The Limit of Anemia Tolerance during Hyperoxic Ventilation with Pure Oxygen in Anesthetized Domestic Pigs

Background: During acellular replacement of an acute blood loss,hyperoxic ventilation (HV) increases the amount of O-2 physicallydissolved in the plasma and thereby improves O-2 supply to the tissues.While this effect could be demonstrated for HV with inspiratory O-2fraction (FiO(2)) 0.6, it was unclear whether HV with pure oxygen(FiO(2) 1.0) would have an additional effect on the physiological limitof acute normovolemic anemia. Methods: Seven anesthetized domestic pigswere ventilated with FiO(2) 1.0 and subjected to an isovolemichemodilution protocol. Blood was drawn and replaced by a 6%hydroxyethyl starch (HES) solution (130/0.4) until a sudden decrease oftotal body O-2 consumption (VO2) indicated the onset of O-2 supplydependency (primary endpoint). The corresponding hemoglobin (Hb)concentration was defined as ‘ critical Hb’ (Hb crit). Secondaryendpoints were parameters of myocardial function, central hemodynamics,O-2 transport and tissue oxygenation. Results: HV with FiO(2) 1.0enabled a large blood-for-HES exchange (156 +/- 28% of the circulatingblood volume) until Hb crit was met at 1.3 +/- 0.3 g/dl. Aftertermination of the hemodilution protocol, the contribution of O 2physically dissolved in the plasma to O-2 delivery and VO2 hadsignificantly increased from 11.7 +/- 2 to 44.2 +/- 9.7% and from 29.1+/- 4.2 to 66.2 +/- 11.7%, respectively. However, at Hb crit,cardiovascular performance was found to have severely deteriorated.Conclusion: HV with FiO(2) 1.0 maintains O-2 supply to tissues duringextensive blood-for-HES exchange. In acute situations, where profoundanemia must be tolerated (e.g. bridging an acute blood loss until redblood cells become available for transfusion), O-2 physically dissolvedin the plasma becomes an essential source of oxygen. However,compromised cardiovascular performance might require additionaltreatment

Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile

The NMDA receptor is thought to play a central role in some forms of neuronal plasticity, including the induction of long-term potentiation. NMDA receptor hypofunction can result in mnemonic impairment and has been implicated in the cognitive symptoms of schizophrenia. The activity of NMDA receptors is controlled by its endogenous coagonist glycine, and a local elevation of glycine levels is expected to enhance NMDA receptor function. Here, we achieved this by the generation of a novel mouse line (CamKIIalphaCre;Glyt1tm1.2fl/fl) with a neuron and forebrain selective disruption of glycine transporter 1 (GlyT1). The mutation led to a significant reduction of GlyT1 and a corresponding reduction of glycine reuptake in forebrain samples, without affecting NMDA receptor expression. NMDA (but not AMPA) receptor-evoked EPSCs recorded in hippocampal slices of mutant mice were 2.5 times of those recorded in littermate controls, suggesting that neuronal GlyT1 normally assumes a specific role in the regulation of NMDA receptor responses. Concomitantly, the mutants were less responsive to phencyclidine than controls. The mutation enhanced aversive Pavlovian conditioning without affecting spontaneous anxiety-like behavior in the elevated plus maze and augmented a form of attentional learning called latent inhibition in three different experimental paradigms: conditioned freezing, conditioned active avoidance, conditioned taste aversion. The CamKIIalphaCre;Glyt1tm1.2fl/fl mouse model thus suggests that augmentation of forebrain neuronal glycine transmission is promnesic and may also offer an effective therapeutic intervention against the cognitive and attentional impairments characteristic of schizophrenia

Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme

Adenosine is a potent modulator of excitatory neurotransmission, especially in seizure-prone regions such as the hippocampal formation. In adult brain ambient levels of adenosine are controlled by adenosine kinase (ADK), the major adenosine-metabolizing enzyme, expressed most strongly in astrocytes. Since ontogeny of the adenosine system is largely unknown, we investigated ADK expression and cellular localization during postnatal development of the mouse brain, using immunofluorescence staining with cell-type specific markers. At early postnatal stages ADK immunoreactivity was prominent in neurons, notably in cerebral cortex and hippocampus. Thereafter, as seen best in hippocampus, ADK gradually disappeared from neurons and appeared in newly developed nestin- and glial fibrillary acidic protein (GFAP)-positive astrocytes. Furthermore, the region-specific downregulation of neuronal ADK coincided with the onset of myelination, as visualized by myelin basic protein staining. After postnatal day 14 (P14), the transition from neuronal to astrocytic ADK expression was complete, except in a subset of neurons that retained ADK until adulthood in specific regions, such as striatum. Moreover, neuronal progenitors in the adult dentate gyrus lacked ADK. Finally, recordings of excitatory field potentials in acute slice preparations revealed a reduced adenosinergic inhibition in P14 hippocampus compared with adult. These findings suggest distinct roles for adenosine in the developing and adult brain. First, ADK expression in young neurons may provide a salvage pathway to utilize adenosine in nucleic acid synthesis, thus supporting differentiation and plasticity and influencing myelination; and second, adult ADK expression in astrocytes may offer a mechanism to regulate adenosine levels as a function of metabolic needs and synaptic activity, thus contributing to the differential resistance of young and adult animals to seizures