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Selected AbstractsCardioprotection of bradykinin at reperfusion involves transactivation of the epidermal growth factor receptor via matrix metalloproteinase-8ACTA PHYSIOLOGICA, Issue 4 2009C. Methner Abstract Aim:, The endogenous autacoid bradykinin (BK) reportedly reduces myocardial infarct size when given exogenously at reperfusion. Muscarinic and opioid G-protein-coupled receptors are equally protective and have been shown to couple through a matrix metalloproteinase (MMP)-dependent transactivation of the epidermal growth factor receptor (EGFR). Here we test whether BK protects the rat heart through the EGFR by an MMP-dependent pathway. Methods:, Infarct size was measured in isolated perfused rat hearts undergoing 30 min regional ischaemia followed by 120 min reperfusion. In additional studies HL-1 cardiomyocytes were loaded with tetramethylrhodamine ethyl to measure their mitochondrial membrane potential (,m). Adding the calcium ionophore calcimycin, causes ,m-collapse presumably due to calcium-induced mitochondrial permeability transition. Results:, As expected, BK (100 nmol L,1) started 5 min prior to reperfusion reduced infarct size from 38.9 ± 2.0% of the ischaemic zone in control hearts to 22.2 ± 3.3% (P < 0.001). Co-infusing the EGFR inhibitor AG1478, the broad-spectrum MMP-inhibitor GM6001, or a highly selective MMP-8 inhibitor abolished BK's protection, thus suggesting an MMP-8-dependent EGFR transactivation in the signalling. Eighty minutes of exposure to calcimycin reduced the mean cell fluorescence to 37.4 ± 1.8% of untreated cells while BK could partly preserve the fluorescence and, hence, protect the cells (50.5 ± 2.3%, P < 0.001). The BK-induced mitochondrial protection could again be blocked by AG1478, GM6001 and MMP-8 inhibitor. Finally, Western blotting revealed that BK's protection was correlated with increased phosphorylation of EGFR and its downstream target Akt. Conclusion:, These results indicate that BK at reperfusion triggers its protective signalling pathway through MMP-8-dependent transactivation of the EGFR. [source] Electroanalysis of Bisphenol A at a Multiwalled Carbon Nanotubes-gold Nanoparticles Modified Glassy Carbon ElectrodeELECTROANALYSIS, Issue 22 2009Xinman Tu Abstract A sensitive electrochemical method was developed for the determination of bisphenol A (BPA) at a glassy carbon electrode (GCE) modified with a multiwalled carbon nanotubes (MWCNTs)-gold nanoparticles (GNPs) hybrid film, which was prepared based on the electrostatic interaction between positively charged cetyltrimethylammonium bromide (CTAB) and negatively charged MWCNTs and GNPs. The MWCNT-GNPs/GCE exhibited an enhanced electroactivity for BPA oxidation versus unmodified GCE and MWCNTs/GCE. The experimental parameters, including the amounts of modified MWCNTs and GNPs, the pH of the supporting electrolyte, scan rate and accumulation time, were examined and optimized. Under the optimal conditions, the differential pulse voltammetric anodic peak current of BPA was linear with the BPA concentration from 2.0×10,8 to 2×10,5 mol L,1, with a limit of detection of 7.5,nmol L,1. The proposed procedure was applied to determine BPA leached from real plastic samples with satisfactory results. [source] Parathyroid hormone stimulates the endothelial expression of vascular endothelial growth factorEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2008G. Rashid ABSTRACT Background, We showed previously that parathyroid hormone (PTH) may stimulate the endothelial expression of pro-atherosclerotic and pro-inflammatory markers. Considering the impact of PTH on vasculature, we decided to evaluate its effect on mRNA and intra-cellular protein expressions of endothelial vascular endothelial growth factor (VEGF) taking into account that VEGF may play a role in the pathogenesis of endothelial dysfunctions. Materials and methods, Human umbilical vein cords endothelial cells (HUVEC) were stimulated for 24 h with 10,12,10,10 mol L,1 PTH. The VEGF-165 mRNA expression (critical in stimulating endothelial cell proliferation) was evaluated by RT/PCR and the intra-cellular VEGF protein expression by flow cytometry. The pathways by which PTH may have an effect on VEGF expression were also evaluated. Results, PTH (10,10 mol L,1) significantly increased VEGF-165 mRNA expression (P < 0·05). The addition of 50 nmol L,1 protein kinase C (PKC) and 10 µmol L,1 protein kinase A (PKA) inhibitors significantly reduced the VEGF-165 mRNA expression (P = 0·01). We also examined whether nitric oxide (NO) may be involved in the PTH-induced stimulation of VEGF-165 expression. Pre-treatment of the cells with 200 µmol L-nitro arginine methyl ester (L-NAME, NO synthase inhibitor) was found to inhibit VEGF-165 mRNA expression (P = 0·006). VEGF protein could not be detected in the medium of HUVEC but it was present in the cell cytoplasm. PTH had no significant effect on cytoplasmatic VEGF protein expression. Conclusion, The stimulatory effect of PTH on endothelial VEGF-165 mRNA expression is partly through PKC and PKA pathways and is also NO dependent. [source] Functional approach to investigate Lp(a) in ischaemic heart and cerebral diseasesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2003A. De La Peńa-Dķaz Abstract Background Lp(a), a major cardiovascular risk factor, contains a specific apolipoprotein, apo(a), which by virtue of structural homology with plasminogen inhibits the formation of plasmin, the fibrinolytic enzyme. A number of clinical reports support the role of Lp(a) as a cardiovascular or cerebral risk factor, and experimental data suggest that it may contribute to atherothrombosis by inhibiting fibrinolysis. Design A well-characterized model of a fibrin surface and an apo(a)-specific monoclonal antibody were used to develop a functional approach to detect pathogenic Lp(a). The assay is based on the competitive binding of Lp(a) and plasminogen for fibrin, and quantifies fibrin-bound Lp(a). High Lp(a) binding to fibrin is correlated with decreased plasmin formation. In a transversal case,control study we studied 248 individuals: 105 had a history of ischaemic cardiopathy (IC), 52 had cerebro-vascular disease (CVD) of thrombotic origin, and 91 were controls. Results The remarkably high apo(a) fibrin-binding in CVD (0·268 ± 0·15 nmol L,1) compared with IC (0·155 ± 0·12 nmol L,1) suggests the existence of peculiar and poorly understood differences in pro- or anti-thrombotic mechanisms in either cerebral and/or coronary arteries. Conclusions Our results demonstrated that Lp(a) fibrin-binding and small Apo(a) isoforms are associated with athero-thrombotic disease. [source] Short-term cortisol infusion in the brachial artery, with and without inhibiting 11,-hydroxysteroid dehydrogenase, does not alter forearm vascular resistance in normotensive and hypertensive subjectsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2002S. H. M. Van Uum Abstract Background Vascular tone is increased in primary hypertension, and glucocorticoids affect vascular tone. Local cortisol availability is modulated by activity of 11,-hydroxysteroid dehydrogenase (11,-HSD). As this activity may be decreased in patients with primary hypertension, vascular sensitivity to cortisol may be increased in these patients. We studied the acute effect of cortisol on forearm vascular resistance (FVR) by infusing cortisol directly into the brachial artery, both with and without inhibition of 11,-HSD, in normotensive and hypertensive subjects. Design Twenty normotensive volunteers and 20 patients with primary hypertension participated in the study. After a 10-min infusion of vehicle (glucose 5%), cortisol was infused into the brachial artery in three stepwise increasing doses (3·5, 10·5 and 35 µg per 100 mL of forearm volume), each for 10 min. Next, the participants received placebo or 500 mg glycyrrhetinic acid (GA) orally, and 150 min later the same infusion schedule was repeated. Forearm vascular resistance was measured during the last 5 min of the infused vehicle and of each dose. Arterial and forearm venous plasma samples for measurement of cortisol and cortisone were taken at the end of the infusions of glucose 5% and the highest cortisol dose. Results In both normotensive and hypertensive subjects, neither the infusion of cortisol nor the administration of GA changed FVR. Also 2 h after the cortisol infusion there remained no change in FVR in both the normotensive and hypertensive groups who received placebo. Following the infusion of the highest cortisol dose, total plasma cortisone levels in the venous plasma were decreased compared with levels in the arterial plasma (36 ± 3 and 49 ± 4 nmol L,1, respectively, P < 0·05). The protein-bound venous cortisone was 37·1 ± 4·8 nmol L,1 during the vehicle compared with 23·9 ± 3·7 nmol L,1 during the cortisol infusion (P < 0·01), whereas the free cortisone level was not altered by the cortisol infusion. Conclusions In both normotensive and hypertensive subjects, high-dose cortisol infusion both with and without 11,-HSD inhibition did not change FVR either immediately or after 2 h. We could not demonstrate in vivo 11,-HSD activity in the forearm vascular tissues. When binding of cortisone to CBG is changed, e.g. during cortisol infusion, arterio-venous changes in cortisone cannot reliably be used to assess (alterations in) local 11,-HSD activity. [source] Bone turnover markers and sex hormones in men with idiopathic osteoporosisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2001P. Pietschmann Background In contrast to osteoporosis in postmenopausal women, osteoporosis in men has received much less attention. Patients and We determined various biochemical parameters of bone metabolism and sex hormones in 31 men with idiopathic osteoporosis and 35 age matched control subjects. Results In the men with osteoporosis, a significantly increased urinary excretion of deoxypyridinoline (5·3 ± 0·2 vs. 4·6 ± 0·2 nmol mmol,1 creatinine; P = 0·033) in addition to increased serum levels of the c-terminal telopeptide of type I collagen (2677 ± 230 vs. 2058 ± 153 pmol; P = 0·037) were found. While parameters of bone formation were not significantly different in the patients and controls, serum bone sialoprotein levels were significantly decreased in the patients (3·7 ± 0·8 vs. 12·4 ± 4·0 ng mL,1; P = 0·021). Moreover, in men with idiopathic osteoporosis, lower levels of estradiol (91·3 ± 5·8 vs. 114·6 ± 7·8 pmol L,1; P = 0·044), higher levels of sex hormone binding globulin (31·5 ± 3·1 vs. 24·2 ± 1·4 nmol L,1; P = 0·034) and a decreased free androgen index (42·6 ± 5·2 vs. 56·4 ± 5·9; P = 0·016) were seen. Serum estradiol levels correlated negatively with several parameters of bone resorption. Conclusions In men with idiopathic osteoporosis, bone resorption is increased and exceeds bone formation. The excessive bone resorption seen in idiopathic male osteoporosis may be due to decreased estradiol levels and low levels of bioavailable testosterone. [source] Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trialJOURNAL OF INTERNAL MEDICINE, Issue 6 2008R. Jorde Abstract. Objectives., The objective of the present study was to examine the cross-sectional relation between serum 25-hydoxyvitamin D [25-(OH) D] levels and depression in overweight and obese subjects and to assess the effect of vitamin D supplementation on depressive symptoms. Design., Cross-sectional study and randomized double blind controlled trial of 20.000 or 40.000 IU vitamin D per week versus placebo for 1 year. Setting., A total of 441 subjects (body mass index 28,47 kg m,2, 159 men and 282 women, aged 21,70 years) recruited by advertisements or from the out-patient clinic at the University Hospital of North Norway. Main outcome measures., Beck Depression Inventory (BDI) score with subscales 1,13 and 14,21. Results., Subjects with serum 25(OH)D levels <40 nmol L,1 scored significantly higher (more depressive traits) than those with serum 25(OH)D levels ,40 nmol L,1 on the BDI total [6.0 (0,23) versus 4.5 (0,28) (median and range)] and the BDI subscale 1,13 [2.0 (0,15) versus 1.0 (0,29.5)] (P < 0.05). In the two groups given vitamin D, but not in the placebo group, there was a significant improvement in BDI scores after 1 year. There was a significant decrease in serum parathyroid hormone in the two vitamin D groups without a concomitant increase in serum calcium. Conclusions., It appears to be a relation between serum levels of 25(OH)D and symptoms of depression. Supplementation with high doses of vitamin D seems to ameliorate these symptoms indicating a possible causal relationship. [source] Prevalence of undiagnosed coeliac syndrome in osteoporotic womenJOURNAL OF INTERNAL MEDICINE, Issue 4 2001R. Nuti Abstract.,Nuti R, Martini G, Valenti R, Giovani S, Salvadori S, Avanzati A (Institute of Internal Medicine, Metabolic Disease Unit, University of Siena, Siena, Italy). Prevalence of undiagnosed coeliac syndrome in osteoporotic women. J Intern Med 2001; 250: 361,366. Objectives.,The aims of the study were to quantify the prevalence of asymptomatic coeliac disease (CD) in a cohort of osteoporotic females, and to investigate the features of bone loss. Design and subjects.,We studied 255 women (mean age 66.6 ± 8.5 SD) with primary osteoporosis (WHO diagnostic criteria). After the first CD screening with the measure of serum IgG antigliadin antibodies (IgG-AGA), 53 women showed a positive test: antibodies to tissue transglutaminase (TG-ab) were subsequently determined to confirm the diagnosis of CD. Bone metabolism was evaluated by: serum and urinary calcium, serum and urinary phosphate, serum alkaline phosphatase, urinary crosslaps, serum 25(OH)D and serum parathyroid hormone. Results.,High levels of IgG-AGA and TG-ab were observed in 24 patients with a prevalence of serological disease of 9.4%. These women were characterized, in comparison with the other patients, by a statistically significant reduction in serum 25(OH)D (17.8 ± 7.2 vs. 55.1 ± 20.3 nmol L,1, P < 0.01) together with a significant increase of iPTH (65.1 ± 29.7 vs. 35.1 ± 20.0 pg mL,1; P < 0.01). Patients with high TG-ab levels showed also slightly raised values of urinary crosslaps (288 ± 88 vs. 270 ± 90 ,m mol,1 Cr). In IgG-AG positive patients a statistically significant inverse correlation was found between 25(OH)D serum levels and log-transformed TG-ab values (r: ,0.95, P < 0.001). Intestinal biopsies were obtained in 10 TG-ab positive women and verified CD in six patients. Conclusions.,These data support the hypothesis that patients with undiagnosed celiac disease develop high remodelling processes related to calcium malabsorption, secondary hyperparathyroidism and unavailability of vitamin D with a consequent more marked bone loss. [source] A high prevalence of hypovitaminosis D in Finnish medical in- and outpatientsJOURNAL OF INTERNAL MEDICINE, Issue 6 2001R. Kauppinen-Mäkelin Abstract.,Kauppinen-Mäkelin R, Tähtelä R, Löyttyniemi E, Kärkkäinen J, Välimäki MJ (Peijas Hospital, Vantaa; United Laboratories, Leiras Research, and Division of Endocrinology; Helsinki University Central Hospital, Helsinki, Finland). A high prevalence of hypovitaminosis D in Finnish medical in- and outpatients. J Intern Med 2001; 249: 559,563. Objective.,To study the prevalence of hypovitaminosis D [serum 25(OH)D , 37 nmol L,1)] in Finnish medical in- and outpatients in a cross-sectional study. Methods.,The subjects were 106 consecutive medical inpatients (57 females, 49 males with mean ages of 65 and 58 years) from the Peijas Hospital, Vantaa, Finland, and 99 ambulatory patients (48 females, 51 males with mean ages of 42 and 46 years) contacting a private outpatient centre in Helsinki, Finland. Serum 25(OH)D, vitamin D binding protein (DBP), free vitamin D index (FDI), intact PTH (iPTH), and albumin-corrected calcium were measured. Results.,Serum 25-hydroxyvitamin D [25(OH)D] was 37 nmol L,1 or less in 70% of female and in 61% of male inpatients and in 44% of female and in 37% of male outpatients. In the whole population, a statistically significant inverse association (P < 0.0001) was detected between iPTH and 25(OH)D levels; the iPTH concentration appeared to start increasing when 25(OH)D concentration was 50 nmol L,1 or less. The association remained the same (P < 0.0001) when FDI was used instead of 25(OH)D in the calculations. When the sexes were analysed separately, the statistically significant association was found only in females (P < 0.0001 for iPTH versus 25(OH)D; P < 0.0001 for iPTH versus FDI) but not in males. Conclusion.,Hypovitaminosis D is very common amongst Finnish in- and outpatients in both sexes, causing secondary hyperparathyroidism in females. More extensive studies are warranted to elucidate the vitamin D status of the Finnish population. [source] Aggregated low density lipoprotein induces tissue factor by inhibiting sphingomyelinase activity in human vascular smooth muscle cellsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2009S. CAMINO-LÓPEZ Summary.,Background: Our previous results demonstrated that aggregated low density lipoprotein (agLDL) induces tissue factor (TF) expression and activation through Rho A translocation in human vascular smooth muscle cells (VSMC). We also previously demonstrated that membrane sphingomyelin (SM) content is higher in agLDL-exposed VSMC than in control cells. The main enzymes regulating cellular SM content are the family of sphingomyelinases (Smases) that hydrolize SM to phosphorylcholine and ceramide (CER). Objectives: We wished to investigate whether agLDL has the ability to modulate acidic- (A-) and neutral (N-) Smase activity and whether or not this effect is related to the upregulatory effect of agLDL on Rho A translocation and TF activation in human VSMC. Methods and Results: By measuring generated [14C]-phosphorylcholine, we found that agLDL significantly decreased A-Smase and specially N-Smase activity. Pharmacological Smase inhibitors increased Rho A and TF. Specific loss-of-function of A-Smase or N-Smase 1 (N1-Smase) by siRNA treatment (500 nmol L,1, 12 hours) dramatically increased membrane Rho A protein levels (5- and 3-fold, respectively). Concomitantly, TF protein expression and TF procoagulant activity were also increased. Inhibition of A-Smase or N-Smase activity by agLDL, siRNA-anti A- or N1-Smase or pharmacological treatment significantly increased the SM content of vascular cells. The inhibition of SM synthesis by fumonisin B1 (FB1) prevented the upregulatory effect of agLDL on TF. Conclusions: These results demonstrate that inhibition of both A- and N1-Smase might explain the upregulatory effect of agLDL on TF activation, and suggest that this effect is related, at least in part, to membrane SM enrichment. [source] Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case,control studyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2006E. OGER Summary.,Background:,Moderate hyperhomocysteinemia and B vitamins deficiency are thought to be risk factors for venous thromboembolism (VTE). The causality and independence of those associations are still questioned. Methods:,We measured fasting serum total homocysteine, folates, and vitamin B12 levels as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotypes in 467 patients hospitalized with a first well-documented deep vein thrombosis and/or pulmonary embolism not related to a major acquired risk factor and 467 controls matched for gender and age. Results:,Mild hyperhomocysteinemia, low serum folates, and vitamin B12 were associated with VTE independently of each other. In multivariate analysis, odds ratios (OR) (95% CI) for VTE associated with mild hyperhomocysteinemia (>15 ,mol L,1), low serum folates (,,4.9 nmol L,1), and vitamin B12 (, 253 pmol L,1) were 1.48 (1.05,2.08), 3.14 (1.35,7.32) and 1.42 (1.03,1.98), respectively. An MTHFRC677T genotype was not significantly associated with VTE; OR (95% CI): 1.13 (0.70,1.81) Conclusions:,The current data provides further knowledge in the complex relationship between hyperhomocysteinemia, low vitamin levels, and VTE. [source] Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2005V. REGNAULT Summary., Postinfectious purpura fulminans is a rare disease. Varicella is one of the precipitating conditions and we recently observed such a case. The 4-year-old child was found to have a severe transient protein S deficiency. By enzyme-linked immunosorbent assay and surface plasmon resonance we first demonstrated that anti-protein S antibodies were present and also transient. Next we characterized the epitopes against which these antibodies were directed and found that they predominantly recognized the N-terminal part of protein S. Finally we showed by thrombography a transient dramatic hypercoagulable state as a result of thrombin being unregulated by the dynamic protein C inhibitory system: in vitro thrombin generation, in response to a low concentration of tissue factor, was almost insensitive to activated protein C up to 25 nmol L,1 on day 4 while it was normally sensitive on day 42. For the first time, we demonstrated a temporal relationship between protein S deficiency, antibodies to protein S and hypercoagulability, thus supporting the pathogenic role of these antibodies. [source] Initiation and propagation of coagulation from tissue factor-bearing cell monolayers to plasma: initiator cells do not regulate spatial growth rate,JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2005M. V. OVANESOV Summary., Exposure of tissue factor (TF)-bearing cells to blood is the initial event in coagulation and intravascular thrombus formation. However, the mechanisms which determine thrombus growth remain poorly understood. To explore whether the procoagulant activity of vessel wall-bound cells regulates thrombus expansion, we studied in vitro spatial clot growth initiated by cultured human cells of different types in contact pathway-inhibited, non-flowing human plasma. Human aortic endothelial cells, smooth muscle cells, macrophages and lung fibroblasts differed in their ability to support thrombin generation in microplate assay with peaks of generated thrombin of 60 ± 53 nmol L,1, 135 ± 57 nmol L,1, 218 ± 55 nmol L,1 and 407 ± 59 nmol L,1 (mean ± SD), respectively. Real-time videomicroscopy revealed the initiation and spatial growth phases of clot formation. Different procoagulant activity of cell monolayers was manifested as up to 4-fold difference in the lag times of clot formation. In contrast, the clot growth rate, which characterized propagation of clotting from the cell surface to plasma, was largely independent of cell type (, 30% difference). Experiments with factor VII (FVII)-, FVIII-, FX- or FXI-deficient plasmas and annexin V revealed that (i) cell surface-associated extrinsic Xase was critical for initiation of clotting; (ii) intrinsic Xase regulated only the growth phase; and (iii) the contribution of plasma phospholipid surfaces in the growth phase was predominant. We conclude that the role of TF-bearing initiator cells is limited to the initial stage of clot formation. The functioning of intrinsic Xase in plasma provides the primary mechanism of sustained and far-ranging propagation of coagulation leading to the physical expansion of a fibrin clot. [source] Dementia in subjects with atrial fibrillation: hemostatic function and the role of anticoagulationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2004M. Barber Summary.,Background: Atrial fibrillation (AF) is associated with cognitive impairment and dementia, perhaps through encouraging a prothrombotic state and cardioembolism. Objectives: We wished to test the hypotheses that hemostatic function is altered in subjects with AF who develop dementia, and that long-term warfarin anticoagulation is protective against this complication. Patients and methods: Recruitment was from an observational cohort study of AF. Baseline assessment included measurement of plasma fibrinogen, fibrin D -dimer, prothrombin fragment 1+2 (F1+2), thrombin,antithrombin complexes (TAT), von Willebrand factor and tissue plasminogen activator. We assessed cognitive function after 3 years' follow-up using the 13-item modified Telephone Interview for Cognitive Status (TICSm) and the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Results: Of the 218 subjects assessed, 145 (66%) were prescribed warfarin. Forty-nine (22%) met TICSm/IQCODE criteria for dementia. D -dimer, F1+2 and TAT levels were higher in AF subjects with dementia compared with those without (medians 81 vs. 60 ng mL,1, P = 0.008; 0.76 vs. 0.49 nmol L,1, P = 0.006; and 1.78 vs. 1.44 µg L,1, P = 0.003, respectively). These associations became of borderline statistical significance following adjustment for age. Logistic regression showed a trend towards warfarin use being independently associated with reduced prevalence of dementia (odds ratio 0.52, P = 0.08). Conclusions: We found evidence of increased thrombin generation and fibrin turnover in subjects with AF and dementia compared with those without dementia. Long-term warfarin use may be protective against the development of dementia in subjects with AF. [source] Increased soluble CD40 ligand levels in cystic fibrosisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2004A. Falco Summary., Chronic inflammation represents a key pathogeneric event in the progression of lung disease in cystic fibrosis (CF). To identify novel mechanisms of the inflammatory reaction in CF and analyze its relation with coagulative activation, we carried-out a cross-sectional study to evaluate circulating levels of the inflammatory mediators soluble (s) CD40L, C-reactive protein (CRP), interleukin (IL)-1,, the coagulation markers activated factor VII (FVIIa) and prothrombin fragment (F) 1+2, as well as urinary 11-dehydro-thromboxane (TX)B2, an index of in vivo platelet activation, in 34 CF patients and 34 matched healthy subjects. We observed that CF patients displayed significantly increased circulating levels of sCD40L compared to controls [2.8 (0.4,15.6) vs 1.1 (0.2,2.7) ng mL,1 ,P = 0.0003]. sCD40L levels inversely correlated with forced expiratory volume at 1 second (FEV1) (, = ,0.788, P = 0.0001), whereas it directly correlated with CRP and IL-1, levels (, = 0.621, P = 0.0004; and , = 0.745, P = 0.0001, respectively), which were also elevated in CF patients. CF patients had also enhanced levels of FVIIa and F1+2 compared to controls [39.2 (22.6,69.8) vs 22.3 (16.2,32.4) mU mL,1, P = 0.0001; 0.60 (0.30,1.80) vs 0.17 (0.10,0.40) nmol L,1, P = 0.0001, respectively]. A direct correlation was observed between sCD40L and both plasma FVIIa (, = 0.691, P = 0.0001) and F1+2 (, = 0.545, P = 0.0017) as well as between sCD40L and urinary 11-dehydro-TXB2 (, = 0.433, P = 0.0129). Our findings suggest that in CF patients, sCD40L could represent a biochemical link between the inflammatory state, and endothelial damage and coagulative activation, leading to progressive impairment of pulmonary function. [source] Reversible inhibitors of TAFIa can both promote and inhibit fibrinolysisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2003M. Schneider Summary., The plasma carboxypeptidase activated thrombin-activable fibrinolysis inhibitor (TAFIa), is thermally unstable at 37 °C, with a half-life of 8 or 15 min depending on the isoform. The arginine analog, 2-guanidinoethylmercaptosuccinate (GEMSA), not only inhibits TAFIa but also slows the spontaneous inactivation of the enzyme, thereby reducing the activity of TAFIa, while extending its apparent half-life. Because, as shown in previous work, the ability of TAFIa to prolong clot lysis can be more dependent on its half-life than its concentration, in this study we determined whether reversible inhibitors of TAFIa could paradoxically prolong clot lysis. Potato tuber carboxypeptidase inhibitor (PTCI) or GEMSA were titrated into normal pooled human plasma, in the presence of soluble thrombomodulin. Both inhibitors mediate a biphasic antifibrinolytic effect, prolonging clot lysis at lower concentrations and enhancing clot lysis at higher concentrations. The antifibrinolytic effect of GEMSA is maximized at 1 mmol L,1, increasing clot lysis time from 100 min to 350 min. The antifibrinolytic effect of PTCI is maximized at 100 nmol L,1, increasing clot lysis time from 100 min to 240 min. To further characterize the nature of this biphasic effect, TAFI at various concentrations was added to TAFI-immunodepleted human plasma in the presence of PTCI or GEMSA. The magnitude of the effect depends on the concentration of TAFIa, the concentration of inhibitor, and the potency of the inhibitor. We propose that the biphasic antifibrinolytic effect is mediated by the dynamic equilibrium of free TAFIa that inactivates quickly, and TAFIa bound to inhibitor that inactivates slowly. TAFIa inhibitors used as therapeutic agents might not only enhance lysis at higher concentrations, but also stabilize fibrin clots at intermediate concentrations. [source] Plasma folate status and dietary folate intake among Chinese women of childbearing ageMATERNAL & CHILD NUTRITION, Issue 2 2009Yaling Zhao Abstract Maternal folic acid deficiency is an underlying risk for neural tube defects (NTDs). China has one of the highest prevalences of NTDs, and the prevalence rates of NTDs vary by region. We characterized plasma folate level and dietary folate intake among Chinese women of childbearing age by region (North and South, East and West, urban and rural) to provide evidence for establishing policy to prevent NTDs. A total of 1003 women of childbearing age from five provinces in China were interviewed. Fasting blood samples were collected. Plasma folate concentrations were determined by a microbiological assay. Dietary intake data were collected using a 24-h recall. Both the plasma folate concentrations and dietary folate intake of women in the South (25.9 nmol L,1 and 211.0 µg day,1) were higher than those of women in the North (13.3 nmol L,1 and 189.2 µg day,1). In the North, plasma folate concentrations and dietary folate intake of women in rural areas were lower than those of women in urban areas, whereas, in the South, an opposite pattern was observed. No difference was found between women in the East and West, in either the North or South regions. Plasma folate and dietary folate intake among Chinese women of childbearing age were suboptimal and varied by region. Different folic acid supplementation approaches and dosage should be undertaken to improve folate status of women in different areas. Particular attention should be paid to women in the North, especially in northern rural areas. [source] Effect of combined maternal and infant vitamin D supplementation on vitamin D status of exclusively breastfed infantsMATERNAL & CHILD NUTRITION, Issue 1 2009Hussein F. Saadi Abstract Severe vitamin D deficiency in mothers and their breastfed infants is a significant health problem in the Middle East. Supplementation of the breastfed infant alone with the recommended dose of vitamin D may be insufficient in high-risk population. We investigated the effect of combined maternal and infant vitamin D supplementation on vitamin D status of the breastfed infant. We examined also the effect of supplementation on vitamin D antirachitic activity of breast milk in a subset of mothers. Healthy breastfeeding mothers (n = 90) were randomly assigned to 2000 IU daily (group 1) or 60 000 IU monthly (group 2) of vitamin D2, and all their infants (n = 92) received 400 IU daily of vitamin D2 for 3 months. Most infants had vitamin D deficiency , 25-hydroxyvitamin D [25(OH)D] , 37.5 nmol L,1, at study entry. Serum 25(OH)D concentrations at 3 months increased significantly from baseline in infants of mothers in group 1 (13.9 ± 8.6 vs. 49.6 ± 18.5 nmol L,1, P < 0.0001) and group 2 (13.7 ± 12.1 vs. 44.6 ± 15.0 nmol L,1, P < 0.0001). Maternal and infant serum 25(OH)D concentrations correlated positively at baseline (r = 0.36, P = 0.01) and 3 months (r = 0.46, P = 0.002). Milk antirachitic activity increased from undetectable (<20 IU L,1) to a median of 50.9 IU L,1. In conclusion, combined maternal and infant vitamin D supplementation was associated with a threefold increase in infants' serum 25(OH)D concentrations and a 64% reduction in the prevalence of vitamin D deficiency without causing hypervitaminosis D. [source] Effect of otilonium bromide on contractile patterns in the human sigmoid colonNEUROGASTROENTEROLOGY & MOTILITY, Issue 6 2010D. Gallego Abstract Background, The mechanism of action of the spasmolytic compound otilonium bromide (OB) on human colonic motility is not understood. The aim of our study was to characterize the pharmacological effects of OB on contractile patterns in the human sigmoid colon. Methods, Circular sigmoid strips were studied in organ baths. Isolated smooth muscle cells from human sigmoid colon were examined using the calcium imaging technique. Key Results, Otilonium bromide inhibited by 85% spontaneous non-neural rhythmic phasic contractions (RPCs), (IC50 = 49.9 nmol L,1) and stretch-induced tone (IC50 = 10.7 nmol L,1) with maximum effects at micromolar range. OB also inhibited by 50% both on- (IC50 = 38.0 nmol L,1) and off- contractions induced by electrical stimulation of excitatory motor neurons. In contrast, the inhibitory latency period prior to off -contractions was unaffected by OB. OB inhibited acetylcholine-, substance P-, and neurokinin A-induced contractions. The L-type Ca2+ channel agonist BayK8644 reversed the effects of OB on RPCs, on- and off -contractions. Hexamethonium, atropine, the NK2 antagonist, or depletion of intracellular Ca2+ stores by thapsigargin did not prevent the inhibitory effect of OB on RPCs and electrical contractions. KCl-induced calcium transients in isolated smooth muscle cells were also inhibited by OB (IC50 = 0.2 ,mol L,1). Conclusions & Inferences, Otilonium bromide strongly inhibited the main patterns of human sigmoid motility in vitro by blocking calcium influx through L-type calcium channels on smooth muscle cells. This pharmacological profile may mediate the clinically observed effects of the drug in patients with irritable bowel syndrome. [source] IL1,- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn's diseaseNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2009M. Kidd Abstract, Gut mucosal enterochromaffin (EC) cells are regarded as key regulators of intestinal motility and fluid secretion via secretion of serotonin (5HT), are increased in numbers in mucosal inflammation and located in close proximity to immune cells. We examined whether interleukin (IL)1, and Escherichia coli lipopolysaccharide (LPS) induced EC cell 5HT release through Toll-like/IL-1 (TIL) receptor activation, nuclear factor kappa B (NF,B) and mitogen-activated protein kinase (MAPK) phosphorylation and evaluated whether somatostatin could inhibit this phenomenon. Pure (>98%) human intestinal EC cells were isolated by fluorescent activated cell sorting from preparations of normal (n = 5) and Crohn's colitis (n = 6) mucosa. 5HT release was measured (ELISA), and NF,B and ERK phosphorylation quantitated (ELISA) in response to IL1, and LPS. 5HT secretion was increased by both E. coli LPS (EC50 = 5 ng mL,1) and IL1, (EC50 = 0.05 pmol L,1) >2-fold (P < 0.05) in Crohn's EC cells compared with normal EC cells. Secretion was reversible by the TLR4 antagonist, E. coli K12 LPS (IC50 = 12 ng mL,1) and the IL1, receptor antagonist (ILRA; IC50 = 3.4 ng mL,1). IL1, caused significant (P < 0.05) NF,B and MAPK phosphorylation (40,55%). The somatostatin analogue, lanreotide inhibited IL1,-stimulated secretion in Crohn's (IC50 = 0.61 nmol L,1) and normal EC cells (IC50 = 1.8 nmol L,1). Interleukins (IL1,) and bacterial products (E. coli LPS) stimulated 5HT secretion from Crohn's EC cells via TIL receptor activation (TLR4 and IL1,). Immune-mediated alterations in EC cell secretion of 5HT may represent a component of the pathogenesis of abnormal bowel function in Crohn's disease. Inhibition of EC cell-mediated 5HT secretion may be an alternative therapeutic strategy in the amelioration of inflammatory bowel disease symptomatology. [source] The incretin hormones GIP and GLP-1 in diabetic rats: effects on insulin secretion and small bowel motilityNEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2009T. Edholm Abstract, Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L,1) or GLP-1 (10 nmol L,1) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1,400 pmol kg,1 min,1) or GLP-1 (0.1,20 pmol kg,1 min,1). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6,16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2. [source] Galanin modulates vagally induced contractions in the mouse oesophagusNEUROGASTROENTEROLOGY & MOTILITY, Issue 2 2009A. Boudaka Abstract, Nitrergic myenteric neurons co-innervating motor endplates were previously shown to inhibit vagally induced contractions of striated muscle in the rodent oesophagus. Immunohistochemical demonstration of putative co-transmitters, e.g. galanin, in enteric neurons prompted us to study a possible role of galanin in modulating vagally mediated contractions in an in vitro vagus nerve-oesophagus preparation of the mouse. Galanin (1,16) (1,100 nmol L,1), in the presence of the peptidase inhibitor, phenanthroline monohydrate, inhibited vagally induced contractions in a concentration-dependent manner (control: 100%; galanin 1 nmol L,1: 95.6 ± 1.6%; galanin 10 nmol L,1: 57.3 ± 6.5%; galanin 100 nmol L,1: 31.2 ± 8.1%, n = 5). The non-selective galanin receptor antagonist, galantide (100 nmol L,1), blocked the inhibitory effect of galanin (10 nmol L,1) while the selective non-galanin receptor 1 and galanin receptor 3 antagonists, M871 (1 ,mol L,1) and SNAP37889 (100 nmol L,1), respectively, and the nitric oxide synthase inhibitor, NG-nitro- l -arginine methyl ester (l - NAME) (200 ,mol L,1), failed to affect this galanin-induced response. Simultaneous application of galantide (100 nmol L,1) and l -NAME (200 ,mol L,1) significantly reduced the inhibitory effect of capsaicin (30 ,mol L,1) on vagally induced contractions when compared with its effect in the presence of l -NAME alone or in combination with the selective galanin receptor 2 or 3 antagonists. An inhibitory effect of piperine on vagally induced contractions was reduced neither by galantide nor by l -NAME. Immunohistochemistry revealed galanin immunoreactive myenteric neurons and nerve fibres intermingling with cholinergic vagal terminals at motor endplates. These data suggest that galanin from co-innervating enteric neurons co-operates with nitric oxide in modulating vagally induced contractions in the mouse oesophagus. [source] Oral administration of a centrally acting ghrelin receptor agonist to conscious rats triggers defecationNEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2009A. D. Shafton Abstract, Agonists of ghrelin receptors that cross the blood,brain barrier, but not ghrelin itself, administered peripherally (intravenous or subcutaneous), cause defecation by acting on centres in the lumbo-sacral spinal cord. It is not established whether orally administered ghrelin receptor agonists can have this action. We tested GSK894281 for its effectiveness at the ghrelin receptor and its ability to cross the blood,brain barrier. GSK894281 was effective at the human and rat ghrelin receptors at 1,10 nmol L,1, but was >1000-fold less potent at the motilin receptor. It achieved a similar blood concentration by oral or intravenous administration. Oral bioavailability was 74% and brain : blood ratio at steady state was 0.7 : 1. GSK894281 administered orally (1,100 mg kg,1) caused a prompt, dose-related production of faecal pellets; at 10 mg kg,1 faecal output was four times greater than after carrier. The output was the greatest in the first half hour and subsided over the next 90 min. At an oral dose of 10 mg kg,1, the compound was effective on eight successive days. Faecal output was, on average, increased threefold over control in the 2 h after administration on each of the 8 days. This dose also significantly increased food consumption. Rats showed no adverse behavioural effects to the drug on a single application, but at the end of a week of administration they avoided the gavaging pipette. Oral administration of ghrelin receptor agonists that enter the central nervous system could possibly be used to relieve acute cases of constipation or to clear the bowel for colonoscopy. [source] Novel pharmacology: asimadoline, a ,-opioid agonist, and visceral sensationNEUROGASTROENTEROLOGY & MOTILITY, Issue 9 2008M. Camilleri Abstract, Asimadoline is a potent ,-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the , receptor, with IC50 of 5.6 nmol L,1 (guinea pig) and 1.2 nmol L,1 (human recombinant), and high selectively with , : , : , binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post- on-demand treatment with asimadoline was not significantly reduced. Post hoc analyses suggest that asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain-free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date. [source] Activation of splanchnic and pelvic colonic afferents by bradykinin in miceNEUROGASTROENTEROLOGY & MOTILITY, Issue 6 2005S. M. Brierley Abstract, Background:, Lumbar splanchnic (LSN) and sacral pelvic (PN) nerves convey different mechanosensory information from the colon to the spinal cord. Here, we determined whether these pathways differ also in their chemosensitivity to bradykinin. Methods:, Using a novel in vitro mouse colon preparation, serosal afferents were recorded from the LSN and PN and distinguished based on their mechanosensitivity to von Frey filaments (70,4000 mg) and insensitivity to colonic stretch (1,5 g) or fine mucosal stroking (10 mg). Bradykinin was applied into a ring around mechanoreceptive fields. Results:, The LSN and PN afferents had different dynamic responses to mechanical stimuli: PN afferents required lower intensity stimuli, evoked larger responses, and displayed more maintained responses than LSN afferents. Bradykinin (1 ,mol L,1) excited 66% (27 of 41) of LSN afferents. Responses to probing were potentiated after bradykinin. The concentration-dependent (EC50: 0.16 ,mol L,1) response was reversed by the B2 -receptor antagonist HOE-140 (10 nmol L,1). Twelve bradykinin responsive afferents were mechanically insensitive. More LSN serosal afferents responded to bradykinin than PN afferents (11%, P < 0.001) , with larger responses (P < 0.05). No mechanically insensitive PN afferents were recruited by bradykinin. Conclusions:, Bradykinin potently stimulates most splanchnic serosal afferents via B2 -receptors, but few pelvic afferents. Mechanically insensitive afferents recruited by bradykinin are exclusive to the LSN. [source] Presynaptic modulation of cholinergic and non-cholinergic fast synaptic transmission in the myenteric plexus of guinea pig ileumNEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2004K. J. LePard Abstract, These studies investigated receptors modulating release of mediators of fast excitatory postsynaptic potentials (fEPSPs) in guinea pig ileum myenteric plexus using electrophysiological methods. Fast EPSPs inhibited by >95% by hexamethonium (100 ,mol L,1) were cholinergic; mixed fEPSPs were inhibited <95% by hexamethonium. Non-cholinergic fEPSPs were studied in the presence of hexamethonium. The ,2-adrenergic receptor agonist UK 14304 inhibited cholinergic (maximum inhibition = 76%, EC50 = 18 nmol L,1), mixed (81%, 21 nmol L,1) and non-cholinergic (76%, 44 nmol L,1) fEPSPs equally. The 5-HT1 receptor agonist 5-carboxamidotryptamine inhibited cholinergic, mixed and non-cholinergic fEPSPs equally. Renzapride, increased non-cholinergic (33%) less than mixed (97%, 13 ,mol L,1) fEPSPs. Renzapride inhibited the purely cholinergic fEPSPs (,29%) but potentiated the cholinergic component of mixed fEPSPs (39%). Prucalopride potentiated all fEPSPs equally (30,33%). 5-HT (0.1 ,mol L,1) induced potentiation of cholinergic (75%), mixed (97%) and non-cholinergic (84%) fEPSPs was not statistically different. The potentiating effects of renzapride and 5-HT on fEPSPs were inhibited by the 5-HT4 receptor antagonist, SB 204070 (10 nmol L,1). Renzapride (0.3 ,mol L,1) blocked 5-HT-induced increases in cholinergic fEPSPs. ,2-Adrenergic and 5-HT1 receptors mediate inhibition of transmitter release from cholinergic and mixed terminals. 5-HT and prucalopride, acting at 5-HT4 receptors, facilitate all fEPSPs; renzapride facilitates the cholinergic and non-cholinergic components of mixed fEPSPs but not purely cholinergic fEPSPs. Cholinergic synapses may express few 5-HT4 receptors or a renzapride-insensitive 5-HT4 receptor isoform. [source] Lower oesophageal sphincter relaxation evoked by stimulation of the dorsal motor nucleus of the vagus in ferretsNEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2002T. P. Abrahams Abstract, An understanding of the neural control of lower oesophageal sphincter (LOS) relaxation is clinically relevant because transient LOS relaxations (TLOSRs) are a mechanism of acid reflux into the oesophagus. Preganglionic motor neurones innervating the LOS are localized in the dorsal motor nucleus of the vagus (DMV). Based on a single study in cats, it is now widely accepted that these neurones are functionally organized into two separate populations, such that stimulation of the caudal and rostral DMV evokes LOS relaxation and contraction, respectively. Our goal was to map the functional LOS responses to chemical stimulation in the DMV and nucleus tractus solitarius (NTS) of ferrets, an animal model commonly used for conscious studies on TLOSRs, and to test whether DMV-evoked LOS relaxation is mediated through hexamethonium-sensitive vagal-inhibitory pathways to the LOS. We used miniaturized manometry with Dentsleeve to monitor LOS and oesophageal pressures in decerebrate unanaesthetized ferrets. LOS relaxation was evoked readily in response to gastric insufflation, which shows that the vago,vagal reflex was intact in this preparation. Microinjections of l -glutamate (12.5 nmol L,1in 25 nL) were made into the DMV from approximately ,,1.5 to +,2.0 mm relative to the obex. Microinjections into the caudal (, 1.5 to +,0.0 mm behind obex) and intermediate (+ 0.1 to +,1.0 mm rostral to obex) DMV both significantly decreased LOS pressure, and complete LOS relaxation was noted in 28/32 and 11/18 cases, respectively. LOS relaxation responses to DMV microinjection were highly reproducible and abolished by bilateral vagotomy or hexamethonium (15 mg kg,1intravenously). A nitric oxide synthase inhibitor (l -NAME 100 mg kg,1intramuscularly) significantly increased the time taken to reach the maximal response. Increases in LOS pressure (24 ± 4 mmHg; n = 3) were obtained only when stimulation sites were located equal to greater than 1.5 mm rostral to the obex. LOS relaxation (, 78 ± 10%; n = 6) was evoked by stimulation of the NTS but not immediately outside of the NTS (11 ± 27%; n = 5). We conclude that there is a very extensive population of ,inhibitory' motor neurones in the DMV that may account for the predominant vagal-inhibitory tone in ferrets. As NTS stimulation evokes LOS relaxation and the predominant response to DMV stimulation is also LOS relaxation, this vago,vagal reflex may involve an excitatory interneurone between the NTS and DMV vagal inhibitory output. [source] Thyrotropin-releasing hormone and oestrogen differentially regulate prolactin and prolactin receptor expression in female human skin and hair follicles in vitroBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2010E.A. Langan Summary Background, Human skin and scalp hair follicles are both a nonclassical target and an extrapituitary source of prolactin (PRL), which is a potent hair growth modulator. However, how the expression of PRL and PRL receptor (PRLR) is regulated in human skin is unknown. Objectives, To investigate whether two key stimulators of pituitary PRL secretion, thyrotropin-releasing hormone (TRH) and oestrogen, also regulate cutaneous PRL and PRLR expression. Methods, Female scalp skin and/or microdissected hair follicles were treated for 6 days in serum-free organ culture with oestrogen (100 nmol L,1), TRH (1,10 ng mL,1, 3,30 nm) or vehicle control. Quantitative immunohistomorphometry of skin and hair follicle sections was complemented with quantitative polymerase chain reaction for PRL and PRLR in cultured hair follicles and/or female human outer root sheath (ORS) keratinocytes. Results, Oestrogen treatment significantly upregulated PRL and PRLR immunoreactivity in selected skin and hair follicle compartments, at the gene and protein level (P < 0·05). TRH significantly increased PRL immunoreactivity and transcription in hair follicles (P < 0·05); however, while it also increased PRLR transcription in hair follicles, it downregulated PRLR immunoreactivity in the hair follicle ORS (P < 0·05). Conclusions, Our pilot study shows that two key endocrine controls of pituitary PRL secretion, oestrogen and TRH, also regulate PRL and PRLR expression in human skin. This provides novel insights into the regulation of extrapituitary PRL and PRLR expression, and invites exploration of oestrogen and TRH as novel therapeutic agents in the management of skin and hair diseases characterized by aberrant PRLR-mediated signalling. [source] Plasma homocysteine and folate levels in patients with chronic plaque psoriasisBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2006M. Malerba Summary Background, Hyperhomocysteinaemia is a well-known risk factor for cardiovascular diseases. Patients with severe chronic plaque psoriasis have a higher risk of death due to arterial and/or venous thrombosis. Objectives, To investigate the relationship among plasma homocysteine and folate levels and severity of chronic plaque psoriasis in a selected cohort of patients with psoriasis without known risk factors for acquired hyperhomocysteinaemia. Methods, We performed a case,control study in 40 patients with chronic plaque psoriasis and 30 age- and sex-matched healthy controls. Cases and controls were selected excluding individuals with conditions or diseases associated with acquired hyperhomocysteinaemia, and were also asked to stop alcohol and coffee consumption for 1 week before blood sampling. The plasma levels of homocysteine and folic acid were measured and were correlated with the severity of psoriasis (Psoriasis Area and Severity Index, PASI). Results, Patients with psoriasis had plasma homocysteine levels higher than controls (mean ± SD 16·0 ± 5·6 vs. 10·4 ± 4·7 ,mol L,1; P < 0·001). Conversely, folic acid levels were lower in patients with psoriasis compared with controls (mean ± SD 3·6 ± 1·7 vs. 6·5 ± 1·7 nmol L,1; P < 0·001). Plasma homocysteine levels in patients with psoriasis correlated directly with disease severity (PASI) and inversely with folic acid levels. Plasma folic acid levels were inversely correlated with the PASI. No abnormalities of plasma vitamin B6 and B12 were found. Conclusions, Patients with psoriasis may have a tendency to hyperhomocysteinaemia, which may predispose to higher cardiovascular risk. Dietary modification of this risk factor appears relevant to the global management of patients with moderate to severe psoriasis. [source] Exercise training attenuates ageing-induced BKCa channel downregulation in rat coronary arteriesEXPERIMENTAL PHYSIOLOGY, Issue 6 2010Sulayma Albarwani Physical inactivity and ageing are widely recognized as risk factors for development of coronary artery disease. One of the characteristic changes that occurs in aged coronary artery is downregulation of their large-conductance voltage- and calcium-activated K+ (BKCa) channels. In this study, we investigated the effects of moderate exercise training (ET) on the activity of BKCa channels in coronary arteries of aged rats. Old Fischer 344 rats (23,26 months old) were randomly assigned to sedentary (O-SED, n= 24) or exercise-trained groups (O-ET, n= 28). The O-ET rats underwent a progressive treadmill exercise-training programme for 60 min day,1, 5 days week,1 for 12 weeks. Young animals were used for comparison. Coronary arteries were mounted on a wire myograph, and contractions in response to 1, 10, 30, 50 and 100 nmol l,1 iberiotoxin were compared. Iberiotoxin (100 nmol l,1) contracted coronary arteries of young, O-SED and O-ET rats by 115 ± 14, 36 ± 5.6 and 61 ± 5% of 5-hydroxytryptamine-induced contractions, respectively. Patch-clamp studies revealed a larger magnitude of BKCa current in young (104 ± 15.6 pA pF,1) compared with O-ET (44 ± 9 pA pF,1) and least in O-SED coronary smooth muscle cells (8.6 ± 2 pA pF,1). Western immunoblotting was performed to study expression levels of BKCa channel proteins. The , and ,1 subunits of the BKCa channel were reduced by 40 ± 3.5 and 30 ± 2.6%, respectively, in coronary arteries of old compared with young rats, and ET attenuated this reduction in expression level to 28 ± 2 and 12 ± 4%, respectively. Our results showed that ageing was associated with a reduction in BKCa channels, and ET partly reversed this reduction. We conclude that low-intensity ET may be beneficial in restoring age-related decline in coronary vasodilatory properties mediated by BKCa channels. [source] | |||||||||||||