Theoretical open-loop model of respiratory mechanics in the extremely preterm infant

Non-invasive ventilation is increasingly used for respiratory support in preterm infants, and is associated with a lower risk of chronic lung disease. However, this mode is often not successful in the extremely preterm infant in part due to their markedly increased chest wall compliance that does not provide enough structure against which the forces of inhalation can generate sufficient pressure. To address the continued challenge of studying treatments in this fragile population, we developed a nonlinear lumped-parameter model of respiratory system mechanics of the extremely preterm infant that incorporates nonlinear lung and chest wall compliances and lung volume parameters tuned to this population. In particular we developed a novel empirical representation of progressive volume loss based on compensatory alveolar pressure increase resulting from collapsed alveoli. The model demonstrates increased rate of volume loss related to high chest wall compliance, and simulates laryngeal braking for elevation of end-expiratory lung volume and constant positive airway pressure (CPAP). The model predicts that low chest wall compliance (chest stiffening) in addition to laryngeal braking and CPAP enhance breathing and delay lung volume loss. These results motivate future data collection strategies and investigation into treatments for chest wall stiffening.Comment: 22 pages, 5 figure

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

ADAM17-Mediated Processing of TNF-α Expressed by Antiviral Effector CD8+ T Cells Is Required for Severe T-Cell-Mediated Lung Injury

Influenza infection in humans evokes a potent CD8+ T-cell response, which is important for clearance of the virus but may also exacerbate pulmonary pathology. We have previously shown in mice that CD8+ T-cell expression of TNF-a is required for severe and lethal lung injury following recognition of an influenza antigen expressed by alveolar epithelial cells. Since TNF-a is first expressed as a transmembrane protein that is then proteolytically processed to release a soluble form, we sought to characterize the role of TNF-a processing in CD8+ T-cell-mediated injury. In this study we observed that inhibition of ADAM17-mediated processing of TNF-a by CD8+ T cells significantly attenuated the diffuse alveolar damage that occurs after T-cell transfer, resulting in enhanced survival. This was due in part to diminished chemokine expression, as TNF-aprocessing was required for lung epithelial cell expression of CXCL2 and the subsequent inflammatory infiltration. We confirmed the importance of CXCL2 expression in acute lung injury by transferring influenza-specific CD8+ T cells into transgenic mice lacking CXCR2. These mice exhibited reduced airway infiltration, attenuated lung injury, and enhanced survival. Theses studies describe a critical role for TNF-a processing by CD8+ T cells in the initiation and severity of acute lung injury, which may have important implications for limiting immunopathology during influenza infection and other human infectious or inflammatory diseases

A review of nitrogen isotopic alteration in marine sediments

Key Points: Use of sedimentary nitrogen isotopes is examined; On average, sediment 15N/14N increases approx. 2 per mil during early burial; Isotopic alteration scales with water depth Abstract: Nitrogen isotopes are an important tool for evaluating past biogeochemical cycling from the paleoceanographic record. However, bulk sedimentary nitrogen isotope ratios, which can be determined routinely and at minimal cost, may be altered during burial and early sedimentary diagenesis, particularly outside of continental margin settings. The causes and detailed mechanisms of isotopic alteration are still under investigation. Case studies of the Mediterranean and South China Seas underscore the complexities of investigating isotopic alteration. In an effort to evaluate the evidence for alteration of the sedimentary N isotopic signal and try to quantify the net effect, we have compiled and compared data demonstrating alteration from the published literature. A >100 point comparison of sediment trap and surface sedimentary nitrogen isotope values demonstrates that, at sites located off of the continental margins, an increase in sediment 15N/14N occurs during early burial, likely at the seafloor. The extent of isotopic alteration appears to be a function of water depth. Depth-related differences in oxygen exposure time at the seafloor are likely the dominant control on the extent of N isotopic alteration. Moreover, the compiled data suggest that the degree of alteration is likely to be uniform through time at most sites so that bulk sedimentary isotope records likely provide a good means for evaluating relative changes in the global N cycle

Literary studies and the academy

In 1885 the University of Oxford invited applications for the newly created Merton Professorship of English Language and Literature. The holder of the chair was, according to the statutes, to ‘lecture and give instruction on the broad history and criticism of English Language and Literature, and on the works of approved English authors’. This was not in itself a particularly innovatory move, as the study of English vernacular literature had played some part in higher education in Britain for over a century. Oxford University had put English as a subject into its pass degree in 1873, had been participating since 1878 in extension teaching, of which literary study formed a significant part, and had since 1881 been setting special examinations in the subject for its non-graduating women students. What was new was the fact that this ancient university appeared to be on the verge of granting the solid academic legitimacy of an established chair to an institutionally marginal and often contentious intellectual pursuit, acknowledging the study of literary texts in English to be a fit subject not just for women and the educationally disadvantaged but also for university men

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Initial conditions.

<p>Initial conditions.</p

Lung, chest wall, and total respiratory system compliance curves for high <i>C</i>_<i>w</i> (left) and low <i>C</i>_<i>w</i> (right).

<p>Curves are described by Eqs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198425#pone.0198425.e016" target="_blank">(9)</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198425#pone.0198425.e017" target="_blank">(10)</a> and parameterized using the procedures described in <b>Parameterization</b>. Tidal breathing loops with normal <i>R</i>_<i>u</i> (grey) and increased <i>R</i>_<i>u</i> (black) are superimposed for each condition over the lung compliance curve and larger in each inset to display hysteresis.</p