bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Regional Pulmonary Blood Flow during Lobar Bronchial Occlusion in Man
Authors: Morrell N. W. , Nijran K. S. , Biggs T. , Seed W. A.
Published: August 2015

1. Acute hypoxic pulmonary vasoconstriction is important in the restoration of ventilation—perfusion balance in the presence of regional alveolar hypoventilation. However, the magnitude and time course of this response in man has not been adequately characterized in regions smaller than an entire lung. We have studied the effectiveness of hypoxic vasoconstriction in diverting blood from hypoxic lobes in normal supine subjects, and have documented the redistribution of pulmonary blood flow under these conditions.

2. Lobar hypoxia was induced for 80–300 s by placing occluding balloon-tipped catheters in lobar bronchi during fibreoptic bronchoscopy in 10 normal subjects. Respiratory gas partial pressures within occluded lobes were measured with a mass spectrometer. The percentage reduction in blood flow to the hypoxic lobes was assessed after injection of 99mTc-labelled albumin by γ-scintigraphy, and compared with a control scan performed 1 week later. A computer program was used to analyse changes in regional pulmonary perfusion.

3. During lobar bronchial occlusion respiratory gas partial pressures rapidly approached reported values for mixed venous partial pressures. After a mean time of occlusion of 3.5 min lobar blood flow was reduced by 47 ± 5%. During occlusions pulmonary blood flow was not evenly redistributed, but was preferentially redistributed to more cranial lung regions.

4. We conclude that acute hypoxic pulmonary vasoconstriction in occluded lobes is more effective at rapidly diverting pulmonary blood flow away from hypoxic lung regions than has previously been reported in man during unilateral hypoxia of an entire lung. Non-uniform redistribution of pulmonary blood flow in the supine subject is likely to be due to compression of the lung bases by the diaphragm in the supine position.
Urinary Endothelin-1-Like Immunoreactivity in Young Male Patients with Testicular Cancer Treated by CIS-Platinum: Comparison with other Urinary Parameters
Authors: Takeda Masayuki , Komeyama Takeshi , Tsutsui Toshiki , Mizusawa Takaki , Hideto GO , Hatano Akihiko , Tanikawa Toshiki
Published: August 2015

1. Urinary excretion of endothelin-1-like immunoreactivity and urinary excretion of other parameters (β2-microglobulin, N-acetyl-β-d-glucosaminidase and microalbumin) were measured before, within 1 week after and 2 weeks after the administration of cis-platinum in five young male patients with testicular cancer (mean age 33.0 years) and were compared.

2. Urinary endothelin-1-like immunoreactivity/creatinine during, 1 week after, and 2 weeks after cis-platinum treatment was significantly higher than before cis-platinum. There was no difference in urinary endothelin-1-like immunoreactivity/creatinine during, 1 week after and 2 weeks after cis-platinum.

3. Among the four parameters, urinary endothelin-1-like immunoreactivity/creatinine showed the highest level after cis-platinum treatment. Urinary β2-microglobulin/creatinine most rapidly returned to normal levels after cis-platinum.

4. Although urinary endothelin-1-like immunoreactivity/creatinine did not show any significant correlations with urinary N-acetyl-β-d-glucosaminidase (r = 0.291, not significant) or urinary microalbumin/creatinine (r = 0.076, not significant), it showed a significant correlation with urinary β2-microglobulin/creatinine (r = 0.475, P < 0.05).

5. These results suggest that endothelin-1 may be a sensitive urinary parameter in detecting cis-platinum-induced renal tubular injury.
Identical Effects of Indomethacin on Renal Function in Healthy Uninephrectomized Subjects and in Healthy Control Subjects
Authors: Nielsen C. B. , Sørensen S. S. , Pedersen E. B.
Published: August 2015

1. Animal studies have shown that prostaglandins are important for renal function after unilateral nephrectomy. In order to investigate the importance of prostaglandins for renal function in the fully adapted remnant kidney in healthy uninephrectomized subjects, the acute effects of indomethacin on renal haemodynamics, lithium clearance, urinary excretion rates of prostaglandin E2, sodium and water, and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide and arginine vasopressin were measured in 14 healthy uninephrectomized subjects (median time after nephrectomy 1.7 years) and in 14 matched healthy control subjects. In addition, nine healthy control subjects were studied without indomethacin and served as a time-control group.

2. Before indomethacin ingestion there was a significantly higher single-kidney urinary excretion rate of prostaglandin E2 in the uninephrectomized group (uninephrectomized group, 349.2 fmol/min; control group, 76.6 fmol/min; time-control group, 96.3 fmol/min).

3. Indomethacin ingestion resulted in equal changes in all parameters in both groups. These were significant decreases in glomerular filtration rate (−11.3% versus −14.6%), renal plasma flow (−6.5% versus −13.0%), urinary flow rate (−49.8% versus −49.4%), fractional sodium excretion (−44.5% versus −47.4%), lithium clearance (−33.2% versus −23.8%) and urinary excretion rate of prostaglandin E2 (−93.8% versus −86.7%) (uninephrectomized versus control subjects, values are medians). In the time-control group no changes were observed in these parameters.

4. It is concluded that healthy uninephrectomized subjects with a fully adapted remnant kidney have a normal renal response to acute indomethacin-induced inhibition of prostaglandin synthesis.
Effects of Physiological Increments in Human α-Atrial Natriuretic Peptide and Human Brain Natriuretic Peptide in Normal Male Subjects
Authors: Cheung B. M. Y. , Dickerson J. E. C. , Ashby M. J. , Brown M. J. , Brown J.
Published: August 2015

1. Brain natriuretic peptide, closely related to atrial natriuretic peptide in structure, may be an important circulating hormone. Its physiological role is unclear. First, we studied the effects of incremental infusions of brain natriuretic peptide in six healthy men on plasma brain natriuretic peptide levels and the pharmacokinetics of brain natriuretic peptide. Synthetic human brain natriuretic peptide-32 was infused intravenously, at an initial rate of 0.4 pmol min−1 kg−1, doubling every 15 min until the dose rate reached 6.4 pmol min−1 kg−1, at which rate the infusion was maintained for 30 min.

2. The brain natriuretic peptide infusion raised the brain natriuretic peptide-like immunoreactivity from 1.4 ± 0.5 pmol/l to 21.4 ± 7.6 pmol/l. Brain natriuretic peptide-like immunoreactivity after the end of infusion was consistent with a bi-exponential decay, with half-lives of 2.1 min and 37 min.

3. Next, we studied the effects of low-dose infusion of brain natriuretic peptide to mimic physiological increments in the circulating levels in comparison with atrial natriuretic peptide. Six dehydrated male subjects received intravenous infusions of atrial natriuretic peptide and brain natriuretic peptide, separately and in combination, in a randomized double-blind, placebo-controlled, four-part cross-over design. Atrial natriuretic peptide and brain natriuretic peptide were given at the rate of 0.75 and 0.4 pmol min−1 kg−1, respectively, for 3 h. The control infusion consisted of the vehicle.

4. Analysis of variance showed that atrial natriuretic peptide and atrial natriuretic peptide plus brain natriuretic peptide, but not brain natriuretic peptide alone, increased urinary flow and decreased urinary osmolality significantly. However, urinary sodium excretion was significantly increased by atrial natriuretic peptide, brain natriuretic peptide and atrial natriuretic peptide plus brain natriuretic peptide.

5. None of the four infusates significantly altered the blood pressure, heart rate or glomerular filtration rate.

6. This study showed, for the first time, that physiological increments in brain natriuretic peptide, like those in atrial natriuretic peptide, are natriuretic. Although atrial natriuretic peptide and brain natriuretic peptide do not appear to interact synergistically, they are likely to act in concert in the physiological regulation of sodium balance.
Expression of Tissue Kallikrein in Human Kidney
Authors: Cumming Allan D. , Walsh Timothy , Wojtacha Davina , Fleming Stewart , Thomson David , Jenkins David A. S.
Published: August 2015

1. We studied the distribution of human tissue kallikrein mRNA in normal and diseased kidney, using in situ hybridization, together with immunohistochemical localization of renal kallikrein protein. Materials studied were (a) normal tissue from kidneys removed because of localized renal carcinoma, (b) kidneys removed because of post-traumatic haemorrhage and (c) renal biopsy specimens from patients with membranous glomerulonephritis and nephrotic syndrome.

2. A 1.35 kb EcoRI fragment of human tissue kallikrein cDNA was labelled with [32P]dCTP using the random-primer technique, and used for in situ hybridization. A specific rabbit antibody to active human urinary kallikrein was employed for immunocytochemistry, using a peroxidase-antiperoxidase method.

3. By in situ hybridization, no tissue kallikrein gene expression was seen in the carcinoma nephrectomy specimens. Positive expression was seen in the trauma nephrectomy tissue, and in four of five nephrotic syndrome biopsies. In all kidneys, expression was confined to the renal cortex. The dominant site of gene expression was the distal tubule. Apart from one area of positive signal related to an epithelial cell of Bowman's capsule, expression was not observed in glomeruli. Expression was also seen in the walls of large- and medium-sized blood vessels.

4. By immunohistochemistry, the dominant site of immunoreactivity was the distal tubule. Dense staining was also seen in granular peripolar cells and in isolated parietal epithelial cells close to the vascular pole. Isolated immunoreactive cells were seen in the media of large- and medium-sized arteries.

5. The tissue kallikrein gene in the kidney may not be constitutively expressed, but is expressed in response to physiological or pathological stimuli. The dominant site of gene expression and tissue kallikrein localization is the distal tubule. Although kallikrein is present in granular peripolar cells in human kidney, mRNA was not located at this site. It is possible that kallikrein in these cells derives from absorption from glomerular filtrate. Tissue kallikrein mRNA and protein are present in the walls of blood vessels in human kidney. The significance of vascular kallikrein expression requires further investigation.
Plasma Adrenaline Concentration is Lower in Post-Obese than in Never-Obese Women in the Basal State, in Response to Sham-Feeding and after Food Intake
Authors: Andersen H. Bryde , Raben A. , Astrup A. , Christensen N. Juel
Published: August 2015

1. Plasma pancreatic polypeptide, plasma catecholamine, blood glucose, plasma insulin and plasma peptide YY concentrations were studied to assess differences between eight formerly obese and eight never-obese control women during 25 min of shamfeeding (with the sight and smell of an English breakfast) and for 5 h after they had ingested the meal (3514kJ, 50% fat, 35% carbohydrate). The post-obese women had maintained their normal body weight for at least 3 months before the study.

2. The plasma noradrenaline concentration was not different between the groups either during fasting (post-obese women 0.08 ± 0.01 ng/ml versus control women 0.10 ± 0.01 ng/ml) or in the significant postprandial increase (P < 0.001). The plasma adrenaline concentration increased significantly during sham-feeding in the control group from 0.024 ± 0.004 ng/ml to 0.033 ± 0.004 ng/ml (P = 0.02) in contrast with the post-obese women, who had significantly lower plasma concentrations of adrenaline in the fasting state (post-obese 0.016 ± 0.003 ng/ml versus control women 0.024 ± 0.004 ng/ml, P = 0.003), during sham-feeding (post-obese women 0.018 ± 0.002 ng/ml versus control women 0.033 ± 0.004 ng/ml, P = 0.003) and in the postprandial increase (P = 0.003). The maximal postprandial response concentrations recorded 5 h after the meal were 0.025 ± 0.003 ng/ml in post-obese women and 0.035 ± 0.004 ng/ml in control subjects (P = 0.04). There were no significant differences in plasma pancreatic polypeptide, plasma peptide YY, plasma insulin, or blood glucose concentrations between the two groups.

3. The plasma adrenaline concentration is lower in post-obese women in the basal fasting state, during sham-feeding and in response to a meal. These results indicate that post-obese subjects respond differently to food stimulation than normal subjects.
Tamm-Horsfall Mucoprotein Reduces Promotion of Calcium Oxalate Crystal Aggregation Induced by Urate in Human Urine In Vitro
Authors: Grover Phulwinder K. , Marshall Villis R. , Ryall Rosemary L.
Published: August 2015

1. Increasing the concentration of dissolved urate promotes calcium oxalate crystallization in urine from which Tamm-Horsfall mucoprotein, an inhibitor of calcium oxalate crystal aggregation, has almost completely been removed. This study aimed to determine whether the effect of urate could be reduced or abolished by a physiological concentration of Tamm-Horsfall mucoprotein. This was approached in two ways.

2. The effect of Tamm-Horsfall mucoprotein on calcium oxalate crystallization induced by urate was tested in ultrafiltered (10 kDa) urine samples from 10 healthy men. Tamm-Horsfall mucoprotein (35 mg/l) was added to half of each specimen, the urate concentration was increased by the addition of sodium urate solution and crystallization was induced by a standard load of oxalate. The remainder of each urine specimen was used as a control; these specimens were treated with an identical amount of urate solution, but contained no Tamm-Horsfall mucoprotein. Tamm-Horsfall mucoprotein had no effect on the urinary metastable limit or on the deposition of calcium oxalate, but significantly reduced the size of the particles precipitated.

3. The effect of increasing the urate concentration in the presence of Tamm-Horsfall mucoprotein was tested. Tamm-Horsfall mucoprotein (35 mg/l) was added to 10 ultrafiltered urine samples as before, the samples were divided, and the concentration of urate was increased in half of each specimen. Compared with the control to which no urate was added, urate significantly reduced the amount of oxalate required to induce spontaneous calcium oxalate nucleation and increased the median volume and the particle size of the material deposited.

4. It was concluded that, in vivo, (a) hyperuricosuria would encourage the formation of calcium oxalate stones by promoting calcium oxalate crystallization, (b) Tamm-Horsfall mucoprotein would not lessen the effect of urate on calcium oxalate nucleation or bulk deposition but would reduce its effect on crystal aggregation; it could therefore reduce the likelihood of stone formation in patients with hyperuricosuria.
Cellular Localization of Inducible Nitric Oxide Synthase in Experimental Endotoxic Shock in the Rat
Authors: Cook H. Terence , Bune Alison J. , Jansen Albertine S. , Taylor G. Michael , Loi Rashpal K. , Cattell Victoria
Published: August 2015

1. Endotoxin induces a shock-like syndrome with increased nitric oxide synthesis. To clarify the cellular source of NO in endotoxic shock we used immunohistochemistry and in situ hybridization to localize inducible NO synthase in rats given lipopolysaccharide or Corynebacterium parvum and lipopolysaccharide. Immunohistochemistry was carried out with an antibody raised against a synthetic peptide of mouse macrophage NO synthase. In situ hybridization was performed with 35S-labelled oligonucleotide probes corresponding to cDNA sequences common to mouse macrophage inducible NO synthase and rat vascular smooth inducible NO synthase. Monocytes and macrophages were identified by immunohistochemistry with the mouse monoclonal antibody ED1.

2. After lipopolysaccharide alone, the major site of NO synthase induction was monocytes and macrophages in multiple organs, principally liver and spleen. Bronchial, bile duct, intestinal and bladder epithelium and some hepatocytes also expressed inducible NO synthase. Expression peaked at 5 h and had returned to normal by 12 h except in spleen.

3. After priming with C. parvum, lipopolysaccharide led to a similar distribution of inducible NO synthase as lipopolysaccharide alone, but in addition there was more prominent hepatocyte staining, staining in macrophage granulomas in the liver and inducible NO synthase was present in some endothelial cells in the aorta.

4. These findings provide a direct demonstration of the cellular localization of inducible NO synthase after lipopolysaccharide.
Physical Fitness and Insulin Sensitivity in Human Subjects with a Low Insulin Response to Glucose
Authors: Pigon Jan , Karlsson Jan , Östenson Claes-Göran
Published: August 2015

1. We have assessed insulin secretion, insulin sensitivity, exercise capacity and muscle fibre composition in healthy men with a low insulin response to glucose (low insulin responders and endurance-trained subjects) and in healthy men with a normally high insulin response. Low insulin responders have been considered as prediabetic subjects.

2. During glucose infusion, low insulin responders and endurance-trained subjects had acute-phase (0-10 min) insulin responses that were 26% (P < 0.001) and 31% (P < 0.001), and C-peptide responses that were 35% (P < 0.001) and 42% (P < 0.01), respectively of the responses in high insulin responders. Also, the late-phase (10-60 min) insulin and C-peptide responses were lower in low insulin responders and endurance-trained subjects. Endurance-trained subjects, compared with high and low insulin responders, had higher insulin sensitivity (blood glucose concentration during a somatostatin-insulin-glucose infusion test 3.6 ± 0.4 versus 6.3 ± 0.6 mmol/l in high insulin responders, P < 0.01, and 5.5 ± 0.4 mmol/l in low insulin responders, P < 0.01), exercise capacity (4.2 ± 0.2 versus 3.0 ± 0.2 W/kg body weight, P < 0.001, and 2.8 ± 0.1 W/kg body weight, P < 0.001) and a higher percentage of slow-twitch fibres (58.2 ± 5.2 versus 38.5 ± 3.5%, P < 0.01 and 40.9 ± 3.0%, P < 0.001).

3. In conclusion, we demonstrate that low insulin responders exhibited decreased insulin and C-peptide responses to glucose, despite normal insulin sensitivity and exercise capacity. Thus, the low insulin response in low insulin responders reflects a true impairment of insulin release and not a compensatory decrease due to increased insulin sensitivity. The insulin response to glucose in endurance-trained subjects was also decreased, probably due to increased insulin sensitivity.
Effect of Sepsis on Mucosal Protein Synthesis in Different Parts of the Gastrointestinal Tract in Rats
Authors: Higashiguchi Takashi , Noguchi Yoshifumi , O'Brien William , Wagner Kenneth , Fischer Josef E. , Hasselgren Per-Olof
Published: August 2015

1. In a previous study we found that the protein synthesis rate was increased by 50–60% in the mucosa of the jejunum and ileum during sepsis in rats. It is not known if sepsis affects protein turnover in other parts of the gastrointestinal tract as well.

2. In the present study, the influence of sepsis on mucosal protein synthesis in different parts of the gastrointestinal tract, from the stomach to the rectum, was determined in rats.

3. Sepsis was induced by caecal ligation and puncture; control rats underwent sham-operation. Protein synthesis rate was measured in vivo after administration of a flooding dose of [14C]leucine.

4. Basal mucosal protein synthesis rates were lower in the colon than in the rest of the gastrointestinal tract. Sixteen hours after caecal ligation and puncture, the protein synthesis rates were increased by 40–85% in the mucosa of the small and large intestine and the rectum, whereas in the gastric mucosa, the protein synthesis rate was reduced by approximately 40%.

5. The results suggest that mucosal protein synthesis rates differ in the various regions of the gastrointestinal tract, and that the metabolic response to sepsis is different in the stomach than in the rest of the gastrointestinal tract. The finding of a reduced protein synthesis rate in the gastric mucosa may partly explain the tendency to gastric stress ulcers and bleeding seen clinically in sepsis.
Haemodynamic and Neurohumoral Effects of Caffeine in Elderly Patients with Symptomatic Postprandial Hypotension: A Double-Blind, Randomized, Placebo-Controlled Study
Authors: Lipsitz Lewis A. , Jansen Rene W. M. M. , Connelly Carolyn M. , Kelley-Gagnon Margaret M. , Parker Anthony J.
Published: August 2015

1. The aim of this study was to determine the effects of caffeine on haemodynamic and neurohumoral responses to meal ingestion in elderly patients with a history of symptomatic postprandial hypotension.

2. Postprandial hypotension is a common disorder of blood pressure regulation in the elderly, associated with falls and syncope. The pathophysiological mechanism is thought to be related to impaired vascular compensation for splanchnic blood pooling after a meal. Since caffeine inhibits vasodilatory adenosine receptors in the splanchnic circulation, we postulated that caffeine would reduce splanchnic blood pooling and prevent the development of postprandial hypotension.

3. We conducted a randomized, double-blind, placebo-controlled, cross-over study in nine elderly patients [age 76 ± 9 (SD) years] with histories of symptomatic postprandial hypotension. Standardized 1674 kJ liquid meals with 250 mg of caffeine or placebo were given on two occasions, at least 1 week apart. Blood pressure, heart rate, forearm vascular resistance (by venous occlusion plethysmography), and plasma caffeine and catecholamine levels were measured. Cardiac and splanchnic blood volume were determined by radionuclide scans.

4. By 30 min after both caffeine and placebo meal studies, supine mean arterial blood pressure fell significantly (P = 0.006) by 31 ± 7 and 19 ± 6 mmHg, respectively (mean ± SEM, between group difference was not significant). Heart rate, cardiac output and splanchnic blood volume increased significantly, but to a similar extent, after caffeine and placebo. Forearm vascular resistance was unchanged after both meals.

5. Oral caffeine given with a meal does not reduce splanchnic blood pooling nor prevent postprandial hypotension in symptomatic elderly patients.
l-Arginine Infusion Decreases Peripheral Arterial Resistance and Inhibits Platelet Aggregation in Healthy Subjects
Authors: Bode-Böger S. M. , Böger R. H. , Creutzig A. , Tsikas D. , Gutzki F.-M. , Alexander K. , Frölich J. C.
Published: August 2015

1. L-Arginine is the physiological precursor of nitric oxide which induces vasodilatation and inhibits platelet aggregation by the formation of cyclic GMP.

2. In the present study we investigated the effects of an intravenous infusion of L-arginine (30 g, 30 min) compared with placebo on blood pressure, heart rate and peripheral haemodynamics in ten healthy male subjects. Cyclic GMP, NO−2 and NO−3 were determined in plasma and urine to assess NO production in vivo by a new, highly specific and sensitive gas chromatography-mass spectrometry method.

3. L-Arginine significantly decreased mean arterial blood pressure and increased heart rate. The effect was more pronounced on diastolic than on systolic blood pressure. This was due to a decreased peripheral arteriolar resistance, as in femoral artery Doppler sonography the arterial diameter was unchanged but blood flow was increased. These haemodynamic effects were not observed after placebo administration.

4. Urinary excretion of cyclic GMP increased by 65.4% after L-arginine and by 25.1% after placebo. Urinary NO−2 excretion was near the threshold of detection. Urinary NO−3 excretion increased by 79.7% after L-arginine. Plasma arginine levels increased nearly ten-fold after the L-arginine infusion, and plasma cyclic GMP increased by a similar rate as in urine. However, plasma NO−2 and NO−3 remained unchanged after both treatments, as did plasma α-atrial natriuretic peptide levels.

5. Platelet aggregation was inhibited by 32.7% after L-arginine (P < 0.05), but was unchanged after placebo. Platelet intracellular cyclic GMP was increased by 43.0% after L-arginine, but not after placebo (P < 0.05).

6. We conclude that intravenous L-arginine decreases peripheral arteriolar tone and inhibits platelet aggregation in healthy human subjects by enhancing nitric oxide formation and, concomitantly, cyclic GMP formation.
Plasma Cysteine and Sulphate Levels in Patients with Cirrhosis of the Liver
Authors: Davies M. H. , Klovrza L. , Waring R. H. , Elias E.
Published: August 2015

1. Fasting levels of plasma cysteine, plasma sulphate and the plasma cysteine/sulphate ratio were measured in patients with primary biliary cirrhosis and compared with those in patients with other liver disease, general intensive therapy unit patients and healthy subjects.

2. Plasma cysteine was significantly elevated in patients with primary biliary cirrhosis (median 0.364 nmol/mg of protein, P < 0.0001) and patients with other liver disease (median 0.445 nmol/mg of protein, P < 0.0001), compared with healthy control subjects (median 0.125 nmol/mg of protein) and increased progressively with the severity of liver disease. Plasma cysteine was also elevated in intensive therapy unit patients (median 1.564 nmol/mg of protein) compared with healthy control subjects (P < 0.0001) and patients with other liver disease (P < 0.0001).

3. Plasma sulphate was reduced significantly only in patients with primary biliary cirrhosis (median 0.822 nmol/mg of protein) compared with healthy control subjects (median 1.37 nmol/mg of protein, P < 0.05). There was no significant difference in plasma sulphate between disease groups.

4. The plasma cysteine/sulphate ratio was significantly elevated in patients with primary biliary cirrhosis (median 0.448, P < 0.0001) and patients with other liver diseases (median 0.394, P < 0.0001) compared with healthy control subjects (median 0.095). The ratio was also elevated in intensive therapy unit patients (median 1.650, P < 0.0001) compared with healthy control subjects and liver disease groups (P < 0.0001).

5. In conclusion, plasma cysteine rises in primary biliary cirrhosis and other forms of liver disease. This effect is not specific to liver disease, since cysteine is elevated in an heterogeneous group receiving intensive care. Impairment of trans-methylation and trans-sulphuration pathways does not explain the finding of increased plasma cysteine. Since cysteine is elevated in non-hepatic disease, it may reflect the effect of muscle breakdown and the catabolic state. Impaired activity of cysteine dioxygenase and impaired mitochondrial function may be contributory, but this requires further study. These metabolic changes may reflect progressively diminished detoxification capacity within the liver and other tissues.
Metabolic Abnormalities in Skeletal Muscle after Myocardial Infarction in the Rat
Authors: Thompson C. H. , Kemp G. J. , Rajagopalan B. , Radda G. K.
Published: August 2015

1. The effect of experimental myocardial infarction on exercise and recovery of rat skeletal muscle was studied using 31P n.m.r. 4 weeks post-operatively.

2. Myocardial infarction (12 ± 3% of left ventricular volume), insufficient to produce haemodynamic manifestations of heart failure, was without significant effect on exercise bioenergetics of skeletal muscle.

3. Citrate synthase activity was reduced by 17% in the infarcted animals and there was a marked slowing of the rate of phosphocreatine recovery after infarction (half-time 0.7 ± 0.1 min to 1.6 ± 0.2 min) in the absence of evidence of left ventricular failure or hypertrophy.

4. The study of recovery bioenergetics could provide a more sensitive measure of mitochondrial function than exercise, where no bioenergetic abnormality was detected.

5. Myocardial infarction can produce evidence of mitochondrial abnormality in skeletal muscle in the absence of haemodynamic compromise.
Glomerular Charge Selectivity in Primary Glomerulopathies
Authors: Fox J. G. , Quin J. D. , O'Reilly D. St. J. , Boulton-Jones J. M.
Published: August 2015

1. Glomerular charge selectivity was assessed using the ratio of the clearance of pancreatic isoamylase to the clearance of the more anionic salivary isoamylase (CPAm/CSAm) in 53 patients with primary glomerulopathies (minimal change nephropathy, idiopathic membranous nephropathy, IgA nephropathy) and a wide range of albumin excretion rates and in 31 healthy subjects. Fractional clearances of pancreatic and salivary isoamylases (FCPAm, FCSAm) and of albumin (FCAlb) were also measured.

2. CPAm/CSAm and FCPAm were negatively correlated with FCAlb for the whole patient group (rs = −0.56 and rs = −0.65, respectively, P < 0.0001 for both), but there was no correlation of FCSAm with FCAlb.

3. For patients with near-normal albumin excretion rates (< 100 mg/24 h), there was no difference in CPAm/CSAm between the three types of glomerulopathy or between patients and healthy subjects.

4. These data suggest that glomerular charge selectivity at the size of amylase (which is smaller than albumin) is progressively lost as albuminuria increases from normal to the nephrotic range. Size restriction progressively increases until albuminuria is very heavy. When the albumin excretion rate is near normal, charge selectivity is also normal in the three main forms of primary glomerulopathy.
Plasma Endogenous Digoxin-Like Substance Levels are Dependent on Blood O2 in Man
Authors: Ferri Claudio , Bellini Cesare , Coassin Simonetta , De Angelis Claudio , Perrone Alessandro , Santucci Anna
Published: August 2015

1. Recently, we have demonstrated that hypoxic breathing is followed by an increase in plasma digoxin-like substance in normal men.

2. This study was undertaken in order to evaluate whether or not a low arterial O2 partial pressure is combined with an increase in plasma digoxin-like substance in chronic pathological conditions also.

3. Sixteen male patients (mean age 53.1 ± 3.7 years) affected by chronic obstructive pulmonary disease of a mild stage were studied. They were further subdivided according to their arterial O2 partial pressure into ‘mild hypoxic’ (n = 8, mean age 52.5 ± 2.7 years), with an arterial O2 partial pressure between 66 and 75 mmHg, and ‘severe hypoxic’ (n = 8, mean age 54.3 ± 5.1 years), with an arterial O2 partial pressure 65 mmHg, groups. Seven healthy men (mean age 48.5 ± 4.8 years) voluntarily participated as the control group.

4. Plasma digoxin-like substance levels were significantly higher in ‘severe hypoxic’ patients (203.5 ± 9.9 pg/ml) than in both ‘mild hypoxic’ patients (169.5 ± 31.4 pg/ml, P < 0.02) and normal subjects (158.9 ± 12.4 pg/ml, P < 0.0001) and were directly correlated with urinary Na+ excretion (severe hypoxic group, r = 0.756, P < 0.007; mild hypoxic group, r = 0.789, P < 0.02). Considering the two hypoxic groups together, plasma digoxin-like substance levels were negatively correlated with arterial O2 partial pressure (r = −0.740, P < 0.001). However, when patients were subdivided according to the degree of hypoxia, the negative correlation between arterial O2 partial pressure and plasma digoxin-like substance persisted only in severe hypoxic patients (r = −0.761, P < 0.03).

5. These results indicate a clear linkage between blood O2 and endogenous digoxin-like substance regulation. In particular, hypoxia may be regarded as an important stimulus for the release of the endogenous digoxin-like substance in man.
Intraluminal Colonic Release of Immunoreactive Tumour Necrosis Factor in Chronic Ulcerative Colitis
Authors: Casellas F. , Papo M. , Guarner F. , Antolín M. , Armengol J. R. , Malagelada J.-R.
Published: August 2015

1. Tumour necrosis factor is a proinflammatory macrophage-derived polypeptide cytokine. Its participation in disease processes has been usually inferred from data obtained from experiments in vitro or from measurements of its plasma circulating levels. To investigate its role in chronic ulcerative colitis, we have quantified in vivo the steady-state release of tumour necrosis factor into the colonic lumen.

2. We studied 19 patients with untreated active ulcerative colitis and seven patients with irritable bowel syndrome as controls. A group of seven patients with active ulcerative colitis were studied before and after 4 weeks on treatment with oral 5-aminosalicylic acid. By means of an intracolonic double-lumen perfusion tube, an isotonic solution was continuously infused 50 cm from the anal verge at a rate of 5 ml/min, and was recovered 30 cm distally by siphonage. Effluents were assayed for tumour necrosis factor by a specific e.l.i.s.a. and for prostaglandin E2 and leukotriene B4 by specific r.i.a.s.

3. The intracolonic release of tumour necrosis factor was undetectable in patients with irritable bowel syndrome, whereas measurable release occurred in 15 out of 19 patients with active ulcerative colitis (P < 0.01). Prostaglandin E2 and leukotriene B4 release were also increased in active ulcerative colitis by comparison with irritable bowel syndrome (P < 0.01). Five out of seven patients with colitis improved with 5-aminosalicylic acid treatment, and tumour necrosis factor release became undetectable or decreased markedly (P < 0.05 compared with before treatment). However, tumour necrosis factor release remained high in the non-responder patients.

4. These findings indicate that intracolonic immunoreactive tumour necrosis factor release is enhanced in active chronic ulcerative colitis, becoming undetectable when mucosal lesions are healed. These results suggest that the luminal release of tumour necrosis factor may serve as an objective index of inflammatory activity in patients with chronic ulcerative colitis.
Multiple Transcripts of the Neurofibromatosis Type I Gene in Human Brain and in Brain Tumours
Authors: Takahashi Kazuhiro , Suzuki Hiroyuki , Kayama Takamasa , Suzuki Youichi , Yoshimoto Takashi , Sasano Hironobu , Shibahara Shigeki
Published: August 2015

1. Neurofibromatosis type 1 is a common hereditary disorder characterized by the presence of multiple neurofibromas and café-au-lait spots, and is frequently associated with intellectual handicaps and brain tumours. The gene responsible for neurofibromatosis (the NF1 gene) codes for a protein of 2818 amino acids, termed neurofibromin, which has a domain related to mammalian ras GTPase-activating protein.

2. The NF1 gene gives rise to multiple transcripts generated by alternative splicing, that encode neurofibromin and its isoforms. These include type I mRNA coding for neurofibromin, type II mRNA coding for neurofibromin containing the insertion of 21 amino acids in the GTPase-activating protein-related domain and mRNA coding for an N-terminal isoform lacking the GTPase-activating protein-related domain (N-isoform).

3. In the present study, the relative levels of mRNAs encoding type I, type II and N-isoform were determined by S1-nuclease mapping analysis in human brain tissue and in primary brain tumours obtained from patients with tumours unrelated to neurofibromatosis type 1.

4. These three mRNAs were expressed in all ten brain tumours and in every region of the brain examined, with the highest levels found in the cerebellum. Type I mRNA was the predominant form in the human brain except for the pons, whereas type II mRNA was predominantly expressed in eight out of ten primary brain tumours.

5. In contrast, N-isoform mRNA was similarly expressed in normal brain tissue and brain tumours.

6. These findings suggest that neurofibromin and its isoforms have important physiological roles in the human brain and that the altered expression of type I and type II mRNAs in brain tumours may be related to the tumorigenesis.
Absence of Mutations in the Gsα and Gi2α Genes in Sporadic Parathyroid Adenomas and Insulinomas
Authors: Vessey S. J. Rupert , Jones Philip M. , Wallis Simon C. , Schofield John , Bloom Stephen R.
Published: August 2015

1. Activating mutations of the α-subunits of the Gs and Gi2 proteins give rise to the oncogenes gsp and gip2, respectively, which are found in a variety of endocrine tumours.

2. In this study the polymerase chain reaction and direct sequencing have been used to screen a small sample of parathyroid adenomas and insulinomas for these mutations.

3. No mutations were identified in nine insulinomas and 13 parathyroid adenomas screened for gsp, and 11 parathyroid adenomas and four insulinomas screened for gip2. In addition, two gastrinomas from patients with multiple endocrine neoplasia type 1 were found to be negative for both oncogenes.

4. This is the first report of screening for gip2 in parathyroid adenomas and gsp/gip2 in insulinomas, and it extends the range of tumours examined for these oncogenes.
Dietary Salt Extremes and Renal Function in Rats: Effect of Atrial Natriuretic Factor
Authors: Honrath U. , Chong C. K. , Wilson D. R. , Sonnenberg H.
Published: August 2015

1. Chronic reduction of salt intake can reduce the natriuretic effect of exogenously administered atrial natriuretic factor. The purpose of this study was to elucidate the intrarenal site(s) of such atrial natriuretic factor resistance. Renal clearance and collecting duct microcatheterization experiments were made before and during infusion of atrial natriuretic factor in three groups of rats: group 1 consisted of rats fed a high salt diet (8% NaCl) for 1 week before the experiment; group II were fed a low salt diet (< 0.008%); group III received the same low salt diet, but were acutely replenished with salt at the time of experiment.

2. Baseline sodium chloride excretion was 6480 ± 810 nmol min−1g−1 kidney weight in group 1 compared to 99 ± 16 in group 1. Fractional re-absorptions in the medullary collecting duct were 37 ± 6% and 95 ± 2% of delivered load, respectively (P < 0.05). The fractions of filtered sodium remaining at the beginning of the medullary duct were 6.6 ± 1.0% of filtered load in group 1 and 2.7 ± 0.7% in group II (P < 0.05), indicating increased tubular reabsorption in group II, not only in the medullary duct, but also in upstream nephron segments.

3. During infusion of atrial natriuretic factor, marked saluresis (13240 ± 750 nmol min−1 g−1 kidney weight), together with decreased fractional reabsorption at both sites (duct, −13 ± 9%; upstream remainder, 7.9 ± 0.7%; P < 0.05 each, compared to corresponding control values) was found in group 1, whereas the excretory (150 ± 28 nmol min−1 g−1 kidney weight), and the tubular transport (duct = 84 ± 3%; upstream remainder =2.2 ± 0.4%) changes were quantitatively insignificant in group II. Glomerular filtration rate was increased in group 1 from 1.07 ± 0.03 to 1.26 ± 0.04 ml min−1g−1 kidney weight (P < 0.05), but not in group II (0.93 ± 0.07 to 0.96 ± 0.09, not significant).

4. In group III, acute salt replenishment was associated with increased excretion (1940 ± 440 nmol mm−1 g−1 kidney weight, P < 0.05 compared to group II) and with reduction of tubular reabsorption in the collecting duct only (69 ± 8%, P < 0.05). Infusion of atrial natriuretic factor in this group further increased natriuresis (7810 ± 780 nmol min−1 g−1 kidney weight) and decreased tubular reabsorption in the duct (−32 ± 22%, P < 0.05 compared to the corresponding control value).

5. We conclude that chronic salt deprivation can effectively prevent, via a rapidly reversible counter-regulatory mechanism, the expected actions of atrial natriuretic factor on sodium reabsorption in the medullary collecting duct. Operation of such a mechanism may explain salt retention despite elevated endogenous levels of atrial natriuretic factor in pathological states such as congestive heart failure and liver cirrhosis.
Effects of Leg Muscle Pumping and Tensing on Orthostatic Arterial Pressure: A Study in Normal Subjects and Patients with Autonomic Failure
Authors: Ten Harkel A. D. J. , Van Lieshout J. J. , Wieling W.
Published: August 2015

1. The effects of leg muscle pumping (tiptoeing) and tensing (leg-crossing) on orthostatic blood pressure were investigated in six healthy adult subjects (aged 28–34 years) and in seven patients with severe hypoadrenergic orthostatic hypotension (aged 20–65 years).

2. Finger arterial pressure was monitored. Relative changes in left ventricular stroke volume were computed by a pulse contour method.

3. Tiptoeing increased mean arterial pressure (7 ± 5 mmHg) in the healthy subjects, but not in the patients, whereas cardiac output increased in both groups, although by more in the healthy adults than in the patients (35 ± 10% versus 20 ± 11%, P < 0.05). Systemic vascular resistance decreased substantially in both groups while tiptoeing. Leg-crossing did not affect arterial pressure in the healthy subjects, although stroke volume had increased. In contrast, in the patients an increase in cardiac output (16 ± 12%) and mean blood pressure (13 ± 13 mmHg) was observed.

4. Tiptoeing and leg-crossing have different effects on orthostatic blood pressure in healthy adult subjects and in patients with autonomic failure. In normal humans, tiptoeing increases arterial pressure, whereas leg-crossing has little effect. In the patients, in contrast, tiptoeing has little effect, whereas leg-crossing increases arterial pressure considerably. Patients with autonomic failure should be instructed to apply leg-crossing to combat orthostatic dizziness.
Aspirin Does Not Affect the Flow Cytometric Detection of Fibrinogen Binding to, or Release of α-Granules or Lysosomes from, Human Platelets
Authors: Chronos Nicolas A. F. , Wilson Darren J. , Janes Sarah L. , Hutton Ronald A. , Buller Nigel P. , Goodall Alison H.
Published: August 2015

1. Aspirin inhibits the conversion of arachidonic acid to thromboxane A2 which reinforces the effects of weak agonists such as ADP in platelets.

2. In this study the effect of aspirin (300 mg/day) on platelet agonist response was measured by whole blood flow cytometry of unfixed blood samples from normal subjects (n = 10), an assay that investigates aggregation-independent changes in the platelet.

3. Fibrinogen binding to unstimulated platelets or to platelets stimulated with ADP or thrombin was unaffected by aspirin.

4. Under the conditions of this assay, platelets undergo a partial degranulation of α-granules and lysosomes (evidenced by expression of P-selectin and CD63, respectively) in response to ADP, and full degranulation in response to thrombin. P-selectin expression was paralleled by release of β-thromboglobulin. None of these events was affected by aspirin.

5. Thromboxane formation was totally prevented by the aspirin treatment, as shown by Born aggregometry in which the platelet aggregatory response to arachidonic acid was abolished and secondary aggregation by ADP was inhibited.

6. The flow cytometric assay can therefore be used to investigate platelets in patients, regardless of aspirin therapy.

7. These findings suggest that platelet fibrinogen binding and the release of platelet α-granule and lysosomal contents, in response to stimulation with physiological agonists, can continue in patients despite aspirin therapy. This may help to explain why aspirin is only partially effective in preventing thrombotic events.
Impaired Left Ventricular Relaxation and Arterial Stiffness in Patients with Essential Hypertension
Authors: Chang K.-C. , Tseng Y. Z. , Kuo T. S. , Chen H. I.
Published: August 2015

1. This study was designed to determine how left ventricular relaxation function in patients with essential hypertension is impaired by arterial haemodynamic load that is increased in early ejection phase. These patients did not suffer from cardiac hypertrophy or disturbed coronary perfusion. We used a high-fidelity multisensor catheter to record pressure and flow signals in the ascending aorta. The timing and magnitude of wave reflection were obtained by decomposing the measured waves into their forward and backward components. Radionuclide angiography was employed to obtain the time-activity curve. The left ventricular relaxation function was assessed by analysing the time-activity curve, which was filtered using Fourier expansion with the number of harmonics for minimum error.

2. In comparison with age-matched normotensive subjects (seven subjects with mean blood pressure 97 mmHg), hypertensive subjects (seven subjects with mean blood pressure 138 mmHg) had a shorter backward wave arrival time (193 ± 26 versus 258 ± 35 ms) and a higher reflection factor (0.58 ± 0.12 versus 0.42 ± 0.07). Isovolumic relaxation period was prolonged in hypertensive subjects (118 ± 19 versus 90 ± 19 ms). There was an inverse correlation between isovolumic relaxation period and backward wave arrival time in all 14 subjects (r = −0.67, P < 0.05). In contrast, there were no significant differences in cardiac output and time to peak ejection rate between the two groups.

3. Our analyses revealed that early return of the enhanced wave reflection may profoundly impair left ventricular relaxation function in patients with hypertension. The prolonged isovolumic relaxation and unaltered cardiac output suggested that relaxation abnormalities may have a tendency to precede systolic dysfunction in our hypertensive subjects.
α1-Antitrypsin Phenotypes in Patients with Anti-Neutrophil Cytoplasmic Antibody-Positive Vasculitis
Authors: Lhotta Karl , Vogel Wolfgang , Meisl Thomas , Buxbaum Martina , Neyer Ulrich , Sandholzer Christoph , König Paul
Published: August 2015

1. The genetic background of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis remains largely unknown. Recently a very high prevalence of medium and severe deficiency of α1-antitrypsin was described in a small group of patients with Wegener's granulomatosis and c-ANCA. c-ANCAs are autoantibodies against proteinase 3, and α1-antitrypsin is the main inhibitor of this enzyme.

2. α1-Antitrypsin phenotypic polymorphism was determined by isoelectric focusing in 32 patients with c-ANCA-associated systemic vasculitis. Twenty-nine patients had Wegener's disease, two had microscopic polyarteritis and one suffered from idiopathic rapidly progressive glomerulonephritis.

3. Two patients were homozygous PiZZ and three were heterozygous PiMZ. These phenotype frequencies differed significantly from expected values, assuming Hardy-Weinberg equilibrium (P < 0.01). Compared with a control group of 868 healthy blood donors, these results meant a significant increase in the PiZ allele (0.0138 versus 0.1094, P< 0.001).

4. Furthermore, the serum of 47 patients with severe α1-antitrypsin deficiency (PiZZ) was tested for the presence of ANCA. All sera were negative for c-ANCA and p-ANCA. None of the patients showed clinical signs of systemic vasculitis.

5. In conclusion, these data indicate that α1-antitrypsin deficiency, despite being significantly more common in patients with c-ANCA-associated systemic vasculitis, is only a minor genetic risk factor for the development of this disease.