MODEM: a comprehensive approach to modelling outcome and costs impacts of interventions for dementia. Protocol paper

Background The MODEM project (A comprehensive approach to MODelling outcome and costs impacts of interventions for DEMentia) explores how changes in arrangements for the future treatment and care of people living with dementia, and support for family and other unpaid carers, could result in better outcomes and more efficient use of resources. Methods MODEM starts with a systematic mapping of the literature on effective and (potentially) cost-effective interventions in dementia care. Those findings, as well as data from a cohort, will then be used to model the quality of life and cost impacts of making these evidence-based interventions more widely available in England over the period from now to 2040. Modelling will use a suite of models, combining microsimulation and macrosimulation methods, modelling the costs and outcomes of care, both for an individual over the life-course from the point of dementia diagnosis, and for individuals and England as a whole in a particular year. Project outputs will include an online Dementia Evidence Toolkit, making evidence summaries and a literature database available free to anyone, papers in academic journals and other written outputs, and a MODEM Legacy Model, which will enable local commissioners of services to apply the model to their own populations. Discussion Modelling the effects of evidence-based cost-effective interventions and making this information widely available has the potential to improve the health and quality of life both of people with dementia and their carers, while ensuring that resources are used efficiently

Decreased TNF-α synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging

Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymphocyte-associated antigen, or CD11a expression by CD4+ T cells or their physical capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject that results from decreased TNF-α secretion by macrophages. This prevents memory T cell entry into the skin after antigen challenge. However, isolated cutaneous macrophages from these subjects can be induced to secrete TNF-α after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro, indicating that the defect is reversible. The decreased conditioning of tissue microenvironments by macrophage-derived cytokines may therefore lead to defective immunosurveillance by memory T cells. This may be a predisposing factor for the development of malignancy and infection in the skin during aging

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25-responder T cells, but not CD4+CD25+regulatory T cells

Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes

The suppression of DC activation by peritoneal fluid from patients with beningn conditions is fully mediated by IL-10 unlike the suppressive activity of OC-associated ascites.

<p>Monocyte-derived DC were stimulated overnight with 3μg/ml R848 in the presence or absence of (A) 10% malignant ascites from OC patients or (B) 10% peritoneal fluid from benign ovarian tumours and IL-10 neutralizing antibody (5μg/ml) as indicated. CD86 expression levels were assessed by flow cytometry, and cytokine levels were measured in cell culture supernatants by flow cytomix analysis (A: IL-6 and TNFα) or sandwich ELISA (A: IL-12p40 and B: TNFα, IL-6 and IL-12p40); for malignant samples n = 6 (6 independent experiments; monocyte-derived DC from 5 different healthy donors, cultured with 1 (n = 4), or 2 (n = 1) different ascites samples); for benign samples n = 9 (9 independent experiments; monocyte-derived DC from 5 different healthy donors, cultured with 1 (n = 3), or 3 (n = 2) different peritoneal fluids); One-way ANOVA (Friedman test with Dunn post test): * = p<0.05, ns = not significant.</p

Neutralisation of IL-10 releases the impairment of DC activation in response to TLR stimulation in the presence of OC-associated ascites.

<p>(A, B) Monocyte derived DC were cultured in the presence of 3μg/ml R848, 10% ascites and neutralizing antibodies (5μg/ml) as indicated. Neutralizing antibodies were added to cultures alone or in combination. (A) CD86 expression levels were measured by flow-cytometry, and (B) cytokine levels were measured in cell culture supernatants by flow cytomix analysis (IL-6, TNFα) or sandwich ELISA (IL-12p40). n = 9–13 (13 independent experiments; monocyte-derived DC from 8 different healthy donors, cultured with 1 (n = 4), 2 (n = 3) or 3 (n = 1) different ascites samples. IL-6 neutralizing antibody was only used in 9 out of 13 experiments). One-way ANOVA (Friedman test with Dunn post test): *** = p<0.001. Please note that the quantification of IL-6 in samples containing IL-6 neutralizing antibody (αIL-6 and all AB) is compromised. (C, D) For allogeneic MLR, monocyte-derived DC from healthy donors were cultured overnight in complete medium only, or stimulated with 3μg/ml R848 in the presence or absence of 10% ascites fluid (AF) and/or IL-10 neutralizing antibody (5μg/ml) as indicated. Subsequently, such pre-treated DC were washed and co-cultured with CFSE-stained CD4⁺ naïve T cells from another healthy donor at a 1:200 ratio for 6 days. Naïve T cells from the same donor were used consistently for all experiments. The proliferation of T cells was determined by CFSE dilution after 6 days. (C) A representative example of flow-cytometry analysis is shown. (D) Cumulative data from 4 independent experiments showing proliferation in percent of CD3⁺ cells that have undergone at least one round of division. n = 4 (4 independent experiments; monocyte-derived DC from 3 different healthy donors, cultured with ascites from two (n = 1) or one (n = 2) OC patient).</p

Up-regulations of CD86 and induction of cytokines in response to TLR stimulation in the presence or absence of peritoneal fluid from patients with benign conditions.

<p>Monocyte-derived DC were stimulated overnight with 3μg/ml R848, 1μg/ml LPS or 100μg/ml polyI:C in the presence of 0%, 10% or 25% peritoneal fluid obtained from patients suffering from benign ovarian conditions. The following day, (A) the MFI of surface marker CD86 was assessed by flow cytometry and (B) cytokines were measured in culture supernatants by flow cytomix analysis or sandwich ELISA (IL-12p40). In total, 12 experiments (n = 12) were performed with DC from 8 different healthy volunteers cultured with ascites from 2 (n = 4) or 1 (n = 4) patient with benign ovarian conditions. One-way ANOVA was used for statistical analysis (Friedman test with Dunn post test); * = p<0.05; ** = p<0.01; *** = p<0.001; ns = not significant.</p