Coagulation and anticoagulation in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an incurable, progressive interstitial lung disease with a prognosis that is worse than that of many cancers. Epidemiological studies have demonstrated a link between IPF and thrombotic vascular events. Coagulation and fibrinolytic systems play central roles in wound healing and repair, processes hypothesised to be abnormal within the IPF lung. Animal models of pulmonary fibrosis have demonstrated an imbalance between thrombosis and fibrinolysis within the alveolar compartment, a finding that is also observed in IPF patients. A systemic prothrombotic state also occurs in IPF and is associated with increased mortality, but trials of anticoagulation in IPF have provided conflicting results. Differences in methodology, intervention and study populations may contribute to the inconsistent trial outcomes. The new oral anticoagulants have properties that may prove advantageous in targeting both thrombotic risk and progression of lung fibrosis

Increased platelet reactivity in idiopathic pulmonary fibrosis is mediated by a plasma factor

Introduction Idiopathic Pulmonary Fibrosis (IPF) is a progressive, incurable fibrotic interstitial lung disease with a prognosis worse than many cancers. Its pathogenesis is poorly understood. Activated platelets can release pro-fibrotic mediators that have the potential to contribute to lung fibrosis. We determine platelet reactivity in subjects with IPF compared to age-matched controls. Methods Whole blood flow cytometry was used to measure platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding at basal levels and following stimulation with platelet agonists. A plasma swap approach was used to assess the effect of IPF plasma on control platelets. Results Subjects with IPF showed greater platelet reactivity than controls. Platelet P-selectin expression was significantly greater in IPF patients than controls following stimulation with 0.1 µM ADP (1.9% positive ±0.5 (mean ± SEM) versus 0.7%±0.1; p = 0.03), 1 µM ADP (9.8%±1.3 versus 3.3%±0.8; p<0.01) and 10 µM ADP (41.3%±4.2 versus 22.5%±2.6; p<0.01). Platelet fibrinogen binding was also increased, and platelet activation resulted in increased platelet-monocyte aggregate formation in IPF patients. Re-suspension of control platelets in plasma taken from subjects with IPF resulted in increased platelet activation compared to control plasma. Conclusions IPF patients exhibit increased platelet reactivity compared with controls. This hyperactivity may result from the plasma environment since control platelets exhibit increased activation when exposed to IPF plasma

On the Quantum Jarzynski Identity

In this note, we will discuss how to compactly express and prove the Jarzynski identity for an open quantum system with dissipative dynamics. We will avoid explicitly measuring the work directly, which is tantamount to continuously monitoring the system, and instead measure the heat flow from the environment. We represent the measurement of heat flow with Hermitian map superoperators that act on the system density matrix. Hermitian maps provide a convenient and compact representation of sequential measurement and correlation functions.Comment: 4 page

Temperature-extended Jarzynski relation: Application to the numerical calculation of the surface tension

We consider a generalization of the Jarzynski relation to the case where the system interacts with a bath for which the temperature is not kept constant but can vary during the transformation. We suggest to use this relation as a replacement to the thermodynamic perturbation method or the Bennett method for the estimation of the order-order surface tension by Monte Carlo simulations. To demonstrate the feasibility of the method, we present some numerical data for the 3D Ising model

Sexual dimorphisms in the dermal denticles of thelesser-spotted catshark, Scyliorhinus canicula (Linnaeus, 1758)

The dermal layers of several elasmobranch species have been shown to be sexually dimorphic. Generally, when this occurs the females have thicker dermal layers compared to those of males. This sexual dimorphism has been suggested to occur as a response to male biting during mating. Although male biting as a copulatory behaviour in Scyliorhinus canicula has been widely speculated to occur, only relatively recently has this behaviour been observed. Male S. canicula use their mouths to bite the female's pectoral and caudal fins as part of their pre-copulatory behaviour and to grasp females during copulation. Previous work has shown that female S. canicula have a thicker epidermis compared to that of males. The structure of the dermal denticles in females may also differ from that of males in order to protect against male biting or to provide a greater degree of friction in order to allow the male more purchase. This study reveals that the length, width and density of the dermal denticles of mature male and female S. canicula are sexually dimorphic across the integument in areas where males have been observed to bite and wrap themselves around females (pectoral fin, area posterior to the pectoral fin, caudal fin, and pelvic girdle). No significant differences in the dermal denticle dimensions were found in other body areas examined (head, dorsal skin and caudal peduncle). Sexually dimorphic dermal denticles in mature S. canicula could be a response to male biting/wrapping as part of the copulatory process

Bleomycin increases neutrophil adhesion to human vascular endothelial cells independently of upregulation of ICAM-1 and E-selectin

© 2016 Taylor & Francis. Aim of the Study: Bleomycin-induced lung disease is a serious complication of therapy characterized by alveolar injury, cytokine release, inflammatory cell recruitment, and eventually pulmonary fibrosis. The mechanisms underlying bleomycin-induced pulmonary fibrosis may be relevant to other progressive scarring diseases of the lungs. Pulmonary vascular endothelial cells are critically involved in immune cell extravasation at sites of injury through adhesion molecule expression and cytokine release. We sought to determine the effects of bleomycin on adhesion molecule expression and cytokine release by pulmonary vascular endothelial cells, and their functional relevance to inflammatory cell recruitment. Materials and Methods: The effects of pharmacologically relevant concentrations of bleomycin on adhesion molecule expression and cytokine release by human vascular endothelial cells in vitro were studied by flow cytometry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. A flow chamber model was used to assess the functional consequences on adhesion of flowing human neutrophils to endothelial cell monolayers. Results: Bleomycin increased intercellular adhesion molecule 1 (ICAM-1; CD54), vascular cell adhesion molecule (VCAM-1; CD106), and E-selectin (CD62E) expression, and increased monocyte chemoattractant protein (MCP-1) and interleukin (IL-8) release by endothelial cells. Increases in protein expression were accompanied by increased mRNA transcription. In contrast, there was no direct effect of bleomycin on the profibrotic cytokines transforming growth factor-beta (TGF-β), platelet-derived growth factor-BB (PDGF-BB), or endothelin-1. Under flow conditions, endothelial cells exposed to bleomycin supported increased neutrophil adhesion which was independent of ICAM-1 or E-selectin. Conclusion: Our findings demonstrate that bleomycin promotes endothelial-mediated inflammation and neutrophil adhesion. These mechanisms may contribute to the development of pulmonary fibrosis by supporting immune cell recruitment in the lungs

Non-equilibrium Relations for Spin Glasses with Gauge Symmetry

We study the applications of non-equilibrium relations such as the Jarzynski equality and fluctuation theorem to spin glasses with gauge symmetry. It is shown that the exponentiated free-energy difference appearing in the Jarzynski equality reduces to a simple analytic function written explicitly in terms of the initial and final temperatures if the temperature satisfies a certain condition related to gauge symmetry. This result is used to derive a lower bound on the work done during the non-equilibrium process of temperature change. We also prove identities relating equilibrium and non-equilibrium quantities. These identities suggest a method to evaluate equilibrium quantities from non-equilibrium computations, which may be useful to avoid the problem of slow relaxation in spin glasses.Comment: 8 pages, 2 figures, submitted to JPS

Lobeline Compounds as a Treatment for Psychostimulant Abuse and Withdrawal, and for Eating Disorders

Methods are disclosed that suggest the use of lobeline and analogs thereof in treating individuals for drug dependence and withdrawal and for eating disorders

Use of Lobeline Compounds in the Treatment of Central Nervous System Diseases and Pathologies

Lobeline and nicotine evoke [3H]overflow from rat striatal slices preloaded with [3H]dopamine ([3H]DA). The lobeline-evoked overflow is calcium-independent and not antagonized by mecamylamine, suggesting a mechanism of action other than the stimulation of nicotinic receptors. Whereas nicotine stimulates nicotinic receptors, lobeline inhibits [3H]DA uptake into synaptic vesicles and striatal synaptosomes. The results suggest that different mechanisms are responsible for the increase in striatal DA release evoked by lobeline and nicotine. [3H]-Dihydrotetrabenazine [3H]DTBZ), used routinely to probe a high-affinity binding site-on the vesicular monoamine transporter (VMAT2) binds to vesicle membranes from rat striatum. Lobeline inhibits [3H]DTBZ binding with an IC50 of 0.90 μM, consistent with its IC50 of 0.88 μM for inhibition of [3H]DA uptake into vesicles. These results suggest that the action of lobeline is similar to that of amphetamine and that it specifically interacts with DTBZ sites on VMAT2 to inhibit DA uptake into synaptic vesicles. d-amphetamine inhibits [3H]DTBZ binding to vesicle membranes with an IC50 of 39.4 μM, a concentration 20 times greater than reported for inhibition of VMAT2 function, suggesting that d-amphetamine interacts with a different site than lobeline on VMAT2 to inhibit monoamine uptake. These results suggest the use of lobeline and analogs thereof in treating individuals for diseases and pathologies of the central nervous system

Posterior probability and fluctuation theorem in stochastic processes

A generalization of fluctuation theorems in stochastic processes is proposed. The new theorem is written in terms of posterior probabilities, which are introduced via the Bayes theorem. In usual fluctuation theorems, a forward path and its time reversal play an important role, so that a microscopically reversible condition is essential. In contrast, the microscopically reversible condition is not necessary in the new theorem. It is shown that the new theorem adequately recovers various theorems and relations previously known, such as the Gallavotti-Cohen-type fluctuation theorem, the Jarzynski equality, and the Hatano-Sasa relation, when adequate assumptions are employed.Comment: 4 page