Role of Oxidants in Interstitial Lung Diseases: Pneumoconioses, Constrictive Bronchiolitis, and Chronic Tropical Pulmonary Eosinophilia

Oxidants such as superoxide anion, hydrogen peroxide, and myeloperoxidase from activated inflammatory cells in the lower respiratory tract contribute to inflammation and injury. Etiologic agents include inorganic particulates such as asbestos, silica, or coal mine dust or mixtures of inorganic dust and combustion materials found in World Trade Center dust and smoke. These etiologic agents are phagocytosed by alveolar macrophages or bronchial epithelial cells and release chemotactic factors that recruit inflammatory cells to the lung. Chemotactic factors attract and activate neutrophils, eosinophils, mast cells, and lymphocytes and further activate macrophages to release more oxidants. Inorganic dusts target alveolar macrophages, World Trade Center dust targets bronchial epithelial cells, and eosinophils characterize tropical pulmonary eosinophilia (TPE) caused by filarial organisms. The technique of bronchoalveolar lavage in humans has recovered alveolar macrophages (AMs) in dust diseases and eosinophils in TPE that release increased amounts of oxidants in vitro. Interestingly, TPE has massively increased eosinophils in the acute form and after treatment can still have ongoing eosinophilic inflammation. A course of prednisone for one week can reduce the oxidant burden and attendant inflammation and may be a strategy to prevent chronic TPE and interstitial lung disease

Solvable 2D superconductors with l-wave pairing

We analyze a family of two-dimensional BCS Hamiltonians with general l-wave pairing interactions, classifying the models in this family that are Bethe-ansatz solvable in the finite-size regime. We show that these solutions are characterized by nontrivial winding numbers, associated with topological phases, in some part of the corresponding phase diagrams. By means of a comparative study, we demonstrate benefits and limitations of the mean-field approximation, which is the standard approach in the limit of a large number of particles. The mean-field analysis also allows to extend part of the results beyond integrability, clarifying the peculiarities associable with the integrability itself.Comment: 9 pages, 1 figur

Density-Dependent Liquid Nitromethane Decomposition: Molecular Dynamics Simulations Based on ReaxFF

The decomposition mechanism of hot liquid nitromethane at various compressions was studied using reactive force field (ReaxFF) molecular dynamics simulations. A competition between two different initial thermal decomposition schemes is observed, depending on compression. At low densities, unimolecular C–N bond cleavage is the dominant route, producing CH_3 and NO_2 fragments. As density and pressure rise approaching the Chapman–Jouget detonation conditions (~30% compression, >2500 K) the dominant mechanism switches to the formation of the CH_(3)NO fragment via H-transfer and/or N–O bond rupture. The change in the decomposition mechanism of hot liquid NM leads to a different kinetic and energetic behavior, as well as products distribution. The calculated density dependence of the enthalpy change correlates with the change in initial decomposition reaction mechanism. It can be used as a convenient and useful global parameter for the detection of reaction dynamics. Atomic averaged local diffusion coefficients are shown to be sensitive to the reactions dynamics, and can be used to distinguish between time periods where chemical reactions occur and diffusion-dominated, nonreactive time periods

Será a insuficiência renal uma contra-indicação relativa para as biópsias broncoscópicas?

Resumo: Em 1977, Cunningham e col. demonstraram que, nos doentes urémicos sujeitos a broncofibroscopia com biopsias, 45% tiveram hemorragias.Actualmente, não há trabalhos publicados que avaliem este risco.Os autores resolveram avaliar os processos de todas as broncofibroscopias realizadas entre 1997 e 2002 no Hospital de Bellvue, Nova Iorque, registando os resultados da ureia, da creatinina, do hemograma, do estudo da coagulação, do tipo de biópsias executadas da pré-medicação e das complicações.Os doentes eram incluídos nos trabalhos desde que tivessem a ureia superior ou igual a 30 mg/dl e/ou a creatinina superior ou igual a 2,0 mg/dl. Perante estes critérios foram incluídos no estudo 72 doentes.Vinte e cinco doentes dos 72(35 %) foram submetidos a biopsias. Sete dos 25 (28 %) foram hemodializados e 18 dos 25(72 %) não foram hemodializados. Todos os doentes hemodializados foram submetidos à broncofibroscopia 24 horas depois da hemodiálise e foram submetidos a uma perfusão de desmopressina pré-broncofibroscopia, e um doente com coagulopatia recebeu plaquetas e plasma fresco.Os doentes hemodializados submetidos a biópsias tinham valores de ureia que oscilavam entre 31-65 mg/ /dl e valores de creatinina que oscilavam entre 5,2-18,7 mg/dl, e o único doente deste grupo que fez punção aspirativa transbrônquica tinha uma ureia de 32 mg/dl e uma creatinina de 4,3 mg/dl.Em doze dos 18 doentes não submetidos a hemodiálise e submetidos a biópsias, os valores de ureia oscilavam entre 20-69 mg/dl e os valores de creatinina entre 0,9-2,5 mg/dl. Deste grupo, os quatro doentes que foram submetidos a punção aspirativa transbrônquica tinham valores de ureia entre 20-62 mg/dl e valores de creatinina entre 1,1-4,5 mg/dl. Os dois doentes sujeitos a biópsias e punção aspirativa transbrônquica tinham valores de ureia de 30 e 35 mg/dl e valores de de 1,4 e 1,5 mg/dl. Um dos 25 doentes não hemodializados teve uma complicação major, hemorragia maciça que obrigou a intervenção. Um outro deste mesmo grupo teve apenas uma hemorragia minor.Não houve complicações nos doentes hemodializados.Estes resultados sugerem que não há tantas complicações como seria de esperar nos doentes com insuficiência renal, como demonstrou Cullingam e col. em 1977. Mostram que não há complicações nos doentes hemodializados e sujeitos a uma perfusão de desmopressina antes de ser efectuada a broncofibroscopia.Estes dados obrigam à realização de novos estudos para avaliar de facto se as biópsias broncoscópicas são uma contra-indicação relativa na insuficiência renal. Palavras-chave: Broncofibroscopia, biópsias broncoscópicas, insuficiência renal, complicações hemorrágica

Unlocking biomarker discovery: Large scale application of aptamer proteomic technology for early detection of lung cancer

Lung cancer is the leading cause of cancer deaths, because ~84% of cases are diagnosed at an advanced stage. Worldwide in 2008, ~1.5 million people were diagnosed and ~1.3 million died – a survival rate unchanged since 1960. However, patients diagnosed at an early stage and have surgery experience an 86% overall 5-year survival. New diagnostics are therefore needed to identify lung cancer at this stage. Here we present the first large scale clinical use of aptamers to discover blood protein biomarkers in disease with our breakthrough proteomic technology. This multi-center case-control study was conducted in archived samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. We measured >800 proteins in 15uL of serum, identified 44 candidate biomarkers, and developed a 12-protein panel that distinguished NSCLC from controls with 91% sensitivity and 84% specificity in a training set and 89% sensitivity and 83% specificity in a blinded, independent verification set. Performance was similar for early and late stage NSCLC. This is a significant advance in proteomics in an area of high clinical need

Multiple strand displacement amplification of mitochondrial DNA from clinical samples

<p>Abstract</p> <p>Background</p> <p>Whole genome amplification (WGA) methods allow diagnostic laboratories to overcome the common problem of insufficient DNA in patient specimens. Further, body fluid samples useful for cancer early detection are often difficult to amplify with traditional PCR methods. In this first application of WGA on the entire human mitochondrial genome, we compared the accuracy of mitochondrial DNA (mtDNA) sequence analysis after WGA to that performed without genome amplification. We applied the method to a small group of cancer cases and controls and demonstrated that WGA is capable of increasing the yield of starting DNA material with identical genetic sequence.</p> <p>Methods</p> <p>DNA was isolated from clinical samples and sent to NIST. Samples were amplified by PCR and those with no visible amplification were re-amplified using the Multiple Displacement Amplificaiton technique of whole genome amplification. All samples were analyzed by mitochip for mitochondrial DNA sequence to compare sequence concordance of the WGA samples with respect to native DNA. Real-Time PCR analysis was conducted to determine the level of WGA amplification for both nuclear and mtDNA.</p> <p>Results</p> <p>In total, 19 samples were compared and the concordance rate between WGA and native mtDNA sequences was 99.995%. All of the cancer associated mutations in the native mtDNA were detected in the WGA amplified material and heteroplasmies in the native mtDNA were detected with high fidelity in the WGA material. In addition to the native mtDNA sequence present in the sample, 13 new heteroplasmies were detected in the WGA material.</p> <p>Conclusion</p> <p>Genetic screening of mtDNA amplified by WGA is applicable for the detection of cancer associated mutations. Our results show the feasibility of this method for: 1) increasing the amount of DNA available for analysis, 2) recovering the identical mtDNA sequence, 3) accurately detecting mtDNA point mutations associated with cancer.</p

Men’s and Women’s Health Beliefs Differentially Predict Coronary Heart Disease Incidence in a Population-Based Sample

Objective. To examine gender differences in the association between beliefs in heart disease preventability and 10-year incidence of coronary heart disease (CHD) in a population-based sample. Methods. A total of 2,688 Noninstitutionalized Nova Scotians without prior CHD enrolled in the Nova Scotia Health Study (NSHS95) and were followed for 10 years. Risk factors, health behaviors, and incident CHD were assessed. Participants responded “yes” or “no” to a question about heart disease preventability. Survival models, adjusted for age, income, total and high-density lipoprotein cholesterol, and systolic blood pressure, were used to estimate the relation between health belief and incident CHD. Gender differences in the relation between health beliefs and health behaviors were assessed. Results. Gender was a significant moderator of the relation between belief and CHD incidence; specifically, women who believed heart disease could be prevented were less likely to have incident CHD events compared with women who believed heart disease could not be prevented (hazard ratio [HR] = 0.36, 95% confidence interval [CI] = 0.24-0.55, p < .001). This relation was not found for men. Belief was also related to smoking behavior for women (β = −0.70, odds ratio [OR] = 0.50, 95% CI = 0.33-0.74, p = .001) but not for men. Smoking significantly mediated the relation between health beliefs and incident CHD for women (z = −1.96, p = .05), but not for men. Conclusion. Health belief in prevention and subsequent smoking was an important independent predictor of incident CHD in women but not in men

Decomposition of Condensed Phase Energetic Materials: Interplay between Uni- and Bimolecular Mechanisms

Activation energy for the decomposition of explosives is a crucial parameter of performance. The dramatic suppression of activation energy in condensed phase decomposition of nitroaromatic explosives has been an unresolved issue for over a decade. We rationalize the reduction in activation energy as a result of a mechanistic change from unimolecular decomposition in the gas phase to a series of radical bimolecular reactions in the condensed phase. This is in contrast to other classes of explosives, such as nitramines and nitrate esters, whose decomposition proceeds via unimolecular reactions both in the gas and in the condensed phase. The thermal decomposition of a model nitroaromatic explosive, 2,4,6-trinitrotoluene (TNT), is presented as a prime example. Electronic structure and reactive molecular dynamics (ReaxFF-lg) calculations enable to directly probe the condensed phase chemistry under extreme conditions of temperature and pressure, identifying the key bimolecular radical reactions responsible for the low activation route. This study elucidates the origin of the difference between the activation energies in the gas phase (∼62 kcal/mol) and the condensed phase (∼35 kcal/mol) of TNT and identifies the corresponding universal principle. On the basis of these findings, the different reactivities of nitro-based organic explosives are rationalized as an interplay between uni- and bimolecular processes

Maximal HIV-1 Replication in Alveolar Macrophages during Tuberculosis Requires both Lymphocyte Contact and Cytokines

HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein β (C/EBPβ) transcription factor and activation of nuclear factor (NF)-κB. Since the cellular immune response in pulmonary TB requires lymphocyte–macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPβ, activated NF-κB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPβ expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-κB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPβ expression. However, the HIV-1 LTR was not maximally stimulated and NF-κB was not activated. Maximal HIV-1–LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1–LTR stimulation was also achieved when IL-1β, IL-6, and TNF-β were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPβ, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-κB, further enhancing the HIV-1 LTR

Correction: Rapid chemokinetic movement and the invasive potential of lung cancer cells; a functional molecular study

This is a correction of an earlier published article