RESUMO
Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test-retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [11C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centers. Instead, the medium affinity radioligand [11C]raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [11C]raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [11C]raclopride and [11C]FLB 457 to assess the correlation in binding potential (BPND) in extrastriatal brain regions. BPND was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BPND values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [11C]raclopride and [11C]FLB 457 BPND extrastriatally (Pearson's R: 0.30-0.56), in contrast to very strong correlations between repeated [11C]FLB 457 measurements (Pearson's R: 0.82-0.98). In comparison, correlations between repeated [11C]raclopride measurements were low to moderate (Pearson's R: 0.28-0.75). These results are likely related to low signal to noise ratio of [11C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [11C]raclopride should be interpreted with caution.
Assuntos
Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Receptores de Dopamina D2/análise , Radioisótopos de Carbono/metabolismo , Radioisótopos de Carbono/farmacologia , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Racloprida/metabolismo , Racloprida/farmacologia , Ensaio Radioligante/métodos , Compostos Radiofarmacêuticos/farmacologia , Salicilamidas/metabolismo , Salicilamidas/farmacologiaRESUMO
BACKGROUND: Epigenetic variation has been linked to several human diseases. Proliferative diabetic retinopathy (PDR) is a major cause of vision loss in subjects with diabetes. However, studies examining the association between PDR and the genome-wide DNA methylation pattern are lacking. Our aim was to identify epigenetic modifications that associate with and predict PDR in subjects with type 1 diabetes (T1D). METHODS: DNA methylation was analyzed genome-wide in 485,577 sites in blood from cases with PDR (n = 28), controls (n = 30), and in a prospective cohort (n = 7). False discovery rate analysis was used to correct the data for multiple testing. Study participants with T1D diagnosed before 30 years of age and insulin treatment within 1 year from diagnosis were selected based on 1) subjects classified as having PDR (cases) and 2) subjects with T1D who had had diabetes for at least 10 years when blood DNA was sampled and classified as having no/mild diabetic retinopathy also after an 8.7-year follow-up (controls). DNA methylation was also analyzed in a prospective cohort including seven subjects with T1D who had no/mild diabetic retinopathy when blood samples were taken, but who developed PDR within 6.3 years (converters). The retinopathy level was classified by fundus photography. RESULTS: We identified differential DNA methylation of 349 CpG sites representing 233 unique genes including TNF, CHI3L1 (also known as YKL-40), CHN2, GIPR, GLRA1, GPX1, AHRR, and BCOR in cases with PDR compared with controls. The majority of these sites (79 %) showed decreased DNA methylation in cases with PDR. The Natural Killer cell-mediated cytotoxicity pathway was found to be significantly (P = 0.006) enriched among differentially methylated genes in cases with PDR. We also identified differential DNA methylation of 28 CpG sites representing 17 genes (e.g. AHRR, GIPR, GLRA1, and BCOR) with P <0.05 in the prospective cohort, which is more than expected by chance (P = 0.0096). CONCLUSIONS: Subjects with T1D and PDR exhibit altered DNA methylation patterns in blood. Some of these epigenetic changes may predict the development of PDR, suggesting that DNA methylation may be used as a prospective marker of PDR.
Assuntos
Metilação de DNA/genética , Diabetes Mellitus Tipo 1/genética , Retinopatia Diabética/genética , Epigênese Genética/genética , Adulto , Estudos de Coortes , Diabetes Mellitus Tipo 1/complicações , Retinopatia Diabética/diagnóstico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: In Scandinavia, people with a severe mental disorder have a reduced life expectancy of 15-20 years compared with the general public. Smoking is a major contributor, and smoke-free policies are increasingly adopted in psychiatric clinics around the world. We compared potential facilitators and barriers among staff and management, for the implementation of smoke-free psychiatric clinics. AIMS: To investigate the attitudes and experiences regarding smoke-free policies among managers and staff involved in the implementation processes of smoke-free psychiatric clinics at hospitals in Malmö (Sweden) and Barcelona (Spain). METHOD: We used a qualitative methodology, with 15 semi-structured interviews. The interviews were conducted with each participant individually, and were subsequently transcribed. The data were analysed with systematic text condensation. RESULTS: There were notable differences in how the smoke-free policies were carried out and experienced, and attitudes regarding the policy changes differed in the two settings. Key differences were the views on the right to smoke in compulsory care and to stay in smoke-free surroundings supported by smoking cessation intervention; the prioritisation of staff facilitation of smoking breaks; and views on smoking and smoke-free psychiatry. In contrast, participants agreed on the importance of staff education and management support. A smoking ban by law and belonging to a network of smoke-free hospitals were also relevant. CONCLUSIONS: Staff education, and support from staff and management for the patients' right to stay in smoke-free surroundings, facilitated successful implementation of smoke-free policies in the psychiatric clinics, whereas supporting the right to smoke was a barrier.