Respiratory effects of an exposure to grain dust among grain workers in the Vaud region (Switzerland)

Introduction: Bioaerosols such as grain dust, via biologically active agents, elicit local inflammation and direct immunological reactions within the human respiratory system. Workplace-dependent exposure to grain dust (GD) may thus induce asthma, chronic bronchitis, and hypersensitivity pneumonitis. The aim of this study is to assess the clinical impact of occupational exposure to GD and to determine quantitative biological markers of bioaerosol exposure in grain workers. Methods: This longitudinal study has been conducted from summer 2012, to summer 2013, comprising 6 groups of 30 active workers with different GD exposure patterns (4 groups of grain workers, 2 control groups). After obtaining informed consent, two evaluations at high- and low-exposing seasons take place, during which an occupational history and a detailed medical history are questionnaire-assessed, lung function is evaluated by spirometry, airway inflammation is measured by exhaled nitric oxide (eNO), and specific blood IgG and IgE are titrated. The preliminary results presented hereafter are those of two of the four exposed groups, namely harvesters and mill workers, compared to the control groups, at first assessment (n=100). Results: Mean age is 38.4 [years]; 98% are male. Exposed groups differ from controls (p<0.05) in daily contact with animals (57% vs. 40%) and active smoking (39% vs. 11%). Grain workers have more respiratory (50%), nasal (57%), ocular (45%), dermatologic (36%) and systemic (20%) occupational symptoms than controls (6.4%, 19%, 16%, 6.4%, 1.6% respectively, p<0.05). Lower mean peak-expiratory-flow (PEF) values (96.1 ± 18.9 vs. 108.2 ± 17.4 [% of predicted], p<0.05) and eNO values (13.9 ± 9.6 vs. 20.5 ± 14.7 [ppm], p<0.05) are observed in the exposed groups. Conclusion: Preliminary results show a higher prevalence of clinical symptoms and a lower mean PEF value in the exposed groups. Detailed supplementary analyses are pending.

The global regulator GacA of Pseudomonas fluorescens CHA0 is required for the suppression of root diseases in dicotyledons but not in Gramineae

Pseudomonas fluorescens strain CHA0 suppresses various plant diseases caused by soil-borne fungi. The pseudomonad produces the antimicrobial metabolites 2,4-diacetylphloroglucinol (Phl), pyoluteorin (Plt) and hydrogen cyanide, which are important for disease suppression, as well as the siderophores pyoverdine (Pvd), salicylic acid (Sal) and pyochelin (Pch). In the current work, a derivative of CHA0 with a mutation in the global regulator gene gacA (GacA−), which is unable to produce Phl, Plt and HCN, failed to protect the dicotyledonous plants cress and cucumber against damping-off caused by Pythium ultimum. In contrast, the GacA− mutant could still protect the Gramineae wheat and maize against damping-off mediated by the same strain of P. ultimum, and wheat against take-all caused by Gaeumannomyces graminis. However, the GacA− mutant overproduced Pch and Pvd. To gain more insight into disease protection afforded by the GacA− mutant, a GacA− Pvd− double mutant (strain CHA496) was constructed by gene replacement. Strain CHA496 overproduced Pch and Sal compared with CHA0 and protected wheat against P. ultimum and G. graminis, whereas cress and cucumber were not protected. Addition of FeCl3 repressed Pch and Sal production by strain CHA496 in vitro and impaired the protection of wheat in soil microcosms. In conclusion, a functional gacA gene was necessary for the protection of dicotyledons against root diseases, but not for that of Gramineae. Results indicated also that Pch and/or Sal were involved in the ability of the GacA− Pvd− mutant of CHA0 to suppress root diseases in Gramineae.

Pharmacogenomics of HIV Therapy: Summary of a Workshop Sponsored by the National Institute of Allergy and Infectious Diseases

Approximately 1 million people in the United States and over 30 million worldwide are living with human immunodeficiency virus type 1 (HIV-1). While mortality from untreated infection approaches 100%, survival improves markedly with use of contemporary antiretroviral therapies (ART). In the United States, 25 drugs are approved for treating HIV-1, and increasing numbers are available in resource-limited countries. Safe and effective ART is a cornerstone in the global struggle against the acquired immunodeficiency syndrome. Variable responses to ART are due at least in part to human genetic variants that affect drug metabolism, drug disposition, and off-site drug targets. Defining effects of human genetic variants on HIV treatment toxicity, efficacy, and pharmacokinetics has far-reaching implications. In 2010, the National Institute of Allergy and Infectious Diseases sponsored a workshop entitled, Pharmacogenomics A Path Towards Personalized HIV Care. This article summarizes workshop objectives, presentations, discussions, and recommendations derived from this meeting.

Gene transfer into the airway epithelium of animals by targeting the polymeric immunoglobulin receptor.

Genes of interest can be targeted specifically to respiratory epithelial cells in intact animals with high efficiency by exploiting the receptor-mediated endocytosis of the polymeric immunoglobulin receptor. A DNA carrier, consisting of the Fab portion of polyclonal antibodies raised against rat secretory component covalently linked to poly-L-lysine, was used to introduce plasmids containing different reporter genes into airway epithelial cells in vivo. We observed significant levels of luciferase enzyme activity in protein extracts from the liver and lung, achieving maximum values of 13,795 +/- 4,431 and 346,954 +/- 199,120 integrated light units (ILU) per milligram of protein extract, respectively. No luciferase activity was detected in spleen or heart, which do not express the receptor. Transfections using complexes consisting of an irrelevant plasmid (pCMV lacZ) bound to the bona fide carrier or the expression plasmid (pGEMluc) bound to a carrier based on an irrelevant Fab fragment resulted in background levels of luciferase activity in all tissues examined. Thus, only tissues that contain cells bearing the polymeric immunoglobulin receptor are transfected, and transfection cannot be attributed to the nonspecific uptake of an irrelevant carrier-DNA complex. Specific mRNA from the luciferase gene was also detected in the lungs of transfected animals. To determine which cells in the lungs are transfected by this method, DNA complexes were prepared containing expression plasmids with genes encoding the bacterial beta-galactosidase or the human interleukin 2 receptor. Expression of these genes was localized to the surface epithelium of the airways and the submucosal glands, and not the bronchioles and alveoli. Receptor-mediated endocytosis can be used to introduce functional genes into the respiratory epithelium of rats, and may be a useful technique for gene therapy targeting the lung.

Mechanical properties of cultured human airway smooth muscle cells from 0.05 to 0.4 Hz.

We investigated the rheological properties of living human airway smooth muscle cells in culture and monitored the changes in rheological properties induced by exogenous stimuli. We oscillated small magnetic microbeads bound specifically to integrin receptors and computed the storage modulus (G') and loss modulus (G") from the applied torque and the resulting rotational motion of the beads as determined from their remanent magnetic field. Under baseline conditions, G' increased weakly with frequency, whereas G" was independent of the frequency. The cell was predominantly elastic, with the ratio of G" to G' (defined as eta) being ~0.35 at all frequencies. G' and G" increased together after contractile activation and decreased together after deactivation, whereas eta remained unaltered in each case. Thus elastic and dissipative stresses were coupled during changes in contractile activation. G' and G" decreased with disruption of the actin fibers by cytochalasin D, but eta increased. These results imply that the mechanisms for frictional energy loss and elastic energy storage in the living cell are coupled and reside within the cytoskeleton.

Limited heterogeneity of autoantigens and T cells in autoimmune diseases?

For many induced and spontaneous autoimmune diseases, a predominant role for T cells in the organ-specific destruction process has been shown. In one of the induced models of autoimmunity, experimental allergic encephalomyelitis (EAE), a very small heterogeneity of T-cell receptor (TcR) molecules is expressed by the pathogenic T cells in both rats and mice. Contrary to induced autoimmune diseases, little is known about the autoantigens recognized by these autoimmune T cells and the heterogeneity of their TcR in spontaneous autoimmune diseases. The aim of this work was to establish a system which allows characterization of relevant autoantigens in spontaneous insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. A completely different approach was taken to characterize the gene products of the minor lymphocyte stimulatory (Mls) loci. These gene products are responsible for the clonal elimination or the clonal stimulation of T cells expressing particular TcR V beta genes and therefore could be implicated in induction of autoimmune diseases by oligoclonal T-cell populations. The finding that Mls antigens are encoded by retroviral sequences leads to the hypothesis that viruses could be the inducing agents of autoimmune diseases.

Drug adherence in chronic kidney diseases and dialysis.

Poor long-term adherence and persistence to drug therapy is universally recognized as one of the major clinical issues in the management of chronic diseases, and patients with renal diseases are also concerned by this important phenomenon. Chronic kidney disease (CKD) patients belong to the group of subjects with one of the highest burdens of daily pill intake with up to >20 pills per day depending on the severity of their disease. The purpose of the present review is to discuss the difficulties encountered by nephrologists in diagnosing and managing poor adherence and persistence in CKD patients including in patients receiving maintenance dialysis. Our review will also attempt to provide some clues and new perspectives on how drug adherence could actually be addressed and possibly improved. Working on drug adherence may look like a long and tedious path, but physicians and healthcare providers should always be aware that drug adherence is in general much lower than what they may think and that there are many ways to improve and support drug adherence and persistence so that renal patients obtain the full benefits of their treatments.

Mandatory infectious diseases consultation for MRSA bacteremia is associated with reduced mortality.

OBJECTIVES: Although infectious disease (ID) consultation has been associated with lower mortality in Staphylococcus aureus bloodstream infections, it is still not mandatory in many centers. This study aimed at assessing the impact of ID consultation on diagnostic and therapeutic management of methicillin-resistant S. aureus (MRSA) bacteremia. METHODS: Retrospective cohort study of all patients with MRSA bacteremia from 2001 to 2010. ID consultations were obtained on request between 2001 and 2006 and became mandatory since 2007. RESULTS: 156 episodes of MRSA bacteremia were included, mostly from central venous catheter (32%) and skin and soft tissue (19%) infections. ID consultation coverage was 58% between 2001 and 2006 and 91% between 2007 and 2010. ID consultation was associated with more echocardiography (59% vs. 26%, p < 0.01), vancomycin trough level measurements (99% vs. 77%, p < 0.01), follow-up blood cultures (71% vs. 50%, p = 0.05), deep-seated infections (43% vs. 16%, p < 0.01), more frequent infection source control (83% vs. 57%, p = 0.03), a longer duration of MRSA-active therapy (median and IQR: 17 days, 13-30, vs. 12, 3-14, p < 0.01) and a 20% reduction in 7-day, 30-day and in-hospital mortality. CONCLUSIONS: ID consultation was associated with a better management of patients with MRSA bacteremia and a reduced mortality.

Neutrophils in infectious diseases

Host defense to intracellular pathogens depends upon both innate and adaptive cell-mediated immune responses. Polymorphonuclear neutrophil leukocytes which belong to the innate immune system are the first cells that are recruited massively within hours of microbial infection. Neutrophils are the main players in the killing of microorganisms and recently new methods of killing including nets formation have been described. Neutrophils mediate tissue damage at infected sites. By promoting tissue injury neutrophils contribute to the initiation of inflammation, which is now recognized as an essential step in launching immunity. The importance of neutrophils as decision shaper in the development of an immune response is only emerging as they have long been considered by immunologists as short lived, non-dividing cells, of poor interest. Now, neutrophils are emerging as key components of the inflammatory response, and are shown to have immunoregulatory roles in microbial infections. In addition, neutrophils were also reported to contribute to the recruitment and activation of antigen presenting cells. Thus early interactions between neutrophils and surrounding cells may influence the development/resolution of both inflammatory lesion and pathogen-specific immune response. The impact of neutrophils on cells present at the site of infection are only beginning to be studied and deserves more attention.In this e-book the reader will find updated information about the role of neutrophils in the pathogenesis of 1) bacterial diseases including sepsis, mycobacteria and Chlamydia infections, and of 2) parasitic diseases including leishmaniasis and toxoplasmosis. The role of neutrophils in the protection against microorganisms has largely been underestimated and, until recently, their role was mostly thought to limited to a "kill and die" response. New neutrophil mode of killing, such as their release of extracellular traps to kill extracellular bacterial pathogens, together with several microbial strategies designed to escape NETs are presented in Chapter 1. We will emphasize standard and advanced light microscopy techniques that allowed major advances in the understanding of neutrophil biology, through the visualization of the interaction of selected pathogens with neutrophils in living animals (Chapter 2).The aim of this e-book is to provide an overview of the recent advances made in the field of neutrophil biology. It will provide a basis for understanding future development that will occur in this area, and provide the reader with a short overview of some of the exciting new directions in which neutrophil research is moving.

Evaluation of prenatal diagnosis of congenital heart diseases by ultrasound: experience from 20 European registries.

OBJECTIVES: To evaluate prenatal diagnosis of congenital heart diseases by ultrasound investigation in well-defined European populations. DESIGN: Data from 20 registries of congenital malformations in 12 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to three ultrasound investigations per patient routinely performed. RESULTS: There were 2454 cases with congenital heart disease with an overall prenatal detection rate of 25%. Termination of pregnancy was performed in 293 cases (12%). There was considerable variation in prenatal detection rate between regions, with the lowest detection rates being in countries without ultrasound screening (11%) and in Eastern European countries (Croatia, Lithuania and Ukraine; 8%). In Western European countries with ultrasound screening, detection rate ranged from 19-48%. There was a significant difference in prenatal detection rate and proportion of induced abortions between isolated congenital heart disease and congenital heart disease associated with chromosome anomalies, multiple malformations and syndromes (P < 0.0001). There were 1694 cases with isolated congenital heart disease of which 16% were diagnosed prenatally. Malformations affecting the size of the ventricles were detected prenatally in half of the cases. CONCLUSIONS: Prenatal detection rate of congenital heart disease varies significantly between countries even with the same screening recommendations. The presence of associated malformations significantly increases the prenatal detection rate.

Obesity and the incidence of chronic diseases: a seemingly unrelated probit approach

Western societies can reduce avoidable mortality and morbidity by better understanding the relationship between obesity and chronic disease. This paper examines the joint determinants of obesity and of heart disease, diabetes, hypertension, and elevated cholesterol. It analyzes a broadly representative Spanish dataset, the 1999 Survey on Disabilities, Impairments and Health Status, using a health production theoretical framework together with a seemingly unrelated probit model approach that controls for unobserved heterogeneity and endogeneity. Its findings provide suggestive evidence of a positive and significant, although specification-dependent, association between obesity and the prevalence of chronic illness

Rituximab dans le traitement des maladies rénales glomérulaires: indications et evidences cliniques [Rationale and clinical evidence for the use of rituximab in glomerular diseases].

Autoimmune glomerulopathies are an important cause of chronic kidney disease. Conventional treatments based on steroids, antiproliferative and cytotoxic agents are efficacious, but highly toxic. Because of their central role in the pathogenesis of autoimmunity, B cells have become an attractive therapeutic target. Rituximab is a monoclonal antibody directed against CD20 expressed on the surface of B cells, inducing profound depletion of B cells in the peripheral blood. In spite of encouraging results regarding the off-label use of Rituximab in membranous nephropathy, systemic lupus erythematosus and small vessel vasculitis, controlled, long-term data, and data with specific renal endpoints are currently lacking.