The European Centre for Medium-Range Weather Forecasts (ECMWF) Ensemble Prediction System (EPS) is described. In addition to an unperturbed (control) forecast, each ensemble comprises 32 10-day forecasts starting from initial conditions in which dynamically defined perturbations have been added to the operational analysis. The perturbations are constructed from singular vectors of a time-evolution operator linearized around the short-rangeforecast trajectory. These singular vectors approximately determine the most unstable phase-space directions in the early part of the forecast period, and are estimated using a forward and adjoint linear version of the ECMWF numerical weather-prediction model. An appropriate norm is chosen, and relationships between the structures of these singular vectors at initial time and patterns showing the sensitivity of short-range forecast error to changes in the analysis are discussed. A methodology to perform a phase-space rotation of the singular vectors is described, which generates hemispheric-wide perturbations and renormalizes them according to analysis-error estimates from the data-assimilation system.The validation of the ensembles is given firstly in terms of scatter diagrams and contingency tables of ensemble spread and control-forecast skill. The contingency tables are compared with those from a perfect-model ensemble system; no significant differences are found in some cases. Brier scores for the probability of European flow clusters are presented, which indicate predictive skill up to forecast-day 8 with respect to climatological probabilities. The dependence of these scores on flow-dependent model errors is also discussed. Finally, ensemble-member skillscore distributions are presented, which confirm the overall satisfactory performance of the EPS, particularly in summer and autumn 1993. In winter, cases of poor performance over Europe were associated with the Occurrence of a split westerly flow with a blocking high and/or a cut-off low in the verifying analysis.' h o cases are studied in detail, one having large ensemble dispersion, the other corresponding to a more predictable situation. The case studies are used to illustrate the range of ensemble products routinely disseminated to ECMWF Member States. These products include clusters of flow types, and probability fields of weather elements.

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The oral glucose tolerance test, a diagnostic procedure used in the detection of human diabetes, was used to study carbohydrate metabolism in rainbow trout, Sulmo guirdneri (Richardson). Fish exhibited pronounced and persistent hyperglycaemia on oral glucose administration. Hyperglycaemia was accompanied by decrease in blood amino acids, serum free fatty acids and cholesterol and marked increase in hepatic storage of glycogen. The incidence of oral glucose intolerance results, at least in part from insufficient circulating insulin. Exogenous insulin exerts a hypoglycaemic action and effectively abolishes the hyperglycacmia resulting from glucose administration. Tolbutamidc, the sulphonylurea hypoglycaemic drug, is without effect. Possibly as an indirect result of hyperadrenocorticism, oral glucose tolerance is markedly improved in the pre-spawning female. Longterm feeding of high carbohydrate diet to goldfish Cnrussiirs aurutus (L.) resultcd in gross hepatomegaly due to excessive hepatic glycogen accumulation and, possibly, fatty change of the liver. Protein metabolism was impaired as evidenced by protein depletion. Such degenerative changes in liver metabolism are probably a direct result of oral glucose intolerance and reflcct a metabolism adapted to diets normally low in available carbohydrate.

Several recent studies have demonstrated that TAT and other arginine-rich cell penetrating peptides (CPPs) have intrinsic neuroprotective properties in their own right. Examples, we have demonstrated that in addition to TAT, poly-arginine peptides (R8 to R18; containing 8-18 arginine residues) as well as some other arginine-rich peptides are neuroprotective in vitro (in neurons exposed to glutamic acid excitotoxicity and oxygen glucose deprivation) and in the case of R9 in vivo (after permanent middle cerebral artery occlusion in the rat). Based on several lines of evidence, we propose that this neuroprotection is related to the peptide's endocytosis-inducing properties, with peptide charge and arginine residues being critical factors. Specifically, we propose that during peptide endocytosis neuronal cell surface structures such as ion channels and transporters are internalised, thereby reducing calcium influx associated with excitotoxicity and other receptor-mediated neurodamaging signalling pathways. We also hypothesise that a peptide cargo can act synergistically with TAT and other arginine-rich CPPs due to potentiation of the CPPs endocytic traits rather than by the cargo-peptide acting directly on its supposedly intended intracellular target. In this review, we systematically consider a number of studies that have used CPPs to deliver neuroprotective peptides to the central nervous system (CNS) following stroke and other neurological disorders. Consequently, we critically review evidence that supports our hypothesis that neuroprotection is mediated by carrier peptide endocytosis. In conclusion, we believe that there are strong grounds to regard arginine-rich peptides as a new class of neuroprotective molecules for the treatment of a range of neurological disorders.

A comparison was made between the time courses of restoration of pyruvate dehydrogenase activities, fructose 2,6-bisphosphate concentrations and lipogenic rates, together with net hepatic glucose flux and glycogen synthesis/deposition in livers of 48 h-starved rats provided with laboratory chow ad libitum for up to 24 h. Increased glycogenesis, lipogenesis and net glucose uptake were observed after 1 h of re-feeding, preceding re-activation of pyruvate dehydrogenase, which occurred after 3-4 h. Increased concentrations of fructose 2,6-bisphosphate were only observed after 5-6 h. The implication of the temporal relationship between these parameters is discussed.

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