The in vitro interaction of modulators of topoisomerase I and II with cisplatin in human ovarian carcinoma cells might be synergistic. The interactions were evaluated by median effect analysis of ...survival data derived from continuous exposure to drug combinations for 10 days in colony-forming assays. The interaction between cisplatin and the topoisomerase I inhibitor camptothecin and the topoisomerase I activator beta-lapachone was additive, as was that between cisplatin and the topoisomerase II inhibitor novobiocin. Despite the clinical efficacy of the combination of etoposide (a topoisomerase II inhibitor) and cisplatin, the combination index at 50% cell kill indicated antagonism between these two drugs. Thus, biochemical synergism at the cellular level is not a prerequisite of improved therapeutic efficacy.
The binding of calcitonin gene-related peptide (CGRP) to L6 myocytes, the coupling of this receptor to adenylyl cyclase and the resultant effects on insulin-stimulated 2-deoxyglucose uptake were ...examined. L6 cells express specific binding sites for CGRP. Binding of human 125ICGRP was inhibited by rat CGRP with an IC50 of approximately 10(-9) M. Synthetic human calcitonin at concentrations up to 10(-6) M had no effect on the binding of CGRP, suggesting that L6 cells express CGRP receptors, rather than calcitonin receptors which are also capable of binding CGRP. The CGRP receptor appeared to be coupled to adenylyl cyclase. Concentrations of CGRP greater than 3 x 10(-9) M increased the cellular content of cAMP. At 3 x 10(-8) M, CGRP increased cAMP 500-fold. CGRP at 10(-10) M and above suppressed the stimulation of 2-deoxyglucose uptake by insulin. Acute incubation of L6 cells with insulin stimulated 2-deoxyglucose uptake 1.6-fold, which was inhibited up to 70% by CGRP. Our results demonstrate that the specific binding of CGRP to L6 cells causes large increase in the cellular content of cAMP - and inhibition of insulin-stimulated 2-deoxyglucose uptake, but the differences in the dose-response curves suggest that the suppression of insulin action by CGRP cannot be solely explained by the increase in cAMP.
The rodent heterotopic ear–heart transplant method is a useful alternative to the more technically demanding vascularized graft technique. We modified the procedure to improve efficiency and used it ...in mice and rats to determine the survival times of both isologous and allogeneic grafts and compare reference immunosuppressants. Bisected rat and mouse cardiac (split-heart) isografts were uniformly viable up to 4 weeks postimplant; however, by 24 weeks only 90% of Lewis rat or C3H mouse split-heart isografts retained electrocardiographic activity, regressing to 81% by 60 weeks for the Lewis rat and to less than 50% for the C3H mouse by 43 weeks post-implant. The potency of tacrolimus, sirolimus, and cyclosporine for prevention of allograft rejection was comparable whether using split-hearts or whole hearts in the Balb/C to C3H mouse model. The maximally effective doses at 2 weeks postimplant for intraperitoneally administered tacrolimus, sirolimus, cyclosporine, and oral leflunomide with Brown-Norway (BN) to Lewis rat ear-split-heart allografts (0.3, 0.1, 3.0, 10, mg/kg/day, respectively) agreed extremely well with published data for the rat primary vascularized heterotopic heart model. This reproducible and efficient transplantation model was improved by using split-hearts to double available donor tissue, a gonadotropin-enhanced breeding strategy that enables routine use of low-fecundity inbred rats as donors, implantation devices that speed and simplify the procedure, and defined electrocardiographic evaluation criteria to maximize sensitivity and provide an objective endpoint for defining rejection.
During the 3 years from 1981 to 1983, 319 consecutive patients in 560 cycles were treated in a program of in vitro fertilization at Norfolk. All patients were stimulated by human menopausal ...gonadotropin supplemented by human chorionic gonadotropin. There were transfers in 429 cycles, resulting in 105 pregnancies. Over the 3-year span, the pregnancy rate by cycle was 19%; by transfer, 25%; and by patient, 33%.
The aim of this study was to investigate whether direct afferent stimulation of the abdominal vagus could promote release of the neurohypophyseal hormones. The nucleus of the solitary tract is the ...major recipient of vagal afferent information, and this region of the brainstem may also be activated by stimulation of the area postrema. For this reason apomorphine, a D2 dopaminergic agonist which acts on the area postrema, and can evoke vasopressin secretion in man, was also investigated for its effect on vasopressin and oxytocin release. Our results show that vasopressin, but not oxytocin is released in vast amounts in response to electrical afferent stimulation of the abdominal vagus. Administration of apomorphine also evoked a massive vasopressin release with less marked effects on oxytocin. The possible functional implications of these results are discussed especially in the context of nausea and vomiting.
Four groups of Wistar rats received either vehicle, quisqualate, or one of two different ibotenic acid infusions into the basal forebrain. Following recovery from surgery, all rats were tested in ...three distinct behavioral paradigms: the Bättig radial arm maze, the Barnes circular platform, and autoshaping in an operant chamber. The results showed that the size and site of the ibotenic acid lesion had a profound effect on acquisition performance in some, but not all, procedures. Performance in the Bättig maze and acquisition of a food-rewarded lever press were in particular disrupted by ibotenic acid lesions. The severity of the reduction in cortical choline acetyltransferase (ChAT) did not correlate with performance in the tests. Quisqualate produced the largest reduction in ChAT levels but had no significant effect on performance in any of the three procedures used. Anatomic analysis revealed severe nonspecific damage to the striatum following ibotenic acid that was more pronounced in the group receiving a highly concentrated solution of ibotenic acid as compared to rats infused with a greater volume but less concentrated solution of the neurotoxin. Striatal damage was much less severe following quisqualic acid infusions. However, both types of neurotoxins produced equivalent nonspecific degeneration of the reticular thalamic nucleus. These data confirm reports that nonspecific damage appears to define the severity of ibotenic acid lesions on subsequent behavioral performance.
APOGEE-2 is a high-resolution, near-infrared spectroscopic survey observing roughly 300,000 stars across the entire sky. It is the successor to APOGEE and is part of the Sloan Digital Sky Survey IV ...(SDSS-IV). APOGEE-2 is expanding upon APOGEE's goals of addressing critical questions of stellar astrophysics, stellar populations, and Galactic chemodynamical evolution using (1) an enhanced set of target types and (2) a second spectrograph at Las Campanas Observatory in Chile. APOGEE-2 is targeting red giant branch (RGB) and red clump (RC) stars, RR Lyrae, low-mass dwarf stars, young stellar objects, and numerous other Milky Way and Local Group sources across the entire sky from both hemispheres. In this paper, we describe the APOGEE-2 observational design, target selection catalogs and algorithms, and the targeting-related documentation included in the SDSS data releases.
Blood and faecal samples were analysed in a study to evaluate the use of ivermectin in red deer hinds (Cervus elaphus elaphus). It was demonstrated that ivermectin, when used at 400 micrograms/kg ...bodyweight, proved to be more efficient than 200 micrograms/kg bodyweight although positive worm egg counts together with the isolation of lungworm (Dictyocaulus species) larvae were recorded from hinds having received the anthelmintic at the higher dose.
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