Low levels of organic and inorganic mercury compounds have been reported previously to induce cell death by apoptosis in human peripheral blood mononuclear cells (MNC). but little is known about their potential effects on the viability and death of polymorphonuclear neutrophils (PMN). In contrast to MNC, PMN are known to undergo readily spontaneous apoptosis both in vivo and in vitro. Therefore, it was hypothesized that PMN may differ from MNC in their reactions to low mercury levels. The effects of methylmercuric chloride (MeHgCl) and mercuric chloride (HgCl2) were evaluated in concentration-response and time-course studies on human PMN viability and on their modes of cell death after in vitro incubation at 37 degrees C. Cell death by apoptosis or necrosis was assessed by annexin V-fluorescein isothiocyanate binding to externalized phosphatidylserine in conjunction with propidium iodide, and flow cytometry analysis. Morphologic counting of pyknotic nuclei and the fluorescence properties of the DNA-binding dye Hoechst 33342 in combination with propidium iodide were used to further confirm apoptotic cell death and to characterize the sequence of Hg-induced cell death. Results show that low concentrations of MeHgCl (1-7.5 microM) that were cytotoxic to MNC actually inhibited PMN spontaneous apoptosis. Low-level HgCl, reproduced the anti-apoptotic effects of MeHgCl on PMN, but to a lower extent. Higher concentrations of MeHgCl and HgCl2 were necrogenic to PMN, but MeHgCl was about an order of magnitude more toxic, and discrete differences were observed in the modalities of cell death induced by both species. These data reveal for the first time that (1) low levels of organic and inorganic mercury species protect human PMN from cell death via inhibition of spontaneous apoptosis, and (2) PMN are more resistant than MNC to mercury-induced cytotoxicity. Since delayed apoptosis and increased resistance to toxicant-induced cell death may lead to excessive accumulation of senescent PMN, evidence indicates that findings of this study may have implications for mercury-induced autoimmunity and inflammation.
Introduction:Stakeholders from the innovation field in Québec (Canada) have collectively stressed the need to formalize the process for evaluating innovative technologies in the province. In the context of innovation, and more so for non-pharmaceutical technologies where the pace of development is rapid and the lifecycle short, evidence supporting the added value can be limited and uncertainties are common. Therefore, pragmatic approaches are needed to guide recommendations and to assure that the process is rigorous, transparent and fair.Methods:Inspired by international experiences, the Institut national d'excellence en santé et services sociaux (INESSS) has developed a novel framework, where four types of recommendations are possible (introduction, refusal, limited or conditional introduction). The starting point is an evaluation of the technology's added value, for the patient, the population and the healthcare system, and the identification of uncertainties. The value of addressing uncertainty with further research is assessed, based on the value-of-information theory, and the distinct characteristics of medical devices are taken into account (e.g. learning curve effect, irrecoverable costs and incremental innovation). Those elements interact to support the formulation of recommendations by INESSS’ advisory committee.Results:The development of the framework was an iterative process supported by the use of the preliminary framework for the assessment of several innovative technologies. Challenges with its use were identified, and led to methodological and operational improvements. So far, the experience with the framework is positive and stakeholders confirm its relevance to support fair and reasonable recommendations for innovations.Conclusions:In the rapidly changing landscape of innovation, HTA has to adapt to the challenges of assessing technologies in a context of promise and uncertainties. The framework developed by INESSS is a tool for supporting timely and fair value-based decision-making, which will benefit the healthcare system, and the patients and population it serves.
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