Improving mental healthcare for the elderly in Belgium.

INTRODUCTION: The organisation of mental healthcare for the elderly (MHCE) remains suboptimal. OBJECTIVE: To identify specific organisational models that could address the mental healthcare needs of the elderly in community and primary care. METHOD: A multi-modal approach, consisting of a literature review, an online survey of Belgian professional stakeholders, and an international comparison. The outcomes of this three-step study process were aggregated. RESULTS: Two general and four operational strategies for organising MHCE were identified as well as barriers and incentives to MHCE in the community and primary care. About half of survey respondents perceived the current MHCE in Belgium not to meet quality criteria as described in the literature and proposed points of improvement. The transversal international comparison revealed interesting approaches for MHCE. Recommendations for the future were formulated. CONCLUSION: MHCE requires a specific, low-threshold, holistic, and transdisciplinary approach. Specific strategies with emphasis on collaborative care should be applied to meet the needs of older adults with mental problems. General practitioners (GPs) can play a central role in community-oriented MHCE but should be supported by specialised healthcare providers (including old-age psychiatrists and geriatricians). Stigma and wrong beliefs, regarding the elderly population, should be tackled by means of campaigns.

Burden of frailty in the elderly population: perspectives for a public health challenge.

Frailty is a major health condition associated with ageing. Although the concept is almost universally accepted, its operational definition remains controversial. Anyway, this geriatric condition represents a huge potential public health issue at both the patient and the societal levels because of its multiple clinical, societal consequences and its dynamic nature. Here, we review existing definitions and assessment tools for frailty, we highlight consequences of this geriatric condition and we discuss the importance of its screening and prevention to limit its public health burden.

Differential IFN-alpha/beta production suppressing capacities of the leader proteins of mengovirus and foot-and-mouth disease virus.

Picornaviruses encompass a large family of RNA viruses. Some picornaviruses possess a leader (L) protein at the N-terminus of their polyprotein. The L proteins of encephalomyocarditis virus, a cardiovirus, and foot-and-mouth disease virus (FMDV), an aphthovirus, are both dispensable for replication and their major function seems to be the suppression of antiviral host cell responses. Previously, we showed that the L protein of mengovirus, a strain of encephalomyocarditis virus, inhibits antiviral responses by inhibiting type I interferon (IFN-alpha/beta) gene transcription. The L protein of the FMDV is a protease (L(pro)) that cleaves cellular factors to reduce cytokine and chemokine mRNA production and to inhibit cap-dependent cellular host mRNA translation, thereby limiting the production of proteins with antiviral activity. In this study, we constructed a viable chimeric mengovirus that expresses FMDV L(pro) in place of the authentic L protein in order to compare the efficiency of the immune evasion mechanisms mediated by L and L(pro) respectively. We show that in this mengovirus background the L protein is more potent than FMDV L(pro) in suppressing IFN-alpha/beta responses. Yet, FMDV L(pro) is important to antagonize infection-limiting responses both in vitro and in vivo.

Random mutagenesis defines a domain of Theiler's virus leader protein that is essential for antagonism of nucleocytoplasmic trafficking and cytokine gene expression.

The leader protein of cardioviruses, Theiler's murine encephalomyelitis virus (TMEV) and encephalomyocarditis virus (EMCV), is a multifunctional protein known to antagonize type I interferon expression and to interfere with nucleocytoplasmic trafficking of host proteins and mRNA. This protein plays an important role in the capacity of TMEV to establish persistent infection of the central nervous system. Mutant forms of the TMEV leader protein were generated by random mutagenesis and selected after retroviral transduction on the basis of the loss of the highly toxic nature of this protein. Selected mutations define a short C-terminal domain of the leader conserved in TMEV and Saffold virus but lacking in the EMCV leader and thus called the Theilo domain. Mutations in this domain had a dramatic impact on TMEV L protein activity. Like the zinc finger mutation, Theilo domain mutations affected all of the activities of the L protein tested: interferon gene transcription and IRF-3 dimerization antagonism, alteration of nucleocytoplasmic trafficking, nucleoporin 98 hyperphosphorylation, and viral persistence in vivo. This suggests that the Zn finger and the Theilo domain of the protein cooperate for function. Moreover, the fact that all of the activities tested were affected by these mutations suggests that the various leader protein functions are somehow coupled.

Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein.

Theiler's murine encephalomyelitis virus (TMEV or Theiler's virus) is a neurotropic picornavirus that can persist lifelong in the central nervous system of infected mice, causing a chronic inflammatory demyelinating disease. The leader (L) protein of the virus is an important determinant of viral persistence and has been shown to inhibit transcription of type I interferon (IFN) genes and to cause nucleocytoplasmic redistribution of host proteins. In this study, it was shown that expression of the L protein shuts off synthesis of the reporter proteins green fluorescent protein and firefly luciferase, suggesting that it induces a global shut-off of host protein expression. The L protein did not inhibit transcription or translation of the reporter genes, but blocked cellular mRNA export from the nucleus. This activity correlated with the phosphorylation of nucleoporin 98 (Nup98), an essential component of the nuclear pore complex. In contrast, the data confirmed that the L protein inhibited IFN expression at the transcriptional level, and showed that transcription of other chemokine or cytokine genes was affected by the L protein. This transcriptional inhibition correlated with inhibition of interferon regulatory factor 3 (IRF-3) dimerization. Whether inhibition of IRF-3 dimerization and dysfunction of the nuclear pore complex are related phenomena remains an open question. In vivo, IFN antagonism appears to be an important role of the L protein early in infection, as a virus bearing a mutation in the zinc finger of the L protein replicated as efficiently as the wild-type virus in type I IFN receptor-deficient mice, but had impaired fitness in IFN-competent mice.

The mengovirus leader protein blocks interferon-alpha/beta gene transcription and inhibits activation of interferon regulatory factor 3.

Viral infection of mammalian cells triggers the synthesis and secretion of type I interferons (i.e. IFN-alpha/beta), which induce the transcription of genes that cause cells to adopt an antiviral state. Many viruses have adapted mechanisms to evade IFN-alpha/beta-mediated responses. The leader protein of mengovirus, a picornavirus, has been implicated as an IFN-alpha/beta antagonist. Here, we show that the leader inhibits the transcription of IFN-alpha/beta and that both the presence of a zinc finger motif in its N-terminus and phosphorylation of threonine-47 are required for this function. Transcription of IFN-alpha/beta genes relies on the activity of a number of transcription factors, including interferon regulatory factor 3 (IRF-3). We show that the leader interferes with the transactivation activity of IRF-3 by interfering with its dimerization. Accordingly, mutant viruses with a disturbed leader function were impaired in their ability to suppress IFN-alpha/beta transcription in vivo. By consequence, the leader mutant viruses had an impaired ability to replicate and spread in normal mice but not in IFNAR-KO mice, which are incapable of mounting an IFN-alpha/beta-dependent antiviral response. These results suggest that the leader, by suppressing IRF3-mediated IFN-alpha/beta production, plays an important role in replication and dissemination of mengovirus in its host.

Type I interferon response in the central nervous system.

This review is dedicated to the influence of type I IFNs (also called IFN-alpha/beta) in the central nervous system (CNS). Studies in mice with type I IFN receptor or IFN-beta gene deficiency have highlighted the importance of the type I IFN system against CNS viral infections and non-viral autoimmune disorders. Direct antiviral effects of type I IFNs appear to be crucial in limiting early spread of a number of viruses in CNS tissues. Type I IFNs have also proved to be beneficial in autoimmune disorders like multiple sclerosis or experimental autoimmune encephalitis, probably through immunomodulatory effects. Increasing efforts are done to characterize IFN expression and response in the CNS: to identify type I IFN producing cells, to decipher pathways leading to type I IFN expression in those cells, and to identify responding cells. However, reversible and irreversible damages consecutive to chronic exposure of the CNS to type I IFNs underline the importance of a tightly regulated type I IFN homeostasis in this organ.