2-arachidonoylglycerol metabolism is differently modulated by oligomeric and fibrillar conformations of amyloid beta in synaptic terminals

Alzheimer´s disease (AD) is the most prevalent disorder of senile dementia mainly characterized by amyloid-beta peptide (Aβ) deposits in the brain. Cannabinoids are relevant to AD as they exert several beneficial effects in many models of this disease. Still, whether the endocannabinoid system is either up- or down-regulated in AD has not yet been fully elucidated. Thus, the aim of the present paper was to analyze endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in cerebral cortex synaptosomes incubated with Aβ oligomers or fibrils. These Aβ conformations were obtained by "aging" the 1-40 fragment of the peptide under different agitation and time conditions. A diminished availability of 2-AG resulting from a significant decrease in diacylglycerol lipase (DAGL) activity was observed in the presence of large Aβ1-40 oligomers along with synaptosomal membrane damage, as judged by transmission electron microscopy and LDH release. Conversely, a high availability of 2-AG resulting from an increase in DAGL and lysophosphatidic acid phosphohydrolase activities occurred in the presence of Aβ1-40 fibrils although synaptosomal membrane disruption was also observed. Interestingly, neither synaptosomal mitochondrial viability assayed by MTT reduction nor membrane lipid peroxidation assayed by TBARS formation measurements were altered by Aβ1-40 oligomers or fibrils. These results show a differential effect of Aβ1-40 peptide on 2-AG metabolism depending on its conformation.Fil: Pascual, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Gaveglio, Virginia Lucía. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Giusto, Norma Maria. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Pasquaré, Susana Juana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentin

Towards a better method of cannabinoid extraction and preservation for cannabis-based products

Recombinant human erythropoietin (Epo) has been successful in the treatment of anemia of different etiologies but high Epo doses, used to reduce the frequency of administration or to treat refractory anemia, have been linked with adverse outcomes. Previously, we observed a decreased effect of high Epo concentrations on endothelial cell migration. Here, we studied the antiapoptotic effect of Epo on erythroleukemia K562 cells exposed to TNF-a (T), after incubation with increasing concentrations of Epo (10, 100 and 400 U/mL) and erythroid differentiation with hemin. While Epo10 prevented the increase in the percentage of apoptotic nuclei observed with TNF-a, Epo100 and Epo400 did not show that protection. Considering that this effect could be related to the decreased availability of the Epo receptor, we investigated the activity of protein tyrosine phosphatase 1B (PTP1B) and the process of proteasomal degradation in this cell model. PTP1B activity, which regulates many aspects of the signaling pathways elicited by Epo upon EpoR activation, showed no significant differences between cultures with low and high Epo concentrations. Then, we used the proteasome inhibitor MG132 to evaluate if EpoR internalization could affect the antiapoptotic effect of Epo against TNF-a. In the presence of MG132, the results with high concentrations of Epo were similar to those observed with Epo10T (Hoechst staining, C 13.5 ± 0.7, T 31.5 ± 1.5*, Epo10T 22.1 ± 1.1*, Epo100T 29.4 ± 1.4*, Epo400T 29.9 ± 2.2*, Epo100TMG 21.7 ± 19, and Epo400TMG 22 ± 1.3 %, *P<0.05, n= 6). Based on this, it can be suggested that the kinetics of EpoR internalization/degradation, mediated by the proteasome, could explain, at least in part, the lack of antiapoptotic effect of high concentrations of Epo. The present results give new insights that may contribute to understand Epo behavior when cells of different tissues are activated by a high concentration of the hormone, and may help to adequate therapeutic strategies.Fil: Chamorro Aguirre, Estefania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Pascual, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Milano, Pablo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bocetti, Marisol Claudia. Provincia de Buenos Aires. Municipalidad de Bahía Blanca; ArgentinaFil: Pasquaré, Susana Juana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaReunión Anual de Sociedades de BiocienciaMar del PlataArgentinaSociedad Argentina de Investigación ClínicaAsociación Argentina de Farmacología ExperimentalSociedad Argentina de BiologíaAsociación Argentina de Nanomedicina

Wind effects on the migration routes of trans-Saharan soaring raptors: geographical, seasonal and interspecific variation.

Wind is among the most important environmental factors shaping birds' migration patterns. Birds must deal with the displacement caused by crosswinds and their behavior can vary according to different factors such as flight mode, migratory season, experience, and distance to goal areas. Here we analyze the relationship between wind and migratory movements of three raptor species which migrate by soaring-gliding flight: Egyptian vulture Neophron percnopterus , booted eagle Aquila pennata , and short-toed snake eagle Circaetus gallicus . We analyzed daily migratory segments (i.e., the path joining consecutive roosting locations) using data recorded by GPS satellite telemetry. Daily movements of Egyptian vultures and booted eagles were significantly affected by tailwinds during both autumn and spring migrations. In contrast, daily movements of short-toed eagles were only significantly affected by tailwinds during autumn migration. The effect of crosswinds was significant in all cases. Interestingly, Egyptian vultures and booted eagles showed latitudinal differences in their behavior: both species compensated more frequently at the onset of autumn migration and, at the end of the season when reaching their wintering areas, the proportion of drift segments was higher. In contrast, there was a higher drift at the onset of spring migration and a higher compensation at the end. Our results highlight the effect of wind patterns on the migratory routes of soaring raptors, with different outcomes in relation to species, season, and latitude, ultimately shaping the loop migration patterns that current tracking techniques are showing to be widespread in many long distance migrants

Search Foraging Strategies of Migratory Raptors Under Different Environmental Conditions

Several studies have shown in different organisms how their movements can be fitted to different patterns to optimize search of food resources. According to abundance and availability of resources, different strategies will be optimal, such as Lévy and Brownian random search. We analyze the movement patterns of four species of migratory raptors with different degrees of ecological specialization in diet during the breeding and wintering periods to evaluate the differences according to species and season: the Egyptian Vulture, the Short-toed Snake Eagle, the Booted Eagle, and the Red Kite. From GPS locations, we obtained a set of segments and lengths that were analyzed to verify their fitting to the functions of Lévy and Brownian strategies. Egyptian Vulture’s trajectories fitted to both patterns during the breeding period, whereas during the wintering period most trajectories fitted a Brownian pattern. In the case of the Short-toed Eagle, fit was greater to a Lévy strategy throughout the year, while Booted Eagles and Red Kites exhibited a combination of search patterns. These differences could be accounted for different feeding strategies and environmental context over the annual cycle. In species with a specialized diet (i.e., Short-toed Eagle) the Lévy pattern would maximize the encounters with scarce and unpredictable resources, whereas for species with a broad trophic niche (i.e., Booted Eagle and Red Kite), movements could be adapted to exploit different resources according to their abundance. Scavengers like the Egyptian Vulture shift also between search strategies according to the distribution of carrion. Therefore, the analysis of food search patterns can be used as an indirect indicator to track changes in food availability across a broad range of environmental conditions. This is particularly important under the current context of global change which is largely expected to affect migratory species that spend their vital cycle in distant areas.Tracking of Booted Eagles and Red Kites has been made within the “Migra” program (www.migraciondeaves.org/en/) developed by SEO/BirdLife and financed by Fundación Iberdrola España. The Basque Government and the Biodiversity Foundation financed the tagging of several Red Kites in Spain. Tracking of Italian individuals was funded by Gallipoli Cognato Piccole Dolomiti Lucane Regional Park (Italy). Servicio de Vida Silvestre (Generalitat Valenciana) and different local governments funded part of the tagging. JV-M was supported by a FPU grant of Spanish Ministry of Education (reference FPU014/04671)

Dietary Patterns in Pregnancy and Biomarkers of Oxidative Stress in Mothers and Offspring: The NELA Birth Cohort

©. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Published, version of a Published Work that appeared in final form in Frontiers in nutrition. To access the final edited and published work see https://doi.org/10.3389/fnut.2022.869357Background: Although adherence to the Mediterranean and antioxidant-rich diets during pregnancy is suggested to improve maternal-fetal health by reducing oxidative stress, yet there is no study available. Objective: We examined whether maternal dietary patterns in pregnancy impact the biomarkers of oxidative stress in mothers and their offspring. Methods: Study population included 642 mothers and 335 newborns of the "Nutrition in Early Life and Asthma" (NELA) birth cohort. Maternal diet during pregnancy was assessed by a validated food frequency questionnaire and a priori-defined dietary indices (relative Mediterranean Diet [rMED], alternative Mediterranean Diet [aMED], Dietary Approach to Stop Hypertension [DASH], Alternate Healthy Index [AHEI], and AHEI-2010) were calculated. Biomarkers measured were: hydroperoxides, carbonyl groups, and 8-hydroxydeoxyguanosine (8OHdG) determined in maternal blood and newborn cord blood, and urinary maternal and offspring 15-F2t-isoprostane. Multivariate linear regression models were performed. Results: Maternal rMED score was inversely associated with the maternal levels of 8OHdG at mid-pregnancy (beta per 1-point increase = -1.61; 95% CI -2.82, -0.39) and the newborn levels of hydroperoxides (beta per 1-point increase = -4.54; 95% CI -9.32, 0.25). High vs. low maternal rMED score was marginally associated with the decreased levels of 8OHdG in newborns (beta = -9.17; 95% CI -19.9, 1.63; p for trend 0.079). Maternal DASH score tended to be inversely associated with maternal urinary 15-F2t-isoprostane (beta per 1-point increase = -0.69; 95% CI, -1.44, 0.06). High vs. low maternal AHEI score was associated with reduced offspring urinary levels of 15-F2t-isoprostane (beta = -20.2; 95% CI -38.0, -2.46; p for trend 0.026). Conclusion: These results suggest that maternal adherence to healthy dietary patterns during pregnancy may reduce DNA damage and lipid oxidation in mothers and offspring

Antibodies against the flotillin-1/2 complex in patients with multiple sclerosis

Lleixa and Caballero-avila et al. report that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis. Multiple sclerosis is a tissue-specific autoimmune disease of the central nervous system in which the antigen(s) remains elusive. Antibodies targeting the flotillin-1/2 complex have been described in 1-2% of the patients in a recent study. Other candidate antigens as anoctamin-2 or neurofascin-155 have been previously described in multiple sclerosis patients, although their clinical relevance remains uncertain. Our study aims to analyse the frequency and clinical relevance of antibodies against neurofascin-155, anoctamin-2 and flotillin-1/2 complex in multiple sclerosis. Serum (n = 252) and CSF (n = 50) samples from 282 multiple sclerosis patients were included in the study. The control group was composed of 260 serum samples (71 healthy donors and 189 with other neuroinflammatory disorders). Anti-flotillin-1/2, anti-anoctamin-2 and anti-neurofascin-155 antibodies were tested by cell-based assays using transfected cells. We identified six multiple sclerosis patients with antibodies against the flotillin-1/2 complex (2.1%) and one multiple sclerosis patient with antibodies against anoctamin-2 (0.35%). All multiple sclerosis patients were negative for anti-neurofascin-155 antibodies. Three of the anti-flotillin-1/2 positive patients showed anti-flotillin-1/2 positivity in other serum samples extracted at different moments of their disease. Immunoglobulin G subclasses of anti-flotillin-1/2 antibodies were predominantly one and three. We confirm that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis

Impact of the COVID-19 pandemic on the self-care and health condition of the older adults. CUIDAMOS+75. A mixed methods study protocol

Aims: To assess the impact of the COVID-19 pandemic on the health condition of people >= 75 years of age and on their family caregivers in Spain. Design: Multicentric, mixed method concurrent study. Methods: This work, which will be conducted within the primary care setting in 11 administrative regions of Spain, will include three coordinated studies with different methodologies. The first is a population-based cohort study that will use real-life data to analyze the rates and evolution of health needs, care provision, and services utilization before, during, and after the pandemic. The second is a prospective cohort study with 18 months of follow-up that will evaluate the impact of COVID-19 disease on mortality, frailty, functional and cognitive capacity, and quality of life of the participants. Finally, the third will be a qualitative study with a critical social approach to understand and interpret the social, political, and economic dimensions associated with the use of health services during the pandemic. We have followed the SPIRIT Checklist to address trial protocol and related documents. This research is being funded by the Instituto de Salud Carlos III since 2021 and was approved by its ethics committee (June 2022). Discussion: The study findings will reveal the long-term impact of the COVID-19 pandemic on the older adults and their caregivers. This information will serve policymakers to adapt health policies to the needs of this population in situations of maximum stress, such as that produced by the COVID-19 pandemic. Trial Registration: Identifier: NCT05249868 [ClinicalTrials.gov]

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections

COVID-19 Severity and Survival over Time in Patients with Hematologic Malignancies: A Population-Based Registry Study

Mortality rates for COVID-19 have declined over time in the general population, but data in patients with hematologic malignancies are contradictory. We identified independent prognostic factors for COVID-19 severity and survival in unvaccinated patients with hematologic malignancies, compared mortality rates over time and versus non-cancer inpatients, and investigated post COVID-19 condition. Data were analyzed from 1166 consecutive, eligible patients with hematologic malignancies from the population-based HEMATO-MADRID registry, Spain, with COVID-19 prior to vaccination roll-out, stratified into early (February–June 2020; n = 769 (66%)) and later (July 2020–February 2021; n = 397 (34%)) cohorts. Propensity-score matched non-cancer patients were identified from the SEMI-COVID registry. A lower proportion of patients were hospitalized in the later waves (54.2%) compared to the earlier (88.6%), OR 0.15, 95%CI 0.11–0.20. The proportion of hospitalized patients admitted to the ICU was higher in the later cohort (103/215, 47.9%) compared with the early cohort (170/681, 25.0%, 2.77; 2.01–3.82). The reduced 30-day mortality between early and later cohorts of non-cancer inpatients (29.6% vs. 12.6%, OR 0.34; 0.22–0.53) was not paralleled in inpatients with hematologic malignancies (32.3% vs. 34.8%, OR 1.12; 0.81–1.5). Among evaluable patients, 27.3% had post COVID-19 condition. These findings will help inform evidence-based preventive and therapeutic strategies for patients with hematologic malignancies and COVID-19 diagnosis.Depto. de MedicinaFac. de MedicinaTRUEFundación Madrileña de Hematología y HemoterapiaFundación Leucemia y LinfomaAsociación Madrileña de Hematología y Hemoterapiapu