Dopamine release during psychological stress in euthymic bipolar I disorder: a Positron Emission Tomography study with [11C]raclopride.

BACKGROUND: Neurochemical mechanisms underlying stress induced relapse of mood episodes in Bipolar I Disorder (BD) remain unknown. This study investigated whether euthymic BD patients have a greater dopamine release in ventral striatum, caudate and putamen in response to psychological stress using Positron Emission Tomography (PET) scanning with the radiotracer [11C]raclopride. METHODS: Euthymic patients with BD (n = 10) and 10 matched healthy controls underwent two [11C]raclopride PET scans, one during a "stress" and the other in a "no stress" condition separated by at least 24 h. Montreal Imaging Stress Test (MIST) was used to induce stress during stress condition. Participants received an injection of [11C]raclopride over one minute followed by PET scan for 60 min. Participants were assessed for mood symptom severity at baseline, and before and after each scan. The reduction in [11C]raclopride binding in stress condition compared with non-stress rest condition for each subject provided an estimate of dopamine release due to stress. RESULTS: There was a significant effect of stress in reducing the [11C]raclopride binding in the ventral striatum, caudate and putamen; however, no significant effects of group or condition x group interaction were found. LIMITATIONS: Small sample size and recruitment of euthymic patients who may be less vulnerable to stress may limit the generalizability of findings. CONCLUSIONS: Our findings showed that psychological stress led to dopamine release in the basal ganglia for all participants but the magnitude of dopamine release during a stress task was not different between euthymic BD patients and healthy controls.

A semantic trajectory data warehouse for improving nursing productivity.

A Trajectory Data Warehouse is a central repository of large amount of data focusing on moving objects, which have been collected and integrated from multiple sources with spatial and temporal dimensions as the main metrics of analysis. By adding semantic-related contextual information, it is converted to a Semantic Trajectory Data Warehouse. It transforms raw trajectories to valuable information that can be utilized for decision-making purposes in ubiquitous applications. Human recourses management is a domain that may benefit significantly from semantic trajectory data warehouses. In particular, employees working shifts can be considered as trajectories. In this work, standard data warehousing tools are used to store data about nursing personnel shifts as trajectories of moving persons. The conceptual and logical modelling of the semantic trajectory data warehouse is developed. The objective is the observation, management and scheduling of nurses' shifts data by the computation of OLAP operations over them. A prototype implementation has also been realized to illustrate the functionality of the proposed model. The produced results prove the efficiency in improving nursing productivity.

Machine learning approaches to drug response prediction: challenges and recent progress.

Cancer is a leading cause of death worldwide. Identifying the best treatment using computational models to personalize drug response prediction holds great promise to improve patient's chances of successful recovery. Unfortunately, the computational task of predicting drug response is very challenging, partially due to the limitations of the available data and partially due to algorithmic shortcomings. The recent advances in deep learning may open a new chapter in the search for computational drug response prediction models and ultimately result in more accurate tools for therapy response. This review provides an overview of the computational challenges and advances in drug response prediction, and focuses on comparing the machine learning techniques to be of utmost practical use for clinicians and machine learning non-experts. The incorporation of new data modalities such as single-cell profiling, along with techniques that rapidly find effective drug combinations will likely be instrumental in improving cancer care.

Serum melatonin in dogs with congenital portosystemic shunting, with and without hepatic encephalopathy.

BACKGROUND: Melatonin is a hormone produced and secreted primarily by the pineal gland and mainly metabolised in the liver. Increased melatonin concentrations have been reported in human cirrhosis and hepatic encephalopathy (HE), a syndrome of neurological dysfunction. The pathogenesis of canine HE is incompletely understood. Melatonin has been hypothesised as a contributor to the development of HE. The aim of this study was to investigate whether serum melatonin concentrations are increased in canine congenital portosystemic shunting (cPSS), with and without HE. METHODS: Medical records were retrospectively reviewed, for which archived (-80°C) serum samples were available. A canine competitive ELISA was used to measure melatonin in two cohorts: dogs with a final diagnosis of cPSS (n=23) with and without clinical signs of HE, and healthy dogs (n=15). RESULTS: Melatonin concentrations were not significantly different (P=0.81) between healthy controls (median 27.2 pg/mL, range 19.8-161.5 pg/mL) and dogs with cPSS (median 25.7 pg/mL, range 18.5-244.9 pg/mL). Serum melatonin did not differ between cPSS patients with and without clinical signs of HE (P>0.99). No correlation was found between serum melatonin and blood ammonia (Spearman rank correlation coefficient, rs =-0.41, P=0.08). CONCLUSION: Serum melatonin is not increased in canine cPSS with and without HE. We found no evidence that altered melatonin metabolism plays a role in the pathogenesis of cPSS-associated HE.

Lactulose drives a reversible reduction and qualitative modulation of the faecal microbiota diversity in healthy dogs.

Hepatic encephalopathy is a frequent and debilitating complication of liver disorders. Lactulose is an established and reasonably effective treatment, yet with incompletely understood mechanisms of action. The aims of this study were to examine how the faecal microbiota composition changed before, during and after lactulose treatment in a large animal model. Healthy, privately owned dogs (n = 18) completed a prospective cohort study. Faecal samples were collected weekly, while the subjects were either on their usual diet (week 1), or a standardised diet (weeks 2-9), with added oral lactulose in weeks 6-7. DNA extraction and 16S rRNA gene sequencing were undertaken. Faecal samples from week 7 had a significantly lower microbiota richness/diversity, based on observed operational taxonomic units, Shannon/Chao1 indexes and Pielou's Evenness. Beta diversity based on UniFrac distances was significantly different in week 7 compared to weeks 1, 5 and 9. At the phylum level, week 7 was associated with a significant increase of Firmicutes and Actinobacteria, and a decrease of Bacteroidetes and Fusobacteria, when compared to weeks 5 and 9. In summary, we have shown that lactulose induces a reversible qualitative and quantitative change of the faecal microbiota, which may explain its clinical efficacy in the management of hepatic encephalopathy.

PharmacoDB: an integrative database for mining in vitro anticancer drug screening studies.

Recent cancer pharmacogenomic studies profiled large panels of cell lines against hundreds of approved drugs and experimental chemical compounds. The overarching goal of these screens is to measure sensitivity of cell lines to chemical perturbations, correlate these measures to genomic features, and thereby develop novel predictors of drug response. However, leveraging these valuable data is challenging due to the lack of standards for annotating cell lines and chemical compounds, and quantifying drug response. Moreover, it has been recently shown that the complexity and complementarity of the experimental protocols used in the field result in high levels of technical and biological variation in the in vitro pharmacological profiles. There is therefore a need for new tools to facilitate rigorous comparison and integrative analysis of large-scale drug screening datasets. To address this issue, we have developed PharmacoDB (pharmacodb.pmgenomics.ca), a database integrating the largest cancer pharmacogenomic studies published to date. Here, we describe how the curation of cell line and chemical compound identifiers maximizes the overlap between datasets and how users can leverage such data to compare and extract robust drug phenotypes. PharmacoDB provides a unique resource to mine a compendium of curated cancer pharmacogenomic datasets that are otherwise disparate and difficult to integrate.

Urine dipstick precision with standard visual and automated methods within a small animal teaching hospital.

Urine dipstick results may vary between operators/methods. The magnitude of variation across the veterinary field is currently unknown. The aim of this study was to compare the precision of urine dipstick results between standard direct visual and automated reading methods when performed by several operators. Urine samples were pooled and divided into three aliquots: one plain, one with glucose and one with serum. Final year students, veterinary surgeons and veterinary nurses, blinded to each sample, were then asked to perform dipstick analysis with direct visualisation and an automated analyser, and their technique was observed. A subsequent session was undertaken with samples which had pH titrated to achieve an acidic, neutral or alkaline value. Sixty-four veterinary students, 20 veterinary surgeons and seven veterinary nurses performed the first (n=61) or second (n=30) part of the study. Precision was greater using the automated reader. The most common observed technique errors were: lack of sample mixing, for both visual and automated methods, and not timing readings as per manufacturer instructions when performing visual analysis. This study suggests that in an environment with multiple operators, as is the case in veterinary teaching or large private hospitals, automated urine dipstick reading improves precision of results.

CrosstalkNet: A Visualization Tool for Differential Co-expression Networks and Communities.

Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. As a case study, we used CrosstalkNet to mine a set of 54 and 22 gene-expression profiles from breast tumor and normal samples, respectively, with epithelial and stromal compartments extracted via laser microdissection. We show how CrosstalkNet can be used to explore large-scale co-expression networks and to obtain insights into the biological processes that govern cross-talk between different tumor compartments.Significance: This web application enables researchers to mine complex networks and to decipher novel biological processes in tumor epithelial-stroma cross-talk as well as in other studies of intercompartmental interactions. Cancer Res; 78(8); 2140-3. ©2018 AACR.

Investigation of manganese homeostasis in dogs with anaemia and chronic enteropathy.

Lethargy is a frequent and important clinical feature of anaemia; however, it does not absolutely correlate with the severity of anaemia. Manganese is efficiently absorbed through the gastrointestinal tract via divalent metal transporter 1 (DMT1), which is also responsible for iron transport. DMT1 is upregulated in iron deficiency (ID). Increased manganese concentrations are reported in ID anaemia (IDA) in various species. Manganese is neurotoxic and therefore may contribute to lethargy observed in some anaemic patients. In addition, anaemia and ID are common in human inflammatory bowel disease. Little is known about how anaemia influences manganese metabolism in veterinary patients and how common is anaemia in dogs with chronic enteropathy (CE). If elevated manganese concentrations are found, then potentially neurotoxicity may be contributing to morbidity in these cases. The objectives of this study were to investigate the hypothesis that whole blood manganese concentrations would be increased in dogs with anaemia, particularly in dogs with confirmed IDA, and that anaemia would be common in canine CE. Medical records from 2012-2016 were reviewed for dogs with CE that were anaemic, as well as dogs with confirmed IDA, where a sample suitable for manganese analysis was held in an archive. Manganese concentration was measured in whole blood from: 11 anaemic dogs with CE, 6 dogs with IDA, 9 non-anaemic ill controls, and 12 healthy controls. Mann-Whitney U and Kruskal-Wallis tests with post-test Dunn's multiple comparisons tests were performed, with P<0.05 considered significant. The prevalence of anaemia in canine CE was 20.6% (33/160). Manganese concentrations were significantly different between all groups (P=0.0001) and higher in non-anaemic than anaemic dogs (P=0.0078). Manganese concentrations were also higher in healthy compared to ill controls (P<0.0001), anaemic dogs with CE (P=0.0056) and to dogs with IDA (P=0.0001). No differences were observed between anaemic dogs with CE, IDA and ill controls. Although anaemia was frequently observed in canine CE, the hypothesis that dogs with anaemia would have increased manganese concentrations, possibly contributing to a lethargic state was not supported. Further research is warranted to understand the influence of anaemia on whole blood manganese.