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Background:Healthcare (HC) providers’ knowledge, attitudes and practices with regard to infection control (IC) may positively or adversely affect rates of institutional healthcare-associated infection (HAI). Objectives:To determine paediatric HC providers’ knowledge, attitudes and practices regarding HAI and guide IC interventions in a resource-limited setting. Methods:Paediatric HC providers at Tygerberg Children’s Hospital, Cape Town, South Africa completed an anonymous, self-administered, 37-item questionnaire. Results:Questionnaires (201, 66.6% participation rate) were completed by medical (90, 44.7%), allied health (16, 8%) and nursing providers (95, 47.3%). Median age was 34 years (IQR 27–43), and 84% were female. Knowledge scores were low [57% correct, mean (SD) 7.7 (1.7)/14 questions] but higher in the medical/allied category (P ≤ 0.001) and those qualified for ≥ 10 years (P = 0.008). Providers lacked knowledge of the main routes of infection transmission and misunderstood hand hygiene and terminal cleaning recommendations. Nurses scored higher for attitude questions [63% desired responses, mean 5 (1.2)/8 questions] (P = 0.02). Only 38% reported adequate undergraduate teaching on HAI and most (93%) wanted more in-service IC training. Providers agreed with punitive measures for colleagues ignoring IC recommendations (89%). Nurses scored higher for practice questions [53% desired responses, mean 3.2 (1.2)/6 questions] (P ≤ 0.001). Self-reported adherence to IC recommendations was high, 88% for hand hygiene and 74% for use of personal protective equipment. However, there was poor uptake of annual influenza vaccination (25%) and N95 respirator fit-testing (28%), and many felt obliged to report for work when sick (67%). Discussion:Expanded in-service and undergraduate training in IC should emphasize methods of hand hygiene and routes of infection transmission. Paediatric providers support mandatory reporting of HAI events and stricter enforcement of IC recommendations. [ABSTRACT FROM AUTHOR]

Background: Vestibular schwannomas (VS) are usually hypovascularized benign tumors. Large VS (Koos grade IV) with unusual vascular architecture are defined as hypervascular (HVVS); the excessive bleeding during microsurgery has a negative impact on results., Methods: Forty consecutive patients were operated on for HVVS (group A). A tendency to bleed and adherence of capsule to nervous structures were evaluated by reviewing intraoperative video records. The cisternal facial nerve (FN) position was reported. Microsurgical removal was classified as total, near-total, subtotal, or partial and the MIB-1 index was evaluated in all. FN results were classified according to the House-Brackmann scale., Results: Results of Group A were compared with those of 45 patients operated on for large low-bleeding VS (group B). Mean tumor diameter was 3.81 cm in group A and 3.58 cm in group B; the mean age was 42.4 and 56.3 years, respectively. The mean American Society of Anesthesiologists Physical Status Scale class of group A was 1.67 versus 2.31 of group B (P < 0.01). Total or near-total resection was accomplished in 76.5% of group A versus 73.3% of group B. Tight capsule adhesion was observed in 67.5% of group A versus 57.8% of group B. Mean MIB-1 was 1.25% and 1.08%, respectively.FN anatomic preservation was possible in 84.6% of group A versus 95.5% of group B; 67.5% of group A had HB grade I or II FN outcome versus 93.3% of group B ( P < 0.001). In group A, 8 patients (20.0%) experienced transient postoperative complications versus 4.4% of group B. Recurrence/regrowth was observed in 4 patients in group A versus 1 in group B., Conclusions: Intraoperative video for classification of HVVS was used. Microsurgery of large HVVS was associated with higher (usually transient) complications and recurrence/regrowth rates and poorer FN outcome, especially in patients with tight capsule adhesion., (© 2022 The Author(s).)

Background: The normal left ventricle shows a systolic wringing motion with clockwise rotation at the base and counterclockwise rotation at the apex. Purpose: The aim of the present study was (1) to assess left ventricular (LV) contraction and relaxation in patients with chronic heart failure (CHF), and (2) to evaluate the effect of medical therapy on LV contraction–relaxation behavior. Methods: Magnetic resonance was used to examine LV motion by labeling specific LV regions in three planes (myocardial tagging). Twenty-three subjects were included, nine healthy controls and 14 CHF patients. Cardiac motion was determined from the deformation of a rectangular grid in a basal and apical plane. CHF patients were put on triple therapy with ACE-inhibitors, β-blockers and spironolactone. Follow-up examination (n=9) was performed after 6 months. Results: In controls, systolic rotation was -9.5±2° at the base and +3.3±1° at the apex. In CHF patients, rotation was reduced both at the base (-3.4±2°, P<0.01) and the apex (+0.9±3°, P<0.05). Similarly, regional ejection fraction (REF) was reduced in CHF patients both at the base and the apex. Medical therapy was associated with an improvement in REF, but systolic rotation improved only at the base (-4.6±2°, P<0.05). Conclusions: Systolic wringing motion with clockwise rotation at the base and counterclockwise rotation at the apex is maintained in CHF although reduced. Heart failure treatment is associated with an improvement in REF, whereas rotation improved only at the base, but not at the apex. Thus, there is an uncoupling between regional shortening and rotation in CHF patients. [Copyright &y& Elsevier]

: Background/AimsChronic hepatitis C patients infected by genotype 1 are the least responsive to combination therapy and therefore monitoring response is important in identifying non-responders quickly, permitting therapy discontinuation and avoiding side effects and costs. We examined the usefulness of measuring total HCV Core Ag in early treatment with peginterferon α-2b and ribavirin in genotype 1 patients in the prediction of response and compared the results with those from HCV RNA quantification.: MethodsTwo hundred and sixty-eight serum samples from 46 genotype 1 patients receiving combination therapy were examined for HCV Core Ag and quantitative HCV RNA.: ResultsAt baseline, mean HCV RNA and HCV Core Ag concentrations were significantly lower in sustained virologic responders than in non-responders. The negative predictive value of HCV Core Ag testing in predicting non-response at week 12 is 100%, and for a 2 log drop in HCV RNA, using two quantitative tests, it is 88%.: ConclusionsHCV Core Ag determination allows the identification of non-responders with only one test at week 12 and permits stopping therapy in these patients. HCV Core Antigen testing is cheaper and easier to perform than HCV RNA quantification. [Copyright &y& Elsevier]

GABAA receptor sites were characterised in cerebral cortex tissue samples from deceased neurologically normal infants who had come to autopsy during the third trimester of pregnancy. Pharmacological parameters were obtained from homogenate binding studies which utilised the ‘central-type’ benzodiazepine ligands [3H]diazepam and [3H]flunitrazepam, and from the GABA activation of [3H]diazepam binding. It was found that the two radioligands behaved differently during development. The affinity of [3H]flunitrazepam for its binding site did not vary significantly between preparations, whereas the [3H]diazepam KD showed marked regional and developmental variations: infant tissues showed a distinctly lower affinity than adults for this ligand. The density of [3H]flunitrazepam binding sites increased ∼35% during the third trimester to reach adult levels by term, whereas [3H]diazepam binding capacity declined slightly but steadily throughout development. The GABA activation of [3H]diazepam binding was less efficient early in the trimester, in that the affinity of the agonist was significantly lower, though it rose to adult levels by term. The strength of the enhancement response increased to adult levels over the same time-frame. The results strongly suggest that the subunit composition of cortical GABAA sites changes significantly during this important developmental stage. [Copyright &y& Elsevier]

This paper describes the effects of elevated CO2 (550 and 680 μl l−1) and O3 (60 nl l−1 O3 as an 8 h mean), alone or in combination, on canopy development and senescence in potato (Solanum tuberosum L. cv Bintje) across a range of European agro-climatic conditions. The assessments were made within the European CHIP project (CHanging climate and potential Impacts on Potato yield and quality) that was conducted for two growing seasons (1998 and 1999) in free air CO2 enrichment systems (FACE) and open-top chamber facilities (OTCs) at seven European sites. A comparison of chambered and unchambered experimental plots was included to examine the effects of chamber enclosure. Phenological growth stages, plant height, leaf area index (LAI) and the number of green and yellow leaves were recorded non-destructively throughout the growing season and by a destructive intermediate harvest at maximum leaf area (MLA). In the dynamic growth analysis CO2 and O3 effects were studied over three developmental stages: canopy expansion, full canopy and canopy senescence. Chamber enclosures promoted potato crop development (taller plants, more leaves) during the initial growth stages and led to a faster decline of LAI and a higher number of yellow leaves. The growth in ambient plots varied between sites and seasons, as did the scale of the treatment responses. Despite the large background variation, some overall treatment effects could be detected across all sites. Both levels of increased CO2 reduced final plant height in comparison to ambient concentrations, which indicates a premature ending of the active plant growth. At the stage of full canopy and crop senescence the average number of green leaves was significantly (P<0.05) decreased by 680 μl l−1 CO2 (OTC experiments) and LAI showed the same tendency (P=0.07). As there was however no indication of a decreased leaf formation during initial growth and at full canopy, this must have been due to an earlier leaf fall. In the FACE experiments LAI had already began to decline at the stage of full canopy at 550 μl l−1 CO2 but not in ambient CO2 (DAE×CO2, P<0.05). These observations strongly indicated that elevated CO2 induced a premature senescence during full canopy. O3 did not have an overall detrimental effect on crop development during initial growth nor at full canopy, but did induce a faster reduction of LAI during crop senescence (DAE×O3, P<0.05). Final plant height was not affected by O3. There were few CO2×O3 interactions detected. There was a suggestion (P=0.06) that O3 counteracted the CO2-induced decrease of green leaves at full canopy, but on the other hand during crop senescence the decline of LAI due to elevated O3 was faster at ambient compared to elevated CO2 (P<0.05). These responses of canopy development to elevated CO2 and O3 help to explain the treatment responses of potato yield within the CHIP project at sites across Europe. [Copyright &y& Elsevier]

Objective: Atrial fibrillation (AF) is a frequent complication following open-heart surgery (OHS). Increased atrial fibrosis may indicate the presence of an intrinsic arrhythmogenic substrate. The aim of this prospective study was to determine whether atrial fibrosis is associated with increased prevalence of AF after OHS. Methods: Right atrial appendages were obtained from 259 patients undergoing OHS; none of the patients had a history of AF. Atrial fibrosis was quantitatively analyzed with point counting. All patients were followed prospectively until hospital discharge. None of the patients received anti-arrhythmic prophylaxis. Post-operative AF was defined as an episode of AF lasting ≥5 min. Results: Quantitation of atrial fibrosis yielded a mean volume percentage of 15.8±4.3% (V%; range 4.6–32.4%). Patient age was found to correlate with the amount of atrial fibrosis (r=0.165; P<0.01) and surface P-wave duration (r=0.249; P<0.01). The degree of fibrosis combined with P-wave duration predicted post-operative AF (P<0.01). Age (>60 years) and P-wave duration (≥100 ms) were independent predictors of post-operative AF (age: relative risk 2.20; P-wave: relative risk 2.69; P<0.05). The patients were divided into three groups: group 1, V%=4.6–13.8%; group 2, V%=13.9–23.1%; group 3, V%=23.2–32.4%. A total of 52 patients (20.1%) developed AF, which occurred least commonly in group 1 (16.3%) and group 2 (21.2%) as compared with group 3 (33.3%). Conclusions: Atrial fibrosis provides a pathophysiological substrate for post-operative AF. The results support the importance of P-wave duration as a predictor of post-operative AF, and explain the increased prevalence of AF in elderly patients after OHS. [Copyright &y& Elsevier]

Arc (also termed activity-regulated cytoskeleton-associated protein or Arg3.1), is an effector immediate early gene whose upregulation has been demonstrated during events of synaptic plasticity. In the present study, the possibility that Arc would be specifically upregulated in rats during the acquisition of a quickly learned behavioral task but not in overtrained animals was investigated. Three groups of rats, pseudotrained, newly trained and overtrained, were examined with respect to Arc expression following training on a simple operant lever-pressing task. Newly trained animals were killed 30 min following the session in which they demonstrated acquisition of the task, and overtrained animals were trained on the same task for 13–14 days and then killed. Relative to base level measures taken 6 h following the session, all three groups demonstrated significant levels of induction of Arc mRNA; however, newly trained animals exhibited heightened induction of Arc mRNA relative to both pseudotrained and overtrained animals. The increased levels of Arc mRNA in newly trained animals were located in the CA1 and CA3 fields of hippocampus, the subiculum, and the anterior cingulate, piriform, infra/prelimbic, perirhinal and entorhinal cortical areas. Additionally, Arc mRNA was expressed differentially across the above anatomic structures in a relative pattern that was the same in all three groups. Finally, levels of Arc mRNA in specific brain regions of newly trained animals correlated negatively with the rate of task acquisition, such that slow learners exhibited higher levels of Arc mRNA than fast learners.From these results we suggest that Arc is upregulated in an experience-dependent manner, with higher levels of induction occurring during the initial stage of learning. Furthermore, the finding of increased Arc levels in slow versus fast learners indicates that Arc expression may be associated with the length of time required to: (1) form new associations or (2) remodel existing connections. These results confirm other reports that Arc is a critical substrate for the synaptic plasticity underlying the acquisition of new behaviors. [Copyright &y& Elsevier]

Somatostatin is synthesized and released by aspiny interneurons of the neostriatum. This work investigates the actions of somatostatin on rat neostriatal neurons of medium size (ca. 6 pF). Somatostatin (1 μM) reduces both calcium action potentials (20 mM tetraethylammonium) by ca. 24% and calcium currents by ca. 35%, in all cells tested. This action was produced in the presence of tetrodotoxin and in dissociated cells and was blocked by cyclo(-7-aminoheptanoyl-phe-d-try-lys-O-benzyl-thr) acetate (CPP-1), a somatostatin receptor antagonist. Except for nitrendipine (5 μM), several calcium channel antagonists, 1 μM ω-conotoxin GVIA, 400 nM ω-agatoxin TK, and 1 μM ω-conotoxin MVIIC, partially occluded somatostatin action. According to the calcium channel types known to be blocked by these antagonists, P/Q-type channels appeared to be the channels mainly modulated by somatostatin, followed by N-type channels. Since these channel types generate the afterhyperpolarizing potential in spiny neurons, we investigated the action of somatostatin on this event. Somatostatin reduces the amplitude of the afterhyperpolarizing potential by ca. 39%. This action is occluded by ω-agatoxin TK and ω-conotoxin MVIIC but not by ω-conotoxin GVIA or nicardipine. Thus, the action of somatostatin on the afterhyperpolarizing potential is mainly mediated by P/Q-type calcium channels. The block of the slow afterhyperpolarizing potential made most neurons exhibit an irregular firing mode, suggesting that ion currents other than calcium may also be affected by somatostatin.We conclude that somatostatin exerts a direct postsynaptic effect on neostriatal neurons via the activation of somatostatin receptors. This action affects non-L-type calcium channels and therefore modifies the afterhyperpolarizing potential and the firing pattern. It is proposed that somatostatin and its analogues may have profound effects on the motor functions controlled by the basal ganglia. [Copyright &y& Elsevier]

Objective: The present study was designed to examine the effects of chronic amiodarone on the different ventricular cell subtypes in situ and to evaluate its interactions with sotalol. Methods: Three groups of dogs were studied. Group I (n=8) received no treatment. Group II (n=7) and group III (n=8) received, respectively, 100 and 200 mg amiodarone orally twice a day for 6 weeks to 8 months. In vivo studies were performed under halothane anesthesia 14 h after the last administration of amiodarone. Three leads ECG, femoral blood pressure and left ventricular intramural monophasic action potentials (MAP) were continuously recorded. Bradycardia was obtained by clamping the sinus node and β-blockade and the heart was driven by atrial pacing. Three weeks before the in vivo experiments, the cellular electrophysiologic properties of right ventricular tissues obtained by cardiac biopsy in six treated and six control dogs were studied with standard microelectrodes. Results: Amiodarone produced a dose-dependent decrease in plasma levels of triiodothyronine (T3; 5.9±0.4 pM in control dogs, 3.1±0.2 pM in group III, P<0.001) without affecting thyroxine (T4). Under anesthesia, the QT interval was 14% larger in group III compared to group I at a paced cycle length (PCL) of 1500 ms (P<0.05). This is consistent with the 10% increase in endocardial MAP duration in group III at the same PCL (P<0.05). There was no significant increase in transmural dispersion of MAP duration. In group I, sotalol induced a significant reverse use-dependent increase in MAP duration. This effect was reduced in group II and completely suppressed in group III. Amiodarone prevented the sotalol-induced increase in transmural dispersion of ventricular repolarization which was 69±12 ms in untreated dogs, 41±8 ms in group II (P<0.05) and 34±8 ms (P<0.05) in group III at PCL=1500 ms. Amiodarone also prevented the sotalol-induced ventricular tachyarrhythmias. In vitro, the action potential duration was longer in amiodarone-treated dogs that in control ones (208±5 ms versus 188±9 ms at PCL=1000 ms, P<0.05).The sotalol-induced prolongation of repolarization was reduced in amiodarone-treated dogs. Conclusion: Chronic treatment of dogs with amiodarone induced a moderate prolongation of the QT interval and MAP duration without affecting transmural dispersion of repolarization and inhibited the effects of acute sotalol, including the prolongation of repolarization, the increase in transmural dispersion of repolarization and the induction of arrhythmias. [ABSTRACT FROM PUBLISHER]

The bacterial C-type lectin domain family 4 member E (CLEC4E) has an important role in sterile inflammation, but its role in myocardial repair is unknown. Using complementary approaches in porcine, murine, and human samples, we show that CLEC4E expression levels in the myocardium and in blood correlate with the extent of myocardial injury and left ventricular (LV) functional impairment. CLEC4E expression is markedly increased in the vasculature, cardiac myocytes, and infiltrating leukocytes in the ischemic heart. Loss of Clec4e signaling is associated with reduced acute cardiac injury, neutrophil infiltration, and infarct size. Reduced myocardial injury in Clec4e -/- translates into significantly improved LV structural and functional remodeling at 4 weeks' follow-up. The early transcriptome of LV tissue from Clec4e -/- mice versus wild-type mice reveals significant upregulation of transcripts involved in myocardial metabolism, radical scavenging, angiogenesis, and extracellular matrix organization. Therefore, targeting CLEC4E in the early phase of ischemia-reperfusion injury is a promising therapeutic strategy to modulate myocardial inflammation and enhance repair after ischemia-reperfusion injury., Competing Interests: This work was supported by a KU Leuven financing grant (C14/20/095). Ms Veltman holds a grant from the Royal Academy for Medicine in Belgium (KAGB, ZDK4478). Dr Janssens is holder of the AstraZeneca chair in Cardiology at KU Leuven. Dr Sinnaeve is co-holder of the Bayer Chair in Cardiology at KU Leuven. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Objective: To assess the safety and efficacy of convalescent plasma (CP) transfusion in elderly people with moderate to severe coronavirus disease 2019 (COVID-19) living in a long-term care facility (LTCF)., Patients and Methods: Twenty-two consecutive elderly patients with COVID-19 infection living in an LTCF in Lombardy, Italy, who were given CP during May 15 to July 31, 2020, were enrolled in a prospective cohort study. Their clinical, instrumental, and laboratory parameters were assessed following the CP treatment. The overall mortality rate in this group was compared with that recorded in other LTCFs in Lombardy during the 3-month period from March to May 2020., Results: Of the 22 patients enrolled, 68.2% (n=15) received 1 CP unit, 27.3% (n=6) received 2 units, and 4.5% (n=1) received 3 units. Of the CP units transfused, 76.7% (23/30) had a neutralizing antibody titer of 1:160 or greater. No adverse reactions were recorded during or after CP administration. Improvements in clinical, functional, radiologic, and laboratory parameters during the 14 days after CP transfusion were observed in all 19 patients who survived. Viral clearance was achieved in all patients by the end of follow-up (median, 66 days; interquartile range, 48-80 days). The overall mortality rate was 13.6% (3/22), which compared favorably with that in the control group (38.3% [281/733]; P =.02) and corresponded to a 65% reduction in mortality risk., Conclusion: Early administration of CP with an adequate anti-severe acute respiratory syndrome coronavirus 2 antibody titer to elderly symptomatic patients with COVID-19 infection in an LTCF was safe and effective in eliminating the virus, restoring patients' immunity, and blocking the progression of COVID-19 infection, thereby improving patients' survival., Trial Registration: ClinicalTrials.gov: NCT04569188., (© 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Neonatal handling is an experimental model of early life experience associated with resilience in later life challenges, altering the ability of animals to respond to stress. The endocannabinoid system of the brain modulates the neuroendocrine and behavioral effects of stress, while this system is also capable of being modulated by stress exposure itself. The present study has addressed the question of whether neonatal handling in rats could affect cannabinoid receptors, in an age- and sex-dependent manner, using in situ hybridization and receptor binding techniques. Different effects of neonatal handling were observed in adolescent and adult brain on CB1 receptor mRNA and [ 3 H]CP55,940 binding levels, which in some cases were sexually dimorphic. Neonatal handling interfered in the developmental trajectories of CB1 receptor mRNA levels in striatum and amygdaloid nuclei, as well as of [ 3 H]CP55,940 binding levels in almost all regions studied. Adult handled rats showed reduced [ 3 H]CP55,940 binding levels in the prefrontal cortex, striatum, nucleus accumbens and basolateral amygdala, while binding levels in prefrontal cortex of adolescent handled rats were increased. Finally, handling resulted in decreases in female [ 3 H]CP55,940 binding levels in the striatum, nucleus accumbens, CA3 and DG of dorsal hippocampus and basolateral amygdala. Our results suggest that a brief and repeated maternal separation during the neonatal period induces changes on cannabinoid receptors differently manifested between adolescence and adulthood, male and female brain, which could be correlated to their stress response.

Background: In India, both genotype 3 and 1 are predominant genotypes in patients with chronic hepatitis C (CHC). However, there is scanty data on sustained viral response (SVR) rate with conventionally recommended dual therapy with PEG-IFN and ribavirin., Methods: In this retrospective study, consecutive patients of CHC of genotypes 1 and 3, attending the single unit of Gastroenterology of our hospital, who received PEG-IFN and ribavirin therapy, were included. Patients who had co-infection with HIV or HBV were excluded., Results: A total of 114 patients were included in the study median age 44 (15-72) years, 79% males. Most common presentation was with chronic hepatitis, while 10 (9%) patients had compensated cirrhosis. Nine (8%) patients had associated diabetes, 16 (14%) patients gave history of significant alcohol abuse. The median baseline HCV RNA level was 3.0 × 10(5) (1.7 × 10(3)-1.8 × 10(7)) IU/mL. The most common genotype was 3 (75%) followed by genotype 1 (25%). 70% patients received PegIFN-α2a (median dose 180 MIU/wk) and 30% patients received PegIFN-α2b (median dose 80 MIU/wk). The median ribavirin dose was 800 (range 800-1200) mg. SVR in genotype 1 was 64% (18/28) while SVR in genotype 3 was 73% (63/86). The factors predicting SVR on univariate analysis were a lower baseline HCV RNA level (less than 3.0 × 10(5)), higher hemoglobin level > 11.8 g/dl, and achievement of rapid virological response (RVR), early virological response (EVR) and end of treatment response (ETR). In multivariate analysis the only baseline factor found independently correlating with SVR was low HCV RNA level (<3.0 × 10(5) IU/mL) (P = 0.003)., Conclusion: In north India, HCV genotype 3 has a SVR rate of 73%, which is comparable to genotype 1 with SVR rate of 64% when treated with PEG-IFN and ribavirin therapy. A baseline HCV RNA level lower than 3.0 × 10(5) best predicts SVR in addition to achievement of RVR, EVR or ETR.

Multiple therapeutic agonists of death receptor 5 (DR5) have been developed and are under clinical evaluation. Although these agonists demonstrate significant anti-tumor activity in preclinical models, the clinical efficacy in human cancer patients has been notably disappointing. One possible explanation might be that the current classes of therapeutic molecules are not sufficiently potent to elicit significant response in patients, particularly for dimeric antibody agonists that require secondary cross-linking via Fcγ receptors expressed on immune cells to achieve optimal clustering of DR5. To overcome this limitation, a novel multivalent Nanobody approach was taken with the goal of generating a significantly more potent DR5 agonist. In the present study, we show that trivalent DR5 targeting Nanobodies mimic the activity of natural ligand, and furthermore, increasing the valency of domains to tetramer and pentamer markedly increased potency of cell killing on tumor cells, with pentamers being more potent than tetramers in vitro. Increased potency was attributed to faster kinetics of death-inducing signaling complex assembly and caspase-8 and caspase-3 activation. In vivo, multivalent Nanobody molecules elicited superior anti-tumor activity compared to a conventional DR5 agonist antibody, including the ability to induce tumor regression in an insensitive patient-derived primary pancreatic tumor model. Furthermore, complete responses to Nanobody treatment were obtained in up to 50% of patient-derived primary pancreatic and colon tumor models, suggesting that multivalent DR5 Nanobodies may represent a significant new therapeutic modality for targeting death receptor signaling.

MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. However, their potential role in the central regulation of whole-body energy homeostasis is still unknown. In this study we show that the expression of Dicer, an essential endoribonuclease for miRNA maturation, is modulated by nutrient availability and excess in the hypothalamus. Conditional deletion of Dicer in POMC-expressing cells resulted in obesity, characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism and alterations in the pituitary-adrenal axis. The development of the obese phenotype was paralleled by a POMC neuron degenerative process that started around 3 weeks of age. Hypothalamic transcriptomic analysis in presymptomatic POMCDicerKO mice revealed the downregulation of genes implicated in biological pathways associated with classical neurodegenerative disorders, such as MAPK signaling, ubiquitin-proteosome system, autophagy and ribosome biosynthesis. Collectively, our results highlight a key role for miRNAs in POMC neuron survival and the consequent development of neurodegenerative obesity.