bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal Tubular Protein Degradation of Radiolabelled Aprotinin (Trasylol) in Patients with Chronic Renal Failure
Authors: Rustom R. , Grime J. S. , Maltby P. , Stockdale H. R. , Jackson M. J. , Critchley M. , Bone J. M.
Published: August 2015

1. The new method developed to measure renal tubular degradation of small filtered proteins in patients with normal renal function, using radio-labelled aprotinin (Trasylol) (R. Rustom, J. S. Grime, P. Maltby, H. R. Stockdale, M. Critchley, J. M. Bone. Clin Sci 1992; 83, 289–94), was evaluated in patients with chronic renal failure.

2. Aprotinin was labelled with either 99mTc (40 MBq) or 131I (0.1 MBq), and injected intravenously in nine patients, with different renal pathologies. 51Cr-EDTA clearance (corrected for height and weight) was 40 + 5.4 (range 11.2-81) ml min−1 1.73 m−2. Activity in plasma and urine was measured over 24–48 h, and chromatography on Sephadex-G-25-M was used to separate labelled aprotinin from free 99mTcO4− or 131I−. Renal uptake was measured for 99mTc-labelled aprotinin only.

3. The volume of distribution was 20.2 + 2.3 litres. Chromatography showed all plasma activity as undegraded aprotinin, and urine activity only as the free labels (99mTcO4− or 131I−).

4. As in patients with normal renal function, activity in the kidney appeared promptly, with 5.7 + 2.5% of the dose detected even at 5 min. Activity rose rapidly to 9.4 + 1.6% of dose after 1.5 h, then more slowly to 15.0 + 0.5% of dose at 4.5 h, and even more slowly thereafter, reaching 24.1 + 2.8% of dose at 24 h. Extra-renal uptake was again insignificant, and both 99mTcO4− and 131I− appeared promptly in the urine, with similar and uniform rates of excretion over 24 h.

5. Both tubular uptake at 24 h and the rate of tubular metabolism over 24 h were lower than in the patients with normal renal function studied previously, but only the rate of tubular metabolism was directly related to the glomerular filtration rate (r = 0.75, P <0.02).

6. Correction for the reduced glomerular filtration rate yielded values for both tubular uptake (0.67 + 0.14 versus 0.32 + 0.03% of dose/ml of glomerular filtration rate, P <0.005), and tubular metabolism (0.033 + 0.07 versus 0.015 + 0.001% of dose h−1 ml−1 of glomerular filtration rate, P <0.005) that were higher by comparison with those for patients with normal renal function studied previously.

7. Fractional renal degradation of 99mTc-aprotinin (in h−1), derived from the mean rate of urinary excretion of the free isotope over a given interval, divided by the mean cumulative kidney uptake over the same interval, also fell steeply early, and then more slowly to 0.07 + 0.01 h−1 at 14.25 h (between 4.5 and 24 h).

8. It is concluded that the method described previously is also suitable in patients with chronic renal failure, allowing further research into renal disease progression.
Erythrocyte Ion Transport Alterations in Hypertriglyceridaemic Rats
Authors: Kuneš Jaroslav , Talib Hassan Karama Bin , DobešOvá Zdena , Vrána Antonín , Zicha Josef
Published: August 2015

1. Hypertension appears to be associated with both abnormalities in ion transport and disturbances in lipid metabolism. The aim of the present study was to search for alterations in erythrocyte ion transport in hereditary hypertriglyceridaemic rats. This strain is characterized by a pronounced elevation of blood pressure which correlates with the plasma triacylglycerol level.

2. Erythrocyte Na+ content was elevated in hypertriglyceridaemic rats due to an increased ouabainresistant Na+ net uptake. This was caused not only by the acceleration of bumetanide-sensitive Na+ inward co-transport, but also by the augmentation of bumetanide-resistant Na+ inward leak. A moderate enhancement of bumetanide-sensitive Rb+ uptake was seen in hypertriglyceridaemic animals, but there were no changes in bumetanide-resistant Rb+ leak.

3. The plasma triacylglycerol level correlated positively not only with blood pressure (P <0.001) but also with ouabain-resistant Na+ transport (P <0.002), bumetanide-sensitive Na+ and K+ (Rb+) co-transport (P <0.01 and P <0.001, respectively), bumetanide-resistant Na+ leak (P <0.02) and erythrocyte Na+ content (P <0.05).

3. Thus the association of augmented ouabain-resistant Na+ transport with elevated blood pressure in this form of experimental hypertension might be mediated by genetic disorders of lipid metabolism.
Platelet Catecholamine Concentrations after Short-Term Stress in Normal Subjects
Authors: Carstensen E. , Yudkin John S.
Published: August 2015

1. Four studies were designed to test the hypothesis that platelet catecholamine levels may provide a stable index of circulating plasma catecholamine concentrations, and that these are unaffected by acute elevations of plasma levels with physical and psychological stress.

2. To assess the biological variability within individuals, ten subjects were sampled on five occasions over 8–30 h. The intra-individual coefficients of variation for plasma and platelet noradrenaline levels were 193 +10% and 9.5 +4.2%, respectively, and for plasma and platelet adrenaline levels 48.3 +22% and 25.3 +8.4%, respectively.

3. Three other studies investigating the response to physical and psychological stress were performed. In the first study, plasma and platelet catecholamine levels were studied in 12 healthy subjects before and after bicycle ergometry. Plasma catecholamine concentrations increased [noradrenaline by +346 + 323% (P = 0.002) and adrenaline by +314 + 352% (P -0.003)], whereas platelet concentrations showed little change [noradrenaline +4+18% (P = 0.94) and adrenaline +38+ 116% (P = 0.67)].

4. In the study, catecholamine concentrations were measured in eight subjects after hand immersion in iced water. Plasma noradrenaline concentrations increased significantly (+58 +19%, P = 0.001), but no significant change was found in plasma adrenaline concentrations (+8+44%, P = 0.48). Platelet catecholamine concentrations showed no significant change (noradrenaline +15 +15%, P = 0.052, and adrenaline 19 +82%, P = 0.84).

5. In the third study, catecholamine concentrations were measured in 22 medical students before and after their end-of-year examination. There was no significant change in plasma noradrenaline or adrenaline concentrations (+20 +39%, P = 0.08, and −2 +33%, P = 0.36, respectively) nor in platelet concentrations (noradrenaline +6+19%, P = 0.15, and adrenaline +34 +72, P = 0.65).

6. In 53 subjects sampled between 08.00 and 12.00 hours, plasma and platelet noradrenaline concentrations were significantly correlated (r, = 0.47, P <0.001), but the relationship between plasma and platelet adrenaline concentrations in these subjects did not achieve significance (rs = 0.17, P <0.23).

7. In conclusion, platelet catecholamine concentrations seem to be unaffected by acute short-term stress and may provide a reliable indicator of chronic sympatho-adrenomedullary arousal.
Heterogeneity of Human Gallbladder Mucin in Bile
Authors: van Wijland Michel J. A. , Klinkspoor J. Henriëtte , de Wit Laurens Th. , Elferink Ronald P. J. Oude , Tytgat Guido N. J. , Groen Albert K.
Published: August 2015

1. Human gallbladder mucin has been implicated to play a role in gallstone disease. In spite of this fact relatively little is known about the structure of human gallbladder mucin. In this study we have investigated the possible heterogeneity of mucin. For this purpose polyclonal and monoclonal antibodies against gallbladder mucin were raised. All antibodies reacted primarily with carbohydrate antigenic determinants. With these antibodies the immunoreactivity of gallbladder mucin from 60 patients with cholesterol gallstones and 20 subjects without stones was screened. In addition, reactivity with several lectins was studied.

2. Considerable heterogeneity was found with both antibody and lectin typing, but there was no significant difference in heterogeneity between mucin from patients with gallstones and control subjects. Immunoblotting revealed that there was similarity between the reaction of the polyclonal antibody and the Helix pomatia agglutinin. All mucin preparations reacting with the polyclonal antibody also bound to Helix pomatia agglutinin. Nineteen of the 21 reacting mucins (90%) were from patients with blood group A (18 patients) or AB (one patient) and expression of A antigen could be demonstrated on the mucin of these patients. The resulting two reacting mucins were from patients with type O. However, expression of the blood group antigen could not account for the lack of reactivity of the mucin of other patients. The Helix pomatia agglutinin partially blocked the reactivity of the polyclonal antibody, whereas anti-A antibody did not show inhibition, indicating that more then only blood group A epitopes were recognized by this antibody.

3. We conclude that considerable patient to patient heterogeneity of human gallbladder mucin exists. This may have functional consequences for the role of mucin in the pathogenesis of gallstone disease.
Effect of Noradrenaline on Glycerol Turnover and Lipolysis in the Whole Body and Subcutaneous Adipose Tissue in Humans in Vivo
Authors: Kurpad A. , Khan K. , Calder A. G. , Coppack S. , Frayn K. , MaCdonald I. , Elia M.
Published: August 2015

1. The effect of infusion of noradrenaline (0.42 μmol min−1 kg−1) on the exchange of non-esterified fatty acids, glycerol and other metabolites across subcutaneous abdominal adipose tissue was investigated in five healthy subjects using an arteriovenous catheterization technique and measurement of adipose tissue blood flow using the 133Xe clearance technique. At the same time, the net rate of fat oxidation in the whole body was assessed by indirect calorimetry, and the turnover of glycerol in the whole body and in subcutaneous adipose tissue was estimated using [5-2H]glycerol, which was administered as a primed constant infusion for 1 h before (basal turnover) noradrenaline administration and continued during the 1 h of noradrenaline infusion.

2. The noradrenaline infusion increased the plasma noradrenaline concentration from a basal value of 0.9 ± 0.1 to 12.6 ± 1.2 nmol/(mean ± SEM) at 60 min. It also increased the arterialized concentration of glycerol by 50% (basal value 81 ± 11/μmol/l−1) and that of plasma non-esterified fatty acids three-fold (basal value 357 ± 86 μmol/l).

3. Noradrenaline increased the net release of glycerol by adipose tissue three-fold and that of non-esterified fatty acids three- to four-fold. Although the ratio of non-esterified fatty acid to glycerol release by adipose tissue increased in all subjects from a mean value of 2.7 in the basal period to 3.6 and 3.9 at 50 and 60 min of the noradrenaline infusion, respectively (P < 0.02), at no time point did the ratio differ significantly from 3.0

4. Noradrenaline increased the estimated rate of appearance of glycerol in the whole body from a basal value of 1.5 ± 0.3 to 2.6 ± 0.3 μmol min−1 kg−1 body weight, and the net rate of triacylglycerol oxidation from 1.2 ± 0.1 to 1.7 ± 0.13 μmol min−1 kg−1. The enrichment of glycerol in venous blood draining adipose tissue was two-fold lower than that predicted from the net addition of glycerol to the blood in the basal period (P < 0.02).

5. This study provides a direct demonstration of a ‘hormone’ stimulating lipolysis in human adipose tissue in viva The effect of noradrenaline in significantly increasing the ratio of non-esterified fatty acid to glycerol release by adipose tissue may be partly explained by accumulation in adipose tissue of diacylglycerol, which is associated with release of non-esterified fatty acids but not glycerol. Finally, since the low enrichment of glycerol in venous blood draining adipose tissue cannot be entirely explained by the net addition of glycerol in adipose tissue, there must be exchange between enriched glycerol in blood and unenriched glycerol in adipose tissue. This raises questions about the accuracy of glycerol turnover studies, which are typically carried out over 1 h.
Effect of Citrate Infusion on Urinary Aluminium Excretion in the Rat
Authors: Cochran Malcolm , Chawtur Vira , Phillips John W. , Dilena Beverley
Published: August 2015

1. Seven pairs of rats received 1 mmol/l aluminium citrate in their drinking water 5 days before the experiments. Five additional rats were treated identically. Six rats received the same food but drank distilled water.

2. After a 6 h fast, the animal was anaesthetized, the jugular vein and femoral artery were cannulated and the bladder was catheterized, after which an intravenous infusion of Hartmann's solution containing [14C]inulin was begun. The urine was collected at 20 min intervals and 1 ml of arterial blood was obtained before the end of each collection. After at least two basal collections, the infusion was modified to contain, in addition, 5 mmol/l NaHCO3 (control) or 5 mmol/l sodium citrate (experimental). The infusion rate, constant in each pair, differed between pairs across the range 60–125 μmol/min.

3. A total of eight collections was made per animal and urine flow, glomerular filtration rate, plasma and urinary aluminium and citrate were measured.

4. Control and experimental rats had a higher mean basal plasma aluminium level (0.39 ± 0.21 μmol/l) than the six rats receiving distilled water (0.16 ± 0.14 mmol/l, P < 0.001). The corresponding urinary aluminium excretion rates were similar (46 ± 31 and 47 ± 23 pmol/min, respectively). There was no significant difference between the basal values of any variable in the control and experimental rats. No significant change was observed in any variable during the infusion of NaHCO3 (controls). Among the experimental rats, there was no significant change in urine flow, glomerular filtration rate or plasma aluminium level. However, the plasma citrate level rose rapidly with the infusion to approach a plateau value in each case, and there were slower rises in urinary citrate and aluminium excretion rates. A renal threshold for citrate appeared to occur at a plasma level of approximately 0.25 mmol/l. The aluminium excretion rate was directly related to the citrate excretion rate (P < 0.01) and the increase in urinary aluminium excretion rate above the basal state was even more closely related (P < 0.001).

5. In the five additional animals pretreated with aluminium, the median ultrafiltrable aluminium was 20% (range 17–24%) of the total plasma level and no change was produced by citrate infused at the maximal rate. The plasma protein concentration also remained unchanged despite the fluid load.

6. We conclude that increased urinary citrate excretion is directly associated with an increase in aluminium excretion in aluminium-loaded animals. The data suggest that this increased excretion is independent of filtered load of aluminium and may therefore be the result of changes in handling of the metal within the kidney.
Effect of Recombinant Human Growth Hormone on Cellular Sodium Metabolism
Authors: Herlitz Hans , Jonsson Olof , Bengtsson Bengt-Åke
Published: August 2015

1. The effect of treatment with recombinant human growth hormone on urinary sodium excretion, total body water, the renin-angiotensin system and erythrocyte sodium metabolism was investigated in 16 adults with growth hormone deficiency.

2. Total body water was determined by isotopic dilution, and erythrocyte electrolyte contents were analysed using flame photometry. The rate of sodium influx and the efflux rate constant of sodium were calculated from values of 22Na in erythrocytes in vitro.

3. One week of treatment with recombinant human growth hormone caused a decrease in urinary sodium excretion in 9/10 patients and an increase in erythrocyte sodium content. Total body water, plasma renin activity, angiotensin II concentration and transmembrane sodium transport were unaltered.

4. Six months of treatment with recombinant human growth hormone caused significant increases in total body water, erythrocyte sodium content and sodium transmembrane influx. Plasma renin activity tended to increase, whereas blood pressure and serum sodium and potassium concentrations remained unchanged. After 6 months on recombinant human growth hormone total body water showed a significant negative correlation with plasma renin activity.

5. The enhanced erythrocyte sodium transport, if this reflects what happens in the renal tubular cell, combined with a decrease in urinary sodium excretion, during treatment with recombinant human growth hormone could indicate an increase in tubular sodium reabsorption induced by the hormone. An increased plasma renin activity associated with the lack of blood pressure rise would reinforce sodium and water retention.
Modulation of the Effect of Atrial Natriuretic Peptide in Human and Bovine Bronchi by Phosphoramidon
Authors: Angus Robert M. , Nally Jane E. , McCall Raymond , Young Louise C. , McGrath John C. , Thomson Neil C.
Published: August 2015

1. We have previously shown that atrial natriuretic peptide causes bronchodilatation and reduces bronchial reactivity when administered intravenously or by inhalation to asthmatic patients. We wished to determine the direct effect of exogenously applied atrial natriuretic peptide on isolated airway and the role of proteases important in atrial natriuretic peptide degradation in other organ systems.

2. The ability of atrial natriuretic peptide (α-human atrial natriuretic peptide 28-amino acid) to relax precontracted tissues and to protect against methacholine-induced contraction was studied in human and bovine tissue. The role of neutral endopeptidase-24.11 and other proteases in regulating the effect of atrial natriuretic peptide on bronchial smooth muscle was also examined by studying the influence of phosphoramidon, a protease inhibitor, whose actions include the inhibition of neutral endopeptidase-24.11, and the protease inhibitors leupeptin, aprotinin and soybean trypsin inhibitor on the airway response to atrial natriuretic peptide.

3. In human and bovine tissue atrial natriuretic peptide (10−6 mol/l) caused a slight relaxation of methacholine-contracted tissue [mean (SEM) percentage inhibition of contraction of 13.2 (3.02)% and 9.41 (2.63)% respectively] and evoked a signficant rightward shift of the cumulative concentration–-response curve to methacholine [pD2 5.15 (0.23) and 4.85 (0.1) compared with control values of 6.14 (0.1) and 5.85 (0.16), respectively].

4. Phosphoramidon potentiated atrial natriuretic peptide-induced relaxation of methacholine-induced tone and the ability of atrial natriuretic peptide to protect against methacholine-induced contraction. The combination of leupeptine, aprotinin and soybean trypsin inhibitor did not significantly alter the bronchial response to atrial natriuretic peptide in either human or bovine tissues.

5. We conclude that in human and bovine tissue, atrial natriuretic peptide confers protection against methacholine-induced contraction and can relax induced tone and that inhibition of phosphoramidon-sensitive protease increases these effects of atrial natriuretic peptide on airway smooth muscle.
Arthrogenic Quadriceps Inhibition and Rehabilitation of Patients with Extensive Traumatic Knee Injuries
Authors: Hurley M. V. , Jones D. W. , Newham D. J.
Published: August 2015

1. The relationship between joint damage, quadriceps weakness and arthrogenic muscle inhibition was investigated in eight patients who had sustained extensive traumatic knee injury. Isometric and isokinetic quadriceps and hamstring voluntary strength, and quadriceps arthrogenic muscle inhibition during isometric contractions, were measured before and after 4 weeks (approximately 100 h) of intensive rehabilitation.

2. Compared with the uninjured leg, before rehabilitation the injured leg had larger amounts of quadriceps arthrogenic muscle inhibition (P < 0.025), quadriceps (P < 0.0001) and hamstring (P < 0.0001) weakness and severe functional joint instability. There was a negative correlation between the amount of arthrogenic muscle inhibition and quadriceps voluntary contraction force (P < 0.025).

3. After rehabilitation in the injured leg there were small hamstring strength increases (P < 0.05–0.025), but no overall significant quadricep strength increase. Arthrogenic muscle inhibition was statistically unchanged. Severe functional joint instability was still reported by all patients.

4. Previous studies have shown that minimal joint damage evokes relatively less arthrogenic muscle inhibition that does not impede rehabilitation. These data indicate that greater joint damage is associated with greater arthrogenic muscle inhibition, quadriceps weakness and joint instability. Furthermore, intensive rehabilitation had little affect on either quadriceps arthrogenic muscle inhibition or atrophy.
Nitric Oxide Production by Human Peripheral Blood Polymorphonuclear Leucocytes
Authors: Goode Helen F. , Webster Nigel R. , Howdle Peter D. , Walker Barry E.
Published: August 2015

1. We describe a rapid and reliable technique for the assessment of basal nitric oxide release in clinical situations, using peripheral blood polymorphonuclear leucocytes isolated by a single-step density gradient procedure. The assay is based on the quantitative conversion of oxyhaemoglobin to methaemoglobin by nitric oxide. We have further examined the ability of these cells to respond to various stimuli.

2. Basal (unstimulated) nitric oxide release occurred, which was augmented by superoxide dismutase. The mean value for healthy subjects was 283 ±96.7 pmolmin−1 10−6 cells.

3. Both phorbol myristate acetate and N-formyl-methionyl-leucylphenylalanine induced further release of nitric oxide, which was increased by preincubation with lipopolysaccharide, interleukin-6 and interferon-γ.

4. Preincubation of cells with NG-monomethyl-l-arginine or l-canavanine sulphate inhibited nitric oxide production.

5. The procedure provides a valuable tool for monitoring nitric oxide up-regulation in clinical situations.
Influence of 1-Desamino-8-d-Vasopressin on Endogenous Fibrinolysis, Haemodynamics and Liver Blood Flow in Healthy Subjects
Authors: Burggraaf J. , Schoemaker H. C. , Kroon J. M. , Huisman L. , Kluft C. , Cohen A. F.
Published: August 2015

1. Endogenous fibrinolytic capacity increases after administration of 1-desamino-8-d-vasopressin. This increase is commonly attributed to an increase in release of tissue-type plasminogen activator from the endothelium. However, the possibility that 1-desamino-8-d-vasopressin influences liver blood flow, which is a major determinant of tissue-type plasminogen activator clearance, cannot be ruled out.

2. The influence of 1-desamino-8-d-vasopressin on haemodynamics, liver blood flow and fibrinolytic parameters was investigated in a randomized double-blind cross-over study in nine healthy male subjects (age 20–26 years).

3. 1-Desamino-8-d-vasopressin exerted significant haemodynamic effects: mean arterial pressure decreased maximally 12 (95% confidence interval 8–15) mmHg and heart rate increased maximally 21 (95% confidence interval 15–27) beats/min.

4. Endogenous fibrinolytic parameters increased after administration of 1-desamino-8-d-vasopressin. Both tissue-type plasminogen activator antigen and tissue-type plasminogen activator activity were elevated and showed the maximal response shortly after drug administration was completed.

5. 1-Desamino-8-d-vasopressin increased portal venous blood flow as measured with echo-Doppler. The maximal increase in mean blood flow of 55 (95% confidence interval 19–92)% was observed at the end of the 1-desamino-8-d-vasopressin infusion and coincided with the maximal changes in systemic haemodynamics and fibrinolytic parameters. The increase in portal blood flow was not reflected in significant changes in Indocyanine Green clearance. It appears that the Indocyanine Green method is relatively insensitive to increases in liver blood flow.

6. The observed increase in fibrinolytic activity due to tissue-type plasminogen activator activity after 1-desamino-8-d-vasopressin administration may be due to an increased release of tissue-type plasminogen activator from the endothelium and is not caused by changes in clearance.
Enhanced Enteric Excretion of Urate in Rats with Chronic Renal Failure
Authors: Hatch Marguerite , Vaziri N. D.
Published: August 2015

1. The potential contribution of enteric pathways to the extra-renal excretion of uric acid in chronic renal failure was evaluated by measuring [14C]-urate and 36Cl− transport in isolated, short-circuited segments of jejunum, ileum and distal colon from normal rats and rats with chronic renal failure (five-sixths nephrectomized) 6 weeks after surgery. Plasma and urine creatinine and urate concentrations were also determined to establish urate status in chronic renal failure.

2. A 40% reduction in creatinine clearance was observed in the group with chronic renal failure, resulting in a two-fold increase in plasma creatinine concentration (0.064 ± 0.001 mmol/l, n = 9, to 0.120 ± 0.008 mmol/l, n = 14). In contrast, there was no change in plasma urate concentration, despite a 75% reduction in urate clearance.

3. The transport studies demonstrated alterations in intestinal urate transport in rats with chronic renal failure compared with normal rats. Net absorption of urate was observed in the distal colon of control rats, whereas a significant secretory flux was observed in rats with chronic renal failure (from 0.88 ± 0.16 to −1.62 ± 0.81 nmol h−1 cm−2, n = 12). Urate secretion was induced in the jejunum of the group with chronic renal failure (−0.15 ± 0.25 in control and −1.67 ± 0.35 nmol h−1 cm−2 in chronic renal failure, n = 11). Urate transport across the ileum was not altered in chronic renal failure and there was no net flux of urate in either the normal group or the group with chronic renal failure. Net Cl− absorption, which was observed in all segments of the control animals, was reversed to net secretion in chronic renal failure.

4. These studies indicate that urate homoeostasis is maintained in chronic renal failure and both the jejunum and colon may be actively involved in the extra-renal excretion of urate. These studies do not exclude the possibility that urate metabolic pathways are involved in urate homoeostasis in chronic renal failure.
Lymphocyte Protein Synthesis In Vivo: a Measure of Activation
Authors: Park Kenneth G. M. , Heys Steven D. , McNurlan Margaret A. , Garlick Peter J. , Eremin Oleg
Published: August 2015

1. The ‘flooding’ dose technique was used to measure rates of lymphocyte protein synthesis after infusion of [1-13C]leucine (20 atoms% enrichment, 4 g/70 kg body weight). Lymphocyte protein synthesis was measured in healthy subjects and in patients with metastatic colorectal cancer before and during infusion of recombinant interleukin-2. Rates of protein synthesis were compared with thymidine uptake in vitro and phenotypic analysis of lymphocytes.

2. The median rate of lymphocyte protein synthesis in four healthy subjects was 9% (range 7.2–11.4%/day) and in seven patients with colorectal cancer was 6.4% (range 4.2–8.2%/day). After recombinant interleukin-2 treatment the median rate of lymphocyte protein synthesis was 27.8% (range 25.2–33.7%/day).

3. The increased rates of lymphocyte protein synthesis in vivo, after recombinant interleukin-2 infusion, corresponded with increased rates of thymidine uptake and changes in the phenotypic expression of lymphocytes, but these were less consistent than the measured rates of protein synthesis.

4. It is concluded that lymphocyte activation is accompanied by a marked increase in lymphocytic protein synthesis which may have important implications for whole body protein metabolism. Furthermore, measurement of lymphocyte protein synthesis may provide a determination of lymphocyte activation in vivo.
Metabolic Effects of Acute Hyperketonaemia in Man before and during An Hyperinsulinaemic Euglycaemic Clamp
Authors: Webber J. , Simpson E. , Parkin H. , MacDonald I. A.
Published: August 2015

1. The effects of acutely raising blood ketone body levels to those seen after 72 h of starvation were examined in 10 subjects after an overnight fast. Metabolic rate and respiratory exchange ratio were measured with indirect calorimetry before and during an insulin—glucose clamp. Arteriovenous differences were measured across forearm and subcutaneous abdominal adipose tissue.

2. In response to the clamp the respiratory exchange ratio rose from 0.82 to 0.83 during 3-hydroxybutyrate infusion and from 0.83 to 0.94 during control (saline) infusion (P < 0.001).

3. Forearm glucose uptake at the end of the clamp was 4.02 ± 0.95 (3-hydroxybutyrate infusion) and 7.09 ± 1.24 mmol min−1 100 ml−1 forearm (saline infusion). Whole body glucose uptake at the end of the clamp was 72.8 ± 7.9 (3-hydroxybutyrate infusion) and 51.0 ± 3.0 (saline infusion) mmol min−1 kg−1 body weight−1.

4. 3-Hydroxybutyrate infusion reduced the baseline abdominal venous—arterialized venous glycerol difference from 84 ± 28 to 25 ± 12 mmol/l and the non-esterified fatty acid difference from 0.60 ± 0.17 to 0.02 ± 0.09 mmol/l (P < 0.05 versus saline infusion).

5. Hyperketonaemia reduces adipose tissue lipolysis and decreases insulin-mediated forearm glucose uptake. Hyperketonaemia appears to prevent insulin-stimulated glucose oxidation, but does not reduce insulin-mediated glucose storage.
Oxygen Reactivity in Diabetes Mellitus: Effect of Hypertension and Hyperglycaemia
Authors: Patel V. , Rassam S. M. B. , Chen H. C. , Kohner E. M.
Published: August 2015

1. Laser Doppler velocimetry and computerized image analysis of retinal photographs were used to define retinal vascular autoregulation to 60% oxygen breathing. This normally causes vasoconstriction in the retinal circulation. Normotensive and hypertensive diabetic subjects were studied under conditions of relative normoglycaemia (< 10 mmol) and hyperglycaemia (> 15 mmol) together with control subjects.

2. Retinal blood flow was significantly higher in diabetic subjects when hypertensive and hyperglycaemic than in the same diabetic subjects when normotensive.

3. In the normotensive non-diabetic subjects the oxygen reactivity was 41.16 ± 14.09%. It was significantly reduced in normotensive ‘hyperglycaemic’ diabetic subjects (21.75 ± 15.56%), hypertensive diabetic subjects with controlled blood pressure and ‘normoglycaemia’ (30.49 ±14.20%), hypertensive diabetic subjects with controlled blood pressure and ‘hyperglycaemia’ (18.36 ±11.42%), hypertensive diabetic subjects with uncontrolled blood pressure and ‘normoglycaemia’ (26.91 ±13.43%) and hypertensive diabetic subjects with uncontrolled blood pressure and ‘hyperglycaemia’ (17.17 ±13.24%) (means±SD, all P values <0.05).

4. In conclusion, retinal vascular reactivity is impaired in diabetic subjects both when they are normotensive and when they are hypertensive. Hyperglycaemia, to a degree commonly encountered in clinical practice, impairs retinal vascular autoregulation even further.
Flow Cytometric Detection of Circulating Activated Platelets and Platelet Hyper-Responsiveness in Pre-Eclampsia and Pregnancy
Authors: Janes Sarah L. , Goodall Alison H.
Published: August 2015

1. Platelet activation status and response to stimulation with agonists ex vivo were studied by whole blood flow cytometry in 15 women with pre-eclampsia, 20 age- and gestational-age-matched women who completed a normal pregnancy, and 20 age-matched non-pregnant women.

2. Women with proteinuric pre-eclampsia showed evidence of activated, degranulated platelets in the circulation, with increased platelet-bound fibrinogen, increased expression of the lysosomal granule membrane antigen, CD63, and raised plasma levels of β-thromboglobulin.

3. CD63 expression and β-thromboglobulin per platelet were also significantly higher in normal pregnant women than in non-pregnant women, but in these subjects fibrinogen binding was normal.

4. There was good correlation for all subjects in degranulation, measured by CD63 antigen expression, and by plasma β-thromboglobulin levels corrected for platelet count (r = 0.65; P < 0.01).

5. Platelet responsiveness to ADP in vitro showed a heightened degranulation response (CD63 expression) in normal pregnancy compared with the non-pregnant control group, which was increased further in women with non-proteinuric and proteinuric pre-eclampsia.

6. However, this response was not accompanied by an increased binding of fibrinogen to GPIIb—IIIa. Fibrinogen binding in response to ‘weak’ agonist stimulation, by low concentrations of ADP or, in a subgroup by adrenaline, was in fact lower in the normal pregnant women than in the non-pregnant women.

7. It is postulated that women at risk of developing pre-eclampsia may have hyper-reactive platelets, primed to undergo release by passage through the abnormal placenta.
Epidemiology of An Outbreak of Drug-Resistant Tuberculosis in the U.K. Using Restriction Fragment Length Polymorphism
Authors: Goyal M. , Ormerod L. P. , Shaw R. J.
Published: August 2015

1. Drug-resistant tuberculosis is a growing health care problem. When a series of cases occur, it is essential to know if patients with multidrug-resistant disease represent one or a number of separate outbreaks.

2. The epidemiology of an outbreak of isoniazid- and streptomycin-resistant tuberculosis in Blackburn was studied by restriction fragment length polymorphism using a probe for the IS6110 DNA sequence.

3. Mycobacterium tuberculosis from four cases of isoniazid- and streptomycin-resistant disease had an identical restriction fragment length polymorphism pattern. This pattern was not shared by drug-sensitive isolates of M. tuberculosis obtained from Blackburn (n = 8) or London (n = 13) or a M. tuberculosis isolate from a fifth Blackburn case which was resistant to isoniazid alone.

4. This methodology confirmed that all four cases of isoniazid- and streptomycin-resistant disease were part of a single epidemiologically related outbreak of drug-resistant disease. This study demonstrates how the epidemiology of an outbreak of multidrug-resistant tuberculosis in the U.K. can be confirmed by restriction fragment length polymorphism.
l-Arginine Reverses the Impairment of Nitric Oxide-Dependent Collateral Perfusion in Dietary-Induced Hypercholesterolaemia in the Rabbit
Authors: Randall Michael D. , Ujiie Hiroshi , Griffith Tudor M.
Published: August 2015

1. We have used an isolated, buffer-perfused, rabbit ear model of acute arterial occlusion to investigate the effects of exogenous l-arginine on the severe impairment of collateral perfusion associated with dietary-induced hypercholesterolaemia. The effects of l-arginine on hypercholesterolaemia-related impairment of endothelium-dependent relaxations to acetylcholine were also investigated in unligated, isolated rabbit ears perfused with buffer.

2. Cholesterol feeding for 8 weeks (blood cholesterol level 66.5 ± 5.3 versus 1.4 ± 0.2 mmol/l, P < 0.001) was associated with almost complete impairment of collateral perfusion, an effect previously observed after inhibition of nitric oxide synthesis. The impairment of collateral perfusion found in hypercholesterolaemia was completely reversed by the addition of 10 mmol/l l-arginine to the perfusion fluid. In control preparations from rabbits fed a normal diet, the addition of 10 mmol/l l-arginine did not influence collateral perfusion.

3. Endothelium-dependent relaxation to acetylcholine was impaired in preparations from the rabbits fed the high cholesterol diet for 8 weeks: the maximum relaxation of tone was 24.6 ± 0.8% and was significantly (P < 0.01) less than that in the controls (70.3 ± 2.4%). Addition of l-arginine to the perfusion fluid caused a modest improvement in the endothelium-dependent relaxations to acetylcholine, with a maximum response of 43.2 ± 1.3%.

4. We conclude that nitric oxide-dependent collateral perfusion is severely impaired in hypercholesterolaemia and that the addition of exogenous l-arginine fully reverses these changes. Endothelium-dependent relaxations to acetylcholine are similarly impaired by hypercholesterolaemia; however, this deficit was only partially reversed by l-arginine. In the context of collateral perfusion, l-arginine treatment may represent a therapeutic strategy to limit the deleterious effects of hypercholesterolaemia on acute arterial occlusion.
Complex Modulation of Cytokine Induction by Endotoxin and Tumour Necrosis Factor from Peritoneal Macrophages of Rats by Diets Containing Fats of Different Saturated, Monounsaturated and Polyunsaturated Fatty Acid Composition
Authors: Tappia P. S. , Grimble R. F.
Published: August 2015

1. Responses to cytokines and other inflammatory stimuli have been shown to be enhanced by fats rich in n − 6 polyunsaturated fatty acids and suppressed by fats rich in n − 3 polyunsaturated fatty acids and oleic acid or poor in n − 6 polyunsaturated fatty acids.

2. Corn oil is rich and coconut oil, olive oil and butter are poor in n − 6 polyunsaturated fatty acids. Olive oil and butter are rich in oleic acid. Fish oil is rich in n − 3 polyunsaturated fatty acids.

3. The present study examines the effects of feeding standard chow or corn, coconut, fish and olive oils and butter for 4 and 8 weeks on subsequent cytokine production by peritoneal macrophages of rats.

4. Tumour necrosis factor production in response to a lipopolysaccharide stimulus and interleukin-1 and interleukin-6 production in response to a tumour necrosis factor challenge were studied.

5. All fats produced a small, but statistically insignificant, reduction in tumour necrosis factor production, which was greatest for olive oil at 8 weeks.

6. After 4 weeks, fish and olive oil significantly reduced interleukin-1 production. After 8 weeks, coconut oil suppressed production of the cytokine, and the inhibitory effect of fish oil was still apparent. After 8 weeks, corn and olive oil enhanced interleukin-1 production.

7. After 4 weeks of feeding, fish and olive oil enhanced interleukin-6 production. After 8 weeks, the enhancement by these fats increased, and corn oil and butter also enhanced production. Coconut oil produced no modulatory effect.

8. Only in the cases of the effect of fish and coconut oil in interleukin-1 production, corn oil on interleukin-1 and interleukin-6 production and olive oil in tumour necrosis factor production, were the effects of fats on cytokine production in concordance with their modulatory effects on responses to cytokines and other inflammatory agents in vivo.
Acute Alcohol Intake Decreases Short-Term Heart Rate Variability in Healthy Subjects
Authors: Koskinen Pekka , Virolainen Juha , Kupari Markku
Published: August 2015

1. The acute effects of a moderate dose of ethanol (1 g/kg body weight) on heart rate and blood pressure variability and baroreflex sensitivity were studied in 12 healthy male subjects in a juice-controlled experiment. Electrocardiographic and finger blood pressure data were recorded and stored in a minicomputer during 5 min of controlled breathing (15 cycles/min) and during deep breathing (5 s inpiration, 5 s expiration, four cycles) before drinking and hourly thereafter for 3 h.

2. Mean breath alcohol concentration rose to 18.9 mg/100 ml. In the time domain analysis, the root mean square difference of successive R-R interval decreased significantly with ethanol as compared with the juice experiment. The difference remained statistically significant even after adjustment for the shorter R-R interval after alcohol. In the frequency domain analysis the high-frequency (0.15-0.5 Hz) spectral power showed a significant decrease after alcohol intake. Also, the index of sensitivity of the baro-receptor reflex (square root of R-R interval power/systolic blood pressure power) decreased significantly in the high-frequency component. Ethanol did not change finger systolic blood pressure, and power spectral analysis did not show significant variability in blood pressure.

3. These data indicate that acute intake of moderate amounts of alcohol causes a significant decrease in heart rate variability owing to diminished vagal modulation of the heart rate.
Effect of ‘Autonomic Blockade’ on Cardiac β-Adrenergic Chronotropic Responsiveness in Healthy Young, Healthy Elderly and Endurance-Trained Elderly Subjects
Authors: Ford G. A. , James O. F. W.
Published: August 2015

1. Cardiac chronotropic responses to isoprenaline are reduced with ageing in man. It is unclear whether this is due to reduced cardiac β-adrenergic sensitivity or to age-associated differences in reflex cardiovascular responses to the vasodilatory effects of isoprenaline. Age-associated changes in physical activity are also reported to influence β-adrenergic sensitivity.

2. The aim of the present study was to determine the contribution of alterations in reflex changes in parasympathetic and sympathetic influences and physical fitness to the age-associated reduction in cardiac chronotropic responses to β-adrenergic agonists.

3. The effect of ‘autonomic blockade’ with atropine (40 μg/kg intravenously) and clonidine (4 μg/kg intravenously) on blood pressure, heart rate and chronotropic responses to intravenous bolus isoprenaline doses was determined in eight healthy young (mean age 21 years), nine healthy elderly (72 years) and 10 endurance-trained elderly (69 years) subjects.

4. Elderly subjects had a reduced increase in heart rate after atropine (young, 49 ± 9 beats/min; elderly, 36 ± 5 beats/min; endurance-trained elderly, 34 ± 12 beats/min; P < 0.01) and did not demonstrate the transient increase in systolic blood pressure after clonidine observed in young subjects (young, 11 ± 10 mmHg; elderly, −12 ± 16 mmHg; endurance-trained elderly, −18 ± 11 mmHg; P < 0.01).

5. Cardiac chronotropic sensitivity to isoprenaline after ‘autonomic blockade’ increased in the young but decreased in the elderly subjects. The isoprenaline dose that increased heart rate by 25 beats/min before and after autonomic blockade' was: young, before 1.6 μg, after 2.8 μg, P < 0.01 (geometric mean, paired test); elderly, before 6.9 μg, after 3.6 μg, P < 0.05; endurance-trained elderly, before 5.9 μg, after 4.0 μg, P < 0.05. Cardiac chronotropic sensitivity to isoprenaline was significantly reduced in elderly compared with young subjects before (P < 0.01) but was similar after (P = 0.09) ‘autonomic blockade’. Chronotropic sensitivity did not differ between healthy and endurance-trained elderly subjects before or after ‘autonomic blockade’.

6. The age-associated reduction in cardiac chronotropic responses to bolus isoprenaline is primarily due to an age-related reduction in the influence of reflex cardiovascular responses on heart rate and not to an age-related reduction in cardiac β-adrenergic sensitivity. Endurance training is not associated with altered β-adrenergic chronotropic sensitivity in the elderly. The transient pressor response to intravenously administered clonidine may be lost in ageing man.
Elevated Plasma C-Type Natriuretic Peptide Concentrations in Patients with Chronic Renal Failure
Authors: Totsune Kazuhito , Takahashi Kazuhiro , Murakami Osamu , Satoh Fumitoshi , Sone Masahiko , Mouri Toraichi
Published: August 2015

1. C-type natriuretic peptide is a neuropeptide, which is also produced by the vascular endothelial cells. Plasma immunoreactive C-type natriuretic peptide concentrations in patients with various diseases have not yet been studied.

2. Plasma immunoreactive C-type natriuretic peptide concentrations were studied by radioimmunoassay in normal subjects, patients with congestive heart failure, non-dialysed patients with chronic renal failure and haemodialysis patients with chronic renal failure. The C-type natriuretic peptide levels were compared with the levels of atrial natriuretic peptide and brain natriuretic peptide.

3. Plasma immunoreactive C-type natriuretic peptide concentrations were greatly elevated in patients with chronic renal failure [non-dialysed, 13.0 ± 4.2 pmol/l (mean ± SEM), n = 9, P < 0.01) compared with normal subjects (4.4 ± 0.4 pmol/l, n = 26); haemodialysis, 16.1 ± 2.1 pmol/l, n = 13, P < 0.01], but not in patients with congestive heart failure (New York Heart Association Class II-IV, 3.0 ± 0.7 pmol/l, n = 11, P > 0.05). Plasma immunoreactive atrial natriuretic peptide and brain natriuretic peptide concentrations were elevated both in patients with congestive heart failure and in haemodialysis patients with chronic renal failure.

4. Reverse-phase high performance liquid chromatography showed that immunoreactive C-type natriuretic peptide in plasma from normal subjects and haemodialysis patients was eluted in the positions of C-type natriuretic peptide −22 and −53.

5. These findings suggest that C-type natriuretic peptide is a non-cardiac circulating hormone and participates in the cardiovascular regulation in a different manner from atrial natriuretic peptide and brain natriuretic peptide.
Atrial Natriuretic Peptide Inhibits Cyclosporin A-Induced Endothelin Production and Calcium Accumulation in Rat Vascular Smooth Muscle Cells
Authors: Bokemeyer Dirk , Friedrichs Ursula , Bäcker Angela , Drechsler Sabine , Kramer Herbert J. , Meyer-Lehnert Harald
Published: August 2015

1. As we have previously shown, cyclosporin A enhances the vasoconstrictor-induced rise in intracellular free calcium in vascular smooth muscle cells. This effect may contribute to important side-effects in cyclosporin therapy, such as hypertension and nephrotoxicity. Atrial natriuretic peptide has been shown to inhibit this effect as well as the cyclosporin-stimulated transmembrane calcium influx in smooth muscle cells.

2. The present study, therefore, was designed to examine the effect of cyclosporin and atrial natriuretic peptide on total cellular calcium content in the rat. Furthermore, since cyclosporin was recently shown to induce endothelin production in smooth muscle cells, we investigated the effect of atrial natriuretic peptide on this potentially adverse cellular effect of cyclosporin therapy.

3. Total cell calcium was measured by atomic absorption, and cellular endothelin production was estimated by radioimmunoassay.

4. Preincubation of the cells with cyclosporin (10 μg/ml) for 30 min increased total cell calcium from 2.6 ± 0.5 to 6.9 ± 0.3 nmol/mg of protein (P < 0.01). Within 24 h endothelin production was significantly enhanced in the presence of cyclosporin (52.2 ± 2.5 versus 65.9 ± 2.7 fmol/mg of protein, P < 0.05). Therefore, the cyclosporin-induced rise in total cell calcium in smooth muscle cells is associated with enhanced production of enthothelin. Thus, it is tempting to speculate that the cyclosporin-induced changes in calcium kinetics may be mediated by endothelin.

5. In the presence of atrial natriuretic peptide (10-8 mol/l), the cyclosporin-induced rise in total cell calcium was significantly reduced (6.9 ± 0.3 versus 5.1 ± 0.2 nmol/mg of protein, P < 0.05). In the presence of atrial natriuretic peptide (5 × 10−9 mol/l) cyclosporin A did not affect the production of endothelin in smooth muscle cells (453 ± 3.5 versus 50.1 ± 2.8 fmol/mg of protein, not significant).

6. These results indicate that endothelin may play a major role in cyclosporin-associated side-effects. By inhibiting the cyclosporin-stimulated production of endothelin, atrial natriuretic peptide may have a beneficial effect on cyclosporin-associated hypertension and nephrotoxicity.