Year in review 2009: Critical Care - shock

The research papers on shock that have been published in Critical Care throughout 2009 are related to four major subjects: first, alterations of heart function and, second, the role of the sympathetic central nervous system during sepsis; third, the impact of hemodynamic support using vasopressin or its synthetic analog terlipressin, and different types of fluid resuscitation; as well as, fourth, experimental studies on the treatment of acute respiratory distress syndrome. The present review summarizes the key results of these studies together with a brief discussion in the context of the relevant scientific and clinical background published both in this and other journals

The PROblem Gambling RESearch Study (PROGRESS) research protocol: a pragmatic randomised controlled trial of psychological interventions for problem gambling.

INTRODUCTION: International prevalence rates for problem gambling are estimated at 2.3%. Problem gambling is a serious global public health concern due to adverse personal and social consequences. Previous research evaluating the effectiveness of psychological interventions for the treatment of problem gambling has been compromised by methodological limitations, including small sample sizes and the use of waitlist control groups. This article describes the study protocol for a pragmatic randomised controlled trial (RCT) evaluating the effectiveness of cognitive-behavioural therapy (CBT), behaviour therapy (BT), motivational interviewing (MI) against a non-directive supportive therapy (NDST) control, in treating problem gambling. METHODS AND ANALYSIS: This study was a mixed-methods design, with a parallel group, pragmatic RCT as the primary component, and embedded qualitative studies conducted alongside. A total of 297 participants were recruited from the community in Victoria, Australia. Individuals aged 18 years and over, could communicate in English and wished to receive treatment for a gambling problem were eligible. Participants were randomly allocated in to 1 of the 4 psychological interventions: CBT, BT, MI and NDST. Repeated measures were conducted at pretreatment and post-treatment, and 6 and 12 months post-treatment. The statistical analysis will use an intention-to-treat approach. Multilevel mixed modelling will be used to examine changes in the primary outcome measures: gambling symptom severity, using the Gambling Symptom Assessment Scale, and gambling behaviours (frequency, time and expenditure). Secondary outcomes are depression, anxiety, stress and alcohol use. Individual semistructured qualitative interviews were conducted at pretreatment and post-treatment and 12 months post-treatment for a subset of participants (n=66). ETHICS AND DISSEMINATION: This study was approved by the Victorian Department of Justice, Monash University and the University of Melbourne Human Research Ethics Committees. Findings will be reported in a government report, peer-reviewed publications and conference presentations

Molecular Structure and Dimeric Organization of the Notch Extracellular Domain as Revealed by Electron Microscopy

Background: The Notch receptor links cell fate decisions of one cell to that of the immediate cellular neighbor. In humans, malfunction of Notch signaling results in diseases and congenital disorders. Structural information is essential for gaining insight into the mechanism of the receptor as well as for potentially interfering with its function for therapeutic purposes. Methodology/Principal Findings: We used the Affinity Grid approach to prepare specimens of the Notch extracellular domain (NECD) of the Drosophila Notch and human Notch1 receptors suitable for analysis by electron microscopy and three-dimensional (3D) image reconstruction. The resulting 3D density maps reveal that the NECD structure is conserved across species. We show that the NECD forms a dimer and adopts different yet defined conformations, and we identify the membrane-proximal region of the receptor and its ligand-binding site. Conclusions/Significance: Our results provide direct and unambiguous evidence that the NECD forms a dimer. Our studies further show that the NECD adopts at least three distinct conformations that are likely related to different functional states of the receptor. These findings open the way to now correlate mutations in the NECD with its oligomeric state and conformation

Negative Staining and Image Classification – Powerful Tools in Modern Electron Microscopy

Vitrification is the state-of-the-art specimen preparation technique for molecular electron microscopy (EM) and therefore negative staining may appear to be an outdated approach. In this paper we illustrate the specific advantages of negative staining, ensuring that this technique will remain an important tool for the study of biological macromolecules. Due to the higher image contrast, much smaller molecules can be visualized by negative staining. Also, while molecules prepared by vitrification usually adopt random orientations in the amorphous ice layer, negative staining tends to induce preferred orientations of the molecules on the carbon support film. Combining negative staining with image classification techniques makes it possible to work with very heterogeneous molecule populations, which are difficult or even impossible to analyze using vitrified specimens

Cardiopulmonary, Histologic, and Inflammatory Effects of Intravenous Na2S After Blunt Chest Trauma-Induced Lung Contusion in Mice

Background: When used as a pretreatment, hydrogen sulfide (H2S) either attenuated or aggravated lung injury. Therefore, we tested the hypothesis whether posttreatment intravenous Na2S (sulfide) may attenuate lung injury.Methods: After blast wave blunt chest trauma or sham procedure, anesthetized and instrumented mice received continuous intravenous sulfide or vehicle while being kept at 37°C or 32°C core temperature. After 4 hours of pressure-controlled, thoracopulmonary compliance-titrated, lung-protective mechanical ventilation, blood and tissue were harvested for cytokine concentrations, heme oxygenase-1, IκBα, Bcl-Xl, and pBad expression (western blotting), nuclear factor-κB activation (electrophoretic mobility shift assay), and activated caspase-3, cystathionine-β synthase and cystathionine-γ lyase (immunohistochemistry). Results: Hypothermia caused marked bradycardia and metabolic acidosis unaltered by sulfide. Chest trauma impaired thoracopulmonary compliance and arterial Po2, again without sulfide effect. Cytokine levels showed inconsistent response. Sulfide increased nuclear factor-κB activation during normothermia, but this effect was blunted during hypothermia. While histologic lung injury was variable, both sulfide and hypothermia attenuated the trauma-related increase in heme oxygenase-1 expression and activated caspase-3 staining, which coincided with increased Bad phosphorylation and Bcl-Xl expression. Sulfide and hypothermia also attenuated the trauma-induced cystathionine-β synthase and cystathionine-γ lyase expression. Conclusions: Posttreatment sulfide infusion after blunt chest trauma did not affect the impaired lung mechanics and gas exchange but attenuated stress protein expression and apoptotic cell death. This protective effect was amplified by moderate hypothermia. The simultaneous reduction in cystathionine-β synthase and cystathionine-γ lyase expression supports the role of H2S-generating enzymes as an adaptive response during stress states