bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Limb Immobilization on Cytochrome C Oxidase Activity and GLUT4 and GLUT5 Protein Expression in Human Skeletal Muscle
Authors: Blakemore Stephen J. , Rickhuss Peter K. , Watt Peter W. , Rennie Michael J. , Hundal Harinder S.
Published: August 2015

1. We investigated the effects of limb immobilization (for 1 or 6 weeks) in a long leg cast after a closed tibial fracture (n = 11). Biopsies of vastus lateralis were taken on admission and after either 1 week (n = 5) or 6 weeks (n = 6) and analysed for muscle fibre type characteristics, cytochrome c oxidase activity and the abundance of GLUT4 and GLUT5 hexose transporters.

2. After 1 week of immobilization there was a significant decrease (8%) in the cross-sectional area of type I, but not type II, muscle fibres and in the protein—DNA ratio (16%) compared with the initial biopsy. Six weeks of immobilization led to further muscle atrophy compared with the initial biopsy and a further reduction in the cross-sectional area of both type I and II fibres (29% and 36% decrease respectively) and in the protein—DNA ratio (25%). No changes were observed in the free leg after 1 week. However, at the end of the 6 week study period, the cross-sectional area of both type I and II fibres of the free leg were increased (7% and 5%) and there was significant increase in the protein—DNA ratio (14%), indicating a net increase in muscle protein content.

3. Assay for cytochrome c oxidase activity showed significant reduction after 1 (30%) or 6 weeks (36%) of immobilization, reflecting a reduced capacity for oxidative metabolism. No significant changes in activity were observed in muscle from the free leg after 1 or 6 weeks of study.

4. The concentrations of GLUT4 and GLUT5 protein were determined by Western blot analysis. Limb immobilization induced a marked (50%) reduction in muscle GLUT4 protein concentration after 1 week that persisted for 6 weeks. A transient but significant increase (approximately twofold) in GLUT4 concentration was detected in muscle from the free leg after 1 week, but this returned to preimmobilization values at 6 weeks. Unlike GLUT4, no significant changes in the abundance of the GLUT5 protein were detected in either the immobilized or free leg at the end of the 1 or 6 week periods.

5. The present findings indicate that disuse rapidly induces a selective loss of activity and abundance of some non-myofibrillar proteins in humans. The decrease in GLUT4 protein abundance and cytochrome c oxidase activity during muscle disuse is consistent with a decreased capacity for glucose uptake and with a lower oxidative potential of inactive muscle. The lack of any major changes in GLUT5 protein abundance during limb immobilization indicates that the expression of some non-myofibrillar proteins is differentially regulated in response to muscle disuse.
Chronic Administration of Octreotide Increases Vascular Responsiveness in Rats with Portal Hypertension
Authors: Huang Yi-Tsau , Tsai Ju-Fen , Liu Tsun-Bin , Hong Chuang-Ye , Yang May C.-M. , Lin Han-Chieh
Published: August 2015

1. It has been reported that octreotide partially corrects the hyperdynamic state in patients and animals with portal hypertension. The aim of the present study was to investigate whether chronic administration of octreotide can increase vascular responsiveness in rats with portal hypertension.

2. Portal hypertension was induced by partial portal vein ligation. Octreotide was given for 9 days subcutaneously (100 μg/kg every 12 h) starting 1 day before ligation. The aorta and mesenteric artery were then removed to study contraction after pressure recording.

3. Octreotide treatment significantly reduced portal pressure and plasma glucagon concentrations compared with the vehicle-treated group. Both phenylephrine and vasopressin induced concentration-dependent contractile responses in the aorta and mesenteric artery from both groups. The maximum contractile responses to phenylephrine and vasopressin in aorta and mesenteric artery were significantly greater in the octreotide-treated group than in the vehicle-treated group. The EC50 values for phenylephrine and vasopressin were significantly different in the aorta, but not in the mesenteric artery, between the two groups. In contrast, octreotide treatment did not alter the contractile responsiveness of arteries from sham-operated rats.

4. These results show that, in rats with portal vein stenosis, octreotide increases arterial contractile responsiveness and reduces portal pressure.
No Relation between Angiotensin-Converting Enzyme Gene Polymorphism and Dermal Responses to Bradykinin in Healthy Subjects
Authors: Chadwick I. G. , Kraskiewicz M. , Yeo W. W. , Higgins K. S. , Jackson P. R. , Ramsay L. E.
Published: August 2015

1. The dermal wheal response to bradykinin is increased by drugs which inhibit angiotensin-converting enzyme, and thus provides a measure of angiotensin-converting enzyme activity at the tissue level. An insertion/deletion polymorphism of the angiotensin-converting enzyme gene predicts serum angiotensin-converting enzyme activity, but its relation to angiotensin-converting enzyme activity in tissue is unclear.

2. The relations between angiotensin-converting enzyme genotype and wheal responses to intradermal bradykinin were studied in 105 healthy subjects: 30 of genotype DD, 51 of genotype ID and 24 of genotype II. Dermal wheal area was measured by digitized planimetry and the angiotensin-converting enzyme genotype by polymerase chain reaction.

3. Bradykinin produced significant linear log dose—wheal area responses. The potency of bradykinin by parallel line bioassay did not differ significantly between the genotypes; the potency in the II subjects relative to DD subjects was 1.25 (95% confidence interval: 0.83–1.88).

4. Although the angiotensin-converting enzyme gene polymorphism is a consistent and powerful predictor of serum angiotensin-converting enzyme activity, it does not appear to predict tissue angiotensin-converting enzyme activity as measured by dermal responses to bradykinin.
Integrins and Disease
Authors: Hillis Graham S. , MacLeod Alison M.
Published: August 2015

1. Adhesion is a vital property of cells. It provides a stable environment for cell growth and differentiation and allows cells to migrate.

2. The interaction between cells and their extracellular matrices is also an important factor in the regulation of further protein deposition. Likewise, matrix proteins can influence cellular function thus creating a complex feedback mechanism.

3. The adherence of cells to each other, their extracellular matrices and endothelial surfaces is mediated by a variety of membrane proteins collectively known as adhesion molecules.

4. Adhesion molecules can be further divided into four subfamilies: the integrins, the selectins, the cadherins and the immunoglobulin superfamily. This article will review our current knowledge of the integrin family of adhesion receptors, focusing principally on their role in the pathogenesis of human disease.
Is there a Therapeutic Future for ‘Potassium Channel Openers’?
Authors: Lawson Kim
Published: August 2015

1. Potassium channels, which control cell electrical activity, are among the most regulated of all ion channels in biology. Promotion of activity in K+ channels by a wide range of physiological factors tends to stabilize cell function.

2. The discovery of synthetic molecules (e.g. cromakalim) that ‘directly’ open ATP-sensitive K+ channels has led to a new direction in pharmacology. ATP-sensitive K+ channel-opening properties have subsequently been demonstrated in a diverse range of chemical structures (synthetic and endogenous).

3. The existence of so many different subtypes of K+ channels has been an impetus in the search of new potassium channel openers with different channel selectivities and thus biological profiles.

4. The decrease in cell excitability following K+ channel opening implies a broad clinical potential in a number of pathological conditions for K+ channel openers. Preclinical and clinical evidence supports therapeutic roles of K+ channel openers in disorders of a wide range of biological cells.

5. Although lack of selectivity of current compounds remains a major hurdle, advances in K+ channel openers and K+ channel pharmacology are encouraging. Differences already observed in the pharmacology of K+ channel openers are important factors for the development of second-generation compounds, when tissue selectivity is sought.

6. The availability of subtype-selective K+ channel openers will facilitate detailed study, through a combined effort of electrophysiology, functional pharmacology and molecular biology, leading to focused therapeutic approaches for defined pathological conditions.
Increased Oxidative and Delayed Glycogenolytic ATP Synthesis in Exercising Skeletal Muscle of Obese (Insulin-Resistant) Zucker Rats
Authors: Sanderson A. L. , Kemp G. J. , Thompson C. H. , Radda G. K.
Published: August 2015

1. To examine metabolic correlates of insulin resistance in skeletal muscle, we used 31P magnetic resonance spectroscopy to study glycogenolytic and oxidative ATP synthesis in leg muscle of lean and obese Zucker rats in vivo during 6 min sciatic nerve stimulation at 2 Hz.

2. The water content of resting muscle was reduced by 21 ± 7% in obese (insulin-resistant) animals compared with lean animals, whereas the lipid content was increased by 140 ± 70%. These results suggest that intracellular water content was reduced by 17% in obese animals.

3. During exercise, although twitch tensions were not significantly different in the two groups, rates of total ATP synthesis (expressed per litre of intracellular water) were 48 ± 20% higher in obese animals, suggesting a 50 ± 8% reduction in intrinsic ‘metabolic efficiency’. Changes in phosphocreatine and ADP concentration were significantly greater in obese animals than in lean animals, whereas changes in intracellular pH did not differ.

4. These results imply that oxidative ATP synthesis during exercise is activated earlier in obese animals than in lean animals. This difference was not fully accounted for by the greater increase in the concentration of the mitochondrial activating signal ADP. Neither the post-exercise recovery kinetics of phosphocreatine nor the muscle content of the mitochondrial marker enzyme citrate synthase was significantly different in the two groups. The increased oxidative ATP synthesis in exercise must therefore be due to altered kinetics of mitochondrial activation by signals other than ADP.

5. Thus, the insulin-resistant muscle of obese animals may compensate for its decreased efficiency (and consequent increased need for ATP) by increased reliance on oxidative ATP synthesis.
Four-Component Model of Body Composition in Chronic Renal Failure Comprising Dual-Energy X-ray Absorptiometry and Measurement of Total Body Water by Deuterium Oxide Dilution
Authors: Woodrow Graham , Oldroyd Brian , Turney John H. , Davies Peter S. W. , Day Janice M. E. , Smith Michael A.
Published: August 2015

1. Assessment of nutrition in patients with chronic renal failure by body composition measurement techniques may be affected by variable hydration.

2. This study aimed to derive a four-component model of body composition (consisting of fat, protein, total body water and body mineral) from a combination of dual-energy X-ray absorptiometry and total body water measured by deuterium oxide dilution, allowing assessment of body protein stores without the effect of variation in hydration. Patients with chronic renal failure on haemodialysis, peritoneal dialysis and conservative treatment and a control group were studied. Patients with chronic renal failure were at an ‘ideal’ state of hydration on clinical assessment.

3. Hydration was defined by total body water as a percentage of fat-free mass measured by dual-energy X-ray absorptiometry, and no differences were found between chronic renal failure subgroups and control subjects (except in the female undialysed chronic renal failure subgroup). Hydration was significantly correlated with percentage total body fat in the control groups but not in patients with chronic renal failure.

4. Lean tissue measured by dual-energy X-ray absorptiometry was significantly reduced in three of the six chronic renal failure groups compared with control subjects (male and female patients on haemodialysis and female patients on peritoneal dialysis). Protein estimated from the four-component model failed to detect these abnormalities.

5. Lean tissue measured by dual-energy X-ray absorptiometry in normal subjects strongly correlated with fat-free mass measured by total body potassium in normal subjects (male r = 0.91; female r = 0.89, both P < 0.0001). The correlation of protein estimated from the four-component model with fat-free mass measured by total body potassium was far weaker in male control subjects (r = 0.51, P < 0.05) and not significant in female control subjects (r = 0.38, P not significant). In the normal subjects protein estimated from the four-component model showed a much greater variation from protein estimated by total body potassium than did protein estimated simply as 27% of dual-energy X-ray absorptiometry fat-free mass minus total body mineral.

6. Hydration in patients with chronic renal failure in whom fluid balance is believed to be normal on clinical criteria does not differ from that in normal subjects. The combined model of dual-energy X-ray absorptiometry and total body water is not a useful method for the measurement of body protein.
Studies on the Interaction of T-Cells with Major Histocompatibility Complex Class II Antigens
Authors: Warrens Anthony N.
Published: August 2015

1. Major histocompatibility complex class II antigens have the central role in the immune response of ‘presenting’ antigenic peptide to CD4+ T-cells. This interaction with a T-cell's receptor may result in activation, but, if recognition occurs without collateral molecular interactions which cause ‘co-stimulation’, these T-cells will be tolerized.

2. In the light of current interest in muscle cell transplantation, a transformed myoblast, TE671, phenotypically comparable to untransformed cells, transfected to express class II, was studied as a stable model of antigen presentation by muscle cells. These cells failed to activate T-cells but induced tolerance.

3. The DRα chain is unusual being the only non-polymorphic classical class II polypeptide, raising the question of its functional contribution. To this end, several single polypeptide constructs were generated with contributions from different class II α-chains. On this basis, it was established that DRα makes significant contributions to peptide binding and that its α2 domain is also important in T-cell recognition, possibly through CD4 binding.

4. One implication of the lack of polymorphism of DRα may be that it has a wider range of pairing partners, possibly including β chains of different isotypes. To address this, it is planned to use transfectants expressing only a mixed isotype pair to generate T-cell clones in vitro. These reagents would be useful tools to detect whether such mixed pairs exist physiologically. In this paper, the development of a system is described which will allow this question to be addressed.
Urinary Albumin Excretion and Atherosclerosis in Essential Hypertension
Authors: Pedrinelli Roberto , Undpaintner Klaus , Dell'omo Giulia , Napoli Vinicio , Di Bello Vitantonio , De Caterina Raffaele , Petrucci Roberto
Published: August 2015

1. Increased urinary albumin excretion is common in patients with essential hypertension and is at least to some extent correlated with prevailing blood pressure levels. However, the generalized vascular dysfunction present in advanced atherosclerotic disease may independently influence this parameter.

2. To evaluate this possibility, we assessed blood pressure, ultrasonographic carotid thickness, cardiac mass, minimum forearm vascular resistances, metabolic parameters and the angiotensin-converting enzyme genotype in patients with untreated essential hypertension and atherosclerotic peripheral vascular disease (n = 11). The results were compared with similar data obtained in matched groups of patients with uncomplicated hypertension and with normotensive control subjects (n = 11 per group).

3. Urinary albumin excretion was higher in hypertensive patients with atherosclerosis than in those without complications; carotid thickness was higher in atherosclerotic patients and a positive, statistically significant correlation existed between this parameter and urinary albumin excretion. In the same patient group, systolic blood pressure, fasting insulin and triacylglycerol levels were elevated and correlated with urinary albumin levels. However, differences in urinary albumin excretion persisted after taking into account the influence of those parameters by analysis of covariance. The distribution of angiotensin-converting enzyme genotype patterns and values of cardiac mass and minimum forearm vascular resistances did not differ significantly among the experimental groups.

4. The data suggest that vascular status may influence urinary albumin excretion in patients with essential hypertension, while confirming the importance of systolic blood pressure levels as a determinant of the raised urinary albumin excretion.
Pathogenesis of Liver Fibrosis
Authors: Alcolado R. , Arthur M. J. P. , Iredale J. P.
Published: August 2015

1. Liver fibrosis is a common sequel to diverse liver injuries. It is characterized by an accumulation of interstitial collagens and other matrix components. The hepatic stellate cell is pivotal to the pathogenic process. Fibrotic liver injury results in activation of the hepatic stellate cell which undergoes a phenotypic change to a proliferative myofibroblast-like cell which synthesizes excess interstitial collagens and other matrix components.

2. The process of initiation of activation and its perpetuation result from complex, often interrelated series of signalling mechanisms which converge on this effector cell. Such mechanisms include alterations in matrix resulting in changed cell—matrix interactions and stimulation by cytokines released from damaged hepatocytes, infiltrating inflammatory cells, Kupffer cells and matrix. Foremost among the profibrotic cytokines is transforming growth factor β1.

3. Once the hepatic stellate cell is activated the preceding matrix changes and recurrent injurious stimuli will perpetuate the activated state.

4. Despite the accumulation of excess collagens, the liver retains a capacity for matrix degradation. This capacity may be overwhelmed and any secreted matrix remodelling enzymes may be inhibited by the concurrently secreted tissue inhibitors of metallo-proteinase-1 and α2-macroglobulin.

5. Our understanding of the molecular pathogenesis of liver fibrosis is increasing. It is anticipated that this knowledge will provide novel therapeutic avenues to treat this disease process.
Postural Vasoconstriction and Leg Ulceration in Homozygous Sickle Cell Disease
Authors: Mohan J. S. , Marshall J. M. , Reid H. L. , Thomas P. W. , Serjeant G. R.
Published: August 2015

1. Chronic leg ulceration is a major cause of morbidity in patients with homozygous sickle cell disease; the ulcers commonly resolve on bed rest. We have therefore compared the cutaneous vascular response to dependency in three groups of eight patients with sickle cell disease (those with an active ulcer, with an ulcer scar and with no history of ulceration) and in eight subjects with normal haemoglobin and no history of leg ulceration.

2. We monitored, with a laser Doppler flowmeter, the change in red cell (erythrocyte) flux induced in the skin of the leg, at two sites proximal to the malleoli, with the leg horizontal and 5 and 10 min after moving the leg to the dependent position.

3. With the leg horizontal, mean cutaneous red cell flux was substantially higher in normal skin of patients with sickle cell disease than in normal subjects and was higher still at the site of the ulcer or scar. On dependency, red cell flux fell not only in normal subjects but also in the patients with sickle cell disease, both in the normal skin and at the site of the ulcer or scar; there was no difference in any group between the 5- and 10-min values. The fall in red cell flux in normal skin of patients with sickle cell disease was smaller than in normal subjects when considered as a percentage of the control values (32%, 36%, 30% and 61% respectively in sickle cell patients with an active ulcer, with an ulcer scar and with no history of ulceration and in normal subjects), but in absolute terms the falls in red cell flux were similar in sickle cell patients and normal subjects. By contrast, the fall in red cell flux at the ulcer or scar site was greater than in normal skin from sickle cell patients whether considered as a percentage of the control value (48% and 49% respectively in those with an active ulcer or ulcer scar) or in absolute terms.

4. We propose that high resting perfusion is important in patients with sickle cell disease to maintain normal integrity of cutaneous tissue and that pronounced vasoconstriction on dependency hinders the healing and encourages recurrence of leg ulcers.
Modulation of Neurocardiac Function by Oesophageal Stimulation in Humans
Authors: Tougas Gervais , Kamath Markad , Watteel Geena , Fitzpatrick Debbie , Fallen Ernest L. , Hunt Richard H. , Upton Adrian R. M.
Published: August 2015

1. The heart and the oesophagus have similar sensory pathways, and sensations originating from the oesophagus are often difficult to differentiate from those of cardiac origin. We hypothesized that oesophageal sensory stimuli could alter neurocardiac function through autonomic reflexes elicited by these oesophageal stimuli. In the present study, we examined the neurocardiac response to oesophageal stimulation and the effects of electrical and mechanical oesophageal stimulation on the power spectrum of beat-to-beat heart rate variability in male volunteers.

2. In 14 healthy volunteers, beat-to-beat heart rate variability was compared at rest and during oesophageal stimulation, using either electrical (200 μs, 16 mA, 0.2 Hz) or mechanical (0.5 s, 14 ml, 0.2 Hz) stimuli. The power spectrum of beat-to-beat heart rate variability was obtained and its low- and high-frequency components were determined.

3. Distal oesophageal stimulation decreased heart rate slightly (both electrical and mechanical) (P < 0.005), and markedly altered heart rate variability (P < 0.001). Both electrical and mechanical oesophageal stimulation increased the absolute and normalized area of the high-frequency band within the power spectrum (P < 0.001), while simultaneously decreasing the low-frequency power (P < 0.005).

4. In humans, oesophageal stimulation, whether electrical or mechanical, appears to amplify respiratory-driven cardiac vagoafferent modulation while decreasing sympathetic modulation. The technique provides access to vagoafferent fibres and thus may yield useful information on the autonomic effects of visceral or oesophageal sensory stimulation.
Contraction Failure of Skeletal Muscle of Rats Recovering from Critical Illness
Authors: Rooyackers Olav E. , Hesselink Matthijs K. C. , Wagenmakers Anton J. M.
Published: August 2015

1. Most patients recovering from critical illness experience enhanced fatiguability. Previously we have shown that zymosan-induced critical illness in rats is attended by a decreased mitochondrial content (maximal aerobic capacity) in skeletal muscle. We investigated whether this decrease results in an increased reduction in high-energy phosphates and a subsequent loss of contractility during in situ electrical stimulation in rats recovering from zymosan treatment.

2. Plantar-flexor muscles of the hindlimb were electrically stimulated via the innervating nerve to develop maximal isometric tetanic contraction.

3. Decreased concentrations of ATP were measured in gastrocnemius muscle of zymosan-treated rats, both at rest and after stimulation, in comparison with ad libitum-fed and pair-fed control rats. However, no differences in the stimulation-induced decreases in high-energy phosphate levels and changes in other metabolites, except ADP, were observed between the groups. Tension development in the zymosan-treated rats was, however, about 85% less compared with the pair-fed controls during the whole stimulation period.

4. We conclude that the primary cause of the loss of muscle tension in zymosan-treated rats is an insensitivity of skeletal muscle to stimulation via the nerve. An additional derangement in ATP production is, however, indicated by the comparable decreases in energy substrates during development of a dramatically lower tension.
Mitochondrial DNA Defects: A Widening Clinical Spectrum of Disorders
Authors: Sherratt Emma J. , Thomas Andrew W. , Alcolado John C.
Published: August 2015

1. Mitochondrial DNA has a number of interesting properties including maternal transmission, the ability to replicate in post-mitotic cells, a high mutation rate and an extremely compact molecular architecture with no introns and no large non-coding sequences.

2. Point mutations, deletions and duplications of mitochondrial DNA may occur. Mitochondrial DNA defects may co-exist with wild-type sequence within a cell (heteroplasmy). The level of heteroplasmy may vary in different tissues within the same individual (segregative replication).

3. A number of neurological disorders are characterized by morphological and biochemical mitochondrial defects. It is now clear that mitochondrial DNA mutations underlie these conditions although there is not always a clear correlation between a particular mutation and clinical presentation.

4. Mitochondrial DNA defects, particularly deletions, accumulate in senescent tissue and studies have been performed with the aim of linking such somatic mutations with degenerative disorders.

5. Recently mitochondrial DNA mutations have been implicated in a wider range of clinical disorders including diabetes and nerve deafness.

6. Nuclear gene defects may result in mitochondrial disorders by predisposing to multiple mitochondrial DNA deletions or quantitative depletions of mitochondrial DNA content.
Sodium—Lithium Countertransport, Sodium—Hydrogen Exchange and Membrane Microviscosity in Patients with Hyperlipidaemia
Authors: MacLeod M. J. , Lee W. K. , Devlin A. M. , Caslake M. , Anderson N. H. , Packard C. J. , Dominiczak M. H. , Reid J. L. , Dominiczak A. F.
Published: August 2015

1. We measured sodium-lithium countertransport, sodium-hydrogen exchange and membrane microviscosity in 48 individuals with familial hypercholesterolaemia, 33 subjects with hypertriglyceridaemia and 54 normolipaemic controls. Full lipid profile, blood pressure, body mass index, fasting glucose and insulin levels were also measured.

2. Subjects with hypertriglyceridaemia had higher blood pressure, body mass index, fasting glucose and insulin levels than normal controls.

3. Vmax of the sodium-lithium countertransport was elevated in the hypertriglyceridaemic group compared with controls. Across the whole group loge triacylglycerols correlated with Vmax of the sodium-lithium countertransport. There was no difference in sodium-lithium countertransport Km between the groups.

4. Sodium-hydrogen maximal proton efflux rate (Vmax) and Km were not different between the three groups. There were no correlations between sodium—hydrogen exchange and sodium—lithium countertransport parameters.

5. Microviscosity as measured by diphenylhexatriene was reduced at the core of the membrane in subjects with hypertriglyceridaemia compared with those with familial hypercholesterolaemia or normolipaemic controls, suggesting an alteration in membrane structure.

6. Changes in sodium transport in hyperlipidaemia may be mediated by changes in membrane structure resulting in altered protein conformation or turnover.
Na+,K+-ATPase Expression in Maleic-Acid-Induced Fanconi Syndrome in Rats
Authors: Castaño Esther , Marzabal PAU , Casado F. Javier , Felipe Antonio , Pastor-Anglada Marçal
Published: August 2015

1. Na+,K+-ATPase activity and its α1 subunit protein and mRNA in kidney cortex were monitored in rats developing Fanconi syndrome after the administration of maleate. Na+,K+-ATPase activity was significantly lower than in saline-injected controls, although this was partially mediated by a general, non-specific decrease in the cortex protein content.

2. The low activity of the sodium pump correlated with low abundance of α1 subunit mRNA and protein levels. Hsp60 protein levels were also decreased in kidney cortex from maleate-treated rats.

3. Kidney cortex brush-border membrane vesicles from maleate-treated rats showed a marked decrease in Na+-dependent alanine and glucose transport, which was not dependent on the Na+-transmembrane gradient itself, a finding which is consistent with a more stable effect at the plasma membrane level.

4. The effect of maleate may be partially nonspecific and involve a great variety of proteins, but seems to be restricted to selected tissues because α1 subunit Na+,K+-ATPase and hsp60 protein amounts were not significantly modified in livers from rats developing Fanconi syndrome.

5. These results show that maleate administration induces a low activity of selected concentrative transport systems and a decrease in Na+,K+-ATPase activity and expression. The combination of both effects may explain the increased excretion of most organic solutes present in rats developing Fanconi syndrome.
Low-Dose Brain Natriuretic Peptide Infusion in Normal Men and the Influence of Endopeptidase Inhibition
Authors: Florkowski C. M. , Richards A. M. , Espiner E. A. , Yandle T. G. , Sybertz E. , Frampton C. M.
Published: August 2015

1. To assess the threshold dose for bioactivity of brain natriuretic peptide and the role of endopeptidase 24.11 in metabolism of brain natriuretic peptide at physiological plasma levels, we studied eight normal men receiving 2 h infusions of low-dose brain natriuretic peptide [0.25 and 0.5 pmol min−1 kg−1 with and without pretreatment with an endopeptidase inhibitor (SCH 32615, 250 mg intravenously)] in placebo-controlled studies.

2. Plasma brain natriuretic peptide increased 2-fold during the infusion of 0.25 pmol min−1 kg−1 (mean increment above control 3.9 pmol/l, P < 0.001), and tripled (P < 0.001) with 0.5 pmol min−1 kg−1. Plasma renin activity was inhibited by both doses (14.8%, P < 0.01, and 20%, P < 0.001, respectively). A significant natriuresis (56% increase in urine sodium/creatinine ratio, P < 0.02) occurred with the higher dose. Blood pressure, haematocrit, plasma cGMP, atrial natriuretic peptide and aldosterone were unaffected by either dose.

3. Compared with brain natriuretic peptide (0.5 pmol min−1 kg−1) alone, SCH 32615 pretreatment increased peak plasma brain natriuretic peptide (13.4±0.78 versus 12.4±0.86 pmol/l, P < 0.05), ANP (7.5±0.96 versus 5.9±0.4 pmol/l, P < 0.01) and cGMP (4.8 ± 1.7 versus 3.9 ± 1.4 nmol/l, P < 0.001). Plasma renin activity was further suppressed with SCH 32615 pretreatment (29% compared with 20%, P < 0.001).

4. Small acute increments in plasma brain natriuretic peptide (4 pmol/l) have significant biological effects in normal men without altering plasma atrial natriuretic peptide or cGMP.
Differential Excretion of Leucocyte Granule Components in Inflammatory Bowel Disease: Implications for Pathogenesis
Authors: Dwarakanath A. D. , Finnie I. A. , Beesley C. M. , O'Dowd G. M. , Nash J. , Tsai H. H. , Parker N. , Rhodes Jonathan M.
Published: August 2015

1. Faecal excretion of the leucocyte primary granule component, myeloperoxidase, and of the secondary granule component, lactoferrín, were compared in inflammatory bowel disease and infective diarrhoea.

2. Faecal lactoferrín correlated with faecal myeloperoxidase in both inflammatory bowel disease (P = 0.0018; n = 32) and infective diarrhoea (P = 0.00013; n = 37), but inflammatory bowel disease was associated with a much higher faecal excretion of lactoferrín but lower excretion of myeloperoxidase than infective diarrhoea. As a consequence, the median ratio of lactoferrin/myeloperoxidase excretion (both expressed as ng/mg of protein) for inflammatory bowel disease was 7.5 (range 3.5–21.3) with similar values for ulcerative colitis (n = 18) and Crohn's disease (n = 14) compared with only 0.9 (range 0.4–2.3; P < 0.0001) for infective diarrhoea. In inflammatory bowel disease faecal lactoferrín and myeloperoxidase excretion remained increased even in clinical remission.

3. In subsequent immunohistochemical studies to assess the possible explanation for these findings, lactoferrín and myeloperoxidase were demonstrated within crypt abscesses and surface mucus, both in inflammatory bowel and in infective diarrhoea mucosal samples. There was a slight increase in the number of lactoferrin-containing cells in the mucosal samples from ulcerative colitis and in the submucosa of samples from Crohn's disease compared with infective diarrhoea, but these changes were not sufficient to account for the marked increase in faecal lactoferrín excretion in inflammatory bowel disease.

4. In all mucosal samples, including those from normal mucosa, lactoferrín was also shown to be contained within mast cells.

5. These results could best be explained by a different mechanism for leucocyte activation in inflammatory bowel disease compared with infective diarrhoea, and are compatible with selective secretion of secondary granule components, which include lactoferrín but not myeloperoxidase, as a result of leucocyte activation by N-formylated bacterial peptides in inflammatory bowel disease.
Serum Levels of Vascular Endothelial Growth Factor in Patients with Acute Myocardial Infarction Undergoing Reperfusion Therapy
Authors: Seko Yoshinori , Imai Yasushi , Suzuki Shin , Kamijukkoku Shuichi , Hayasaki Kazuya , Sakomura Yasuinari , Tobe Kazuyuki , Kadowaki Takashi , Maekawa Hiromitsu , Takahashi Naoyuki , Yazaki Yoshio
Published: August 2015

1. Vascular endothelial growth factor, a potent angiogenic mitogen, is known to be induced in response to ischaemia as well as being secreted from tumour cells. However, the precise mechanism of vascular endothelial growth factor release in acute myocardial infarction and the effects of coronary reperfusion on the circulating levels of vascular endothelial growth factor are still unknown.

2. Nineteen patients with acute myocardial infarction who underwent early reperfusion therapy were studied. Serum levels of vascular endothelial growth factor before reperfusion were markedly increased as compared with those in 19 healthy control subjects [252.4 ± 158.1 pg/ml (mean ± SD) compared with undetectable]. After reperfusion, the serum vascular endothelial growth factor levels rapidly returned almost completely to the normal control range.

4. These data strongly suggest that the serum level of vascular endothelial growth factor is one of the most sensitive indicators of myocardial ischaemia.
Renal Afferents Responsive to Chemical and Mechanical Pelvic Stimuli in the Rabbit
Authors: Genovesi Simonetta , Pieruzzi Federico , Camisasca Paola , Golin Raffaello , Zanchetti Alberto , Stella Andrea
Published: August 2015

1. Afferent nerve fibres sensitive to changes in the renal chemical environment have been found in the rat. To verify the existence of these fibres in the rabbit and their response pattern, afferent renal nerve activity was recorded during pelvic perfusions with NaCl solutions at different concentrations.

2. The experiments were carried out in 13 anaesthetized rabbits. Arterial pressure from a femoral catheter and afferent renal nerve activity from the distal stump of a cut renal nerve bundle were recorded. Three catheters were inserted into the renal pelvis to measure pelvic pressure, to allow pelvic perfusions at constant rates and to drain pelvic fluids.

3. After a control period, the pelvis was perfused with physiological saline (0.14 mol/l for 2 min), followed by one of a series of solutions containing increasing concentrations of NaCl (0.5, 0.75, 1.0 and 1.5 mol/l for 2 min). Pelvic perfusion was performed both at a low (0.2 ml/min) and a high (0.8 ml/min) flow rate for each solution tested.

4. In all animals arterial pressure was not modified during pelvic perfusions. Physiological saline did not change afferent renal nerve activity at the low perfusion rate, but it significantly increased afferent renal nerve activity and pelvic pressure at the high rate. Hypertonic NaCl solutions caused progressive increases in afferent renal nerve activity at both perfusion rates, and these effects were larger at the high perfusion rate.

5. These data demonstrate, in the rabbit, the existence of renal afferent nerves sensitive to discrete changes in pelvic ionic or osmotic concentration. The neural response is enhanced when renal mechano- and chemo-receptors are simultaneously activated.
Blood Pressure Parameters as Determinants of Small Artery Structure in Human Essential Hypertension
Authors: Cooper Anne , Heagerty Anthony M.
Published: August 2015

1. Adaptive changes in small arteries may be more closely correlated with pulse pressure than with systolic, diastolic or mean blood pressures in human essential hypertension.

2. An analysis was performed on the structure of small arteries, age and blood pressure measurements obtained from 56 patients with untreated essential hypertension and 56 matched normotensive volunteers to examine the association between age, blood pressure and small artery structural parameters.

3. Essential hypertension was associated with an increase in media thickness and a decrease in lumen diameter, resulting in an increase in media/lumen ratio.

4. There was a significant correlation between age and media/lumen ratio in normotensive volunteers but not in patients with essential hypertension.

5. There was no correlation between any blood pressure and structural parameter in normotensive volunteers.

6. Both diastolic and mean blood pressures in essential hypertension correlated with media/lumen ratio (P < 0.01); systolic blood pressure correlated less well (P < 0.02). However, pulse pressure did not correlate with media/lumen ratio, suggesting that it is not a significant determinant of small artery structure in untreated essential hypertension.
Epithelial Migration in the Colon: Filling in the Gaps
Authors: Wilson Andrew J. , Gibson Peter R.
Published: August 2015

1. The efficient repair of gastrointestinal mucosal injuries is essential in the preservation of the epithelial barrier to luminal antigens. Accumulated evidence suggests that epithelial migration plays a major part in this repair by rapidly resealing defects induced by both physiological and pathological insults, a process termed restitution.

2. This migration has been modelled in various ways, most commonly in mechanically wounded monolayers of cell lines or cells in primary culture, and in wounded human or animal tissue. Evidence from these models indicates that migration is a highly complex process, which is likely to involve the tightly controlled spatial and temporal interaction of multiple factors: (i) extracellular molecules such as soluble factors (e.g. growth factors, trefoil peptides, cytokines) and matrix components (e.g. collagen, laminin, fibronectin); (ii) signalling molecules activated by the interaction of these factors with cell surface receptors (e.g. protein kinases, phospholipases, low-molecular-weight GTPases); (iii) factors which regulate adhesion to other cells (e.g. E-cadherin) and to matrix components (e.g. integrins, hyaluronic acid receptors); (iv) factors which regulate detachment from the extracellular matrix (e.g. urokinase-type plasminogen activator, matrix metalloproteinases); and (iv) molecules which regulate cytoskeletal function (e.g. Rac), which allows the formation of specialized cellular processes termed lamellipodia.

3. The identification of physiologically relevant factors that stimulate epithelial cell migration, and a better understanding of their mechanism of action, may be beneficial in the development of novel therapeutic approaches in diseases such as inflammatory bowel disease through the pharmacological or dietary enhancement of this migration.
Dose-Related Effect of Intravenous l-Arginine on Muscular Blood Flow of the Calf in Patients with Peripheral Vascular Disease: A H215O Positron Emission Tomography Study
Authors: Schellong Sebastian M. , Böger Rainer H. , Burchert Wolfgang , Bode-Böger Stefanie M. , Galland Andrea , Frölich Jürgen C. , Hundeshagen Heinz , Alexander Klaus
Published: August 2015

1. Endothelium-derived nitric oxide (NO) contributes to the regulation of vascular tone and blood pressure. Infusion of l-arginine produces systemic vasodilatation via stimulation of endogenous NO formation. Vasodilatation is accompanied by an increase in peripheral arterial blood flow. However, it is not known whether capillary nutritive blood flow increases as well. The time course and dose-response pattern of this effect remain to be elucidated.

2. Two groups of ten patients with peripheral vascular disease (PVD) received an intravenous infusion of 8 g or 30 g of l-arginine over a period of 40 min. Blood pressure and heart rate were monitored non-invasively. Muscular blood flow (MBF) of the calf was determined at 0, 20, 40, 60, 80 min by positron emission tomography with H215O as flow tracer. Plasma l-arginine and cyclic GMP (cGMP) levels were determined at the same time points.

3. l-arginine induced a dose-related decrease in blood pressure during the infusion period. MBF and plasma cGMP levels during and after the infusion of 8 g of l-arginine did not change significantly. In the patients receiving 30 g of l-arginine, MBF was enhanced significantly from 1.56 ± 0.14 to 2.09 ± 0.21 ml min−1 100 ml−1 at 40 min and 2.23 ± 0.15 ml min−1 100 ml−1 after 80 min (+43.0%). The increase in MBF was paralleled by an increase in plasma cGMP from 4789.8 ± 392.2 nmol/l at baseline to 9223.2 ± 1233.6 nmol/l at 40 min.

4. We conclude that intravenous l-arginine enhances nutritive capillary MBF in patients with PVD via the NO—cGMP pathway in a dose-related manner. This effect might be therapeutically beneficial in patients with PVD.
Functional Analysis of Histamine Release from Basophils and Mast Cells in Subjects with the Ile-181→Leu Variant of FcεRI-β
Authors: Airong LI , MacKay Graham A. , Hopkin Julian M.
Published: August 2015

1. Atopy is a genetically heterogeneous disorder, but there is now strong evidence that one important locus is on chromosome 11q13. FcεRI-β at that location has been identified as a candidate gene and variants have been associated with atopy in population studies.

2. No information is available on the functional consequences of any of these variants, and defining this may prove difficult because of the complexity of the atopy phenotype and because FcεRIβ is expressed on a range of cells with different functions, including basophils, mast cells, eosinophils and antigen-presenting Langerhan's cells.

3. We have conducted a qualitative study of mast cell and basophil histamine release in nine atopic individuals with Ile-181→Leu mutation of FcεRIβ, and ten unrelated similarly atopic individuals without Ile-181→Leu mutation. There were non-significant trends for Ile-181→Leu-positive atopic subjects to produce wheal responses at lower allergen challenge in skin prick tests, and to release more histamine from basophils following in vitro allergen challenge.

4. The data do not provide decisive evidence of functional differences between atopic subjects with Ile-181→Leu and other atopic individuals; more discriminating functional experiments are required.
Age- and Gender-Related Changes in Endothelin and Catecholamine Release, and in Autonomic Balance in Response to Head-Up Tilt
Authors: White Michel , Courtemanche Marc , Stewart Duncan J. , Talajic Mario , Mikes Ethel , Cernacek Peter , Vantrimpont Pascal , Leclerc Diane , Bussières Lizanne , Rouleau Jean L.
Published: August 2015

1. There is an increase in circulating levels of vasoconstrictive hormones and an alteration in baroreceptor responsiveness with aging. The role of changes in endothelium-dependent and -independent vasoconstrictive hormones in relation to age and gender, with simultaneous assessment of autonomic balance in response to head-up tilt, has been incompletely studied.

2. Sixteen young [25 ± 3 years (mean ± SEM)] and 16 older normal volunteers (68 ± 7 years) underwent a 30 min head-up tilt test at 60°. Haemodynamics were measured every 5 min and blood samples for neurohormone measurement were drawn at baseline, 5, 10, 15 and 30 min into the test. Heart rate variability was analysed in 5 min segments at the baseline, and during the test. The younger subjects exhibited a greater increase in heart rate and diastolic blood pressure, despite lower absolute levels of noradrenaline (norepinephrine) and endothelin-1. Analysis of heart rate variability yielded a decrease in both high- and low-frequency bands in the aged; power at low-frequency decreased only in the young subjects. The age-related differences in blood pressure and noradrenaline levels were markedly attenuated in the female subjects. In addition, endothelin-1 levels and power spectral measurements at low frequency were the lowest in younger females throughout the tilt.

3. Despite attenuated cardiovascular response to tilt, both systemic adrenergic ‘drive’ and endothelin-1 levels increase in parallel with aging. Thus, endothelium-dependent and -independent vasoconstrictive hormone levels increase with age in the resting state and in response to neurohumoral stimulation in humans.
Spontaneous and Induced Minisatellite Instability in the Human Genome
Authors: Jeffreys Alec J.
Published: August 2015

1. Minisatellites, originally developed for forensic DNA fingerprinting and profiling, have also provided extremely informative systems for analysing processes of tandem repeat DNA turnover in the human genome.

2. Minisatellite instability involves distinct mutation processes in somatic and germline cells. In sperm, tandem repeat instability most likely arises at meiosis as a by-product of high-frequency meiotic recombination events occurring in and near minisatellites. Instability is not an intrinsic property of minisatellite repeat DNA, but instead appears to be controlled by flanking recombination initiation elements.

3. Minisatellites not only show high-frequency spontaneous mutation in the germline, but also appear to be very sensitive to mutation induction by ionizing radiation, both in experimentally irradiated mice and in human populations exposed following the Chernobyl disaster; the mechanisms of mutation induction by radiation remain enigmatic.