bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes
Authors: Lund S. S. , Tarnow L. , Astrup A. S. , Hovind P. , Jacobsen P. K. , Alibegovic A. C. , Parving I. , Pietraszek L. , Frandsen M. , Rossing P. , Parving H.‐H. , Vaag A. A. 
Published: June 2009

Background: In addition to its glucose‐lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1‐year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control.Methods: One hundred T1DM patients with haemoglobinA1c (HbA1c) ≥8.5% during the year before enrolment entered a 1‐month run‐in period on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year.Results: After 1 year, in those patients who did not start or stop statin therapy during the trial, metformin treatment significantly reduced total and LDL cholesterol by approximately 0.3 mmol/l compared with placebo (p = 0.021 and p = 0.018 respectively). Adjustment for statin use or known cardiovascular disease did not change conclusions. In statin users (metformin: n = 22, placebo: n = 13), metformin significantly lowered levels of LDL and non‐HDL cholesterol by approximately 0.5 mmol/l compared with placebo (adjusted for changes in statin dose or agent: p = 0.048 and p = 0.033 respectively). HbA1c (previously reported) was not significant different between treatments.Conclusion: In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy.
The dentition of Goodrichthys, a Carboniferous ctenacanthiform shark from Scotland
Authors: Ginter Michal 
Published: June 2009

AbstractStudy of three sets of chondrichthyan teeth from the Mississippian (Viséan) of Glencartholm, Scotland, namely the dentition of the holotype of a ctenacanthiform shark Goodrichthys eskdalensis, the dentition of a recently found, yet undescribed shark (NMS 2000.14.2), and a group of isolated teeth probably found in a nodule, tentatively suggests that all of them represent the same species. The combined characters of these teeth show that the dentition of Goodrichthys was moderately heterodont, of a cladodont design, in which larger teeth may have had three, and smaller ones only two, lateral cusps on each side of a prominent, coarsely cristated median cusp. The base is similar to that of Cladodus and Famennian representatives of Ctenacanthus, with a prominent, undivided basolabial shelf and an almost straight orolingual ridge.
The Risk Microstructure of Corporate Bonds: A Case Study from the German Corporate Bond Market
Authors: Frühwirth Manfred , Schneider Paul , Sögner Leopold 
Published: June 2009

Abstract This article presents joint econometric analysis of interest rate risk, issuer‐specific risk (credit risk) and bond‐specific risk (liquidity risk) in a reduced‐form framework. We estimate issuer‐specific and bond‐specific risk from corporate bond data in the German market. We find that bond‐specific risk plays a crucial role in the pricing of corporate bonds. We observe substantial differences between different bonds with respect to the relative influence of issuer‐specific vs. bond‐specific spread on the level and the volatility of the total spread. Issuer‐specific risk exhibits strong autocorrelation and a strong impact of weekday effects, the level of the risk‐free term structure and the debt to value ratio. Moreover, we can observe some impact of the stock market volatility, the respective stock's return and the distance to default. For the bond‐specific risk we find strong autocorrelation, some impact of the stock market index, the stock market volatility, weekday effects and monthly effects as well as a very weak impact of the risk‐free term structure and the specific stock's return. Altogether, the determinants of the spread components vary strongly between different bonds/issuers.
Modelling the dynamic biogeography of the wildcat: implications for taxonomy and conservation
Authors: Kitchener A. C. , Rees E. E. 
Published: June 2009

AbstractThere is still no clear consensus on how to relate geographical variation in the morphology and genetics of the globally widespread wildcatFelis silvestristo its taxonomy and systematics. Reconstructing the dynamic biogeography of the wildcat provides insight into how current geographical patterns of morphological and molecular variation may have developed. A geographical information system was used to infer climate‐change influences using a deduced distribution model (DDM) to reconstruct the wildcat's geographical distribution at four points in time from the Last Glacial Maximum [LGM; 18 000 years before present (bp)] until today. The DDM for 9000 bp, when mean global temperatures were 2 °C more than today, provides insight into how current global warming will affect the wildcat's distribution 50–100 years into future. Modelled distributions were assessed against known geographical barriers or unsuitable habitats, which may have separated populations and led to known morphological and genetic divergence. The DDMtodaycorresponds well with known contemporary wildcat distribution records, except where wildcats would be expected to be excluded (e.g. high human population densities, potential competitors, inaccessible islands). The DDMtodayalso corresponds closely with the results of recent studies on skull morphometrics and phylogeography, which support hypothesized colonizations of Africa and Asia from Europe during the late Pleistocene. Although DDM palaeo‐distributions are more uncertain, they correspond to expected dramatic declines in northern Eurasia during the LGM, and significant distributional decline in central Asia, the Sahara and southern Africa, owing to increased aridity during climate cooling. From the DDM9000model moderate global warming is hypothesized to impact minimally on wildcats, except in the Middle East and south‐west Asia.
Effects of AT1 receptor and beta1 receptor blocking on blood pressure, peripheral hemodynamic and lipid profile in statin‐treated hypertensive hypercholesterolemic patients
Authors: Cicero Arrigo F.G. , Veronesi Maddalena , Prandin Maria Grazia , Di Gregori Valentina , Ambrosioni Ettore , Borghi Claudio 
Published: June 2009

AbstractRecent evidences suggest a relationship between angiotensin 1 (AT1) receptor gene expression and low density lipoprotein cholesterol (LDL‐C) plasma level. We enrolled 16 untreated hypertensive hypercholesterolemic patients (57.4 ± 7 years old) in a randomized, single‐blind, cross‐over design. All the patients were allocated to treatment with simvastatin 20 mg/day for 2 weeks, then randomly assigned to telmisartan (40–80 mg/day) or bisoprolol (5–10 mg/day). After 4 weeks the antihypertensive drugs have been withdrawn for a wash‐out period of 2 weeks when they were treated with simvastatin alone, then they have been allocated to the alternative antihypertensive treatment for four additional weeks. We measured: systolic (SBP) and diastolic BP (DBP), 24‐h mean BP (MBP), Baseline and post‐ischemia forearm blood flow (FBF) and vascular resistance (FVR), and Lipid profile. After 2 weeks of treatment with Simvastatin, baseline and post‐ischemic FBF increased (both P < 0.05), while baseline and post‐ischemic FVR decreased (both P < 0.05). Standing DBP and MBP were reduced more after treatment with telmisartan than with bisoprolol (P < 0.05). Basal and post‐ischemic FBF were significantly increased (P < 0.05 and P < 0.005, respectively) and basal and post‐ischemic FVR significantly decreased (both P < 0.005) only after treatment with telmisartan, as well as plasma triglycerides (TG) (P < 0.05). From this preliminary study carried out on hypercholesterolemic hypertensive patients it appears that the association of telmisartan and simvastatin (but not of bisoprolol and simvastatin) could exert positive effects on a large quantity of vascular functionality parameters, just after a short treatment.
Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants
Authors: Park Sang‐Kyu , Kim Kyoungmi , Page Grier P. , Allison David B. , Weindruch Richard , Prolla Tomas A. 
Published: June 2009

SummaryWe used DNA microarrays to identify panels of transcriptional markers of aging that are differentially expressed in young (5 month) and old (25 month) mice of multiple inbred strains (129sv, BALB/c, CBA, DBA, B6, C3H and B6C3F1). In the heart, age‐related changes of five genes were studied throughout the mouse lifespan: complement component 4, chemokine ligand 14, component of Sp100‐rs, phenylalanine hydroxylase and src family associated phosphoprotein 2. A similar analysis in the brain (cerebellum) involved complement component 1q (alpha polypeptide), complement component 4, P lysozyme structural, glial fibrillary acidic protein and cathepsin S. Caloric restriction (CR) inhibited age‐related expression of these genes in both tissues. Parametric analysis of gene set enrichment identified several biological processes that are induced with aging in multiple mouse strains. We also tested the ability of dietary antioxidants to oppose these transcriptional markers of aging. Lycopene, resveratrol, acetyl‐l‐carnitine and tempol were as effective as CR in the heart, and α‐lipoic acid and coenzyme Q10 were as effective as CR in the cerebellum. These findings suggest that transcriptional biomarkers of aging in mice can be used to estimate the efficacy of aging interventions on a tissue‐specific basis.
A pseudo‐stochastic approach for optimal decision making under limited information: a case of an aggregate production system
Authors: Herbon Avi , Khmelnitsky Eugene 
Published: June 2009

AbstractIn this study, which is both analytical and numerical, we compute the effective information horizon (EIH), i.e., the minimal time interval over which future information is relevant for optimal control and for measuring the performance of a single part‐type production system. Optimal control modeling and process solving, which consider aspects of decision making with limited forecast, are exemplified by a single part‐type production system. Specifically, the analysis reveals practical situations in which there is both a performance loss as well as feasibility violation when only information expected within the planning horizon is considered. The analysis is carried out by developing a pseudo‐stochastic model. We follow previous “pseudo‐stochastic” approaches that solve stochastic control problems by using deterministic, optimal control methods. However, we model the expected influences of all future events, including those that are beyond the planning horizon, as encapsulated by their density functions and not only by their mean values.
Drug‐induced QT interval shortening: potential harbinger of proarrhythmia and regulatory perspectives
Authors: Shah Rashmi R 
Published: June 2009

ATP‐dependent potassium channel openers such as pinacidil and levcromakalim have long been known to shorten action potential duration and to be profibrillatory in non‐clinical models, raising concerns on the clinical safety of drugs that shorten QT interval. Routine non‐clinical evaluation of new drugs for their potential to affect cardiac repolarization has revealed that drugs may also shorten QT interval. The description of congenital short QT syndrome in 2000, together with the associated arrhythmias, suggests that drug‐induced short QT interval may be proarrhythmic, and an uncanny parallel is evolving between our appreciation of the short and the long QT intervals. Epidemiological studies report an over‐representation of short QT interval values in patients with idiopathic ventricular fibrillation. Therefore, as new compounds that shorten QT interval are progressed further into clinical development, questions will inevitably arise on their safety. Arising from the current risk‐averse clinical and regulatory environment and concerns on proarrhythmic safety of drugs, together with our lack of a better understanding of the clinical significance of short QT interval, new drugs that substantially shorten QT interval will likely receive an unfavourable regulatory review unless these drugs fulfil an unmet clinical need. This review provides estimates of parameters of QT shortening that may be of potential clinical significance. Rufinamide, a recently approved anticonvulsant, illustrates the current regulatory approach to drugs that shorten QT interval. However, to further substantiate or confirm the safety of these drugs, their approval may well be conditional upon large‐scale post‐marketing studies with a focus on cardiac safety.This article is commented on by Malik, pp. 70–76 of this issue and is part of a themed section on QT safety. To view this issue visithttp://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010
Induction of a reversible, non‐cytotoxic S‐phase delay by resveratrol: implications for a mechanism of lifespan prolongation and cancer protection
Authors: Zhou Ru , Fukui Masayuki , Choi Hye Joung , Zhu Bao Ting 
Published: June 2009

Background and purpose:  Resveratrol (RES) has been shown to prolong lifespan and prevent cancer formation. At present, the precise cellular mechanisms of RES actions are still not clearly understood, and this is the focus of this study.Experimental approach:  Using human hepatocellular carcinoma‐derived HepG2 cells as a model, we studied RES‐induced changes in cell growth, cell cycle progression and apoptosis.Key results:  RES at lower concentrations induced a strong but reversible S‐phase delay and mild DNA synthesis inhibition, yet without causing apoptotic or necrotic cell death. At high concentrations, RES induced apoptosis, which is mainly mediated by the mitochondrial pathway. Overall, RES was a relatively weak apoptotic agent. Mechanistically, MEK inhibition was identified as an important early signalling event for RES‐induced apoptosis. In comparison, activation of CDK2 and checkpoint kinase 2, and inhibition of phosphatidylinositol 3′‐kinase/Akt signalling pathway contributed to the induction by RES of a reversible, non‐cytotoxic S‐phase delay.Conclusion and implications:  It is hypothesized that the induction of a non‐cytotoxic S‐phase delay may represent a useful mechanistic strategy for lifespan prolongation and cancer prevention. When cell cycles are selectively slowed down in the S phase, it would cumulatively increase the total lifespan of an organism if the total numbers of cell divisions of a given organism are assumed to remain basically constant. Likewise, when cells proceed through the cell cycles at a reduced pace during DNA replication, it may allow cells more time to repair the damaged DNA, and thereby reduce the chances for mutagenesis and tumour initiation.
Sphingolipids in inflammation: pathological implications and potential therapeutic targets
Authors: Nixon Graeme F. 
Published: June 2009

Sphingolipids are formed via the metabolism of sphingomyelin, a constituent of the plasma membrane, or by de novo synthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1‐phosphate and sphingosine 1‐phosphate (S1P), are likely to have an integral role in inflammation. This can involve, for example, activation of pro‐inflammatory transcription factors in different cell types and induction of cyclooxygenase‐2, leading to production of pro‐inflammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide‐rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high‐affinity G‐protein‐coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on inflammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in inflammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and inflammatory bowel disease, which involve important inflammatory components. A significant body of research now indicates that sphingolipids are intimately involved in the inflammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological inflammation.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Analysis of binding site for the novel small‐molecule TLR4 signal transduction inhibitor TAK‐242 and its therapeutic effect on mouse sepsis model
Authors: Takashima K , Matsunaga N , Yoshimatsu M , Hazeki K , Kaisho T , Uekata M , Hazeki O , Akira S , Iizawa Y , Ii M 
Published: June 2009

Background and purpose:  TAK‐242, a novel synthetic small‐molecule, suppresses production of multiple cytokines by inhibiting Toll‐like receptor (TLR) 4 signalling. In this study, we investigated the target molecule of TAK‐242 and examined its therapeutic effect in a mouse sepsis model.Experimental approach:  Binding assay with [3H]‐TAK‐242 and nuclear factor‐κB reporter assay were used to identify the target molecule and binding site of TAK‐242. Bacillus calmette guerin (BCG)‐primed mouse sepsis model using live Escherichia coli was used to estimate the efficacy of TAK‐242 in sepsis.Key results:  TAK‐242 strongly bound to TLR4, but binding to TLR2, 3, 5, 9, TLR‐related adaptor molecules and MD‐2 was either not observed or marginal. Mutational analysis using TLR4 mutants indicated that TAK‐242 inhibits TLR4 signalling by binding to Cys747 in the intracellular domain of TLR4. TAK‐242 inhibited MyD88‐independent pathway as well as MyD88‐dependent pathway and its inhibitory effect was largely unaffected by lipopolysaccharide (LPS) concentration and types of TLR4 ligands. TAK‐242 had no effect on the LPS‐induced conformational change of TLR4‐MD‐2 and TLR4 homodimerization. In mouse sepsis model, although TAK‐242 alone did not affect bacterial counts in blood, if co‐administered with ceftazidime it inhibited the increases in serum cytokine levels and improved survival of mice.Conclusions and implications:  TAK‐242 suppressed TLR4 signalling by binding directly to a specific amino acid Cys747 in the intracellular domain of TLR4. When co‐administered with antibiotics, TAK‐242 showed potent therapeutic effects in an E. coli‐induced sepsis model using BCG‐primed mice. Thus, TAK‐242 may be a promising therapeutic agent for sepsis.
Pals‐associated tight junction protein functionally links dopamine and angiotensin II to the regulation of sodium transport in renal epithelial cells
Authors: Chen Z , Leibiger I , Katz AI , Bertorello AM 
Published: June 2009

Background and purpose:  Dopamine inhibits renal cell Na+,K+‐ATPase activity and cell sodium transport by promoting the internalization of active molecules from the plasma membrane, whereas angiotensin II (ATII) stimulates its activity by recruiting new molecules to the plasma membrane. They achieve such effects by activating multiple and distinct signalling molecules in a hierarchical manner. The purpose of this study was to investigate whether dopamine and ATII utilize scaffold organizer proteins as components of their signalling networks, in order to avoid deleterious cross talk.Experimental approach:  Attention was focused on a multiple PDZ domain protein, Pals‐associated tight junction protein (PATJ). Ectopic expression of PATJ in renal epithelial cells in culture was used to study its interaction with components of the dopamine signalling cascade. Similarly, expression of PATJ deletion mutants was employed to analyse its functional relevance during dopamine‐, ATII‐ and insulin‐dependent regulation of Na+,K+‐ATPase.Key results:  Dopamine receptors and components of its signalling cascade mediating inhibition of Na+,K+‐ATPase interact with PATJ. Inhibition of Na+,K+‐ATPase by dopamine was prevented by expression of mutants of PATJ lacking PDZ domains 2, 4 or 5; whereas the stimulatory effect of ATII and insulin on Na+,K+‐ATPase was blocked by expression of PATJ lacking PDZ domains 1, 4 or 5.Conclusions and implications:  A multiple PDZ domain protein may add functionality to G protein‐coupled and tyrosine kinase receptors signalling during regulation of Na+,K+‐ATPase. Signalling molecules and effectors can be integrated into a functional network by the scaffold organizer protein PATJ via its multiple PDZ domains.
The phospholipase A2 inhibitor methyl indoxam suppresses diet‐induced obesity and glucose intolerance in mice
Authors: Hui DY , Cope MJ , Labonté ED , Chang H‐T , Shao J , Goka E , Abousalham A , Charmot D , Buysse J 
Published: June 2009

Background and purpose:  Previous results have shown that mice lacking in the group 1B phospholipase A2 (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high‐fat/high‐carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet‐induced obesity and diabetes.Experimental approach:  Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared.Key results:  Wild‐type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg·kg−1 of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet‐induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b‐mediated postprandial lysophospholipid absorption.Conclusions and implications:  These results show that oral supplementation of a diabetogenic diet with the Pla2g1b inhibitor methyl indoxam effectively suppresses diet‐induced obesity and diabetes in mice. This suggests that Pla2g1b inhibition may be a potentially effective oral therapeutic option for treatment of obesity and diabetes.