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Kinds of Lowering Terms modified by Lowering Selected AbstractsInterpreting clinical trials of diabetic dyslipidaemia: new insightsDIABETES OBESITY & METABOLISM, Issue 3 2009A. S. Wierzbicki Current treatment guidelines highlight the importance of aggressive lipid-modifying therapy in reducing cardiovascular risk in patients with type 2 diabetes. Statins are established as the cornerstone of dyslipidaemia management in diabetic patients, based on their efficacy in lowering levels of low-density lipoprotein cholesterol (LDL-C). However, statins fail to address the high residual cardiovascular risk in treated patients, some of which may be attributable to low HDL cholesterol (HDL-C) and elevated triglycerides and to a preponderance of small, dense LDL particles, indicating the need for further intervention. Fibrates are effective against all components of atherogenic dyslipidaemia associated with type 2 diabetes. Clinical studies, most notably the Fenofibrate Intervention and Event Lowering in Diabetes, indicate that fibrates, most likely in combination with a statin, have a secondary role in reducing cardiovascular risk in patients with type 2 diabetes, particularly in those without prior cardiovascular disease or patients with low HDL-C. Results are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes trial to fully evaluate the outcome benefits of this combination strategy. [source] Lipid-lowering therapy in patients with type 2 diabetes: the case for early interventionDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2008Armin Steinmetz Abstract Chronic complications of type 2 diabetes, in particular, macrovascular complications, confer substantial morbidity and mortality and adversely affect a patient's quality of life. Early intensive intervention to control cardiovascular risk factors is essential in clinical management. Atherogenic dyslipidaemia characterized by elevated triglycerides, a low level of high-density lipoprotein cholesterol (HDL-C), and an increase in the preponderance of small, dense low-density lipoprotein (LDL) particles, is a key modifiable risk factor for macrovascular diabetic complications. Lowering low-density lipoprotein cholesterol (LDL-C) with a statin (or the combination of statin and ezetimibe) is the main focus for reducing cardiovascular risk in patients with diabetes. However, statins fail to address the residual cardiovascular risk associated with low HDL-C. Fibrates are effective against all components of the atherogenic dyslipidaemia associated with type 2 diabetes. Secondary analyses of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study suggest a role for early treatment with fenofibrate in improving cardiovascular risk reduction in type 2 diabetes and provide safety data supporting the use of fenofibrate in combination with a statin. Data from the FIELD study suggest that fenofibrate may also have potential to impact on microvascular diabetic complications associated with type 2 diabetes. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the outcome benefits of combining fenofibrate with a statin in patients with type 2 diabetes. Finally, in view of divergent study results and outstanding data, assessment of the risk of the individual with type 2 diabetes is mandatory to assist clinical decision-making when initiating lipid therapy. Copyright © 2008 John Wiley & Sons, Ltd. [source] Clinical insights from the Fenofibrate Intervention and Event Lowering in Diabetes study: a community practice perspectiveINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2009P. P. Toth Summary Achieving adequate control of cardiovascular risk in type 2 diabetes mellitus (DM) is crucially important; however, the atherogenic dyslipidaemia (including low high-density lipoprotein cholesterol and hypertriglyceridaemia) typically encountered in type 2 DM is often managed inadequately. Evidence from the Fenofibrate Intervention and Event Lowering in Diabetes study suggests that fenofibrate reduces the risk of long-term macrovascular and microvascular type 2 diabetic complications, especially in patients demonstrating features of the metabolic syndrome. Fenofibrate represents a useful treatment option for controlling cardiovascular risk in type 2 diabetes patients in the community setting. [source] Cardiovascular Events in Hypertension Trials of Angiotensin-Converting Enzyme InhibitorsJOURNAL OF CLINICAL HYPERTENSION, Issue 2005William J. Elliott MD Angiotensin-converting enzyme inhibitors are widely-prescribed drugs for hypertension and are supported by clinical trials in which they reduce cardiovascular events. In the high-risk patients in the Heart Outcomes Prevention Evaluation, the Perindopril Protection Against Recurrent Stroke Study, and European Trial of Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease, ramipril and perindopril showed impressive benefits. One reason trandolapril did somewhat less well in the Prevention of Events With Angiotensin-Converting Enzyme Inhibition trial may be that its patients were very well treated with other effective modalities. In the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial, lisinopril-treated patients had a slightly lower incidence of myocardial infarction, despite much poorer control of blood pressure, perhaps because a second-line diuretic was prohibited by protocol. Although angiotensin-converting enzyme inhibitors can cause cough and angioedema (more common among blacks), angiotensin receptor blockers are currently more expensive and have fewer outcome trials to support their use. [source] Obesity and Hypertension in Children; Caffeine, Stress, and Elevated Blood Pressure; Resistant Hypertension; and Is It Lowering of Blood Pressure Alone That Accounts for Reduction in Cardiovascular Events?JOURNAL OF CLINICAL HYPERTENSION, Issue 6 2001Comments on the JCH Contents No abstract is available for this article. [source] Assessment of lovastatin application as tool in probing cytokinin-mediated cell cycle regulationPHYSIOLOGIA PLANTARUM, Issue 2 2005Katja Hartig Lovastatin, a potent inhibitor of the mevalonate pathway, has been used in plant cell cycle studies to eliminate the cytosolic cytokinin biosynthesis. However, several implications can blur the results, as cytokinins may be alternatively formed from isopentenylpyrophosphate produced by the plastid 1-deoxy-xylulose 5-phosphate pathway and because the endogenous cytokinin levels oscillate considerably in the course of a cell cycle. In the work presented here, short- and long-term effects of lovastatin on suspension- cultured Nicotiana tabacum (L.) BY-2 cells were differentiated. The short-term experiments revealed a fast action of lovastatin, resulting in a significantly, though not completely, decreased content of endogenous cytokinins that became visible already after 10 min and was most pronounced after 30 min. But the impact of lovastatin on cell cycle progression depended also on the phase of the cell cycle at which it was administered. Lowering of the cytokinin level during the early S phase, when the endogenous cytokinin levels increased, delayed the S/G2 transition, whereas the same treatment in the late S phase, when the cellular cytokinin concentrations had already started to decrease, promoted it. Incubation periods longer than 48 h resulted in about 50% loss of viable of the cells and also in a reduced capability of division of the survivors. These cells later on resumed cell division. A second treatment with lovastatin of that culture again killed about 50% of the cells, but the surviving cells showed faster re-growth. In conclusion, lovastatin appears as a useful inhibitor of cytokinin biosynthesis in short-term studies, but its use in long-term experiments may create complex effects and therefore requires substantial caution. [source] The "Null Effect" of Low-Density Lipoprotein Cholesterol Lowering on a Modest Baseline Intima-Media Thickness: Lessons Learned From the ENHANCE TrialPREVENTIVE CARDIOLOGY, Issue 3 2008Barry A. Franklin PhD No abstract is available for this article. [source] Preventive Cardiology: More than Just Lipid LoweringPREVENTIVE CARDIOLOGY, Issue 3 2001Edward D. Frohlich MD No abstract is available for this article. [source] Proteomics reveals lowering oxygen alters cytoskeletal and endoplasmatic stress proteins in human endothelial cellsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 19 2009Louise Østergaard Abstract A proteomic approach was applied to explore the signalling pathways elicited by lowering O2 in endothelial cells. Endothelial cells isolated from native umbilical cords were subjected to 21, 5, or 1% O2 for 24,h. 2-D PAGE was performed and candidate proteins were identified using LC-MS/MS. Lowering of O2 from 21 to 5% induced upregulation of cofilin-1, cyclophilin A, tubulin and tubulin fragments, a fragment of glucose-regulated protein 78 (Grp78) and calmodulin. The upregulation of Grp78 suggested that ER stress proteins were altered and indeed Grp94 and caspase 12 expression were increased in cells exposed to 5% O2. The presence of ER stress is also supported by findings of blunted caffeine-evoked ER calcium release in cells exposed to 5 and 1% O2. Exposure to 1% O2 caused increases in cofilin-1, cyclophilin A, and caspase 12 as well as a decrease of ,-actin, but it did not alter the expression of calmodulin, tubulin, Grp78, and Grp94. Incubation with CoCl2, a stabilizer of the hypoxia-inducible factor, increased the expression of several of the proteins. The present investigations reveal that lowering O2, probably in part through hypoxia-inducible factor, alter the expression of a series of proteins mainly involved in cytoskeletal changes (e.g. cofilin-1, tubulin, and ,-actin) and in ER stress/apoptosis (e.g. Grp78/94, caspase 12, and cyclophilin A). [source] The Fluid-Mosaic Model, Homeoviscous Adaptation, and Ionic Liquids: Dramatic Lowering of the Melting Point by Side-Chain Unsaturation,ANGEWANDTE CHEMIE, Issue 15 2010Samuel Unerwartet: Ionische Flüssigkeiten mit langen ungesättigten Alkylresten (obere Struktur) trotzen den gängigen Trends, nach denen lange ionengebundene Alkylgruppen höhere Schmelzpunkte bedeuten, und sind weniger viskos als ein gesättigter Standard (untere Struktur) bei derselben Temperatur. Diese Merkmale ähneln denjenigen bei der Viskositätsanpassung der Zellmembran in manchen Organismen und sprechen für einen Flüssig-Mosaik-Charakter im Nanomaßstab. [source] Fluvial response to sea-level changes: a quantitative analogue, experimental approachBASIN RESEARCH, Issue 3 2001M. W. I. M. Van Heijst ABSTRACT Quantitative evaluation of fluvial response to allogenic controls is crucial for further progress in understanding the stratigraphic record in terms of processes that control landscape evolution. For instance, without quantitative insight into time lags that are known to exist between sea-level change and fluvial response, there is no way to relate fluvial stratigraphy to the sea-level curve. It is difficult to put firm constraints on these time-lag relationships on the basis of empirical studies. Therefore, we have started to quantify time-averaged erosion and deposition in the fluvial and offshore realms in response to sea-level change by means of analogue modelling in a 4 × 8-m flume tank. The rate of sea-level change was chosen as an independent variable, with other factors such as sediment supply, discharge and initial geometry kept constant over the course of 18 experiments. Our experimental results support the common view that neither fall nor rise in sea level affects the upstream fluvial system instantaneously. An important cause for the delayed fluvial response is that a certain amount of time is required to connect initial incisions on the newly emergent shelf (canyons) with the fluvial valley. Lowering of the fluvial longitudinal profile starts only after the connection of an active shelf canyon with the fluvial valley; until that moment the profile remains steady. We quantified the process of connection and introduced the quantity ,connection rate'. It controlled, in conjunction with the rate of sea-level fall: (1) the amount of fluvial degradation during sea-level fall; (2) the total sediment volume that bypasses the shelf edge; (3) the percentage of fluvial relative to shelf sediment in the lowstand delta; (4) the volume of the transgressive systems tract and (5) the amount of diachroneity along the sequence boundary. Our experiments demonstrate also that the sequence-stratigraphic concept is difficult to apply to continental successions, even when these successions have been deposited within the influence of sea level. [source] Development of the Thyroid Hormone Receptor ,-Subtype Agonist KB-141 : A Strategy for Body Weight Reduction and Lipid Lowering with Minimal Cardiac Side EffectsCARDIOVASCULAR THERAPEUTICS, Issue 2 2005Gary J. Grover ABSTRACT Few treatments for obesity exist and improvements for treatment of hyperlipidemia are still desirable. Thyroid hormone receptors (TRs) regulate body weight, adiposity, and cholesterol levels. However, thyroid hormones can have deleterious effects, particularly cardiac acceleration, that limits the use of hormones in the treatment of obesity. There is evidence that the TR, subtype mediates lowering of blood cholesterol levels and possibly elevation of metabolic rate, whereas TR, appears to control heart rate. In studies, described in this review article, we examined the effects of selective TR, activation on metabolic rate and heart rate in mice, rats and monkeys. T3 had a greater effect on increasing heart rate in wild type (WT) than in TR,-/- mice (ED15 values of 34 and 469 nmol/kg/day, respectively). T3 increased metabolic rate (MVO2) in both WT and TR,-/- mice, but the effect on TR,-/- mice was less pronounced compared to WT mice. Stimulation of MVO2 is mediated by both TR, and TR,, but with different profiles. In cholesterol-fed rats, KB-141, a selective TR, agonist, increased MVO2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. tachycardia. In primates, KB-141 caused significant, cholesterol, Lp(a) and body weight reduction after 1 week of treatment with no effect on heart rate. These data suggest that selective TR, agonists may represent a novel class of drugs for the treatment of obesity, hypercholesterolemia and elevated Lp(a), which may make them useful therapeutics for patients with metabolic syndrome. [source] Synthesis and Reactivity of Enediynyl Amino Acids and Peptides: A Novel Concept in Lowering the Activation Energy of Bergman Cyclization by H-Bonding and Electrostatic Interactions.CHEMINFORM, Issue 7 2004Amit Basak No abstract is available for this article. [source] Lowering of blood pressure during chronic suppression of central sympathetic outflow: Insight from computer simulationsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 2 2010Radu Iliescu Summary 1. Chronic electrical stimulation of the carotid sinuses has provided unique insight into the mechanisms that cause sustained reductions in blood pressure during chronic suppression of central sympathetic outflow. 2. Because renal denervation does not abolish the sustained fall in arterial pressure in response to baroreflex activation, this observation has seemingly challenged the concept that the kidneys play a critical role in the long-term control of arterial pressure during chronic changes in sympathetic activity. The aim of the present study was to use computer simulations to provide a more comprehensive understanding of physiological mechanisms that mediate sustained reductions in arterial pressure during prolonged baroreflex-mediated suppression of central sympathetic outflow. 3. Physiological responses to baroreflex activation under different conditions were simulated by an established mathematical model of human physiology (QHP2008; see Supporting Information (Appendix S1) provided in the online version of this article and/or http://groups.google.com/group/modelingworkshop). The model closely reproduced empirical data, providing important validation of its accuracy. 4. The simulations indicated that baroreflex-mediated suppression of renal sympathetic nerve activity does chronically increase renal excretory function but that, in addition, hormonal and haemodynamic mechanisms also contribute to this natriuretic response. The contribution of these redundant natriuretic mechanisms to the chronic lowering of blood pressure is of increased importance when suppression of renal adrenergic activity is prevented, such as after renal denervation. Activation of these redundant natriuretic mechanisms occurs at the expense of excessive fluid retention. 5. More broadly, the present study illustrates the value of numerical simulations in elucidating physiological mechanisms that are not obvious intuitively and, in some cases, not readily testable in experimental studies. [source] Effect Of Anti-Oxidant Treatment And Cholesterol Lowering On Resting Arterial Tone, Metabolic Vasodilation And Endothelial Function In The Human Forearm: A Randomized, Placebo-Controlled StudyCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2001Stephen J Duffy SUMMARY 1. The aim of the present study was to determine whether anti-oxidant therapy with vitamin E and/or cholesterol-lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia. 2. Endothelium-dependent and -independent, nitric oxide (NO)-mediated vasodilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies suggest that vascular function may be improved with anti-oxidant or cholesterol- lowering therapy, although these treatments may be synergistic. 3. We compared FBF at rest, in response to isotonic exercise, the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator sodium nitroprusside (SNP) and the NO synthase inhibitor NG -monomethyl- L -arginine (L -NMMA) in 26 young, otherwise healthy volunteers (mean (±SD) age 29±7 years; 14 female, 12 male) with hypercholesterolaemia, before and after 6 months treatment with vitamin E, simvastatin and/or placebo. Treatment was randomized, double-blinded in a 2 × 2 factorial design. Forearm blood flow was measured using venous occlusion plethysmography. 4. Vitamin E therapy increased plasma ,-tocopherol from 39.5±9.6 to 75.7±33.8 ,mol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9±1.7 to 4.9±0.8 mmol/L and low- density lipoprotein (LDL) from 4.8±1.7 to 3.0±0.7 mmol/L (both P < 0.001), although total and LDL,cholesterol also decreased slightly in the placebo group. Vitamin E increased resting FBF from 2.1±0.3 to 2.4±0.3 mL/100 mL per min (P = 0.04) and decreased resting forearm vascular resistance from 42.1±4.2 to 36.1±3.4 units (P = 0.01), but the reduction in resting FBF with L -NMMA was not affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin and in the combined vitamin E,simvastatin groups. NG -Monomethyl- L -arginine infusion reduced resting FBF and functional hyperaemia in response to exercise and these responses were not altered by treatment. 5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subjects, these effects may not be via NO-dependent pathways. Metabolic vasodilation and responses to the NO-mediated vasodilators ACh and SNP were not favourably affected by anti-oxidant or cholesterol-lowering therapy, either alone or in combination. [source] Aortic sclerosis,a marker of coronary atherosclerosisCLINICAL CARDIOLOGY, Issue 12 2004Yogendra Prasad M.D. Abstract Aortic valve sclerosis is defined as calcification and thickening of a trileaflet aortic valve in the absence of obstruction of ventricular outflow. Its frequency increases with age, making it a major geriatric problem. Of adults aged> 65 years, 21,29% exhibit aortic valve sclerosis. Incidence of aortic sclerosis increases with age, male gender, smoking, hypertension, high lipoprotein (Lp) (a), high low-density lipoprotein (LDL), and diabetes mellitus. Aortic valves affected by aortic sclerosis contain a higher amount of oxidized LDL cholesterol and show increased expression of metalloproteinases. Clinically, it can be suspected in the presence of soft ejection systolic murmur at the aortic area, normal split of the second heart sound, and normal volume carotid pulse, but it can be best detected by echocardiography. Aortic sclerosis may be accompanied by mitral annulus calcification up to 50% of cases. It is associated with an increase of approximately 50% in the risk of death from cardiovascular causes and the risk of myocardial infarction. The mechanism by which aortic sclerosis contributes to or is associated with increased cardiovascular risk is not known. Aortic sclerosis is associated with systemic endothelial dysfunction, and a small percentage of cases may progress to aortic stenosis. Lowering of LDL cholesterol by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to decrease progression of aortic valve calcification. Aortic sclerosis is not a mere benign finding. Once diagnosis of aortic sclerosis has been made, it should be considered a potential marker of coexisting coronary disease. Aggressive management of modifiable risk factors, especially LDL cholesterol lowering, may slow progression of the disease. [source] Virtual reality simulations in Web-based science educationCOMPUTER APPLICATIONS IN ENGINEERING EDUCATION, Issue 1 2002Young-Suk Shin Abstract This article presents the educational possibilities of Web-based science education using a desktop virtual reality (VR) system. A Web site devoted to science education for middle school students has been designed and developed in the areas of earth sciences: meteorology, geophysics, geology, oceanography, and astronomy. Learners can establish by themselves the pace of their lessons using learning contents considered learner level and they can experiment in real time with the concepts they have learned, interacting with VR environments that we provide. A VR simulation program developed has been evaluated with a questionnaire from learners after learning freely on the Web. This study shows that Web-based science education using VR can be effectively used as a virtual class. When we consider the rapid development of VR technology and lowering of cost, the study can construct more immersive environments for the education in the near future. © 2002 Wiley Periodicals, Inc. Comput Appl Eng Educ 10: 18,25, 2002; Published online in Wiley InterScience (www.interscience.wiley.com.); DOI 10.1002/cae.10014 [source] Budesonide delivered by dosimetric jet nebulization to preterm very low birthweight infants at high risk for development of chronic lung diseaseACTA PAEDIATRICA, Issue 12 2000B Jónsson We investigated the effect of an aerosolized corticosteroid (budesonide) on the oxygen requirement of infants at high risk for developing chronic lung disease (CLD) in a randomized, double-blind study. The study objective was to attain a 30% decrease in FiO2 levels in the budesonide treatment group after 14 d of therapy. Thirty very low birthweight (VLBW) infants (median (range)) gestational age 26 wk (23,29) and birthweight 805 g (525,1227) were randomized. Inclusion criteria were mechanical ventilation on day 6 of life, or if extubated on nasal continuous positive airway pressure with FiO2± 0.3. The budesonide (PulmicortÔ dose was 500 ,g bid, or placebo. The aerosol was delivered with a dosimetric jet nebulizer, with variable inspiratory time and breath sensitivity. Inhalations were started on day 7 of life. Twenty-seven patients completed the study. A significant lowering of the FiO2 levels at 21 d of life was not detected. Infants who received budesonide were more often extubated during the study period (7/8 vs 2/9) and had a greater relative change from baseline in their oxygenation index (budesonide decreased 26% vs placebo increased 60%). Subsequent use of intravenous dexamethasone or inhaled budesonide in the treatment group was significantly less. All patients required O2 supplementation on day 28 of life. At 36 wk postconceptual age, 61% of infants in the budesonide group needed supplemental O2 as opposed to 79% in the placebo group. No side effects on growth or adrenal function were observed Conclusion: We conclude that inhaled budesonide aerosol via dosimetric jet nebulizer started on day 7 of life for infants at high risk for developing CLD decreases the need for mechanical ventilation similar to intravenous dexamethasone, but without significant side effects. [source] Platelet activating factor (PAF) increases plasma protein extravasation and induces lowering of interstitial fluid pressure (Pif) in rat skinACTA PHYSIOLOGICA, Issue 1 2005V. V. Iversen Abstract Aim:, To investigate the ability of the microdialysis technique to measure capillary selectivity of different sized plasma proteins induced by local administration of platelet activating factor (PAF). Methods:, We used hollow plasmapheresis fibres with 3 cm membrane (cut off 3000 kDa) placed on the back of anaesthetized rats. Results:, Platelet activating factor (50 ,g mL,1) administered locally via the fibre, increased extravasation of radiolabelled 125I-HSA from plasma to the microdialysis fibre by approximately 900% compared both to baseline and the control fibre within 70 min (n = 6, P < 0.05). The extravasation in the control fibre did not change over time. HPLC measurement of plasma proteins in the microdialysis perfusate also demonstrated decreased capillary selectivity for proteins in the diameter range of 73 Å, 56 Å and 39 Å after local administration of PAF (n = 6, P < 0.05). PAF also significantly lowered interstitial fluid (Pif) pressure after subcutaneous administration (50 ,g mL,1). Mean arterial pressure (MAP) after intravenous injection of PAF (0.4 ,g kg,1) fell instantly by about 50 mmHg, and stabilized at 50 mmHg after 15 min (n = 6). MAP was unaltered when PAF was given through the microdialysis fibre (n = 4). Both total tissue water (TTW) and extravasation of albumin, measured as the plasma-to-tissue clearance (E-alb) showed a significant increase after PAF (n = 7, P < 0.05). Conclusions:, The present study demonstrates that PAF induces plasma protein extravasation and decrease capillary selectivity of different sized plasma proteins. It also increases transcapillary fluid flux, and lowers Pif, indicating a role for PAF in the interstitium for generation of transcapillary transport of water and large molecules followed by formation of oedema. [source] Association between fatigue and failure to preserve cerebral energy turnover during prolonged exerciseACTA PHYSIOLOGICA, Issue 1 2003L. Nybo Abstract Aim: This study evaluated if the fatigue and apathy arising during exercise with hypoglycaemia could relate to a lowering of the cerebral metabolic rates of glucose and oxygen. Methods and results: Six males completed 3 h of cycling with or without glucose supplementation in random order. Cerebral blood flow, metabolism and interleukin-6 (IL-6) release were evaluated with the Kety,Schmidt technique. Blood glucose was maintained during the glucose trial, while it decreased from 5.2 ± 0.1 to 2.9 ± 0.3 mmol L,1 (mean ± SE) after 180 min of exercise in the placebo trial with a concomitant increase in perceived exertion (P < 0.05). During hypoglycaemia, the cerebral glucose uptake was reduced from 0.34 ± 0.05 to 0.28 ± 0.04 ,mol g,1 min,1, while the cerebral uptake of , -hydroxybutyrate increased to 5 ± 1 pmol g,1 min,1 (P < 0.05). The reduced glucose uptake was accompanied by a lowering of the cerebral metabolic rate of oxygen from 1.84 ± 0.19 mmol g,1 min,1 during exercise with glucose supplementation to 1.60 ± 0.16 mmol g,1 min,1 during hypoglycaemia (P < 0.05). In addition, the cerebral IL-6 release was reduced from 0.4 ± 0.1 to 0.0 ± 0.1 pg g,1 min,1 (P < 0.05). Conclusions: Exercise-induced hypoglycaemia limits the cerebral uptake of glucose, exacerbates exercise, reduces the cerebral metabolic rate of oxygen and attenuates the release of IL-6 from the brain. [source] Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitusDIABETES OBESITY & METABOLISM, Issue 5 2009E. Bosi Aim:, To compare the efficacy and safety of vildagliptin and metformin initial combination therapy with individual monotherapies in treatment-naive patients with type 2 diabetes mellitus (T2DM). Methods:, This was a 24-week, randomized, double-blind, active-controlled study. Treatment-naive patients with T2DM who had a glycated haemoglobin (HbA1c) of 7.5,11% (N = 1179) were randomized equally to receive vildagliptin plus high-dose metformin combination therapy (50 mg + 1000 mg twice daily), vildagliptin plus low-dose metformin combination therapy (50 mg + 500 mg twice daily), vildagliptin monotherapy (50 mg twice daily) or high-dose metformin monotherapy (1000 mg twice daily). The primary objective was to demonstrate that HbA1c reduction from baseline with either combination therapy is superior to both monotherapies at the week 24 endpoint. Patients who failed glycaemic-screening criteria [HbA1c >11% or fasting plasma glucose (FPG) >15 mmol/l (270 mg/dl)] could enter a 24-week, single-arm substudy. These patients (N = 94) received open-label vildagliptin plus high-dose metformin combination therapy (100 mg + 1000 mg twice daily). Results:, From comparable baseline values (8.6,8.7%), HbA1c decreased in all four treatment groups, to the greatest extent with vildagliptin plus high-dose metformin combination therapy. Mean (SE) HbA1c change from baseline was ,1.8% (0.06%), ,1.6% (0.06%), ,1.1% (0.06%) and ,1.4% (0.06%) with vildagliptin plus high-dose metformin combination therapy, vildagliptin plus low-dose metformin combination therapy, and vildagliptin and metformin monotherapies respectively. The between-group difference was superior with vildagliptin plus high-dose metformin combination therapy (p < 0.001 vs. both monotherapies) and vildagliptin plus low-dose metformin combination therapy (p < 0.001 and p = 0.004, vs. vildagliptin and metformin monotherapies, respectively). Higher baseline HbA1c values were linked to greater HbA1c reductions, with changes of ,3.2% (0.22%), ,2.7% (0.22%), ,1.5% (0.24%) and ,2.6% (0.26%) respectively, occurring in patients with baseline HbA1c,10%. Reductions in FPG were superior with vildagliptin plus high-dose metformin combination therapy [change from baseline ,2.63 (0.13) mmol/l] compared with both monotherapies [,1.26 (0.13) mmol/l and ,1.92 (0.13) mmol/l, respectively; p < 0.001]. There was no incidence of hypoglycaemia or severe hypoglycaemia with either combination therapy, and neither was associated with weight gain. All treatments were well tolerated and displayed a comparable incidence of adverse events overall. Despite superior HbA1c lowering, the vildagliptin plus low-dose metformin combination therapy group demonstrated a favourable gastrointestinal (GI) tolerability profile compared with metformin monotherapy. Conclusions:, In treatment-naive patients, combinations of vildagliptin and both high-dose and low-dose metformin provide superior efficacy to monotherapy treatments with a comparable overall tolerability profile and low risk of hypoglycaemia. The potential dose-sparing effect of adding vildagliptin to low-dose metformin in preference to the up-titration of metformin may allow patients to achieve equivalent or superior HbA1c lowering without the GI tolerability issues associated with higher doses of metformin. [source] Premixed insulin treatment for type 2 diabetes: analogue or human?DIABETES OBESITY & METABOLISM, Issue 5 2007Alan J. Garber The progressive nature of type 2 diabetes makes insulin initiation a necessary therapeutic step for many patients. Premixed insulin formulations containing both basal and prandial insulin (so called biphasic insulin) are often prescribed because they are superior to long- or intermediate-acting insulin in obtaining good metabolic control. In addition, they are considered as an attractive alternative to classical basal-bolus therapy as fewer daily injections are required. Premixed insulin formulations include conventional (e.g. biphasic human insulin 70/30, or 30/70 in European countries, BHI 30) and newer premixed human analogues (e.g. biphasic insulin aspart 70/30, or 30/70 in Europe, BIAsp 30; insulin lispro mix 75/25,Mix 75/25, or Mix 25/75 in Europe). Like conventional premixed human insulin, premixed insulin analogues contain a fixed proportion of soluble, rapid-acting insulin analogue, with protaminated analogue comprising the remainder. Unlike conventional premixes, analogue premixes have more physiological pharmacokinetic and therapeutically more desirable pharmacodynamic profiles than premixed human insulin. Consequently, postprandial glycaemic control is better with premixed insulin analogues than with premixed human insulin. In nontreat-to-target registration trials, the lowering of haemoglobin A1c with premixed insulin analogues was not inferior to that seen with premixed human insulin. Minor hypoglycaemia was similar for premixed analogue and premixed human insulins, while major hypoglycaemia appears to be rare with either formulation. The occurrence of adverse events, other than hypoglycaemia, was also similar between various premix insulins. The premixed insulin analogues, BIAsp 30 and Mix 75/25, like the fast-acting analogues from which they are derived, also allow flexible injection timing, relative to meal timing, thus improving adherence, compliance and quality of life compared with premixed human insulin. Overall, the evidence suggests that premixed insulin analogues are cost effective and have useful advantages over premixed human insulin for the treatment of type 2 diabetes. [source] Insulin resistance in type 2 diabetes: role of fatty acids,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S2 2002Peter Arner Abstract Insulin resistance is one of the key factors responsible for hyperglycaemia in type 2 diabetes and can result in a number of metabolic abnormalities associated with cardiovascular disease (insulin resistance syndrome), even in the absence of overt diabetes. The mechanisms involved in the development of insulin resistance are multifactorial and are only partly understood, but increased availability of free fatty acids (FFAs) is of particular importance for the liver and skeletal muscle. The role of FFAs in type 2 diabetes is most evident in obese patients who have several abnormalities in FFA metabolism. Because of a mass effect, the release of FFAs from the total adipose tissue depot to the blood stream is increased and the high concentration of circulating FFAs impairs muscle uptake of glucose by competitive inhibition. In upper-body obesity, which predisposes individuals to type 2 diabetes, the rate of lipolysis is accelerated in visceral adipose tissue. This results in a selective increase in FFA mobilisation to the portal vein, which connects visceral fat to the liver. A high ,portal' FFA concentration has undesirable effects on the liver, resulting in dyslipidaemia, hyperinsulinaemia, hyperglycaemia and hepatic insulin resistance. Recently, a new class of antidiabetic agents, the thiazolidinediones (TZDs) or ,glitazones' has been developed. A prominent effect of these agents is the lowering of circulating FFA levels and it is believed, but not yet proven, that this interaction with FFAs constitutes a major mechanism behind the glucose-lowering effect of the TZDs. Copyright © 2002 John Wiley & Sons, Ltd. [source] Reflux and pH: ,alkaline' components are not neutralized by gastric pH variationsDISEASES OF THE ESOPHAGUS, Issue 1 2000P. Bechi The ability of the ,alkaline' components of reflux to cause harm in vivo is still open to debate, although these components have been shown in vitro to be capable of damaging the mucosa. The precipitation of bile acids and lysolecithin that occurs at low pH values is the main reason for questioning in vivo mucosal damage. This study was undertaken to determine the composition of gastric aspirates at different original pH values and the degree of solubility of the alkaline components when pH modifications are artificially induced. The samples for chemical analysis were collected from indwelling nasogastric tubes after surgical procedures that did not involve the upper gastrointestinal tract. Bile acid and lysolecithin concentrations were assessed by means of dedicated methods. Thirty-five samples were available for bile acid evaluation and 27 for lysolecithin evaluation. Bile acid and lysolecithin assessments were repeated after pH adjustment at 2, 3.5, 5.5 and 7. For easier assessment of the results, three ranges of the original pH were selected (pH,<,2, 2 , pH < 5, pH , 5). For each pH range, results were pooled together and compared with those in the other pH ranges. Bile acid concentrations were 113 ± 48, 339 ± 90 and 900 ± 303 (mean ± s.e.m. ,mol/L), respectively, in the three groups selected on account of the different original pH values. Differences were significant (p < 0.001). Both taurine- and glycine-conjugated bile acids were represented even at pH < 2. No major differences were observed in bile acid concentration with the artificially induced pH variations. Lysolecithin concentrations were 5.99 ± 3.27, 30.80 ± 8.43 and 108.37 ± 22.17 (mean ± SEM ,g/ml), respectively, in the three groups selected on account of the different original pH ranges. Differences were significant (p < 0.001). No significant differences in lysolecithin concentration were detected with the artificially induced pH variations. In conclusion, both bile acids and lysolecithin are naturally represented in the gastric environment even at very low pH values, although their concentrations decrease on lowering of the naturally occurring pH. Given the concentration variability of bile acids and lysolecithin, further studies are needed to assess the minimal concentration capable of mucosal damage in vivo. [source] Nonsteroidal antiinflammatory drugs as therapeutic agents for Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 3 2002Todd E. Golde One feature of the end-stage pathology of Alzheimer's disease (AD) is the presence of numerous inflammatory markers associated with the amyloid , protein (A,) deposits in the brain. Experimental data strongly suggests that A, aggregates can incite an inflammatory response, but there are also data suggesting that inflammation can promote A, production and deposition. Thus, antiinflammatory drugs may have some role in AD therapy. This idea is supported by epidemiologic data, which shows that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) confers protection from the development of AD. Significantly, oral salicylates have not been consistently shown to confer protection. Such studies have raised questions regarding the target or targets of NSAIDs that account for their apparent protection from AD. We have recently found that some NSAIDs have a novel mechanism of action, namely, selective lowering of the pathogenic A,42 peptide, that could contribute to their efficacy in AD. Further study will be needed to determine if the classic antiinflammatory properties of NSAIDs, the A,42-lowering property, another known or unknown property, or a combination of these contributes to NSAIDs apparent ability to protect individuals from the development of AD. Drug Dev. Res. 56:415,420, 2002. © Wiley-Liss, Inc. [source] Long-term landscape evolution: linking tectonics and surface processesEARTH SURFACE PROCESSES AND LANDFORMS, Issue 3 2007Paul Bishop Abstract Research in landscape evolution over millions to tens of millions of years slowed considerably in the mid-20th century, when Davisian and other approaches to geomorphology were replaced by functional, morphometric and ultimately process-based approaches. Hack's scheme of dynamic equilibrium in landscape evolution was perhaps the major theoretical contribution to long-term landscape evolution between the 1950s and about 1990, but it essentially ,looked back' to Davis for its springboard to a viewpoint contrary to that of Davis, as did less widely known schemes, such as Crickmay's hypothesis of unequal activity. Since about 1990, the field of long-term landscape evolution has blossomed again, stimulated by the plate tectonics revolution and its re-forging of the link between tectonics and topography, and by the development of numerical models that explore the links between tectonic processes and surface processes. This numerical modelling of landscape evolution has been built around formulation of bedrock river processes and slope processes, and has mostly focused on high-elevation passive continental margins and convergent zones; these models now routinely include flexural and denudational isostasy. Major breakthroughs in analytical and geochronological techniques have been of profound relevance to all of the above. Low-temperature thermochronology, and in particular apatite fission track analysis and (U,Th)/He analysis in apatite, have enabled rates of rock uplift and denudational exhumation from relatively shallow crustal depths (up to about 4 km) to be determined directly from, in effect, rock hand specimens. In a few situations, (U,Th)/He analysis has been used to determine the antiquity of major, long-wavelength topography. Cosmogenic isotope analysis has enabled the determination of the ,ages' of bedrock and sedimentary surfaces, and/or the rates of denudation of these surfaces. These latter advances represent in some ways a ,holy grail' in geomorphology in that they enable determination of ,dates and rates' of geomorphological processes directly from rock surfaces. The increasing availability of analytical techniques such as cosmogenic isotope analysis should mean that much larger data sets become possible and lead to more sophisticated analyses, such as probability density functions (PDFs) of cosmogenic ages and even of cosmogenic isotope concentrations (CICs). PDFs of isotope concentrations must be a function of catchment area geomorphology (including tectonics) and it is at least theoretically possible to infer aspects of source area geomorphology and geomorphological processes from PDFs of CICs in sediments (,detrital CICs'). Thus it may be possible to use PDFs of detrital CICs in basin sediments as a tool to infer aspects of the sediments' source area geomorphology and tectonics, complementing the standard sedimentological textural and compositional approaches to such issues. One of the most stimulating of recent conceptual advances has followed the considerations of the relationships between tectonics, climate and surface processes and especially the recognition of the importance of denudational isostasy in driving rock uplift (i.e. in driving tectonics and crustal processes). Attention has been focused very directly on surface processes and on the ways in which they may ,drive' rock uplift and thus even influence sub-surface crustal conditions, such as pressure and temperature. Consequently, the broader geoscience communities are looking to geomorphologists to provide more detailed information on rates and processes of bedrock channel incision, as well as on catchment responses to such bedrock channel processes. More sophisticated numerical models of processes in bedrock channels and on their flanking hillslopes are required. In current numerical models of long-term evolution of hillslopes and interfluves, for example, the simple dependency on slope of both the fluvial and hillslope components of these models means that a Davisian-type of landscape evolution characterized by slope lowering is inevitably ,confirmed' by the models. In numerical modelling, the next advances will require better parameterized algorithms for hillslope processes, and more sophisticated formulations of bedrock channel incision processes, incorporating, for example, the effects of sediment shielding of the bed. Such increasing sophistication must be matched by careful assessment and testing of model outputs using pre-established criteria and tests. Confirmation by these more sophisticated Davisian-type numerical models of slope lowering under conditions of tectonic stability (no active rock uplift), and of constant slope angle and steady-state landscape under conditions of ongoing rock uplift, will indicate that the Davis and Hack models are not mutually exclusive. A Hack-type model (or a variant of it, incorporating slope adjustment to rock strength rather than to regolith strength) will apply to active settings where there is sufficient stream power and/or sediment flux for channels to incise at the rate of rock uplift. Post-orogenic settings of decreased (or zero) active rock uplift would be characterized by a Davisian scheme of declining slope angles and non-steady-state (or transient) landscapes. Such post-orogenic landscapes deserve much more attention than they have received of late, not least because the intriguing questions they pose about the preservation of ancient landscapes were hinted at in passing in the 1960s and have recently re-surfaced. As we begin to ask again some of the grand questions that lay at the heart of geomorphology in its earliest days, large-scale geomorphology is on the threshold of another ,golden' era to match that of the first half of the 20th century, when cyclical approaches underpinned virtually all geomorphological work. Copyright © 2007 John Wiley & Sons, Ltd. [source] Two-hourly surface change on supra-tidal rock (Marengo, Victoria, Australia)EARTH SURFACE PROCESSES AND LANDFORMS, Issue 1 2007Lluís Gómez-Pujol Abstract A traversing micro-erosion meter was used to measure rock surface micro-topography over 40 cm2 on a supra-tidal cliff face from early morning to late evening in late spring. From 06:00 hours to 22:00 hours the relative heights of 188 coordinates were obtained using the meter at 2-hour intervals, resulting in a data set of 1607 readings. Monitoring shows that rock surfaces are dynamic entities, with significant rise and fall relative to the first measurement at shorter timescales than previously reported. The maximum positive rise between readings was 0·261 mm and lowering was 0·126 mm. The pattern of change did not relate as expected to environmental variables such as temperature or insolation. Rather, the surface showed greater surface change in the early morning and late afternoon. It is hypothesized that this pattern relates to the expansion and contraction of lichen thalli as moisture is absorbed during higher humidity in the morning and late afternoon. The implications of these results for weathering studies are considered. Copyright © 2006 John Wiley & Sons, Ltd. [source] Modelling the effect of form and profile adjustments on channel equilibrium timescalesEARTH SURFACE PROCESSES AND LANDFORMS, Issue 12 2003Martin W. Doyle Abstract A model for describing river channel pro,le adjustments through time is developed and applied to a river responding to base-level lowering in order to examine the effect of channel widening and downstream aggradation on equilibrium timescales. Across a range of boundary conditions, downstream aggradation controlled how quickly a channel reached equilibrium. Channel widening either increased or decreased the equilibrium timescale, depending on whether or not sediment derived from widening was deposited downstream. Results suggest that pro,le adjustments are more important than channel width adjustments in controlling equilibrium timescales for a channel responding to base-level lowering. Copyright © 2003 John Wiley & Sons, Ltd. [source] Recent channel adjustments in alluvial rivers of Tuscany, central ItalyEARTH SURFACE PROCESSES AND LANDFORMS, Issue 6 2003Massimo RinaldiArticle first published online: 19 JUN 200 Abstract Drastic channel adjustments have affected the main alluvial rivers of Tuscany (central Italy) during the 20th century. Bed-level adjustments were identified both by comparing available topographic longitudinal profiles of different years and through field observations. Changes in channel width were investigated by comparing available aerial photographs (1954 and 1993,98). Bed incision represents the dominant type of vertical adjustment, and is generalized along all the fluvial systems investigated. The Arno River system is the most affected by bed-level lowering (up to 9 m), whereas lower incision (generally less than 2 m) is observed along the rivers of the southern part of the region. Human disturbances appear to be the dominant factors of adjustments: the main phase of vertical change occurred during the period 1945,80, in concomitance with the phase of maximum sediment mining activity at the regional scale. The second dominant type of adjustment that involved most of the rivers in the region consists of a narrowing of the active channel. Based on measurements of channel width conducted on aerial photographs, 38% of the reaches analysed experienced a narrowing greater than 50% of the initial channel width. The largest values of channel narrowing were observed along initially braided or sinuous with alternate bars morphologies in the southern portion of the region. A regional scheme of channel adjustments is derived, based on initial channel morphology and on the amounts of incision and narrowing. Different styles of channel adjustments are described. Rivers that were originally sinuous with alternate bars to braided generally became adjusted by a moderate incision and a moderate to intense narrowing; in contrast, sinuous-meandering channels mainly adjusted vertically, with a minor amount of narrowing. Copyright © 2003 John Wiley & Sons, Ltd. [source] A rare landform: Yerköprü travertine bridges in the Taurids Karst Range, TurkeyEARTH SURFACE PROCESSES AND LANDFORMS, Issue 6 2002C. Serdar Bayari Abstract Two examples of travertine bridges are observed at 8 to 15 m above stream level in the Lower Zamanti Basin, Eastern Taurids, Turkey. Yerköprü-1 and Yerköprü-2 bridges are currently being deposited from cool karstic groundwaters with log PCO2 > 10,2 atm. The surface area and the total volume of travertine in Yerköprü-1 bridge are 4350 m2 and 40 000 m3, whereas the values for Yerköprü-2 are 2250 m2 and 20 000 m3, respectively. The interplay of hydrogeological structure, local topography, calcite-saturated hanging springs, algal activity and rapid downcutting in the streambed appear to have led to the formation of travertine bridges. Aeration through cascades and algal uptake causes efficient carbon dioxide evasion that enhances travertine formation. Algal curtains aid lateral development of travertine rims across the stream. Model calculations based on a hypothetical deposit in the form of a half-pyramid implied that lateral development should have occurred from both banks of the stream in the Yerköprü-1 bridge, whereas one-sided growth has been sufficient for Yerköprü-2. The height difference between travertine springs and the main stream appears to be a result of Pleistocene glaciation during which karstic base-level lowering was either stopped or slowed down while downcutting in the main stream continued. Copyright © 2002 John Wiley & Sons, Ltd. 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