Spinal anaesthesia in the elderly.
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Aged↗
Biomedical subjects
C Brocklehurst
Publications and source records attributed to C Brocklehurst.
Monoclonal antibody SEN7 recognizes a new epitope on the neural cell adhesion molecule present on small cell lung cancer but not on lymphocytes.
In our continuing attempt to select monoclonal antibodies for immunotargeting of small cell lung carcinoma (SCLC) we have developed the IgG1 murine antibody SEN7 which by immunofluorescence stained all SCLC cell lines tested. On frozen tumor section six of seven SCLCs were positively stained. The reactivity of this antibody in a series of lung tumors and on normal tissues has some similarities with cluster 1 antibodies and cluster w4 antibodies, as defined by the First and Second International Workshop on Lung Cancer Antigens [P.C.L. Beverley, Y. Olabrian, J.A. Ledermann, L.G. Bobrow, and R.L. Souhami, Br. J. Cancer, 63 (Suppl): 10-19, 1991], particularly with regard to staining of neuroendocrine tissues. The similarities in staining of neuroendocrine tissues between antibody SEN7 and cluster 1 and cluster w4 antibodies prompted us to examine the binding of SEN7 with transfectants expressing the respective antigens. On the murine lymphoma cells B-9, stably transfected with a complementary DNA clone coding for an M(r) 140,000 isoform of human SCLC neural cell adhesion molecule (NCAM), antibody SEN7 reacted positively whereas the cluster w4 antibody was negative. The reaction of antibody SEN7 with the NCAM transfected murine lymphoma cells was unexpected in view of its lack of binding to peripheral blood mononuclear cells which regularly stain positive with NCAM antibodies. Western blotting of a renatured SCLC extract revealed a strong band around M(r) 180,000 in contrast to other cluster 1 antibodies which recognized a broad polydisperse band with a molecular weight of 140,000 to 210,000. Antibody binding was sensitive to tunicamycin treatment, suggesting the epitope to reside on an N-linked carbohydrate structure. No significant competition for SEN7 binding on SCLC cells was seen with other NCAM antibodies against the three distinct epitopes described on SCLC. This finding together with the lack of staining of peripheral blood mononuclear cells and the selected reactivity with the M(r) 180,000 band of NCAM indicate the antibody SEN7 recognizes an epitope on NCAM which has not been described previously. Biodistribution studies with radiolabeled SEN7 in nude mice bearing s.c. SCLC xenografts demonstrated the selective localization of more than 30% of the total injected dose per g tissue at day 4 following i.v. injection. The homogeneous binding to SCLC, the lack of binding to peripheral blood mononuclear cells, and the favorable tumor localization in a xenograft model indicates that SEN7 is a good antibody for immunotargeting of SCLC.
Animals↗
A distinct wave of human T cell receptor gamma/delta lymphocytes in the early fetal thymus: evidence for controlled gene rearrangement and cytokine production.
The rearrangement and expression of human T cell receptor (TCR)-gamma and -delta gene segments in clonal and polyclonal populations of early fetal and postnatal human TCR-gamma/delta thymocytes were examined. The data suggest that the TCR-gamma and -delta loci rearrange in an ordered and coordinated fashion. Initial rearrangements at the TCR-delta locus join V delta 2 to D delta 3, and initial rearrangements at the TCR-gamma locus join downstream V gamma gene segments (V gamma 1.8 and V gamma 2) to upstream J gamma gene segments associated with C gamma 1. These rearrangements are characterized by minimal junctional diversity. At later times there is a switch at the TCR-delta locus such that V delta 1 is joined to upstream D delta gene segments, and a switch at the TCR-gamma locus such that upstream V gamma gene segments are joined to downstream J gamma gene segments associated with C gamma 2. These rearrangements are characterized by extensive junctional diversity. Programmed rearrangement explains in part the origin of discrete subpopulations of peripheral blood TCR-gamma/delta lymphocytes that have been defined in previous studies. In addition, cytokine production by early fetal and postnatal TCR-gamma/delta thymocyte clones was examined. Fetal thymocyte clones produced significant levels of IL-4 and IL-5 following stimulation, whereas postnatal thymocyte clones did not produce these cytokines. Thus, these cell populations may represent functionally distinct subsets as well.
Amino Acid Sequence↗
A T cell-specific transcriptional enhancer within the human T cell receptor delta locus.
The T cell antigen receptor (TCR) delta gene is located within the TCR alpha locus. A T cell-specific transcriptional enhancer, distinct from the TCR alpha enhancer, has been identified within the J delta 3-C delta intron of the human T cell receptor delta gene. This enhancer activates transcription from the V delta 1 and V delta 3 promoters as well as from heterologous promoters. Enhancer activity has been localized to a 250-bp region that contains multiple binding sites for nuclear proteins. Thus, transcriptional control of the TCR delta and TCR alpha genes is mediated by distinct regulatory elements.
Base Sequence↗
Differential antagonism by naltrexone of the effects of opioids on a fixed-ratio discrimination in rats.
In the presence of a stimulus above the center lever, rats were required to complete one of two fixed-ratios (FRs) on the center lever (FR 8 or FR 16). Completion of the ratio turned off the center-lever stimulus and produced a stimulus above each of the two side levers. If the completed ratio was high (e.g., FR 16), a response on the left lever produced a food pellet. If the ratio was low (e.g., FR 8) a response on the right lever produced food. Errors produced a brief timeout. When administered alone, morphine, cyclazocine, pentazocine, dl-N-allylnormetazocine (NANM), d-NANM, I-NANM and phencyclidine each produced dose-related decreases in accuracy and response rate. Ketocyclazocine decreased response rate in a dose-related manner but had little or no effect on accuracy. Naltrexone (0.1 mg/kg) shifted to the right by approximately 0.75 log unit the morphine dose-effect curves. This same dose of naltrexone tended to produce greater antagonism of the effects of pentazocine on accuracy than on rate which was shifted by only 0.25 log unit. Naltrexone (0.1 mg/kg) produced little or no antagonism of the effects of cyclazocine, whereas naltrexone (1 mg/kg) shifted the dose-effect curves to the right by about 0.25 log unit. Naltrexone (0.1 and 1 mg/kg) shifted the ketocyclazocine dose-effect curves to the right by approximately 0.5 and 1 log unit, respectively. Although variable among subjects, across a range of doses (0.1-10 mg/kg), naltrexone failed to antagonize the effects of dl-NANM, d-NANM, l-NANM and phencyclidine. Rather, in some subjects naltrexone tended to shift the dose-effect curves to the left. Fluphenazine (0.1 mg/kg) also failed to antagonize the effects of d-, l-NANM and phencyclidine. In summary, whereas mu and sigma agonists produce qualitatively similar effects on the performance of a discrimination in the rat, they do so through different mechanisms of action.
Animals↗
Effects of kappa agonists and dexoxadrol on the acquisition of conditional discriminations in monkeys.
In each of two components of a multiple schedule, patas monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was conditional upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-lever responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). Dose-effect curves were determined for the kappa agonists bremazocine, tifluadom, ethylketocyclazocine and U50488H. Each drug produced dose-related decreases in overall response rate but had little or no effect on accuracy in either learning or performance. The rate-decreasing effects of ethylketocyclazocine and tifluadom were due to a dose-related pause at the start of the session, whereas those of bremazocine and U50488 were due largely to sporadic pausing throughout the session. Naltrexone blocked the effects of each drug whereas quaternary naltrexone had no effect. In contrast to the kappa agonists, dexoxadrol produced a dose-related disruption in accuracy of responding in learning. Dexoxadrol also decreased response rate in both acquisition and performance in a dose-related manner. Naltrexone attenuated the effects of low doses of dexoxadrol on accuracy, but failed to block the disruptive effects of higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Analgesics↗
Effects of mixed agonist-antagonist opioids on the acquisition of conditional discriminations in monkeys.
Responding in patas monkeys was maintained under a multiple schedule of food presentation. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-key responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). The mixed agonist-antagonists dezocine, GPA 1657 and nalbuphine each produced dose-related decreases in the overall rate of responding in each component of the multiple schedule. In general each drug produced greater rate-decreasing effects in the learning than in the performance component, although this differential effect between components was less apparent with dezocine. In the learning component low doses of nalbuphine and GPA 1657 produced small increases in percentage of errors but had little or no effect on response rate. A similar effect was obtained with dezocine in only one of four subjects tested. At doses which produced comparable rate-decreasing effects dezocine also exerted the least disruptive effect on the within-session pattern of acquisition. High doses of each drug disrupted accuracy in each component of the multiple schedule. In contrast to the other drugs tested, buprenorphine had virtually no effect on response rate or percentage of errors in either component of the multiple schedule across a wide range of doses (0.01-3.2 mg/kg). The results suggest that, among the mixed agonist-antagonist, buprenorphine is unique in that it does not disrupt the acquisition or performance of complex discrimination in patas monkeys.
Animals↗