Neurological and pulmonary adverse effects of subcutaneous methotrexate therapy.

We report the case of a patient receiving subcutaneous methotrexate (MTX) treatment for rheumatoid arthritis (RA) who developed a complex pattern of neurological and pulmonary symptoms. Fluctuant dysarthria, magnetic gait, weakness and dysmetria of the lower limbs, as well as symptoms and signs consistent with a diagnosis of pneumonitis started within 6 weeks of initiating MTX treatment and slowly resolved after its discontinuation. This case highlights the fact that even the relatively low doses of MTX in the therapy of RA can produce neurotoxicity, which can become manifest in a broad range of symptoms.

Real-life versus package insert: a post-marketing study on adverse-event rates of the virosomal hepatitis A vaccine Epaxal® in healthy travellers.

There are various methods to collect adverse events (AEs) in clinical trials. The methods how AEs are collected in vaccine trials is of special interest: solicited reporting can lead to over-reporting events that have little or no biological relationship to the vaccine. We assessed the rate of AEs listed in the package insert for the virosomal hepatitis A vaccine Epaxal(®), comparing data collected by solicited or unsolicited self-reporting. In an open, multi-centre post-marketing study, 2675 healthy travellers received single doses of vaccine administered intramuscularly. AEs were recorded based on solicited and unsolicited questioning during a four-day period after vaccination. A total of 2541 questionnaires could be evaluated (95.0% return rate). Solicited self-reporting resulted in significantly higher (p<0.0001) rates of subjects with AEs than unsolicited reporting, both at baseline (18.9% solicited versus 2.1% unsolicited systemic AEs) and following immunization (29.6% versus 19.3% local AEs; 33.8% versus 18.2% systemic AEs). This could indicate that actual reporting rates of AEs with Epaxal(®) may be substantially lower than described in the package insert. The distribution of AEs differed significantly between the applied methods of collecting AEs. The most common AEs listed in the package insert were reported almost exclusively with solicited questioning. The reporting of local AEs was more likely than that of systemic AEs to be influenced by subjects' sex, age and study centre. Women reported higher rates of AEs than men. The results highlight the need for detailing the methods how vaccine tolerability was reported and assessed.

The implementation of liquid chromatography tandem mass spectrometry for the official control of lipophilic toxins in seafood: Single-laboratory validation under four chromatographic conditions

We performed a comprehensive study to assess the fit for purpose of four chromatographic conditions for the determination of six groups of marine lipophilic toxins (okadaic acid and dinophysistoxins, pectenotoxins, azaspiracids, yessotoxins, gymnodimine and spirolides) by LC-MS/MS to select the most suitable conditions as stated by the European Union Reference Laboratory for Marine Biotoxins (EURLMB). For every case, the elution gradient has been optimized to achieve a total run-time cycle of 12 min. We performed a single-laboratory validation for the analysis of three relevant matrices for the seafood aquaculture industry (mussels, pacific oysters and clams), and for sea urchins for which no data about lipophilic toxins have been reported before. Moreover, we have compared the method performance under alkaline conditions using two quantification strategies: the external standard calibration (EXS) and the matrix-matched standard calibration (MMS). Alkaline conditions were the only scenario that allowed detection windows with polarity switching in a 3200 QTrap mass spectrometer, thus the analysis of all toxins can be accomplished in a single run, increasing sample throughput. The limits of quantification under alkaline conditions met the validation requirements established by the EURLMB for all toxins and matrices, while the remaining conditions failed in some cases. The accuracy of the method and the matrix effects where generally dependent on the mobile phases and the seafood species. The MMS had a moderate positive impact on method accuracy for crude extracts, but it showed poor trueness for seafood species other than mussels when analyzing hydrolyzed extracts. Alkaline conditions with EXS and recovery correction for OA were selected as the most proper conditions in the context of our laboratory. This comparative study can help other laboratories to choose the best conditions for the implementation of LC-MS/MS according to their own necessities.

Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging.

Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain plasticity involved in learning and memory. The proliferation of adult neural stem or progenitor cells is regulated by several extrinsic factors such as experience, disease or aging and intrinsic factors originating from the neurogenic niche. Microglia is very abundant in the dentate gyrus (DG) and increasing evidence indicates that these cells mediate the inflammation-induced reduction in neurogenesis. However, the role of microglia in neurogenesis in physiological conditions remains poorly understood. In this study, we monitored microglia and the proliferation of adult hippocampal stem/progenitor cells in physiological conditions known to increase or decrease adult neurogenesis, voluntary running and aging respectively. We found that the number of microglia in the DG was strongly inversely correlated with the number of stem/progenitor cells and cell proliferation in the granule cell layer. Accordingly, co-cultures of decreasing neural progenitor/glia ratio showed that microglia but not astroglia reduced the number of progenitor cells. Together, these results suggest that microglia inhibits the proliferation of neural stem/progenitor cells despite the absence of inflammatory stimulus.

Positive and negative regulation of cellular immune responses in physiologic conditions and diseases.

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

Adverse effects of industrial multiwalled carbon nanotubes on human pulmonary cells

The aim of this study was to evaluate adverse effects of multiwalled carbon nanotubes (MWCNT), produced for industrial purposes, on the human epithelial cell line A549. MWCNT were dispersed in dipalmitoyl lecithin (DPL), a component of pulmonary surfactant, and the effects of dispersion in DPL were compared to those in two other media: ethanol (EtOH) and phosphate-buffered saline (PBS). Effects of MWCNT were also compared to those of two asbestos fibers (chrysotile and crocidolite) and carbon black (CB) nanoparticles, not only in A549 cells but also in mesothelial cells (MeT5A human cell line), used as an asbestos-sensitive cell type. MWCNT formed agglomerates on top of both cell lines (surface area 15-35 μm2) that were significantly larger and more numerous in PBS than in EtOH and DPL. Whatever the dispersion media, incubation with 100 μg/ml MWCNT induced a similar decrease in metabolic activity without changing cell membrane permeability or apoptosis. Neither MWCNT cellular internalization nor oxidative stress was observed. In contrast, asbestos fibers penetrated into the cells, decreased metabolic activity but not cell membrane permeability, and increased apoptosis, without decreasing cell number. CB was internalized without any adverse effects. In conclusion, this study demonstrates that MWCNT produced for industrial purposes exert adverse effects without being internalized by human epithelial and mesothelial pulmonary cell lines. [Authors]

Inflammatory responses in aggregating rat brain cell cultures subjected to different demyelinating conditions.

To study inflammatory reactions occurring in relation to demyelination, aggregating rat brain cell cultures were subjected to three different demyelinating insults, i.e., (i) lysophosphatidylcholine (LPC), (ii) interferon-gamma combined with lipopolysaccharide (IFN-gamma+LPS), and (iii) anti-MOG antibodies plus complement (alpha-MOG+C). Demyelination was assessed by measuring the expression of myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), and the activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP). The accompanying inflammatory reactions were examined by the quantification of microglia-specific staining, by immunostaining for glial fibrillary acidic protein (GFAP), and by measuring the mRNA expression of a panel of inflammation-related genes. It was found that all three demyelinating insults decreased the expression of MBP and MOG, and induced microglial reactivity. LPC and alpha-MOG+C, but not IFN-gamma+LPS, decreased CNP activity; they also caused the appearance of macrophagic microglia, and increased GFAP staining indicating astrogliosis. LPC affected also the integrity of neurons and astrocytes. LPC and IFN-gamma+LPS upregulated the expression of the inflammation-related genes IL-6, TNF-alpha, Ccl5, Cxcl1, and iNOS, although to different degrees. Other inflammatory markers were upregulated by only one of the three insults, e.g., Cxcl2 by LPC; IL-1beta and IL-15 by IFN-gamma+LPS; and IFN-gamma by alpha-MOG+C. These findings indicate that each of the three demyelinating insults caused distinct patterns of demyelination and inflammatory reactivity, and that of the demyelinating agents tested only LPC exhibited general toxicity.

Health at work and risk factors related to ergonomics: some results from the Swiss sample of the 4th European working conditions survey

Introduction The European Foundation for the improvement of living and working conditions conducts a survey every 5 years since 1990. The foundation also offers the possibility to non-EU countries to be included in the survey: in 2005, Switzerland took part for the first time in the fourth edition of this survey. The Institute for Work and Health (IST) has been associated to the Swiss project conducted under the leadership of the SECO and the Fachhochschule Nordwestschweiz. The survey covers different aspects of work like job characteristics and employment conditions, health and safety, work organization, learning and development opportunities, and the balance between working and non-working life (Parent-Thirion, Fernandez Macias, Hurley, & Vermeylen, 2007). More particularly, one question assesses the worker's self-perception of the effects of work on health. We identified (for the Swiss sample) several factors affecting the risk to report health problems caused by work. The Swiss sample includes 1040 respondents. Selection of participants was based on a random multi-stage sampling and was carried out by M.I.S Trend S.A. (Lausanne). Participation rate was 59%. The database was weighted by household size, gender, age, region of domicile, occupational group, and economic sector. Specially trained interviewers carried out the interviews at the respondents home. The survey was carriedout between the 19th of September 2005 and the 30th of November 2005. As detailed in (Graf et al., 2007), 31% of the Swiss respondents identify work as the cause of health problems they experience. Most frequently reported health problems include back pain (18%), stress (17%), muscle pain (13%), and overall fatigue (11%). Ergonomic aspects associated with higher risk of reporting health problems caused by work include frequent awkward postures (odds ratio [OR] 4.7, 95% confidence interval [CI] 3.1 to 5.4), tasks involving lifting heavy loads (OR 2.7, 95% CI 2.0 to 3.6) or lifting people (OR 2.2, 95% CI 1.4 to 3.5), standing or walking (OR 1.4, 95% CI 1.1 to 1.9), as well as repetitive movements (OR 1.7, 95% CI 1.3 to 2.3). These results highlight the need to continue and intensify the prevention of work related health problems in occupations characterized by risk factors related to ergonomics.

Effect of initial conditions on the speed of reaction-diffusion fronts

The effect of initial conditions on the speed of propagating fronts in reaction-diffusion equations is examined in the framework of the Hamilton-Jacobi theory. We study the transition between quenched and nonquenched fronts both analytically and numerically for parabolic and hyperbolic reaction diffusion. Nonhomogeneous media are also analyzed and the effect of algebraic initial conditions is also discussed

Close-Clearance Conditions Near Railroad Tracks: A report to the Iowa Legislature as per Section 24, HF2614, Seventy-Ninth General Assembly, December 6, 2002

Close-Clearance Conditions Near Railroad Tracks for the Iowa Department of Transportation

Constraint satisfaction techniques under uncertain conditions for fault diagnosis in nonlinear dynamic systems

The speed of fault isolation is crucial for the design and reconfiguration of fault tolerant control (FTC). In this paper the fault isolation problem is stated as a constraint satisfaction problem (CSP) and solved using constraint propagation techniques. The proposed method is based on constraint satisfaction techniques and uncertainty space refining of interval parameters. In comparison with other approaches based on adaptive observers, the major advantage of the presented method is that the isolation speed is fast even taking into account uncertainty in parameters, measurements and model errors and without the monotonicity assumption. In order to illustrate the proposed approach, a case study of a nonlinear dynamic system is presented

Formation of chlorite during thrust fault reactivation. Record of fluid origin and P-T conditions in the Monte Perdido thrust fault (southern Pyrenees)

The chemical and isotopic compositions of clay minerals such as illite and chlorite are commonly used to quantify diagenetic and low-grade metamorphic conditions, an approach that is also used in the present study of the Monte Perdido thrust fault from the South Pyrenean fold-and-thrust belt. The Monte Perdido thrust fault is a shallow thrust juxtaposing upper Cretaceous-Paleocene platform carbonates and Lower Eocene marls and turbidites from the Jaca basin. The core zone of the fault, about 6 m thick, consists of intensely deformed clay-bearing rocks bounded by major shear surfaces. Illite and chlorite are the main hydrous minerals in the fault zone. Illite is oriented along cleavage planes while chlorite formed along shear veins (< 50 mu m in thickness). Authigenic chlorite provides essential information about the origin of fluids and their temperature. delta O-18 and delta D values of newly formed chlorite support equilibration with sedimentary interstitial water, directly derived from the local hanging wall and footwall during deformation. Given the absence of large-scale fluid flow, the mineralization observed in the thrust faults records the P-T conditions of thrust activity. Temperatures of chlorite formation of about 240A degrees C are obtained via two independent methods: chlorite compositional thermometers and oxygen isotope fractionation between cogenetic chlorite and quartz. Burial depth conditions of 7 km are determined for the Monte Perdido thrust reactivation, coupling calculated temperature and fluid inclusion isochores. The present study demonstrates that both isotopic and thermodynamic methods applied to clay minerals formed in thrust fault are useful to help constrain diagenetic and low-grade metamorphic conditions.

A better understanding of ecological conditions for Leontopodium alpinum Cassini in the Swiss Alps

Although Leontopodium alpinum is considered to be threatened in many countries, only limited scientific information about its autecology is available. In this study, we aim to define the most important ecological factors which influence the distribution of L. alpinum in the Swiss Alps. These were assessed at the national scale using species distribution models based on topoclimatic predictors and at the community scale using exhaustive plant inventories. The latter were analysed using hierarchical clustering and principal component analysis, and the results were interpreted using ecological indicator values. L. alpinum was found almost exclusively on base-rich bedrocks (limestone and ultramaphic rocks). The species distribution models showed that the available moisture (dry regions, mostly in the Inner Alps), elevation (mostly above 2000 m.a.s.l.) and slope (mostly >30°) were the most important predictors. The relevés showed that L. alpinum is present in a wide range of plant communities, all subalpine-alpine open grasslands, with a low grass cover. As a light-demanding and short species, L. alpinum requires light at ground level; hence, it can only grow in open, nutrient-poor grasslands. These conditions are met in dry conditions (dry, summer-warm climate, rocky and draining soil, south-facing aspect and/or steep slope), at high elevations, on oligotrophic soils and/or on windy ridges. Base-rich soils appear to also be essential, although it is still unclear if this corresponds to physiological or ecological (lower competition) requirements.

Adverse life events among community-dwelling persons aged 65-70 years: gender differences in occurrence and perceived psychological consequences.

OBJECTIVES: To describe the occurrence of selected adverse life events in young-old men and women, as well as their perceived psychological consequences. METHODS: In 2005, 1,422 participants in the Lausanne Cohort 65+ study, born in 1934-1938, self-reported whether they experienced any of 26 life events during the preceding year. Most participants (N = 1,309, 92%) completed the geriatric adverse life events scale during a face-to-face interview, by rating the level of stress associated with each event, as well as its impact on their psychological well-being. RESULTS: Overall, 72% of the participants experienced at least one of the 26 events in the preceding year (range 1-9). Disease affecting the respondent (N = 525) or a close relative (N = 276) was most frequent, as well as the death of a friend or non-close relative (N = 274). Women indicated a higher frequency of events (mean 2.1 vs. 1.7 events, P < 0.001), as well as a higher level of stress and a stronger negative impact on well-being than men. In multivariate analyses adjusting for self-rated health, depressive symptoms and comorbidity, female gender remained significantly associated with the level of stress and negative impact on psychological well-being. CONCLUSION: This exploratory study shows that several types of adverse life events frequently occur at age 65-70, with gender differences both in the frequency of reporting and consequences of these events. However, information on this topic is limited and studies based on different populations and designs are needed to better understand the impact of such events.