IntroductionAlthough shortcomings in clinician–family communication and decision making for incapacitated, critically ill patients are common, there are few rigorously tested interventions to improve ...outcomes. In this manuscript, we present our methodology for the Pairing Re-engineered Intensive Care Unit Teams with Nurse-Driven Emotional support and Relationship Building (PARTNER 2) trial, and discuss design challenges and their resolution.Methods and analysisThis is a pragmatic, stepped-wedge, cluster randomised controlled trial comparing the PARTNER 2 intervention to usual care among 690 incapacitated, critically ill patients and their surrogates in five ICUs in Pennsylvania. Eligible subjects will include critically ill patients at high risk of death and/or severe long-term functional impairment, their main surrogate decision-maker and their clinicians. The PARTNER intervention is delivered by the interprofessional ICU team and overseen by 4–6 nurses from each ICU. It involves: (1) advanced communication skills training for nurses to deliver support to surrogates throughout the ICU stay; (2) deploying a structured family support pathway; (3) enacting strategies to foster collaboration between ICU and palliative care services and (4) providing intensive implementation support to each ICU to incorporate the family support pathway into clinicians’ workflow. The primary outcome is surrogates’ ratings of the quality of communication during the ICU stay as assessed by telephone at 6-month follow-up. Prespecified secondary outcomes include surrogates’ scores on the Hospital Anxiety and Depression Scale, the Impact of Event Scale, the modified Patient Perception of Patient Centredness scale, the Decision Regret Scale, nurses’ scores on the Maslach Burnout Inventory, and length of stay during and costs of the index hospitalisation.We also discuss key methodological challenges, including determining the optimal level of randomisation, using existing staff to deploy the intervention and maximising long-term follow-up of participants.Ethics and disseminationWe obtained ethics approval through the University of Pittsburgh, Human Research Protection Office. The findings will be published in peer-reviewed journals.Trial registration numberNCT02445937
The article discusses the findings of a study to evaluate the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients ...with sepsis and acute respiratory distress failure (ARDS), which revealed that among these patients, a 96-hour infusion of vitamin C did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. The need is for further research to find an effective therapy for sepsis.
Methods for assaying serine/threonine protein phosphatases are discussed. Three commonly used protocols are presented that employ either colorimetric or radiometric assays. These methods can be used ...to assay a variety of preparations of serine/threonine phosphatases, from crude lysates to purified proteins. Strategies for the application of a particular protocol for a particular purpose are discussed. The assays can be used in either a high-throughput mode where simple comparison of activities can be done, or in specific assays where kinetic data can be derived.
NOTCH and PTEN in prostate cancer Bertrand, Fred E.; McCubrey, James A.; Angus, C. William ...
Advances in biological regulation
56
Journal Article
Recenzirano
Over the past decade, our understanding of the role that Notch-signaling has in tumorigenesis has shifted from leukemogenesis into cancers of solid tumors. Emerging data suggests that in addition to ...direct effects mediated through the canonical Notch pathway, Notch may participate in epithelial tumor development through regulation of pathways such as PTEN/PI3K/Akt. Prostate cancer is a disease for which PTEN gene expression is especially essential. This review will summarize a role for Notch in prostate development and cancer with an emphasis on how the Notch pathway may intersect with PTEN/PI3K/Akt and mTOR signaling.
Since the publication of the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07), diagnostic criteria and severity assessment criteria for acute cholangitis have been ...presented and extensively used as the primary standard all over the world. However, it has been found that there are crucial limitations in these criteria. The diagnostic criteria of TG07 do not have enough sensitivity and specificity, and its severity assessment criteria are unsuitable for clinical use. A working team for the revision of TG07 was organized in June, 2010, and these criteria have been updated through clinical implementation and its assessment by means of multi-center analysis. The diagnostic criteria of acute cholangitis have been revised as criteria to establish the diagnosis where cholestasis and inflammation demonstrated by clinical signs or blood test in addition to biliary manifestations demonstrated by imaging are present. The diagnostic criteria of the updated Tokyo Guidelines (TG13) have high sensitivity (87.6 %) and high specificity (77.7 %). TG13 has better diagnostic capacity than TG07. Severity assessment is classified as follows: Grade III: associated with organ failure; Grade II: early biliary drainage should be conducted; Grade1: others. As for the severity assessment criteria of TG07, separating Grade II and Grade I at the time of diagnosis was impossible, so they were unsuitable for clinical practice. Therefore, the severity assessment criteria of TG13 have been revised so as not to lose the timing of biliary drainage or treatment for etiology. Based on evidence, five predictive factors for poor prognosis in acute cholangitis––hyperbilirubinemia, high fever, leukocytosis, elderly patient and hypoalbuminemia––have been extracted. Grade II can be diagnosed if two of these five factors are present.
Free full-text articles and a mobile application of TG13 are available via
http://www.jshbps.jp/en/guideline/tg13.html
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Regulator of calmodulin (CaM) signaling (RCS), when phosphorylated by protein kinase A (PKA) on Ser55, binds to CaM and inhibits CaM‐dependent signaling. RCS expression is high in the dorsal ...striatum, nucleus accumbens and amygdala, suggesting that the protein is involved in limbic‐striatal function. To test this hypothesis, we examined RCS knockout (KO) mice in behavioral models dependent on these brain areas. Mice were tested for food‐reinforced instrumental conditioning and responding under a progressive ratio (PR) schedule of reinforcement and in models of anxiety (elevated plus maze and open field). While RCS KO mice showed normal acquisition of a food‐motivated instrumental response, they exhibited a lower breakpoint value when tested on responding under a PR schedule of reinforcement. RCS KO mice also displayed decreased exploration in both the open arms of an elevated plus maze and in the center region of an open field, suggesting an enhanced anxiety response. Biochemical studies revealed a reduction in the levels of dopamine and cAMP‐regulated phosphoprotein (DARPP‐32) in the striatum of RCS KO mice. DARPP‐32 is important in reward‐mediated behavior, suggestive of a possible role for DARPP‐32 in mediating some of the effects of RCS. Together these results implicate a novel PKA‐regulated phosphoprotein, RCS, in the etiology of motivational deficits and anxiety.
Regulator of calmodulin (CaM) signaling (RCS), when phosphorylated by protein kinase A (PKA) on Ser55, binds to CaM and inhibits CaM‐dependent signaling. RCS expression is high in the dorsal striatum, nucleus accumbens and amygdala, suggesting that the protein is involved in limbic‐striatal function.
The Mg2+-inhibited cation (MIC) current, believed to represent activity of TRPM7 channels, is found in lymphocytes and mast cells, cardiac and smooth muscle, and several other eukaryotic cell types. ...MIC current is activated during whole-cell dialysis with divalent-free internal solutions. Millimolar concentrations of intracellular Mg2+ (or other divalent metal cations) inhibit the channels in a voltage-independent manner. The nature of divalent inhibition and the mechanism of channel activation in an intact cell remain unknown. We show that the polyamines (spermine, spermidine, and putrescine) inhibit the MIC current, also in a voltage-independent manner, with a potency that parallels the number of charges. Neomycin and poly-lysine also potently inhibited MIC current in the absence of Mg2+. These same positively charged ions inhibited IRK1 current in parallel with MIC current, suggesting that they probably act by screening the head group phosphates on PIP2 and other membrane phospholipids. In agreement with this hypothesis, internal protons also inhibited MIC current. By contrast, tetramethylammonium, tetraethylammonium, and hexamethonium produced voltage-dependent block but no inhibition. We show that inhibition by internal polyvalent cations can be relieved by alkalinizing the cytosol using externally applied ammonium or by increasing pH in inside-out patches. Furthermore, in perforated-patch and cell-attached recordings, when intracellular Mg2+ is not depleted, endogenous MIC or recombinant TRPM7 currents are activated by cytosolic alkalinization and inhibited by acidification; and they can be reactivated by PIP2 following rundown in inside-out patches. We propose that MIC (TRPM7) channels are regulated by a charge screening mechanism and may function as sensors of intracellular pH.
Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those ...involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of short non-coding RNAs that regulate mRNA stability/translation, remains largely unexplored. Here we show that transcription of the miR-183 cluster (miR-183, miR-96, and miR-182) is selectively induced by HSV-1 during productive infection of primary fibroblasts and neurons. ICP0, a viral E3 ubiquitin ligase expressed as an immediate-early protein, is both necessary and sufficient for this induction. Nuclear exclusion of ICP0 or removal of the RING (really interesting new gene) finger domain that is required for E3 ligase activity prevents induction. ICP0 promotes the degradation of numerous host proteins and for the most part, the downstream consequences are unknown. Induction of the miR-183 cluster can be mimicked by depletion of host transcriptional repressors zinc finger E-box binding homeobox 1 (ZEB1)/-crystallin enhancer binding factor 1 (δEF1) and zinc finger E-box binding homeobox 2 (ZEB2)/Smad-interacting protein 1 (SIP1), which we establish as new substrates for ICP0-mediated degradation. Thus, HSV-1 selectively stimulates expression of the miR-183 cluster by ICP0-mediated degradation of ZEB transcriptional repressors.
OBJECTIVE:Quality improvement is an important activity for all members of the interdisciplinary critical care team. Although an increasing number of resources are available to guide clinicians, ...quality improvement activities can be overwhelming. Therefore, the Society of Critical Care Medicine charged this Outcomes Task Force with creating a “how-to” guide that focuses on critical care, summarizes key concepts, and outlines a practical approach to the development, implementation, evaluation, and maintenance of an interdisciplinary quality improvement program in the intensive care unit.
DATA SOURCES AND METHODS:The task force met in person twice and by conference call twice to write this document. We also conducted a literature search on “quality improvement” and “critical care or intensive care” and searched online for additional resources.
DATA SYNTHESIS AND OVERVIEW:We present an overview of quality improvement in the intensive care unit setting and then describe the following steps for initiating or improving an interdisciplinary critical care quality improvement programa) identify local motivation, support teamwork, and develop strong leadership; b) prioritize potential projects and choose the first target; c) operationalize the measures, build support for the project, and develop a business plan; d) perform an environmental scan to better understand the problem, potential barriers, opportunities, and resources for the project; e) create a data collection system that accurately measures baseline performance and future improvements; f) create a data reporting system that allows clinicians and others to understand the problem; g) introduce effective strategies to change clinician behavior. In addition, we identify four steps for evaluating and maintaining this programa) determine whether the target is changing with periodic data collection; b) modify behavior change strategies to improve or sustain improvements; c) focus on interdisciplinary collaboration; and d) develop and sustain support from the hospital leadership. We also identify a number of online resources to complement this overview.
CONCLUSIONS:This Society of Critical Care Medicine Task Force report provides an overview for clinicians interested in developing or improving a quality improvement program using a step-wise approach. Success depends not only on committed interdisciplinary work that is incremental and continuous but also on strong leadership. Further research is needed to refine the methods and identify the most cost-effective means of improving the quality of health care received by critically ill patients and their families.
•A variety of reinforcing strategies are proposed for double-coped beams.•The failure mechanism of reinforced double-coped beams is investigated.•Extensive numerical models are established and ...analysed.•A comprehensive set of design rules is proposed.
This paper presents a comprehensive numerical study on the strength and behaviour of double-coped beams (DCBs), with the focus on reinforcing strategies against local web buckling. Four reinforcement types, namely, longitudinal web stiffener (Type A), combined longitudinal and vertical web stiffeners (Type B), vertical and double longitudinal web stiffeners (Type C), and full-depth doubler plate (Type D), are considered. Through examining a suite of validated numerical models with a spectrum of cope details, it is found that the considered reinforcement types are in general effective, especially for the models with long or deep copes. Depending on the cope details and stiffener type, a series of failure modes, including local web buckling, web shear yielding, web shear buckling, tensile fracture of the bottom cope corner, and web crippling, are identified, and the effectiveness of the different reinforcement types on preventing or postponing these failure modes is discussed in detail. A preliminary design rule for checking the capacity of the reinforced coped section is also proposed in the paper, and additional analysis is performed to further evaluate the influences of varying reinforcement dimensions and boundary conditions on the ultimate capacity of the DCBs. Based on the numerical analysis, a set of prescriptive recommendations on reinforcement details is finally proposed, offering a simple yet safe guidance for new design or upgrade of DCB members.
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