Bench-to-bedside review: Mechanisms of critical illness – classifying microcirculatory flow abnormalities in distributive shock

Over 30 years ago Weil and Shubin proposed a re-classification of shock states and identified hypovolemic, cardiogenic, obstructive and distributive shock. The first three categories have in common that they are associated with a fall in cardiac output. Distributive shock, such as occurs during sepsis and septic shock, however, is associated with an abnormal distribution of microvascular blood flow and metabolic distress in the presence of normal or even supranormal levels of cardiac output. This Bench-to-bedside review looks at the recent insights that have been gained into the nature of distributive shock. Its pathophysiology can best be described as a microcirculatory and mitochondrial distress syndrome, where time and therapy form an integral part of the definition. The clinical introduction of new microcirculatory imaging techniques, such as orthogonal polarization spectral and side-stream dark-field imaging, have allowed direct observation of the microcirculation at the bedside. Images of the sublingual microcirculation during septic shock and resuscitation have revealed that the distributive defect of blood flow occurs at the capillary level. In this paper, we classify the different types of heterogeneous flow patterns of microcirculatory abnormalities found during different types of distributive shock. Analysis of these patterns gave a five class classification system to define the types of microcirculatory abnormalities found in different types of distributive shock and indicated that distributive shock occurs in many other clinical conditions than just sepsis and septic shock. It is likely that different mechanisms defined by pathology and treatment underlie these abnormalities observed in the different classes. Functionally, however, they all cause a distributive defect resulting in microcirculatory shunting and regional dysoxia. It is hoped that this classification system will help in the identification of mechanisms underlying these abnormalities and indicate optimal therapies for resuscitating septic and other types of distributive shock

An accurate test for homogeneity of odds ratios based on Cochran's Q-statistic

Background: A frequently used statistic for testing homogeneity in a meta-analysis of K independent studies is Cochran's Q. For a standard test of homogeneity the Q statistic is referred to a chi-square distribution with K - 1 degrees of freedom. For the situation in which the effects of the studies are logarithms of odds ratios, the chi-square distribution is much too conservative for moderate size studies, although it may be asymptotically correct as the individual studies become large. Methods: Using a mixture of theoretical results and simulations, we provide formulas to estimate the shape and scale parameters of a gamma distribution to t the distribution of Q. Results: Simulation studies show that the gamma distribution is a good approximation to the distribution for Q. Conclusions: : Use of the gamma distribution instead of the chi-square distribution for Q should eliminate inaccurate inferences in assessing homogeneity in a meta-analysis. (A computer program for implementing this test is provided.) This hypothesis test is competitive with the Breslow-Day test both in accuracy of level and in power

Withdrawing intra-aortic balloon pump support paradoxically improves microvascular flow

Introduction: The Intra-Aortic Balloon Pump (IABP) is frequently used to mechanically support the heart. There is evidence that IABP improves microvascular flow during cardiogenic shock but its influence on the human microcirculation in patients deemed ready for discontinuing IABP support has not yet been studied. Therefore we used sidestream dark field imaging (SDF) to test our hypothesis that human microcirculation remains unaltered with or without IABP support in patients clinically ready for discontinuation of mechanical support. Methods: We studied 15 ICU patients on IABP therapy. Measurements were performed after the clinical decision was made to remove the balloon catheter. We recorded global hemodynamic parameters and performed venous oximetry during maximal IABP support (1:1) and 10 minutes after temporarily stopping the IABP therapy. At both time points, we also recorded video clips of the sublingual microcirculation. From these we determined indices of microvascular perfusion including perfused vessel density (PVD) and microvascular flow index (MFI). Results: Ceasing IABP support lowered mean arterial pressure (74 +/- 8 to 71 +/- 10 mmHg; P = 0.048) and increased diastolic pressure (43 +/- 10 to 53 +/- 9 mmHg; P = 0.0002). However, at the level of the microcirculation we found an increase of PVD of small vessels <20 mu m (5.47 +/- 1.76 to 6.63 +/- 1.90; P = 0.0039). PVD for vessels >20 mu m and MFI for both small and large vessels were unaltered. During the procedure global oxygenation parameters (ScvO(2)/SvO(2)) remained unchanged. Conclusions: In patients deemed ready for discontinuing IABP support according to current practice, SDF imaging showed an increase of microcirculatory flow of small vessels after ceasing IABP therapy. This observation may indicate that IABP impairs microvascular perfusion in recovered patients, although this warrants confirmatio

Machine learning in intensive care medicine: ready for take-off?

In 1986 the world was shaken by the Challenger space shuttle disaster. In the years that followed, the American National Aeronautics and Space Administration (NASA) called for a strategy change in space technology development [1]. Allowing technology to be developed without a specific space program in mind was central to the new strategy [2]. In order to evaluate resulting projects with no direct contribution to a space mission, NASA introduced the general concept of technology readiness levels (TRLs) [3]. These nine levels, adopted by many EU institutions, assess the maturity level of technology and estimate its readiness to fly

The deubiquitylating enzyme UCHL3 regulates Ku80 retention at sites of DNA damage.

Non-homologous end-joining (NHEJ), which can promote genomic instability when dysfunctional, is a major DNA double-strand break (DSB) repair pathway. Although ubiquitylation of the core NHEJ factor, Ku (Ku70-Ku80), which senses broken DNA ends, is important for its removal from sites of damage upon completion of NHEJ, the mechanism regulating Ku ubiquitylation remains elusive. We provide evidence showing that the ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) interacts with and directly deubiquitylates one of the Ku heterodimer subunits, Ku80. Additionally, depleting UCHL3 resulted in reduced Ku80 foci formation, Ku80 binding to chromatin after DSB induction, moderately sensitized cells to ionizing radiation and decreased NHEJ efficiencies. Mechanistically, we show that DNA damage induces UCHL3 phosphorylation, which is dependent on ATM, downstream NHEJ factors and UCHL3 catalytic activity. Furthermore, this phosphorylation destabilizes UCHL3, despite having no effect on its catalytic activity. Collectively, these data suggest that UCHL3 facilitates cellular viability after DSB induction by antagonizing Ku80 ubiquitylation to enhance Ku80 retention at sites of damage.This work was funded by Grant-in-Aid for Research Activity start-up 15H06738 (R.N.), Grant-in Aid for Young Scientists (A) 16H05888 (R.N.), Daiichi Sankyo Foundation of Life Science (R.N.), Mochida Memorial Foundation for Medical and Pharmaceutical Research (R.N.), Cancer Research UK (CRUK) Grant C6/A11224 and C6/A18796 (P.W.), CRUK Project Grant C6/A14831 (R.N.). T.L.B. and Q.W. are funded by Wellcome Trust Investigator Award (200814_Z_16_Z). Research in the B.M.K. laboratory is supported by a John Fell Fund 133/075, the Wellcome Trust (097813/Z/11/Z) and the Engineering and Physical Sciences Research Council (EP/N034295/1). Research in the S.P.J. laboratory is funded by CRUK Program Grant C6/A18796, and Wellcome Trust Grant WT206388/Z/17/Z. Cancer Research UK Grant C6946/A24843 and Wellcome Trust Grant WT203144 provided core infrastructure funding

Historical Criminology and the Explanatory Power of the Past

To what extent can the past ‘explain’ the present? This deceptively simple question lies at the heart of historical criminology (research which incorporates historical primary sources while addressing present-day debates and practices in the criminal justice field). This article seeks first to categorise the ways in which criminologists have used historical data thus far, arguing that it is most commonly deployed to ‘problematize’ the contemporary rather than to ‘explain’ it. The article then interrogates the reticence of criminologists to attribute explicative power in relation to the present to historical data. Finally, it proposes the adoption of long time-frame historical research methods, outlining three advantages which would accrue from this: the identification and analysis of historical continuities; a more nuanced, shared understanding of micro/macro change over time in relation to criminal justice; and a method for identifying and analysing instances of historical recurrence, particularly in perceptions and discourses around crime and justice

Oh, Jeremy Corbyn! Why did Labour Party membership soar after the 2015 general election?

This article investigates the remarkable surge in individual membership of the Labour Party after the general election of May 2015, particularly after Jeremy Corbyn was officially nominated as a candidate for the leadership in June of that year. Using both British Election Study and Party Members Project data, we explain the surge by focussing on the attitudinal, ideological and demographic characteristics of the members themselves. Findings suggest that, along with support for the leader and yearning for a new style of politics, feelings of relative deprivation played a significant part: many ‘left-behind’ voters (some well-educated, some less so) joined Labour for the first time when a candidate with a clearly radical profile appeared on the leadership ballot. Anti-capitalist and left-wing values mattered too, particularly for those former members who decided to return to the party

Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141.

Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane Profiling revealed US2 was unique in downregulating additional cellular targets, including: five distinct integrin α-chains, CD112, the interleukin-12 receptor, PTPRJ and thrombomodulin. US2 recruited the cellular E3 ligase TRC8 to direct the proteasomal degradation of all its targets, reminiscent of its degradation of MHC-I. Whereas integrin α-chains were selectively degraded, their integrin β1 binding partner accumulated in the ER. Consequently integrin signaling, cell adhesion and migration were strongly suppressed. US2 was necessary and sufficient for degradation of the majority of its substrates, but remarkably, the HCMV NK cell evasion function UL141 requisitioned US2 to enhance downregulation of the NK cell ligand CD112. UL141 retained CD112 in the ER from where US2 promoted its TRC8-dependent retrotranslocation and degradation. These findings redefine US2 as a multifunctional degradation hub which, through recruitment of the cellular E3 ligase TRC8, modulates diverse immune pathways involved in antigen presentation, NK cell activation, migration and coagulation; and highlight US2's impact on HCMV pathogenesis.This study was financially supported by grant 101-2917-I-564-035 from the Taiwan National Science Council to JLH; by a Wellcome Trust Fellowship (093966/Z/10/Z) to MPW; an MRC Project Grant and Wellcome Trust Programme Grant (G1000236, WT090323MA) to GWW and PT, European Regional Development Fund and the State Budget of Czech Republic (RECAMO, CZ.1.05/ 2.1.00/03.0101) to ER; a Wellcome Trust Principal Research Fellowship (084957/Z/08/Z) to PJL; and a Medical Research Council (MRC) grant (MC_UU_12014/3) to GSW and AJD. This study was additionally supported by the Cambridge Biomedical Research Centre, UK.This is the final published version. It first appeared at http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004811