Spinal cord injury often leads to permanent incapacity because long axons cannot regenerate in the CNS. Eph receptors inhibit axon extension through an effect on the actin cytoskeleton. We have previously reported that after injury EphA4 appears at high levels in stumps of corticospinal axons, while a cognate ligand, ephrinB2, is upregulated at the lesion site so as to confine the injured axons. In this study we have infused lesioned spinal cords with a peptide antagonist of EphA4. In treated animals the retrograde degeneration that normally follows corticospinal tract injury is absent. Rather, corticospinal tract axons sprout up to and into the lesion centre. In a behavioural test of corticospinal tract function, peptide treatment substantially improved recovery relative to controls. These results suggest that blocking EphA4 is likely to contribute to a future successful clinical treatment for spinal cord injury.

We have examined the expression of Eph receptors and their ephrin ligands in adult rat spinal cord before and after lesion. Neurons in adult motor cortex express EphA4 mRNA, but the protein is undetectable in uninjured corticospinal tract. In contrast, after dorsal column hemisection EphA4 protein accumulates in proximal axon stumps. One of the ligands for EphA4, ephrinB2, is normally present in the grey matter flanking the corticospinal tract but after injury is markedly up-regulated in astrocytes in the glial scar. The result is that, after a lesion, corticospinal tract axons bear high levels of EphA4 and are surrounded to front and sides by a continuous basket of cognate inhibitory ephrin ligand. We suggest that a combination of EphA4 accumulation in the injured axons and up-regulation of ephrinB2 in the surrounding astrocytes leads to retraction of corticospinal axons and inhibition of their regeneration in the weeks after a spinal lesion.

SummaryCritical care admission may be necessary for surgical patients requiring organ support or invasive monitoring in the peri‐operative period. Unplanned critical care admission poses a potential risk to patients and pressure on services. Existing guidelines base admission criteria on predicted risk of 30‐day mortality; however, this may not provide the best predictor of which patients would benefit from this service, and how unplanned admission might be avoided. A systematic review of MEDLINE, Embase, CINAHL, Web of Science, the Cochrane database and the grey literature identified 44 studies assessing risk factors for unplanned critical care admission in adult populations undergoing non‐cardiac, non‐thoracic and non‐neurological surgery. Comparative, quantitative analysis of the admission criteria was not feasible due to heterogeneity in study design. Age, anaemia, ASA physical status, body mass index, comorbidity burden, emergency surgery, high‐risk surgery, male sex, obstructive sleep apnoea, increased blood loss and operative duration were all independent risk factors for unplanned critical care admission. Age, body mass index, comorbidity extent and emergency surgery were the most common independent risk factors identified in the USA, UK, Asia and Australia. These risk factors could be used in the development of a risk tool or decision tree for determining which patients might benefit from planned critical care admission. Future work should involve testing the sensitivity and specificity of these measures, either alone or in combination, to guide planned critical care admission, reduce patient deterioration and unplanned admissions.

Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia (Review)

Fluctuations in cytosolic Ca2؉ are crucial for a variety of cellular processes including many aspects of development. Mobilization of intracellular Ca 2؉ stores via the production of inositol trisphosphate (IP 3 ) and the consequent activation of IP 3 -sensitive Ca 2؉ channels is a ubiquitous means by which diverse stimuli mediate their cellular effects. Although IP 3 receptors have been well studied at fertilization, information regarding their possible involvement during subsequent development is scant. In the present study we examined the role of IP 3 receptors in early development of the zebrafish. We report the first molecular analysis of zebrafish IP 3 receptors which indicates that, like mammals, the zebrafish genome contains three distinct IP 3 receptor genes. mRNA for all isoforms was detectable at differing levels by the 64 cell stage, and IP 3 -induced Ca 2؉ transients could be readily generated (by flash photolysis) in a controlled fashion throughout the cleavage period in vivo. Furthermore, we show that early blastula formation was disrupted by pharmacological blockade of IP 3 receptors or phospholipase C, by molecular inhibition of the former by injection of IRBIT (IP 3 receptorbinding protein released with IP 3 ) and by depletion of thapsigargin-sensitive Ca 2؉ stores after completion of the second cell cycle. Inhibition of Ca 2؉ entry or ryanodine receptors, however, had little effect. Our work defines the importance of IP 3 receptors during early development of a genetically and optically tractable model vertebrate organism.Cytosolic Ca 2ϩ regulates a whole host of cellular processes (1). Ca 2ϩ is involved in all stages of development of an organism from fertilization and cell division to cell proliferation and differentiation and, ultimately, cell death (1). How the same signaling ion can control such a vast array of diverse processes is perplexing. The exact form that the Ca 2ϩ signal takes is likely a key factor. Complexities in the Ca 2ϩ signals with respect to time and space are apparent and appear to be decoded by the cell to mediate a given response (1). Ca 2ϩ signals often derive from the mobilization of intracellular Ca 2ϩ stores. Inositol 1,4,5-trisphosphate (IP 3 ), 4 which is produced by the enzyme phospholipase C in response to a range of extracellular cues, activates intracellular Ca 2ϩ channels located predominantly in the membrane of the endoplasmic reticulum (2). Three isoforms of the IP 3 receptor have been described with distinct properties (3-5). IP 3 -sensitive Ca 2ϩ channels are regulated by interactions with accessory proteins (6) including protein kinases (7-13), calmodulin (14 -16), homer (17), and IRBIT (18 -20). They are also regulated by smaller ligands such as Ca 2ϩ itself (21, 22). The latter is particularly important for the generation of complex Ca 2ϩ signals, perhaps the most striking example of which are those generated at fertilization (23). In nearly all species studied, a large transient increase in cytosolic Ca 2ϩ concentration is observed that originates fr...