Principal component analysis for geographical data: the role of spatial effects in the definition of composite indicators

This paper investigates the role of spatial dependence, spatial heterogeneity and spatial scale in principal component analysis for geographically distributed data. It considers spatial heterogenei..

917-97 Decreased Resistance Against Oxidation of LDL from Patients with Homozigous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) was the first genetic disorder recognized to cause myocardial infarction. Homozigotes (H) inherit two mutant genes at the low density lipoprotein (LDL) receptor locus, and as a result of the increased levels and prolonged residence time of LDL in plasma, there is a strong tendency toward accumulation of LDL in the arterial wall, causing early atherogenesis. It has been shown that LDL might undergo oxidation before it can be taken up by macrophages and it become foam cells. Thus, one additional explanation for atherogenesis in FH may be the extent to which LDL is susceptible to oxidation. We selected 8 homozigous FH pts (mean total-cholesterol 825±70mg/dl) matched with 8 healthy subjects to investigate the LDL oxidizability. Skin fibroblast cultures showed that one patient was receptor negative, while others were receptor-defective. LDL were isolated from serum by ultracentrifugations in KBr. Purified LDL was exposed to oxygen radicals generated by the xanthine/xanthine oxidase reaction (2mM and 100mU, respectively for 18hs at 37°C). Malonildihaldehyde (MDAI content was evaluated by the thiobarbiturate method. LDL analysis was carried on polyacrylamide (PAGE; 5 to 16% gradient) and agarose gel electrophoresis (0.8% in Tris-HCL buffer). No significant increase was observed in the basal concentration of MDA between LDL from H and controls (0.8±0.12 and 0.9±0.15nmoles of MDAlmg of protein, respectively). Instead, afteroxidation MDAwas 35.1±4.5* nmoles/mg of protein LDL from H, and 23.5±4.1 in controls (*p<0.05). PAGE confirmed the purity of LDL, present as an intact apolipoprotein B100(apo-B100). When oxidized LDL was run on PAGE an extensive apo-B100fragmentation, replaced by lower fragments ranging from 97.400 to 205.000 m.w., was only observed in LDL from H but not in controls in our experimental conditions. MDA content after oxidation of LDL correlated well with the loss of intact apo-B100. Finally, the relative LDL mobility on agarose gel was evaluated. This assay allows to detect changes in electric charge induced by oxidation. Basal LDL from H and controls migrated as homogeneous bands to 1.2±0.2 and 1.1±0.2cm from the origin. In contrast, oxidized LDL from H migrated to 2.1±0.3*cm from the origin while those of controls migrated to 1.5±0.2 (*p<0.05). Thus, in FH LDL appear to be more susceptible to oxidationin vitro; the indices for LDL oxidizability were all significantly different from those of controls. This phenomenon may be an important additional mechanism of atherogenesis in homozigous FH

Implementing an ict-based polypharmacy management program in Italy

Although there is evidence of a growing awareness of the problem, no official policy statements or regulatory guidelines on polypharmacy have been released up to date by Italian Health Authorities. Medication review, application of appropriateness criteria and computerized prescription support systems are all possible approaches in order to improve the quality of prescribing in older persons. More focused training courses on multimorbidity and polytherapy management are encouraged. Furthermore a multidisciplinary approach integrating different health care professionals (physicians, pharmacists, and nurses) may positively impact on reducing the sense of fear related to discontinue or substitute drugs prescribed by others; the fragmentation of therapy among different specialists; reducing costs; and improving adverse drug reaction detection and reporting. Aiming at achieving the individualized pharmacotherapy, a multidisciplinary approach starting with identification of patients and risk for drug-related problems, followed by medication review overtime and use of inappropriateness criteria, supported by computerized systems has been proposed

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Funder: QingLan Research Project of Jiangsu for Outstanding Young TeachersFunder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical UniversityFunder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical UniversityAbstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once