Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3

INTRODUCTION: Involution of the mammary gland is a complex process of controlled apoptosis and tissue remodelling. The aim of the project was to identify genes that are specifically involved in this process. METHODS: We used Affymetrix oligonucleotide microarrays to perform a detailed transcript analysis on the mechanism of controlled involution after withdrawal of the pups at day seven of lactation. Some of the results were confirmed by semi-quantitative reverse transcriptase polymerase chain reaction, Western blotting or immunohistochemistry. RESULTS: We identified 145 genes that were specifically upregulated during the first 4 days of involution; of these, 49 encoded immunoglobulin genes. A further 12 genes, including those encoding the signal transducer and activator of transcription 3 (STAT3), the lipopolysaccharide receptor (CD14) and lipopolysaccharide-binding protein (LBP), were involved in the acute-phase response, demonstrating that the expression of acute-phase response genes can occur in the mammary gland itself and not only in the liver. Expression of LBP and CD14 was upregulated, at both the RNA and protein level, immediately after pup withdrawal; CD14 was strongly expressed in the luminal epithelial cells. Other genes identified suggested neutrophil activation early in involution, followed by macrophage activation late in the process. Immunohistochemistry and histological staining confirmed the infiltration of the involuting mammary tissue with neutrophils, plasma cells, macrophages and eosinophils. CONCLUSION: Oligonucleotide microarrays are a useful tool for identifying genes that are involved in the complex developmental process of mammary gland involution. The genes identified are consistent with an immune cascade, with an early acute-phase response that occurs in the mammary gland itself and resembles a wound healing process

Protecting the Health of First Nation Personnel at Contaminated Sites: A Case Study of Mid-Canada Radar Line Site 050 in Northern Canada

Recently, First Nation (FN) organizations have entered into agreements with federal and provincial government representatives to remediate radar-line sites in Ontario. These agreements stipulated that FN people would take part in the site delineation and remediation process to gain job experience and economic benefits. One important aspect of the process was protecting FN personnel from contaminant exposure and thus, from potential negative health outcomes associated with the cleanup work itself. In this paper, we describe the safety precautions used by FN workers preparing Mid-Canada Radar Line (MCRL) Site 050 for Phase 2 of the delineation process and the health monitoring protocol that was tested. We measured concentrations of total polychlorinated biphenyls (PCBs as Aroclor 1260), 14 individual PCB congeners, p,p’-DDT, p,p’-DDE, nine other organochlorine pesticides, and lead in the blood of Fort Albany FN workers before they started work at Site 050 and approximately a week before they completed their three-month work period in the contaminated zone. No significant differences were found in the paired samples. These results indicate that the safety precautions taken were adequate for the work and the site in question. The monitoring protocol discussed here may be used as a template and modified to meet the specific needs of other projects. The results of this study are important because other Aboriginal groups have entered or will be entering into agreements with government organizations for the remediation of other MCRL sites in Ontario and across Canada.Les stations de ligne radar désaffectées situées tant dans l’Arctique que dans le Subarctique canadiens seraient des sources ponctuelles de contamination. Des organismes des Premières nations ont participé dernièrement, avec des représentants des gouvernements fédéral et provinciaux, à des accords visant l’assainissement des stations de ligne radar en Ontario. Ces accords stipulaient que des membres des Premières nations prendraient part à la délimitation des sites et au processus d’assainissement afin d’acquérir de l’expérience de travail et de profiter des retombées économiques. Un volet important de ce processus visait à protéger le personnel autochtone de l’exposition aux contaminants et donc, d’effets potentiels négatifs pour la santé associés aux opérations de nettoyage mêmes. Dans cet article, on décrit les mesures de sécurité utilisées par les travailleurs autochtones oeuvrant sur le site 050 de la ligne radar Mid-Canada durant la phase 2 du processus de délimitation, ainsi que le protocole de contrôle de la santé mis alors à l’essai. On a mesuré les concentrations de l’accumulation de diphényles polychlorés (PCB comme l’Arochlore 1260), de 14 congénères de PCB, de p,p’-DDT, de p,p’-DDE, de neuf autres pesticides organochlorés ainsi que de plomb dans le sang des travailleurs autochtones de Fort Albany avant qu’ils commencent à travailler au site 050 et une semaine environ avant qu’ils terminent leur période de travail de trois mois dans la zone contaminée. On n’a pas trouvé de différences significatives entre les échantillons appariés. Ces résultats révèlent que les mesures de sécurité prises étaient adéquates pour le travail et le site en question. Le protocole de contrôle discuté ici pourrait servir de modèle et être adapté pour répondre aux critères spécifiques d’autres projets. Les résultats de cette étude sont importants car d’autres groupes autochtones participent actuellement ou vont participer à des accords avec des agences gouvernementales visant l’assainissement d’autres sites de la ligne radar Mid-Canada en Ontario et à travers le Canada

Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course.

Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as "functional" prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients

Pasteurella multocida infections: Report of 34 cases and review of the literature

Pasteurella multocida, a small gram-negative coccobacillus, is part of the normal oral flora of many animals, including the cat and dog. P. multocida is a major pathogen in wound infections due to animal bites and can cause cellutitis, abscess, osteomyelitis, septic arthritis, or a variety of other infectious syndromes (Table 1). Over the years, P. multocida has been the subject of a number of short general reviews (74, 80, 91, 96, 158). More recently, reviews have focused on selected aspects of P. multocida infection including meningitis (44), empyema (112), spontaneous bacterial peritonitis (160), bone and joint infections (56), and septicemia (111). A large series of cases with a comprehensive review, however, has not been published. We therefore report here 34 cases from the Massachusetts General Hospital and review the English literature

Correlated electron emission in laser-induced nonsequence double ionization of Helium

In this paper, we have investigated the correlated electron emission of the nonsequence double ionization (NSDI) in an intense linearly polarized field. The theoretical model we employed is the semiclassical rescattering model, the model atom we used is the helium. We find a significant correlation between magnitude and direction of the momentum of two emission electrons, and give a good explanation for this striking phenomenon by observing the classical collisional trajectories. We argue that this correlation phenomenon is universal in NSDI process, as revealed by the recent experiment on the argon.Comment: 4 pages, 3 figures, accepted for publication in Phys. Rev.

Theory of proximity effect in superconductor/ferromagnet heterostructures

We present a microscopic theory of proximity effect in the ferromagnet/superconductor/ferromagnet (F/S/F) nanostructures where S is s-wave low-T_c superconductor and F's are layers of 3d transition ferromagnetic metal. Our approach is based on the solution of Gor'kov equations for the normal and anomalous Green's functions together with a self-consistent evaluation of the superconducting order parameter. We take into account the elastic spin-conserving scattering of the electrons assuming s-wave scattering in the S layer and s-d scattering in the F layers. In accordance with the previous quasiclassical theories, we found that due to exchange field in the ferromagnet the anomalous Green's function F(z) exhibits the damping oscillations in the F-layer as a function of distance z from the S/F interface. In the given model a half of period of oscillations is determined by the length \xi_m^0 = \pi v_F/E_ex, where v_F is the Fermi velocity and E_ex is the exchange field, while damping is governed by the length l_0 = (1/l_{\uparrow} + 1/l_{\downarrow})^{-1} with l_{\uparrow} and l_{\downarrow} being spin-dependent mean free paths in the ferromagnet. The superconducting transition temperature T_c(d_F) of the F/S/F trilayer shows the damping oscillations as a function of the F-layer thickness d_F with period \xi_F = \pi/\sqrt{m E_ex}, where m is the effective electron mass. We show that strong spin-conserving scattering either in the superconductor or in the ferromagnet significantly suppresses these oscillations. The calculated T_c(d_F) dependences are compared with existing experimental data for Fe/Nb/Fe trilayers and Nb/Co multilayers.Comment: 13 pages, REVTeX4, 8 PS-figures; improved version, submitted to PR

Onset of Vortices in Thin Superconducting Strips and Wires

Spontaneous nucleation and the consequent penetration of vortices into thin superconducting films and wires, subjected to a magnetic field, can be considered as a nonlinear stage of primary instability of the current-carrying superconducting state. The development of the instability leads to the formation of a chain of vortices in strips and helicoidal vortex lines in wires. The boundary of instability was obtained analytically. The nonlinear stage was investigated by simulations of the time-dependent generalized Ginzburg-Landau equation.Comment: REVTeX 3.0, 12 pages, 5Postscript figures (uuencoded). Accepted for Phys. Rev.

The Nursing Home Pneumonia Risk Index: A Simple, Valid MDS-Based Method of Identifying 6-Month Risk for Pneumonia and Mortality

Background Pneumonia is the leading infectious cause of hospitalization and death for nursing home (NH) residents; however, diagnosis is often delayed because classic signs of infection are not present. We sought to identify NH residents at high risk for pneumonia, to identify persons to target for more intensive surveillance and preventive measures. Methods Based on a literature review, we identified key risk factors for pneumonia and compiled them for use as prediction tool, limiting risk factors to those available on the Minimum Data Set (MDS). Next, we tested the tool's ability to predict 6-month pneumonia incidence and mortality rates in a sample of 674 residents from 7 NHs, evaluating it both as a continuous and a dichotomous variable, and applying both logistic regression and survival analysis to calculate estimates. Results NH Pneumonia Risk Index scores ranged from −1 to 6, with a mean of 2.1, a median of 2, and a mode of 2. For the outcome of pneumonia, a 1-point increase in the index was associated with a risk odds ratio of 1.26 (P =.038) or a hazard ratio of 1.24 (P =.037); using it as a dichotomous variable (≤2 vs ≥3), the corresponding figures were a risk odds ratio of 1.78 (P =.045) and a hazard ratio of 1.82 (P =.025). For the outcome of mortality, a 1-point increase in the NH Pneumonia Risk Index was associated with a risk odds ratio of 1.58 (P =.002) and a hazard ratio of 1.45 (P =.013); using the index as a dichotomous variable, the corresponding figures were a risk odds ratio of 3.71 (P <.001) and a hazard ratio of 3.29 (P =.001). Conclusions The NH Pneumonia Risk Index can be used by NH staff to identify residents for whom to apply especially intensive preventive measures and surveillance. Because of its strong association with mortality, the index may also be valuable in care planning and discussion of advance directives

Neutrophil Extracellular Traps in COVID-19

In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have potential to propagate inflammation and microvascular thrombosis - including in the lungs of patients with acute respiratory distress syndrome. While elevated levels of blood neutrophils predict worse outcomes in COVID-19, the role of NETs has not been investigated. We now report that sera from patients with COVID-19 (n = 50 patients, n = 84 samples) have elevated levels of cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3); the latter two are highly specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute phase reactants including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. In summary, these data reveal high levels of NETs in many patients with COVID-19, where they may contribute to cytokine release and respiratory failure. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts, and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19