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.

Do different measures of early life socioeconomic circumstances predict adult mortality? Evidence from the British Whitehall II and French GAZEL studies

BACKGROUND: Father's occupational position, education and height have all been used to examine the effects of adverse early life socioeconomic circumstances on health, but it remains unknown whether they predict mortality equally well. METHODS: We used pooled data on 18,393 men and 7060 women from the Whitehall II and GAZEL cohorts to examine associations between early life socioeconomic circumstances and all-cause and cause-specific mortality. RESULTS: During the 20-y follow-up period, 1487 participants died. Education had a monotonic association with all mortality outcomes; the age, sex and cohort-adjusted HR for the lowest versus the highest educational group was 1.45 (95% CI 1.24 to 1.69) for all-cause mortality. There was evidence of a U-shaped association between height and all-cause, cancer and cardiovascular mortality robust to adjustment for the other indicators (HR 1.41, 95% CI 1.03 to 1.93 for those shorter than average and HR 1.36, 95% CI 0.98 to 1.88 for those taller than average for cardiovascular mortality). Greater all-cause and cancer mortality was observed in participants whose father's occupational position was manual rather than non-manual (HR 1.11, 95% CI 1.00 to 1.23 for all-cause mortality), but the risks were attenuated after adjusting for education and height. CONCLUSIONS: The association between early life socioeconomic circumstances and mortality depends on the socioeconomic indicator used and the cause of death examined. Height is not a straightforward measure of early life socioeconomic circumstances as taller people do not have a health advantage for all mortality outcomes.

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.

Facteurs influençant le retour au travail après transplantation chez 61 patients rénaux ou hépatiques

Le taux de retour au travail après greffe est généralement bas. Or, on sait que le retour au travail après greffe améliore la qualité de vie des transplantés. Le but de notre étude était donc de comprendre les raisons possibles à ce faible taux en montrant les facteurs professionnels, individuels ou médicaux pouvant l'influencer. Parmi les 61 greffés rénaux ou hépatiques suivis au centre de transplantation d'organe (CTO) du CHUV, 39% ont repris le travail après greffe. Trois facteurs étaient significatifs de retour au travail après greffe, à savoir «travail avant greffe», «diplôme» et «âge < 45 ans». Ainsi, il est utile pour la pratique médicale de connaître les facteurs potentiels influençant le retour au travail car cela permet d'évaluer, au stade prégreffe, les chances de retour au travail et si besoin de proposer des mesures spécifiques le favorisant.

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.

Divergent effect of cobalt and beryllium salts on the fate of peripheral blood monocytes and T lymphocytes.

Occupational exposure to metals such as cobalt and beryllium represents a risk factor for respiratory health and can cause immune-mediated diseases. However, the way they act may be different. We show here that the two metals have a divergent effect on peripheral T lymphocytes and monocytes: BeSO(4) induces cell death in monocytes but not in T lymphocytes, which instead respond by producing Interferon gamma (IFN-γ); conversely, CoCl(2) induces apoptosis in T lymphocytes but not in monocytes. Interestingly, both metals induce p53 overexpression but with a dramatic different outcome. This is because the effect of p53 in CoCl(2)-treated monocytes is counteracted by the antiapoptotic activity of cytoplasmic p21(Cip1/WAF1), the activation of nuclear factor κB, and the inflammasome danger signaling pathway leading to the production of proinflammatory cytokines. However, CoCl(2)-treated monocytes do not fully differentiate into macrophage or dendritic cells, as inferred by the lack of expression of CD16 and CD83, respectively. Furthermore, the expression of HLA-class II molecules, as well as the capability of capturing and presenting the antigens, decreased with time. In conclusion, cobalt keeps monocytes in a partially activated, proinflammatory state that can contribute to some of the pathologies associated with the exposure to this metal.

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.

Occupational respiratory exposures to irritating and sensitizing volatile compounds deriving from cleaning products

Recent findings suggest an association between exposure to cleaning products and respiratory dysfunctions including asthma. However, little information is available about quantitative airborne exposures of professional cleaners to volatile organic compounds deriving from cleaning products. During the first phases of the study, a systematic review of cleaning products was performed. Safety data sheets were reviewed to assess the most frequently added volatile organic compounds. It was found that professional cleaning products are complex mixtures of different components (compounds in cleaning products: 3.5 ± 2.8), and more than 130 chemical substances listed in the safety data sheets were identified in 105 products. The main groups of chemicals were fragrances, glycol ethers, surfactants, solvents; and to a lesser extent phosphates, salts, detergents, pH-stabilizers, acids, and bases. Up to 75% of products contained irritant (Xi), 64% harmful (Xn) and 28% corrosive (C) labeled substances. Hazards for eyes (59%), skin (50%) and by ingestion (60%) were the most reported. Monoethanolamine, a strong irritant and known to be involved in sensitizing mechanisms as well as allergic reactions, is frequently added to cleaning products. Monoethanolamine determination in air has traditionally been difficult and air sampling and analysis methods available were little adapted for personal occupational air concentration assessments. A convenient method was developed with air sampling on impregnated glass fiber filters followed by one step desorption, gas chromatography and nitrogen phosphorous selective detection. An exposure assessment was conducted in the cleaning sector, to determine airborne concentrations of monoethanolamine, glycol ethers, and benzyl alcohol during different cleaning tasks performed by professional cleaning workers in different companies, and to determine background air concentrations of formaldehyde, a known indoor air contaminant. The occupational exposure study was carried out in 12 cleaning companies, and personal air samples were collected for monoethanolamine (n=68), glycol ethers (n=79), benzyl alcohol (n=15) and formaldehyde (n=45). All but ethylene glycol mono-n-butyl ether air concentrations measured were far below (<1/10) of the Swiss eight hours occupational exposure limits, except for butoxypropanol and benzyl alcohol, where no occupational exposure limits were available. Although only detected once, ethylene glycol mono-n-butyl ether air concentrations (n=4) were high (49.5 mg/m3 to 58.7 mg/m3), hovering at the Swiss occupational exposure limit (49 mg/m3). Background air concentrations showed no presence of monoethanolamine, while the glycol ethers were often present, and formaldehyde was universally detected. Exposures were influenced by the amount of monoethanolamine in the cleaning product, cross ventilation and spraying. The collected data was used to test an already existing exposure modeling tool during the last phases of the study. The exposure estimation of the so called Bayesian tool converged with the measured range of exposure the more air concentrations of measured exposure were added. This was best described by an inverse 2nd order equation. The results suggest that the Bayesian tool is not adapted to predict low exposures. The Bayesian tool should be tested also with other datasets describing higher exposures. Low exposures to different chemical sensitizers and irritants should be further investigated to better understand the development of respiratory disorders in cleaning workers. Prevention measures should especially focus on incorrect use of cleaning products, to avoid high air concentrations at the exposure limits. - De récentes études montrent l'existence d'un lien entre l'exposition aux produits de nettoyages et les maladies respiratoires telles que l'asthme. En revanche, encore peu d'informations sont disponibles concernant la quantité d'exposition des professionnels du secteur du nettoyage aux composants organiques volatiles provenant des produits qu'ils utilisent. Pendant la première phase de cette étude, un recueil systématique des produits professionnels utilisés dans le secteur du nettoyage a été effectué. Les fiches de données de sécurité de ces produits ont ensuite été analysées, afin de répertorier les composés organiques volatiles les plus souvent utilisés. Il a été mis en évidence que les produits de nettoyage professionnels sont des mélanges complexes de composants chimiques (composants chimiques dans les produits de nettoyage : 3.5 ± 2.8). Ainsi, plus de 130 substances listées dans les fiches de données de sécurité ont été retrouvées dans les 105 produits répertoriés. Les principales classes de substances chimiques identifiées étaient les parfums, les éthers de glycol, les agents de surface et les solvants; dans une moindre mesure, les phosphates, les sels, les détergents, les régulateurs de pH, les acides et les bases ont été identifiés. Plus de 75% des produits répertoriés contenaient des substances décrites comme irritantes (Xi), 64% nuisibles (Xn) et 28% corrosives (C). Les risques pour les yeux (59%), la peau (50%) et par ingestion (60%) était les plus mentionnés. La monoéthanolamine, un fort irritant connu pour être impliqué dans les mécanismes de sensibilisation tels que les réactions allergiques, est fréquemment ajouté aux produits de nettoyage. L'analyse de la monoéthanolamine dans l'air a été habituellement difficile et les échantillons d'air ainsi que les méthodes d'analyse déjà disponibles étaient peu adaptées à l'évaluation de la concentration individuelle d'air aux postes de travail. Une nouvelle méthode plus efficace a donc été développée en captant les échantillons d'air sur des filtres de fibre de verre imprégnés, suivi par une étape de désorption, puis une Chromatographie des gaz et enfin une détection sélective des composants d'azote. Une évaluation de l'exposition des professionnels a été réalisée dans le secteur du nettoyage afin de déterminer la concentration atmosphérique en monoéthanolamine, en éthers de glycol et en alcool benzylique au cours des différentes tâches de nettoyage effectuées par les professionnels du nettoyage dans différentes entreprises, ainsi que pour déterminer les concentrations atmosphériques de fond en formaldéhyde, un polluant de l'air intérieur bien connu. L'étude de l'exposition professionnelle a été effectuée dans 12 compagnies de nettoyage et les échantillons d'air individuels ont été collectés pour l'éthanolamine (n=68), les éthers de glycol (n=79), l'alcool benzylique (n=15) et le formaldéhyde (n=45). Toutes les substances mesurées dans l'air, excepté le 2-butoxyéthanol, étaient en-dessous (<1/10) de la valeur moyenne d'exposition aux postes de travail en Suisse (8 heures), excepté pour le butoxypropanol et l'alcool benzylique, pour lesquels aucune valeur limite d'exposition n'était disponible. Bien que détecté qu'une seule fois, les concentrations d'air de 2-butoxyéthanol (n=4) étaient élevées (49,5 mg/m3 à 58,7 mg/m3), se situant au-dessus de la frontière des valeurs limites d'exposition aux postes de travail en Suisse (49 mg/m3). Les concentrations d'air de fond n'ont montré aucune présence de monoéthanolamine, alors que les éthers de glycol étaient souvent présents et les formaldéhydes quasiment toujours détectés. L'exposition des professionnels a été influencée par la quantité de monoéthanolamine présente dans les produits de nettoyage utilisés, par la ventilation extérieure et par l'emploie de sprays. Durant la dernière phase de l'étude, les informations collectées ont été utilisées pour tester un outil de modélisation de l'exposition déjà existant, l'outil de Bayesian. L'estimation de l'exposition de cet outil convergeait avec l'exposition mesurée. Cela a été le mieux décrit par une équation du second degré inversée. Les résultats suggèrent que l'outil de Bayesian n'est pas adapté pour mettre en évidence les taux d'expositions faibles. Cet outil devrait également être testé avec d'autres ensembles de données décrivant des taux d'expositions plus élevés. L'exposition répétée à des substances chimiques ayant des propriétés irritatives et sensibilisantes devrait être investiguée d'avantage, afin de mieux comprendre l'apparition de maladies respiratoires chez les professionnels du nettoyage. Des mesures de prévention devraient tout particulièrement être orientées sur l'utilisation correcte des produits de nettoyage, afin d'éviter les concentrations d'air élevées se situant à la valeur limite d'exposition acceptée.

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.