Event-related brain potentials in elderly dippers and nondippers with recently diagnosed hypertension

Several studies have shown a relationship between pressure (BP) and cognitive function. Yet very few studies have addressed circadian BP patterns in this context, perhaps due to poor availability of suitable methods to detect slight changes in the cognitive state. Today, brain event-related potentials (ERPs) allow us to detect subclinical changes in cognitive function. We enrolled 30 elderly patients with recently diagnosed hypertension (<2 years) that had never been treated: 18 dippers and 12 nondippers. Patients underwent 24-h ambulatory blood pressure monitoring (ABPM). Careful assessment of their cognitive state was carried out using the mini mental state examination (MMSE), and the recording of P300 and N2 ERPs. No significant differences between the two groups were found. MMSE scores in dippers and nondippers were similar (29.5±0.71 vs. 29.3±1.07, respectively; p=0.611), as were P300 latency values (377.78±33.28 vs. 364.67±35.12 in the central (Cz) position, p=0.310; 379.22±32.94 vs. 365.25± 35.07 in the occipital (Pz) position, p=0.277) and N2 wave latency values (253.83±24.9 vs. 249.17±24.47 in the Cz position, p=0.617; 251.56±25.86 vs. 246.58±25.46 in the Pz position, p=0.608 . These data show no association between the nondipping pattern and lower cognitive function in elderly subjects with recent hypertension

Arc 3ʹ UTR splicing leads to dual and antagonistic effects in fine-tuning arc expression upon BDNF signaling

Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis-Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3′ UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3′ UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3′ UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2α dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3′ UTR-splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans-acting factors. Overall, splicing of Arc 3′ UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity

Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling

Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis-Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3′ UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3′ UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3′ UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2α dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3′ UTR-splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans-acting factors. Overall, splicing of Arc 3′ UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity

Data_Sheet_1_With a little help from our pediatrician: An intervention to promote mathematics-related home activities through regular well-child visits.pdf

IntroductionChildren’s involvement in mathematics-related activities in the home environment is associated with the development of their early numeracy over the preschool years. Intervention studies to promote parents’ awareness and provision of mathematics-related home activities are however scant. In this study we developed and tested the effectiveness of a non-intensive intervention program delivered by community pediatricians to promote mathematics-related activities in the home environment.MethodsParents of 204 Italian children were invited to report on the frequency of mathematics-related home activities when children attended the first preschool year (3 years, 8 months of age on average) and, subsequently, the third preschool year (5 years, 6 months of age on average). At both waves, children were also assessed on their early numeracy. In occasion of the routine well-child visit at age 5, parents who were randomly allocated to the intervention condition (vs. a business-as-usual control condition) received guidance on age-appropriate home mathematics-related practices to sustain children’s numerical development.ResultsResults revealed that parents in the intervention group improved their provision of home mathematics-related activities at the post-intervention assessment (relative to baseline) to a greater extent than parents in the control condition. No effect was observed on children’s early numeracy.DiscussionOverall, results are promising in suggesting that community pediatricians may be a resource to promote home mathematics-related activities though non-intensive low-cost interventions.</p

Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer's disease and other tauopathies

open20The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH2-derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer's disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH2tau 26-44 (aka NH2htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K+-evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca2+ dynamics. Neuritic dystrophy, microtubules breakdown, deregulation in presynaptic proteins and loss of mitochondria located at nerve endings are detected in hippocampal cultures only after prolonged exposure to NH2htau. The specificity of these biological effects is supported by the lack of any significant change, either on neuronal activity or on cellular integrity, shown by administration of its reverse sequence counterpart which behaves as an inactive control, likely due to a poor conformational flexibility which makes it unable to dynamically perturb biomembrane-like environments. Our results demonstrate that one of the AD-relevant, soluble and secreted N-terminally truncated tau forms can early contribute to pathology outside of neurons causing alterations in synaptic activity at presynaptic level, independently of overt neurodegeneration.openFlorenzano, Fulvio; Veronica, Corsetti; Ciasca, Gabriele; Ciotti, Maria Teresa; Pittaluga, Anna; Olivero, Guendalina; Feligioni, Marco; Iannuzzi, Filomena; Latina, Valentina; Sciacca, Michele Francesco Maria; Sinopoli, Alessandro; Milardi, Danilo; Pappalardo, Giuseppe; De Spirito, Marco; Papi, Massimiliano; Atlante, Anna; Bobba, Antonella; Borreca, Antonella; Calissano, Pietro; Amadoro, GiuseppinaFlorenzano, Fulvio; Veronica, Corsetti; Ciasca, Gabriele; Ciotti, Maria Teresa; Pittaluga, Anna; Olivero, Guendalina; Feligioni, Marco; Iannuzzi, Filomena; Latina, Valentina; Sciacca, Michele Francesco Maria; Sinopoli, Alessandro; Milardi, Danilo; Pappalardo, Giuseppe; De Spirito, Marco; Papi, Massimiliano; Atlante, Anna; Bobba, Antonella; Borreca, Antonella; Calissano, Pietro; Amadoro, Giuseppin

Bv8/prokineticin 2 is involved in Aβ-induced neurotoxicity

Bv8/Prokineticin 2 (PROK2) is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Among multiple biological roles demonstrated for PROK2, it was recently established that PROK2 is an insult-inducible endangering mediator for cerebral damage. Aim of the present study was to evaluate the PROK2 and its receptors' potential involvement in amyloid beta (Aβ) neurotoxicity, a hallmark of Alzheimer's disease (AD) and various forms of traumatic brain injury (TBI). Analyzing primary cortical cultures (CNs) and cortex and hippocampus from Aβ treated rats, we found that PROK2 and its receptors PKR1 and PKR2 mRNA are up-regulated by Aβ, suggesting their potential involvement in AD. Hence we evaluated if impairing the prokineticin system activation might have protective effect against neuronal death induced by Aβ. We found that a PKR antagonist concentration-dependently protects CNs against Aβ(1-42)-induced neurotoxicity, by reducing the Aβ-induced PROK2 neuronal up-regulation. Moreover, the antagonist completely rescued LTP impairment in hippocampal slices from 6 month-old Tg2576 AD mice without affecting basal synaptic transmission and paired pulse-facilitation paradigms. These results indicate that PROK2 plays a role in cerebral amyloidosis and that PROK2 antagonists may represent a new approach for ameliorating the defining pathology of AD

Image_1_Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling.PDF

<p>Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis-Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3′ UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3′ UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3′ UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2α dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3′ UTR-splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans-acting factors. Overall, splicing of Arc 3′ UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity.</p

Use of High-Dose Nebulized Colistimethate in Patients with Colistin-Only Susceptible <i>Acinetobacter baumannii</i> VAP: Clinical, Pharmacokinetic and Microbiome Features

(1) Background: Colistin-only susceptible (COS) Acinetobacter baumannii (AB) ventilator-associated pneumonia (VAP) represents a clinical challenge in the Intensive Care Unit (ICU) due to the negligible lung diffusion of this molecule and the low-grade evidence on efficacy of its nebulization. (2) Methods: We conducted a prospective observational study on 134 ICU patients with COS-AB VAP to describe the ‘real life’ clinical use of high-dose (5 MIU q8) aerosolized colistin, using a vibrating mesh nebulizer. Lung pharmacokinetics and microbiome features were investigated. (3) Results: Patients were enrolled during the COVID-19 pandemic with the ICU presenting a SAPS II of 42 [32–57]. At VAP diagnosis, the median PaO2/FiO2 was 120 [100–164], 40.3% were in septic shock, and 24.6% had secondary bacteremia. The twenty-eight day mortality was 50.7% with 60.4% and 40.3% rates of clinical cure and microbiological eradication, respectively. We did not observe any drug-related adverse events. Epithelial lining fluid colistin concentrations were far above the CRAB minimal-inhibitory concentration and the duration of nebulized therapy was an independent predictor of microbiological eradication (12 [9.75–14] vs. 7 [4–13] days, OR (95% CI): 1.069 (1.003–1.138), p = 0.039). (4) Conclusions: High-dose and prolonged colistin nebulization, using a vibrating mesh, was a safe adjunctive therapeutic strategy for COS-AB VAP. Its right place and efficacy in this setting warrant investigation in interventional studies