bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of cyclosporin A on glomerular barrier function in the nephrotic syndrome
Authors: Zietse Robert , Wenting Gerrit J. , Kramer Pieter , Schalekamp Maarten A. , Weimar Willem
Published: August 2015

1. To elucidate the mechanisms by which cyclosporin A diminishes proteinuria, we studied 20 patients with severe nephrotic syndrome. Biopsy-established pathologies included minimal change disease (n = 5), membranous glomerulopathy (n = 6), membranoproliferative glomerulonephritis (n = 5) and focal segmental glomerulosclerosis (n = 4). Before, at the end of a 90 day course of cyclosporin A, and finally 1 month after stopping cyclosporin A we determined 24 h protein excretion. Measurements of glomerular filtration rate, effective renal plasma flow, fractional clearance rates of albumin and immunoglobulins with different charges and the transglomerular sieving of uncharged dextrans of broad size distribution were used to study the effects of cyclosporin A on renal perfusion and the glomerular filtration barrier. The findings were analysed with a theoretical model of solute transport.

2. Among the different forms of glomerulopathy the response to low-dose cyclosporin A (trough levels 32.0–36.9 ng/ml) varied markedly. In minimal change disease, proteinuria decreased from 9.5 ± 3.1 to 1.3 ± 0.2 g/24 h (mean ± sem, P < 0.01). This response was due to restoration of the charge selectivity of the glomerular barrier. The depressed value of the glomerular permeability coefficient also returned to normal. Glomerular filtration rate, effective renal plasma flow and renal vascular resistance did not change. Proteinuria returned after stopping cyclosporin A, although it did not reach pretreatment levels. In membranous glomerulopathy, proteinuria fell from 9.9 ± 1.5 to 1.8 ± 0.3 g/24 h (P < 0.01). Changes in protein excretion and dextran sieving were compatible with an increase in glomerular permselectivity and a decrease in filtrate flow through the ‘shunt’ pathway. Glomerular filtration rate was maintained, although effective renal plasma flow fell significantly. Proteinuria relapsed after stopping cyclosporin A. In membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis proteinuria did not respond to cyclosporin A, although cyclosporin A exerted important haemodynamic effects.

3. In minimal change disease and membranous glomerulopathy cyclosporin A exerts its beneficial effects on proteinuria through changes in the properties of the glomerular barrier, resulting in increased charge and size selectivity, respectively.
Four-component model for the assessment of body composition in humans: comparison with alternative methods, and evaluation of the density and hydration of fat-free mass
Authors: Fuller N. J. , Jebb S. A. , Laskey M. A. , Coward W. A. , Elia M.
Published: August 2015

1. Body composition was assessed in 28 healthy subjects (body mass index 20–28 kg/m2) by dual-energy X-ray absorptiometry, deuterium dilution, densitometry, 40K counting and four prediction methods (skinfold thickness, bioelectrical impedance, near-i.r. interactance and body mass index). Three- and four-component models of body composition were constructed from combinations of the reference methods. The results of all methods were compared. Precision was evaluated by analysis of propagation of errors. The density and hydration fraction of the fat-free mass were determined.

2. From the precision of the basic measurements, the propagation of errors for the estimation of fat (± sd) by the four-component model was found to be ± 0.54 kg, by the three-component model, ± 0.49 kg, by deuterium dilution, ± 0.62 kg, and by densitometry, ± 0.78 kg. Precision for the measurement of the density and hydration fraction of fat-free mass was ± 0.0020 kg/l and ± 0.0066, respectively.

3. The agreement between reference methods was generally better than between reference and alternative methods. Dual-energy X-ray absoptiometry predicted three- and four-component model body composition slightly less well than densitometry or deuterium dilution (both of which greatly influence these multi-component models).

4. The hydration fraction of fat-free mass was calculated to be 0.7382 ± 0.0213 (range 0.6941–0.7837) and the density of fat-free mass was 1.1015 ± 0.0073 kg/1 (range 1.0795–1.1110 kg/1), with no significant difference between men and women for either.

5. The results suggest that the three- and four-component models are not compromised by errors arising from individual techniques. Dual-energy X-ray absorptiometry would appear to be a suitable alternative method for the assessment of body composition in these healthy adults. The traditional mean value assumed for density of the fat-free mass in classic densitometry (1.1 kg/l) appears to be appropriate, and the mean hydration fraction was close to values which are generally applied to the fat-free mass (0.72–0.73). Despite concealing considerable inter-individual variation, these mean values may be applied to groups with characteristics similar to those in this study. Finally, with the notable exception of skinfold thickness, bedside prediction methods show poor agreement with both the three- and the four-component models.
Measurement of plasma volume in pregnancy
Authors: Brown Mark A. , Mitar Dina A. , Whitworth Judith A.
Published: August 2015

1. Determination of the plasma volume in pregnant women is a useful research tool and may become an important clinical measurement. We used three methods to determine plasma volume using Evans Blue dye: (1) the ‘usual’ method, measuring serum absorbance at a wavelength of 610 nm, (2) a two-wavelength method, and (3) precipitation of non-albumin proteins by the addition of polyethyleneglycol before measuring serum absorbance at a wavelength of 620 nm. These were each compared with the standard 125I-human serum albumin method in 20 non-pregnant subjects. Subsequently, the polyethylene glycol method was considered the standard and the three Evans Blue dye methods were compared in 20 pregnant women.

2. In non-pregnant subjects mean plasma volumes did not differ significantly according to the method used. However, the limits of agreement with 125I-human serum albumin method were closest for the polyethyleneglycol method, for both clear and turbid sera.

3. In pregnant women, mean plasma volume values did not differ according to the Evans Blue dye method used, but the limits of agreement were significantly closer with the two-wavelength method than with the ‘usual’ method (P<0.05) largely owing to the effects of turbid sera.

4. These studies demonstrate that considerable error may occur when the Evans Blue dye concentration is determined in turbid sera by the ‘usual’ method. This can be overcome by the use of the two-wavelength method or the polyethyleneglycol method. The most accurate results will be obtained if the latter method is employed routinely to determine plasma volume in pregnant women.
Intrasplenic blood cell kinetics in man before and after brief maximal exercise
Authors: Allsop P. , Peters A. M. , Arnot R. N. , Stuttle A. W. J. , Deenmamode M. , Gwilliam M. E. , Myers M. J. , Hall G. M.
Published: August 2015

1. After a 4 min period of maximal exercise in 10 normal subjects (14 studies), there was a consistent decrease in total blood volume and a consistent increase in erythrocyte indices, which were maximal immediately after exercise. Peripheral platelet and leucocyte counts increased, but did not reach maximal values until 5–10 min after the end of exercise.

2. The distributions of 99mTc-Iabelled erythrocytes (five studies), 111In-labelled platelets (five studies) and 111In-labelled granulocytes (four studies) were monitored with a γ-camera immediately after injection and before and after maximal exercise performed 60 min after injection.

3. Labelled erythrocytes equilibrated rapidly between the spleen and circulating blood after injection, whereas labelled platelets and granulocytes equilibrated more slowly. After exercise, each cell type was released from the spleen with a time course that was the reciprocal of the time course of the corresponding cell count in peripheral blood. Thus, whereas the radioactivity of 99mTc-labelled erythrocytes in the spleen, which fell to 0.46 (SD 0.09) of the pre-exercise value, increased towards its baseline value as soon as exercise was completed, the radioactivities of 111In-labelled platelets and 111In-labelled granulocytes decreased, to respective minimum values of 0.61 (0.09) and 0.63 (0.09) of the pre-exercise levels, 5–10 min after the end of exercise. The exercise-induced changes in lung radioactivity for each cell type, and their time courses, broadly reflected those in the corresponding cell counts in peripheral blood. Liver radioactivity tended to decrease for each cell type.

4. Because of the dissociation of the time courses of splenic expulsion of erythrocytes (intrasplenic transit time about 1 min) from those of platelets and granulocytes (intrasplenic transit times both of 8–10 min), we conclude that blood cell expulsion from the spleen in man is not the result of active splenic contraction but probably the passive result of a decrease in splenic blood flow.
Measurement of pelvic blood flow changes in response to posture in normal subjects and in women with pelvic pain owing to congestion by using a thermal technique
Authors: Thomas D. C. , Stones R. W. , Farquhar C. M. , Beard R. W.
Published: August 2015

1. A method is described for studying pelvic blood flow in women by the indirect method of measuring vaginal temperature changes in response to a posture change. Ten women with chronic pelvic pain and venous congestion and 10 normal subjects were observed during posture changes over a 2 h period.

2. Vaginal temperature minus axillary temperature rose after subjects changed from the supine to the seated position, indicating a fall in the rate of pelvic blood flow.

3. A significantly greater variance in the rate of change in vaginal temperature minus axillary temperature was found in patients with pelvic venous congestion compared with control subjects (P> 0.005).

4. The findings are consistent with a disorder of blood flow regulation in women with pelvic pain owing to congestion.
Sympathoadrenal contribution to plasma dopa (3,4-dihydroxyphenylalanine) in rats
Authors: Grossman Ehud , Hoffman Aaron , Armando Ines , Abassi Zaid , Kopin Irwin J. , Goldstein David S.
Published: August 2015

1. To determine the sources of dopa (3,4-dihydroxyphenylalanine) in plasma, we measured regional arteriovenous differences, tissue concentrations and urinary excretion of dopa during systemic intravenous infusions of I-[3H]dopa into anaesthetized intact rats and rats pretreated with the sympathetic neurotoxin, 6-hydroxydopamine.

2. In intact rats, large arteriovenous increments in plasma dopa concentrations were noted in the femoral (47%) and adrenal (141%) beds, with a small arterial-portal venous increment (11%), whereas in the kidney there was a substantial (47%) arteriovenous decrement in plasma dopa levels. Skeletal muscle appeared to be a major source of dopa in arterial plasma.

3. Treatment with 6-hydroxydopamine abolished the afferent-efferent increment of plasma dopa concentrations in the femoral bed. The arteriovenous decrement of plasma dopa concentrations in the kidney was preserved, and the arteriovenous increment in the adrenal bed was decreased by about half. Arterial plasma dopa levels fell by 41%.

4. Regional extraction percentages of I-[3H]dopa were used to estimate the clearances and rates of appearance (spillovers) of dopa in plasma. Dopa spillover was detected in the femoral, renal, splanchnic and adrenal beds, with skeletal muscle accounting for about 44% and the kidneys accounting for about 18% of dopa in arterial plasma. Whereas chemical sympathectomy decreased the femoral and renal spillover of dopa by 90% or more, arterial dopa levels and estimated dopa spillover into arterial plasma were decreased by only about 45%.

5. The kidneys accounted for 22% of dopa clearance from arterial plasma. From the renal extraction of I-[3H]dopa and the urinary excretion of [3H]dopamine, it was estimated that 77% of dopa removed in the kidneys was excreted as dopamine in intact animals and 69% was excreted as dopamine in sympathectomized animals. Conversely, about 80% of urinary endogenous dopamine was derived from plasma dopa, regardless of 6-hydroxydopamine treatment.

6. The results indicate that endogenous dopa in arterial plasma is derived substantially but not exclusively from sympathetic nerve endings that are destroyed by 6-hydroxydopamine, especially in skeletal muscle and the kidneys. Regional dopa spillover therefore probably reflects regional catecholamine biosynthesis. In rats, urinary dopamine is derived mainly from renal decarboxylation of circulating dopa.
Comparative study of platelet angiotensin II binding and the angiotensin II sensitivity test as predictors of pregnancy-induced hypertension
Authors: Baker Philip N. , Pipkin Fiona Broughton , Symonds E. Malcolm
Published: August 2015

1. Platelet angiotensin II binding was measured in 34 primigravid women (between 28 and 32 weeks gestation), in whom the pressor response to infused angiotensin II was also determined.

2. There was a significant correlation between the platelet angiotensin II binding and the slope of the curve relating the diastolic pressor response to infused angiotensin II (P<0.01), suggesting that co-linearity between the two techniques exists and supporting the use of platelet angiotensin II binding as a model of vascular smooth muscle pressor responsiveness.

3. Ten of the 34 women subsequently developed pregnancy-induced hypertension. Platelet angiotensin II binding in the patients who subsequently developed pregnancy-induced hypertension was sixfold higher than in the patients who remained normotensive (P < 0.001). There were, however, no significant differences between the groups in any of the parameters derived from the angiotensin II infusion experiments.

4. The use of platelet angiotensin II binding alone in predicting the outcome of the pregnancies, as assessed using discriminant analysis, was more successful than when any of the infusion parameters were used, with 77% of patients being correctly classified.
Diet as a source of phospholipid esterified 9,11-octadecadienoic acid in humans
Authors: Britton Mary , Fong Christopher , Wickens David , Yudkin John
Published: August 2015

1. Diene-conjugated fatty acids are one of the products of free-radical attack upon lipids and therefore have been used as markers of such attack. The major diene-conjugated fatty acid in human tissue and serum is an isomer of linoleic acid (9,12-octadecadienoic acid), namely 9,11-octadecadienoic acid. Diet may be another source of this isomer, raising questions as to its value as a free-radical marker. The aim of this study was to determine the importance of diet as a source of 9,11-octadecadienoic acid in phospholipid esterified fatty acids in human serum.

2. Foodstuffs rich in 9,11-octadecadienoic acid were identified. Fourteen subjects volunteered to alter their diets, either increasing ('high diet') or decreasing ('low diet') their intake of these foodstuffs for 3 weeks. Where subjects undertook both diets, a washout period of at least 3 weeks was allowed between phases.

3. Seven-day diet histories were kept and scored with respect to their content of 9,11-octadecadienoic acid. The concentrations of 9,11-octadecadienoic acid and linoleic acid in serum phospholipids were measured by h.p.l.c. with u.v. detection.

4. The percentage molar ratio of 9,11-octadecadienoic acid to linoleic acid was calculated. The percentage molar ratio rose significantly on the ‘high diet’ [1.3(0.4) versus 1.9(0.7), P=0.01, mean (SD)] and fell significantly on the ‘low diet’ [1.6(0.4) versus 1.1(0.4), P=0.004, means (SD)]. There was a significant correlation between the change in dietary intake of 9,11-octadecadienoic acid and the change in the percentage molar ratio (r= 0.829, P = 0.001).

5. The concentration of 9,11-octadecadienoic acid in serum phospholipids is influenced by diet. Its use as a marker of free-radical activity is questionable and at least in need of careful interpretation.
Limits of adaptation to a diet low in protein in normal man: urea kinetics
Authors: Danielsen M. , Jackson A. A.
Published: August 2015

1. Urea kinetics were measured using prime/intermittent oral doses of [15N15N]urea in six healthy men taking diets adequate in energy and containing either 74 or 30 g of protein/day.

2. On 74 g of protein/day, urea production (199 mg of N day−1 kg−1) was 121% of intake, with 60% of the urea produced being excreted in the urine and 40% being salvaged in the colon; 69% of the salvaged nitrogen was retained in the metabolic nitrogen pool.

3. Nitrogen balance was not maintained on 30 g of protein/day. There was a significant decrease in the urea production rate (123 mg of N day−1 kg−1) and 54% of production was excreted in urine, with 46% being salvaged.

4. The pattern of urea production and salvaging on 30 g of protein/day was different to that seen in an earlier study on 35 g of protein/day, with a significant decrease in both production (71%) and salvaging (50%).

5. These data reinforce the conclusions drawn from an earlier study, that the salvaging of urea nitrogen by the colon is an integral part of the process of adaptation to low protein diets. The salvage system appears to fail on an intake of 30 g of protein/day and nitrogen is no longer conserved in sufficient amounts for balance to be maintained.

6. The changes seen in urea kinetics reinforce the conclusion based upon nitrogen balance that the minimum physiological requirement for protein in normal adult man lies between 30 and 35 g of protein/day.
Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man
Authors: Walker Brian R. , Connacher Alan A. , Webb David J. , Edwards Christopher R.W.
Published: August 2015

1. 11β-Hydroxysteroid dehydrogenase converts cortisol to inactive cortisone in man. In distal renal tubules, this inactivation protects mineralocorticoid receptors from cortisol. Congenital 11β-hydroxysteroid dehydrogenase deficiency and inhibition of 11β-hydroxysteroid dehydrogenase by liquorice or carbenoxolone result in cortisol-dependent hypokalaemia and hypertension.

2. 11β-Hydroxysteroid dehydrogenase is expressed in vascular smooth muscle. Both glucocorticoids and mineralocorticoids potentiate vascular responses to noradrenaline. 11β-Hydroxysteroid dehydrogenase activity may therefore influence vascular tone.

3. Experiments were performed in healthy subjects with and without 7 days of oral administration of 11β-hydroxysteroid dehydrogenase inhibitors (liquorice or carbenoxolone), and in a patient with congenital 11β-hydroxysteroid dehydrogenase deficiency. We measured the following parameters: dermal vasoconstriction after topical application of cortisol, forearm blood flow during brachial artery infusion of cortisol or noradrenaline, and blood pressure during systemic infusion of noradrenaline.

4. Cortisol-induced dermal vasoconstriction was increased by liquorice (23 ± 6 to 52 ± 7 units; P<0.04) and in congenital 11β-hydroxysteroid dehydrogenase deficiency (87 units). In congenital 11β-hydroxysteroid dehydrogenase deficiency intraarterial infusion of cortisol caused vasoconstriction (20% reduction in blood flow in the infused arm) and accentuated the response to application of lower-body negative pressure, which stimulates sympathetically mediated vasoconstriction (35% reduction). However, intra-arterial infusion of cortisol had no effect in healthy subjects either with or without administration of liquorice.

5. Carbenoxolone potentiated both noradrenaline-induced forearm vasoconstriction (P<0.01) and pressor response (P<0.001).

6. We conclude that 11β-hydroxysteroid dehydrogenase modulates the access of cortisol to vascular receptors and thereby influences vascular sensitivity to noradrenaline. Complementary to its role in kidney, 11β-hydroxysteroid dehydrogenase could influence blood pressure by this mechanism, which may underlie our observations of impairment of 11β-hydroxysteroid dehydrogenase and increased dermal vascular sensitivity to cortisol in patients with essential hypertension.
Autoimmunity to glomerular antigens in Henoch—Schoenlein nephritis
Authors: O'Donoghue D. J. , Jewkes F. , Postlethwaite R. J. , Ballardie F. W.
Published: August 2015

1. Henoch—Schoenlein nephritis and IgA nephropathy share clinical and immunological features, but the pathogenesis of neither condition is established. We have recently described IgG autoantibodies to glomerular components in active IgA nephropathy and have now sought evidence for a similar autoimmune component in Henoch—Schoenlein purpura.

2. Sera from 26 patients with Henoch—Schoenlein nephritis and six patients with Henoch—Schoenlein purpura without accompanying nephritis were studied and compared with sera from 20 patients with other forms of glomerulonephritis and 40 normal subjects. E.l.i.s.a.s were developed to detect IgA and IgG binding to the ligand from whole human glomeruli previously described, laminin, DNA, cardiolipin (diphosphatidylglycerol) and a panel of dietary constituents (BSA, α-caesin, β-lactoglobulin, ovalbumin and wheat gliadin).

3. Sera from 16 of the 26 patients with Henoch—Schoenlein nephritis displayed increased IgG binding to the human glomerular extract compared with the normal control group (P<0.001), whereas IgG binding was not significantly raised in the patients with Henoch—Schoenlein purpura without evidence of renal involvement. IgA binding was not raised compared with control subjects. Serum IgA and IgG binding to other potential autoantigens or antigens present on dietary constituents was not significantly different in patients with Henoch—Schoenlein nephritis or patients with Henoch—Schoenlein purpura without nephritis compared with control subjects.

4. Western blotting of the denatured and reduced glomerular extract revealed binding of IgG, from the sera of patients with active Henoch—Schoenlein nephritis, to glomerular components of Mr 48000 and 58000, similar to the Mr of the glomerular antigens identified in IgA nephropathy. Immunoglobulin binding was shown to be specific antibody binding using F(ab')2 fragments from the IgG fraction of e.l.i.s.a.-positive sera.

5. Clinical associations showed in 10 of 11 patients with Henoch—Schoenlein nephritis whose sera were studied in remission: IgG antiglomerular antibody binding fell to within the normal range (P<0.05).

6. These results demonstrate an autoimmune component in Henoch—Schoenlein nephritis, and the close temporal relationship with active nephritis implies that this may be a critical component in the pathogenesis of glomerular injury. The absence of specific antibody, or non-specific immunoglobulin binding, to any of the range of dietary constituents or other putative autoantigens tested suggests that polyclonal B-cell activation is not an important feature of Henoch—Schoenlein nephritis.
A new method to measure renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol)
Authors: Rustom R. , Grime S. , Maltby P. , Stockdale H. R. , Critchley M. , Bone J. M.
Published: August 2015

1. A method has been developed to measure the renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol), a 6500 Da cationic polypeptide.

2. Aprotinin (0.5 or 5.0 mg) was labelled with either 99mTc (40 MBq) or 131I (1 MBq) and injected intravenously in 19 renal patients (10 with normal renal function and nine on haemodialysis). Activity in plasma and urine was measured over 48 h, and chromatography with Sephadex-G-25-M was used to separate labelled aprotinin from free 99mTcO-4 or 131I-. Renal uptake was measured for 99mTc-labelled aprotinin only.

3. The volumes of distribution were similar in all patients: 18.2 ± 0.4 litres in those with normal renal function and 20.2 ± 0.1 litres in the others. Chromatography showed all plasma activity as undegraded aprotinin and urine activity only as the free labels (99mTcO-4 or 131I-).

4. In patients with normal renal function, activity in the kidneys rose rapidly to 24.2 ± 2.8% of dose after 90 min and to 42.2 ± 3.4% of dose after 24 h. In the dialysis patients, activity over the kidneys was only 2.7 ± 0.8% of dose at 24 h. Extra-renal uptake was insignificant in all patients with normal kidney function.

5. Both 99mTcO-4 and 131I- appeared in the urine promptly after injection, and the rates of excretion of the two isotopes were similar, varying little over 24 h (1.8 ± 0.04% of dose/h and 1.7 ± 0.04% of dose/h for 99mTc and 131I, respectively).

6. Fractional renal tubular degradation of 99mTc-aprotinin (in h−1) is a measure of its turnover value over a given interval and is given by: Mean urinary appearance of free isotope (% of dose/h)/mean cumulative kidney uptake over the same interval (% of dose) The rate of fractional degradation fell rapidly from 0.20 ± 0.02 h−1 between 0 and 90 min to 0.08 ± 0.01 h−1 between 90 min and 3 h to 0.07 ± 0.01 h−1 between 3 and 4.5 h and to 0.05 ± 0.002 h−1 between 4.5 and 24 h.

7. The stability of urinary excretion of free isotope during the 24 h after injection, together with the relative stability of fractional degradation after 4.5 h, and the reproducibility of the technique offer a practical method for the further study of filtered protein catabolism by the renal tubules in man. This has hitherto not been possible.
Technique for the primary culture of human breast cancer cells and measurement of their prostaglandin secretion
Authors: Watson John , Chuah Siew Yeam
Published: August 2015

1. A method is described for the primary culture of human breast tumour cells on feeder layers of the STO mouse embryo fibroblast cell line.

2. The secretion of the prostaglandins E2 and F2α from the cells was measured and the results indicate that the secretion of both prostaglandins was dependent on oestrogen-receptor status, with cells from oestrogen-receptor-positive tumours secreting significantly more prostaglandin than cells from oestrogen-receptor-negative tumours.

3. Postaglandin E2, but not prostaglandin F2α, secretion was also significantly greater from cells of tumours from postmenopausal women than from cells of tumours from premenopausal women. Small (< 3 cm) tumours secreted significantly more prostaglandin than large (> 3 cm) tumours, and increased levels of prostaglandin were secreted with advancing clinical stage (T1-T4).

4. Additional evidence for increased prostaglandin metabolism in oestrogen-receptor-positive tumours compared with oestrogen-receptor-negative tumours was obtained from studies on the uptake of [14C]arachidonic acid from the cultures. Significantly more labelled arachidonic acid was incorporated into cells from oestrogen-receptor-positive tumours compared with oestrogen-receptor-negative tumours, with the subsequent release of more prostaglandin in response to various stimuli.
Responses of airway rapidly adapting receptors to bradykinin before and after administration of enalapril in rabbits
Authors: Hargreaves M. , Ravi K. , Senaratne M. P. J. , Kappagoda C. T.
Published: August 2015

1. The present study was performed in anaesthetized, artificially ventilated, open-chested rabbits to examine whether (a) the rapidly adapting receptors of the airways were stimulated by exogenously administered bradykinin, and (b) if this sensitivity could be enhanced by the angiotensin-converting-enzyme inhibitor, enalapril.

2. Rapidly adapting receptor activity (n = 8) was recorded from the cervical vagus. Bradykinin was injected intravenously (0.25–1.0 μg/kg) and a dose—response curve relating receptor activity to bradykinin was elicited. In the control state, the threshold dose of bradykinin required for stimulation of rapidly adapting receptors was 0.53 ± 0.11 μg/kg. Five minutes after the administration of enalapril maleate (2 mg intravenously), the dose—response curve was shifted to the left significantly (P<0.01).

3. In seven other rapidly adapting receptors, enalapril (2 mg) increased the resting activity significantly (P<0.05) over a period of 60 min. This increase was significantly different from the spontaneous variation in neural activity of rapidly adapting receptors (n = 7) recorded over a period of 60 min.

4. Bradykinin either alone (0.25–1.0 μg/kg) or in the presence of enalapril did not stimulate the slowly adapting receptors (n = 5) of the airways.

5. These results show that (a) exogenous bradykinin stimulates the rapidly adapting receptors, (b) the sensitivity of rapidly adapting receptors to bradykinin is enhanced by enalapril and (c) enalapril increases the resting activity of rapidly adapting receptors. It is suggested that the cough reported after the administration of enalapril may be due to stimulation of rapidly adapting receptors of the airways.
Effect of citrate on plasma aluminium concentration and aluminium excretion in the rat
Authors: Lote C. J. , Saunders H. C. , Wood J. A. , Spencer A. J.
Published: August 2015

1. Plasma aluminium concentration and urinary aluminium excretion were monitored for 4.5 h in rats after the administration of 25 μg or 800 μg of aluminium as an intravenous bolus, either as aluminium chloride or as aluminium citrate (i.e. aluminium chloride together with sodium citrate).

2. Immediately after the bolus aluminium administration, the plasma aluminium concentration was higher in the groups given aluminium chloride than in those which received aluminium citrate, although the difference was significant (P<0.05) only for the 25 μg dose. This difference between aluminium chloride and citrate indicates that the citrate form has a higher volume of distribution (i.e. is able to leave the plasma). The calculated volume of distribution for the 25 μg dose of aluminium chloride (17.5 ml) was similar to the plasma volume of the rats used (15 ml).

3. In experiments in vitro, the ultrafilterability of aqueous solutions of aluminium chloride and aluminium citrate were compared. Only 1.05 ± 0.09% of the aluminium chloride solution was ultrafilterable (aluminium concentration 28 200 ± 730 ng/ml), whereas 97.3 ± 2.4% of the aluminium citrate was ultrafilterable (aluminium concentration 42000 ± 370 ng/ml). When the filterability of aluminium in plasma was examined, the aluminium chloride ultrafilterability was identical with that in aqueous solution (1.06 ± 0.13%, aluminium concentration 19 800 ± 2956 ng/ml), but the aluminium citrate was 79.8 ± 7.1% ultrafilterable (aluminium concentration 10125 ± 591 ng/ml).

4. The differences in ultrafilterability in vitro were reflected in the urinary aluminium excretion in vivo. Even though the plasma levels of aluminium were lower in the groups that received citrate, the aluminium administered as citrate was excreted much more rapidly than the aluminium chloride. With the 25 μg dose of aluminium as chloride, 13.39 ± 0.87 μg (i.e. 53%) was excreted in 4.5 h, whereas with the citrate form 21.85 ± 3.05 μg (87%) was excreted in 4.5 h (P<0.01). For the 800 μg dose of aluminium, the excretion was 160.03 ± 18.40 μg (chloride) and 451.16 ± 36.76 μg (citrate) (P<0.01).

5. It is clear that renal aluminium excretion is much more efficient if aluminium citrate is administered rather than aluminium chloride. The findings raise the possibility that intravenous citrate could have therapeutic applications in patients who have accumulated aluminium.
2,3-Dinor metabolites of thromboxane A2 and prostacyclin in urine from healthy human subjects: diurnal variation and relation to 24 h excretion
Authors: Wennmalm Å. , Benthin G. , Granström E.F. , Persson L. , Winell S.
Published: August 2015

1. Urinary levels of the 2,3-dinor metabolites of thromboxane A2 (2,3-dinor-thromboxane A2, Tx-M) and prostacyclin (2,3-dinor-6-keto-prostaglandin F1α, PGI-M) are frequently analysed as indices of platelet and endothelial activity and interaction in vivo. Despite this, little is known about the possible diurnal variations in urinary Tx-M and PGI-M in healthy human subjects, and how the urinary levels of Tx-M and PGI-M in single samples reflect their respective 24 h excretion rates. We addressed this by determining Tx-M, PGI-M and creatinine in consecutive portions of urine collected during 24 h in 15 healthy non-smoking subjects.

2. The total 24 h excretion of Tx-M and PGI-M did not differ between men (223 ± 31 and 132 ± 27 ng, respectively) and women (215 ± 44 and 127 ± 29 ng, respectively). Neither the excretion of Tx-M nor that of PGI-M displayed any significant diurnal variation.

3. The excretion of Tx-M during a 3 h period and the Tx-M/creatinine ratio in a urine sample accurately reflected the 24 h excretion of Tx-M (correlation coefficient ranges 0.74–0.94 and 0.74–0.86, respectively). The excretion of PGI-M during a 3 h period and the PGI-M/creatinine ratio in a urinary sample were accurate measures of 24 h excretion of PGI-M (correlation coefficient ranges 0.76–0.94 and 0.72–0.83, respectively). Urinary Tx-M and PGI-M expressed as simple concentrations were poor indices of their respective 24 h excretion.

4. We conclude that time-related excretions of Tx-M and PGI-M may be the best indices ex vivo of the cardiovascular formation of thromboxane A2 and prostacyclin, but that urinary creatinine-related concentrations of Tx-M and PGI-M in a urine sample are accurate measures as well.
Relative effects of fat-, carbohydrate- and protein-containing liquid diets on cardiac output in healthy adult subjects
Authors: Hawley Susan K. , Channer Kevin S.
Published: August 2015

1. Nine healthy adult subjects consumed four types of proprietary liquid diet of similar volume and calorific value but of different nutritional composition. The effects on resting cardiac output, mean blood pressure and pulse rate were measured.

2. A significant rise in cardiac output occurred with the balanced, protein and carbohydrate diets but not with the fat diet. The greatest rise was seen with the balanced diet. Water alone had no effect on cardiac output.

3. The average time taken to reach peak cardiac output was shortest with the carbohydrate diet and longest with the fat diet.

4. The increases in cardiac output resulted from a rise in both pulse rate and stroke volume. The carbohydrate diet produced the most sustained rise in pulse rate but the least sustained elevation in stroke volume.

5. No significant changes were seen in mean blood pressure when each liquid meal was compared with water.

6. Our data show that the increase in cardiac output with liquid ingestion is related to the dietary components. These effects are additive.
Carotid arterial haemodynamics after mild degrees of lower-body negative pressure in man
Authors: Lacolley P. J. , Pannier B. M. , Slama M. A. , Cuche J. L. , Hoeks A. P. G. , Laurent S. , London G. M. , Safar M. E.
Published: August 2015

1. Pulsatile changes in the diameter of the common carotid artery were studied transcutaneously using an echo-tracking technique in 15 normal subjects: eight subjects before and during application of graded lower-body negative pressure from −5 to −15 mmHg, and seven subjects before and during weight-bearing head-up tilt at 30 and 60 degrees.

2. In concomitant studies of changes in forearm vascular resistance, it was seen that mild lower-body negative pressure produced deactivation of cardiopulmonary receptors without changes in systemic blood pressure or heart rate.

3. After lower-body negative pressure, a significant decrease in carotid arterial diastolic diameter [from 0.662 ± 0.028 to 0.624 ± 0.033 cm (lower-body negative pressure −10 mmHg) and 0.640 ± 0.030 cm lower-body negative pressure −15 mmHg), P<0.001 and <0.05] was observed.

4. After head-up tilt, carotid arterial diameter was also significantly decreased at 30 and 60 degrees, whereas a significant increase in heart rate occurred only at 60 degrees and mean blood pressure did not change.

5. The study provides evidence that the geometry of the arterial wall is substantially modified by noninvasive manoeuvres such as head-up tilting and lower-body negative pressure. The latter is assumed to selectively deactivate human cardiopulmonary receptors, but the present data suggest that local changes may also influence carotid baroreceptors.
Renal divalent cation excretion in secondary hypertension
Authors: Barbagallo Mario , Resnick Lawrence M. , Sosa R. Ernest , Corbett Mary Lou , Laragh John H.
Published: August 2015

1. To determine whether abnormal renal calcium excretion is unique to primary genetic hypertension, blood pressure and 24 h urinary excretion of calcium, magnesium, sodium and creatinine were measured in deoxycorticosterone—saline and two-kidney, one-clip Goldblatt hypertensive rats and in their respective controls on low (0.2%) and high (1.8%) dietary calcium intakes.

2. Calcium supplementation lowered blood pressure (P<0.05) in deoxycorticosterone—saline rats and in control saline-loaded rats, raised blood pressure in two-kidney, one clip rats, and had no effect in sham-operated control rats.

3. On both diets, calcium excretion was higher in hypertensive than in normotensive rats. The high calcium diet increased urinary calcium excretion in all rats, but the changes in urinary calcium excretion closely paralleled the diet-induced changes in blood pressure. Thus, urinary calcium excretion in deoxycorticosterone—saline animals, in whom calcium lowered blood pressure the most, rose the least (107%). Urinary calcium excretion rose the most in two-kidney, one-clip animals (1113%), whose blood pressure also rose the most.

4. Urinary magnesium excretion was also abnormal in hypertensive rats compared with normotensive rats, falling on the high compared with the low calcium diet in normotensive rats, but not in either hypertensive strain. Furthermore, urinary magnesium excretion was closely linked to urinary calcium excretion in saline-loaded control rats (r = 0.78; P = 0.008), but was dissociated from urinary calcium excretion in deoxycorticosterone—saline rats (r = 0.02; not significant).

5. We conclude (a) that the renal handling of both calcium and magnesium is altered in secondary hypertension, and (b) that dietary calcium supplementation may have different effects on blood pressure in different forms of hypertensive disease. We hypothesize that elevated blood pressure per se may be responsible for the exaggerated calciuresis of hypertension.
Paradoxical effects of mild hypoxia and moderate altitude on human visual perception
Authors: Schlaepfer Thomas E. , Bärtsch Peter , Fisch Hans U.
Published: August 2015

1. Prolonged (> 10h) exposure to hypoxia and high altitude (> 5000 m) invariably have detrimental effects on cognitive performance. Paradoxically, mild improvements in cognitive function in patients with chronic obstructive pulmonary disease after cessation of oxygen therapy have been reported.

2. We studied in each of 10 healthy subjects the effect of an acute altitude challenge [rapid helicopter transport to the Jungfraujoch (3450 m), experiment 1] and of an acute exposure to mild hypoxia (fractional inspiratory oxygen concentration 14.5%, experiment 2) on a simple test of cognitive performance (the time needed to read briefly displayed letters).

3. Under both hypoxic conditions the time needed to read briefly presented letters decreased, from 12.1 ± sd 3.8 ms to 8.3 ± 1.5 ms (P<0.01) in experiment 1, and from 11.9 ± 1.9 ms to 8.1 ± 1.1 ms (P<0.01) in experiment 2.

4. A rapid and mild hypoxic challenge seems to improve a simple measure of cognitive performance above normal values. The common notion that exposure to hypoxia and altitude invariably impairs cognitive performance may have to be re-evaluated.
Evidence for the indirect utilization of glucose for the synthesis of hepatic glycogen in man
Authors: King R. F. G. J. , Madan M. , Alexander D. , Boyd A. , Ibrahim K. , McMahon M. J. , Johnston D.
Published: August 2015

1. This study was designed to test the hypothesis that three-carbon intermediates can be used in the ‘indirect’ pathway of glycogen synthesis in human liver (i.e. a route additional to the use of glucose by the ‘direct’ pathway).

2. After an overnight fast, 13 patients were given an infusion of 20% (w/v) glucose before elective abdominal operation. All received a 2.5 g bolus of 2220 kBq of selectively 3H- and 14C-labelled glucose before removal of a 1 g biopsy of liver. 3H and 14C were determined in purified glycogen as well as in glucose and lactate from samples of peripheral blood.

3. The ratio and specific activities of 3H and 14C in glycogen were found to be significantly lower than those in administered glucose. By calculation, 7–74% of glycogen repletion occurred by indirect pathways and not all of this was from the glucose supplied.

4. This study suggests that the operation of a direct pathway in man is not exclusive and that significant repletion of hepatic glycogen occurs by an indirect route.
Relationship between hepatic lipid peroxidation and fibrogenesis in carbon tetrachloride-treated rats: effect of zinc administration
Authors: Camps Jordi , Bargallo Teresa , Gimenez America , Alie Silvia , Caballeria Joan , Pares Albert , Joven Jorge , Masana Lluis , Rodes Joan
Published: August 2015

1. Lipid peroxidation and hepatic fibrogenesis were investigated in 25 carbon tetrachloride-treated rats and in 25 control animals. Rats were further divided into two groups to receive either a standard diet or one supplemented with zinc. From each group, animals were killed at weeks 3 and 18 of the experiment for histological and biochemical assessments which included hepatic lipid peroxide and collagen concentrations and plasma zinc concentration as well as the hepatic activities of proline hydroxylase and collagenase.

2. Results indicated that oral zinc supplementation was associated with a decrease in lipid peroxidation (mean 51%; P<0.05), collagen deposition (mean 32%; P< 0.001) and proline hydroxylase activity (mean 30%; P<0.05) at week 18, together with an increase in collagenase activity (mean 208%; P<0.01) at week 3, in carbon tetrachloride-treated rats.

3. There was a significant direct correlation between lipid peroxidation and proline hydroxylase activity in carbon tetrachloride-treated rats (r = 0.52; P<0.01) and also a significant inverse correlation between lipid peroxidation and plasma zinc concentration in these animals (r = −0.62; P<0.001).

4. These findings are consistent with the hypothesis that hepatic lipid peroxidation plays an important role in the aetiology of hepatic fibrogenesis and that zinc mitigates the process.
Evidence against the formation of 2-amino-6-(2-formyl-5-hydroxymethyl-pyrrol-l-yl)-hexanoic acid ('pyrraline') as an early-stage product or advanced glycation end product in non-enzymic protein glycation
Authors: Smith Patricia R. , Somani Hanif H. , Thornalley Paul J. , Benn Jonathan , Sonksen Peter H.
Published: August 2015

1. It has been suggested that 2-amino-6-(2-formyl-5-hydroxymethyl-pyrrol-l-yl)-hexanoic acid ('pyrraline') is formed as an advanced glycation end product in the Maillard reaction under physiological conditions. Antibodies were raised to caproyl-pyrraline linked to keyhole-limpet haemocyanin and were used to develop an e.l.i.s.a. and Western blotting system for the specific detection of pyrraline in samples in vivo and in vitro.

2. Human serum albumin was isolated from the serum samples of diabetic and non-diabetic subjects. Pyrraline was not detected (<1.2 pmol) in any of the samples, indicating that it was not a major advanced glycation end product in vivo.

3. BSA was incubated separately with D-glucose and a model fructosamine, N-(l-deoxy-D-fructos-l-yl)-hippuryl-lysine, under physiological conditions for 30 days. Aliquots removed from the incubations at 5 day intervals contained no detectable pyrraline, indicating that pyrraline was not an early-stage product of the Maillard reaction in vitro.

4. The model fructosamine, N>-(1-deoxy-D-fructos-l-yl)-hippuryl-lysine, was incubated at pH 7.4 and 37°C for 25 days during which it degraded to hippuryl-lysine and N>-carboxymethyl-hippuryl-lysine. Aliquots were removed at 5 day intervals and assayed for pyrraline. None was detected (<23 pmol/ml) in the course of the degradation of the fructosamine (400 nmol/ml degraded), indicating that pyrraline was not a major product of the degradation of fructosamine under physiological conditions in vitro.

5. We conclude that pyrraline is not a major intermediate or advanced glycation end product in the Maillard reaction under physiological conditions in vitro and in vivo. A previous report of immunoassay of pyrraline may have given positive results because of non-specific antibodies raised to impure hapten.
Muscle weakness in women occurs at an earlier age than in men, but strength is preserved by hormone replacement therapy
Authors: Phillips S. K. , Rook K. M. , Siddle N. C. , Bruce S. A. , Woledge R. C.
Published: August 2015

1. The time-course of the age-related decline in specific muscle force (maximum voluntary force per cross-sectional area) in men and women was determined by measuring the maximum voluntary force and cross-sectional area of the adductor pollicis muscle in 273 subjects aged 17–90 years (176 men, 30 premenopausal women and 67 peri- or post-menopausal women who were not receiving hormone replacement therapy).

2. To determine whether the loss of specific muscle force is hormone-dependent in women, we studied a further 25 women, aged 42–72 years, who were receiving hormone replacement therapy.

3. There was no significant difference in specific force between young men and pre-menopausal women. Around the time of the menopause there was a dramatic decline in specific force in women which was prevented by the use of hormone replacement therapy. In men the weakness started later (around the age of 60 years) and the decline in specific force was more gradual, reaching the level seen in postmenopausal women after the age of 75 years.

4. The protective effect of hormone replacement therapy on muscle strength is likely to be an important contributory factor to its proven action in preventing osteoporotic fractures. The dramatic peri-menopausal decline in muscle strength is a likely explanation for the known increases in falls and Colles’ fractures around the time of the menopause.
Glycerol exchange across the human forearm assessed by a combination of tracer and arteriovenous exchange techniques
Authors: Elia M. , Khan K. , Calder G. , Kurpad A.
Published: August 2015

1. Whole-body kinetics and regional exchange of glycerol across forearm muscle were assessed in eight lean subjects by a combination of a tracer method (infusion of [2H5]glycerol) and arteriovenous catheterization.

2. During an apparent steady state, the enrichment of glycerol in deep venous blood from the muscle bed of the forearm was about half (4.40 ± 1.72 atom per cent excess) that observed in arterialized blood (8.41 ± 4.30 atom per cent excess). Under the same conditions, the circulating concentrations of glycerol in arterialized (91 ± 24 μmol/l) and venous (87 ± 32 μmol/l) blood were similar.

3. In a further group of 37 subjects it was found that about half had a positive arteriovenous concentration difference and the other had half a negative arteriovenous concentration difference (mean −1.6 ± 11.9 μmol/l; range −25 to +22 μmol/l).

4. These results suggest: (a) that human muscle does not always release glycerol and may take it up; (b) that there is substantial isotopic exchange of glycerol across forearm muscle tissue, which is not reflected by the net exchange of glycerol; this could be due to slow equilibrium of enriched glycerol from the circulation, with unenriched free glycerol in the muscle pool, or due to the simultaneous metabolic utilization of enriched glycerol and metabolic production of unenriched glycerol; (c) that the estimation of glycerol flux rates is strongly dependent on whether the blood is arterialized or deep venous.