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Introduction: A comprehensive pathophysiological mechanism to explain the relationship between high-salt intake and hypertension remains undefined. Evidence suggests that chloride, as the accompanying anion of sodium in dietary salt, is necessary to develop hypertension. We evaluated whether reducing dietary Cl− while keeping a standard Na+ intake modified blood pressure, cardiac hypertrophy, renal function, and vascular contractility after angiotensin II (AngII) infusion. Methods: C56BL/6J mice fed with standard Cl− diet or a low-Cl− diet (equimolar substitution of Cl− by a mixture of Na+ salts, both diets with standard Na+ content) received AngII (infusion of 1.5 mg/kg/day) or vehicle for 14 days. We measured systolic blood pressure (SBP), glomerular filtration rate (GFR), natriuretic response to acute saline load, and contractility of aortic rings from mice infused with vehicle and AngII, in standard and low-Cl− diet. Results: The mice fed the standard diet presented increased SBP and cardiac hypertrophy after AngII infusion. In contrast, low-Cl− diet prevented the increase of SBP and cardiac hypertrophy. AngII-infused mice fed a standard diet presented hampered natriuretic response to saline load, meanwhile the low-Cl− diet preserved natriuretic response in AngII-infused mice, without change in GFR. Aortic rings from mice fed with standard diet or low-Cl− diet and infused with AngII presented a similar contractile response. Conclusion: We conclude that the reduction in dietary Cl− as the accompanying anion of sodium in salt is protective from AngII pro-hypertensive actions due to a beneficial effect on kidney function and preserved natriuresis.

Transient receptor potential melastatin-like 4 (TRPM4) is a Ca(2+)-activated non-selective cation channel expressed in a wide range of human tissues. TRPM4 participates in a variety of physiological processes such as T cell activation, myogenic vasoconstriction, and allergic reactions. TRPM4 Ca(2+) sensitivity is enhanced by calmodulin (CaM) and phosphathydilinositol 4, 5-bisphosphate (PI(4,5)P2) binding, as well as, under certain conditions, PKC activation. However, information as to the mechanisms of modulation of this channel remains unknown, including direct identification of phosphorylation sites on TRPM4 and their role in channel features. Here, we use mass-spectrometric-based proteomic approaches (immunoprecipitation and tandem mass spectrometry) to unambiguously identify S839 as a phosphorylation site present on human TRPM4 expressed in a human cell line. Site-directed mutagenesis employing a serine to alanine mutation to eliminate phosphorylation, and a phospho-mimetic aspartate mutation, as well as biochemical and immunocytochemical experiments, revealed a role for S839 phosphorylation in the basolateral expression of TRPM4 channels in epithelial cells. Moreover, we demonstrated that casein kinase 1 (CK1) phosphorylates S839 and is responsible for the basolateral localization of TRPM4.

Las movilizaciones feministas estudiantiles de 2018 en Chile plantearon una serie de desafíos en el ámbito universitario, transversalizando la demanda por una educación no sexista. El presente artículo busca problematizar dicha demanda, tomando en cuenta la teoría y trayectoria de las pedagogías feministas interseccionales, con el objetivo de complejizar y profundizar el debate en torno al sexismo en la educación. Para ello, comenzamos con una contextualización de la movilización feminista en Chile —señalando sus principales reivindicaciones—, para luego enfatizar en el enfoque interseccional, a modo de posicionamiento y conceptualización. En un segundo momento nos situamos desde las pedagogías feministas interseccionales analizando cuatro ejes que nos parecen sustantivos en relación con las demandas que plantea el movimiento: epistemologías feministas y saberes situados; las pedagogías feministas como prácticas encarnadas y afectivas; relaciones y jerarquías de poder y el énfasis en la dimensión relacional y colectiva de la construcción de saberes; y, por último, la preocupación por mejorar las condiciones materiales de vida de las personas. Finalmente, en las conclusiones, enfatizamos cómo las pedagogías feministas interseccionales permiten ir más allá de una educación no sexista, proponiendo un proyecto estructural, complejo y liberador de transformación social.

Abstract Background Migrant children have specific health needs, and may face difficulties in accessing health care, but not enough is known about their health service use. This study aims to describe patterns of use of health services of international migrant children and differences to respective native populations. Methods Electronic databases PubMed and Web of Science, references of identified publications, and websites of relevant international agencies were searched. We included observational studies published between 2006 and 2016 that reported use of formal health services by migrant children (0–18 years), including first and second generation migrants. Data on study characteristics, study theme, main outcome and study quality were extracted. Results One hundred seven full texts were included in the review. Of the studies that reported comparable outcomes, half (50%) indicated less use of healthcare by migrants compared with non-migrants; 25% reported no difference, 18% reported greater use, and 7% did not report this outcome. There was variation by theme, so that the proportion of conclusions “less use” was most common in the categories “general access to care”, “primary care” and “oral health”, whereas in the use of emergency rooms or hospitalisations, the most common conclusion was “greater use”. Conclusions Migrant children appear to use different types of healthcare services less than native populations, with the exception of emergency and hospital services. Systematic review registration PROSPERO systematic review registration number: CRD42016039876.

Increased expression of the TRPM4 channel has been reported to be associated with the progression of prostate cancer. However, the molecular mechanism underlying its effect remains unknown. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β‐catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/Thr41 β‐catenin phosphorylated population and reduces the phosphorylation of GSK‐3β at Ser9, suggesting an increase in β‐catenin degradation as the underlying mechanism. Conversely, TRPM4 overexpression in LNCaP cells increases the Ser9 inhibitory phosphorylation of GSK‐3β and the total levels of β‐catenin and its nonphosphorylated form. Finally, PC3 cells with reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation of Akt1, which is likely responsible for the decrease in GSK‐3β activity in these cells. Our results also suggest that the effect of TRPM4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin‐EGFR axis, linking TRPM4 activity with the observed effects in β‐catenin‐related signaling pathways. These results suggest a role for TRPM4 channels in β‐catenin oncogene signaling and underlying mechanisms, highlighting this ion channel as a new potential target for future therapies in prostate cancer.

Introduction: A comprehensive pathophysiological mechanism to explain the relationship between high-salt intake and hypertension remains undefined. Evidence suggests that chloride, as the accompanying anion of sodium in dietary salt, is necessary to develop hypertension. We evaluated whether reducing dietary Cl− while keeping a standard Na+ intake modified blood pressure, cardiac hypertrophy, renal function, and vascular contractility after angiotensin II (AngII) infusion. Methods: C56BL/6J mice fed with standard Cl− diet or a low-Cl− diet (equimolar substitution of Cl− by a mixture of Na+ salts, both diets with standard Na+ content) received AngII (infusion of 1.5 mg/kg/day) or vehicle for 14 days. We measured systolic blood pressure (SBP), glomerular filtration rate (GFR), natriuretic response to acute saline load, and contractility of aortic rings from mice infused with vehicle and AngII, in standard and low-Cl− diet. Results: The mice fed the standard diet presented increased SBP and cardiac hypertrophy after AngII infusion. In contrast, low-Cl− diet prevented the increase of SBP and cardiac hypertrophy. AngII-infused mice fed a standard diet presented hampered natriuretic response to saline load, meanwhile the low-Cl− diet preserved natriuretic response in AngII-infused mice, without change in GFR. Aortic rings from mice fed with standard diet or low-Cl− diet and infused with AngII presented a similar contractile response. Conclusion: We conclude that the reduction in dietary Cl− as the accompanying anion of sodium in salt is protective from AngII pro-hypertensive actions due to a beneficial effect on kidney function and preserved natriuresis. [ABSTRACT FROM AUTHOR]

Background: The CanRisk tool enables the collection of risk factor information and calculation of estimated future breast cancer risks based on the multifactorial Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. Despite BOADICEA being recommended in National Institute for Health and Care Excellence (NICE) guidelines and CanRisk being freely available for use, the CanRisk tool has not yet been widely implemented in primary care. Aim: To explore the barriers to and facilitators of the implementation of the CanRisk tool in primary care. Design and setting: A multi-methods study was conducted with primary care practitioners (PCPs) in the East of England. Method: Participants used the CanRisk tool to complete two vignette-based case studies; semi-structured interviews gained feedback about the tool; and questionnaires collected demographic details and information about the structural characteristics of the practices. Results: Sixteen PCPs (eight GPs and eight nurses) completed the study. The main barriers to implementation included: time needed to complete the tool; competing priorities; IT infrastructure; and PCPs' lack of confidence and knowledge to use the tool. Main facilitators included: easy navigation of the tool; its potential clinical impact; and the increasing availability of and expectation to use risk prediction tools. Conclusion: There is now a greater understanding of the barriers and facilitators that exist when using CanRisk in primary care. The study has highlighted that future implementation activities should focus on reducing the time needed to complete a CanRisk calculation, integrating the CanRisk tool into existing IT infrastructure, and identifying appropriate contexts in which to conduct a CanRisk calculation. PCPs may also benefit from information about cancer risk assessment and CanRisk-specific training. [ABSTRACT FROM AUTHOR]

Formylated peptides are chemotactic agents generated by pathogens. The most relevant peptide is fMLF (formyl-Met-Leu-Phe) which participates in several immune functions, such as chemotaxis, phagocytosis, cytokine release and generation of reactive oxygen species. In macrophages fMLF-dependent responses are dependent on both, an increase in intracellular calcium concentration and on a hyperpolarization of the membrane potential. However, the molecular entity underlying this hyperpolarization remains unknown and it is not clear whether changes in membrane potential are linked to the increase in intracellular Ca2+. In this study, differentiated U937 cells, as a macrophage-like cell model, was used to characterize the fMLF response using electrophysiological and Ca2+ imaging techniques. We demonstrate by means of pharmacological and molecular biology tools that fMLF induces a Ca2+-dependent hyperpolarization via activation of the K+ channel KCa3.1 and thus, enhancing fMLF-induced intracellular Ca2+ increase through an amplification of the driving force for Ca2+ entry. Consequently, enhanced Ca2+ influx would in turn lengthen the hyperpolarization, operating as a positive feedback mechanism for fMLF-induced Ca2+ signaling.

Necrosis is considered as a non-specific form of cell death that induces tissue inflammation and is preceded by cell swelling. This increase in cell volume has been ascribed mainly to defective outward pumping of Na+ caused by metabolic depletion and/or to increased Na+ influx via membrane transporters. A specific mechanism of swelling and necrosis driven by the influx of Na+ through nonselective cation channels has been recently proposed (Barros et al., 2001a). We have characterized further the properties of the nonselective cation channel (NSCC) in HTC cells. The NSCC shows a conductance of ~18 pS, is equally permeable to Na+ and K+, impermeant to Ca2+, requires high intracellular Ca2+ as well as low intracellular ATP for activation and is inhibited by flufenamic acid. Hydrogen peroxide induced a significant increase in cell volume that was dependent on external Na+. We propose that the NSCC, which is ubiquitous though largely inactive in healthy cells, becomes activated under severe oxidative stress. The ensuing Na+ influx initiates via positive feedback a series of metabolic and electrolytic disturbances, resulting in cell death by necrosis

Las movilizaciones feministas estudiantiles de 2018 en Chile plantearon una serie de desafos en el mbito universitario, transversalizando la demanda por una educacin no sexista. El presente artculo busca problematizar dicha demanda, tomando en cuenta la teora y trayectoria de las pedagogas feministas interseccionales, con el objetivo de complejizar y profundizar el debate en torno al sexismo en la educacin. Para ello, comenzamos con una contextualizacin de la movilizacin feminista en Chile sealando sus principales reivindicaciones, para luego enfatizar en el enfoque interseccional, a modo de posicionamiento y conceptualizacin. En un segundo momento nos situamos desde las pedagogas feministas interseccionales analizando cuatro ejes que nos parecen sustantivos en relacin con las demandas que plantea el movimiento: epistemologas feministas y saberes situados; las pedagogas feministas como prcticas encarnadas y afectivas; relaciones y jerarquas de poder y el nfasis en la dimensin relacional y colectiva de la construccin de saberes; y, por ltimo, la preocupacin por mejorar las condiciones materiales de vida de las personas. Finalmente, en las conclusiones, enfatizamos cmo las pedagogas feministas interseccionales permiten ir ms all de una educacin no sexista, proponiendo un proyecto estructural, complejo y liberador de transformacin social.

Prion-related disorders (PrDs) are fatal neurodegenerative disorders characterized by progressive neuronal impairment as well as the accumulation of an abnormally folded and protease resistant form of the cellular prion protein, termed PrP(RES). Altered endoplasmic reticulum (ER) homeostasis is associated with the occurrence of neurodegeneration in sporadic, infectious and familial forms of PrDs. The ER operates as a major intracellular calcium store, playing a crucial role in pathological events related to neuronal dysfunction and death. Here we investigated the possible impact of PrP misfolding on ER calcium homeostasis in infectious and familial models of PrDs. Neuro2A cells chronically infected with scrapie prions showed decreased ER-calcium content that correlated with a stronger upregulation of UPR-inducible chaperones, and a higher sensitivity to ER stress-induced cell death. Overexpression of the calcium pump SERCA stimulated calcium release and increased the neurotoxicity observed after exposure of cells to brain-derived infectious PrP(RES). Furthermore, expression of PrP mutants that cause hereditary Creutzfeldt-Jakob disease or fatal familial insomnia led to accumulation of PrP(RES) and their partial retention at the ER, associated with a drastic decrease of ER calcium content and higher susceptibility to ER stress. Finally, similar results were observed when a transmembrane form of PrP was expressed, which is proposed as a neurotoxic intermediate. Our results suggest that alterations in calcium homeostasis and increased susceptibility to ER stress are common pathological features of both infectious and familial PrD models.