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1.
Nat Med ; 25(11): 1706-1714, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31686036

RESUMO

Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-ß and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.

2.
Transl Psychiatry ; 9(1): 313, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748505

RESUMO

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies - including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites - markers of the brain's primary excitatory and inhibitory system - in both the 'typical' and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the 'shift' in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.

3.
J Med Chem ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31596080

RESUMO

The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective positive allosteric modulator (PAM) for GLP-1R based on a 3,4,5,6-tetrahydro-1H-1,5-epiminoazocino[4,5-b]indole scaffold is reported. Optimization of this series from HTS was supported by a GLP-1R ligand binding model. Biological in vitro testing revealed favorable ADME and pharmacological profiles for the best compound 19. Characterization by in vivo pharmacokinetic and pharmacological studies demonstrated that 19 activates GLP-1R as positive allosteric modulator (PAM) in the presence of the much less active endogenous degradation product GLP1(9-36)NH2 of the potent endogenous ligand GLP-1(7-36)NH2. While these data suggest the potential of small molecule GLP-1R PAMs for T2DM treatment, further optimization is still required towards a clinical candidate.

4.
Int J Equity Health ; 18(1): 156, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615530

RESUMO

BACKGROUND: With the adoption of the Sustainable Development Goals (SDGs), there is a renewed commitment of tackling the varied challenges of undernutrition, particularly stunting (SDG 2.2). Health equity is also a priority in the SDG agenda and there is an urgent need for disaggregated analyses to identify disadvantaged subgroups. We compared time trends in socioeconomic inequalities obtained through stratification by wealth quintiles and deciles for stunting prevalence. METHODS: We used 37 representative Demographic and Health Surveys and Multiple Indicator Cluster surveys from nine Latin American and Caribbean (LAC) countries conducted between 1996 and 2016. Stunting in children under-5 years was assessed according to the 2006 WHO Child Growth Standards and stratified by wealth quintiles and deciles. Within-country socioeconomic inequalities were measured through concentration index (CIX) and slope index of inequality (SII). We used variance-weighted least squares regression to estimate annual changes. RESULTS: Eight out of nine countries showed a statistical evidence of reduction in stunting prevalence over time. Differences between extreme deciles were larger than between quintiles in most of countries and at every point in time. However, when using summary measures of inequality, there were no differences in the estimates of SII with the use of deciles and quintiles. In absolute terms, there was a reduction in socioeconomic inequalities in Peru, Honduras, Dominican Republic, Belize, Suriname and Colombia. In relative terms, there was an increase in socioeconomic inequalities in Peru, Bolivia, Haiti, Honduras and Guatemala. CONCLUSIONS: LAC countries have made substantial progress in terms of reducing stunting,. Nevertheless, renewed actions are needed to improve equity. Particularly in those countries were absolute and relative inequalities did not change over time such Bolivia and Guatemala. Finer breakdowns in wealth distribution are expected to elucidate more differences between subgroups; however, this approach is relevant to cast light on those subgroups that are still lagging behind within populations and inform equity-oriented health programs and practices.

5.
Org Lett ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31403317

RESUMO

The greater geometric lability of hydrazones compared to that of oxime ethers is used as a basis to overcome the reluctance of Z-oxime ether azatrienes to undergo electrocyclization toward the synthesis of borylated (heteroaromatic) pyridines and ring-fused analogues. Such hydrazones now allow access to previously inaccessible tri- and tetrasubstituted 3-borylpyridines in high yields.

6.
Philos Trans A Math Phys Eng Sci ; 377(2152): 20180315, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31280718

RESUMO

Previous reports have observed a direct relationship between the polymer poly(3-hexylthiophene) molecular weight (MW) and the perovskite solar cell (PSC) efficiency. Herein, we analyse how the differences in MW and the differences in energetic disorder influence the interfacial carrier losses in the PSCs under operation conditions and explain the observed differences. This article is part of a discussion meeting issue 'Energy materials for a low carbon future'.

7.
Pediatr Infect Dis J ; 38(8): 816-824, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31306396

RESUMO

BACKGROUND: Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI. METHODS: Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit. RESULTS: Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.

8.
J Psychopharmacol ; 33(9): 1141-1148, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31237191

RESUMO

BACKGROUND: The potential benefits of cannabis and its major non-intoxicating component cannabidiol (CBD) are attracting attention, including as a potential treatment in neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the neural action of CBD, and its relevance to ASD, remains unclear. We and others have previously shown that response to drug challenge can be measured using functional magnetic resonance imaging (fMRI), but that pharmacological responsivity is atypical in ASD. AIMS: We hypothesized that there would be a (different) fMRI response to CBD in ASD. METHODS: To test this, task-free fMRI was acquired in 34 healthy men (half with ASD) following oral administration of 600 mg CBD or matched placebo (random order; double-blind administration). The 'fractional amplitude of low-frequency fluctuations' (fALFF) was measured across the whole brain, and, where CBD significantly altered fALFF, we tested if functional connectivity (FC) of those regions was also affected by CBD. RESULTS: CBD significantly increased fALFF in the cerebellar vermis and the right fusiform gyrus. However, post-hoc within-group analyses revealed that this effect was primarily driven by the ASD group, with no significant change in controls. Within the ASD group only, CBD also significantly altered vermal FC with several of its subcortical (striatal) and cortical targets, but did not affect fusiform FC with other regions in either group. CONCLUSION: Our results suggest that, especially in ASD, CBD alters regional fALFF and FC in/between regions consistently implicated in ASD. Future studies should examine if this affects the complex behaviours these regions modulate.

9.
Front Immunol ; 10: 1013, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134083

RESUMO

Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from encapsulated microorganisms, respiratory tract infections related to respiratory syncytial virus or influenza, and even the development of bronchiectasis and asthma, are often reported as the first symptom of primary immunodeficiencies. In the same way, neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis, and mycobacterial infections. However, in the last decades a better knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. On the other hand, the use of monoclonal antibodies targeting cytokines, such as tumor necrosis factor alpha has revealed new risk groups for infections, such as tuberculosis. The use of biological response modifiers has spread to almost all medical specialties, including inflammatory diseases and neoplasia, and are being used to target different signaling networks that may mirror some of the known immune deficiencies. From a clinical perspective, the individual contribution of genetics, and/or targeted treatments, to immune dysregulation is difficult to assess. The aim of this article is to review the known and newly described mechanisms of impaired immune signaling that predispose to RTI, including new insights into host genetics and the impact of biological response modifiers, and to summarize clinical recommendations regarding vaccines and prophylactic treatments in order to prevent infections.

10.
Adv Nutr ; 10(suppl_2): S251-S271, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31089744

RESUMO

There is insufficient evidence on the role of functional fortified dairy products in improving health and in preventing risk factors associated with noncommunicable chronic diseases. This systematic review was conducted to summarize effects of the consumption of fortified dairy products on biomarkers of cardiometabolic risk. MEDLINE and SCOPUS databases were used to perform searches to include studies published up to 30 April 2018. Randomized clinical trials with human subjects consuming dairy products fortified with phytosterols, FAs, vitamins or minerals and relating this consumption with cardiometabolic health were included in this review. Risk of bias assessment according to Cochrane guidelines was performed to determine the quality of the trials. Forty-one studies were finally selected for this synthesis; the selected studies tested dairy products fortified with the following nutrients and bioactive components: phytosterols (n = 31), FAs (n = 8), and vitamin D (n = 2). We found that the consumption of phytosterol-fortified dairy, led to an overall LDL cholesterol reduction of -0.36 (-0.41, -0.31) mmol/L, P < 0.001; this decrease was mainly related to the dosage. Likewise, consumption of ω-3 FA-fortified dairy products resulted in a plasma LDL cholesterol reduction of -0.18 (-0.27, -0.09) mmol/L as well as a decrease of -0.18 (-0.32, -0.05) mmol/L in triacylglycerols (TG). Performing meta-analyses of the consumption of dairy products fortified with vitamin D or FAs other than ω-3 FAs and biomarkers of cardiometabolic risk was not possible because of the few available publications. Our results indicate that consumption of dairy products fortified with phytosterols and ω-3 FAs can lead to a reduction of LDL cholesterol and consumption of fortified dairy products fortified with ω-3 FAs can reduce TG concentration. However, more studies with homogeneous designs are needed to determine the advantages of using dairy products as fortification vehicles to prevent cardiometabolic risk.

11.
Biomater Sci ; 7(6): 2511-2519, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30968104

RESUMO

Herein, we demonstrate the use of lysozyme (Lys) as a model to fabricate a protein carrier system based on gold nanoparticles (AuNPs) via the Layer-by-Layer (LbL) technology. Poly(ethyleneimine) (PEI) and poly(sodium 4-styrenesulfonate) (PSS) were used as cationic and anionic polymers respectively to grow oppositely charged layers. Mild aqueous conditions were utilized to avoid protein denaturation and activity instead of organic solvents that have been used in other encapsulation systems. Two different strategies were used: (A) lysozyme acting as a reducing and stabilizing agent in the formation of AuNPs at a temperature of 45 ± 2 °C followed by only two subsequent polymeric layers deposited by LbL, and (B) citrate acting as a reducing agent prior to stabilization of the AuNPs by mercaptoundecanoic acid. Dynamic light scattering, UV-vis spectroscopy, IR spectroscopy and transmission electron microscopy were used to characterize the nanoconjugates. Furthermore, the enzymatic activity of the resulting protein/nanoparticle conjugates was evaluated using the bacteria Micrococcus lysodeikticus as a substrate.

12.
Health Promot Int ; 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31006021

RESUMO

The Aim of this scoping review was to explore the available literature on volunteerism in adolescence and the benefits that this activity may report in their healthy development, from a salutogenic perspective. Searches were conducted in Pubmed, Cinahl, PsycINFO and Cochrane Library home databases; 15 articles were selected. Almost all of the studies were conducted in the United States between 1990 and 2000, primarily developed by psychologists and sociologists. The impact of volunteering was reflected in aspects that can be classified based on Lerner's dimensions of the PYD model. Volunteer activities promote an Improved academic, social, cognitive, and vocational competence in adolescents. An increase in conflict resolution capacity, leadership and personal agency, as well as improved pro-social attitudes and relationships with adults and peers, all of which contributed to their self-identification with the community. Moreover, increased positive development of adolescents reduces the rates of risky behaviors. Volunteerism may represent an opportunity for health promotion in adolescence. The concept of volunteering as an asset for health promotion during adolescence evokes the need to adopt and favor this view with regard to key areas of study associated with this stage such as education and health. Teams that work in community health, especially those in primary care, should recognize and value existing volunteer groups as an asset to promote the healthy development of adolescents. Friendlier health services should be encouraged that include comprehensive services from within educational institutions to community actions.

14.
J Adv Nurs ; 75(8): 1764-1781, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30972808

RESUMO

AIM: To show the results of an exploratory trial based on social and emotional learning to promote healthy lifestyles in 5-6 aged children. DESIGN: A randomized controlled trial. METHOD: The study was conducted from 2015-2016. Thirty-seven children were allocated to the intervention group (N = 19) and control group (N = 18). A multi-method and multi-component evaluation approach was used to capture the preliminary efficacy, acceptability, and feasibility of the programme. Repeat measures ANOVA followed by an ANCOVA tests were applied for the inferential analysis and for qualitative data, a content analysis was used. RESULTS: Positive effects on emotional perception and resilience were found in children's intervention group. Children and families showed high programme's acceptability and a wide range of barriers and facilitators were identified during the implementation process. CONCLUSION: Predicted mechanisms to improve healthy lifestyles in children throughout social and emotional competence seem to be supported by some of the study's results. However more research is needed to replicate such results and confirm these mechanisms. ClinicalTrials.gov Identifier: NCT02975544.

15.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 30(1): 38-43, ene.-feb. 2019. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-181460

RESUMO

Papillary tumor of the pineal region is a rare neuroepithelial tumor characterized by papillary architecture and epithelial cytology, immunopositivity for cytokeratin and ependymal differentiation. It is considered grade II–III by the World Health Organization and was first described by Jouvet in 2003. We present a 34-year-old male with headaches, blurred vision and normal examination. Radiological study showed a nodulocystic lesion in the pineal region compatible with pineocytoma. Surgery was performed using an infratentorial supracerebellar approach, finding a cystic tumor in the quadrigeminal cistern which was completely resected. Histopathology reported a papillary tumor of the pineal region. The patient made good progress without adjuvant therapy, and after 57 months of follow-up he remained asymptomatic and free of recurrence. A review of the literature was performed to collect all the cases published with gross total resection and no complementary treatment. In conclusion, there is still much to be learned about the pathogenesis, prognosis and management of this tumor


El tumor papilar de la región pineal es un infrecuente tumor neuroepitelial con arquitectura y citología epitelial, citoqueratina positiva y signos de diferenciación ependimaria. Descrito por Jouvet en 2003 es considerado grado II-III de la Organización Mundial de la Salud. Presentamos el caso de un varón de 34 años con cefalea, visión borrosa y exploración normal. El estudio radiológico muestra una lesión noduloquística en región pineal compatible con pineocitoma. Es intervenido mediante abordaje supracerebeloso infratentorial apreciándose lesión de aspecto quístico en cisterna cuadrigémina que es resecada por completo. El resultado histopatológico es tumor papilar de la región pineal. El paciente presenta buena evolución sin tratamiento adyuvante y tras 57 meses de seguimiento permanece asintomático y sin recidiva. Realizamos una revisión sistemática sobre la evolución de los casos publicados tratados mediante resección completa y sin tratamiento complementario, concluyendo que continuamos necesitando aprender sobre la patogénesis, pronóstico y manejo de este tumor


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Glândula Pineal/cirurgia , Pinealoma/cirurgia , Neoplasias Encefálicas/patologia , Pinealoma/diagnóstico por imagem , Procedimentos Neurocirúrgicos , Imuno-Histoquímica , Pinealoma/patologia , Diagnóstico Diferencial , Transtornos de Enxaqueca/etiologia
16.
Neuropsychopharmacology ; 44(8): 1398-1405, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30758329

RESUMO

There is increasing interest in the use of cannabis and its major non-intoxicating component cannabidiol (CBD) as a treatment for mental health and neurodevelopmental disorders, such as autism spectrum disorder (ASD). However, before launching large-scale clinical trials, a better understanding of the effects of CBD on brain would be desirable. Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels, including in brain regions linked to ASD, such as the basal ganglia (BG) and the dorsomedial prefrontal cortex (DMPFC). However, differences in glutamate and GABA pathways in ASD mean that the response to CBD in people with and without ASD may be not be the same. To test whether CBD 'shifts' glutamate and GABA levels; and to examine potential differences in this response in ASD, we used magnetic resonance spectroscopy (MRS) to measure glutamate (Glx = glutamate + glutamine) and GABA+ (GABA + macromolecules) levels in 34 healthy men (17 neurotypicals, 17 ASD). Data acquisition commenced 2 h (peak plasma levels) after a single oral dose of 600 mg CBD or placebo. Test sessions were at least 13 days apart. Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant. Thus, CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD. Our results do not speak to the efficacy of CBD. Future studies should examine the effects of chronic administration on brain and behaviour, and whether acute brain changes predict longer-term response.

17.
Sci Rep ; 8(1): 17143, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30464185

RESUMO

The Golgi apparatus (GA) is a bona fide Ca2+ store; however, there is a lack of GA-specific Ca2+ mobilizing agents. Here, we report that emetine specifically releases Ca2+ from GA in HeLa and HL-1 atrial myocytes. Additionally, it has become evident that the trans-Golgi is a labile Ca2+ store that requires a continuous source of Ca2+ from either the external milieu or from the ER, to enable it to produce a detectable transient increase in cytosolic Ca2+. Our data indicates that the emetine-sensitive Ca2+ mobilizing mechanism is different from the two classical Ca2+ release mechanisms, i.e. IP3 and ryanodine receptors. This newly discovered ability of emetine to release Ca2+ from the GA may explain why chronic consumption of ipecac syrup has muscle side effects.

18.
Pediatr Dent ; 40(4): 253-258, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30345963

RESUMO

Purpose: The purpose of this study was to evaluate the clinical success of a new primary zirconia molar crown compared with stainless steel crowns (SSCs). Methods: This randomized, controlled clinical trial was designed as a split-mouth study. Fifty three- to seven-year-old children were recruited to provide a total of 50 pairs of teeth requiring primary molar crowns, with each participant receiving a SSC and zirconia crown. Restorations were evaluated at six-month, 12-month, and 24-month recall appointments examining the following criteria: gingival health; estimate of extent the crown was high in occlusion; surface roughness; staining on crown surface; wear of opposing arch tooth; color match; anatomic form; marginal integrity; marginal discoloration; proximal contact area; secondary caries at crown margin; and parent/guardian satisfaction with crown appearance. Results: The 24-month follow-up included 39 patients (78 percent). Seventy crowns (70 percent) were evaluated; of the 36 zirconia crowns and 34 SSCs, there were no failures at the 24-month evaluation. The only significant difference in the parameters evaluated was in parental satisfaction with the zirconia crown preference (P<0.05). Conclusion: Current 24-month results indicate that zirconia primary molar crowns perform similarly to an established stainless steel crown for restoration of primary molar teeth.

19.
Sci Transl Med ; 10(461)2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30282698

RESUMO

Preliminary studies have suggested that γ-aminobutyric acid type A (GABAA) receptors, and potentially the GABAA α5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAA and GABAA α5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAA receptor or GABAA α5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAA receptor or GABAA α5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAA receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired.

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