bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-Regulation of the Acute-Phase Response in Patients with Pancreatic Cancer Cachexia Receiving Oral Eicosapentaenoic Acid is Mediated via Suppression of Interleukin-6
Authors: Wigmore Stephen J. , Fearon Kenneth C. H. , Maingay Jean P. , Ross James A. 
Published: August 2015

1. Weight loss in pancreatic cancer is associated with persistent elevation of the acute-phase protein response. The effect of oral administration of eicosapentaenoic acid on the regulation of the acute-phase response in weight-losing patients with pancreatic cancer was investigated in vitro and in vivo.
2. Oral supplementation with eicosapentaenoic acid, in patients with cancer cachexia, resulted in a significant reduction in the serum concentration of the acute-phase protein C-reactive protein (11.0 ± 4.8 mg/l before eicosapentaenoic acid compared with 0.8 ± 0.8 mg/l after 4 weeks of eicosapentaenoic acid, P &lt; 0.05), but no significant reduction in the serum concentration of the hepatocyte-stimulating cytokine interleukin-6. Production of interleukin-6 by peripheral blood mononuclear cells isolated from patients was significantly reduced after supplementation with eicosapentaenoic acid (interleukin-6 production by peripheral blood mononuclear cells exposed to 10 μg of lipopolysaccharide/ml: 10.2 ± 2.1 ng/ml before supplementation with eicosapentaenoic acid compared with 3.5 ± 1.7 ng/ml after supplementation, P &lt; 0.05) and supernatants from these cells had reduced potential to stimulate C-reactive protein production by isolated human hepatocytes (hepatocyte C-reactive protein production in response to supernatants from peripheral blood mononuclear cell cultures exposed to 10 μg of lipopolysaccharide/ml: 150.4 ± 18.6 ng/ml before eicosapentaenoic acid versus 118 ± 14.9 ng/ml after 4 weeks of eicosapentaenoic acid, P &lt; 0.05). The potential of lipopolysaccharide-stimulated peripheral blood mononuclear cell supernatants to stimulate C-reactive protein production by hepatocytes could be attenuated by neutralizing anti-interleukin-6 antibody in control subjects and in patients before, but not after, treatment with eicosapentaenoic acid.
3. In conclusion, eicosapentaenoic acid can down-regulate the acute-phase response in patients with pancreatic cancer cachexia and this process is likely to involve suppression of interleukin-6 production.
Nitric Oxide is Involved in the Inhibitory Neurotransmission and Endothelium-Dependent Relaxations of Human Small Penile Arteries
Authors: Simonsen ULF , Prieto Dolores , Delgado Jose Angel , Hernández Medardo , Resel Luis , De Tejada Iñigo Saenz , García-Sacristán Albino 
Published: August 2015

1. Alteration in the flow of blood to the penis is thought to be the most frequent organic cause of erectile dysfunction or impotence. However, information concerning the penile small arteries (helicine arteries) which control blood flow between the arterial systemic circulation and the cavernous sinusoids is scarce. Therefore, the purpose of the present study was to investigate the involvement of nitric oxide, which is considered to be the main neurotransmitter in corpus cavernosum, in both the non-adrenergic non-cholinergic inhibitory neurotransmission and the endothelium-dependent responses in human penile small arteries.
2. Penile small arteries (lumen diameter 200-700 μm), which were branches of the human deep penile arteries obtained either from patients undergoing penile surgery or from organ donors, were mounted in microvascular myographs for isometric tension recording and electrical field stimulation was performed in the presence of guanethidine and atropine to block adrenergic neurotranmission and muscarinic receptors, respectively.
3. In phenylephrine-contracted penile small arteries, electrical field stimulation (0.5–32 Hz) induced frequency-dependent relaxations of both endothelium-intact and -denuded preparations. The inhibitor of nitric oxide synthase, NG-nitro-l-arginine (3 × 10−5 mol/l), abolished the relaxations at the lowest frequencies, while slow-developing relaxations were still observed at high frequencies (16 and 32 Hz). The inhibitory effect of NG-nitro-l-arginine was reversed in the presence of l-arginine (3 × 10−3 mol/l). Tetrodotoxin totally abolished the relaxations to electrical field stimulation. In contracted small penile arteries in the presence of NG-nitro-l-arginine, the nitrovasodilator sodium nitroprusside induced potent relaxations.
4. The endothelium-dependent vasodilator acetylcholine induced relaxations of penile small arteries, which were only partially reduced in the presence of NG-nitro-l-arginine. In contrast, the relaxations to acetylcholine of trabecular corpus cavernosum preparations were almost abolished in the presence of NG-nitro-l-arginine.
5. The present study suggests that relaxations of human intracavernosal small penile arteries induced by non-adrenergic non-cholinergic nerve stimulation partially involve nitric oxide and also another inhibitory transmitter causing relaxations resistant to nitric oxide synthase blockade. In addition, endothelium-dependent relaxations in human small penile arteries are mediated by both nitric oxide and a factor resistant to NG-nitro-l-arginine.
Combination Oral Antioxidant Supplementation Reduces Blood Pressure
Authors: Galley Helen F. , Thornton Judith , Howdle Peter D. , Walker Barry E. , Webster Nigel R 
Published: August 2015

1. Hypertension affects 30% of adults and low intakes of antioxidants have been associated with increased risk of hypertension and cardiovascular disease. To investigate the effect of short-term high-dose antioxidant supplementation on blood pressure in hypertensive and normotensive outpatients, we undertook a randomized, double-blind, crossover design placebo-controlled study.
2. Forty subjects were recruited from medical outpatient clinics, of whom 38 completed the study. Twenty-one were attending for treatment of hypertension and 17 were normotensive, attending for minor gastrointestinal complaints. Subjects were randomly assigned to receive either 8 weeks placebo followed by 2 weeks washout then 8 weeks antioxidants or vice versa. The combination of antioxidants consisted of 200 mg of zinc sulphate, 500 mg of ascorbic acid, 600 mg of α-tocopherol (sodium succinate salt) and 30 mg of β-carotene daily.
3. Systolic blood pressure fell at the end of the antioxidant phase compared with the placebo phase both in subjects receiving anti-hypertensive therapy (P &lt; 0.01) and those who were normotensive (P = 0.067). Circulating levels of β-carotene and α-tocopherol increased in all subjects during supplementation (P &lt; 0.01) and urine nitrite increased in hypertensive patients (P &lt; 0.05).
4. Short-term oral high-dose combination antioxidant therapy reduces blood pressure, possibly via increased availability of nitric oxide. This study may have implications for the innovative use of antioxidants as an adjunct to anti-hypertensive therapy.
The Steroid Vitamin D3 Reduces Cell Proliferation in Human Duodenal Epithelium
Authors: Thomas M. G. , Sturgess R. P. , Lombard M. 
Published: August 2015

1. The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, controls calcium absorption in the human duodenum, an effect that is mediated by mucosal vitamin D receptor expression. Functional vitamin D receptor signalling in the human colon is suggested by the reduced colonic mucosal cell proliferation seen in response to 1,25-dihydroxyvitamin D3. Thus 1,25-dihydroxyvitamin D3 might be expected to reduce cell proliferation in the small-bowel epithelium.
2. We have used an organ-culture system combined with the metaphase arrest technique to study the effects of 1,25-dihydroxyvitamin D3 on human duodenal mucosal proliferation. To validate our technique, multiple human mucosal explants were established in organ culture and vincristine (0.6μg/ml) was added at 10 h. Explants were removed sequentially from 10 to 15 h and metaphase arrest figures were demonstrated by using the Feulgen reaction. The mean number of metaphase arrest figures was plotted against time in culture to show a linear accumulation of metaphases between 11 and 15 h (correlation coefficient = 0.93, r2 = 0.87, P &lt; 0.0001). The mean crypt cell production rate was 2.01 (0.27) cells/h per crypt.
3. Paired normal duodenal mucosal biopsies from six patients were then established in organ culture with or without 10−10 mol/l (100 pmol/l) 1,25-dihydroxyvitamin D3. The crypt cell production rate was determined between 12 and 15 h after vincristine-induced metaphase arrest. 1,25-Dihydroxyvitamin D3 reduced the median crypt cell production rate from 2.42 (1.15–4.82) to 1.41 (0.03–2.05) cells/h per crypt (P &lt; 0.05). Thus, vitamin D3 reduces human duodenal epithelial cell proliferation.
Intestinal Absorption of Trace Amounts of Aluminium in Rats Studied with 26Aluminium and Accelerator Mass Spectrometry
Authors: Schönholzer K. W. , Sutton R. A. L. , Walker V. R. , Sossi V. , Schulzer M. , Orvig C. , Venczel E. , Johnson R. R. , Vetterli D. , Dittrich-Hannen B. , Kubik P. , Suter M. 
Published: August 2015

1. Until recently studies of intestinal aluminium absorption used pharmacological amounts of stable 27Al.
2. To examine the intestinal absorption of trace amounts of different chemical compounds of aluminium, in the present study we have employed the long half-life isotope of aluminium, 26Al, and accelerator mass spectrometry. Trace amounts of 26Al (2.7–12.1 ng) as the hydroxide, citrate, citrate plus 1 mmol/kg sodium citrate, or maltolate respectively, were administered to four groups of rats (n = 9 per group) by gavage. Blood and urine samples were collected for 5 h and the 26Al content (as a percentage of the administered dose) determined by accelerator mass spectrometry.
3. The 5 h urinary 26Al excretion amounted to 0.1 ± 0.02, 0.7 ± 0.2, 5.1 ± 1.5 and 0.1 ± 0.1% of administered dose in the four groups respectively. There was a strong positive correlation between peak plasma 26Al (r = 0.98) and urinary 26Al excretion in individual animals (P &lt; 0.001).
4. We conclude that the fractional intestinal absorption of trace oral doses of aluminium hydroxide is at least 0.1% (compared with the previous estimate of 0.01% using large 27Al oral loads). Absorption of aluminium citrate given alone is significantly greater (0.7%) and is further increased to 5% by the accompanying sodium citrate, consistent with an enhancing effect of added citrate upon mucosal aluminium permeability. Aluminium maltolate absorption approximates that of aluminium hydroxide (0.1%).
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 &gt;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 &lt; 0.05) values and raised membrane microviscosity measured by 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene anisotropy (P &lt; 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 &lt; 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 &lt; 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 &lt; 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 &lt; 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.