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

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

Dielectric material options for integrated capacitors

Future MIM capacitor generations will require significantly increased specific capacitances by utilization of high-k dielectric materials. In order to achieve high capacitance per chip area, these dielectrics have to be deposited in three-dimensional capacitor structures by ALD or AVD (atomic vapor deposition) process techniques. In this study eight dielectric materials, which can be deposited by these techniques and exhibit the potential to reach k-values of over 50 were identified, prepared and characterized as single films and stacked film systems. To primarily focus on a material comparison, preliminary processes were used for film deposition on planar test devices. Measuring leakage current density versus the dielectric constant k shows that at low voltages (=1 V) dielectrics with k-values up to 100 satisfy the typical leakage current density specification o

Forced Moves or Good Tricks in Design Space? Landmarks in the Evolution of Neural Mechanisms for Action Selection

This review considers some important landmarks in animal evolution, asking to what extent specialized action-selection mechanisms play a role in the functional architecture of different nervous system plans, and looking for “forced moves” or “good tricks” (see Dennett, D., 1995, Darwin’s Dangerous Idea, Penguin Books, London) that could possibly transfer to the design of robot control systems. A key conclusion is that while cnidarians (e.g. jellyfish) appear to have discovered some good tricks for the design of behavior-based control systems—largely lacking specialized selection mechanisms—the emergence of bilaterians may have forced the evolution of a central ganglion, or “archaic brain”, whose main function is to resolve conflicts between peripheral systems. Whilst vertebrates have many interesting selection substrates it is likely that here too the evolution of centralized structures such as the medial reticular formation and the basal ganglia may have been a forced move because of the need to limit connection costs as brains increased in size

Angiosperm phylogeny: 17 genes, 640 taxa

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/1/ajb20704-sup-0010.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/2/ajb20704.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/3/ajb20704-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/4/ajb20704-sup-0016.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/5/ajb20704-sup-0017.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/6/ajb20704-sup-0021.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/7/ajb20704-sup-0003.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/8/ajb20704-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/9/ajb20704-sup-0011.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/10/ajb20704-sup-0019.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/11/ajb20704-sup-0015.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/12/ajb20704-sup-0006.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/13/ajb20704-sup-0020.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/14/ajb20704-sup-0013.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/15/ajb20704-sup-0004.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/16/ajb20704-sup-0012.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/17/ajb20704-sup-0005.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/18/ajb20704-sup-0018.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/19/ajb20704-sup-0009.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/20/ajb20704-sup-0014.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/21/ajb20704-sup-0007.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142064/22/ajb20704-sup-0008.pd

N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial

AIMS/HYPOTHESIS: The aim of this study was to determine whether oral dosing with N-acetylcysteine (NAC) increases intraplatelet levels of the antioxidant, glutathione (GSH), and reduces platelet–monocyte conjugation in blood from patients with type 2 diabetes. METHODS: In this placebo-controlled randomised crossover study, the effect of oral NAC dosing on platelet–monocyte conjugation and intraplatelet GSH was investigated in patients with type 2 diabetes (eligibility criteria: men or post-menopausal women with well-controlled diabetes (HbA(1c) < 10%), not on aspirin or statins). Patients (n = 14; age range 43–79 years, HbA(1c) = 6.9 ± 0.9% [52.3 ± 10.3 mmol/mol]) visited the Highland Clinical Research Facility, Inverness, UK on day 0 and day 7 for each arm of the study. Blood was sampled before and 2 h after oral administration of placebo or NAC (1,200 mg) on day 0 and day 7. Patients received placebo or NAC capsules for once-daily dosing on the intervening days. The order of administration of NAC and placebo was allocated by a central office and all patients and research staff involved in the study were blinded to the allocation until after the study was complete and the data fully analysed. The primary outcome for the study was platelet–monocyte conjugation. RESULTS: Oral NAC reduced platelet–monocyte conjugation (from 53.1 ± 4.5% to 42.5 ± 3.9%) at 2 h after administration and the effect was maintained after 7 days of dosing. Intraplatelet GSH was raised in individuals with depleted GSH and there was a negative correlation between baseline intraplatelet GSH and platelet–monocyte conjugation. There were no adverse events. CONCLUSIONS/INTERPRETATION: The NAC-induced normalisation of intraplatelet GSH, coupled with a reduction in platelet–monocyte conjugation, suggests that NAC might help to reduce atherothrombotic risk in type 2 diabetes. FUNDING: Chief Scientist Office (CZB/4/622), Scottish Funding Council, Highlands & Islands Enterprise and European Regional Development Fund. TRIAL REGISTRATION: isrctn.org ISRCTN89304265 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-012-2685-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users

Angiosperm Phylogeny: 17 Genes, 640 Taxa

• Premise of the study : Recent analyses employing up to fi ve genes have provided numerous insights into angiosperm phylogeny, but many relationships have remained unresolved or poorly supported. In the hope of improving our understanding of angiosperm phylogeny, we expanded sampling of taxa and genes beyond previous analyses. • Methods : We conducted two primary analyses based on 640 species representing 330 families. The fi rst included 25 260 aligned base pairs (bp) from 17 genes (representing all three plant genomes, i.e., nucleus, plastid, and mitochondrion). The second included 19 846 aligned bp from 13 genes (representing only the nucleus and plastid). • Key results : Many important questions of deep-level relationships in the nonmonocot angiosperms have now been resolved with strong support. Amborellaceae, Nymphaeales, and Austrobaileyales are successive sisters to the remaining angiosperms ( Mesangiospermae ), which are resolved into Chloranthales + Magnoliidae as sister to Monocotyledoneae + [Ceratophyllaceae + Eudicotyledoneae ]. Eudicotyledoneae contains a basal grade subtending Gunneridae . Within Gunneridae , Gunnerales are sister to the remainder ( Pentapetalae ), which comprises (1) Superrosidae , consisting of Rosidae (including Vitaceae) and Saxifragales; and (2) Superasteridae , comprising Berberidopsidales, Santalales, Caryophyllales , Asteridae , and, based on this study, Dilleniaceae (although other recent analyses disagree with this placement). Within the major subclades of Pentapetalae , most deep-level relationships are resolved with strong support. • Conclusions : Our analyses confi rm that with large amounts of sequence data, most deep-level relationships within the angiosperms can be resolved. We anticipate that this well-resolved angiosperm tree will be of broad utility for many areas of biology, including physiology, ecology, paleobiology, and genomics

Know Thyself: Behavioral Evidence for a Structural Representation of the Human Body

Background: Representing one's own body is often viewed as a basic form of self-awareness. However, little is known about structural representations of the body in the brain.Methods and Findings: We developed an inter-manual version of the classical "in-between'' finger gnosis task: participants judged whether the number of untouched fingers between two touched fingers was the same on both hands, or different. We thereby dissociated structural knowledge about fingers, specifying their order and relative position within a hand, from tactile sensory codes. Judgments following stimulation on homologous fingers were consistently more accurate than trials with no or partial homology. Further experiments showed that structural representations are more enduring than purely sensory codes, are used even when number of fingers is irrelevant to the task, and moreover involve an allocentric representation of finger order, independent of hand posture.Conclusions: Our results suggest the existence of an allocentric representation of body structure at higher stages of the somatosensory processing pathway, in addition to primary sensory representation