3,213 research outputs found
Effect of Statins on Functional Expression of Membrane Transporters in L6 Rat Skeletal Muscle Cells
Statins reduce LDL-cholesterol and the risk of
atherosclerosis. They are generally safe, although statin-induced myopathy is
relatively common. Membrane transporters play a crucial role in determining
statin side effects. Little is known regarding the interaction of drug transporters
in muscle cells with statins. Study aims: The present study aimed to determine
the effect of statins on functional expression of monocarboxylate transporters
(MCTs) and multidrug resistance-associated proteins (MRPs) in L6 rat
skeletal myotube cells. Methods: Relative gene expression at mRNA level
was confirmed by RT2 ProfilerTM Rat Drug Transporter PCR array. The uptake
of 3H-labelled DL-lactate (1 ÎŒCi/ml) was measured to functionally expressed
MCT function. The inhibition of [3H]-DL-lactate uptake was assessed in the
presence or absence of statins and compared to that of the MCT inhibitors,
phloretin and CHC. Transporter-mediated dye efflux was used as functional
assay for the MRP efflux transporters. Results: In L6 rat skeletal myotubes,
relatively high mRNA expression level was observed for Mct1and Mrp1for
uptake and efflux transporters, respectively. The [3H]-DL-lactate uptake was
shown to be a concentration-, pH-dependent and Na+-independent manner
with Michaelis-Menten constant (Km) value of 16.17 ± 2.4 mM vs 15.63 ± 3.0
mM in the presence and absence of Na+, respectively. The maximum velocity
of substrate binding (Vmax) of the DL-lactate uptake inhibition by lipophilic
statins; simvastatin and atorvastatin, were in the same order as phloretin and
CHC, while no significant inhibitory magnitude with hydrophilic statins;
pravastatin and rosuvastatin. However, the L6 rat skeletal myotubes did not
exhibit lactate efflux function. Among four of statins used, only simvastatin
showed an affinity inhibition of MRP function in L6 cells. Conclusions: This
study has shown that lipophilic statins significantly inhibit functional
expression of MCTs, even though they have not shown relatively high
inhibition impact on MRPs
UK export performance research - review and implications
Previous research on export performance has been criticized for being a mosaic of autonomous endeavours and for a lack of theoretical development. Building upon extant models of export performance, and a review and analysis of research on export performance in the UK for the period 1990-2005, an integrated model of export performance is developed and theoretical explanations of export performance are put forward. It is suggested that a multi-theory approach to explaining export performance is viable. Management and policy implications for the UK emerging from the review and synthesis of the literature and the integrated model are discussed
A first--order irreversible thermodynamic approach to a simple energy converter
Several authors have shown that dissipative thermal cycle models based on
Finite-Time Thermodynamics exhibit loop-shaped curves of power output versus
efficiency, such as it occurs with actual dissipative thermal engines. Within
the context of First-Order Irreversible Thermodynamics (FOIT), in this work we
show that for an energy converter consisting of two coupled fluxes it is also
possible to find loop-shaped curves of both power output and the so-called
ecological function against efficiency. In a previous work Stucki [J.W. Stucki,
Eur. J. Biochem. vol. 109, 269 (1980)] used a FOIT-approach to describe the
modes of thermodynamic performance of oxidative phosphorylation involved in
ATP-synthesis within mithochondrias. In that work the author did not use the
mentioned loop-shaped curves and he proposed that oxidative phosphorylation
operates in a steady state simultaneously at minimum entropy production and
maximum efficiency, by means of a conductance matching condition between
extreme states of zero and infinite conductances respectively. In the present
work we show that all Stucki's results about the oxidative phosphorylation
energetics can be obtained without the so-called conductance matching
condition. On the other hand, we also show that the minimum entropy production
state implies both null power output and efficiency and therefore this state is
not fulfilled by the oxidative phosphorylation performance. Our results suggest
that actual efficiency values of oxidative phosphorylation performance are
better described by a mode of operation consisting in the simultaneous
maximization of the so-called ecological function and the efficiency.Comment: 20 pages, 7 figures, submitted to Phys. Rev.
Effective actions with fixed points, (error in derivation of coefficient corrected)
The specific form of the constant term in the asymptotic expansion of the
heat-kernel on an axially-symmetric space with a codimension two fixed-point
set of conical singularities is used to determine the associated conformal
change of the effective action in four dimensions. Another derivation of the
relevant coefficient is presented.Comment: 10p,uses JyTeX,MUTP/94/1
Shifting perspectives on coastal impacts and adaptation
The Intergovernmental Panel on Climate Change reports reflect evolving attitudes in adapting to
sea-level rise by taking a systems approach and recognizing that multiple responses exist to achieve a
less hazardous coast.info:eu-repo/semantics/publishedVersio
Frequent Cross-Species Transmission of Parvoviruses among Diverse Carnivore Hosts
Although parvoviruses are commonly described in domestic carnivores, little is known about their biodiversity in nondomestic species. A phylogenetic analysis of VP2 gene sequences from puma, coyote, gray wolf, bobcat, raccoon, and striped skunk revealed two major groups related to either feline panleukopenia virus (âFPV-likeâ) or canine parvovirus (âCPV-likeâ). Crossspecies transmission was commonplace, with multiple introductions into each host species but, with the exception of raccoons, relatively little evidence for onward transmission in nondomestic species
On the alleged simplicity of impure proof
Roughly, a proof of a theorem, is âpureâ if it draws only on what is âcloseâ or âintrinsicâ to that theorem. Mathematicians employ a variety of terms to identify pure proofs, saying that a pure proof is one that avoids what is âextrinsic,â âextraneous,â âdistant,â âremote,â âalien,â or âforeignâ to the problem or theorem under investigation. In the background of these attributions is the view that there is a distance measure (or a variety of such measures) between mathematical statements and proofs. Mathematicians have paid little attention to specifying such distance measures precisely because in practice certain methods of proof have seemed self- evidently impure by design: think for instance of analytic geometry and analytic number theory. By contrast, mathematicians have paid considerable attention to whether such impurities are a good thing or to be avoided, and some have claimed that they are valuable because generally impure proofs are simpler than pure proofs. This article is an investigation of this claim, formulated more precisely by proof- theoretic means. After assembling evidence from proof theory that may be thought to support this claim, we will argue that on the contrary this evidence does not support the claim
Polymorphisms in Cyclooxygenase, Lipoxygenase and TP53 genes predict colorectal polyp risk reduction by aspirin in the seAFOod polyp prevention trial
Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 single nucleotide polymorphisms (SNPs) in oxylipin metabolism genes such as cyclooxygenase [PTGS] and lipoxygenase [ALOX], as well as 7 SNPs already associated with colorectal cancer (CRC) risk reduction by aspirin (eg. TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomised 2x2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. Five hundred and forty-two (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with non-aspirin users was restricted to rs4837960 (PTGS1) common homozygotes (IRR 0.69 [95%CI 0.53,0.90]; q=0.06), rs2745557 (PTGS2) compound heterozygote-rare homozygotes (IRR 0.60 [0.41,0.88]; q=0.06), rs7090328 (ALOX5) rare homozygotes (IRR 0.27 [0.11,0.64]; q=0.05), rs2073438 (ALOX12) common homozygotes (IRR 0.57 [0.41,0.80]; q=0.05), and rs104522 (TP53) rare homozygotes (IRR 0.37 [0.17,0.79]; q=0.06). No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalised, predictive models of CRC chemoprevention by aspirin
Coronary CT Angiography and 5-Year Risk of Myocardial Infarction.
BACKGROUND: Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5-year clinical outcomes is unknown. METHODS: In an open-label, multicenter, parallel-group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow-up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years. RESULTS: The median duration of follow-up was 4.8 years, which yielded 20,254 patient-years of follow-up. The 5-year rate of the primary end point was lower in the CTA group than in the standard-care group (2.3% [48 patients] vs. 3.9% [81 patients]; hazard ratio, 0.59; 95% confidence interval [CI], 0.41 to 0.84; P=0.004). Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard-care group in the first few months of follow-up, overall rates were similar at 5 years: invasive coronary angiography was performed in 491 patients in the CTA group and in 502 patients in the standard-care group (hazard ratio, 1.00; 95% CI, 0.88 to 1.13), and coronary revascularization was performed in 279 patients in the CTA group and in 267 in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91 to 1.27). However, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). There were no significant between-group differences in the rates of cardiovascular or noncardiovascular deaths or deaths from any cause. CONCLUSIONS: In this trial, the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization. (Funded by the Scottish Government Chief Scientist Office and others; SCOT-HEART ClinicalTrials.gov number, NCT01149590 .)
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