Soluble Semicarbazide Sensitive Amine Oxidase (SSAO) catalysis induces apoptosis in vascular smooth muscle cells

AbstractSemicarbazide sensitive amine oxidase (SSAO) metabolizes oxidative deamination of primary aromatic and aliphatic amines. It is selectively expressed in vascular cells of blood vessels, but it is also circulating in blood plasma. SSAO activity in plasma is increased in some diseases associated with vascular complications and its catalytic products may cause tissue damage. We examined the effect of the oxidation of the SSAO substrate, methylamine, on cultured smooth muscle cells. Cell incubation with methylamine plus soluble SSAO, contained in bovine serum, resulted toxic to rat aorta A7r5 and human aortic smooth muscle cells, as measured by MTT reduction. This effect was completely reverted by specific SSAO inhibitors, indicating that the toxicity was mediated by the end products generated. Moreover, SSAO-mediated deamination of methylamine induced apoptosis in A7r5 cells, detected by chromatin condensation, Caspase-3 activation, PARP cleavage and cytochrome c release to cytosol. Formaldehyde, rather than H2O2, resulted to be a strong apoptotic inducer to A7r5 cells. Taken together, the results suggest that increased plasma SSAO activity in pathological conditions, could contribute to apoptosis in smooth muscle cells, leading to vascular tissue damage

Estudio longitudinal de la comunicación referencial en niños de 4 a 8 años

This paper analyzes communicative behaviour in a longitudinal study with ten pairs of children, evaluated for the first time at age 4;6 and reevaluated at age 6;6 and 8;7. The procedure used follows the lines of referential-ecological research which incorporates an appraisal of the guidance offered by the adult examiner. The results refect the structural characteristics of communication, the communicative strategies produced by the three interlocutors and the sequential interaction patterns. They show the persistence of certain structures, an increase in the number of strategies used, and an increase in the complexity of communicative patterns with age. These results confirm the hypothesis of increasing communicative competence with age while simultaneously confirming the fall in the adult's guiding function, thus implying greater awareness of the processes involved in language emission-comprehension. The relationship between awareness, regulation and metacognitive processes should be explored further in future studies.El presente trabajo analiza las conductas comunicativas en un estudio longitudinal de 10 parejas de niños, evaluados por primera vez a los 4;6 años y reevaluados a los 6;6 y 8;7 años de edad. El procedimiento utilizado se sitúa en la línea de investigación referencial-ecológica, caracterizada por incorporar al paradigma referencial clásico el análisis de la guia que proporciona el adulto experimentador. Los resultados presentados conciernen a las características estructurales de la comunicación, las estrategias comunicativas producidas por los tres interlocutores y los patrones secuenciales de la interacción. Los resultados muestran la permanencia de ciertas estructuras y un incremento de las estrategias y la complejidad de los patrones comunicatives con la edad. Estos resultados confirman la hipótesis del incremento de competencia comunicativa con la edad, que simultáneamente a la constatación del descenso de la función de tutela del adulto, implican una mayor toma de conciencia de los procesos involucrados en la emisión-comprensión del lenguaje. La relación entre toma de conciencia, regulación y procesos metacognitivos deberá continuar explordndose en próximos estudios

Estudio longitudinal de la comunicación referencial en niños de 4 a 8 años

El presente trabajo analiza las conductas comunicativas en un estudio longitudinal de 1O parejas de niños, evaluados por primera vez a los 4;6 años y reevaluados a los 6;6 y 8;7 años de edad. El procedimiento utilizado se sitúa en la línea de investigación referencial-ecológica, caracterizada por incorporar al paradigma referencial clásico el análisis de la guia que proporciona el adulto experimentador. Los resultados presentados conciemen a las características estructurales de la comunicación, las estrategias comunicativas producidas por los tres interlocutores y los patrones secuenciales de la interacción. Los resultados muestran la permanencia de ciertas estructuras y un incremento de las estrategias y la complejidud de los patrones comunicatives con la edad. Estos resultados confirman la hipótesis del incremento de competencia comunicativa con la edad, que simultáneamente a la constatación del descenso de la función de tutela del adulto, implican una mayor toma de conciencia de loss procesos involucrados en la emisión-comprensión del lenguaje. La relación entre toma de conciencia, regulación y procesos metacognitivos deberd continuar explorándose en próximos estudios

Stromal vascular fraction therapy for knee osteoarthritis: a systematic review

Background: Regenerative cell therapies, such as adipose-derived stromal vascular fraction (SVF), have been postulated as potential treatments for knee osteoarthritis (KOA). Objectives: To assess the efficacy and safety of SVF treatment against placebo and other standard therapies for treating KOA in adult patients. Design: A systematic review. Data sources and methods: We searched the following databases: MEDLINE via PubMed, Epistemonikos, PEDro, DynaMed, TripDatabase, Elsevier via Clinicalkey and Cochrane Controlled Trials Register. We included prospective interventional studies where treatment with SVF in adults with KOA was compared against placebo or other standard therapies, and results were objectively measured with at least one widely recognised osteoarthritis scale. Results: Among 266 studies published until May 2021, nine met our inclusion criteria. A total of 239 patients (274 knees) were included in our study. The follow-up ranged from 6 to 24 months. Six studies had a control group (only one being placebo). All studies showed that SVF improved pain and functionality measured, in most cases, with the visual analogue scale and the Western Ontario and McMaster Universities Osteoarthritis Index. In addition, five studies reported an improvement in anatomical structures, as detected in MR images. However, the number of cells contained in SVF varied substantially between different studies, which could induce a comparison bias. Conclusion: Although based on a small number of dissimilar studies, SVF was considered a safe treatment for KOA and could be promising in terms of pain, functionality and anatomical structure improvement. However, SVF products need to be standardised, the number of cells homogenised and the use of concomitant treatments reduced to establish proper comparisons

Ubiquitin-negative mini-pick like bodies in the dentate gyrus of p30l tauopathy.

Neuropathological and biochemical findings are reported in a patient who had suffered from frontotemporal dementia associated with a P310L mutation in the tau gene and included in the H1 haplotype. Tau accumulation, as revealed with phospho-specific anti-tau antibodies Thr181, Ser199, Ser202, Ser214, Ser262, Ser396, Ser422 and AT8 (Ser202 and Thr205), was found in neurons with pre-tangles, and astrocytes and oligodendrocytes through the brain. The most characteristic feature was tau immunoreactivity decorating the perinuclear region and small cytoplasmic aggregates designed as mini-Pick-like bodies, mainly in the dentate gyrus. Inclusions were not stained with anti-ubiquitin antibodies and did not recruit tubulins. Tau accumulation in individual cells was associated with increased expression of kinases linked with tau phosphorylation, mainly active (phosphorylated) stress kinases SAPK/JNK and p38 (SAPK/JNK-P and p38-P). Phosphorylated GSK-3 beta at Ser9 (GSK-3 beta-P), that inactivates the kinase, was particularly abundant in mini-Pick-like bodies, thus suggesting alternative roles of GSK-3 probably involved in cell survival. Western blots of sarkosyl-insoluble fractions revealed a double band pattern of phospho-tau of 68/66 kDa and 64 kDa in the hippocampus and white matter in the P310L mutation. Sarkosyl-insoluble fractions of the hippocampus were enriched in p38-P and GSK-3 beta-P in Alzheimer's disease (AD) cases, processed in parallel for comparative purposes, but not in the P310L mutation. In addition, no bands of high molecular weight were found in P310L in contrast with AD in these fractions. These findings indicate that the major sites of tau phosphorylation, and the expression of kinases involved in tau phosphorylation are active in P310L mutation as in AD and other tauopathies. Yet the P310L mutation has particular phospho-tau inclusions that are not tag with ubiquitin and appear to be rather soluble when compared with AD

Design of a comprehensive Alzheimer’s disease clinic and research center in Spain to meet critical patient and family needs

AbstractObjectivesAlzheimer's disease (AD) affects people worldwide, and the prevalence is increasing as the population ages. There is an international effort to understand the biology of AD to develop primary and secondary prevention strategies, and to develop effective therapeutic interventions for individuals who are already symptomatic. One of the critically important pieces of all national plans to address AD is the call for the development of service models to deliver quality, effective care based on the best evidence available.MethodsWe describe one type of care model developed by the Fundacio ACE, Institut Catala de Neurociencies Aplicades (Fundacio ACE, Barcelona, Spain) that integrates diagnosis, therapy, follow-up care, daycare, and a day hospital, and does so in the context of an active clinical research and educational program.ResultsThere were 13,048 individuals newly evaluated and diagnosed in Fundacio ACE between 1996 and 2011. Of these, 6132 had AD (47.0%), 3871 had mild cognitive impairment (MCI) (29.7%), and 1958 had no cognitive impairment (15.0%). Follow-up information is available on 4735 (47.3%) AD and MCI patients, and these data indicate that MCI develops into dementia at a rate of 222.6/1000 person-years. Apolipoprotein E (APOE) genotyping was available in 22.4% of the patients. The ε4 allele occurred in 45.7% of the AD patients, in 37.8% of the MCI subjects, and in 31.6% of those without cognitive impairment.ConclusionsFundació ACE can serve as a model system that can be adapted to other settings within their specific cultural, governmental, and legal constraints

Complementary pre-screening strategies to uncover hidden prodromal and mild Alzheimer's disease: Results from the MOPEAD project

Diagnostic gap; Early diagnosis; PopulationBrecha de diagnóstico; Diagnóstico precoz; PoblaciónBretxa de diagnòstic; Diagnòstic precoç; PoblacióIntroduction: The Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project was conceived to explore innovative complementary strategies to uncover hidden prodromal and mild Alzheimer's disease (AD) dementia cases and to raise awareness both in the general public and among health professionals about the importance of early diagnosis. Methods: Four different strategies or RUNs were used: (a) a web-based (WB) prescreening tool, (2) an open house initiative (OHI), (3) a primary care-based protocol for early detection of cognitive decline (PC), and (4) a tertiary care-based pre-screening at diabetologist clinics (DC). Results: A total of 1129 patients at high risk of having prodromal AD or dementia were identified of 2847 pre-screened individuals (39.7%). The corresponding proportion for the different initiatives were 36.8% (WB), 35.6% (OHI), 44.4% (PC), and 58.3% (DC). Conclusion: These four complementary pre-screening strategies were useful for identifying individuals at high risk of having prodromal or mild AD.This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No 115985. This Joint Undertaking receives support from the European Union's Horizon 2020 Research and Innovation program and the European Federation of Pharmaceutical Industries and Associations. www.imi.europa.eu/. All participants provided informed consent

Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer’s disease: additional results from the AMBAR study

Albumin; Intravenous immunoglobulin; PlasmapheresisAlbúmina; Inmunoglobulina intravenosa; PlasmaféresisAlbúmina; Immunoglobulina intravenosa; PlasmafèresiPurpose This study was designed to detect structural and functional brain changes in Alzheimer’s disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. Methods Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) were performed. Results MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. Conclusions PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG.The AMBAR study is sponsored by Grifols, a manufacturer of therapeutic human serum albumin and intravenous immune globulin. GC-B, IR, JC-C, DP, MBo, and OLL received direct or indirect funding from Grifols to carry out the study and the preparation of the manuscript

Analysis of embodied energy and product lifespan: the potential embodied power sustainability indicator

In the context of life cycle assessment sustainability indicators, this article proposes a new indicator that is related to the embodied energy, in order to assess the lifespan of products based on their components. The indicator, called 'potential embodied power' (PEP), considers that a non-replaceable component with a shorter lifespan will determine the lifetime of the product. The PEP indicator can be considered as an inherent property of the product, and it can be optimized by using a material selection method based on the concept of annualized embodied energy. This indicator can be used for product design decision making, since it determines the impact of product disposal in relation to the lifespan for which the product was designed. Also, a methodology is proposed to contribute to evaluating the environmental impact caused by the energy discarded resulting from the design decisions. A case study was performed on smartphones, and the results show that the variation of factors such as module lifespan or embodied energy allows achieving a lower value of the embodied power

Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer's disease

Altres ajuts: This work was supported by grants from , Fundació La Marató TV3 (TV3-2014-3610), CIBERNED (CB06/05/0042 and PI2017/01) to JRA. DSW was supported by the Fundació La Marató TV3. JCS is a recipient of a Ph.D. Fellowship from the Ministerio de Ciencia, Innovación y Universidades. CF is a recipient of a Ph.D. Fellowship from the Department of Biochemistry and Molecular Biology of the Universitat Autònoma de Barcelona.Several evidences suggest that failure of synaptic function occurs at preclinical stages of Alzheimer's disease (AD) preceding neuronal loss and the classical AD pathological hallmarks. Nowadays, there is an urgent need to identify reliable biomarkers that could be obtained with non-invasive methods to improve AD diagnosis at early stages. Here, we have examined plasma levels of a group of miRNAs related to synaptic proteins in a cohort composed of cognitive healthy controls (HC), mild cognitive impairment (MCI) and AD subjects. Plasma and brain levels of miRNAs were analysed in two different cohorts including 38 HC, 26 MCI, 56 AD dementia patients and 27 frontotemporal dementia (FTD) patients. D'Agostino and Pearson and Shapiro-Wilk tests were used to evaluate data normality. miRNA levels between groups were compared using a two-sided nonparametric Mann-Whitney test and sensitivity and specificity was determined by receiver operating characteristic curve analysis. Significant upregulation of miR-92a-3p, miR-181c-5p and miR-210-3p was found in the plasma of both MCI and AD subjects. MCI patients that progress to AD showed higher plasma levels of these miRNAs. By contrast, no changes in miR-92a-3p, miR-181c-5p or miR-210-3p levels were observed in plasma obtained from a cohort of FTD. Our study shows that plasma miR-92a-3p, miR-181c-5p and miR-210-3p constitute a specific molecular signature potentially useful as a potential biomarker for AD. The online version of this article (10.1186/s13195-019-0501-4) contains supplementary material, which is available to authorized users