Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a key regulator in cholesterol biosynthesis and HMG CoA reductase inhibitors (statins) have become a widely prescribed family of lipid lowering agents. Cholesterol synthesis occurs predominantly in liver which is the target organ of statins. We studied the effects of fluvastatin (Lescol®), a member of the statin family, on hepatic protein regulation. Male F344 rats treated with 0.8 mg/kg per day fluvastatin or 24 mg/kg per day fluvastatin for 7 days showed treatment-related changes in 58 liver proteins (P<0.005). Major effects were evident in the cholesterol biosynthesis pathway including the induction of enzymes upstream and downstream of the target enzyme HMG CoA reductase. Treatment also triggered alterations in key enzymes of carbohydrate metabolism and was associated with changes in a heterogeneous set of cellular stress proteins involved in cytoskeletal structure, calcium homeostasis and protease activity. The latter set of protein alterations indicates that hepatotoxicity is associated with high-dose treatment. Based on the results it is suggested that HMG-CoA synthase and isopentenyl-diphosphate delta-isomerase may be explored as alternative drug targets and that the induction levels of these enzymes may serve as a measure of potency of individual statin drugs. It is proposed that efficacy and cellular stress markers discovered in this study may be used in a high throughput screen (HTS) assay format to compare efficiently and accurately the therapeutic windows of different members of the statin family.     

Maintaining cell sensitivity to G-protein coupled receptor agonists: neurotensin and the role of receptor gene activation

In the last few years, a number of studies have brought new insights into the fundamental mechanisms of cell desensitization and internalization of G-protein coupled receptors. Such studies have demonstrated that cells remain desensitized from a few minutes to several hours, after exposure to high concentrations of agonist. However, in vivo, agonists such as hormones are always present, even in small amounts, and such long desensitization is not conceivable, since constant stimulation of cells is required for physiological responses. Under such circumstances, cells would require a means to permanently maintain sensitivity to various internal or external stimuli. In the present review, we have taken as an example the expression of the high affinity neurotensin receptor, a seven transmembrane G-protein coupled receptor, upon prolonged exposure to its agonist, and observed that cells remained sensitive only if the receptor gene was activated by the agonist. Consequently, new receptors were synthesized, and either delivered to the cell surface or accumulated in submembrane pools. This regulation takes place only after prolonged and intense agonist stimulation. Under these conditions, it is proposed that receptor turnover is accelerated in proportion to the agonist concentration in order to allow the cells to produce an adapted cellular response to external stimuli. Such mechanisms thus play a key role in cell sensitivity to hormones.     

Absent voices compromise the effectiveness of nursing home regulation: a critique of regulatory reform in the UK nursing home industry

Over the last decade there has been consistent pressure for the healthcare services in the UK to become more accountable to users. Now over half the healthcare beds in England are in the privatised nursing home sector, and regulation of the sector is under reform. Yet requirements for user accountability have not been reflected in these reforms. In other sectors, consumer involvement in regulatory agencies and processes is seen as important to the success of the regulatory enterprise. But in the care sector neither users nor their representatives have been given legal rights of involvement in the National Care Standards Commission or in regulatory processes. This paper argues that failure to involve users not only places the regulation enterprise at risk of capture by the industry, but will also weaken the legitimacy of the new Commission.     

Arterial baroreflex influence on heart rate variability: A mathematical model-based analysis

The influence of the arterial baroreflex on the heart rate variability is analysed by using a mathematical model of heart rate baroreceptor control. The basic mechanisms of the model, sufficient to elicit heart rate variability include: systemic circulation, a non-pulsatile cardiac pump and nonlinear negative feedback simulating arterial baroreflex closed-loop control of the heart rate (−3bpm/mmHg as maximum reflex sensitivity). The latter reproduces, through two distinct delayed branches (0.8 and 2.8 s), the short-term autonomic control effected respectively by sympathetic and parasympathetic divisions on the sinus node. By means of this model, two distinct self-sustained oscillatory components with incommensurate frequencies (0.1 and 0.26 Hz) are reproduced. Frequencies of these two oscillatory components closely agree with the main heart rate rhythms in humans (0.09±0.01 Hz and 0.26±0.01 Hz). When sympathetic-mediated regulation prevails over parasympathetic activity, simulated heart rate oscillation is characterised by a low frequency (∼0.1 Hz). On the other hand, a high-frequency oscillatory component (∼0.26 Hz) appears when enhanced vagal activation or partial inhibition of the sympathetic control is simulated. When both autonomic divisions are operative, both low- and high-frequency components are present and the heart rate oscillates quasi-periodically. This variability in heart rate at different frequencies is reproduced without including outside perturbations and is due to the nonlinear delayed structure of the closed-loop control. Bifurcation theory of nonlinear system is used to explain the high sensitivity of the heart rate oscillatory pattern to model parameter changes.     

Fibroblast growth factor-2 is selectively modulated in the rat brain by E-5842, a preferential sigma-1 receptor ligand and putative atypical antipsychotic

Fibroblast growth factor-2 (FGF-2) is a member of a large family of trophic factors whose expression is regulated under several conditions in different areas of the brain. The goal of our experiments was to determine whether the administration of 4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-[4-(1,2,4-triazol-1-il)butyl] pyridine citrate (E-5842), a sigma-1 receptor ligand and putative atypical antipsychotic, could regulate the expression of FGF-2. After chronic treatment with E-5842 (21 days, and the animals killed 24 h after the last administration), an up-regulation was observed of the expression of FGF-2 mRNA in the prefrontal cortex and the striatum, and a down-regulation of the expression of FGF-2 mRNA in the hypothalamus of the rat brain. Acute treatment with E-5842 (one single administration and animals killed 6 h later) up-regulated FGF-2 expression in the prefrontal cortex, the striatum, the hypothalamus and the hippocampus in a dose-dependent manner. The acute up-regulation was transient and disappeared 24 h after E-5842 administration. The induction of FGF-2 in the striatum after repeated administration has been described for clozapine, but our data concerning regulation in the prefrontal cortex suggest that this effect is unique to E-5852 among other antipsychotics. Given the neuroprotective activity of FGF-2, the data presented here might be relevant to the deficit in cognition and other symptoms that appear in schizophrenia.     

对某基层医疗机构药事管理混乱引发问题的思考

对某基层医疗机构在药事管理工作中存在的违规问题及其原因进行分析,提出了应加大药事管理工作的监管力度,规范基层医疗机构药事管理工作行为的建议。     

Translational Regulation as a Novel Mechanism for the Development of Cellular Drug Resistance

Cellular drug resistance is one of the principal obstacles to the clinical efficacy of cancer chemotherapy. In this review, we describe the potential role for translational regulation as a novel mechanism for modulating chemosensitivity. The evidence for the translational control of thymidylate synthase, dihydrofolate reductase, and p53 will be presented, as will experimental data showing how disruptions in this important regulatory process can lead to the rapid emergence of cellular drug resistance.     

情绪调节量表的信度和效度研究

目的考察情绪调节量表的信度和效度。方法采用新近编制的情绪调节量表对5个样本共1163名大学生被试进行了测试。结果情绪调节量表具有良好的信度指标,重新评价和表达抑制维度的重测信度系数分别是0.85和0.87;5个样本和总样本两个维度的α系数和G系数均达到了0.76以上。验证性因素分析的结果显示两因子相关为自由估计的标准测量模型与实际数据的拟合程度良好（2为364.21,2/DF为4.79,NFI为0.96,NNFI为0.96,IFI为0.97,CFI为0.97,RMSEA为0.057）,两因子相关为0的独立模型与标准测量模型之间无显著差异。效标效度的研究显示5个样本和总样本两个维度的效标指数均达到了0.70以上。实证效度的研究发现男性被试在表达抑制维度上的得分要显著高于女性被试。结论情绪调节量表具有良好的心理测量学品质,值得进一步推广和应用。