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The pseudokinase, MLKL (mixed-lineage kinase domain-like), is the most terminal obligatory component of the necroptosis cell death pathway known. Phosphorylation of the MLKL pseudokinase domain by the protein kinase, receptor interacting protein kinase-3 (RIPK3), is known to be the key step in MLKL activation. This phosphorylation event is believed to trigger a molecular switch, leading to exposure of the N-terminal four-helix bundle (4HB) domain of MLKL, its oligomerization, membrane translocation and ultimately cell death. To examine how well this process is evolutionarily conserved, we analysed the function of MLKL orthologues. Surprisingly, and unlike their mouse, horse and frog counterparts, human, chicken and stickleback 4HB domains were unable to induce cell death when expressed in murine fibroblasts. Forced dimerization of the human MLKL 4HB domain overcame this defect and triggered cell death in human and mouse cell lines. Furthermore, recombinant proteins from mouse, frog, human and chicken MLKL, all of which contained a 4HB domain, permeabilized liposomes, and were most effective on those designed to mimic plasma membrane composition. These studies demonstrate that the membrane-permeabilization function of the 4HB domain is evolutionarily conserved, but reveal that execution of necroptotic death by it relies on additional factors that are poorly conserved even among closely related species.

This study presents an approach to provide seamless climate information by concatenating decadal climate predictions and climate projections in time. Results for near‐surface air temperature over 29 regions indicate that such an approach has potential to provide meaningful information but can also introduce significant inconsistencies. Inconsistencies are often most pronounced for relatively extreme quantiles of the CMIP6 multi‐model ensemble distribution, whereas they are generally smaller and mostly insignificant for quantiles close to the median. The regions most affected are the North Atlantic, Greenland and Northern Europe. Two potential ways to reduce inconsistencies are discussed, including a simple calibration method and a weighting approach based on model performance. Calibration generally reduces inconsistencies but does not eliminate all of them. The impact of model weighting is minor, which is found to be linked to the small size of the decadal climate prediction ensemble, which in turn limits the applicability of that method. Continuous and consistent information about the evolution of climate in next 1–40 years is crucial for the development of mitigation and adaptation strategies. Historically, scientific products providing weather and climate information have been designed for specific time scales, for example, seasonal or decadal climate predictions (1–10 years), or long‐term climate projections (1–100 + years). As a consequence, currently only climate projections can be used to provide continuous information beyond the 10 years time scale. However, as climate projections are not initialized using observations, they are likely – depending on the variable and region – less skillful than initialized predictions for shorter lead times. In this study we assess if meaningful continuous climate information can be obtained by concatenating decadal climate predictions and climate projections in time. Results suggest that significant inconsistencies (materialized in jumpsin the resulting time series) can be introduced by this approach, however, for some regions temporal concatenation might provide meaningful climate information beyond decadal time scales. Furthermore, potential ways to reduce inconsistencies when concatenating are discussed. Concatenating climate predictions and projections can introduce inconsistenciesConcatenation is less problematic for quantiles close to the median compared to more extreme quantiles of the ensemble distributionA simple calibration method reduces but does not eliminate inconsistencies Concatenating climate predictions and projections can introduce inconsistencies Concatenation is less problematic for quantiles close to the median compared to more extreme quantiles of the ensemble distribution A simple calibration method reduces but does not eliminate inconsistencies

Alcohol and drug abuse continue to be a major public health problem in the United States and other industrialized nations. Extensive preclinical research indicates the mesolimbic dopamine (DA) pathway and associated regions mediate the rewarding and reinforcing effects of drugs of abuse and natural rewards, such as food and sex. The serotonergic (5-HT) system, in concert with others neurotransmitter systems, plays a key role in modulating neuronal systems within the mesolimbic pathway. A substantial portion of this modulation is mediated by activity at the 5-HT3 receptor. The 5- HT3 receptor is unique among the 5-HT receptors in that it directly gates an ion channel inducing rapid depolarization that, in turn, causes the release of neurotransmitters and/or peptides. Preclinical findings indicate that antagonism of the 5- HT3 receptor in the ventral tegmental area, nucleus accumbens or amygdala reduces alcohol self-administration and/or alcohol- associated effects. Less is known about the effects of 5-HT3 receptor activity on the self-administration of other drugs of abuse or their associated effects. Clinical findings parallel the preclinical findings such that antagonism of the 5- HT3 receptor reduces alcohol consumption and some of its subjective effects. This review provides an overview of the structure, function, and pharmacology of 5-HT3 receptors, the role of these receptors in regulating DA neurotransmission in mesolimbic brain areas, and discusses data from animal and human studies implicating 5-HT3 receptors as targets for the development of new pharmacological agents to treat addictions.

Over the past five years, significant new evidence has documented the link between eating breakfast and learning. Recent studies show that skipping breakfast is relatively common among children in the U.S. and other industrialized nations and is associated with quantifiable negative consequences for academic, cognitive, health, and mental health functioning. When combined with new data on the prevalence and impact of hunger/food insecurity, the preponderance of recent evidence is that lack of optimal nutrition is a problem for millions of U.S. students and that increased breakfast eating could be part of a solution. Literature reviews published in the late 1990s set the stage for understanding this new evidence by showing the associations between regular breakfast consumption/skipping and student outcomes. Research over the past five years has provided new evidence for these associations and definitive evidence for others: most notably that universally free school breakfast programs increase the rate of overall-breakfast eating and are judged to improve learning by teachers and school principals. These findings, along with accumulating evidence for the danger of nutritional risks, provide a clear rationale for continued efforts to promote breakfast eating for children, schools, and the nation as a whole.

Background: The behavioral effects of neuropeptide Y (NPY) attributed to its actions in the hypothalamus are complex and include effects on feeding, sedation, and the hypothalamic‐pituitary‐adrenal axis. NPY infused into the paraventricular nucleus (PVN) increases ethanol intake in unselected rats. High‐alcohol‐drinking (HAD1) and low‐alcohol‐drinking (LAD1) rats differ in basal NPY levels in the PVN, and HAD1, but not LAD1, rats exhibit decreases in ethanol intake after infusion of NPY into the ventricles. This study examined whether NPY infused into the PVN alters ethanol intake in HAD1 and LAD1 rats.

Abstract: Background: The low‐dose stimulatory effect of ethanol (EtOH) in rats has been hypothesized to reflect its hedonic effects and to be associated with a genetic predisposition toward high alcohol preference. To test the hypothesis that phenotypes associated with high alcohol preference in adulthood are also present in adolescent rats at the time of onset of alcohol drinking, the current study examined the effects of EtOH on locomotor activity (LMA) during adolescence in lines of rats selectively bred for divergent alcohol intakes.

Background: In a previous study, neuropeptide Y (NPY) administered into the lateral ventricles decreased ethanol intake in alcohol‐preferring (P) rats but not in alcohol‐nonpreferring (NP) or unselected Wistar rats. The purpose of the present investigation is to extend these findings in selectively‐bred high‐alcohol‐drinking (HAD)1 and low‐alcohol‐drinking (LAD)1 rats by examining the effects of intracerebroventricularly administered NPY on the elevated plus maze test of anxiety and on ethanol and sucrose intake.

Background: The ventral tegmental area (VTA) dopamine (DA) system is considered to be involved in mediating the actions of ethanol (EtOH). The objective of the present study was to examine the role of VTA DA D2receptors in regulating EtOH intake of alcohol‐preferring P rats.

This study tested the hypothesis that eliminating in vivocompression to the wrap‐around, fibrocartilage‐rich zone of the flexor digitorum profundus tendon results in rapid depletion of fibrocartilage and changes in its mechanical properties, microstructure, extracellular matrix composition, and cellularity. The right flexor digitorum profundus tendons of 2.5‐3‐year‐old rabbits were translocated anteriorly to eliminate in vivocompression and shear to the fibrocartilage zone and, at 4 weeks after surgery, were compared with tendons that had sham surgery and with untreated tendons. The translocated tissue showed a significant increase in equilibrium strain under a compressive creep load (p < 0.05). The thickness and area of the fibrocartilage zone also decreased significantly (p < 0.05). The nuclear density decreased by 40% in the fibrocartilage zone (p < 0.005); however, nuclear shape and orientation were not significantly altered. Glycosaminoglycan content in the fibrocartilage zone was also depleted by 40% (p < 0.02). The tightly woven basket weave‐like mesh of collagen fibers in the zone appeared more loosely organized, suggesting matrix reorganization due to translocation. Moreover, immunoreactive type‐II collagen and link protein in the fibrocartilage zone also decreased. With use of this unique in vivomodel, this research clearly elucidates how changing tissue function (by removing compressive forces) rapidly alters tissue form.

A characteristic of heritable alcoholism is an early onset of alcohol abuse, which may begin at or before the age of adolescence. The objective of the present study was to determine the ontogeny of alcohol drinking behavior before and during puberty in the selectively bred alcohol‐preferring (P), alcohol‐nonpreferring (NP), high alcohol drinking (HAD), and low alcohol drinking (LAD) lines of rats. In addition, the effects of postweaning housing conditions (single‐ or pair‐housed) and initiation procedure (4 days forced ethanol or free‐choice) were evaluated in male and female P rats. Results indicate that high alcohol drinking in P and HAD (replicate line 2) rats, as well as low alcohol drinking behavior in NP and LAD (replicate line 2) rats, is present as early as 3 to 4 weeks of age. Ethanol intakes in juvenile P and HAD rats reached levels of ∼4 to 5 g/kg/day by 38 to 41 days of age and were comparable with levels observed in adults. Neither housing conditions nor ethanol initiation procedure significantly altered the acquisition or magnitude of alcohol intake levels in juvenile male and female P rats. These results suggest that the neural substrates underlying divergent ethanol drinking behavior in P/NP and HAD/LAD lines of rats are present early in life.

The aim of this study was to report the high-resolution computed tomography (HRCT) appearances of linear opacities that may occur in isolation or in combination with other changes in bronchiolitis obliterans organising pneumonia (BOOP). Eleven patients with BOOP and linear opacities on HRCT were identified at three independent teaching hospitals. The HRCT images and clinical course of each patient were reviewed. Two distinct types of linear opacity were identified. The type-1 opacity extended in a radial manner along the line of the bronchi towards the pleura and was usually intimately related to bronchi. The type-2 opacity occurred in a sub-pleural location and bore no relationship to the bronchi. Both types occurred most commonly in the lower lobes, frequently were associated with multi-focal areas of consolidation and usually completely resolved with treatment. There was no associated bronchiectasis, irreversible volume loss or a reticular or honeycomb pattern. In 2 patients linear opacities were the sole abnormality on HRCT. Bronchiolitis obliterans organising pneumonia may occur in a pure "linear form" or HRCT may demonstrate linear opacities in addition to multi-focal consolidation.

The purpose of this article is to report four patients with massive pulmonary embolism treated with percutaneous catheter and guidewire fragmentation and local administration of recombinant tissue plasminogen activator (r-TPA). Four patients with massive pulmonary embolism initially underwent pulmonary angiography. Thrombus fragmentation was performed with both standard angiographic guidewires and catheters followed by local infusion of 41-200 mg of r-TPA. Pulmonary angiography was repeated after treatment. All patients survived with improvement in their clinical status and eventual discharge from hospital. Angiography in all patients post treatment demonstrated improvement in pulmonary perfusion (mean Miller score before treatment 22.5; mean Miller score after treatment 5.75). No patient had a significant complication. Mechanical fragmentation of the thrombus followed by local infusion of r-TPA was an effective treatment for massive pulmonary embolism in these four patients with no significant complications.

AbstractA high-resolution (2.75° lat × ° 3.75° long) coupled ocean-atmosphere model has been used to simulate the transient response of climate to a gradual increase in atmospheric carbon dioxide concentrations. Although the radiative forcing increases linearly, there is a delay of about 30 yr before the ocean warms appreciably. This “cold start” is, at least partly, an artifact of the experimental design. At the time of doubling (after 70 yr), the patterns of change are similar to those found in comparable studies of the equilibrium response, except in the high latitudes of the Southern Ocean and the North Atlantic, where the warming is considerably reduced. The mechanisms leading to this reduction are discussed. After two to three decades, the pattern of warming is well established. The warming over land is substantially larger than that over the sea, with a consequent lowering of surface pressure over the northern continents in summer. The patterns of changes in precipitation and soil moisture take longer to establish themselves, although locally there are consistent changes after the third decade.

AbstractThis paper describes the initialization of an experiment to study the time-dependent response of a high-resolution global coupled ocean-atmosphere general circulation model to a gradual increase in carbon dioxide. The stability of the control integration with respect to climate drift is assessed, and aspects of the model climatology relevant to the simulation of climate change are discussed. The observed variation of oceanic temperature with latitude and depth is basically well simulated, although, in common with other ocean models, the main thermocline is too diffuse. Nevertheless, it is found that large heat and water flux adjustments must be added to the surface layer of the ocean in order to prevent the occurrence of unacceptable climate drift. The ocean model appears to achieve insufficient meridional heat transport, and this is supported by the pattern of the heat flux adjustment term, although errors in the simulated atmosphere-ocean heat flux also contribute to the latter. The application of the flux adjustments restricts climate drift during the 75-year control experiment. However, a gradual warming still occurs in the surface layers of the Southern Ocean because the flux adjustments are inserted as additive terms in this integration and cannot therefore be guaranteed to prevent climate drift completely.

AbstractThe roles of surface, atmospheric, and oceanic feedbacks in controlling the global-mean transient response of a coupled ocean-atmosphere general circulation model to increasing carbon dioxide are investigated. The analysis employs a four-box energy balance model and an oceanic box-diffusion model, both tuned to the simulated general circulation model response. The land-sea contrast in the surface warming is explained almost entirely by the shortwave radiative feedbacks associated with changes in cloud and surface albedo. The oceanic thermal inertia delays the response; however, the initial delay is enhanced by increases in Antarctic sea-ice cover, which substantially reduce the effective climate sensitivity of the model in the first half of the 75-year experiment. When driven by the observed anthropogenic greenhouse forcing from the pre-industrial period to present day, the energy balance model overestimates the warming observed over land. However, inclusion of the direct forcing due to anthropogenic tropospheric sulphate aerosol eliminates the landsea contrast in the response at 1990, leaving the simulated warming over land slightly below the observed value, although the rapid warming observed during the 1980s is well reproduced.The vertical penetration of the oceanic response is small below 1000 m. Within the top 1000 m the effective diffusivities are substantially enhanced by reduced convection and thermohaline overturning, driven by increased precipitation minus evaporation at high latitudes. These changes in ocean heat transport become significant after year 30, whereupon the effective oceanic heat capacity increases substantially, although this increase is partially offset by the effect of changes in the sea-ice margin.

The time course of the novel benzodiazepine inverse agonist, RO19--4603 (0.075 or 0.150 mg/kg) in antagonizing the depressant effects of ethanol (EtOH) (0.50, 1.0 and 1.5 g/kg) and the development of tolerance on locomotor behaviors (e.g., ambulatory count, total distance and stereotypy count) were investigated in Sprague-Dawley rats given EtOH injections spaced at 24-hr intervals. A single dose of RO19--4603 prevented the development of tolerance to the 0.50- and 1.0-g/kg EtOH doses 24-hr post-RO19--4603 administration on most locomotor behaviors. On Day 1, the 0.150-mg/kg RO19--4603 dose prevented the reduction of motor behaviors after the 1.0- and 1.5-g/kg EtOH doses, whereas the 0.075-mg/kg RO19--4603 dose prevented the reduction of motor behaviors only after the 1.5-g/kg EtOH dose. The 0.075- and 0.150-mg/kg RO19--4603 doses also prevented the EtOH-induced reduction of motor behaviors after the 1.5-g/kg EtOH dose 24-hr post-RO19--4603 administration. RO19--4603 was without effect on activity when given alone. These data suggest that the motor impairing effects of EtOH and the development of tolerance to them may involve gamma-aminobutyric acidA-benzodiazepine receptor mechanisms that when occupied, even briefly by certain benzodiazepine inverse agonists, produce long-lasting effects on locomotion and tolerance.

Apatite fission-track thermochronology reveals that hydrothermal activity was pervasive during mid-Tertiary time within the Paralana Fault zone and adjacent country rocks of the northern Flinders Ranges, South Australia. Apatite fission-track ages from the Mt Painter block, west of the Paralana Fault zone, range between ∼ 175 and 260 Ma. The mean lengths of confined fission-tracks for these samples are ∼ 12 μm with s.d. of the track length distributions of ∼ 2 μm. These data suggest that rocks exposed in the Mt Painter block cooled slowly though the apatite partial annealing zone (∼ 110-50°C) starting before 200 Ma and continuing into the Tertiary. In contrast, apatite samples from the Paralana Fault zone yield apparent ages as young as 25-30 Ma and mean track lengths mostly < 12 μm, with s.d. ∼ 3 μm. These young apparent ages and relatively short track lengths require mid-Tertiary palaeotemperatures of 90-105°C for the fault zone, assuming a heating time in the order of 1 Ma. This heating is interpreted to be the result of hydrothermal activity within the fault zone when it was buried beneath Mesozoic and Tertiary sedimentary strata. At least one stage of uplift of the northern Flinders Ranges during Miocene time elevated these rocks above the basin sediments, resulting in cooling due to a significant reduction in hot springs activity.

Methods for the detection of Alicyclobacillus acidoterrestrisat a level of 1 cell per 100 ml and enumeration with a sensitivity of 5 cells ml−1were developed. Spores of A. acidoterrestrissurvived pasteurization and outgrew and multiplied at a similar rate to vegetative cells in both orange juice and apple juice. Alicyclobacillus acidoterrestrisgrew readily in orange juice, apple juice and a non‐carbonated fruit juice‐containing drink at temperatures of 25–44°C producing a taint and elevated levels (1–100 ppb) of guaiacol. Isolates of A. acidoterrestriscan be identified using the DuPont RiboPrinter. It was isolated from apple drinks, apple juice concentrate and freshly squeezed orange juice.

The production of climate simulations using global coupled ocean–atmosphere models at high resolution is currently limited by computational expense and the long periods of integration that are necessary. A method of increasing the number of experiments that can be performed is the so-called time-slice technique. Using the Arpège-climat atmospheric model three 5-yr integrations of this type were run: a control and two integrations forced with sea surface temperatures derived from coupled model simulations of the transient response to increasing carbon dioxide. These coupled models are the ECHAM1 model of the Max-Planck Institute (Hamburg, Germany) and the U.K. Meteorological Office model of the Hadley Centre. The sensitivity of the response to the oceanic forcing is studied. The results are compared with the 10-yr mean atmospheric response of the coupled models at the time of the doubling of CO2. Global warmings ranging from 1.3 K to 1.9 K are obtained. Special attention is given to the modifications that occur in the hydrological cycle and their sensitivity to the SSTs. Climatic signals related to oceanic forcing, such as the modification of the ITCZ maximum of precipitation, are separated from signals due to the internal feedbacks and physical parameterizations of the models.

The production of climate simulations using global coupled ocean–atmosphere models at high resolution is currently limited by computational expense and the long periods of integration that are necessary. A method of increasing the number of experiments that can be performed is the so-called time-slice technique. Using the Arpège-climat atmospheric model three 5-yr integrations of this type were run: a control and two integrations forced with sea surface temperatures derived from coupled model simulations of the transient response to increasing carbon dioxide. These coupled models are the ECHAM1 model of the Max-Planck Institute (Hamburg, Germany) and the U.K. Meteorological Office model of the Hadley Centre. The sensitivity of the response to the oceanic forcing is studied. The results are compared with the 10-yr mean atmospheric response of the coupled models at the time of the doubling of CO2. Global warmings ranging from 1.3 K to 1.9 K are obtained. Special attention is given to the modifications that occur in the hydrological cycle and their sensitivity to the SSTs. Climatic signals related to oceanic forcing, such as the modification of the ITCZ maximum of precipitation, are separated from signals due to the internal feedbacks and physical parameterizations of the models.

Seasonal simulations of the Indian summer monsoon using a 50-km regional climate model (RCM) are described. Results from three versions of the RCM distinguished by different domain sizes are compared against those of the driving global general circulation model (AGCM). Precipitation over land is 20% larger in the RCMs due to stronger vertical motions arising from finer horizontal resolution. The resulting increase in condensational heating helps to intensify the monsoon trough relative to the AGCM. The RCM precipitation distributions show a strong orographically forced mesoscale component (similar in each version). This component is not present in the AGCM. The RCMs produce two qualitatively realistic intraseasonal oscillations (ISOs) associated respectively with monsoon depressions which propagate northwestward from the Bay of Bengal and repeated northward migrations of the regional tropical convergence zone. The RCM simulations are relatively insensitive to domain size in several respects: (1) the mean bias relative to the AGCM is similar for all three domains; (2) the variability simulated by the RCM is strongly correlated with that of the driving AGCM on both daily and seasonal time scales, even for the largest domain; (3) the mesoscale features and ISOs are not damped by the relative proximity of the lateral boundaries in the version with the smallest domain. Results (1) and (2) contrast strongly with a previous study for Europe carried out with the same model, probably due to inherent differences between mid-latitude and tropical dynamics.

Copper removal from aqueous solutions by chelation in supercritical carbon dioxide was investigated. The chelating agents were 1,1,1-trifluoroacetylacetone (TFA) and 2,2-dimethyl-6,6,7,7,8,8,8-heptafluoro-3,5-octanedione (FOD). Extraction efficiencies were determined for a single equilibrium stage in the temperature range 308−328 K and the pressure range 9.9−24.0 MPa and ranged from 4% to 84%. The extraction efficiencies increased with increasing the initial amount of chelating agent and with decreasing the initial copper concentration. No significant changes in extraction efficiencies were observed with temperature and pressure at a fixed initial amount of chelating agent. A thermodynamic model based on combined reaction and phase equilibria was also developed for prediction of extraction efficiencies.

Results are assessed from a 10‐year simulation of the equilibrium response to doubled carbon dioxide (CO2) over Europe made with a nested high‐resolution regional‐climate model (RCM). the simulated changes are compared against those produced by the driving global general‐circulation model (GCM). the domain‐averaged increases in temperature and moisture content are similar in both models. Because of a stronger hydrological cycle the increases in precipitation and evaporation are larger in the RCM than in the GCM, whereas the reductions in lower and middle tropospheric relative humidity and cloud cover are smaller. The frequency of intense precipitation events increases substantially in both models; however, the fractional changes are significantly smaller in the RCM. the proportion of precipitation associated with convection also increases in both models; however, much of the increase in intense events is explained simply by increased atmospheric moisture concentrations, especially in the RCM. The time‐averaged precipitation changes in the RCM contain a substantial mesoscale component on scales not resolved by the GCM. Attempts are made to reconstruct this component from the changes in the large‐scale atmospheric circulation using empirical relationships calibrated from the 1 x CO2integration. These are largely unsuccessful, indicating that simple downscaling schemes to generate high‐resolution scenarios of climate change from coarse‐grid GCM data may be of only limited applicability. Further statistical calculations suggest that longer integrations (∼ 30 years) are needed to reduce the sampling uncertainty associated with the simulated mesoscale component to an acceptable level. The large‐scale patterns of change of surface temperature and precipitation reveal significant regional contrasts which are influenced both by changes in atmospheric circulation and regional physical feedbacks. the RCM changes are similar to those of the driving GCM except in summer. the differences in the summer changes are traced to differences between the 1 x CO2integrations, in which the influence of the lateral boundary forcing on the RCM simulation is found to be anomalously weak. It is argued that any development of significant divergence between the RCM and GCM solutions on scales resolved by the latter may imply the need to refine or replace the one‐way nesting technique currently used in many regional modelling experiments.

The last British Dental Journal article on child protection was in 1986. Since then there have been major changes in both legislation and approaches to child protection. A local authority child protection specialist and a consultant in paediatric dentistry outline the development of child protection and the dental practitioner's role in the inter-agency child protection system in this, the first of three inter-related articles

The types of prevalence of the various orofacial injuries that may be sustained in child abuse have been presented. Table 2 gives the dental practitioner a summary check-list of five questions they must ask themselves and five observations they must make whenever doubts and suspicions of child abuse arise

The alcohol‐deprivation effect (ADE) was examined under 4‐hr operant and 24‐hr free‐choice alcohol access in the alcohol‐preferring (P) rat after deprivation intervals from 2 to 4 weeks. Results indicated that adult male P rats responding for 6 weeks on a concurrent FR‐5/ FR‐1 schedule of reinforcement for alcohol and water, respectively, and then deprived of alcohol for 2 weeks, demonstrated a 40% increase in alcohol responding during the first 60 min of alcohol reinstatement. The alcohol deprivation effect was temporary, however, as responding did not differ from baseline levels on the second day of reinstatement. In a second experiment, weanling male and female P rats received 7 weeks of continuous access to alcohol, beginning at 21 days of age, and were then deprived of alcohol for 4 weeks. On the first day of alcohol reinstatement, P rats exhibited a 40% to 45% increase from baseline alcohol drinking levels, with alcohol intake returning to baseline levels by the 3rd day of reinstatement. Although alcohol intake was higher in females than in males when adjustment was made for body weight, there were no gender differences in the magnitude of the alcohol deprivation effect. Taken together, these results indicate that the ADE is a long‐lasting phenomenon that occurs under both operant and continuous access conditions in the P rat, and thus these rats may be useful models for the study of factors involved in relapse of alcohol drinking.

Abstract.:  The Hadley Centre coupled ocean-atmosphere general circulation model (AOGCM) has been used to study the effect of including the historical increase in greenhouse gases from 1860 to 1990 on the response to a subsequent 1% per year increase in CO2. Results from an ensemble of four experiments which include the historical increase, warm start (WS) experiments, are compared with an ensemble of four experiments which do not include the historical increase, cold start (CS) experiments. In the WS experiments, oceanic thermal inertia prevents the model from reaching equilibrium with the historical change in forcing from 1860 to 1990. This implies an unrealised warming at 1990, defined here as the ‘warming commitment’, increasing the subsequent warming in WS relative to that in CS. The difference in response between a WS experiment and a CS experiment is defined as the cold start error. For surface temperature the ensemble-mean cold start error is 20% of the WS response after year 30 and 10% at the time of doubling CO2 (year 70). For sea level the reduction in the CS response is more pronounced, amounting to 60% at year 30 and 40% at the time of doubling. The vertical transfer of heat in the ocean is found to correspond to an equivalent diffusion process. This result supports the use of simple ocean models with constant diffusivity to produce time-dependent scenarios of globally averaged climate change, subject to the caveat that the changes in ocean circulation simulated by the present AOGCM were smaller than in some previous cases. In the WS integrations the vertical temperature gradient is larger than in CS due to the historical forcing influence, leading to more efficient heat loss from the base of the mixed layer and hence a larger effective heat capacity. This explains why the cold start error for surface temperature is smaller than for sea level. By year 50 the global patterns of temperature change in individual integrations are highly correlated in both the WS and CS ensembles, indicating that natural variability is too small to conceal the climate change signal. The simulated regional changes are statistically significant almost everywhere after 30 y. Before year 30, when the signal-to-noise ratio is smaller, ensemble averaging the changes leads to a substantial increase in significance. In contrast to a previous study also based on an ensemble of integrations, significant changes in precipitation and soil moisture are found. For these quantities the area of significant change grows more slowly with time, however ensemble averaging increases the significant area throughout. The characteristic patterns of change in WS and CS are similar, and evident in the simulation of the past record. This suggests that the component of the historical patterns of change, driven by greenhouse gas forcing, is likely to bear significant similarities to the patterns expected in the future. However, significant regional differences do develop between the WS and CS ensembles. The cold start error has a non-uniform pattern which becomes established in the second half of the experiment, and is not a simple amplification or modulation of the CS or WS response pattern. In northern summer the warming and drying over parts of the Northern Hemisphere continents is larger in CS than in WS, due to a smaller net moisture flux from sea to land. The conclusions are: (1) climate predictions should be based on warm start experiments in order to obtain the best estimates of future changes; (2) ensemble means give predictions of regional changes which are statistically more robust than predictions from individual integrations. Note, however, that neither the removal of the cold start error nor the use of ensemble averaging can reduce uncertainties in the regional changes arising from model deficiencies, which remain considerable at the present stage of development.

The in vitro release of endogenous norepinephrine (NE), dopamine (DA), serotonin (5-HT), GABA, glutamate (GLU), aspartate (ASP), glycine (GLY), taurine (TAU) and alanine (ALA) from superfused slices of cerebral cortex (CTX), striatum (STR), hippocampus (HIP), hypothalamus (HYPO), midbrain (MB), thalamus (THAL), nucleus accumbens (ACC), pons-medulla (PM) and spinal cord (SC) was studied. Under resting conditions or with 60 mM K+ in the absence of Ca2+, there was little or no release of NE, DA, 5-HT, GABA, GLU or ASP from any region. In most regions, there was a measurable resting release of ALA, GLY and TAU; of these three amino acids, only GLY in the PM and SC showed an increased release in the 60 mM K+ plus 2.5 mM Ca2+ medium. In 8 of the regions studied, the release of both GABA and GLU were stimulated by 60 mM K+ in the presence of 2.5 mM Ca2+. For the amino acids, no reliable data were obtained for release from the ACC because of its small size. The highest amount of K+-stimulated, Ca2+-dependent release of GABA was found with slices from the HYPO, THAL and MB while the highest amount of GLU was released from slices of STR, HIP and CTX. In those regions where reliable levels of K+-stimulated, Ca2+-dependent release of ASP were observed (STR, CTX, THAL), the amount of ASP was at least 5-fold lower than the values for GLU. A K+-stimulated, Ca2+-dependent release of NE, DA and 5-HT was observed for all 9 CNS regions studied. The highest release of (a) DA occurred from slices of CTX, STR and ACC; (b) NE was found in the HYPO and ACC; and (c) 5-HT occurred in the HYPO. The data (a) do not support a transmitter role for ALA and TAU in the CNS; (b) support a major transmitter function for GLY only in the PM and SC; and (c) support a transmitter role for GABA, GLU, NE, DA and 5-HT in the CNS regions examined (with the exception of GABA and GLU in the ACC where no data were obtained).