Medical record weight (MRW): a new reliable predictor of hospital stay, morbidity and mortality in the hip fracture population?

We sought to compare the weight of patient's medical records (MRW) to that of standardised surgical risk scoring systems in predicting postoperative hospital stay, morbidity, and mortality in patients with hip fracture. Patients admitted for surgical treatment of a newly diagnosed hip fracture over a 3-month period were enrolled. Patients with documented morbidity or mortality had significantly heavier medical records. The MRW was equivalent to the age-adjusted Charlson co-morbidity index and better than the American Society of Anaesthesiologists physical status score (ASA), the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM,) and Portsmouth-POSSUM score (P-POSSUM) in correlation with length of hospital admission, p = .003, 95% CI [.15 to .65]. Using logistic regression analysis MRW was as good as, if not better, than the other scoring systems at predicting postoperative morbidity and 90-day mortality. Medical record weight is as good as, or better than, validated surgical risk scoring methods. Larger, multicentre studies are required to validate its use as a surgical risk prediction tool, and it may in future be supplanted by a digital measure of electronic record size. Given its ease of use and low cost, it could easily be used in trauma units globally.

Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F.

Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.

Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits.

Studies in the past have revealed serotonin to play a role in regulating the development and maturation of the mammalian brain, largely through the release of the astroglial protein S-100beta. S-100beta plays a role in neurite extension, microtubule and dendritic stabilization and regulation of the growth associated protein GAP-43, all of which are key elements in the production of synapses. Depletion of serotonin, and thus of S-100beta, during synaptogenesis should lead to a loss of synapses and the behaviors dependent on those synapses. The current study was undertaken to test this hypothesis. In order to assess the influence of serotonin we have looked at the synaptic density in the adult after depletion, by using immunodensitometry of synaptic markers (synaptophysin and MAP-2) and by studying behaviors thought to be highly dependent on synaptic plasticity and density. Male Sprague-Dawley rats were depleted of serotonin on postnatal days (PND) 10-20 by treating with the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA; 100 mg/kg, s.c.). On PND's 30 and 62, animals were perfused for immunodensitometry. Littermates were used for behavioral testing. At PND 55-62, the animals were tested in an interchangeable maze with olfactory cues and in an eight-arm radial maze. Our results show a loss of both synaptic markers in the hippocampus on PND 30. At PND 62, the only remaining loss was of the dendritic marker MAP-2. The animals had deficits in both behaviors tested, suggestive of spacial learning deficits and of the failure to extinguish learned behaviors or to re-learn in a new set. Our findings show the long-term consequences of interfering with the role of serotonin in brain development on the morphology and function of the adult brain. These findings may have implications for human diseases, including schizophrenia, thought to be related to neurodevelopmental insults such as malnutrition, hypoxia, viruses or in utero drug exposure. Moreover, they provide further insights into the functioning of serotonin and S-100beta in development and aging.