Role of KCNK3 Dysfunction in Dasatinib-associated PAH and Endothelial Cell Dysfunction.

Pulmonary arterial hypertension (PAH) is severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. We discovered a KCNK3 gene (coding for outward K+ channel) variant in a patient with dasatinib-associated PAH, and we investigated the impact of this variant on KCNK3 function. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression. In control-human in pulmonary arterial smooth muscle cells (hPASMCs) and pulmonary endothelial cells (hPECs), we evaluated the consequence of KCNK3 knockdown on cell migration, mitochondrial membrane potential, ATP production, and in vitro tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Patch-clamp revealed that the KCNK3 variant represents a loss-of-function variant. Dasatinib contributed to pulmonary artery constriction by decreasing KCNK3 function and expression. In control-hPASMCs, KCNK3 knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Dasatinib exposure or KCNK3 knockdown reduced the number of caveolae in hPECs. Moreover, KCNK3 knockdown in control-hPECs reduced migration, proliferation, and in vitro tubulogenesis. Using proximity labeling and mass spectrometry, we identified the KCNK3 interactome, revealing that KCNK3 interacts with various proteins across different cellular compartments. We identified a novel pathogenic variant in the KCNK3 and showed that dasatinib downregulates KCNK3, emphasizing the relationship between dasatinib-associated PAH and KCNK3 dysfunction. We demonstrated that loss of KCNK3-dependent signaling contributes to endothelial dysfunction in PAH and glycolytic switch of hPASMCs.

Lateral fluid percussion injury: A rat model of experimental traumatic brain injury.

Traumatic brain injury (TBI) represents one of the leading causes of disability and death worldwide. The annual economic impact of TBI-including direct and indirect costs-is high, particularly impacting low- and middle-income countries. Despite extensive research, a comprehensive understanding of the primary and secondary TBI pathophysiology, followed by the development of promising therapeutic approaches, remains limited. These fundamental caveats in knowledge have motivated the development of various experimental models to explore the molecular mechanisms underpinning the pathogenesis of TBI. In this context, the Lateral Fluid Percussion Injury (LFPI) model produces a brain injury that mimics most of the neurological and systemic aspects observed in human TBI. Moreover, its high reproducibility makes the LFPI model one of the most widely used rodent-based TBI models. In this chapter, we provide a detailed surgical protocol of the LFPI model used to induce TBI in adult Wistar rats. We further highlight the neuroscore test as a valuable tool for the evaluation of TBI-induced sensorimotor consequences and their severity in rats. Lastly, we briefly summarize the current knowledge on the pathological aspects and functional outcomes observed in the LFPI-induced TBI model in rodents.

Distinct potassium channel types in brain capillary pericytes.

Capillaries, composed of electrically coupled endothelial cells and overlying pericytes, constitute the vast majority of blood vessels in the brain. The most arteriole-proximate three to four branches of the capillary bed are covered by α-actin-expressing, contractile pericytes. These mural cells have a distinctive morphology and express different markers compared with their smooth muscle cell (SMC) cousins but share similar excitation-coupling contraction machinery. Despite this similarity, pericytes are considerably more depolarized than SMCs at low intravascular pressures. We have recently shown that pericytes, such as SMCs, possess functional voltage-dependent Ca2+ channels and ATP-sensitive K+ channels. Here, we further investigate the complement of pericyte ion channels, focusing on members of the K+ channel superfamily. Using NG2-DsRed-transgenic mice and diverse configurations of the patch-clamp technique, we demonstrate that pericytes display robust inward-rectifier K+ currents that are primarily mediated by the Kir2 family, based on their unique biophysical characteristics and sensitivity to micromolar concentrations of Ba2+. Moreover, multiple lines of evidence, including characteristic kinetics, sensitivity to specific blockers, biophysical attributes, and distinctive single-channel properties, established the functional expression of two voltage-dependent K+ channels: KV1 and BKCa. Although these three types of channels are also present in SMCs, they exhibit distinctive current density and kinetics profiles in pericytes. Collectively, these findings underscore differences in the operation of shared molecular features between pericytes and SMCs and highlight the potential contribution of these three K+ ion channels in setting pericyte membrane potential, modulating capillary hemodynamics, and regulating cerebral blood flow.

CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries.

The arterial myogenic response to intraluminal pressure elicits constriction to maintain tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, tied to L-type (CaV1.2) Ca2+ channels. While important, other Ca2+ channels, particularly T-type could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca2+ channel (CaV3.1) using C57BL/6 wild type and CaV3.1-/- mice. Patch-clamp electrophysiology, pressure myography, blood pressure and Ca2+ imaging defined the CaV3.1-/- phenotype relative to C57BL/6. CaV3.1-/- mice had absent CaV3.1 expression and whole-cell current, coinciding with lower blood pressure and reduced mesenteric artery myogenic tone, particularly at lower pressures (20-60 mmHg) where membrane potential is hyperpolarized. This reduction coincided with diminished Ca2+ wave generation, asynchronous events of Ca2+ release from the sarcoplasmic reticulum, insensitive to L-type Ca2+ channel blockade (Nifedipine, 0.3 µM). Proximity ligation assay (PLA) confirmed IP3R1/CaV3.1 close physical association. IP3R blockade (2-APB, 50 µM or xestospongin C, 3 µM) in nifedipine-treated C57BL/6 arteries rendered a CaV3.1-/- contractile phenotype. Findings indicate that Ca2+ influx through CaV3.1 contributes to myogenic tone at hyperpolarized voltages through Ca2+-induced Ca2+ release tied to the sarcoplasmic reticulum. This study helps establish CaV3.1 as a potential therapeutic target to control blood pressure.

Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity.

Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (Vdr-/-). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. Vdr-/- mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, Vdr-/- mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of Vdr in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr-/- mice, resembling animals and humans suffering from PAH.

The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Release Kinetics of Monomers from Dental Composites Containing Fluoride-Doped Calcium Phosphates.

This study analyse the type of release kinetic of specific monomers from dental resin composites containing various fluoride-doped calcium phosphates. The release behavior of urethane dimethacrylate (UDMA), ethoxylated bisphenol-A dimethacrylate (bis-EMA) and 1.6-hexanediol ethoxylate diacrylate (HEDA) was evaluated over a period of 35 days. Two tailored calcium phosphates doped with different concentrations of fluoride salts (VS10% and VS20%) were prepared and incorporated in the dimethacrylate matrix at various concentrations to generate a range of experimental composites. The release kinetics were characterized using mathematical models such as zero-order, first-order, Peppas and Higuchi models. The results showed that the first-order model best described the release kinetics. UDMA and HEDA exhibited significant differences in release compared to bis-EMA from day 1, while no significant differences were observed between UDMA and HEDA, except on day 35, when UDMA exhibited a higher release rate than HEDA. When comparing the release of each monomer, VS20-R20% had the highest total release percentage, with 3.10 ± 0.25%, whereas the composite VS10-R5% showed the lowest release percentage, with a total of 1.66 ± 0.08%. The release kinetics were influenced by the composition of the resin composites and the presence of calcium fluoride and sodium fluoride in the calcium phosphate played a role in the maximum amounts of monomer released. In conclusion, the release of monomers from the tested resin composites followed a first-order kinetic behaviour, with an initial rapid release that decreased over time. The composition of the resin monomers and the presence of fluoride salts influenced the release kinetics. The VS10-R5% and VS10-R10% resin composites exhibited the lowest total monomer release, suggesting its potential favourable composition with reduced monomer elution. These findings contribute to understanding the release behavior of dental resin composites and provide insights for the development of resin-based bioactive dental materials.

Relationship between Falls and the Use of Medications and Diseases in an Otago Exercise Programme in Old People Living in the Community in Spain.

(1) Background: Falls are a significant health problem among older adults, and can result in severe injuries, disability, and even death. In Spain, the prevalence of falls is lower if the person lives in the community than if they are institutionalized. Research has shown that exercise is an effective strategy for reducing the risk of falls among older adults. The objective of this study was to study the influence of a multicomponent exercise intervention on falls in people between 65 and 80 years of age despite the presence of diseases and drug use that are risk factors for falls; (2) Methods: This is a quasi-experimental study that focuses on people aged 65-80 who attended 21 primary healthcare centres. Target: Inclusion criteria were people between 65 and 80 years of age, living in the community with independent ambulation, and who were served by the healthcare centre of their region. Variables analysed: The number and characteristics of falls, sociodemographic, drug use, and previous diseases; (3) Results: The drugs associated with falls are benzodiazepines (OR 2.58), vasodilators (OR = 2.51), and psychotropics (OR = 1.61). For one of the years, a relationship was found between the consumption of antidepressants and falls (OR = 1.83). The associated diseases were mental and behavioural (OR = 2.53); (4) Discussion: The intervention has been related to the reduction in falls in people who consumed benzodiazepines, vasodilators, and psychotropics and in people with mental disorders; (5) Conclusion: This research concludes the importance of the implementation of the Otago Exercise Programme in the prevention of falls in the elderly.

Intraluminal pressure elevates intracellular calcium and contracts CNS pericytes: Role of voltage-dependent calcium channels.

Arteriolar smooth muscle cells (SMCs) and capillary pericytes dynamically regulate blood flow in the central nervous system in the face of fluctuating perfusion pressures. Pressure-induced depolarization and Ca2+ elevation provide a mechanism for regulation of SMC contraction, but whether pericytes participate in pressure-induced changes in blood flow remains unknown. Here, utilizing a pressurized whole-retina preparation, we found that increases in intraluminal pressure in the physiological range induce contraction of both dynamically contractile pericytes in the arteriole-proximate transition zone and distal pericytes of the capillary bed. We found that the contractile response to pressure elevation was slower in distal pericytes than in transition zone pericytes and arteriolar SMCs. Pressure-evoked elevation of cytosolic Ca2+ and contractile responses in SMCs were dependent on voltage-dependent Ca2+ channel (VDCC) activity. In contrast, Ca2+ elevation and contractile responses were partially dependent on VDCC activity in transition zone pericytes and independent of VDCC activity in distal pericytes. In both transition zone and distal pericytes, membrane potential at low inlet pressure (20 mmHg) was approximately -40 mV and was depolarized to approximately -30 mV by an increase in pressure to 80 mmHg. The magnitude of whole-cell VDCC currents in freshly isolated pericytes was approximately half that measured in isolated SMCs. Collectively, these results indicate a loss of VDCC involvement in pressure-induced constriction along the arteriole-capillary continuum. They further suggest that alternative mechanisms and kinetics of Ca2+ elevation, contractility, and blood flow regulation exist in central nervous system capillary networks, distinguishing them from neighboring arterioles.

Hydrogen sulfide as a neuromodulator of the vascular tone.

Hydrogen sulfide (H2S) is a unique signaling molecule that, along with carbon monoxide and nitric oxide, belongs to the gasotransmitters family. H2S is endogenously synthesized by enzymatic and non-enzymatic pathways. Three enzymatic pathways involving cystathionine-γ-lyase, cystathionine-ß-synthetase, and 3-mercaptopyruvate sulfurtransferase are known as endogenous sources of H2S. This gaseous molecule has recently emerged as a regulator of many systems and physiological functions, including the cardiovascular system where it controls the vascular tone of small arteries. In this context, H2S leads to vasorelaxation by regulating the activity of vascular smooth muscle cells, endothelial cells, and perivascular nerves. Specifically, H2S modulates the functionality of different ion channels to inhibit the autonomic sympathetic outflow-by either central or peripheral mechanisms-or to stimulate perivascular sensory nerves. These mechanisms are particularly relevant for those pathological conditions associated with impaired neuromodulation of vascular tone. In this regard, exogenous H2S administration efficiently attenuates the increased activity of the sympathetic nervous system often seen in patients with certain pathologies. These effects of H2S on the autonomic sympathetic outflow will be the primary focus of this review. Thereafter, we will discuss the central and peripheral regulatory effects of H2S on vascular tone. Finally, we will provide the audience with a detailed summary of the current pathological implications of H2S modulation on the neural regulation of vascular tone.

Variability in Healthcare Expenditure According to the Stratification of Adjusted Morbidity Groups in the Canary Islands (Spain).

Morbidity is the main item in the distribution of expenditure on healthcare services. The Adjusted Morbidity Group (AMG) measures comorbidity and complexity and classifies the patient into mutually exclusive clinical categories. The aim of this study is to analyse the variability of healthcare expenditure on users with similar scores classified by the AMG. Observational analytical and retrospective study. Population: 1,691,075 subjects, from Canary Islands (Spain), aged over 15 years with data from health cards, clinical history, Basic Minimum Specialised Healthcare Data Set, AMG, hospital agreements information system and Electronic Prescriptions. A descriptive, bivariant (ANOVA coefficient η2) and multivariant analysis was conducted. There is a correlation between the costs and the weight of AMG (rho = 0.678) and the prescribed active ingredients (rho = 0.689), which is smaller with age and does not exist with the other variables. As for the influence of the AMG morbidity group on the total costs of the patient, the coefficient η2 (0.09) obtains a median effect in terms of the variability of expenditure, hence there is intra- and inter-group variability in the cost. In a first model created with all the variables and the cost, an explanatory power of 36.43% (R2 = 0.3643) was obtained; a second model that uses solely active ingredients, AMG weight, being female and a pensioner obtained an explanatory power of 36.4%. There is room for improvement in terms of predicting the expenditure.

Inward Rectifier Potassium Channels: Membrane Lipid-Dependent Mechanosensitive Gates in Brain Vascular Cells.

Cerebral arteries contain two primary and interacting cell types, smooth muscle (SMCs) and endothelial cells (ECs), which are each capable of sensing particular hemodynamic forces to set basal tone and brain perfusion. These biomechanical stimuli help confer tone within arterial networks upon which local neurovascular stimuli function. Tone development is intimately tied to arterial membrane potential (V M ) and changes in intracellular [Ca2+] driven by voltage-gated Ca2+ channels (VGCCs). Arterial V M is in turn set by the dynamic interplay among ion channel species, the strongly inward rectifying K+ (Kir) channel being of special interest. Kir2 channels possess a unique biophysical signature in that they strongly rectify, display negative slope conductance, respond to elevated extracellular K+ and are blocked by micromolar Ba2+. While functional Kir2 channels are expressed in both smooth muscle and endothelium, they lack classic regulatory control, thus are often viewed as a simple background conductance. Recent literature has provided new insight, with two membrane lipids, phosphatidylinositol 4,5-bisphosphate (PIP2) and cholesterol, noted to (1) stabilize Kir2 channels in a preferred open or closed state, respectively, and (2) confer, in association with the cytoskeleton, caveolin-1 (Cav1) and syntrophin, hemodynamic sensitivity. It is these aspects of vascular Kir2 channels that will be the primary focus of this review.

Adenosine signaling activates ATP-sensitive K+ channels in endothelial cells and pericytes in CNS capillaries.

The dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuron- and glial-derived compounds that enhance regional and global cerebral perfusion. The membrane potential (VM) of vascular cells serves as the physiological bridge that translates brain activity into vascular function. In other beds, the ATP-sensitive K+ (KATP) channel regulates VM in vascular smooth muscle, which is absent in the capillary network. Here, with transgenic mice that expressed a dominant-negative mutant of the pore-forming Kir6.1 subunit specifically in brain cECs or pericytes, we demonstrated that KATP channels were present in both cell types and robustly controlled VM. We further showed that the signaling nucleotide adenosine acted through A2A receptors and the Gαs/cAMP/PKA pathway to activate capillary KATP channels. Moreover, KATP channel stimulation in vivo increased cerebral blood flow (CBF), an effect that was blunted by expression of the dominant-negative Kir6.1 mutant in either capillary cell type. These findings establish an important role for KATP channels in cECs and pericytes in the regulation of CBF.

Neural Network-Based Calculator for Rat Glomerular Filtration Rate.

Glomerular filtration is a pivotal process of renal physiology, and its alterations are a central pathological event in acute kidney injury and chronic kidney disease. Creatinine clearance (ClCr), a standard method for glomerular filtration rate (GFR) measurement, requires a long and tedious procedure of timed (usually 24 h) urine collection. We have developed a neural network (NN)-based calculator of rat ClCr from plasma creatinine (pCr) and body weight. For this purpose, matched pCr, weight, and ClCr trios from our historical records on male Wistar rats were used. When evaluated on the training (1165 trios), validation (389), and test sets (660), the model committed an average prediction error of 0.196, 0.178, and 0.203 mL/min and had a correlation coefficient of 0.863, 0.902, and 0.856, respectively. More importantly, for all datasets, the NN seemed especially effective at comparing ClCr among groups within individual experiments, providing results that were often more congruent than those measured experimentally. ACLARA, a friendly interface for this calculator, has been made publicly available to ease and expedite experimental procedures and to enhance animal welfare in alignment with the 3Rs principles by avoiding unnecessary stressing metabolic caging for individual urine collection.

The effect that the Otago Exercise Programme had on fear of falling in community dwellers aged 65-80 and associated factors.

BACKGROUND: Falls are a major public health problem. Fear of falling is highly prevalent amongst community-dwelling older adults who have already fallen and it is also a risk factor for recurrent falls. There has been limited research about the impact that exercises programs have on the fear of falling. The aim of this study was to evaluate whether the Otago Exercise Programme (OEP) reduced the fear of falling in non-institutionalised people aged 65-80 years in Spain. It also evaluated the factors associated with the fear of falling. METHODS: This was a quasi-experimental study that focused on people aged 65-80 who attended 21 primary healthcare centres, lived in the community, were able to walk independently and provided written, informed consent. They were recruited from September 2017 to December 2019. The OEP sessions took place at the primary healthcare centres and were provided on an individual or group basis by trained OEP instructors. The participants attended five weekly sessions, where they were given exercises to develop their strength, balance and endurance. They then continued the programme at home. The subjects were followed up 12 months after baseline and the analyses included a bivariate analysis and a multivariate analysis with logistic regression. RESULTS: We enroled 498 patients (67.07% female) with an average age of 71.81 years. More than two-thirds (65.06%) lived with a partner and 42.37% were overweight. Significant reductions were observed in the mean level of fear of falling between baseline and 12 months (p = 0.000). A number of factors associated with fear of falling also showed significant differences. These were: age (p = 0.033), sex (p = 0.000), living alone (p = 0.000), body mass index (p = 0.003) and whether psychotropic drugs were used (p = 0.000). The multivariate analysis showed a moderate to high fear of falling amongst participants who were female (p = 0.000), 72-80 years of age (p = 0.017), obese (p = 0.045) and used psychotropic drugs (p = 0.021). CONCLUSIONS: Taking part in the OEP reduced the overall fear of falling. There were significant associations between fear of falling and being female, taking psychotic drugs and having a history of falls. This study is a quasi-experimental sign nested an experimental study (randomized controlled trial previously published and registered on ClinicalTrials.org (NCT03320668)). Retrospectively registered on 25/10/2017.

The Large-Conductance, Calcium-Activated Potassium Channel: A Big Key Regulator of Cell Physiology.

Large-conductance Ca2+-activated K+ channels facilitate the efflux of K+ ions from a variety of cells and tissues following channel activation. It is now recognized that BK channels undergo a wide range of pre- and post-translational modifications that can dramatically alter their properties and function. This has downstream consequences in affecting cell and tissue excitability, and therefore, function. While finding the "silver bullet" in terms of clinical therapy has remained elusive, ongoing research is providing an impressive range of viable candidate proteins and mechanisms that associate with and modulate BK channel activity, respectively. Here, we provide the hallmarks of BK channel structure and function generally, and discuss important milestones in the efforts to further elucidate the diverse properties of BK channels in its many forms.

[Nurses in the approach to frailty. Reflective analysis on the importance of nursing care in frail elderly.] / Profesionales de enfermería en el abordaje de la fragilidad. Análisis reflexivo sobre la importancia de los cuidados en la atención a la persona mayor frágil.

At present, the definition of frailty provided by the World Health Organization (WHO), which incorporates the concepts of intrinsic capacity and functional capacity, as well as the increasing prevalence of these situations in elderly people, reflect the need to develop intervention strategies in the different health systems to prevent and address frailty. This article analyzes the implication of the nursing role, as well as its framework of action and specific competencies for the prevention and addressing of the health needs related to the frail elderly person.This role is developed through the systematic use of comprehensive assessment, existence of nursing diagnoses related to frailty and its risks and the interventions and outcome criteria related to the care of the frail elderly person. Specifically, this article expose the actions and competences of nurses who carry out their activity in primary care and in the community context, in care programs for the elderly and home care, which involve both the frail elderly person and the people who care for them.

En la actualidad, una mayor unanimidad con la definición de la fragilidad, aportada por la Organización Mundial de la Salud (OMS), que incorporan los conceptos de capacidad intrínseca (CI) y capacidad funcional (CF), así como la cada vez mayor prevalencia de estas situaciones en la población mayor, reflejan la necesidad de desarrollar estrategias de intervención en los diferentes sistemas sanitarios para prevenir y abordar la fragilidad. En este artículo se analiza la implicación del rol del enfermero, así como su marco de actuación y competencias específicas para la prevención y abordaje de las necesidades y problemas de salud relacionados con la persona mayor frágil, a través del uso sistemático de la valoración integral, la existencia de diagnósticos enfermeros relativos a la fragilidad y sus riesgos y de las intervenciones y criterios de resultados vinculados a los cuidados de la persona mayor frágil. Especialmente, se exponen las actuaciones y competencias de los enfermeros que desarrollan su actividad en atención primaria y el contexto comunitario, en los programas de atención al mayor y atención domiciliaria, que implican tanto a la persona mayor frágil como a las personas que los cuidan.

[Limited Reuse and Extended Use of Filtering Facepiece Respirators]. / Reutilización limitada y uso extendido de mascarillas de media-alta filtración.

AIM: Personal protective equipment (PPE), including respirators, is essential in a pandemic like COVID-19, which has required, on many occasions, the reuse of material due to its shortage. The aim of this review is to summarize available evidence on the reuse and extended use of filtering facepiece respirator. METHOD: Scoping review. Search through natural language in PUBMED and Centers, Agencies and Organizations for Disease Control. Limited to articles published between 2010-2020 in English and Spanish. RESULTS: 83 articles were located, 14 were selected, plus 5 recommendations. The topics included in this study are classified in 7 sections: expiration, extended use and reuse of masks, handling techniques, sealing, physical-psychological effects and compliance, contamination and decontamination of respirators. CONCLUSIONS: The reuse of masks is not recommended by official organizations or manufacturers, and is only accepted in extraordinary cases, such as pandemics. The studies are characterized by having small samples, using different models of respirators adjusting their recommendation to the model.

Biomarkers of persistent renal vulnerability after acute kidney injury recovery.

Acute kidney injury (AKI) is a risk factor for new AKI episodes, chronic kidney disease, cardiovascular events and death, as renal repair may be deficient and maladaptive, and activate proinflammatory and profibrotic signals. AKI and AKI recovery definitions are based on changes in plasma creatinine, a parameter mostly associated to glomerular filtration, but largely uncoupled from renal tissue damage. The evolution of structural and functional repair has been incompletely described. We thus aimed at identifying subclinical sequelae persisting after recovery from cisplatin-induced AKI in rats. Compared to controls, after plasma creatinine recovery, post-AKI kidneys showed histological alterations and attendant susceptibility to new AKI episodes. Tubular function (assessed by the furosemide stress test, FST) also remained affected. Lingering parenchymal and functional subclinical alterations were paralleled by tapering, but abnormally high levels of urinary albumin, transferrin, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and, especially, the [TIMP-2]*[IGFBP7] product. As subclinical surrogates of incomplete renal recovery, the FST and the urinary [TIMP-2]*[IGFBP7] product provide two potential diagnostic tools to monitor the sequelae and kidney vulnerability after the apparent recovery from AKI.