http://repub.eur.nl/res/aut/227/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/27867/ 2010-01-01T00:00:00Z The objective of this study was to evaluate the antipsychotic drug prescribing pattern in the Italian general population, elderly, and especially elderly with dementia, in relation to the safety warnings issued by international regulatory agencies about the risk of cerebrovascular adverse events and mortality in 2004 and 2005. A cohort study was conducted using the electronic medical records of the Italian general practice database 'Health Search/Thales'. On the basis of prescription data, 1-year and monthly prevalence estimates were calculated for atypical and typical antipsychotic use in general population, elderly, and elderly demented outpatients. One-year prevalence of individual medication use in elderly demented patients was calculated as well. The prevalence of use of atypical agents in demented patients progressively increased from 2000 [0.2 (0.05-0.7) per 10000] until the beginning of 2004 [9.7 (8.1-11.6) per 10000], after which a slight decrease started, whereas the prevalence of use of typical antipsychotics decreased from 2001 [15.7 (13.5-18.2) per 10000] until 2004 [10.7 (9.0-12.7) per 10000], then slightly increased in December 2005 [12.1 (10.4-14.2) per 10000]. Monthly trends in general population and elderly were quite similar and differed significantly from the trend in elderly with dementia: stable use of atypicals from 2002 to 2005 and strong reduction of typicals from 2001 to the end of 2004. The recent safety warnings led to an increasing trend in the use of typical agents and decreasing trend in the use of atypical agents in elderly demented outpatients in Italy. Similar trends were not observed in general population and elderly as a whole. http://repub.eur.nl/res/pub/36806/ 2007-04-01T00:00:00Z PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n=5) or heterozygous (n=15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation. http://repub.eur.nl/res/pub/5904/ 2003-10-01T00:00:00Z Four chromosomal loci ( PARK2, PARK6, PARK7, and PARK9) associated with autosomal recessive, early onset parkinsonism are known. We mapped the PARK7 locus to chromosome 1p36 in a large family from a genetically isolated population in the Netherlands, and confirmed this linkage in an Italian family. By positional cloning within the refined PARK7 critical region we recently identified mutations in the DJ-1 gene in the two PARK7-linked families. The function of DJ-1 remains largely unknown, but evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role for DJ-1 as an antioxidant and/or a molecular chaperone. Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson's disease. http://repub.eur.nl/res/pub/5901/ 2002-09-01T00:00:00Z Autosomal recessive, early onset parkinsonism (AREP) is genetically heterogeneous. Mutations in the parkin gene (PARK2 locus, chromosome 6q) account for up to 50% of AREP families. The parkin protein displays ubiquitin-ligase activity for different targets, which accumulate in the brain of patients with parkin defect and might cause neurodegeneration. Two new AREP loci (PARK6 and PARK7) have been recently mapped on chromosome 1p and confirmed in independent datasets, suggesting that both might be frequent. The three AREP forms display similar clinical phenotypes. Recruiting new families will help cloning the defective genes at PARK6 and PARK7 loci. This will contribute to unraveling the pathogenesis of AREP, and it is also expected to foster our understanding of molecular events underlying classic Parkinson's disease. http://repub.eur.nl/res/pub/5900/ 2002-02-11T00:00:00Z Two new loci, PARK6 and PARK7, for autosomal recessive early-onset parkinsonism have recently been identified on chromosome 1p, in single large pedigrees. Among 4 autosomal recessive early-onset families analyzed here, 2 supported linkage to PARK7, 1 with conclusive evidence. These data confirm localization of autosomal recessive early-onset parkinsonism to PARK7, suggesting it to be a frequent locus. Assignment of families to either PARK6 or PARK7 might be difficult because of the proximity of the two loci on chromosome 1p.