bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in the pattern of bile acids in the nuclei of rat liver cells during hepatocarcinogenesis
Authors: MENDOZA M.E. , MONTE M.J. , EL-MIR M.Y. , BADIA M.D. , MARIN J.J.G.
Published: August 2015

Bile acids reach the nuclei of hepatocytes, where they may play an important role in controlling gene expression by binding to nuclear receptors. In previous studies, changes in the amounts of the different molecular species of bile acids in the hepatocyte nucleus during rat liver regeneration have been reported. The aim of the present work was to investigate whether this also occurs during rat hepatocarcinogenesis. Liver cell nuclei were isolated after homogenization of livers from healthy adult rats (controls) and from rats at different time points during chemically induced hepatocarcinogenesis, corresponding to the stages of foci (12 weeks), hepatoma (20 weeks) and carcinoma (32 weeks). Bile samples from the cannulated common bile duct were collected for 1h from different sets of animals undergoing hepatocarcinogenesis. Bile acids in bile, liver homogenates and isolated nuclei were measured by GC-MS. Because the yield of nuclei isolated changed during the course of hepatocarcinogenesis (control, 20.1%; 12 weeks, 23.6%; 20 weeks, 7.8%; 32 weeks, 5.1%), amounts of bile acids in nuclei were corrected for the amount of DNA in each preparation. During hepatocarcinogenesis, bile acid concentrations in liver homogenates were reduced to approximately half the values obtained in control livers, while the levels of bile acids in both isolated nuclei and bile were not decreased. Hepatocarcinogenesis induced changes in the composition of bile acid pools. These were manifest as an increase in the proportion of cholic acid and a decrease in that of ursodeoxycholic acid in both bile and liver. These modifications differed from the changes seen in the nuclear bile acid pool, where a decrease in the proportion of cholic acid together with an increase in that of ursodeoxycholic acid were the major changes observed during hepatocarcinogenesis. With regard to the ‘flat’ bile acids (allo-cholic acid plus Δ5- or Δ4-unsaturated bile acids), a marked hepatocarcinogenesis-induced increase in the output of these species in bile was found. However, these bile acids were only found in liver homogenates at the hepatoma stage, whereas they were not detected in isolated nuclei at any stage of hepatocarcinogenesis. In summary, these results support the existence of a bile acid pool in hepatocyte nuclei whose composition differs from that of the extranuclear bile acid pool. Moreover, they indicate that, during hepatocarcinogenesis, the composition of the nuclear pool undergoes important alterations.
Alcohol consumption, the metabolic syndrome and insulin resistance in 58-year-old clinically healthy men (AIR study)
Authors: GOUDE Daniel , FAGERBERG Björn , HULTHE Johannes
Published: August 2015

It has been shown that a light-to-moderate intake of alcohol may enhance insulin sensitivity; a decrease in insulin sensitivity is a component of the clustering of risk factors known as the metabolic syndrome. However, previous studies have been limited to relatively small or heterogeneous study groups, or have used suboptimal methods of measuring insulin action. Hence the aim of the present study was to examine whether the metabolic syndrome (as recently defined), components of this syndrome and smoking are associated with alcohol consumption. The study was performed in a population-based sample of clinically healthy men (n = 391), all 58 years old and not undergoing any treatment with cardiovascular drugs. Insulin-mediated glucose uptake (euglycaemic hyperinsulinaemic clamp) was measured in a subgroup of these subjects (n = 104). Trend analysis showed no difference in alcohol intake across the groups of men with none of the criteria in the definition of the metabolic syndrome (n = 77), men with one or more of the criteria (n = 252) and men fulfilling all criteria (n = 62). However, in the whole group (n = 391), alcohol consumption was significantly positively associated with serum triacylglycerols (triglycerides), high-density lipoprotein (HDL) cholesterol and cigarette-years. Furthermore, alcohol consumption was positively associated with insulin-mediated glucose uptake (r = 0.20, P < 0.05). In multiple regression analyses, body mass index, alcohol consumption and serum triacylglycerols were independent co-variates to insulin-mediated glucose uptake. Thus, in 58-year-old healthy men recruited from the general population, there was a significant association between alcohol consumption, serum triacylglycerols, HDL cholesterol and cigarette-years. In a subgroup of 104 subjects, alcohol consumption was independently and positively associated with insulin-mediated glucose uptake. To our knowledge, this is the first study to show an independent relationship between insulin sensitivity, as measured by the clamp technique, and alcohol intake.
Aldosterone synthase (CYP11B2) expression and myocardial fibrosis in the failing human heart
Authors: SATOH Mamoru , NAKAMURA Motoyuki , SAITOH Hidenori , SATOH Hidetoshi , AKATSU Tomonari , IWASAKA Junji , MASUDA Tomoyuki , HIRAMORI Katsuhiko
Published: August 2015

The pathway of tissue aldosterone production may exist in the heart, and may be an important contributory factor to myocardial fibrosis and cardiac remodelling in the failing heart. CYP11B2 (aldosterone synthase) catalyses the final step of aldosterone production. The aim of the present study was to determine whether CYP11B2 and CYP11B1 (11β-hydroxylase) are expressed in myocardial tissues, and whether these enzymes contribute to collagen accumulation and myocardial dysfunction in the failing human heart. Endomyocardial tissues were obtained from 23 patients with chronic heart failure (CHF) and 10 controls. CYP11B2 and CYP11B1 mRNA levels were measured by real-time quantitative reverse transcriptase-PCR. The myocardial collagen volume fraction (CVF) was determined by digital planimetry. CYP11B2 mRNA expression was greater in the CHF group than in the controls (P < 0.05), while CYP11B1 mRNA was barely expressed in either group. There was a positive correlation between CYP11B2 mRNA levels and CVF (r = 0.64, P =0.001). CYP11B2 mRNA was particularly highly expressed in subgroups of CHF patients with a large left ventricular end-systolic diameter (>55mm) or a low left ventricular ejection fraction (< 30%). CYP11B2 mRNA expression and CVF were lower in a CHF subgroup treated with a combination of spironolactone and angiotensin-converting enzyme inhibitors (ACEIs) than in a subgroup not treated with these drugs. In conclusion, this study has shown that increased myocardial expression of CYP11B2 mRNA is associated with increased myocardial fibrosis and with the severity of left ventricular dysfunction in human CHF. In addition, CYP11B2 expression and cardiac fibrosis are found to be decreased in CHF patients on drug therapy comprising spironolactone combined with ACEIs.
Non-competitive immunochemiluminometric assay for cardiotrophin-1 detects elevated plasma levels in human heart failure
Authors: NG Leong L. , O'BRIEN Russell J. , DEMME Bettina , JENNINGS Sonja
Published: August 2015

Cardiotrophin-1 (CT-1) leads to a specific form of ventricular hypertrophy characterized by sarcomeres added in series, and has been reported to be elevated in heart failure. Previous competitive assays for CT-1 necessitate the extraction of plasma and involve prolonged incubations. We describe the development of a non-competitive assay for CT-1 that can measure plasma levels without the need for extraction. Two antibodies specific for the mid-section (amino acids 105-120) and C-terminal (amino acids 186-199) portions of CT-1 were developed in rabbits. One antibody was immobilized and used as the capture antibody. The other antibody was affinity purified and biotinylated. Unextracted plasma was incubated with these antibodies, and detection was with methylacridinium ester-labelled streptavidin. Plasma was obtained from 40 patients with heart failure and 40 normal control subjects. The non-competitive assay demonstrated a linear increase in chemiluminescence (measured as relative light units) with increasing amounts of full-length recombinant CT-1, with no evidence of a hook effect at high concentrations. The lower limit of detection was 2.9 fmol/ml. Intra-assay coefficients of variation ranged from 3.1% to 4.2% in the 10-40fmol/well concentration range, and interassay coefficients of variation ranged from 3.5% to 4.5% in the 550-950fmol/ml range. Measurements of CT-1 levels in patients with heart failure (median 166.5fmol/ml; range 49.5-2788fmol/ml) revealed very significantly elevated levels compared with those in normal controls (median 43.5fmol/ml; range 11.2-258.6fmol/ml; P < 0.0001 by Mann-Whitney test). At a CT-1 concentration of 68fmol/ml, sensitivity and specificity were 95% and 82.5% respectively. Thus this new non-competitive immunochemiluminometric assay for CT-1 could successfully detect full-length recombinant CT-1 in unextracted plasma, and demonstrated that plasma levels of CT-1 were significantly elevated in patients with heart failure.
Extracellular matrix regulation of drug resistance in small-cell lung cancer
Authors: RINTOUL Robert C. , SETHI Tariq
Published: August 2015

Tumour recurrence following chemotherapy remains a major obstacle to the cure of many cancers. This is exemplified by small-cell lung cancer (SCLC). Host-tumour interactions are central to tumour survival and proliferation. We hypothesized that a factor(s) within the local environment of SCLC cells could provide a survival signal or block a death signal, thereby accounting for the protection of SCLC cells from chemotherapy-induced apoptosis. Here we review recent work undertaken in our laboratory addressing this issue. We have shown that, in vivo, SCLC cells are surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites which contains, among other proteins, fibronectin, laminin and collagen IV. Furthermore, adhesion of SCLC cells to fibronectin, laminin and collagen IV through β1 integrins enhances tumorigenicity and confers resistance to apoptosis induced by standard chemotherapeutic agents, including etoposide, cis-platinum and adriamycin. Adhesion to ECM proteins stimulated protein tyrosine kinase (PTK) activity in both untreated and etoposide-treated cells. This effect could be completely blocked by a selective PTK inhibitor or by a function-blocking β1 integrin antibody. PTK activation was found to block chemotherapy-induced activation of the death protease caspase-3 and, hence, apoptosis. Adhesion to ECM or treatment with a PTK inhibitor did not affect etoposide inhibition of topoisomerase II. Thus adhesion to ECM through β1 integrins protects SCLC cells from chemotherapy-induced caspase-3 activation and apoptosis by activating PTK signalling downstream of DNA damage. Survival of tumour cells attached to ECM within this microenvironment could explain the local recurrence of SCLC and other tumours that is often seen clinically after chemotherapy.
The immunopathogenesis of paraneoplastic neurological syndromes
Authors: SUTTON Ian , WINER John B.
Published: August 2015

Paraneoplastic neurological syndromes are rare non-metastatic complications of cancer that have an immune-mediated aetiology. The central and peripheral nervous systems are considered to be immune-privileged sites, since the presence of the ‘blood-brain/nerve barrier’ means that antigens sequestered within the nervous system do not normally induce an immune response. Aberrant expression of a neuronal antigen by a tumour arising outside this barrier can lead to the breakdown of immune tolerance to the nervous system. However, in many cases the immune mechanisms that result in neurological dysfunction remain poorly defined. Furthermore, aberrant expression of neuronal antigens can be detected in many tumours that are not complicated by non-metastatic neurological syndromes. This review article examines current concepts in the immunopathogenesis of paraneoplastic neurological syndromes.
Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism
Authors: PASCUAL Maria J. , SERRANO Maria A. , EL-MIR Mohamad Y. , MACIAS Rocio I.R. , JIMÉNEZ Felipe , MARIN Jose J.G.
Published: August 2015

The aim of this study was to identify a subgroup of pregnant women with asymptomatic hypercholanaemia of pregnancy (AHP), in which the relationship between alterations in the level and pattern of serum bile acids (BAs) and of progesterone plus progesterone metabolites could be investigated in the absence of overt impairment of hepatobiliary function. Cholanaemia and serum concentrations of progesterone were assayed by an enzymic technique and by ELISA respectively, while BA molecular species and progesterone metabolites were measured by GC-MS, in the serum of 411 healthy pregnant women. Samples were collected after an overnight fast in the final week of each trimester of gestation. Two pregnant women were excluded because of the suspicion of intrahepatic cholestasis of pregnancy (ICP). Cholanaemia was found to increase progressively throughout pregnancy, but with normal mean values lower than 3.0μM. Thus in our series AHP was defined arbitrarily as the presence of serum total BA concentrations 2-fold higher than this value, i.e. 6μM, in the absence of hepatobiliary disease or symptoms of ICP. The prevalence of this condition was observed to increase with gestational age. Changes in the pattern of serum BAs in AHP were also found. These were reflected in a marked increase in the proportion of cholic acid together with a decrease in that of deoxycholic acid, while the proportions of chenodeoxycholic acid and lithocholic acid changed only moderately. When groups at the same gestational age were compared, serum progesterone levels were always significantly lower, while those of progesterone metabolites were higher, in women with AHP. Our results suggest that AHP is a relatively common condition in our geographical location, where ICP is rarely diagnosed. Changes in the serum BA pattern in hypercholanaemia resemble these described in ICP. The simultaneous finding of lower serum total progesterone levels along with an increase in its metabolites supports the hypothesis that a primary defect in progesterone metabolism may be involved in the aetiology of ICP.
Does the menstrual cycle influence the sensitivity of vagally mediated baroreflexes?
Authors: COOKE William H. , LUDWIG David A. , HOGG Paul S. , ECKBERG Dwain L. , CONVERTINO Victor A.
Published: August 2015

The menstrual cycle provokes several physiological changes that could influence autonomic regulatory mechanisms. We studied the carotid-cardiac baroreflex in ten healthy young women on four occasions over the course of their menstrual cycles (days 0-8, 9-14, 15-20 and 21-25). We drew blood during each session for analysis of oestrogen, progesterone and noradrenaline (norepinephrine) levels, and assessed carotid-cardiac baroreflex function by analysing R-R interval responses to graded neck pressure sequences. Oestrogen levels followed a classical two-peak (cubic) response, with elevated levels on days 9-14 and 21-25 compared with days 0-8 and 15-20 (P =0.0032), while progesterone levels increased exponentially from days 9-14 to days 21-25 (P = 0.0063). Noradrenaline levels increased from an average of 137pg/ml during the first three measurement periods to 199pg/ml during days 21-25 (P = 0.0456). Carotid-cardiac baroreflex gain and operational point were not statistically different at any of the time points during the menstrual cycle (P⩾0.18). These findings are consistent with the notion that beat-to-beat vagal-cardiac regulation does not change over the course of the normal menstrual cycle.
Empirical estimates of mean aortic pressure: advantages, drawbacks and implications for pressure redundancy
Authors: CHEMLA Denis , HÉBERT Jean-Louis , APTECAR Eduardo , MAZOIT Jean-Xavier , ZAMANI Karen , FRANK Robert , FONTAINE Guy , NITENBERG Alain , LECARPENTIER Yves
Published: August 2015

Mean arterial pressure (MAP) is estimated at the brachial artery level by adding a fraction of pulse pressure (form factor; = 0.33) to diastolic pressure. We tested the hypothesis that a fixed form factor can also be used at the aortic root level. We recorded systolic aortic pressure (SAP) and diastolic aortic pressure (DAP), and we calculated aortic pulse pressure (PP) and the time-averaged MAP in the aorta of resting adults (n = 73; age 43±14 years). Wave reflection was quantified using the augmentation index. The aortic form factor (range 0.35-0.53) decreased with age, MAP, PP and augmentation index (each P<0.001). The mean form factor value (0.45) gave a reasonable estimation of MAP (MAP = DAP+0.45PP; bias = 0±2mmHg), and the bias increased with MAP (P<0.001). An alternative formula (MAP = DAP+PP/3+5mmHg) gave a more precise estimation (bias = 0±1mmHg), and the bias was not related to MAP. This latter formula was consistent with the previously reported mean pulse wave amplification of 15mmHg, and with unchanged MAP and diastolic pressure from aorta to periphery. Multiple linear regression showed that 99% of the variability of MAP was explained by the combined influence of DAP and SAP, thus confirming major pressure redundancy. Results were obtained irrespective of whether the marked differences in heart period and extent of wave reflection between subjects were taken into account. In conclusion, the aortic form factor was strongly influenced by age, aortic pressure and wave reflection. An empirical formula (MAP = DAP+PP/3+5mmHg) that is consistent with mechanical principles in the arterial system gave a more precise estimate of MAP in the aorta of resting humans. Only two distinct pressure-powered functions were carried out in the (SAP, DAP, MAP, PP) four-pressure set.
Circulating ICAM-1 (intercellular cell-adhesion molecule 1) is associated with early stages of atherosclerosis development and with inflammatory cytokines in healthy 58-year-old men: the Atherosclerosis and Insulin Resistance (AIR) study
Authors: HULTHE Johannes , WIKSTRAND John , MATTSSON-HULTÉN Lillemor , FAGERBERG Björn
Published: August 2015

There is a lack of data on circulating levels of cell-adhesion molecules in relation to subclinical atherosclerosis measured in both the carotid and femoral arteries in humans. The aim of the present study was to investigate the relationship between clinically silent atherosclerosis and cell-adhesion molecules, and to explore the relationship between these molecules, C-reactive protein and the inflammatory cytokines interleukin-6, tumour necrosis factor-α (TNF-α), soluble TNF-α receptor p55 and soluble TNF-α receptor p75. The study group (n = 391) consisted of clinically healthy 58-year-old men recruited from the general population. The results showed a positive trend between levels of soluble intercellular cell-adhesion molecule 1 (sICAM-1) and plaque occurrence in the carotid and femoral arteries (P = 0.008), and also a univariate correlation between sICAM-1 levels and the composite variable of carotid and femoral intima-media thickness (P<0.001). When adjusted for other risk factors, the relationship between sICAM-1 and intima-media thickness no longer reached statistical significance. The level of sICAM-1 was associated with those of the pro-inflammatory cytokine TNF-α, its two soluble receptors, and also interleukin-6 and C-reactive protein. Levels of soluble E-selectin and vascular cell-adhesion molecule 1 (VCAM-1) showed weak or no association with subclinical atherosclerosis and inflammatory variables. Thus, in clinically healthy middle-aged men, levels of sICAM-1, but not of soluble VCAM-1 or E-selectin, were associated with both subclinical atherosclerosis and inflammatory variables.
Finapres arterial pulse wave analysis with Modelflow® is not a reliable non-invasive method for assessment of cardiac output
Authors: REMMEN Jaap J. , AENGEVAEREN Wim R.M. , VERHEUGT Freek W.A. , VAN DER WERF Tjeerd , LUIJTEN Hans E. , BOS Anja , JANSEN René W.M.M.
Published: August 2015

Non-invasive continuous monitoring of cardiac output could be very useful in clinical care and in research settings, particularly in elderly subjects. We studied whether Finapres arterial pulse wave analysis with Modelflow® is a reliable non-invasive method for the assessment of cardiac output in healthy elderly subjects. We compared Modelflow® cardiac output (MFCO) with thermodilution cardiac output (TDCO) in 28 healthy subjects, aged 70±4years (mean±S.D.). TDCO was measured during right-sided heart catheterization, while MFCO was calculated with Modelflow® software from non-invasive arterial Finapres blood pressure, which was measured simultaneously. The two methods were compared using a paired t-test, by Pearson correlation, and by Bland–Altman analysis. TDCO was 6.4±1.1litres/min (mean±S.D.) and MFCO was 4.7±1.3litres/min (P<0.001). There was no significant correlation between MFCO and TDCO (r = 0.28, P = 0.13). Mean difference (bias) was -1.7litres/min (S.E.M. 0.27litres/min), with an S.D. (precision) of 1.5litres/min. The 95% limits of agreement were -4.6 to +1.1litres/min. In conclusion, non-invasive MFCO values differed significantly from and showed no significant correlation with invasively determined TDCO values in the normal range. Although simple, non-invasive and patient-friendly, the Modelflow® method is inaccurate for assessment of cardiac output without invasive calibration.
Glucose, but not glutamine, protects against spontaneous and anti-Fas antibody-induced apoptosis in human neutrophils
Authors: HEALY Declan A. , WATSON R. William G. , NEWSHOLME Philip
Published: August 2015

Neutrophils are phagocytic cells of the innate immune system that use a combination of reactive oxygen species and anti-microbial toxins to kill and destroy ingested micro-organisms. Once they have performed their function, neutrophils die by apoptosis, which is important for the effective resolution of the inflammatory response. Both glucose and glutamine are important fuels for neutrophils, yet little has been done to investigate the comparative effects of glucose and glutamine on neutrophil apoptosis. We hypothesized that glucose and/or glutamine significantly alter rates of spontaneous and anti-Fas antibody-induced apoptosis of human neutrophils cultured ex vivo. Neutrophil apoptosis was reduced by increasing the extracellular concentration of glucose, but was unaffected by glutamine concentration. The protective effect of glucose appeared to correlate with the rate of glucose utilization. The addition of a competitive inhibitor of glycolysis, 2-deoxy-d-glucose (10mM), attenuated the protective effect of 5.5mM glucose, indicating that glucose metabolism is essential for its protective effect against apoptosis. There was a significant (P<0.05) reduction in the intracellular ATP concentration of neutrophils incubated in the absence of extracellular glucose compared with cells incubated in the presence of 5.5mM glucose. The protective effect of glucose against apoptosis may be mediated by maintenance of the intracellular ATP concentration.
Taurocholate induces changes in rat cardiomyocyte contraction and calcium dynamics
Authors: GORELIK Julia , HARDING Sian E. , SHEVCHUK Andrew I. , KORALAGE Duleepa , LAB Max , DE SWIET Michael , KORCHEV Yuri , WILLIAMSON Catherine
Published: August 2015

Obstetric cholestasis is characterized by raised bile acids, and can be complicated by intrauterine death. We have shown that the bile acid taurocholate causes loss of synchronous beating, bradycardia and cessation of contraction in cultured rat cardiomyocytes [Williamson, Gorelik, Eaton, Lab, de Swiet and Korchev (2001) Clin. Sci. 100, 363–369]. The aim of the present study was to investigate the effect of taurocholate on cardiomyocytes further. We demonstrated a reduced rate of contraction and proportion of beating cells when rat cardiomyocytes were exposed to increasing concentrations of taurocholate (0.1–3.0mM); more marked at higher concentrations (P<0.001). Using scanning ion-conductance microscopy, we also demonstrated reduced amplitude of contraction and calcium transients with taurocholate. Our observations indicate that taurocholate affects calcium release from the sarcoplasmic reticulum and this parallels changes in contractile function. The relationship between the contraction amplitude and calcium transient is not linear, particularly at higher concentrations of taurocholate. We observed different effects in individual cultured neonatal cells; a reversible reduction in rate and amplitude of contraction in some, and irreversible oscillatory (fibrillatory) cessation of beating in others. The effects were more marked with higher concentrations. The contraction amplitude was also reduced in adult cardiomyocytes. The changes were reversible following removal of taurocholate in adult, but not in neonatal, cardiomyocytes exposed to higher concentrations (>0.3mM) (P<0.001). In conclusion we have demonstrated that the bile acid taurocholate can cause different types of dysrhythmia in individual cardiomyocytes. These results provide further support for the hypothesis that obstetric cholestasis may produce cardiac-related sudden intrauterine death.
Dynamic computed tomography with low- and high-molecular-mass contrast agents to assess microvascular permeability modifications in a model of liver fibrosis
Authors: MATERNE Roland , ANNET Laurence , DECHAMBRE Stéphane , SEMPOUX Christine , SMITH Anne M. , COROT Claire , HORSMANS Yves , VAN BEERS Bernard E.
Published: August 2015

Interstitial collagen formation and transformation of the fenestrated hepatic sinusoids into continuous capillaries are major ultrastructural changes that occur in liver cirrhosis and fibrosis. These modifications lead to progressive restriction of blood–liver exchanges. The purpose of our study was to evaluate the permeability changes in a model of hepatic fibrosis by using dynamic computed tomography (CT) enhanced with contrast agents of different molecular masses. Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass contrast agent (iobitridol) and an experimental high-molecular-mass agent (P840) in normal control rabbits and in rabbits with hepatic fibrosis. Hepatic, aortic and portal venous time–density curves were fitted with a dual-input one-compartmental model to calculate the hepatic mean transit time and distribution volume of the contrast agents. In the rabbits with liver fibrosis, the mean transit time of the high-molecular-mass agent was shorter than that of the low-molecular-mass agent (10.0±1.8s and 12.0±1.2s respectively; P<0.05). The distribution volume accessible to the high-molecular-mass agent was also smaller (22.2±4.8% compared with 32.0±6.7%; P<0.01). In the normal rabbits, the mean transit times of the high- and low-molecular-mass agents did not differ significantly, and nor did their distribution volumes. Our results demonstrate decreased sinusoidal permeability for the high-molecular-mass agent P840 in a model of hepatic fibrosis. Non-invasive assessment of permeability changes in liver fibrosis can be performed with dynamic CT and contrast agents of different molecular masses.
Influence of drugs and gender on the arterial pulse wave and natriuretic peptide secretion in untreated patients with essential hypertension
Authors: DEARY Alison J. , SCHUMANN Anne L. , MURFET Helen , HAYDOCK Stephen , FOO Roger S. , BROWN Morris J.
Published: August 2015

Recent studies have suggested a differential influence of mean pressure and pulse pressure on myocardial infarction and stroke, and differences among the major drugs in their efficacy at preventing these individual endpoints. We hypothesized that antihypertensive drugs have differing influences upon the pulse wave even when their effects on blood pressure are the same. We studied 30 untreated hypertensive patients, aged 28—55 years, who were rotated through six 6-week periods of daily treatment with amlodipine 5mg, doxazosin 4mg, lisinopril 10mg, bisoprolol 5mg, bendrofluazide 2.5mg or placebo. The best drug was repeated at the end of the rotation. Blood pressure readings and radial pulse tonometry (by Sphygmocor®) were performed at each visit, and blood was taken for measurement of levels of atrial natriuretic peptide and brain natriuretic peptide (BNP). The Sphygmocor derivation of the central aortic pulse wave was used to measure time for transmission of the reflected wave (TR) and the augmentation index (AI), which is the proportional increase in systolic pressure due to the reflected wave. There was a dissociation between the effects of the drugs on blood pressure and pulse wave analysis. Bisoprolol caused the greatest falls in blood pressure and TR, but was the only drug to increase AI. This paradoxical response to bisoprolol was associated with a 3-fold increase in plasma BNP levels. There was a smaller elevation of BNP in women compared with men, as described previously, and this elevation also was associated with significantly higher values of AI. Other drugs reduced AI, and this was associated with a significant decrease in BNP by amlodipine. In conclusion, antihypertensive drugs differ in their short-term effects on augmentation of the systolic pulse wave and secretion of BNP from the heart, regarded as a sensitive measure of strain on cardiomyocytes. These differences may help to explain cause-specific differences in outcome in recent trials.
Association of calcium channel blockers and mortality in haemodialysis patients
Authors: TEPEL Martin , VAN DER GIET Markus , PARK Alexander , ZIDEK Walter
Published: August 2015

Patients with end-stage renal disease show disturbances of calcium metabolism, including calcification of arterial walls. Such patients show increased mortality, in particular due to increased cardiovascular-associated deaths. The association of calcium channel blockers and mortality in patients undergoing haemodialysis was investigated. A total of 188 patients who were receiving haemodialysis as of July 1998 were followed up for 30 months. Baseline characteristics, including age, sex, laboratory and clinical data, medication and dialysis prescription, were obtained. As of December 2000, 51 of the patients (27%) had died. In the deceased group, age was significantly higher, body mass index was significantly lower, and smoking was significantly more frequent compared with the survival group (each P<0.001). The percentage of patients taking calcium channel blockers was significantly higher in the survival group. Cox proportional hazard regression analysis showed that haemodialysis patients assigned calcium channel blocker therapy had a significantly lower risk of mortality [relative risk 0.33 (95% confidence interval 0.17–0.67); P<0.001]. Thus, in haemodialysis patients who were at high risk of cardiovascular events, administration of calcium channel blockers was associated with lower mortality.
Deletion polymorphism in the α2B-adrenergic receptor gene is associated with flow-mediated dilatation of the brachial artery
Authors: HEINONEN Paula , JARTTI Laura , JÄRVISALO Mikko J. , PESONEN Ullamari , KAPRIO Jaakko A. , RÖNNEMAA Tapani , RAITAKARI Olli T. , SCHEININ Mika
Published: August 2015

A deletion variant of the α2B-adrenergic receptor (α2B-AR) has been associated with an increased risk of acute cardiac events in middle-aged men. Our aim was to determine the possible associations between the α2B-AR gene deletion variant and indicators of subclinical atherosclerosis in the brachial and carotid arteries. A total of 148 middle-aged men participating in an epidemiological twin study on risk factors for subclinical coronary heart disease were genotyped using PCR. Flow-mediated dilatation (FMD) of the brachial artery, carotid artery compliance and carotid intima-media thickness were measured using high-resolution ultrasound. FMD was 6.2±5.0% in subjects with the I/I (insertion/insertion) genotype, 5.5±4.1% in the I/D (insertion/deletion) group and 4.1±3.8% in the D/D (deletion/deletion) group (P = 0.03 for trend). In multivariate regression analysis controlling for age, presence of hypertension, smoking, use of angiotensin-converting enzyme inhibitors and plasma levels of low-density lipoprotein cholesterol and lipoprotein (a), the association between the α2B-AR genotype and FMD remained significant (P = 0.04 for trend). The α2B-AR genotype was not associated with intima-media thickness or carotid artery compliance. These findings indicate that subjects homozygous for the deletion allele of α2B-AR appear to have an increased risk of impaired endothelial function, which may provide an explanation for the previously observed increased risk of myocardial infarction in male subjects with this genotype. It is not known whether the association of the α2B-AR polymorphism with endothelial function is direct, or is mediated via altered sympathetic activation.
Nitric oxide inhibits endothelin-1 production through the suppression of nuclear factor κB
Authors: OHKITA Mamoru , TAKAOKA Masanori , SHIOTA Yasuko , NOJIRI Rumi , MATSUMURA Yasuo
Published: August 2015

We have reported previously that the nitric oxide (NO) donor FK409 {(±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide} improved renal dysfunction as well as renal lesions in rats with ischaemia/reperfusion injury. We also found that FK409 substantially reduced endothelin-1 (ET-1) production in cultured vascular endothelial cells (ECs). Nuclear factor κB (NF-κB) is known to play a key role in the development of ischaemic disorders through regulation of the expression of a variety of genes. In the present study, we examined the effects of FK409 on ET-1 production in cultured pig aortic ECs, and the possible involvement of NF-κB in the inhibitory effect of NO on ET-1 production. FK409 significantly attenuated basal and tumour necrosis factor-α (TNF-α)-induced preproET-1 mRNA expression in ECs. In addition, FK409 diminished basal and TNF-α-stimulated NF-κB activation in ECs. Pretreatment with N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal or BAY 11-7082, both of which are suppressors of NF-κB activation, effectively attenuated basal and TNF-α-induced ET-1 mRNA expression. These findings suggest that the suppression of NF-κB activation is at least partly involved in the FK409-induced inhibition of ET-1 production in ECs. We propose that NF-κB activation plays an important role in ET-1 production.
Response of glucose disposal to hyperinsulinaemia in human hypothyroidism and hyperthyroidism
Authors: ROCHON C. , TAUVERON I. , DEJAX C. , BENOIT P. , CAPITAN P. , FABRICIO A. , BERRY C. , CHAMPREDON C. , THIEBLOT P. , GRIZARD J.
Published: August 2015

We have examined insulin action on glucose metabolism in six hypothyroid patients before and after regular thyroid hormone treatment, and in six healthy volunteers before and after transient induction of moderate hyperthyroidism. Insulin was infused under euglycaemic and eukalaemic clamps. An appropriate amino acid infusion was used to blunt insulin-induced decreases in amino acid levels. Glucose kinetics were assessed using a primed continuous infusion of [6,6-2H2]glucose. The results showed that basal plasma insulin and glucose levels (i.e. before infusion) were similar in each case. Despite similar insulin infusion rates, the plateau value of insulin was lower after thyroid treatment in both hypothyroid patients and healthy volunteers. The rate of exogenous glucose needed to maintain plasma glucose at a steady-state level was increased by thyroid hormone in hypothyroid patients (P<0.05), but not in healthy volunteers. Thyroid treatment resulted in a significant increase in basal glucose disposal in both groups (P<0.05). Insulin, in conjunction with glucose and amino acids, significantly stimulated glucose disposal (P<0.05) under all conditions. The incremental increase in glucose disposal after infusion tended to be higher following thyroid hormone treatment, but this was not statistically significant. However, the ratio of the incremental increase in glucose disposal to the increase in plasma insulin was significantly improved after thyroid hormone treatment in hypothyroid patients (P<0.05). It was also increased in healthy volunteers, but not significantly. We conclude that thyroid hormones improve the ability of insulin to stimulate glucose disposal related to insulinaemia. This phenomenon may be highly sensitive, because it was only apparent at low thyroid hormone levels.
Elevated β2-adrenoceptor protein concentration in adipose tissue from obese subjects is closely related to the body mass index and waist/hip ratio
Authors: RASMUSSEN Mads , ALMDAL Thomas , BRATHOLM Palle , CHRISTENSEN Niels Juel
Published: August 2015

The aim of the present study was to quantify β2-adrenoceptor protein content in adipose tissue during fasting, and to study the relationships between β2-adrenoceptor protein and mRNA levels and changes in metabolites related to lipolysis. Groups of male subjects with a body mass index of <25kg/m2 or >30kg/m2 fasted for 60h. Abdominal subcutaneous fat biopsies were analysed for receptor mRNA levels by reverse transcription–PCR–HPLC. The β2-adrenoceptor protein concentration was measured by Western blotting using fluorescence laser scanning for detection. The β2-adrenoceptor protein concentration per cell (on a DNA basis) was higher in obese subjects (P<0.03). There were highly significant relationships between β2-adrenoceptor protein concentration and both body mass index and waist/hip ratio (P<0.001 for both). Furthermore, there was an inverse relationship between the receptor protein concentration and the serum β-hydroxybutyrate level during fasting (P<0.005). β2-Adrenoceptor protein levels decreased in both groups during fasting, to a similar degree. Basal β2-adrenoceptor mRNA levels were similar in the two groups, but there was a smaller increase in the obese group during fasting (P<0.03). The increased β2-adrenoceptor protein level in obese subjects is likely to be related to the greater plasma membrane area of their adipocytes. The decrease during fasting may be due to increased binding of noradrenaline and subsequent internalization and degradation of the receptor. Elevated levels of less responsive β2-adrenoceptor protein in obese subjects may contribute to the development of obesity.
Haematological phenotypes in relation to the C1797T β-adducin polymorphism in a Caucasian population
Authors: WANG Ji-Guang , BARLASSINA Cristina , BIANCHI Giuseppe , FAGARD Robert , ZAGATO Laura , STAESSEN Jan A.
Published: August 2015

β-Adducin plays a role in maintaining the structural integrity of the red blood cell (erythrocyte) membrane. Moreover, β-adducin-deficient knock-out mice show a phenotype characterized by mild anaemia and compensated haemolysis. We therefore investigated whether, in humans, common haematological phenotypes of red blood cells were associated with a polymorphism in exon 15 of the human β-adducin gene (C1797T). We studied 802 unrelated individuals and 294 families (459 parents and 609 offspring) randomly selected from a Caucasian population. We employed generalized estimating equations to allow for the non-independence of the observations within families, while controlling for co-variables. In 917 men, with adjustments applied for age, body mass index, serum total cholesterol, smoking and alcohol intake, CC homozygotes had significantly (P = 0.02) lower values for red blood cell count (4.93×1012/l compared with 4.86×1012/l), haemoglobin level (9.30 compared with 9.18mmol/l) and haematocrit (45.0% compared with 44.4%) than T allele carriers. In the 329 men who consumed alcohol, the differences between CC homozygotes and T allele carriers were 0.13×1012/l (P = 0.02) for red blood cell count, 0.23mmol/l (P = 0.005) for haemoglobin and 1.08% (P = 0.02) for haematocrit. In 953 women, none of these associations was significant (P⩾0.06), regardless of alcohol intake [13.3% of women (n = 127) consmued alcohol]. In conclusion, in men consuming alcohol, the β-adducin CC genotype was associated with lower red blood cell count, haemoglobin level and haematocrit. We hypothesize that, in CC homozygotes, alcohol consumption may unveil the greater fragility of the red blood cell membrane. This genotype may slightly potentiate the structural and functional haematological disturbances associated with alcohol intake.
Epithelial sodium channel (ENaC) subunit mRNA and protein expression in rats with puromycin aminonucleoside-induced nephrotic syndrome
Authors: AUDIGÉ A. , YU Z.R. , FREY B.M. , UEHLINGER D.E. , FREY F.J. , VOGT B.
Published: August 2015

In experimental nephrotic syndrome, urinary sodium excretion is decreased during the early phase of the disease. The molecular mechanism(s) leading to salt retention has not been completely elucidated. The rate-limiting constituent of collecting duct sodium transport is the epithelial sodium channel (ENaC). We examined the abundance of ENaC subunit mRNAs and proteins in puromycin aminonucleoside (PAN)-induced nephrotic syndrome. The time courses of urinary sodium excretion, plasma aldosterone concentration and proteinuria were studied in male Sprague–Dawley rats treated with a single dose of either PAN or vehicle. The relative amounts of αENaC, βENaC and γENaC mRNAs were determined in kidneys from these rats by real-time quantitative TaqMan PCR, and the amounts of proteins by Western blot. The kinetics of urinary sodium excretion and the appearance of proteinuria were comparable with those reported previously. Sodium retention occurred on days 2, 3 and 6 after PAN injection. A significant up-regulation of αENaC and βENaC mRNA abundance on days 1 and 2 preceded sodium retention on days 2 and 3. Conversely, down-regulation of αENaC, βENaC and γENaC mRNA expression on day 3 occurred in the presence of high aldosterone concentrations, and was followed by a return of sodium excretion to control values. The amounts of αENaC, βENaC and γENaC proteins were not increased during PAN-induced sodium retention. In conclusion, ENaC mRNA expression, especially αENaC, is increased in the very early phase of the experimental model of PAN-induced nephrotic syndrome in rats, but appears to escape from the regulation by aldosterone after day 3.
Endothelial progenitor cells: novel biomarker and promising cell therapy for cardiovascular disease
Authors: Sen Shaundeep , McDonald Stephen P. , Coates P. Toby H. , Bonder Claudine S.
Published: August 2015

Bone-marrow-derived EPCs (endothelial progenitor cells) play an integral role in the regulation and protection of the endothelium, as well as new vessel formation. Peripheral circulating EPC number and function are robust biomarkers of vascular risk for a multitude of diseases, particularly CVD (cardiovascular disease). Importantly, using EPCs as a biomarker is independent of both traditional and non-traditional risk factors (e.g. hypertension, hypercholesterolaemia and C-reactive protein), with infused ex vivo-expanded EPCs showing potential for improved endothelial function and either reducing the risk of events or enhancing recovery from ischaemia. However, as the number of existing cardiovascular risk factors is variable between patients, simple EPC counts do not adequately describe vascular disease risk in all clinical conditions and, as such, the risk of CVD remains. It is likely that this limitation is attributable to variation in the definition of EPCs, as well as a difference in the interaction between EPCs and other cells involved in vascular control such as pericytes, smooth muscle cells and macrophages. For EPCs to be used regularly in clinical practice, agreement on definitions of EPC subtypes is needed, and recognition that function of EPCs (rather than number) may be a better marker of vascular risk in certain CVD risk states. The present review focuses on the identification of measures to improve individual risk stratification and, further, to potentially individualize patient care to address specific EPC functional abnormalities. Herein, we describe that future therapeutic use of EPCs will probably rely on a combination of strategies, including optimization of the function of adjunct cell types to prime tissues for the effect of EPCs.
Integrating Language, Pragmatics, and Social Intervention in a Single-Subject Case Study of a Child With a Developmental Social Communication Disorder
Authors: Adams Catherine , Gaile Jacqueline , Lockton Elaine , Freed Jenny
Published: August 2015

Purpose

This clinical focus article presents an illustration of a complex communication intervention, the Social Communication Intervention Programme (SCIP), as delivered to a child who has a social communication disorder (SCD). The SCIP intervention combined language processing and pragmatic and social understanding therapies in a program of individualized therapy activities and in close liaison with families.

Method

The study used an enhanced AB single-subject design in which an 8-year-old child with an SCD participated in 20 therapy sessions with a specialist speech-language pathologist. A procedure of matching assessment findings to intervention choices was followed to construct an individualized treatment program. Examples of intervention content and the embedded structure of SCIP are illustrated. Observational and formal measurements of receptive and expressive language, conversation, and parent–teacher ratings of social communication were completed before therapy, after therapy, and at a 6-month follow-up session.

Results

Outcomes revealed change in total and receptive language scores but not in expressive language. Conversation showed marked improvement in responsiveness, appreciation of listener knowledge, turn taking, and adaptation of discourse style. Teacher-reported outcomes included improved classroom behavior and enhanced literacy skills. Parent-reported outcomes included improved verbal interactions with family members and personal narratives.

Conclusions

This clinical focus article demonstrates the complexity of needs in a child with an SCD and how these can be addressed in individualized intervention. Findings are discussed in relation to the essential nature of language support including pragmatic therapy for children with SCDs. Discussion of the role of formal and functional outcome measurement as well as the proximity of chosen outcomes to the intervention is included.
Resonant tunnelling diode photodetector operating at near‐infrared wavelengths with high responsivity
Authors: Dong Yu , Xu Jianxing , Wang Guanglong , Ni Haiqiao , Pei Kangming , Chen Jianhui , Gao Fengqi , Li Baochen , Niu Zhichuan
Published: August 2015

Resonant tunnelling diode photodetectors with a 600 nm In0.53Ga0.47As absorption layer were fabricated by molecular beam epitaxy. The current–voltage characteristics of devices with different mesa diameters were tested and the negative differential resistance was observed in all devices. The responsivity of the detector was measured to be 4.19 × 105 A/W at 77 K and 1.92 × 104 A/W at room temperature under incident light with a power of 3.1 nW.
Total least‐squares formulation of Wahba's problem
Authors: Chang Guobin
Published: August 2015

The Wahba's problem is widely recognised as a least‐square problem in three‐axis attitude estimation from vector measurements. However, both the observation and the reference vectors can be corrupted by errors, so a total least‐square problem considering both errors should be formulated to be rigorous. It is found that for errors with heteroscedastic and isotropic covariance structures, the total least‐square problem degenerates to be the Wahba's problem. A method for solving this problem is presented. Errors corrupting both observation and reference vectors can be equivalent to pseudo errors corrupting only observation vectors in the case of isotropic covariance structures, so the Wahba's problem can also be formulated as a least‐square problem adjusting these pseudo errors in a somewhat simpler manner.