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Identification and delineation of brain regions in histologic mouse brain sections is especially pivotal for many neurogenomics, transcriptomics, proteomics, and connectomics studies, yet this process is prone to observer error and bias. Here we present a novel brain navigation system, named NeuroInfo, whose general principle is similar to that of a global positioning system (GPS) in a car. NeuroInfo automatically navigates an investigator through the complex microscopic anatomy of histologic sections of mouse brains (thereafter: "experimental mouse brain sections"). This is achieved by automatically registering a digital image of an experimental mouse brain section with a three-dimensional (3D) digital mouse brain atlas that is essentially based on the third version of the Allen Mouse Brain Common Coordinate Framework (CCF v3), retrieving graphical region delineations and annotations from the 3D digital mouse brain atlas, and superimposing this information onto the digital image of the experimental mouse brain section on a computer screen. By doing so, NeuroInfo helps in solving the long-standing problem faced by researchers investigating experimental mouse brain sections under a light microscope-that of correctly identifying the distinct brain regions contained within the experimental mouse brain sections. Specifically, NeuroInfo provides an intuitive, readily-available computer microscopy tool to enhance researchers' ability to correctly identify specific brain regions in experimental mouse brain sections. Extensive validation studies of NeuroInfo demonstrated that this novel technology performs remarkably well in accurately delineating regions that are large and/or located in the dorsal parts of mouse brains, independent on whether the sections were imaged with fluorescence or bright-field microscopy. This novel navigation system provides a highly efficient way for registering a digital image of an experimental mouse brain section with the 3D digital mouse brain atlas in a minute and accurate delineation of the image in real-time., (© 2019 Wiley Periodicals, Inc.)

Advances in molecular neuroanatomical tools have expanded the ability to map in detail connections of specific neuron subtypes in the context of behaviorally driven patterns of neuronal activity. Analysis of such data across the whole mouse brain, registered to a reference atlas, aids in understanding the functional organization of brain circuits related to behavior. A process is described to image mouse brain sections labeled with standard histochemical techniques, reconstruct those images into a whole brain image volume and register those images to the Allen Mouse Brain Common Coordinate Framework. Image analysis tools automate detection of cell bodies and quantification of axon density labeling in the structures in the annotated reference atlas. Examples of analysis are provided for mapping the axonal projections of layer-specific cortical neurons using Cre-dependent AAV vectors and for mapping inputs to such neurons using retrograde transsynaptic tracing with modified rabies viral vectors., (© 2018 Wiley Periodicals, Inc.)

Background: English national prospective, observational cohort study of patients continuously enrolled for five years in opioid substitution treatment (OST) with oral methadone and sublingual buprenorphine. This is a secondary outcome analysis of change in use of alcohol and other drug use (AOD) following identification of heroin use trajectories during OST., Methods: All adults admitted to community OST in 2008/09 and enrolled to 2013/14 (n = 7717). Data from 11 sequential, six-monthly clinical reviews were used to identify heroin and AOD use trajectories by multi-level Latent Class Growth Analysis. OST outcome in the sixth and seventh year was 'successful completion and no re-presentation' (SCNR) to structured treatment and was assessed using multi-level logistic regression., Results: With 'rapid decreasing' heroin use trajectory as referent, 'continued high-level' heroin use predicted 'continued high-level' crack cocaine use (relative risk ratio [RRR] 58.7; 95% confidence interval [CI] 34.2-100.5),'continued high-level' alcohol use (RRR 1.2; 95% CI 1.0-1.5), 'increasing' unspecified drug use (RRR 1.7; 95% CI 1.4-2.1) and less 'high and increasing' cannabis use (RRR 0.5; 95% CI 0.4-0.6). 'Increasing' crack use was negatively associated with SCNR outcome for the 'decreasing then increasing' and 'gradual decreasing' heroin use groups (adjusted odds ratio [AOR] 0.5; 95% CI 0.3-0.9 and AOR 0.2; 95% CI 0.1-0.7, respectively)., Conclusions: Continued high-level heroin use non-response during long-term OST is associated with high-level crack cocaine and alcohol use, increasing unspecified drug use, but less high and increasing cannabis use. Increasing use of crack cocaine is negatively associated with the likelihood that long-term OST is completed successfully., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Background: This is the first national study in England of continuous long-term opioid substitution treatment (OST)., Methods: All adults were admitted to community OST for opioid use disorder (OUD) in 2008/09 with continuous enrolment to 2013/14 (n = 7719). Heroin use trajectories were identified by multilevel Latent Class Growth Analysis. In Year 6 and 7 of follow-up, the outcome measure (analysed by multilevel, multivariable logistic regression) was 'successful completion and no re-presentation' (SCNR) to community treatment within six months., Results: Five heroin use trajectory classes were identified: 'gradual decreasing' (20.9%), 'decreasing then increasing' (21.7%), 'continued low-level' (17.0%), 'rapid decreasing' (25.6%), and 'continued high-level' (14.8%). At the end of Year 7, 4616 people (60.3%) remained in OST. Of those discharged, 28.8% achieved the SCNR follow-up outcome. SCNR was more likely in the 'gradual decreasing' (adjusted odds ratio [AOR] 2.40; 95% confidence interval [CI] 1.77-3.26), 'continued low-level' (AOR 2.46; CI 1.78-3.40), and 'rapid decreasing' (AOR 3.40; CI 2.43-4.37) classes relative to the 'continued high-level' class. SCNR was more likely among patients employed at admission (AOR 1.45; 95% CI 1.15-1.83) and those receiving adjunctive psychosocial interventions (AOR 1.44; 95% CI 1.03 to 2.02)., Conclusions: Among English patients in OST for 5 years, heroin use trajectories were clearly delineated with a gradient of response on the study outcome. Successful completion and no re-presentation was achieved by 28.8% of discharged patients. The rapid decreasing trajectory had the greatest likelihood of positive outcome. Adjunctive psychosocial intervention during OST was associated with positive outcome., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Background: This was a national English observational cohort study using administrative data to estimate the effectiveness of community pharmacological and psychosocial treatment for alcohol use disorder (AUD)., Methods: All adults commencing AUD treatment in the community reported to the National Drug Treatment Monitoring System (April 1 2014-March 31 2015; N = 52,499). Past 28-day admission drinking pattern included drinks per drinking day (DDD): 0 ('Abstinent'), 1-15 ('Low-High'), 16-30 ('High-Extreme') and over 30 DDD ('Extreme'). The primary outcome was successful completion of treatment within 12 months of commencement with no re-presentation (SCNR) in the subsequent six months, analysed by multi-level, mixed effects, multivariable logistic regression., Results: The majority reported DDD in the 'Low-High' (n = 17,698, 34%) and 'High-Extreme' (n = 21,383, 41%) range. Smaller proportions were categorised 'Extreme' (n = 7759, 15%) and 'Abstinent' (n = 5661, 11%). Three-fifths (58%) achieved SCNR. Predictors of SCNR were older age, black/minority ethnic group, employment, criminal justice system referral, and longer treatment exposure. Predictors of negative outcome were AUD treatment history, lower socio-economic status, housing problems, and 'Extreme' drinking at admission. In addition to psychosocial interventions, pharmacological interventions and recovery support increased the likelihood of SCNR. Pharmacological treatment was only beneficial for the 'Low-High' groups with recovery support., Conclusions: Over half of all patients admitted for community AUD treatment in England are reported to successfully complete treatment within 12 months and are not re-admitted for further treatment in the following 6 months. Study findings underscore efforts to tailor AUD treatment to the severity of alcohol consumption and using recovery support., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This was a national English observational cohort study to estimate the effectiveness of inpatient withdrawal (IW) and residential rehabilitation (RR) interventions for alcohol use disorder (AUD) using administrative data., Methods: All adults commencing IW and/or RR intervention for AUD between April 1, 2014 and March 31, 2015 reported to the National Drug Treatment Monitoring System (n=3812). The primary outcome was successful completion of treatment within 12months of commencement, with no re-presentation (SCNR) in the subsequent six months, analysed by multi-level, mixed effects, multivariable logistic regression., Results: The majority (70%, n=2682) received IW in their index treatment journey; one-quarter (24%, n=915) received RR; 6% (n=215) received both. Of treatment leavers, 59% achieved the SCNR outcome (IW: 57%; RR: 64%; IW/RR: 57%). Positive outcome for IW was associated with older age, being employed, and receiving community-based treatment prior to and subsequent to IW. Patients with housing problems were less likely to achieving the outcome. Positive outcome for RR was associated with paid employment, self/family/peer referral, longer duration of RR treatment, and community-based treatment following discharge. Community-based treatment prior to entering RR, and receiving IW during the same treatment journey as RR, were associated with lower likelihood of SCNR., Conclusions: In this first national effectiveness study of AUD in the English public treatment system for alcohol-use disorders, 59% of patients successfully completed treatment within 12months and did not represent for more treatment within six months. Longer duration of treatment and provision of structured continuing care is associated with better treatment outcomes., (Copyright © 2018. Published by Elsevier Inc.)

Background: Cocaine use disorder (CUD) is a debilitating condition with no NICE-recommended medication or specific psychosocial interventions. In the United Kingdom (UK), general counselling (treatment-as-usual; TAU) is widely delivered, but has limited effectiveness. We tested the feasibility, safety and preliminary efficacy of a novel, adjunctive psychosocial intervention for CUD, called 'memory-focused cognitive therapy' (MFCT)., Methods: We did a two-arm, external pilot randomised controlled trial at a specialist community National Health Service addictions clinic in London, UK. 30 adults (≥18years), voluntarily seeking treatment for CUD (enrolled ≥14days; all with moderate-to-severe DSM5 CUD), were individually randomised (1:1) to a control group (ongoing TAU; 3×90min CUD cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; and 3×30min research follow-ups); or to an intervention group (ongoing TAU; 3×90min cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; 5×120min, one-to-one, MFCT sessions [in 1week]; and 3×60min research follow-ups and MFCT-relapse prevention). The primary outcome was the total percentage score on the frequency version of the Craving Experiences Questionnaire (CEQ-F) at 1-month follow-up after the intensive intervention week (clinical endpoint; recall period past 2weeks; higher score indicating greater craving). Secondary outcomes at the 1-month follow-up were percentage days abstinent (PDA) from cocaine, and longest period (days) of continuous abstinence (LPA) in the prior 28days. Outcomes were analysed as an unadjusted group mean difference (with Hedge's g effect size [ES]) and a 95% Confidence Interval [CI] for the primary outcome and a 90% CI for the secondary outcomes. Exploratory, multivariable linear (primary outcome) and Poisson regression models (secondary outcomes), with sex, age, months of regular cocaine use, baseline outcome score, and group estimated the effectiveness of the intervention. The trial is registered with the ISCRTN (ISRCTN16462783)., Findings: Between July 15, 2015, and November 27, 2016, 58 patients were assessed for eligibility and 30 participants were randomised (14 to the control group and 16 to the intervention). With outcome data collected for all participants at the endpoint, the intervention group mean CEQ-F score (14·77; SD 21·47) was lower than the control group mean (51·75; SD 22·72); ES -1·62; 95% CI -2·45 to -0·80. MFCT was associated with more cocaine abstinence in the intervention group (PDA 85·94; SD 18·96) than the control group (PDA 54·59; SD 30·29); ES 1·19; 90% CI 0·54 to 1·84. There was also greater maximum abstinence in the intervention group (LPA 15·69; SD 10·10) than the control group (6·00; SD 7·36); ES 1·06; 90% CI 0·41 to 1·70. Exploratory, confounder-adjusted regression models for this preliminary effect supported the treatment association for reduced craving experiences (CEQ-F Coef. -28·25; 95% CI -45·15 to -11·35); more abstinence (PDA Incidence Rate Ratio [IRR] 1·56; 95% CI 1·31 to 1·88); and greater maximum abstinence (LPA IRR 2·56; 95% CI 1·96 to 3·35), although relative weak unmeasured confounding could overturn these model-adjusted exposure-outcome associations. There were four serious adverse events (among three participants). None were judged related to study procedures or interventions., Interpretation: In this first external pilot randomised controlled trial of MFCT for CUD, we have shown that the intervention and control procedures and acceptable feasible and safe, and report preliminary evidence that MFCT is associated with reduced craving and increased abstinence. These findings support progression to a substantive trial., Funding Source: UK National Institute for Health Research, Biomedical Research Centre., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Skeletal muscle wasting occurs in a great majority of cancer patients with advanced disease and is associated with a poor prognosis and decreased survival. Myostatin functions as a negative regulator of skeletal muscle mass and has recently become a therapeutic target for reducing the loss of skeletal muscle and strength associated with clinical myopathies. We generated neutralizing antibodies to myostatin to test their potential use as therapeutic agents to attenuate the skeletal muscle wasting due to cancer. We show that our neutralizing antimyostatin antibodies significantly increase body weight, skeletal muscle mass, and strength in non-tumor-bearing mice with a concomitant increase in mean myofiber area. The administration of these neutralizing antibodies in two preclinical models of cancer-induced muscle wasting (C26 colon adenocarcinoma and PC3 prostate carcinoma) resulted in a significant attenuation of the loss of muscle mass and strength with no effect on tumor growth. We also show that the skeletal muscle mass- and strength-preserving effect of the antibodies is not affected by the coadministration of gemcitabine, a common chemotherapeutic agent, in both non-tumor-bearing mice and mice bearing C26 tumors. In addition, we show that myostatin neutralization with these antibodies results in the preservation of skeletal muscle mass following reduced caloric intake, a common comorbidity associated with advanced cancer. Our findings support the use of neutralizing antimyostatin antibodies as potential therapeutics for cancer-induced muscle wasting., (©2015 American Association for Cancer Research.)

This paper investigates the problem of image alignment for multiple camera high dynamic range (HDR) imaging. HDR imaging combines information from images taken with different exposure settings. Combining information from multiple cameras requires an alignment process that is robust to the intensity differences in the images. HDR applications that use a limited number of component images require an alignment technique that is robust to large exposure differences. We evaluate the suitability for HDR alignment of three exposure-robust techniques. We conclude that image alignment based on matching feature descriptors extracted from radiant power images from calibrated cameras yields the most accurate and robust solution. We demonstrate the use of this alignment technique in a high dynamic range video microscope that enables live specimen imaging with a greater level of detail than can be captured with a single camera.

An analog of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series (LY255582) exhibits high in vitro binding affinity and antagonist potency for the mu-, delta-, and kappa-opioid receptors. In vivo, LY255582 exhibits potent effects in reducing food intake and body weight in several rodent models of obesity. In the present study, we evaluated the effects of LY255582 to prevent the consumption of a highly palatable (HP) diet (a high-fat/high-carbohydrate diet) both when the food was novel and following daily limited access to the HP diet. Additionally, we examined the effects of consumption of the HP diet and of LY255582 treatment on mesolimbic dopamine (DA) signaling by in vivo microdialysis. Consumption of the HP diet increased extracellular DA levels within the nucleus accumbens (NAc) shell. Increased DA in the NAc shell was not related to the quantity of the HP diet consumed, and the DA response did not habituate following daily scheduled access to the HP diet. Interestingly, treatment with LY255582 inhibited consumption of the HP diet and the HP diet-associated increase in NAc shell DA levels. Moreover, the increased HP diet consumption observed following daily limited access to the HP diet was completely prevented by LY255582 treatment. LY255582 may be a useful tool in understanding the neural mechanisms involved in the reinforcement mechanisms regulating food intake.

Agonists to opioid receptors induce a positive energy balance, whereas antagonists at these receptors reduce food intake and body weight in rodent models of obesity. An analog of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, LY255582, is a potent non-morphinan antagonist for mu-, kappa-, and delta-receptors (K(i) of 0.4, 2.0, and 5.2 nM, respectively). In the present study, we examined the effects of oral LY255582 treatment on caloric intake, calorie expenditure, and body composition in dietary-induced obese rats. Acute oral treatment of LY255582 produced a dose-dependent decrease in energy intake and respiratory quotient (RQ), which correlated with the occupancy of central opioid receptors. Animals receiving chronic oral treatment with LY255582 for 14 days maintained a negative energy balance that was sustained by increased lipid use. Analysis of body composition revealed a reduction in fat mass accretion, with no change in lean body mass, in animals treated with LY255582. Therefore, chronic treatment with LY255582 reduces adipose tissue mass by reducing energy intake and stimulating lipid use.