Predicting human cardiac QT alterations and pro-arrhythmic effects of compounds with a 3D beating heart-on-chip platform.

Determining the potential cardiotoxicity and pro-arrhythmic effects of drug candidates remains one of the most relevant issues in the drug development pipeline (DDP). New methods enabling to perform more representative preclinical in vitro studies by exploiting induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) are under investigation to increase the translational power of the outcomes. Here we present a pharmacological campaign conducted to evaluate the drug-induced QT alterations and arrhythmic events on uHeart, a 3D miniaturized in vitro model of human myocardium encompassing iPSC-CM and dermal fibroblasts embedded in fibrin. uHeart was mechanically trained resulting in synchronously beating cardiac microtissues in 1 week, characterized by a clear field potential (FP) signal that was recorded by means of an integrated electrical system. A drug screening protocol compliant with the new International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines was established and uHeart was employed for testing the effect of 11 compounds acting on single or multiple cardiac ion channels and well-known to elicit QT prolongation or arrhythmic events in clinics. The alterations of uHeart's electrophysiological parameters such as the beating period, the FP duration, the FP amplitude, and the detection of arrhythmic events prior and after drug administration at incremental doses were effectively analyzed through a custom-developed algorithm. Results demonstrated the ability of uHeart to successfully anticipate clinical outcome and to predict the QT prolongation with a sensitivity of 83.3%, a specificity of 100% and an accuracy of 91.6%. Cardiotoxic concentrations of drugs were notably detected in the range of the clinical highest blood drug concentration (Cmax), qualifying uHeart as a fit-to-purpose preclinical tool for cardiotoxicity studies.

International perspective on integrated care models in child and adult mental health.

The dearth of child and adolescent mental health services (CAMHS) is a global problem. Integrating CAMHS in primary care has been offered as a solution. We sampled integrated care perspectives from colleagues around the world. Our findings include various models of integrated care namely: the stepped care model in Australia; shared care in the United Kingdom (UK) and Spain; school-based collaborative care in Qatar, Singapore and the state of Texas in the US; collaborative care in Canada, Brazil, US, and Uruguay; coordinated care in the US; and, developing collaborative care models in low-resource settings, like Kenya and Micronesia. These findings provide insights into training initiatives necessary to build CAMHS workforce capacity using integrated care models, each with the ultimate goal of improving access to care. Despite variations and progress in implementing integrated care models internationally, common challenges exist: funding within complex healthcare systems, limited training mechanisms, and geopolitical/policy issues. Supportive healthcare policy, robust training initiatives, ongoing quality improvement and measurement of outcomes across programs would provide data-driven support for the expansion of integrated care and ensure its sustainability.

Directed Network Mapping Approach to Rotor Localization in Atrial Fibrillation Simulation.

Catheter ablation for atrial fibrillation (AF) is one of the most commonly performed electrophysiology procedures. Despite significant advances in our understanding of AF mechanisms in the last years, ablation outcomes remain suboptimal for many patients, particularly those with persistent or long-standing AF. A possible reason is that ablation techniques mainly focus on anatomic, rather than patient-specific functional targets for ablation. The identification of such ablation targets remains challenging. The purpose of this study is to investigate a novel approach based on directed networks, which allow the automatic detection of important arrhythmia mechanisms, that can be convenient for guiding the ablation strategy. The networks are generated by processing unipolar electrograms (EGMs) collected by the catheters positioned at the different regions of the atria. Network vertices represent the locations of the recordings and edges are determined using cross-covariance time-delay estimation method. The algorithm identifies rotational activity, spreading from vertex to vertex creating a cycle. This work is a simulation study and it uses a highly detailed computational 3D model of human atria in which sustained rotor activation of the atria was achieved. Virtual electrodes were placed on the endocardial surface, and EGMs were calculated at each of these electrodes. The propagation of the electric wave fronts in the atrial myocardium during AF is very complex, so in order to properly capture wave propagation patterns, we split EGMs into multiple short time frames. Then, a specific network for each of these time frames was generated, and the cycles repeating in consecutive networks point us to the stable rotor's location. The respective atrial voltage map served as reference. By detecting a cycle between the same 3 nodes in 19 out of 58 networks, where 10 of these networks were in consecutive time frames, a stable rotor was successfully located.

Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

Cultivation of freshwater microalgae in biodiesel wash water.

Biodiesel wash water is a contaminating industrial effluent that must be treated prior to disposal. The use of this effluent as a low-cost alternative cultivation medium for microalgae could represent a viable supplementary treatment. We cultivated 11 microalgae species with potential use for biodiesel production to assess their growth capacities in biodiesel industrial washing waters. Only Monoraphidium contortum, Ankistrodesmus sp., Chlorococcum sp., and one unidentified Chlorophyceae species grew effectively in that effluent. M. contortum showed the highest growth capacity and had the second highest fatty acid content (267.9 mg g-1 of DW), predominantly producing palmitic (20.9%), 7,10,13-hexadecatrienoic (14%), oleic (16.2%), linoleic (10.5%), and linolenic acids (23.2%). In the second phase of the experiment, the microalgae were cultivated in biodiesel wash water at 75% of its initial concentration as well as in WC (control) medium. After 21 days of cultivation, 25.8 and 7.2% of the effluent nitrate and phosphate were removed, respectively, and the chemical oxygen demand was diminished by 31.2%. These results suggest the possibility of cultivating biodiesel producing microalgae in industrial wash water effluents.

Injuries caused by venomous animals and folk medicine in farmers from Cuite, State of Paraiba, Northeast of Brazil / Relatos de acidentes por animais peconhentos e medicina popular em agricultores de Cuite, regiao do Curimatau, Paraiba, Brasil

Injuries caused by venomous animals reported by the agricultural workers from the municipality of Cuité, Curimataú region of Paraiba State, Northeast of Brazil, and the practices of folk medicine which they use to treat these cases were studied in this work from June to August 2010. The farmers studied aged from 11 to 90 years. The number of people who reported cases of injury by these animals in their families was high (89.3%). Scorpions, wasps, bees and snakes were the most cited and the extremities of the body (hands, feet, legs and head) were the most affected. The practice of folk medicine to treat these injuries includes various procedures ranging from ritualistic treatments, use of animals or parts of them, and some herbal preparations. The folk treatment was reported as effective by most of the workers injured (63.9%). Body parts of dead snakes are used in various zootherapic treatments. In the imaginary of the agricultural workers the venomous animals are considered hazardous (48.7%) or disgusting (11.3%), and several parts of such animals as the rattle, bee sting or snake leather are used as amulet. Several legends have also been reported about snakes, scorpions and bees. The need for educational activities that aim to clarify these workers about the dangers of such practices is urgent.

Acidentes por animais peçonhentos ocorridos com agricultores sindicalizados do município de Cuité, região do Curimataú paraibano, e práticas de medicina popular por eles utilizadas foram estudadas neste trabalho, através de entrevistas livres e questionários semiestruturados durante o período de junho a agosto de 2010. A idade dos agricultores pesquisados variou de 11 a 90 anos e a incidência de pessoas que sofreram algum acidente com esses animais chegou a 89,3%. Escorpiões, marimbondos, abelhas e serpentes foram os animais mais citados. As extremidades do corpo (mãos, pés, pernas e cabeça) foram as regiões mais atingidas. A prática da medicina popular para tratar desses acidentes inclui vários procedimentos que vão desde tratamentos ritualísticos, uso de animais ou partes dele, até preparos fitoterápicos. O tratamento caseiro é reconhecido como sendo eficaz pela maioria dos que sofreram acidentes (63,9%). Serpentes mortas têm várias partes do corpo arrancadas e usadas em tratamentos zooterápicos diversos. No imaginário dos agricultores, os animais peçonhentos são vistos como perigosos (48,7%) ou nojentos (11,3%), e diversas partes desses animais como chocalho, ferrão da abelha ou couro da cobra são usadas como amuletos de sorte. Inúmeras lendas também foram relatadas com cobras, escorpiões e abelhas. A necessidade de atividades educacionais visando esclarecer esses trabalhadores sobre os perigos dessas práticas é urgente.

Injuries caused by venomous animals and folk medicine in farmers from Cuité, State of Paraiba, Northeast of Brazil.

Injuries caused by venomous animals reported by the agricultural workers from the municipality of Cuité, Curimataú region of Paraiba State, Northeast of Brazil, and the practices of folk medicine which they use to treat these cases were studied in this work from June to August 2010. The farmers studied aged from 11 to 90 years. The number of people who reported cases of injury by these animals in their families was high (89.3%). Scorpions, wasps, bees and snakes were the most cited and the extremities of the body (hands, feet, legs and head) were the most affected. The practice of folk medicine to treat these injuries includes various procedures ranging from ritualistic treatments, use of animals or parts of them, and some herbal preparations. The folk treatment was reported as effective by most of the workers injured (63.9%). Body parts of dead snakes are used in various zootherapic treatments. In the imaginary of the agricultural workers the venomous animals are considered hazardous (48.7%) or disgusting (11.3%), and several parts of such animals as the rattle, bee sting or snake leather are used as amulet. Several legends have also been reported about snakes, scorpions and bees. The need for educational activities that aim to clarify these workers about the dangers of such practices is urgent.

MRI study of thalamus volumes in juvenile patients with bipolar disorder.

In vivo imaging studies suggest functional abnormalities of the thalamus in adult patients with bipolar disorder, but the presence of anatomical abnormalities is controversial. Our objective in this study was to compare the thalamus volumes of children and adolescents with bipolar disorder versus healthy controls to determine whether any morphological abnormalities exist early in illness course. We studied 16 patients with bipolar disorder according to DSM-IV criteria (mean age+/-SD=15.5+/-3.4 years) and 21 healthy control subjects (mean age+/-SD=16.9+/-3.8 years). Blinded examiners measured thalamic gray matter volumes with a semiautomated technique. Analysis of covariance, with age, gender, and intracranial brain volume as covariates, revealed no significant differences in left and right thalamic volumes between patients with bipolar disorder and healthy controls. Our findings indicate there are no significant differences in thalamus size between children and adolescents with bipolar disorder and healthy comparison subjects, in contrast to available findings for schizophrenia and first-break psychosis. Any differences in thalamus size that may exist between patients with bipolar disorder and healthy controls must amount to small effect sizes.