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Social dysfunction is commonly present in neuropsychiatric disorders of schizophrenia (SZ) and Alzheimer's disease (AD). Theory of Mind (ToM) deficits have been linked to social dysfunction in disease-specific studies. Nevertheless, it remains unclear how ToM is related to social functioning across these disorders, and which factors contribute to this relationship. We investigated transdiagnostic associations between ToM and social functioning among SZ/AD patients and healthy controls, and explored to what extent these associations relate to information processing speed or facial emotion recognition capacity. A total of 163 participants were included (SZ: n=56, AD: n=50 and age-matched controls: n=57). Social functioning was assessed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness Scale (LON). ToM was measured with the Hinting Task. Information processing speed was measured by the Digit Symbol Substitution Test (DSST) and facial emotion recognition capacity by the facial emotion recognition task (FERT). Case-control deficits in Hinting Task performance were larger in AD (rrb = -0.57) compared to SZ (rrb = -0.35). Poorer Hinting Task performance was transdiagnostically associated with the SFS (ßHinting-Task = 1.20, p<0.01) and LON (ßHinting-Task = -0.27, p<0.05). DSST, but not FERT, reduced the association between the SFS and Hinting Task performance, however the association remained significant (ßHinting-Task = 0.95, p<0.05). DSST and FERT performances did not change the association between LON and Hinting Task performance. Taken together, ToM deficits are transdiagnostically associated with social dysfunction and this is partly related to reduced information processing speed.
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BACKGROUND: Half of mental health disorders begin before the age of 14, highlighting the importance of prevention and early-intervention in childhood. Schools have been identified globally by policymakers as a platform to support good child mental health; however, the majority of the research is focused on secondary schools, with primary schools receiving very little attention by comparison. The limited available evidence on mental health initiatives in primary schools is hindered by a lack of rigorous evaluation. This quasi-experimental cluster study aims to examine the implementation and effectiveness of a Mental Health and Wellbeing Co-ordinator role designed to build mental health capacity within primary schools. METHODS: This is a primary (ages 5-12) school-based cluster quasi-experimental study in Victoria, Australia. Before baseline data collection, 16 schools selected by the state education department will be allocated to intervention, and another 16 matched schools will continue as 'Business as Usual'. In intervention schools, a mental health and well-being coordinator will be recruited and trained, and three additional school staff will also be selected to receive components of the mental health training. Surveys will be completed by consenting staff (at 2-, 5-, 10- and 17-months post allocation) and by consenting parents/carers (at 3-, 10- and 17-months post allocation) in both intervention and business as usual schools. The primary objective is to assess the change in teacher's confidence to support student mental health and wellbeing using the School Mental Health Self-Efficacy Teacher Survey. Secondary objectives are to assess the indirect impact on systemic factors (level of support, prioritisation of child mental health), parent and teachers' mental health literacy (stigma, knowledge), care access (school engagement with community-based services), and student mental health outcomes. Implementation outcomes (feasibility, acceptability, and fidelity) and costs will also be evaluated. DISCUSSION: The current study will examine the implementation and effectiveness of having a trained Mental Health and Wellbeing Coordinator within primary schools. If the intervention increases teachers' confidence to support student mental health and wellbeing and builds the capacity of primary schools it will improve student mental health provision and inform large-scale mental health service reform. TRIAL REGISTRATION: The trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) on July 6, 2021. The registration number is ACTRN12621000873820 .
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Salud Mental , Servicios de Salud Escolar , Niño , Preescolar , Humanos , Instituciones Académicas , Estudiantes , VictoriaRESUMEN
Intellectual functioning is a critical determinant of economic and personal productivity. Identifying early neural predictors of cognitive function in infancy will allow us to map the neurodevelopmental pathways that underpin individual differences in intellect. Here, in three different cohorts we investigate the association between a putative neurophysiological indicator of information encoding (change in frontal theta during a novel video) in infancy and later general cognitive outcome. In a discovery cohort of 12-month-old typically developing infants, we recorded EEG during presentation of dynamic movies of people and objects. Frontal theta power (3-6 Hz) significantly increased during the course of viewing each video. Critically, increase in frontal theta during viewing of a video was associated with a differential response to repetition of that specific video, confirming relation to learning. Further, individual differences in the magnitude of change in frontal theta power were related to concurrent nonverbal cognitive level. We then sought to extend this association in two independent samples enriched for variation in cognitive outcome due to the inclusion of infants at familial risk for autism. We observed similar patterns of theta EEG change at 12 months, and found a predictive relation to verbal and nonverbal cognitive skills measured at 2, 3 and 7 years of age. For the subset of high-risk infants later diagnosed with autism, infant theta EEG explained over 80% of the variance in nonverbal skills at age 3 years. We suggest that EEG theta change in infancy is an excellent candidate predictive biomarker that could yield substantial insight into the mechanisms that underlie individual differences in childhood intelligence, particularly in high risk populations.
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Trastorno del Espectro Autista/diagnóstico , Desarrollo Infantil/fisiología , Inteligencia/fisiología , Ritmo Teta/fisiología , Trastorno del Espectro Autista/fisiopatología , Niño , Preescolar , Cognición/fisiología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Aprendizaje/fisiología , Estudios Longitudinales , Masculino , PronósticoRESUMEN
Racial bias in sport is a prevalent research topic. Much of the previous research regarding bias among referees in sport focused on sports such as baseball, basketball, hockey, and soccer. Professional American football is unique because race is more clearly defined when compared to these other sports. Additionally, by examining holding penalties, which are known to be more subjective and called predominately by a single official on the field (i.e., the umpire), racial bias in officiating can be more efficiently analyzed in professional American football. The purpose of this study is to examine potential racial bias regarding holding penalties in the National Football League (NFL). Three years of data from the 2013 to 2014 through 2015 to 2016 NFL seasons were used, including the races of officials and players involved in holding penalties. Results showed no evidence of racial bias in the calling of holding penalties by White officials. However, Black umpires were found to call more holding penalties when led by a White referee. Additionally, Black players were more likely to have holding penalties called on them earlier in the game by all officials.
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Short-term low intensity parent implemented intervention studies for toddlers with autism spectrum disorder (ASD) have found it difficult to demonstrate significantly improved developmental scores or autism severity compared to community treatment. We conducted a randomized comparative intent-to-treat study of a parent implemented intervention to (1) test the effects of an enhanced version on parent and child learning, and (2) evaluate the sensitivity to change of proximal versus distal measures of child behavior. We randomized 45 children with ASD, 12-30 months of age, into one of two versions of parent-implemented Early Start Denver Model (P-ESDM), the basic model, in which we delivered 1.5 h of clinic-based parent coaching weekly, and an enhanced version that contained three additions: motivational interviewing, multimodal learning tools, and a weekly 1.5-h home visit. We delivered the intervention for 12 weeks and measured child and parent change frequently in multiple settings. We found a time-by-group interaction: parents in the enhanced group demonstrated significantly greater gains in interaction skills than did parents in the non-enhanced group. Both interventions were associated with significant developmental acceleration; however, child outcomes did not differ by group. We found a significant relationship between degree of change in parental interaction skill and rate of children's improvement on our proximal measure. Parents in both groups reported satisfaction with the intervention. These findings suggest that parent skills improved more in the enhanced group than the comparison group. Children in the two groups showed similar improvements. Rate of individual parent learning was associated with greater individual child progress on a measure quite proximal to the treatment, though not on standardized assessments.
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Trastorno Autístico/terapia , Desarrollo Infantil , Intervención Educativa Precoz/métodos , Intervención Médica Temprana/métodos , Tutoría/métodos , Padres , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
Sensory sensitivity is prevalent among young children with ASD, but its relation to social communication impairment is unclear. Recently, increased sensory hypersensitivity has been linked to greater activity of the neural salience network (Green et al., 2016). Increased neural sensitivity to stimuli, especially social stimuli, could provide greater opportunity for social learning and improved outcomes. Consistent with this framework, in Experiment 1 we found that parent report of greater sensory hypersensitivity at 2 years in toddlers with ASD (N=27) was predictive of increased neural responsiveness to social stimuli (larger amplitude event-related potential/ERP responses to faces at P1, P400 and Nc) at 4 years, and this in turn was related to parent report of increased social approach at 4 years. In Experiment 2, parent report of increased perceptual sensitivity at 6 months in infants at low and high familial risk for ASD (N=35) predicted larger ERP P1 amplitude to faces at 18 months. Increased sensory hypersensitivity in early development thus predicted greater attention capture by faces in later development, and this related to more optimal social behavioral development. Sensory hypersensitivity may index a child's ability to benefit from supportive environments during development. Early sensory symptoms may not always be developmentally problematic for individuals with ASD.
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Atención/fisiología , Trastorno del Espectro Autista/fisiopatología , Cara , Reconocimiento Facial/fisiología , Preescolar , Potenciales Evocados/fisiología , Femenino , Humanos , Lactante , Masculino , Riesgo , Conducta SocialRESUMEN
Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.
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Cognición/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Vortioxetina/farmacología , Adulto , Afecto/efectos de los fármacos , Antidepresivos/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Depresión/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Resultado del Tratamiento , Vortioxetina/uso terapéuticoRESUMEN
The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of 'low schizotypes' was significantly different from 'high schizotypes' with 'average schizotypes' having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes.
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Disfunción Cognitiva/tratamiento farmacológico , Nootrópicos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Disfunción Cognitiva/clasificación , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Descubrimiento de Drogas , Medidas del Movimiento Ocular , Femenino , Humanos , Masculino , Esquizofrenia/clasificación , Esquizofrenia/fisiopatología , Investigación Biomédica TraslacionalRESUMEN
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1 % of the population and close to 20 % of prospectively studied infants with an older sibling with ASD. Although significant progress has been made in characterizing the emergence of behavioral symptoms of ASD, far less is known about the underlying disruptions to early learning. Recent models suggest that core aspects of the causal path to ASD may only be apparent in early infancy. Here, we investigated social attention in 6- and 12-month-old infants who did and did not meet criteria for ASD at 24 months using both cognitive and electrophysiological methods. We hypothesized that a reduction in attention engagement to faces would be associated with later ASD. METHODS: In a prospective longitudinal design, we used measures of both visual attention (habituation) and brain function (event-related potentials to faces and objects) at 6 and 12 months and investigated the relationship to ASD outcome at 24 months. RESULTS: High-risk infants who met criteria for ASD at 24 months showed shorter epochs of visual attention, faster but less prolonged neural activation to faces, and delayed sensitization responses (increases in looking) to faces at 6 months; these differences were less apparent at 12 months. These findings are consistent with disrupted engagement of sustained attention to social stimuli. CONCLUSIONS: These findings suggest that there may be fundamental early disruptions to attention engagement that may have cascading consequences for later social functioning.
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Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.
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Amnesia/fisiopatología , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Navegación Espacial/fisiología , Interfaz Usuario-Computador , Anciano , Anciano de 80 o más Años , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas NeuropsicológicasRESUMEN
In recent years, there has been increasing use of the gap detection reflex test to demonstrate induction of tinnitus in animals. Animals with tinnitus show weakened gap detection ability for background noise that matches the pitch of the tinnitus. The usual explanation is that the tinnitus 'fills in the gap'. It has recently been shown, however, that tinnitus is commonly associated with hyperacusis-like enhancements of the acoustic startle response, a change which might potentially alter responses in the gap detection test. We hypothesized that such enhancements could lead to an apparent reduction of gap suppression, resembling that caused by tinnitus, by altering responses to the startle stimulus or the background noise. To test this hypothesis, we compared gap detection abilities in 3 subsets of noise-exposed animals with those in unexposed controls. The results showed that exposed animals demonstrated altered gap detection abilities, but these alterations were sometimes explained as consequences of hyper-responsiveness to either the startle stimulus or to the background noise. Two of the three subsets of animals studied, however, displayed weakened gap detection abilities that could not be explained by enhanced responses to these stimuli or by reduced sound sensitivity or a reduction of temporal processing speed, consistent with the induction of tinnitus. These results demonstrate that not only hearing loss but also changes in sensitivity to background noise or to startle stimuli are potential confounds that, when present, can underlie changes in gap detection irrespective of tinnitus. We discuss how such confounds can be recognized and how they can be avoided.
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Hiperacusia/etiología , Acúfeno/etiología , Acúfeno/fisiopatología , Estimulación Acústica/efectos adversos , Animales , Umbral Auditivo/fisiología , Conducta Animal , Cricetinae , Audición , Pérdida Auditiva/complicaciones , Ruido , Reflejo de Sobresalto/efectos de los fármacos , Filtrado Sensorial/fisiología , SonidoRESUMEN
Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.
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Encéfalo/patología , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/patología , Trastornos de la Memoria/etiología , Memoria a Corto Plazo/fisiología , Anciano , Análisis de Varianza , Encéfalo/irrigación sanguínea , Mapeo Encefálico , Función Ejecutiva , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/irrigación sanguínea , Vías Nerviosas/patología , Pruebas Neuropsicológicas , Oxígeno/sangre , Desempeño Psicomotor , Tiempo de ReacciónRESUMEN
The non-competitive N-methyl-D-aspartate receptor antagonist ketamine leads to transient psychosis-like symptoms and impairments in oculomotor performance in healthy volunteers. This study examined whether the adverse effects of ketamine on oculomotor performance can be reversed by the atypical antipsychotic risperidone. In this randomized double-blind, placebo-controlled study, 72 healthy participants performed smooth pursuit eye movements (SPEM), prosaccades (PS) and antisaccades (AS) while being randomly assigned to one of four drug groups (intravenous 100 ng ml(-1) ketamine, 2 mg oral risperidone, 100 ng ml(-1) ketamine plus 2 mg oral risperidone, placebo). Drug administration did not lead to harmful adverse events. Ketamine increased saccadic frequency and decreased velocity gain of SPEM (all P < 0.01) but had no significant effects on PS or AS (all P > or = 0.07). An effect of risperidone was observed for amplitude gain and peak velocity of PS and AS, indicating hypometric gain and slower velocities compared with placebo (both P < or = 0.04). No ketamine by risperidone interactions were found (all P > or = 0.26). The results confirm that the administration of ketamine produces oculomotor performance deficits similar in part to those seen in schizophrenia. The atypical antipsychotic risperidone did not reverse ketamine-induced deteriorations. These findings do not support the cognitive enhancing potential of risperidone on oculomotor biomarkers in this model system of schizophrenia and point towards the importance of developing alternative performance-enhancing compounds to optimise pharmacological treatment of schizophrenia.
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Antipsicóticos/uso terapéutico , Antagonistas de Aminoácidos Excitadores/efectos adversos , Ketamina/efectos adversos , Trastornos de la Motilidad Ocular/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Risperidona/uso terapéutico , Adolescente , Adulto , Antipsicóticos/farmacología , Método Doble Ciego , Antagonistas de Aminoácidos Excitadores/farmacología , Medidas del Movimiento Ocular , Movimientos Oculares/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Ketamina/farmacología , Masculino , Trastornos de la Motilidad Ocular/inducido químicamente , Seguimiento Ocular Uniforme/efectos de los fármacos , Risperidona/farmacología , Movimientos Sacádicos/efectos de los fármacos , Esquizofrenia , Adulto JovenRESUMEN
Learning abstract rules is central to social and cognitive development. Across two experiments, we used Delayed Non-Matching to Sample tasks to characterize the longitudinal development and nature of rule-learning impairments in children with Autism Spectrum Disorder (ASD). Results showed that children with ASD consistently experienced more difficulty learning an abstract rule from a discrete physical reward than children with DD. Rule learning was facilitated by the provision of more concrete reinforcement, suggesting an underlying difficulty in forming conceptual connections. Learning abstract rules about social stimuli remained challenging through late childhood, indicating the importance of testing executive functions in both social and non-social contexts.
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Trastornos Generalizados del Desarrollo Infantil/psicología , Aprendizaje , Refuerzo Verbal , Recompensa , Estudios de Casos y Controles , Niño , Desarrollo Infantil , Preescolar , Discapacidades del Desarrollo/fisiopatología , Discapacidades del Desarrollo/psicología , Femenino , Humanos , Estudios Longitudinales , Masculino , Medio Social , Régimen de RecompensaRESUMEN
Allogenic stem cell transplantation can reduce lysosomal storage of heparan sulfate-derived oligosaccharides by up to 27 % in Sanfilippo MPS3a brain, but does not reduce the abnormal storage of sialolactosylceramide (G(M3)) or improve neurological symptoms, suggesting that ganglioside storage is in a non-lysosomal compartment. To investigate this further we isolated the Triton X100-insoluble at 4 °C, lipid raft (LR) fraction from a sucrose-density gradient from cerebral hemispheres of a 7 month old mouse model of Sanfilippo MPS3a and age-matched control mouse brain. HPLC/MS/MS analysis revealed the expected enrichment of normal complex gangliosides, ceramides, galatosylceramides and sphingomyelin enrichment in this LR fraction. The abnormal HS-derived oligosaccharide storage material was in the Triton X100-soluble at 4 °C fractions (8-12),whereas both GM3 and sialo[GalNAc]lactosylceramide (GM2) were found exclusively in the LR fraction (fractions 3 and 4) and were >90 % C18:0 fatty acid, suggesting a neuronal origin. Further analysis also revealed a >threefold increase in the late-endosome marker bis (monoacylglycerol) phosphate (>70 % as C22:6/22:6-BMP) in non-LR fractions 8-12 whereas different forms of the proposed BMP precursor, phosphatidylglycerol (PG) were in both LR and non-LR fractions and were less elevated in MPS3a brain. Thus heparan sulfate-derived oligosaccharide storage is associated with abnormal lipid accumulation in both lysosomal (BMP) and non-lysosomal (GM3 and GM2) compartments.
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Encéfalo/metabolismo , Gangliósido G(M3)/metabolismo , Gangliósidos/metabolismo , Microdominios de Membrana/metabolismo , Mucopolisacaridosis III/metabolismo , Animales , Gangliósido G(M2)/metabolismo , Lisofosfolípidos/metabolismo , Lisosomas/metabolismo , Ratones , Monoglicéridos/metabolismo , Espectrometría de Masas en TándemRESUMEN
Linkage to 7q has been the most robust genetic finding in familial autism. A previous scan of multiplex families with autism spectrum disorders found a linkage signal of genome-wide significance at D7S530 on 7q32. We searched a candidate imprinted region at this location for genetic variants in families with positive linkage scores. Using exon resequencing, we identified three rare potentially pathogenic variants in the TSGA14 gene, which encodes a centrosomal protein. Two variants were missense mutations (c.664C>G; p.P206A and c.766T>G; p.C240G) that changed conserved residues in the same protein domain; the third variant (c.192+5G>A) altered splicing, which resulted in a protein with an internal deletion of 16 residues and a G33D substitution. These rare TSGA14 variants are enriched in the affected subjects (6/348 patients versus 2/670 controls, Fisher's exact two tailed P = 0.022). This is the first report of a possible link of a gene with a centrosomal function with familial autism.
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Trastornos Generalizados del Desarrollo Infantil/genética , Mutación/genética , Proteínas/genética , Alelos , Secuencia de Aminoácidos , Estudios de Casos y Controles , Niño , Trastornos Generalizados del Desarrollo Infantil/etnología , Cromosomas Humanos Par 7/genética , Familia , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Datos de Secuencia Molecular , Linaje , Proteínas/química , Empalme del ARN/genética , Población Blanca/genéticaRESUMEN
In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (â¼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.
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Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Agonistas de Receptores de GABA-A/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Hidrocarburos Fluorados/farmacología , Adolescente , Adulto , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Agonistas de Receptores de GABA-A/administración & dosificación , Agonistas de Receptores de GABA-A/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Hidrocarburos Fluorados/administración & dosificación , Hidrocarburos Fluorados/efectos adversos , Masculino , Ratones , Persona de Mediana Edad , Subunidades de Proteína , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Saimiri , Especificidad de la Especie , Factores de Tiempo , Adulto JovenRESUMEN
MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from â¼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (â¼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.
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Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Agonistas de Receptores de GABA-A/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Hidrocarburos Fluorados/farmacología , Adolescente , Adulto , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/efectos adversos , Sitios de Unión , Encéfalo/metabolismo , Clordiazepóxido/administración & dosificación , Clordiazepóxido/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Agonistas de Receptores de GABA-A/administración & dosificación , Agonistas de Receptores de GABA-A/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Hidrocarburos Fluorados/administración & dosificación , Hidrocarburos Fluorados/efectos adversos , Masculino , Ratones , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Unión Proteica , Subunidades de Proteína , Ratas , Ratas Sprague-Dawley , Saimiri , Especificidad de la Especie , Distribución Tisular , Adulto JovenRESUMEN
GABA(A) receptor α5-selective inverse agonists enhance cognitive performance in pre-clinical species. However, a key aspect of the clinical development of such compounds is the demonstration that in man such compounds are devoid of the anxiogenic-like activity associated with non-selective inverse agonists such as FG 7142. The triazolophthalazine α5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is an α5-selective inverse agonist which enhances cognitive performance in rodents and encouragingly in human Phase I Safety and Tolerability studies it was devoid of the anxiogenic-like activity associated with FG 7142. However, in order to appropriately interpret this latter observation, it was considered important to demonstrate that the absence of anxiogenic-like activity occurs at significant levels of receptor occupancy. Consequently, the occupancy of human brain GABA(A) receptors was measured using [¹¹C]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg α5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma α5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an α5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give ~50% occupancy.
Asunto(s)
Flumazenil/metabolismo , Agonistas de Receptores de GABA-A/farmacocinética , Ftalazinas/farmacocinética , Receptores de GABA-A/metabolismo , Triazoles/farmacocinética , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Carbono , Agonismo Inverso de Drogas , Humanos , Masculino , Tomografía de Emisión de Positrones , Subunidades de Proteína/agonistas , Subunidades de Proteína/metabolismo , Adulto JovenRESUMEN
For luminescent quantum dots (QDs) to realize their full potential as intracellular labeling, imaging and sensing reagents, robust noninvasive methods for their delivery to the cellular cytosol must be developed. Our aim in this study was to explore a range of methods aimed at delivering QDs to the cytosol. We have previously shown that QDs functionalized with a polyarginine 'Tat' cell-penetrating peptide (CPP) could be specifically delivered to cells via endocytic uptake with no adverse effects on cellular proliferation. We began by assessing the long-term intracellular fate and stability of these QD-peptide conjugates. We found that the QDs remained sequestered within acidic endolysosomal vesicles for at least three days after initial uptake while the CPP appeared to remain stably associated with the QD throughout this time. We next explored techniques designed to either actively deliver QDs directly to the cytosol or to combine endocytosis with subsequent endosomal escape to the cytosol in several eukaryotic cell lines. Active delivery methods such as electroporation and nucleofection delivered only modest amounts of QDs to the cytosol as aggregates. Delivery of QDs using a variety of transfection polymers also resulted in primarily endosomal sequestration of QDs. However, in one case the commercial PULSin reagent did facilitate a modest cytosolic dispersal of QDs, but only after several days in culture and with significant polymer-induced cytotoxicity. Finally, we demonstrated that an amphiphilic peptide designed to mediate cell penetration and vesicle membrane interactions could mediate rapid QD uptake by endocytosis followed by a slower efficient endosomal release which peaked at 48 h after initial delivery. Importantly, this QD-peptide bioconjugate elicited minimal cytotoxicity in the cell lines tested.