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As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy analysis do not distinguish differences caused by early-life factors, such as prenatal care and nutrition, from those caused by ongoing changes in people's bodies due to aging. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in data from N=13,626 older adults in the US Health and Retirement Study, integrates longitudinal data on blood biomarkers, physical measurements, and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability, and mortality. Pace of Aging can advance the population science of healthy longevity.
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BACKGROUND: Associations of socioenvironmental features like urbanicity and neighborhood deprivation with psychosis are well-established. An enduring question, however, is whether these associations are causal. Genetic confounding could occur due to downward mobility of individuals at high genetic risk for psychiatric problems into disadvantaged environments. METHODS: We examined correlations of five indices of genetic risk [polygenic risk scores (PRS) for schizophrenia and depression, maternal psychotic symptoms, family psychiatric history, and zygosity-based latent genetic risk] with multiple area-, neighborhood-, and family-level risks during upbringing. Data were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins born in 1994-1995 and followed to age 18 (93% retention). Socioenvironmental risks included urbanicity, air pollution, neighborhood deprivation, neighborhood crime, neighborhood disorder, social cohesion, residential mobility, family poverty, and a cumulative environmental risk scale. At age 18, participants were privately interviewed about psychotic experiences. RESULTS: Higher genetic risk on all indices was associated with riskier environments during upbringing. For example, participants with higher schizophrenia PRS (OR = 1.19, 95% CI = 1.06-1.33), depression PRS (OR = 1.20, 95% CI = 1.08-1.34), family history (OR = 1.25, 95% CI = 1.11-1.40), and latent genetic risk (OR = 1.21, 95% CI = 1.07-1.38) had accumulated more socioenvironmental risks for schizophrenia by age 18. However, associations between socioenvironmental risks and psychotic experiences mostly remained significant after covariate adjustment for genetic risk. CONCLUSION: Genetic risk is correlated with socioenvironmental risk for schizophrenia during upbringing, but the associations between socioenvironmental risk and adolescent psychotic experiences appear, at present, to exist above and beyond this gene-environment correlation.
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Trastornos Psicóticos , Esquizofrenia , Adolescente , Humanos , Estudios Longitudinales , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/genética , Características de la Residencia , Esquizofrenia/complicaciones , Esquizofrenia/epidemiología , Esquizofrenia/genética , Medio Social , Reino Unido/epidemiologíaRESUMEN
Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.
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Éxito Académico , Trastorno de Personalidad Antisocial/genética , Trastorno de la Conducta/genética , Criminales , Estudio de Asociación del Genoma Completo , Problema de Conducta , Adolescente , Adulto , Trastorno de Personalidad Antisocial/epidemiología , Niño , Preescolar , Trastorno de la Conducta/epidemiología , Criminales/estadística & datos numéricos , Femenino , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Estudios Longitudinales , Masculino , Herencia Multifactorial , Nueva Zelanda/epidemiología , Factores de Riesgo , Reino Unido/epidemiología , Adulto JovenRESUMEN
Accumulating mental-health research encourages a shift in focus toward transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology-sometimes called the 'p factor'- that underlies shared risk for a wide range of mental disorders. Identifying neural correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the 'p factor' contributes to risk. Here we believe we first replicate the 'p factor' using cross-sectional data from a volunteer sample of 1246 university students, and then using high-resolution multimodal structural neuroimaging, we demonstrate that individuals with higher 'p factor' scores show reduced structural integrity of white matter pathways, as indexed by lower fractional anisotropy values, uniquely within the pons. Whole-brain analyses further revealed that higher 'p factor' scores are associated with reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, we observed a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher 'p factor' scores. The results of our analyses provide initial evidence that structural alterations in corticocerebellar circuitry supporting core functions related to the basic integration, coordination and monitoring of information may contribute to a general liability for common mental disorders.
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Cerebelo/diagnóstico por imagen , Trastornos Mentales/diagnóstico por imagen , Neuroimagen/métodos , Adulto , Anisotropía , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Estudios Transversales , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Sustancia Gris/diagnóstico por imagen , Humanos , Masculino , Vías Nerviosas , Factores de Riesgo , Sustancia Blanca/diagnóstico por imagen , Adulto JovenRESUMEN
BACKGROUND: Feelings of loneliness are common among young adults, and are hypothesized to impair the quality of sleep. In the present study, we tested associations between loneliness and sleep quality in a nationally representative sample of young adults. Further, based on the hypothesis that sleep problems in lonely individuals are driven by increased vigilance for threat, we tested whether past exposure to violence exacerbated this association. METHOD: Data were drawn from the Environmental Risk (E-Risk) Longitudinal Twin Study, a birth cohort of 2232 twins born in England and Wales in 1994 and 1995. We measured loneliness using items from the UCLA Loneliness Scale, and sleep quality using the Pittsburgh Sleep Quality Index. We controlled for covariates including social isolation, psychopathology, employment status and being a parent of an infant. We examined twin differences to control for unmeasured genetic and family environment factors. RESULTS: Feelings of loneliness were associated with worse overall sleep quality. Loneliness was associated specifically with subjective sleep quality and daytime dysfunction. These associations were robust to controls for covariates. Among monozygotic twins, within-twin pair differences in loneliness were significantly associated with within-pair differences in sleep quality, indicating an association independent of unmeasured familial influences. The association between loneliness and sleep quality was exacerbated among individuals exposed to violence victimization in adolescence or maltreatment in childhood. CONCLUSIONS: Loneliness is robustly associated with poorer sleep quality in young people, underscoring the importance of early interventions to mitigate the long-term outcomes of loneliness. Special care should be directed towards individuals who have experienced victimization.
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Adultos Sobrevivientes de Eventos Adversos Infantiles/estadística & datos numéricos , Exposición a la Violencia/estadística & datos numéricos , Soledad/psicología , Trastornos del Sueño-Vigilia/epidemiología , Sueño/fisiología , Adolescente , Adultos Sobrevivientes del Maltrato a los Niños/estadística & datos numéricos , Inglaterra/epidemiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Gales/epidemiologíaRESUMEN
BACKGROUND/OBJECTIVES: Endothelial dysfunction predicts mortality but it is unknown whether childhood obesity predicts adult endothelial dysfunction. The aim of this study was to determine whether anthropometric indices of body fat in childhood, adolescence and early midlife are associated with endothelial dysfunction in early midlife. SUBJECTS/METHODS: Participants belonged to a representative birth cohort of 1037 individuals born in Dunedin, New Zealand in 1972 and 1973 and followed to age 38 years, with 95% retention (the Dunedin Multidisciplinary Health and Development Study). We assessed anthropometric indices of obesity at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32 and 38 years. We tested associations between endothelial function assessed by peripheral arterial tonometry (PAT) at age 38 and; age 38 cardiovascular risk factors; age 3 body mass index (BMI); and four BMI trajectory groups from childhood to early midlife. RESULTS: Early midlife endothelial dysfunction was associated with BMI, large waist circumference, low high-density lipoprotein cholesterol, low cardiorespiratory fitness and increased high-sensitivity C-reactive protein. After adjustment for sex and childhood socioeconomic status, 3-year-olds with BMI 1 s.d. above the mean had Framingham-reactive hyperemia index (F-RHI) ratios that were 0.10 below those with normal BMI (ß=-0.10, 95% confidence interval (CI) -0.17 to -0.03, P=0.007) at age 38. Cohort members in the 'overweight', 'obese' and 'morbidly obese' trajectories had F-RHI ratios that were 0.08 (ß=-0.08, 95% CI -0.14 to -0.03, P=0.003), 0.13 (ß=-0.13, 95% CI -0.21 to -0.06, P<0.001) and 0.17 (ß=-0.17, 95% CI -0.33 to -0.01, P=0.033), respectively, below age-peers in the 'normal' trajectory. CONCLUSIONS: Childhood BMI and the trajectories of BMI from childhood to early midlife predict endothelial dysfunction evaluated by PAT in early midlife.
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Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/fisiopatología , Lipoproteínas HDL/sangre , Manometría , Obesidad Infantil/fisiopatología , Adolescente , Adulto , Factores de Edad , Biomarcadores/sangre , Índice de Masa Corporal , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Preescolar , Femenino , Humanos , Estudios Longitudinales , Masculino , Nueva Zelanda , Obesidad Infantil/sangre , Obesidad Infantil/complicaciones , Factores de Riesgo , Circunferencia de la Cintura/fisiologíaRESUMEN
BACKGROUND: To our knowledge, there are no universal screening tools for substance dependence that (1) were developed using a population-based sample, (2) estimate total risk briefly and inexpensively by incorporating a relatively small number of well-established risk factors, and (3) aggregate risk factors using a simple algorithm. We created a universal screening tool that incorporates these features to identify adolescents at risk for persistent substance dependence in adulthood. METHOD: Participants were members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972-1973 and followed prospectively to age 38 years, with 95% retention. We assessed a small set of childhood and adolescent risk factors: family history of substance dependence, childhood psychopathology (conduct disorder, depression), early exposure to substances, frequent substance use in adolescence, sex, and childhood socioeconomic status. We defined the outcome (persistent substance dependence in adulthood) as dependence on one or more of alcohol, tobacco, cannabis, or hard drugs at ⩾3 assessment ages: 21, 26, 32, and 38 years. RESULTS: A cumulative risk index, a simple sum of nine childhood and adolescent risk factors, predicted persistent substance dependence in adulthood with considerable accuracy (AUC = 0.80). CONCLUSIONS: A cumulative risk score can accurately predict which adolescents in the general population will develop persistent substance dependence in adulthood.
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Conducta del Adolescente , Trastorno de la Conducta/epidemiología , Depresión/epidemiología , Clase Social , Trastornos Relacionados con Sustancias/epidemiología , Tabaquismo/epidemiología , Adolescente , Adulto , Alcoholismo/epidemiología , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Abuso de Marihuana/epidemiología , Nueva Zelanda/epidemiología , Estudios Prospectivos , Medición de Riesgo , Adulto JovenRESUMEN
The serotonin-transporter-linked polymorphic region (5-HTTLPR) is one of the most extensively investigated candidates to be involved in gene-environment interaction associated with depression. Nevertheless, the interaction remains controversial. In an original study, we tested the hypothesis that risk for use of antidepressants following a diagnosis of colorectal cancer is associated with bi- and triallelic genotypes of 5-HTTLPR. In addition, in an inclusive meta-analysis, we tested the hypothesis that depression following a diagnosis of cancer is associated with biallelic 5-HTTLPR genotype. We created an exposed-only cohort of 849 colorectal cancer patients from the Danish Diet, Cancer and Health cohort study. The hypothesized association was investigated with Cox regression models and competing risk analyses. Five studies comprising a total of 1484 cancer patients were included in the meta-analysis. Nationwide registries provided information on dates of diagnosis of colorectal cancer and use of antidepressants. Unadjusted odds ratios of depression according to the biallelic 5-HTTLPR genotype were included in the meta-analysis. 5-HTTLPR genotypes were not associated with use of antidepressants after colorectal cancer. Estimated hazard ratios ranged 0.92-1.08, and we observed no statistically significant associations across biallelic and triallelic genotypes in crude as well as adjusted models. The meta-analysis showed no statistically significant associations of 5-HTTLPR biallelic genotype with depression after cancer. Our findings in an original study and a meta-analysis do not support the hypothesis of an association between the 5-HTTLPR genotype and depression after cancer.
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Antidepresivos/uso terapéutico , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/psicología , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Trastorno Depresivo/complicaciones , HumanosRESUMEN
BACKGROUND: Obesity is one of the leading causes of preventable death worldwide. Circadian rhythms are known to control both sleep timing and energy homeostasis, and disruptions in circadian rhythms have been linked with metabolic dysfunction and obesity-associated disease. In previous research, social jetlag, a measure of chronic circadian disruption caused by the discrepancy between our internal versus social clocks, was associated with elevated self-reported body mass index, possibly indicative of a more generalized association with obesity and metabolic dysfunction. METHODS: We studied participants from the population-representative Dunedin Longitudinal Study (N=1037) to determine whether social jetlag was associated with clinically assessed measurements of metabolic phenotypes and disease indicators for obesity-related disease, specifically, indicators of inflammation and diabetes. RESULTS: Our analysis was restricted to N=815 non-shift workers in our cohort. Among these participants, we found that social jetlag was associated with numerous clinically assessed measures of metabolic dysfunction and obesity. We distinguished between obese individuals who were metabolically healthy versus unhealthy, and found higher social jetlag levels in metabolically unhealthy obese individuals. Among metabolically unhealthy obese individuals, social jetlag was additionally associated with elevated glycated hemoglobin and an indicator of inflammation. CONCLUSIONS: The findings are consistent with the possibility that 'living against our internal clock' may contribute to metabolic dysfunction and its consequences. Further research aimed at understanding that the physiology and social features of social jetlag may inform obesity prevention and have ramifications for policies and practices that contribute to increased social jetlag, such as work schedules and daylight savings time.
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Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/prevención & control , Obesidad/etiología , Obesidad/metabolismo , Trastornos del Sueño del Ritmo Circadiano/metabolismo , Adulto , Índice de Masa Corporal , Ritmo Circadiano , Femenino , Encuestas Epidemiológicas , Humanos , Estudios Longitudinales , Masculino , Enfermedades Metabólicas/epidemiología , Nueva Zelanda/epidemiología , Obesidad/prevención & control , Factores de Riesgo , Sueño , Trastornos del Sueño del Ritmo Circadiano/complicaciones , Trastornos del Sueño del Ritmo Circadiano/epidemiología , Tolerancia al Trabajo ProgramadoRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Carvedilol is the standard of care for heart failure (HF) patients. Carvedilol is partially metabolized by the highly polymorphic enzyme, CYP2D6. To reach an effective dose while avoiding adverse drug reactions (ADRs), testing of CYP2D6 genotype prior to carvedilol initiation may be considered. The objectives of this study were to determine CYP2D6 metabolic genotypes in an Israeli cohort of HF patients and to investigate the relationship between genotype, carvedilol dose and number of ADRs to determine the importance of CYP2D6 genotyping prior to treatment initiation. METHODS: Ninety-three patients with HF on carvedilol were CYP2D6 genotyped and classified as poor (PM), intermediate (IM), extensive (EM) or ultrarapid (UM) metabolizers. Carvedilol dose and ADRs were calculated and correlated with genotype using linear regression statistic analysis. RESULTS AND DISCUSSION: The distribution of the CYP2D6 phenotype in the Israeli population with HF is similar to the European general population. There were no significant differences of carvedilol dose and number of ADRs among genotype groups. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose changes. WHAT IS NEW AND CONCLUSION: Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose during therapy for patients with HF. The Israeli CYP2D6 phenotype distribution in HF patients was consistent with the frequency in the general European population.
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Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Carbazoles/administración & dosificación , Citocromo P-450 CYP2D6/genética , Insuficiencia Cardíaca/tratamiento farmacológico , Propanolaminas/administración & dosificación , Antagonistas de Receptores Adrenérgicos alfa 1/efectos adversos , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Anciano , Carbazoles/efectos adversos , Carbazoles/uso terapéutico , Carvedilol , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Insuficiencia Cardíaca/genética , Humanos , Israel , Modelos Lineales , Masculino , Persona de Mediana Edad , Farmacogenética , Polimorfismo Genético , Propanolaminas/efectos adversos , Propanolaminas/uso terapéutico , Estudios RetrospectivosRESUMEN
There is evidence that persistent psychiatric disorders lead to age-related disease and premature mortality. Telomere length has emerged as a promising biomarker in studies that test the hypothesis that internalizing psychiatric disorders are associated with accumulating cellular damage. We tested the association between the persistence of internalizing disorders (depression, generalized anxiety disorder and post-traumatic stress disorder) and leukocyte telomere length (LTL) in the prospective longitudinal Dunedin Study (n=1037). Analyses showed that the persistence of internalizing disorders across repeated assessments from ages 11 to 38 years predicted shorter LTL at age 38 years in a dose-response manner, specifically in men (ß=-0.137, 95% confidence interval (CI): -0.232, -0.042, P=0.005). This association was not accounted for by alternative explanatory factors, including childhood maltreatment, tobacco smoking, substance dependence, psychiatric medication use, poor physical health or low socioeconomic status. Additional analyses using DNA from blood collected at two time points (ages 26 and 38 years) showed that LTL erosion was accelerated among men who were diagnosed with internalizing disorder in the interim (ß=-0.111, 95% CI: -0.184, -0.037, P=0.003). No significant associations were found among women in any analysis, highlighting potential sex differences in internalizing-related telomere biology. These findings point to a potential mechanism linking internalizing disorders to accelerated biological aging in the first half of the life course, particularly in men. Because internalizing disorders are treatable, the findings suggest the hypothesis that treating psychiatric disorders in the first half of the life course may reduce the population burden of age-related disease and extend health expectancy.
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Trastornos de Ansiedad/fisiopatología , Trastorno Depresivo/fisiopatología , Leucocitos/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Telómero/metabolismo , Adolescente , Adulto , Envejecimiento/genética , Envejecimiento/fisiología , Trastornos de Ansiedad/genética , Niño , Trastorno Depresivo/genética , Femenino , Humanos , Estudios Longitudinales , Masculino , Estudios Prospectivos , Caracteres Sexuales , Trastornos por Estrés Postraumático/genética , Adulto JovenRESUMEN
PURPOSE: The Argus II epiretinal prosthesis has been developed to provide partial restoration of vision to subjects blinded from outer retinal degenerative disease. Participants were surgically implanted with the system in the United States and Europe in a single arm, prospective, multicenter clinical trial. The purpose of this investigation was to determine which factors affect electrical thresholds in order to inform surgical placement of the device. METHODS: Electrode-retina and electrode-fovea distances were determined using SD-OCT and fundus photography, respectively. Perceptual threshold to electrical stimulation of electrodes was measured using custom developed software, in which current amplitude was varied until the threshold was found. Full field stimulus light threshold was measured using the Espion D-FST test. Relationships between electrical threshold and these three explanatory variables (electrode-retina distance, electrode-fovea distance, and monocular light threshold) were quantified using regression. RESULTS: Regression analysis showed a significant correlation between electrical threshold and electrode-retina distance (R2 = 0.50, P = 0.0002; n = 703 electrodes). 90.3% of electrodes in contact with the macula (n = 207) elicited percepts at charge densities less than 1 mC/cm2/phase. These threshold data also correlated well with ganglion cell density profile (P = 0.03). A weaker, but still significant, inverse correlation was found between light threshold and electrical threshold (R2 < 0.52, P = 0.01). Multivariate modeling indicated that electrode-retina distance and light threshold are highly predictive of electrode threshold (R2 = 0.87; P < 0.0005). CONCLUSIONS: Taken together, these results suggest that while light threshold should be used to inform patient selection, macular contact of the array is paramount. TRANSLATIONAL RELEVANCE: Reported Argus II clinical study results are in good agreement with prior in vitro and in vivo studies, and support the development of higher-density systems that employ smaller diameter electrodes. (clinicaltrials.gov identifier: NCT00407602).
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BACKGROUND: Childhood psychotic symptoms have been used as a subclinical phenotype of schizophrenia in etiological research and as a target for preventative interventions. However, recent studies have cast doubt on the specificity of these symptoms for schizophrenia, suggesting alternative outcomes such as anxiety and depression. Using a prospective longitudinal birth cohort we investigated whether childhood psychotic symptoms predicted a diagnosis of schizophrenia or other psychiatric disorders by 38 years of age. METHOD: Participants were drawn from a birth cohort of 1037 children from Dunedin, New Zealand, who were followed prospectively to 38 years of age (96% retention rate). Structured clinical interviews were administered at age 11 to assess psychotic symptoms and study members underwent psychiatric assessments at ages 18, 21, 26, 32 and 38 to obtain past-year DSM-III-R/IV diagnoses and self-reports of attempted suicides since adolescence. RESULTS: Psychotic symptoms at age 11 predicted elevated rates of research diagnoses of schizophrenia and posttraumatic stress disorder (PTSD) and also suicide attempts by age 38, even when controlling for gender, social class and childhood psychopathology. No significant associations were found for persistent anxiety, persistent depression, mania or persistent substance dependence. Very few of the children presenting with age-11 psychotic symptoms were free from disorder by age 38. CONCLUSIONS: Childhood psychotic symptoms were not specific to a diagnosis of schizophrenia in adulthood and thus future studies of early symptoms should be cautious in extrapolating findings only to this clinical disorder. However, these symptoms may be useful as a marker of adult mental health problems more broadly.
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Trastornos Psicóticos/epidemiología , Esquizofrenia/epidemiología , Adolescente , Adulto , Niño , Comorbilidad , Humanos , Nueva Zelanda/epidemiología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Trastornos por Estrés Postraumático/epidemiología , Intento de Suicidio/estadística & datos numéricos , Adulto JovenRESUMEN
Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.
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Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiología , Ácidos Araquidónicos/fisiología , Endocannabinoides/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Adaptación Psicológica/fisiología , Adulto , Alcanosulfonatos/administración & dosificación , Alcanosulfonatos/farmacología , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/genética , Amígdala del Cerebelo/efectos de los fármacos , Animales , Ácidos Araquidónicos/metabolismo , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas de Receptores de Cannabinoides/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Miedo/efectos de los fármacos , Miedo/psicología , Femenino , Neuroimagen Funcional , Estudios de Asociación Genética , Habituación Psicofisiológica/efectos de los fármacos , Habituación Psicofisiológica/fisiología , Humanos , Masculino , Ratones , Microinyecciones , Persona de Mediana Edad , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Personalidad/genética , Personalidad/fisiología , Fenoles/administración & dosificación , Fenoles/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Polimorfismo de Nucleótido Simple , Alcamidas Poliinsaturadas/metabolismo , Pirazoles/administración & dosificación , Pirazoles/farmacología , RimonabantRESUMEN
There is increasing interest in discovering mechanisms that mediate the effects of childhood stress on late-life disease morbidity and mortality. Previous studies have suggested one potential mechanism linking stress to cellular aging, disease and mortality in humans: telomere erosion. We examined telomere erosion in relation to children's exposure to violence, a salient early-life stressor, which has known long-term consequences for well-being and is a major public-health and social-welfare problem. In the first prospective-longitudinal study with repeated telomere measurements in children while they experienced stress, we tested the hypothesis that childhood violence exposure would accelerate telomere erosion from age 5 to age 10 years. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA samples, using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-5 baseline and age-10 follow-up measurements, even after adjusting for sex, socioeconomic status and body mass index (B=-0.052, s.e.=0.021, P=0.015). This finding provides support for a mechanism linking cumulative childhood stress to telomere maintenance, observed already at a young age, with potential impact for life-long health.
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Víctimas de Crimen/psicología , Homeostasis del Telómero , Telómero/genética , Telómero/patología , Violencia/psicología , Factores de Edad , Índice de Masa Corporal , Niño , Preescolar , Femenino , Humanos , Estudios Longitudinales , Masculino , Relaciones Padres-Hijo , Clase Social , Estudios en Gemelos como Asunto , Reino UnidoRESUMEN
BACKGROUND: Very few longitudinal studies have evaluated prospective neurodevelopmental and psychosocial risk factors for obsessive-compulsive disorder (OCD). Furthermore, despite the heterogeneous nature of OCD, no research has examined risk factors for its primary symptom dimensions, such as contamination/washing. METHOD: Potential risk factors for symptoms or diagnosis of OCD in adulthood and for specific adult obsessive-compulsive (OC) symptom dimensions were examined in the Dunedin Study birth cohort. The presence of obsessions and compulsions and psychological disorders was assessed using the Diagnostic Interview Schedule (DIS) at ages 26 and 32 years. Individuals with a diagnosis of OCD at either age (n=36) were compared to both a healthy control group (n=613) and an anxious control group (n=310) to determine whether associations between a risk factor and an OCD diagnosis were specific. RESULTS: Childhood neurodevelopmental, behavioral, personality and environmental risk factors were associated with a diagnosis of OCD and with OC symptoms at ages 26 and 32. Social isolation, retrospectively reported physical abuse and negative emotionality were specific predictors of an adult OCD diagnosis. Of note, most risk factors were associated with OC symptoms in adulthood and several risk factors predicted specific OCD dimensions. Perinatal insults were linked to increased risk for symmetry/ordering and shameful thoughts dimensions, whereas poor childhood motor skills predicted the harm/checking dimension. Difficult temperament, internalizing symptoms and conduct problems in childhood also predicted specific symptom dimensions and lower IQ non-specifically predicted increased risk for most dimensions. CONCLUSIONS: The current findings underscore the need for a dimensional approach in evaluating childhood risk factors for obsessions and compulsions.
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Trastorno Obsesivo Compulsivo/etiología , Adulto , Adultos Sobrevivientes del Maltrato a los Niños/psicología , Estudios de Casos y Controles , Niño , Conducta Compulsiva/complicaciones , Conducta Compulsiva/psicología , Femenino , Humanos , Inteligencia , Entrevista Psicológica , Masculino , Trastorno Obsesivo Compulsivo/psicología , Estudios Prospectivos , Psicología Infantil , Factores de Riesgo , TemperamentoRESUMEN
BACKGROUND/AIMS: To determine to what extent subjects implanted with the Argus II retinal prosthesis can improve performance compared with residual native vision in a spatial-motor task. METHODS: High-contrast square stimuli (5.85 cm sides) were displayed in random locations on a 19â³ (48.3 cm) touch screen monitor located 12â³ (30.5 cm) in front of the subject. Subjects were instructed to locate and touch the square centre with the system on and then off (40 trials each). The coordinates of the square centre and location touched were recorded. RESULTS: Ninety-six percent (26/27) of subjects showed a significant improvement in accuracy and 93% (25/27) show a significant improvement in repeatability with the system on compared with off (p<0.05, Student t test). A group of five subjects that had both accuracy and repeatability values <250 pixels (7.4 cm) with the system off (ie, using only their residual vision) was significantly more accurate and repeatable than the remainder of the cohort (p<0.01). Of this group, four subjects showed a significant improvement in both accuracy and repeatability with the system on. CONCLUSION: In a study on the largest cohort of visual prosthesis recipients to date, we found that artificial vision augments information from existing vision in a spatial-motor task. Clinical trials registry no NCT00407602.
Asunto(s)
Ceguera/cirugía , Retina/cirugía , Análisis y Desempeño de Tareas , Prótesis Visuales , Adulto , Anciano , Anciano de 80 o más Años , Ceguera/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora/fisiología , Orientación/fisiología , Diseño de Prótesis , Retina/fisiopatología , Tacto/fisiología , Resultado del TratamientoRESUMEN
The effects of cannabis on lung function remain unclear and may be different from those of tobacco. We compared the associations between use of these substances and lung function in a population-based cohort (n = 1,037). Cannabis and tobacco use were reported at ages 18, 21, 26 and 32 yrs. Spirometry, plethysmography and carbon monoxide transfer factor were measured at 32 yrs. Associations between lung function and exposure to each substance were adjusted for exposure to the other substance. Cumulative cannabis use was associated with higher forced vital capacity, total lung capacity, functional residual capacity and residual volume. Cannabis was also associated with higher airway resistance but not with forced expiratory volume in 1 s, forced expiratory ratio or transfer factor. These findings were similar among those who did not smoke tobacco. In contrast, tobacco use was associated with lower forced expiratory volume in 1 s, lower forced expiratory ratio, lower transfer factor and higher static lung volumes, but not with airway resistance. Cannabis appears to have different effects on lung function from those of tobacco. Cannabis use was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance, but there was little evidence for airflow obstruction or impairment of gas transfer.
Asunto(s)
Fumar Marihuana/fisiopatología , Fumar/fisiopatología , Capacidad Pulmonar Total , Adolescente , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND: Most information about the lifetime prevalence of mental disorders comes from retrospective surveys, but how much these surveys have undercounted due to recall failure is unknown. We compared results from a prospective study with those from retrospective studies. METHOD: The representative 1972-1973 Dunedin New Zealand birth cohort (n=1037) was followed to age 32 years with 96% retention, and compared to the national New Zealand Mental Health Survey (NZMHS) and two US National Comorbidity Surveys (NCS and NCS-R). Measures were research diagnoses of anxiety, depression, alcohol dependence and cannabis dependence from ages 18 to 32 years. RESULTS: The prevalence of lifetime disorder to age 32 was approximately doubled in prospective as compared to retrospective data for all four disorder types. Moreover, across disorders, prospective measurement yielded a mean past-year-to-lifetime ratio of 38% whereas retrospective measurement yielded higher mean past-year-to-lifetime ratios of 57% (NZMHS, NCS-R) and 65% (NCS). CONCLUSIONS: Prospective longitudinal studies complement retrospective surveys by providing unique information about lifetime prevalence. The experience of at least one episode of DSM-defined disorder during a lifetime may be far more common in the population than previously thought. Research should ask what this means for etiological theory, construct validity of the DSM approach, public perception of stigma, estimates of the burden of disease and public health policy.