General practitioner views of an electronic high-risk medicine proforma to facilitate information transfer.

Background The potential of warfarin related harm is increased if clinicians lack the full patient specific information to make informed decisions—an e-proforma has been developed to communicate this information on hospital discharge. Objective To determine the views of general practitioners (GPs) on a warfarin discharge e-proforma. Method A cross-sectional survey of all GPs (n=272) within the Raigmore Hospital catchment area of NHS Highland, Scotland. Results The response rate was 39.3% (107/272). 84 (78.5%) noticed recent changes to information supplied on discharge for warfarin patients. 64 (59.8%) respondents thought this would result in more informed prescribing with regards to dosing, while 65 (60.7%) felt this would improve safety. Accurate completion, timely receipt of the e-proforma and a realistic date for subsequent INR tests were considered important by GPs. Conclusion This study suggests the use of an e-proforma to communicate information about a high-risk medication, warfarin, to GPs on discharge optimises safe, informed prescribing and monitoring in primary care. The development of a discharge e-proforma for other high-risk medication as a patient safety improvement measure should be explored

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Palynology, Phytoliths and Diatoms in and adjacent to the Great Cave: stratigraphic and taphonomic studies of Late Quaternary vegetation history

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Synthesis of Carboxamides Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors for AML

Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues containing a carboxamide at the 4-position of the aryl ring and novel carbamates. These compounds were potent submicromolar LSD1 inhibitors in enzyme assays and were anti-proliferative against a panel of AML cell lines. LSD1 target engagement in cells was demonstrated through the effects on H3K4me2 protein expression, CD86, CD11b and CD14 levels

Impulsive choice in hippocampal but not orbitofrontal cortex-lesioned rats on a nonspatial decision-making maze task

Orbitofrontal cortical (OFC) and hippocampal (HPC) lesions in primates and rodents have been associated with impulsive behaviour. We showed previously that OFC- or HPC-lesioned rats chose the immediate low-reward (LR) option in preference to the delayed high-reward (HR) option, where LR and HR were associated with different spatial responses in a uniform grey T-maze. We now report that on a novel nonspatial T-maze task in which the HR and LR options are associated with patterned goal arms (black-and-white stripes vs. gray), OFC-lesioned rats did not show impulsive behaviour, choosing the delayed HR option, and were indistinguishable from controls. In contrast, HPC-lesioned rats exhibited impulsive choice in the nonspatial decision-making task, although they chose the HR option on the majority of trials when there was a 10-s delay associated with both goal arms. The previously reported impairment in OFC-lesioned rats on the spatial version of the intertemporal choice task is unlikely to reflect a general problem with spatial learning, because OFC lesions were without effect on acquisition of the standard reference memory water-maze task and spatial working memory performance (nonmatching-to-place) on the T-maze. The differential effect of OFC lesions on the two versions of the intertemporal choice task may be explained instead in terms of the putative role of OFC in using associative information to represent expected outcomes and generate predictions. The impulsivity in HPC-lesioned rats may reflect impaired temporal information processing, and emphasizes a role for the hippocampus beyond the spatial domain

Epitaxial lithium niobate thin films grown by chemical beam epitaxy on sapphire

Lithium Niobate (LiNbO3) is a versatile material with a number of remarkable qualities. It finds application in optical modulators because of its electro-optic properties. Nonlinearity opens its use in bio-physical applications where particles or wires of LiNbO3 can be used as highly localized optical probes. Optical frequency conversion is another possible use, as well. One of the current commercial applications of the material is in optical modulators in telecomunication devices. Nowadays bulk crystals of the material are used. However, in order to make devices more compact and affordable it is necessary to be able to produce LiNbO3 films on suitable substrates with sufficient crystalline and optical quality

Mitigation measures to reduce entanglements of migrating whales with commercial fishing gear

The West Coast Rock Lobster Managed Fishery (WCRLMF) transitioned to a quota based fishery, and year-round fishing, which corresponded with a spike in whale entanglements in 2013. This presented industry with a challenging social issue, to reduce entanglements without impacting on the financial benefits that the shift to year-round quota fishing had afforded