Astrocyte Ca2+-evoked ATP release regulates myelinated axon excitability and conduction speed

INTRODUCTION: Astrocytes support neuronal function throughout the central nervous system. In the gray matter, they regulate synapse number during development, remove synaptically released neurotransmitters to terminate their action and prevent excitotoxicity, control the extracellular potassium concentration to prevent hyperexcitability, regulate blood flow to ensure an adequate energy supply, provide lactate to neurons for energy, and respond to rises of intracellular calcium concentration ([Ca2+]i) by releasing adenosine triphosphate (ATP) and other gliotransmitters that act on neuronal receptors to modulate information processing. However, their role is unclear in the white matter, which transmits information rapidly between gray matter areas using axons wrapped with capacitance-reducing myelin (although they have been suggested to regulate myelination during development and during normal function). RATIONALE: Recently, it has been suggested that learning and memory may reflect not only changes in synaptic function in the gray matter, but also changes in white matter function. In particular, neural circuit function might be regulated by changes in the conduction speed of myelinated axons that result in an altered arrival time of action potentials at a distant neuron. These speed changes might be brought about by alterations of the properties of the passively conducting myelinated internodes or of the intervening excitable nodes of Ranvier, where the action potential is generated. We applied immunohistochemistry to assess how astrocytes interact with myelinated axons, neuronal stimulation and light-evoked calcium uncaging in astrocytes to evoke Ca2+-dependent release of gliotransmitters, and electrophysiology and pharmacology to characterize how astrocyte-released substances might affect the axon initial segment (AIS) and nodes of Ranvier of myelinated neurons. Measurements of conduction velocity and computer modeling allowed us to interpret the results. RESULTS: Astrocytes closely approach the axons of myelinated neurons in layer V of the cerebral cortex that enter the corpus callosum. Uncaging Ca2+ within astrocytes or stimulating spike trains in neurons evoked a rise of astrocyte [Ca2+]i that triggered the release of ATP-containing vesicles from these cells. This evoked an inward current in the AIS and nodes of Ranvier of the pyramidal neurons. Pharmacology showed that this was mediated by the activation of Gs-linked adenosine A2a receptors (A2aRs), implying that the released ATP was converted to adenosine by extracellular enzymes. The A2aRs raise the intracellular concentration of cyclic AMP, which activates hyperpolarization-activated cyclic nucleotide–gated (HCN) channels mediating the inward hyperpolarization-activated current (Ih) and thus depolarizes the cell. In the AIS, the activation of A2aRs alters excitability and hence action potential generation, whereas in the nodes of Ranvier, it decreases the conduction speed of the action potential along the axon. CONCLUSION: As in the gray matter, astrocyte [Ca2+]i regulates the release of ATP into the extracellular space in the white matter. After conversion to adenosine, this regulates the excitability and conduction speed of myelinated axons. The changes in excitability at the AIS will lead to changes in the relationship between the synaptic input and action potential output of the cell. The altered conduction speed of the myelinated axon may change neural circuit function by changing the action potential arrival time at the cell’s output synapses, thus altering the integration of signals in postsynaptic neurons. Variations in astrocyte-derived adenosine level can occur between wake and sleep states, and the extracellular adenosine concentration rises during energy deprivation conditions. These changes in adenosine level could thus control white matter information flow and neural circuit function

Twenty-four-hour, weekly and annual patterns in serious falls of non-institutionalized independent Spanish seniors.

OBJECTIVE: The study aimed to explore clock hour, day-of-week, and month-of-year patterns of serious falls experienced by non-institutionalized Spanish seniors (age ≥65 years) in relation to associated conventional intrinsic and extrinsic factors. PATIENTS AND METHODS: Intake emergency department records from January 1 to December 31, 2013 of a tertiary hospital of southern Spain were abstracted for particulars of falls, including the time of occurrence, experienced specifically by non-institutionalized seniors. Chi-squares and Single and Multiple-Component Cosinor (time series) Analyses were applied to determine the statistical significance of observed 24-hour, 7-day, and annual variation. RESULTS: Falls were ~2.5-fold more numerous in older women than older men and ~7-fold more frequent between 12:00 and 14:00 hours than ~02:00 hours, respectively, the time spans corresponding to the absolute peak and trough of the 24-hour pattern in falls. The midday/early afternoon peak primarily represented incidents of women ≥75 years of age that occurred inside the home while walking, standing, or moving on stairs. A late evening less prominent excess of mostly inside-the-home incidents of women ≥75 years of age, largely due to fragility, slipping, stumbling, or tripping, was additionally detected. Cosinor Analysis substantiates statistical significance of the 24-hour patterning of falls of men and women (both p<0.001). Day-of-week differences, with prominent Thursday peak and Sunday minimum, were additionally detected, but only for falls of women occurring outside the home (Cosinor Analysis: p=0.007). Day-of-week discrepancy in female/male sex ratio (SR) of fallers was demonstrated, arising from day-of-week disparity in the SR of inside-the-home incidents, with ~4.5-fold more elderly women than elderly men falling Thursday than any other day of the week (p=0.005). Non-statistically significant month-of-year difference in falls, lowest in autumn and highest (~60% more) in winter, was observed and explained by prominent seasonal difference in incidents by elderly women. CONCLUSIONS: Serious falls of non-institutionalized independent seniors are characterized according to intrinsic and extrinsic factors by prominent 24-hour and 7-day patterning. These findings complement the understanding of the epidemiology of falls of the elderly and further inform fall prevention programs

Anisotropic Radial Layout for Visualizing Centrality and Structure in Graphs

This paper presents a novel method for layout of undirected graphs, where nodes (vertices) are constrained to lie on a set of nested, simple, closed curves. Such a layout is useful to simultaneously display the structural centrality and vertex distance information for graphs in many domains, including social networks. Closed curves are a more general constraint than the previously proposed circles, and afford our method more flexibility to preserve vertex relationships compared to existing radial layout methods. The proposed approach modifies the multidimensional scaling (MDS) stress to include the estimation of a vertex depth or centrality field as well as a term that penalizes discord between structural centrality of vertices and their alignment with this carefully estimated field. We also propose a visualization strategy for the proposed layout and demonstrate its effectiveness using three social network datasets.Comment: Appears in the Proceedings of the 25th International Symposium on Graph Drawing and Network Visualization (GD 2017

From modular to centralized organization of synchronization in functional areas of the cat cerebral cortex

Recent studies have pointed out the importance of transient synchronization between widely distributed neural assemblies to understand conscious perception. These neural assemblies form intricate networks of neurons and synapses whose detailed map for mammals is still unknown and far from our experimental capabilities. Only in a few cases, for example the C. elegans, we know the complete mapping of the neuronal tissue or its mesoscopic level of description provided by cortical areas. Here we study the process of transient and global synchronization using a simple model of phase-coupled oscillators assigned to cortical areas in the cerebral cat cortex. Our results highlight the impact of the topological connectivity in the developing of synchronization, revealing a transition in the synchronization organization that goes from a modular decentralized coherence to a centralized synchronized regime controlled by a few cortical areas forming a Rich-Club connectivity pattern.Comment: 24 pages, 8 figures. Final version published in PLoS On

Applications of telemedicine in the integral management of chronic obstructive pulmonary disease: systematic review

Resumen: Introducción. La enfermedad pulmonar obstructiva crónica es una enfermedad común, prevenible y tratable. Constitu- ye en la actualidad la 4a causa de mortalidad a nivel mundial con tendencia ascendente. Es una entidad muy infradiag- nosticada, que supone un elevado gasto a la Sanidad Pública y una importante pérdida de calidad de vida de las perso- nas que la padecen. En la actualidad no existe un programa de cribado eficaz y el seguimiento de los pacientes es una tarea difícil. Material y métodos. Se ha realizado una búsqueda sistemática de artículos relacionados con el manejo de la EPOC basado en el uso de las tecnologías. Las bases de datos utilizadas han sido: MEDLINE, Web of Science y Cochrane Library, además de las páginas web de organismos como WHO, SEPAR y GOLD. Se han incluido un total de 12 ar- tículos. Resultados. Del total de 12 artículos, 7 encontraron beneficios estadísticamente significativos de la aplicación de estas intervenciones en comparación con la asistencia sanitaria habitual. Entre los beneficios observados se encuentran un aumento de la adherencia a los tratamientos, un aumento de la calidad de vida, un mejor control sintomático y una re- ducción del número de exacerbaciones agudas. Conclusiones. La telemedicina es una herramienta potente que ofrece un amplio abanico de posibilidades para el mane- jo de la EPOC: telemonitorización, coaching electrónico, prevención temprana de las exacerbaciones, screening, tele- rehabilitación... Sin embargo, las evidencias existentes son insuficientes por lo que se requieren estudios potentes para poder extraer conclusiones firmes. Palabras clave: telemedicina; EPOC; telemonitorización; telerehabilitación. Abstract: Introduction. Chronic Obstructive Pulmonary Disease is a common, preventable and treatable disease. It is currently the 4th cause of mortality worldwide with an upward trend. It is a underdiagnosed entity, which implies a high cost to Public Health, and a huge loss of quality of life for the people who suffer it. Currently, there is no effective screening program, and follow-up is a difficult task. Material and methods. A systematic review was made of articles related to the management of COPD based on the use of the technologies. The databases used were: MEDLINE, Web of Science and Cochrane Library in addition to the websites of organizations such as WHO, SEPAR and GOLD. A total of 12 articles have been included. Results. Of the total of 12 articles, 7 found statistically significant benefits of the application of these interventions in comparison with the usual healthcare. Among the benefits there is an increase in treatment adherence, an increase in quality of life, better control of their symptoms and a reduction in the number of accute exacerbations. Conclusions. Telemedicine is a powerful tool that offers a wide range of possibilities for the management of COPD: telemonitoring, electronic coaching, early prevention of exacerbations, screening, telerehabilitation... However, the existing evidence is weak so it is required the development of powerful studies in order to establish firm conclusions. Keywords: telemedicine; COPD; telemonitoring; telerehabilitation

Simplified form of tinnitus retraining therapy in adults: a retrospective study.

BACKGROUND: Since the first description of tinnitus retraining therapy (TRT), clinicians have modified and customised the method of TRT in order to suit their practice and their patients. A simplified form of TRT is used at Ealing Primary Care Trust Audiology Department. Simplified TRT is different from TRT in the type and (shorter) duration of the counseling but is similar to TRT in the application of sound therapy except for patients exhibiting tinnitus with no hearing loss and no decreased sound tolerance (wearable sound generators were not mandatory or recommended here, whereas they are for TRT). The main goal of this retrospective study was to assess the efficacy of simplified TRT. METHODS: Data were collected from a series of 42 consecutive patients who underwent simplified TRT for a period of 3 to 23 months. Perceived tinnitus handicap was measured by the Tinnitus Handicap Inventory (THI) and perceived tinnitus loudness, annoyance and the effect of tinnitus on life were assessed through the Visual Analog Scale (VAS). RESULTS: The mean THI and VAS scores were significantly decreased after 3 to 23 months of treatment. The mean decline of the THI score was 45 (SD = 22) and the difference between pre- and post-treatment scores was statistically significant. The mean decline of the VAS scores was 1.6 (SD = 2.1) for tinnitus loudness, 3.6 (SD = 2.6) for annoyance, and 3.9 (SD = 2.3) for effect on life. The differences between pre- and post-treatment VAS scores were statistically significant for tinnitus loudness, annoyance, and effect on life. The decline of THI scores was not significantly correlated with age and duration of tinnitus. CONCLUSION: The results suggest that benefit may be obtained from a substantially simplified form of TRT

Simplified form of tinnitus retraining therapy in adults: a retrospective study

BACKGROUND: Since the first description of tinnitus retraining therapy (TRT), clinicians have modified and customised the method of TRT in order to suit their practice and their patients. A simplified form of TRT is used at Ealing Primary Care Trust Audiology Department. Simplified TRT is different from TRT in the type and (shorter) duration of the counseling but is similar to TRT in the application of sound therapy except for patients exhibiting tinnitus with no hearing loss and no decreased sound tolerance (wearable sound generators were not mandatory or recommended here, whereas they are for TRT). The main goal of this retrospective study was to assess the efficacy of simplified TRT. METHODS: Data were collected from a series of 42 consecutive patients who underwent simplified TRT for a period of 3 to 23 months. Perceived tinnitus handicap was measured by the Tinnitus Handicap Inventory (THI) and perceived tinnitus loudness, annoyance and the effect of tinnitus on life were assessed through the Visual Analog Scale (VAS). RESULTS: The mean THI and VAS scores were significantly decreased after 3 to 23 months of treatment. The mean decline of the THI score was 45 (SD = 22) and the difference between pre- and post-treatment scores was statistically significant. The mean decline of the VAS scores was 1.6 (SD = 2.1) for tinnitus loudness, 3.6 (SD = 2.6) for annoyance, and 3.9 (SD = 2.3) for effect on life. The differences between pre- and post-treatment VAS scores were statistically significant for tinnitus loudness, annoyance, and effect on life. The decline of THI scores was not significantly correlated with age and duration of tinnitus. CONCLUSION: The results suggest that benefit may be obtained from a substantially simplified form of TRT

Seasonal pattern in elderly hospitalized with acute kidney injury: a retrospective nationwide study in Italy

Purpose: Acute kidney injury (AKI) frequently complicates hospitalization and is associated with in-hospital mortality (IHM). It has been reported a seasonal trend in different clinical conditions. The aim of this study was to evaluate the possible relationship between seasons of the year and IHM in elderly hospitalized patients with AKI. Methods: We selected all admissions complicated by AKI between 2000 and 2015 recorded in the Italian National Hospital Database. ICD-9-CM code 584.xx identified subjects with age ≥ 65 years and age, sex, comorbidity burden, need of dialysis treatment and IHM were compared in hospitalizations recorded during the four seasons. Moreover, we plotted the AKI observed/expected ratio and percentage of mortality during the study period. Results: We evaluated 759,720 AKI hospitalizations (mean age 80.5 ± 7.8 years, 52.2% males). Patients hospitalized with AKI during winter months had higher age, prevalence of dialysis-dependent AKI, and number of deceased patients. In whole population IHM was higher in winter and lower in summer, while the AKI observed/expected ratio demonstrated two peaks, one in summer and one in winter. Logistic regression analysis demonstrated that parameters such as age, autumn, winter, comorbidity burden were positively associated with IHM. Conclusion: We conclude that a seasonality exists in AKI, however, relationship between seasons and AKI could vary depending on the aspects considered. Both autumn and winter months are independent risk factors for IHM in patients with AKI regardless of age, sex and comorbidity burden. On the contrary, summer time reduces the risk of death during hospitalizations with AKI

COVID-19 pandemic on coronary artery and cerebrovascular diseases in Southern Spain: interrupted time series analysis

Objective: Healthcare systems have been put under intense pressure by the COVID-19 pandemic, although some studies have shown a decline in hospital admissions for cardiovascular and cerebrovascular diseases during the first and second wave of the pandemic. In addition, studies analyzing gender and procedural differences are scarce. The present study aimed to determine the impact of the pandemic on hospital admissions for acute myocardial infarction (AMI) and cerebrovascular disease (CVD) in Andalusia (Spain) and analyzed differences by gender and by percutaneous coronary interventions performed. Patients and methods: An interrupted time series analysis of AMI and CVD hospital admissions in Andalusia (Spain) was carried out to measure the impact of the COVID-19 outbreak. AMI and CVD cases admitted daily in public hospitals of Andalusia between January 2018 and December 2020 were included. Results: During the pandemic, significant reductions in AMI [-19%; 95% confidence interval (CI): (-29%, -9%), p<0.001] and CVD [-17%; 95% CI: (-26%, -9%); p<0.01] in daily hospital admissions were observed. Differences were also produced according to the diagnosis (ST-Elevation Myocardial Infarction, Non-ST-Elevation Myocardial Infarction, other AMI and stroke), with a greater reduction in females for AMI and in males for CVD. Although there were more percutaneous coronary interventions during the pandemic, no significant reductions were observed. Conclusions: A decline in AMI and CVD daily hospital admissions during the first and second wave of COVID-19 pandemic was noted. Gender differences were observed, but no clear impact was observed in percutaneous interventions

CHRONOFALLS: A multicentre nurse-led intervention in the chronoprevention of in-hospital falls in adults

Background: Falls are among the most common and serious adverse events for hospitalised patients. In-hospital falls pose a major medical and economic challenge for public health worldwide. Nevertheless, the issue is often addressed without regard to certain relevant variables such as the time of the fall. The aim of this study was to determine the effect of the implementation of a nurse-led intervention based on the temporal patterns of falls and their aetiology on the occurrence of falls. Methods: A mixed-method research design was carried out in three phases: a) a longitudinal prospective study (audits, chronobiological analyses and implementation of a multicentre nurse-led intervention based on temporal patterns of falls); b) a retrospective study of fall records; and c) a qualitative study based on focus groups. The protocol was published in 2021. Results: A difference was observed in the number of fall records before and after the chronopreventive intervention (retrospective: 64.4% vs. 35.6%; p < 0,001). According to the interrupted series analysis, considering the influence of the COVID-19 pandemic, a reduction in falls of 2.96% (95% CI 1.70%-4.17%) was observed. The concepts of falls, the COVID-19 pandemic and the causes of non-registration have emerged as categories for qualitative analysis. Conclusions: A multicentric nurse-led program based on tailored organisational, educational and behavioural chronopreventive measures seems to lead to a reduction in the number of in-hospital falls. The findings of the present study, highlighting the implementation of chronopreventive measures, can serve as a basis for future health policies