bluuebunny/crossref_metadata_2025 huggingface dataset:
The Hepatorenal Syndrome
Authors: Moore Kevin
Published: August 2015

1. The hepatorenal syndrome is the development of renal failure in patients with severe liver disease in the absence of any identifiable renal pathology.

2. Decreased glomerular filtration is caused by a reduction in both renal blood flow and the renal filtration fraction. These changes arise as a consequence of a fall in mean arterial pressure due to systemic vasodilatation, activation of the sympathetic nervous system causing renal vasoconstriction, and increased synthesis of several vasoactive mediators, which together modulate both renal blood flow and the glomerular capillary ultrafiltration coefficient, and thence filtration fraction.

3. Patients with liver disease developing renal failure should have hypovolaemia excluded by volume challenge, and all nephrotoxic drugs including diuretics should be stopped. Broad-spectrum antibiotics should be given for subclinical infection, which may be a treatable precipitant of renal failure in cirrhosis. Renal perfusion should be optimized by ensuring that the blood pressure and systemic haemodynamics are adequate, and that if renal venous pressure is elevated, due to tense ascites, it is alleviated.

4. The prognosis of hepatorenal syndrome is poor with a >90% mortality. However, patients can and do recover from the hepatorenal syndrome, but only if there is a significant improvement of their liver function, or if they undergo liver transplantation.
Raised Affinity for Extracellular Sodium of the Sodium-Lithium Countertransporter is Associated with a Family History of Hypertension and Uraemia in Patients with Renal Disease
Authors: Carr Susan J. , Moore Debbie , Sikand Kulvinder , Norman Robert I.
Published: August 2015

1. Increased affinity for sodium (Km) at an external site of the sodium—lithium countertransporter and altered membrane microviscosity in the surface regions of the lipid bilayer identifies a group of essential hypertensive patients with a genetic predisposition to hypertension. The present study investigated the kinetic properties of the sodium—lithium countertransporter and membrane microviscosity in patients with hypertension, renal disease and impaired renal function.

2. Sixty patients with renal disease (28 chronic renal failure, 30 hypertensive, 23 family history of hypertension) were investigated. Standard erythrocyte sodium—lithium countertransport activity, sodium affinity constant (Km), maximum reaction velocity (Vmax) and membrane microviscosity were measured.

3. Patients with renal disease and a family history of hypertension had significantly lower Km (P < 0.05) values and raised membrane microviscosity measured by 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene anisotropy (P < 0.05) compared with patients without a family history of hypertension.

4. Uraemic subjects had low Km values compared with patients with renal disease and normal renal function (P < 0.05). However, there was no significant difference in membrane microviscosity between uraemic and non-uraemic subjects.

5. In patients with a family history of hypertension, sodium-lithium countertransport activity and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene anisotropy are important markers of cellular changes in essential hypertension, independent of renal disease. Uraemia, independently of hypertension, produces an alteration in the function of the sodium—lithium countertransporter which has previously been associated with a genetic predisposition to hypertension and cardiovascular disease.
Sepsis and Endotoxaemia in mice Stimulate the Expression of Interleukin-1 and Interleukin-6 in the Central Nervous System
Authors: Meyer Tory A. , Wang Jing Jing , Tiao Gregory M. , Ogle Cora K. , Fischer Josef E. , Hasselgren Per-Olof
Published: August 2015

1. In previous studies, experimental endotoxaemia was found to stimulate cytokine production in the central nervous system. The effect of sepsis on brain cytokines is not fully known. We compared the effect of endotoxaemia and sepsis on brain interleukin-1 and interleukin-6 expression.

2. Male A/J mice were injected subcutaneously with lipopolysaccharide (10 mg/kg) or an equal volume of saline as control. Sepsis was induced by caecal ligation and puncture (CLP); control mice underwent sham-operation. Brain tissue was assayed for interleukin-1 and interleukin-6 by ELISA. Northern blotting or the polymerase chain reaction was used to determine cytokine mRNA levels.

3. Administration of endotoxin induced a greater than fourfold increase in brain interleukin-1, a greater than threefold increase in interleukin-6 and an increase in mRNA for both cytokines. Caecal ligation and puncture resulted in increased brain interleukin-1 and interleukin-6 levels, but the changes were less pronounced and occurred later than after injection of endotoxin. There was no detectable difference in brain interleukin-1 mRNA between septic and sham-operated mice, whereas interleukin-6 mRNA was increased in brains of septic animals.

4. Sepsis and endotoxaemia resulted in similar, although not identical, changes in brain interleukin-1 and interleukin-6 concentrations and mRNA levels, suggesting that increased cytokine production in the central nervous system is part of the systemic response to sepsis and may be mediated by endotoxin.
Effect of Temperature Reduction on Myotonia in Rat Skeletal Muscles in vitro
Authors: Fanning Lorna , MacDermott Mary
Published: August 2015

1. The objective of the study was to determine the effect of temperature reduction on the response of rat skeletal muscles to myotonia-inducing agents.

2. A model myotonia was induced in the muscles in vitro, using either the chloride channel blocker anthracene-9-carboxylic acid or chloride-free Krebs solution. This model is similar in its characteristics to the myotonia which occurs in autosomal recessive generalized myotonia congenita in humans.

3. Isometric twitch contractions were recorded in the muscles in Krebs solution before and after the addition of the myotonia-inducing agent. The presence of myotonia was confirmed when the half-relaxation time of the twitch contraction after the addition of the agent was significantly greater than that before its addition.

4. Recordings were made at 37°C, 30°C, 25°C and 15°C. Myotonia developed at 37°C, 30°C and 25°C, but not at 15°C, indicating that at a temperature between 25°C and 15°C, anthracene-9-carboxylic acid-induced myotonia failed to develop. This supports the results obtained in humans suffering from myotonia congenita where myotonic contractions in the adductor pollicis muscle disappeared when the muscle temperature was cooled to 20°C.

5. The myotonia which developed at 37°C could be significantly reduced by exposure to 1 × 10−4 mol/l ouabain or by elevation of the K+ concentration of the Krebs solution to 7.5 mmol/l.

6. Measurements made using microelectrodes showed that the conditions under which myotonia either did not develop or was significantly reduced, i.e. a temperature of 15°C, exposure to 7.5 mmol/l K+ at 37°C or exposure to 1 × 10−4 mol/l ouabain at 37°C, were each associated with membrane depolarization. The results are discussed in terms of a possible role for depolarization in preventing/reducing the myotonic response.
Repeatability of Spectral Components of Short-Term Blood Pressure and Heart Rate Variability during Acute Sympathetic Activation in Healthy Young Male Subjects
Authors: Cloarec-Blanchard Laure , Funck-Brentano Christian , Lipski Margorzata , Jaillon Patrice , MacQuin-Mavier Isabelle
Published: August 2015

1. Changes in the low-frequency (LF) components of blood pressure and heart rate variability and in the ratio of LF to high-frequency (HF) components of heart rate variability (LF/HF ratio) are used to assess acute changes in sympathetic control of blood pressure or heart rate and in sympathovagal balance that occur in response to physiological or pharmacological stimuli. Before these spectral indexes can be used to assess the effects of drug therapy or other clinical interventions on reflex sympathetic activity, their repeatability must be evaluated.

2. Intra-observer repeatability was studied by analysing changes in the LF components (expressed as absolute or normalized units) of cardiovascular variability and in the LF/HF ratio during sympathetic activation induced by nitroglycerin infusion (n = 10 subjects) or 60° head-up tilt (n = 13 subjects) repeated on two occasions, 2 days and 1 week apart respectively, in healthy young male volunteers. Repeatability was estimated as recommended by Bland and Altman.

3. Bland and Altman's plots of the repeatability of changes in the LF components and LF/HF ratio showed that measurements were sufficiently repeatable to be used over periods of time of up to 1 week in clinical studies.

4. The sample-size tables derived from our results show that expression of spectral components as normalized units, and use of a cross-over design, minimize the number of subjects to be included in clinical studies conducted using similar designs and LF component changes as endpoints.
Inhibition of Neutral Endopeptidase, the Degradative Enzyme for Natriuretic Peptides, in rat Kidney after Oral SCH 42495
Authors: Burrell Louise M. , Farina Nicole , Risvanis John , Woollard David , Casely David , Johnston Colin I.
Published: August 2015

1. Inhibition of neutral endopeptidase (NEP), the degradative enzyme for atrial natriuretic peptide, was studied in vitro and in vivo using a previously characterized NEP inhibitor radioligand, 125I-labelled RB104.

2. SCH 42354, the active di-acid of the ethylester prodrug, SCH 42495, caused a concentration-dependent displacement of 125I-labelled RB104 from rat renal NEP. The concentration of SCH 42354 that displaced 50% of radioligand bound to the enzyme NEP (IC50) was 3.3 ± 0.1 nmol/1 (mean ± SEM). Enalaprilat, an angiotensin converting enzyme inhibitor, did not displace 125I-labelled RB104 in concentrations up to 10 μmol/1.

3. In adult normotensive Sprague—Dawley rats, oral SCH 42495 (3–300 mg/kg) caused significant inhibition of renal NEP (P < 0.001). SCH 42495 had no effect on renal or plasma angiotensin converting enzyme activity, but high-dose SCH 42495 (300 mg/kg) caused a significant increase in plasma renin activity (P < 0.01).

4. In a time course study, oral SCH 42495 (30 mg/kg) caused rapid (within 30 min) and significant inhibition of renal NEP for up to 48 h (P < 0.001). No changes in plasma atrial natriuretic peptide or plasma angiotensin converting enzyme activity were seen.

5. These data provide evidence that short-term administration of the NEP inhibitor SCH 42495 results in inhibition of renal NEP and does not inhibit the circulating or the tissue renin—angiotensin system. The NEP inhibitor radioligand 125I-labelled RB104, is a useful tool to study tissue NEP inhibition after administration of NEP inhibitors.
Reduction of Placental Nitric Oxide Synthase Activity in Pre-Eclampsia
Authors: Brennecke S. P. , Gude N. M. , Di Iulio J. L. , King R. G.
Published: August 2015

1. The role of the potent vasodilator nitric oxide in the pathogenesis of pre-eclampsia is unclear. We have tested the hypothesis that placental activity of the enzyme which synthesizes nitric oxide (nitric oxide synthase) is reduced in pre-eclampsia.

2. Placentae were obtained after vaginal delivery or Caesarean section from women who had been assigned to the following groups according to standard obstetric criteria: term non-pre-eclamptic control, term pre-eclamptic, preterm non-pre-eclamptic control and preterm pre-eclamptic. Nitric oxide synthase activity of placental tissue homogenates was assessed by measuring conversion of [3H]l-arginine into [3H]l-citrulline in the presence of NADPH, FAD, tetrahydrobiopterin, calmodulin, CaCl2, magnesium acetate and a range of l-arginine concentrations. Michaelis Menton constants (Km) amd maximum velocities of reaction (Vmax) were calculated using Lineweaver—Burk analysis.

3. Vmax was significantly reduced in both term and preterm pre-eclamptic placentae compared with placentae from corresponding gestation-matched controls. There were no significant differences in the Km values for nitric oxide synthase between any of the four groups, nor were Vmax or Km values significantly influenced by mode of delivery.

4. These results provide evidence that human placental nitric oxide synthase activity is significantly reduced in pre-eclampsia. Such a reduction was evident at both term and preterm gestations. Reduced placental nitric oxide synthase activity may have an adverse effect on placental haemodynamic function in pre-eclampsia, and could be involved in the pathogenesis of this important and common obstetric complication.
Change in Blood Pressure during Altered Sodium Intake is not Associated with Calciotropic Hormone Level
Authors: Ozono Ryoji , Oshima Tetsuya , Matsuura Hideo , Ishibashi Katsuhiko , Watanabe Mitsuaki , Yoshimura Mitsuisa , Kajiyama Goro , Kambe Masayuki
Published: August 2015

1. We evaluated the effects of the dietary restriction of sodium chloride on blood pressure and systemic calcium metabolism in 19 in-patients with essential hypertension (11 men and 8 women, mean age 49.9 ± 12.1 years).

2. All patients received a high-sodium diet (250 mmol/day) for 1 week, followed by a low-sodium diet (10 mmol/day) for another week. Intake of potassium (100 mmol/day) and of calcium (15 mmol/day) were kept constant throughout the study.

3. Sodium restriction significantly reduced the mean blood pressure (from 114.0 ± 1.9 to 105.0 ± 13.7 mmHg, P < 0.01). Urinary calcium excretion was significantly reduced (from 5.1 ± 2.4 to 2.2 ± 1.0 mmol/day, P < 0.01).

4. The change in mean blood pressure after sodium restriction was not correlated with a change in any parameter of calcium metabolism [whole blood ionized calcium, plasma intact parathyroid hormone, or 1,25-(OH)2 vitamin D3].

5. Plasma renin activity during a regular sodium diet, an index of renin status, was significantly and inversely correlated with the change in blood pressure during sodium restriction, but not with any change in the parameters of calcium metabolism.

6. We conclude that sodium restriction reduces blood pressure and decreases urinary calcium excretion. However, we observed no significant role of extracellular calcium concentration or of calciotropic hormone concentration in the mechanism of sodium sensitivity.
Non-invasive Measurement of Cardiac Output and Ventricular Ejection Fractions in Chronic Cardiac Failure: Relationship to Impaired Exercise Tolerance
Authors: Steele Ian C. , Moore ANN , Nugent Anne-Marie , Riley Marshall S. , Campbell Norman P. S. , Nicholls D. Paul
Published: August 2015

1. The role of cardiac output limitation in the pathophysiology of exercise in patients with chronic failure remains undefined. During steady-state submaximal exercise, oxygen uptake is similar in patients and control subjects, but it is not known if cardiac output is also similar. We wished to determine if the reduced exercise tolerance of patients with chronic cardiac failure during such exercise is related to reduced cardiac output, or to peripheral factors.

2. Ten male patients with stable chronic failure and ten age-matched male normal controls were studied at rest and during exercise. Each subject performed a familiarization exercise test, a symptom-limited maximal exercise test and two submaximal exercise tests. Cardiac output was measured by a carbon dioxide rebreathing method. We also measured oxygen consumption, ventilation, Borg score of perceived exertion and venous lactate concentration, and ejection fractions.

3. As expected, patients had lower peak oxygen consumption [median (range) 1.18 (0.98–1.76) versus 1.935 (1.53–2.31) 1/min; P < 0.001], lower peak venous lactate concentration but a similar overall level of perceived exertion. At the same submaximal workload, patients and control subjects had similar oxygen consumption [0.67 (0.59–0.80) versus 0.62 (0.52–0.82) 1/min] and cardiac output [6.92 (5.79–9.76) versus 7.3 (5.99–10.38) 1/min] but the patients had a greater perceived level of exertion [Borg score: 4 (1–6) versus 3 (1–5); P < 0.005], higher venous lactate concentration [1.6 (1–3.3) versus 1.14 (0.7–1.7) mmol/l; P < 0.05] and higher heart rate [106 (89–135) versus 87 (69–112) beats/min;P < 0.005].

4. During submaximal exercise at a similar absolute workload, patients with cardiac failure have a similar oxygen uptake and cardiac output but greater anaerobiosis and increased fatigue when compared with normal subjects. These findings appear to relate predominantly to changes that occur in the periphery rather than abnormalities of central cardiac function.
Beneficial Effect of the Calcium-Sensitizing Drug EMD 57033 in a Canine Model of Dilated Heart Failure
Authors: Drake-Holland Angela J. , Lee John A. , Hynd John , Clarke Sinéad B. , Noble Mark I. M.
Published: August 2015

1. Pacing-induced heart failure was studied in eight dogs. Heart failure was induced by right ventricular pacing at 250–260 beats/min for 6 weeks. Evidence of heart failure was determined clinically and by measurement of left ventricular (LV) dimensions by transoesophageal echocardiography.

2. Haemodynamic measurements of LV pressure, maximum rate of rise of LV pressure (LVdP/dtmax), cardiac output, mean arterial pressure, heart rate, pulmonary artery and pulmonary wedge pressures were made during infusion of solvent (control) and the calcium sensitizer EMD 57033 (0.6 mg min−1 kg−1).

3. The degree of heart failure varied from mild to severe in different individuals, but in each case EMD 57033 exerted a positive inotropic effect on LV haemodynamics and dimension.

4. The positive inotropic effect of the calcium sensitizer was manifest by increased peak LVdP/dt with a subsequent increase in cardiac output at the same mean arterial pressure.

5. This study clearly demonstrates that there is the potential for improvement of contractility of the failing myocardium of the intact mammal by an agent with a mechanism of action which does not involve an increase in intracellular calcium.
Plasma Concentration of Total Leptin and Human Lung-Cancer-Associated Cachexia
Authors: Simons Jean Paul F.H.A. , Schols Annemie M.W.J. , Campfield L. Arthur , Wouters Emiel F.M. , Saris Wim H.
Published: August 2015

1. Adipocyte-derived leptin is postulated to represent the afferent hormonal signal to the hypothalamus in a feedback mechanism that regulates fat mass. In this proposed feedback mechanism, increased fat mass leads to an elevated plasma leptin level that eventually induces a decrease in appetite and an increase in energy expenditure, and vice versa.

2. As anorexia and hypermetabolism play a role in the development of cancer cachexia, we investigated the hypothesis that underlying abnormalities in the leptin feedback mechanism (in particular relatively high plasma leptin levels or, on the other hand, a hypothalamic insensitivity to a fall in leptin levels) might be involved. For this purpose, total plasma leptin, body composition (fat mass and fat-free mass), appetite and resting energy expenditure were assessed in 21 male lung-cancer patients.

3. Total leptin was detectable in six patients and non-detectable in 15. In comparison with the latter, the patients with detectable leptin were characterized by a trend towards less weight loss (3.4% compared with 11.0%, P = 0.07), as being less underweight (body mass index 23.8 kg/m2 compared with 19.4 kg/m2, P = 0.004) and by a higher fat mass (21.4 kg compared with 9.7 kg, P = 0.001). Significant between-group differences in appetite and resting energy expenditure were lacking.

4. Based on these findings, we conclude that in cancer the afferent part of the leptin feedback mechanism functions normally and that, in particular, elevated leptin levels are not involved in the development of cachexia. Since the absence of plasma leptin was not associated with an increased appetite and decreased energy expenditure, disturbances in the hypothalamic part of the feedback mechanism are hypothesized.
Mutations at the Lipoprotein Lipase Gene Locus in Subjects with Diabetes Mellitus, Obesity and Lipaemia
Authors: Zhang Qiuping , Cavallero Elisabeth , Hoffmann Michael M. , Cavanna Julian , Kay Andrea , Charles Aline , Braschi Sylvie , Marz Winfried , Perlemuter Leon , Jacotot Bernard , Galton David J.
Published: August 2015

1. The common association of obesity, diabetes mellitus and hyperlipidaemia may have a primary aetiological basis. Insulin resistance has been postulated as a possible cause, but defects in the plasma transport of triacylglycerol or fatty acids could also be primary determinants.

2. We have therefore, studied 18 patients with diabetes mellitus, obesity and severe hypertriglyceridaemia for defects of a key protein involved in the clearance of plasma triacylglycerols, lipoprotein lipase.

3. DNA was prepared from leucocytes of 18 patients with the above syndrome, and exons encoding lipoprotein lipase were amplified by PCR. The products were sequenced using the dideoxy chain-termination method.

4. Eight of the subjects were found to possess genetic variants at the lipoprotein lipase gene locus. These were: (a) G579→A, V108V; (b) G818→A, G188E; (c) C829→T, R192; (d) A1127→G, N291S; (e) C1308→G, F351L;(f) C1338→A, T361T; and (g) C1595→G, S447. Three of these, (c), (e) and (f), have not hitherto been described. Variant (f), appears to be a population polymorphism whose allele frequency in normolipidaemic diabetics was found to be 0.12 (162 chromosomes studied). The others are all rare at frequencies of <0.01 and may contribute to the phenotype by impairing clearance of plasma triacylglycerols.

5. We conclude that genetic variants at the lipoprotein lipase locus occur commonly in subjects with this syndrome (four out of 18 subjects with probably functional mutants) and may affect the individual's response to obesity and diabetes mellitus for the development of lipaemia.
Elevated Post-Prandial Gastric Inhibitory Polypeptide Concentrations in Hypertriglyceridaemic Subjects
Authors: Gama Rousseau , Norris Fiona , Morgan Linda , Hampton Shelagh , Wright John , Marks Vincent
Published: August 2015

1. We investigated whether abnormalities of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (7–36 amide) (GLP-1) contribute to the hypertriglyceridaemia and hyperinsulinaemia in hypertriglyceridaemic subjects. Serum triglycerides and plasma glucose GIP, GLP-1 and immunoreactive insulin (IRI) concentrations were measured before and after a mixed meal in 15 hypertriglyceridaemic patients and in eight healthy normotriglyceridaemic control subjects.

2. Integrated post-prandial GIP concentrations were greater than in controls (P < 0.05) and correlated positively with both fasting and integrated post-prandial triglyceride concentrations (P < 0.05 for both). Fasting and integrated post-prandial IRI levels were higher in hypertriglyceridaemic subjects than in controls (P < 0.02 and P < 0.05 respectively) and correlated positively with fasting triglycerides (P < 0.02 and P < 0.001 respectively) and integrated post-prandial triglycerides (P < 0.005 and P < 0.05 respectively). There was no correlation between GIP concentrations and either fasting or post-prandial IRI levels. Fasting and post-prandial concentrations of GLP-1 were similar in patients and controls.

3. Hypertriglyceridaemic subjects have post-prandial hyperGIPaemia in addition to the well-documented hyperinsulinaemia. We found no association between GIP and insulin. There is, however, clear evidence for an association between post-prandial GIP concentrations and triglyceride levels. We suggest that this association may depend on changes in lipoprotein lipase activity and that there may be a feedback loop between GIP and triglyceride lipolysis.
Selective Migration of α-Smooth Muscle Actin-Positive Myofibroblasts toward Fibronectin in the Boyden's Blindwell Chamber
Authors: Kawamoto Masashi , Matsunami Takakuni , Ertl Ronald F. , Fukuda YUH , Ogawa Maki , Spurzem John R. , Yamanaka Nobuaki , Rennard Stephen I.
Published: August 2015

1. In order to address the hypothesis that migrating fibroblasts have a different phenotype, human fetal lung fibroblasts (HFL-1) cells were evaluated in the Boyden blindwell chamber migration assay followed by immunoelectron microscopy.

2. HFL-1 cells were placed on nucleopore filters and incubated for 2 h using purified human plasma fibronectin (pFn) as a chemoattractant. Filters were then processed for immunoelectron microscopy using antibodies for α-smooth muscle (α-SM) actin as a marker for myofibroblasts, cellular fibronectin (cFn) and VLA-5.

3. Cells which had migrated to the bottom side of the filter were more likely to express α-SM actin, 29.1 ± 3.4% of cells, compared with cells which did not migrate through the filter, 12.4 ± 1.3% (P < 0.05). The total proportion of α-SM-actin-positive cells located on both sides of the filter showed no difference between those which had migrated toward pFn and controls (17.7 ± 1.0% compared with 20.2 ± 2.5%).

4. cFn-positive cells showed minimal differences compared with control cells, while perinuclear and endoplasmic reticulum staining of VLA-5 was observed only in the cells treated with pFn.

5. The results show that HFL-1 cells are heterogenous for α-SM actin expression. Short-term incubation with pFn did not change the proportion of α-SM-actin-positive HFL-1 cells. Cells which migrate, however, are enriched for α-SM actin expression. pFn-induced fibroblast chemotaxis can selectively recruit myofibroblasts with increased α-SM actin expression, a feature which may contribute to the altered population of cells at sites of fibrosis.
Mast Cell Activation in Arthritis: Detection of α- and β-tryptase, Histamine and Eosinophil Cationic Protein in Synovial Fluid
Authors: Buckley M. G. , Walters C. , Wong W. M. , Cawley M. I. D. , Ren S. , Schwartz L. B. , Walls A. F.
Published: August 2015

1. Although mast cell hyperplasia is a feature of rheumatoid arthritis and osteoarthritis, the extent and nature of mast cell activation in joint disease have not been clearly established.

2. We have investigated the levels of mast cell tryptase and histamine and also of eosinophil cationic protein in synovial fluid collected from 31 patients with rheumatoid arthritis, 14 with seronegative spondyloarthritis and nine with osteoarthritis. Two RIAs for tryptase were employed: one with monoclonal antibody AA5, which was found to bind equally well to both α and β isoforms on Western blots of the recombinant enzyme, and the other with antibody G5, which recognizes predominantly β-tryptase.

3. α-Tryptase, which is likely to be released constitutively from mast cells, appeared to be the major form in synovial fluid, as the assay with antibody AA5 detected appreciably more tryptase than that with antibody G5. β-Tryptase, which is released on anaphylactic activation of mast cells, was detected in 14 out of 45 synovial fluid samples studied, with concentrations of up to 12 μg/l measured by the G5 assay. The apparent levels of β-tryptase, but not of α-tryptase, were closely correlated with those of histamine in the synovial fluid. Patients with osteoarthritis appeared to have a greater proportion of β-tryptase in the synovial fluid than those with rheumatoid arthritis, as well as higher concentrations of histamine. Eosinophil cationic protein was present at high levels in the synovial fluid, although eosinophil numbers were low, and its concentrations were not correlated with the concentrations of the mast cell products.

4. These data suggest that anaphylactic degranulation of mast cells may have occurred to a greater extent in osteoarthritis than in rheumatoid arthritis, despite the relative lack of synovial inflammation in osteoarthritis. Although the eosinophil cationic protein detected may not reflect eosinophilic inflammation in the joint, the presence in synovial fluid of tryptase of both major forms, and of histamine, appears to indicate that mast cell products are secreted constitutively, as well as by processes of anaphylactic degranulation in rheumatoid arthritis, seronegative spondyloarthritis and osteoarthritis.
A Single Dose of Intravenously Injected Poloxamine-Coated Long-Circulating Particles Triggers Macrophage Clearance of Subsequent Doses in Rats
Authors: Moghimi S. M. , Gray T.
Published: August 2015

1. Adsorption of the block copolymer non-ionic surfactant poloxamine-908 on to the surface of polystyrene nanospheres (60 nm in diameter) produced ‘phagocyte-resistant’ particles (otherwise known as long-circulating particles). This was reflected by a profound reduction in uptake of such engineered nanospheres by macrophages of the reticuloendothelial system and extended blood circulation time, after intravenous administration to rats.

2. A single intravenous administration of poloxamine-908-coated particles dramatically affected the circulation half-life and body distribution of a second subsequent dose. The degree of alteration depended on the interval between the two doses. At 3 days after a single intravenous injection of poloxamine-coated particles, Kupffer cells and spleen macrophages could clear a second dose of long-circulating beads from the blood. When tested at day 14, the second dose of intravenously injected poloxamine-coated particles avoided rapid uptake by liver and spleen macrophages and remained in the blood.

3. The coating polymer (poloxamine-908) apparently triggered bead clearance by resident Kupffer cells and certain sub-populations of spleen macrophages, since a single intravenous dose of an endotoxin-free solution of poloxamine 3 days before the administration of long-circulating particles induced similar effects. When the interval between the two injections was 2 weeks, poloxamine-coated particles again exhibited long circulation half-life. This cycle could be repeated after intravenous administration of a second poloxamine dose 2 weeks after the first poloxamine injection.

4. The mechanism of particle recognition by resident tissue macrophages was found to be independent of opsonization processes.

5. These studies could have important implications in biomedical application, design and engineering of poloxamine-based long-circulating drug carriers for repeated intravenous administration.
Nitric Oxide in Different Types of Hypertension during Pregnancy
Authors: Garmendia Jenny V. , Gutiérrez Ylse , Blanca Isaac , Bianco N. E. , De Sanctis J. B.
Published: August 2015

1. Serum nitric oxide (NO) levels (determined by its products of oxidation) were assessed in nonpregnant women, normal pregnant women and patients suffering from mild pre-eclampsia (MPE), severe pre-eclampsia (SPE), chronic hypertension (CHT) and CHT with pre-eclampsia (CHT+PE). The levels of NO products were significantly reduced during pregnancy in MPE (P < 0.001), CHT+PE (P < 0.01) and SPE (P < 0.05). Significant reductions of NO products were also observed in puerperium (P < 0.001) in all groups except CHT+PE (P < 0.05).

2. In normal pregnancy, three events were related to NO levels: (1) negative correlations were found between the levels of nitrite (r = −0.73, P = 0.0003), nitrate (r = −0.53, P = 0.017) and the number of weeks of gestation; (2) in the caesarean section group, the levels of NO at puerperium were significantly lower (P < 0.05) than those during pregnancy; and (3) there was a significant reduction in NO levels in the pregnant women carrying male fetuses as compared with female fetuses (P < 0.05).

3. In SPE, the patients with a family history of hypertension had lower levels of NO compared with the patients without such a history (P < 0.05).

4. A negative correlation was observed between systolic blood pressure, diastolic blood pressure and NO levels in MPE (r = −0.62, P = 0.013 and r = −0.68, P = 0.0049 respectively) and SPE (r = −0.72, P = 0.004 and r = −0.53, P = 0.037 respectively).

5. In SPE, positive correlations were observed between platelet count and nitrite (r = 0.67, P = 0.006) and nitrate levels (r = 0.56, P = 0.028).

6. In MPE, patients with anti-hypertensive treatment showed significantly (P < 0.05) higher levels of NO compared with the non-treated patients.

7. NO may be important in the physiopathology of hypertension during pregnancy, although several factors may affect its levels.
Renovascular Hypertension with Low-to-Normal Plasma Renin: Clinical and Angiographic Features
Authors: Rossi Gian Paolo , Pavan Edoardo , Chiesura-Corona Matteo , Bader Michael , Paganini Giovanni , Cesari Maurizio , De Toni Renzo , Feltrin Gian Pietro , Ganten Detlev , Pessina Achille C.
Published: August 2015

1. Low-to-normal renin renovascular hypertension (RVH) and the accuracy of renal vein renin ratios were investigated in 129 consecutive patients referred for suspected RVH. Forty-nine had essential hypertension, 24 unilateral renoparenchymal hypertension and 56 renal artery obstruction. Of the latter, 86% were diagnosed retrospectively as RVH, based on fall in blood pressure with correction of renal ischaemia. We measured baseline, captopril-stimulated and renal vein plasma renin activity (PRA) levels, as well as several other parameters.

2. PRA was low-to-normal in 37% of the RVH patients [low-to-normal renin (LNR-) RVH group] and elevated in the remaining 63% [high-renin (HR-) RVH group]. In the LNR-RVH group, low-to-normal renin levels, by immunoreactive active renin and plasma renin concentration measurements, and a blunted response of PRA to captopril, were seen. As compared with HR-RVH, LNR-RVH patients had a longer duration of hypertension (P < 0.05), higher serum K+ (P = 0.04) and lower diastolic blood pressure (P = 0.02). However, they did not differ for the other variables, including the fall in blood pressure after correction of renal ischaemia. Although the number of bilateral stenoses was similar in the two groups, no patient in the LNR-RVH group had total renal artery occlusion compared with 53% in the HR-RVH group (P = 0.00015). The accuracy of renal vein renin indices were high enough to justify their use only in the patients with total occlusion of a renal artery.

3. Thus LNR-RVH is common in patients with longstanding hypertension without a totally occluded renal artery. Since the sensitivity of renin measurements is low, cure of hypertension would be precluded for more than one third of RVH patients, if these tests were a prerequisite for identifying RVH.
Comparative Kinetics of Microvascular Inulin and 99mTc-Labelled Diethylenetriaminepenta-Acetic Acid Exchange
Authors: Cousins C. , Gunasekera R. D. , Mubashar M. , Mohammadtaghi S. , Strong R. , Myers M. J. , Peters A. M.
Published: August 2015

1. After simultaneous intravenous injection as a mixture, 99mTc-labelled diethylenetriaminepentaacetic acid (99mTc-DTPA; molecular mass 492 Da) and inulin (∼6000 Da) gave arterial plasma clearance curves consisting of three exponentials, the time courses of which were not significantly different between the two solutes.

2. The ratio of 99mTc-DTPA to inuiin concentration in antecubital venous plasma (normalized to the ratio in arterial plasma at 30 s) was 0.6, significantly less than unity, within 2 min after intravenous injection, but increased to reach unity by 60 min. The minimun concentration ratio of 99mTc-DTPA to inulin in arterial plasma was 0.75 at 4 min, also rising to just above unity at 60 min.

3. The extraction fraction from plasma to interstitial space was higher for 99mTc-DTPA (∼0.5) than for inuiin (∼0.2). For both solutes, the net extraction fraction decreased with time, becoming negative at about 25 min after injection. Thereafter, the net extraction fractions remained negative, between −0.05 and −0.1, and not significantly different between the two solutes.

4. 99mTc-DTPA time—activity curves recorded over the limbs with scintillation probes were biphasic, with an initial phase corresponding closely in time with the first exponential of the arterial 99mTc-DTPA plasma clearance curve. The second phase corresponded in time to the intermediate exponential of the arterial 99mTc-DTPA plasma clearance curve.

5. The time course of net 99mTcm-DTPA extraction fraction across the forearm vascular bed was bi-exponential, with phases corresponding in time with the two phases of the limb uptake curves.

6. Deconvolution analysis of the limb time—activity curves, using the arterial time—concentration curve as the input function, gave bi-exponential 99mTc-DTPA impulse response curves in which the time courses of the exponentials corresponded with the first and intermediate exponentials of the arterial 99mTc-DTPA clearance curve.

7. The bi-exponential nature of the equilibrium of 99mTc-DTPA between vascular and interstitial compartments suggests the presence of two separate functional volumes within the interstitial space. Although 99mTc-DTPA and inuiin clearly diffuse at different rates across the endothelium, as would be expected from their disparate sizes, the similarity in the time courses of their initial exponentials and simultaneous equalization of transfer rates (i.e. when net extraction fraction was zero) is consistent with the hypothesis that inuiin moves initially into a smaller functional interstitial fluid volume than 99mTc-DTPA. The total distribution volumes, however, are not significantly different between the two solutes.
Effect of Red Wine on Endothelium-Dependent Relaxation in Rabbits
Authors: Cishek Mary Beth , Galloway Michael T. , Karim Malina , German J. Bruce , Kappagoda C. Tissa
Published: August 2015

1. Published data on the effects of red wine, ethanol and flavonoids on endothelium-dependent relaxation are equivocal. The present study was undertaken to determine the effects of red wine, ethanol and selected flavonoids present in red wine on endothelium-dependent relaxation.

2. Aortic rings from New Zealand White rabbits were set up in organ baths (20 ml) and contracted with noradrenaline (10−6 mol/l). An attempt was made to elicit dose-dependent relaxant responses to red wine (15, 30, 40, 80 or 120 μl), ethanol (5.4, 10.8 and 16.2 μl) and the flavonoids catechin, epicatechin, quercetin and polymeric phenols (10−7 to 10−4 mol/l). In some experiments, endothelium-dependent relaxation to cumulative doses of acetylcholine (10−9 to 10−6 mol/l) was determined before and after incubating the rings for 15 min with red wine (120 μl), ethanol (16.2 μl), quercetin (10−5 mol/l), catechin (10−5 mol/l), epicatechin (10−5 mol/l) and PPs (10−5 mol/l) respectively. cGMP was also measured in some rings in the control state and after addition of 120 μl of red wine, sodium nitroprusside (10−4 mol/l) and polymeric phenols (10−5 mol/l).

3. Red wine evoked a dose-dependent relaxation in aortic rings. The highest volumes of wine (120 μl) relaxed the vessels by 71.35 ± 7.89% of the maximal contraction (8.95 ± 0.97 g). Polymeric phenols also relaxed the precontracted rings. These responses were abolished by NG-l-argine methyl ester (l-NAME) and by removal of endothelium. Addition of red wine, polymeric phenols and sodium nitroprusside increased the cGMP content of the rings. In tissues previously incubated with red wine and polymeric phenols, endothelium-dependent relaxation in response to acetylcholine was attenuated. Ethanol had no such effect.

4. Acute exposure of aortic rings to red wine and polymeric phenols evokes an endothelium-dependent relaxation which is mediated by nitric oxide. However, prior exposure to both red wine and polymeric phenols has a second effect in that it attenuates the endothelium-dependent relaxation evoked by acetylcholine. Since this effect is restored by arginine, it is likely to be due to depletion of substrate for nitric oxide synthase.
Effect of Narcotic Agents and of Bleeding on Systemic and Renal Haemodynamics in Healthy and CCl4-treated Cirrhotic Rats
Authors: Van Roey G. , Lijnen P. , Verbesselt R. , Verbruggen A. , Fevery J.
Published: August 2015

1. The haemodynamic effects of different narcotic agents have been tested in healthy rats and in rats with cirrhosis.

2. Pentobarbital suppresses the sympathetic nervous system. Susceptibility to ketamine is unpredictable, leading to both insufficient pain relief and narcosis related mortality. The combination diazepam—fluanisone induces profound hypotension. After insertion of catheters, awake, freely moving rats are stable and not distressed. This allows repeated measurements after manipulation. Moreover, procedure-related mortality is low and rats have a better stress response.

3. In the awake animal, arterial pressure is 126 ± 10 for healthy animals, and 111 ± 16 and 102 ± 10 mmHg for cirrhotic animals without and with ascites, respectively (P = 0.018). The respective values for portal pressure are 6.9 ± 1.4, 11.6 ± 2.5 and 16.2 ± 2.9 mmHg (P = 0.0001). After a bleeding, arterial pressure is better preserved than portal pressure in the three groups (P < 0.0001). Plasma volume in cirrhotic rats exceeds that of healthy rats. Plasma renin activity, aldosterone and catecholamines do not differ between the groups studied. In cirrhotic rats with and without ascites, glomerular filtration rate tends to be higher (P = 0.12), renal plasma flow is elevated (P = 0.001) and nitration fraction is lower (P = 0.002) than in healthy rats.

4. In conclusion, haemodynamic experiments in the cirrhotic rat should be performed in the awake rat. Arterial hypotension, impaired filtration fraction, enlarged plasma volume and portal hypertension are present in cirrhosis before the development of ascites. This can as well be explained by splanchnic pooling of blood, as by peripheral vasodilatation. The decrease in portal pressure with preserved arterial pressure after a bleeding protects cirrhotic rats from ongoing variceal bleeding.
Determinative Role of Peroxidized Low-Density Lipoprotein in Myocardial Thromboxane Synthesis during Pacing-Induced Ischaemia in Humans
Authors: Hsu Hsiu-Ching , Chen Ming-Fong , Lee Chii-Ming , Lee Yuan-Teh
Published: August 2015

1. Myocardial thromboxane A2 production increases in patients with pacing-induced ischaemia and correlates with a decrease in myocardial lactate extraction. The release of myocardial thromboxane A2 before any lactate production was observed in patients with unstable angina. This study was proposed to clarify whether the early thromboxane A2 release contributed to the ongoing myocardial ischaemia and to determine which metabolites can be attributed to the thromboxane A2 release. Thirty-five patients with chest pain and positive treadmill exercise test underwent atrial pacing to the predicted maximal heart rate. The pacing was maintained at this peak rate for 10 min, then ceased. Blood samples of the ascending aorta and coronary sinus were drawn simultaneously at rest, at 2 and 10 min of peak-pacing, and 5 and 10 min after termination of the pacing; samples were used for analyses of lipid profiles, prostacyclin, thromboxane A2, lactate and lipid peroxides on plasma and low-density lipoprotein particles.

2. Twenty out of 35 patients who displayed pacing-induced ischaemia were documented by electrocardiographic evidence of ST depression >2 mm developing after 2 min of peak-pacing [ischaemic group, STΔ(+)]. They had (i) negative fractional lactate extraction; (ii) pacing-induced decreases of plasma thromboxane A2 levels in the coronary sinus blood (564 ± 57 versus 479 ± 47 ng/l, P < 0.05) at 2 min of peak-pacing; the data increased at 10 min of peak-pacing (564 ± 57 versus 620 ± 60 ng/l, P < 0.05), then returned to baseline levels at 5 and 10 min post-pacing; (iii) significantly increased lipid peroxides on low-density lipoprotein of the coronary sinus blood at 2 and 10 min of peak-pacing (each P < 0.001), as well as at 5 min post-pacing (P < 0.05); (iv) significant correlation between thromboxane A2 levels and lipid peroxides on low-density lipoprotein of the coronary sinus blood samples.

3. In STΔ(+) patients, myocardial thromboxane synthesis changed before lactate production and correlated with the increase of lipid peroxides on low-density lipoprotein of the coronary venous blood. This implies that lipid peroxides on low-density lipoprotein participate in thromboxane production and play a determinative role in pacing-induced ischaemia.
Rate of Gastric Emptying is a Determinant of Postprandial Hypotension in Non-Insulin-Dependent Diabetes Mellitus
Authors: Jones K. L. , Tonkin A. , Horowitz M. , Wishart J. M. , Carney B. I. , Guha S. , Green L.
Published: August 2015

1. Postprandial hypotension is now recognized as an important clinical problem, particularly in the elderly and in patients with autonomic dysfunction. The mechanisms responsible are poorly understood; however, impaired regulation of splanchnic blood flow and the release of gastrointestinal hormones appear to be important The effect of gastric emptying on the magnitude of the postprandial fall in blood pressure has not been evaluated.

2. The aim of this study was to determine whether there is a relationship between changes in blood pressure and the rate of gastric emptying after ingestion of 75 g of glucose in patients with noninsulin-dependent diabetes mellitus (NIDDM) and both young and older normal subjects. Sixteen patients with recently diagnosed NIDDM, median age 57 (39–79) years, 10 ‘young’ subjects with a median age of 23 (19–26) years and nine ‘older’ subjects, median age 48 (40–68) years, were measured simultaneously for gastric emptying of 75 g of glucose in 350 ml of water, blood pressure and blood glucose concentrations, commencing at approximately 10.00 hours after an overnight fast. Measurements of blood pressure were made in the sitting position immediately before glucose ingestion and at 15 min intervals up to 180 min.

3. Gastric emptying of glucose was not significantly different between the three groups [50% emptying time (T50): 95 ± 73 min in patients with NIDDM compared with 120 ± 13.2 min in the ‘young’ group and 97 ± 8.1 min in the ‘older’ group]. There was a significant fall in mean blood pressure after the glucose load in the patients with NIDDM (P < 0.0001) and the ‘older’ normal subjects (P < 0.05), but not the ‘young’ normal subjects. Postprandial hypotension (fall in systolic blood pressure ≥20 mmHg) was evident in seven (44%) patients with NIDDM and three (33%) ‘older’ normal subjects. The area under the change in mean blood pressure curve was related significantly to the gastric emptying T50 (r = 0.67, P < 0.005) in the patients with NIDDM, but not in either control group.

4. In conclusion, in patients with recently diagnosed NIDDM the fall in blood pressure after an oral glucose load is (i) greater than in both young and older normal subjects and (ii) related to the rate of gastric emptying.
Influences on Adrenaline-Induced Thermogenesis in Obese Women and Relationship to Cardiovascular Responses
Authors: Walsh Kevin M. , Adams Calam , Sinclair Annemarie , Leen Eddie , Lean Michael E. J.
Published: August 2015

1. In order to evaluate factors influencing thermogenesis in obesity, energy expenditure was measured before and during an adrenaline infusion (25 ng min−1 kg−1 ideal body weight for 30 min) in 22 obese females.

2. Thermogenic responses were related to body morphology, age and biochemistry. In addition, thermogenic responses were related to cardiovascular responses by simultaneously measuring blood pressure, pulse rate and cardiac output using Doppler sonography.

3. Resting energy expenditure was predicted by body weight, lean body mass and fat mass.

4. Adrenaline-induced thermogenesis was predicted by fasting insulin, low basal respiratory quotient and body fat.

5. There was a significant relationship between the cardiac output and thermogenic responses to adrenaline (r = 0.63 P < 0.015) but there was no relationship to the heart rate or blood pressure responses. For every 1% increase in energy expenditure, there was a 5% increase in cardiac output.

6. In conclusion, the factors predicting resting energy expenditure and adrenaline-induced thermogenesis are different. Increased lipid oxidation and central fat distribution (with hyperinsulinaemia) are associated with a greater thermogenic response. The proportionately greater cardiac output responses may have implications for thermogenic agents designed to induce weight loss.