bluuebunny/crossref_metadata_2025 huggingface dataset:
Autonomic Nervous Function during Haemodialysis Assessed by Spectral Analysis of Heart-Rate Variability
Authors: Cavalcanti Silvio , Severi Stefano , Chiari Lorenzo , Avanzolini Guido , Enzmann Guido , Bianco Francesco , Panzetta Giovanni
Published: August 2015

1. Short-term autonomic response to haemodialysis-induced hypovolaemia was studied in 30 patients undergoing chronic haemodialysis by analysing power spectra of heart-period variability. Patients were classified as haemodynamically stable (15 patients) and unstable (15 patients) according to their past history of cardiovascular collapse during the treatment. Blood volume, systolic arterial pressure and heart period were measured during sessions that ended without the occurrence of collapse.

2. No significant differences were observed when comparing blood volume, heart rate and arterial pressure of stable and unstable patients during the dialysis, and the two groups could not be distinguished merely on the basis of these haemodynamic parameters. Conversely, spectral analysis of beat-to-beat heart-period variability showed markedly different power patterns: in stable patients power was mainly in the low-frequency (LF) band (0.06–0.15 Hz), whereas in unstable patients it was mainly in the high-frequency (HF) band (0.15–0.4 Hz).

3. The efficiency of the autonomic response to hypovolaemia was evaluated by the ratio between the powers in the LF and HF bands. Stable patients exhibited an LF/HF power ratio systematically greater than unstable patients during the entire dialysis, and on the basis of this index the two groups were clearly separated.

4. Results obtained with spectral analysis lead us to conclude that reduced efficiency in the autonomic control of cardiovascular functions could be the main cause of the haemodynamic instability of patients prone to collapse.
Haemodynamic and Biochemical Responses to l-Arginine and l-Lysine Infusions in Normal Subjects: l-Arginine-Induced Vasodilatation Cannot be Explained by Non-Specific Effects of Cationic Amino Acids
Authors: Smulders R. A. , Aarsen M. , Teerlink T. , De Vries P. M. J. M. , Van Kamp G. J. , Donker A. J. M. , Stehouwer C. D. A.
Published: August 2015

1. Pharmacological stimulation of the synthesis of nitric oxide (NO) may be important in the prevention or treatment of cardiovascular diseases.

2. There is much discussion as to whether the precursor of NO, l-arginine, is able to stimulate basal endothelial NO production. l-Arginine is known to have vasodilating effects. However, it is not clear whether l-arginine-induced vasodilatation is attributable to an increase in NO production or to other systemic effects of l-arginine.

3. To investigate further the mechanisms of the l-arginine-induced vasodilatation, we compared the responses to l-arginine with those to saline and l-lysine in healthy subjects. l-Lysine is not a substrate for NO synthesis, but shares many of l-arginine's other properties.

4. During l-arginine infusion, blood pressure decreased [systolic blood pressure from 120.2 (SD 8.8) to 117.3 (12.1) mmHg (P = 0.05); diastolic blood pressure from 65.3 (5.9) to 61.6 (7.9) mmHg (P < 0.01)], and heart rate and extracellular fluid volume increased. The total peripheral vascular resistance decreased during l-arginine infusion by 18.0 (11.4)% (P ≤ 0.05 compared with baseline and compared with l-lysine infusion). These results indicate vasodilatation. No changes were observed during l-lysine and saline infusion.

5. Plasma cyclic GMP (the second messenger for NO) increased during l-arginine but also during l-lysine infusion [from 5.7 (1.2) to 6.8 (1.7) nmol/l (P < 0.01), and from 5.8 (1.8) to 7.0 (2.9) nmol/l (P < 0.05) respectively]. Plasma l-citrulline (a by-product of NO synthesis from l-arginine) increased during l-arginine infusion from 30.6 (7.5) to 47.1 (9.9) μmol/l (P < 0.001), but also during l-lysine infusion from 32.7 (6.5) to 42.0 (8.3) μmol/l (P < 0.001).

6. Plasma electrolytes and atrial natriuretic peptide concentrations responded similarly to l-arginine and l-lysine infusion, indicating similar effects on osmolality, plasma volume expansion and potassium distribution.

7. In conclusion, although l-lysine infusion had effects that were similar to those of l-arginine infusion, no vasodilatation was observed. Therefore, these effects cannot account for the l-arginine-induced vasodilatation. This finding indirectly supports the hypothesis that the vasodilatation during l-arginine infusion might be mediated by an increase in NO synthesis. If so, our data suggest that the presumed markers for NO synthesis, plasma cyclic GMP and l-citrulline concentrations, do not accurately reflect this increase. Instead, the rise in plasma cyclic GMP may be related to the rise in ANP. The rise in l-citrulline may be related to competition with l-arginine for the same cell membrane transport mechanism and to stimulation of the urea cycle.
Resting Membrane Potential of Skeletal Muscle Calculated from Plasma and Muscle Electrolyte and Water Contents
Authors: Forsberg A. M. , Bergström J. , Lindholm B. , Hultman E.
Published: August 2015

1. A method is described that enables the calculation of resting membrane potential from the electrolyte and water contents in blood plasma and in a sample of human muscle tissue obtained by the percutaneous needle-biopsy technique. In this calculation, the previously described equations for calculating resting membrane potential via the intra- and extra-cellular distribution of chloride were combined with the equation utilizing potassium distribution over the cell membrane.

2. The method of calculation was applied to 60 healthy subjects divided into three groups aged 19–40, 41–60 and 61–85 years. The calculated resting membrane potential in the subjects as a whole was −88.4 mV (SD 1.35; n = 60). A lower value was observed in the group aged 61–85 years (−87.7 mV, SD 1.0; n = 12) than in the group aged 19–40 years (−88.6 mV; SD 1.4; n = 32). No difference was observed between female and male subjects.

3. The RMP calculated with the present method in 60 healthy subjects was also compared with previously published values in healthy subjects, measured by the Clarke electrode method, and with values calculated from electrolyte and water distribution measured by isotope-dilution techniques. The results obtained in healthy subjects with different techniques were very similar. Data were analysed from earlier published studies in experimental animals in which resting membrane potential ranged from −91 to −65 mV. The resting membrane potential calculated from electrolytes in plasma and muscle showed a very good agreement with resting membrane potential recorded directly.
Comparison of the Effects on Urinary Sodium Excretion of Indomethacin and of Carbidopa in normal Volunteers given an Intravenous Saline Infusion
Authors: Stokes G. S. , Monaghan J. C. , Pillai D. N.
Published: August 2015

1. Dopamine and prostaglandins are putative endogenous natriuretic hormones. The role of each in facilitating natriuresis induced by intravenous saline infusion was examined in normal volunteers in relation to administration of carbidopa, a dopadecarboxylase inhibitor, and indomethacin, an inhibitor of prostaglandin synthetase.

2. In a placebo-controlled, randomized study, 13 subjects received carbidopa (100 mg) and 12 received indomethacin (50 mg). Proximal and distal renal tubular Na+ reabsorption were determined using exogenous lithium clearance.

3. On the control day, 2 litres of 0.9% saline (308 mmol Na+) given intravenously in 3 h, resulted in volume expansion and natriuresis. Carbidopa reduced the urinary dopamine/noradrenaline ratio but showed no anti-natriuretic effect and no effect on fractional Na+ reabsorption. Indomethacin diminished natriuresis and increased distal fractional Na+ reabsorption in proportion to the anti-natriuretic effect.

4. The changes in plasma concentrations of albumin, aldosterone, atrial natriuretic peptide and renin activity associated with volume expansion were not modified by either carbidopa or indomethacin. Urinary prostaglandin E2 excretion was decreased transiently by indomethacin and was unaffected by carbidopa.

5. This study suggests that prostaglandins may modulate urinary Na+ excretion during saline-induced natriuresis through inhibition of distal tubular Na+ reabsorption. No role for free dopamine as a modulator of renal Na+ handling could be assigned on the basis of the findings with carbidopa.
The Effects of Low-Density Lipoprotein and High-Density Lipoprotein on Blood Viscosity Correlate with their Association with Risk of Atherosclerosis in Humans
Authors: Sloop Gregory D. , Garber David W.
Published: August 2015

1. Increased blood or plasma viscosity has been observed in almost all conditions associated with accelerated atherosclerosis. Cognizant of the enlarging body of evidence implicating increased viscosity in atherogenesis, we hypothesize that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis.

2. Blood viscometry was performed on samples from 28 healthy, non-fasting adult volunteers using a capillary viscometer. Data were correlated with haematocrit, fibrinogen, serum viscosity, total cholesterol, high-density lipoprotein-cholesterol, triglycerides and calculated low-density lipoprotein-cholesterol.

3. Low-density lipoprotein-cholesterol was more strongly correlated with blood viscosity than was total cholesterol (r = 0.4149, P = 0.0281, compared with r = 0.2790, P = 0.1505). High-density lipoprotein-cholesterol levels were inversely associated with blood viscosity (r = −0.4018, P = 0.0341).

4. To confirm these effects, viscometry was performed on erythrocytes, suspended in saline, which had been incubated in plasma of various low-density lipoprotein/high-density lipoprotein ratios. Viscosity correlated directly with low-density lipoprotein/high-density lipoprotein ratio (n = 23, r = 0.8561, P < 0.01).

5. Low-density lipoprotein receptor occupancy data suggests that these effects on viscosity are mediated by erythrocyte aggregation.

6. These results demonstrate that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity in healthy subjects correlate with their association with risk of atherosclerosis. These effects on viscosity may play a role in atherogenesis by modulating the dwell or residence time of atherogenic particles in the vicinity of the endothelium.
Effects of Hydroxyurea Administration on the Body Weight, Body Composition and Exercise Performance of Patients with Sickle-Cell Anaemia
Authors: Hackney A. C. , Hezier W. , Gulledge T. P. , Jones S. , Strayhorn D. , Busby M. , Hoffman E. , Orringer E. P.
Published: August 2015

1. As an ancillary study carried out during the recently completed Multicenter Study of Hydroxyurea, we examined the effect of hydroxyurea on the body weight, body composition and exercise capacity of adult patients with sickle-cell anaemia.

2. The subjects received either hydroxyurea (six males and four females) or placebo (eight males and six females). Data for each subject were generated during four separate 24 h admissions to the General Clinical Research Center. These admissions occurred at baseline and then at 6, 12 and 18 months after the start of study drug (hydroxyurea or placebo) administration. During each admission, body composition was measured by using a dual X-ray absorptiometer, and exercise testing was performed by cycle ergometry. Anaerobic performance was assessed according to a ‘Wingate’ protocol (20 s at maximal intensity against a cycling resistance of 7.5% body weight). Aerobic performance was examined using a steady state submaximal exercise protocol (10 min cycling time).

3. At baseline, no significant difference in any parameter was found between the hydroxyurea- and placebo-treated groups. At 18 months, the hydroxy-urea-treated subjects exhibited an average weight gain of 3.16 kg. The mean weight gain in the placebo-treated subjects was 1.82 kg. Body composition analysis showed that the additional weight in both groups involved both lean and fat body mass components. In anaerobic performance, the subjects given hydroxyurea showed an increase in peak muscle power of 104.9 W. The placebo group also showed an increase, but theirs was a more modest gain of 57.7 W. The most marked improvement in anaerobic performance was observed in the hydroxyurea-treated men (P < 0.05). In aerobic performance, the hydroxyurea-treated subjects exhibited a decrease in peak heart rate response to a standardized workload of 15.2 beats/min, as compared with a decrease of only 4.3 beats/min in the placebo-treated patients.

4. Taken together, the overall weight gain, combined with increases in both anaerobic muscular performance and aerobic cardiovascular efficiency, provides objective data to support the subjective impression that hydroxyurea administration produces an improvement in the physical capacity of patients with sickle-cell anaemia.
Renal Endothelin System in Obstructive Jaundice: Its Role in Impaired Renal Function of Bile-Duct Ligated Rats
Authors: Kramer Herbert J. , Schwarting Kriemhild , Backer Angela , Meyer-Lehnert Harald
Published: August 2015

1. Obstructive jaundice predisposes the kidney to acute renal failure. Endothelin (ET), a potent renal vasoconstrictor and modulator of the tubular action of arginine vasopressin, has been suggested to play a pathogenetic role in acute renal failure. In the present study we therefore investigated renal function and the renal ET system in rats on day 4 after bile-duct ligation (BDL) or sham-operation (SO), without (n = 7 in each group) and with treatment with bosentan, a combined ETA/ETB receptor blocker, (n = 5 in each group).

2. On day 4 after BDL, serum bilirubin had increased to 226 ± 10 μmol/l (SEM) as compared with 6 ± 2 μmol/l in SO rats. Endogenous creatinine clearance, an index of glomerular filtration rate, was significantly reduced to 0.7 ± 0.1 ml min−1 g−1 of kidney weight after BDL as compared with 1.1 ± 0.1 ml min−1 g−1 of kidney weight after SO (P < 0.05). Bosentan prevented the decrease in glomerular filtration rate (1.0 ± 0.2 ml min−1 g−1 of kidney weight), as well as polyuria and defective concentrating ability, in BDL rats.

3. Plasma ET concentration on day 4 after surgery (28.2 ± 1.5 pmol/l) was higher (P < 0.01) in BDL than in SO rats (12.9 ± 1.5 pmol/l) and rose further in bosentan-treated BDL and SO rats (43.4 ± 5.1 compared with 21.9 ± 6.6 pmol/l). Urinary ET excretion was significantly higher in BDL rats than in SO rats (1.58 ± 0.22 compared with 1.28 ± 0.18 pmol 24h−1 100 g−1 of body weight; P < 0.05).

4. ET synthesis by glomeruli isolated from BDL rats was lower [81 ± 19 fmol h−1 (mg of protein)−1] than that from SO-rats [139 ± 28 fmol h−1 mg of protein)−1; P < 0.05], whereas papillary ET synthesis was higher in BDL [10 ± 3 fmol h−1 (mg of protein)−1] than in SO rats [4 ± 1 fmol h−1 (mg of protein)−1; P < 0.05].

5. The results indicate that BDL is associated with increased plasma ET concentration and suppression of GFR. Enhanced renal inner medullary collecting-duct ET synthesis, which is reflected by increased urinary ET excretion, may reduce distal tubular water absorption in BDL rats. Increased circulating and renal papillary ET synthesis may thus contribute to renal dysfunction and predispose the kidney to acute renal failure in obstructive jaundice.
13C-Urea Breath Test for Helicobacter Pylori: Cut-off Point Determination by Cluster Analysis
Authors: Mion Françcois , Rosner Gaëlle , Rousseau Marina , Minaire Yves
Published: August 2015

1. This study was performed on a large set of 13C-urea breath test results to determine the optimal cut-off point of the test for the diagnosis of Helicobacter pylori (Hp) infection.

2. The following steps were applied to three sets of urea breath test results obtained in three groups of subjects (696 adults before anti-Hp treatment, 1056 adults after anti-Hp treatment and 173 children under 17 years of age): (1) demonstrate the distribution of urea breath test results as a mix of two normal populations (Hp negative and Hp positive) by logarithmic transformation of the results in each group of subjects; (2) apply statistical cluster analysis to determine the separation point between Hp-negative and -positive populations; (3) calculate the mean and SD of each population, and use these parameters in the equation of the normal distribution to establish the frequency curves of Hp-negative and -positive populations; and (4) determine the cut-off point of the urea breath test as the intersection of the two curves, and the risks of error related to it.

3. The optimal cut-off point was found at +3.00 δ%0/00, with a risk of false-negative or -positive response of the urea breath test of less than 3%. From this, a cut-off point of +3.00 δ%0/00 for the 13C-urea breath test is recommended, with an indetermined zone between +2.5 and +3.5 δ0/00 to account for the spontaneous variation of 13CO2 in breath and the limits of GC—isotope ratio-MS analytical precision.
Transport of l-Arginine and the Nitric Oxide Inhibitor NG-Monomethyl-l-Arginine in Human Erythrocytes in Chronic Renal Failure
Authors: Ribeiro A. C. Mendes , Hanssen H. , Kiessling K. , Roberts N. B. , Mann G. E. , Ellory J. C.
Published: August 2015

1. Transport of l-arginine and the nitric oxide synthase inhibitors NG-monomethyl-l-arginine and NG-nitro-l-arginine was investigated in human erythrocytes from healthy donors and uraemic patients on haemodialysis.

2. Although Km values for total l-arginine influx were not significantly different in erythrocytes freshly isolated from controls or uraemic patients, uraemia was associated with an increase in the Vmax for transport (826 compared with 1176 μmol h−1 l−1 of cells) which was reduced to control values after dialysis.

3. Saturable influx of l-arginine was mediated by the classical cationic amino acid transport system y+ and system y+L, known to transport cationic and neutral amino acids with higher affinity.

4. Under zero-trans conditions, the Vmax for l-arginine transport via system y+ increased from 271 to 700 μmol h−1 l−1 of cells in uraemia, while Km values increased from 44 to 94 μmol/l. Dialysis had no significant effect on the kinetic parameters altered by uraemia.

5. Under zero-trans conditions, and with system y+ inhibited by N-ethylmaleimide (0.2 mmol/l), transport of l-arginine via system y+L was unaffected by uraemia.

6. Saturable influx of NG-monomethyl-l-arginine was also mediated by systems y+ (Km = 56 μmol/l, Vmax = 353 μmol h−1 l−1 of cells) and y+L (Km = 17 μmol/l, Vmax = 51.3 μmol h−1 l−1 of cells) and, as with l-arginine, uraemia increased the transport capacity for NG-monomethyl-l-arginine.

7. Influx of the neutral nitric oxide synthase inhibitor NG-nitro-l-arginine was not readily saturable.

8. Intracellular concentrations of l-arginine and NG-monomethyl-l-arginine were significantly increased in erythrocytes from uraemic patients when compared with controls, consistent with an increased transport capacity for l-arginine and NG-monomethyl-l-arginine.

9. The present study provides evidence that system y+ mediates the increased transport of l-arginine and NG-monomethyl-l-arginine in human erythrocytes from patients with chronic renal failure. Our findings may have implications for the activity of the l-arginine—nitric oxide signalling pathway in vascular endothelial and smooth-muscle cells in uraemia.
Effects of Physical Training on Metabolic Control in Elderly Type 2 Diabetes Mellitus Patients
Authors: Ligtenberg P.C. , Hoekstra J.B.L. , Bol E. , Zonderland M.L. , Erkelens D.W.
Published: August 2015

1. The specific role of physical activity in the treatment of type 2 diabetes is still subject to discussion. A randomized prospective study was performed, investigating both the influence of physical training on metabolic control and the feasibility of physical training in the elderly.

2. A total of 58 patients (mean age: 62 ± 5 years; range: 55–75 years) with type 2 diabetes were randomized to either a physical training or a control programme. The training programme consisted of three sessions a week, aiming at 60–80% of the maximal oxygen uptake (VO2max). The 12 week supervised period was followed by a 14 week non-supervised one. The control group followed an educational programme. VO2max was assessed during exercise on a cycle ergometer. Glycosylated haemoglobin (HbA1c) was used as a measure for glucose control, and an insulin tolerance test was performed to test insulin sensitivity. Multivariate analysis of variance, with repeated measures design, was used to test differences between groups.

3. Fifty-one patients completed the study. VO2max was higher in the training group than in the control group both after 6 weeks (P ≤ 0.01 between groups) and after 26 weeks [training group: 1796 ± 419 ml/min (prestudy), 1880 ± 458 ml/min (6 weeks), 1786 ± 591 ml/min (26 weeks); control group: 1859 ± 455 ml/min (prestudy), 1742 ± 467 ml/min (6 weeks), 1629 ± 504 ml/min (26 weeks)]. Blood glucose control and insulin sensitivity did not change during the study. Levels of total triacyl-glycerols, very-low-density lipoprotein-triacyl-glycerols and apolipoprotein B were significantly lower after 6 weeks (P ≤ 0.01, P ≤ 0.05, P ≤ 0.05 between groups respectively), and so was the level of total cholesterol after 12 weeks of training (P ≤ 0.05 between groups).

4. Physical training in obese type 2 diabetic patients over 55 years of age does not change glycaemic control or insulin sensitivity in the short-term. Regular physical activity may lower triacylglycerol and cholesterol levels in this group of patients.

5. Finally, physical training in motivated elderly type 2 diabetic patients without major cardiovascular or musculoskeletal disorders is feasible, but only under supervision.
Early Protein Restriction and Obesity Independently Induce Hypertension in 1-Year-Old Rats
Authors: Petry Clive. J. , Ozanne Susan E. , Wang Chun Li , Hales C. Nicholas
Published: August 2015

1. Recent studies have revealed a link between fetal and early post-natal growth retardation and the development of features of the insulin resistance syndrome in later life. Obesity is also a strong risk factor for this syndrome. The aim of this study was to assess whether maternal and early protein restriction, which causes growth retardation, and obesity are risk factors that are independent for the development of certain features of the insulin resistance syndrome, especially hypertension.

2. Pregnant Sprague—Dawley rats were given either 20% or 8% protein isocaloric diets throughout pregnancy and lactation. Female offspring were weaned onto the same diets as their mothers and they remained on these diets until 70 days of age. Half the rats were then given standard laboratory chow, whilst the remainder were fed a highly palatable cafeteria-style diet. Rats were maintained on these diets for the remainder of the study.

3. Rats given the 8% protein diet remained physically lighter than comparable animals fed the 20% protein diet throughout the study. In contrast, cafeteria-fed rats showed excessive weight gain. At 1 year of age the rats had their systolic blood pressures and fasting lipids measured, as well as undergoing an intraperitoneal glucose-tolerance test.

4. Cafeteria-fed rats had worse glucose tolerances than controls and hypertriacylglycerolaemia. The early 8% protein rats had significantly increased blood pressures, as did the cafeteria-fed rats. These increases were additive, suggesting that early protein restriction, and later obesity, are indeed independent risk factors for the development of hypertension.
Impaired Insulin-Induced Attenuation of Noradrenaline-Mediated Vasoconstriction in Insulin-Resistant Obese Zucker Rats
Authors: Walker A. B. , Dores J. , Buckingham R. E. , Savage M. W. , Williams G.
Published: August 2015

1. Insulin resistance is associated with hypertension but the underlying mechanism is unclear. We tested the hypothesis that insulin-induced vasodilatation is impaired in insulin-resistant obese Zucker rats. We studied mesenteric artery (≈ 220 μm diameter) function before the development of hypertension in 3-month old obese Zucker rats and age-matched lean rats.

2. In vessels from lean rats, insulin at concentrations of 50, 500 and 5000 m-units/l attenuated the constriction in response to noradrenaline (50 m-units/l: 8 ± 3%, P < 0.05; 500 m-units/l: 13 ± 3%, P < 0.02; 5000 m-units/l: 13 ± 2%, P < 0.02).

3. Vessels from obese rats failed to show any such response to insulin (2 ± 6% increase in maximal tension with 5000 m-units/l; not significant), both in the presence and absence of l-arginine (3 mmol/l).

4. Vessels from obese rats showed slight but significant impairment in the vasodilator response to acetylcholine (5 × 10−8−10−4 mol/l) (obese: 64.1 ± 3.7% relaxation; lean: 77.3 ± 3.7% relaxation; P < 0.05); however, relaxation in response to A23187 was not significantly different between the phenotypes (obese: 81.3 ± 10.6% relaxation; lean: 79.1 ± 9.7% relaxation; not significant).

5. Systolic blood pressure was not significantly different in lean (126 ± 8 mmHg) and obese (127 ± 7 mmHg) rats at the time of study (not significant).

6. We conclude that insulin-induced attenuation of noradrenaline-mediated vasoconstriction is impaired in the obese Zucker rat and that this defect precedes and therefore could contribute to the development of hypertension in this insulin-resistant model. The defect in insulin action could reside in the endothelial generation of nitric oxide, as endothelial function is also abnormal.
Pharmacological Evidence of Calcium-Activated and Voltage-Gated Potassium Channels in Human Platelets
Authors: de Silva H. A. , Carver J. G. , Aronson J. K.
Published: August 2015

1. Previous electrophysiological studies have suggested the presence of KCa and Kv channels in human platelets. However, the pharmacology of these channels has not been defined.

2. We have studied potassium channels in human platelets by measuring the efflux of 86Rb+ (a marker for K+) from 86Rb+-loaded cells, and have defined their responses to stimulation by the platelet agonist thrombin and the calcium ionophore ionomycin.

3. Thrombin (0.1–0.6 i.u./ml) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l), charybdotoxin (300 nmol/l) and α-dendrotoxin (100–200 nmol/l), blockers of SKCa channels, KCh channels and Kv channels respectively. Iberiotoxin (300 nmol/l), a specific inhibitor of BKCa channels, had no effect on the thrombin-stimulated 86Rb+ efflux. Although glibenclamide, an inhibitor of KATP channels, inhibited the thrombin-stimulated efflux, it did so only in a high concentration (20 μmol/l).

4. Ionomycin (1–5 μmol/l) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l) and charybdotoxin (300 nmol/l). However, iberiotoxin (300 nmol/l) had no effect on the ionomycin-stimulated 86Rb+ efflux.

5. These findings suggest that 86Rb+ efflux from platelets stimulated by thrombin and ionomycin occurs via two types of KCa channel: SKCa and KCh channels. Thrombin also stimulated efflux via Kv channels.
Glycoprotein Changes in Tumours: A Renaissance in Clinical Applications
Authors: Hounsell Elizabeth F. , Young MIA , Davies Michael J.
Published: August 2015

1. Oligosaccharides linked to protein (glycoprotein) or lipid (glycolipid) are the major components at the outer surface of mammalian cells. Studies using antibodies and lectins have shown in the past that the oligosaccharides they recognize exhibit tumour-associated changes, i.e. they are carbohydrate tumour-associated antigens.

2. The oligosaccharides have been further characterized in recent years by structural analysis using high-resolution chromatographic techniques, MS and NMR. NMR gives an oligosaccharide fingerprint that is characteristic of monosaccharide type and linkage and which can be correlated with magnetic resonance spectroscopic data on fine-needle tissue aspirates.

3. Also of relevance is the new understanding of the molecular biology of MUC genes, which code for mucin protein backbones, and of the glycosyltransferase genes, which determine oligosaccharide structure and immunological recognition.

4. For these reasons, we believe that tumour-associated oligosaccharide changes should be revisited in the context of what we now know about structure and expression. This review synopsizes the past data using the detection of carbohydrate tumour-associated antigens by binding of lectins and antibodies, and puts it into the context of NMR fingerprints or signatures.
Iron-Binding Antioxidant Potential of Plasma Albumin
Authors: Loban Amanda , Kime Robert , Powers Hilary
Published: August 2015

1. The extracellular proteins caeruloplasmin and transferrin have important antioxidant properties by virtue of the fact that they inhibit iron-dependent free radical production, and ensuing damage to cells.

2. Albumin is a plasma protein which can loosely bind iron, but the redox activity of this iron has not been fully investigated.

3. The ability of albumin to bind iron and to prevent iron-dependent lipid peroxidation in vitro was investigated using liposomes and a rat brain homogenate system.

4. The iron-binding capacity of albumin was found to be substantial, and albumin inhibited lipid peroxidation in a concentration-dependent manner in both systems used.

5. This antioxidant property of albumin may be especially important in the plasma of babies born prematurely, in whom transferrin and caeruloplasmin concentrations are often very low, and in whom non-transferrin-bound iron has been detected in the plasma.
Increased Plasma Levels of Adrenomedullin in Patients with Hypertrophic Cardiomyopathy: Its Relation to Endothelin-1, Natriuretic Peptides and Noradrenaline
Authors: Hamada Mareomi , Shigematsu Yuji , Kawakami Hideo , Minamino Naoto , Kangawa Kenji , Matsuo Hisayuki , Hiwada Kunio
Published: August 2015

1. The aim of this study was to elucidate the pathophysiological role of adrenomedullin and the relation between adrenomedullin and other hormones in patients with hypertrophic cardiomyopathy.

2. Fourteen patients with hypertrophic obstructive cardiomyopathy (HOCM), 26 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) and 14 normal control subjects participated in this study. Radioimmunoassay for plasma adrenomedullin concentration was performed with adrenomedullin-M antibody. Plasma levels of endothelin-1, atrial and brain natriuretic peptides and noradrenaline were also measured.

3. Plasma levels of adrenomedullin were higher in patients with hypertrophic cardiomyopathy (8.43 ± 3.73 pmol/l) than in normal controls (5.24 ± 0.44 pmol/l, P < 0.005). There was no significant difference between HOCM and HNCM patients. There was a weak correlation between plasma levels of adrenomedullin and total 12-lead QRS voltage in patients with hypertrophic cardiomyopathy (r = 0323, P < 0.05)

4. Plasma levels of endothelin-1, atrial and brain natriuretic peptides were higher in hypertrophic cardiomyopathy than in normal controls. Endothelin-1 showed no significant difference between HOCM and HNCM patients, but atrial and brain natriuretic peptides were higher in HOCM than in HNCM patients. There was a positive correlation between plasma levels of adrenomedullin and endothelin-1 (r = 0.575, P < 0.0001), but no correlation between plasma levels of adrenomedullin and atrial natriuretic peptide, brain natriuretic peptide and noradrenaline.

5. Our results indicate that adrenomedullin may play an important role to maintain haemodynamics in patients with hypertrophic cardiomyopathy, and its action may be related to endothelin-1 but independent of atrial natriuretic peptide, brain natriuretic peptide and noradrenaline.
Changes to Mucins in Uninvolved Mucosa and at the Tumour Site in Gastric Adenocarcinoma of Intestinal Type
Authors: Sidebotham R. L. , Dhir N. K. , Elder J. B. , Spencer J. , Walker M. M. , Schrager J.
Published: August 2015

1. Mucin histochemistry is markedly altered in the stomach in intestinal-type adenocarcinoma. To increase understanding of these changes we have examined the content and distribution of carbohydrate in mucus glycopolypeptides isolated from non-malignant antrum, and from the uninvolved gastric mucosa and tumour site of patients with this disease.

2. The content of carbohydrate declined by 12.6% (P = 0.02) in mucus glycopolypeptides from uninvolved gastric mucosa when compared with those from non-malignant antrum, and by a further 25.4% (P < 0.001) in mucus glycopolypeptides from the tumour site. The first of these changes was accompanied by a significant decrease in the number of carbohydrate chains/1000 amino acid residues, and a significant increase in the number of monosaccharide units in each carbohydrate chain. The second of these changes was accompanied by significant decreases in both the number of carbohydrate chains/1000 amino acid residues, and in the number of monosaccharide units in each carbohydrate chain.

3. The number of sulphated monosaccharide units/100 carbohydrate chains increased from a mean of 7.2 in mucus glycopolypeptides from non-malignant antrum to a mean of 27.2 (P < 0.001) in preparations from uninvolved gastric mucosa and 22.7 (P < 0.001) in preparations from the tumour site.

4. Evidence is presented that these structural changes to mucus glycopolypeptides from the malignant stomach are due to an abnormal mucin biosynthesis by metaplastic goblet cells and/or immature gastric-type mucous cells within the uninvolved mucosa, and immature mucous cells at the tumour site.
An Early Prenatal Exposure to Excess Glucocorticoid Leads to Hypertensive Offspring in Sheep
Authors: Dodic M. , May C. N. , Wintour E. M. , Coghlan J. P.
Published: August 2015

1. Recent studies in animals have linked fetal exposure to excess maternal glucocorticoids with the later occurrence of cardiovascular disorders, particularly hypertension.

2. To test the hypothesis that prenatal treatment could impact on adult blood pressure two groups of pregnant ewes were transported from the farm to the Institute at either 22–29 days of pregnancy (pretreatment group 1) or 59–66 days of pregnancy (pretreatment group 2), subjected to 48 h treatment with dexamethasone (0.28 mg day−1 kg−1 for 2 days) and then returned to the farm. The control group remained at the farm for the entire pregnancy. Lambs were then studied at approximately 4, 10 and 19 months after birth.

3. The basal mean arterial pressure in pretreatment group 1 (80 ± 1 mmHg at 124 days; 83 ± 1 mmHg at 309 days and 89 ± 1 mmHg at 558 days; n = 6) was significantly different (P < 0.05 in all groups) from that in the control group of lambs (74 ± 2 mmHg at 110 days; 76 ± 1 mmHg at 323 days and 81 ± 1 mmHg at 568 days; n = 7). However, prenatal glucocorticoid exposure did not alter vascular sensitivity to noradrenaline, angiotensin II and adrenocorticotropic hormone in these sheep at any of the ages studied, nor did it affect basal or adrenocorticotropic hormone-induced concentrations of Cortisol or basal plasma renin concentrations in the lambs at any age.

4. These data support the hypothesis that excess glucocorticoid exposure in early pregnancy, during a critical developmental stage or ‘window’, programmes higher blood pressure that persists in later life.
Intravenous Lactate Prevents Cerebral Dysfunction during Hypoglycaemia in Insulin-Dependent Diabetes Mellitus
Authors: King P. , Kong M.-F. , Parkin H. , MacDonald I. A. , Barber C. , Tattersall R. B.
Published: August 2015

1. Intravenous lactate prevents cerebral dysfunction during hypoglycaemia in healthy volunteers. This study examines whether this also occurs in insulin-dependent diabetes. Changes in four-choice reaction time, auditory brain stem response, and P300 latency were used as measures of cerebral function.

2. Ten subjects were studied twice at least 4 weeks apart. Blood glucose was maintained between 5 and 8 mmol/l for 1 h before starting a 60 m-unit min−1 m−2 stepped hyperinsulinaemic clamp, achieving blood glucose concentrations of 4.5, 33 and 2.5 mmol/l. At one visit, 40 μmol min−1 kg−1 sodium lactate was infused, and at the other, normal saline. Cerebral function was measured at each blood glucose concentration.

3. Blood lactate rose to 3.32 ± 0.06 mmol/l during lactate infusion compared with 0.9 ± 0.03 mmol/l during saline infusion. Compared with the results at 4.5 mmol/l there were no significant changes at 33 mmol/l in any measure of cerebral function at either visit. At 2.5 mmol/l a significant increase in reaction time and P300 latency occurred with saline [mean change 33.1 ± 8.6 ms (P < 0.01) and 30.1 ± 9.2 ms (P < 0.01) respectively] but not lactate [mean change −5.9 ± 3.7 ms (P > 0.05) and −6 ± 7.6 ms (P > 0.05) respectively]. No significant changes occurred in auditory brain stem response. The catecholamine response to hypoglycaemia was attenuated by lactate (P < 0.05 for adrenaline and noradrenaline).

4. Thus intravenous lactate prevents cerebral dysfunction during hypoglycaemia in insulin-dependent diabetes.
Rapid Communication: Epidermal Growth Factor Protects against Carbon Tetrachloride-Induced Hepatic Injury
Authors: Berlanga J. , Caballero M. E. , Ramirez D. , Torres A. , Valenzuela C. , Lodos J. , Playford R. J.
Published: August 2015

1. Epidermal growth factor (EGF) is known to protect the gastrointestinal tract against various noxious agents. Its potential value in preventing/treating hepatic injury is, however, largely unexplored. We therefore examined whether EGF could influence CCl4-induced hepatic injury.

2. Female Sprague—Dawley rats (8 per group) received saline or recombinant EGF (500 or 750 μg/kg, intraperitoneal) 30 min before CCU (20% v/v, in olive oil, intraperitoneal). Eighteen hours later, animals were killed, serum was collected for assay of biochemical markers of hepatic injury and livers were removed for histological analyses.

3. Administration of CCl4 resulted in severe hepatic necrosis and caused a 10-fold rise in plasma alanine aminotransferase levels compared with levels seen in control animals (218 ± 15 compared with 23 ± 9 μmol/l in controls, mean ± SEM, P < 0.01). Serum malondialdehyde levels, used as a marker of lipid peroxidation, showed a 2-fold rise in response to CCl4 treatment (median 4.0, quartile range 3.3–5.8 units/l compared with median 2.3, quartile range 2.1–2.5 units/l in controls, P < 0.05). Administration of EGF at 500 μg/kg, before the CCl4, did not protect against injury, as assessed by histology or rise in plasma alanine aminotransferase levels. In contrast, animals given EGF at 750 μg/kg, before the CCl4, had only minimal changes in histology, with only a minor rise in alanine aminotransferase levels (37 ± 4 compared with 23 ± 9 μmol/l in animals not given CCl4) and had no significant rise in malondialdehyde levels.

4. EGF protects against CCl4-induced hepatic injury and may provide a novel approach to the treatment of liver damage.
Skin Microcirculation in Patients with Type I Diabetes with and without Neuropathy after Neurovascular Stimulation
Authors: Forst Thomas , Pfützner Andreas , Kunt Thomas , Pohlmann Thomas , Schenk Ulrike , Bauersachs Rupert , Küstner Ernst , Beyer Jürgen
Published: August 2015

1. Neurovascular inflammation is impaired in patients suffering from diabetic neuropathy. The aim of our study was to evaluate the distribution of nutritive and total skin blood flow in diabetic patients with and without neuropathy after neurovascular stimulation with acetylcholine.

2. Twenty patients with Type I diabetes, 10 with and 10 without neuropathy, and 10 age-matched non-diabetic control subjects, underwent microvascular investigations before and after neurovascular stimulation by intracutaneous application of acetylcholine. The capillary blood cell velocity in the nailfold of the hallux was measured by videophotometric capillaroscopy, and the total skin microcirculation in the same area by laser Doppler flowmetry.

3. The increase in total skin blood flow was significantly impaired in the group of neuropathic diabetic patients compared with the non-neuropathic diabetic patients (17.5 ± 83 versus 51.0 ± 16.2; P < 0.05) and the non-diabetic subjects (17.5 ± 8.3 versus 67.8 ± 19.7; P < 0.01). The increase in capillary blood flow was not significantly impaired in Type 1 diabetes patients with neuropathy.

4. The ratio between capillary blood flow and total skin perfusion decreased significantly in the control group (from 0.82 ± 0.15 to 0.47 ± 0.11; P < 0.005) and in the Type I diabetes patients without neuropathy (from 0.79 ± 0.12 to 0.43 ± 0.12; P < 0.05), whereas the decrease in the neuropathic group was statistically insignificant (from 1.05 ± 0.19 to 0.72 ±0.16).

5. Diminished total skin perfusion in the foot after intracutaneous stimulation with acetylcholine in Type I diabetes patients is associated with diabetic neuropathy, indicating a disturbance in the neurovascular reflex arc. This impaired neurovascular response is caused by a diminished total and sub-papillary blood flow and not by a diminished nutritive capillary flow. There is no evidence of a diminished nutritive capillary blood flow during neurogenic inflammation in Type I diabetes patients suffering from diabetic neuropathy.
Autoimmune and Clinical Characteristics of Type 1 Diabetes in Children with Different Genetic Risk Loads Defined by HLA-DQBI Alleles
Authors: Komulainen J. , Knip M. , Sabbah E. , Vähäsalo P. , Lounamaa R. , Åkerblom H. K. , Reijonen H. , Ilonen J. ,   Childhood Diabetes in Finland Study Group
Published: August 2015

1. The impact of different genetic risk loads defined by HLA-DQBI alleles on the autoimmune and clinical characteristics of 647 children and adolescents with recent-onset Type I diabetes was evaluated in a prospective population-based study. The subjects were divided into four groups based on HLA-DQBI genotypes: DQB1*0302/0201 (high risk), *0302/x (moderate risk), *0201/y (low risk) and *z/z (decreased risk).

2. Close to two thirds (62.3%) of the subjects possessed a high or moderate risk genotype. A decreased frequency of positivity for islet cell antibodies (ICA) and insulin autoantibodies (IAA) (76.8% compared with 85.3%; P = 0.05, and 30.5% compared with 50.8%, P = 0.0006, respectively) but not of positivity for antibodies to the 65 kDa isoform of glutamate decarboxylase was observed in children with the DQB1*0201/y genotype compared with other children. Among ICA-negative subjects, those with the DQB1*0201/y genotype had higher serum C-peptide levels over the first 2 years after the diagnosis of Type I diabetes than those with other genotypes (P = 0.028).

3. Our data provide some evidence of HLA-DQB1-determined heterogeneity in the autoimmune and clinical characteristics of childhood Type I diabetes at the time of the clinical manifestation. This suggests differences between children with various HLA-DQBI genotypes in the pace and/or intensity of the beta-cell destructive process leading to clinical Type I diabetes.
Distribution of Glutaminase and Glutamine Synthetase Activities in the Human Gastrointestinal Tract
Authors: James L. A. , Lunn P. G. , Middleton S. , Elia M.
Published: August 2015

1. The activities of the two key enzymes involved in glutamine metabolism, glutaminase and glutamine synthetase, were measured in mucosal biopsies taken from different sites throughout the human gastrointestinal tract, from oesophagus to rectum.

2. The specific activity of glutamine synthetase was highest in the stomach (4.5 nmol glutamine formed per minute per mg of protein), but both small and large intestine and the oesophagus had little synthesizing capacity (less than 0.3 nmol of glutamine formed per minute per mg of protein).

3. Glutaminase specific activity was highest in the small intestine (53 nmol glutamate formed per minute per mg of protein by duodenal mucosa), intermediate in the large intestine and lowest in the oesophagus and stomach (less than 13 nmol of glutamate formed per minute per mg of protein).

4. The glutamine concentration in the mucosa was lower in the duodenum than in the colon (0.62 and 0.95 mmol/kg wet weight respectively), but both were much lower than the measured Km values of glutaminases obtained from these sites (3.8 and 4.0 mmol/kg wet weight respectively).

5. The concentration of glutamine in saliva, stomach juice, bile and duodenal juice suggests that very little glutamine passes into the gastrointestinal tract via these secretions.

6. The study provides the most complete information on the distribution of glutamine synthetase and glutaminase along the human gastrointestinal tract, and suggests that (i) both the small and large intestines have a high potential for glutamine metabolism, but little synthesizing capacity, thus both must derive their glutamine from other sources, and (ii) neither the stomach nor the oesophagus have a high glutaminase activity, although the stomach has substantial capacity to synthesize glutamine. The distribution of the enzymes along the gastrointestinal tract may help rationalize the use of glutamine for treating diseases that affect different parts of the gastrointestinal tract.
Chronic Administration of Octreotide Ameliorates Portal Hypertension and Portal Hypertensive Gastropathy in Rats with Cirrhosis
Authors: Chan Che-Chang , Lee Fa-Yauh , Wang Sun-Sang , Chang Full-Young , Lin Han-Chieh , Lin Hwai-Jeng , Chu Chi-Jen , Wu Shwu-Ling , Tai Chun-Ching , Lee Shou-Dong
Published: August 2015

1. Portal hypertension and hyperdynamic circulation have been postulated to play a role in the pathogenesis of portal hypertensive gastropathy. Administration of octreotide to portal hypertensive rats has been shown to reduce portal pressure and ameliorate hyperdynamic circulation.

2. This study investigated the effects of chronic administration of octreotide on systemic and portal haemodynamics and the development of portal hypertensive gastropathy in carbon tetrachloride-induced cirrhotic rats.

3. After 12 weeks of carbon tetrachloride induction, cirrhotic rats were randomly assigned to receive either placebo (5% dextrose in water) or octreotide (65 μg/kg in 5% dextrose in water) subcutaneously twice daily for 10 days. Haemodynamic studies with a thermodilution technique and gastric morphometric analyses were performed at 10 days after treatment.

4. In cirrhotic rats, octreotide treatment induced a significant increase in systemic vascular resistance (2.7 ± 0.2 versus 3.4 ± 0.2 mmHg/ml · min−1 · 100 g−1, P < 0.05) and decrease in portal pressure (12.5 ± 1.2 versus 9.9 · 0.5 mmHg, P < 0.05) compared with placebo-treated rats. In addition, octreotide treatment significantly reduced the mean cross-sectional area of gastric mucosal vessels (2290 ± 145 versus 1810 ± 101 μm2, P < 0.05).

5. This study shows that chronic octreotide treatment ameliorates the development of portal hypertensive gastropathy in cirrhotic rats. The effect of octreotide on portal hypertensive gastropathy may, at least partly, be due to the alleviation of portal hypertension and hyperdynamic circulation.