bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological Evidence of Calcium-Activated and Voltage-Gated Potassium Channels in Human Platelets
Authors: de Silva H. A. , Carver J. G. , Aronson J. K. 
Published: August 2015

1. Previous electrophysiological studies have suggested the presence of KCa and Kv channels in human platelets. However, the pharmacology of these channels has not been defined.
2. We have studied potassium channels in human platelets by measuring the efflux of 86Rb+ (a marker for K+) from 86Rb+-loaded cells, and have defined their responses to stimulation by the platelet agonist thrombin and the calcium ionophore ionomycin.
3. Thrombin (0.1–0.6 i.u./ml) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l), charybdotoxin (300 nmol/l) and α-dendrotoxin (100–200 nmol/l), blockers of SKCa channels, KCh channels and Kv channels respectively. Iberiotoxin (300 nmol/l), a specific inhibitor of BKCa channels, had no effect on the thrombin-stimulated 86Rb+ efflux. Although glibenclamide, an inhibitor of KATP channels, inhibited the thrombin-stimulated efflux, it did so only in a high concentration (20 μmol/l).
4. Ionomycin (1–5 μmol/l) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l) and charybdotoxin (300 nmol/l). However, iberiotoxin (300 nmol/l) had no effect on the ionomycin-stimulated 86Rb+ efflux.
5. These findings suggest that 86Rb+ efflux from platelets stimulated by thrombin and ionomycin occurs via two types of KCa channel: SKCa and KCh channels. Thrombin also stimulated efflux via Kv channels.
Glycoprotein Changes in Tumours: A Renaissance in Clinical Applications
Authors: Hounsell Elizabeth F. , Young MIA , Davies Michael J. 
Published: August 2015

1. Oligosaccharides linked to protein (glycoprotein) or lipid (glycolipid) are the major components at the outer surface of mammalian cells. Studies using antibodies and lectins have shown in the past that the oligosaccharides they recognize exhibit tumour-associated changes, i.e. they are carbohydrate tumour-associated antigens.
2. The oligosaccharides have been further characterized in recent years by structural analysis using high-resolution chromatographic techniques, MS and NMR. NMR gives an oligosaccharide fingerprint that is characteristic of monosaccharide type and linkage and which can be correlated with magnetic resonance spectroscopic data on fine-needle tissue aspirates.
3. Also of relevance is the new understanding of the molecular biology of MUC genes, which code for mucin protein backbones, and of the glycosyltransferase genes, which determine oligosaccharide structure and immunological recognition.
4. For these reasons, we believe that tumour-associated oligosaccharide changes should be revisited in the context of what we now know about structure and expression. This review synopsizes the past data using the detection of carbohydrate tumour-associated antigens by binding of lectins and antibodies, and puts it into the context of NMR fingerprints or signatures.
Iron-Binding Antioxidant Potential of Plasma Albumin
Authors: Loban Amanda , Kime Robert , Powers Hilary 
Published: August 2015

1. The extracellular proteins caeruloplasmin and transferrin have important antioxidant properties by virtue of the fact that they inhibit iron-dependent free radical production, and ensuing damage to cells.
2. Albumin is a plasma protein which can loosely bind iron, but the redox activity of this iron has not been fully investigated.
3. The ability of albumin to bind iron and to prevent iron-dependent lipid peroxidation in vitro was investigated using liposomes and a rat brain homogenate system.
4. The iron-binding capacity of albumin was found to be substantial, and albumin inhibited lipid peroxidation in a concentration-dependent manner in both systems used.
5. This antioxidant property of albumin may be especially important in the plasma of babies born prematurely, in whom transferrin and caeruloplasmin concentrations are often very low, and in whom non-transferrin-bound iron has been detected in the plasma.
Increased Plasma Levels of Adrenomedullin in Patients with Hypertrophic Cardiomyopathy: Its Relation to Endothelin-1, Natriuretic Peptides and Noradrenaline
Authors: Hamada Mareomi , Shigematsu Yuji , Kawakami Hideo , Minamino Naoto , Kangawa Kenji , Matsuo Hisayuki , Hiwada Kunio 
Published: August 2015

1. The aim of this study was to elucidate the pathophysiological role of adrenomedullin and the relation between adrenomedullin and other hormones in patients with hypertrophic cardiomyopathy.
2. Fourteen patients with hypertrophic obstructive cardiomyopathy (HOCM), 26 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) and 14 normal control subjects participated in this study. Radioimmunoassay for plasma adrenomedullin concentration was performed with adrenomedullin-M antibody. Plasma levels of endothelin-1, atrial and brain natriuretic peptides and noradrenaline were also measured.
3. Plasma levels of adrenomedullin were higher in patients with hypertrophic cardiomyopathy (8.43 ± 3.73 pmol/l) than in normal controls (5.24 ± 0.44 pmol/l, P &lt; 0.005). There was no significant difference between HOCM and HNCM patients. There was a weak correlation between plasma levels of adrenomedullin and total 12-lead QRS voltage in patients with hypertrophic cardiomyopathy (r = 0323, P &lt; 0.05)
4. Plasma levels of endothelin-1, atrial and brain natriuretic peptides were higher in hypertrophic cardiomyopathy than in normal controls. Endothelin-1 showed no significant difference between HOCM and HNCM patients, but atrial and brain natriuretic peptides were higher in HOCM than in HNCM patients. There was a positive correlation between plasma levels of adrenomedullin and endothelin-1 (r = 0.575, P &lt; 0.0001), but no correlation between plasma levels of adrenomedullin and atrial natriuretic peptide, brain natriuretic peptide and noradrenaline.
5. Our results indicate that adrenomedullin may play an important role to maintain haemodynamics in patients with hypertrophic cardiomyopathy, and its action may be related to endothelin-1 but independent of atrial natriuretic peptide, brain natriuretic peptide and noradrenaline.
Changes to Mucins in Uninvolved Mucosa and at the Tumour Site in Gastric Adenocarcinoma of Intestinal Type
Authors: Sidebotham R. L. , Dhir N. K. , Elder J. B. , Spencer J. , Walker M. M. , Schrager J. 
Published: August 2015

1. Mucin histochemistry is markedly altered in the stomach in intestinal-type adenocarcinoma. To increase understanding of these changes we have examined the content and distribution of carbohydrate in mucus glycopolypeptides isolated from non-malignant antrum, and from the uninvolved gastric mucosa and tumour site of patients with this disease.
2. The content of carbohydrate declined by 12.6% (P = 0.02) in mucus glycopolypeptides from uninvolved gastric mucosa when compared with those from non-malignant antrum, and by a further 25.4% (P &lt; 0.001) in mucus glycopolypeptides from the tumour site. The first of these changes was accompanied by a significant decrease in the number of carbohydrate chains/1000 amino acid residues, and a significant increase in the number of monosaccharide units in each carbohydrate chain. The second of these changes was accompanied by significant decreases in both the number of carbohydrate chains/1000 amino acid residues, and in the number of monosaccharide units in each carbohydrate chain.
3. The number of sulphated monosaccharide units/100 carbohydrate chains increased from a mean of 7.2 in mucus glycopolypeptides from non-malignant antrum to a mean of 27.2 (P &lt; 0.001) in preparations from uninvolved gastric mucosa and 22.7 (P &lt; 0.001) in preparations from the tumour site.
4. Evidence is presented that these structural changes to mucus glycopolypeptides from the malignant stomach are due to an abnormal mucin biosynthesis by metaplastic goblet cells and/or immature gastric-type mucous cells within the uninvolved mucosa, and immature mucous cells at the tumour site.
An Early Prenatal Exposure to Excess Glucocorticoid Leads to Hypertensive Offspring in Sheep
Authors: Dodic M. , May C. N. , Wintour E. M. , Coghlan J. P. 
Published: August 2015

1. Recent studies in animals have linked fetal exposure to excess maternal glucocorticoids with the later occurrence of cardiovascular disorders, particularly hypertension.
2. To test the hypothesis that prenatal treatment could impact on adult blood pressure two groups of pregnant ewes were transported from the farm to the Institute at either 22–29 days of pregnancy (pretreatment group 1) or 59–66 days of pregnancy (pretreatment group 2), subjected to 48 h treatment with dexamethasone (0.28 mg day−1 kg−1 for 2 days) and then returned to the farm. The control group remained at the farm for the entire pregnancy. Lambs were then studied at approximately 4, 10 and 19 months after birth.
3. The basal mean arterial pressure in pretreatment group 1 (80 ± 1 mmHg at 124 days; 83 ± 1 mmHg at 309 days and 89 ± 1 mmHg at 558 days; n = 6) was significantly different (P &lt; 0.05 in all groups) from that in the control group of lambs (74 ± 2 mmHg at 110 days; 76 ± 1 mmHg at 323 days and 81 ± 1 mmHg at 568 days; n = 7). However, prenatal glucocorticoid exposure did not alter vascular sensitivity to noradrenaline, angiotensin II and adrenocorticotropic hormone in these sheep at any of the ages studied, nor did it affect basal or adrenocorticotropic hormone-induced concentrations of Cortisol or basal plasma renin concentrations in the lambs at any age.
4. These data support the hypothesis that excess glucocorticoid exposure in early pregnancy, during a critical developmental stage or ‘window’, programmes higher blood pressure that persists in later life.
Intravenous Lactate Prevents Cerebral Dysfunction during Hypoglycaemia in Insulin-Dependent Diabetes Mellitus
Authors: King P. , Kong M.-F. , Parkin H. , MacDonald I. A. , Barber C. , Tattersall R. B. 
Published: August 2015

1. Intravenous lactate prevents cerebral dysfunction during hypoglycaemia in healthy volunteers. This study examines whether this also occurs in insulin-dependent diabetes. Changes in four-choice reaction time, auditory brain stem response, and P300 latency were used as measures of cerebral function.
2. Ten subjects were studied twice at least 4 weeks apart. Blood glucose was maintained between 5 and 8 mmol/l for 1 h before starting a 60 m-unit min−1 m−2 stepped hyperinsulinaemic clamp, achieving blood glucose concentrations of 4.5, 33 and 2.5 mmol/l. At one visit, 40 μmol min−1 kg−1 sodium lactate was infused, and at the other, normal saline. Cerebral function was measured at each blood glucose concentration.
3. Blood lactate rose to 3.32 ± 0.06 mmol/l during lactate infusion compared with 0.9 ± 0.03 mmol/l during saline infusion. Compared with the results at 4.5 mmol/l there were no significant changes at 33 mmol/l in any measure of cerebral function at either visit. At 2.5 mmol/l a significant increase in reaction time and P300 latency occurred with saline [mean change 33.1 ± 8.6 ms (P &lt; 0.01) and 30.1 ± 9.2 ms (P &lt; 0.01) respectively] but not lactate [mean change −5.9 ± 3.7 ms (P &gt; 0.05) and −6 ± 7.6 ms (P &gt; 0.05) respectively]. No significant changes occurred in auditory brain stem response. The catecholamine response to hypoglycaemia was attenuated by lactate (P &lt; 0.05 for adrenaline and noradrenaline).
4. Thus intravenous lactate prevents cerebral dysfunction during hypoglycaemia in insulin-dependent diabetes.
Rapid Communication: Epidermal Growth Factor Protects against Carbon Tetrachloride-Induced Hepatic Injury
Authors: Berlanga J. , Caballero M. E. , Ramirez D. , Torres A. , Valenzuela C. , Lodos J. , Playford R. J. 
Published: August 2015

1. Epidermal growth factor (EGF) is known to protect the gastrointestinal tract against various noxious agents. Its potential value in preventing/treating hepatic injury is, however, largely unexplored. We therefore examined whether EGF could influence CCl4-induced hepatic injury.
2. Female Sprague—Dawley rats (8 per group) received saline or recombinant EGF (500 or 750 μg/kg, intraperitoneal) 30 min before CCU (20% v/v, in olive oil, intraperitoneal). Eighteen hours later, animals were killed, serum was collected for assay of biochemical markers of hepatic injury and livers were removed for histological analyses.
3. Administration of CCl4 resulted in severe hepatic necrosis and caused a 10-fold rise in plasma alanine aminotransferase levels compared with levels seen in control animals (218 ± 15 compared with 23 ± 9 μmol/l in controls, mean ± SEM, P &lt; 0.01). Serum malondialdehyde levels, used as a marker of lipid peroxidation, showed a 2-fold rise in response to CCl4 treatment (median 4.0, quartile range 3.3–5.8 units/l compared with median 2.3, quartile range 2.1–2.5 units/l in controls, P &lt; 0.05). Administration of EGF at 500 μg/kg, before the CCl4, did not protect against injury, as assessed by histology or rise in plasma alanine aminotransferase levels. In contrast, animals given EGF at 750 μg/kg, before the CCl4, had only minimal changes in histology, with only a minor rise in alanine aminotransferase levels (37 ± 4 compared with 23 ± 9 μmol/l in animals not given CCl4) and had no significant rise in malondialdehyde levels.
4. EGF protects against CCl4-induced hepatic injury and may provide a novel approach to the treatment of liver damage.
Skin Microcirculation in Patients with Type I Diabetes with and without Neuropathy after Neurovascular Stimulation
Authors: Forst Thomas , Pfützner Andreas , Kunt Thomas , Pohlmann Thomas , Schenk Ulrike , Bauersachs Rupert , Küstner Ernst , Beyer Jürgen 
Published: August 2015

1. Neurovascular inflammation is impaired in patients suffering from diabetic neuropathy. The aim of our study was to evaluate the distribution of nutritive and total skin blood flow in diabetic patients with and without neuropathy after neurovascular stimulation with acetylcholine.
2. Twenty patients with Type I diabetes, 10 with and 10 without neuropathy, and 10 age-matched non-diabetic control subjects, underwent microvascular investigations before and after neurovascular stimulation by intracutaneous application of acetylcholine. The capillary blood cell velocity in the nailfold of the hallux was measured by videophotometric capillaroscopy, and the total skin microcirculation in the same area by laser Doppler flowmetry.
3. The increase in total skin blood flow was significantly impaired in the group of neuropathic diabetic patients compared with the non-neuropathic diabetic patients (17.5 ± 83 versus 51.0 ± 16.2; P &lt; 0.05) and the non-diabetic subjects (17.5 ± 8.3 versus 67.8 ± 19.7; P &lt; 0.01). The increase in capillary blood flow was not significantly impaired in Type 1 diabetes patients with neuropathy.
4. The ratio between capillary blood flow and total skin perfusion decreased significantly in the control group (from 0.82 ± 0.15 to 0.47 ± 0.11; P &lt; 0.005) and in the Type I diabetes patients without neuropathy (from 0.79 ± 0.12 to 0.43 ± 0.12; P &lt; 0.05), whereas the decrease in the neuropathic group was statistically insignificant (from 1.05 ± 0.19 to 0.72 ±0.16).
5. Diminished total skin perfusion in the foot after intracutaneous stimulation with acetylcholine in Type I diabetes patients is associated with diabetic neuropathy, indicating a disturbance in the neurovascular reflex arc. This impaired neurovascular response is caused by a diminished total and sub-papillary blood flow and not by a diminished nutritive capillary flow. There is no evidence of a diminished nutritive capillary blood flow during neurogenic inflammation in Type I diabetes patients suffering from diabetic neuropathy.
Autoimmune and Clinical Characteristics of Type 1 Diabetes in Children with Different Genetic Risk Loads Defined by HLA-DQBI Alleles
Authors: Komulainen J. , Knip M. , Sabbah E. , Vähäsalo P. , Lounamaa R. , Åkerblom H. K. , Reijonen H. , Ilonen J. ,   Childhood Diabetes in Finland Study Group
Published: August 2015

1. The impact of different genetic risk loads defined by HLA-DQBI alleles on the autoimmune and clinical characteristics of 647 children and adolescents with recent-onset Type I diabetes was evaluated in a prospective population-based study. The subjects were divided into four groups based on HLA-DQBI genotypes: DQB1*0302/0201 (high risk), *0302/x (moderate risk), *0201/y (low risk) and *z/z (decreased risk).
2. Close to two thirds (62.3%) of the subjects possessed a high or moderate risk genotype. A decreased frequency of positivity for islet cell antibodies (ICA) and insulin autoantibodies (IAA) (76.8% compared with 85.3%; P = 0.05, and 30.5% compared with 50.8%, P = 0.0006, respectively) but not of positivity for antibodies to the 65 kDa isoform of glutamate decarboxylase was observed in children with the DQB1*0201/y genotype compared with other children. Among ICA-negative subjects, those with the DQB1*0201/y genotype had higher serum C-peptide levels over the first 2 years after the diagnosis of Type I diabetes than those with other genotypes (P = 0.028).
3. Our data provide some evidence of HLA-DQB1-determined heterogeneity in the autoimmune and clinical characteristics of childhood Type I diabetes at the time of the clinical manifestation. This suggests differences between children with various HLA-DQBI genotypes in the pace and/or intensity of the beta-cell destructive process leading to clinical Type I diabetes.
Distribution of Glutaminase and Glutamine Synthetase Activities in the Human Gastrointestinal Tract
Authors: James L. A. , Lunn P. G. , Middleton S. , Elia M. 
Published: August 2015

1. The activities of the two key enzymes involved in glutamine metabolism, glutaminase and glutamine synthetase, were measured in mucosal biopsies taken from different sites throughout the human gastrointestinal tract, from oesophagus to rectum.
2. The specific activity of glutamine synthetase was highest in the stomach (4.5 nmol glutamine formed per minute per mg of protein), but both small and large intestine and the oesophagus had little synthesizing capacity (less than 0.3 nmol of glutamine formed per minute per mg of protein).
3. Glutaminase specific activity was highest in the small intestine (53 nmol glutamate formed per minute per mg of protein by duodenal mucosa), intermediate in the large intestine and lowest in the oesophagus and stomach (less than 13 nmol of glutamate formed per minute per mg of protein).
4. The glutamine concentration in the mucosa was lower in the duodenum than in the colon (0.62 and 0.95 mmol/kg wet weight respectively), but both were much lower than the measured Km values of glutaminases obtained from these sites (3.8 and 4.0 mmol/kg wet weight respectively).
5. The concentration of glutamine in saliva, stomach juice, bile and duodenal juice suggests that very little glutamine passes into the gastrointestinal tract via these secretions.
6. The study provides the most complete information on the distribution of glutamine synthetase and glutaminase along the human gastrointestinal tract, and suggests that (i) both the small and large intestines have a high potential for glutamine metabolism, but little synthesizing capacity, thus both must derive their glutamine from other sources, and (ii) neither the stomach nor the oesophagus have a high glutaminase activity, although the stomach has substantial capacity to synthesize glutamine. The distribution of the enzymes along the gastrointestinal tract may help rationalize the use of glutamine for treating diseases that affect different parts of the gastrointestinal tract.
Chronic Administration of Octreotide Ameliorates Portal Hypertension and Portal Hypertensive Gastropathy in Rats with Cirrhosis
Authors: Chan Che-Chang , Lee Fa-Yauh , Wang Sun-Sang , Chang Full-Young , Lin Han-Chieh , Lin Hwai-Jeng , Chu Chi-Jen , Wu Shwu-Ling , Tai Chun-Ching , Lee Shou-Dong 
Published: August 2015

1. Portal hypertension and hyperdynamic circulation have been postulated to play a role in the pathogenesis of portal hypertensive gastropathy. Administration of octreotide to portal hypertensive rats has been shown to reduce portal pressure and ameliorate hyperdynamic circulation.
2. This study investigated the effects of chronic administration of octreotide on systemic and portal haemodynamics and the development of portal hypertensive gastropathy in carbon tetrachloride-induced cirrhotic rats.
3. After 12 weeks of carbon tetrachloride induction, cirrhotic rats were randomly assigned to receive either placebo (5% dextrose in water) or octreotide (65 μg/kg in 5% dextrose in water) subcutaneously twice daily for 10 days. Haemodynamic studies with a thermodilution technique and gastric morphometric analyses were performed at 10 days after treatment.
4. In cirrhotic rats, octreotide treatment induced a significant increase in systemic vascular resistance (2.7 ± 0.2 versus 3.4 ± 0.2 mmHg/ml · min−1 · 100 g−1, P &lt; 0.05) and decrease in portal pressure (12.5 ± 1.2 versus 9.9 · 0.5 mmHg, P &lt; 0.05) compared with placebo-treated rats. In addition, octreotide treatment significantly reduced the mean cross-sectional area of gastric mucosal vessels (2290 ± 145 versus 1810 ± 101 μm2, P &lt; 0.05).
5. This study shows that chronic octreotide treatment ameliorates the development of portal hypertensive gastropathy in cirrhotic rats. The effect of octreotide on portal hypertensive gastropathy may, at least partly, be due to the alleviation of portal hypertension and hyperdynamic circulation.
Vascular Endothelial Growth Factor (VEGF) is Released from Platelets during Blood Clotting: Implications for Measurement of Circulating VEGF Levels in Clinical Disease
Authors: Webb Nicholas J. A. , Bottomley Martyn J. , Watson Carolyn J. , Brenchley Paul E. C. 
Published: August 2015

1. Dysregulated vascular endothelial growth factor (VEGF) expression has been reported in several pathological states based upon evidence of elevated serum VEGF levels. Using two immunoassays for VEGF, this study determines normal plasma and serum VEGF ranges, determines which are more likely to reflect circulating VEGF levels and investigates a potential contribution of VEGF from platelets to VEGF levels detected in serum.
2. The presence of soluble VEGF receptor, sflt-1, at a molar excess of 7:1 significantly reduced measured VEGF levels in both assays. Serum VEGF levels were higher than plasma levels in children [(mean ± S.E.M.) 306.1 ± 39.4 versus 107.4 ± 24.9 pg/ml, P &lt; 0.0001] and adults (249.4 ± 46.4 versus 76.1 ± 10.7 pg/ml, P &lt; 0.0001). Serum VEGF increased with clotting time (P = 0.0005 t0 compared with 2 h samples); plasma VEGF levels were not affected by time between sampling and centrifugation.
3. Calcium-induced clotting of platelet-rich but not platelet-poor plasma induced VEGF release with a proportional response between platelet count and VEGF level and isolated platelets released significant quantities of VEGF upon incubation with thrombin. Reverse transcriptase—PCR studies confirmed that platelets express VEGF121 and VEGF165 mRNA.
4. These data suggest that plasma is the preferred medium to measure VEGF levels; a significant and highly variable platelet-mediated secretion of VEGF during the clotting process invalidates the use of serum as an indicator of circulating VEGF levels in disease states.