Strategies to improve oxygenation in experimental acute lung injury

One of the most important clinical syndromes, in which failure of oxygen uptake in the lung leads to severe hypoxia, is the so-called acute respiratory distress syndrome (ARDS). ARDS is a complex of clinical signs and symptoms which occur following diverse pulmonary or systemic insults, including sepsis. shock, pneumonia. trauma, liquid aspiration. hematological disorders, smoke inhalation, and many others, In ARDS, the treatments available are still inadequate and morbidity, mortality, and costs remain unacceptably high. The failure of the lung as a gas exchange organ results in peripheral tissue hypoxia, which appears to be related to the development of multiple organ failure (MOF). Since MOF is the predominant cause of death in ARDS, therapeutic efforts are aimed at improving oxygen delivery to the tissues. Available treatments include mechanical ventilation with positive end-expiratory pressure (PEEP) and high inspiratory oxygen concentration. However, despite extensive research on new ventilation modes, mortality has 110t changed much and remains 30-70%, as high as when first rcported by Ashbaugh et al. in 1967. It should be realized that mechanical ventilation is only a supportive strategy and that some ventilatory strategies even contribute to lung injury. That is why ARDS may, in part. be a product of our therapy - rather than the progression of the underlying disease. Several strategies for ARDS, such as exogenous surfactant therapy, ventilation according to the "Open Lung Concept" and partial liquid ventilation are currently under evaluation. In this chapter, we describe the central role of pulmonary surfactant in the pathophysiology of ARDS, and discuss the impact of these new strategies on surfactant function

Advances in Distributed Fiber-Optic Sensing for Monitoring Marine Infrastructure, Measuring the Deep Ocean, and Quantifying the Risks Posed by Seafloor Hazards

Distributed optical fiber sensors provide new opportunities for monitoring the marine environment. We review the physical foundations of this sensor technology and discuss how it can be applied to radically augment the networks of subseasensors that help monitor fundamental marine processes and to complete our understanding of local, regional, and global interactions in this environment

Insulin amyloidosis: A case report

Insulin amyloidosis is a rare form of localized amyloidosis due to insulin aggregation into subcutaneous amyloid fibrils. We describe the case of a 55 years old male with insulin-requiring type 1 diabetes presenting with two non-inflammatory intra-dermal nodules associated with local lymph node enlargement. Diagnosis was confirmed by Congo red coloration of the amyloid deposit and insulin protein identification on mass spectrometry. Insulin amyloidosis is a potential complication of repeated subcutaneous insulin injections. The main risk factor is the intrinsic characteristic of the insulin used. Insulin amyloidosis leads to systemic metabolic consequences such as chronic hyperglycemia or unpredictable hypoglycemia, as well as unesthetic cutaneous lumps or abscesses. Standard-of-care is yet to be defined but mainly rely on therapeutical education of insulin injections, while surgical excision is reported to improve glycemic control in some patients

Capturing complexity: developing an integrated approach to analysing HRM in SMEs

This article presents a framework to evaluate HRM in small and medium-sized enterprises (SMEs), using an open systems theoretical perspective. In presenting an open systems perspective the objective is to overcome the limitations of existing theorising in HRM, in particular to facilitate a move away from the ‘small is beautiful’ versus ‘bleak house’ stereotypes evident in much of the literature concerned with HRM in SMEs. The evidence is drawn from six SMEs operating in the Republic of Ireland, using a case study method. The findings show that a complex interplay of external structural factors and internal dynamics shaped HRM in each of the companies. HRM was not the coherent set of practices typically identified in the literature but rather was often informal and emergent. It is argued that the open systems theoretical framework enables a move beyond mere recognition of the complexity and heterogeneity of HRM in SMEs, towards an understanding, accommodation and explanation of particularistic factors

Wild-Type p53 Enhances Endothelial Barrier Function by Mediating RAC1 Signalling and RhoA Inhibition

Inflammation is the major cause of endothelial barrier hyper-permeability, associated with acute lung injury and acute respiratory distress syndrome. This study reports that p53 orchestrates the defence of vascular endothelium against LPS, by mediating the opposing actions of Rac1 and RhoA in pulmonary tissues. Human lung microvascular endothelial cells treated with HSP90 inhibitors activated both Rac1- and P21-activated kinase, which is an essential element of vascular barrier function. 17AAG increased the phosphorylation of both LIMK and cofilin, in contrast to LPS which counteracted those effects. Mouse lung microvascular endothelial cells exposed to LPS exhibited decreased expression of phospho-cofilin. 17AAG treatment resulted in reduced levels of active cofilin. Silencing of cofilin pyridoxal phosphate phosphatase (PDXP) blocked the LPS-induced hyper-permeability, and P53 inhibition reversed the 17AAG-induced PDXP down-regulation. P190RHOGAP suppression enhanced the LPS-triggered barrier dysfunction in endothelial monolayers. 17AAG treatment resulted in P190RHOGAP induction and blocked the LPS-induced pMLC2 up-regulation in wild-type mice. Pulmonary endothelial cells from super p53 mice, which carry additional p53-tg alleles, exhibited a lower response to LPS than the controls. Collectively, our findings help elucidate the mechanisms by which p53 operates to enhance barrier function

Regional growth dynamics in the service sector: The determinants of employment change in UK regions 1971-2005

There is a need to better understand the dynamics relating to the evolving economic structure of regions, in particular factors concerning deindustrialisation and the growth of service sector activities. In order to unpick the dynamics relating to contemporary regional evolution, this paper examines regional employment in the UK's service sector from 1971-2005. The analysis utilises the statistical technique of multi-factor partitioning to examine the evolutionary dynamics of employment change in the UK service sector. Overall, differing growth trajectories in service sector employment across regions appear to be the result of the different underlying industrial structure observed within the regions themselves. The findings indicate that the industrial structure of a region has a significant influence on employment change in the service sector, with related variety being of greater consequence than specialisation. This suggests that diversity, or urbanisation, effects have a greater influence than specialisation effects on 'lighter' industries than 'heavier' industries. Spatio-temporal variations within the development of the service sector are evident in the analysis and there is evidence of convergence across the regions for all sub-sectors examined. It is concluded that in an increasingly service dominated economy, diversity and related variety have some weight in explaining regional development paths

How does the social context fuel the proactive fire? A multilevel review and theoretical synthesis

© 2018 John Wiley & Sons, Ltd. The role of social context (e.g., leadership, team climate, and organizational support) in shaping employee proactive behavior has received considerable attention and has been investigated across multiple forms of proactive behavior. However, the research has not been well integrated. In this review, we adopt a multilevel approach to synthesize what is known about how social context factors influence employees' proactive behavior, as well as what mechanisms underpin these effects. Our analyses show that leader-, team-, and organization-related social context factors mainly influence employee proactivity through shaping “reason to,” “can do,” and “energized to” states (i.e., proactive motivational states) via individual-, team-, and cross-level processes. That has been most frequently investigated is the effect of the discretionary social context, particularly leadership, on proactive behavior. We also review the interaction effects between social context factors and other factors on employee proactive behavior and found inconsistent support for the motivational-fit perspective that stimuli with the same directions enhance each other's effect. We offer a research agenda to advance theoretical insights on this important topic

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Petrophysical, Geochemical, and Hydrological Evidence for Extensive Fracture-Mediated Fluid and Heat Transport in the Alpine Fault's Hanging-Wall Damage Zone

International audienceFault rock assemblages reflect interaction between deformation, stress, temperature, fluid, and chemical regimes on distinct spatial and temporal scales at various positions in the crust. Here we interpret measurements made in the hanging‐wall of the Alpine Fault during the second stage of the Deep Fault Drilling Project (DFDP‐2). We present observational evidence for extensive fracturing and high hanging‐wall hydraulic conductivity (∼10−9 to 10−7 m/s, corresponding to permeability of ∼10−16 to 10−14 m2) extending several hundred meters from the fault's principal slip zone. Mud losses, gas chemistry anomalies, and petrophysical data indicate that a subset of fractures intersected by the borehole are capable of transmitting fluid volumes of several cubic meters on time scales of hours. DFDP‐2 observations and other data suggest that this hydrogeologically active portion of the fault zone in the hanging‐wall is several kilometers wide in the uppermost crust. This finding is consistent with numerical models of earthquake rupture and off‐fault damage. We conclude that the mechanically and hydrogeologically active part of the Alpine Fault is a more dynamic and extensive feature than commonly described in models based on exhumed faults. We propose that the hydrogeologically active damage zone of the Alpine Fault and other large active faults in areas of high topographic relief can be subdivided into an inner zone in which damage is controlled principally by earthquake rupture processes and an outer zone in which damage reflects coseismic shaking, strain accumulation and release on interseismic timescales, and inherited fracturing related to exhumation