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Human peripheral blood granulocytes previously were found to contain opioid delta 2-receptors mediating stimulation by opioid peptides of chemotaxis. Studies presented in this work indicate that granulocytes also contain opiate alkaloid-selective, opioid peptide-insensitive receptors mediating inhibition by morphine and other opiates of cytokine-induced activation and chemotaxis. Binding studies with [3H]morphine and [3H]diprenorphine ([3H]DPN) indicated the presence of receptor sites, at considerable density with affinities and selectivity for opiates comparable with those of the mu 3-receptor of human peripheral blood monocytes (macrophages). The influence of the guanosine 5'-triphosphate (GTP) analogue GppNHp on binding indicated that the granulocyte receptor was linked to a G protein. Morphine but not opioid peptides interfered with activation and/or chemotaxis of the granulocytes induced by TNF-alpha, IL-1 alpha, IL-8, and FMLP (chemotactic peptide). These effects of morphine were blocked by the antagonist naloxone. Levorphanol inhibited TNF-alpha-induced activation, and also potentiated the inhibition by morphine. Furthermore, in binding assays, levorphanol enhanced the affinity of the receptor for morphine. Dextrorphan had no effect on activation or chemotaxis, and it also had no effect on binding, indicative of stereoselectivity for the effect of levorphanol. It is concluded that human granulocytes contain opiate alkaloid-selective mu 3-receptors that mediate inhibitory effects of morphine on cellular activation by cytokines. 相似文献
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It has been shown that tilt and exercise elicit significant changes in autonomic activity in normal subjects and that submaximal exercise causes a greater reduction in heart rate variability (HRV) in animals susceptible to ventricular fibrillation (VF). Whether there is an abnormal HRV response to tilt and exercise in patients at risk of sudden cardiac death (SCD) remains unknown. Short-term HRV before and during passive tilt and exercise was studied in 12 survivors of out-of-hospital cardiac arrest with documented VF and compared with 12 age- and sex-matched normal controls. No patient had significant structural heart disease or left ventricular dysfunction. HRV was computed as total-frequency (TF, 0.01 to 1.00 Hz), low-frequency (LF, 0.04 to 0.15 Hz) and high-frequency (HF, 0.15 to 0.40 Hz) components. There was no significant difference between normal controls and SCD survivors in HRV before or during tilt or submaximal exercise testing. The HF component was significantly decreased during tilt compared with that in the supine position in both normal controls (5.85 +/- 0.61 vs 5.08 +/- 0.95 In(msec2), p = 0.005) and patients (5.58 +/- 1.49 versus 4.74 +/- 1.18 In(msec2), p = 0.003). There was again no significant change in the TF or LF components during tilt in either patients or controls. All frequency components were significantly decreased during submaximal exercise testing in both patients and controls. However, there was no significant difference in any of these tilt- and exercise-induced changes in HRV between normal controls and SCD survivors.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process. 相似文献
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A retrospective cross-sectional cephalometric investigation was undertaken to examine the facial form of a group of Finnish children with juvenile chronic arthritis (JCA). Following digitization, the radiographs were divided into three age groups, and according to whether or not 'bird-face' deformity was present. From a total of 67 cases (39 females and 28 males) 19 per cent were judged to be 'affected'. Analyses were carried out and the groups compared using t-tests. The mandible was found to be smaller both in ramal height and body length in the affected sample, with reduction in posterior face height being only partly compensated by increase in bony apposition at the angle producing antegonial notching. There was posterior rotation of the mandible with a reduction in angles S-N-B and S-N-Pog, and an increase in the gonial angle, the angle between the mandibular plane and S-N, maxillary, and occlusal planes. The changes in the maxilla were less marked. Although S-N-A was reduced in all three age groups, it was not significantly so. Maxillary length (ANS-PNS) was significantly smaller in the two younger age groups. In the vertical plane maxillary dimensions were reduced in the two younger age groups. A highly significant increase in the occlusal to maxillary planes angle was observed in all groups. There was, however, no difference in S-N to maxillary planes angle, indicating a more steeply inclined occlusal plane due to subnormally erupted maxillary molars. Although the inter-incisal angle was reduced there was no significant difference in the incisor inclinations in relation to the jaws and despite the posterior rotation of the mandible there was no significant increase in size of overjet or in the frequency of anterior open bite. 相似文献
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Y Munakata JL McClelland MH Johnson RS Siegler 《Canadian Metallurgical Quarterly》1997,104(4):686-713
Infants seem sensitive to hidden objects in habituation tasks at 3.5 months but fail to retrieve hidden objects until 8 months. The authors first consider principle-based accounts of these successes and failures, in which early successes imply knowledge of principles and failures are attributed to ancillary deficits. One account is that infants younger than 8 months have the object permanence principle but lack means-ends abilities. To test this, 7-month-olds were trained on means-ends behaviors and were tested on retrieval of visible and occluded toys. Means-ends demands were the same, yet infants made more toy-guided retrievals in the visible case. The authors offer an adaptive process account in which knowledge is graded and embedded in specific behavioral processes. Simulation models that learn gradually to represent occluded objects show how this approach can account for success and failure in object permanence tasks without assuming principles and ancillary deficits. 相似文献
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