bluuebunny/crossref_metadata_2025 huggingface dataset:
Difference in leptin response to a high-fat meal between lean and obese men
Authors: IMBEAULT P. , DOUCET E. , MAURIÈGE P. , ST-PIERRE S. , COUILLARD C. , ALMÉRAS N. , DESPRÉS J.-P. , TREMBLAY A.
Published: August 2015

The aim of this study was to compare the leptin responses to a high-fat meal in lean and obese men, and to investigate whether the net leptin response (area under the incremental curve) after the meal was related to the thermic effect of food (TEF). Blood samples were collected after an overnight fast and every 2h for 8h after a high-fat breakfast (60g of fat/m2 body surface area) in 12 lean and 12 obese men for determination of glucose, insulin and leptin. The TEF was calculated as postprandial energy expenditure minus fasting energy expenditure, as measured by indirect calorimetry. Fasting plasma glucose levels were similar in lean and obese men, and increased in the same way after the meal. Fasting and postprandial plasma insulin concentrations were significantly greater in obese than in lean men (P < 0.01 and P < 0.05 respectively). Accordingly, obese men showed a significantly higher net insulin response than lean subjects (P < 0.001). Fasting plasma leptin levels were greater in obese than in lean men (P < 0.001). After the meal, plasma leptin increased significantly in lean men, whereas it decreased in obese men (group by time interaction, P < 0.01). The net response of leptin was greater in lean than in obese men, but this did not reach statistical significance (P = 0.07). Moreover, the TEF was similar in the two groups. No significant relationship was observed between either the net insulin response or the net leptin response after the high-fat meal and the TEF of lean subjects (-0.05 < r < 0.31). In obese men, the net response of insulin was correlated significantly with TEF (r = 0.70, P < 0.05), whereas the net response of leptin was not (r = -0.40). These results suggest that obesity is related to an impaired regulation of leptin by insulin, since leptin levels increased in lean men but decreased in obese men following a high-fat meal. Moreover, the fact that the postprandial leptin responses of both lean and obese men were not significantly related to the TEF suggests that the ob gene product is probably not acutely involved in the control of this energy expenditure component in humans.
Effects of blood pressure lowering with amlodipine or lisinopril on vascular structure of the common carotid artery
Authors: STANTON Alice V. , CHAPMAN Jeremy N. , MAYET Jamil , SEVER Peter S. , POULTER Neil R. , HUGHES Alun D. , McG. THOM Simon A.
Published: August 2015

Increased intima-media thickness of the common carotid artery predicts increased risk of myocardial infarction and stroke. Preliminary evidence suggests that a decrease in blood pressure (BP) is associated with diminished wall thickness. It is not known if all classes of anti-hypertensive agents have similar protective effects. In this double-blind parallel-group clinical trial, 69 previously untreated patients with hypertension were allocated randomly to 1 year of treatment with either amlodipine (5-10mg daily) or lisinopril (5-20mg daily). Doxazosin and bendrofluazide were added if required to achieve BP control. After 12 months of treatment, clinic BP, ambulatory BP and cardiac mass were reduced similarly by the two treatment regimens. Common carotid artery intima-media thickness decreased by 0.048mm (95% confidence intervals -0.066, -0.031mm) in the amlodipine-treated group, but decreased by only 0.027 mm (-0.046, -0.007mm) in the lisinopril-treated group (P < 0.05 for difference between treatments). Common carotid artery lumen diameter declined significantly only in patients treated with lisinopril [amlodipine, -0.02mm (-0.14, 0.10mm); lisinopril, -0.21mm (-0.32, -0.11mm); P < 0.02], while intima-media area declined similarly in the two treatment groups [amlodipine -1.32mm2 (-1.91, -0.74mm2), lisinopril -1.26mm2 (-1.80, -0.72mm2); not significant]. The results confirm that a decrease in BP causes regression of structural changes in the carotid artery in hypertensive patients. The nature of the structural regression differed markedly between the two treatment regimens, in spite of similar decreases in BP. The calcium channel blocker induced greater regression of common carotid artery intima-media thickness than the angiotensin-converting enzyme inhibitor. However, carotid artery wall mass, as indicated by intima-media area, was reduced to a similar extent by the two treatments. It remains to be established whether such differences confer a prognostic advantage.
Assessment of microvascular endothelial function in human skin
Authors: NEWTON David J. , KHAN Faisel , BELCH Jill J.F.
Published: August 2015

Endothelial dysfunction is an important factor in many cardiovascular diseases, and is commonly associated with impaired endothelium-mediated vasodilatation. Information about the mechanisms behind this dysfunction has come largely from animal studies or, in humans, through invasive techniques that are not specific to one vascular bed. We have developed protocols to assess endothelial function non-invasively in the cutaneous microcirculation by measuring blood flow responses to four receptor-specific vasoactive compounds. Cumulative doses of acetylcholine, methacholine, bradykinin and substance P were administered iontophoretically to the forearm skin of healthy volunteers on two to three occasions. Dose-dependent increases in skin microvascular blood flow in response to these drugs were measured with laser Doppler imaging. Vascular responses to acetylcholine and methacholine were reasonably consistent, with coefficients of variation of approx. 17%. The coefficients of variation for bradykinin and substance P were much poorer, as high as 70% for some doses. This might partly be a consequence of the more unpredictable effects of histamine release in the vasoactive behaviour of these two agonists. Although it might be advantageous to find other agonists with which to test the function of different receptor pathways, we have shown that just acetylcholine and methacholine can currently be used with iontophoresis to allow sensitive and reproducible assessment of endothelial function.
Differential roles of nitric oxide and oxygen radicals in chondrocytes affected by osteoarthritis and rheumatoid arthritis
Authors: MAZZETTI Ilaria , GRIGOLO Brunella , PULSATELLI Lia , DOLZANI Paolo , SILVESTRI Tania , ROSETI Livia , MELICONI Riccardo , FACCHINI Andrea
Published: August 2015

Osteoarthritis and rheumatoid arthritis are characterized by focal loss of cartilage due to an up-regulation of catabolic pathways, induced mainly by pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor α (TNFα). Since reactive oxygen species are also involved in this extracellular-matrix-degrading activity, we aimed to compare the chondrocyte oxidative status responsible for cartilage damage occurring in primarily degenerative (osteoarthritis) and inflammatory (rheumatoid arthritis) joint diseases. Human articular chondrocytes were isolated from patients with osteoarthritis or rheumatoid arthritis, or from multi-organ donors, and stimulated with IL-1β and/or TNFα. We evaluated the oxidative stress related to reactive nitrogen and oxygen intermediates, measuring NO2- as a stable end-product of nitric oxide generation and superoxide dismutase as an antioxidant enzyme induced by radical oxygen species. We found that cells from patients with osteoarthritis produced higher levels of NO2- than those from patients with rheumatoid arthritis. In addition, IL-1β was more potent than TNFα in inducing nitric oxide in both arthritides, and TNFα alone was almost ineffective in cells from rheumatoid arthritis patients. We also observed that the intracellular content of copper/zinc superoxide dismutase (Cu/ZnSOD) was always lower in rheumatoid arthritis chondrocytes than in those from multi-organ donors, whereas no differences were found in intracellular manganese SOD (MnSOD) or in supernatant Cu/ZnSOD and MnSOD levels. Moreover, intracellular MnSOD was up-regulated by cytokines in osteoarthritis chondrocytes. In conclusion, our results suggest that nitric oxide may play a major role in altering chondrocyte functions in osteoarthritis, whereas the harmful effects of radical oxygen species are more evident in chondrocytes from patients with rheumatoid arthritis, due to an oxidant/antioxidant imbalance.
Bradykinin in the ascitic fluid of patients with liver cirrhosis
Authors: CUGNO Massimo , SALERNO Francesco , NUSSBERGER Jürg , BOTTASSO Bianca , LORENZANO Elettra , AGOSTONI Angelo
Published: August 2015

Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-Mr (‘high-molecular-weight’) kininogen by kallikrein, and its generation is facilitated by plasmin. In the ascitic fluid of patients with cirrhosis, there is massive cleavage of high-Mr kininogen and activation of fibrinolysis, but bradykinin has never been measured directly. In the ascitic fluid of 24 patients with cirrhosis, we measured bradykinin-(1-9)-nonapeptide levels by RIA after liquid-phase and subsequent HPLC extraction, and those of its catabolic product bradykininin-(1-5)-pentapeptide by ELISA after liquid-phase extraction. Cleaved high-Mr kininogen, activated factor XII and plasmin-antiplasmin complexes were measured in ascitic fluid and plasma. Plasma renin activity (PRA) was also determined. As a control, we also analysed plasma from 24 healthy subjects matched for sex and age with the patients. In the ascitic fluid from patients with cirrhosis, the median bradykinin-(1-9) concentration was 3.3fmol/ml (range 0.2-29.0fmol/ml), and the median bradykinin-(1-5) concentration was 210fmol/ml (range 58-7825 fmol/ml). The levels of bradykinin-(1-5) in ascitic fluid were higher in patients with refractory ascites [median 1091fmol/ml (range 58-7825fmol/ml)] than in patients with responsive ascites [134 fmol/ml (72-1084fmol/ml)] (P = 0.010). Ascitic fluid levels of bradykinin-(1-9) were not related to the severity of ascites. PRA was higher in patients with refractory ascites [23.0ngċh-1ċml-1 (7.9-80.0ngċh-1ċml-1)] than in patients with responsive ascites [6.9ngċh-1ċml-1 (0.9-29.4ngċh-1ċml-1)] (P = 0.002). In ascitic fluid, 48% (19-68%) of high-Mr kininogen was cleaved, and plasmin-antiplasmin complexes were more concentrated than in plasma (P = 0.0001). In conclusion, in the ascitic fluid of patients with cirrhosis, both bradykinin-(1-9) and bradykinin-(1-5) are present, with cleavage of high-Mr kininogen and activation of fibrinolysis. The highest levels of the long-lived metabolite bradykinin-(1-5) were found in the ascitic fluid of patients with refractory ascites and high PRA. Activation of the kinin system may therefore be involved in decompensating cirrhosis, but a cause-effect relationship remains to be established.
The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56)
Authors: STEVENS Richard J. , KOTHARI Viti , ADLER Amanda I. , STRATTON Irene M. , HOLMAN Rury R.
Published: August 2015

A definitive model for predicting absolute risk of coronary heart disease (CHD) in male and female people with Type II diabetes is not yet available. This paper provides an equation for estimating the risk of new CHD events in people with Type II diabetes, based on data from 4540 U.K. Prospective Diabetes Study male and female patients. Unlike previously published risk equations, the model is diabetes-specific and incorporates glycaemia, systolic blood pressure and lipid levels as risk factors, in addition to age, sex, ethnic group, smoking status and time since diagnosis of diabetes. All variables included in the final model were statistically significant (P < 0.001, except smoking for which P = 0.0013) in likelihood ratio testing. This model provides the estimates of CHD risk required by current guidelines for the primary prevention of CHD in Type II diabetes.
Influence of methylenetetrahydrofolate reductase genotype, exercise and other risk factors on endothelial function in healthy individuals
Authors: PULLIN Catherine H. , WILSON John F. , ASHFIELD-WATT Pauline A.L. , CLARK Zoë E. , WHITING Jenny M. , LEWIS Malcolm J. , McDOWELL Ian F.W.
Published: August 2015

Cardiovascular disease has a multifactorial aetiology that is influenced by both genetic and environmental factors. Endothelial dysfunction is a key event in the pathogenesis of vascular disease that occurs before structural vascular changes or clinical symptoms are evident. Conventional risk factors, for example hypertension and diabetes mellitus, are associated with endothelial dysfunction, but the influence of other putative risk factors is not clear. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as being a genetic risk factor for cardiovascular disease. A total of 126healthy adults recruited by MTHFR C677T genotype (42 of each genotype, i.e. CC, CT and TT) underwent assessment of endothelial function. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) was measured using high-resolution ultrasonic vessel ‘wall-tracking’. Using multiple regression analysis, MTHFR genotype and 21 other subject and subject-lifestyle variables were investigated as potential predictors of endothelial function. FMD was influenced positively by frequency of aerobic exercise and by hormone replacement therapy, and negatively by increases in systolic blood pressure. MTHFR C677T genotype and the associated variation in plasma homocysteine levels did not influence FMD. Additionally, other factors, including plasma cholesterol and self-supplementation with either antioxidant vitamins or cod liver oil, showed no significant relationship with FMD, although these findings are compromised by the narrow range studied for cholesterol and the small number of subjects taking supplements. These observations have implications for risk factor management in the primary prevention of cardiovascular disease in healthy individuals.
Abnormalities in primary granule exocytosis in neutrophils from Type I diabetic patients with nephropathy
Authors: FARDON Nicholas J.M. , WILKINSON Robert , THOMAS Trevor H.
Published: August 2015

Microalbuminuria in Type I diabetes involves a cell membrane abnormality and is associated with a large increase in cardiovascular risk. The hypothesis that the membrane abnormality alters granule exocytosis in neutrophils, which could contribute to the increased incidence of cardiovascular disease, was investigated. PMA-stimulated expression of CD11b and CD69 on neutrophils from normal controls (NC), long-term uncomplicated Type I diabetic control patients (DC) and diabetic nephropathy patients (DN) was determined by fluorescence activated cell scanning. Neutrophils from DN were faster than neutrophils from either NC or DC to exocytose primary granules with CD69 following initial expression of the adhesion molecule CD11b. However, a larger proportion of neutrophils from DN failed to withdraw CD11b from the cell membrane after 90min incubation. The protein kinase C (PKC) inhibitor, bisindolylmaleimide (BIM), showed that a larger proportion of neutrophils from DN, compared with DC or NC, exocytosed primary granules independent of PKC. The calpain inhibitor, E64d, showed that a larger proportion of neutrophils from both groups of diabetic patients, compared with NC, exocytosed primary granules independent of calpain. Cytoskeletal disruption with cytochalasin D had an effect on CD11b and CD69 exocytosis similar to that of BIM and E64d. The pathways controlling granule exocytosis in neutrophils from diabetic patients are abnormal. A change characteristic of DN causes rapid exocytosis of primary granules, and also causes the adhesion molecule CD11b to persist on an increased proportion of neutrophils. This will make an important contribution to increased vascular damage in these patients.
Circulating nitrite anions are a directly acting vasodilator and are donors for nitric oxide
Authors: DEMONCHEAUX E.A.G. , HIGENBOTTAM T.W. , FOSTER P.J. , BORLAND C.D.R. , SMITH A.P.L. , MARRIOTT H.M. , BEE D. , AKAMINE S. , DAVIES M.B.
Published: August 2015

Inhaled nitric oxide (NO) is a pulmonary vasodilator, but also acts systemically, causing negative cardiac inotropic effects and a fall in systemic vascular resistance. Circulating metabolites of NO are presumed to be responsible. We questioned the role of nitrite anions and the manner in which they might contribute to these effects. Nitrite and nitrate anions coexist in blood, while circulating levels of dissolved NO are very low. Nitrate anions are not biologically active, but nitrite anions may have a biological role through the release of NO. In vitro, at 37°C and in aerated Krebs bicarbonate solution, the steady-state concentration of dissolved NO was proportional to the concentration of NO in the gas. Nanomolar concentrations of dissolved NO coexisted with micromolar concentrations of nitrite anions. The idea of an equilibrium between the two in solution was also supported by the observed release of NO from nitrite anions in the absence of gas. With rings of precontracted pig pulmonary arteries (prostaglandin F2α; 10μmol/l), the steady-state concentration of dissolved NO causing 50% relaxation (EC50) was 0.84±0.25nmol/l, corresponding to a gaseous concentration of 2.2p.p.m. The EC50 of nitrite was 4.5±0.7μmol/l, a concentration normally found in plasma. The estimated concentration of dissolved NO derived from this nitrite was 4.5pmol/l, some 100 times lower than would be needed to cause relaxation. The rate of exhalation of NO was increased and pulmonary vascular resistance was reduced by the addition of nitrite solution to the perfusate of isolated perfused and ventilated pig lungs, but only when millimolar concentrations were achieved. Thus circulating nitrite anions are a direct vasodilator, only being a carrier of effective amounts of ‘free’ NO at higher than physiological concentrations.
Soluble tumour necrosis factor α receptor 2, a serum marker of resistance to the anabolic actions of growth hormone in subjects with HIV disease
Authors: GELATO Marie C. , MYNARCIK Dennis , MCNURLAN Margaret A.
Published: August 2015

Therapies are still being sought for the prevention of loss of body weight and lean body mass in HIV disease. The purpose of the present study was to identify a serum marker that would help in selecting patients who may be appropriate candidates for the use of anabolic agents, such as growth hormone, to restore lean body mass. This study included 26 HIV-infected patients and nine healthy controls, assessed previously for the effectiveness of 2 weeks of growth hormone administration in the stimulation of protein synthesis in skeletal muscle. Serum levels of interleukins-1β, -6 and -10 were not useful predictors of the anabolic response to growth hormone. Serum concentrations of tumour necrosis factor α (TNFα) were significantly elevated (P < 0.05) in patients with AIDS and AIDS-related weight loss, and there was a significant correlation between the serum concentration of interleukin-1 receptor antagonist and stage of disease (P = 0.03). However, the serum concentration of the soluble TNFα receptor type 2 was most predictive of an inability of muscle protein synthesis to respond anabolically to growth hormone (r = -0.42, P = 0.01). These data suggest that inflammation impacts on the responsiveness of muscle tissue to an anabolic stimulus, and that the soluble TNFα receptor type 2 provides a useful serum marker for metabolic dysfunction in HIV disease, which can be used to identify individuals likely to respond to growth hormone-based anabolic therapy.
Determinants of brachial artery mean 24 h pulse pressure in individuals with Type II diabetes mellitus and untreated mild hypertension
Authors: VAN DIJK Robert A.J.M. , VAN ITTERSUM Frans J. , WESTERHOF Nico , VAN DONGEN Els M. , KAMP Otto , STEHOUWER Coen D.A.
Published: August 2015

Brachial artery pulse pressure is a predictor of (cardiovascular) morbidity, but its determinants in individuals with Type II diabetes and untreated mild hypertension have not been elucidated. We therefore cross-sectionally investigated determinants of brachial artery mean 24h pulse pressure in 60 individuals (40 males; age, mean±S.D., 57.8±7.5 years) with Type II diabetes [median diabetes duration (interquartile range), 6.3 (3.6-10.1) years] and untreated mild hypertension [sitting blood pressure >140/90mmHg and <190/120mmHg (mean of two consecutive auscultatory office measurements after 5min of rest)]. We measured (1) three potential determinants reflecting different aspects of central artery stiffness [the overall systemic arterial compliance, the aortic augmentation index and 1/(regional carotido-femoral transit time)], (2) structural and functional changes of the circulatory system often observed in Type II diabetes, and (3) diabetes-associated metabolic variables. After adjustment for age, gender and mean arterial pressure, brachial artery pulse pressure was associated with autonomic function [standardized regression coefficient (β), -0.27 (P = 0.01)], blood pressure decline during sleep [standardized β, -0.32 (P = 0.002)], fasting glucose concentration [standardized β, 0.26 (P = 0.01)], HbA1c concentration [standardized β, 0.27 (P = 0.003)] and diabetes duration [standardized β, 0.28 (P = 0.002)] in linear regression analyses. In a combined multivariate model, brachial artery pulse pressure was independently determined by gender [1 = male, 2 = female; standardized β, 0.24 (P = 0.01)], diabetes duration [standardized β, 0.18 (P = 0.03)], mean arterial pressure [standardized β, 0.32 (P = 0.002)], systemic arterial compliance [standardized β, -0.23 (P = 0.02)] and fasting glucose concentration [standardized β, 0.20 (P = 0.02)]. Aortic augmentation index and 1/(carotido-femoral transit time) were not independently associated with pulse pressure. In conclusion, in individuals with Type II diabetes and untreated mild hypertension, brachial artery pulse pressure is determined mainly by proximal aortic stiffness in a way which is not strongly influenced by peripheral pulse wave reflection. Approx. 60% of the variance in brachial artery pulse pressure could be explained by potentially modifiable determinants.
Altered balance of main vasopressor and vasodepressor systems in rats with genetic hypertension and hypertriglyceridaemia
Authors: KUNEŠ Jaroslav , DOBEŠOVÁ Zdenka , ZICHA Josef
Published: August 2015

The precise role of nitric oxide (NO) in hypertension is still not fully understood, although this vasodilator system represents the main counterbalance of major pressor systems. The aim of our study was to determine the contributions of superoxide anions, the renin-angiotensin system (RAS), the sympathetic nervous system (SNS) and NO to the maintenance of blood pressure (BP) in Prague hereditary hypertriglyceridaemic (HTG) rats with genetic hypertension. Conscious chronically cannulated rats were subjected to the consecutive blockade of the RAS (losartan, 10mg/kg), the SNS (pentolinium, 5mg/kg) and NO synthase [Nω-nitro-l-arginine (l-NAME), 30mg/kg]. Some additional rats were pretreated with tempol (a membrane-permeable mimetic of superoxide dismutase). A subsequent genetic study in HTG×Lewis F2 hybrid rats (n = 284) was designed to reveal potential associations of particular BP components with baseline BP. The progenitor study indicated that BP elevation was more pronounced in male than female HTG rats (as compared with normotensive Lewis controls). Higher BP in HTG rats was due to the increased residual BP (measured after combined RAS and SNS blockade) and the augmentation of BP responses to tempol or losartan. In contrast, BP responses to pentolinium or l-NAME were similar in all experimental groups. It should, however, be noted that the baseline BP of progenitor animals was correlated positively with both residual BP and the magnitude of the BP response to pentolinium, but not with BP response to l-NAME. Similarly, the baseline BP of F2 hybrid rats was positively associated with residual BP, the BP response to pentolinium and the relative SNS contribution to BP maintenance [expressed as a percentage of baseline mean arterial pressure (MAP) values], as well as with the ratio of BP changes elicited by ganglion blockade and NO synthase inhibition (ΔMAPpentolinium/ΔMAPl-NAME ratio), reflecting the balance of main vasopressor and vasodepressor systems. Thus our studies, performed in progenitor and F2 hybrid rats, revealed that changes in BP induced by l-NAME do not keep pace with the progressive augmentation of pentolinium-induced changes in BP occurring over a wide range of increasing BP. The altered balance between enhanced SNS-dependent vasoconstriction and unchanged NO-dependent vasodilation (‘relative NO deficiency’ in rats with high BP) might result in BP elevation in this form of genetic hypertension.
Increases in circulating levels of monocyte–platelet and neutrophil–platelet complexes following hip arthroplasty
Authors: BUNESCU A. , WIDMAN J. , LENKEI R. , MENYES P. , LEVIN K. , EGBERG N.
Published: August 2015

Platelets and leucocytes are important effector cells of the haemostatic and inflammatory responses to tissue injury. To investigate the effects of surgical trauma on platelet activation (assessed by measuring levels of P-selectin and β-thromboglobulin), leucocyte activation (CD11b expression) and leucocyte-platelet interactions (leucocyte-platelet complexes), 30 patients undergoing primary hip arthroplasty were studied before and at the end of surgery, and on days 1 and 10 post-operatively, using a whole-blood flow cytometry assay. The inflammatory response was followed by measurement of the levels of C-reactive protein and interleukin-6 in plasma, and the activation of coagulation was monitored by determination of prothrombin fragment 1+2 levels. On day 1 post-operatively a significantly increased expression of CD11b on monocytes was noted, but no direct correlation was found between monocyte activation and interleukin-6 production or C-reactive protein at this time point. The percentage of monocyte-platelet and neutrophil-platelet complexes was markedly increased on day 10 post-operatively compared with pre-operative levels, and levels of these complexes were significantly positively correlated with β-thromboglobulin levels. Activation of coagulation (prothrombin fragment 1+2) on day 10 post-operatively was positively correlated with the extent of surgical trauma (duration of surgery, amount of blood loss) and with the increase in platelet activation (β-thromboglobulin). In conclusion, hip arthroplasty induces platelet and coagulation activation, and also an inflammatory response that is maintained for more than 10 days post-operatively. This indicates an interaction between the immune and the haemostatic systems in the post-operative phase after hip arthroplasty.
Liver electrolysis: pH can reliably monitor the extent of hepatic ablation in pigs
Authors: FINCH J. Guy , FOSH Beverley , ANTHONY Adrian , SLIMANI Eric , TEXLER Michael , BERRY David P. , DENNISON Ashley R. , MADDERN Guy J.
Published: August 2015

Electrolysis is a method of tissue ablation that creates chemical species and a pH gradient in response to direct current. Initial studies of electrolysis in animal models and humans have shown that it is a safe, predictable and effective process for destroying normal and tumour-bearing liver in a linear, dose-dependent manner. Presently, the amount of current that is applied (in coulombs) has to be calculated using historical data, with inherent inaccuracy. The present study tested whether pH could be used as a real-time monitor in order to predict more accurately the extent of necrosis. A total of 70 electrolytic lesions were created in 14 pigs, with pH monitoring of the lesion edge. The normal range of pH values was 6.5-8.7. A pH of less than 6 (at the anode) or more than 9 (at the cathode) reflected total cellular necrosis. When a pH value was recorded between 6.0 and 6.5 at the anode or between 8.7 and 9.0 at the cathode, the presence of necrosis was variable. In conclusion, during electrolytic ablation, pH measurement can monitor the extent of the induced necrosis.
Fatty acids and cytokine mRNA expression in human osteoblastic cells: a specific effect of arachidonic acid
Authors: PRIANTE G. , BORDIN L. , MUSACCHIO E. , CLARI G. , BAGGIO B.
Published: August 2015

Epidemiological, clinical and experimental evidence suggests that fatty acids have a modulatory effect on bone metabolism in animals and humans. To investigate this hypothesis, we evaluated the effects of three different fatty acids, arachidonic acid (AA), eicosapentaenoic acid (EPA) and oleic acid (OA), on the expression of cytokines involved in bone remodelling. Cytokine mRNAs in the human osteoblast-like cell line MG-63 were quantified by reverse transcription-PCR. AA induced increased expression of interleukin-1α, interleukin-1β, tumour necrosis factor-α and macrophage colony-stimulating factor mRNAs in a time- and dose-dependent manner. EPA and OA had no stimulatory effects, but instead caused a significant inhibition of AA-induced cytokine mRNA expression. Cell treatment with calphostin C, an inhibitor of protein kinase C (PKC), and cellular PKC down-regulation experiments independently resulted in significant inhibition of AA-induced cytokine expression, suggesting that a PKC-dependent mechanism accounts for the effects of AA on cytokine production. In conclusion, our study demonstrates specific effects of fatty acids on cytokine gene expression in human osteoblast-like cells. The clinical relevance of our findings requires further investigation.
Glucose flux is normalized by compensatory hyperinsulinaemia in growth hormone-induced insulin resistance in healthy subjects, while skeletal muscle protein synthesis remains unchanged
Authors: NYGREN Jonas , THORELL Anders , BRISMAR Kerstin , ESSÉN Pia , WERNERMAN Jan , MCNURLAN Margaret A. , GARLICK Peter J. , LJUNGQVIST Olle
Published: August 2015

The aim of this present investigation was to study the relationship between the reduction in insulin sensitivity accompanying 5 days of treatment with growth hormone (GH; 0.05mgċ24h-1ċkg-1) and intracellular substrate oxidation rates in six healthy subjects, while maintaining glucose flux by a constant glucose infusion and adjusting insulin infusion rates to achieve normoglycaemia (feedback clamp). Protein synthesis rates in skeletal muscle (flooding dose of L-[2H5]phenylalanine) were determined under these conditions. We also compared changes in insulin sensitivity after GH treatment with simultaneous changes in energy requirements, protein synthesis rates, nitrogen balance, 3-methylhistidine excretion in urine, body composition and the hormonal milieu. After GH treatment, 70% more insulin was required to maintain normoglycaemia (P < 0.01). The ratio between glucose infusion rate and serum insulin levels decreased by 34% at the two levels of glucose infusion tested (P < 0.05). Basal levels of C-peptide, insulin-like growth factor (IGF)-I and IGF-binding protein-3 increased almost 2-fold, while levels of glucose, insulin, glucagon, GH and IGF-binding protein-1 remained unchanged. Non-esterified fatty acid levels decreased (P < 0.05). In addition, 24h urinary nitrogen excretion decreased by 26% (P < 0.01) after GH treatment, while skeletal muscle protein synthesis and 3-methylhistidine excretion in urine remained unchanged. Energy expenditure increased by 5% (P < 0.05) after treatment, whereas fat and carbohydrate oxidation were unaltered. In conclusion, when glucose flux was normalized by compensatory hyperinsulinaemia under conditions of GH-induced insulin resistance, intracellular rates of oxidation of glucose and fat remained unchanged. The nitrogen retention accompanying GH treatment seems to be due largely to improved nitrogen balance in non-muscle tissue.
Type I IgE receptor, interleukin 4 receptor and interleukin 13 polymorphisms in children with nephrotic syndrome
Authors: TENBROCK K. , SCHUBERT A. , STAPENHORST L. , KEMPER M.J. , GELLERMANN J. , TIMMERMANN K. , MÜLLER-WIEFEL D.E. , QUERFELD U. , HOPPE B. , MICHALK D.
Published: August 2015

Polymorphisms in the genes encoding the high-affinity IgE receptor, the interleukin 4 (IL4) receptor and IL13 can be associated with the development of asthma and allergy. Although several studies have described an association between atopy and idiopathic childhood nephrotic syndrome (NS), it is not clear whether this association is of a causal nature. Furthermore, it is not known whether these polymorphisms are associated with the clinical course of NS. A total of 84 children (52 male and 32 female; mean age 12.1 years) with NS were included in the present study. Of these, 78 could be classified as either atopic or non-atopic. Atopy was defined by elevated IgE levels (>100k-units/l) and/or a positive history of atopy (33 of 78 patients). DNA was extracted from blood collected in EDTA tubes, and polymorphisms at positions 50 and 551 of the IL4 receptor, position 110 of IL13 and position 181 of the high-affinity IgE receptor were investigated by sequence-specific PCR or direct sequencing. Although we noted a strong tendency towards a higher allele frequency of polymorphisms in children with atopy and NS compared with children with NS but without atopy (IL4 50, 30% compared with 18%; IL4 551, 39% compared with 31%; IL13 110, 45% compared with 33%; IgE 181, 12% compared with 13%), these differences did not reach statistical significance. There were no differences in the frequency of polymorphisms between the different clinical courses of NS (frequent relapsers, steroid-dependent or steroid-resistant NS). We conclude that polymorphisms in the IL4 receptor, the high-affinity IgE receptor and IL13 do not seem to predict the clinical course of NS, despite the fact that serum IgE elevations are more frequent in patients with NS than in normal control subjects. The investigated polymorphisms may contribute to the IgE switch in patients with NS.
Muscle function during repetitive moderate-intensity muscle contractions in myoadenylate deaminase-deficient Dutch subjects
Authors: DE RUITER C.J. , MAY A.M. , VAN ENGELEN B.G.M. , WEVERS R.A. , STEENBERGEN-SPANJERS G.C. , DE HAAN A.
Published: August 2015

We investigated whether the capacity for repetitive submaximal muscle contraction was reduced in a group of subjects (n = 8) with a primary deficiency of myoadenylate deaminase (MAD). Quadriceps femoris muscle fatigue was evaluated using voluntary and electrically stimulated contractions during 20min of repetitive voluntary isometric contractions at 40% of maximal force-generating capacity (MFGC). After 5min of exercise, MFGC had declined significantly to 70.6±4.1% (mean±S.E.M.) and 87.2±1.6% of baseline values in MAD-deficient and sedentary control subjects (n = 8) respectively (P = 0.002 between groups). After 5min of exercise, the half-relaxation time had increased significantly to 113.4±6.1% of basline in MAD-deficient muscle, but had decreased significantly to 94.1±1.3% in control subjects (P = 0.003 between groups). All control subjects completed the 20-min exercise test. Five of the MAD-deficient subjects had to stop exercising due to early muscle fatigue; however, three of the MAD-deficient subjects were able to complete the 20-min exercise test. In conclusion, although the capacity for repetitive submaximal isometric muscle contractions for the group of MAD-deficient subjects was significantly decreased, it remains uncertain whether MAD deficiency is the sole cause of pronounced muscle fatigue.
Effects of hepatic ischaemia/reperfusion injury in a rabbit model of Indocyanine Green clearance
Authors: SEIFALIAN Alexander M. , EL-DESOKY Hamid , DELPY David T. , DAVIDSON Brian R.
Published: August 2015

Hepatic ischaemia/reperfusion (I/R) injury is a major cause of primary non-function of the graft after liver transplantation. The ability to assess the severity of ischaemic injury would be of prognostic value and allow the possibility of therapeutic interventions. Currently there is no reliable clinical method for assessing the severity of hepatic ischaemic injury. The hepatic handling of Indocyanine Green as a technique for monitoring the severity of I/R injury has been investigated in the present study. A rabbit model of lobar ischaemia was used. At laparotomy, left lobe hepatic ischaemia was produced for 30, 45 or 60min, followed by 60min of reperfusion. Liver function tests, bile excretion and flow in the hepatic microcirculation were measured in animals subjected to I/R injury and in controls. Indocyanine Green was given after reperfusion and its concentration was measured directly in the liver using near-infrared spectroscopy. Indocyanine Green hepatic uptake and excretion rates were calculated. I/R injury produced significant increases in hepatic serum enzymes and decreases in bile excretion and hepatic microcirculation in all I/R groups in comparison with controls. There was a significant reduction in Indocyanine Green uptake and excretion in the I/R groups in comparison with controls, which was correlated with the duration of ischaemia. Indocyanine Green uptake was correlated significantly with flow in the hepatic microcirculation, and its excretion was correlated significantly with the severity of liver damage, as reflected by the changes in serum enzymes and bile excretion. In conclusion, I/R injury affects the hepatic handling of Indocyanine Green, and direct quantification of the uptake and excretion of this dye by near-infrared spectroscopy may be used to objectively assess the degree of I/R injury.
Impaired cardiovascular responses to baroreflex stimulation in open-angle and normal-pressure glaucoma
Authors: BROWN Clive M. , DÜTSCH Matthias , MICHELSON Georg , NEUNDÖRFER Bernhard , HILZ Max J.
Published: August 2015

Autonomic neuropathy may contribute to the pathophysiology of both open-angle and normal-pressure glaucoma. However, autonomic function has not been studied extensively in these diseases. We evaluated baroreflex control of the heart and blood vessels in open-angle and normal-pressure glaucoma. We studied 14 patients with open-angle glaucoma, 15 with normal-pressure glaucoma and 17 controls. Sinusoidal neck suction (0 to -30mmHg) was applied at 0.1Hz to assess the sympathetic modulation of the heart and blood vessels, and at 0.2Hz to assess the effect of parasympathetic stimulation on the heart. Baseline recordings showed no significant differences between the groups. The RR-interval response of the controls to neck suction at 0.1Hz (3.88±0.32 to 6.65±0.44lnms2) was significantly greater than that of the open-angle glaucoma patients (4.22±0.28 to 5.56±0.26lnms2) and the normal-pressure glaucoma patients (4.53±0.27 to 5.53±0.37lnms2) (P<0.05). The low-frequency power of diastolic blood pressure increased significantly in the controls (0.48±0.08 to 2.76±0.72mmHg2; P<0.01) during 0.1Hz neck suction, but did not change significantly in patients with either open-angle glaucoma or normal-pressure glaucoma. The RR-interval response in the control group (3.45±0.52lnms2) to neck suction at 0.2Hz was significantly greater than that of the normal-pressure glaucoma patients (1.84±0.32lnms2) and the open-angle glaucoma patients (1.58±0.35lnms2) (P<0.05). The decreased sympathetic and parasympathetic modulation during baroreceptor stimulation in patients with open-angle glaucoma and normal-pressure glaucoma suggests that autonomic dysfunction may contribute to the pathogenesis of both diseases.
Impaired sympathetic regulation of cerebral blood flow in patients with cirrhosis of the liver
Authors: LAGI Alfonso , LAFFI Giacomo , CENCETTI Simone , BARLETTA Giuseppe , FOSCHI Marco , VIZZUTTI Francesco , BANDINELLI Renzo , PANTALEO Pietro , TOSTI GUERRA Cristina , GENTILINI Paolo , LA VILLA Giorgio
Published: August 2015

Continuous recording of mean cerebral blood flow velocity (MCBFV) by Doppler ultrasound allows detection of low-frequency (LF) oscillations, which reflect sympathetic activity in the cerebral circulation. To establish whether the sympathetic drive to the cerebral circulation is altered in patients with compensated cirrhosis, and, if so, where alterations take place, LF oscillations of MCBFV, heart rate (RR interval) and systolic arterial pressure (SAP) were analysed in 10 patients with cirrhosis and 10 control subjects during supine rest and on stimulation of carotid baroreceptors using a neck chamber applying sinusoidal suction. Bivariate analysis was used to study the relationship between pairs of oscillations. In the case of a significant association, the delay in the appearance of the oscillation in MCBFV, SAP and RR was calculated. Baroreceptor stimulation induced significant increases in SAP LF and RR LF power in both groups, while MCBFV LF power increased only in controls. During baroreceptor stimulation, the lag phase between SAP LF and MCBFV LF power was significantly lower in cirrhotic patients than in control subjects (0.96 compared with 1.59 rad; P<0.01), indicating altered sympathetic regulation of the cerebral circulation. The baroreflex arc was intact, as indicated by the similar pattern of RR-SAP interval in patients and controls. Plasma noradrenaline levels increased significantly in both groups in response to head-up tilt. These results indicate that patients with cirrhosis have an altered sympathetic regulation of the cerebral circulation that is characterized by an inadequate response of resistance microvessels, despite adequate baroreceptor function.
Reproducibility of derived central arterial waveforms in patients with chronic renal failure
Authors: SAVAGE M. Tessa , FERRO Charles J. , PINDER Sarah J. , TOMSON Charles R.V.
Published: August 2015

Arterial stiffness potently predicts mortality in dialysis patients. Pulse-wave analysis permits the non-invasive assessment of indices of arterial stiffness and the central pressure waveform by applanation tonometry. The aim of this study was to assess the reproducibility of pulse-wave analysis in patients with chronic renal failure. A total of 188 subjects (23 healthy controls, along with 71 pre-dialysis, 67 dialysis and 27 transplant patients) took part. Duplicate measurements were recorded of brachial blood pressure using the semi-automated Omron 705 device and of the radial artery pressure waveform using applanation tonometry. The central pressure aortic waveform was then obtained by application of a transfer function incorporated into the SphygmoCor software. Central aortic mean blood pressure (MBP), indices of arterial stiffness [augmentation index (AIx) and time to reflection (TR)] and the subendocardial viability ratio (SEVR) were analysed for intra-observer, inter-observer and long-term reproducibility using Bland-Altman plots. The mean (±S.D.) intra-observer difference was 0±4% for AIx, 0±20 ms for TR, 0±3 mmHg for aortic MBP and 0±18% for the SEVR. Inter-observer mean differences were 0±3% for AIx, 1±7ms for TR, 1±4mmHg for aortic MBP and 1±9% for the SEVR. For the long-term study, the mean differences were -1±9% for AIx, -2±13mmHg for aortic MBP, -2±12ms for TR and 1±29% for the SEVR. Pulse-wave analysis showed excellent reproducibility in all the studies, and is therefore suitable for use in all patients with chronic renal failure. Further prospective and interventional studies are now required to assess whether AIx and TR are important prognostic indices of cardiovascular events, and therefore relevant surrogate indices of arterial stiffness in this susceptible population.
Measuring baroreflex sensitivity from the gain function between arterial pressure and heart period
Authors: PINNA Gian Domenico , MAESTRI Roberto , RACZAK Grzegorz , LA ROVERE Maria Teresa
Published: August 2015

We tested an innovative approach for estimating baroreflex sensitivity (BRS) from the gain function between spontaneous oscillations of systolic arterial pressure (SAP) and heart period (HP). The major goal was to assess the practical implications of abandoning the classical coherence criterion (⩾0.5) as regards measurability of BRS, and agreement with values of BRS obtained using the phenylephrine test (Phe-BRS). We studied 19 normal subjects, 44 patients with a history of previous myocardial infarction (MI) and 45 patients with chronic heart failure (CHF). The experimental protocol included recording of SAP and HP for 10min of supine rest, and evaluation of Phe-BRS. From resting SAP and HP, the gain and coherence functions were computed. The new BRS index was obtained in all subjects by averaging the gain function over the whole low-frequency band (0.04-0.15Hz) (whole-band average BRS, WBA-BRS). WBA-BRS was 7.4 (5.8-10.8)ms/mmHg [median (25th-75th percentile)] in normal controls, 3.1 (1.4-5.4)ms/mmHg in MI patients (P<0.001 compared with normals) and 5.0 (3.2-6.9)ms/mmHg in CHF patients (P<0.01 compared with normals). Using the coherence criterion, BRS could be measured in only 43% and 49% of MI and CHF patients respectively, and the proportion of the low-frequency band contributing to the measurement was 21% (14-47%) and 29% (16-35%) respectively. The correlation between WBA-BRS and Phe-BRS was 0.47, 0.63 and 0.36 in the normal, MI and CHF groups respectively (all P<0.001). The relative bias of WBA-BRS was -5.2ms/mmHg (P<0.001) in normals, -1.4ms/mmHg (P = 0.004) in MI patients and -1.0ms/mmHg (P = 0.11) in CHF patients. The limits of agreement were -13 to 2.6, -7.4 to 4.6 and -9.3 to 7.3ms/mmHg in the normal, MI and CHF groups respectively. Thus the WBA-BRS method standardizes the computation of BRS among subjects, and dramatically increases its measurability in subjects with pathology compared with the classical spectral technique based on the coherence criterion. Compared with Phe-BRS, WBA-BRS tends to give negatively biased results. The correlation and the magnitude of the limits of agreement between the two methods are similar to those observed previously using coherence-based spectral methods.
Effects of smoking cessation or alcohol restriction on metabolic and fibrinolytic variables in Japanese men
Authors: MINAMI Junichi , TODOROKI Masakatsu , YOSHII Masayoshi , MITA Shinichiro , NISHIKIMI Toshio , ISHIMITSU Toshihiko , MATSUOKA Hiroaki
Published: August 2015

We investigated the effects of smoking cessation or alcohol restriction on metabolic and fibrinolytic variables in Japanese men. In the smoking study, 35 male subjects [32±1 (S.E.M.) years] who habitually smoked cigarettes (29±3cigarettes/day) were told either to keep their usual smoking habits for 1week, or to abstain from cigarette smoking, using a randomized crossover design. In the alcohol study, 33 male subjects (37±1years) who habitually drank alcohol (64±6ml of ethanol/day) were told either to keep their usual drinking habits for 3weeks, or to reduce alcohol intake by at least up to a half of their usual drinking amount, using a randomized crossover design. In each study, venous blood samples were drawn after a 12-h overnight fast on the last day of each period, and metabolic and fibrinolytic variables were measured. One-week smoking cessation significantly increased serum high-density lipoprotein (HDL) cholesterol levels (P<0.05), and significantly decreased serum lipoprotein (a) levels (P<0.01) and plasma plasminogen activator inhibitor-1 levels (P<0.05). In contrast, 3-week alcohol restriction significantly decreased serum HDL cholesterol levels (P<0.05) and plasma tissue plasminogen activator levels (P<0.05). These results suggest that smoking cessation has substantial and immediate benefits on lipid and fibrinolytic variables in habitual smokers, whereas alcohol restriction increases cardiovascular risks, in some respects, in habitual drinkers.