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Notes: β-Adrenergic receptor subtypes, β1 and β2, were studied during pre-and postnatal development in the rat brain. [125I]Iodocyanopindolol (6–300 pmol/L) binding assays in the presence of 5-hydroxytryptamine (0.6–6 μmol/L) were used to measure exclusively β-adrenergic receptors. In forebrain tissue, saturable and stereoselective binding was detected on gestational day 13. The amount of β-adrenergic binding increased until postnatal day 23, when adult values were reached. The dissociation constants of [125I]iodocyanopindolol binding remained the same throughout development, as did the affinity of several β-adrenergic and non-β-adrenergic compounds. The proportion of the β2-adrenergic receptors was determined using the β1-selective antagonist ICI-89406 (7–150 nmol/L) and was found to change from 65% in prenatal forebrain tissue to 28% in adulthood. In cerebellum/medulla pons tissue, however, the proportion of β2-receptor binding (80%) remained unchanged during the whole developmental period.

Notes: Chronic suppression of spontaneously occurring bioelectric activity (BEA) has been shown to increase neuronal cell death in tissue culture, but may also affect astrocytes. We investigated this process in primary cultures of rat cerebral cortex by measuring the levels of NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) in relation to general tissue markers, including measurements for cell death and proliferation. In electrically active (control) cultures, the content of DNA, protein, and NSE became maximal between 21 and 28 days in vitro (DIV) and thereafter decreased, whereas the content of GFAP rose continuously up to 43 DIV. Chronic suppression of BEA by tetrodotoxin (TTX; from 6 DIV) decreased the content of DNA, total protein, and especially NSE. The content of GFAP was decreased in all culture series investigated, but with great temporal variations among culture series. Chronic TTX treatment (started at 6 DIV) increased the efflux of lactate dehydrogenase, a marker for cell lysis, between 12 and 21 DIV, but this efflux was mainly derived from the supporting glial cells with which the cerebral cortex cultures were cocultured. Chronic, but not acute (7 h) TTX treatment decreased total [3H]thymidine incorporation into DNA from 14 DIV; this appeared to be due to a reduced number of astrocytes. Chronic suppression of BEA with xylocaine from 6 DIV had similar effects on DNA-, protein-, and NSE-content as TTX, but led to an increased content of GFAP at 21 DIV. Chronic suppression of synaptic transmission with 10 mM Mg2+ and 0.2 mM Ca2+, starting at 6 DIV, increased the content of DNA, protein, and GFAP at 21 DIV, but NSE was still decreased. We conclude that chronic suppression of BEA in cerebral cortex cultures enhances neuronal cell death, whereas astrocytes are differentially affected, depending on the suppressing agent. As astrocytes may have a modulating effect on neuronal survival, their involvement should be regarded when studying the effects of chronic suppression of BEA on neuronal development.

Notes: In contrast to the acute toxic effect of NMDA on mature cerebellar granule cells, chronic treatment with NMDA (140 μM from 1 to 9 days in vitro) did not compromise cell survival. Such treatment markedly suppressed NMDA receptor activity: at 8 days in vitro NMDA-induced 45Ca2+ influx was reduced by -60% and acute exposure to NMDA (highest concentration tested, 1 mM) at 9 days in vitro did not cause detectable toxicity. The reduction in NMDA receptor activity was accompanied by a significant decrease (±80% at 9 days in vitro) in the level of the NR1 and the NR2A NMDA receptor subunit protein, detected using the selective photoaffinity ligand [125I]CGP55802A. It seems, therefore, that the agonist-induced decrease in NMDA receptor activity is due to receptor down-regulation. In contrast to the marked influence of chronic NMDA exposure on the cellular content of the NMDA receptor subunit proteins, mRNA levels of the different subunits (NR1, NR2A, NR2B and NR2C) were not significantly affected. It seems, therefore, that agonist-induced down-regulation of the NMDA receptor involves critically mRNA translation and/or post-translational regulation.

Notes: The anatomy of haemopoietic cells in human fetal liver was examined using immunohistological techniques on frozen sections of 31 fetuses (10–28 weeks gestational age). The immunohistological findings were consistent with reported cell suspension data. With regard to the location of haemopoietic activity no particular relationship existed between the various haemopoietic cell lineages. A large number of proliferating cells was present; only a few of these were reactive with haemopoietic progenitor cell monoclonal antibodies (MoAb) CD34. A population of haemopoietic cells expressed CD43 antigen (MoAb MTI) alone or together with anti-vimentin MoAb reactivity; this population needs further delineation. Erythropoiesis and myelopoiesis occurred in clusters around sinusoids and portal triad vessels respectively. Lack of MoAb reacting exclusively with early developmental stages of erythropoiesis and myelopoiesis precluded dissection of these lineages. Lymphopoiesis occurred in a loosely scattered pattern without any sign of focal development. Pre-B and B-cell numbers increased with gestational age. Cells expressing markers of more mature B cells (surface IgD, CD35, and CD21) were rare. Also, few cells reacted with mature T-cell markers, but CD7+ cells were obviously present. This expression of CD7 on haemopoietic fetal liver cells suggests that T-cell precursors develop in fetal liver as well as B cells.

Notes: Abstract Purpose: We studied vincristine disposition after 169 weekly i.v. bolus injections in 32 children with acute lymphoblastic leukemia, non-Hodgkin lymphoma, or Wilms' tumor. The aim of the study was to determine intrapatient and interpatient variability in vincristine disposition and demographic, clinical, and biochemical characteristics influencing this variability. Methods: Vincristine plasma concentrations were measured by a high-performance liquid chromatography assay with electrochemical detection. A limited sampling strategy was used based on a bayesian parameter estimation algorithm that is part of the ADAPT II software package. A two-compartment, first-order model was fitted to the data, and pharmacokinetic parameters were calculated from the model using the ADAPT II software. For statistical analysis, analysis of variance (ANOVA), t test, simple and multiple regression analysis, and non-parametric or robust equivalents were used. Results: Results showed a large intrapatient and interpatient variability in distribution half-life, elimination half-life, total body clearance, apparent volume of distribution at steady state, and area under the concentration–time curve. Intrapatient variability was significantly smaller than interpatient variability for all these parameters except distribution half-life. The diagnosis or treatment protocol turned out to be the most predictive characteristic; leukemia and non-Hodgkin lymphoma patients had a significantly higher total body clearance than Wilms' tumor patients. Conclusions: We conclude that both intrapatient and interpatient variability in vincristine pharmacokinetics is large in pediatric cancer patients and that variability, although significantly influenced by diagnosis, largely remains unpredictable.

Notes: Abstract.  Atmospheric general circulation models (GCMs) are characterized by many features but especially by: (1) the manner of discretizing the governing equations and of representing the variables involved at a given resolution, and (2) the manner of parameterizing unresolved physical processes in terms of those resolved variables. These two aspects of model formulation are not independent and it is difficult to untangle their intertwined effects when assessing model performance. The attempt here is to separate these aspects of GCM behaviour and to ask, “Given a perfect parameterization of the physical processes in a model, what resolution is needed to capture the dominant dynamical aspects of the atmospheric climate?” Alternatively, “At what resolution do the dynamics of a GCM converge”? The perfect parameterization approach assumes that the calculation of the physical terms returns the “correct” result at all resolutions. In the idealized case, a time-independent forcing is one of the simplest that satisfies this condition. However, experiments show that it is difficult for the dynamics of a GCM to balance a time-independent forcing with atmosphere-like flows and structures. The model requires, and the atmosphere presumably includes, physical feedback mechanisms which act so as to maintain the kinds of flows and structures that are observed. Resolution experiments are performed with a simplified forcing function for the thermodynamic equation which combines a dominant time-independent specified forcing with a weak linear relaxation feedback. These experiments show that the dynamics of the GCM have essentially converged at T32 and certainly by T63 which is the next resolution considered. This is shown by the constancy of structures, variances, covariances, transports and energy budgets with increasing resolution. Experiments with an alternative forcing proposed by Held and Suarez, which has the form of a linear relaxation, show somewhat less evidence of convergence at these resolutions. In both cases the “physics” are known by assumption. However, the form and nature of the forcing is different, as is the behaviour with resolution. The implication for the real system is that the resolution required for simulating the dynamical aspects of climate is rather modest. The simulated climate does, however, apparently depend on the ability to correctly and consistently parameterize the physical processes in a GCM, involving both forcing and feedback mechanisms, as a function of resolution.

Notes: Abstract  A global, three-dimensional climate model, developed by coupling the CCCma second-generation atmospheric general circulation model (GCM2) to a version of the GFDL modular ocean model (MOM1), forms the basis for extended simulations of past, current and projected future climate. The spin-up and coupling procedures are described, as is the resulting climate based on a 200 year model simulation with constant atmospheric composition and external forcing. The simulated climate is systematically compared to available observations in terms of mean climate quantities and their spatial patterns, temporal variability, and regional behavior. Such comparison demonstrates a generally successful reproduction of the broad features of mean climate quantities, albeit with local discrepancies. Variability is generally well-simulated over land, but somewhat underestimated in the tropical ocean and the extratropical storm-track regions. The modelled climate state shows only small trends, indicating a reasonable level of balance at the surface, which is achieved in part by the use of heat and freshwater flux adjustments. The control simulation provides a basis against which to compare simulated climate change due to historical and projected greenhouse gas and aerosol forcing as described in companion publications.

Notes: Abstract  The potential climatic consequences of increasing atmospheric greenhouse gas (GHG) concentration and sulfate aerosol loading are investigated for the years 1900 to 2100 based on five simulations with the CCCma coupled climate model. The five simulations comprise a control experiment without change in GHG or aerosol amount, three independent simulations with increasing GHG and aerosol forcing, and a simulation with increasing GHG forcing only. Climate warming accelerates from the present with global mean temperatures simulated to increase by 1.7 °C to the year 2050 and by a further 2.7 °C by the year 2100. The warming is non-uniform as to hemisphere, season, and underlying surface. Changes in interannual variability of temperature show considerable structure and seasonal dependence. The effect of the comparatively localized negative radiative forcing associated with the aerosol is to retard and reduce the warming by about 0.9 °C at 2050 and 1.2 °C at 2100. Its primary effect on temperature is to counteract the global pattern of GHG-induced warming and only secondarily to affect local temperatures suggesting that the first order transient climate response of the system is determined by feedback processes and only secondarily by the local pattern of radiative forcing. The warming is accompanied by a more active hydrological cycle with increases in precipitation and evaporation rates that are delayed by comparison with temperature increases. There is an “El Nino-like” shift in precipitation and an overall increase in the interannual variability of precipitation. The effect of the aerosol forcing is again primarily to delay and counteract the GHG-induced increase. Decreases in soil moisture are common but regionally dependent and interannual variability changes show considerable structure. Snow cover and sea-ice retreat. A PNA-like anomaly in mean sea-level pressure with an enhanced Aleutian low in northern winter is associated with the tropical shift in precipitation regime. The interannual variability of mean sea-level pressure generally decreases with largest decreases in the tropical Indian ocean region. Changes to the ocean thermal structure are associated with a spin-down of the Atlantic thermohaline circulation together with a decrease in its variability. The effect of aerosol forcing, although modest, differs from that for most other quantities in that it does not act primarily to counteract the GHG forcing effect. The barotropic stream function in the ocean exhibits modest change in the north Pacific but accelerating changes in much of the Southern Ocean and particularly in the north Atlantic where the gyre spins down in conjunction with the decrease in the thermohaline circulation. The results differ in non-trivial ways from earlier equilibrium 2 × CO2 results with the CCCma model as a consequence of the coupling to a fully three-dimensional ocean model and the evolving nature of the forcing.