Effects of environmental enrichment upon ethanol-induced conditioned place preference and pre-frontal BDNF levels in adolescent and adult mice

Environmental enrichment (EE) provides a non-pharmacological tool to alter drug-induced reward, yet its effects on ethanol-induced reward remain controversial. We analyzed adolescent vs. adult (mice) differences in the influence of EE on ethanol-induced conditioned place preference (CPP). The effects of these treatments on brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex were examined in a separate group of animals. Ethanol-induced CPP was found in adults, and it was similar in EE and in animals reared under standard housing conditions (SC). Adolescents kept under EE, but not those in SC, exhibited CPP. Among SC, but not among EE, adolescents, BDNF levels were significantly lower in those treated with ethanol than in those given vehicle. These results indicate that, compared to adults, adolescent exhibited reduced sensitivity to ethanol's rewarding effects, yet the youth but not the adults exhibited sensitivity to the promoting effect of EE upon CPP by ethanol. Ethanol significantly reduced BDNF levels in adolescents reared under standard housing conditions, but not in adult mice nor in adolescents given EE housing conditions. The present results add to the plethora of adolescent-specific responses to ethanol or to environmental stimuli that may put the youth at risk for escalation of ethanol intake.Fil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; ArgentinaFil: Suarez, Andrea Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Hoffmann, Lucas Barbosa. Universidade de Sao Paulo; BrasilFil: Rueda, André Veloso. Universidade de Sao Paulo; BrasilFil: Rae, Mariana. Universidade de Sao Paulo; BrasilFil: Marianno, Priscila. Universidade de Sao Paulo; BrasilFil: Camarini, Rosana. Universidade de Sao Paulo; Brasi

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Avaliação dos efeitos da exposição ambiental paterna no fenótipo da prole de camundongos Swiss.

É crescente o interesse nos efeitos que o ambiente parental exerce sobre o fenótipo da prole, a chamada herança epigenética. Tem sido mostrado que essa herança ocorre especialmente para efeitos de plasticidade do desenvolvimento, os quais derivam de alteração ambiental durante o desenvolvimento parental. Dentre os estudados realizados em camundongos, várias estratégias ambientais foram abordadas, como o estresse durante a infância e o enriquecimento ambiental, com a avaliação da prole em relação a parâmetros comportamentais, fisiológicos e moleculares. De modo a estudar o fenômeno, o presente trabalho investigou, em camundongos Swiss machos, os efeitos de um estresse durante a infância, a Privação Materna em PND 9, com avaliação de comportamentos exploratório (Campo Aberto), do tipo ansioso (Labirinto em Cruz Elevado), depressivo (Nado Forçado) e relacionados ao álcool (Condicionamento Condicionado por Lugar e Sensibilização Comportamental), e, numa outra abordagem, do Enriquecimento Ambiental do desmame (PND 21) à idade adulta (PND 70), com avaliação de parâmetros fisiológicos diversos (peso corporal, de depósito de gordura, de baço e glândulas adrenais) e comportamentos exploratório (Campo Aberto), memória espacial (Labirinto de Barnes), dominância social (Tubo de Dominância Social), atratividade (Teste de Escolha de Parceiro), além de avaliação de corticosterona plasmática e BDNF hipocampal. A privação materna não promoveu diferenças para os parâmetros comportamentais avaliados. Optou-se pela utilização do paradigma do Enriquecimento Ambiental para investigação dos efeitos sobre o fenótipo da prole (machos e fêmeas). Foram observados nos filhotes machos resultados comportamentais opostos aos apresentados pela geração paterna. Porém, quando os filhos foram expostos a um período breve de enriquecimento durante a idade adulta, essas diferenças não foram mais encontradas. Portanto, conclui-se que o enriquecimento ambiental paterno foi capaz de gerar efeitos na prole, tornando os filhotes machos menos adaptados ao ambiente não enriquecido.There is a growing interest in the effects of the parental environment on the offspring phenotype, the so-called epigenetic inheritance. It has been shown that this inheritance occurs especially for developmental plasticity effects, which stem from environmental changes during parental development. Studies carried out in mice have adopted several environmental strategies, such as early life stress and environmental enrichment, and the offspring have been assessed for behavioural, physiological and molecular parameters. In order to study the phenomenon, the present work investigated, in Swiss male mice, the effects of an early-life stress protocol, the Maternal Deprivation on PND 9, assessing behaviours such as exploratory (Open Field), anxiety-like (Elevated-Plus Maze), depressive-like (Forced Swim) and alcohol-related behaviours (Conditioned Place Preference and Behavioural Sensitisation) and, through a different approach, the environmental enrichment, from weaning (PND 21) to adulthood (PND 70), assessing diverse physiological parameters (body weight, fat pad weight, spleen and adrenal glands weights) and behaviours such as exploratory (Open Field), spatial memory (Barnes Maze), social dominance (Social Dominance Tube Test), attractiveness (Mate Choice Teste) as well as plasmatic corticosterone and hippocampal BDNF. The maternal deprivation did not yield any differences in the behavioural parameters assessed. The Environmental Enrichment paradigm was adopted for studying its effects on the offspring phenotype (males and females). Behavioural results were observed in the male offspring, which were the opposite of those found in the paternal generation. However, when the male offspring was exposed to a brief period of enrichment during adulthood, these differences were no longer found. Therefore, paternal environmental enrichment was able to induce effects on the offspring, turning male offspring less adapted to the non-enriched environment

Cocaine-induced behavioral sensitization is greater in adolescent than in adult mice and heightens cocaine-induced conditioned place preference in adolescents

Adolescents are more sensitive than adults to the neural and behavioral effects of psychostimulants, and exhibit greater vulnerability to drug abuse, dependence or relapse into these conditions. We have reported that cocaine pretreatment during adolescence promotes the expression of behavioral sensitization to a greater extent than when the pretreatment occurs at adulthood. Behavioral sensitization has been associated to the transition from drug use to addiction and is postulated to indicate heightened sensitivity to the appetitive motivational effects of drugs. The relationship between behavioral sensitization and conventional measures of drug reward, such as conditioned place preference (CPP), has yet to be thoroughly investigated, and little is known about age-related differences in this phenomenon. The present study tested cocaine-induced CPP in adolescent and adult mice exposed to cocaine (or vehicle) pretreatment, either in an intermittent or “binge” (i.e., heavy cocaine use on a single occasion, which increases the likelihood of experiencing cocaine-related problems) fashion. Cocaine administration induced behavioral sensitization to a greater extent in adolescent than in adult mice. Cocaine-induced CPP was fairly similar in vehicle pretreated adolescent and adult mice, yet greater in adolescent vs. adults after cocaine-induced sensitization. The results confirmed the higher sensitivity of adolescent mice to cocaine-induced behavioral sensitization and suggest its association with greater sensitivity to cocaine's rewarding effects.Fil: Camarini, Rosana. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Hoffmann, Lucas Barbosa. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Suarez, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Rae, Mariana. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Marcourakis, Tania. Universidade do Sao Paulo. Instituto de Ciencias Biomedicas; BrasilFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee

Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin