bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress response decreases the interleukin-1β-induced production of complement component C3 in human intestinal epithelial cells
Authors: MOON Ryan , PRITTS Timothy A. , PARIKH Alexander A. , FISCHER Josef E. , SALZMAN Andrew L. , RYAN Marnie , WONG Hector R. , HASSELGREN Per-Olof
Published: August 2015

Interleukin-1β (IL-1β) increases the production of complement component C3 in enterocytes. Heat shock regulates the response to cytokines and other inflammatory mediators in various cell types. We tested the hypothesis that the heat-shock response regulates IL-1β-induced C3 production in the enterocyte. Cultured Caco-2 cells, a human intestinal epithelial cell line, were treated with sodium arsenite (10–500 µM) for 1 h or subjected to hyperthermia (43 °C) for 1–4 h, and allowed to recover for 1 h. The cells were then treated with IL-1β (0.5 ng/ml) for up to 24 h, whereafter C3 levels were measured by ELISA and C3 mRNA by Northern blot analysis. Heat-shock protein of 72 kDa (hsp72) was determined by Western blot analysis. Treatment of the cells with sodium arsenite or subjecting them to hyperthermia induced the expression of hsp72. The IL-1β-induced expression of C3 mRNA and C3 production were down-regulated by hyperthermia and sodium arsenite in a dose-dependent fashion. The results suggest that the stress response induced by hyperthermia or sodium arsenite decreases IL-1β-induced C3 production in human enterocytes.
Tissue- and isoform-specific effects of aging in rats on protein kinase C in insulin-sensitive tissues
Authors: QU Xianqin , SEALE J. Paul , DONNELLY Richard
Published: August 2015

The mechanisms responsible for the age-related decline in insulin sensitivity have not been clearly identified, but activation of the diacylglycerol/protein kinase C (PKC) signalling pathway (often confined to individual isoforms of PKC) has recently been implicated in the pathogenesis of other insulin-resistant states in both humans and animal models. Fasting serum glucose, insulin and triacylglycerol (triglyceride) concentrations, and results of oral glucose tolerance tests, were compared in groups of 6-week-old (n = 8) and 6-month-old (n = 8) Sprague–Dawley rats. Insulin-responsive tissues (liver, soleus muscle and epididymal fat pad) were collected to compare levels of diacylglycerol, PKC enzyme activity and protein expression of individual PKC isoforms in cytosol and membrane fractions. The older group were heavier (556±14 g, compared with 188±7 g) and relatively insulin-resistant and hyperinsulinaemic (477±73 pM compared with 293±51 pM; P < 0.05) compared with young rats; they also had greater areas under the serum glucose (old, 20.3±1.1; young, 17.3±0.7 mmol·h-1·l-1) and insulin (old, 1254±76; young, 721±113 mmol·h-1·l-1) profiles following an oral glucose tolerance test, and significantly higher fasting triacylglycerol levels (old, 1.24±0.06 mM; young, 0.92±0.07 mM; P < 0.01). There were no age-related differences in diacylglycerol levels or PKC activity in muscle and liver, but membrane-associated PKC activity was 2.5-fold higher in the adipose tissue of older rats (101±19 compared with 40±5 pmol·min-1·mg-1 protein; P < 0.05) due to increased translocation of PKC-βI, -βII and -ε. Thus insulin resistance due to normal aging is associated with tissue- and isoform-specific changes in diacylglycerol/PKC signalling. In contrast with diabetes and dietary-induced insulin resistance, there were no changes in diacylglycerol/PKC signalling in skeletal muscle and liver, but isoform-specific translocation and higher PKC activity in adipose tissue may blunt the insulin-mediated inhibition of lipolysis and contribute to the increased triacylglycerol levels observed in older animals.
Maximization of skin capillaries during intravital video-microscopy in essential hypertension: comparison between venous congestion, reactive hyperaemia and core heat load tests
Authors: ANTONIOS Tarek F. T. , RATTRAY Fraser E. M. , SINGER Donald R. J. , MARKANDU Nirmala D. , MORTIMER Peter S. , MACGREGOR Graham A.
Published: August 2015

Intravital capillary video-microscopy is a dynamic method for studying skin capillaries. The technique of direct intravital microscopy (without dyes) depends on the presence of red blood cells inside capillaries for their identification. The aim of the present study was to compare different techniques to try to establish the best method for maximizing the number of visible perfused capillaries during intravital capillary microscopy. We compared the effects of venous congestion with those of post-occlusive reactive hyperaemia (Study 1). We also investigated venous congestion followed first by post-occlusive reactive hyperaemia and then by a core heat load test (Study 2). Finally we investigated venous congestion followed by post-occlusive reactive hyperaemia combined with venous congestion (Study 3). In Study 1, capillary density increased with venous congestion from a baseline value of 74±2 (mean±S.E.M.) per field to 82±3 per field (P< 0.0001; analysis of variance). With reactive hyperaemia, there was an apparent decrease in visible capillary density to 69±2 per field. In Study 2, baseline capillary density was 69±4 per field, and this increased significantly with venous congestion to 74±4 per field (P = 0.01). With both reactive hyperaemia and core heat load, the apparent density was 62±4 per field. In Study 3 the baseline density was 70±2 per field, and this increased significantly with venous congestion to 80±3 per field (P< 0.0001). With reactive hyperaemia combined with venous congestion, the density was 81±3 per field (P = 0.328 compared with venous congestion alone). The results show that venous congestion at 60 mmHg for 2 min is the most effective method for visualization of the maximal number of perfused skin capillaries during intravital video-microscopy.
Markers of systemic inflammation predicting organ failure in community-acquired septic shock
Authors: TAKALA Annika , JOUSELA Irma , JANSSON Sten-Erik , OLKKOLA Klaus T. , TAKKUNEN Olli , ORPANA Arto , KARONEN Sirkka-Liisa , REPO Heikki
Published: August 2015

To obtain predictors of organ failure (OF), we studied markers of systemic inflammation [circulating levels of interleukin-6 (IL-6), IL-8, soluble IL-2 receptor (sIL-2R), soluble E-selectin and C-reactive protein, and neutrophil and monocyte CD11b expression] and routine blood cell counts in 20 patients with systemic inflammatory response syndrome and positive blood culture. Eight patients with shock due to community-acquired infection developed OF, whereas 11 normotensive patients and one patient with shock did not (NOF group). The first blood sample was collected within 48 h after taking the blood culture (T1). OF patients, as compared with NOF patients, had at T1 a lower monocyte count, a lower platelet count, higher levels of CD11b expression on both neutrophils and monocytes, and higher concentrations of IL-6, IL-8 and sIL-2R. C-reactive protein and soluble E-selectin concentrations did not differ between groups. No parameter alone identified all patients that subsequently developed OF. However, a sepsis-related inflammation severity score (SISS), developed on the basis of the presence or absence of shock and on the levels of markers at T1, identified each patient that developed OF. The maximum SISS value was 7. The range of SISS values in OF patients was 2–5, and that in NOF patients was 0–1. In conclusion, high levels of CD11b expression, depressed platelet and monocyte counts, and high concentrations of IL-6, IL-8 and sIL-2R predict OF in patients with community-acquired septic shock, and the combination of these markers may provide the means to identify sepsis patients who will develop OF.
Oxygen uptake kinetics during exercise in chronic heart failure: influence of peripheral vascular reserve
Authors: HEPPLE Russell T. , LIU Peter. P. , PLYLEY Michael J. , GOODMAN Jack M.
Published: August 2015

Exercise performance in chronic heart failure is severely impaired, due in part to a peripherally mediated limitation. In addition to impaired maximal exercise capacity, the O2 uptake (O2) response during submaximal exercise may be affected, with a greater reliance on anaerobiosis leading to early fatigue. However, the response of O2 kinetics to submaximal exercise in chronic heart failure has not been studied extensively; in particular, the relationship between oxygen utilization and the peripheral response to exercise has not been studied. The present investigation examined the time-constant (τ, corresponding to 63% of the total response fitted from exercise onset) of the O2 kinetics on-response to submaximal exercise and its relationship to maximal peripheral blood flow in patients with chronic heart failure, and compared responses with those in healthy sedentary subjects. Subjects were 10 patients with chronic heart failure (NYHA class II/III). The mean age was 50±12 years, with a mean resting left ventricular ejection fraction of 25±9%. Controls were 10 age-matched healthy subjects. O2(max) was first determined for all subjects. Repeated transitions from rest to exercise were performed on a cycle ergometer while measuring breath-by-breath responses of O2 at a fixed work rate of 50% of O2(max) (heart failure patients and healthy controls) and at a work rate equivalent to the average in heart failure patients (65 W; healthy controls only). On a separate occasion, post-maximal ischaemic exercise calf blood flow was measured (strain-gauge plethysmography).Whereas heart failure subjects displayed a significantly prolonged O2 kinetics response at a similar absolute workload (i.e. 65 W), as indicated by a longer τ value (42 s, compared with 22 s in controls; P< 0.01), there was no difference in τ at a similar relative work rate [50% of O2(max)]. In addition, heart failure subjects demonstrated a lower maximal calf blood flow (P< 0.05) than control subjects. These results indicate that patients with heart failure have a prolonged O2 kinetics on-response compared with healthy subjects at a similar absolute work rate (i.e. 65 W), but not at a similar relative work rate [50% of O2(max)]. Thus, despite a reduced maximal calf blood flow response associated with heart failure, it does not appear that this contributes to an impairment of the submaximal exercise response beyond that explained by a reduced maximal exercise capacity [O2(max)].
Baseline heart rate variability in healthy centenarians: differences compared with aged subjects (>75 years old)
Authors: PAOLISSO Giuseppe , MANZELLA Daniela , BARBIERI Michelangela , RIZZO Maria Rosaria , GAMBARDELLA Antonio , VARRICCHIO Michele
Published: August 2015

Healthy centenarians have better anthropometric, endocrine, metabolic and immunological parameters than aged subjects (> 75 years old). Heart rate variability (HRV) has been demonstrated to be a good index of the cardiac autonomic nervous system. It is not known whether there are any differences in cardiac autonomic nervous system activity between aged subjects and healthy centenarians. It is possible that differences in cardiac autonomic nervous system activity could represent one of a cluster of factors explaining the extreme survival of centenarians. Thus we aimed to answer the following question: is there any difference in baseline HRV parameters between aged subjects and healthy centenarians? Therefore power spectral analysis of HRV at baseline was investigated in 25 aged subjects (age ⩾ 75 years) and 30 healthy centenarians (age ⩾ 100 years). Anthropometric measurements were made in all subjects, fasting blood samples were drawn for metabolite determinations, and HRV was determined. Independent of age, gender, body mass index and fasting plasma noradrenaline and free 3,3′,5-tri-iodothyronine concentrations, healthy centenarians had lower basal values for total power (1318±546 compared with 1918±818 ms2; P< 0.01) and the low-frequency component (33±21 compared with 50±11 normalized units; P< 0.03) and a higher value for the high-frequency component (77±15 compared with 61±18 normalized units; P< 0.05) than aged subjects. Consequently, the low-frequency/high-frequency ratio (0.43±0.07 compared with 0.91±0.05; P< 0.02) was also lower in the healthy centenarians than in the aged subjects. Our study demonstrates that the basal low-frequency/high-frequency ratio, an indirect index of cardiac sympathovagal balance, is lower in healthy centenarians than in aged subjects.
Amino acid nutrition and immune function in tumour-bearing rats: a comparison of glutamine-, arginine- and ornithine 2-oxoglutarate-supplemented diets
Authors: ROBINSON Lindsay E. , BUSSIÈRE Françoise I. , LE BOUCHER Jacques , FARGES Marie-Chantal , CYNOBER Luc A. , FIELD Catherine J. , BARACOS Vickie E.
Published: August 2015

Dietary supplementation with glutamine (Gln), arginine (Arg) or ornithine 2-oxoglutarate (α-ketoglutarate; OKG) has attracted recent attention for the potential to improve anti-cancer immune function. However, since these compounds have not been compared systematically in an internally controlled study, their relative efficacy is difficult to estimate. Buffalo rats were fed on nutritionally complete semi-purified diets supplemented with Gln, Arg or OKG for 14 days after implantation of the Morris hepatoma 7777 (n⩾ 7 per diet). The control diet was made isonitrogenous and isoenergetic by addition of a mixture of non-essential amino acids. After 14 days, peritoneal macrophages and splenocytes were isolated to determine cell phenotypes, macrophage cytostatic activity and natural killer (NK) cell cytotoxicity, as well as nitric oxide (NO) and cytokine production. Diet had no effect on tumour weight (1.6±0.2 g; n = 59). However, rats fed OKG had increased macrophage cytostatic activity and NK cell cytotoxicity (P< 0.05). Although enhanced killing ability by NK cells was associated with higher splenocyte NO production (P< 0.04), increased cytotoxicity was not inhibited by a specific inhibitor of inducible NO synthase. The proportion of interleukin-2-receptor-positive T cells after stimulation increased in rats fed OKG (P< 0.05); however, cytokine production was not affected by diet. None of OKG, Gln or Arg altered tumour growth compared with a control mixture of non-essential amino acids. These results suggest no net advantage for anti-cancer immunity, but do not preclude benefits in immune responses to disease recurrence or metastasis, therapy or secondary infection.
Renal effects of hyperinsulinaemia in subjects with two hypertensive parents
Authors: ANDERSEN Ulrik B. , SKØTT Peter , BRUUN Niels E. , DIGE-PETERSEN Harriet , IBSEN Hans
Published: August 2015

The aim of this investigation was to study the effects of isoglycaemic hyperinsulinaemia on the renal metabolism of electrolytes and water in subjects with a strong genetic predisposition to essential hypertension, compared with that in non-predisposed subjects. We studied 25 normotensive subjects aged 18–35 years whose parents both had essential hypertension, and 22 age- and sex-matched subjects whose parents were both normotensive. Diabetes or morbid obesity in any subject or parent excluded the family. The 24-h blood pressure was measured. The subjects received an isocaloric diet with a fixed content of sodium and potassium for 4 days before the study. An isoglycaemic, hyperinsulinaemic clamp with infusion of insulin (40 munits·min-1·m-2) was performed. We measured the renal clearance of diethylenetriaminepenta-acetic acid, sodium, potassium and lithium both under basal conditions and during hyperinsulinaemia. In response to hyperinsulinaemia, renal sodium clearance decreased to a significantly greater extent in the hypertension-prone subjects [0.57 (0.74, 0.36) ml·min-1·1.73 m2 (median and quartiles)] than in the controls [0.34 (0.56, 0.18) ml·min-1·1.73 m2] (P = 0.04). Compared with the controls, the subjects predisposed to hypertension had a higher 24-h diastolic blood pressure [78 (70, 82) mmHg, compared with 73 (68, 77) mmHg], but a similar insulin sensitivity index {107×[313 (225, 427)] compared with 107×[354 (218, 435)] l2·min-1·pmol-1·kg-1}. Thus the sodium-retaining effect of insulin was more pronounced in subjects with a strong genetic predisposition to essential hypertension than in subjects with normotensive parents. This effect may contribute to the development of hypertension in subjects with a genetic predisposition to hypertension.
Modulation of the intrahepatic renin–angiotensin system after stimulation of the gastric sodium monitor in the rat
Authors: YE V. Z. C. , DUGGAN K. A.
Published: August 2015

Changes in the rate of formation of angiotensin II (ANG II) participate in mediating the natriuresis that occurs in direct response to a gastric sodium stimulus (upper-gut sodium monitor). As this natriuresis is also dependent on intrahepatic events, we investigated whether changes in hepatic and plasma angiotensinogen levels and hepatic angiotensin-converting enzyme (ACE) activity might explain the decrease in ANG II synthesis. Male Sprague–Dawley rats, equilibrated on a low-sodium diet, were anaesthetized and received a sodium load of 1.5 mmol/kg (using 3× normal saline) either intragastrically or intravenously. Blood and livers were sampled before and at various times after sodium administration. ACE activity in serum and tissues was determined by generation of histidyl-leucine. Angiotensinogen was determined by radioimmunoassay of angiotensin I generated by incubation in the presence of exogenous renin. Plasma angiotensinogen had decreased significantly by 15 min after sodium administration (P< 0.005), while hepatic angiotensinogen was also decreased significantly from 30 min after the sodium load (P< 0.01). Hepatic ACE activity decreased in response to sodium (P< 0.005) from 30 min. We conclude that stimulation of the gastric sodium monitor regulates angiotensinogen synthesis and secretion by the liver, as well as hepatic ACE activity.
Peak expiratory flow at increased barometric pressure: comparison of peak flow meters and volumetric spirometer
Authors: THOMAS Paul S. , NG Clifford , BENNETT Michael
Published: August 2015

Increasing numbers of patients are receiving hyperbaric oxygen therapy as an intensive care treatment, some of whom have pre-existing airway obstruction. Spirometers are the ideal instruments for measuring airway obstruction, but peak flow meters are useful and versatile devices. The behaviour of both types of device was therefore studied in a hyperbaric unit under conditions of increased pressure. It is important to have a non-electrical indicator of airway obstruction, to minimize the fire risk in the hyperoxic environment. The hypothesis was tested that, assuming that dynamic resistance is unchanged, both the Wright's standard and mini-peak flow meters would over-read peak expiratory flow (PEF) under increased pressure when compared with a volumetric spirometer, as the latter is unaffected by air density. It was postulated that a correction factor could be derived so that PEF meters could be used in this setting. Seven normal subjects performed volume-dependent spirometry to derive PEF, and manoeuvres using both standard and mini PEF meters at sea level, under hyperbaric conditions at 303, 253 and 152 kPa (3, 2.5 and 1.5 atmospheres respectively; 1 atmosphere absolute = 101.08 kPa), and again at sea level. There was a progressive and significant decline in PEF with increasing pressure as measured by the spirometer (69.46±0.8% baseline at 303 kPa compared with 101 kPa), while the PEF meters showed a progressive increase in their readings (an increase of 7.86±1.69% at 303 kPa with the mini PEF meter). Using these data points, a correction factor was derived which allows appropriate values to be calculated from the Wright's meter readings under these conditions.
Chylomicron-remnant-induced foam cell formation and cytotoxicity: a possible mechanism of cell death in atherosclerosis
Authors: YU Kenneth C.-W. , MAMO John C. L.
Published: August 2015

The effects of chylomicron remnants on cytoplasmic lipid loading and cell viability were assessed in cultures of human monocyte-derived macrophages and rabbit arterial smooth muscle cells. At a cholesterol concentration of 150 μg/ml, chylomicron remnants induced substantial cytoplasmic lipid loading of macrophages, but not of smooth muscle cells, within 6 h of exposure. Chylomicron remnants were found to be cytotoxic to macrophages and smooth muscle cells, although the latter were generally more resistant. Chylomicron remnants contained no detectable oxysterols (> 1 ng) and contained less non-esterified (‘free’) fatty acids than non-lipolysed nascent chylomicrons. Chylomicron-remnant-induced cytotoxicity appeared to be time- and dose-dependent. Macrophage and smooth muscle cell viability were inversely related to the production of superoxide free radicals and were significantly improved in the combined presence of superoxide dismutase and catalase. Collectively, our data suggest that, in macrophages, cell viability is compromised as a consequence of superoxide free radical production following uptake of chylomicron remnants. We would suggest that, in arterial smooth muscle cells, chylomicron-remnant-induced cell death also occurs as a consequence of superoxide free radical production. Our observations in the present study suggest that macrophage foam cells in atherosclerotic plaques might be derived from the cellular uptake of chylomicron remnants. Furthermore, arterial accumulation of chylomicron remnants might contribute to plaque destabilization as a consequence of cell death following superoxide free radical production by macrophages and smooth muscle cells.
Genetic analysis of the atrial natriuretic peptide gene in essential hypertension
Authors: KATO Norihiro , SUGIYAMA Takao , MORITA Hiroyuki , NABIKA Toru , KURIHARA Hiroki , YAMORI Yukio , YAZAKI Yoshio
Published: August 2015

Atrial natriuretic peptide (ANP) plays an important role in the regulation of blood pressure through sodium–water homoeostasis. Accordingly, several investigators have raised the question of whether the gene encoding ANP is involved in the aetiology of essential hypertension or related phenotypes such as salt sensitivity. Most of the studies have used anonymous polymorphic markers of the gene, and made inconclusive claims about the disease relevance of ANP. Therefore, in order to find sequence variations with potential functional significance and to characterize the pattern of linkage disequilibrium between polymorphisms, we screened a 3368-bp genomic fragment of ANP. Subsequently we tested the association of detected polymorphisms with plasma ANP levels and with hypertension status. Two new polymorphisms were identified, in the 5′-untranslated region and exon 1 respectively, as well as three previously reported polymorphisms in intron 2 and exon 3. When analysed in 102 healthy normotensive subjects, none of the polymorphisms appeared to significantly affect plasma ANP levels. A case–control study in a Japanese population (255 hypertensive and 225 normotensive individuals) revealed a marginally significant association (P = 0.026) between an ANP polymorphism located in the 5′-untranslated region (C-664G) and hypertension, but no association for the other polymorphisms. Each of the uncommon variants has an allele frequency of less than 10% in Japanese people, which may have hampered our detection of a significant association between ANP variants and hypertension status (and plasma ANP levels). The pathophysiological relevance of ANP, however, needs to be further defined in relation to hypertension-associated phenotypes, and also should be examined in different ethnic groups.
Changes in baroreceptor sensitivity for heart rate during normotensive pregnancy and the puerperium
Authors: BLAKE Melanie J. , MARTIN Allison , MANKTELOW Brad N. , ARMSTRONG Charles , HALLIGAN Aidan W. , PANERAI Ronney B. , POTTER John F.
Published: August 2015

Normal pregnancy is associated with marked changes in cardiovascular haemodynamics, which in part may be due to changes in autonomic control mechanisms. Baroreflex sensitivity for heart rate (BRS) was calculated in the supine and standing positions using power spectral analysis of pulse interval (PI) and systolic blood pressure (SBP) in 16 normotensive pregnant women and 10 normotensive non-pregnant controls. The pregnant women were studied on three occasions during their pregnancy (early, mid- and late gestation) and once during the puerperium. Supine total SBP variability increased between early and late pregnancy by 79% [95% confidence intervals (CI) 30%, 145%; P < 0.001], and supine high-frequency PI variability decreased by 75% (CI 51%, 88%; P < 0.001). Supine BRS fell by 50% (P < 0.001), with values returning to early-pregnancy levels in the puerperium, which were similar to those recorded in the control group. Standing SBP variability and BRS values were unchanged during pregnancy and post partum. The low/high frequency ratio of PI variability, taken as a surrogate measure of sympathovagal balance, increased by 137% (CI 42%, 296%; P < 0.01) in the supine but not the standing position from early to late pregnancy. This was due to a decrease in high-frequency variability rather than to an increase in low-frequency variability, suggesting that these changes may have been due to vagal withdrawal rather than increased sympathetic activity. Normotensive pregnancy is associated with a marked decrease in supine BRS, although the exact mechanisms for these changes remain unclear. Further studies are required to define whether changes in BRS and sympathovagal tone in early pregnancy can be used to predict the onset of pregnancy-induced hypertension.
Deleterious effects of chronic clenbuterol treatment on endurance and sprint exercise performance in rats
Authors: DUNCAN Noel D. , WILLIAMS David A. , LYNCH Gordon S.
Published: August 2015

The β2-adrenergic agonist, clenbuterol, has powerful muscle anabolic and lipolytic effects and is used by athletes to improve exercise performance; however, its use in conjunction with different forms of exercise training has received limited attention. Since previous studies have reported that chronic use of other β2-adrenergic agonists has deleterious effects on cardiac muscle structure and function, the aim of the present study was to determine whether chronic clenbuterol administration would reduce the exercise capabilities of rats subjected to long-term treadmill sprint running, endurance swimming or voluntary wheel running training. The effect of clenbuterol treatment on exercise performance in rats was evaluated in three separate studies. Different groups of male rats were assigned to an endurance swimming (2 h/day, 5/7 days, 18 weeks) group, a treadmill sprint running (8×1 min bouts, 1.05 m/s, 20 weeks) group, or a voluntary wheel running (16 weeks) group. In each study, rats were allocated into either a treated group that received clenbuterol (2 mg·kg-1·day-1) in their drinking water or an untreated control group. In each of the three studies, treated rats exhibited a reduction in exercise performance compared with untreated rats. Treated rats ran ∼ 57% less total distance than untreated rats in the voluntary running programme and were unable to complete the swimming and sprinting protocols performed by the untreated rats. In each of the studies, the treated rats exhibited cardiac hypertrophy, with absolute heart mass increased by ∼ 19% and heart mass relative to body mass increased by ∼ 20%. The hearts of sedentary rats treated with clenbuterol exhibited extensive collagen infiltration surrounding blood vessels and in the wall of the left ventricle. The results indicate strongly that chronic clenbuterol administration deleteriously affects exercise performance in rats, potentially due to alterations in cardiac muscle structure and function.
Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement
Authors: BARBER Matthew D. , MCMILLAN Donald C. , PRESTON Tom , ROSS James A. , FEARON Kenneth C. H.
Published: August 2015

Weight-losing patients with advanced cancer often fail to gain weight with conventional nutritional support. This suboptimal response might be explained, in part, by an increased metabolic response to feeding. It has been suggested that eicosapentaenoic acid (EPA) can modify beneficially the metabolic response to cancer. The aim of the present study was to examine the metabolic response to feeding in cancer and the effects of an EPA-enriched oral food supplement on this response. A total of 16 weight-losing, non-diabetic patients with unresectable pancreatic adenocarcinoma and six healthy, weight-stable controls were studied by indirect calorimetry in the fasting and fed states. Body composition was estimated by bioimpedence analysis. Cancer patients were then given a fish-oil-enriched nutritional supplement providing 2 g of EPA and 2550 kJ daily, and underwent repeat metabolic study after 3 weeks of such supplementation. At baseline, resting energy expenditure whether expressed per kg body weight, lean body mass or body cell mass was significantly greater in the cancer patients compared with controls. Fat oxidation was significantly higher in the fasting state in cancer patients [median 1.26 g·kg-1·min-1 (interquartile range 0.95–1.38)] than in controls [0.76 g·kg-1·min-1 (0.62–0.92); P < 0.05]. Over the 4 h feeding period, changes in insulin and glucose concentrations in cancer patients suggested relative glucose intolerance. In response to oral meal feeding, the percentage change in the area under the curve of energy expenditure was significantly lower in the cancer patients [median 7.9% (interquartile range 3.4–9.0)] than in controls [12.6% (9.9–15.1); P < 0.01]. After 3 weeks of the EPA-enriched supplement, the body weight of the cancer patients had increased and the energy expenditure in response to feeding had risen significantly [9.6% (6.3–12.4)], such that it was no different from baseline healthy control values. Similarly, fasting fat oxidation fell to 1.02 g·kg-1·min-1 (0.8–1.18), again no longer significantly different from baseline healthy control values. While weight-losing patients with advanced pancreatic cancer have an increased resting energy expenditure and increased fat oxidation, the energy cost of feeding is, in fact, reduced. Provision of a fish-oil-enriched nutritional supplement results in some normalization of the metabolic response in both the fasted and fed states, in association with an improvement in nutritional status.
Differential timing for programming of glucose homoeostasis, sensitivity to insulin and blood pressure by in utero exposure to dexamethasone in sheep
Authors: GATFORD Kathryn L. , WINTOUR E. Marelyn , DE BLASIO Miles J. , OWENS Julie A. , DODIC Miodrag
Published: August 2015

Numerous epidemiological studies have related an increased risk of adult-onset cardiovascular and metabolic disease to an adverse intra-uterine environment at critical periods. We have shown that fetal sheep exposed to dexamethasone for only 2 days at 27 days of gestation (term ≈ 150 days) became hypertensive adults, whereas those exposed at 64 days of gestation remained normotensive, as did controls. In the same sheep, now nearly 5 years old, we performed glucose tolerance tests and hyperinsulinaemic euglycaemic clamps to study the insulin sensitivity of glucose, amino acid and non-esterified fatty acid metabolism. Glucose tolerance, calculated as the area under the curve, after intravenous administration of bolus glucose and insulin secretion in response to a glucose challenge were not altered in any group. There were no significant differences in the insulin sensitivity of net whole-body glucose or amino acid uptake. However, suppression of lipolysis by insulin, measured as the proportional decrease in the circulating concentration of non-esterified fatty acids during the hyperinsulinaemic clamp, was 69±1.2% at steady-state plasma insulin levels (≈ 1000 m-units/l) in the group exposed to dexamethasone at 27 days of gestation, but only 50.8±6.5% in the controls (P < 0.05). In the group exposed to dexamethasone at 64 days of gestation, the decrease was 66.4±5.1%, which did not reach significance compared with the controls (P = 0.10). Thus brief dexamethasone exposure during early gestation programmed hypertension independently of insulin resistance of glucose or amino acid metabolism; however, it did lead to increased insulin sensitivity of the inhibition of lipolysis, which may increase susceptibility to the development of obesity postnatally.
Effects of organic and inorganic selenium supplementation on selenoenzyme activity in blood lymphoctyes, granulocytes, platelets and erythrocytes
Authors: BROWN K. M. , PICKARD K. , NICOL F. , BECKETT G. J. , DUTHIE G. G. , ARTHUR J. R.
Published: August 2015

The blood selenium (Se) concentration in the U.K. population has declined by approx. 50% between 1974 and 1991, reflecting a large decrease in dietary Se supply, with intakes only half the reference nutrient intake of 1 µg/kg body weight. Tissue levels of Se are readily influenced by dietary intake. Therefore selenoprotein activity may be sub-optimal due to low Se status, and thus compromise normal cell function. To examine the effects of changing Se intake on selenoproteins, we have determined the relative effectiveness of organic selenomethionine and inorganic sodium selenite (50 µg of Se daily for 28 days) in modulating glutathione peroxidase activities in blood cells from 45 healthy men and women, from a U.K. population. Transient and acute changes in lymphocyte, granulocyte and platelet phospholipid-hydroperoxide glutathione peroxidase (GP×4) activity occurred by day 7 or 14 of sodium selenite treatment and by day 7 in lymphocytes from selenomethionine-treated subjects compared with controls taking a placebo. In contrast, GP×4 activity in granulocytes and platelets in the selenomethionine group increased gradually over the 28 days. Cytosolic glutathione peroxidase (GP×1) activity in these blood cells from both treatment groups increased gradually over the 28 days. For each cellular selenoenzyme activity a significant inter-individual difference (P < 0.001) in the extent of the response to Se supplementation was observed, but this was not related to blood Se concentrations either before or after treatments. Significant inverse correlations were evident between baseline enzyme activities and percentage change in activity after 28 days of supplementation [e.g. lymphocyte GP×4, r =-0.695 (P < 0.001)], indicating that pre-treatment activity may be sub-optimal as a result of poor Se status. The different and contrasting effects that Se supplementation had on blood selenoenzyme activities may be indicative of a difference in metabolic need for Se regulated at the level of Se-dependent cell function.
Supplemental oxygen does not modulate responses to acetylcholine or ascorbic acid in the forearm of patients with congestive heart failure
Authors: MURCHIE Karen J. , JENNINGS Garry L. , KINGWELL Bronwyn A.
Published: August 2015

Despite providing symptomatic relief in patients with congestive heart failure (CHF), supplemental oxygen (O2) has been demonstrated to increase total peripheral resistance. The present study investigated the possibility that O2 inhalation reduces nitric oxide (NO) bioavailability, using endothelium-dependent (acetylcholine) and -independent (phentolamine) vasodilators, and the antioxidant ascorbic acid. Ten patients (nine male and one female) with primary left ventricular failure participated in the study. Forearm venous occlusion plethysmography was used to study blood flow responses to acetylcholine and the α-adrenergic antagonist phentolamine during inhalation of either room air or 100% O2, with and without the simultaneous infusion of ascorbic acid. Neither O2 inhalation (3.9±0.4 compared with 3.8±0.3 ml⋅min-1⋅100 ml-1) nor ascorbic acid infusion (5.2±0.4 compared with 5.5±0.4 ml⋅min-1⋅100 ml-1) affected resting forearm blood flow. The percentage increase from basal blood flow after acetylcholine infusion was not altered by either O2 inhalation or ascorbic acid infusion (room air, 140±55%; O2, 118±46%; ascorbic acid, 147±39%; ascorbic acid+O2, 109±31%). O2 inhalation did, however, reduce the dilation induced by phentolamine (room air, 131±24%; O2, 80±14%; P < 0.05). These data indicate that oxygen inhalation does not increase forearm vascular resistance. Secondly, preservation of reactivity to acetylcholine during O2 inhalation suggests that degradation of NO by O2-derived free radicals is not enhanced. Attenuation of phentolamine-induced vasodilation during O2 inhalation, however, implies increased adrenergic activity, which may possibly exacerbate the detrimental effects of elevated sympathetic activity in CHF.
A guardian angel: the involvement of dipeptidyl peptidase IV in psychoneuroendocrine function, nutrition and immune defence
Authors: HILDEBRANDT Martin , REUTTER Werner , ARCK Petra , ROSE Matthias , KLAPP Burghard F.
Published: August 2015

Dipeptidyl peptidase IV (DPP IV, also known as CD26; EC 3.4.14.5) is a non-integrin receptor glycoprotein with multiple functions, including cell adhesion, cellular trafficking through the extracellular matrix and co-stimulatory potential during T cell activation. By virtue of its exopeptidase activity, DPP IV plays a key regulatory role in the metabolism of peptide hormones. Based on data emerging from different biomedical specialties, it appears worthwhile to highlight the different facets of DPP IV in nutrition, immune responses and peptide hormone metabolism. The presentation of the complex regulatory circuits in which DPP IV appears to be involved may also serve as a note of caution, in view of attempts to apply selective inhibitors of DPP IV enzymic activity for the treatment of disease, e.g. Type II diabetes.
Cardiocirculatory coupling during sinusoidal baroreceptor stimulation and fixed-frequency breathing
Authors: KEYL Cornelius , DAMBACHER Martin , SCHNEIDER Annette , PASSINO Claudio , WEGENHORST Ulrike , BERNARDI Luciano
Published: August 2015

The question of whether respiratory sinus arrhythmia (RSA) originates mainly from a central coupling between respiration and heart rate, or from baroreflex mechanisms, is a subject of controversy. If there is a major contribution of baroreflexes to RSA, cardiocirculatory coupling during breathing and during cyclic baroreflex stimulation should show similarities. We applied a sinusoidal stimulus to the carotid baroreceptors and generated heart rate fluctuations of the same magnitude as RSA with a frequency similar to, but different from, the breathing frequency (0.2 Hz, compared with 0.25 Hz), and at 0.1 Hz, in 17 supine healthy subjects (age 28–39 years). The data were analysed using discrete Fourier-transform and transfer function analysis. Respiratory fluctuations in systolic blood pressure preceded RSA with a time lag equal to that between baroreceptor stimulation and oscillations in RR interval (0.62±0.18 s compared with 0.57±0.28 s at 0.2 Hz neck suction). The response of systolic blood pressure to neck suction at 0.2 Hz was 5 times less than the respiratory blood pressure fluctuations. Neck suction at 0.1 Hz largely increased fluctuations in blood pressure and RR interval, whereas the spontaneous phase relationship between blood pressure and RR interval remained unchanged. Our results are not consistent with the hypothesis that the origin of RSA is predominantly a central phenomenon which secondarily generates fluctuations in blood pressure, but suggest that, under the condition of fixed-frequency breathing at 0.25 Hz, baroreflex mechanisms contribute to respiratory fluctuations in RR interval.
Transvenous echo Doppler in baboons: a new window to the cardiovascular system
Authors: PREMAWARDHANA Upul , HOSKINS Matthew , CELERMAJER David S.
Published: August 2015

Ultrasound examinations of the heart and major peripheral arteries have been performed as separate procedures; both potentially limited by suboptimal views in certain subjects and the inability to obtain ideal pictures of particular intracardiac structures. Transvenous ultrasound may offer new advantages in certain areas, we therefore studied six adult baboons using a single-plane 5.5–10 MHz transducer mounted on a 10 French (10F) catheter, introduced via the right femoral vein and positioned under fluoroscopic control. Imaging and Doppler studies were performed to delineate cardiovascular anatomy as well as ventricular function response to positive (dobutamine) and negative inotropic (esmolol) agents. The procedure was safe and feasible in all cases. Clear and novel two-dimensional and flow information were obtained from the iliac arteries, descending aorta, both renal artery origins, ascending aorta, including the aortic arch, main pulmonary artery and its bifurcation, as well as head and neck vessels. Novel intracardiac views were obtained, including right ventricular long axis, left ventricular apex and ‘flask’ views of the left ventricle. Excellent dynamic information for left ventricular function was also available [e.g. myocardial Vmax of the anterior left ventricular wall was 6.8±2.5 cm/s at rest, 14.6±5.5 cm/s after dobutamine (P = 0.009) and 4.5±1 cm/s after esmolol (P = 0.03 compared with control)]. We conclude that, in adult primates, transvenous ultrasound safely and reliably provides novel information of cardiovascular structure and function.
Burn injury upregulates the activity and gene expression of the 20 S proteasome in rat skeletal muscle
Authors: FANG Cheng-Hui , LI Bing-Guo , FISCHER David R. , WANG Jing Jing , RUNNELS Herbert A. , MONACO John J. , HASSELGREN Per-Olof
Published: August 2015

There is evidence that burn injury stimulates ubiquitin–proteasome-dependent protein breakdown in skeletal muscle. In this proteolytic pathway, protein substrates are conjugated to multiple molecules of ubiquitin, whereafter they are recognized, unfolded and degraded by the multicatalytic 26 S protease complex. The 20 S proteasome is the catalytic core of the 26 S protease complex. The influence of burn injury on the expression and activity of the 20 S proteasome has not been reported. We tested the hypothesis that burn injury increases 20 S proteasome activity and the expression of mRNA for the 20 S proteasome subunits RC3 and RC7. Proteolytic activity of isolated 20 S proteasomes, assessed as activity against fluorogenic peptide substrates, was increased in extensor digitorum longus muscles from burned rats. Northern-blot analysis revealed that the expression of mRNA for RC3 and RC7 was increased by 100% and 80% respectively following burn injury. Increased activity and expression of the 20 S proteasome in muscles from burned rats support the concept that burn-induced muscle cachexia is at least, in part, regulated by the ubiquitin–proteasome proteolytic pathway.
Comparison of pulse-wave velocity in different aortic regions in relation to the extent and severity of atherosclerosis between young and older Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits
Authors: KATSUDA Shin-ichiro , HASEGAWA Masamitsu , KUSANAGI Masahiko , SHIMIZU Tsuyoshi
Published: August 2015

The present study was performed to investigate the effects of the development of atherosclerosis on foot-to-foot pulse-wave velocity (PWV) from the ascending aorta to different positions along the aorta in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits aged 10–12 and 22–24 months old, in relation to the percentage fractional lesioned area (PFLA) in different aortic regions through which the pulse wave travels, as well as the rheological and pathohistological properties of the aortic wall. PWV, when measured in the KHC rabbit from the ascending aorta to each aortic position, showed the highest value on passage through the aortic arch, decreased with conduction to the distal thoracic aorta, reached the minimal value on passage to the distal thoracic aorta or to the middle abdominal aorta in the 10–12- and 22–24-month-old animals respectively, and increased gradually on conduction to the iliac artery. PWV at all aortic regions examined was significantly greater in the 22–24-month-old than in the 10–12-month-old KHC rabbits. PFLA, when measured in the aortic region from the ascending aorta to each aortic position, was maximal in the aortic arch and decreased gradually towards the peripheral aorta in both age groups. PFLA in the 22–24-month-old group was significantly greater than that in the 10–12-month-old group in all aortic regions examined. The atherosclerotic aortic wall showed a significantly lower elastic modulus in the young KHC rabbits compared with age-matched normal rabbits. A significantly higher elastic modulus was observed in the older KHC rabbits compared with that in the younger animals of both strains, associated with the progression of sclerosis. These findings indicate that the increase in PWV is due mainly to an increase with aging in the extent and severity of atherosclerosis in vessels in which the pulse wave travels.
Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: role of nitric oxide and bradykinin
Authors: CHU Chi-Jen , WU Shwu-Ling , LEE Fa-Yauh , WANG Sun-Sang , CHANG Full-Young , LIN Han-Chieh , CHAN Che-Chang , LEE Shou-Dong
Published: August 2015

Hyposensitivity to vasopressin is a well documented phenomenon in animals with portal hypertension and patients with cirrhosis subject to haemorrhage. Haemorrhage is associated with the endogenous release of bradykinin, which may subsequently stimulate the formation of nitric oxide (NO). The present study investigated the relative contribution of NO synthase (NOS) isoforms and the role of bradykinin in the pathogenesis of splanchnic hyposensitivity to a long-acting vasopressin analogue, glypressin, in rats with portal hypertension induced by partial portal vein ligation (PVL). At 14 days after the operation, systemic and portal haemodynamics were measured in stable or bleeding PVL rats receiving an intravenous infusion of glypressin (0.07 mg/kg). In the treatment groups, NG-nitro-L-arginine methyl ester (L-NAME; a non-selective NOS inhibitor), L-canavanine (a specific inhibitor of inducible NOS) or HOE 140 (a bradykinin B2 receptor antagonist) was administered 45 min before the infusion of glypressin. In rats with a hypotensive haemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was re-infused before the administration of glypressin or various inhibitors. Splanchnic hyposensitivity to glypressin was demonstrated in the haemorrhage/transfused PVL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding PVL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin. It is concluded that constitutive NOS and bradykinin are responsible, at least partly, for the splanchnic hyposensitivity to glypressin observed in the early stages of the haemorrhage/transfused rat model of portal hypertension.