Inhibition of neurite outgrowth in differentiating mouse N2a neuroblastoma cells by phenyl saligenin phosphate: Effects on MAP kinase (ERK 1/2) activation, neurofilament heavy chain phosphorylation and neuropathy target esterase activity

Sub-lethal concentrations of the organophosphate phenyl saligenin phosphate (PSP) inhibited the outgrowth of axon-like processes in differentiating mouse N2a neuroblastoma cells (IC50 2.5 μM). A transient rise in the phosphorylation state of neurofilament heavy chain (NFH) was detected on Western blots of cell extracts treated with 2.5 μM PSP for 4 h compared to untreated controls, as determined by a relative increase in reactivity with monoclonal antibody Ta51 (anti-phosphorylated NFH) compared to N52 (anti-total NFH). However, cross-reactivity of PSP-treated cell extracts was lower than that of untreated controls after 24 h exposure, as indicated by decreased reactivity with both antibodies. Indirect immunofluorescence analysis with these antibodies revealed the appearance of neurofilament aggregates in the cell bodies of treated cells and reduced axonal staining compared to controls. By contrast, there was no significant change in reactivity with anti-a tubulin antibody B512 at either time point. The activation state of the MAP kinase ERK 1/2 increased significantly after PSP treatment compared to controls, particularly at 4 h, as indicated by increased reactivity with monoclonal antibody E-4 (anti-phosphorylated MAP kinase) but not with polyclonal antibody K-23 (anti-total MAP kinase). The observed early changes were concomitant with almost complete inhibition of the activity of neuropathy target esterase (NTE), one of the proposed early molecular targets in organophosphate-induced delayed neuropathy (OPIDN)

Assessing the uncertainties of model estimates of primary productivity in the tropical Pacific Ocean

Author Posting. © Elsevier B.V., 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Marine Systems 76 (2009): 113-133, doi:10.1016/j.jmarsys.2008.05.010.Depth-integrated primary productivity (PP) estimates obtained from satellite ocean color based models (SatPPMs) and those generated from biogeochemical ocean general circulation models (BOGCMs) represent a key resource for biogeochemical and ecological studies at global as well as regional scales. Calibration and validation of these PP models are not straightforward, however, and comparative studies show large differences between model estimates. The goal of this paper is to compare PP estimates obtained from 30 different models (21 SatPPMs and 9 BOGCMs) to a tropical Pacific PP database consisting of ~1000 14C measurements spanning more than a decade (1983- 1996). Primary findings include: skill varied significantly between models, but performance was not a function of model complexity or type (i.e. SatPPM vs. BOGCM); nearly all models underestimated the observed variance of PP, specifically yielding too few low PP (< 0.2 gC m-2d-2) values; more than half of the total root-mean-squared model-data differences associated with the satellite-based PP models might be accounted for by uncertainties in the input variables and/or the PP data; and the tropical Pacific database captures a broad scale shift from low biomass-normalized productivity in the 1980s to higher biomass-normalized productivity in the 1990s, which was not successfully captured by any of the models. This latter result suggests that interdecadal and global changes will be a significant challenge for both SatPPMs and BOGCMs. Finally, average root-mean-squared differences between in situ PP data on the equator at 140°W and PP estimates from the satellite-based productivity models were 58% lower than analogous values computed in a previous PP model comparison six years ago. The success of these types of comparison exercises is illustrated by the continual modification and improvement of the participating models and the resulting increase in model skill.This research was supported by a grant from the National Aeronautics and Space Agency Ocean Biology and Biogeochemistry program (NNG06GA03G), as well as by numerous other grants to the various participating investigator

Agreement between routine electronic hospital discharge and Scottish Stroke Care Audit (SSCA) data in identifying stroke in the Scottish population

Background In Scotland all non-obstetric, non-psychiatric acute inpatient and day case stays are recorded by an administrative hospital discharge database, the Scottish Morbidity Record (SMR01). The Scottish Stroke Care Audit (SSCA) collects data from all hospitals managing acute stroke in Scotland to support and improve quality of stroke care. The aim was to assess whether there were discrepancies between these data sources for admissions from 2010 to 2011. Methods Records were matched when admission dates from the two data sources were within two days of each other and if an International Classification of Diseases (ICD) code of I61, I63, I64, or G45 was in the primary or secondary diagnosis field on SMR01. We also carried out a linkage analysis followed by a case-note review within one hospital in Scotland. Results There were a total of 22 416 entries on SSCA and 22 200 entries on SMR01. The concordance between SSCA and SMR01 was 16 823. SSCA contained 5593 strokes that were not present in SMR01, whereas SMR01 contained 185 strokes that were not present in SSCA. In the case-note review the concordance was 531, with SSCA containing 157 strokes that were not present in SMR01 and SMR01 containing 32 strokes that were not present in SSCA. Conclusions When identifying strokes, hospital administrative discharge databases should be used with caution. Our results demonstrate that SSCA most accurately represents the number of strokes occurring in Scotland. This resource is useful for determining the provision of adequate patient care, stroke services and resources, and as a tool for research

Effector Memory Th1 CD4 T Cells Are Maintained in a Mouse Model of Chronic Malaria

Protection against malaria often decays in the absence of infection, suggesting that protective immunological memory depends on stimulation. Here we have used CD4+ T cells from a transgenic mouse carrying a T cell receptor specific for a malaria protein, Merozoite Surface Protein-1, to investigate memory in a Plasmodium chabaudi infection. CD4+ memory T cells (CD44hiIL-7Rα+) developed during the chronic infection, and were readily distinguishable from effector (CD62LloIL-7Rα−) cells in acute infection. On the basis of cell surface phenotype, we classified memory CD4+ T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62LloCD27+) dominated the chronic infection. We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells. In adoptive transfer, CD44hi memory cells from chronically infected mice were more effective at delaying and reducing parasitemia and pathology than memory cells from drug-treated mice without chronic infection, and contained a greater proportion of effector cells producing IFN-γ and TNFα, which may have contributed to the enhanced protection. These findings may explain the observation that in humans with chronic malaria, activated effector memory cells are best maintained in conditions of repeated exposure

An exploration of influences on women’s birthplace decision-making in New Zealand: a mixed methods prospective cohort within the Evaluating Maternity Units study

BACKGROUND: There is worldwide debate surrounding the safety and appropriateness of different birthplaces for well women. One of the primary objectives of the Evaluating Maternity Units prospective cohort study was to compare the clinical outcomes for well women, intending to give birth in either an obstetric-led tertiary hospital or a free-standing midwifery-led primary maternity unit. This paper addresses a secondary aim of the study – to describe and explore the influences on women’s birthplace decision-making in New Zealand, which has a publicly funded, midwifery-led continuity of care maternity system. METHODS: This mixed method study utilised data from the six week postpartum survey and focus groups undertaken in the Christchurch area in New Zealand (2010–2012). Christchurch has a tertiary hospital and four primary maternity units. The survey was completed by 82% of the 702 study participants, who were well, pregnant women booked to give birth in one of these places. All women received midwifery-led continuity of care, regardless of their intended or actual birthplace. RESULTS: Almost all the respondents perceived themselves as the main birthplace decision-makers. Accessing a ‘specialist facility’ was the most important factor for the tertiary hospital group. The primary unit group identified several factors, including ‘closeness to home’, ‘ease of access’, the ‘atmosphere’ of the unit and avoidance of ‘unnecessary intervention’ as important. Both groups believed their chosen birthplace was the right and ‘safe’ place for them. The concept of ‘safety’ was integral and based on the participants’ differing perception of safety in childbirth. CONCLUSIONS: Birthplace is a profoundly important aspect of women’s experience of childbirth. This is the first published study reporting New Zealand women’s perspectives on their birthplace decision-making. The groups’ responses expressed different ideologies about childbirth. The tertiary hospital group identified with the ‘medical model’ of birth, and the primary unit group identified with the ‘midwifery model’ of birth. Research evidence affirming the ‘clinical safety’ of primary units addresses only one aspect of the beliefs influencing women’s birthplace decision-making. In order for more women to give birth at a primary unit other aspects of women’s beliefs need addressing, and much wider socio-political change is required

A descriptive exploratory study of how admissions caused by medication-related harm are documented within inpatients' medical records.

BACKGROUND: Adverse drug reactions, poor patient adherence and errors, here collectively referred to as medication-related harm (MRH), cause around 2.7-8.0% of UK hospital admissions. Communication gaps between successive healthcare providers exist, but little is known about how MRH is recorded in inpatients' medical records. We describe the presence and quality of MRH documentation for patients admitted to a London teaching hospital due to MRH. Additionally, the international classification of disease 10th revision (ICD-10) codes attributed to confirmed MRH-related admissions were studied to explore appropriateness of their use to identify these patients. METHODS: Clinical pharmacists working on an admissions ward in a UK hospital identified patients admitted due to suspected MRH. Six different data sources in each patient's medical record, including the discharge summary, were subsequently examined for MRH-related information. Each data source was examined for statements describing the MRH: symptom and diagnosis, identification of the causative agent, and a statement of the action taken or considered. Statements were categorised as 'explicit' if unambiguous or 'implicit' if open to interpretation. ICD-10 codes attributed to confirmed MRH cases were recorded. RESULTS: Eighty-four patients were identified over 141 data collection days; 75 met our inclusion criteria. MRH documentation was generally present (855 of 1307 statements were identified; 65%), and usually explicit (705 of 855; 82%). The causative agent had the lowest proportion of explicit statements (139 of 201 statements were explicit; 69%). For two (3%) discharged patients, the causal agent was documented in their paper medical record but not on the discharge summary. Of 64 patients with a confirmed MRH diagnosis at discharge, only six (9%) had a MRH-related ICD-10 code. CONCLUSIONS: Availability of information in the paper medical record needs improving and communication of MRH-related information could be enhanced by using explicit statements and documenting reasons for changing medications. ICD-10 codes underestimate the true occurrence of MRH

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Synergistic Reversal of Intrahepatic HCV-Specific CD8 T Cell Exhaustion by Combined PD-1/CTLA-4 Blockade

Viral persistence is associated with hierarchical antiviral CD8 T cell exhaustion with increased programmed death-1 (PD-1) expression. In HCV persistence, HCV-specific CD8 T cells from the liver (the site of viral replication) display increased PD-1 expression and a profound functional impairment that is not reversed by PD-1 blockade alone. Here, we report that the inhibitory receptor cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is preferentially upregulated in PD-1+ T cells from the liver but not blood of chronically HCV-infected patients. PD-1/CTLA-4 co-expression in intrahepatic T cells was associated with a profound HCV-specific effector dysfunction that was synergistically reversed by combined PD-1/CTLA-4 blockade in vitro, but not by blocking PD-1 or CTLA-4 alone. A similar effect was observed in circulating HCV-specific CD8 T cells with increased PD-1/CTLA-4 co-expression during acute hepatitis C. The functional response to combined blockade was directly associated with CTLA-4 expression, lost with CD28-depletion and CD4-independent (including CD4+FoxP3+ Tregs). We conclude that PD-1 and CTLA-4 pathways both contribute to virus-specific T cell exhaustion at the site of viral replication by a redundant mechanism that requires combined PD-1/CTLA-4 blockade to reverse. These findings provide new insights into the mechanisms of virus-specific T cell dysfunction, and suggest that the synergistic effect by combined inhibitory receptor blockade might have a therapeutic application against chronic viral infection in vivo, provided that it does not induce autoimmunity

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy