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991.
Chen W Yang JZ Andersen R Nielsen LH Borchardt RT 《The Journal of pharmacology and experimental therapeutics》2002,303(2):849-857
The permeation characteristics of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs [acyloxyalkoxy-based cyclic prodrug of DADLE (AOA-DADLE), coumarinic acid-based cyclic prodrug of DADLE (CA-DALE), and oxymethyl-modified coumarinic acid-based cyclic prodrug of DADLE (OMCA-DADLE)] across the blood-brain barrier (BBB) were determined using an in situ perfused rat brain model. The rat brains were perfused with Krebs-bicarbonate buffer containing test compounds in the absence or presence of a specific P-glycoprotein inhibitor (GF-120918). Brain samples were collected after perfusion and processed by a capillary depletion method. After liquid phase extraction with acetonitrile, samples were analyzed using high-performance liquid chromatography with tandem mass spectrometric detection. Linear uptake kinetics of DADLE and its cyclic prodrugs was observed within the range of 60 to 240 s of perfusion. The apparent permeability coefficient (P(app)) of DADLE across the BBB was very low (<10(-7) cm/s), probably due to its unfavorable physicochemical properties (e.g., charge, hydrophilicity, and high hydrogen-bonding potential). All three cyclic prodrugs, however, also exhibited low membrane permeation (P(app) <10(-7) cm/s) in spite of their more favorable physicochemical properties (e.g., no charge, high hydrophobicity, and low hydrogen-bonding potential). Inclusion of GF-120918 (10 microM) in the perfusates fully inhibited the P-gp activity in the BBB and dramatically increased the P(app) values of AOA-DADLE, CA-DADLE, and OMCA-DADLE by approximately 50-, 460-, and 170-fold, respectively. In contrast, GF-120918 had no effect on the P(app) value of DADLE. In addition, the observed bioconversions of the prodrugs to DADLE in the rat brains after 240-s perfusion were very low (5.1% from AOA-DADLE, 0.6% from CA-DADLE, and 0.2% from OMCA-DADLE), which was consistent with the in vitro bioconversion rates determined previously in rat brain homogenates. 相似文献
992.
993.
The effect of purified human plasma fibronectin (FN) on the reactivity of human lymphocyte-rich mononuclear cells to mitogens and allogeneic cell interactions was studied. Concentrations of FN from 25 to 100 micrograms per 250 microL of culture consistently depressed phytohemagglutinin (PHA) responses. To exert an inhibitory effect, FN must be present within 20 hours after the addition of PHA to cells, and, therefore, it appears to interfere with early events in the transformation process. Increasing the concentration of PHA failed to reduce the inhibitory effect of FN, which suggests that the depressed response was not the result of FN-PHA complex formation, which would reduce the amount of mitogen available for stimulation. This possibility was supported by the finding that FN also inhibited the mixed lymphocyte response (MLR), in a reaction that was not dependent on the activity of soluble antigen or mitogen. In contrast, the stimulation of lymphocytes to undergo transformation that is induced by the nonlectin mitogen, sodium periodate, was unaffected by FN. Periodate-treated cells are, however, already stimulated to undergo transformation, prior to their exposure to FN. FN did not interfere with the activity of interleukin-2, nor did it indirectly regulate lymphocyte responses by modifying the production and/or effect of humoral regulatory factors released from the adherent accessory cells (macrophages). These studies show that FN is a potent immunosuppressive agent in vitro. 相似文献
994.
人白细胞介素24mRNA在瘢痕疙瘩中的表达及意义 总被引:1,自引:0,他引:1
目的:从基因水平测量瘢痕疙瘩组织中白细胞介素24的表达水平,探讨白细胞介素24在瘢痕疙瘩发生、发展过程中的作用和意义。方法:实验于2005-10/2006-09在广东医学院整形外科研究所完成。①选取2004-06/2005-10广东医学院附属医院整形外科收治的患者,瘢痕疙瘩标本12例,正常瘢痕标本10例,行巨乳缩小、除皱术、植皮等患者正常皮肤标本12例,患者均知情同意且自愿捐献标本,实验经医学伦理委员会批准。标本取材部位为颜面、前胸、四肢等,切取后液氮保存。②低温条件下切取秤量组织,采用Trizol法提取总RNA。电泳鉴定总RNA完整性,并统一调整总RNA含量为10g/L,-70℃储存。RT-PCR二步法合成cDNA。③以正常皮肤、正常瘢痕为对照,以GAPDH作为扩增内参照基因,将正常皮肤、正常瘢痕和瘢痕疙瘩各类标本总RNA反转录的cDNA模板浓度调整相对一致进行扩增反应。以白细胞介素24mRNA与GAPDHmRNA的光密度积分值之比作为各类组织标本中白细胞介素24的相对含量,比较白细胞介素24mRNA在正常皮肤、正常瘢痕及瘢痕疙瘩组织中的表达情况。结果:①各类组织标本中总RNA抽提结果:正常皮肤、正常瘢痕和瘢痕疙瘩组织中抽提总RNA经甲醛变性凝胶电泳后显示较清晰的18s和28s条带,经紫外分光光度计测定A260/A280≈2.0。②各类组织标本中白细胞介素24mRNA的表达:白细胞介素24和GAPDH基因表达产物通过RT-PCR方法得到的特异性DNA片段长度分别为173bp和577bp。瘢痕疙瘩的白细胞介素24mRNA与GAPDHmRNA的吸光度比值明显低于正常皮肤、正常瘢痕(0.577±0.113,1.070±0.185,1.139±0.195;t=7.436×10-8~4.745×10-8,P均<0.01),正常皮肤与正常瘢痕白细胞介素24mRNA的相对表达量基本一致(t=0.405,P>0.05)。结论:瘢痕疙瘩的形成可能与白细胞介素24在组织中的表达降低有关。提示采用基因疗法提高早期瘢痕疙瘩中白细胞介素24的含量与活性,可能为瘢痕疙瘩的康复治疗提供有效途径。 相似文献
995.
Høilund-Carlsen PF Marving J Gadsbøll N Rasmussen S Lønborg-Jensen H Nielsen MD Christensen NJ Jensen BH 《Clinical physiology and functional imaging》2004,24(4):216-223
Systolic left ventricular function was examined by radionuclide ventriculography in 12 habitual smokers with known or suspected ischaemic heart disease, aged 33-69 years, before, during, and after smoking of two cigarettes in a row and was repeated on a non-smoking control day. Plasma concentrations of adrenaline, noradrenaline, renin, and angiotensin II were determined on the smoking day, before and immediately after smoking. During smoking, there were significant increases in heart rate (+27%), rate-pressure product (+23%), and cardiac output (+14%) in the face of a significant increase in left ventricular end-systolic volume (+5%) and significant decreases in ejection fraction (-6%) and stroke volume (-8%). Blood pressure was virtually unchanged, and total peripheral resistance remained constant. Plasma adrenaline increased by 100%, renin decreased by 21%, and noradrenaline and angiotensin II did not change. The humoral changes were not correlated to changes in any of the haemodynamic variables. Areas of myocardial hypokinesis emerged or widened during smoking in 11 of 12 patients. Thus, in patients with known or suspected ischaemic heart disease, smoking was associated with an acute decrease in systolic ventricular function and development of widespread hypokinesis despite adrenaline stimulation. 相似文献
996.
P. Madsen F. Lyck M. Pedersen H. L. Olesen H. Bay Nielsen N. H. Secher 《Clinical physiology and functional imaging》1995,15(5):523-533
Summary. Near-infrared spectrophotometry-determined cerebral (ScO2) and muscle oxygen saturations (SmO2) were followed in 15 volunteers during passive 50° head-up-tilt-induced central hypovolaemia, and in nine volunteers during ventilatory manoeuvres affecting arterial carbon dioxide tension. During head-up tilt, mean arterial pressure [MAP, 88 (77–118) to 97 (80–136) mmHg, median and range] and heart rate [HR; 66 (49–77) to 87 (42–132) beats min-1 P<0.01] increased, but after 22 (1–45) min they declined [to 61 (40–91) mmHg and 69 (38–109) beats min-1, respectively, P=0.001] and pre-syncopal symptoms developed. Central hypovolaemia was indicated by an increased thoracic electrical impedance, and a decreased cardiac output and central venous oxygen saturation. The arterial oxygen saturation, pulmonal oxygen uptake and skin temperatures remained constant. The ScO2 remained stable at 72 (62–77)% until the pre-syncopal incidence, when it decreased to 62 (31–73)% (P=0–001), and tilt down made it increase to 75 (36–87)% (P<0.05) before the recovery value was established. In contrast, SmO2 decreased during tilting [75 (70–87) to 65 (53–70)%], and recovered to 70 (53–83)%, P<0.01) during the hypotensive episode. The end-tidal CO2 tension decreased only during tilt-up. The ScO2 decreased, and SmO2 increased during hyperventilation, and ScO2 increased during breathing of 5% carbon dioxide. Rebreathing from a bag made SmO2 decrease and resulted in a biphasic ScO2 response: it first increased and subsequently decreased. Cardiovascular changes during tilt were not reflected in skin temperature. The ScO2 reflected the maintained autoregulation of cerebral blood flow until the perfusion pressure decreased markedly. In contrast, SmO2 mirrored muscle vasoconstriction early during tilt, and vasodilatation when pre-syncopal symptoms appeared. 相似文献
997.
Per Hildebrandt Jesper Mehlsen Leif Sestoft Steen Levin Nielsen 《Clinical physiology and functional imaging》1985,5(4):371-376
Summary. A TV-game of tennis of 20 min duration was used to study the influence of mild mental stress on subcutaneous blood-flow (SBF), blood-pressure and heart rate in nine insulin-dependent diabetics and nine healthy subjects. SBF was measured on the thigh by local clearance of xenon-133. Measurements were made before, during and after the period of stress. During stress, SBF increased significantly by 26% in the healthy subjects, while SBF remained unchanged in the diabetics. The difference between the two groups was significant (P<0–05). Following stress, SBF returned to pre-stress level in the healthy subjects, while a significant decrease of 33% was observed in the diabetics. The pre-stress heart rate level was higher and the stress-induced increase in heart rate was less in the diabetics compared with the healthy subjects (P<005). During the stress a slight–but insignificant–increase in blood-pressure was observed in both groups. In conclusion, we found that even mild mental strain influences SBF in both normal subjects and in diabetics. The induced alterations in the two groups are different, probably because of a slight parasympathetic dysfunction in the diabetics. 相似文献
998.
H Nielsen F V Mortensen H K Pilegaard J M Hasenkam M J Mulvany 《The Journal of pharmacology and experimental therapeutics》1992,260(2):637-643
Human s.c. resistance arteries (internal diameters 158-353 microns) were mounted in a microvascular myograph, and experiments were designed to examine the calcium pools utilized by selective stimulation of alpha-1 and alpha-2 adrenoceptors. In a concentration-dependent manner, phenylephrine and B-HT 933 evoked contractions mediated by alpha-1 and alpha-2 adrenoceptors, respectively, both in calcium-containing and in calcium-free saline. With respect to the maximum response to potassium in calcium-containing saline, the maximum responses to phenylephrine and B-HT 933 were 96 +/- 6 and 85 +/- 8%, respectively, in calcium-containing saline, and 79 +/- 4 and 14 +/- 2%, respectively, in calcium-free saline. A qualitatively similar difference in maximum responses to alpha-1 vs. alpha-2 adrenoceptor stimulation in calcium-free saline was demonstrated for norepinephrine in the presence of antagonists selective for the two alpha adrenoceptor subtypes. The maximum relaxation in calcium-containing saline produced by the calcium antagonist nitrendipine was 52 +/- 3% in vessels precontracted with phenylephrine, but 80 +/- 5% in vessels precontracted with B-HT 933. A quantitative difference in receptor reserves was demonstrated between alpha-1 and alpha-2 adrenoceptors; 90% of the maximum response was obtained at 34 +/- 5 and 57 +/- 8% receptor occupation, respectively. These data suggest that compared to responses mediated by stimulation of postjunctional alpha-1 adrenoceptors, stimulation of postjunctional alpha-2 adrenoceptors relies heavily on calcium influx. Stimulation of postjunctional alpha-2 adrenoceptors is, however, also coupled to intracellular release of calcium in isolated human s.c. resistance arteries. 相似文献
999.
Plasma citrate was determined in seven subjects working 45 min at 50-60% of their maximal aerobic power and in six subjects who were exercised intermittently for five periods of 1 min at supramaximal work loads. Determinations of plasma lactate, glucose, free fatty acids and insulin were carried out simultaneously. During submaximal work the mean plasma citrate concentration decreased from 116 +/- 4 mumol/1 at rest to 108 +/- 5 mumol/1 after 10 min exercise (P less than 0.05) and increased above resting level to 136 +/- 5 mumol/1 40 min after cessation of work (P less than 0.05). During intermittent supramaximal exercise, mean plasma citrate concentration rose after the third work period and during recovery from 117 +/- 6 mumol/1 at rest to 181 +/- 9 mumol/1 40 min after last work period (P less than 0.05). Plasma citrate varied similarly to variations in plasma free fatty acids and inversely to changes of lactate concentrations during submaximal exercise. Opposite interrelationships were demonstrated during intermittent supramaximal exercise. Plasma citrate concentration varied in the same way as might be expected for changes in cytosolic citrate levels of muscle from in vitro knowledge of the regulatory role of citrate on glucose oxidation. 相似文献
1000.
Paul M Nielsen AD Goldberg E Andreassen S Tacconelli E Almanasreh N Frank U Cauda R Leibovici L;TREAT Study Group 《The Journal of antimicrobial chemotherapy》2007,59(6):1204-1207
BACKGROUND: Prediction of bacterial infections and their pathogens allows for early, directed investigation and treatment. We assessed the ability of TREAT, a computerized decision support system, to predict specific pathogens. METHODS: TREAT uses data available within the first few hours of infection presentation in a causal probabilistic network to predict sites of infection and specific pathogens. We included 3529 patients (920 with microbiologically documented infections) participating in the observational and interventional trials of the TREAT system in Israel, Germany and Italy. Discriminatory performance of TREAT to predict individual pathogens was expressed by the AUC with 95% confidence intervals. Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit statistic. RESULTS: The AUCs for Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. and Escherichia coli, ranged between 0.70 and 0.80 (all significant). Adequate calibration was demonstrated for any Gram-negative infection and individual bacteria, except for E. coli. Discrimination and calibration were acceptable for Enterococcus spp. (AUC 0.71, 0.65-0.78), but not for Staphylococcus aureus (AUC 0.63, 0.55-0.71). The few infections caused by Candida spp. and Clostridium difficile were well predicted (AUCs 0.74, 0.54-0.95; and 0.94, 0.88-1.00, respectively). The coverage with TREAT's recommendation exceeded that observed with physicians' treatment for all pathogens, except Candida spp. CONCLUSIONS: TREAT predicted individual pathogens causing infection well. Prediction of S. aureus was inferior to that observed with other pathogens. TREAT can be used to triage patients by the risk for specific pathogens. The system's predictions enable it to prescribe appropriate antibiotic treatment prior to pathogen identification. 相似文献