Identification of a set of KSRP target transcripts upregulated by PI3K-AKT signaling

BACKGROUND: KSRP is a AU-rich element (ARE) binding protein that causes decay of select sets of transcripts in different cell types. We have recently described that phosphatidylinositol 3-kinase/AKT (PI3K-AKT) activation induces stabilization and accumulation of the labile β-catenin mRNA through an impairment of KSRP function. RESULTS: Aim of this study was to identify additional KSRP targets whose stability and steady-state levels are enhanced by PI3K-AKT activation. First, through microarray analyses of the AU-rich transcriptome in pituitary αT3-1 cells, we identified 34 ARE-containing transcripts upregulated in cells expressing a constitutively active form of AKT1. In parallel, by an affinity chromatography-based technique followed by microarray analyses, 12 mRNAs target of KSRP, additional to β-catenin, were identified. Among them, seven mRNAs were upregulated in cells expressing activated AKT1. Both steady-state levels and stability of these new KSRP targets were consistently increased by either KSRP knock-down or PI3K-AKT activation. CONCLUSION: Our study identified a set of transcripts that are targets of KSRP and whose expression is increased by PI3K-AKT activation. These mRNAs encode RNA binding proteins, signaling molecules and a replication-independent histone. The increased expression of these gene products upon PI3K-AKT activation could play a role in the cellular events initiated by this signaling pathway

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance–related processes may be involved in several phenotypes, including the TRD

Presenilin 1 Protein Directly Interacts with Bcl-2

Presenilin proteins are involved in familial Alzheimer's disease, a neurodegenerative disorder characterized by massive death of neurons. We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by co-immunoprecipitation, and by cross-linking experiments. Our data show that PS1 and Bcl-2 assemble into a macromolecular complex, and that they are released from this complex in response to an apoptotic stimulus induced by staurosporine. The results support the idea of cross-talk between these two proteins during apoptosis

Radiological assessment of dementia: the Italian inter-society consensus for a practical and clinically oriented guide to image acquisition, evaluation, and reporting

Background: Radiological evaluation of dementia is expected to increase more and more in routine practice due to both the primary role of neuroimaging in the diagnostic pathway and the increasing incidence of the disease. Despite this, radiologists often do not follow a disease-oriented approach to image interpretation, for several reasons, leading to reports of limited value to clinicians. In our work, through an intersocietal consensus on the main mandatory knowledge about dementia, we proposed a disease-oriented protocol to optimize and standardize the acquisition/evaluation/interpretation and reporting of radiological images. Our main purpose is to provide a practical guideline for the radiologist to help increase the effectiveness of interdisciplinary dialogue and diagnostic accuracy in daily practice. Results: We defined key clinical and imaging features of the dementias (A), recommended MRI protocol (B), proposed a disease-oriented imaging evaluation and interpretation (C) and report (D) with a glimpse to future avenues (E). The proposed radiological practice is to systematically evaluate and score atrophy, white matter changes, microbleeds, small vessel disease, consider the use of quantitative measures using commercial software tools critically, and adopt a structured disease-oriented report. In the expanding field of cognitive disorders, the only effective assessment approach is the standardized disease-oriented one, which includes a multidisciplinary integration of the clinical picture, MRI, CSF and blood biomarkers and nuclear medicine

"Delirium Day": a nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy

The RNA-Binding Protein KSRP Promotes Decay of β-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling

β-catenin plays an essential role in several biological events including cell fate determination, cell proliferation, and transformation. Here we report that β-catenin is encoded by a labile transcript whose half-life is prolonged by Wnt and phosphatidylinositol 3-kinase–AKT signaling. AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP's ability to promote rapid mRNA decay. Our results uncover an unanticipated level of control of β-catenin expression pointing to KSRP as a required factor to ensure rapid degradation of β-catenin in unstimulated cells. We propose KSRP phosphorylation as a link between phosphatidylinositol 3-kinase–AKT signaling and β-catenin accumulation

A new generation of Parsec-Colibri stellar isochrones including the TP-AGB phase

We introduce a new generation of PARSEC-COLIBRI stellar isochrones that includes a detailed treatment of the thermally pulsing asymptotic giant branch (TP-AGB) phase, covering a wide range of initial metallicities (0.0001. < Z(i) < 0.06). Compared to previous releases, the main novelties and improvements are use of new TP-AGB tracks and related atmosphere models and spectra for M and C-type stars; inclusion of the surface H+He +CNO abundances in the isochrone tables, accounting for the effects of diffusion, dredge-up episodes and hot-bottom burning; inclusion of complete thermal pulse cycles, with a complete description of the in-cycle changes in the stellar parameters; new pulsation models to describe the long-period variability in the fundamental and firstovertone modes; and new dust models that follow the growth of the grains during the AGB evolution, in combination with radiative transfer calculations for the reprocessing of the photospheric emission. Overall, these improvements are expected to lead to a more consistent and detailed description of properties of TP-AGB stars expected in resolved stellar populations, especially in regard to their mean photometric properties from optical to mid-infrared wavelengths. We illustrate the expected numbers of TP-AGB stars of different types in stellar populations covering a wide range of ages and initial metallicities, providing further details on the "C-star island" that appears at intermediate values of age and metallicity, and about the AGB-boosting effect that occurs at ages close to 1.6-Gyr for populations of all metallicities. The isochrones are available through a new dedicated web server

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys

L’anziano attivo. Proposte e riflessioni per la terza e la quarta età

Il problema della senilità si pone ormai in Italia, come in tutte le società avanzate, in termini assai diversi dal passato. I saggi compresi nel presente volume intervengono su tutti gli aspetti della senilità - da quelli psicologici, sanitari e affettivi a quelli assistenziali, economici e giuridici - per suggerire indicazioni operative e possibili soluzioni.- Indice #4- Prefazione, Marcello Pacini #10- Introduzione, Giuliano Urbani #12- Prima parte Per una nuova concezione della condizione anziana #20- L’età del tempo libero, Norberto Bobbio #22- L’anziano protagonista in una società che cambia, Gian Maria Capuani e Giannino Piana #26- La piccola immortalità, Nando dalla Chiesa #36- L’anziano come risorsa sociale: il volontariato dopo la pensione, Fausto Melloni #44- Seconda Parte Aspetti sociali della condizione anziana #62- Psicogerontologia: attualità e nuove prospettive, Maria Antonietta Aveni Casucci #64- L’invecchiamento della popolazione italiana in un contesto internazionale, Antonio Golini e Agostino Lori #82- L’anziano e l’innovazione tecnologica, Francesco Jovane e Roberto Groppetti #114- La tutela giuridica dell’anziano, Luigi Mengoni #128- La salute dell’anziano: valutazione dei meccanismi di plasticità, Renzo Rozzini, Angelo Bianchetti e Marco Trabucchi #140- Lavoratori anziani: ambivalenza e interventi, Harris T. Schrank e Joan M. Waring #156- Il medico e l’anziano, Carlo Vergani #176- La normalità incerta, Virginio Oddone e Fabrizio Fabris #188- Il quadro organizzativo per una corretta assistenza socio-sanitaria alla popolazione anziana, Gaetano Maria Fara #200- Terza Parte Le tendenze della riflessione #216- La condizione degli anziani in Italia, Claudio Calvaruso #218- Anziani attivi: un possibile esempio di nuova centralità del sociale, Vincenzo Cesareo #228- Appendice Un contributo di ricerca #246- Figli adulti e genitori anziani: una nuova relazione tra le generazioni, Giovanna Rossi #24

Delirium Superimposed on Dementia Strongly Predicts Worse Outcomes in Older Rehabilitation Inpatients

AbstractObjectiveDelirium superimposed on dementia (DSD) is common in many settings. Nonetheless, little is known about the association between DSD and clinical outcomes. The study aim was to evaluate the association between DSD and related adverse outcomes at discharge from rehabilitation and at 1-year follow-up in older inpatients undergoing rehabilitation.DesignProspective cohort study.SettingHospital rehabilitation unit.ParticipantsA total of 2642 patients aged 65 years or older admitted between January 2002 and December 2006.MeasurementsDementia predating rehabilitation admission was detected by DSM-III-R criteria. Delirium was diagnosed with the DSM-IV-TR. The primary outcome was that of walking dependence (Barthel Index mobility subitem score of <15) captured as a trajectory from discharge to 1-year follow-up. A mixed-effects multivariate logistic regression model was used to analyze the association between DSD and outcome, after adjusting for relevant covariates. Secondary outcomes were institutionalization and mortality at 1-year follow-up, and logistic regression models were used to analyze these associations.ResultsThe median age was 77 years (interquartile range: 71–83). The prevalence of DSD was 8%, and the prevalence of delirium and dementia alone were 4% and 22%, respectively. DSD at admission was found to be significantly associated with almost a 15-fold increase in the odds of walking dependence (odds ratio [OR] 15.5; 95% Confidence Interval [CI] 5.6–42.7; P < .01). DSD was also significantly associated with a fivefold increase in the risk of institutionalization (OR 5.0; 95% CI 2.8–8.9; P < .01) and an almost twofold increase in the risk of mortality (OR 1.8; 95% CI 1.1–2.8; P = .01).ConclusionsDSD is a strong predictor of functional dependence, institutionalization, and mortality in older patients admitted to a rehabilitation setting, suggesting that strategies to detect DSD routinely in practice should be developed and DSD should be included in prognostic models of health care