A cross-sectional study of Victorian mobile intensive care ambulance paramedics knowledge of the Valsalva manoeuvre

<p>Abstract</p> <p>Background</p> <p>The Valsalva Manoeuvre (VM) is a primary measure for terminating haemodynamically stable supraventricular tachycardia (SVT) in the emergency care setting. The clinical use and termination success of the VM in the prehospital setting has not been investigated to date. The objective of this study was to determine Melbourne Mobile Intensive Care Ambulance (MICA) Paramedic knowledge of the VM, and to compare this understanding with an evidence-based model of VM performance.</p> <p>Methods</p> <p>A cross-sectional study in the form of a face-to-face interview was used to determine Melbourne MICA Paramedic understanding of VM instruction between January and February, 2008. The results were then compared with an evidence-based model of VM performance to ascertain compliance with the three criteria of position, pressure and duration. Ethics approval was granted.</p> <p>Results</p> <p>There were 28 participants (60.9%) who elected a form of supine posturing, some 23 participants (50%) selected the syringe method of pressure generation, with 16 participants (34.8%) selecting the "as long as you can" option for duration. On comparison, one out of 46 MICA Paramedics correctly identified the three evidence-based criteria.</p> <p>Conclusions</p> <p>The formal education of Melbourne's MICA Paramedics would benefit from the introduction of an evidence based model of VM performance, which would impact positively on patient care and may improve reversion success in the prehospital setting. The results of this study also demonstrate that an opportunity exists to promote the evidence-based VM criteria across the primary emergency care field.</p

Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis

RATIONALE Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-Aa and VEGF-Ab, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF. OBJECTIVES To establish VEGF-A isoform expression and functional effects in IPF. METHODS We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTATetoCreLoxP-VEGF-Ato conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice. MEASUREMENTS AND MAIN RESULTS IPF and normal lung fibroblasts differentially expressed and responded to VEGF-Aa and VEGF-Ab in terms of proliferation and matrix expression. Increased VEGF-Ab was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-Ab inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-Ab to wild-type mice. CONCLUSIONS These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Aa to VEGF-Ab, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Scaling Up Global Health Interventions: A Proposed Framework for Success

Drawing upon interviews with experts and a review of the literature, Gavin Yamey proposes a new framework for scaling up global health interventions

Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells

The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage

c-Rel Controls Multiple Discrete Steps in the Thymic Development of Foxp3+ CD4 Regulatory T Cells

The development of natural Foxp3+ CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25+GITRhiFoxp3−CD4+ nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-κB transcription factor required for nTreg differentiation, we establish that c-Rel regulates both of these developmental steps. c-Rel controls the generation of nTreg precursors via a haplo-insufficient mechanism, indicating that this step is highly sensitive to c-Rel levels. However, maintenance of c-Rel in an inactive state in nTreg precursors demonstrates that it is not required for a constitutive function in these cells. While the subsequent IL-2 induction of Foxp3 in nTreg precursors requires c-Rel, this developmental transition does not coincide with the nuclear expression of c-Rel. Collectively, our results support a model of nTreg differentiation in which c-Rel generates a permissive state for foxp3 transcription during the development of nTreg precursors that influences the subsequent IL-2 dependent induction of Foxp3 without a need for c-Rel reactivation

Impaired Innate Immunity in Tlr4−/− Mice but Preserved CD8+ T Cell Responses against Trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-Deficient Mice

The murine model of T. cruzi infection has provided compelling evidence that development of host resistance against intracellular protozoans critically depends on the activation of members of the Toll-like receptor (TLR) family via the MyD88 adaptor molecule. However, the possibility that TLR/MyD88 signaling pathways also control the induction of immunoprotective CD8+ T cell-mediated effector functions has not been investigated to date. We addressed this question by measuring the frequencies of IFN-γ secreting CD8+ T cells specific for H-2Kb-restricted immunodominant peptides as well as the in vivo Ag-specific cytotoxic response in infected animals that are deficient either in TLR2, TLR4, TLR9 or MyD88 signaling pathways. Strikingly, we found that T. cruzi-infected Tlr2−/−, Tlr4−/−, Tlr9−/− or Myd88−/− mice generated both specific cytotoxic responses and IFN-γ secreting CD8+ T cells at levels comparable to WT mice, although the frequency of IFN-γ+CD4+ cells was diminished in infected Myd88−/− mice. We also analyzed the efficiency of TLR4-driven immune responses against T. cruzi using TLR4-deficient mice on the C57BL genetic background (B6 and B10). Our studies demonstrated that TLR4 signaling is required for optimal production of IFN-γ, TNF-α and nitric oxide (NO) in the spleen of infected animals and, as a consequence, Tlr4−/− mice display higher parasitemia levels. Collectively, our results indicate that TLR4, as well as previously shown for TLR2, TLR9 and MyD88, contributes to the innate immune response and, consequently, resistance in the acute phase of infection, although each of these pathways is not individually essential for the generation of class I-restricted responses against T. cruzi

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Assessing the predictability of self-harm in a high-risk adult prisoner population: a prospective cohort study

Background: Prisoners are at increased risk of self-harm and when either intent is expressed, or an act of self-harm carried out, prisoners in the UK are subject to self-harm/suicide monitoring (referred to as “open ACCT” monitoring). However, there is a paucity of validated instruments to identify risk of self-harm in prisoner populations. In response to the need to support prison staff to determine who is at increased risk of self-harm or repeat self-harm, the aim of this study was to determine whether any pre-existing, standardised instruments could usefully identify future self-harm events in prisoners undergoing ACCT monitoring. Methods: A multi-stage prospective cohort study was conducted, where the Prison Screening Questionnaire (PriSnQuest), a modified Borderline Symptom List-23 (BSL-23), Self-Harm Inventory (SHI), Patient Health Questionnaire-9 (PHQ-9) and Clinical Outcomes in Routine Evaluation – Outcome Measure (CORE-OM) instruments were administered to prisoners aged 18 and above, who were judged to be at an increased risk of self-harm (on open ACCT monitoring) during the recruitment phase. A 6-month follow-up determined self-harm occurrence since baseline, and Area-Under-the-Curve (AUC) analysis examined the ability of the instruments to predict future self-harm. Results: Prison records established that 29.1% self-harmed during the follow up period, involving a total of 423 self-harm events reported from 126 individuals, followed up for 66,789 prisoner days (median 167 days; IQR 71–207.5 days). This translated to an ‘event incidence’ of 6.33 per 1000 prisoner days of those who had been placed upon an ACCT, or ‘prisoner incidence’ of 1.89 per 1000 days, with considerable variation for both gender and participating prisons. None of the summary scores derived from the selected instruments showed a meaningful ability to predict self-harm, however, exploratory logistic regression analysis of individual background and instrument items revealed gender-specific item sets which were statistically significant in predicting future self-harm. Conclusions: Prospective self-harm was not predicted by any of the pre-existing instruments that were under consideration. Exploratory logistic regression analysis did reveal gender-specific item sets, producing predictive algorithms which were statistically significant in predicting future self-harm; however, the operational functionality of these item sets may be limited