Antagonism of Host Antiviral Responses by Kaposi's Sarcoma-Associated Herpesvirus Tegument Protein ORF45

Virus infection of a cell generally evokes an immune response by the host to defeat the intruder in its effort. Many viruses have developed an array of strategies to evade or antagonize host antiviral responses. Kaposi's sarcoma-associated herpesvirus (KSHV) is demonstrated in this report to be able to prevent activation of host antiviral defense mechanisms upon infection. Cells infected with wild-type KSHV were permissive for superinfection with vesicular stomatitis virus (VSV), suggesting that KSHV virions fail to induce host antiviral responses. We previously showed that ORF45, a KSHV immediate-early protein as well as a tegument protein of virions, interacts with IRF-7 and inhibits virus-mediated type I interferon induction by blocking IRF-7 phosphorylation and nuclear translocation (Zhu et al., Proc. Natl. Acad. Sci. USA. 99:5573-5578, 2002). Here, using an ORF45-null recombinant virus, we demonstrate a profound role of ORF45 in inhibiting host antiviral responses. Infection of cells with an ORF45-null mutant recombinant KSHV (BAC-stop45) triggered an immune response that resisted VSV super-infection, concomitantly associated with appreciable increases in transcription of type I IFN and downstream anti-viral effector genes. Gain-of-function analysis showed that ectopic expression of ORF45 in human fibroblast cells by a lentivirus vector decreased the antiviral responses of the cells. shRNA-mediated silencing of IRF-7, that predominantly regulates both the early and late phase induction of type I IFNs, clearly indicated its critical contribution to the innate antiviral responses generated against incoming KSHV particles. Thus ORF45 through its targeting of the crucial IRF-7 regulated type I IFN antiviral responses significantly contributes to the KSHV survival immediately following a primary infection allowing for progression onto subsequent stages in its life-cycle

Anthrax Edema Toxin Modulates PKA- and CREB-Dependent Signaling in Two Phases

Background: Anthrax edema toxin (EdTx) is an adenylate cyclase which operates in the perinuclear region of host cells. However, the action of EdTx is poorly understood, especially at molecular level. The ability of EdTx to modulate cAMPdependent signaling was studied in Jurkat T cells and was compared with that of other cAMP-rising agents: Bordetella pertussis adenylate cyclase toxin, cholera toxin and forskolin. Methodology/Principal Findings: EdTx caused a prolonged increase of the intracellular cAMP concentration. This led to nuclear translocation of the cAMP-dependent protein kinase (PKA) catalytic subunit, phosphorylation of cAMP response element binding protein (CREB) and expression of a reporter gene under control of the cAMP response element. Neither p90 ribosomal S6 kinase nor mitogen- and stress-activated kinase, which mediate CREB phosphorylation during T cell activation, were involved. The duration of phospho-CREB binding to chromatin correlated with the spatio-temporal rise of cAMP levels. Strikingly, EdTx pre-treated T cells were unresponsive to other stimuli involving CREB phosphorylation such as addition of forskolin or T cell receptor cross-linking. Conclusions/Significance: We concluded that, in a first intoxication phase, EdTx induces PKA-dependent signaling, which culminates in CREB phosphorylation and activation of gene transcription. Subsequently CREB phosphorylation is impaired and therefore T cells are not able to respond to cues involving CREB. The present data functionally link the perinuclea

Combined instruments for the screening of dementia in older people with low Education Instrumentos combinados para o rastreio de demência em idosos com baixo nível educacional

OBJECTIVE: To determine which combination of cognitive tests and informant reports can improve the diagnostic accuracy of dementia screening in low educated older people. METHOD: Patients with mild to moderate dementia (n=34) according to ICD-10 and DSM-III-R criteria and 59 older controls were assessed with the Mini-Mental State Examination (MMSE) and the Fuld Object Memory Evaluation (FOME). Informants were assessed using the Informant Questionnaire on Cognitive Decline in the Elderly and the Bayer-Activities of Daily Living Scale. RESULTS: The 4 instruments combined with the mixed rule correctly classified 100% and the logistic regression (weighted sum) classified 95.7% of subjects. The weighted sum had a significantly larger ROC area compared to MMSE (p=0.008) and FOME (p=0.023). The specificity of the tested combinations was superior to the MMSE alone (p=0.002). CONCLUSIONS: Cognitive tests combined with informant reports can improve the screening of mild to moderate dementia in low educated older people.<br>OBJETIVO: Determinar qual combinação de testes cognitivos e avaliações do informante pode melhorar o rastreio de demência em idosos com baixo nível educacional. MÉTODO: Pacientes com demência leve a moderada (n=34) de acordo com critérios da CID-10 e DSM-III-R, e 59 controles idosos foram avaliados com o Mini-Exame do Estado Mental (MEEM) e com o "Fuld Object Memory Evaluation" (FOME). Informantes foram avaliados com o "Informant Questionnaire on Cognitive Decline in the Elderly" e a escala Bayer-Atividades da Vida Diária. RESULTADOS: Os quatro instrumentos combinados com a regra mista classificaram 100% e a regressão logística (soma ponderada) classificou 95,7% dos sujeitos. A soma ponderada teve uma área da curva ROC significativamente maior comparada ao MEEM (p=0,008) e FOME (p=0,023). A especificidade das combinações testadas foi superior ao MEEM isolado (p=0,002). CONCLUSÕES: Testes cognitivos combinados com relatos dos informantes podem melhorar o rastreio de demência leve a moderada em idosos com baixo nível educacional

Assessment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a devastating illness, affecting over 5.5 million adults in the United States and costing over 200 billion dollars annually. In this chapter, we describe the clinical manifestations of mild cognitive impairment (MCI), which constitutes a risk factor for AD and other neurodegenerative disorders, and describe the appropriate neuropsychological measures that tap the important cognitive domains that should be assessed in these conditions. We also highlight advances in the field related to the clinical diagnosis and biomarkers associated with AD, as well as novel measures that have shown increased sensitivity for early identification of preclinical AD. A summary of useful clinical tips and future directions in the field are addressed