Epidemiology and social impact of early onset dementia in the province of Modena, Northern Italy

Aims of the study. Early onset dementia (EOD), defined as onset of dementia <65 years, has a much higher social impact compared to the more common late onset dementia. EOD epidemiologic data in Italy are extremely scarce, and international estimates of prevalence are considerably variable, ranging between 15.1 and 153/100.000 in the age 45-65. We present data from an ongoing study aimed at establishing EOD epidemiology in a Northern Italy community (Modena province, around 700.000 inhabitants). Materials. We retrospectively recruited all patients residing in Modena province referred to the Modena Baggiovara Hospital Neurologic Clinic CDCD (Centro disturbi cognitivi e demenze), by family practitioners and geriatricians of the province. Eligible patients were those affected by EOD from 2012 to January 2019. EOD was diagnosed in patients <65 years presenting with cognitive/behavioral symptoms, following a comprehensive neurological examination by a cognitive neurologist, as well as brain MRI, FDG PET scanning and CSF analyses when appropriate. Methods. We collected clinical data such as age at onset, disease severity at time of diagnosis, time delay from onset to diagnosis, and epidemiologic data including residence and occupational status. Results. We identified 223 patients with an EOD diagnosis from 2012 to January 2019. Of these, 103 are males (46,2%). 97 patients have AD (21 lvPPA, 13 PCA, 2 frontal variant), 47 have FTD (33 bvFTD, 14 svPPA), 6 have leucoencephalopathy. Mean onset age was 58,6 years (SD 5,1). Median time from symptoms onset to diagnosis was 3.1 years (SD 29,83). Mean MMSE score at diagnosis was 22,63/30 (SD 5,2). 24 patients were working at time of diagnosis (10,76%) and had to quit working due to the cognitive impairment. Two patients (0,89%) had young children (<18) at time of diagnosis. Discussion. We provide the first epidemiological data on EOD in Italy. These are consistent with the estimates calculated by transposing European data to the population of Modena province (estimated prevalence=200 patients, detected prevalence=223 patients)1. Our data show a higher percentage of atypical AD phenotypes and FTD in the EOD group compared to late onset disease2. Also, CAA and leucoencephalopaties were over-represented compared to LOD. From a social perspective, EOD has significant impacts on patients and their families: patients are generally forced to leave work, and their children are expected to need psychological support, currently not routinely available. Conclusions. Our population study provides the first data regarding EOD epidemiology and social impact in Italy

IRF-5-dependent signaling restricts Orthobunyavirus dissemination to the central nervous system

ABSTRACT Interferon (IFN)-regulatory factor 5 (IRF-5) is a transcription factor that induces inflammatory responses after engagement and signaling by pattern recognition receptors. To define the role of IRF-5 during bunyavirus infection, we evaluated Oropouche virus (OROV) and La Crosse virus (LACV) pathogenesis and immune responses in primary cells and in mice with gene deletions in Irf3 , Irf5 , and Irf7 or in Irf5 alone. Deletion of Irf3 , Irf5 , and Irf7 together resulted in uncontrolled viral replication in the liver and spleen, hypercytokinemia, extensive liver injury, and an early-death phenotype. Remarkably, deletion of Irf5 alone resulted in meningoencephalitis and death on a more protracted timeline, 1 to 2 weeks after initial OROV or LACV infection. The clinical signs in OROV-infected Irf5 −/− mice were associated with abundant viral antigen and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in several regions of the brain. Circulating dendritic cell (DC) subsets in Irf5 −/− mice had higher levels of OROV RNA in vivo yet produced lower levels of type I IFN than wild-type (WT) cells. This result was supported by data obtained in vitro , since a deficiency of IRF-5 resulted in enhanced OROV infection and diminished type I IFN production in bone marrow-derived DCs. Collectively, these results indicate a key role for IRF-5 in modulating the host antiviral response in peripheral organs that controls bunyavirus neuroinvasion in mice. IMPORTANCE Oropouche virus (OROV) and La Crosse virus (LACV) are orthobunyaviruses that are transmitted by insects and cause meningitis and encephalitis in subsets of individuals in the Americas. Recently, we demonstrated that components of the type I interferon (IFN) induction pathway, particularly the regulatory transcription factors IRF-3 and IRF-7, have key protective roles during OROV infection. However, the lethality in Irf3 −/− Irf7 −/− (DKO) mice infected with OROV was not as rapid or complete as observed in Ifnar −/− mice, indicating that other transcriptional factors associated with an IFN response contribute to antiviral immunity against OROV. Here, we evaluated bunyavirus replication, tissue tropism, and cytokine production in primary cells and mice lacking IRF-5. We demonstrate an important role for IRF-5 in preventing neuroinvasion and the ensuing encephalitis caused by OROV and LACV

The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione

Exposure to environmental toxins, including hydrocarbon solvents, increases the risk of developing Parkinson's disease. An emergent hypothesis considers microtubule dysfunction as one of the crucial events in triggering neuronal degeneration in Parkinson's disease. Here, we used 2,5-hexanedione (2,5-HD), the toxic metabolite of n-hexane, to analyse the early effects of toxin-induced neurodegeneration on the cytoskeleton in multiple model systems. In PC12 cells differentiated with nerve growth factor for 5 days, we found that 2,5-HD treatment affected all the cytoskeletal components. Moreover, we observed alterations in microtubule distribution and stability, in addition to the imbalance of post-translational modifications of \u3b1-tubulin. Similar defects were also found in vivo in 2,5-HD-intoxicated mice. Interestingly, we also found that 2,5-HD exposure induced significant changes in microtubule stability in human skin fibroblasts obtained from Parkinson's disease patients harbouring mutations in PRKN gene, whereas it was ineffective in healthy donor fibroblasts, suggesting that the genetic background may really make the difference in microtubule susceptibility to this environmental Parkinson's disease-related toxin. In conclusion, by showing the imbalance between dynamic and stable microtubules in hydrocarbon-induced parkinsonism, our data support the crucial role of microtubule defects in triggering neurodegeneration

Search for correlation between GRB's detected by BeppoSAX and gravitational wave detectors EXPLORER and NAUTILUS

Data obtained during five months of 2001 with the gravitational wave (GW) detectors EXPLORER and NAUTILUS were studied in correlation with the gamma ray burst data (GRB) obtained with the BeppoSAX satellite. During this period BeppoSAX was the only GRB satellite in operation, while EXPLORER and NAUTILUS were the only GW detectors in operation. No correlation between the GW data and the GRB bursts was found. The analysis, performed over 47 GRB's, excludes the presence of signals of amplitude h >=1.2 * 10^{-18}, with 95 % probability, if we allow a time delay between GW bursts and GRB within +-400 s, and h >= 6.5 * 10^{-19}, if the time delay is within +- 5 s. The result is also provided in form of scaled likelihood for unbiased interpretation and easier use for further analysis.Comment: 14 pages, 7 figures. Latex file, compiled with cernik.cls (provided in the package

Methods and approaches for blind test predictions of out-of-plane behavior of masonry walls: a numerical comparative study

Earthquakes cause severe damage to masonry structures due to inertial forces acting in the normal direction to the plane of the walls. The out-of-plane behavior of masonry walls is complex and depends on several parameters, such as material and geometric properties of walls, connections between structural elements, the characteristics of the input motions, among others. Different analytical methods and advanced numerical modeling are usually used for evaluating the out-of-plane behavior of masonry structures. Furthermore, different types of structural analysis can be adopted for this complex behavior, such as limit analysis, pushover, or nonlinear dynamic analysis.Aiming to evaluate the capabilities of different approaches to similar problems, blind predictions were made using different approaches. For this purpose, two idealized structures were tested on a shaking table and several experts on masonry structures were invited to present blind predictions on the response of the structures, aiming at evaluating the available tools for the out-of-plane assessment of masonry structures. This article presents the results of the blind test predictions and the comparison with the experimental results, namely in terms of formed collapsed mechanisms and control outputs (PGA or maximum displacements), taking into account the selected tools to perform the analysis.info:eu-repo/semantics/publishedVersio

Strong El Niño reduces fruit production of Brazil-nut trees in the eastern Amazon.

The Brazil-nut tree (Bertholletia excelsa) is native to the Amazon rainforest, and its fruit production varies naturally with climatic conditions. Our aim was to evaluate the temporal variation in Brazil-nut production associated with climatic variables, including the strong El Niño of 2015/2016. The study was carried out in two 9-ha permanent plots in the northeastern Brazilian Amazon from 2007 to 2018: one in forest (12-year monitoring) and the other in savannah/forest transition (eight years). Overall, we monitored fruit production of 205 trees with diameter at breast height ≥ 50 cm. Annual fruit production was related to temporal series (2005-2018) of climatic data (the Oceanic Niño Index; and precipitation and air temperature from two local meteorological stations). Average fruit production per tree in 2017 was eight times lower than in 2015 and two times lower than the general average for both sites, and was significantly associated to the El Niño of 2015/2016, that increased average maximum monthly temperature and reduced the precipitation in the region, extending the dry season from three to six months. Years with higher and lower fruit production per tree coincided in both sites. Annual fruit production was significantly and negatively correlated with thermal anomalies that occurred in the third semester prior to harvest monitoring. Years with higher production were related with predominance of neutrality or the La Niña phenomenon at the global scale, and higher rainfall at the local scale. The relationship of fruit production with climate was independent of the local habitat

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes