bluuebunny/crossref_metadata_2025 huggingface dataset:
Capillary Permeability and Extracellular Fluid Volumes in Pregnancy-Induced Hypertension
Authors: Brown Mark A. , Zammit Vivienne C. , Lowe Sandra A.
Published: August 2015

1. Capillary permeability was determined by the disappearance rate of Evans Blue dye from plasma in healthy non-pregnant women, normal third-trimester primigravidae and primigravidae with pregnancy-induced hypertension

2. Extracellular fluid volume was determined from the disappearance curves of injected mannitol in the same subjects and the plasma volume was measured by the Evans Blue dye dilution technique

3. In normal pregnancy capillary permeability was not altered from that of non-pregnant subjects. Although extracellular fluid volume and plasma volume were increased in normal pregnant compared with nonpregnant women, the distribution of fluid between plasma volume and interstitial fluid volume was unaltered

4. Women with established pregnancy-induced hypertension had a more rapid Evans Blue disappearance rate and a lower plasma volume than normal pregnant women, independent of the presence of proteinuria. Maternal plasma volume correlated positively and significantly with fetal birth weight in women with pregnancy-induced hypertension, emphasizing the important relationship between maternal plasma volume and fetal outcome

5. The increased capillary permeability in women with pregnancy-induced hypertension was associated with a reduction in the plasma volume/interstitial fluid volume ratio but a normal extracellular fluid volume, suggesting that the reduced plasma volume did not result from sodium loss but rather from a redistribution of the total extracellular fluid volume. These changes did not differ significantly in subgroups with and without oedema.
Production of Methylguanidine in Dogs with Acute and Chronic Renal Failure
Authors: Brooks David P. , Rhodes Gerald R. , Woodward Paul , Boppana Venkata K. , Mallon Francine M. , Griffin H. Eugene , Kinter Lewis B.
Published: August 2015

1. Methylguanidine is a suspected uraemic toxin that accumulates in renal failure

2. We measured methylguanidine in the plasma of dogs with acute ischaemic-induced renal failure and in the plasma and urine of dogs with spontaneous chronic renal insufficiency, using a highly sensitive method involving solid-phase extraction followed by h.p.l.c. with post-column fluorescence detection

3. Constriction of the remaining renal artery of four uninephrectomized dogs for 90 min resulted in a significant (P < 0.01) increase in plasma creatinine concentration after 24 h (from 113 ± 3 to 303 ± 50 μmol/l; mean ± sem). Over the next 14 days, plasma creatinine fell towards baseline concentrations. Plasma methylguanidine also increased significantly (P < 0.05) 24 h after renal occlusion (from 0.16 ± 0.04 to 0.86 ± 0.32 μmol/l) and showed a similar pattern to the plasma creatinine concentration

4. In a further four dogs, administration of mannitol (2 g/kg) at the time of reperfusion significantly attenuated these responses

5. Dogs with chronic renal failure demonstrated increased plasma concentrations and urinary excretion of methylguanidine, and the levels appeared to be related to the severity of renal insufficiency. Thus, the dogs with the highest plasma creatinine concentrations and lowest creatinine clearances had the highest plasma methylguanidine concentrations. The clearance of methylguanidine exceeded that of creatinine, indicating that the toxin undergoes renal tubular secretion.
Pulmonary Endothelium-Derived Relaxing Factor is Impaired in Hypoxia
Authors: Warren J. B. , Maltby N. H. , MacCormack D. , Barnes P. J.
Published: August 2015

1. The vasoconstrictor and vasodilator activity of cultured bovine pulmonary artery endothelial cells was measured to determine how exposure to different partial pressures of O2 [Po2 142, 42 and 15 mmHg (18.9, 5.6 and 2 kPa)] affects the production of endothelial-derived relaxing and constrictor factors

2. A de-endothelialized rat aortic ring [maintained at a Po2 of 142 mmHg (18.9 kPa)] was used to bioassay the effluent from a perfused column of bovine endothelial cells grown on microcarrier beads. The endothelial cells were stimulated by 10−7 mol/l bradykinin given for 1 min at 12 min intervals

3. At the start, middle and end of the experiment the bovine endothelial cells were exposed to a Po2 of 142 mmHg (18.9 kPa) and when stimulated by bradykinin the perfusate caused respectively a 70 ± 4%, 63 ± 6% and 63 ± 6% (mean ± sem) relaxation of an aortic ring which had been pre-contracted by 10−6 mol/l phenylephrine. At a Po2 of 42 mmHg (5.6 kPa) the relaxation induced by the cells was not significantly altered, but this tailed to zero after 26–38 min exposure of the cells to a Po2 of 15 mmHg(2 kPa)

4. These responses were unaltered by the presence of 10−5 mol/l indomethacin, suggesting that prostacyclin is not a significant vasodilator in this system

5. Reduced production of endothelium-derived relaxant factor rather than production of a constrictor factor, or a direct effect on the smooth muscle, may be involved in pulmonary hypoxic vasoconstriction.
Monophasic action potential recordings in response to rapid transient elevation of extracellular potassium and their modification by β-adrenoceptor blockade in the anaesthetized dog
Authors: Sutton P. M. I. , Taggart P. , Swanton R. H. , Emanuel R. W.
Published: August 2015

1. Monophasic action potentials (MAPs) were recorded simultaneously from the endocardium and the epicardium in open-chested dogs (n = 16) during bolus intravenous injections of potassium chloride at 0.1 mmol/kg and 0.2 mmol/kg. MAP duration was measured at 90% repolarization. Local conduction was measured as the delay between the pacing artefact and upstroke of the MAP.

2. The animals were anaesthetized with α-chloralose and urethane. Heart block was created by atrioventricular nodal ablation with 0.1% (v/v) formalin. Infra-nodal pacing was established.

3. Bolus injections of potassium chloride at 0.1 mmol/kg shortened MAP duration. The effect was maximal at 15 s after the injection [epicardium: 171.5 ± 3.0 (control) and 148.9 ± 5.2 ms at 15 s (P < 0.001); endocardium: 178.7 ± 4.4 (control) and 165.6 ± 5.3 ms (P < 0.001)]. The shortening on the epicardium was significantly greater than on the endocardium (P < 0.05).

4. Local conduction time showed no significant change [epicardium: 37.8 ± 1.8 (control) and 41.2 ± 2.4 at 15 s; endocardium: 41.1 ± 1.6 (control) and 45.0 ± 3.4 at 15 s].

5. After β-adrenoceptor blockade, MAP duration shortened, exhibiting a maximum effect at 20 s after a bolus injection of potassium chloride at 0.1 mmol/kg [epicardium: 184.7 ± 7.1 (control) and 130.7 ± 9.0 ms at 20 s (P < 0.001); endocardium 192.0 ± 7.4 (control) and 148.6 ± 10.8 ms at 20 s (P < 0.001)]. The greater shortening observed on the epicardial surface did not reach statistical significance.

6. Local conduction time after β-adrenoceptor blockade was prolonged, reaching a maximum at 20 s [epicardium: 41.2 ± 4.8 (control) and 65.9 ± 8.6 ms at 20 s: endocardium: 47.5 ± 7.4 (control) and 87.3 ± 13.1 ms at 20 s].

7. Doubling of the dose of potassium chloride to 0.2 mmol/kg was usually terminal and often showed bizarre electrophysiological responses with striking regional differences.

8. Our results show that bolus injections of potassium chloride exert a differential influence on the time course of epicardial and endocardial repolarization by an effect on MAP duration rather than on local conduction time. After β-adrenoceptor blockade the effect of a bolus injection of potassium chloride on MAP duration was greater and conduction time was increased.
Alterations in β-adrenergic sensitivity and platelet α2-adrenoceptors in obese women: effect of exercise and caloric restriction
Authors: Berlin Ivan , Berlan Michel , Crespo-Laumonnier Brigitte , Landault Catherine , Payan Christine , Puech Alain J. , Turpin Gérard
Published: August 2015

1. Peripheral adrenergic responses were studied in eight obese women before and after 15 days of caloric restriction (2500 kJ/day) and in eight sex- and age-matched lean controls.

2. β-Adrenergic sensitivity (defined as the dose of isoprenaline required to increase resting heart rate by 25 beats/min) was evaluated before and after the diet. Density and affinity (determined as the apparent dissociation constant) of platelet α2-adrenergic receptors, and plasma adrenaline and noradrenaline levels, were measured after overnight bed-rest and after 9 min of standardized exercise performed before and after the low caloric diet.

3. Before the diet basal antecubital venous plasma noradrenaline concentrations were lower in obese women when compared with lean women (0.94 ± 0.06 vs 1.27 ± 0.17 nmol/l, P < 0.02). Isoprenaline sensitivity did not differ between lean and obese women.

4. At rest, platelet α2-adrenoceptor density was lower in overweight than in lean women (129 ± 21 vs 168 ± 16 fmol/mg of protein, P < 0.02). Exercise significantly increased platelet α2-adrenoceptor density and decreased affinity in lean women. This decrease correlated with the rise in plasma noradrenaline.

5. In obese women exercise did not modify platelet α2-adrenoceptor density or affinity, despite a significant increase in plasma catecholamines. However, the increase in plasma noradrenaline during exercise was lower in obese women.

6. The low caloric diet produced a β-adrenergic supersensitivity.

7. We conclude that (a) obesity does not alter β-adrenergic sensitivity; (b) 15 days of caloric restriction produces a β-adrenergic supersensitive state; (c) obese women show an inability to desensitize platelet α2-adrenoceptors in response to exercise.
Biphasic response to acetylcholine in human veins in vivo: the role of the endothelium
Authors: Collier Joe , Vallance Patrick
Published: August 2015

1. The dose-response to acetylcholine has been examined in dorsal hand veins of healthy volunteers before and after removal of the endothelium.

2. Measurements were made in single dorsal hand veins during local infusions of acetylcholine. The vein was irrigated with distilled water to remove the endothelium. Dilator studies were performed in vessels preconstricted by a continuous infusion of noradrenaline.

3. In the endothelium-intact vessel the dose-response to acetylcholine was biphasic; low doses produced venodilatation with higher doses causing venoconstriction.

4. Dilatation to low doses of acetylcholine was abolished by prior irrigation with distilled water, consistent with denudation of the endothelium by this process. Irrigation augmented the constriction seen in response to higher doses of acetylcholine.

5. This is the first demonstration of an endothelium-dependent biphasic dose-response to acetylcholine in man. The results raise questions as to the possible physiological actions of endogenous acetylcholine and as to the use of the acetylcholine dose-response curve as a marker of endothelial function.
Ethanol predominantly alters sodium influx in human leucocytes
Authors: Main J. , Thomas T.
Published: August 2015

1. Although ethanol appears to alter cellular sodium transport, the exact nature of its effects has not been clearly defined. We have studied the effects of different concentrations of ethanol on human leucocyte sodium content, and on the rise in leucocyte sodium content which occurs during sodium pump blockade with ouabain.

2. Sodium content was significantly reduced after a 20 min incubation with ethanol at concentrations between 17 and 170 mmol/l.

3. The rise in sodium content during a 20 min incubation with ouabain was significantly less in the presence of 170 mmol/l ethanol as compared with 17 mmol/l ethanol.

4. These results suggest that the effect of ethanol on intracellular sodium content is independent of sodium pump activity, i.e. it is mediated through reduced sodium influx.
Severe metabolic acidosis and disturbances of calcium metabolism induced by acetazolamide in patients on haemodialysis
Authors: De Marchi Sergio , Cecchin Emanuela
Published: August 2015

1. To investigate mechanisms of extrarenal buffering in uraemic acidosis, we studied the effects of the carbonic anhydrase inhibitor, acetazolamide, in normal subjects and in patients with end-stage kidney disease on maintenance haemodialysis with virtually no urine output.

2. Acetazolamide (500 mg) was administered daily for 7 days, after pretreatment for 1 month with 1,25-dihydroxyvitamin D (n = 12) or placebo (n = 12); only placebo was administered to a third group (n = 12) of haemodialysis patients. In addition, acetazolamide was administered to normal control subjects (n = 12).

3. Treatment with acetazolamide resulted in a more marked metabolic acidosis in haemodialysis patients than in normal control subjects and the effect in haemodialysis patients was attenuated by prior treatment with 1,25-dihydroxyvitamin D.

4. The administration of acetazolamide to haemodialysis patients led to an increase in serum inorganic phosphorus, bone isoenzyme of alkaline phosphatase and parathyroid hormone, and a reduction in serum calcium, whereas acetazolamide had no effect on these variables in normal subjects. In contrast, in the haemodialysis patients previously treated with 1,25-dihydroxyvitamin D, acetazolamide increased serum inorganic phosphorus, bone isoenzyme of alkaline phosphatase, parathyroid hormone and serum calcium.

5. We hypothesize that the metabolic acidosis induced by acetazolamide in haemodialysis patients may result from interference with the mechanisms of extrarenal buffering.

6. As parathyroid hormone, 1,25-dihydroxyvitamin D and carbonic anhydrase are thought to be involved in bone buffering, we suggest that the marked acidosis seen in haemodialysis patients treated with acetazolamide may be due to impaired parathyroid hormone-mediated bone buffering.
myo-Inositol influx into human leucocytes: methods of measurement and the effect of glucose
Authors: Simmons D. , Bomford J. , Ng L. L.
Published: August 2015

1. Low intracellular concentrations of myo-inositol in diabetic cells may contribute to the development of tissue damage. The cause of these low levels is unknown, but inhibition of a putative myo-inositol transporter by high concentrations of glucose has been proposed. We have developed a triple-isotope method for estimating myo-inositol influx into human leucocytes and so investigated both the kinetics of this uptake in normal volunteers and the effect of glucose upon it.

2. Uptake was composed of a passive component with a rate constant of 2.4 ± 0.3 × 10−2 min−1 and a saturable component with a Km of 61 ± 23 μmol/l and a Vmax. of 11.3 ± 4.5 × 10−4 mmol min−1 l−1. Ouabain and low extracellular concentrations of sodium partly inhibited influx. Uptake was predominantly into the cytosolic fraction of the cell with 12% entering the membrane-associated fraction at both 5 and 10 min.

3. myo-inositol influx was significantly inhibited by both d- and l-glucose but not by sucrose. Neither cytochalasin B nor ethyl isopropyl amiloride significantly inhibited uptake.

4. It is concluded that a myo-inositol transporter exists in human leucocytes which is similar to that found in other species and tissues. Our technique allows myoinositol influx in diabetic subjects to be related to varying glycaemic control and tissue damage.
Genes encoding the β-chains of HLA-DR7 and HLA-DQw2 define major susceptibility determinants for idiopathic nephrotic syndrome
Authors: Clark A. Godfrey B. , Vaughan Robert W. , Stephens Henry A. F. , Chantler Cyril , Williams D. Gwyn , Welsh Kenneth I.
Published: August 2015

1. We have investigated the frequencies of the major histocompatibility complex class II alleles by restriction fragment length polymorphism analysis, using DR, DQ and DP complementary DNA probes, in 40 Caucasoid steroid-sensitive nephrotic children.

2. A significant association with HLA-DR7 was demonstrated (P = 2 × 10−5; aetiological fraction 0.6). The DQB1 gene of HLA-DQw2 was present in 83% of our patients (P = 2 × 10−4; aetiological fraction 0.7). We present evidence that it contributes a second susceptibility allele.

3. A weak association between the uncommon HLA-DP-Cp63 allele and the disease was also observed.

4. Our data suggest that the immune events in steroid-sensitive nephrotic syndrome are defined by a particular immunogenetic background involving the β-chain genes of HLA-DR7 and HLA-DQw2.
Elevated expression of heat-shock protein gene in the fibroblasts of patients with scleroderma
Authors: Deguchi Yasuhiro , Kishimoto Susumu
Published: August 2015

1. Scleroderma is a systemic autoimmune disorder characterized by fibrosis affecting the skin, lung, kidney and other organs. The 70 kDa heat-shock protein has been implicated as essential for cell function during cell growth and differentiation. To study the molecular basis of intracellular events in sclerotic fibroblasts, we compared the expression of the hsp 70 gene in sclerotic and normal control fibroblasts by a run on nuclear transcription assay and a Northern blot assay.

2. In the run on nuclear transcription assay, sclerotic fibroblasts expressed an approximately eightfold higher level of hsp 70 transcription than normal fibroblasts in the quiescent condition after serum starvation. After stimulation with serum, the transcription level of the hsp 70 gene was almost similar in sclerotic and normal control fibroblasts.

3. In the Northern blot assay, the hsp 70 gene transcript, which was present in increased amounts in sclerotic fibroblasts, exhibited normal size.
Transcutaneous electrical stimulation applied to the infratrochlear nerve induces a homatropine-resistant miosis in humans
Authors: Fusco B. M. , Alessandri M. , Campagnolo V. , Fanciullacci M.
Published: August 2015

1. Both high- and low-intensity transcutaneous electrical stimuli were applied to the emergence of the infratrochlear nerve in 18 healthy subjects. The effect on the size of the homolateral pupil was investigated. The width of the pupil was also measured when high-intensity transcutaneous electrical stimulation was applied to the contralateral side.

2. The high-intensity pulse resulted in constriction of the pupil when the stimulation was homolateral. The miosis was slow in onset (120 s latency) and long-lasting (80 s). No pupillary changes were detected after either ipsilateral low-intensity or contralateral high-intensity stimuli.

3. In 11 healthy subjects, the pupillary response to transcutaneous electrical stimulation was evaluated during iris parasympathetic blockade induced by homatropine eyedrops. The disappearance of the light reflex due to homatropine was considered an index of the parasympathetic blockade. Afterwards, a high-intensity pulse was transcutaneously delivered to the emergence of the infratrochlear nerve and the ipsilateral pupil size was measured.

4. A reduction in the pupillary size followed the electrical stimulation, still under the effect of homatropine which abolished the light reflex. The time course of this pupillary constriction was similar to that seen without the influence of homatropine.

5. The findings suggest that homolateral miosis, observed after unilateral high-intensity stimulation of the infratrochlear nerve, does not stem from cholinergic activation. It has been suggested that miosis induced by transcutaneous electrical stimulation may be due to an antidromic activation of the iris sensory fibres.
Aortic compliance measured by non-invasive Doppler ultrasound: Description of a method and its reproducibility
Authors: Wright J. S. , Cruickshank J. K. , Kontis S. , Doré Caroline , Gosling R. G.
Published: August 2015

1. Aortic compliance (expressed as percentage increase in lumen diameter for a pulse pressure of 10 mmHg) was calculated from the characteristic pulse wave velocity deduced from ‘foot to foot’ transit times of the blood flow pulse over a measured length of aorta. Two continuous wave Doppler ultrasound transducers were used: one insonating the root of the left subclavian artery, the other the abdominal aorta proximal to its bifurcation. Measurements were made after the subject had been supine for 5 min to achieve stable conditions.

2. Transit times were calculated on-line in real-time from the delay between the start of the systolic upstroke in the flow velocity sonograms recorded by the two transducers.

3. Within-visit variation was minimized by measuring over 45 cardiac cycles repeated three separate times and calculating an overall mean value for aortic compliance. A full measurement took 5–10 min.

4. Reproducibility of this overall mean value of aortic compliance was assessed at 1 month in 30 subjects (aged 60 ± 7 years, mean ± sd) and at 3 months in 23 different subjects (59 ± 8 years). Aortic compliance values ranged from 0.1 to 2.0%/10 mmHg (see eqn 4).

5. The mean paired difference between aortic compliance values was −0.02 between 0 and 1 month, and 0.03 between 0 and 3 months, with respective 95% confidence limits of −0.06 to 0.03 and −0.03 to 0.09 embracing zero, thus not differing significantly from baseline.

6. Aortic compliance can be both simply and reproducibly measured non-invasively; if an individual was measured on two occasions, then 95% of the time the difference between the two measurements of aortic compliance would be <0.28 (twice the sd of the 3 month differences).
Patients' Perception of Distress Due to Symptoms and Effects of Asthma on Daily Living and an Investigation of Possible Influential Factors
Authors: Quirk F. H. , Jones P. W.
Published: August 2015

1. Distress ratings for questions relating to the symptoms and impacts of asthma on daily living have been examined in 40 adult asthmatic outpatients.

2. The patients responded to each item in a 76-item questionnaire by marking a 10 cm visual analogue scale to indicate the degree of distress associated with the symptoms or state described in the question. The resulting score (as a percentage of 10 cm) was interpreted as the degree of distress associated with a particular item.

3. The possible influence on these distress scores of five factors, age, duration (time in years from diagnosis to interview), variability [recorded variability of forced expiratory volume in 1 s (FEV1) expressed as amplitude per cent mean], sex and FEV1 (current and worst recorded in the clinic, expressed as per cent of predicted) was investigated.

4. From correlations of each item with age, 11/76 items were significant at P < 0.05. Taking the results from all 76 items in a repeated measures analysis of variance, there was a small significant relationship between age and distress score (P = 0.048). The direction of the association was negative, suggesting that younger patients were less tolerant of asthma; however, the effect of age only explained 1.5% of the total variance in scores of the 76 items.

5. From correlations of visual analogue scale score for each item against duration, 10/76 items were significant at P < 0.05, but taking the 76 items overall there was no significant association (P = 0.2).

6. The remaining factors, sex, variability and FEV1, only showed a significant effect in 1/76, 1/76 and 5/76 items, respectively (P < 0.05). Taking the 76 items overall did not demonstrate significant effects for any of these factors.

7. We conclude that age, sex, FEV1, duration and variability have little influence as predictors of patients' perception of their distress due to asthma.
Glycosaminoglycan Content, Oxalate Self-Exchange and Protein Phosphorylation in Erythrocytes of Patients with ‘Idiopathic’ Calcium Oxalate Nephrolithiasis
Authors: Baggio Bruno , Marzaro Giovanni , Gambaro Giovanni , Marchini Francesco , Williams Hibbard E. , Borsatti Arturo
Published: August 2015

1. This study was performed to test the hypothesis that glycosaminoglycans may play an important role in the observed abnormalities in oxalate flux seen in patients with calcium oxalate nephrolithiasis.

2. Oxalate flux rate, erythrocyte membrane glycosaminoglycan content, membrane protein phosphorylation and effect of heparan sulphate on erythrocyte oxalate flux in vitro were studied in control subjects and patients with calcium oxalate nephrolithiasis.

3. In comparison with control subjects, renal stone-formers showed a significantly higher oxalate self-exchange, a lower erythrocyte membrane glycosaminoglycan content and a higher membrane phosphorylation rate. In stone-formers, erythrocyte glycosaminoglycan content correlated inversely with both oxalate flux rate and protein phosphorylation. In vitro, heparan sulphate promoted a significant fall in the rate of oxalate self-exchange.

4. These findings support the hypothesis that a lower erythrocyte membrane content of glycosaminoglycans enhances membrane protein phosphorylation, leading to an increased rate of transmembrane oxalate flux.
Fluoride Therapy and Parathyroid Hormone Activity in Osteoporosis
Authors: Stamp T. C. B. , Saphier P. W. , Loveridge N. , Kelsey C. R. , Goldstein A. J. , Katakity M. , Jenkins M. V. , Rose G. A.
Published: August 2015

1. To determine the relationships between parathyroid hormone activity and long-term sodium fluoride therapy in osteoporosis, cytochemical bioassays (for biologically active parathyroid hormone) were performed in 22 osteoporotic control patients and in 18 patients after 15 ± 10 months of treatment (60 mg of sodium fluoride daily). Ten patients were studied longitudinally by repeated metabolic balances and were therefore common to both groups. All patients were receiving mineral supplements.

2. Cross-sectional data showed a fourfold mean increase in biologically active parathyroid hormone on fluoride treatment (P < 0.005) together with a 51% increase in serum alkaline phosphatase (P < 0.005). Longitudinal data showed, in addition, a significant increase in the calcium balance of 2.4 ± 1.2 (sem) mmol daily (P < 0.05) and the development of a positive phosphorus balance (P < 0.02).

3. Fluoride-treated patients were then analysed in two groups according to the level of biologically active parathyroid hormone. Thirty-two per cent of values were above the upper limit of normal (18 pg/ml). The mean serum alkaline phosphatase level in this group showed no elevation above that of the control patients, the overall rise being accounted for entirely by patients with normal levels of biologically active parathyroid hormone. High levels of biologically active parathyroid hormone were also associated with relative hypophosphataemia (P < 0.01), relative hypercalciuria (P < 0.05) and an increased urine/faecal calcium ratio (P < 0.025).

4. Results show that long-term fluoride and calcium therapy increase biologically active parathyroid hormone in osteoporosis and that excessive parathyroid hormone activity may account for certain features of the refractory state.
Effects of Blood Glucose Concentration on Thermogenesis and Glucose Disposal during Hyperinsulinaemia
Authors: Gallen I. W. , MacDonald I. A.
Published: August 2015

1. The thermogenic and cardiovascular responses to glucose ingestion or infusion are altered by undernutrition. These changes may be due, in part, to alterations in the blood glucose concentration. This study investigates the effect of variation in the blood glucose concentration on the thermogenic and cardiovascular responses to a hyperinsulinaemic glucose clamp.

2. Ten healthy post-absorptive subjects (six male, aged 21–30 years) were studied on two occasions. Baseline measurements were made for 30 min, followed by a 90 min continuous insulin infusion (100 m-units min−1 m−2), during which the arterialized venous blood glucose concentration was maintained at 4.5 mmol/l (euglycaemia) or 3.5 mmol/l (mild hypoglycaemia). Measurements were made of glucose infusion rate and respiratory gas exchange from which glucose storage and oxidation and metabolic rate were calculated.

3. During the final 30 min of each hyperinsulinaemic clamp, the rates of glucose disposal (53.5 ± 1.4 versus 38.2 ± 1.0 μmol min−1 kg−1, P<0.01) and glucose storage (32.4 ± 1.1 versus 22.8 ± 1.2 μmol min−1 kg−1, P < 0.05), and the increase in metabolic rate (0.44 ± 0.08 versus 0.11 ± 0.09 kJ min, P < 0.01), were all greater with a blood glucose concentration of 4.5 mmol/l than of 3.5 mmol/l.

4. Plasma noradrenaline rose during the clamp to significantly higher levels at a blood glucose concentration of 4.5 mmol/l (1.18 ± 0.06 nmol/l) than at a blood glucose concentration of 3.5 mmol/l (1.02 ± 0.06 nmol/l, P<0.05), although the absolute changes were not significantly different (+ 0.17 ± 0.06 and +0.14 ± 0.05 nmol/l at blood glucose concentrations of 4.5 and 3.5 mmol/l, respectively). Plasma adrenaline did not change at a blood glucose concentration of 4.5 mmol/l but increased slightly (to 0.36 + 0.04 nmol/l, P<0.05) at a blood glucose concentration of 3.5 mmol/l. During hyperinsulinaemia, heart rate and forearm blood flow rose and diastolic blood pressure fell similarly (P<0.01) at both blood glucose concentrations.

5. Mild hypoglycaemia reduces the thermogenic response to glucose infusion to a greater extent than the reduction in storage, but does not alter the noradrenaline or cardiovascular responses to hyperinsulinaemia. Thus, the cardiovascular and noradrenaline responses during the infusions may be linked and dependent upon the hyperinsulinaemia, whereas some other aspect of glucose metabolism influences the thermogenic response.
Postprandial Substrate Deposition in Human Forearm and Adipose Tissues in Vivo
Authors: Coppack S. W. , Fisher R. M. , Gibbons G. F. , Humphreys S. M. , McDonough M. J. , Potts J. L. , Frayn K. N.
Published: August 2015

1. Substrate movements in forearm muscle and subcutaneous adipose tissue were studied, by measurement of arteriovenous differences and blood flow, in seven normal subjects after an overnight fast and then for 6 h after ingestion of a mixed meal. Overall substrate balances were examined in terms of the flux of gram-atoms of carbon.

2. As found previously, the forearm was approximately in carbon balance (import equal to export) after the overnight fast, whereas adipose tissue was a net exporter of carbon, mainly in the form of non-esterified fatty acids.

3. After the meal, arterialized plasma concentrations of glucose and lactate rose sharply (peak at 60 min), whereas those of non-esterified fatty acids and glycerol fell (nadir at 60–120 min). Plasma triacylglycerol concentrations rose slowly to peak at 240 min; much of this rise was accounted for by a rise in the chylomicron fraction.

4. Both tissues took up glucose at an increased rate after the meal. Release of non-esterified fatty acids and glycerol from adipose tissue was suppressed. Clearance of triacylglycerol by both tissues increased after the meal, but was more marked in adipose tissue, where the fractional extraction of chylomicron-triacylglycerol reached 44% at 240 min.

5. The forearm rapidly became a considerable net importer of carbon, and remained so until 6 h after the meal when it was again in approximate carbon balance. Glucose uptake dominated the forearm carbon balance. Adipose tissue was a net importer of carbon from 30 min until 5 h after the meal and then reverted to net export. Clearance of triacylglycerol carbon made the largest contribution to this positive balance, but towards the end of the study this was increasingly counterbalanced by simultaneous non-esterified fatty acid release.

6. Skeletal muscle plays a major role, and adipose tissue a minor one, in the disposal of ingested carbohydrate; adipose tissue plays a major role and skeletal muscle a minor one in clearance of dietary-derived triacylglycerol. The role of adipose tissue lipoprotein lipase is not, however, simply the uptake of triacylglycerol for storage within the tissue; rather, it appears to play a central role in the distribution of dietary-derived lipid energy.
Effect of Natriuretic Agents, Vasoactive Agents and of the Inhibition of Metabolism on Sodium Handling in the Isolated Perfused Kidney of the Nephrotic Rat
Authors: Firth J. D. , Ledingham J. G. G.
Published: August 2015

1. The kidney taken from a rat rendered nephrotic by exposure to puromycin aminonucleoside retains sodium abnormally when perfused in isolation and has an abnormally low vascular resistance (J. D. Firth et al., Clin. Sci. 1989; 76, 387–95). In this study the relation of oxygen consumption to sodium reabsorption has been examined in the isolated nephrotic organ, which has also been exposed to a variety of natriuretic agents and to the effect of inhibition of metabolism by cooling, in an attempt to discern the transport process, or processes, responsible for abnormal tubular handling of sodium. In addition, the effects of three endogenous vasconstrictors, noradrenaline, angiotensin II and endothelin, on the function of the isolated nephrotic kidney have been examined.

2. The ratio of mol of sodium reabsorbed by the tubules of the isolated nephrotic kidney to mol of oxygen consumed was reduced in comparison with the control kidney (means ±sem): 9.22±0.97 versus 15.43 ±1.55 (P < 0.002).

3. In the presence of ouabain (1 mmol/l), acetazolamide (1 mmol/l), frusemide (200 μmol/l), the combination of these three agents together, hydroflumethiazide (100 μmol/l), benzamil (100 nmol/l) or atrial natriuretic peptide (1000 pmol/l), a lesser increment in sodium excretion was induced in the isolated nephrotic kidney than in the control kidney and the nephrotic organ continued to excrete less sodium in both absolute and fractional terms.

4. This suggests that enhanced tubular sodium reabsorption in the isolated nephrotic kidney does not depend upon abnormally increased activity of the Na+/K+-adenosine triphosphatase, bicarbonate-dependent sodium transport, Na+/K+/2Cl− co-transport, electrically neutral proportionate reabsorption of sodium and chloride (distal tubule), epithelial sodium channel (distal tubule) or atrial natriuretic peptide-sensitive sodium transport processes.

5. When isolated nephrotic kidneys and normal kidneys were cooled to 8–10°C the handling of sodium became virtually identical in the two groups. On re-warming to 37°C, the original differences in sodium handling between nephrotic and control kidneys were restored. This implies that the mechanism responsible for the abnormal tendency to retain sodium is temperature-sensitive; as yet it remains otherwise undefined.

6. The sensitivity of the renal vessels to noradrenaline, angiotensin II and endothelin, as judged by the percentage reduction in perfusate flow rate produced by a given concentration of any of these agents, was not substantially altered in the nephrotic kidney compared with the control kidney. Increase in vascular tone was not associated with amelioration of the tendency of the isolated nephrotic organ to retain sodium. Increasing concentrations of angiotensin II caused the filtration rate to increase in the nephrotic kidney. This effect was unexpected: in the control preparation, as anticipated, angiotensin II caused the filtration rate to decrease.
Endothelin Immunoreactivity in Mice with Gram-Negative Bacteraemia: Relationship to Tumour Necrosis Factor-α
Authors: Takahashi Kazuhiro , Silva Ayona , Cohen Jonathan , Lam Hing-Chung , Ghatei Mohammad A. , Bloom Stephen R.
Published: August 2015

1. To investigate the role of endothelin in Gram-negative bacteraemia and the possible involvement of tumour necrosis factor-α in its pathophysiology, we measured plasma and tissue (lung, kidney and spleen) immunoreactive endothelin levels in Gram-negative bacteraemic mice, with and without passive immunization by anti-(tumour necrosis factor-α) antibody.

2. Plasma immunoreactive endothelin levels were greatly increased after the Escherichia coli injection. Pre-treatment with anti-(tumour necrosis factor-α) antibody did not suppress elevated plasma immunoreactive endothelin levels (P > 0.1).

3. Lung tissue immunoreactive endothelin levels in mice were increased 16 h after the E. coli injection and were not affected by prior passive immunization with anti-(tumour necrosis factor-α) antibody. Immunoreactive endothelin in spleen and kidney was undetectable (< 34 fmol/g wet weight).

4. Injection of rMu tumour necrosis factor-α into mice did not increase plasma immunoreactive endothelin levels.

5. Antibody to endothelin given 30 min after a 90% lethal dose challenge with E. coli did not affect mortality.

6. We conclude that the rise in plasma and tissue endothelin that occurs in Gram-negative bacteraemia is independent of tumour necrosis factor-α.
Effect of theophylline and dipyridamole on the respiratory response to isocapnic hypoxia in normal human subjects
Authors: Parsons S. T. , Griffiths T. L. , Christie J. M. L. , Holgate S. T.
Published: August 2015

1. Twelve healthy young men took part in this investigation of the effect of oral theophylline and dipyridamole (two drugs known to affect the pharmacological effects of the purine nucleoside adenosine) on the respiratory response to isocapnic hypoxia.

2. The subjects underwent hypoxic rebreathing manoeuvres after 3-day pretreatments with each of the drugs for 12 h and were at least 2 h postprandial. For each in-Minute ventilation, the maximum rate of isometric inspiratory pressure development at the mouth and the ratio of inspiratory duration to total breath duration were analysed breath-by-breath and regressions of these variables upon the haemoglobin oxygen saturation were performed.

3. The slopes and intercepts of the lines describing the relationships of minute ventilation and the maximum rate of isometric inspiratory pressure development at the mouth with haemoglobin oxygen saturation were unaffected by the study drugs, and no differences in the pattern of breathing were observed.

4. We conclude that oral administration of these drugs does not result in alteration of the response of the respiratory system to progressive isocapnic hypoxia.

5. This suggests that either adenosine has no physiological role in hypoxic respiratory control as measured, or that it has opposing peripheral chemoreceptor and central respiratory centre effects which could not be distinguished by the techniques used.
Influence of Neuropathy on the Microvascular Response to Local Heating in the Human Diabetic Foot
Authors: Stevens M. J. , Edmonds M. E. , Douglas S. L. E. , Watkins P. J.
Published: August 2015

1. The diabetic neuropathic foot exhibits excess arteriovenous anastomotic shunt flow due to a reduced sympathetic vasoconstrictor tone. Local axon reflexes (mediating postural vasoconstriction, for example) are preserved even in severe diabetic neuropathy. This excess shunt flow and its local neurogenic control may be important in the development of complications of the neuropathic limb.

2. The response of arteriovenous anastomoses to local heating was assessed in 13 diabetic patients with neuropathy (12 insulin-dependent), 10 diabetic control patients (seven insulin-dependent) and 10 normal control subjects. The aim was to study the local reflex control of arteriovenous flow when central sympathetic tone had been largely removed.

3. The change in skin blood flow on local heating to 44°C was measured by using a laser Doppler flowmeter in standard environmental conditions with the foot at heart level. Two sites were assessed: (i) the plantar surface of the great toe (a site in which skin blood flow is dominated by arteriovenous shunt flow) and (ii) the dorsum of the foot (a site without anastomotic flow).

4. It was found that when heat was applied to the plantar surface of the great toe in the diabetic patients with neuropathy a paradoxical decrease in flow through arteriovenous anastomoses occurred, flow declining to 65% (P < 0.05) of its resting value. This could be compared with an increase in flow over the same time period of 262% and 228% (P < 0.01) in diabetic control patients and normal subjects, respectively. When the foot dorsum was heated flow increased in a similar fashion in all patient groups, and a decline in flow was not observed.

5. Peak flow at the great toe was significantly lower in the diabetic patients with neuropathy compared with both the diabetic control patients and the normal subjects [23.68 (44.64) flow units versus 57.0 (43.92) flow units and 76.32 (40.88) flow units, respectively, medians and interquartile ranges, P < 0.02].

6. Thus we have demonstrated that in the presence of neuropathy local heating of the toe pulp may produce (i) a paradoxical fall in skin blood flow and (ii) a greatly reduced peak skin blood flow. The importance of this abnormal vascular control in the pathogenesis of complications of the neuropathic limb has now to be determined.
Long-term reproducibility of Borg scale estimates of breathlessness during exercise
Authors: Wilson Rachel C. , Jones P. W.
Published: August 2015

1. The intensity of breathlessness in normal subjects during exercise was measured on seven occasions over a 40-week study period to assess the long-term repeatability of Borg scale estimates of breathlessness.

2. In all subjects there was a significant correlation (P = 0.0001) between breathlessness and minute ventilation. Minute ventilation measured at each work rate did not differ between the seven exercise tests (P >0.05).

3. There was no significant difference between the mean Borg scores (measured with respect to a given level of ventilation) in 5 of the 7 test weeks (P >0.05). The slope of the relationship Borg score/minute ventilation did not differ between the seven exercise tests (P >0.05).

4. Breathlessness estimation was highly reproducible both after 1 week and after 40 weeks of the study (both P >0.05).

5. The duration without testing between consecutive tests did not affect reproducibility: the mean Borg score was as equally reproducible after an interval of 22 weeks without testing as after an interval of 1 week (P >0.05).

6. The Borg scale provides a reliable technique for studying the sensation of breathlessness over extended time periods.
Basal fuel homoeostasis in symptomatic human immunodeficiency virus infection
Authors: Hommes M. J. T. , Romijn J. A. , Endert E. , Schattenkerk J. K. M. Eeftinck , Sauerwein H. P.
Published: August 2015

1. In eight clinically stable symptomatic human-immunodeficiency-virus-infected patients and in seven healthy control subjects, glucose and fat metabolism were studied, using indirect calorimetry and primed continuous infusions of [3-3H]glucose and [14C]palmitate.

2. Studies were performed in the post-absorptive state (16 h of overnight fasting) and again after 22 h of overnight fasting.

3. In the post-absorptive state, net fat oxidation and triacylglycerol (‘triglyceride’) concentrations were significantly higher in the patients, but concentrations and turnover of free fatty acids were not significantly different between patients and control subjects. After 22 h of overnight fasting, free fatty acid turnover in the patients rose to significantly higher levels when compared with the control subjects.

4. Post-absorptive glucose oxidation, glucose turnover and glucose clearance did not differ between patients and control subjects. Although fasting induced a significantly greater decline in glucose turnover in the patients, plasma glucose concentrations decreased comparably in patients and control subjects.

5. No differences were found in plasma concentrations of insulin or of the counter-regulatory hormones between patients and control subjects.

6. It is concluded that the metabolic adaptation to short-term starvation in clinically stable human-immunodeficiency-virus-infected patients differs from that in healthy control subjects. Short-term starvation results in a significantly greater fall in glucose turnover, whereas fat metabolism is clearly stimulated. These alterations cannot be explained by differences in the concentrations of insulin or of the counter-regulatory hormones.
Effects of contractile activity on muscle damage in the dystrophin-deficient mdx mouse
Authors: McArdle A. , Edwards R. H. T. , Jackson M. J.
Published: August 2015

1. Isolated extensor digitorum longus muscles from control C57BL/10 and mutant dystrophin-deficient C57BL/10 mdx mice have been studied in vitro to determine whether dystrophin deficiency influences the susceptibility of muscle to contractile activity-induced damage.

2. mdx muscles were found to release reduced amounts of intracellular creatine kinase compared with control tissue in response to excessive contractile activity with or without simultaneous stretching of the muscle to 130% of its resting length.

3. In contrast, prostaglandin E2 release from mdx muscle was elevated compared with control tissue in response to either form of contractile activity or to treatment with the calcium ionophore A23187.

4. These results do not support the hypothesis that dystrophin-deficient muscle is more susceptible to damage induced by contractile activity, but suggest that dystrophin deficiency influences the activity of muscle membrane phospholipase enzymes.
Influence of the plasma protein concentration on renal function
Authors: Cumming Allan D. , Linton Adam
Published: August 2015

1. The effect of the plasma protein concentration on renal function remains controversial. Most, but not all, experimental studies suggest that a reduced plasma protein concentration perfusing the kidney may reduce tubular sodium reabsorption. Hypoproteinaemic disease states are usually associated with sodium retention, which is not always volume-dependent.

2. We induced a 21% and 24% reduction in plasma total protein and plasma albumin, respectively, in unanaesthetized sheep by acute extracorporeal plasmapheresis. Arterial pressure did not change, and changes in circulatory volume were minimised by infusion of crystalloid to maintain pulmonary artery occlusion pressure, measured using a Swann-Ganz pulmonary artery catheter.

3. After plasmapheresis, there was no significant change in creatinine clearance, sodium excretion, plasma renin activity or urinary kallikrein excretion.

4. After plasmapheresis, there was a significant reduction in plasma osmolality, increase in urine osmolality and fall in free water clearance.

5. The results suggest that in the absence of detectable changes in circulating volume or arterial pressure, acute hypoproteinaemia is associated with significant changes in renal water handling, but has no direct effect on sodium excretion or on renal release of renin and kallikrein.
Effect of α-ketoglutarate infusions on organ balances of glutamine and glutamate in anaesthetized dogs in the catabolic state
Authors: Roth E. , Karner J. , Roth-Merten A. , Winkler S. , Valentini L. , Schaupp K.
Published: August 2015

1. The salt complex of l-(+)-ornithine and α-ketoglutarate (2-oxoglutarate) has recently been proposed for the treatment of patients in the catabolic state. As yet, it is unclear which of the two substrates (ornithine or α-ketoglutarate) is responsible for the anticatabolic effect. We infused α-ketoglutarate into anaesthetized postoperative dogs in order to investigate whether infusion of α-ketoglutarate affects the flux of glutamine and glutamate between skeletal muscle and the splanchnic bed. We used three infusion rates: 3, 10 and 20 μmol min−1 kg−1. A steady state of α-ketoglutarate concentration in arterial whole-blood was attained only when the infusion rate was 3 μmol min−1 kg−1.

2. Arterial whole-blood concentrations of α-ketoglutarate were 8.8 ± 1.2 μmol/l in the basal period and rose to 208 ± 41, 344 ± 61 and 1418 ± 315 μmol/l after 60 min infusions of α-ketoglutarate at 3, 10 and 20 μmol min−1 kg−1, respectively.

3. α-Ketoglutarate uptake was measured in skeletal muscle, liver, gut and kidneys in the basal period and during the infusion of α-ketoglutarate. The net uptake of infused α-ketoglutarate was highest in the skeletal muscle, followed by kidneys, liver and gut.

4. The α-ketoglutarate load increased the muscular tissue content of α-ketoglutarate from 49.5 ± 5 to 142 ± 15 nmol/g of dry substance (P < 0.001), but did not alter the muscular glutamate or glutamine contents.

5. Infusion of α-ketoglutarate had no effect on the plasma glutamine concentration, nor on the glutamine and glutamate balances across the skeletal muscle, liver and gut. However, α-ketoglutarate infusion significantly reduced the renal extraction of glutamine (P < 0.05) and enhanced the renal production of glutamate (P < 0.05).

6. We conclude that an intravenous α-ketoglutarate load affects the renal balances of glutamine and glutamate, but does not alter the nitrogen flux of glutamine and glutamate between skeletal muscle, liver and gut.