bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of acute administration of gliclazide on the glucose sensitivity of pancreatic B-cells in healthy subjects
Authors: Veneman T. F. , van Haeften T. W. , van der Veen E. A.
Published: August 2015

1. Sulphonylurea derivatives are commonly used in the treatment of non-insulin-dependent diabetes mellitus. It is, however, unclear whether the hypoglycaemic effect of sulphonylurea derivatives is additive to the effect of glucose, or whether sulphonylurea derivatives act by increasing B-cell glucose sensitivity.

2. We assessed the effect of gliclazide on glucose-stimulated insulin secretion in eight healthy volunteers. Sixty minute hyperglycaemic glucose clamps (blood glucose levels of 8, 11 and 32 mmol/l) were performed, with and without prior administration of gliclazide (80 mg) 90 min before the glucose clamp.

3. Dose-response characteristics were assessed with a modified Michaelis-Menten equation. The Vmax. (maximal B-cell responsiveness) was not significantly changed (1.5 ± 0.1 versus 1.3 ± 0.2 and 5.0 ± 0.5 versus 4.8 ± 0.5 mmol/l for the first- and second-phase insulin secretion, respectively), whereas the ED50 (half-maximally stimulating blood glucose concentration) was significantly decreased by gliclazide for first-phase insulin secretion (7.6 ± 0.3 versus 9.1 ± 0.6 mmol/l) but not for second-phase insulin secretion (12.0 ± 0.5 versus 12.3 ± 0.5 mmol/l).

4. We conclude that gliclazide indeed leads to a shift to the left of the dose-response curve of first-phase insulin release in vivo without a change in Vmax., which indicates an apparent enhancement of B-cell glucose sensitivity.
Effects of dietary Ca2+ on erythrocyte Na+-transport systems in spontaneously hypertensive rats
Authors: Fujito K. , Yokomatsu M. , Ishiguro N. , Numahata H. , Tomino Y. , Koide H.
Published: August 2015

1. The purpose of this study was to determine the effect of dietary Ca2+ intake on blood pressure and erythrocyte Na+ transport in spontaneously hypertensive rats.

2. Spontaneously hypertensive rats and Wistar-Kyoto rats were fed diets with three different Ca2+ contents, 0.1% (low-Ca2+ diet), 0.6% (normal-Ca2+ diet) and 4.0% (high-Ca2+ diet), between 6 and 20 weeks of age. At 20 weeks of age, the levels of erythrocyte Na+ efflux, as well as Na+ and K+ contents in erythrocytes, were measured.

3. On the low-Ca2+ diet, spontaneously hypertensive rats showed an enhancement of hypertension. Conversely, on the high-Ca2+ diet, they showed an attenuation of the increase in blood pressure. Spontaneously hypertensive rats had a lower erythrocyte Na+ content and increased activity of the Na+ pump at higher levels of dietary Ca2+. Passive Na+ permeability and Na+-K+ co-transport were similar in spontaneously hypertensive rats on the low-, normal- and high-Ca2+ diets. There were no significant differences in blood pressure and in Na+ pump activity in WKY on the three different diets.

4. It is concluded that dietary Ca2+ might affect the regulation of blood pressure in spontaneously hypertensive rats by changing the activity of Na+ pump in the cell membrane.
Effect of insulin on intracellular pH and phosphate metabolism in human skeletal muscle in vivo
Authors: Taylor D. J. , Coppack S. W. , Cadoux-Hudson T. A. D. , Kemp G. J. , Radda G. K. , Frayn K. N. , NG L. L.
Published: August 2015

1. 31P nuclear magnetic resonance spectroscopy and the hyperinsulinaemic-euglycaemic clamp were used simultaneously to assess the effect of insulin on intracellular pH and the major phosphorus-containing metabolites of normal human skeletal muscle in vivo in four normal subjects.

2. Insulin and glucose were infused for 120 min. Plasma insulin increased approximately 10-fold over pre-clamp levels (5.6 ± 0.9 m-units/l pre-clamp and 54 ± 5 m-units/l over the last hour of infusion; mean ± sem, n = 4). Plasma glucose concentration did not change significantly (5.4 ± 0.2 mmol/l pre-clamp and 5.5 ± 0.1 mmol/l over the last hour of infusion).

3. Insulin and glucose infusion resulted in a decline in the intracellular pH of forearm muscle of 0.027 ± 0.007 unit/h (P < 0.01), whereas in control studies of the same subjects, pH rose by 0.046 ± 0.005 unit/h (P < 0.001).

4. In the clamp studies, intracellular inorganic phosphate concentration rose by 18%/h, whereas ATP, phosphocreatine and phosphomonoester concentrations did not change. In plasma, inorganic phosphate concentration was 1.16 ± 0.05 mmol/l before infusion, and this decreased by a mean rate of 0.14 mmol h−1 l−1. No change was observed in any of these intracellular metabolites in the control studies.

5. The results show that, under physiological conditions, insulin does not raise intracellular pH in human muscle, and thus cannot influence muscle metabolism by this mechanism. The results also suggest that insulin causes a primary increase in the next flux of inorganic phosphate across the muscle cell membrane.
Bicarbonate reabsorption and electrophysiology of proximal tubules in uninephrectomized rats
Authors: Limongi Dirce M. Zanetta , Cassola Antonio Carlos , Woronik Viktoria , Malnic Gerhard
Published: August 2015

1. The kinetics of acidification of luminal fluid in hypertrophied proximal tubules after unilateral nephrectomy was studied by stationary microperfusion and continuous measurement of luminal pH with antimony microelectrodes.

2. Trans-epithelial and basolateral membrane electrical potential differences were measured in order to detect modifications in electrogenic transport mechanisms under these conditions.

3. The values of stationary pH and HCO−3 concentration were significantly lower, the mean acidification half-time was not different and net reabsorptive HCO−3 fluxes in proximal tubules were significantly increased in uninephrectomized rats. According to an electrical analogue model, these results suggest (a) a reduction in the internal series resistance of the H+ pump, caused perhaps by an increased density of pump sites, and (b) an increase in the protonmotive force of the pump.

4. The trans-epithelial electrical potential difference measured in free flow conditions was significantly more lumen-positive in uninephrectomized rats. The trans-epithelial electrical potential difference measured during intraluminal perfusion with Ringer solution containing 30 mmol/l HCO−3 was significantly more negative in all groups studied. In uninephrectomized rats treated with acetazolamide, the trans-epithelial electrical potential difference was more lumen-negative than that in untreated uninephrectomized rats. These results are compatible with a steeper transepithelial Cl− gradient as well as with electrogenic, active H+ secretion.

5. There was no significant difference in the basolateral electrical potential difference between control and uninephrectomized rats.

6. In conclusion, our data show an increase in the transport rates of HCO−3 in the proximal tubule of uninephrectomized rats, which may be due to an increase in the density of transporters in the brush-border membrane, and an increased ability of the transport mechanism to create H+ gradients.
Calcium and phosphate metabolism in acute falciparum malaria
Authors: DAVIS T. M. E. , Pukrittayakamee S. , Woodhead J. S. , Holloway P. , Chaivisuth B. , White N. J.
Published: August 2015

1. Mineral homoeostasis was investigated in 172 Thai adults with acute falciparum malaria at presentation (87 males, 85 females; mean age 30 years), and prospectively in a subgroup of 10 severely ill patients.

2. Mild, asymptomatic hypocalcaemia (corrected plasma calcium concentration 1.79–2.11 mmol/l) was found in 61 cross-sectional study patients (35.5%), with no difference between those with uncomplicated (2.16 ± 0.10 mmol/l, mean ± sd, n = 89) and severe (2.18 ± 0.15 mmol/l, n = 83, P = 0.36) infections. Six prospectively studied patients were hypocalcaemic during treatment; simultaneous serum intact parathormone concentrations were inappropriately low (< 5.0 pmol/l), but rose in three patients to high levels (11.8–16.4 pmol/l) on the fifth day.

3. Plasma phosphate concentration was decreased (< 0.80 mmol/l) on admission in 74 patients (43.0%) and increased (> 1.45 mmol/l) in 15 (8.7%). Severe phosphate depletion (plasma phosphate concentration < 0.30 mmol/l) occurred in 14 patients, of whom 11 had severe infections. Serum phosphate concentrations in the prospective study patients on admission (0.59 ± 0.23 mmol/l) correlated significantly with the simultaneous renal threshold phosphate concentration (0.68 ± 0.33 mmol/l; r = 0.607, P < 0.025) and both parameters rose in parallel during treatment.

4. Plasma magnesium concentrations were normal (0.75–1.05 mmol/l) in 108 patients (62.8%); 45 cases (26.1%) had hypermagnesaemia and 19 (11.0%) had hypomagnesaemia.

5. These data suggest that mild hypocalcaemia is common in malaria regardless of disease severity; a depressed parathormone response may contribute. Despite malaria-associated haemolysis, hypophosphataemia is also common, but can be severe. Phosphate replacement should therefore be considered where strict monitoring of plasma phosphate concentrations is feasible.
Basal metabolic rate, body composition and whole-body protein turnover in Indian men with differing nutritional status
Authors: Soares M. J. , Piers L. S. , Shetty P. S. , Robinson S. , Jackson A. A. , Waterlow J. C.
Published: August 2015

1. Three groups of adult men were studied in Bangalore, India: two groups were controls who had been receiving an adequate diet. Of these, one group, designated ‘normal weight controls', had a mean body mass index of 22; the other group, ‘underweight controls', had a mean body mass index of 16.7. The third group consisted of poor labourers, whose daily food intake had been less than 10 MJ and whose mean body mass index was 16.6. Previous studies had shown that such men had a lower basal metabolic rate than well-nourished Indian control subjects.

2. The object of the present study was to find out whether a reduced rate of protein turnover, measured after a single dose of [15N]glycine, contributed to a lower basal metabolic rate. It was found, however, that after adjusting for body weight and fat-free mass by analysis of co-variance there was no significant difference in basal metabolic rate between the three groups. Adjusted rates of protein synthesis were higher in the underweight controls and the undernourished labourers than in the normal weight controls, but not significantly so.

3. Estimates based on creatinine excretion showed that within the fat-free mass the underweight groups had a higher proportion of non-muscle to muscle mass. This may explain the somewhat higher rates of protein turnover in these groups.

4. Nitrogen flux (Q) was determined from 15N abundance in two end products, urea (QU) and ammonia (QA). In the underweight and undernourished groups the ratio QU/QA was increased compared with the normal weight group. This fits in with the finding of a greater proportion of visceral mass in the underweight subjects and with the compartmental model of protein metabolism that we have previously proposed.
Feedback-mediated reduction in glomerular filtration during acetazolamide infusion in insulin-dependent diabetic patients
Authors: Hannedouche T. , Lazaro M. , Delgado A. G. , Boitard C. , Lacour B. , Grünfeld J.-P.
Published: August 2015

1. A sustained high glomerular filtration rate in diabetes mellitus is associated with increased proximal reabsorption, suggesting alterations in the tubulo-glomerular feedback system. To test this hypothesis, renal function was studied in eight control subjects and 14 recent-onset euglycaemic insulin-dependent diabetic patients before and after infusion of the carbonic anhydrase inhibitor, acetazolamide (5 mg/kg body weight).

2. Acetazolamide induced a dramatic fall in glomerular filtration rate in both diabetic patients and control subjects (from 138 ± 5 to 114 ± 4 and from 127 ± 3 to 113 ± 2 ml min−1 1.73 m−2, respectively, P < 0.0001). This fall in glomerular filtration rate was strongly correlated with the acetazolamide-induced decrease in absolute proximal reabsorption calculated by using lithium clearance.

3. To further assess the potential role of angiotensin II in the acetazolamide-induced tubulo-glomerular feedback response, 11 additional diabetic patients were investigated before and after the administration of acetazolamide plus the angiotensin-converting enzyme inhibitor, enalaprilat (1.25 mg intravenously). Despite the effective blockade of angiotensin II formation and a slight decrease in renal vascular resistance, the glomerular filtration rate fell significantly and by a similar magnitude as seen with acetazolamide alone.

4. These results indirectly suggest that there is an altered basal tubulo-glomerular feedback system in diabetic patients but a normal response to the increase in distal delivery. No convincing role for an angiotensin II-mediated effect on the afferent limb of the tubulo-glomerular feedback response could be demonstrated.
Effect of aluminium on urinary acidification in the rat: influence of parathyroid hormone
Authors: Gil F. Zaladek , Costa Silva V. L. , Cavanal M. F.
Published: August 2015

1. The influence of thyroparathyroidectomy and/or acidosis on renal function and specifically on acid excretion was studied in rats treated with a cumulative dose of 2 mg of aluminium.

2. Aluminium-treated and non-treated thyroparathyroidectomized rats showed a significant decrease in glomerular filtration rate and in the urinary/plasma inulin ratio without alteration in net acid excretion.

3. Non-treated thyroparathyroidectomized acidotic rats showed a significant fall in the amount of ammonium excreted and in overall acid excretion, suggesting that parathyroid hormone participates in an important way in the defence against metabolic acidosis.

4. The effects of acidosis, thyroparathyroidectomy and aluminium treatment on renal function parameters were not additive, suggesting a common final mechanism. In normal or acidotic aluminium-treated rats, thyroparathyroidectomy had no effect on renal acid excretion, suggesting that aluminium even in low doses inhibited the action of PTH on the renal tubule.

5. After exposure to aluminium, the relative inhibition of PTH on the renal tubule may become an additional factor that could contribute to the worsening of clinical conditions in which an inappropriate retention of acid loads can occur.
Urinary excretion of digoxin-like immunoreactive factor and arginine-vasopressin in hyper- and hypo-thyroid rats
Authors: Vargas Felix , Baz Maria J. , de D. Luna Juan , Andrade Jesus , Jodar Esteban , Haro Jose M.
Published: August 2015

1. Urinary excretion of digoxin-like immunoreactive factor and arginine-vasopressin and other parameters related to salt and water metabolism were studied in hyper- and hypo-thyroid rats after different tests.

2. Urinary excretion of arginine-vasopressin was increased in hyperthyroid and reduced in hypothyroid rats with respect to controls, in response to water deprivation or a hypertonic saline load.

3. Control and hypothyroid rats showed the highest urinary excretion of digoxin-like immunoreactive factor after a hypertonic saline load. However, hyperthyroid rats had the highest urinary levels of digoxin-like immunoreactive factor under normal conditions.

4. From these results it is suggested that: (a) hyper- and hypo-thyroid rats exhibit hyper- and hypo-responsiveness of arginine-vasopressin secretion to osmotic stimuli, respectively; (b) an unidentified digoxin-like immunoreactive factor measured in unextracted rat urine may be related to diuresis and natriuresis in control and hypothyroid rats; however, dissociation between this factor and natriuresis is observed in hyperthyroid rats.
Low-concentration ouabain does not inhibit noradrenaline-induced contraction of human resistance arteries
Authors: Woolfson Robin G. , Richards Nicholas T. , Poston Lucilla
Published: August 2015

1. Using a Mulvany-Halpern myograph to measure changes in isometric tension, we have investigated the effect of ouabain on noradrenaline-induced contraction of human subcutaneous resistance arteries.

2. Low concentrations of ouabain (10 nmol/l or less) were shown not to alter vascular smooth muscle contractility or sensitivity to noradrenaline.

3. In contrast, higher concentrations of ouabain (100 nmol/l or more) were found to depress vascular smooth muscle contractility and to reduce the sensitivity of the noradrenaline concentration-response relationship.

4. These findings may have implications regarding the presence of an endogenous inhibitor of the sodium pump in essential hypertension and in pregnancy-associated hypertension.
Stanozolol stimulates remodelling of trabecular bone and net formation of bone at the endocortical surface
Authors: Benéton M. N. C. , Yates A. J. P. , Rogers S. , McCloskey E. V. , Kanis J. A.
Published: August 2015

1. We studied the mechanism of action of the anabolic steroid, stanozolol, in 23 patients with osteoporosis, using a combination of biochemical and histomorphometric techniques.

2. Treatment with stanozolol (5 mg/day) for 1 year was associated with a marked and significant decrease in the fasting urinary excretion of calcium (P < 0.01) but not with changes in the serum concentrations of calcium and phosphate, the serum activity of alkaline phosphatase, the renal tubular reabsorption of calcium or the urinary excretion of hydroxyproline.

3. Histological examination of trabecular bone showed an increase in bone turnover and the bone formation rate increased twofold (P < 0.02). There were no significant changes in bone volume or wall thickness after treatment. Tetracycline labelling was used to discriminate bone structural units completed before and during treatment. Measurements of the wall thickness of those bone structural units formed during treatment showed no significant change.

4. Measurements made on the endocortical surface also showed an increase in bone turnover, but in contrast to trabecular bone, the bone structural units formed at endocortical sites during treatment had a significantly greater wall thickness than those formed before treatment (P < 0.05).

5. We conclude that stanozolol increases the turnover of trabecular bone and increases the endocortical apposition of bone.
Effect of adrenaline infusion on fatty acid and glucose turnover in lean and obese human subjects in the post-absorptive and fed states
Authors: Connacher Alan A. , Bennet William M. , Jung Roland T. , Bier Dennis M. , Smith Christopher C. T. , Scrimgeour Charles M. , Rennie Michael J.
Published: August 2015

1. Energy expenditure, plasma glucose and palmitate kinetics and leg glycerol release were determined simultaneously both before and during adrenaline infusion in lean and obese human subjects. Seven lean subjects (mean 96.5% of ideal body weight) were studied in the post-absorptive state and also during mixed nutrient liquid feeding, eight obese subjects (mean 165% of ideal body weight) were studied in the post-absorptive state and six obese subjects (mean 174% of ideal body weight) were studied during feeding.

2. Resting energy expenditure was higher in the obese subjects, but the thermic response to adrenaline, both in absolute and percentage terms, was similar in lean and obese subjects. Plasma adrenaline concentrations attained (3 nmol/l) were comparable in all groups and the infusion had no differential effects on the plasma insulin concentration. Before adrenaline infusion the plasma glucose flux was higher in the obese than in the lean subjects in the fed state only (45.8 ± 3.8 versus 36.6 ± 1.0 mmol/h, P <0.05); it increased to the same extent in both groups with the adrenaline infusion.

3. Before the adrenaline infusion plasma palmitate flux was higher in the obese than in the lean subjects (by 51%, P <0.01, in the post-absorptive state and by 78%, P <0.05, in the fed state). However, there was no significant change during adrenaline infusion in the obese subjects (from 13.5 ± 1.00 to 15.0 ± 1.84 mmol/h, not significant, in the post-absorptive state and from 14.4 ± 2.13 to 15.7 ± 1.74 mmol/h, not significant, in the fed state), whereas there were increases in the lean subjects (from 8.93 ± 1.10 to 11.2 ± 1.19 mmol/h, P <0.05, in the post-absorptive state, and from 8.06 ± 1.19 to 9.86 ± 0.93 mmol/h, P <0.05, in the fed state).

4. Before adrenaline infusion the palmitate oxidation rate was also higher in the obese than in the lean subjects (1.86 ± 0.14 versus 1.22 ± .09 mmol/h, P <0.01, in the post-absorptive state and 1,73 ± 0.25 versus 1.12 ± 0.12 mmol/h, P <0.05, in the fed state). However, in response to adrenaline the fractional oxidation rate (% of flux) increased less in the obese than in the lean subjects, especially in the post-absorptive state (from 13.8 ± 1.02 to 14.9 ± 1.39%, not significant, versus from 13.7 ± 0.98 to 19.3 ± 1.92%, P <0.05). These effects were independent of feeding. Leg glycerol release increased more in the lean subjects with adrenaline infusion, although increases in the plasma glycerol concentration did not differ between the groups.

5. These results suggest that in obese subjects plasma inter-organ transport of fatty acids and the subsequent fractional oxidation responses favour storage of triacylglycerol. These factors may be important determinants for the development and maintenance of the obese state.
Observations on the chemical nature of lead in human blood serum
Authors: Al-Modhefer A. J. A. , Bradbury M. W. B. , Simons T. J. B.
Published: August 2015

1. The binding of lead to human blood serum, and components of serum, was studied by titration with the addition of Pb(NO3)2 solution, monitoring the free Pb2+ concentration with a Pb2+ electrode, and by equilibrium dialysis.

2. In fresh serum, about 4999 out of 5000 parts of added lead were bound. This suggests that the free Pb2+ concentration is around 1/5000th of the total lead concentration in the serum of normal subjects, i.e. about 1 × 10−12 mol/l.

3. About 60% of the binding of lead in serum is abolished by standing in air, by dialysis or by treatment with N-ethylmaleimide. This appears to be due to the presence of thiol compounds, mainly cysteine. The remaining 40% appears to be due to protein, mainly albumin.
Persistent albuminuria in normotensive non-insulin-dependent (type II) diabetic patients: comparative effects of angiotensin-converting enzyme inhibitors and β-adrenoceptor blockers
Authors: Stornello Michele , Valvo Enrico V. , Scapellato Luigi
Published: August 2015

1. Some non-insulin-dependent (type II) diabetic patients show albuminuria without arterial hypertension. In these patients, angiotensin-converting enzyme inhibitors reduce urinary albumin excretion without producing any changes in systemic blood pressure and renal haemodynamics. However, up to now it has not been clear whether these favourable renal effects are specifically related to angiotensin-converting enzyme inhibition or not.

2. Twelve type II diabetic outpatients with persistent macroalbuminuria (greater than 300 mg/daily on at least three consecutive occasions), without any other signs of renal disease and whose blood pressure was persistently below 140/90 mmHg, were studied.

3. In a randomized sequence and in a double-blind fashion, after a 2-month run-in period, patients were allocated to receive 5 mg of enalapril or 50 mg of atenolol daily for the next 6 months. At the end of this first period and after 6 months on placebo in a cross-over fashion, active treatment was replicated. Blood pressure and urinary albumin excretion were measured every 2 months, whereas the other variables studied were determined at the end of each period.

4. Kidney function and blood pressure did not change significantly, whereas albuminuria decreased significantly, after both of the drugs.

5. These data suggest that the inhibition of tissue angiotensin formation and the consequent reduction in glomerular permeability, rather than changes in renal and systemic haemodynamics, are the common mechanisms by which both enalapril and atenolol decreased albuminuria in our patients.
Model-based determination of cut-off values for left ventricular hypertrophy from echocardiographic myocardial mass data
Authors: Morvan Daniel , Golmard Jean-Louis , Komajda Michel , Drobinski Gérard
Published: August 2015

1. The left ventricular myocardial mass is a measurement that is easy to obtain by echocardiography. It is currently used for the definition of left ventricular hypertrophy, but cut-off values are often critical, since they depend on covariates of left ventricular myocardial mass such as sex, age, body surface area, physical training, blood pressure, etc. As it is very difficult in any laboratory to obtain a sufficient number of normal subjects for the establishment of left ventricular myocardial mass experimental distributions, we propose a non-linear model for the calculation of echocardiographic left ventricular myocardial mass distribution in normal subjects, from personal and literature data. Left ventricular myocardial mass probability density function was computed from the following two assumptions: the joint distribution of the internal and external left ventricular diameters is assumed to be bivariate normal, and the relation between left ventricular myocardial mass and ventricular diameters is given by the formula of Devereux & Reicheck (Devereux, R. B. & Reicheck, N. Circulation 1977; 55, 613-8).

2. The Gaussian assumption was tested by using skewness tests. The model was further developed for the myocardial mass index distribution. The calculated probability density functions were compared with experimental data and showed very good agreement. Furthermore, they were used to define cut-off values of left ventricular hypertrophy at selected false-positive ratios. Finally, since left ventricular myocardial mass may vary under normal conditions with co-variates, the model may provide co-variate-matched cut-off values for any, even small, series of non-diseased control subjects.
Effects of chronic administration of ephedrine during very-low-calorie diets on energy expenditure, protein metabolism and hormone levels in obese subjects
Authors: Pasquali Renato , Casimirri Francesco , Melchionda Nazario , Grossi Gabriele , Bortoluzzi Lucia , Labate Antonio Maria Morselli , Stefanini Chiara , Raitano Antonino
Published: August 2015

1. We investigated the effects of the chronic administration of a sympathomimetic agent on energy expenditure, protein metabolism and levels of thyroid hormones and catecholamines in 10 obese subjects after a 6-week very-low-calorie-diet programme (1965 kJ, 60 g of protein, 45 g of carbohydrates). l-(-)-Ephedrine hydrochloride (50 mg three times a day by mouth) or placebo were administered during 2-week periods (weeks 2-5 of the VLCD programme) in a randomized, double-blind, crossover design. Five subjects began with ephedrine and five with placebo.

2. The results were analysed separately in the two groups. No difference was found between them as regards weight loss during the very-low-calorie diet and drug treatments. Conversely, ephedrine therapy induced a significantly lower daily urinary excretion of nitrogen (and, consequently, a better nitrogen balance) with respect to placebo, independently of the drug sequence. Daily urinary levels of 3-methylhistidine during ephedrine and placebo treatments were similar. The fasting resting metabolic rate (oxygen consumption, ml STP/min) fell significantly during the very-low-calorie diet in both groups, but this effect was partially and significantly prevented by administration of ephedrine. Diet therapy significantly reduced 24 h urine levels of vanillylmandelic acid and homovanillic acid, which, however, increased to pretreatment values during ephedrine treatment. No significant effects were shown on 24 h urinary concentrations of adrenaline, noradrenaline and dopamine during the very-low-calorie diet and/or ephedrine treatment. There were also no effects on the serum levels of thyrotropin, thyroxine, free-tri-iodothyronine and free-thyroxine, but ephedrine significantly prevented a further fall in the serum tri-iodothyronine level and the serum triiodothyronine/thyroxine ratio during the very-low-calorie diet.

3. These findings demonstrate that in obese subjects following a very-low-calorie-diet programme, administration of chronic adrenoceptor agonists, such as ephedrine, partially prevented the fall in resting metabolic rate and significantly improved the nitrogen balance. These effects may be of importance in the treatment of patients in whom a reduced capacity for energy expenditure may be involved in their obese state.
Correlation of the ratio of S-adenosyl-l-methionine to S-adenosyl-l-homocysteine in the brain and cerebrospinal fluid of the pig: implications for the determination of this methylation ratio in human brain
Authors: Weir D. G. , Molloy A. M. , Keating J. N. , Young P. B. , Kennedy S. , Kennedy D. G. , Scott J. M.
Published: August 2015

1. Pigs were maintained in air or in an atmosphere of nitrous oxide which dramatically changes the S-adenosyl-l-methionine to S-adenosyl-l-homocysteine ratio in neural tissues. Samples of cerebrospinal fluid, cortex, cerebellum and spinal cord were then extracted and analysed for S-adenosyl-l-methionine and S-adenosyl-l-homocysteine. Regression analyses were carried out on values obtained in cerebrospinal fluid and in neural tissues.

2. Highly significant correlations were obtained between levels of S-adenosyl-l-homocysteine (r2 = 0.42-0.69; P < 0.001) and S-adenosyl-l-methionine/S-adenosyl-l-homocysteine ratios (r2 = 0.56-0.65; P < 0.001) in cerebrospinal fluid and levels and ratios in cortex, cerebellum and spinal cord. The levels of S-adenosyl-l-methionine did not show a significant correlation.

3. We conclude that the ratio of these metabolites in the cerebrospinal fluid may reflect the ratio in the central nervous system and we suggest that this may also be true in human tissues. This finding will permit the determination of the probable methylation ratio in the central nervous system in human conditions, such as vitamin B12 deficiency and acquired immune deficiency syndrome, where a similar myelopathy occurs to that seen in the nitrous oxide-treated pig. All three myelopathies may arise from an inhibition of methyltransferases involved in the synthesis of myelin that would occur when the methylation ratio is reduced.
Renal haemodynamic, hormonal and excretory effects of low-dose atrial natriuretic factor infusion in renal transplant recipients
Authors: Lipkin G. W. , Dawnay A. B. S. , Harwood S. M. , Kendall R. G. , Cattell W. R. , Raine A. E. G.
Published: August 2015

1. In experimental studies, activation of renal sympathetic nerves attenuates the natriuretic response to atrial natriuretic factor. We therefore investigated the response to low-dose infusion of atrial natriuretic factor in renal transplant recipients.

2. Eight male cyclosporin-treated renal transplant recipients received human-α atrial natriuretic factor (1–28) at a dose of 1.2 pmol min−1 kg−1 or placebo for 2 h in a placebo-controlled, randomized, cross-over study. The plasma atrial natriuretic factor concentration rose from 18.5 to 49.2 pmol/l in association with an immediate natriuresis (a rise of 49.1 μmol/min in the first 30 min, P<0.05; peaking at a 61% increase from baseline, P<0.01), diuresis (from 3.37 to 7.46 ml/min) and a threefold rise in urinary cyclic GMP excretion.

3. In response to infusion of atrial natriuretic factor, the packed cell volume rose by 4.2% (P < 0.001) and the filtration fraction by 5% (from 22 to 27%, P<0.05), but there was no significant change in renal plasma flow, glomerular filtration rate or mean arterial blood pressure. Likewise, the plasma catecholamine concentrations, plasma renin activity and serum erythropoietin concentration remained unchanged.

4. The sensitivity of the renal allograft to plasma atrial natriuretic factor concentrations in the high physiological range suggests a role for endogenous atrial natriuretic factor in the modulation of graft function. Furthermore, the immediate natriuretic response to atrial natriuretic factor in the effectively denervated transplant kidney, in contrast to the delayed response seen in normal subjects, may imply that sympathetic nerves have an inhibitory effect on the renal response to atrial natriuretic factor in normal man.

5. In contrast to the findings of studies in vitro, infusion of atrial natriuretic factor had no effect on the serum erythropoietin concentration.
Mutual interactions of respiratory sinus arrhythmia and the carotid baroreceptor-heart rate reflex
Authors: Cross S. J. , Cowie M. R. , Rawles J. M.
Published: August 2015

1. In six healthy subjects the amplitude and phase of respiratory sinus arrhythmia were determined at five different respiratory cycle lengths ranging from 3 to 9.5 s.

2. At each respiratory cycle length the carotid baroreceptor-heart rate reflex response was determined by cyclical neck suction at −40 mmHg at five different cycle lengths covering the same range of 3–9.5 s.

3. The application of cyclical neck suction increased the amplitude of respiratory sinus arrhythmia in all but the longest respiratory cycle lengths.

4. With increasing respiratory cycle length the amplitude of sinus arrhythmia increased, and R-R intervals were at their longest at an earlier phase of the respiratory cycle. Similarly, with increasing suction cycle length the amplitude of the cardiac interval response increased and the phase angle decreased.

5. The cardiac interval responses to respiration and to neck suction at different frequencies were independent of each other, the heart rate at any moment resulting from the algebraic summation of the two responses.
Comparative study of pressor and heart rate responses to angiotensin II and noradrenaline in pregnant and non-pregnant women
Authors: Ramsay Margaret , Pipkin Fiona Broughton , Rubin Peter
Published: August 2015

1. Twenty-eight healthy non-pregnant women and 28 women in the first or second trimester of pregnancy were studied. They were given an incremental intravenous infusion of either noradrenaline or angiotensin II. Pressor and heart rate responses were documented.

2. Dose-pressor response curves were constructed for the two agents in pregnant and non-pregnant women (n=14 in each group). The regression parameters of slope and intercept were calculated, and were used to derive the variables of dose required to elicit a 10 mmHg rise in systolic or diastolic blood pressure.

3. The pressor response to angiotensin II was diminished in pregnancy, with approximately twice the dose being required to raise the systolic or diastolic arterial blood pressure as in non-pregnant subjects.

4. The systolic pressor response to noradrenaline was slightly diminished in pregnancy, but the diastolic pressor response was unchanged. There were no significant differences between the doses of noradrenaline required to elicit a 10 mmHg rise in systolic or diastolic arterial blood pressure in pregnant or non-pregnant subjects.

5. There was a diminution in the bradycardia evoked in response to both hormones in pregnancy.

6. We conclude that the well-documented pressor insensitivity to angiotensin II during pregnancy is a specific phenomenon, not a manifestation of a generalized reduction in vascular reactivity.
Effects of methotrexate on rat liver regeneration after partial hepatectomy
Authors: Tsukamoto Ikuyo , Kojo Shosuke
Published: August 2015

1. Methotrexate was administered immediately after partial (70%) hepatectomy, resulting in complete inhibition of dihydrofolate reductase in 24 h-regenerating liver.

2. At 48 h and 72 h after partial hepatectomy, thymidylate synthase activity was increased, whereas thymidine kinase was inhibited, by the injection of methotrexate. The DNA and RNA contents and the liver weight were also reduced in methotrexate-treated rats.

3. The immunoblotting assay showed that methotrexate stimulated the synthesis of thymidylate synthase protein in 48 h-regenerating liver. At the same time, thymidylate synthase activity was directly inhibited by methotrexate. The mechanisms of inhibition of these enzymes by methotrexate appeared to be different.
Effects of early amino acid administration during total parenteral nutrition on protein metabolism in pre-term infants
Authors: van Lingen R. A. , van Goudoever J. B. , Luijendijk I. H. T. , Wattimena J. L. D. , Sauer P. J. J.
Published: August 2015

1. We investigated the effects of starting amino acid administration on post-natal day 2 on protein turnover and nitrogen balance in appropriate-for-gestational-age, very-low-birth-weight infants. Eighteen infants were divided into two groups. Group A received from day 2 onwards an amino acid solution, whereas group B started on this solution after day 4. Both groups were exclusively parenterally fed, 200 kJ day−1 kg−1 on post-natal days 3 and 4. Group A (birth weight 1.5 ± 0.3 kg) received 4.6 g of glucose, 1.9 g of fat and 2.3 g of amino acids day−1 kg−1 body weight. Group B (birth weight 1.4 ± 0.2 kg) received 7.0 g of glucose and 1.9 g of fat day−1 kg−1 body weight.

2. At post-natal day 3, a primed constant infusion of 3 mg of [15N]glycine day−1 kg−1 was given. Protein flux, protein synthesis and protein breakdown were calculated from the 15N enrichment in urinary ammonia. In five out of nine infants in group B no plateau of 15N enrichment in urinary urea could be detected, whereas in group A two out of nine infants did not reach a plateau. For this reason we did not use the end product urea for our calculations.

3. The administration of the amino acids resulted in a higher protein flux (6.9 ± 1.5 g day−1 kg−1 versus 5.2 ± 0.9 g day−1 kg−1) and a higher protein synthesis rate (6.0 ± 1.4 g day−1 kg−1 versus 4.6 ± 0.8 g day−1 kg−1) in group A. There was no statistically significant difference in protein breakdown. The administration of amino acids reversed a negative protein balance (−0.6 ± 0.2 g day−1 kg−1) into a positive one (1.4 ± 0.2 g day−1 kg−1. No adverse effects of the amino acid infusion were seen.

4. We conclude that the early introduction of amino acids has, even at this relatively low energy intake of 200 kJ day−1 kg−1, a positive effect on protein balance by increasing protein synthesis.
Contractile properties and susceptibility to exercise-induced damage of normal and mdx mouse tibialis anterior muscle
Authors: Sacco P. , Jones D. A. , Dick J. R. T. , Vrbová G.
Published: August 2015

1. The functional properties of tibialis anterior muscles of normal adult (C57BL/10) and age-matched dystrophin-deficient (C57BL/10 mdx) mice have been investigated in situ. Comparisons were made between tibialis anterior muscle strength, rates of force development and relaxation, force-frequency responses and fatiguability. Subjecting mdx and C57 muscles to a regimen of eccentric exercise allowed the hypothesis to be tested that dystrophin-deficient muscles are more susceptible to exercise-induced muscle damage.

2. mdx muscles were, on average, 30% stronger than C57 muscles and almost 80% heavier, but both had similar muscle lengths. Thus, although mdx muscles were stronger in absolute terms, their estimated force per unit cross-sectional area was significantly less than that of C57 muscles.

3. The force-frequency relationships of C57 and mdx muscles differed in that whilst, at 40 Hz, the former developed 70% of the force developed at 100 Hz, the latter developed only 55% of the maximal force. Twitch force was normal in mdx muscles, but contraction time was shortened, and the consequent reduction in fusion frequency probably explains the force-frequency differences observed between the two groups.

4. mdx muscles were less fatiguable than normal muscles when stimulated repeatedly at a frequency of 40 Hz. It is possible that the lower relative force at 40 Hz in mdx muscles entailed a lower energy demand and thus a slower rate of fatigue than seen in normal muscles.

5. Eccentrically exercised C57 muscles showed a large loss of maximal force for up to 12 days after exercise. Maximal force loss occurred 3 days after exercise (55% of non-exercised tibialis anterior muscle), which also corresponded with the period of greatest fibre necrosis. C57 muscles showed a significantly reduced 40 Hz/100 Hz force-frequency ratio at 1 and 3 days after exercise. This was primarily due to a reduced twitch amplitude rather than to a change in the time course of the twitch. It is unlikely, therefore, that the altered contractile characteristics of mdx muscle were a result of the presence of damaged but otherwise normal fibres.

6. C57 and mdx tibialis anterior muscles displayed similar degrees of force loss after exercise. Furthermore, the rate of recovery after the nadir of force loss was very similar for the two groups. By 12 days after exercise, force recovered to 76% and 80% of control in C57 and mdx muscles, respectively. Our findings do not support the hypothesis that dystrophin-deficient muscle is more susceptible to exercise-induced muscle damage.
Granulocyte margination in the human lung and its response to strenuous exercise
Authors: Peters A. M. , Allsop P. , Stuttle A. W. J. , Arnot R. N. , Gwilliam M. , Hall G. M.
Published: August 2015

1. It is widely believed that the lung is an important site of granulocyte margination and releases most of the granulocytes of the peripheral neutrophilia of exercise.

2. We measured granulocyte margination in the lung in terms of the lung total blood granulocyte pool and the lung circulating granulocyte pool in eight patients without inflammatory disease or evidence of lung pathology by comparing the regional γ-camera lung count rate of 111In-labelled granulocytes with that of 111In-labelled erythrocytes. According to the respective 111In activities in peripheral blood samples taken between 5 and 40 min after granulocyte injection, the lung marginating granulocyte pool was 0.78 (sem 0.045) of the lung total blood granulocyte pool or 4.6 (0.92) of the lung circulating granulocyte pool 5 min after injection, decreasing to plateau values of 0.57 (0.053) and 1.53 (0.28) from 20 min after injection. This compared with corresponding whole-body ratios of about 0.6 and 1.5, respectively.

3. After 4 min of maximal exercise in four normal subjects given 111In-labelled granulocytes 60 min before exercise, the 111In-labelled granulocyte count rate over the lung increased to 1.23 (0.05) of the pre-exercise value with a time course that was essentially identical with the time course of the peripheral native neutrophilia. The spleen 111In signal decreased with the same time course, reaching a minimum of 0.63 (0.05) of the pre-exercise level at 5–10 min after the end of exercise.

4. In a further four normal subjects given 99mTc-labelled erythrocytes, exercise resulted in an increase in the lung 99mTc count rate to 1.11 (0.05) of the pre-exercise value. This increase was maximal immediately after the end of exercise. Based on changes in peripheral haemoglobin, total blood volume decreased in the eight normal subjects to 0.89 (0.01) of the pre-exercise value.

5. Using (a) the mean increases seen in lung 111In and 99mTc count rates in the normal subjects, (b) the mean haemoconcentration recorded in the normal subjects and (c) the mean baseline ratio of lung marginating granulocyte pool/lung total blood granulocyte pool measured in the patients, we calculated that the lung marginating granulocyte pool after exercise declined to only 0.94 of the pre-exercise value in the four normal subjects given 111In-labelled granulocytes.

6. We conclude (a) that although granulocytes marginate in the lung, they do not do so to an extent greater than the average for the whole body, and (b) that there is no significant release of granulocytes from the lungs as a result of exercise.
Plasma levels of endothelin in chronic renal failure and after renal transplantation: Impact on hypertension and cyclosporin A-associated nephrotoxicity
Authors: Stockenhuber F. , Gottsauner-Wolf M. , Marosi L. , Liebisch B. , Kurz R. W. , Balcke P.
Published: August 2015

1. Plasma levels of endothelin were measured in 30 patients with chronic renal failure, 32 patients on chronic haemodialysis treatment and 25 renal graft recipients with stable renal graft function.

2. In patients with chronic renal failure as well as in patients on regular haemodialysis treatment, mean plasma levels of endothelin were significantly increased (4.59 ± 2.09 pg/ml, 10.08 ± 3.12 pg/ml, respectively) when compared with normal subjects (1.88 ± 0.6 pg/ml, P <0.01, P <0.001, respectively).

3. In the group with chronic renal failure a positive correlation between the plasma level of endothelin and the plasma concentration of creatinine was observed (P<0.003).

4. Renal graft recipients on cyclosporin A with stable renal graft function had a normal plasma level of endothelin suggesting that cyclosporin A nephrotoxicity is not mediated by endothelin.

5. Hypertensive patients with chronic renal failure or on regular haemodialysis and hypertensive renal graft recipients did not differ from the corresponding normotensive population with regard to the plasma level of endothelin, demonstrating that an increased plasma level of endothelin does not play a major role in the pathogenesis of renal hypertension.
Renal, haemodynamic and hormonal interactions between atrial natriuretic factor and arginine vasopressin in patients with congestive heart failure
Authors: Nakamura Motoyuki , Yoshida Hiroaki , Funakoshi Tsutomu , Arakawa Naoshi , Hiramori Katsuhiko
Published: August 2015

1. Nine patients with compensated heart failure were infused with synthetic arginine vasopressin at a rate of 0.1 m-units min−1 kg−1 for 60 min to increase their plasma arginine vasopressin concentration. Synthetic human atrial natriuretic factor (3 pmol min−1 kg−1) or placebo was co-infused with the arginine vasopressin in random order in a single-blind cross-over design.

2. The resultant plasma concentrations of arginine vasopressin and atrial natriuretic factor fell to within the upper range observed in congestive heart failure. Compared with the infusion of arginine vasopressin alone, atrial natriuretic factor co-infusion enhanced both the urine flow rate and the sodium excretion rate (both P < 0.05) without significant haemodynamic and hormonal effects.

3. Systematic blood pressure was elevated by arginine vasopressin infusion (P < 0.05) without any change in heart rate. Co-infusion of atrial natriuretic factor did not affect these haemodynamic parameters.

4. These results suggest that an increased release of atrial natriuretic factor maintains water and sodium excretion in the presence of arginine vasopressin-induced renal modulations, and that the pressor effect of arginine vasopressin is not antagonized by the increased plasma level of atrial natriuretic factor in patients with congestive heart failure.