Neural correlates of anxious distress in depression:A neuroimaging study of reactivity to emotional faces and resting-state functional connectivity

Background: Comorbid anxiety disorders and anxious distress are highly prevalent in major depressive disorder (MDD). The presence of the DSM-5 anxious distress specifier (ADS) has been associated with worse treatment outcomes and chronic disease course. However, little is known about the neurobiological correlates of anxious distress in MDD. Methods: We probed the relation between the DSM-5 ADS and task-related reactivity to emotional faces, as well as resting-state functional connectivity patterns of intrinsic salience and basal ganglia networks in unmedicated MDD patients with (MDD/ADS+, N = 24) and without ADS (MDD/ADS−, N = 48) and healthy controls (HC, N = 59). Both categorical and dimensional measures of ADS were investigated. Results: MDD/ADS+ patients had higher left amygdala responses to emotional faces compared to MDD/ADS− patients (p =.015)—part of a larger striato-limbic cluster. MDD/ADS+ did not differ from MDD/ADS− or controls in resting-state functional connectivity of the salience or basal ganglia networks. Conclusions: Current findings suggest that amygdala and striato-limbic hyperactivity to emotional faces may be a neurobiological hallmark specific to MDD with anxious distress, relative to MDD without anxious distress. This may provide preliminary indications of the underlying mechanisms of anxious distress in depression, and underline the importance to account for heterogeneity in depression research

Radioimmune Imaging of α4β7 Integrin and TNFα for Diagnostic and Therapeutic Applications in Inflammatory Bowel Disease

Imaging using radiolabelled monoclonal antibodies can provide, non-invasively, molecular information which allows for the planning of the best treatment and for monitoring the therapeutic response in cancer, as well as in chronic inflammatory diseases. In the present study, our main goal was to evaluate if a pre-therapy scan with radiolabelled anti-α4β7 integrin or radiolabelled anti-TNFα mAb could predict therapeutic outcome with unlabelled anti-α4β7 integrin or anti-TNFα mAb. To this aim, we developed two radiopharmaceuticals to study the expression of therapeutic targets for inflammatory bowel diseases (IBD), to be used for therapy decision making. Both anti-α4β7 integrin and anti-TNFα mAbs were successfully radiolabelled with technetium-99m with high labelling efficiency and stability. Dextran sulfate sodium (DSS)-induced colitis was used as a model for murine IBD and the bowel uptake of radiolabelled mAbs was evaluated ex vivo and in vivo by planar and SPECT/CT images. These studies allowed us to define best imaging strategy and to validate the specificity of mAb binding in vivo to their targets. Bowel uptake in four different regions was compared to immunohistochemistry (IHC) score (partial and global). Then, to evaluate the biomarker expression prior to therapy administration, in initial IBD, another group of DSS-treated mice was injected with radiolabelled mAb on day 2 of DSS administration (to quantify the presence of the target in the bowel) and then injected with a single therapeutic dose of unlabelled anti-α4β7 integrin or anti-TNFα mAb. Good correlation was demonstrated between bowel uptake of radiolabelled mAb and immunohistochemistry (IHC) score, both in vivo and ex vivo. Mice treated with unlabelled α4β7 integrin and anti-TNFα showed an inverse correlation between the bowel uptake of radiolabelled mAb and the histological score after therapy, proving that only mice with high α4β7 integrin or TNFα expression will benefit of therapy with unlabelled mAb.This work has been supported by grants of Boehringer Ingelheim Pharma GmbH, & Co. KG, Biberach an der Riß, Germany. This work was partially supported by Instituto de Salud Carlos III (grant PT20/00044), co-funded by European Regional Development Fund (ERDF), “A way to make Europe” and by Comunidad de Madrid (S2022/BMD-7403 RENIM-CM), co-funded by European Structural and Investment Fund. And by the Fundación Ramón Areces

Phosphodiesterase 2 Protects against Catecholamine-induced Arrhythmias and Preserves Contractile Function after Myocardial Infarction

International audienceRationale: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown.Objective: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction.Methods and Results: Pharmacological inhibition of phosphodiesterase 2 (BAY 60–7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β-adrenoceptor–mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+ leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction.Conclusions: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction

External validation and adaptation of a dynamic prediction model for patients with high‐grade extremity soft tissue sarcoma

Background and Objectives: A dynamic prediction model for patients with soft tissue sarcoma of the extremities was previously developed to predict updated overall survival probabilities throughout patient follow‐up. This study updates and externally validates the dynamic model. Methods: Data from 3826 patients with high‐grade extremity soft tissue sarcoma, treated surgically with curative intent were used to update the dynamic PERsonalised SARcoma Care (PERSARC) model. Patients were added to the model development cohort and grade was included in the model. External validation was performed with data from 1111 patients treated at a single tertiary center. Results: Calibration plots show good model calibration. Dynamic C‐indices suggest that the model can discriminate between high‐ and low‐risk patients. The dynamic C‐indices at 0, 1, 2, 3, 4, and 5 years after surgery were equal to 0.697, 0.790, 0.822, 0.818, 0.812, and 0.827, respectively. Conclusion: Results from the external validation show that the dynamic PERSARC model is reliable in predicting the probability of surviving an additional 5 years from a specific prediction time point during follow‐up. The model combines patient‐, treatment‐specific and time‐dependent variables such as local recurrence and distant metastasis to provide accurate survival predictions throughout follow‐up and is available through the PERSARC app.Peer reviewe

From food to pest: Conversion factors determine switches between ecosystem services and disservices

Ecosystem research focuses on goods and services, thereby ascribing beneficial values to the ecosystems. Depending on the context, however, outputs from ecosystems can be both positive and negative. We examined how provisioning services of wild animals and plants can switch between being services and disservices. We studied agricultural communities in Laos to illustrate when and why these switches take place. Government restrictions on land use combined with economic and cultural changes have created perceptions of rodents and plants as problem species in some communities. In other communities that are maintaining shifting cultivation practices, the very same taxa were perceived as beneficial. We propose conversion factors that in a given context can determine where an individual taxon is located along a spectrum from ecosystem service to disservice, when, and for whom. We argue that the omission of disservices in ecosystem service accounts may lead governments to direct investments at inappropriate targets