Sexual Dimorphism in the Brain Correlates of Adult-Onset Depression: A Pilot Structural and Functional 3T MRI Study

Major Depressive Disorder (MDD) is a disabling illness affecting more than 5% of the elderly population. Higher female prevalence and sex-specific symptomatology have been observed, suggesting that biologically-determined dimensions might affect the disease onset and outcome. Rumination and executive dysfunction characterize adult-onset MDD, but sex differences in these domains and in the related brain mechanisms are still largely unexplored. The present pilot study aimed to explore any interactions between adult-onset MDD and sex on brain morphology and brain function during a Go/No-Go paradigm. We hypothesized to detect diagnosis by sex effects on brain regions involved in self-referential processes and cognitive control. Twenty-four subjects, 12 healthy (HC) (mean age 68.7 y, 7 females and 5 males) and 12 affected by adult-onset MDD (mean age 66.5 y, 5 females and 7 males), underwent clinical evaluations and a 3T magnetic resonance imaging (MRI) session. Diagnosis and diagnosis by sex effects were assessed on regional gray matter (GM) volumes and task-related functional MRI (fMRI) activations. The GM volume analyses showed diagnosis effects in left mid frontal cortex (p < 0.01), and diagnosis by sex effects in orbitofrontal, olfactory, and calcarine regions (p < 0.05). The Go/No-Go fMRI analyses showed MDD effects on fMRI activations in left precuneus and right lingual gyrus, and diagnosis by sex effects on fMRI activations in right parahippocampal gyrus and right calcarine cortex (p < 0.001, ≥ 40 voxels). Our exploratory results suggest the presence of sex-specific brain correlates of adult-onset MDD-especially in regions involved in attention processing and in the brain default mode-potentially supporting cognitive and symptom differences between sexes

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study

Introduction: Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. Aim: To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. Patients and methods: Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th\ue2\u80\u9375th IQR). Results: Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received \ue2\u89\ua5 3 vs \ue2\u89\ua4 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1\ue2\u80\u932 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. Conclusions: The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases

Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3:a multicenter cohort study

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1–2 (G1–G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21–54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3–4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.acceptedVersio

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes

Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS

Continuing Medical Education in six European countries: A comparative analysis

Objective We examined Continuing Medical Education (CME) systems in a sample of six EU countries: Austria, Belgium, France, Italy, Norway, and the UK. The aim of this comparative study was to assess the main country-specific institutional settings applied by governments.Methods A common scheme of analysis was applied to investigate the following variables: (i) CME institutional framework; (ii) benefits and/or penalties to participants; (iii) types of CME activities and system of credits; (iv) accreditation of CME providers and events; (v) CME funding and sponsorship. The analysis involved reviewing the literature on CME policy and interviewing a selected panel of local experts in each country (at least one public manager, one representative of medical associations and one pharmaceutical manager).Results CME is formally compulsory in Austria, France, Italy and the UK, although no sanctions are enforced against non-compliant physicians in practice. The only two countries that offer financial incentives to enhance CME participation are Belgium and Norway, although limited to specific categories of physicians. Formal accreditation of CME providers is required in Austria, France and Italy, while in the other three countries accreditation is focused on activities. Private sponsorship is allowed in all countries but Norway, although within certain limits.Conclusions This comparative exercise provides an overview of the CME policies adopted by six EU countries to regulate both demand and supply. The substantial variability in the organization and accreditation of schemes indicates that much could be done to improve effectiveness. Although further analysis is needed to assess the results of these policies in practice, lessons drawn from this study may help clarify the weaknesses and strengths of single domestic policies in the perspective of pan-European CME harmonization.Continuing Medical Education European Union Comparative analysis

A permissive role of serotonergic neurons on hedonic behavior

By densely innervating multiple forebrain targets, serotonin-producing neurons affect complex physiological and behavioral responses, an effect that may involve cross-talk with additional neurotransmitter systems. To selectively manipulate endogenous serotonergic activity in the living brain and identify the brainwide substrates modulated by serotonin (5-HT) neurotransmission, we generated two novel DREADD (Designed Receptors Exclusively Activated by Designed Drugs) conditional knock-in mouse models (hMD3q and hM4Di) that, crossed with Pet1-Cre transgenic mice, allowed us to activate (hM3Dq) or inhibit (hM4Di) 5-HT neurons firing in a time-controlled manner by systemic administration of Clozapine-N-Oxide (CNO). By using functional magnetic resonance imaging (fMRI) and c-Fos immunostaining, we demonstrate that chemogenetically evoked 5-HT results in region-specific activation of cortical and subcortical brain substrates involved in emotional responses, plus a specific and robust activation of focal terminals of the dopamine (DA) reward-systems, suggesting a possible 5-HT-mediated modulation of reward processing. To probe this hypothesis, we chemogenetically inhibited 5-HT raphe neurons during a sucrose preference test and show that serotonergic neurons exerts a permissive role for the expression of this hedonic behavior. We also demonstrate that the same inhibition does not induce depressive-like behaviors, arguing against contribution of confounding hypo-hedonic states. Collectively, our results document a previously unreported permissive role of 5-HT neurons on hedonic behavior and corroborate the emerging view of a central role of 5-HT neurotransmission in reward processin

Excitatory serotonergic signaling regulates synaptic plasticity at striatal glutamatergic inputs

The dorsal striatum receives glutamatergic cortical and thalamic afferents, which are extensively modulated by monoaminergic inputs, such as dopamine and serotonin (5-HT). Various models have been proposed regarding the interactions between reward and punishment, with serotonin closely associated with learning of negative events, and countervailing dopamine regulation of corticostriatal circuits and reward. Recent evidence has challenged this view, suggesting that 5-HT signaling can synergize with dopamine signaling to shape reward-guided behavior. However, the molecular and synaptic correlates of this behavioral role of 5-HT at striatal circuits remain to be established. In the dorsolateral striatum, we found that the chemogenetic inhibition of 5-HT release resulted in a spike-timing-dependent form of long-term depression (t-LTD) at glutamatergic synapses on striatal projection neurons of the direct pathway (dSPNs). These synaptic effects of chemogenetic inhibition of 5-HT release were recapitulated by the pharmacological inhibition of the Gs-coupled 5-HT4 receptor subtype (5-HT4R). t-LTD is independent from endocannabinoid signaling, shows a postsynaptic locus of expression, and it is associated with an increased dendritic Ca2+ signal. Additionally, optogenetic interrogation of glutamatergic inputs to dSPNs indicated that this form of t-LTD is expressed at thalamostriatal synapses. Inhibiting in-vivo 5-HT4R during instrumental conditioning of nose-poke for food reward affected goal-directed control of behavior, thus supporting the role of striatal 5-HT signaling in mediating aspects of reward-guided behavior