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2.
Psychol Med ; : 1-11, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32539883

RESUMO

BACKGROUND: Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. METHODS: Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. RESULTS: Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. CONCLUSIONS: The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions.

3.
Nat Commun ; 11(1): 3065, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528103

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
Heart Rhythm ; 2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32454219

RESUMO

BACKGROUND: Twelve-lead electrocardiogram (ECG) criteria have been developed to identify idiopathic ventricular arrhythmias (VAs) from the left ventricular (LV) papillary muscles (PAPs), but accurate localization remains a challenge. OBJECTIVE: The purpose of this study was to develop electrocardiogram criteria for accurate localization of LV PAP VAs using lead V1 exclusively. METHODS: Consecutive patients undergoing mapping and ablation of VAs from the LV PAPs guided by intracardiac echocardiography from 2007 to 2018 were reviewed (study group). The QRS morphology in lead V1 was compared to patients with VAs with a "right bundle branch block" morphology from other LV locations (reference group). Patients with structural heart disease were excluded. RESULTS: One hundred eleven patients with LV PAP VAs (mean age 54 ± 16 years; 59% men) were identified, including 64 (55%) from the posteromedial PAP and 47 (42%) from the anterolateral PAP. The reference group included patients with VAs from the following LV locations: fascicles (n = 21), outflow tract (n = 36), ostium (n = 37), inferobasal segment (n = 12), and apex (5). PAP VAs showed 3 distinct QRS morphologies in lead V1 93% of the time: Rr (53%), R with a slurred downslope (29%), and RR (11%). Sensitivity, specificity, positive predictive value, and negative predictive value for the 3 morphologies combined are 93%, 98%, 98%, and 93%, respectively. The intrinsicoid deflection of PAP VAs in lead V1 was shorter than that of the reference group (63 ± 13 ms vs 79 ± 24 ms; P < .001). An intrinsicoid deflection time of <74 ms best differentiated the 2 groups (sensitivity 79%; specificity 87%). CONCLUSION: VAs originating from the LV PAPs manifest unique QRS morphologies in lead V1, which can aid in rapid and accurate localization.

5.
Psychol Med ; : 1-10, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31736460

RESUMO

BACKGROUND: Maladaptive learning linking environmental food cues to high-palatability food reward plays a central role in overconsumption in obesity and binge eating disorders. The process of memory reconsolidation offers a mechanism to weaken such learning, potentially ameliorating over-eating behaviour. Here we investigated whether putatively interfering with synaptic plasticity using the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, could weaken retrieved chocolate reward memories through blockade of reconsolidation. METHODS: Seventy five healthy volunteers with a tendency to binge eat chocolate were randomised to retrieve chocolate reward memory under 10 mg rapamycin (RET + RAP, active condition), or placebo (RET + PBO), or they received 10 mg rapamycin without subsequent retrieval (NO RET + RAP). Indices of chocolate reward memory strength were assessed one week pre and post manipulation and at one month follow-up. RESULTS: Contrary to hypotheses, the RET + RAP group did not show any greater reduction than control groups on indices of motivational salience of chocolate cues, motivation to consume chocolate or liking of chocolate. Mild evidence of improvement in the RET + RAP group was found, but this was limited to reduced chocolate binge episodes and improved healthy food choices. CONCLUSIONS: We did not find convincing evidence of comprehensive naturalistic chocolate reward memory reconsolidation blockade by rapamycin. The effects on chocolate bingeing and food choices may warrant further investigation. These limited positive findings may be attributable to insufficient interference with mTOR signalling with 10 mg rapamycin, or failure to destabilise chocolate memories during retrieval.

6.
Nat Commun ; 10(1): 5187, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772157

RESUMO

Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation - where stored memories become briefly labile upon retrieval - may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval + ketamine (RET + KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical 'reconsolidation window' predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptive memory and should be further pursued in alcohol and drug use disorders.


Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Consumo de Bebidas Alcoólicas/psicologia , Ketamina/farmacologia , Adaptação Psicológica , Adulto , Biomarcadores/sangue , Feminino , Humanos , Ketamina/análogos & derivados , Ketamina/sangue , Masculino , Memória/efeitos dos fármacos , Reforço Psicológico , Resultado do Tratamento
7.
Mol Cancer Ther ; 18(10): 1696-1707, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31575759

RESUMO

BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31165967

RESUMO

PURPOSE: Left atrial (LA) fibrosis plays an important role in the pathogenesis and perpetuation of atrial fibrillation (AF). It may be identified by bipolar voltage (BiV) mapping, but quantification of fibrosis which previously relied on visual estimation of scar has been shown to be inaccurate. Our aim was to use a novel automated voltage histogram analysis (VHA) tool to quantify LA scar burden accurately in patients with AF. METHODS: LA voltage was assessed in 100 consecutive patients undergoing first pulmonary vein isolation (PVI) for paroxysmal or persistent AF using a circular multielectrode catheter to create high-density LA BiV maps which were analysed using the VHA tool after the procedure. RESULTS: High-density electro-anatomic maps took 10 min to create and contained a median of 1049 points. The VHA algorithm accurately quantified the burden of Diseased LA Tissue (≤ 0.5 mV) and Dense LA Scar (≤ 0.2 mV) with a median of 17.8% and 3.5% respectively. A quartile classification was applied based on diseased LA tissue burden. Patients in class IV with the highest diseased LA burden were older (p < 0.0001), more likely female (p = 0.0095), had higher CHA2DS2-VASc scores (p = 0.0024) and were more likely to have persistent rather than paroxysmal AF (p = 0.0179) than those in classes I-III. CONCLUSIONS: The VHA algorithm is able to quantify percentage surface area voltage rapidly and according to preset ranges for the first time. The algorithm offers the potential for classification of patients undergoing AF ablation into different classes of diseased LA burden, which may have diagnostic, therapeutic and prognostic implications.

9.
Conf Proc IEEE Eng Med Biol Soc ; 2019: 5941-5944, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31947201

RESUMO

Left atrial voltage maps are routinely acquired during electroanatomic mapping in patients undergoing catheter ablation for atrial fibrillation (AF). For patients, who have prior catheter ablation when they are in sinus rhythm (SR), the voltage map can be used to identify low voltage areas (LVAs) using a threshold of 0.2 - 0.45 mV. However, such a voltage threshold for maps acquired during AF has not been well established. A prerequisite for defining a voltage threshold is to maximize the topologically matched LVAs between the electroanatomic mapping acquired during AF and SR. This paper demonstrates a new technique to improve the sensitivity and specificity of the matched LVA. This is achieved by computing omni-directional bipolar voltages and applying Gaussian Process Regression based interpolation to derive the AF map. The proposed method is evaluated on a test cohort of 7 male patients, and a total of 46,589 data points were included in analysis. The LVAs in the posterior left atrium and pulmonary vein junction are determined using the standard method and the proposed method. Overall, the proposed method showed patient-specific sensitivity and specificity in matching LVAs of 75.70% and 65.55% for a geometric mean of 70.69%. On average, there was an improvement of 3.00% in the geometric mean, 7.88% improvement in sensitivity, 0.30% improvement in specificity compared to the standard method. The results show that the proposed method is an improvement in matching LVA. This may help develop the voltage threshold to better identify LVA in the left atrium for patients in AF.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Cicatriz/diagnóstico por imagem , Átrios do Coração/diagnóstico por imagem , Técnicas Eletrofisiológicas Cardíacas , Humanos , Masculino
10.
Psychopharmacology (Berl) ; 235(9): 2507-2527, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30091003

RESUMO

BACKGROUND: Consolidated memories can undergo enduring modification through retrieval-dependent treatments that modulate reconsolidation. This represents a potentially transformative strategy for weakening or overwriting the maladaptive memories that underlie substance use and anxiety/trauma-related disorders. However, modulation of naturalistic maladaptive memories may be limited by 'boundary conditions' imposed on the reconsolidation process by the nature of these memories. METHODS: We conducted a systematic review and meta-analyses of behavioural and pharmacological studies examining retrieval-dependent modulation of reward- and threat-related memories in (sub) clinical substance use and anxiety/trauma, respectively. RESULTS: Of 4938 publications assessed for eligibility, 8 studies of substance use and 10 of anxiety (phobia)- and trauma-related symptoms were included in the meta-analyses. Overall, the findings were in the predicted direction, with most studies favouring the 'retrieval + treatment' condition. However, the magnitude of effects was dependent upon the nature of treatment, with pharmacological interventions showing a medium-sized effect (g = 0.59, p = 0.03) and behavioural treatments, a relatively small effect (g = 0.32, p = 0.10) in studies of phobia/trauma. Among studies of substance use, post-retrieval behavioural interventions yielded a larger effect (g = 0.60, p < 0.001) relative to pharmacological treatments (g = - 0.03, p = 0.91), with treatment type being a statistically significant moderator (χ2(1) = 4.20, p = 0.04). CONCLUSION: Modification of naturalistic maladaptive memories during reconsolidation appears to be a viable treatment strategy for substance use and phobias/trauma disorders. However, high levels of heterogeneity and methodological variation limit the strength of conclusions that can be drawn from the reviewed studies at this stage.


Assuntos
Transtornos de Ansiedade/terapia , Terapia Comportamental/métodos , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Transtornos de Estresse Pós-Traumáticos/terapia , Transtornos Relacionados ao Uso de Substâncias/terapia , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Transtornos de Ansiedade/psicologia , Antagonistas de Hormônios/farmacologia , Antagonistas de Hormônios/uso terapêutico , Humanos , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
11.
Expert Rev Cardiovasc Ther ; 16(9): 679-692, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30101627

RESUMO

INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Ablation is an excellent treatment option for appropriately selected patients. Catheter ablation tools and techniques have evolved since AF ablation was first introduced, but pulmonary vein isolation remains the cornerstone of the procedure. Outcomes from ablation have improved dramatically over the last 20 years, but remain less than optimal for certain patient groups. Areas covered: This review outlines the process of patient selection for AF ablation in contemporary practice, from diagnosis and AF classification to procedural risk assessment. Current guideline indications for AF ablation are reviewed. We discuss current reported outcomes from AF ablation and predictors for arrhythmia recurrence after ablation. The evolution of AF ablation technology and change in patient selection patterns are also discussed. Expert commentary: AF ablation is an attractive alternative to antiarrhythmic drug therapy for many patients. Patient selection for ablation is an important part of management. Careful patient selection requires thorough, individualized clinical assessment based on symptoms, alternative treatment options, an estimation of procedural risk, and predicted recurrence rate to allow the patient to participate in shared decision-making.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Seleção de Pacientes , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Humanos , Veias Pulmonares/fisiopatologia , Recidiva , Resultado do Tratamento
12.
BMJ Open ; 8(3): e019082, 2018 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-29602838

RESUMO

INTRODUCTION: Dementia is the fastest growing major cause of disability globally and may have a profound impact on the health-related quality of life (HRQoL) of both the patient with dementia and those who care for them. This review aims to systematically identify and synthesise the measurements of HRQoL for people with, and their caregivers across the full spectrum of, dementia from its preceding stage of predementia to end of life. METHODS AND ANALYSIS: A systematic literature review was conducted in Medical Literature Analysis and Retrieval System Online , ExcerptaMedicadataBASE, Cochrane Database of Systematic Reviews , Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, National Health Service Economic Evaluation Database and PsycINFO between January 1990 and the end of April 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. HRQoL measurements will be presented separately for people with dementia and caregivers by instrument used and, when possible, HRQoL will be reported by disease type and stage of the disease. Descriptive statistics of the results will be provided. A narrative synthesis of studies will also be provided discussing differences in HRQoL measurements by instrument used to estimate it, type of dementia and disease severity. ETHICS AND DISSEMINATION: This systematic literature review is exempt from ethics approval because the work is carried out on published documents. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer's disease spectrum for better care: multimodal data access platform (ROADMAP). TRIAL REGISTRATION NUMBER: CRD42017071416.


Assuntos
Cuidadores , Demência , Qualidade de Vida , Cuidadores/psicologia , Demência/enfermagem , Demência/psicologia , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Revisões Sistemáticas como Assunto
13.
Clin Res Cardiol ; 107(7): 578-585, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29476203

RESUMO

AIMS: Zero- and near-zero-fluoroscopic ablation techniques reduce the harmful effects of ionizing radiation during invasive electrophysiology procedures. We aimed to test the feasibility and safety of a zero-fluoroscopic strategy using a novel integrated magnetic and impedance-based electroanatomical mapping system for radiofrequency ablation (RFA) of supraventricular tachycardias (SVTs). METHODS: We retrospectively studied 92 consecutive patients undergoing electrophysiology studies with/without RFA for supraventricular tachycardia (SVT) performed by a single operator at a single center. The first 42 (Group 1) underwent a conventional fluoroscopic-guided approach and the second 50 (Group 2) underwent a zero-fluoroscopic approach using the Ensite Precision™ 3-D magnetic and impedance-based mapping system (Abbott Inc). RESULTS: Group 1 comprised 14 AV-nodal re-entrant tachycardia (AVNRT), 12 typical atrial flutter, 4 accessory pathway (AP), 2 atrial tachycardia (AT), and 9 diagnostic EP studies (EPS). Group 2 comprised 16 AVNRT, 17 atrial flutter, 6 AP, 3 AT, 2 AV-nodal ablations, and 7 EPS. A complete zero-fluoroscopic approach was achieved in 94% of Group 2 patients. All procedures were acutely successful, and no complications occurred. There was a significant reduction in fluoroscopy dose, dose area product, and time (p < 0.0001, for all), with no difference in procedure times. Ablation time for typical atrial flutter was shorter in Group 2 (p = 0.006). CONCLUSIONS: A zero-fluoroscopic strategy for diagnosis and treatment of SVTs using this novel 3D-electroanatomical mapping system is feasible in majority of patients, is safe, reduces ionizing radiation exposure, and does not compromise procedural times, success rates, or complication rates.


Assuntos
Flutter Atrial/cirurgia , Ablação por Cateter/métodos , Técnicas Eletrofisiológicas Cardíacas , Magnetismo/métodos , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Taquicardia Supraventricular/cirurgia , Feixe Acessório Atrioventricular , Potenciais de Ação , Adulto , Idoso , Flutter Atrial/diagnóstico , Flutter Atrial/fisiopatologia , Ablação por Cateter/efeitos adversos , Estudos de Viabilidade , Feminino , Fluoroscopia , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Valor Preditivo dos Testes , Doses de Radiação , Exposição à Radiação , Radiografia Intervencionista/métodos , Estudos Retrospectivos , Taquicardia por Reentrada no Nó Atrioventricular/diagnóstico , Taquicardia por Reentrada no Nó Atrioventricular/fisiopatologia , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
14.
BMJ Open ; 8(1): e019060, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362261

RESUMO

INTRODUCTION: Dementia is the fastest growing major cause of disability globally with a mounting social and financial impact for patients and their families but also to health and social care systems. This review aims to systematically synthesise evidence on the utilisation of resources and costs incurred by patients and their caregivers and by health and social care services across the full spectrum of dementia, from its preceding preclinical stage to end of life. The main drivers of resources used and costs will also be identified. METHODS AND ANALYSIS: A systematic literature review was conducted in MEDLINE, EMBASE, CDSR, CENTRAL, DARE, EconLit, CEA Registry, TRIP, NHS EED, SCI, RePEc and OpenGrey between January 2000 and beginning of May 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. The reporting of costing methodology will be assessed using the British Medical Journal checklist. A narrative synthesis of all studies will be presented for resources used and costs incurred, by level of disease severity when available. If feasible, the data will be synthesised using appropriate statistical techniques. ETHICS AND DISSEMINATION: Included articles will be reviewed for an ethics statement. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer's disease spectrum for better care: multi-modal data access platform (ROADMAP). TRIAL REGISTRATION NUMBER: CRD42017071413.


Assuntos
Cuidadores/economia , Demência/economia , Recursos em Saúde/estatística & dados numéricos , Análise Custo-Benefício , Humanos , Projetos de Pesquisa , Medição de Risco , Revisões Sistemáticas como Assunto
16.
J Interv Card Electrophysiol ; 49(1): 21-25, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28357713

RESUMO

BACKGROUND: Symptoms of possible lung and pleural injury such as chest pain and hemoptysis occur during and after radiofrequency ablation (RFA) and cryoablation (CA) of the left atrium (LA) for treatment of atrial fibrillation (AF). We determined the anatomical relationship of the lungs to the LA with particular reference to areas commonly targeted during AF ablation. METHODS: Distances from the LA endocardium to the lungs were measured from pre-procedure CT angiograms of 100 consecutive patients (71 males, age 60 ± 8 years) who underwent AF ablation. RESULTS: In 97% of the patients, the posterior right pulmonary vein antrum was <5 mm from the lower lobe of the right lung (RLL) over a supero-inferior distance of 3.6 ± 1.5 cm (minimum distance 1.2 ± 0.7 mm). The right inferior pulmonary vein (RIPV) ostium was <5 mm from the RLL in 94% (mean 2.7 ± 1.9 mm). The right superior pulmonary vein ostium was <5 mm from the RLL in 29% (mean 7.1 ± 3.8 mm). The medial segment of the right middle lobe was <5 mm from the carina between right pulmonary veins in 83% (mean 3.6 ± 1.9 mm). The mitral isthmus was <5 mm from the lingula in 5% (mean 9.4 ± 3.6 mm). The inferior lobe of the left lung was <5 mm from the posterior aspect of the ostia of the left inferior and superior pulmonary veins in 9 and 0%, respectively. The bronchi were <5 mm from the LA in 5%. CONCLUSIONS: The lungs are intimately related to sites of the LA commonly targeted during AF RFA. Whether this anatomical proximity translates into clinically significant potential for collateral lung damage during RFA merits further study.


Assuntos
Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Traumatismos Cardíacos/diagnóstico por imagem , Lesão Pulmonar/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Órgãos em Risco/diagnóstico por imagem , Pontos de Referência Anatômicos , Ablação por Cateter/métodos , Feminino , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/lesões , Traumatismos Cardíacos/etiologia , Traumatismos Cardíacos/prevenção & controle , Humanos , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodos
17.
Int J Neuropsychopharmacol ; 20(4): 346-350, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27401180

RESUMO

Background: Healthy people with a family history of alcohol problems show a pattern of subjective responses to alcohol that resemble those of affected probands. Studies on ketamine suggest that up-regulation of N-methyl-D-aspartate receptors (NMDARs) underlies these effects, and point to a pharmacologically-responsive endophenotype reflecting enhanced risk for alcohol-use disorders. Methods: Subjective stimulant and sedative effects were assessed before and during nitrous oxide (N2O; 50%) inhalation in heavy drinkers who were otherwise healthy. Results: Participants with an ostensible family history of alcohol-use disorders (n = 23) were distinguishable from those without such familial risk (n = 37) by an enhanced stimulation-to-sedation ratio during N2O inhalation. Conclusion: The pattern of subjective effects of N2O according to familial risk is remarkably similar to that previously seen with ketamine, supporting the idea of a common, NMDAR-mediated mechanism of action. N2O may prove to be a safe and accessible alternative to ketamine for probing heritable NMDAR dysregulation in neuropsychiatric disorders.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/psicologia , Analgésicos não Entorpecentes/administração & dosagem , Endofenótipos/metabolismo , Óxido Nitroso/administração & dosagem , Adolescente , Adulto , Analgésicos não Entorpecentes/metabolismo , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Fissura/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nitroso/metabolismo , Escalas de Graduação Psiquiátrica , Inquéritos e Questionários , Adulto Jovem
18.
BMC Med Genet ; 17(1): 83, 2016 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-27855642

RESUMO

BACKGROUND: The genetic basis for dilated cardiomyopathy (DCM) can be difficult to determine, particularly in familial cases with complex phenotypes. Next generation sequencing may be useful in the management of such cases. METHODS: We report two large families with pleiotropic inherited cardiomyopathy. In addition to DCM, the phenotypes included atrial and ventricular septal defects, cardiac arrhythmia and sudden death. Probands underwent whole exome sequencing to identify potentially causative variants. RESULTS: Each whole exome sequence yielded over 18,000 variants. We identified distinct mutations affecting a common amino acid in NKX2.5. Segregation analysis of the families support the pathogenic role of these variants. CONCLUSION: Our study emphasizes the utility of next generation sequencing in identifying causative mutations in complex inherited cardiac disease. We also report a novel pathogenic NKX2.5 mutation.


Assuntos
Aminoácidos/genética , Cardiomiopatia Dilatada/genética , Proteína Homeobox Nkx-2.5/genética , Aminoácidos/metabolismo , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/patologia , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Análise Mutacional de DNA , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único
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