Исследование изменений твёрдости поверхности при азотировании сталей

Contact allergies are complex diseases, and one of the important challenges for public health and immunology. The German 'Federal Institute for Risk Assessment' hosted an 'International Workshop on Contact Dermatitis'. The scope of the workshop was to discuss new discoveries and developments in the field of contact dermatitis. This included the epidemiology and molecular biology of contact allergy, as well as the development of new in vitro methods. Furthermore, it considered regulatory aspects aiming to reduce exposure to contact sensitisers. An estimated 15-20% of the general population suffers from contact allergy. Workplace exposure, age, sex, use of consumer products and genetic predispositions were identified as the most important risk factors. Research highlights included: advances in understanding of immune responses to contact sensitisers, the importance of autoxidation or enzyme-mediated oxidation for the activation of chemicals, the mechanisms through which hapten-protein conjugates are formed and the development of novel in vitro strategies for the identification of skin-sensitising chemicals. Dendritic cell cultures and structure-activity relationships are being developed to identify potential contact allergens. However, the local lymph node assay (LLNA) presently remains the validated method of choice for hazard identification and characterisation. At the workshop the use of the LLNA for regulatory purposes and for quantitative risk assessment was also discussed

Methodological needs in the quality and safety characterisation of nanotechnology-based health products: Priorities for method development and standardisation

Nanotechnology-based health products are providing innovative solutions in health technologies and the pharmaceutical field, responding to unmet clinical needs. However, suitable standardised methods need to be available for quality and safety assessments of these innovative products prior to their translation into the clinic and for monitoring their performance when manufacturing processes are changed. The question arises which technological solutions are currently available within the scientific community to support the requested characterisation of nanotechnology-based products, and which methodological developments should be prioritized to support product developers in their regulatory assessment. To this end, the work presented here explored the state-of-the-art methods to identify methodological gaps associated with the preclinical characterisation of nanotechnology-based medicinal products and medical devices. The regulatory information needs, as expressed by regulatory authorities, were extracted from the guidance documents released so far for nanotechnology-based health products and mapped against available methods, thus allowing an analysis of methodological gaps and needs. In the first step, only standardised methods were considered, leading to the identification of methodological needs in five areas of characterisation, including: (i) surface properties, (ii) drug loading and release, (iii) kinetic properties in complex biological media, (iv) ADME (absorption, distribution, metabolism and excretion) parameters and (v) interaction with blood and the immune system. In the second step, a detailed gap analysis included analytical approaches in earlier stages of development, and standardised test methods from outside of the nanotechnology field that could address the identified areas of gaps. Based on this analysis, three categories of methodological needs were identified, including (i) method optimisation/adaptation to nanotechnological platforms, (ii) method validation/standardisation and (iii) method development for those areas where no technological solutions currently exist. The results of the analysis presented in this work should raise awareness within the scientific community on existing and emerging methodological needs, setting priorities for the development and standardisation of relevant analytical and toxicological methods allowing the development of a robust testing strategy for nanotechnology-based health products

Atrazine-induced apoptosis of splenocytes in BALB/C mice

<p>Abstract</p> <p>Background</p> <p>Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR), is the most commonly applied broad-spectrum herbicide in the world. Unintentional overspray of ATR poses an immune function health hazard. The biomolecular mechanisms responsible for ATR-induced immunotoxicity, however, are little understood. This study presents on our investigation into the apoptosis of splenocytes in mice exposed to ATR as we explore possible immunotoxic mechanisms.</p> <p>Methods</p> <p>Oral doses of ATR were administered to BALB/C mice for 21 days. The histopathology, lymphocyte apoptosis and the expression of apoptosis-related proteins from the Fas/Fas ligand (FasL) apoptotic pathway were examined from spleen samples.</p> <p>Results</p> <p>Mice administered ATR exhibited a significant decrease in spleen and thymus weight. Electron microscope histology of ultrathin sections of spleen revealed degenerative micromorphology indicative of apoptosis of splenocytes. Flow cytometry revealed that the percentage of apoptotic lymphocytes increased in a dose-dependent manner after ATR treatment. Western blots identified increased expression of Fas, FasL and active caspase-3 proteins in the treatment groups.</p> <p>Conclusions</p> <p>ATR is capable of inducing splenocytic apoptosis mediated by the Fas/FasL pathway in mice, which could be the potential mechanism underlying the immunotoxicity of ATR.</p

Lung response to Bordetella pertussis infection in mice identified by gene-expression profiling

Host genetics determines the course of Bordetella pertussis infection in mice. Previously, we found four loci, Tlr4 and three novel loci, designated Bps 1–3, that are involved in the control of B. pertussis infection. The purpose of the present study was to identify candidate genes that could explain genetic differences in the course of B. pertussis infection, assuming that such genes are differentially regulated upon infection. We, therefore, studied the course of mRNA expression in the lungs after B. pertussis infection. Of the 22,000 genes investigated, 1,841 were significantly differentially expressed with 1,182 genes upregulated and 659 genes downregulated. Upregulated genes were involved in immune-related processes, such as the acute-phase response, antigen presentation, cytokine production, inflammation, and apoptosis, while downregulated genes were mainly involved in nonimmune processes, such as development and muscle contraction. Pathway analysis revealed the involvement of granulocyte function, toll-like receptor signaling pathway, and apoptosis. Nine of the differentially expressed genes were located in Bps-1, 13 were located in Bps-2, and 62 were located in Bps-3. We conclude that B. pertussis infection induces a wide and complex response, which appears to be partly specific for B. pertussis and partly nonspecific. We envisage that these data will be helpful in identifying polymorphic genes that affect the susceptibility and course of B. pertussis infection in humans

Methyl methacrylate and respiratory sensitization: A Critical review

Methyl methacrylate (MMA) is a respiratory irritant and dermal sensitizer that has been associated with occupational asthma in a small number of case reports. Those reports have raised concern that it might be a respiratory sensitizer. To better understand that possibility, we reviewed the in silico, in chemico, in vitro, and in vivo toxicology literature, and also epidemiologic and occupational medicine reports related to the respiratory effects of MMA. Numerous in silico and in chemico studies indicate that MMA is unlikely to be a respiratory sensitizer. The few in vitro studies suggest that MMA has generally weak effects. In vivo studies have documented contact skin sensitization, nonspecific cytotoxicity, and weakly positive responses on local lymph node assay; guinea pig and mouse inhalation sensitization tests have not been performed. Cohort and cross-sectional worker studies reported irritation of eyes, nose, and upper respiratory tract associated with short-term peaks exposures, but little evidence for respiratory sensitization or asthma. Nineteen case reports described asthma, laryngitis, or hypersensitivity pneumonitis in MMA-exposed workers; however, exposures were either not well described or involved mixtures containing more reactive respiratory sensitizers and irritants.The weight of evidence, both experimental and observational, argues that MMA is not a respiratory sensitizer

Is protein citrullination by nanomaterials a risk factor for inducing autoimmune reactions?

Sinds 2012 is bekend dat eiwitten in cellen of proefdieren op een bepaalde manier veranderen als zij aan nanodeeltjes worden blootgesteld. Dit proces heet citrullinering. Onder bepaalde omstandigheden ontstaan antilichamen die gericht zijn tegen deze veranderde eiwitten. Omdat deze antilichamen zijn aangetroffen bij reumapatiënten wordt aangenomen dat er een verband bestaat tussen citrullinering van eiwitten, de ontstane antistoffen en processen die leiden tot auto-immuunziekten zoals reuma. Vanuit die veronderstelling wordt gespeculeerd dat blootstelling aan nanomaterialen een risicofactor kan zijn voor het ontstaan van auto-immuunziekten zoals reuma. In een literatuuronderzoek door het RIVM is dit verband echter niet gevonden. Er is namelijk nog nooit via metingen aangetoond dat antistoffen tegen gecitrullineerde eiwitten ontstaan na blootstelling aan nanomaterialen. Verder is alléén de aanwezigheid van antistoffen tegen gecitrullineerde eiwitten onvoldoende om artritis in proefdieren op te wekken. Dit literatuuronderzoek levert dus geen direct causaal verband tussen blootstelling aan nanomaterialen en reuma. Om meer inzicht in deze complexe processen te krijgen worden enkele vervolgonderzoeken aanbevolen. Ten eerste gaat het daarbij om het meten van antistoffen tegen gecitrullineerde eiwitten in proefdieren die aan nanomaterialen zijn blootgesteld. Ten tweede is het van belang te onderzoeken welk effect nanomaterialen in een proefdiermodel voor reuma hebben op de ontwikkeling van gewrichtsontsteking. Wordt de artritis dan erger, treedt het eerder op of zijn er meer dieren die het krijgen?Since 2012 it is known that proteins in cells or laboratory animals change in a specific way if they are exposed to nanoparticles. This process is called citrullination. Under certain circumstances, antibodies directed against these altered proteins develop. Since these antibodies have been found in patients with rheumatoid arthritis (RA) it is assumed that there is a correlation between citrullination of proteins, the resulting antibodies, and processes that lead to auto-immune diseases such as RA. From this assumption it is speculated that exposure to nanomaterials is a risk factor for the development of autoimmune diseases such as RA. In a literature review by the RIVM, this link has however not been found. Indeed, antibodies against citrullinated proteins have never been measured after exposure to nanomaterials. In addition, the mere presence of antibodies against citrullinated proteins is insufficient to induce arthritis in laboratory animals. Thus, these studies do not provide a direct causal link between exposure to nanomaterials and RA. To gain more insight into these complex processes, some follow-up studies are recommended. Firstly, this involves the measurement of antibodies against citrullinated proteins in laboratory animals exposed to nanomaterials. Secondly, it is of importance to investigate the effect of the nano-materials in an animal model for RA on the development of joint inflammation. Is arthritis aggravated, does it develop earlier or are more animals affected?NVW