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821.
822.
S. NYLANDER B. KULL J. A. BJÖRKMAN J. C. ULVINGE N. OAKES B. M. EMANUELSSON M. ANDERSSON T. SKÄRBY T. INGHARDT O. FJELLSTRÖM D. GUSTAFSSON 《Journal of thrombosis and haemostasis》2012,10(10):2127-2136
Nylander S, Kull B, Björkman JA, Ulvinge JC, Oakes N, Emanuelsson BM, Andersson M, Skärby T, Inghardt T, Fjellström O, Gustafsson D. Human target validation of phosphoinositide 3‐kinase (PI3K)β:effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor. J Thromb Haemost 2012; 10: 2127–36. See also Jackson SP, Schoenwaelder SM. Antithrombotic phosphoinositide 3‐kinase β inhibitors in humans – a ‘shear’ delight! This issue, pp 2123–6. Summary. Background: Based on in vitro and animal data, PI3Kβ is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear. Objective: To strengthen the PI3Kβ target validation using the novel, short‐acting inhibitor AZD6482. Methods and results: AZD6482 is a potent, selective and ATP competitive PI3Kβ inhibitor (IC50 0.01 μm ). A maximal anti‐platelet effect was achieved at 1 μm in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti‐thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3‐h infusion. The ex vivo anti‐platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin‐induced human adipocyte glucose uptake in vitro (IC50 of 4.4 μm ). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 μm but reduced by about 60% at a plasma exposure of 27 μm . In man, the homeostasis model analysis (HOMA) index increased by about 10–20% at the highest plasma concentration of 5.3 μm . Conclusions: This is the first human target validation for PI3Kβ inhibition as anti‐platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at ‘supratherapeutic’ plasma concentrations may attenuate insulin signaling, most likely through PI3Kα inhibition. 相似文献
823.
K. B. BJÖRKELUND A. HOMMEL K.‐G. THORNGREN L. GUSTAFSON S. LARSSON D. LUNDBERG 《Acta anaesthesiologica Scandinavica》2010,54(6):678-688
Background: There is an evident need for improved management of elderly patients with trauma in order to avoid common and troublesome complications such as delirium. The aim of this study was to investigate whether an implementation of a multi‐factorial program including intensified pre‐hospital and perioperative treatment and care could reduce the incidence of delirium in elderly patients with hip fracture, cognitively intact at admission to the hospital. In addition, we explored the factors that characterize patients who developed delirium. Methods: A prospective, quasi‐experimental design was used. A total of 263 patients with hip fracture (≥65 years), cognitively intact at admission, were consecutively included between April 2003 and April 2004. On 1 October 2003, a new program was introduced. All patients were screened for cognitive impairment within 30 min after admission to the emergency department using The Short Portable Mental Status Questionnaire (SPMSQ). To screen for delirium, patients were tested within 4 h of admission and thereafter daily, using the Organic Brain Syndrome scale. Results: The number of patients who developed delirium during hospitalization was 74 (28.1%), with a decrease from 34% (45 of 132) in the control group to 22% (29 of 131) in the intervention group (P=0.031). Patients who developed delirium were statistically older, more often had >4 prescribed drugs at admission and scored less well in the SPMSQ test. Conclusion: The use of a multi‐factorial intervention program in elderly hip fracture patients, lucid at admission, reduced the incidence of delirium during hospitalization by 35%. 相似文献
824.
Background and purpose:
Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence-type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II-III neurones in piriform cortical brain slices.Experimental approach:
Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings.Key results:
Carisbamate (50–400 µmol·L−1) reversibly decreased amplitude, duration and rise-time of evoked action potentials and inhibited repetitive firing, consistent with use-dependent Na+ channel block; 150–400 µmol·L−1 carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl− loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100–400 µmol·L−1) also selectively depressed lateral olfactory tract-afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl− conductance. Lidocaine (40–320 µmol·L−1) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 µmol·L−1) had no effect on spontaneous GABAA miniature inhibitory postsynaptic currents and at lower concentrations (50–200 µmol·L−1) inhibited Mg2+-free or 4-aminopyridine-induced seizure-like discharges.Conclusions and implications:
Carisbamate blocked evoked action potentials use-dependently, consistent with a primary action on Na+ channels and increased Cl− conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia-afferent terminals. 相似文献825.
All humans receive some radiation exposure and the risk for radiation-induced cancer at low doses is based on the assumption that there is a linear non-threshold relationship between dose and subsequent effect. Consequently, risk is extrapolated linearly from high radiation doses to very low doses. However, adaptive responses, bystander effects, and death-inducing effect may influence health effects associated with low-dose radiation exposure. Adaptive response is the phenomenon by which cells irradiated with a sublethal radiation dose can become less susceptible to subsequent high-dose radiation exposure. Bystander effects are nontargeted effects observed in cells that were not irradiated but were either in contact with or received soluble signals from irradiated cells. These non-hit bystander cells can exhibit damage typically associated with direct radiation exposure. Death-inducing effect is a phenomenon whereby medium from human-hamster hybrid cells displaying radiation-induced chromosomal instability is toxic to unirradiated parental cells. In this study, we show that human RKO cells do not exhibit adaptive response, bystander effect, or death-inducing effect, as measured by cell killing, or delayed genomic instability in a stably transfected plasmid-based green fluorescent protein assay measuring homologous recombination and delayed mutation/deletion events. However, growth medium conditioned by some chromosomally unstable RKO derivatives induced genomic instability, indicating that these cells can secrete factor(s) that elicit responses in nonirradiated cells. Furthermore, low radiation doses suppressed the induction of delayed genomic instability by a subsequent high dose, indicative of an adaptive response for radiation-induced genomic instability. These results highlight the inherent variability in cellular responses to low-dose radiation exposure and add to the uncertainties associated with evaluating potential hazards at these low doses. 相似文献
826.
目的:克隆人T-bet基因,构建其真核表达载体pEGFP-C1-T-bet。方法:实验于2005-07/2006-07在北京大学深圳医院中心实验室完成。①根据Genebank的人T-bet基因的全长cDNA序列,设计合成一对附加BglⅡ和SalⅠ两个限制性内切酶酶切位点的特异性引物。②分离人外周血单个核细胞,提取RNA,用反转录-聚合酶链反应方法将T-bet的编码序列cDNA扩增,装入pMD18-T载体并送去测序。③BglⅡ SalⅠ双酶切质粒pMD18-T-bet,经琼脂糖电泳切胶回收T-bet片段,将T-bet插入载体pEGFP-C1构建成重组真核表达载体pEGFP-C1-T-bet。④用双酶切和聚合酶链反应对插入片段进行分析和验证。结果:①反转录-聚合酶链反应产物经琼脂糖电泳结果显示在预期位置有相对分子质量为1608bp的特异性扩增带。②测序结果证实,T-bet的编码序列和Genbank中T-bet mRNA序列相同。③双酶切和聚合酶链反应结果证实插入片段序列正确。结论:实验成功扩增出人T-bet基因,构建了基因重组真核表达载体pEGFP-C1-T-bet,为探索T-bet基因对免疫细胞的调节作用和肿瘤基因治疗奠定了基础。 相似文献
827.
Carlene Tsai Luis A. Diaz Nora G. Singer Lan Lan Li Anita H. Kirsch Raj Mitra Brian J. Nickoloff Leslie J. Crofford David A. Fox 《Arthritis \u0026amp; Rheumatology》1996,39(1):125-136
Objective. Type B fibroblastic synoviocytes are abundant in inflamed joints of patients with rheumatoid arthritis (RA), and can secrete cytokines and other mediators of inflammation. The aim of this study was to determine whether cell lines derived from RA type B synoviocytes could also serve as accessory cells for T lymphocyte activation. Methods. Cells from RA synoviocyte lines, with or without preculture in interferon-γ (IFNγ), were cultured with purified peripheral blood T cells, in the presence or absence of superantigens or other accessory cell–dependent T cell mitogens. T cell proliferation was measured by thymidine incorporation, and synoviocyte surface markers were analyzed by flow cytometry. Results. RA type B synoviocyte lines were potent accessory cells for T cell responses to bacterial superantigens or lectins, and direct cell-cell contact was required. Preculture in IFNγ augmented synoviocyte expression of major histocompatibility complex (MHC) class II molecules and of ligands for some T cell costimulatory receptors, but synoviocyte accessory cell function was evident even in the absence of IFNγ. Blocking studies using monoclonal antibodies supported the notion of a role for CD2, CD11a/CD18 and MHC class II molecules in synoviocyte-dependent T cell activation. Monoclonal antibodies against IFNγ, interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor α failed to block the T cell proliferative responses, but anti–IL-2 was strongly inhibitory. Conclusion. Cultured RA type B synoviocytes can perform some of the functions of professional antigen-presenting cells. If such cells have similar properties in vivo, they may be important participants in activation of immune responses, in addition to their previously described synthetic and proinflammatory roles. If RA synovial tissue T cells, like normal peripheral blood T cells, can respond to superantigens presented by synoviocytes, this interaction could be important in the pathogenesis of RA. 相似文献