bluuebunny/crossref_metadata_2025 huggingface dataset:
Flow Motion in Peripheral Diabetic Neuropathy
Authors: Benbow S. J. , Pryce D. W. , Noblett K. , MacFarlane I. A. , Friedmann P. S. , Williams G.
Published: August 2015

1. Flow motion is the cyclical variation in blood flow owing to the rhythmical opening and closing of arterioles. Previous studies have suggested that cutaneous flow motion may be altered in diabetic neuropathy but have not been consistent in their findings.

2. In order to assess the effect of diabetic peripheral neuropathy on flow motion, we have examined the frequency and amplitude of flow motion in 12 patients with diabetic peripheral neuropathy, 10 age-matched diabetic patients without peripheral neuropathy and 10 age-matched non-diabetic controls.

3. Peripheral neuropathy was diagnosed by a history of foot ulceration or chronic painful neuropathy, clinical examination and abnormal peroneal nerve conduction velocities. Blood flow, using laser Doppler flowmetry, was measured at four sites on the dorsum of both hands and feet. Flow motion was analysed using fast Fourier transform analysis, between 0.05 and 0.2 Hz, and displayed on a power spectral density graph. Predominant frequency and relative amplitude of flow motion were calculated.

4. Relative amplitude and frequency of flow motion were similar in the hands of all three groups, as was the frequency in the feet of the three groups. Relative amplitude was significantly smaller in the feet of diabetic patients with neuropathy (median 7.2%, 95% confidence interval 4.9–9.4%) than in diabetic patients without neuropathy (median 13.5%, 95% confidence interval 6.3–21.5%, P < 0.02) or in non-diabetic control subjects (median 10.3%, 95% confidence interval 6.9–27.4%, P < 0.02).

5. Flow motion amplitude is reduced in diabetic peripheral neuropathy. The control of flow motion amplitude appears to be at least partly under neurological control.
Insulin Unresponsiveness of Tubular Monovalent Cation Transport during Fructose-Induced Hypertension in Rats
Authors: Féraille Eric , Marsy Sophie , Barlet-Bas Catherine , Rousselot Martine , Cheval Lydie , Favre Herve , Doucet Alain
Published: August 2015

1. Hyperinsulinaemia is considered to be a pathogenic factor for human and experimental hypertension. Thus, the contribution of the known insulin-stimulated tubular sodium reabsorption to this aetiological process has to be discussed.

2. Rats fed a fructose-enriched diet develop hyperinsulinaemia and hypertension, providing a model for studying the regulation of the tubular sodium handling and its possible relationship to hypertension. For this purpose, the sodium transport capacity of isolated nephron segments from control rats and from rats fed a fructose-enriched diet was investigated by measurement of ouabain-sensitive 86Rb uptake and of the hydrolytic activity of Na,K-ATPase. The number and affinity of insulin receptors were estimated from the specific [125I]insulin binding.

3. In rats fed a fructose-enriched diet, mild hypertension developed during the 14-day fructose diet. There were no differences, along the nephron, in basal 86Rb uptakes and ATPase activities between control rats and fructose-induced hypertensive rats. In control rats, insulin stimulated 86Rb uptake in the proximal convoluted tubule and cortical collecting duct, but exhibited an inhibitory action in the medullary thick ascending limb. In contrast, in fructose-induced hypertensive rats, 86Rb influx remained unresponsive to insulin concentrations ranging from 10−11 to 10−7 mol/l in the proximal convoluted tubule and cortical collecting duct. In the medullary thick ascending limb, the threshold of inhibition was displaced from 10−11 mol/l up to 10−7 mol/l. Insulin binding to the proximal convoluted tubule, medullary thick ascending limb and collecting duct were similar in control rats and in rats fed a fructose-enriched diet.

4. We conclude that hypertension developed in rats fed a fructose-enriched diet regardless of change in renal sodium handling since (1) the basal tubular sodium reabsorption capacity of the nephron remained unchanged and (2) the response of the tubular cation transport to insulin was abolished. These results strongly argue against the participation of insulin-mediated tubular sodium retention in the pathogenesis of hypertension and suggest that insulin-related mechanisms modulate the blood vessel reactivity.
Development of Decreased Insulin-Induced Glucose Transport in Skeletal Muscle of Glucose-Intolerant Hybrids of Diabetic GK Rats
Authors: Nolte Lorraine A. , Abdel-Halim Samy M. , Martin Iva K. , Guenifi Amel , Zierath Juleen R. , Östenson Claes-Göran , Wallberg-Henriksson Harriet
Published: August 2015

1. The effect of glucose intolerance on insulin-stimulated glucose transport in isolated skeletal muscles was investigated in male F, hybrids of spontaneously diabetic GK (Goto—Kakizaki) and control Wistar rats at 1 and 2 months of age.

2. Hybrid rats are characterized by markedly impaired glucose-induced insulin secretion. The area under the blood glucose curve was significantly higher following an intraperitoneal glucose injection (2 g/kg) in hybrid rats in both age groups than in the control rats (P < 0.001). In 2-month-old hybrid rats the incremental area under the insulin curve during the intraperitoneal glucose tolerance test was not different from that of control rats. Serum cholesterol, triacylglycerol or plasma free fatty acid levels did not differ between the groups. Fasting and post-prandial plasma glucose concentrations were elevated in 2-month-old hybrid rats compared with control rats (54%, P < 0.05, and 27%, P < 0.05, respectively), but were not differerent in 1-month-old rats. Plasma insulin did not differ between the hybrid and control rats in the fasting or post-prandial state at either age studied.

3. The insulin dose—response curves for 3-O-methylglucose transport did not differ between 1-month-old hybrid and control rats for either the soleus or epitrochlearis muscle. The insulin dose—response curve for the epitrochlearis, but not for the soleus, muscle from 2-month-old hybrid rats was shifted to the right compared with the curve from the control animals (P < 0.05).

4. In conclusion, the hybrid rat is a non-obese, non-hyperinsulinaemic animal model, which at a young age is characterized by impaired insulin secretion and moderate glucose intolerance. In this glucose-intolerant rat model, mild peripheral insulin resistance gradually develops, as reflected by the decreased insulin-induced glucose transport in the fast-twitch epitrochlearis muscle. It is suggested that the elevated blood glucose per se may have contributed to the slight decrease in peripheral insulin action.
Dual-Energy X-Ray Absorptiometry Measurements of Body Composition: Effects of Depth and Tissue Thickness, Including Comparisons with Direct Analysis
Authors: Jebb Susan A. , Goldberg Gail R. , Jennings Graham , Elia Marinos
Published: August 2015

1. There are few data regarding the accuracy of Hologic QDR-1000W dual-energy X-ray absorptiometry for the measurement of body composition. In two studies, one in an in vitro experimental system using oil and water mixtures and the other in samples of pork meat, the effect of depth and tissue thickness on the measured composition was assessed. In the latter study the measured fat mass was compared with that measured by direct analysis.

2. All data indicated a trend in the measured fat mass with depth, such that more fat was measured at extremes of depth (<10 cm and >25 cm) than at intermediate depths.

3. In samples of meat weighing approximately 55 kg, dual X-ray absorptiometry significantly underestimated the absolute fat mass compared with direct analysis (mean 20.4 ± 1.65%) by 5–8% or 1–4 kg of fat.

4. These findings are of direct relevance to both clinical and research work using this technique to measure body composition, in particular in circumstances in which changes in body composition and/or tissue thickness are anticipated.
Effect of Fenspiride on Pulmonary Function in the Rat and Guinea Pig
Authors: Bee D. , Laude E. A. , Emery C. J. , Howard P.
Published: August 2015

1. Fenspiride is an anti-inflammatory agent that may have a role in reversible obstructive airways disease. Small, but significant, improvements have been seen in airways function and arterial oxygen tension in patients with mild chronic obstructive pulmonary disease. These changes have been attributed to the anti-inflammatory properties of the drug. However, airways function can be improved by other means, e.g. improved ventilation/perfusion ratio or reduced airways resistance. The possibility that fenspiride may have actions other than anti-inflammatory was investigated in two animal species.

2. In the rat, actions on the pulmonary circulation were investigated in the isolated perfused lung, but fenspiride proved to be a poor pulmonary vasodilator, showing only a small reversal of the raised pulmonary artery pressure induced by hypoxia.

3. Ventilation was measured in the anaesthetized rat using whole-body plethysmography. Fenspiride caused no increase in ventilation or changes in arterial blood gases. However, a profound hypotensive action was observed with high doses.

4. The possibility that a decrease in airways resistance (Raw) might occur with fenspiride was investigated in anaesthetized guinea pigs. Capsaicin (30 μmol/l) was used to increase baseline Raw through bronchoconstriction. Fenspiride gave a dose-dependent partial reversal of the raised Raw, and its administration by aerosol proved as efficacious as the intravenous route. In addition, the hypotensive side-effect found with intravenous injection was alleviated by aerosolized fenspiride.

5. An anti-bronchoconstrictor action of fenspiride could be one of the mechanisms involved in improving airways function and Pao2, seen in mild chronic obstructive pulmonary disease.
Cigarette Smoke Stimulates Release of Neutrophil Chemotactic Activity from Cultured Bovine Bronchial Epithelial Cells
Authors: Shoji Shunsuke , Ertl Ronald F. , Koyama Sekiya , Robbins Richard , Leikauf George , Von Essen Susanna , Rennard Stephen I.
Published: August 2015

1. Recruitment of neutrophils into the airway is a prominent feature of chronic bronchitis, a syndrome often associated with exposure to cigarette smoke. Since bronchial epithelial cells are the ‘first’ lung cells to come into contact with smoke, these cells may be responsible for neutrophil recruitment into the airway by release of neutrophil chemotactic activity in response to cigarette smoke.

2. To evaluate this hypothesis, we prepared bovine bronchial epithelial cells and measured their ability to release neutrophil chemotactic activity following exposure to cigarette smoke. Bronchial epithelial cells were prepared by overnight digestion with protease, filtered through 100-μm Nitex mesh and resuspended in Dulbecco's modified Eagle medium supplemented with 10% fetal calf serum and antibiotics and cultured at 2×106 cells in 2 ml of medium in 35-mm culture dishes. After 4 days, dishes were rinsed and refed with medium without fetal calf serum and incubated with and without 1:10 diluted smoke extract for 6 h at 37°C. The neutrophil chemotactic activity of the supernatant fluids was measured by the blindwell chamber technique.

3. Cigarette smoke itself added to medium did not stimulate chemotaxis. In contrast, cigarette smoke did stimulate the release of neutrophil chemotactic activity from bovine bronchial epithelial cells [15 ± 3 (control) versus 74 ± 5 (smoke), P < 0.01].

4. This neutrophil chemotactic activity was dialysable, pepsin and acid stable, heat sensitive and lipid extractable. Sephadex G-75 column chromatography demonstrated two peaks of neutrophil chemotactic activity.

5. The lipoxygenase inhibitors diethylcarbamazine and nordihydroguaratic acid both diminished the release of chemotactic activity, suggesting that the activity may be a lipoxygenase product(s).

6. Dibutyryl cyclic AMP also blocked the smoke-stimulated release of neutrophil chemotactic activity, suggesting that its release may be regulated by intracellular cyclic AMP.

7. Thus, bovine bronchial epithelial cells release neutrophil chemotactic activity in response to cigarette smoke, suggesting that bronchial epithelial cells may be modulators of the airway inflammatory response caused by cigarette smoke.
Hering—BreüEr Reflexes in High-Altitude Infants
Authors: Mortola J. P. , Trippenbach T. , Rezzonico R. , Fisher J. T. , Diaz M. , Villena-Cabrera N. , Peña F.
Published: August 2015

1. Pulmonary ventilation was found to be similar in high-altitude and low-altitude newborn infants, but the breathing pattern was deeper and slower at high altitude (Mortola, J. P., Frappell, P. B., Frappell, D. E., Villena-Cabrera, N., Villena-Cabrera, M., Peña, F., Am Rev Respir Dis 1992, 46: 1206–9). We questioned the contribution of vagal reflexes to these differences in breathing pattern.

2. Measurements were performed on high-altitude (La Paz, Bolivia, 3600–4050 m, inspired O2 pressure ∼92 mmHg, n = 34) and low-altitude infants (Santa Cruz, Bolivia, 400 m, Pio2 ∼141 mmHg, n = 26). The strength of the Hering—Breüer inspiratory inhibitory reflex was estimated from the inspiratory time during a respiratory effort against airways closed at end-expiration (TIoccl). The strength of the Hering—Breüer expiratory facilitatory reflex was estimated from the expiratory duration when airways were occluded during expiration (TEoccl).

3. TIoccl was significantly longer than the open-airways TI at both low and high altitude, but significantly more so (∼14%) at high altitude. TEoccl was longer than open-airways TE in both groups of infants, but significantly less so at high altitude, whether TEoccl was compared between occlusions of similar tidal volume (on average, TEoccl at high altitude was 79% of that at low altitude) or similar airway pressure (87%).

4. The results suggest that at high altitude the contribution of the phasic volume-dependent vagal input to the inspiratory off-switch threshold is higher, and that the tonic vagal expiratory facilitation is lower, than at low altitude, presumably because of hypoxia. The larger VT and longer TE of the HA infant cannot be explained by these differences in vagal pulmonary reflexes.
Metabolic Acidosis is a Potent Stimulus for Cellular Inorganic Phosphate Generation in Uraemia
Authors: Bevington Alan , Brough Dennis , Baker Frease E. , Hattersley Jane , Walls John
Published: August 2015

1. During metabolic acidosis, significant fluxes of inorganic phosphate (Pi) may occur from cellular to extracellular fluid. In this study Pi was measured in erythrocytes of uraemic patients before and after haemodialysis and was related to their plasma pH (acidosis), plasma Pi (hyperphosphataemia) and cellular organic phosphate concentrations.

2. Before dialysis, the ratio of cellular to extracellular Pi concentration correlated inversely with plasma pH, increasing 2.5-fold as pH fell from 7.4 to 7.2.

3. An increase in cellular Pi similar to that seen in the patients was observed within 90 min of adding acid to normal erythrocytes in vitro.

4. The total Pi content of the cell suspension increased 25% on decreasing plasma pH from 7.4 to 7.2, largely as a result of generation of Pi from 2,3-bisphosphoglycerate in the cells. This was accompanied by net efflux of Pi into plasma.

5. In addition, the increase in the steady-state cellular Pi concentration on adding a constant extracellular Pi load was 50% greater at pH 7.2 than at 7.4, implying that alterations in the regulation of the transmembrane Pi gradient also contribute to the rise in cellular Pi observed at low pH.

6. At normal plasma Pi concentration (1 mM), glycolytic flux (lactate production) was inhibited by 20% when pH was lowered from 7.4 to 7.2. However, this inhibition was blocked when cellular Pi was increased by adding Pi to the plasma in vitro.

7. Metabolic acidosis is therefore a potent stimulus for Pi generation in erythrocytes, and this Pi may serve to stimulate glycolysis which is normally inhibited by low pH.
Comparison of Intraperitoneal and Subcutaneous Insulin Administration on Insulin Sensitivity and Serum Lipids in Type I Diabetic Patients on Continuous Ambulatory Peritoneal Dialysis Treatment
Authors: Lahtela Jorma T. , Mustonen Jukka , Pasternack Amos
Published: August 2015

1. The metabolic effects of intraperitoneal and subcutaneous insulin delivery were compared in a crossover manner in six C-peptide-negative diabetic patients with end-stage renal disease on continuous ambulatory peritoneal dialysis. Each treatment period lasted at least 3 months. Hyperinsulinaemic euglycaemic clamp was performed and glucose turnover assessed using [3-3H]glucose as a tracer.

2. During intraperitoneal delivery the daily insulin dose was 2.4 times higher than during subcutaneous administration and glycaemic control was significantly better (HbA1c 7.63% ± 0.46% and 9.52% ± 0.51% during intraperitoneal and subcutaneous insulin respectively, P < 0.01). The number of hypoglycaemic episodes was lower during intraperitoneal insulin than during subcutaneous therapy.

3. Intraperitoneal insulin resulted in an enhanced glucose disposal rate (P < 0.01) and reduced fasting hepatic glucose production (P < 0.01). High-density lipoprotein-cholesterol decreased and the ratio of low-density lipoprotein/high-density lipoprotein-cholesterol increased significantly (P < 0.05) during intraperitoneal insulin delivery.

4. The results suggest that intraperitoneal insulin, while resulting in better glycaemic control and improved insulin sensitivity than subcutaneous insulin, increases serum triacylglycerol and total cholesterol and reduces high-density lipoprotein-cholesterol, possibly via a direct effect on the liver.
Is Voluntary Control of Breathing Impaired in Patients with Chronic Obstructive Pulmonary Disease?
Authors: Cohen Eytan , Murphy Kevin , Adams Lewis , Guz Abraham , Benchetrit Gila
Published: August 2015

1. To assess whether voluntary control of breathing is impaired in patients with chronic obstructive pulmonary disease, a group of such patients performed a tracking task, requiring volitional control of respiratory muscles.

2. Eight patients (mean age 60 years; mean ratio of forced expiratory volume in 1 s to forced vital capacity = 31%) took part in the study. Five of the seven patients in whom blood gas measurements were made were mildly hypoxaemic (Pao2 = 53–71 mmHg), and one of these was hypercapnic (Paco2 = 55 mmHg). Each subject performed a compensatory ventilatory tracking task using a tracking system which comprised a fixed target displayed on a monitor screen and a cursor moving in a line bisecting the target. The position of the cursor was perturbed by a forcing function and patients were required to keep the cursor on the target by breathing in and out of a spirometer.

3. To allow for any non-specific deficiency in motor control, patients performed a similar manual tracking task, using their dominant arm to move a joystick. As a control group, 11 healthy subjects (mean age 58 years; mean ratio of forced expiratory volume in 1 s to forced vital capacity = 77%) underwent an identical experimental protocol.

4. Motor control performances were measured in terms of the error between the target position and the subject's positioning of the cursor. Indices of performance were the root mean square of the error and the averages of the zero errors (i.e. end expiration/arm movement towards the trunk) and the peak errors (i.e. end inspiration/arm movement from the trunk).

5. For manual tracking, patients with chronic obstructive pulmonary disease, were not significantly different from control subjects in terms of mean root mean square (69.3 versus 60.9), mean zero error (93.8 versus 72.2) or mean peak error (99.5 versus 82.7). For ventilatory tracking, mean root mean square was significantly higher in patients (83.4 versus 65.9). This was due to a significantly higher mean zero error (101.4 versus 66.1); mean peak error was not significantly different (68.3 versus 82.1). Comparison of flows achieved during ventilatory tracking with those possible during a maximal forced expiratory manoeuvre in the patients suggested that poor expiratory control in this group could be explained by their degree of airflow limitation rather than a deficiency in motor control per se.

6. These results provide no evidence that patients with chronic obstructive pulmonary disease have any impairment in their voluntary motor control of breathing.
Human Skeletal Muscle Protein: Effect of Malnutrition, Elective Surgery and Total Parenteral Nutrition
Authors: Petersson Benny , Hultman Eric , Andersson Kerstin , Wernerman Jan
Published: August 2015

1. The concentration of alkali-soluble protein, DNA and RNA in percutaneous muscle biopsy specimens was analysed. Tissue alkali-soluble protein/DNA ratio is a measure of muscle protein concentration, while tissue RNA/DNA ratio may reflect the capacity for protein synthesis.

2. Patients with weight loss due to cancer (n = 6) were compared with metabolically healthy patients before elective surgery (n = 7). Alkali-soluble protein/DNA and RNA/DNA ratios in the weight loss group were 248 (14) g/g and 1.3 (0.1) g/g respectively as compared with 404 (13) g/g and 2.1 (0.1) g/g in otherwise healthy patients. All of the alkali-soluble protein/DNA ratios and 5/6 of the RNA/DNA ratios in the weight loss group were below the 95% confidence interval for the healthy control subjects.

3. Patients undergoing elective open cholecystectomy (n = 7) were studied preoperatively and on days 3, 10, 20 and 30 post-operatively. The alkali-soluble protein/DNA ratio remained unchanged on postoperative day 3 but decreased by 8.7% (P < 0.01), 9.6% (P < 0.05) and 20.4% (P < 0.01) on days 10, 20 and 30 respectively in patients eating at will after the operation. No significant post-operative changes in alkali-soluble protein/DNA ratio were seen in patients given post-operative total parenteral nutrition with (n = 9) or without (n = 7) glycyl-glutamine supplementation for 3 days after surgery.

4. In conclusion, patients with weight loss due to malignant disease have a low muscle protein concentration. Elective surgery of medium magnitude results in a decrease in muscle protein lasting for more than 30 days. This is in contrast to patients receiving post-operative total parenteral nutrition, in whom no significant reduction in muscle protein was noted following surgery regardless of whether or not the total parenteral nutrition was supplemented with glutamine.
Adriamycin-Related Hypertension in Pregnant Rats: Response to a Thromboxane Receptor Antagonist
Authors: Rathaus Mauro , Podjarny Eduardo , Pomeranz Avishalom , Green Janice , Bernheim Jacques
Published: August 2015

1. In previous works we have described the development of hypertension and aggravation of proteinuria in rats who became pregnant after the administration of Adriamycin. This was associated with an increase in the glomerular thromboxane B2—prostaglandin E2 ratio.

2. To assess the pathogenetic role of thromboxane in this model, female Wistar rats were mated 2 weeks after receiving Adriamycin (3.5 mg/kg intravenously). Rats were then treated with the thromboxane-receptor antagonist daltroban, 60 mg day−1 kg−1 orally, beginning on day 11 of pregnancy. Systolic blood pressure, proteinuria and the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1α and prostaglandin E2 were measured serially before mating, and on days 14 and 21 of pregnancy. The results were compared with those in Adriamycin-(treated) pregnant rats not treated with daltroban, Adriamycin-treated virgin rats and normal virgin or pregnant rats either treated or untreated with daltroban.

3. In daltroban-treated pregnant and virgin rats treated with Adriamycin, systolic blood pressure remained normal, whereas it increased significantly (P < 0.05) in untreated animals. On day 14, blood pressure was higher in non-daltroban-treated Adriamycin-treated pregnant rats than in non-daltroban-treated Adriamycin-treated virgin rats. Treatment had no effect on blood pressure in normal virgin or pregnant rats. Proteinuria was higher in pregnant rats treated with Adriamycin than in Adriamycin-treated virgin rats, but it was not reduced by daltroban. Urinary thromboxane B2 tended to increase in Adriamycin-treated virgin rats and was significantly higher than in the other groups at the period corresponding to end-pregnancy, whereas in Adriamycin-treated pregnant rats thromboxane B2 was not significantly increased. Daltroban did not change the urinary excretion of thromboxane B2, whereas urinary 6-keto-prostaglandin F1α increased significantly.

4. We conclude that elevation of blood pressure after Adriamycin in rats is mediated by thromboxane B2/endoperoxide receptors. This suggests a further analogy, in this model, with one of the pathogenetic mechanisms of pregnancy-related hypertension.
Effects of Exercise and Nitrates on Blood Flow in Internal Mammary Artery to Coronary Artery Grafts: A Non-Invasive Study
Authors: Mauric Andrea , Samani Nilesh J. , de Bono David P.
Published: August 2015

1. The aim of the present study was to investigate the effects of exercise and of sublingual glyceryl trinitrate on the pattern of blood flow, as studied by Doppler ultrasound, in internal mammary artery grafts performed to relieve severe stenosis of the left anterior descending coronary artery. The accessibility of the graft to transcutaneous ultrasound examination allows the effects of exercise and nitrate administration on coronary blood flow to be studied non-invasively.

2. Angina-free patients with left internal mammary to left anterior descending coronary artery grafts were studied using transcutaneous duplex ultrasound at rest, after leg exercise and after sublingual administration of 0.5 mg or 1 mg of glyceryl trinitrate.

3. Resting graft blood flow showed a biphasic pattern, with forward flow in both systole and diastole. Exercise caused an increase in time-averaged velocity of graft blood flow from 17.3 (3.3) to 24.0 (7.2) cm/s (P = 0.001), and of calculated volume flow from 44.7 (3.08) to 59.8 (5.89) ml/min (P = 0.002). Diastolic peak velocity increased from 36.1 (9.9) cm/s to 46.8 (16.2) cm/s (P = 0.04), while peak systolic velocity was unchanged. Nitrate administration caused a fall in systolic and diastolic blood pressure and an increase in heart rate; graft flow was maintained [time-averaged velocity 18.3 (6.2) cm/s before and 16.7 (5.7) cm/s after 500 μg of glyceryl trinitrate], but systole was shortened and the proportion of blood flow in diastole increased [systolic/diastolic flow ratio 0.558 (0.139) before and 0.374 (0.156) after 500 μg of glyceryl trinitrate, P = 0.01].

4. Doppler ultrasound examination of internal mammary artery to coronary artery grafts is one of the few ways in which physiological changes in coronary flow can be assessed non-invasively in human subjects. Exercise-induced increases in graft flow involve both increased graft distension in systole and increased run-off in diastole — the elasticity of internal mammary artery grafts may be important in sustaining an exercise-induced increase in graft flow. Limitations of the technique include the difficulty of accurately measuring graft diameter, the possibility of flow through persisting connections between the graft and chest wall vessels and competing flow from the native circulation.
Down-Regulation of Vasopressin VlA Receptor mRNA in Diabetes Mellitus in the Rat
Authors: Phillips Paddy A. , Risvanis John , Hutchins Anne-Marie , Burrell Louise M. , MacGregor Duncan , Gundlach Andrew L , Johnston Colin I.
Published: August 2015

1. To investigate the mechanism of hepatic V1a vasopressin receptor down-regulation in streptozotocin-induced diabetes mellitus in the rat, we measured hepatic V1a receptor mRNA by in situ hybridization histochemistry using oligonucleotide probes to the V1a receptor and Northern blotting.

2. Diabetes mellitus caused hyperglycaemia, hyperosmolality and increased plasma vasopressin concentrations (P < 0.01). Hepatoycte V1a receptor mRNA was reduced by 76% in diabetic rats (P < 0.01) and by 53% in insulin-treated diabetic rats (P < 0.01) versus control rats, in parallel with reduced V1a radioligand binding and vasopressin-stimulated inositol phosphates production. There was a similar decrease in hepatic V1a/18S mRNA density ratio in the diabetic and diabetic + insulin groups (both P < 0.05 versus control).

3. These findings suggest that altered V1a mRNA transcription is responsible for the reduced hepatic V1a receptor density in diabetes mellitus.
Renal Handling of Lithium and the Effects of Mannitol and Arginine Vasopressin in man
Authors: Noormohamed Faruq H. , Lant Ariel F.
Published: August 2015

1. A study has been undertaken in six healthy male subjects to clarify whether post-proximal segments of the nephron contribute to the renal handling of lithium under conditions of maximal forced osmotic load diuresis and arginine vasopressin-induced antidiuresis. Increments in the fractional clearance of free water, as a measure of effect at the proximal tubule, were positively correlated with incremental changes in flow rate, factored for glomerular filtration rate (mean r = 0.80 ± 0.12, P < 0.001), and fractional excretion of lithium (mean r = 0.84 ± 0.06, P < 0.001). Changes in flow rate and fractional excretion of lithium were also closely correlated with one another (mean r = 0.81 ± 0.06, P < 0.001), and the mean slope of these regression lines was not significantly different from unity (1.18; 95% confidence interval 0.76–1.59). These results show that, under conditions of maximal hydration, mannitol-induced changes in proximal tubular function were closely correlated with induced changes in the fractional excretion of lithium.

2. Infusion of arginine vasopressin alone (0.5 m-units/min) caused a marked reduction in both fractional clearance of free water (10.7% ± 1.2% to −1.2% ± 0.2%, P < 0.001) and flow rate factored for glomerular filtration rate (14.0 ± 1.5 to 0.8 ± 0.2%; P < 0.001) while the fractional excretion of lithium showed only a small non-significant decrease (25.3% ± 2.0% to 23.3% ± 2.2%). A similar dissociation was noted between fluid and lithium excretion when arginine vasopressin was superimposed on mannitol infusion with reductions in the fractional clearance of free water (12.7% ± 1.0% to −0.9% ± 0.7%, P < 0.001) and flow rate (18.6% ± 1.5% to 5.7% ± 1.0%; P < 0.001), while the fractional excretion of lithium showed a significant increase (28.4% ± 1.7% to 33.1% ± 2.4%; P < 0.05). The lack of correlation between fluid and lithium excretion, in the presence of arginine vasopressin with or without mannitol, indicates that the late distal tubule and collecting duct have little or no significant capacity to reabsorb lithium.

3. These findings, taken as a whole, strengthen the view that renal tubular handling of lithium is primarily a proximal event.
Longitudinal Studies of Platelet Cyclic AMP during Healthy Pregnancy and Pregnancies at Risk of Pre-Eclampsia
Authors: Horn E. H. , Cooper J. A. , Hardy E. , Heptinstall S. , Rubin P. C.
Published: August 2015

1. Platelet behaviour in vitro in relation to cyclic AMP was studied longitudinally during pregnancy and in the same women when they were not pregnant. Subjects comprised a group of healthy primigravidae and a group of women deemed at risk of pre-eclampsia, on the basis of a previous history of the condition.

2. There was a progressive decline during pregnancy in sensitivity of platelets to inhibition of the arachidonic acid-induced release reaction by agents which act via cyclic AMP. This effect was maximum at 36 weeks' gestation.

3. Basal platelet cyclic AMP levels, and those in the presence of a phosphodiesterase inhibitor, did not change throughout the period of the study.

4. By contrast, platelet cyclic AMP accumulation in response to a variety of adenylate cyclase stimulators was reduced from early pregnancy, throughout the gestational period, compared with post-natally. This effect was noted when platelets were incubated with prostaglandins acting via different surface receptors or with forskolin and was most marked on co-incubation with a phosphodiesterase inhibitor.

5. Compared with healthy women, platelets from women with a previous history of pre-eclampsia tended to accumulate less cyclic AMP in response to adenylate cyclase stimulators. This was the case both during pregnancy and post-natally. Further investigation of adenylate cyclase activity in platelets in relation to pre-eclampsia is required.
Insensitivity of the HEring—Breüer Reflex to Spontaneous Changes in Metabolic Rate in the Infant
Authors: Mortola Jacopo P. , Saiki Chikako , Fox Gordon
Published: August 2015

1. In infants, metabolic rate is highly variable. We investigated whether the strength of the vagal ventilatory inhibitory reflex was modified by the spontaneous changes in metabolic rate.

2. In 20 2-day-old infants, we measured the intensity of the Hering—Breüer expiratory-promoting reflex (inhibition of breathing during maintained lung inflation), the inspired and expired O2 and minute ventilation (V̇E), from which oxygen consumption (V̇o2) was calculated. The measurements were performed twice, a few hours apart [6 ± 1 h SEM)].

3. On average, V̇o2 differed by 39 ± 7% between the two measurements, with no correlation with the time of the day (morning/afternoon) or the time interval from a meal. V̇E was also significantly higher (19 ± 6%) when V̇o2 was higher, because of a larger tidal volume. The Hering—Breüer reflex (quantified as the apnoea time during lung inflation, either the absolute value or normalized by the airway pressure or lung volume) did not differ significantly between the two tests (<5% difference, P > 0.05), and did not correlate with the changes in V̇o2 or V̇E.

4. We conclude that, in the infant, pulmonary vagal inhibition is not sensitive to changes in metabolic drive, presumably because of the low ventilatory chemosensitivity of the newborn.
Biliary Excretion of Chylomicron Remnant Cholesterol in the Rat: Responses to the Expansion of Their Plasma Pool and Promoting Role of Stimulated Bile-Acid Synthesis
Authors: Carrella Massimino , Csillaghy Annalisa , de Mercato Renato , D'Arienzo Agesilao
Published: August 2015

1. Chylomicron remnants, the intermediate intestinal lipoproteins carrying the bulk of dietary cholesterol, are actively taken up and degraded in the hepatocytes, releasing cholesterol which can be excreted in bile. To study this pathway, a mass of remnants, leading to a consistent rise in hepatic cholesterol, was administered as an intravenous bolus in rats with chronic bile fistula equilibrated by water, electrolyte and taurocholate infusions, and changes in biliary lipids and bile acids were evaluated for up to 24 h in comparison with baseline.

2. A mean 16% increase in the net output of bile acids was observed at each time interval after lipoprotein injection, accounting for a 24 h cumulative excretion of approximately one-third of the administered cholesterol mass. These changes did not reach statistical significance however. The cholesterol output and concentrations of all biliary lipids did not vary either. Without taurocholate replacement, remnants injection was followed by a 15–20% decrease in bile acid and bile lipid secretion, presumably due to an insufficient hepatic bile-acid flux.

3. When [3H]cholesterol-labelled remnants were administered at the same mass in the chronic equilibrated bile fistula model, 21% of injected radioactivity was excreted in 24 h, distributing mostly in acidic rather than neutral sterols (20.02 ± 1.85 compared with 1.07 ± 0.04), with an acidic to neutral sterol mean ratio of 16.

4. To exclude interfering effects from the administered cholesterol mass and chronic bile fistula, 3H-labelled remnants were also studied as a cholesterol trace injected in rats with acute bile fistula. In this case, however, 24 h total sterol radioactivity only reached approximately 10% of that injected, and partitioned relatively less in acidic (6.84 ± 0.59) than in neutral (3.15 ± 0.39) sterols, with an acidic to neutral sterol mean ratio of 2.

5. The study suggests that remnant cholesterol reaches bile mainly in the form of bile acids, by a steady slow-rate process which is magnified under conditions of stimulated bile-acid synthesis.
Human Gastrin and Vasoactive Intestinal Polypeptide Responses to Endurance Running in Relation to Training Status and Fluid Ingested
Authors: MacLaren D. P. , Raine N. M. , O'Connor A. M. , Buchanan K. D.
Published: August 2015

1. Plasma concentrations of gastrin, glucose, vasoactive intestinal polypeptide and non-esterified fatty acid were analysed in six male endurance runners and six male hockey players before, during and 15 min after 90 min treadmill running at 65% maximum oxygen uptake under two conditions: no fluid ingestion (trial A) and ingestion of 8% maltodextrin solution (trial B).

2. Exercise resulted in significantly elevated plasma gastrin concentrations compared with resting values in both groups after trial A (endurance runners, 69.4 ng/l; hockey players 71.4 ng/l) and trial B (endurance runners, 105.5 ng/l; hockey players, 83.2 ng/l). The gastrin response was not significantly different between the trials.

3. Plasma vasoactive intestinal polypeptide levels increased significantly beyond resting levels for both groups during trial A (endurance runners, 76.1 ± 53.7 ng/l; hockey players 155.6 ± 41.9 ng/l) and trial B (endurance runners 47.5 ± 21.3 ng/l; hockey players 132.9 ± 43.9 ng/l). The vasoactive intestinal polypeptide response to trial B was significantly attenuated compared with trial A.

4. There were no significant differences between endurance runners and hockey players for plasma gastrin, although hockey players produced significantly elevated concentrations of plasma vasoactive intestinal polypeptide after both trials compared with endurance runners.

5. Plasma glucose levels throughout trial B were significantly greater than after trial A irrespective of the group. Plasma glucose concentrations were not significantly different between endurance runners and hockey players.

6. Plasma non-esterified fatty acid concentrations rose significantly for both groups throughout exercise. Trial B resulted in an attenuated non-esterified fatty acid response compared with trial A.

7. No significant relationships were identifed between metabolite and gastrointestinal hormone concentrations, or between maximum oxygen uptake and the hormonal response to exercise.

8. These results highlight the attenuating role of carbohydrate fluid ingestion and level of aerobic fitness in the responses of plasma vasoactive intestinal polypeptide during prolonged exercise, whereas plasma gastrin is not significantly affected by either.
Sympathetic Stimulations by Exercise-Stress Testing and by Dobutamine Infusion Induce Similar Changes in Heart Rate Variability in Patients with Chronic Heart Failure
Authors: Piepoli Massimo , Adamopoulos Stamatis , Bernardi Luciano , Sleight Peter , Coats Andrew J. S.
Published: August 2015

1. Heart rate variability can be used to evaluate autonomic balance, but it is unclear how inotropic therapy may affect the findings. The aim of the study was to assess whether heart rate variability can differentiate between sympathetic stimulation induced by inotrope infusion or by physical exercise.

2. Ten patients with chronic heart failure (64.3 ± 5.4 years of age) underwent four dobutamine infusions (8-min steps of 5 μg min−1 kg−1) and four supine bicycle exercise tests (5-min steps of 25 W). Plasma noradrenaline was evaluated, as well as the SD of R—R intervals, together with low-frequency (0.03–0.14 Hz) and high-frequency (0.15–0.4 Hz) components of heart rate variability using autoregressive spectral analysis.

3. Exercise and inotrope infusion produced similar changes in heart rate variability. An exercise load of 50 W and a dobutamine infusion of 15 μg min−1 kg−1 gave the following results respectively: heart rate, 120.3 ± 3.0 beats/min versus 110.2 ± 3.0 beats/min; SD, 16.0 ± 1.1 ms versus 16.3 ± 2.5 ms; low-frequency component, 4.3 ± 0.3 ln-ms2 versus 4.4 ± 0.3 ln-ms2 and high-frequency component, 2.6 ± 0.3 ln-ms2 versus 2.2 ± 0.3 ln-ms2. All comparisons were non-significant. The variables of heart rate variability showed high reproducibility in the same subject during different conditions. Noradrenaline was elevated by exercise from 326.0 ± 35.2 pg/ml to 860.1 ± 180.4 pg/ml (P < 0.05), but was unchanged by dobutamine infusion.

4. Heart rate variability changes cannot differentiate between dobutamine infusions and physical exercise, indicating that we should be cautious in evaluating patients undergoing inotropic therapy. The degree of receptor stimulations, rather than the level of sympathetic drive, would appear to determine the changes in heart rate variability.
Effects of Maternal Diabetes on Blood Pressure and Glucose Tolerance in Offspring of Spontaneously Hypertensive Rats: Relation to Birth Weight
Authors: Iwase Masanori , Wada Miya , Wakisaka Masanori , Yoshizumi Hideyuki , Yoshinari Mototaka , Fujishima Masatoshi
Published: August 2015

1. We studied the effects of maternal diabetes on blood pressure and glucose tolerance in the adult female offspring of spontaneously hypertensive rats.

2. Female spontaneously hypertensive rats were rendered diabetic by neonatal streptozotocin treatment, and then were mated with untreated male spontaneously hypertensive rats. Moderately severe hyperglycaemia was maintained during the gestation.

3. The birth weight was significantly lower in the female offspring of the diabetic dams than in the female offspring of the non-diabetic dams. The systolic blood pressure was significantly higher in the offspring from the diabetic dams than that from the control dams at 6 months of age (192 ± 4 mmHg versus 213 ± 4 mmHg, P < 0.01). The heart weight was also significantly increased in the offspring of the diabetic dams. Both the blood pressure and heart weight were inversely related to the birth weight. On the other hand, glucose tolerance was unaffected by maternal diabetes.

4. Maternal diabetes aggravated the severity of hypertension in the adult female offspring of spontaneously hypertensive rats. This suggests the importance of the metabolic environment during fetal growth for the development of hypertension.
Isogravitational Heterogeneity of Perfusion after Unilateral Lung Transplantation
Authors: Ross D. J. , Koerner S. K. , Elashoff J. , Waxman A. D. , Mohsenifar Z.
Published: August 2015

1. Single-photon emission computerized tomography in both an intact canine model and man has demonstrated an aspect of pulmonary perfusion to be independent of gravitational forces.

2. Using technetium 99 m-labelled macroaggregated albumin single-photon emission computerized tomographic imaging, we investigated normal human subjects (n = 5), stable unilateral lung transplant recipients (n = 6) and transplant recipients with chronic allograft dysfunction related to obliterative bronchiolitis (n = 5).

3. In coronal isogravitational sections, a 1 × 1 × N pixel strip (medial to lateral) was constructed through the ‘core’ pixel of maximal radioactive counts. The counts were measured for the ‘core’ pixel and at two mid-points (medial and lateral) between the core pixel and the lung edges. Coefficients of variation were computed for each isogravitational strip and compared between groups. Fractional whole-lung perfusion was determined for left versus right lungs of normal subjects and allograft versus native lungs of transplant recipients.

4. Using these indices, ‘isogravitational heterogeneity’ (i.e. increased ‘core’ versus peripheral perfusion) was observed in allografts and native diseased lungs after unilateral transplantation. Despite significantly increased fractional whole-lung perfusion directed to the allografts (84.8% ± 3.0% and 75.8% + 12.1% for stable unilateral lung transplant recipients and patients with obliterative bronchiolitis respectively) compared with normal lungs (50.2% ± 1.2% and 49.8% ± 1.2% for left and right respectively), ‘isogravitational flow heterogeneity’ (i.e. increased ‘core’ versus peripheral perfusion) was preserved after transplantation.

5. These findings suggest that ‘isogravitational heterogeneity’ was maintained despite increased unilateral pulmonary perfusion and the presumed increase in pulmonary capillary recruitment and/or distension.
Effect of the Transmembrane Gradient of Magnesium and Sodium on the Regulation of Cytosolic Free Magnesium Concentration in Human Platelets
Authors: Yoshimura Mitsuisa , Oshima Tetsuya , Matsuura Hideo , Watanabe Mitsuaki , Higashi Yukihito , Ono Norihisa , Hiraga Hiroyuki , Kambe Masayuki , Kajiyama Goro
Published: August 2015

1. To clarify the mechanism by which cytosolic free Mg2+ concentrations ([Mg2+]i) are regulated in human platelets, we investigated platelet membrane permeability to Mg2+ by altering extracellular Mg2+ concentrations, and tested the existence of a Na+-Mg2+ exchanger by manipulating the transmembrane Na+ gradient.

2. Platelet [Mg2+], was 421 ± 52 μmol/l in healthy men. [Mg2+]; remained constant during a 120 min exposure to nominally zero (low) or 5 mmol/l (high) external Mg2+ concentrations.

3. Preincubation of platelets with 10−4 mol/l ouabain effectively decreased the transmembrane Na+ gradient. The ouabain-induced increase in [Mg2+], was statistically significant after 30 min of exposure (14.6 ± 2.0%) and reached 24.6 ± 4.5% after 60 min. Similarly, the replacement of extracellular Na+ with N-methyl-d-glucamine significantly increased [Mg2+]i by 48.5 ± 3.9% and 78.8 ± 12.5%, respectively.

4. These results suggest that [Mg2+]i is well controlled in the presence of large transmembrane Mg2+ concentration gradients, and a Na+-Mg2+ exchanger may be involved in the regulation of [Mg2+]i in human platelets.
Effect of Water-Loading on the Performance of Polyethylene Glycol as a Marker of Small Intestinal Permeability
Authors: Iqbal Tariq H. , Cox Mark A. , Lewis Kenneth O. , Cooper Brian T.
Published: August 2015

1. Polyethylene glycol has been used extensively to measure small intestinal permeability in vivo. However, polyethylene glycol seems to traverse the intestinal mucosa in much greater quantities than sugar molecules of equivalent Mr. In addition, the recovery of the lowest Mr polymers of administered polyethylene glycol has been found to be both low and unreliable.

2. To compare the behaviour of a range of polyethylene glycol polymers with sugar probes in vivo, a combined polyethylene glycol/mannitol/lactulose probe was administered sequentially to healthy individuals in the fasted state and under conditions of water-loading. Timed hourly urine collections were made for 6 h.

3. Mannitol and lactulose recoveries were all within the normal range and were unaffected by coadministration of water. The lactulose/mannitol recovery ratios did not vary significantly over the 6 h collection period. In contrast, the recovery of total polyethylene glycol was significantly greater when subjects were water-loaded. Futhermore, proportionally greater quantities of polyethylene glycol Mr 370 than Mr 854 were recovered towards the end of the collection period than at the start.

4. Our results show that, in contrast to lactulose and mannitol, excretion of low—medium Mr polyethylene glycol polymers is highly dependent on coadministration of water. Futhermore, the differential rate of excretion of the low compared with the high Mr polyethylene glycol polymers suggests that the volume of distribution of the individual polymers may vary with Mr, and smaller polyethylene glycol molecules may undergo considerable renal tubular reabsorption.