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1.
Br J Soc Psychol ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31595987

RESUMO

Life-history narratives describing how a transgressor developed aversive traits can mitigate blame. How is their effectiveness affected by narrative perspective? In particular, how is blame mitigation impacted when the transgressor appears to be knowledgeable of the story of his self-formation? In three experiments, we compare the effectiveness of narratives that reflect an objective perspective to those that reflect the transgressor's perspective. The experiments contrast two hypotheses. The Perspective Taking hypothesis asserts that the transgressor perspective will be especially effective for blame mitigation because it encourages 'stepping into the shoes' of the transgressor. In contrast, the Should Know Better hypothesis asserts that the transgressor perspective will be especially ineffective because it reveals the transgressor to have self-knowledge, which triggers an inference that he deeply comprehends the suffering he causes. Results support the Should Know Better hypothesis. Furthermore, Experiment 3 shows that the transgressor perspective increases blameworthiness regardless of whether the transgressor's prior life experiences parallel what he inflicts on his victims.

2.
Elife ; 82019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31482844

RESUMO

TMEM16B (ANO2) is the Ca2+-activated chloride channel expressed in multiple brain regions, including the amygdala. Here we report that Ano2 knockout mice exhibit impaired anxiety-related behaviors and context-independent fear memory, thus implicating TMEM16B in anxiety modulation. We found that TMEM16B is expressed in somatostatin-positive (SOM+) GABAergic neurons of the central lateral amygdala (CeL), and its activity modulates action potential duration and inhibitory postsynaptic current (IPSC). We further provide evidence for TMEM16B actions not only in the soma but also in the presynaptic nerve terminals of GABAergic neurons. Our study reveals an intriguing role for TMEM16B in context-independent but not context-dependent fear memory, and supports the notion that dysfunction of the amygdala contributes to anxiety-related behaviors.

4.
Genes Brain Behav ; : e12602, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31385409

RESUMO

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune-relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene-set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene-set was enriched for genes associated with human intelligence and SZ risk, using genome-wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene-set analysis with a complement gene-set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene-based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome-wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.

5.
Psychol Med ; : 1-10, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391132

RESUMO

BACKGROUND: Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient. METHODS: Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology. RESULTS: Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions. CONCLUSION: These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the 'dysconnectivity hypothesis' of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31325214

RESUMO

OBJECTIVES: This study aimed to identify and prioritize factors important to patients and caregivers with regard to medication adherence in gout, osteoporosis (OP) and rheumatoid arthritis (RA), and to describe the reasons for their decisions. METHODS: Patients with gout, OP and RA, and their caregivers purposively sampled from five rheumatology clinics in Australia, identified and ranked factors considered important for medication adherence using nominal group technique and discussed their decisions. An importance score (scale 0-1) was calculated, and qualitative data were analysed thematically. RESULTS: From 14 focus groups, 82 participants (67 patients, 15 caregivers) identified 49 factors. The top five factors based on the ranking of all participants were trust in doctor (importance score 0.46), medication effectiveness (0.31), doctor's knowledge (0.25), side effects (0.23), medication taking routine (0.13). The order of the ranking varied by participant groupings with patients ranking trust in doctor the highest whilst caregivers ranked side effects the highest. Five themes reflecting the reasons for factors influencing adherence were: motivation and certainty in supportive individualised care; living well and restoring function; fear of toxicity and cumulative harm; seeking control and involvement; and unnecessarily difficult and inaccessible. CONCLUSIONS: Factors related to the doctor, medication properties and patients' medication knowledge and routine were important for adherence. Strengthening doctor-patient trust and partnership, managing side effects, and empowering patients with knowledge and skills for medicine-taking could enhance medication adherence in patients with rheumatic conditions. This article is protected by copyright. All rights reserved.

7.
PLoS One ; 14(7): e0218111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31283791

RESUMO

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

8.
Neuroscience ; 413: 183-205, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229631

RESUMO

Rett Syndrome (RTT) is a neurological disorder mainly associated with mutations in the X-linked gene coding for the methyl-CpG binding protein 2 (MECP2). To assist in studying MECP2's function, researchers have generated Mecp2 mouse mutants showing that MECP2's product (MeCP2) mostly functions as a transcriptional regulator. During the last two decades, these models have been used to determine the genes that are regulated by MeCP2, slowly dissecting the etiological mechanisms underlying RTT. In the present review, we describe the findings of these transcriptomic studies, and highlight differences between them, and discuss how studies on these genetic models can sharpen our understanding of the human disorder. We conclude that - while there's large variability regarding the number of differentially expressed genes identified - there are overlapping features that inform on the biology of RTT.

9.
J Rheumatol ; 46(10): 1355-1359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30936284

RESUMO

OBJECTIVE: Establishing a research agenda on standardizing pain measurement in clinical trials in rheumatic and musculoskeletal diseases (RMD). METHODS: Discussion during a meeting at the Outcome Measures in Rheumatology (OMERACT) 2018, prepared by a systematic review of existing core outcome sets and a patient online survey. RESULTS: Several key questions were debated: Is pain a symptom or a disease? Are pain core (sub)domains consistent across RMD? How to account for pain mechanistic descriptors (e.g., central sensitization) in pain measurement? CONCLUSION: Characterizing and assessing the spectrum of pain experience across RMD in a standardized fashion is the objective of the OMERACT Pain Working Group.

10.
Am J Med Genet B Neuropsychiatr Genet ; 180(3): 223-231, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30801977

RESUMO

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

11.
J Rheumatol ; 46(9): 1202-1206, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30647162

RESUMO

OBJECTIVE: The OMERACT-Adherence meeting was convened to discuss the conceptual and methodological challenges in developing a core domain set (Adherence-CDS) for trials of interventions for medication adherence in rheumatology. METHODS: Forty participants from nine countries participated. RESULTS: Four ideas emerged: for adherence trials, the Adherence-CDS could include adherence and the condition-specific CDS; many factors affect adherence and are intervention targets, contextual factors, or outcome domains; adherence is a critical factor in drug trials; and standardized adherence measures are needed. CONCLUSION: Despite the challenges, the meeting clarified an approach to developing an Adherence-CDS that complements existing OMERACT work and methodology.

13.
Transl Psychiatry ; 8(1): 284, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563984

RESUMO

It is well-established that there is a strong genetic contribution to the aetiology of attention deficit hyperactivity disorder (ADHD). Here, we employed a hypothesis-free genome-wide association study (GWAS) design in a sample of 480 clinical childhood ADHD cases and 1208 controls to search for novel genetic risk loci for ADHD. DNA was genotyped using Illumina's Human Infinium PsychArray-24v1.2., and the data were subsequently imputed to the 1000 Genomes reference panel. Rigorous quality control and pruning of genotypes at both individual subject and single nucleotide polymorphism (SNP) levels was performed. Polygenic risk score (PGRS) analysis revealed that ADHD case-control status was explained by genetic risk for ADHD, but no other major psychiatric disorders. Logistic regression analysis was performed genome-wide to test the association between SNPs and ADHD case-control status. We observed a genome-wide significant association (p = 3.15E-08) between ADHD and rs6686722, mapped to the Tenascin R (TNR) gene. Members of this gene family are extracellular matrix glycoproteins that play a role in neural cell adhesion and neurite outgrowth. Suggestive evidence of associations with ADHD was observed for an additional 111 SNPs (⩽9.91E-05). Although intriguing, the association between DNA variation in the TNR gene and ADHD should be viewed as preliminary given the small sample size of this discovery dataset.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Tenascina
14.
Nutr Neurosci ; : 1-14, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30537908

RESUMO

OBJECTIVE: Mitochondrial dysfunction has been implicated in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Though the exact mechanisms and clinical implications for this dysfunction are not fully determined, there is a hypothesis that deficiency in coenzyme Q10 (CoQ10) may contribute to mitochondrial impairments and be reflected in cognitive, affective, and energy disturbances in the disorders. CoQ10 is a critical component of the mitochondrial respiratory chain and an essential free radical scavenger, necessary for mitochondrial function. Here, we review the results of CoQ10 supplementation interventions for adults with various neurological and neuropsychiatric disorders and consider the therapeutic potential of CoQ10 supplementation for schizophrenia in light of these studies. METHODS: A literature review of randomised controlled trials and open-label studies investigating the effect of CoQ10 as a single intervention in adults with neurological and neuropsychiatric disorders was conducted. RESULTS: CoQ10 supplementation has some positive effects on fatigue, cognitive impairment and affective difficulties in several neurological and neuropsychiatric conditions with associated mitochondrial dysfunction. DISCUSSION: CoQ10 may be of therapeutic value to schizophrenia given evidence of mitochondrial dysfunction in the disorder.

15.
Biol Psychiatry ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30420267

RESUMO

BACKGROUND: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. METHODS: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. RESULTS: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10-4) and NMDAR (p = 1.7 × 10-5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10-4). CONCLUSIONS: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes.

16.
J Acquir Immune Defic Syndr ; 79(4): 421-429, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211722

RESUMO

BACKGROUND: It is not known whether immune dysfunction is associated with increased risk of death after cancer diagnosis in persons with HIV (PWH). AIDS-defining illness (ADI) can signal significant immunosuppression. Our objective was to determine differences in cancer stage and mortality rates in PWH with and without history of ADI. METHODS: PWH with anal, oropharynx, cervical, lung cancers, or Hodgkin lymphoma diagnoses from January 2000 to December 2009 in the North American AIDS Cohort Collaboration on Research and Design were included. RESULTS: Among 81,865 PWH, 814 had diagnoses included in the study; 341 (39%) had a history of ADI at time of cancer diagnosis. For each cancer type, stage at diagnosis did not differ by ADI (P > 0.05). Mortality and survival estimates for cervical cancer were limited by n = 5 diagnoses. Adjusted mortality rate ratios showed a 30%-70% increase in mortality among those with ADI for all cancer diagnoses, although only lung cancer was statistically significant. Survival after lung cancer diagnosis was poorer in PWH with ADI vs. without (P = 0.0001); the probability of survival was also poorer in those with ADI at, or before other cancers although not statistically significant. CONCLUSIONS: PWH with a history of ADI at lung cancer diagnosis had higher mortality and poorer survival after diagnosis compared to those without. Although not statistically significant, the findings of increased mortality and decreased survival among those with ADI (vs. without) were consistent for all other cancers, suggesting the need for further investigations into the role of HIV-related immune suppression and cancer outcomes.

17.
Twin Res Hum Genet ; 21(5): 394-397, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30001766

RESUMO

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

18.
J Int AIDS Soc ; 21(6): e25149, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29956882

RESUMO

INTRODUCTION: In 2015, the World Health Organization recommended that all HIV-infected individuals consider ART initiation as soon as possible after diagnosis. Sex differences in choice of initial ART regimen, indications for switching, time to switching and choice of second-line regimens have not been well described. The aims of this study were to describe first-line ART and CD4 count at ART initiation by sex, calendar year and region, and to analyse time to change or interruption in first-line ART, according to sex in each region. METHODS: Participating cohorts included: Southern, East and West Africa (IeDEA-Africa), North America (NA-ACCORD), Caribbean, Central/South America (CCASAnet) and Asia-Pacific including Australia (IeDEA Asia-Pacific). The primary outcomes analysed for each region and according to sex were choice of initial ART, time to switching and time to discontinuation of the first-line regimen. RESULTS AND DISCUSSION: The combined cohort data set comprised of 715,252 participants across seven regions from low- to high-income settings. The median CD4 count at treatment initiation was lower in men compared with women in nearly all regions and time periods. Women from North America and Southern Africa were more likely to switch ART compared to men (p < 0.001) with approximately 90% of women reporting a major change after 10 years in North America. Overall, after 8 years on ART, >50% of HIV- positive men and women from Southern Africa, East Africa, South and Central America remained on their original regimen. Men were more likely to have a treatment interruption compared with women in low- and middle-income countries from the Asia/Pacific region (p < 0.001) as were men from Southern Africa (p < 0.001). Greater than 75% of men and women did not report a treatment interruption after 10 years on ART from all regions except North America and Southern Africa. CONCLUSIONS: There are regional variations in the ART regimen commenced at baseline and rates of major change and treatment interruption according to sex. Some of this is likely to reflect changes in local and international antiretroviral guideline recommendations but other sex-specific factors such as pregnancy may contribute to these differences.

19.
Nat Genet ; 50(5): 668-681, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29700475

RESUMO

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

20.
Br J Cancer ; 118(8): 1098-1106, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29576623

RESUMO

BACKGROUND: Optoacoustic tomography (OT) of breast tumour oxygenation is a promising new technique, currently in clinical trials, which may help to determine disease stage and therapeutic response. However, the ability of OT to distinguish breast tumours displaying different vascular characteristics has yet to be established. The aim of the study is to prove OT as a sensitive technique for differentiating breast tumour models with manifestly different vasculatures. METHODS: Multispectral OT (MSOT) was performed in oestrogen-dependent (MCF-7) and oestrogen-independent (MDA-MB-231) orthotopic breast cancer xenografts. Total haemoglobin (THb) and oxygen saturation (SO2MSOT) were calculated. Pathological and biochemical evaluation of the tumour vascular phenotype was performed for validation. RESULTS: MCF-7 tumours show SO2MSOT similar to healthy tissue in both rim and core, despite significantly lower THb in the core. MDA-MB-231 tumours show markedly lower SO2MSOT with a significant rim-core disparity. Ex vivo analysis revealed that MCF-7 tumours contain fewer blood vessels (CD31+) that are more mature (CD31+/aSMA+) than MDA-MB-231. MCF-7 presented higher levels of stromal VEGF and iNOS, with increased NO serum levels. The vasculogenic process observed in MCF-7 was consistent with angiogenesis, while MDA-MB-231 appeared to rely more on vascular mimicry. CONCLUSIONS: OT is sensitive to differences in the vascular phenotypes of our breast cancer models.

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