bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired fatty-meal-stimulated gallbladder contractility in patients with Crohn's disease
Authors: Murray F. E. , McNicholas M. , Stack W. , O'Donoghue D. P.
Published: August 2015

1. The incidence of gallstones in patients with Crohn's disease is increased compared with that in healthy control subjects. This is in part due to reduced terminal ileal bile salt absorption and consequent increased cholesterol saturation in bile. The aim of this study was to evaluate gallbladder contractility, a second important factor in the pathogenesis of gallstones, in Crohn's disease.

2. Thirty patients with Crohn's disease and no known biliary tract disease and nine healthy control subjects were studied. After an overnight fast, gallbladder volume was determined by real-time ultrasonography before and 10, 20, 30, 40, and 50 min after ingestion of a standard liquid fatty meal.

3. Compared with healthy control subjects, patients with Crohn's disease had similar fasting gallbladder volumes (control, 18.7 ± 2.3 ml; Crohn's disease, 18.2 ± 2.3 ml). Percentage emptying was significantly impaired at 30, 40 and 50 min in patients with Crohn's disease compared with control subjects. Patients with Crohn's disease limited to the small bowel had gallbladder contractility that was comparable with that of control subjects, whereas in those with large-bowel disease, minimum residual gallbladder volume was significantly smaller than in control subjects. Patients with both large- and small-bowel Crohn's disease demonstrated the most marked abnormalities, with gallbladder volumes significantly larger than those of control subjects at 30, 40 and 50 min. Likewise, patients with Crohn's disease who had undergone previous bowel resection had impaired emptying at 30, 40 and 50 min.

4. In summary, gallbladder contractility is significantly impaired in patients with Crohn's disease, an abnormality which is most marked in those patients who have undergone bowel resection or have both large- and small-bowel disease. Impaired gallbladder contractility may thus be a second factor contributing to gallstone formation in certain patients with Crohn's disease.
Glucocorticoid ameliorates altered gene expression of extracellular matrix components in kidneys of New Zealand Black/White F1 mice
Authors: Nakamura Tsukasa , Ebihara Isao , Tomino Yasuhiko , Koide Hikaru
Published: August 2015

1. We examined the effects of methylprednisolone on the levels of messenger RNA encoding for extracellular matrix components, including α1(IV) collagen chain, laminin B1 and B2 chains, heparan sulphate proteoglycan and α1(I) and α1(III) collagen chains, and on the accumulation of these proteins in the renal cortex of New Zealand Black/White F1 mice.

2. At the onset of nephritis, at about 5 months of age, New Zealand Black/White F1 mice were divided in two groups that received either methylprednisolone or saline injections for 5 months.

3. The development of histological lesions and the glomerular deposition of IgG, IgM and C3 were suppressed by methylprednisolone treatment from 5 to 10 months of age.

4. The distribution and intensity of type IV collagen, laminin, heparan sulphate proteoglycan, type I collagen and type III collagen in renal cortex were decreased by the administration of methylprednisolone.

5. Levels of messenger RNA encoding for α1(IV) collagen chain, laminin B1 and B2 chains, heparan sulphate proteoglycan and α1(I) and α1(III) collagen chains in the renal cortex of New Zealand Black/White F1 mice were significantly ameliorated at 8–10 months of age by methylprednisolone administration.

6. These results indicate that methylprednisolone treatment can serve as an effective therapeutic approach to abnormal extracellular matrix regulation in murine lupus nephritis.
Influence of butter and of corn, coconut and fish oils on the effects of recombinant human tumour necrosis factor-α in rats
Authors: Mulrooney Hilda M. , Grimble Robert F.
Published: August 2015

1. Tumour necrosis factor-α is produced in response to inflammatory stimuli. Fish oil can suppress the production and actions of cytokines. Little information is available on the effects of other fats on cytokine biology. We compared the effects of fats, with a wide range of fatty acid characteristics, on the effects of tumour necrosis factor-α on protein and zinc metabolism in rats.

2. Weanling rats were fed for 8 weeks on diets containing 10% fat in the form of corn, fish or coconut oils or butter before an intraperitoneal injection of recombinant human tumour necrosis factor-α was given. Measurements were made 24 h after the injection.

3. In rats fed corn oil, food intake was reduced by 62% and rates of protein synthesis were increased by 86, 32 and 39% in the liver, lung and kidney, respectively. Zinc concentrations increased by 23% in the liver but decreased by 10% in the kidney. Plasma caeruloplasmin and complement C3 levels increased by 25% and 28%, respectively, and plasma albumin level decreased by 24%.

4. Fish oil prevented the increase in hepatic protein synthesis and changed the response of protein synthesis in lung and kidney to a decrease. Changes in hepatic and renal zinc concentrations were prevented. The response of the plasma caeruloplasmin level was unaltered but those of the plasma complement C3 and albumin concentrations were prevented.

5. Coconut oil and butter, although similarly low in linoleic acid, differed in their modulatory effects. With the exception of the rise in the plasma complement C3 concentration, all responses were prevented or greatly inhibited in rats fed butter. In rats fed coconut oil the increase in liver protein synthesis was reduced but that in the lung and kidney was unaffected. Changes in hepatic zinc concentration were unaffected but those in renal zinc concentration were prevented.

6. Fish and coconut oils and butter reduced the intensity of anorexia caused by tumour necrosis factor-α. The extent to which fats rich in (n-3) polyunsaturates or poor in linoleic acid modulate the metabolic response to tumour necrosis factor-α depends upon additional fatty acid characteristics.
Splanchnic blood flow in man: evidence for mediation via a β-adrenergic mechanism
Authors: Braatvedt G. D. , Flynn M. D. , Stanners A. , Halliwell M. , Corrall R. J. M.
Published: August 2015

1. Superior mesenteric artery blood flow was examined by Doppler ultrasound in six male subjects aged 19–23 years during the infusion of saline (control), 10 and 40 ng of adrenaline min−1 kg−1 for 30 min, or propranolol and 10 ng of adrenaline min−1kg−1 for 30 min, on four separate occasions.

2. Adrenaline infusion resulted in significant peak mean (SEM) rises in circulating adrenaline concentrations during the infusion period only [control, 0.20 (0.05) nmol/l; 10 ng of adrenaline min−1 kg−1, 1.37 (0.29) nmol/l; 40 ng of adrenaline min−1kg−1, 3.73 (0.40) nmol/l; 10 ng of adrenaline min−1kg−1 and propranolol, 1.48 (0.16) nmol/l, P < 0.001 versus control]. These values are within the physiological range.

3. Superior mesenteric artery blood flow rose in a dose-dependent manner during the adrenaline infusions alone, but not during the infusion of adrenaline and propranolol [mean (95% confidence interval) area under the curve: control, −4.2 (−11 to +2.7)%; 10 ng of adrenaline min−1kg−1, +4 (−1 to 11.9)%; 40 ng of adrenaline min−1kg−1, +34 (+ 6.5 to + 61.5)%; 10 ng of adrenaline min−1kg−1 and propranolol, −8.4 (−23 to +6)%].

4. Superior mesenteric artery resistance fell during the adrenaline infusions alone and rose during the combined adrenaline and propranolol infusion [mean (SEM) area under the curve: control, 6.4 (2.7)%; 10 ng of adrenaline min−1kg−1, −2.9 (2.5)%; 40 ng of adrenaline min−1kg−1, −15 (1.4)%; 10 ng of adrenaline min−1kg−1 and propranolol, 16.9 (10)%].

5. These data suggest that splanchnic vasodilatation is mediated via a β-adrenergic mechanism.
Observations on the early renal uptake and later tubular metabolism of radiolabelled aprotinin (Trasylol) in man: theoretical and practical considerations
Authors: Rustom R. , Grime J. S. , Maltby P. , Stockdale H. R. , Critchley M. , Bone J. M.
Published: August 2015

1. The novel method recently developed to measure renal tubular degradation of filtered proteins in man using radiolabelled aprotinin (Trasylol) has been modified to allow the fate and the significance of the renal catabolism of radiolabelled aprotinin to be determined beyond 24 h.

2. Ten renal patients with normal kidney function and variable proteinuria each received two separate intravenous injections of radiolabelled aprotinin, 5.0 mg of 99mTc-labelled aprotinin (40 MBq) and 0.5 mg of 131I-labelled aprotinin (5 MBq). Chromatography (Sephadex-G-25-M) was used to separate undegraded radiolabelled aprotinin from the free isotope in urine and plasma. Renal uptake from σ-camera images (24 h for 99mTc-Iabelled aprotinin and up to 96 h for 131I-labelled aprotinin) and urinary activity (48 and 96 h, respectively) were measured.

3. The renal handling of radiolabelled aprotinin was similar with the two isotopes. Chromatography showed that all plasma activity was undegraded radiolabelled aprotinin, and urine activity was only the free isotopic label.

4. Kidney uptake of 131I-labelled aprotinin was prompt, reaching a cumulative maximum of 37.1 ± 3.0% of dose at 24 h, but falling exponentially thereafter to 5.6 ± 1.0% of dose at 96 h.

5. The rate of excretion of the free label in urine, i.e. the metabolic rate of radiolabelled aprotinin, was relatively constant over the first 24 h (1.6 ± 0.09% of dose/h), but then fell in parallel with the diminishing activity over the kidney, i.e. to 1.0 ± 0.1% of dose/h over 24–48 h and to only 0.4 ± 0.08% of dose/h over 72–96 h.

6. Fractional renal degradation of radiolabelled aprotinin, derived from the mean rate of urinary excretion of the free isotope over a given interval divided by the mean cumulative kidney uptake over the same interval (h−1), fell steeply early and then more slowly to 0.05 ± 0.003 h−1 at 14.25h, and stabilized thereafter varying little between 0.04 ± 0.01 h−1 and 0.05 ± 0.01 h−1 over 36–84 h.

7. Thus, the maximum cumulative kidney uptake of radiolabelled aprotinin is achieved by 24 h, when the metabolic rate and fractional degradation are reliable indices of catabolism. The falling metabolic rate after 24 h, together with the constant rate of fractional degradation, suggests that there is a readily saturable step in the metabolic process. Hence, duplicate measurements of radiolabelled aprotinin uptake and metabolism around 24 h only (12–36 h) are sufficient and offer a simple and a reliable tool in clinical studies for determining the link between renal tubular protein degradation and renal disease progression.
Genetics of a multifactorial disease: Autoimmune type I diabetes mellitus
Authors: Cornall Richard John
Published: August 2015

1. Three non-major histocompatability complex genes, Idd-3, Idd-4 and Idd-5, that influence the onset of autoimmune type 1 diabetes in the non-obese diabetic mouse have been located on chromosomes 3, 11 and 1.

2. In undertaking this study, a new map of the mouse genome has been created from polymerase chain reaction-analysable mouse microsatellite markers.

3. The homologues of these genes may reside on human chromosomes 1 or 4 (Idd-3), 17 (Idd-4) and 2q (Idd-5).
Effects of correcting arterial hypoxaemia on respiratory resistance in patients with chronic obstructive pulmonary disease
Authors: Coe C. I. , Pride N. B.
Published: August 2015

1. We have re-examined the effects of breathing 100% O2 on airflow resistance in hypoxaemic patients with chronic obstructive pulmonary disease. We measured arterial O2 saturation with an ear oximeter and total respiratory resistance by imposing forced oscillations at the mouth over the range 6–26 Hz during tidal breathing. Six normal subjects (mean age, 27.3 years; forced expiratory volume in 1 s, 3.82 litres) and 18 patients with severe chronic obstructive pulmonary disease and hypoxaemia (mean age, 66.6 years; forced expiratory volume in 1 s, 0.61 litres; O2 saturation breathing air, 88.4%) were examined in the sitting position breathing air and 100% O2. Eleven of the patients with chronic obstructive pulmonary disease were also studied before and after treatment with nebulized salbutamol (2.5 mg).

2. In normal subjects total respiratory resistance at 8 Hz breathing air was 2.35(0.16) cmH2Ol−1 s [mean (SEM)]; after salbutamol there was a small decrease in total respiratory resistance to 1.99(0.12) cmH2Ol−1 s. Breathing 100% O2 had no effect on total respiratory resistance either before or after salbutamol treatment.

3. In the patients with chronic obstructive pulmonary disease, values of total respiratory resistance fell with increasing frequency of oscillation; at 8 Hz, total respiratory resistance was 4.53(0.35) cmH2Ol−1 s breathing air and 3.73(0.28) cmH2Ol−1 s breathing 100% O2 (paired t-test, P = 0.001). The reduction in total respiratory resistance with O2 breathing varied between patients but was not related to the severity of hypoxaemia breathing air. Inhaled salbutamol had no significant effect on total respiratory resistance breathing air or 100% O2.

4. These studies show that arterial hypoxaemia contributes to increased airflow resistance in patients with chronic obstructive pulmonary disease. Our results show that the airway response to correcting hypoxaemia is independent of the response to β-adrenoceptor agonists. Further studies are required to investigate the site and mechanism of the airway effects of hypoxaemia.
Enteric disease in Early Childhood Inhibits Microvillus Expression by Potential Stem Cells
Authors: Borg M. , Phillips A. D. , Smith M. W. , Brown D.
Published: August 2015

1. Enterocyte development of microvillus structure has been measured in intestinal biopsies obtained from children suffering from coeliac disease, cow's milk protein intolerance and microvillus atrophy, and the results compared with similar measurements carried out in control children.

2. All types of enteric disease caused a significant 30% reduction in the length of microvilli present on undifferentiated basal crypt enterocytes, here referred to as potential stem cells.

3. Microvillus growth measured in control enterocytes took place mainly over the basal third of the villus. There was then little further change in structure during subsequent enterocyte migration to the villus tip.

4. Microvillus length in diseased tissue remained more or less constant during enterocyte migration to the crypt-villus junction. Microvillus length then decreased slightly during subsequent enterocyte migration over stunted villi.

5. The present results are discussed in relation to the supposed properties of potential stem cells. Comparisons are also made between profiles of microvillus development measured in healthy children and mature adults.
Dissociation between Pressor Sensitivity in Vivo and Contractile Reactivity in Vitro to Angiotensin II in Rats with Experimental Cirrhosis
Authors: Leehey David J.
Published: August 2015

1. Decreased pressor sensitivity to angiotensin II occurs in cirrhosis, but the mechanism remains unclear.

2. Angiotensin II dose-response studies were performed in conscious, chronically instrumented cirrhotic and control rats, and angiotensin II concentration-response studies were performed in isolated blood vessels obtained from similar groups of animals.

3. Cirrhotic rats demonstrated a significantly decreased pressor response to angiotensin II (5-80 ng/kg intravenously). However, angiotensin II-generated tension in thoracic aortic rings isolated from cirrhotic rats and studied in vitro was not impaired. These findings are consistent with the concept that circulating vasodilator substances in cirrhosis rather than an abnormality intrinsic to vascular smooth muscle cells are responsible for the decreased pressor sensitivity to angiotensin II in vivo.

4. Pretreatment with the cyclo-oxygenase inhibitor indomethacin (3 mg/kg intravenously) restored pressor sensitivity to angiotensin II to normal, suggesting that cyclo-oxygenase products, possibily vasodilator prostaglandins, may be involved in mediating pressor resistance to this hormone in vivo.
Biochemical Correlates of Aortic Distensibility in vivo in Normal Subjects
Authors: Hopkins K. D. , Lehmann E. D. , Gosling R. G. , Parker J. R. , Sönksen P. H.
Published: August 2015

1. Non-invasive aortic compliance measurements have been used previously to assess the distensibility of the aorta in several pathological conditions associated with increased cardiovascular risk. In adult patients with familial hypercholesterolaemia and those with growth hormone deficiency, aortic compliance has been found to correlate inversely with plasma cholesterol levels and age. We set out to establish if a relationship existed between the biophysical measurement of aortic compliance and biochemical variables in normal healthy adult subjects.

2. Blood pressure-corrected aortic distensibility, fasting insulin, insulin-like growth factor-I, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triacylgiycerol were measured in 38 (18 males, 20 females) normotensive healthy adults.

3. Blood pressure-corrected aortic distensibility was found to correlate inversely with age (r = −0.67, P <0.001), low-density lipoprotein-cholesterol (r = −0.37, P <0.02) and the low-density lipoprotein-/high density lipoprotein-cholesterol ratio (r = −0.33, P <0.05) and positively with insulin-like growth factor-I (r = 0.47, P <0.01). On separate analysis by sex, significant inverse correlations were observed in females between aortic distensbility and total cholesterol (r = −0.50, P <0.02), low-density lipoprotein-cholesterol (r = −0.55, P <0.01) and age (r = −0.74, P <0.001). A positive correlation was found between aortic distensibility and insulin-like growth factor-I (r = 0.48, P <0.05). On forced stepwise regression analysis, however, only age (P <0.02) was found to be significant. In males, an inverse correlation was found between aortic distensibility and age (r = −0.57, P <0.01), low-density lipoprotein-cholesterol (r = −0.51, P <0.05) and the low-density lipoprotein-/high-density lipoprotein-cholesterol ratio (r = −0.63, P <0.01). Positive correlations were observed between aortic distensibility and high-density lipoprotein-cholesterol (r = 0.48, P <0.05) and insulinlike growth factor-I (r = 0.48, P <0.05). On forced stepwise regression analysis the low-density lipoprotein-/high-density lipoprotein-cholesterol ratio (P <0.02) and age (P <0.04) were found to be the only significant independent predictors of aortic distensibility in males.

4. In normal adult subjects insulin-like growth factor-I and high-density lipoprotein-cholesterol are associated with increased aortic distensibility, whereas low-density lipoprotein-cholesterol is associated with aortic stiffening. We suggest that the measurement of blood pressure-corrected aortic distensibility in normal, healthy subjects may potentially be a useful, non-invasive research tool for investigating the effect of biochemical factors on the biophysical properties of the aortic wall.
Neutrophil Platelet-Activating Factor in Normal and Hypertensive Pregnancy and in Pregnancy-Induced Hypertension
Authors: Beilin L. J. , Croft K. D. , Michael C. A. , Ritchie J. , Schmidt L. , Vandongen R. , Walters B. N. J.
Published: August 2015

1. Platelet-activating factor is a phospholipid with potent vasodilator and platelet-activating properties. To test the hypothesis that a generalized change in cellular platelet-activating factor metabolism may be involved in the systemic vasodilatation of normal pregnancy or pregnancy-induced hypertension, we studied platelet-activating factor and eicosanoid synthesis in isolated leucocytes obtained from pregnant women before and after delivery compared with age-matched non-pregnant control subjects. Parallel observations were carried out in age- and gestation-matched women with uncomplicated hypertension in pregnancy and in women with pregnancy-induced hypertension and a further set of normotensive pregnant control subjects.

2. Leucocyte counts were higher in all pregnant groups compared with non-pregnant control subjects. Neutrophil production of platelet-activating factor and metabolites of prostacyclin, prostaglandin E2 and thromboxane in response to calcium ionophore stimulation were all lower in pregnant women compared with non-pregnant control subjects, but returned to similar levels 6 weeks post partum. There was no significant difference between essential hypertensive and normotensive groups. When women with pregnancy-induced hypertension were a priori subdivided into those with or without proteinuria, subjects with proteinuria showed significantly lower levels of neutrophil platelet-activating factor synthesis.

3. Plasma levels of the platelet-activating factor metabolite (lyso-platelet-activating factor) were also lower in pregnancy, suggesting alterations in the activity of enzymes controlling synthesis or degradation of this phospholipid in pregnancy. In pregnancy-induced hypertension the levels of plasma lyso-platelet-activating factor were higher than in normal pregnancy.

4. Thus this study demonstrates a reduction in the maximum capacity of neutrophils to synthesize platelet-activating factor and the three main classes of eicosanoids in vitro and a reduction in plasma lyso-platelet-activating factor levels in normotensive and essential hypertensive pregnancies. Contrary to expectation neutrophil prostacyclin metabolite generation was reduced in normal pregnancy. In pregnancy-induced hypertension with proteinuria the suppression of neutrophil platelet-activating factor synthesis was more pronounced. The results do not support the involvement of platelet-activating factor in the vasodilatation of pregnancy, but indicate profound changes in cellular phospholipid metabolism in normal pregnancy with further disturbances in pregnancy-induced hypertension by as yet unexplained mechanisms.
Is Receptor Cross-Regulation in Human Heart Caused by Alterations in Cardiac Guanine Nucleotide-Binding Proteins?
Authors: Ferro A. , Plumpton C. , Brown M. J.
Published: August 2015

1. Guanine nucleotide-binding proteins (G-proteins) play a central role in signal transduction between a wide variety of cell-surface receptors and intracellular second messenger systems. Recently, we and others have demonstrated that cross-regulation can occur between a variety of G-protein-linked receptors in human heart. Chronic β1-adrenoceptor blockade gives rise to sensitization of β2-adrenoceptor and of 5HT4-receptor responses, both of which are mediated via stimulation of adenylate cyclase through stimulatory G-proteins (Gs), and also gives rise to desensit-ization of muscarinic M2-receptor responses, which inhibit adenylate cyclase through inhibitory G-proteins (Gi).

2. In order to investigate whether these effects are due to quantitative changes in cardiac G-protein isoforms, we measured their abundance in right atrial appendage from patients taking or not taking β1-adrenoceptor antagonists, by immunoblotting.

3. Samples of right atrial appendage homogenate were subjected to SDS/PAGE, and proteins were electroblotted on to nitrocellulose membranes. These were then probed with specific anti-G protein anti-sera, and binding was revealed by means of a secondary antibody labelled with alkaline phosphatase and using a chromogenic substrate. The resulting bands were quantified by laser densitometry.

4. No quantitative differences were detected, between these two groups of patients, in the amounts of α-subunit of ‘long’ or ‘short’ Gs isoforms (GsαL and GsαS), or in the amounts of Gi 1 + 2 α-subunit (Giα1 + 2). Nor was any difference found in the abundance of the β-subunit of G-proteins. No ‘other’ G-protein (Go) was detectable in these samples by immunoblotting.

5. We conclude that the phenomenon of receptor cross-regulation which we have previously observed in human right atrial appendage is unlikely to be explained by quantitative changes at the G-protein level.
Plasma Levels of Brain Natriuretic Peptide in Healthy Subjects and Patients with Essential Hypertension: Response to Posture
Authors: La Villa Giorgio , Vena Silvio , Conti Alberto , Fronzaroli Caterina , Brat Aldo , Lazzeri Chiara , Guerra Cristina Tosti , Madiai Stefania , Marra Nazzareno , Franchi Franco
Published: August 2015

1. To examine whether posture-induced changes in central volume affect brain natriuretic peptide secretion, plasma levels of human brain natriuretic peptide-32-like immunoreactivity (hBNP-32-li) were measured by radioimmunoassay in 11 healthy subjects and 20 patients with essential hypertension after 15 min supine, 15 min sitting and 15 min with the legs raised at 60°, together with plasma atrial natriuretic peptide concentration, plasma renin activity and plasma aldosterone concentration.

2. In the supine position, the plasma hBNP-32-li level was 1.57 + 0.10 fmol/ml in healthy subjects and significantly higher in hypertensive patients (2.39 +0.13 fmol/ml, P <0.001). In both groups, plasma hBNP-32-li level significantly (P <0.001) decreased when sitting (normotensive, 1.22 +0.08 fmol/ml; hypertensive, 1.85 +0.15 fmol/ml, P <0.001 versus normotensive) and increased again after leg raising (normotensive, 2.13+0.12 fmol/ml; P <0.002 versus resting; hypertensive, 2.84 + 0.16 fmol/min, P <0.001 versus resting, P <0.025 versus normotensive).

3. The plasma atrial natriuretic peptide concentration showed similar behaviour to the plasma hBNP-32-li, whereas plasma renin activity and plasma aldosterone concentration increased during sitting and decreased during leg raising in both healthy subjects and hypertensive patients, who had significantly higher plasma aldosterone levels when supine and sitting.

4. The plasma hBNP-32-li level, measured in all postural positions, was directly correlated with plasma atrial natriuretic peptide concentration (normotensive: r = 0.55, P <0.001; hypertensive: r = 0.69, P <0.001) and inversely correlated with plasma renin activity (r = −0.56, P <0.001 and r = −0.58, P <0.001).

5. We have shown that two physiological procedures, assumption of the sitting position and raising the legs to 60°, significantly affect the plasma hBNP-32-li level in healthy subjects. The response of the plasma hBNP-32-li level to postural changes is maintained in patients with essential hypertension, who have increased plasma levels of this hormone. The relevance of the observed modifications in the plasma hBNP-32-li level to the homoeostatic response to posture remains to be established.
Insulin Resistance of Stress: Sites and Mechanisms
Authors: Brandi Luigi S. , Santoro Donatella , Natali Andrea , Altomonte Fiorella , Baldi Simona , Frascerra Silvia , Ferrannini Eleuterio
Published: August 2015

1. Stress is associated with a severe, yet reversible, form of insulin resistance. The aim of this study was to quantify the kinetics of insulin action (sensitivity and responsiveness) on intermediary metabolism during post-surgical stress.

2. We studied nine patients 6–8 h after major uncomplicated surgery, and eight healthy subjects matched for age, weight, glucose tolerance and duration of fast. A three-step isoglycaemic insulin clamp was combined with indirect calorimetry, [6-3H]glucose infusion and the forearm technique.

3. The following significant (P <0.05 or less) abnormalities were found in the patients. Hepatic glucose production was higher at baseline, and less suppressed by insulin. Whole-body glucose disposal was impaired at all insulin doses (by 33–60%). Glucose oxidation was depressed throughout the dose range but its increments in response to insulin were normal. In contrast, non-oxidative glucose disposal was essentially unresponsive. At all insulin levels, forearm glucose extraction was markedly depressed and forearm lactate release was in excess of concurrent glucose uptake, suggesting ongoing glycogenolysis despite insulin. Total lipolysis (plasma free fatty acid and glycerol levels) promptly responded to insulin but remained higher than in the control subjects throughout. In the forearm, even the highest insulin dose could not suppress net free fatty acid and glycerol release. Total lipid oxidation was increased throughout the insulin range, and calculated direct free fatty acid (as opposed to plasma free fatty acid) oxidation was virtually unaffected by insulin. Protein oxidation was slightly (35%) increased, but was suppressed normally in response to insulin. Energy expenditure was 20% higher at baseline, and tailed to rise with insulin. Arterial blood pH values were consistently (if slightly) lower, and net forearm proton release was higher, both at baseline and daring insulin infusion.

4. Post-surgical unsulin resistance is characterized by normal sensitivity but decreased responsiveness of glucose oxidation, lipolysis and plasma free fatty acid oxidation, whereas glycogen synthesis and direct free fatty acid oxidation are virtually unresponsive. For both glucose and lipid metabolism, the insulin resistance is particularly severe in forearm tissues, in which mild metabolic acidosis may play an additional role.
Free-Radical Activity after Reperfusion in Diabetic and non-diabetic Patients with Acute Myocardial Infarction
Authors: Gray Rosaire P. , Wickens David G. , Patterson David L. H. , Yudkin John S.
Published: August 2015

1. Oxygen-derived free radicals have been implicated in reperfusion injury after thrombolytic therapy in acute myocardial infarction. To test the hypothesis that diabetic patients may have increased oxidative stress which may lead to increased reperfusion damage and thereby contribute to a poorer outcome in these patients, we measured two indices of free-radical activity, diene conjugate molar ratios as an index of lipid isomerization and thiobarbituric acid-reactive material as an index of lipid peroxidation, in 66 non-diabetic and 26 diabetic patients admitted with acute myocardial infarction who received thrombolytic therapy and in whom reperfusion was assessed using early time to peak creatine kinase-MB isoenzyme release.

2. Baseline diene conjugate molar ratios or thiobarbituric acid-reactivity did not differ significantly between diabetic and non-diabetic patients (1.97 + 0.98 versus 2.16 + 1.34; not significant and 2.10 + 0.60 versus 1.99 + 0.73 μmol/l; not significant). In patients with enzymic evidence of reperfusion (i.e. time to peak enzyme release ≦12h) diene conjugate molar ratios peaked at 6 h compared with 12 h in those with unsuccessful reperfusion (i.e. time to peak enzyme release >12 h). In patients with unstable angina the maximum increase in the diene conjugate molar ratios was significantly less than in patients with acute myocardial infarction (6.80 + 12.3 versus 15.82 + 22.55%; P = 0.035). There was a significant fall in thiobarbituric acid-reactivity at 24 h in patients with enzymic evidence of reperfusion (P = 0.017). There were no major differences in these rises and falls between diabetic and non-diabetic patients.

3. These findings suggest the free-radical activity as assessed by diene conjugate molar ratios was increased after myocardial infarction, but the increase was not significantly different in diabetic and non-diabetic patients. Early peaking of free-radical activity was associated with enzymic evidence of reperfusion.
Change in Macro Molecular Composition of Interstitial Fluid from Swollen Arms after Breast Cancer Treatment, and Its Implications
Authors: Bates D. O. , Levick J. R. , Mortimer P. S.
Published: August 2015

1. The pathophysiology of chronic arm oedema after treatment of breast cancer was investigated by collecting serum and subcutaneous interstitial fluid from the affected and contralateral arms by the wick method (both arms) and by aspiration (oedematous arm). The fluids were analysed for total protein, albumin, glycosaminoglycan and viscosity, and arm volume was measured.

2. Total protein concentration in the aspirated oedema fluid was 32.4 + 7.5 g/l (mean + SD throughout; n = 39). Protein concentration in wick fluid from the oedematous arm (35.8 + 7.3 g/l, n = 14) was not significantly different from that in aspirated fluid. The oedema protein concentrations were significantly lower than in wick fluid from the non-swollen arm (41.4 + 6.7 cmH2O, n = 13, P <0.01, analysis of variance). This was surprising in view of the common assumption that, the condition being of lymphatic origin, the oedema protein concentration should be raised.

3. The ratio of aspirate protein concentration to serum protein concentration showed a weak but highly significant negative correlation with the percentage increase in arm volume (r = −0.47, n = 35, P <0.005), again in contrast to conventional expectation. The demonstration of a reduced protein concentration in the swollen arm did not therefore depend solely on a comparison with the wick control results. The volume increased by on average 33% and the ratio of aspirate protein concentration to serum protein concentration averaged 0.52 + 0.11 on the swollen side and 0.64 + 0.13 on the unaffected side.

4. Serum protein concentration in the patients with arm swelling (61.2 + 4.9 g/l) was significantly lower than that in postmastectomy patients without this complication (65.0 + 6.2 g/l). Most of the decrease occurred in the albumin fraction (oedema patients, 383 + 5.1 g/l; control patients, 42.0 + 2.1 g/l). In oedema patients receiving the anti-oestrogen tamoxifen serum albumin concentration was on average 23 g/l lower than in oedema patients not under medication (P <0.05, t-test).

5. Glycosaminoglycan concentration in oedema fluid was 0.8 +0.14 g/l (n = 21) and 75% was sulphated. Along with the plasma protein this raised the relative viscosity of the fluid to 1.34 + 0.16 (n = 11).

6. The reduction in interstitial protein concentration in the swollen arm, contrary to expectation in lymph-oedema, could be explained in several ways. One possible hypothesis in light of reported haemodynamic abnormalities in such arms is that capillary pressure rises, increasing capillary filtration rate. We conclude that the pathophysiology of postmastectomy oedema involves additional factors besides axillary node trauma, and we suggest that input (filtration) as well as output (lymph flow) requires evaluation.
Interactions of Hydrogen Peroxide with Interleukin-6 and Platelet-Derived Growth Factor in Determining Mesangial Cell Growth: Effect of Repeated Oxidant Stress
Authors: D'Souza R. J. , Phillips H. M. , Jones P. W. , Strange R. C. , Aber G. M.
Published: August 2015

1. This study examined the influence of H2O2, interleukin-6 and platelet-derived growth factor on the proliferation of rat mesangial cells. Mesangial cells were exposed to either a single pulse or three daily pulses of H2O2 (10−8-10−4 mol/l), alone or in combination with interleukin-6 (5 ng/ml) and/or platelet-derived growth factor (10 ng/ml). Proliferation was assessed after 24 h and 72 h of incubation using [3H]thymidine incorporation and cell counts.

2. Although one pulse of H2O2 had no significant effect on mesangial cell proliferation, three daily pulses of 10−6 mol/l H2O2 resulted in a significant increase in [3H]thymidine incorporation of 31 (52.6, 10.3)% (median and 75th-25th interquartile range) (P <0.001). Both interleukin-6 and platelet-derived growth factor were also mitogenic to mesangial cells, [3H]thymidine incorporation increasing by 19 (36.7, −6.7)% (P <0.05) and 53.5 (107, 21.9)% (P <0.001), respectively. The mitogenic effect of interleukin-6 was enhanced by 10−6 mol/l H2O2 [49.9 (77.7, 12.3)%] (P <0.01), whereas the addition of 10−6 mol/l H2O2 to platelet-derived growth factor resulted in a summated increase in [3H]thymidine incorporation of 82.7 (113, 57.4)% (P <0.001). Incubation with all three substances simultaneously resulted in down-regulation of growth compared with H2O2 plus platelet-derived growth factor by 55.4 (77.7, 103)% (P <0.05).

3. These findings suggest that reactive oxygen species may play a major role in determining the mesangial cell proliferation that occurs in certain forms of glomerulonephritis, acting either alone or in combination with other growth factors.
Viral Infection of Bovine Bronchial Epithelial Cells Induces Increased Neutrophil Chemotactic Activity and Neutrophil Adhesion
Authors: Raz Meir , Robbins Richard A. , Kelling Clayton L. , Stine Lisa C. , Leikauf George D. , Rennard Stephen I. , Spurzem John R.
Published: August 2015

1. Acute bronchitis secondary to viral infection is associated with an influx of neutrophils. We hypothesized that bronchial epithelial cells are capable of releasing neutrophil chemotactic activity in response to viral infection.

2. To test this hypothesis, primary cultures of bovine bronchial epithelial cells were inoculated with a bovine respiratory pathogen, bovine herpes virus-1.

3. Supernatants collected from inoculated cells, before signs of toxicity, demonstrated significant neutrophil chemotactic activity using a blind well chamber neutrophil chemotaxis assay. Lipoxygenase inhibitors markedly reduced the amount of neutrophil chemotactic activity released after bovine herpes virus-1 inoculation. Analysis of arachidonic acid metabolites in cell supernatants by reverse-phase h.p.l.c. confirmed that leukotriene B4, a potent neutrophil chemoattractant, was released.

4. We also confirmed that adhesion of neutrophils to bovine herpes virus-1-inoculated bronchial epithelial cells was increased and mediated in part by the neutrophil integrin, LFA-1.

5. Thus, virally infected airway epithelial cells release leucocyte chemoattractants and hence adhesive interactions, functions that are likely to be important in the inflammatory acute response to viral infection.
Pretreatment with Methylprednisolone in Coronary Artery Bypass Grafting Influences the Levels of Histamine and Tryptase in Serum but Not in Bronchoalveolar Lavage Fluid
Authors: van Overveld F. J. , De Jongh R. F. , Jorens P. G. , Walter P. , Bossaert L. , De Backer W. A.
Published: August 2015

1. The presence of histamine and tryptase in serum during and after coronary artery bypass grafting may be an indication of the induction of inflammation.

2. One group of patients received no glucocorticoids and a second group received methylprednisolone before extracorporeal circulation. In the steroid group no effects were seen on the basal levels of histamine (2.84 + 0.12 ng/ml) and tryptase (030 + 0.05 ng/ml) during and after surgery. In the other group two peak levels of histamine were observed: one at 10 min after starting extracorporeal circulation (4.19 +1.79 ng/ml) and another at 4h after surgery (8.26 +4.85 ng/ml). In this group tryptase was only elevated during the period of extracorporeal circulation (1.54+ 0.16 ng/ml).

3. There were no differences between the two groups in complement activation. C3a levels rose to 170 +8% and 180 +10% of the initial value in the steroid and non-steroid group, respectively.

4. It was concluded that during surgery mast cells were activated, but since tryptase levels decreased in the post-operative period, the second increase in the histamine level can be explained by activation of basophils or by an unknown mechanism for the release of histamine but not tryptase by mast cells.

5. In the bronchoalveolar lavage fluid the levels of histamine and tryptase showed no differences between the two groups of patients, but histamine was enhanced compared with normal levels.
Heterogeneity of Human Biliary Mucin: Functional Implications
Authors: Klinkspoor J. Henriëtte , van Wijland Michel J. A. , Koeleman Carolien A. M. , van Dijk Willem , Tytgat Guido N. J. , Groen Albert K.
Published: August 2015

1. Human gallbladder mucin has been implicated as playing a role in the pathogenesis of gallstones. In previous studies no differences have been found in the content or composition of mucins derived from control bile or cholesterol gallstone bile. Until now, no differences were also found between these two groups of mucins with regard to their ability to cause cholesterol nucleation. In the accompanying paper we have reported that there is a strong heterogeneity of gallbladder mucins derived from individual patients (M. J. A. van Wijland, J. H. Klinkspoor, L. Th. de Wit, R. P. J. Oude Elferink, G. N. J. Tytgat and A. K. Groen, Clin Sci 1994; 86: 67–74). In the present study we further investigated a possible patient to patient heterogeneity of mucin by means of immunological and functional characterization of mucins isolated from hepatic bile of six different patients with gallstones.

2. Considerable heterogeneity was found. Two of the mucins barely reacted with a polyclonal anti-mucin antibody, whereas the other four mucins reacted very strongly. Lectin-binding studies indicated that the glycans of these two mucins expressed less D-N-acetylgalactosamine residues than the other four mucins. This was confirmed by analyses of the glycan compositions. These studies furthermore indicated that the glycans were of the O-linked type, contained α-D-N-acetylglucosamine and were fucosylated, sialy-lated and sulphated to different extents. Except for a strong heterogeneity in the sugar composition of the mucins, heterogeneity was also found in the biological activity of the mucins. The two immunologically diverging mucins nucleated cholesterol from model bile 1–2 days earlier and also caused an almost threefold more rapid rupture of cholesterol/phospholipid vesicles than the other mucins.

3. We conclude that considerable differences exist between mucins derived from individual patients and that the heterogeneity in glycan composition might play a role in the pathogenesis of gallstone disease.
Secretion of Ions and Pharmacological Responsiveness in the Mouse Paw Sweat Gland
Authors: Sato K. , Cavallin S. , Sato K. T. , Sato F.
Published: August 2015

1. Some of the basic functional features of the mouse paw eccrine sweat gland were delineated to allow comparison with those of transgenic mice in the future.

2. The mouse sweat secretory coil responds to methacholine, elaborating a K+-rich (> 120 mmol/l), Na+-poor (< 70 mmol/l) primary fluid as does the rat paw sweat gland, as previously reported. The methacholine-induced sweat rate increases with age in parallel with the growth of the sweat gland over the first 6 weeks of life.

3. The sweating response to cyclic AMP-elevating agents, such as isoprenaline or forskolin, is as much as 40% of the methacholine-induced sweat rate at 1 week of age, but falls to 10% by 6 weeks of age despite the fact that the agonist-induced tissue accumulation of cyclic AMP expressed on a per μg of protein basis triples with age over the same period.

4. A marked K+ outflux was also noted in response to methacholine and a small K+ outflux was seen in response to cyclic AMP-elevating agonists in super-fused adult mouse secretory coils in vitro.

5. Since sweat secretion is usually associated with activation of either K+ channels or Cl− channels or both, and since the sweating occurred in response to cyclic AMP-elevating agonists, we speculate that the cyclic AMP-activated Cl− channels (the mouse version of the cystic fibrosis transmembrane conductance regulator) may also occur in the mouse sweat gland, but that the degree of their expression may be influenced by the age of the mice.
Insulin—like Growth Factor-1 is Partially Responsible for Fibroblast Proliferation Induced by Bronchoalveolar Lavage Fluid from Patients with Systemic Sclerosis
Authors: Harrison Nicholas K. , Cambrey Alison D. , Myers Allen R. , Southcott Anne M. , Black Carol M. , du Bois Roland M. , Laurent Geoffrey J. , McAnulty Robin J.
Published: August 2015

1. Interstitial lung disease is a common complication of systemic sclerosis. The mechanism by which excess collagen is deposited in the lung is poorly understood, but is thought to involve release of mediators which activate lung fibroblasts. In this study we investigated and partially characterized the fibroblast proliferative activity of bronchoalveolar lavage fluid from 29 patients with systemic sclerosis, 19 with and 10 without evidence of lung disease assessed by thin-section computed tomography.

2. Bronchoalveolar lavage fluid from both groups of patients stimulated fibroblast proliferation compared with control subjects: systemic sclerosis with normal computed tomography, 27.7 (range 10.5–57.9)% above control; systemic sclerosis with abnormal computed tomography, 26.7 (range 5.0–47.8)% above control, P < 0.02 in both cases.

3. The activity was reduced by about one-third by neutralizing antibodies to insulin-like growth factor-1 but not platelet-derived growth factor. Levels of insulin-like growth factor-1 of bronchoalveolar fluid were increased in patients with systemic sclerosis [2.10 (range 1.10–3.48) ng/ml of bronchoalveolar lavage fluid] compared with controls [1.45 (range 1.10–2.05) ng/ml; P < 0.01]. When patients were subdivided into those with abnormal computed tomography [2.10 (range 1.20–3.48) ng/ml] and those with normal computed tomography [1.85 (range 1.10–2.90) ng/ml] only the values for the group with evidence of lung disease were increased compared with control subjects (P < 0.02). Platelet-derived growth factor could not be detected in bronchoalveolar lavage fluid from any group. Fractionation of bronchoalveolar lavage fluid demonstrated activity in several fractions consistent with the molecular masses of insulin-like growth factor-1 associated with binding proteins.

4. We conclude that bronchoalveolar lavage fluid from patients with systemic sclerosis contains increased levels of insulin-like growth factor-1 and this contributes to the increased fibroblast-growth-promoting activity of this fluid. The data also suggest that other mitogens are involved, but we were unable to demonstrate a role for platelet-derived growth factor.
Tumour Necrosis Factor Receptor Levels Are Linked to the Acute-Phase Response and Malnutrition in Human-Immunodeficiency-Virus-Infected Patients
Authors: Süttmann U. , Selberg O. , Gallati H. , Ockenga J. , Deicher H. , Müller M. J.
Published: August 2015

1. Increased release of tumour necrosis factor is thought to contribute to human-immunodeficiency-virus-associated wasting syndrome. Elevated serum concentrations of tumour necrosis factor have, however, mainly been found during acute opportunistic infections and were not correlated with the degree of wasting. This finding may be explained by the paracrine release and the rapid inactivation of tumour necrosis factor. Serum levels of the two recently detected soluble tumour necrosis factor receptor proteins (p55 and p75) are assumed to reflect tumour necrosis factor release.

2. Serum levels of soluble tumour necrosis factor receptors 55 and 75 were measured by an enzyme-linked immunological and biological binding assay in 45 human-immunodeficiency-virus-infected patients and seven healthy control subjects. Patients were followed up for survival. Serum albumin, prealbumin, total iron-binding capacity (transferrin) and C-reactive protein concentrations were measured using standard laboratory methods. Body composition was determined by bioelectrical impedance analysis.

3. Serum concentrations of soluble tumour necrosis factor receptor 55 and 75 were both significantly increased in human-immunodeficiency-virus-infected patients as compared with the healthy control subjects (P < 0.05); soluble tumour necrosis factor receptor concentrations were even more increased in patients with elevated C-reactive protein levels (≥ 5 mg/l) as compared with those with normal C-reactive protein levels (< 5 mg/l; P < 0.0001 and P < 0.01, respectively). An association was observed between serum soluble tumour necrosis factor receptor 55 and 75 concentration and (i) serum albumin concentration (r = −0.46, P < 0.005 and r = −0.63, P < 0.001, respectively), (ii) serum prealbumin concentration (r = −0.42, P < 0.005 and r = −0.57, P < 0.001, respectively), and (iii) serum total iron-binding capacity (transferrin; r = −0.31, P < 0.05 and r = −0.44, P < 0.005, respectively). A correlation was also found between serum soluble tumour necrosis factor receptor 55 level and the extracellular mass-body cell mass quotient (r = 0.63, P < 0.001).

4. The present data provide evidence that the tumour necrosis factor system is involved in the genesis of human-immunodeficiency-virus-associated malnutrition. Serum levels of soluble tumour necrosis factor receptors may be useful for diagnosis and management of the wasting syndrome.