Active screening for tuberculosis in high-incidence Inuit communities in Canada: a cost-effectiveness analysis.

BACKGROUND: Active screening for tuberculosis (TB) involves systematic detection of previously undiagnosed TB disease or latent TB infection (LTBI). It may be an important step toward elimination of TB among Inuit in Canada. We aimed to evaluate the cost-effectiveness of community-wide active screening for TB infection and disease in 2 Inuit communities in Nunavik. METHODS: We incorporated screening data from the 2 communities into a decision analysis model. We predicted TB-related health outcomes over a 20-year time frame, beginning in 2019. We assessed the cost-effectiveness of active screening in the presence of varying outbreak frequency and intensity. We also considered scenarios involving variation in timing, impact and uptake of screening programs. RESULTS: Given a single large outbreak in 2019, we estimated that 1 round of active screening reduced TB disease by 13% (95% uncertainty range -3% to 27%) and was cost saving compared with no screening, over 20 years. In the presence of simulated large outbreaks every 3 years thereafter, a single round of active screening was cost saving, as was biennial active screening. Compared with a single round, we also determined that biennial active screening reduced TB disease by 59% (95% uncertainty range 52% to 63%) and was estimated to cost Can$6430 (95% uncertainty range -$29 131 to $13 658 in 2019 Can$) per additional active TB case prevented. With smaller outbreaks or improved rates of treatment initiation and completion for people with LTBI, we determined that biennial active screening remained reasonably cost-effective compared with no active screening. INTERPRETATION: Active screening is a potentially cost-saving approach to reducing disease burden in Inuit communities that have frequent TB outbreaks.

Apolipoprotein D deficiency is associated to high bone turnover, low bone mass and impaired osteoblastic function in aged female mice.

BACKGROUND: Apolipoprotein D (ApoD) is a member of the lipocalin family known to transport small hydrophobic ligands. A major site of ApoD expression in mice is the central nervous system where evidence suggests that it plays a protective role. Gene expression of ApoD was reported in bone-forming osteoblasts but its impact on bone metabolism remains undocumented. METHODS: We compared basic bone parameters of ApoD(-/-) (null) and transgenic (tg) mice to wild-type (wt) littermates through microCT and histochemistry, as well as ApoD expression and secretion in osteoblasts under various culture conditions through real-time PCR and immunoblotting. RESULTS: ApoD-null females displayed progressive bone loss with aging, resulting in a 50% reduction in trabecular bone volume and a 23% reduction in cortical bone volume by 9months of age. Only cortical bone volume was significantly reduced in ApoD-null males by an average of 24%. Histochemistry indicated significantly higher osteoblast surface and number of osteoclasts in femora from ApoD-null females. ApoD gene expression was confirmed in primary cultures of bone marrow mesenchymal cells (MSC), with higher expression levels in MSC from females compared to males. ApoD-null MSC exhibited impaired proliferation and differentiation potentials. Moreover, exogenous ApoD partially rescued the osteogenic potential of null MSC, which were shown to readily uptake the protein from media. ApoD expression was upregulated under low proliferation conditions, by contact inhibition and osteoblastic differentiation in MC3T3-E1 osteoblast-like cells. CONCLUSION: Our results indicate that ApoD influences bone metabolism in mice in a gender-specific manner, potentially through an auto-/paracrine pathway.

Expression of macrophage migration inhibitory factor by osteoblastic cells: protection against cadmium toxicity.

Exposition to cadmium (Cd) has been linked to bone metabolism alterations and occurrence of osteoporosis. Despite its known renal toxicity which indirectly disrupts bone metabolism through impairment of vitamin D synthesis, increasing evidence argues for the direct action of Cd on bone-forming osteoblasts. Indeed, accumulation of Cd in osteoblasts and metal-induced cell death has been documented but little is known about the intracellular mechanisms of protection against this stress. In this work, we investigated the protection afforded by thiol-containing proteins against Cd cytotoxicity in MC3T3 osteoblastic cells. Viability of MC3T3 cells was reduced by Cd in a concentration-dependent manner with a LC(50) of 7.6±1.1µM. Depletion of glutathione by l-buthionine sulphoximine (BSO) increased cell sensitivity to Cd cytotoxicity, suggesting the involvement of thiol-containing peptides as a mechanism of protection. Accordingly, Cd was shown to promote progressive depletion of reduced thiol content and to stimulate the production of reactive oxygen species (ROS). Interestingly, low non cytotoxic concentrations of Cd increased the gene expression of macrophage migration inhibitory factor (MIF), also a thiol-containing protein. Inhibition of the transcription factor NFκB prevented Cd-dependent upregulation of MIF expression and consequently, increased Cd cytotoxicity in osteoblasts. Moreover, MIF deficient mouse osteoblasts were more sensitive to Cd cytotoxicity than the corresponding control cells. By gel-filtration chromatography, we demonstrated that MIF acts as a thiol-containing protein and thereby promotes Cd complexation. In accordance with its binding ability, addition of recombinant MIF to the culture medium reduced Cd cytotoxicity. Overall, upregulation of MIF expression by Cd may protect against the cytotoxicity of this metal in the osteoblasts.