Adenosine A2A receptor antagonism and genetic deletion attenuate the effects of dopamine D2 antagonism on effort-based decision making in mice

Brain dopamine (DA) and adenosine interact in the regulation of behavioral activation and effort-related processes. In the present studies, a T-maze task was developed in mice for the assessment of effort-related decision making. With this task, the two arms of the maze have different reinforcement densities, and a vertical barrier is positioned in the arm with the higher density (HD), presenting the animal with an effort-related challenge. Under control conditions mice prefer the HD arm, and climb the barrier to obtain the larger amount of food. The DA D(2) receptor antagonist haloperidol decreased selection of the HD arm and increased selection of the arm with the low density of reinforcement. However, the HD arm was still the preferred choice in haloperidol-treated mice trained with barriers in both arms. Pre-feeding the mice to reduce food motivation dramatically increased omissions, an effect that was distinct from the actions of haloperidol. Co-administration of theophylline, a nonselective adenosine receptor antagonist, partially reversed the effects of haloperidol. This effect seems to be mediated by the A(2A) receptor but not the A(1) receptor, since the A(2A) antagonist MSX-3, but not the A(1) antagonist CPT, dose dependently reversed the effects of haloperidol on effort-related choice and on c-Fos expression in the dorsal striatum and nucleus accumbens. In addition, adenosine A(2A) receptor knockout mice were resistant to the effects of haloperidol on effort-related choice in the maze. These results indicate that DA D(2) and adenosine A(2A) receptors interact to regulate effort-related decision making and effort expenditure in mice.     

Understanding the complexity of IgE-related phenotypes from childhood to young adulthood: a Mechanisms of the Development of Allergy (MeDALL) seminar

Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach. This article provides a summary of the meeting. It develops challenges in IgE-related phenotypes and new clinical and epidemiologic approaches to the investigation of allergic phenotypes, including cluster analysis, scale-free models, candidate biomarkers, and IgE microarrays; the particular case of severe asthma was reviewed. Then novel approaches to the IgE-associated phenotypes are reviewed from the individual mechanisms to the systems, including epigenetics, human in?vitro immunology, systems biology, and animal models. The last chapter deals with the understanding of the population-based IgE-associated phenotypes in children and adolescents, including age effect in terms of maturation, observed effects of early-life exposures and shift of focus from early life to pregnancy, gene-environment interactions, cohort effects, and time trends in patients with allergic diseases. This review helps to define phenotypes of allergic diseases in MeDALL.     

Involvement of the endocannabinoid system in drug addiction

Recent studies have shown that the endocannabinoid system is involved in the common neurobiological mechanism underlying drug addiction. This system participates in the primary rewarding effects of cannabinoids, nicotine, alcohol and opioids, through the release of endocannabinoids in the ventral tegmental area. Endocannabinoids are also involved in the motivation to seek drugs by a dopamine-independent mechanism, demonstrated for psychostimulants and opioids. The endocannabinoid system also participates in the common mechanisms underlying relapse to drug-seeking behaviour by mediating the motivational effects of drug-related environmental stimuli and drug re-exposure. In agreement, clinical trials have suggested that the CB(1) cannabinoid antagonist rimonabant can cause smoking cessation. Thus, CB(1) cannabinoid antagonists could represent a new generation of compounds to treat drug addiction.     

Emerging therapies for urothelial cancer

Urothelial carcinoma is one of the leading causes of death in Europe and the United States. Despite its chemosensitivity, median overall survival for advanced disease is still nearly 1 year. Most second-line chemotherapeutic agents tested have been disappointing. Thus, new treatment strategies are clearly needed. This review focuses on emerging therapies in urothelial carcinoma. Results from recent clinical trials, investigating the activity of new generation cytostatic agents, as well as results from studies assessing the toxicity and efficacy of novel targeted therapies, are discussed. In this setting, anti-epidermal growth factor receptor, angiogenesis, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors account for the majority of phase I and II trials.     

Hepatitis B viremia in HIV-coinfected individuals under antiretroviral therapy

BackgroundAntiretroviral therapy (ART) has decreased AIDS incidence and mortality, rendering comorbidities, such as hepatitis B more relevant for people living with human immunodeficiency virus (HIV). Since antiretroviral drugs may also inhibit hepatitis B virus (HBV) replication, analyzing the impact of ART on management of hepatitis B in this population is important.ObjectiveTo assess HBV viremia among HIV/HBV coinfected individuals on ART and its associated factors.MethodFor this cross-sectional study, HIV/HBV-coinfected individuals, aged over 18 years, who were on ART for over six months and receiving care at an outpatient clinic in São Paulo were recruited. Sociodemographic characteristics, information about viral exposure, clinical and laboratory data, including evaluation of liver fibrosis were obtained. Plasma HBV DNA was measured by polymerase chain reaction. Viral genome sequencing was conducted for genotyping and identification of drug resistance-conferring mutations if viral load exceeded 900 IU/mL.ResultsOut of 2,946 patients who attended the clinic in 2015, 83 were eligible and 56 evaluated. Plasma HBV DNA was detected in 16 (28.6%) (95% CI: 18.0–41.3%), all on lamivudine and tenofovir treatment. HBV DNA detection was associated with lower education (p = 0.015), higher international normalized ratios (p = 0.045), history of an AIDS-defining illness [OR: 3.43 (95% CI: 1.10–11.50)], and HBeAg detection [OR: 6.60 (95% CI: 1.84–23.6)]. In contrast, a last CD4+ count above 500 cells/mm³ in the year prior to inclusion [OR: 0.18 (95% CI: 0.04–0.71)] and detection of anti-HBe [OR: 0.21 (95% CI: 0.04–0.99)] were negatively associated. Patients with HBV DNA above 900 IU/mL were infected with subgenotypes A1 (n = 3) and D2 (n = 1), and exhibited viral mutations associated with total resistance to lamivudine and partial resistance to entecavir.ConclusionsDespite being on ART, a significant proportion of HIV/HBV-coinfected individuals present HBV viremia. Characterization of factors that are associated with this finding may help professionals provide better management to these patients.     

Cardiovascular MR dobutamine stress in adult tetralogy of Fallot: disparity between CMR volumetry and flow for cardiovascular function

Purpose:

To evaluate the MR agreement of cardiac function parameters between volumetric (cine SSFP) and phase contrast flow (PC‐flow) assessment in patients with repaired tetralogy of Fallot (r‐TOF) and chronic pulmonary regurgitation (PR) at rest and under dobutamine stress (DS‐MR).

Materials and Methods:

We studied 18 patients with r‐TOF and severe chronic PR (34 ± 12.7 years, PR fraction_[flow] 44 ± 15%) by cardiac MR at rest, 10 and 20 μg/kg/min of dobutamine. We compared analogous functional parameters by volumetry and PC‐flow: (i) Systemic output [left ventricle stroke volume (LV_SV) versus aortic forward flow (AO_FF)], (ii) Pulmonary output [right ventricle stroke volume (RV_SV) versus pulmonary forward flow (PA_FF)], (iii) PR volume [(RV_SV‐LV_SV) versus pulmonary backward flow (PA_BF)], (iv) PR fraction [(RV_SV‐LV_SV/RV_SV) versus (PA_BF/PA_FF)].

Results:

We found excellent Bland‐Altman agreement (mean difference ± limits of agreement, mL/beat/m²) at rest for both the systemic (?0.8 ± 5.7) and pulmonary strokes volumes (?0.1 ± 7.6), which slightly deteriorates during DS‐MR. The PR volume showed acceptable agreement at rest (?3.6 ± 15.1), but also further deteriorated during stress (5.4 ± 24). In contrast, the PR fraction showed poor agreement equally at rest (?5.6 ± 22.8) and DS‐MR (3.2 ± 19.2).

Conclusion:

In r‐TOF with chronic PR, analogous functional parameters should not be used interchangeably between volumetric and PC‐flow assessment during DS‐MR evaluation. J. Magn. Reson. Imaging 2011;33:1341–1350. © 2011 Wiley‐Liss, Inc.

     

Statistical structure of host-phage interactions

Interactions between bacteria and the viruses that infect them (i.e., phages) have profound effects on biological processes, but despite their importance, little is known on the general structure of infection and resistance between most phages and bacteria. For example, are bacteria–phage communities characterized by complex patterns of overlapping exploitation networks, do they conform to a more ordered general pattern across all communities, or are they idiosyncratic and hard to predict from one ecosystem to the next? To answer these questions, we collect and present a detailed metaanalysis of 38 laboratory-verified studies of host–phage interactions representing almost 12,000 distinct experimental infection assays across a broad spectrum of taxa, habitat, and mode of selection. In so doing, we present evidence that currently available host–phage infection networks are statistically different from random networks and that they possess a characteristic nested structure. This nested structure is typified by the finding that hard to infect bacteria are infected by generalist phages (and not specialist phages) and that easy to infect bacteria are infected by generalist and specialist phages. Moreover, we find that currently available host–phage infection networks do not typically possess a modular structure. We explore possible underlying mechanisms and significance of the observed nested host–phage interaction structure. In addition, given that most of the available host–phage infection networks examined here are composed of taxa separated by short phylogenetic distances, we propose that the lack of modularity is a scale-dependent effect, and then, we describe experimental studies to test whether modular patterns exist at macroevolutionary scales.