Clinical Aspects of Melatonin Intervention in Alzheimer’s Disease Progression

Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called “sundowning”). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were “Alzheimer” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated

Evolution of innovation policy in Emilia-Romagna and Valencia: Similar reality, similar results?

This is an author's accepted manuscript of an article published in: “European Planning Studies"; Volume 22, Issue 11, 2014; copyright Taylor & Francis; available online at: http://dx.doi.org/10.1080/09654313.2013.831398[EN] This paper examines the evolution of regional innovation policy in Emilia-Romagna and Valencia, two regions with similar economic features that implemented close innovation policies in the 1970s and 1980s. We investigate whether their similarities have led to parallel targets, policy tools and governance developments. We show that innovation policy in both regions suffered from the effects of privatization, budget constraints and changes to manufacturing during the 1990s and we highlight the consequences. Although Emilia-Romagna experienced deeper changes to its innovation policy, privatizations and/or the replacement of public funds promoted commercial approaches and induced market failures in both regions. The worst effects of these policies were the implementation of less-risky innovation projects, the shift towards extraregional projects and markets, and the favouring of large firms.López Estornell, M.; Barberá Tomás, JD.; Garcia Reche, A.; Mas Verdú, F. (2013). Evolution of innovation policy in Emilia-Romagna and Valencia: Similar reality, similar results?. European Planning Studies. 22(11):2287-2304. doi:10.1080/09654313.2013.831398S22872304221

A renewable energy community of DC nanogrids for providing balancing services

The massive expansion of Distributed Energy Resources and schedulable loads have forced a variation of generation, transmission, and final usage of electricity towards the paradigm of Smart Communities microgrids and of Renewable Energy Communities. In the paper, the use of multiple DC microgrids for residential applications, i.e., the nanogrids, in order to compose and create a renewable energy community, is hypothesized. The DC Bus Signaling distributed control strategy for the power management of each individual nanogrid is applied to satisfy the power flow requests sent from an aggregator. It is important to underline that this is an adaptive control strategy, i.e., it is used when the nanogrid provides a service to the aggregator and when not. In addition, the value of the DC bus voltage of each nanogrid is communicated to the aggregator. In this way, the aggregator is aware of the regulation capacity that each nanogrid can provide and which flexible resources are used to provide this capacity. The effectiveness of the proposed control strategy is demonstrated via numerical experiments. The energy community considered in the paper consists of five nanogrids, interfaced to a common ML-LV substation. The nanogrids, equipped with a photovoltaic plant and a set of lithium-ion batteries, participate in the balancing service depending on its local generation and storage capacity. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

New insights into potocki-shaffer syndrome: Report of two novel cases and literature review

Potocki-Shaffer syndrome (PSS) is a rare non-recurrent contiguous gene deletion syndrome involving chromosome 11p11.2. Current literature implies a minimal region with haploinsufficiency of three genes, ALX4 (parietal foramina), EXT2 (multiple exostoses), and PHF21A (craniofacial anomalies, and intellectual disability). The rest of the PSS phenotype is still not associated with a specific gene. We report a systematic review of the literature and included two novel cases. Because deletions are highly variable in size, we defined three groups of patients considering the PSS-genes involved. We found 23 full PSS cases (ALX4, EXT2, and PHF21A), 14 cases with EXT2-ALX4, and three with PHF21A only. Among the latter, we describe a novel male child showing developmental delay, café-au-lait spots, liner postnatal overgrowth and West-like epileptic encephalopathy. We suggest PSS cases may have epileptic spasms early in life, and PHF21A is likely to be the causative gene. Given their subtle presentation these may be overlooked and if left untreated could lead to a severe type or deterioration in the developmental plateau. If our hypothesis is correct, a timely therapy may ameliorate PSS phenotype and improve patients’ outcomes. Our analysis also shows PHF21A is a candidate for the overgrowth phenotype

A novel SDS-stable dimer of a heterogeneous nuclear ribonucleoprotein at presynaptic terminals of squid neurons

Author Posting. © The Author(s), 2015. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Neuroscience 300 (2015): 381-392, doi:10.1016/j.neuroscience.2015.05.040.The presence of mRNAs in synaptic terminals and their regulated translation are important factors in neuronal communication and plasticity. Heterogeneous nuclear ribonucleoprotein (hnRNP) complexes are involved in the translocation, stability, and subcellular localization of mRNA and the regulation of its translation. Defects in these processes and mutations in components of the hnRNP complexes have been related to the formation of cytoplasmic inclusion bodies and neurodegenerative diseases. Despite much data on mRNA localization and evidence for protein synthesis, as well as the presence of translation machinery, in axons and presynaptic terminals, the identity of RNA-binding proteins involved in RNA transport and function in presynaptic regions is lacking. We previously characterized a strongly basic RNA-binding protein (p65), member of the hnRNP A/B subfamily, in squid presynaptic terminals. Intriguingly, in SDS-PAGE, p65 migrated as a 65 kDa protein, whereas members of the hnRNP A/B family typically have molecular masses ranging from 35 to 42 kDa. In this report we present further biochemical and molecular characterization that shows endogenous p65 to be an SDS-stable dimer composed of ~37 kDa hnRNPA/B-like subunits. We cloned and expressed a recombinant protein corresponding to squid hnRNPA/B-like protein and showed its propensity to aggregate and form SDS-stable dimers in vitro. Our data suggest that this unique hnRNPA/B-like protein co-localizes with synaptic vesicle protein 2 and RNA-binding protein ELAV and thus may serve as a link between local mRNA processing and presynaptic function and regulation.Research was supported by grants to REL from the Fundação de Amparo à Pesquisa do Estado de Sao Paulo (FAPESP), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da FMRP-USP (FAEPA). JAD received financial support from the RI-INBRE Program Grant #8 P20 GM103430-12 from the National Institute of General Medical Sciences, NIH, Bethesda, MD. DTPL and GSL received research fellowships from FAPESP and CNPq. REL and JCR received the Productivity-in-Research fellowship from CNPq

High frequency of ribosomal protein gene deletions in Italian Diamond-Blackfan anemia patients detected by multiplex ligation-dependent probe amplification assay

Diamond-Blackfan anemia is an autosomal dominant disease due to mutations in nine ribosomal protein encoding genes. Because most mutations are loss of function and detected by direct sequencing of coding exons, we reasoned that part of the approximately 50% mutation negative patients may have carried a copy number variant of ribosomal protein genes. As a proof of concept, we designed a multiplex ligation-dependent probe amplification assay targeted to screen the six genes that are most frequently mutated in Diamond-Blackfan anemia patients: RPS17, RPS19, RPS26, RPL5, RPL11, and RPL35A. Using this assay we showed that deletions represent approximately 20% of all mutations. The combination of sequencing and multiplex ligation-dependent probe amplification analysis of these six genes allows the genetic characterization of approximately 65% of patients, showing that Diamond-Blackfan anemia is indisputably a ribosomopathy

Postnatal Changes in K+/Cl- Cotransporter-2 Expression in the Forebrain of Mice Bearing a Mutant Nicotinic Subunit Linked to Sleep-Related Epilepsy

ABSTRACT The Na+/K+/Cl- cotransporter-1 (NKCC1) and the K+/Cl- cotransporter-2 (KCC2) set the transmembrane Cl- gradient in the brain, and are implicated in epileptogenesis. We studied the postnatal distribution of NKCC1 and KCC2 in wild-type (WT) mice, and in a mouse model of sleep-related epilepsy, carrying the mutant \u3b22-V287L subunit of the nicotinic acetylcholine receptor (nAChR). In WT neocortex, immunohistochemistry showed a wide distribution of NKCC1 in neurons and astrocytes. At birth, KCC2 was localized in neuronal somata, whereas at subsequent stages it was mainly found in the somatodendritic compartment. The cotransporters\u2019 expression was quantified by densitometry in the transgenic strain. KCC2 expression increased during the first postnatal weeks, while the NKCC1 amount remained stable, after birth. In mice expressing \u3b22-V287L, the KCC2 amount in layer V of prefrontal cortex (PFC) was lower than in the control littermates at postnatal day 8 (P8), with no concomitant change in NKCC1. Consistently, the GABAergic excitatory to inhibitory switch was delayed in PFC layer V of mice carrying \u3b22-V287L. At P60, the amount of KCC2 was instead higher in mice bearing the transgene. Irrespective of genotype, NKCC1 and KCC2 were abundantly expressed in the neuropil of most thalamic nuclei since birth. However, KCC2 expression decreased by P60 in the reticular nucleus, and more so in mice expressing \u3b22-V287L. Therefore, a complex regulatory interplay occurs between heteromeric nAChRs and KCC2 in postnatal forebrain. The pathogenetic effect of \u3b22-V287L may depend on altered KCC2 amounts in PFC during synaptogenesis, as well as in mature thalamocortical circuits

A programme evaluation of \u27First Steps\u27: A peer-conceived, developed and led self-management intervention for people after a Parkinson\u27s diagnosis

\ua9 The Author(s) 2023. Objective: A diagnosis of Parkinson\u27s often leads to uncertainty about the future and loss of perceived control. Peer support may offer a means to address these concerns and promote self-management. Design: A programme evaluation of the feasibility and potential effects of ‘First Steps’, utilising a pragmatic step wedge approach. Comparing First Steps (intervention) to (control) conditions. Setting: In the community at four sites in southern England. Participants: Newly diagnosed (≤ 12months) people with Parkinson\u27s. Intervention: First Steps was a 2-day peer-conceived, developed and led intervention to support self-management. Main measures: At 0, 12 and 24 weeks anxiety and depression (Hospital, Anxiety and Depression Scale, HADS), daily functioning (World Health Organisation Disability Assessment Schedule, WHODAS), physical activity, quality of life (EQ5D), carer strain and service utilisation were assessed. Results: Between February 2018 and July 2019, 36 participants were enrolled into intervention and 21 to control conditions, all were included in statistical analysis. Lost to follow up was n = 1 (intervention) and n = 1 adverse event was reported (control, unrelated). Of the 36 allocated to the intervention n = 22 participants completed both days of First Steps during the study period. Completion of outcome measures was >95% at 24 weeks. Small effects favouring the intervention were found for HADS (odds ratio (OR) = 2.06, 95% confidence interval (CI) 0.24:17.84), Carer Strain Index (OR = 2.22, 95% CI 0.5:9.76) and vigorous (d = 0.42, 95% CI −0.12:0.97) and total physical activity (d = 0.41, 95% CI −0.13:0.95). EQ5D, WHOSDAS and service utilisation, was similar between groups. Conclusions: First Steps was feasible and safe and we found potential to benefit physical activity, mental health and carer strain. Further research with longer-term follow up is warranted