bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Haemodynamic Responses and Inhibition of Tumour Necrosis Factor-α by Pentoxifylline in Rats with Cirrhosis
Authors: Soupison Thierry , Yang Song , Bernard Catherine , Moreau Richard , Kirstetter Philippe , D'Almeida Mark , Cailmail Stéphane , Tedgui Alain , Lebrec Didier
Published: August 2015

1. Although pentoxifylline has been shown to reduce portal hypertension, the mechanism for this is unclear. Since pentoxifylline decreases tumour necrosis factor-α production and since this cytokine may induce vasodilatation per se, a pentoxifylline-induced decrease in tumour necrosis factor-α production may limit arterial vasodilatation and decrease portal pressure. The aim of the present study was to examine the effects of pentoxifylline administration on plasma tumour necrosis factor-α concentrations and haemodynamics in normal and cirrhotic rats.

2. In both groups, systemic and splanchnic haemodynamics and plasma tumour necrosis factor-α concentrations were measured before and 120 min after the administration of saline or pentoxifylline (20 mg/kg intravenous bolus).

3. In cirrhotic rats, pentoxifylline significantly decreased portal pressure (24 ± 13%) and tributary blood flow (33 ± 30%). On the other hand, pentoxifylline significantly increased vascular resistance in portal and hepatic arterial territories. Systemic haemodynamics were not altered. In normal rats, pentoxifylline significantly decreased portal pressure but induced no other significant changes in splanchnic or systemic haemodynamics. In cirrhotic rats, plasma tumour necrosis factor-α concentrations were significantly reduced after pentoxifylline administration but not after saline administration. No significant correlations were found between pentoxifylline-induced changes in tumour necrosis factor-α levels and changes in splanchnic haemodynamics. In normal rats, plasma tumour necrosis factor-α concentrations significantly decreased after pentoxifylline or saline administration.

4. This study shows that in rats with cirrhosis, pentoxifylline induces a decrease in both portal pressure and plasma tumour necrosis factor-α concentrations. These reductions were not correlated however.
Non-Invasive Measurement of Cardiac Oxygenation and Haemodynamics during Transient Episodes of Coronary Artery Occlusion and Reperfusion in the Pig
Authors: Thorniley M. S. , Lahiri A. , Glenville B. , Shurey C. , Baker G. , Ravel U. , Crawley J. , Green C. J.
Published: August 2015

1. The non-invasive method of near-infrared spectroscopy was used to measure myocardial oxygenation and haemodynamics in response to left anterior descending coronary artery occlusion in a porcine model.

2. Near-infrared spectroscopy measures changes in haemoglobin (and myoglobin) oxygenation and blood volume to yield information on tissue perfusion and flow. It also measures the redox state of cytochrome aa3, thus providing information about intracellular oxygen utilization.

3. Left anterior descending coronary artery occlusion was induced to produce periods of ischaemia lasting between 24 s and 13.5 min (n = 13). The changes in deoxyhaemoglobin, oxyhaemoglobin and cytochrome aa3 measured during occlusion were all highly significant compared with baseline variation. In all occlusions (n = 13) a rapid decrease in oxyhaemoglobin concentration (−75.83 ± 3.27 μmol/l, mean ± SEM) with a simultaneous increase in deoxyhaemoglobin of 9.27 ± 1.69 μmol/l was measured. The total haemoglobin concentration also fell by −71.3 ± 5.32 μmol/l. Cytochrome aa3 was also reduced during occlusion (–8.35 ± 1.044) μmol/l.

4. Over the range 24–60 s occlusion, the magnitude of the fall in total haemoglobin and oxyhaemoglobin correlated with the duration of occlusion (P > 0.003 and 0.013 respectively). For total haemoglobin only the magnitude of the fall correlated with the increase upon release of occlusion (r = 0.89, P > 0.003).

5. Release of occlusion (n = 8) resulted in an immediate increase in the concentration of deoxyhaemoglobin at 9.88 ± 1.06 s, then total haemoglobin at 13.62 ± 1.23 s and finally oxyhaemoglobin at 29.75 ± 5.96 s. The difference between the timing of the maxima after reperfusion is significant (P > 0.002 and P > 0.007 respectively). Moreover, the time for the deoxyhaemoglobin signal to reach maximum values was found to correlate with the duration of occlusion (P > 0.04). This could be indicative of the Po2 of the ischaemic tissues and an immediate off-loading of oxygen from oxyhaemoglobin. The results are reliable, reproducible and sensitive enough to detect the kinetics of haemoglobin oxygenation from a beating heart in situ.
Abnormal Baroreceptor—Cardiac Reflex Sensitivity is Not Detected by Conventional Tests of Autonomic Function in Patients with Insulin-Dependent Diabetes Mellitus
Authors: Weston Philip J. , James Martin A. , Panerai Ronnie , McNally Paul G. , Potter John F. , Thurston Herbert , Swales John D.
Published: August 2015

1. Autonomic neuropathy is a common complication of diabetes mellitus and is a major risk factor for sudden death.

2. A group of 30 patients with insulin-dependent diabetes mellitus and 30 age-, sex- and blood pressure-matched control subjects underwent traditional tests of autonomic function. Resting supine R—R interval and systolic blood pressure variability were assessed using spectral analysis methods. In addition, we assessed the baroreceptor—cardiac reflex from the linear relation of the change in R—R interval to the increasing systolic blood pressure measured noninvasively with the Finapres monitor during phase 4 of the Valsalva manoeuvre and from resting heart rate and systolic blood pressure power spectra.

3. Whereas standard tests of autonomic function revealed no differences between patients with insulin-dependent diabetes mellitus and control subjects, there was a significant reduction in power spectral density of heart rate variability around the high-frequency region (125.2 ± 112.9 versus 459.3 ± 189.8 ms2, mean ± SD). Furthermore, reductions in baroreflex sensitivity calculated from the Valsalva manoeuvre were detected in diabetics compared with controls (3.3 ± 1.6 versus 9.5 ± 2.5 ms/mmHg, mean ± SD, P > 0.00001). There were significant relations between impairment of the baroreflex and duration of diabetes (P > 0.001) and poor diabetic control (P > 0.05).

4. In summary, autonomic dysfunction occurs much more frequently in diabetic patients than conventional tests would suggest. Abnormal baroreceptor—cardiac reflex sensitivity in patients with insulin-dependent diabetes mellitus may in part be explained by abnormal parasympathetic function. This unrecognized abnormality may have a role in the increased incidence of sudden death seen in young diabetic subjects.
Potential Confounding Effect of Hand-Warming on the Measurement of Insulin Sensitivity
Authors: Petrie John R. , Ueda Shinichiro , Morris Andrew D. , Elliott Henry L. , Connell John M. C.
Published: August 2015

1. Hand-warming is employed during metabolic studies to ‘arterialize’ venous blood, but also has systemic haemodynamic effects. Study 1 aimed to determine if hand-warming affects the value for whole-body insulin sensitivity derived from the hyperinsulinaemic euglycaemic clamp technique. Study 2 was designed to assess the effect of hand-warming on contralateral forearm blood flow.

2. In study 1, eight healthy male subjects attended for four modified euglycaemic clamp studies, during which the right hand was placed in a heated-air hand box (55°C), and the glucose infusion rate was adjusted according to blood samples from a cannula in either an ipsilateral dorsal hand vein or a contralateral antecubital vein with the box switched either on or off. In study 2, five healthy subjects attended two study days when the effect of 2h of hand-warming (or control) on contralateral forewarm blood flow was measured.

3. Study 1: when clamps were performed according to samples taken from the contralateral antecubital vein, insulin sensitivity values were significantly lower during box-on versus box-off clamps (mean ± SD 10.2 ± 3.0 versus 13.0 ± 3.8 ingrain−1 kg−1, P > 0.05, 95% confidence interval −0.2, −5.3). When clamps were performed according to samples taken from the ipsilateral hand, there was no difference in insulin sensitivity during box-on versus box-off clamps (9.2 ± 2.1 versus 9.0 ± 1.7 mg min−1 kg−1, P not significant, 95% confidence interval −0.5, +0.9). There was a mean increase in heart rate of 6 beats/min in the box-on conditions (P > 0.05, analysis of variance). Study 2: forearm blood flow in the contralateral arm during hand-warming was significantly higher than in the control condition (P > 0.05, analysis of variance), although heart rate was similar on both study days.

4. Hand-warming had a detectable effect on insulin sensitivity when clamps were performed according to samples withdrawn from the contralateral arm, but no measurable effect when clamps were performed in the conventional manner. In addition, hand-warming increased heart rate during hyperinsulinaemia and contralateral FBF under basal conditions. These findings raise concern about unwanted (potentially confounding) systemic haemodynamic effects of hand-warming on the measurement of insulin sensitivity and insulin-mediated vasodilatation.
Effects of Vitamin E Supplementation on Erythrocyte Antioxidant Defence Mechanisms of Smoking and Non-Smoking Men
Authors: Brown K. M. , Morrice P. C. , Arthur J. R. , Duthie G. G.
Published: August 2015

1. During all aerobic metabolism, free radicals generated by the partial reduction of oxygen are potentially injurious to cells. Highly efficient antioxidant defence systems exist to inhibit oxidative damage to cellular lipids and proteins. Specific enzymes have a crucial role in these antioxidant defences, and their activity may be induced by regulatory mechanisms that respond to oxygen metabolite concentration.

2. To assess whether smoking induces an additional adaptive response, we compared antioxidant defence systems in erythrocytes from smokers and non-smokers and assessed whether a high intake of vitamin E (280 mg/day), a major lipophilic free-radical-scavenging antioxidant, affects the activity of antioxidant enzymes.

3. A total of 100 men, 50 smokers and 50 non-smokers, were allocated to four treatment groups in a 2 × 2 factorial design (smokers versus non-smokers and placebo versus vitamin E). For 10 weeks each subject took one capsule per day of either 280 mg dl-α-tocopherol acetate or a visually identical placebo (hydrogenated coconut oil with negligible vitamin E content).

4. Despite increased erythrocyte cytosolic antioxidant enzyme activities in smokers compared with non-smokers, erythrocytes from smokers were more susceptible to hydrogen peroxide-induced lipid peroxidation in vitro.

5. Vitamin E supplementation further increased erythrocyte catalase (EC 1.11.1.6) activity in both smokers and non-smokers (P > 0.001) and erythrocyte glutathione peroxidase (EC 1.11.1.9) and glutathione reductase (EC 1.6.4.2) activities in non-smokers (P > 0.001). After supplementation with vitamin E there was a concomitant fall in erythrocyte superoxide dismutase (EC 1.15.1.1) activity (P > 0.001) and total glutathione concentration (P > 0.01). Furthermore, in both smokers and non-smokers there was a significant decrease in the susceptibility of erythrocytes to peroxidation (P > 0.001).

6. Various endogenous and exogenous factors exert control over cellular protection against reactive oxygen species, and our data suggest that one such factor is the supply of vitamin E.
Peripheral Haemodynamics and Renal Function in Relation to the Menstrual Cycle
Authors: Van Beek E. , Houben A. J. H. M. , Van Es P. N. , Willekes C. , Korten E. C. C. M. , De Leeuw P.W. , Peeters L. L. H.
Published: August 2015

1. The objective of this study was to investigate whether the luteal phase of the menstrual cycle differs from the follicular phase by the development of a state of general vascular relaxation.

2. Once in the follicular and once in the luteal phase of the menstrual cycle, we measured by non-invasive techniques: arterial blood pressure (by finger blood pressure measurements), vascular tone (by pulse-wave velocity and plethysmography), blood flow to skin (by laser-Doppler), blood flow to forearm (by plethysmography) and blood flow to kidneys (by para-aminohippurate clearance), and the glomerular filtration rate (by inulin clearance). The data points obtained in the luteal phase were compared with those in the follicular phase by non-parametric tests.

3. Arterial blood pressure, vascular tone and the blood flows to the forearm and kidneys were comparable in the two phases of the menstrual cycle. In contrast, the blood flow to the skin was consistently lower, and the glomerular filtration rate higher in the luteal phase of the menstrual cycle.

4. The results of the present study do not support our hypothesis of a general vascular relaxation in the luteal phase of the menstrual cycle. The lower skin flow in the luteal phase may be an adaptation needed to ensure the higher core temperature of 0.3–0.5°C in the luteal phase. The higher glomerular filtration rate was in most cases paralleled by a higher renal blood flow in the luteal phase. This suggests that the higher glomerular filtration rate is secondary to a selective vasorelaxation of the afferent renal arterioles.
Behaviour of Adrenomedullin during Acute and Chronic Salt Loading in Normotensive and Hypertensive Subjects
Authors: Ishimitsu Toshihiko , Nishikimi Toshio , Matsuoka Hiroaki , Kangawa Kenji , Kitamura Kazuo , Minami Jun-Ichi , Matsuo Hisayuki , Eto Tanenao
Published: August 2015

1. Responses of adrenomedullin to acute and chronic salt loading were examined in normotensive and hypertensive subjects.

2. In the acute salt load study, isotonic saline (50 ml/kg for 1 h) was intravenously infused into nine normotensive subjects and 11 patients with essential hypertension. Plasma adrenomedullin was higher in hypertensive than in normotensive subjects but was unchanged by saline infusion in either the normotensive (before infusion, 2.4 ± 0.2 fmol/ml; after infusion, 2.4±0.1 fmol/ml) or hypertensive (before infusion, 3.0±0.1 fmol/ml; after infusion, 2.9 ± 0.2 fmol/ml) group, while renin was suppressed and atrial natriuretic peptide was markedly increased. Plasma endothelin was not affected either.

3. In the chronic salt load study, seven normotensive subjects and 23 patients with essential hypertension underwent two 7-day periods of 30 and 260 mmol/day sodium intake. Depending on the blood pressure change, 13 hypertensive subjects were classified as salt-resistant and 10 as salt-sensitive. Salt-sensitive hypertensive subjects had suppressed plasma renin activity even during low salt intake. Plasma adrenomedullin or endothelin were not affected by the salt intake changes in any group; however, the high salt intake increased atrial natriuretic peptide in all groups.

4. These data indicate that the circulating level of adrenomedullin is not changed by either acute or chronic salt loading in normotensive subjects and patients with essential hypertension.
Impairment of Intracellular Calcium Homoeostasis in the Exocrine Pancreas after Caerulein-Induced Acute Pancreatitis in the Rat
Authors: Bragado M. J. , Roman J. I. San , González A. , García L. J. , López M. A. , Calvo J. J.
Published: August 2015

1. We have measured intracellular calcium concentrations in basal conditions and in response to cholecystokinin-octapeptide and acetylcholine in pancreatic acini isolated from rats with caerulein-induced acute pancreatitis and compared them with those in control rats.

2. We also measured amylase secretion in basal conditions and in response to cholecystokinin-octapeptide in both groups.

3. In pancreatic acini from rats with pancreatitis the basal intracellular calcium concentration was significantly increased (134.9±7.1 nmol/l compared with 71.8 ± 2.9 nmol/l, P < 0.001). Moreover, the maximum values of intracellular calcium attained during the stimulation period were equivalent in acini from control and pancreatitic rats with no statistically significant differences.

4. In acini from control rats the differences between the resting levels of intracellular calcium and the maximum intracellular calcium values (Δ[Ca2+]i) in response to several concentrations of cholecystokinin-octapeptide showed a clear dose—response relationship, with a half-maximal increase at 0.1 nmol/l and a maximal difference (Δ[Ca2+]i = 259 ±50 nmol/l) at 1 nmol/l. In contrast, a right-shifted response, with a statistically significant smaller increase, was observed in acini from pancreatitic rats.

5. Basal amylase release was significantly higher in acini from rats with pancreatitis (11.7 ±1.0% of total compared with 5.9 ±1.1% of total, P < 0.001). In contrast, cholecystokinin-octapeptide and acetylcholine-evoked amylase secretion was reduced by more than 85% in acini from pancreatitic rats.

6. In conclusion, calcium homoeostasis in pancreatic acinar cells from rats with caerulein-induced pancreatitis seems to be impaired. These results suggest excessive release of acinar free ionized calcium, or damage to the integrity of mechanisms that restore low resting levels of intracellular free ionized calcium, and the consequent calcium toxicity could be the key trigger in caerulein-induced acute pancreatitis.
Suppression of Oxidant Production by Diltiazem, Nifedipine and Verapamil in Human Neutrophils
Authors: Feng Y.-H. , Hart G.
Published: August 2015

1. Polymorphonuclear leucocytes are a major source of toxic oxidants in vivo, causing tissue injury in certain circumstances such as ischaemia and reperfusion. Calcium ions are a key mediator in the production of oxidants by these cells. The aim of this study was to examine the effects of the widely used calcium antagonists diltiazem, nifedipine and verapamil on the production of oxidants in neutrophils.

2. Human neutrophils were freshly prepared, suspended in different luminol media and mixed with varying amounts of each calcium antagonist. They were then stimulated with either serum-opsonized zymosan or phorbol 12-myristate 13-acetate. Oxidant production was determined by three methods, namely luminol-enhanced chemiluminescence, oxygen consumption and cytochemical staining.

3. Calcium antagonists inhibited oxidant production by neutrophils. IC50 values for diltiazem, nifedipine and verapamil in calcium-free medium were 0.32 mmol/l (SEM 0.02), 0.27 mmol/l (SEM 0.02) and 0.24 mmol/l (SEM 0.02) respectively under zymosan stimulation, and 0.33 mmol/l (SEM 0.02), 0.26 mmol/l (SEM 0.02) and 0.13 mmol/l (SEM 0.07) respectively under phorbol 12-myristate 13-acetate stimulation. These effects were independent of the presence of Ca2+ in the extracellular solution. Some inhibition was also observed when the calcium antagonists were added during the course of a respiratory burst. Oxygen uptake by the cells was reduced in the presence of each calcium antagonist. Phagocytosis by the stimulated neutrophils was not affected despite inhibition of oxidant production.

4. We conclude that calcium antagonists can suppress the capacity of neutrophils to produce oxidants. This result may provide a novel explanation for the observation that delayed treatment with calcium antagonists may attenuate post-ischaemic myocardial dysfunction.
Lymphocyte cAMP and Ageing: Significance of Subset Composition, Plasma Noradrenaline, Regular Physical Training and Long-Term Smoking
Authors: Knudsen J. H. , Gustafsson F. , Toft J. , Christensen N. J.
Published: August 2015

1. We studied 37 healthy men at rest in the supine position to examine the effect of ageing, smoking and physical training on β2-adrenoceptor function, plasma catecholamines and the proportions of various lymphocyte subsets.

2. In 14 young subjects the proportion of natural killer cells was correlated with cAMP production in lymphocytes and inversely correlated with plasma noradrenaline level.

3. In 16 elderly non-smokers plasma noradrenaline was negatively correlated with the natural killer cell subset CD3–CD16+. Lymphocyte cAMP responses did not differ between young and elderly non-smokers, whereas plasma noradrenaline increased slightly but significantly with age. Physical training did not influence either plasma noradrenaline or adrenaline at rest or cAMP in lymphocytes.

4. In seven elderly long-term smokers cAMP production and the viability of lymphocytes were reduced. Plasma noradrenaline attained its highest values in long-term smokers.

5. It is concluded that cAMP production and plasma noradrenaline are related to lymphocyte subset composition. The greater the proportion of natural killer cells and related subsets, the higher is cAMP production and the lower is plasma noradrenaline. Thus, the inverse correlation between lymphocyte cAMP and plasma noradrenaline is indirect and most likely mediated by variability in lymphocyte subset composition. In elderly subjects, reduced cAMP production was observed in long-term smokers, and this abnormality was probably due to a reduced viability of lymphocytes and especially of natural killer cells. The negative correlation between the proportion of natural killer cells and plasma noradrenaline at rest contrasts with a well-known mobilizing effect of adrenaline on natural killer cells.
Effect of Protein Kinase C Inhibitors and 2,3-Butanedione Monoxime on the Long-Term Hypothermic Preservation of Isolated Rat Hearts
Authors: Fagbemi Oluwole S. , Northover Basil J.
Published: August 2015

1. This study examines the protective effect of staurosporine, chelerythrine, Ro 31-8220 and 2,3-butanedione monoxime in rat hearts during hypothermic storage.

2. Hearts were microperfused at 4°C for 24 or 48 h with a storage buffer that in some cases contained one of these protein kinase C inhibitors either alone or in combination with 2,3-butanedione monoxime. After hypothermic storage, hearts were rewarmed to 37°C with Krebs—Henseleit buffer. Cardiac function was then assessed in either Langendorff mode or working heart mode.

3. Compared with values from fresh non-stored hearts, hypothermic stored hearts showed a significant decrease in both coronary flow and left ventricular developed pressure when the stored hearts were reperfused in Langendorff mode. The decrease in coronary flow and left ventricular developed pressure was more pronounced in hearts stored for 48 h than in those stored for 24 h.

4. Hearts stored for 24 or 48 h, with or without the protein kinase C inhibitors, and then perfused in working mode generated less aortic flow and less cardiac output than fresh unstored hearts.

5. Hearts preserved in solutions containing staurosporine, chelerythrine, Ro 31-8220 or 2,3-butanedione monoxime had significantly higher left ventricular developed pressure values on reperfusion than hearts stored without any such drug.

6. Addition of 2,3-butanedione monoxime to a storage buffer containing either staurosporine, chelerythrine or Ro 31-8220 further improved left ventricular developed pressure, aortic flow and cardiac output values in these stored hearts. The group of hearts stored in a buffer containing 2,3-butanedione monoxime and chelerythrine gave the highest left ventricular developed pressure value seen during reperfusion.

7. The ATP and creatine phosphate concentrations of hearts stored in buffer alone were significantly lower than those of fresh unstored hearts, irrespective of the duration of storage. ATP concentrations were better preserved in hearts stored in a buffer containing 2,3-butanedione monoxime or/and one of the protein kinase C antagonists than those stored without such antagonists. A positive correlation was found between peak cardiac output values and the concentrations of combined high-energy phosphates in various groups of stored and reperfused hearts.

8. The present study showed that inhibition of protein kinase C during long-term hypothermic storage significantly increased high-energy phosphate concentrations and also improved contractile function during reperfusion.
Neutrophil CD11B Expression and Neutrophil Activation in Pre-Eclampsia
Authors: Barden A. , Graham D. , Beilin L. J. , Ritchie J. , Baker R. , Walters B. N. , Michael C. A.
Published: August 2015

1. Neutrophil activation was examined in 22 women with pre-eclampsia and 22 age- and gestation-matched control subjects using whole-blood flow cytometry to assess basal and platelet-activating factor stimulated CD11b and CD18.

2. Basal neutrophil CD11b expression was significantly increased in women with pre-eclampsia compared with normal pregnancy before delivery. A similar non-significant trend for CD18 was also observed.

3. Before delivery, neutrophil CD11b expression increased in a dose-dependent fashion after platelet-activating factor stimulation, with the differences between the groups maintained. A similar dose-dependent increase in CD18 expression was observed after platelet-activating factor.

4. There were no between-group differences in expression of either CD11b or CD18 at either 6 weeks or 6 months post partum, either before or after platelet-activating factor stimulation.

5. Neutrophil CD11b was positively correlated with plasma uric acid (r = 0.44, P = 0.04) in women with pre-eclampsia, suggesting that the extent of neutrophil activation correlates with disease severity.

6. An increase in basal neutrophil CD11b expression in women with pre-eclampsia is likely to be an index of neutrophil activation in vivo. Neutrophil release of free radicals and proteases may then help perpetuate a vicious cycle of endothelial and vascular dysfunction in the placental and systemic circulations. The cause of this activation is not known but could involve platelet activation, increased production of endothelin-1 or release of cytokines. Further studies will be required to elucidate the consequences of neutrophil activation in pre-eclampsia.
Renal Handling of Urate and Sodium during Acute Physiological Hyperinsulinaemia in Healthy Subjects
Authors: Maaten J. C. Ter , Voorburg A. , Heine R. J. , Wee P. M. Ter , Donker A. J. M. , Gans R. O. B.
Published: August 2015

1. The renal effects of insulin may play a central role in the association between insulin resistance, hypertension and hyperuricaemia. After a 2-h baseline period, we investigated the effects of exogenous insulin for 4 h (50 m-units h−1 kg−1) on fractional renal sodium and urate excretion in 13 healthy subjects, using the euglycaemic clamp and lithium clearance technique, and performed a control experiment in eight of the subjects.

2. Insulin caused a decline in both fractional renal sodium excretion, from 1.13 ± 0.41% to 0.88 ± 0.58% (control study: 0.81 ± 0.35 to 1.35 ± 0.49%; P < 0.001, insulin versus control), and fractional renal urate excretion, from 6.72 ± 1.87% to 5.71 ± 2.02% (control study: 7.03 ± 2.06 to 7.05 ± 1.94%; P = 0.085, insulin versus control). The changes in fractional renal sodium and urate excretion were positively correlated (r = 0.71, P < 0.01). Estimated fractional distal sodium reabsorption increased during insulin infusion from 93.7 ± 2.8% to 96.7 ± 1.9% (control study: 95.7 ± 1.5% to 93.6 ± 1.1%; P < 0.001, insulin versus control). Estimated fractional proximal tubular sodium reabsorption fell from 81.0 ± 0.5% to 73.7 ± 4.7% during insulin infusion, but less in the control study (81.5 ± 4.3% to 79.3 ± 4.8%; P = 0.056, insulin versus control). The changes in fractional proximal tubular sodium reabsorption and fractional distal sodium reabsorption during insulin infusion were inversely correlated (r = −0.59, P = 0.03).

3. During the course of the insulin infusion experiment an inverse correlation between the changes in fractional sodium and urate excretion, and the insulin-mediated glucose disposal, became gradually evident (r = −0.73, P < 0.01, and r = −0.71, P < 0.01, respectively; fourth hour of the insulin infusion period).

4. We conclude that exogenous insulin acutely decreases renal sodium and urate excretion, and that this effect is probably exerted at a site beyond the proximal tubule.
Effect of Seed Crystals of Uric Acid and Monosodium Urate on the Crystallization of Calcium Oxalate in Undiluted Human Urine in Vitro
Authors: Grover Phulwinder K. , Ryall Rosemary L.
Published: August 2015

1. The aim of this study was to determine whether seed crystals of uric acid or monosodium urate promote the epitaxial deposition of calcium oxalate in undiluted human urine. The effects of seed crystals of uric acid, monosodium urate or calcium oxalate on calcium oxalate crystallization induced in pooled 24-h urine samples collected from six healthy men were determined by [14C]oxalate deposition and Coulter counter particle analysis. The precipitated crystals were examined by scanning electron microscopy.

2. Seed crystals of uric acid, monosodium urate and calcium oxalate increased the precipitated particle volume in comparison with the control containing no seeds by 13.6%, 56.8% and 206.5% respectively, whereas the deposition of [14C]oxalate in these samples relative to the control was 1.4% (P < 0.05), 5.2% (P < 0.01) and 54% (P < 0.001) respectively. The crystalline particles deposited in the presence of monosodium urate seeds were smaller than those in the control samples. Scanning electron microscopy showed that large aggregates of calcium oxalate were formed in the presence of calcium oxalate seeds, which themselves were not visible. In contrast, monosodium urate and, to a lesser extent, uric acid seeds were scattered free on the membrane surfaces and attached like barnacles upon the surface of the calcium oxalate crystals.

3. It was concluded that seed crystals of monosodium urate and uric acid do not promote calcium oxalate deposition to a physiologically significant degree in urine. Howsever, binding of monosodium urate and uric acid crystals and their subsequent enclosure within actively growing calcium oxalate crystals might occur in vivo, thereby explaining the occurrence of mixed urate/oxalate stones.
Fetal Growth and Insulin Resistance in Adult Life: Role of Skeletal Muscle Morphology
Authors: Thompson C. H. , Sanderson A. L. , Sandeman D. , Stein C. , Borthwick A. , Radda G. K. , Phillips D. I. W.
Published: August 2015

1. Thinness at birth is associated with insulin resistance in adult life and an apparent delay in activation of glycolysis/glycogenolysis in exercising skeletal muscle. As developmental abnormalities of skeletal muscle histology or metabolism may explain this association we examined muscle histology, biochemistry and blood flow in a group of 27 adult women whose birth details were known.

2. Subjects were examined by near-infrared spectroscopy to determine forearm muscle oxygen supply, and by muscle biopsy and forearm plethysmography. Those with a ponderal index at birth < 23 kg/m3 were insulin resistant (assessed by the short insulin-tolerance test — mean rate constants for glucose disappearance = 4.14 compared with 4.83%/min, P = 0.045) and had significantly more rapid muscle reoxygenation than the remainder of the subjects (13 compared with 22 s, P = 0.004).

3. Thinness at birth did not influence muscle capillary density, muscle glycogen content, glycogen synthase activity, citrate synthase activity or resting forearm blood flow.

4. Insulin resistance seen after fetal malnutrition was not associated with abnormal muscle histology, resting muscle blood flow, mitochondrial volume or glycogen content.

5. The increase in muscle reoxygenation rate in adult subjects who were thin at birth could occur to promote oxidative ATP synthesis in compensation for the delay in activation of glycolysis/glycogenolysis. It suggests altered regulation rather than structure of the muscle microcirculation. These changes appear to antedate the structural and biochemical changes seen in muscle from patients with established diabetes.
Heart Rate Variability in Patients with Daytime Sleepiness Suspected of Having Sleep Apnoea Syndrome: A Receiver-Operating Characteristic Analysis
Authors: Keyl Cornelius , Lemberger Peter , Pfeifer Michael , Hochmuth Karin , Geisler Peter
Published: August 2015

1. Periodic breathing is known to be associated with cyclic fluctuations in heart rate. The purpose of this study was to evaluate the capability of spectral analysis of heart rate variability to identify episodes with periodic breathing in patients suspected of having sleep apnoea syndrome.

2. Forty-eight subjects complaining of chronic daytime sleepiness were studied using polysomnography and additional monitoring of Holter-ECG and synchronized pulse oximetry. The recordings were divided into 20 min episodes which were identified as recordings registered during normal breathing, periodic breathing, and periods of both normal and abnormal breathing. Power spectral analysis was performed on episodes which met the criteria of stationarity of data (313 episodes with normal breathing, 264 episodes with continuous periodic breathing, 80 episodes with both normal and periodic breathing pattens).

3. The ability of parameters, derived from analysis of heart rate variability, to discriminate between episodes with normal and periodic breathing was assessed by receiver-operating characteristic analysis.

4. The spectral power component in the frequency range 0.01–0.07 Hz revealed the greatest accuracy for discriminating between normal and periodic breathing (area under the receiver-operating characteristic curve = 0.929; standard error = 0.009). The analysis of the episodes classified as false-positive at a given test sensitivity of 90% and a corresponding specificity of 77% revealed that half of these episodes had been recorded during transient central nervous arousal reactions related to periodic leg movements or heavy snoring.

5. We concluded that power spectral analysis of heart rate variability offers a possible means of identifying episodes of sleep-related breathing disorders or periodic leg movements. Therefore, analysis of heart rate variability may be a valuable additional diagnostic tool in patients undergoing Holter-ECG recording.
Effect of Urodilatin Infusion on Renal Haemodynamics, Tubular Function and Vasoactive Hormones
Authors: Carstens JAN , Jensen Kaare T. , Pedersen Erling B.
Published: August 2015

1. The renal efficacy of urodilatin in humans has only been partly investigated. It is unknown whether intravenously infused urodilatin has an effect on sodium reabsorption in both the proximal and distal part of the nephron.

2. Twelve healthy subjects participated in this double-blind, placebo-controlled study in a crossover design. They received, in a randomized order, a short term (60 min) infusion of urodilatin in three different doses (10, 20 and 40 ng min−1 kg−1 of body weight) and placebo. Renal haemodynamics were estimated by clearance technique with radioactive tracers, and proximal tubular handling of sodium was evaluated by lithium clearance.

3. The 20 ng min−1 kg−1 dose increased the urinary sodium excretion and urinary flow rate compared with the effects of placebo. It increased the glomerular filtration rate and decreased the effective renal plasma flow. In addition, the dose increased the lithium clearance compared with placebo, but did not significantly change the fractional excretion of lithium. On the other hand, it markedly decreased the distal fractional reabsorption of sodium. It also had a suppressive effect on renin secretion. The systemic arterial blood pressure was unchanged, but the dose increased the pulse rate and the haematocrit. The highest dose (40 ng min−1 kg−1) induced a wide variation in the natriuretic and diuretic responses, probably due to a blood-pressure-lowering effect.

4. We conclude, that the urodilatin dose of 20 ng min−1 kg−1 of body weight was most efficacious in this short-term infusion study, and that it had potent natriuretic and diuretic qualities, probably due to stimulation of the glomerular filtration rate and inhibition of sodium reabsorption in the distal part of the nephron.
Mild Endotoxaemia and the Inflammatory Response Induced by a Marathon Race
Authors: Camus G. , Poortmans J. , Nys M. , Deby-Dupont G. , Duchateau J. , Deby C. , Lamy M.
Published: August 2015

1. To address the question of whether endotoxaemia could be involved in the inflammatory response induced by long-term strenuous exercise, 18 male marathon runners [mean age 41±2 (SEM) years] were studied. Their performance in the marathon ranged from 2 h 46 min to 4 h 42 min.

2. Four venous blood samples were drawn: at rest, just before the race (baseline); within 15 min following the completion of the marathon; after 1 h of recovery; and the morning after the race.

3. The following humoral markers of the inflammatory response to exercise were measured: polymorphonuclear myeloperoxidase (MPO), anaphylatoxin C5a (C5a), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Plasma endotoxin was measured by a sensitive and rapid chromogenic Limulus assay. All inflammatory markers were significantly increased (P < 0.001) after the race, reaching in most cases peak values in the first blood sample drawn following the completion of the marathon [MPO, 298±19 ng/ml (SEM); C5a, 1.45±0.32 ng/ml; TNF-α, 20±3 pg/ml; IL-6, 88 + 13 pg/ml] when compared with baseline [MPO, 146 ±16 ng/ml (SEM); C5a, 0.27±0.2 ng/ml; TNF-α, 12 ± 1.5 pg/ml: IL-6, 1.0±0.5 pg/ml]. Traces of plasma endotoxin (ranging from 5 to 13 pg/ml, with one exceptionally high value of 72 pg/ml measured in one runner) were detected in seven subjects within the first hour of recovery. An ELISA method was used to determine the endogenous IgG antibodies toward a range of Gram-negative bacterial lipopolysaccharides (LPSs) of different sizes and structures. A transient decrease in certain anti-LPS activities, mainly against rough LPS, occurred in most cases in the first blood sample drawn after the race. There was no correlation between the magnitude of the inflammatory response to exercise, as assessed by the increase in blood levels of humoral markers of inflammation, and the changes in circulating endotoxin levels of anti-LPS IgG activity following the race.

4. From these results, we conclude that the mild, transient endotoxaemia detected in some of our subjects does not play a major role in the observed inflammatory response to a marathon competition.
Signalling Pathways Involved in the Mitogenic Effects of cAMP
Authors: Withers D. J.
Published: August 2015

1. Elevation of intracellular cyclic AMP (cAMP) is a potent mitogenic signal for a number of cell types, including Swiss 3T3 cells, thyroid epithelial cells and the somatotroph cells of the anterior pituitary.

2. Activation of the mitogen-activated protein kinase (MAPK) cascade has been shown to underlie the mitogenic effects of many growth factors. However, the precise relationship between the mitogenic effects of cAMP and the MAPK cascade is not fully defined.

3. In Swiss 3T3 cells, elevation of cAMP did not stimulate kinases at all three levels of the MAPK cascade. Additionally, blockade of the MAPK pathway failed to inhibit cAMP-stimulated DNA synthesis.

4. Mitogenic combinations of cAMP strongly stimulated the phosphorylation and activation of the serine/threonine kinase p70 S6 kinase, p70S6K, an effect that was inhibited by rapamycin. This agent markedly inhibited cAMP-stimulated DNA synthesis, suggesting a critical role for p70S6K in cAMP mitogenic signalling.

5. Thus, multiple parallel but distinct signalling pathways may be involved in the action of mitogens. This redundancy has important implications for the pathogenesis and treatment of conditions characterized by inappropriate activation of growth factor signalling pathways.
Adrenomedullin: A Hypotensive Hormone in Man
Authors: Lainchbury John G. , Cooper Garth J. S. , Coy David H. , Jiang Ning-Yi , Lewis Lynley K. , Yandle Timothy G. , Richards A. Mark , Nicholls M. Gary
Published: August 2015

1. Adrenomedullin, a recently discovered 52-amino-acid peptide hormone, circulates in plasma at low picomolar levels in man. Animal studies and studies in vitro indicate that it has diverse biological actions, including vasodilatation, natriuresis and diuresis, and positive inotropism as well as antiproliferative effects. We investigated the bioactivity of two doses of adrenomedullin in healthy human subjects.

2. Human adrenomedullin was given intravenously to eight male subjects at 2 and 8 ng min−1 kg−1, and haemodynamic, hormonal, renal and biochemical responses were recorded in a placebo (vehicle)-controlled, randomized study.

3. Compared with vehicle, adrenomedullin reduced mean arterial pressure (P = 0.05 for duration of infusion, mean difference at end of infusion 7.7 mmHg), systolic arterial pressure (P = 0.04 for duration of infusion, mean difference at end of infusion 10.7 mmHg) and at the lower dose reduced diastolic arterial pressure (P = 0.05 for lower dose, mean difference at end of infusion 6.3 mmHg) in the absence of compensatory responses in sympathetic activity or renin release. Urine volume and electrolyte excretion were unaffected.

4. The threshold for biological activity of adrenomedullin in man is lower for arterial pressure than for renal or hormonal responses, and is evident at plasma concentrations seen in disorders of the circulation. Adrenomedullin may be an important hormone under pathophysiological circumstances.
Serum Leptin and Short-Term Regulation of Eating in Obese Women
Authors: Karhunen Leila , Haffner Steven , Lappalainen Raimo , Turpeinen ANU , Miettinen Heikki , Uusitupa Matti
Published: August 2015

1. Leptin is generally thought to play a key role in the regulation of eating. However, its real role in human eating behaviour is still poorly known. Therefore, the role of leptin in the regulation of eating was examined in obese binge- and non-binge-eating women during exposure to food and food-related stimuli.

2. Eleven binge- and ten non-binge-eating obese women took part in the study. In addition to serum leptin, serum insulin, non-esterified fatty acids, plasma glucose, salivation, the feeling of hunger and the desire to eat were repeatedly measured during the experiment.

3. Serum leptin levels did not differ between the binge- and non-binge-eating women. Neither were leptin levels associated with the feeling of hunger or the desire to eat food, nor with the amount or composition of food eaten. During food exposure leptin levels did not change, whereas at the same time serum insulin levels increased and serum non-esterified fatty acid levels decreased. The change in salivation during food exposure was inversely associated with the fasting leptin level.

4. This study indicates that serum leptin does not play a role in the regulation of eating in obese women, at least not in the short term. Furthermore, leptin levels are not different in obese binge-eating women as compared with obese non-binge-eating women. Interestingly, high fasting leptin levels may be associated with a decreased salivation response in the presence of food and food-related stimuli.
Hypoxia, Hypocapnia and Spirometry at Altitude
Authors: Pollard Andrew J. , Barry Peter W. , Mason Nick P. , Collier David J. , Pollard Rachel C. , Pollard Peter F. A. , Martin Isla , Fraser R. Scott , Miller Martin R. , Milledge James S.
Published: August 2015

1. Both hypoxia and hypocapnia can cause broncho-constriction in humans, and this could have a bearing on performance at high altitude or contribute to altitude sickness. We studied the relationship between spirometry, arterial oxygen saturation and end-tidal carbon dioxide (ETCO2) concentration in a group of healthy lowland adults during a stay at high altitude, and then evaluated the response to supplementary oxygen and administration of a β2 agonist

2. We collected spirometric data from 51 members of the 1994 British Mount Everest Medical Expedition at sea level (barometric pressure 101.2–101.6 kPa) and at Mount Everest Base Camp in Nepal (altitude 5300 m, barometric pressure 53–54.7 kPa) using a pocket turbine spirometer. A total of 205 spirometric measurements were made on the 51 subjects during the first 6 days after arrival at Base Camp. Further measurements were made before and after inhalation of oxygen (n = 47) or a β2 agonist (n = 39). ETCO2 tensions were measured on the same day as spirometric measurements in 30 of these subjects.

3. In the first 6 days after arrival at 5300 m, lower oxygen saturations were associated with lower forced expiratory volume in 1 s (FEV1; P < 0.02) and forced vital capacity (FVC; P < 0.01), but not with peak expiratory flow (PEF). Administration of supplementary oxygen for 5 min increased oxygen saturation from a mean of 81%–94%, but there was no significant change in FEV1 or FVC, whilst PEF fell by 2.3% [P < 0.001; 95% confidence intervals (CI) −4 to −0.7%]. After salbutamol administration, there was no significant change in PEF, FEV1 or FVC in 35 non-asthmatic subjects. Mean ETCO2 at Everest Base Camp was 26 mmHg, and a low ETCO2 was weakly associated with a larger drop in FVC at altitude compared with sea level (r = 0.38, P < 0.05). There was no correlation between either ETCO2 or oxygen saturation and changes in FEV1 or PEF compared with sea-level values.

4. In this study, in normal subjects who were acclimatized to hypobaric hypoxia at an altitude of 5300 m, we found no evidence of hypoxic broncho-constriction. Individuals did not have lower PEF when they were more hypoxic, and neither PEF nor FEV1 were increased by either supplementary oxygen or salbutamol. FVC fell at altitude, and there was a greater fall in FVC for subjects with lower oxygen saturations and probably lower ETCO2.
Clinical and Haemodynamic Sequelae of Deep Venous Thrombosis: Retrospective Evaluation after 7–13 Years
Authors: Janssen M. C. H. , Haenen J. H. , Van Asten W. N. J. C. , Wollersheim H. , Heijstraten F. M. J. , De Rooij M. J. M. , Thien TH
Published: August 2015

1. In contrast to the extensive documentation on diagnosis and treatment of deep venous thrombosis (DVT), information about long-term complications, clike the post-thrombotic syndrome (PTS), is scarce. Most studies report on clinical examination only, whereas adequate haemodynamic investigation is lacking. Therefore 81 patients with venographically confirmed lower extremity DVT were clinically and haemodynamically reexamined 7–13 years after DVT (mean 10 years) to assess PTS. Interest was focused on the relation between clinical and haemodynamic PTS and the relation between location of the initial DVT and incidence of PTS.

2. Clinical signs and symptoms of PTS were classified according to the latest consensus of the international consensus committee on chronic venous disease. Non-invasive venous vascular laboratory tests were performed to assess the venous outflow resistance and calf muscle pump function (CMP). CMP was determined by the supine venous pump function test (SVPT).

3. Clinically only 20 of 81 patients (25%) were asymptomatic, 34 (42%) had mild PTS (class 1–3), 25 (31%) moderate PTS (class 4) and 2 (2%) severe PTS (class 5–6); 57% had an abnormal CMP. Both the severity of clinical symptoms and the haemodynamic abnormalities were related to the location of the initial thrombus. Of the patients with distal DVT 11% developed moderate clinical PTS and 39% developed an abnormal CMP. CMP and difference in CMP between post-thrombotic and non-thrombotic leg were significantly related to the different classes of PTS.

4. This study indicates that 7–13 years after DVT 31% of the patients had moderate and 2% had severe clinical PTS, while 57% of the patients had abnormal haemodynamic findings (both related to the initial site of the thrombosis). Secondly, it reveals that the risk of PTS after distal DVT is not negligible, which causes concern about not diagnosing and treating patients with distal DVT. Thirdly, we have demonstrated that a functional test, such as the SVPT, is a sensitive test to assess post-thrombotic damage. Therefore its use as a screening tool after a period of DVT should be investigated to select patients at risk of PTS.