bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between Serum Butyrylcholinesterase Activity, Hypertriglyceridaemia and Insulin Sensitivity in Diabetes Mellitus
Authors: Abbott C. A. , MacKness M. I. , Kumar S. , Olukoga A. O. , Gordon C. , Arrol S. , Bhatnagar D. , Boulton A. J. M. , Durrington P. N.
Published: August 2015

1. The activity of serum butyrylcholinesterase (‘pseudocholinesterase’, EC3.1.1.8) was investigated in 56 patients with type 1 diabetes mellitus, 51 patients with type 2 diabetes mellitus and 101 healthy control subjects.

2. Butyrylcholinesterase activity was significantly elevated in both type 1 (8.10 ± 3.35 units/ml) and type 2 (7.22 ± 1.95 units/ml) diabetes compared with the control subjects (4.23 ± 1.89 units/ml) (P <0.001).

3. In the patients with type 1 and type 2 diabetes, serum butyrylcholinesterase activity was correlated with log serum fasting triacylglycerol concentration (r = 0.41 and r = 0.43, respectively, P <0.001). In the type 2 population serum butyrylcholinesterase activity was also correlated with insulin sensitivity (r = −0.51, P <0.001).

4. Serum butyrylcholinesterase activity was unrelated to age, gender, serum γ-glutamyltranspeptidase activity, body mass index, or treatment for diabetes in both the diabetic populations.

5. In 37 non-diabetic patients with butyrylcholinesterase deficiency serum triacylglycerol levels were in the normal range.

6. These results are consistent with the view that butyrylcholinesterase may have a role in the altered lipoprotein metabolism in hypertriglyceridaemia associated with insulin insensitivity or insulin deficiency in diabetes mellitus.
Hyperproinsulinaemia in Impaired Glucose Tolerance
Authors: Krentz Andrew J. , Clark Penelope M. , Cox Lorna , Nattrass Malcolm
Published: August 2015

1. Basal circulating concentrations of islet B cell products were measured using two-site monoclonal antibody-based immunoradiometric assays after a 10 h overnight fast in a group of non-obese subjects with recently diagnosed impaired glucose tolerance (World Health Organization criteria). A group of healthy subjects with normal oral glucose tolerance matched for age and body mass index served as normal controls.

2. Fasting blood glucose concentration was normal in all subjects with mean (±SEM) levels of 5.1 ± 0.2 and 4.8 ± 0.2 mmol/l (P >0.1) for the group with impaired glucose tolerance and the healthy control group, respectively.

3. There was no significant difference (P >0.1) in fasting plasma insulin or C-peptide concentrations between the groups.

4. By contrast, the fasting concentration of intact proinsulin was nearly four-fold higher in the subjects with impaired glucose tolerance than in the matched healthy control subjects (4.5 ± 1.0 versus 1.2 ± 0.2 pmol/l, P <0.005).

5. Similarly, the fasting plasma concentration of 32–33 split proinsulin in the subjects with impaired glucose tolerance was almost twice that of the control subjects (7.4 ± 1.3 versus 3.9 ± 0.8 pmol/l, P <0.02).

6. In conclusion, fasting concentrations of proinsulin-like molecules are elevated in non-obese subjects with newly diagnosed impaired glucose tolerance. This observation is consistent with defective islet B cell proinsulin processing in this syndrome.
A Novel Computer-Driven, Servo-Controlled Fluid Replacement Technique and Its Application to Renal Function Studies in Conscious Rats
Authors: Burgess W. J. , Shalmi M. , Petersen J. S. , Plange-Rhule J. , Balment R. J. , Atherton J. C.
Published: August 2015

1. A new rat model has been developed allowing body fluid status to be accurately controlled and maintained throughout experimentation by computer-driven, servo-controlled replacement of spontaneous urinary fluid losses.

2. Experiments in vitro were performed to test the accuracy of the servo system, and experiments in vivo were carried out to re-assess basic renal function in servo-controlled vasopressin-replete Long Evans and vasopressin-deficient Brattleboro rats. The model was further evaluated in water-diuretic Wistar rats with or without administration of a vasopressin V2-receptor agonist, 1-desamino-8-d-arginine vasopressin.

3. The data gained from the present study indicate the suitability of the servo-controlled replacement system for conscious renal function studies in three different rat strains. Haemodynamic and renal function variables measured were demonstrated to be stable throughout a 5 h experimental procedure and reproducible between repeated experimental occasions over a 14 day post-operative period.

4. Using the servo-control technique, the expected action of 1-desamino-8-d-arginine vasopressin on renal water handling was demonstrated, but the natriuretic effect reported by some workers was not evident.

5. Since the servo-controlled fluid replacement technique maintains many of the inherent differences between vasopressin-replete Long Evans and vasopressin-deficient Brattleboro rats and eliminates the changes in body fluid volume during transition from a diuretic to an antidiuretic state, the model confers an advantage over previously employed constant infusion protocols.
Circulating Angiotensin II and Renal Sodium Handling in Man: A Dose-Response Study
Authors: Rahman A. R. A. , Motwani J. G. , Lang C. C. , Struthers A. D.
Published: August 2015

1. Animal studies have shown that angiotensin II has a biphasic effect on urinary sodium excretion. To examine whether this is also true in man, we studied seven salt-replete male subjects in a single-blind placebo-controlled manner.

2. While undergoing maximum diuresis, subjects were infused with 0, 1, 2, 5 or 10 ng of angiotensin II min−1 kg−1 over 80 min. Subjects were studied while seated, and stood every 20 min for urine collection.

3. Angiotensin II produced a dose-dependent antidiuretic effect. The urine flow rate, in ml/min expressed as the change from baseline with increasing dose of angiotensin, was: + 3.4 ±1.77, −1.26 ±0.49 (P <0.05), −2.75±1.23 (P <0.05), −4.21 ± 0.82 (P <0.05) and −6.51 ±1.07 (P <0.01).

4. In contrast, the effect of angiotensin II on sodium excretion showed a flat dose-response curve beyond 5 ng min−1 kg−1. The urinary sodium excretion, in μmol/min expressed as the change from baseline with increasing dose of angiotensin, was: 9.5 ±21.2, −18.9± 29.6, −37.0±11.6 (P <0.05), −67.7 ± 19.6 (P <0.01) and −63.8±14.3 (P <0.01).

5. The fractional distal reabsorption of sodium, determined by using the lithium clearance technique, showed a rise with all doses of angiotensin II used and reached statistical significance with the top two doses.

6. Unlike antidiuresis, antinatriuresis after graded doses of angiotensin II in human subjects showed a flat dose-response curve beyond 5 ng min−1 kg−1. Pressor doses of angiotensin II also have a significant effect on the distal tubule in promoting sodium reabsorption.
Plasma Membrane Form of Phosphatidate Phosphohydrolase: A Possible Role in Signal Transduction during Liver Fibrogenesis
Authors: Day Christopher P. , Burt Alastair D. , Brown Ashley Stj. M. , Bennett Mark K. , Farrell Desmond J. , James Oliver F. W. , Yeaman Stephen J.
Published: August 2015

1. Several growth factors important in liver regeneration and fibrosis stimulate phospholipase D in plasma membranes via a receptor/G-protein-coupled mechanism resulting in hydrolysis of phosphatidylcholine to phosphatidate. Phosphatidate can be further hydrolysed to diacylglycerol by phosphatidate phosphohydrolase. Phosphatidate and diacylglycerol can act as ‘second-messengers’ and regulation of phosphatidate phosphohydrolase activity could control the balance between them.

2. A form of phosphatidate phosphohydrolase, located in the plasma membrane and insensitive to inhibition by N-ethylmaleimide, has recently been identified that is distinct from the ‘metabolic’ form, which is present in the cytosol and microsomes and is sensitive to N-ethylmaleimide.

3. We have investigated the hypothesis that the balance between regeneration and fibrosis is, in part, determined by the activity of plasma membrane phosphatidate phosphohydrolase through its effect on the phosphatidate/diacylglycerol ratio. N-Ethylmaleimide-insensitive and -sensitive phosphatidate phosphohydrolase activities were measured in three hepatic conditions characterized by regeneration and/or fibrosis: alcoholic liver disease in humans (regeneration and fibrosis) and rat livers after either acute CCl-4-induced injury (regeneration) or common bile duct ligation (fibrosis).

4. In patients with alcoholic liver disease, N-ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was higher in cirrhotic biopsies (5.82±0.3 nmol of Pi min−1 mg−1 of protein, n = 19) than in non-cirrhotic biopsies (2.17 ±0.2, n = 23) or in wedge biopsies from healthy subjects undergoing routine cholecystectomy (2.16 ±0.5, n = 6). N-Ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was unchanged in the 10 days after CCl4 treatment but increased progressively in common bile duct-ligated rats (e.g. day 28: ‘sham’ operation, 1.97 ±0.3, chronic bile duct ligation, 6.91 ±1.24 nmol of Pi min−1 mg−1 of protein). N-Ethylmaleimide-insensitive phosphatidate phosphohydrolase activity correlated closely with the degree of fibrosis in humans and rats. N-Ethylmaleimide-sensitive phosphatidate phosphohydrolase activity was unchanged after CCI4 treatment or common bile duct ligation and was not increased in cirrhotic livers.

5. Plasma membrane N-ethylmaleimide-insensitive phosphatidate phosphohydrolase increases in liver fibrosis but not regeneration. Stimulation of phosphatidate phosphohydrolase activity with its effect on the diacylglycerol/phosphatidate ratio may play a role in transduction of the fibrosis signal.
Effect of Acute Mild Hypoglycaemia on Counterregulatory Responses to Moderate Hypoglycaemia Induced Immediately Afterwards in Healthy Men
Authors: Moriarty K. T. , Simpson E. J. , Brown N. S. , MaCdonald I. A. , Tattersall R. B.
Published: August 2015

1. This study was designed to determine whether a 1 h period of mild hypoglycaemia (33 or 3.7 mmol/l) affected the response to an episode of moderate hypoglycaemia (2.5 mmol/l) immediately afterwards.

2. Eleven non-obese healthy men (age 26 + 1 years, mean + SEM) underwent three separate 3 h hyperinsulinaemic glucose clamps in single-blind, random order. On all three occasions, blood glucose was 4.5 mmol/l for the first hour, and on a control visit was maintained at this level for the second hour. In the other two visits, blood glucose was lowered to 3.7 or 33 mmol/l during the second hour. In the third hour, blood glucose was lowered to 2.5 mmol/l on all three visits.

3. In the second hour, adrenaline rose significantly (P <0.05, analysis of variance) with a blood glucose of 33 and 3.7 mmol/l, as did cortisol and heart rate at 33 mmol/l, but glucagon, prolactin, sweating rate, symptom score and blood pressure were the same during the second hour on all three visits.

4. In the final hour at 2.5 mmol/l, there were no differences in adrenaline, noradrenaline, glucagon, prolactin, cortisol, symptom score, heart rate, blood pressure or sweating rate.

5. Thus, the overall magnitude of hormonal responses to moderate hypoglycaemia (2.5 mmol/l) are not modified by exposure to mild hypoglycaemia (33 or 3.7 mmol/l) for 1 h immediately beforehand.
Cold-induced Increases in Erythrocyte Count, Plasma Cholesterol and Plasma Fibrinogen of Elderly People without a Comparable Rise in Protein C or Factor X
Authors: Neild Penelope J. , Syndercombe-Court Denise , Keatinge W. R. , Donaldson G. C. , Mattock M. , Caunce Maria
Published: August 2015

1. Six elderly (66-71 years) and six young (20-23 years) subjects (half of each group women) were cooled for 2 h in moving air at 18°C to investigate possible causes of increased mortality from arterial thrombosis among elderly people in cold weather. Compared with thermoneutral control experiments, skin temperature (trunk) fell from 35.5 to 29.5°C, with little change in core temperature.

2. Erythrocyte count rose in the cold from 4.29 to 4.69 × 1012/l, without a change in mean corpuscular volume, indicating a 14% or 438 ml decline in plasma volume; increased excretion of water, Na+ and K+ accounted for loss of only 179 ml of extracellular water.

3. Plasma cholesterol and fibrinogen concentrations rose in the elderly subjects from 4.9 mmol/l and 2.97 g/l (control) to 5.45 mmol/l and 3.39 g/l in the cold, and in the young subjects from 3.33 mmol/l and 1.84 g/l (control) to 3.77 mmol/l and 2.07 g/l in the cold. Increases were significant for the elderly subjects, the young subjects and the group as a whole, except for cholesterol in the young subjects, and all were close to those expected from the fall in plasma volume.

4. Plasma levels of Protein C and factor X did not increase significantly in the cold in the elderly subjects, young subjects, or the group as a whole.

5. The results suggest that loss of plasma fluid in the cold concentrates major risk factors for arterial thrombosis, while small molecules, including protective Protein C, redistribute to interstitial fluid.
Increase in Muscle Nerve Sympathetic Activity in Humans after Food Intake
Authors: Fagius JAN , Berne Christian
Published: August 2015

1. The influence of the intake of different nutrients on muscle nerve sympathetic activity was studied by use of microneurography. Muscle nerve sympathetic activity, heart rate, blood pressure and the insulin response were monitored for 90 min in 39 healthy, lean, normotensive subjects (mean age 26 years) who received 100 g of glucose in 300 ml of water (n = 8), 50 g of fat in 250 ml of water (n = 8), 100 g of lean meat corresponding to 40 g of protein with 250 ml of water (n = 8), 300 ml of water only (n = 7) or a mixed meal (1750 kJ) (n = 8).

2. All types of food evoked an increase in muscle nerve sympathetic activity whereas water caused no change. The increase in muscle nerve sympathetic activity was already significant at 15–30 min and was still strongly significant at 90 min. The effect of glucose was significantly greater than that of fat and protein; the mixed meal caused an intermediate response. Blood pressure changes were minor.

3. It is concluded that a sustained increase in muscle nerve sympathetic activity occurs regularly after any type of food intake. A rise in muscle nerve sympathetic activity takes place in the absence of an insulin response, and insulin contributes to only part of the increase after ingestion of glucose or a mixed meal. The muscle nerve sympathetic activity response is thought to be of importance for the redistribution of blood to the splanchnic region after a meal. Lack of this response is likely to explain postprandial hypotension in autonomic failure.
Atrial Natriuretic Factor Potentiates the Human Forearm Vasoconstrictor Response to Sympathetic Stimulation
Authors: Jansen Tim L. Th. A. , Smits Dr Paul , Lenders Jacques W. M. , Jacobs Marie-Cécile G. S. , Willemsen Jacques , Thien Theo
Published: August 2015

1. Atrial natriuretic factor has been suggested to affect human sympathetic nervous system activity. The interaction between atrial natriuretic factor and the sympathetic nervous system has not been fully elucidated yet, but may occur at different sites. We studied this modulator effect at the level of the forearm vascular bed: the forearm vasoconstrictor response was examined after α-adrenergic sympathetic stimulation in healthy subjects during the loco-regional administration of atrial natriuretic factor, sodium nitroprusside and placebo. As a sympathetic stimulation test, the technique of the lower body negative pressure (–20 mmHg) was used.

2. Lower body negative pressure increased the forearm vascular resistance by +37 ± 8% during concomitant intra-arterial infusion of placebo (n = 10). During a predilator state achieved by infusion of atrial natriuretic factor (10 ng min−1 100 ml−1 forearm volume) into the brachial artery, lower body negative pressure subsequently induced a forearm vasoconstrictor response of +153 ± 22% (P < 0.05 versus placebo), whereas this was +64 ± 14% when predilatation was achieved by infusion of an equipotent vasodilator dose of sodium nitroprusside (P > 0.1 versus placebo; P < 0.05 versus atrial natriuretic factor). The potentiation of the forearm vasoconstrictor response to lower body negative pressure by atrial natriuretic factor only occurred in the experimental and not in the contralateral arm. According to calculations on simultaneously sampled arterial and venous plasma catecholamine concentrations, the augmented forearm vasoconstrictor response seemed not to be caused by an increased release of noradrenaline.

3. In a second experiment (n = 10), we demonstrated that atrial natriuretic factor did not alter the forearm vasoconstrictor response to the intra-arterial administration of exogenous noradrenaline, thereby excluding a postsynaptic modulation by atrial natriuretic factor. In the presence of atrial natriuretic factor, the subsequent infusion of two dosages of noradrenaline (0.1 and 1.0 ng min−1 100 ml−1 forearm volume) increased the forearm vascular resistance by +118 ± 29% and +387 ± 79%, respectively, whereas these numbered +129 ± 18% and + 316 ± 41% when atrial natriuretic factor was replaced by an equipotent dose of sodium nitroprusside.

4. We conclude that atrial natriuretic factor potentiates the forearm vasoconstrictor response to α-adrenergic sympathetic stimulation in man, and that this effect may be located at the level of the forearm vascular bed. This potentiation cannot be explained by an increased vascular α-adrenergic sensitivity. More detailed studies are needed to analyse the effects of atrial natriuretic factor on local noradrenaline kinetics to elucidate influences on sympathetic neurotransmission.
Whole Body Protein Turnover in Chronically Undernourished Individuals
Authors: Soares M. J. , Piers L. S. , Shetty P. S. , Jackson A. A. , Waterlow J. C.
Published: August 2015

1. Two groups of adult men were studied in Bangalore, India, under identical conditions: the ‘normal weight’ subjects (mean body mass index 20.8 kg/m2) were medical students of the institute with access to habitual energy and protein intakes ad libitum. The other group, designated ‘undernourished’, were labourers on daily wages (mean body mass index 16.7 kg/m2).

2. In an earlier study we obtained lower absolute values for both basal metabolic rate and protein synthesis in the undernourished subjects; however, when the data were expressed on a body weight or fat-free mass basis, a trend towards higher rates of protein synthesis, as well as higher basal metabolic rate, was evident. The suggestion was made that such results reflected the relatively higher energy intakes per kg body weight of the undernourished subjects on the day of study. The objective of the present study was therefore to control for the dietary intake during the measurement of whole body protein turnover.

3. In the present study dietary intakes were equated on a body weight basis; however, expressed per kg fat-free mass, the normal weight subjects had received marginally higher intakes of energy and protein. The results, however, were similar to those of the previous study. In absolute terms, basal metabolic rate, protein synthesis and breakdown were lower in the undernourished subjects. When expressed per kg body weight or per kg fat-free mass, the undernourished subjects had higher basal metabolic rates than the well-nourished subjects, whereas no differences were seen in the rate of protein synthesis or breakdown.

4. Estimates of muscle mass, based on creatinine excretion, indicated that the undernourished subjects had a higher proportion of non-muscle to muscle mass. Nitrogen flux (Q) was determined from 15N abundance in two end products, urea (Qu) and ammonia (Qa). The ratio Qu/Qa was increased in the undernourished subjects and was significantly correlated with the ratio of non-muscle to muscle mass (r = 0.81; P < 0.005). These results fit in with our earlier suggestion of a greater proportion of non-muscle (visceral) mass in undernourished subjects.

5. The present data suggest that there are no changes in the rate of protein synthesis or breakdown in chronic undernutrition when results are expressed, conventionally, per kg fat-free mass. It can be theoretically shown, however, that there could be a 15% reduction in the rate of turnover of the visceral tissues in chronic undernutrition. This, together with the reduced urinary nitrogen excretion, would contribute to nitrogen economy in these individuals.
Impaired Renin Stimulation in Pre-Eclampsia
Authors: Brown Mark A. , Reiter Loretta , Rodger Alison , Whitworth Judith A.
Published: August 2015

1. Pre-eclampsia is characterized by reduced plasma active renin concentration and renal prostacyclin production. The aim of this study was to determine whether the plasma active renin concentration could be stimulated in women with pre-eclampsia by intravenous frusemide, which stimulates renin acutely through a prostacyclin-mediated mechanism.

2. Plasma active renin concentration, plasma aldosterone concentration, haematocrit and urinary sodium, creatinine and 6-keto-prostaglandin F1α were measured before (0) and 15, 30 and 60 min after intravenous frusemide in 10 non-pregnant women, 10 normal pregnant women and nine women with pre-eclampsia. Six normal pregnant and six non-pregnant women underwent the same measurements after injection of 2ml of saline to control for effects of time and posture.

3. Baseline plasma active renin concentration (but not plasma aldosterone concentration) was lower in pre-eclamptic women [4.0 (1.7–6.2) pmol of angiotensin I h−1 ml−1; median (interquartile range)] than in normal pregnant women [6.7 (5.3–12.2) pmol of angiotensin I h−1 ml−1] (P < 0.05). Baseline urinary 6-keto-prostaglandin F1α/creatinine ratio, urinary sodium excretion and fractional sodium excretion did not differ between normal pregnant and pre-eclamptic women.

4. After frusemide, plasma active renin concentration rose significantly in non-pregnant (P = 0.002) and normal pregnant (P = 0.008) women, but not in women with pre-eclampsia. Individual results showed stimulation in all non-pregnant and normal pregnant women but in only six out of nine pre-eclamptic women, significantly fewer than in normal pregnancy (P < 0.05). The overall magnitude of the response of plasma active renin concentration to frusemide was blunted significantly in pre-eclamptic compared with normal pregnant women (P = 0.022).

5. Absolute and fractional sodium excretion and haematocrit rose significantly in all groups and the magnitude of change did not differ among groups for any of these parameters. The urinary 6-keto-prostaglandin F1α/creatinine ratio increased significantly only in non-pregnant women (P = 0.01), with variable individual responses in normal and hypertensive pregnant women.

6. This study shows that normal pregnant women exhibit natriuresis and stimulation of plasma renin after frusemide similar to that of non-pregnant women. However, pre-eclamptic women, as a group, have impaired renin stimulation after frusemide but a similar natriuresis to that of normal pregnant women. The mechanisms of these changes are unclear but are consistent with the notion of ‘exhausted’ renal renin in some women with pre-eclampsia.
Cyclosporin a and Vitamin D Metabolism: Studies in Patients with Psoriasis and in Rats
Authors: Shaw A. J. , Hayes M. E. , Davies M. , Edwards B. D. , Ballardie F. W. , Chalmers R. J. G. , Mawer E. B.
Published: August 2015

1. Cyclosporin A, an immunosuppressive drug used to treat psoriasis, stimulates renal synthesis of 1,25-dihydroxyvitamin D in rats. 1,25-Dihydroxy vitamin D can also reduce the activity of psoriasis, and in the present study we have examined the possibility that cyclosporin A mediates some of its actions in psoriasis by renal or extra-renal production of 1,25-dihydroxyvitamin D.

2. Treatment of 12 psoriatic patients with cyclosporin A (5 mg day−1 kg−1) for 3 months significantly improved the psoriasis activity and severity index and reduced glomerular filtration rate, but serum 1,25-dihydroxyvitamin D levels were not changed. However, 1–3 months after stopping cyclosporin A treatment, an increase in the psoriasis activity and severity index score was accompanied by a small, but significant, increase in serum 1,25-dihydroxyvitamin D concentration. Plasma 1,25-dihydroxyvitamin D levels in rats gavaged with cyclosporin A (15 mg day−1 kg−1 for 2 weeks) were significantly increased compared with controls, but a lower dose of cyclosporin A (2.4 mg day−1 kg−1) had no effect. Renal 25-hydroxyvitamin D-24-hydroxylase activity in rat kidney homogenates was not different between control and cyclosporin A-treated rats. Renal 25-hydroxyvitamin D-1α-hydroxylase activity was not detectable in these homogenates. Extra-renal production of 1,25-dihydroxyvitamin D by activated macrophages isolated from the synovial fluid of patients with inflammatory arthritis was reduced after incubation with cyclosporin A (0.1–10 μmol/l) for 30 h or 5 days.

3. It is unlikely that alteration of circulating 1,25-dihydroxyvitamin D concentration is one of the modes of action of cyclosporin A in psoriasis. Since cyclosporin A inhibits 1,25-dihydroxyvitamin D production by activated synovial fluid macrophages, it is unlikely that cyclosporin A mediates some of its therapeutic actions by local synthesis of 1,25-dihydroxyvitamin D within the psoriatic lesion.
The Transplanted Human Kidney Does Not Achieve Functional Reinnervation
Authors: Hansen Jesper Melchior , Abildgaard Ulrik , Fogh-Andersen Niels , Kanstrup Inge-Lis , Bratholm Palle , Plum Inger , Strandgaard Svend
Published: August 2015

1. Previous histological studies have demonstrated partial reinnervation of the human transplanted kidney. However, it remains unknown whether this reinnervation is of any functional significance.

2. The effects of noradrenaline infusion (2 μgh−1kg−1) and lower body negative pressure (−27 mmHg) on renal haemodynamics, sodium excretion and tubular function were investigated in 25 renal transplant recipients and 10 normal subjects. Sixteen of the transplant recipients had all been transplanted for more than 27 months, and nine had all been transplanted for less than 2 months.

3. After an overnight fast, the subjects were water-loaded, and clearance studies were performed with a 1 h baseline period, a 1 h period with noradrenaline infusion, another 1 h baseline period, and a final 1 h period with lower body negative pressure.

4. During noradrenaline infusion the relative decrease in effective renal plasma flow, glomerular filtration rate and clearance of lithium and sodium was significantly more pronounced in the long-term transplanted patients than in the control subjects.

5. Lower body negative pressure only depressed the glomerular filtration rate significantly in the control subjects. Further, the relative decrease in effective renal plasma flow and clearance of lithium and sodium was significantly greater in the control subjects than in the two groups of transplanted patients.

6. The present study thus demonstrated that in short- and long-term transplanted kidneys in man, supersensitivity to circulating noradrenaline and an inadequate response to lower body negative pressure was present. This strongly suggests that the human transplanted kidney remains functionally denervated.
Detection of Changes in Intrathoracic Fluid in Man Using Electrical Impedance Tomography
Authors: Campbell J. H. , Harris N. D. , Zhang F. , Morice A. H. , Brown B. H.
Published: August 2015

1. The Sheffield electrical impedance tomography system produces information on changes in the distribution of resistivity within tissue. We report on the assessment of electrical impedance tomography in monitoring changes in lung resistivity during a fluid challenge in normal man.

2. Eight normal subjects were studied. Electrical impedance tomography recordings were made at three different lung volumes before, during and after the intravenous infusion of 1 litre of 0.9% NaCl (saline).

3. The mean fall in lung resistivity during the infusion was −22% at total lung capacity (range −10% to −28%), −24% at tidal breathing (−15% to −37%) and −11% at residual volume (-5% to −19%) (P < 0.05 mean pre-infusion resistivity compared with the nadir value after infusion, Wilcoxon).

4. These changes in lung resistivity were probably due to a combination of a fall in haematocrit and an expansion of pulmonary blood volume.
Predictive Value of Soluble Immunological Mediators in Neonatal Infection
Authors: Edgar J. D. M. , Wilson D. C. , McMillan S. A. , Crockard A. D. , Halliday M. I. , Gardiner K. R. , Rowlands B. J. , Halliday H.L. , McNeill T. A.
Published: August 2015

1. Infection in the neonatal period is difficult to diagnose and is a significant cause of morbidity and mortality in preterm infants.

2. We investigated prospectively the predictive value of plasma measurement of bacterial endotoxin (lipo-polysaccharide), tumour necrosis factor-α, interleukin-6, interleukin-8, intercellular adhesion molecule-1 and C-reactive protein in 60 consecutive newborn infants suspected of having neonatal infection. Plasma samples were taken at the time of acute clinical deterioration. Sixty-two cord blood samples were studied as controls taken at elective Caesarean section.

3. Forty-three infants had confirmed infections, 25 with positive blood cultures. Tumour necrosis factor-α and bacterial endotoxin levels were not significantly elevated over controls, whereas interleukin-6, interleukin-8 and intercellular adhesion molecule-1 levels were all significantly increased in the infected group compared with controls (all P < 0.001).

4. Increased plasma intercellular adhesion molecule-1 levels were a highly sensitive (88%) indicator of clinical infection and were independent of C-reactive protein. Use of these two assays in combination improved the diagnostic sensitivity to 95% and gave a negative predictive value of 97%. Addition of interleukin-6 or interleukin-8 measurements failed to further significantly enhance the prediction of infection.

5. Measurement of intercellular adhesion molecule-1 level may have a clinical role in rapidly confirming, or predicting, the likely diagnosis in cases of suspected neonatal infection.
Vascular Responses to Vasopressin Antagonists in Man and Rat
Authors: Burrell Louise M. , Phillips Paddy A. , Rolls K. A. , Buxton B. F. , Johnston C. I. , Liu J. J.
Published: August 2015

1. The effects of the non-peptide arginine vasopressin V1 receptor antagonist (OPC-21268) and the non-peptide V2 receptor antagonist (OPC-31260) on vasopressin-induced contraction of human internal mammary arteries and rat mesenteric resistance arteries were investigated.

2. In human internal mammary arteries, the non-peptide V1 receptor antagonist, OPC-21268, failed to antagonize vasopressin-induced contraction at low concentrations and potentiated the contraction at higher concentrations (300 nmol/l, P < 0.05). A peptide selective V1 receptor antagonist {[d(CH2)5, sarcosine7]arginine vasopressin} potently inhibited the vasopressin-induced contraction, indicating the presence of functionally constrictor V1 receptors in human internal mammary arteries. Both peptide (desGly-NH29[d(CH2)5, D-Ile2, Ile4]arginine vasopressin) and non-peptide ‘selective’ V2 receptor antagonists (OPC-31260, 3 μmol/l) significantly antagonized vasopressin-induced contraction (P < 0.01), indicating partial V1 receptor antagonist activity.

3. The vasopressin-induced contraction in human internal mammary arteries was reversed by high concentrations of the non-peptide V2 receptor antagonist, OPC-31260, but not by the non-peptide V1 receptor antagonist, OPC-21268.

5. In rat mesenteric resistance arteries, both OPC-21268 (10 nmol/l) and OPC-31260 (1 μmol/l) antagonized vasopressin-induced contraction (P < 0.01).

6. The results of this study in vitro indicate that in human internal mammary arteries, the non-peptide OPC-21268 is a partial V1 receptor agonist with no V1 receptor antagonist activity, whereas the non-peptide OPC-31260 acts as a V1 receptor antagonist. Both OPC-21268 and OPC-31260 have V1 receptor antagonistic activity in vitro in the rat mesenteric resistance arteries.

7. These findings illustrate the complexity of the vasopressin receptor system and highlight the variability in results with peptide or non-peptide vasopressin analogues, between studies in vivo or in vitro, between species and across vascular beds.
Insulin Sensitivity in Post-Obese Women
Authors: Toubro Søren , Western Philip , Bülow Jens , Macdonald Ian , Raben Anne , Christensen Niels Juel , Madsen Joop , Astrup Arne
Published: August 2015

1. Both increased and decreased sensitivity to insulin has been proposed to precede the development of obesity. Therefore, insulin sensitivity was measured during a 2 h hyperinsulinaemia (100 m-units min−1 m−2) euglycaemic (4.5 mmol/l) glucose clamp combined with indirect calorimetry in nine weight-stable post-obese women and in nine matched control women preceded by 12 h fasting after 48 h on a standardized diet.

2. Both glucose disposal rate (post-obese women, 9.5 ± 2.2 mg min−1 kg−1, control women, 11.2 ± 1.4 mg min−1 kg−1, not significant) and glucose oxidation (3.6 ± 0.5 mg min−1 kg−1 versus 4.0 ± 0.7 mg min−1 kg−1, not significant) were similar in the two groups during the last 30 min of the clamp. Lipid oxidation also decreased similarly during the clamp in the post-obese women (from 30.4 ± 12 to 2.0 ± 7 J min−1 kg−1) and in the control women (from 33.6 ± 11 to 5.4 ± 8 J min−1 kg−1, not significant). Basal plasma concentrations of free fatty acids were similar, but at the end of the clamp free fatty acids were lower in the post-obese women than in the control women (139 ± 19 and 276 ± 48 μmol/l, P = 0.02).

3. We conclude that the insulin sensitivity of glucose metabolism is unaltered in the post-obese state. The study, however, points to an increased antilipolytic insulin action in post-obese subjects, which may favour fat storage and lower lipid oxidation rate post-prandially. The results suggest that alterations in lipid metabolism may contribute to the explanation of the propensity to obesity in susceptible individuals.
Cardiac Muscle Protein Gene Expression in the Endotoxin-Treated Rat
Authors: Macallan D. C. , Griffin G. E.
Published: August 2015

1. Sepsis is associated with marked changes in cardiac muscle protein synthesis. Such changes may be the result of altered transcription of specific myofibrillar protein mRNAs.

2. In order to investigate myofibrillar protein gene expression, a rat model of sepsis was used. Adult rats were given a single sub-lethal dose of lipopolysaccharide by the intraperitoneal route. At various times thereafter, rats were killed and ventricular muscle was removed. RNA was extracted and transferred to nylon membranes. Changes in expression of mRNA for α- and β-myosin heavy chain, α-actin, cardiac troponin C and carbonic anhydrase III were detected by Northern hybridization.

3. After treatment with lipopolysaccharide, mRNA for β-myosin heavy chain increased to 260% of control values at 24 h and reached a maximum of 310% at 48 h. α-Myosin heavy chain mRNA levels fell to 72% of control values at 24 h. mRNA levels for α-actin, cardiac troponin C and carbonic anhydrase III remained unchanged.

4. In order to investigate the role of tumour necrosis factor-α in this process, some rats were pretreated with monoclonal antibody against tumour necrosis factor-α before receiving lipopolysaccharide. Such animals showed an absence of tumour necrosis factor-α bioactivity in plasma, but changes in myocardial protein mRNA levels were no different from those seen in animals receiving lipopolysaccharide alone.

5. The reduction in protein synthesis in cardiac muscle in sepsis does not appear to be the result of reduced expression of genes for structural or soluble muscle protein. Rather there is a paradoxical increase in β-myosin heavy chain expression, which may represent a protective mechanism. Tumour necrosis factor-α does not appear to be involved in the mediation of these changes.
Increased Serum Concentrations of Adhesion Molecules after Coronary Angioplasty
Authors: Kurz Robert W. , Graf Bernhard , Gremmel Franz , Wurnig Christian , Stockenhuber Felix
Published: August 2015

1. Reocclusion is still a significant complication after percutaneous transluminal coronary angioplasty. The injury of coronary arteries resulting from PTCA plays an important role in the pathophysiology of both abrupt closure and late restenosis after an initially successful procedure. Cytokines play a pivotal role in the accumulation of circulating blood cells at the endothelium and are known to regulate their interaction with the vessel wall.

2. To obtain further information about this interaction, serum concentrations of soluble endothelial leukocyte adhesion molecule 1 (sELAM-1), leucocyte endothelial cell adhesion molecule 1 (sL-selectin), intercellular adhesion molecule 1 (sICAM-1), interleukin 2 receptor (sIL-2R) and interleukin 8 (IL-8) detected by enzyme-linked immunosorbent assay were monitored in 30 consecutive patients referred for elective PTCA. Fifteen patients who underwent elective coronary angiography without PTCA served as controls.

3. All patients underwent successful first PTCA. Within 24 h the serum concentrations of sELAM-1 increased gradually from 21.7 (SD 7.1) to 48.2 (SD 8.6) ng/ml (P < 0.01); levels of sL-selectin rose from 982.1 (SD 128.7) to 1541.3 (SD 104.6) ng/ml after 48h (P < 0.01). Serum levels of IL-8 remained stable initially, but peaked at the end of the observation time of 72 h (9.4, SD 3.8, versus 16.1, SD 4.9 ng/ml; P < 0.05). A positive correlation was found between the number of dilatations and the rise in these parameters (P < 0.01). No significant changes were found in the serum concentrations of sICAM-1 and sIL-2R after PTCA or in any of the parameters in patients after coronary angiography.

4. We conclude that PTCA induces a significant rise in the concentration of certain adhesion molecules in serum. Thus, we provide preliminary data on the potential role of cytokines for blood cell-endothelium interaction after PTCA. Further investigations and larger numbers of patients are needed to clarify the role of circulating cytokines for endothelial injury and restenosis after PTCA.
Low-Frequency Spontaneous Fluctuations of R-R Interval and Blood Pressure in Conscious Humans: A Baroreceptor or Central Phenomenon?
Authors: Bernardi Luciano , Leuzzi Stefano , Radaelli Alberto , Passino Claudio , Johnston James A. , Sleight Peter
Published: August 2015

1. We have tested the hypothesis that the non-respiratory, low-frequency (around 0.1 Hz) fluctuations of heart rate variability are generated by the baroreflexes, but with a delay caused by the slower response of the efferent sympathetic arm, (compared with the vagus), in 11 healthy subjects (mean age ± SD 27 ± 5 years).

2. In random order, at the onset of 20 s of apnoea starting at end expiration, we applied either 600 ms neck suction (−40 mmHg) to the carotid sinus region, or no stimulus (anticipation control), or a loud whistle (alerting control), every 60s, for 30 min. (i.e. 10 of each ‘stimulus’). We recorded neck pressure, blood pressure (Finapres), R-R interval (ECG), infra-red plethysmographic skin blood flow and respiration (impedance). By subtracting the alerting response from the neck suction response we obtained the responses caused purely by baroreceptor stimulation.

3. The initial reflex bradycardia and hypotension was followed by arteriolar vasoconstriction, presumably due to recompensation by the baroreflex, and then by a further reflex bradycardia—producing a decaying oscillation of the R-R interval about the control R-R. The period of this damped oscillation was 0.103 ± 0.024 Hz, similar to the frequency of the low-frequency peak obtained by power spectral analysis of heart rate variability (0.093 ± 0.016 Hz, not significant) at rest. These two values were significantly correlated in individual subjects (r = 0.715, P < 0.025).

4. These findings support the hypothesis that the low-frequency waves of heart rate variability can be generated from baroreceptor sensed blood pressure fluctuations.
Plasma Natriuretic Peptides and Cardiac Volume during Acute Changes in Intravascular Volume in Haemodialysis Patients
Authors: Corboy John C. , Walker Robert J. , Simmonds Mark B. , Wilkins Gerard T. , Richards A. Mark , Espiner Eric A.
Published: August 2015

1. Plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptides (BNP) were measured, along with left and right atrial and left ventricular volumes, in eight patients with chronic renal failure before and after the removal of 2.1 ± 0.61 of fluid by ultrafiltration and again during volume repletion with intravenous sodium chloride solution (150 mmol/l saline) to restore body weight plus 0.5 kg.

2. Baseline levels of ANP (46.0 ± 7.5 pmol/l) and BNP (22.0 ± 4.4 pmol/l) were elevated above normal. There was a significant reduction in plasma ANP (26.5 ± 4.7 pmol/l, P < 0.05) and BNP (19.1 ± 4.9 pmol/l, P < 0.05)) following ultrafiltration. Changes in plasma ANP during ultrafiltration correlated significantly with changes in left atrial volume (r = 0.643, P < 0.05).

3. During volume repletion there was an exaggerated release of ANP (mean level post repletion 71.3 ± 20.8 pmol/l) which was not paralleled by changes in BNP. Changes in BNP were small, showing no correlation with atrial or ventricular volumes during either ultrafiltration or volume repletion.

4. These findings indicate that in chronic renal failure without left ventricular dysfunction, moderate acute changes in volume status elict only small immediate responses in plasma BNP. Changes in plasma ANP are greater than BNP and more responsive to changes in left atrial volume.
Impaired Renal Function in Obstructive Jaundice: Enhanced Glomerular Thromboxane Synthesis and Effects of Thromboxane Receptor Blockade in Bile Duct-Ligated Rats
Authors: Kramer Herbert J. , Schwarting Kriemhild , Bäcker Angela
Published: August 2015

1. Patients with obstructive jaundice are especially susceptible to acute renal failure. We have previously observed that in rats with bile duct ligation impaired renal function is associated with increased urinary thromboxane excretion.

2. In the present study we therefore investigated, in rats with bile duct ligation, renal function, urinary thromboxane excretion and thromboxane B2 synthesis by isolated glomeruli as well as the effects of the thromboxane A2/prostaglandin H2 receptor antagonist Daltroban on renal function in rats with bile duct ligation as compared with sham-operated rats.

3. On the fourth day after bile duct ligation (n = 7 rats) endogenous creatinine clearance as an estimate of glomerular filtration rate was significantly reduced to 0.74 ± 0.05 (SEM) as compared with 1.06 ± 0.09 ml min−1 g−1 kidney weight in sham-operated rats (n = 7, P < 0.01). In rats with bile duct ligation, urine volume was slightly increased, whereas urinary sodium (Na+) (P < 0.001) and potassium (K+) (P < 0.01) excretion as well as urine osmolarity (P < 0.05) were significantly reduced and lower than in sham-operated rats.

4. Urinary thromboxane excretion was significantly higher in rats with bile duct ligation than in sham-operated rats: 116.6 ± 22.3 versus 56.8 ± 10.2 pmol 24h−1 100 g−1 body weight (P < 0.05). Thromboxane B2 synthesis in glomeruli isolated from rats with bile duct ligation was also significantly higher than in sham-operated rats: 12.6 ± 2.0 versus 6.4 ± 0.9 pmol h−1 mg−1 protein (P < 0.05).

5. The thromboxane A2/prostaglandin H2 receptor antagonist Daltroban normalized glomerular filtration rate in a second group of rats with bile duct ligation (n = 7) to 1.03 ± 0.08 (P < 0.01) and slightly increased it in sham-operated rats (n = 7) to 1.24 ± 0.11 ml min−1 g−1 kidney weight (not significant). Daltroban, while without effects on urine volume and osmolarity in sham-operated rats, further increased urine volume and decreased osmolarity in rats with bile duct ligation after surgery. After surgery Daltroban reduced fractional Na+ and K+ excretion in sham-operated rats and in rats with bile duct ligation.

6. The results suggest that obstructive jaundice following bile duct ligation is associated with enhanced renal glomerular thromboxane A2 synthesis, which suppresses glomerular filtration rate and predisposes to acute renal failure. Treatment with Daltroban, a specific thromboxane A2/prostaglandin H2 receptor antagonist, restores glomerular filtration rate to normal, probably secondary to normalization of disturbed intrarenal blood flow following bile duct ligation.
Comparative Effects of Atrial Natriuretic Peptide and Brain Natriuretic Peptide on the Aldosterone and Pressor Responses to Angiotensin Ii in Man
Authors: Cargill Robert I. , Struthers Allan D. , Lipworth Brian J.
Published: August 2015

1. Atrial natriuretic peptide and brain natriuretic peptide have similar vasodilator and natriuretic properties, although little information is available regarding their relative effects as antagonists of the renin—angiotensin—aldosterone system. We have therefore compared how atrial natriuretic peptide and brain natriuretic peptide affect the systemic pressor and aldosterone responses to angiotensin II in eight male subjects.

2. Each subject was studied on three separate occasions, when they received a 60-min infusion of placebo, atrial natriuretic peptide (10 pmol min−1 kg−1) or brain natriuretic peptide (10 pmolmin−1 kg−1), with a concomitant infusion of angiotensin II (6 ng min−1 kg−1) given for the final 30 min of the infusion period. The change in haemodynamic parameters and plasma aldosterone induced by angiotensin II was measured. Plasma concentrations of atrial natriuretic peptide (182 ± 23 pmol/l) and brain natriuretic peptide (193 ± 25 pmol/l) achieved at steady-state during the infusion on each study day were not significantly different.

3. Increases in mean arterial pressure in response to angiotensin II were significantly lowered by concomitant infusion of atrial natriuretic peptide (21.0 ± 1.7 mmHg) and brain natriuretic peptide (20.1 ± 1.9 mmHg) compared with placebo (29.0 ± 4.1 mmHg). There were similar effects on systolic and diastolic blood pressure. Cardiac output was decreased on each study day to the same extent by angiotensin II infusion. Total systemic vascular resistance showed a non-significant trend towards an attenuated response to angiotensin II when atrial natriuretic peptide or brain natriuretic peptide was infused concomitantly in comparison with placebo.

4. Plasma aldosterone increased by 326 ± 49 pmol/l when angiotensin II was infused with placebo. Both atrial natriuretic peptide and brain natriuretic peptide significantly blunted this response, although the increase with atrial natriuretic peptide (19 ± 35 pmol/l) was significantly lower than the increase with brain natriuretic peptide (133 ± 19 pmol/l).

5. Atrial natriuretic peptide and brain natriuretic peptide were therefore equally effective in blunting the systemic pressor response to angiotensin II. It was apparent, however, in view of similar plasma concentrations at steady state, that on a molar basis atrial natriuretic peptide was a more potent inhibitor of angiotensin II-induced aldosterone secretion than brain natriuretic peptide. These results suggest a dissociation between the haemodynamic and hormonal effects of atrial natriuretic peptide and brain natriuretic peptide in terms of antagonism of the renin—angiotensin—aldosterone system.