flow rate. Within the next 5 days, we determined the bronchial response by measuring the forced expiratory volume in 1 s and the specific resistance of airways to either carbachol or salbutamol according to baseline airway obstruction.

3. We characterized dyspnoea for each patient by using two parameters: (1) the relationship with underlying airway obstruction, as assessed by the correlation coefficient r between dyspnoea scores and corresponding values of peak expiratory flow rate (r DSc-PEFR), and (2) the intensity, as assessed by the mean visual analogue scale dyspnoea score adjusted for comparable airway obstruction. Bronchial lability was characterized by (1) variability in mean daily peak expiratory flow rate and (2) bronchial responsiveness to either carbachol (as assessed by the threshold dose and the slope of the dose-response curve) or salbutamol (as assessed by the threshold dose and maximal response). We assessed the relationship between dyspnoea and bronchial lability by correlating each of their respective characteristics.

4. We found large inter-subject differences in both characteristics of dyspnoea, r DSc-PEFR was unrelated to variability in mean daily peak expiratory flow rate and to all characteristics of bronchial responsiveness used, except for maximal salbutamol-induced increase in forced expiratory volume in 1 s (as a percentage of predicted). Adjusted visual analogue scale dyspnoea scores were unrelated to all characteristics of bronchial lability.

5. Our results suggest that spontaneous dyspnoea, as characterized by its intensity at comparable levels of airway obstruction and by its relationship with underlying airway obstruction, is poorly related to the degree of bronchial lability in stable symptomatic asthmatic patients.
Selective downregulation of rat renal clearance receptors for atrial natriuretic peptide by chronic high-salt intake: study on isolated membranes using 125I-labelled c-atrial natriuretic peptide-(4–23)
Authors: Michel Harald , Bäcker Angela , Kramer Herbert J.
Published: August 2015

1. 125I-labelled c-atrial natriuretic peptide-(4–23) was used as radioligand for the direct quantification of atrial natriuretic peptide clearance receptors, and 125I-labelled rat atrial natriuretic peptide-(1–28) was used for the determination of total and biologically active atrial natriuretic peptide receptors, in renal glomerular and papillary membrane preparations of chronically salt-loaded and control rats.

2. The membrane preparation technique included acid-washing (pH 5), and receptor binding was assessed by saturation studies at 4°C for 3 h. Chronic salt loading revealed a 35% decrease in clearance receptor number in the glomerular membrane and a 42% decrease in the papillary membranes. The absolute decrease in clearance receptor number was almost identical with the observed reduction in absolute number of total atrial natriuretic peptide receptors. Biologically active receptors were not affected by chronic salt loading.

3. Selective downregulation of clearance receptors for atrial natriuretic peptide may reflect an important role for the rat renal atrial natriuretic peptide system in long-term fluid and electrolyte regulation.
Effect of angiotensin-converting enzyme inhibition on plasma brain natriuretic peptide levels in patients with heart failure
Authors: Lang Chim C. , Motwani Joseph G. , Rahman Abdul R. , Coutie Wendy J. , Struthers Allan D.
Published: August 2015

1. The aim of this study was to examine the effect of captopril, an angiotensin-converting enzyme inhibitor, on plasma levels of human brain natriuretic peptide-like immunoreactivity (hBNP-li) in patients with congestive heart failure.

2. Six male patients (aged 52–74 years) with mild to moderate congestive heart failure were studied on two occasions in the semi-recumbent position. After a 30 min rest, patients were randomized to receive oral tablets of either captopril (6.25 mg followed by 25 mg 2 h later) or placebo in a single-blind manner. Plasma hBNP-li, atrial natriuretic peptide-like immunoreactivity (ANP-li) and angiotensin II-like immunoreactivity (ANG II-li) levels and blood pressure were measured.

3. Baseline plasma hBNP-li and ANP-li levels in these patients with mild to moderate congestive heart failure were 13.5 ± 3.2 pmol/l and 50.9 ± 11.8 pmol/l, respectively. In 11 healthy male subjects aged 20–23 years, the peripheral plasma hBNP-li and ANP-li levels were 1.3 ± 0.2 pmol/l and 5.6 ± 1.7 pmol/l, respectively. In all patients, captopril decreased the plasma ANG II-li level (from 24.3 ± 8.1 to 6.6 ± 3.2 pmol/l, P<0.05) and mean arterial blood pressure (from 92 ± 3 to 80 ± 3 mmHg, P<0.05). Compared with placebo, captopril treatment was associated with significant reductions in plasma hBNP-li (from 14.3 ± 3.0 to 12.8 ± 2.1 pmol/l, P<0.05) and in plasma ANP-li (from 53.9 ± 1.11 to 36.8 ± 7.6 pmol/l, P<0.05) levels.

4. Our results show that in patients with heart failure, acute inhibition of angiotensin-converting enzyme with captopril results in falls in both plasma hBNP-li (10% fall) and ANP-li (32% fall) levels. Our results do not support a major role for angiotensin-converting enzyme in the metabolism of human brain natriuretic peptide in heart failure, although a minor role cannot be excluded since the fall in the plasma ANP-li level was greater than the fall in the plasma hBNP-li level. However, the fall in the plasma hBNP-li level is most probably related to the changes induced in intra-cardiac volume/pressure by the angiotensin-converting enzyme inhibitor.
Disparities in circulatory adjustment to standing between young and elderly subjects explained by pulse contour analysis
Authors: Wieling W. , Veerman D. P. , Dambrink J. H. A. , Imholz B. P. M.
Published: August 2015

1. The circulatory adjustment to standing was investigated in two age groups. Young subjects consisted of 20 healthy 10–14-year-old girls and boys. Elderly subjects consisted of 40 70–86-year-old healthy and active females and males. Continuous responses of blood pressure and heart rate were recorded by Finapres. A pulse contour algorithm applied to the finger arterial pressure waveform was used to assess stroke volume responses.

2. During the first 30 s (initial phase), an almost identical drop in mean blood pressure was found in both age groups (young, 16 ± 10 mmHg; old, 17 ± 10 mmHg), but the initial heart rate increase was attenuated in the elderly subjects (young, 29 ± 7 beats/min; old, 17 ± 7 beats/min).

3. During the period from 30 s to 10 min of standing, mean blood pressure increased from 96 ± 12 to 106 ± 12 mmHg in the elderly subjects compared with almost no change in the young subjects (from 82 ± 8 to 84 ± 7 mmHg). In the elderly subjects a progressive increase in total peripheral resistance (from 114 ± 14% to 146 ± 29%) was found, compared with an initial rapid increase in total peripheral resistance (126 ± 18% after 30 s) with no further change during prolonged standing (124 ± 17% after 10 min) in the young subjects. In this age group the decrease in stroke volume and the increase in heart rate after 10 min of standing were large (young, −37 ± 11% and 27 ± 11 beats/min; old, −31 ± 9% and 7 ± 6 beats/min, respectively).

4. In conclusion, young subjects adjust to orthostatic stress mainly by a marked increase in heart rate. In healthy elderly subjects an attenuation of the heart rate response during orthostatic stress is compensated by a pronounced increase in total peripheral resistance resulting in an increase in blood pressure.
Actions of cyclosporin A preparation and Cremophor-EL in rabbit mesenteric artery and thoracic aorta in vitro
Authors: Yaris Ersin , Tuncer Meral , Ilhan Mustafa
Published: August 2015

1. We studied the in vitro and direct effects of intravenous cyclosporin A preparation (Sandimmun) and its solvent (Cremophor-EL) on acetylcholine-induced endothelium-dependent relaxation, phenylephrine-induced contraction and drug-induced contraction of rabbit thoracic aorta and superior mesenteric artery segments.

2. At the lower concentration (5 μg/ml), cyclosporin A preparation inhibited endothelium-dependent relaxation of the superior mesenteric artery but not of the thoracic aorta. At this concentration cyclosporin A preparation augmented phenylephrine-induced contraction in both segments but by more in the superior mesenteric artery, and induced a slow increase in the tone of isolated superior mesenteric artery and thoracic aortic rings, which was greater in magnitude in the superior mesenteric artery than in the thoracic aorta.

3. Acetylcholine-induced endothelium-dependent relaxation was inhibited by cyclosporin A preparation (50 μg/ml) in both arteries but to a greater extent in the superior mesenteric artery.

4. The solvent of the intravenous cyclosporin A preparation (Cremophor-EL) in concentrations corresponding to those of the drug caused less inhibitory effects than cyclosporin A preparation on acetylcholine-induced endothelium-dependent relaxation, had comparable effects on phenylephrine-induced contraction, and produced similar contractions of both arteries.

5. The results indicate that Cremophor-EL may contribute to the inhibitory action of cyclosporin A preparation on acetylcholine-induced endothelium-dependent relaxation in the superior mesenteric artery, but is fully responsible for the smooth-muscle-contracting effect and the potentiation of phenylephrine-induced contraction in both arteries.
Neuropeptide Y as a plasma marker for phaeochromocytoma, ganglioneuroblastoma and neuroblastoma
Authors: Mouri Toraichi , Sone Masahiko , Takahashi Kazuhiro , Itoi Keiichi , Totsune Kazuhito , Hayashi Yutaka , Hasegawa Sumio , Ohneda Makoto , Murakami Osamu , Miura Yukio , Katakura Ryuichi , Tachibana Shinro , Maebashi Masaru
Published: August 2015

1. We investigated the usefulness of neuropeptide Y as a plasma marker for phaeochromocytoma, ganglioneuroblastoma and neuroblastoma using a simple and highly sensitive r.i.a. for human neuropeptide Y.

2. Plasma immunoreactive neuropeptide Y concentrations were measured without extraction in plasma samples (100 μl) from patients with various diseases.

3. The plasma immunoreactive neuropeptide Y concentration in patients with phaeochromocytoma (172.3 ± 132.4 pmol/l, mean ± sd, n = 23) was significantly higher than that in healthy adult subjects (40.1 ± 10.1 pmol/l, n = 40, P<0.0001). The plasma immunoreactive neuropeptide Y concentrations in patients with ganglioneuroblastoma (590.7 ± 563.6 pmol/l, n = 6) and patients with neuroblastoma (566.9 ± 524.4 pmol/l, n = 15) were significantly higher than those in control children (1–9 years old, 82.2 ± 39.9 pmol/l, n = 72, P<0.0001).

4. The plasma immunoreactive neuropeptide Y concentration in patients with essential hypertension (34.0 ± 3.7 pmol/l, n = 18) was within the normal range, but in patients with chronic renal failure undergoing maintenance haemodialysis (192.1 ± 68.0 pmol/l, n = 25) and in non-dialysed patients with chronic renal failure (85.1 ± 23.1 pmol/l, n = 7) it was significantly higher than that in healthy adult subjects (P<0.0001).

5. Eighty-seven per cent of the patients with phaeochromocytoma, 67% of the patients with ganglioneuroblastoma and 80% of the patients with neuroblastoma showed plasma immunoreactive neuropeptide Y concentrations higher than the upper limits in the control subjects [62 pmol/l (adult) and 160 pmol/l (children)].

6. These results suggest that neuropeptide Y is a useful plasma marker for these tumours in addition to other factors unless the patients have renal failure.
Circulating histamine and eosinophil cationic protein levels in nocturnal asthma
Authors: Fitzpatrick Michael F. , MacKay Thomas , Walters Carol , Tai Po-Chun , Church Martin K. , Holgate Stephen T. , Douglas Neil J.
Published: August 2015

1. To investigate the role of mast cells and eosinophils in the pathogenesis of nocturnal asthma, the plasma methylhistamine concentration, serum eosinophil cationic protein level and peak expiratory flow rate were measured 2-hourly for 24 h in 10 patients with nocturnal asthma and in 10 healthy control subjects. Nocturnal asthma was defined as at least one nocturnal awakening per week due to cough, wheeze or breathlessness with an average overnight fall in peak expiratory flow rate of at least 15% during a 2-week run-in period.

2. The lowest peak expiratory flow rate occurred at 02.00–04.00 hours in the group with nocturnal asthma, whose overnight fall in peak expiratory flow rate was 29 ± 5% in comparison with 5 ± 1% (means ± sem) in the normal subjects.

3. Plasma methylhistamine levels at night (0.200–04.00 hours) were lower than during the day (10.00–20.00 hours) in both asthmatic patients and normal subjects (asthmatic patients: day, median 0.22 ng/ml, 95% confidence intervals 0.18–0.34 ng/ml; night, 0.17 ng/ml, 0.13–0.24 ng/ml; P<0.01; normal subjects: day, 0.31 ng/ml, 0.24–0.41 ng/ml; night, 0.24 ng/ml, 0.21–0.33 ng/ml; P<0.01).

4. The serum eosinophil cationic protein level was higher by day (30 ng/ml, 8–47 ng/ml) than by night (21 ng/ml, 5–34 ng/ml; P<0.04) in the group with nocturnal asthma, but did not change significantly with the time of day in the normal subjects (day: 8 ng/ml, 4–14 ng/ml; night: 8 ng/ml, 5–21 ng/ml).

5. Peripheral blood eosinophil counts fell in the early morning in the patients with nocturnal asthma (day: 0.52 × 109/l, 0.14–0.76 × 109/l; night: 0.29 × 109/l, 0.13–0.57 × 109/l; P= 0.03), but did not change significantly in the normal subjects.

6. This study indicates that a rise in plasma histamine concentration is not a prerequisite for nocturnal asthma.
Atrial natriuretic peptide and urinary dopamine output in non-insulin-dependent diabetes mellitus
Authors: Chan J. C. N. , Critchley J. A. J. H. , Ho C. S. , Nicholls M. G. , Cockram C. S. , Swaminathan R.
Published: August 2015

1. Disturbances of sodium and water homoeostasis may contribute to the close association between diabetes, hypertension and proteinuria. We therefore studied the patterns of two natriuretic hormones, plasma atrial natriuretic peptide and urinary dopamine, in 165 Chinese patients with non-insulin-dependent diabetes mellitus controlled by diet or oral hypoglycaemic agents on two occasions over a 6-week period. Patients were divided into three groups based on the mean value of two 24 h urinary albumin excretion measurements. In group 1, 88 patients had normoalbuminuria (urinary albumin excretion ≤ 30 mg/day), in group 2, 48 patients had microalbuminuria (urinary albumin excretion between 30 and 300 mg/day), and in group 3, 29 patients had macroalbuminuria (urinary albumin excretion ≥ 300 mg/day).

2. The supine systolic blood pressure (mean ± sd) was higher in patients with abnormal albuminuria (group 1: 140.9 ± 27.4 mmHg; group 2: 158.1 ± 26.4 mmHg; group 3: 166.7 ± 23.9 mmHg; F = 13.1, P<0.001, analysis of variance). Urinary sodium output was similar in these three groups of patients. The geometric means (anti-logarithm of 95% confidence interval logarithm) of plasma atrial natriuretic peptide concentrations increased with increasing proteinuria [group 1: 33.3 (29.9–37.1) pg/ml; group 2: 39.1 (34.2–44.6) pg/ml; group 3: 50 (38.6–54.7) pg/ml; F = 4.24, P<0.01; analysis of variance], whereas those of urinary dopamine output were related inversely to proteinuria [group 1: 1291.7 (1167.2–1437.0) nmol/day; group 2: 1142.3 (975.9–1337.2) nmol/day; group 3: 982.7 (775.7–1245) nmol/day; F = 3.10, P<0.05, analysis of variance]. Using stepwise multiple regression analysis, plasma atrial natriuretic peptide concentration (r2 = 0.31, F = 56.2, P<0.001) was associated with supine systolic blood pressure (β = 0.56, P<0.001), which was (r2 = 0.38, P<0.001) related to urinary albumin excretion (β = 0.23, P<0.001). In patients with urinary albumin excretion > 30 mg/day, plasma atrial natriuretic peptide concentration was negatively correlated with urinary dopamine output (r = −0.25, P<0.02).

3. Based on these observations, we hypothesize that, in patients with non-insulin-dependent diabetes mellitus, defective dopamine mobilization in the renal tubules may cause impaired natriuresis with increased blood pressure. A compensatory rise in the plasma atrial natriuretic peptide concentration may then contribute to the development of abnormal albuminuria.
Effects of lysine infusion on the renal metabolism of aprotinin (Trasylol) in man
Authors: Rustom R. , Maltby P. , Grime J. S. , Stockdale H. R. , Critchley M. , Bone J. M.
Published: August 2015

1. Aprotinin (Trasylol) is a cationic 6500 Da polypeptide that inhibits proteolytic enzymes, and when labelled with 99mTc it is a reproducible marker for the renal tubular turnover of small filtered proteins in man. Lysine potently inhibits tubular peptide uptake, and may thus depress the uptake and metabolism of aprotinin. This was investigated in 14 glomerulonephritic patients with normal renal function and variable proteinuria and in one healthy subject.

2. 99mTc-labelled aprotinin was given intravenously alone, and again 3 days later, immediately after the intravenous administration of 3–6 g of lysine, followed by an infusion over 1 h of 0.3–1.9 g of lysine/kg in individual patients. Activity over kidneys and in urine was measured over 24 h and chromatography was used to separate the undegraded peptide from free isotope.

3. At the low dosage of lysine (< 0.8 g/kg) given to six patients, kidney activity (representing tubular uptake) was unchanged, but early urine samples contained some undegraded aprotinin. Urinary excretion of free isotope, representing tubular metabolism, fell from 1.6 ± 0.2% of dose/h with no lysine to 0.9 ± 0.1% of dose/h in the 24 h after lysine, suggesting suppression of tubular aprotinin degradation. Corrected fractional degradation was calculated from the mean urinary excretion of free isotope over a given interval, determined by chromatography, divided by the mean cumulative kidney counts over this same interval, and this also fell after lysine from 0.06 ± 0.006 to 0.03 ± 0.006 h−1 (P<0.005) between 3.75 and 24 h.

4. By contrast, in nine subjects given more lysine (> 0.8 g/kg) tubular uptake fell and urine contained more undegraded aprotinin at all times. However, the corrected urinary excretion of free isotope (determined by chromatography) was unchanged and, paradoxically, fractional degradation rose from 0.06 + 0.01 to 0.10 ± 0.01% of dose/h (P<0.025) between 3.75 and 24 h.

5. Thus, lysine seemed to have a biphasic effect, inhibiting tubular peptide degradation at the low dosage, but depressing uptake into the tubular cell at the high dosage. This, in turn, might relieve intra cellular proteolytic enzymes from autoinhibition by aprotinin and result in a paradoxical restoration of tubular metabolism.
Indomethacin and sodium retention in the rat: role of inhibition of prostaglandin E2 synthesis
Authors: Scherzer Pnina , Wald Hanna , Rubinger Dvora , Popovtzer Mordecai M.
Published: August 2015

1. To further explore the Na+-retaining effect of indomethacin along the whole length of the nephron, the Na+-K+-ATPase activity of isolated tubules from indomethacin-pretreated rats was compared with that of tubules isolated from intact rats and exposed directly to prostaglandin E2.

2. Indomethacin increased Na+-K+-ATPase activity in the proximal convoluted tubule (+24%, P<0.001 versus control), proximal straight tubule (+75%, P<0.001 versus control), medullary thick ascending limb (+68%, P<0.001 versus control), cortical thick ascending limb (+7%, not significant) and cortical collecting duct (+18%, P<0.025 versus control). In contrast, in the distal convoluted tubule indomethacin decreased Na+-K+-ATPase activity by −42% (P<0.001 versus control).

3. Indomethacin also strongly increased Na+-K+-ATPase activity in the cortical collecting duct of adrenalectomized rats.

4. In isolated tubules from control rats, prostaglandin E2 reduced Na+-K+-ATPase activity in the proximal convoluted tubule (−33%, P<0.05), proximal straight tubule (−60%, P<0.001), medullary thick ascending limb (−43%, P<0.001), cortical thick ascending limb (−25%, P<0.001) and cortical collecting duct (−45%, P<0.001) and in the distal convoluted tubule, prostaglandin E2 increased Na+-K+-ATPase activity (+32%, P<0.05).

5. That these changes in Na+-K+-ATPase activity in indomethacin-pretreated rats and prostaglandin E2-treated controls are similar in magnitude but occur in opposite directions suggests that the response to indomethacin is mediated by inhibition of prostaglandin E2 synthesis in the nephron. In the cortical collecting duct the effect of indomethacin is aldosterone-independent.
Plasma, platelet and erythrocyte glutathione peroxidases as risk factors in ischaemic heart disease in man
Authors: Porter M. , Pearson D. J. , Suarez-Mendez V. J. , Blann A. D.
Published: August 2015

1. Plasma, platelet and erythrocyte glutathione peroxidase activities and serum lipid concentrations were measured in patients with ischaemic heart disease and matched control subjects.

2. Mean plasma and platelet glutathione peroxidase activities were significantly lower in the patients with ischaemic heart disease. Erythrocyte glutathione peroxidase activities and serum lipid concentrations were similar in patients with ischaemic heart disease and control subjects.

3. No correlations between plasma, platelet and erythrocyte glutathione peroxidase activities were observed.

4. The combination of plasma and platelet glutathione peroxidase activities provided an 86% discrimination between patients with ischaemic heart disease and matched control subjects.

5. Our data suggest that plasma and platelet glutathione peroxidases may be significant risk factors for ischaemic heart disease. Plasma glutathione peroxidase is a previously unrecognized risk factor.
Decreased faecal exoglycosidase activities identify a subset of patients with active Crohn's disease
Authors: Yamani Jamal El , Mizon Charlotte , Capon Calliope , Colombel Jean-Frederic , Fournet Bernard , Cortot Antoine , Mizon Jacques
Published: August 2015

1. α1-Proteinase inhibitor (α1-antitrypsin) is excreted in a deglycosylated form (Mr 38000) in the faeces of healthy subjects and in patients with quiescent Crohn's disease. By contrast, in most patients with active Crohn's disease, α1-proteinase inhibitor is excreted in a glycosylated form (Mr 51000).

2. Faecal extracts containing deglycosylated α1-proteinase inhibitor are able to deglycosylate α1-proteinase inhibitor by an exoglycosidic process. Conversely, we demonstrate that in faecal extracts from patients excreting glycosylated α1-proteinase inhibitor, glycosidase activities, such as N-acetyl-β-glucosaminidase (EC 3.2.1.30), α1-mannosidase (EC 3.2.1.24) and particularly β-galactosidase (EC 3.2.1.23), are strongly decreased.

3. Degradation of glycosidases by proteases could not explain the decreased glycosidase activity in these faecal extracts.

4. Our data suggest that a modification of the bacterial colonic flora (or of its metabolic activity) occurs in most patients with active Crohn's disease and could be responsible for an impaired colonic salvage of carbohydrates.
Effects of spermine on water absorption, polyethylene glycol 4000 permeability and collagenase activity in rat descending colon in vivo
Authors: Mendizabal M. V. , Naftalin R. J.
Published: August 2015

1. The effects of spermine in the concentration range 0–10 mmol/l on (a) the fluid absorption, (b) the polyethylene glycol permeability, (c) the release of collagenase activity activity into the lumen and (d) the histological appearance of rat descending colon were examined.

2. Spermine (5 mmol/l) decreased fluid absorption from 48.83 ± 2.98 (n = 7) to 23.98 ± 2.32 (n = 6) μl h−1 cm−2 (P<0.01); polyethylene glycol 4000 permeability was increased from 0.030 ± 0.001 (n = 7) to 0.047 ± 0.003 (n = 6) cm/h (P<0.01) and luminal collagenase activity increased from a negligible control value to 250 ± 39 (n = 6) units/ml (P<0.001). Spermine also caused oedema formation within the mucosal interstitial fluid, without inducing an overt breakdown of the mucosa at the luminal surface.

3. Polyamine-free dialysed seminal plasma had no effect on polyethylene glycol 4000 permeability, although it still caused a significant decrease in colonic fluid absorption from 48.83 ± 2.98 (n = 7) (control) to 31.41 ± 2.08 (n = 5) μl h−1 cm−2 (P<0.01).

4. Low-molecular-mass heparin (600 units/ml) prevented the spermine (5 mmol/l)- and whole-semen-induced increase in colonic polyethylene glycol 4000 permeability and reduced the effect of semen on fluid absorption by 63% (P<0.001) and that of spermine by 56% (P<0.01).

5. The Zn2+ chelator and collagenase inhibitor o-phenanthroline reduced the effect of spermine on fluid absorption and polyethylene glycol 4000 permeability by 100% (P<0.001) and on interstitial oedema formation. o-Phenanthroline also reduced the effects of whole semen on fluid absorption (by 70%, P<0.01) and on polyethylene glycol 4000 permeability by 95%, P<0.01).

6. A synthetic peptide inhibitor of mammalian collagenase activity with high affinity reduced the effects of whole semen on polyethylene glycol 4000 permeability (P<0.01) and on fluid absorption (P<0.01) in a dose-dependent manner. The inhibitor (2 mmol/l) also reduced the effects of spermine (5 mmol/l) on fluid absorption and polyethylene glycol 4000 permeability.

7. These results indicate that polyamines that are present within semen in the concentration range 5–15 mmol/l act co-operatively with seminal collagenases to disrupt the colonic barrier. Cationic polyamines may activate collagenases by binding to and neutralizing the anionic charge of heparins within the interstitial matrix.
Determinants of intra-individual variation in kidney function in normoalbuminuric insulin-dependent diabetic patients: importance of atrial natriuretic peptide and glycaemic control
Authors: Pedersen M. Mau , Christiansen J. Sandahl , Pedersen E. B. , Mogensen C. E.
Published: August 2015

1. In order to investigate the modulation of kidney function in insulin-dependent diabetes mellitus, intra-individual variation in glomerular filtration rate, renal plasma flow, urinary albumin excretion rate and mean arterial blood pressure was assessed in 22 normoalbuminuric patients [age 31 ± 8 years, duration of diabetes 9 ± 5 years, mean arterial blood pressure 90 ± 5 mmHg (means ± sd), urinary albumin excretion rate 5.4 × / ÷ 1.6 μg/min]. The variation in these parameters was calculated from the results of two clearance studies (continuous infusion of [125I]-iothalamate and 131I-hippuran as markers for glomerular filtration rate and renal plasma flow, respectively) and was subsequently analysed in relation to individual variation in plasma concentrations of atrial natriuretic peptide, arginine vasopressin, angiotensin II and aldosterone and measures of glycaemic control.

2. Simple correlation analysis showed a significant association between intra-individual variation in glomerular filtration rate and atrial natriuretic peptide (σ = 0.66, P = 0.003). Besides variation in atrial natriuretic peptide, multiple regression analysis identified variation in glycated haemoglobin (P = 0.026) and arginine vasopressin (P = 0.057) as variables having independent association with variation in glomerular filtration rate [R2 with the three variables included (adjusted for degrees of freedom) = 0.50, analysis of variance: P = 0.002].

3. With respect to variation in renal plasma flow, differences in fasting blood glucose concentration and mean arterial blood pressure were suggested as determinants (R2 = 0.36, analysis of variance: P = 0.009).

4. Variation in urinary albumin excretion rate (after log transformation) was statistically associated with variation in glycated haemoglobin.

5. When compared with eight healthy control subjects, atrial natriuretic peptide was moderately increased in the diabetic patients [4.7(4.2–6.2) versus 3.9 (3.4–4.6) pmol/l, median (first and third quartile), 2P<0.05].

6. In conclusion, the study identified individual changes in atrial natriuretic peptide, arginine vasopressin and long-term glycaemic control as factors associated with intra-individual variation in glomerular filtration rate. It is suggested that atrial natriuretic peptide is involved in the regulation of glomerular filtration rate and possibly specifically in diabetic hyperfiltration.
Post-operative changes in hepatic, intestinal, splenic and muscle fluxes of amino acids and ammonia in pigs
Authors: Deutz N. E. P. , Reijven P. L. M. , Athanasas G. , Soeters P. B.
Published: August 2015

1. After operation, changes in nitrogen metabolism occur. Although increased flux of amino acids from peripheral to splanchnic organs after operation has been described, substrate utilization by the individual organs in the splanchnic area is less well characterized. We were specifically interested in substrate flux across the spleen as it is an organ with important immunological functions.

2. Therefore, hindquarter, gut, spleen and liver fluxes of amino acids, ammonia, glucose, lactate and blood gases were measured for 4 days after a standard operation in pigs. In a separate control group, fluxes were measured 2–3 weeks after this operation and these values were assumed to represent the normal situation.

3. One day after operation, the hindquarter effluxes of glutamine, alanine and several essential amino acids were increased (P<0.001), but these normalized at the end of the observation period. In the same period, liver glutamine uptake increased (P<0.01), concomitantly with increased HCO-3, glucose and urea production, which also normalized. Portal drained viscera ammonia production decreased, concomitant with decreased glutamine uptake (P<0.001). After operation, the splenic release of ammonia increased sevenfold (P<0.05) and that of lactate increased from −158 ± 544 to 3294 ± 642 nmol min−1 kg−1 body weight (P<0.001). Glucose uptake increased from −964 ± 632 to −3933 ± 1524 nmol min−1 kg−1 body weight and glutamine efflux (391 ± 143) reversed to uptake (−752 ± 169 nmol min−1 kg−1 body weight) (P<0.001).

4. The experiments show that after operation in the pig, amino acid flow is from peripheral tissue to liver, probably for gluconeogenesis. The increased postoperative splenic metabolism possibly represents an indication of increased substrate utilization by the immune system.
Salbutamol, a β2-adrenoceptor agonist, increases skeletal muscle strength in young men
Authors: Martineau Lucie , Horan Michael A. , Rothwell Nancy J. , Little Roderick A.
Published: August 2015

1. β2-Adrenoceptor agonists have been shown to increase rapidly lean body mass and reverse muscle wasting in several animal models of human illness. However, no published information is available for humans. In the present study, we investigated the effects of a slow-release preparation of salbutamol or a placebo on skeletal muscle functional capacity in 12 healthy men. The strength of different muscle groups was measured on two occasions before and after 14 and 21 days of treatment.

2. No significant changes in muscle strength were observed with placebo during the trial. In contrast, the strength of both quadriceps muscles increased significantly (12 ± 3%) after 14 days on salbutamol, and remained elevated at 21 days. Whereas the strength of the hamstring muscles of the dominant leg significantly increased after 21 days on salbutamol (22 ± 6%), the strength of the non-dominant hamstring muscles returned to baseline values.

3. There was no significant change in the grip strength of either hand in these subjects during the trial. The maximal static inspiratory mouth pressure increased significantly (7 ± 2%) after 14 days on salbutamol, and increased further after 21 days (15 ± 4%); the expiratory mouth pressure remained constant. No significant changes in body weight, skinfold thickness, lean body mass or limb circumferences were measured in either group.

4. These data demonstrate that short-term administration of salbutamol increases voluntary muscle strength in man. However, the magnitude and duration of this effect vary between muscle groups. This study implies that the β2-adrenoceptor agonists may be of therapeutic potential in altering skeletal muscle function in humans.