Cholinergic-mediated IP3-ereceptor activation induces long-lasting synaptic enhancement in CA1 pyramidal neurons

Cholinergic–glutamatergic interactions influence forms of synaptic plasticity that are thought to mediate memory and learning. We tested in vitro the induction of long-lasting synaptic enhancement at Schaffer collaterals by acetylcholine (ACh) at the apical dendrite of CA1 pyramidal neurons and in vivo by stimulation of cholinergic afferents. In vitro ACh induced a Ca2+ wave and synaptic enhancement mediated by insertion of AMPA receptors in spines. Activation of muscarinic ACh receptors (mAChRs) and Ca2+ release from inositol 1,4,5-trisphosphate (IP3)-sensitive stores were required for this synaptic enhancement that was insensitive to blockade of NMDA receptors and also triggered by IP3 uncaging. Activation of cholinergic afferents in vivo induced an analogous atropine-sensitive synaptic enhancement. We describe a novel form of synaptic enhancement (LTPIP3) that is induced in vitro and in vivo by activation of mAChRs. We conclude that Ca2+ released from postsynaptic endoplasmic reticulum stores is the critical event in the induction of this unique form of long-lasting synaptic enhancement

Single Cord Blood Combined with HLA-Mismatched Third Party Donor Cells: Comparable Results to Matched Unrelated Donor Transplantation in High-Risk Patients with Hematologic Disorders

AbstractMatched unrelated donor (MUD) transplantation is the first alternative in the absence of a matched sibling donor. For patients without a suitable adult donor, we have adopted the dual stem cell transplantation protocol consisting of cord blood (CB) in combination with CD34+ cells from a third party HLA-mismatched donor. We analyzed the outcomes of patients undergoing both procedures in a single center. Starting in 2004, a total of 20 patients with high-risk disease underwent 22 dual transplants and 25 patients underwent myeloablative MUD transplantation. The 30-day cumulative incidence of neutrophil engraftment was similar in both groups (91% and 95%), with a median time to engraftment of 14 and 16 days, respectively. Grade II-IV acute graft-versus-host disease was more frequent in the MUD group (40% versus 5%). Except for a tendency toward a higher incidence of viral hemorrhagic cystitis in the dual transplantation group, posttransplantation infectious events were comparable in the 2 groups. The 3-year cumulative incidence rates of relapse (41% versus 44%) and nonrelapse mortality (30% versus 25%) were similar in the MUD and dual transplantation cohorts. Estimated 3-year overall survival and disease-free survival were 47% and 41%, respectively, with no survival advantage for either group. In our experience, dual transplantation offers survival rates comparable to those from myeloablative MUD transplantation with similar nonrelapse mortality rates

Metabolic syndrome and Growth Differentiation Factor 15 in older adults

This is a pre-print of an article published in GeroScience. The final authenticated version is available online at: https://doi.org/10.1007/s11357-021-00370-wGrowth Differentiation Factor 15 (GDF-15) is a cytokine produced in response to tissue injury and inflammatory states that may capture distinct pathways between the risk factors aggregated within metabolic syndrome (MS) and the development of diabetes and cardiovascular disease. Objective: To study the association of MS and its components with GDF-15 among older adults, examining the roles of body fat distribution, glucose metabolism, and inflammation. Methods: Data were taken from the Seniors-ENRICA-2 study in Spain, which included 1938 non-institutionalized individuals aged ≥65 years free of diabetes and cardiovascular disease. MS was defined as the presence of ≥3 of the following components: high waist circumference, elevated fasting blood glucose levels, raised blood pressure, increased triglyceride levels; and low serum high-density lipoprotein (HDL) cholesterol. Statistical analyses were performed with linear regression models and adjusted for potential sociodemographic and lifestyle confounders. Results: MS was associated with higher GDF-15 levels (fully adjusted mean increase [95% confidence interval] = 9.34% [5.16,13.7]). The MS components showing the strongest associations were high waist circumference (6.74% [2.97,10.6]), elevated glucose levels (4.91% [0.77,9.23]), and low HDL-cholesterol (8.13% [3.51,13.0]). High waist-to-hip ratio (7.07% [2.63,11.7]), urine albumin (12.1% [2.57,22.5]), and C-reactive protein (10.4% [3.89,17.3]) were also associated with increased GDF-15. Conclusion: MS was associated with higher GDF-15 levels in older adults. Abdominal obesity, hyperglycemia -possibly linked to microvascular disease, as inferred from elevated urine albumin-, low HDL-cholesterol, and inflammation were the main drivers of this associationThis work was supported by the Instituto de Salud Carlos III, State Secretary of R+D+I and FEDER/FSE (FIS grants 18/287, 19/319); grant 2020/017 from the National Plan on Drug Addiction (Ministry of Health), and the MITOFUN project grant from the Fundación Francisco Soria Melguiz

Biochemical algorithm to identify individuals with ALPL variants among subjects with persistent hypophosphatasaemia

Hypophosphatasia (HPP) is a rare and underdiagnosed condition characterized by deficient bone and teeth mineralization. The aim of this study was first, to evaluate the diagnostic utility of employing alkaline phosphatase (ALP) threshold levels to identify adults with variants in ALPL among individuals with persistently low ALP levels and second, to determine the value of also including its substrates (serum pyridoxal-5′-phosphate—PLP—and urinary phosphoetanolamine-PEA) for this purpose in order to create a biochemical algorithm that could facilitate the diagnostic work-up of HPP. Results: The study population comprised 77 subjects with persistent hypophosphatasaemia. They were divided into two groups according to the presence (+GT) or absence (−GT) of pathogenic ALPL variants: 40 +GT and 37 −GT. Diagnostic utility measures were calculated for different ALP thresholds and Receiver Operating Characteristic (ROC) curves were employed to determine PLP and PEA optimal cut-off levels to predict the presence of variants. The optimal threshold for ALP was 25 IU/L; for PLP, 180 nmol/L and for PEA, 30 µmol/g creatinine. Biochemical predictive models were assessed using binary logistic regression analysis and bootstrapping machine learning technique and results were then validated. For ALP 180 nmol/L) that when combined, seem to be very useful to identify individuals with ALPL variant

Efectos de la pandemia COVID-19 en la actividad asistencial de los laboratorios clínicos españoles, evolución 2019–2021

Objetivos. Cuantificar el impacto de la pandemia en la actividad asistencial de los laboratorios clínicos españoles. Métodos. Estudio descriptivo, observacional, retrospectivo y multicéntrico. Resultados. De marzo a diciembre de 2020 hubo un descenso estadísticamente significativo en el número de solicitudes (−17.7%, p=<0,001) y análisis totales (−18,3%, p<0,001) respecto al mismo periodo de 2019. Se redujo el número de solicitudes de Atención Primaria en un 37,4% (p<0,001) y el número de mediciones de sangre oculta en heces (−45,8%), análisis cualitativo de orina (−30,1%), antígeno prostático específico (PSA) (−28,5%), tirotropina (TSH) (−27,8%), colesterol total (−27,2%) y hemoglobina glicosilada (HbA1c) (−24,7%), p<0,001. Se observó un aumento significativo del número de solicitudes de UCI (76,6%, p<0,001) y del número de mediciones de IL-6 (+22,350,9), dímero-D (+617,2%), troponina (+46,8%) y gasometría arterial (+35,9%), p<0,001. Durante los seis primeros meses de 2021, existieron diferencias significativas para análisis cualitativo de orina (−8,7%, p<0,001), PSA (−6,3%, p=0,009), IL-6 (+66.269,2, p<0,001), dímero-D (+603,6%, p<0,001), troponina (+28,7%, p<0,001), gasometría arterial (+26,2%, p=0,014) y ferritina (+16,0%, p=0,002). Conclusiones. Los laboratorios clínicos españoles han sufrido un cambio en el origen de sus solicitudes y en la demanda de pruebas. Se han incrementado aquellas utilizadas en la evaluación y seguimiento de los pacientes COVID-19, y han disminuido las dirigidas al control de los pacientes no-COVID y a cribados poblacionales. El análisis a más largo plazo refleja una recuperación en las pruebas dirigidas al control de las enfermedades crónicas y se mantiene el aumento del número de mediciones de los biomarcadores utilizados en el manejo de los pacientes COVID-19

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase-ALP-measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. Results: Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9-30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9-13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively. Conclusions: In subjects with persistent hypophosphatasaemia -secondary causes excluded- one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variantGenetic testing was supported by a grant from Alexion Pharmaceuticals Inc., which had no role in the study design or data analysi

Effects of the COVID-19 pandemic on the activity of clinical laboratories in Spain, evolution in the 2019–2021 period

Objectives. To assess the impact of the COVID-19 pandemic on the activity of clinical laboratories in Spain. Methods. A descriptive, observational, retrospective, multicenter study. Results. Between March and December 2020, there was a statistically significant decrease in the number of test requests (−17.7%, p=<0.001) and total tests performed (−18.3%, p<0.001) with respect to the same period in 2019. A decrease was observed in the number of requests from primary care (−37.4%) (p<0.001) and in the number of foecal occult blood (−45.8%); qualitative urine (−30.1%); PSA (−28.5%); TSH (−27.8%); total cholesterol (−27.2%) and HbA1c (−24.7%) tests performed, p<0.001. A significant increase was found in the number of requests from ICUs (76.6%, p<0.001) and number of IL-6 (+22,350.9), D-dimer (+617.2%), troponin (+46.8%) and arterial blood gas (+3.9%) tests carried out, p<0.001. During the first months of 2021, there were significant changes in the number of requests for qualitative urine (−8.7%, p<0.001), PSA (−6.3%, p=0.009), IL-6 (+66,269.2, p<0.001), D-dimer (+603.6%, p<0.001), troponin (+28.7%, p<0.001), arterial blood gas (+26,2%, p=0.014) and ferritin (+16.0%, p=0.002) tests performed. Conclusions. There were changes in the origin and number of test requested to clinical laboratories in Spain. The number of requests for the evaluation and monitoring of COVID-19 patients increased, whereas requests for the control of non-COVID patients and for population screening decreased. Long-term analysis reveals that the volume of tests performed for the control of chronic diseases returned to normal over time, whereas the increase observed in the volume of tests performed for the management of COVID-19 patients is maintained

Perfiles analíticos pre-configurados en insuficiencia cardiaca: implementación y uso en el Sistema Nacional de Salud Español

Objetivos: El uso de los perfiles analíticos pre-configurados (PAPs) en el contexto de la insuficiencia cardíaca (IC) podría ayudar a realizar un mejor manejo clínico y gestión eficiente del paciente. Los objetivos del estudio son entender el grado actual de implantación de los PAPs en el manejo de la IC en España y conocer la opinión de expertos sobre los mismos, prestando particular atención a los parámetros del metabolismo del hierro. Métodos: Se recopiló la opinión de expertos en IC en tres fases. FASE 1: nivel de implantación de los PAPs (n=40). FASE 2: ventajas y desventajas de su uso (n=12). FASE 3: grado de conformidad con la composición de tres PAPs específicos de IC (perfil de evaluación inicial, perfil de seguimiento y perfil de novo; n=16). Resultados: Un 62, 5% de los hospitales hacen uso de PAPs para el manejo clínico de la IC, sin encontrarse asociación con su nivel de referencia (p=0, 132), localización (p=0, 486) o presencia de Unidad de Insuficiencia Cardíaca (p=0, 737). Los expertos opinaron que emplear los PAPs en la práctica clínica presenta más ventajas que inconvenientes (8 vs. 3), resaltando los beneficios sobre el diagnóstico. Se identificaron un total de 3 motivaciones y 3 barreras para la implantación de los PAPs. Los expertos valoraron positivamente la composición de los 3 PAPs de IC propuestos. Conclusiones: La estandarización y homogenización de las pruebas de diagnóstico y seguimiento en los pacientes con IC es un área de mejora en los hospitales españoles analizados, a pesar de que los expertos consultados se han mostrado partidarios de su utilización

Matrix representation and simulation algorithm of spiking neural P systems with structural plasticity

Abstract(#br)In this paper, we create a matrix representation for spiking neural P systems with structural plasticity (SNPSP, for short), taking inspiration from existing algorithms and representations for related variants. Using our matrix representation, we provide a simulation algorithm for SNPSP systems. We prove that the algorithm correctly simulates an SNPSP system: our representation and algorithm are able to capture the syntax and semantics of SNPSP systems, e.g. plasticity rules, dynamism in the synapse set. Analyses of the time and space complexity of our algorithm show that its implementation can benefit using parallel computers. Our representation and simulation algorithm can be useful when implementing SNPSP systems and related variants with a dynamic topology, in software or..