Synergism of small molecules targeting VDAC with sorafenib, regorafenib or lenvatinib on hepatocarcinoma cell proliferation and survival.

Voltage dependent anion channels (VDAC) in the outer mitochondrial membrane regulate the influx of metabolites that sustain mitochondrial metabolism and the efflux of ATP to the cytosol. Free tubulin and NADH close VDAC. The VDAC-binding small molecules X1 and SC18 modulate mitochondrial metabolism. X1 antagonizes the inhibitory effect of tubulin on VDAC. SC18 occupies an NADH-binding pocket in the inner wall of all VDAC isoforms. Here, we hypothesized that X1 and SC18 have a synergistic effect with sorafenib, regorafenib or lenvatinib to arrest proliferation and induce death in hepatocarcinoma cells. We used colony formation assays to determine cell proliferation, and a combination of calcein/propidium iodide, and trypan blue exclusion to assess cell death in the well differentiated Huh7 and the poorly differentiated SNU-449 cells. Synergism was assessed using the Chou-Talalay method. The inhibitory effect of X1, SC18, sorafenib, regorafenib and lenvatinib was concentration and time dependent. IC50s calculated from the inhibition of clonogenic capacity were lower than those determined from cell survival. At IC50s that inhibited cell proliferation, SC18 arrested cells in G0/G1. SC18 at 0.25-2 IC50s had a synergistic effect with sorafenib on clonogenic inhibition in Huh7 and SNU-449 cells, and with regorafenib or lenvatinib in SNU-449 cells. X1 or SC18 also had synergistic effects with sorafenib on promoting cell death at 0.5-2 IC50s for SC18 in Huh7 and SNU-449 cells. These results suggest that small molecules targeting VDAC represent a potential new class of drugs to treat liver cancer.

Predictive factors of selective transarterial embolization failure in acute renal bleeding: a single-center experience.

PURPOSE: Transarterial embolization of renal artery branches (RTE) is a minimally invasive procedure commonly performed in life-threatening renal bleeding of different etiologies. Despite the widespread use of RTE, no consensus guidelines are currently available. Our aim was to investigate clinical and technical efficacy and to identify potential predictors for clinical failure of this procedure. METHODS: All the RTE procedures performed in our Interventional Radiology unit in last 10 years were retrospectively collected and analyzed. All selected patients underwent both pre-procedural computed tomography angiography (CTA) and post-procedural CTA within 30 days. Clinical success was considered as primary endpoint. Demographic, laboratory, and diagnostic findings predictive of clinical failure of RTE were identified. RESULTS: Over a total of 51 patients enrolled, 27 (53%) were females and 33 (64.7%) had a renal bleeding of iatrogenic origin. Technical and clinical success was 100% and 80.4%, respectively. Hematoma volumes > 258.5 cm3 measured at CTA, higher pre- and post-procedural serum creatinine (Scr) levels, an increase in Scr value > 0.135 mg/dl after the procedure, a worse post-procedural estimated glomerular filtration rate (eGFR), a post-procedural reduction of eGFR < 3.350 ml/min, and a post-procedural reduction of platelet count (PLT) > 46.50 × 103/mmc showed a significantly higher rate of clinical failure. CONCLUSION: RTE is a safe and effective procedure in the management of acute renal bleeding of various origins. Hematoma volume, Scr, PLT, and eGFR values were found to be predictive factors of poor clinical outcome and should be closely monitored.

Thyroid dysfunction in pregnancy - a retrospective observational analysis of a Maltese cohort.

BACKGROUND: Thyroid dysfunction is known to adversely affect pregnancy. This study evaluates the prevalence of thyroid disorders and explores their association with pregnancy complications/comorbidities and modes of delivery in the Maltese pregnant population over a ten year period. DESIGN: A population based observational study. METHOD: We analysed data from the National Obstetrics Information Service of the Department of Health Informations and Research (NOIS) for all births delivered in Malta between 2006 and 2016. Cases identified and recorded by NOIS to have had some form of thyroid dysfunction during pregnancy were confirmed by cross-referencing  with laboratory results found in patients' medical records and/or iSOFT® database system. Using the Statistical Package for the Social sciences (SPSS®)  demographic data, past obstetric and medical history and obstetric outcomes were analysed for pregnancies with thyroid dysfunction and compared to data pertaining to pregnancies in euthyroid patients, that is those with no recorded thyroid dysfunction on NOIS. Chi square/Fisher's exact test were used to compare categorical variables while ANOVA/Mann-Whitney U test was used to compare continuous variables. Statistical significance was defined by a two-sided p value <0.05. RESULTS: Data was available for 46,283 women (mean [SD] age = 29.2 [5.4] years). 587 pregnancies (1.3%) suffered from thyroid dysfunction. Of these, 67.3% were hypothyroid, 3.2% had hyperthyroidism, 28.3% had isolated hypothyroxinaemia (IHT) while 1.2% had a history of thyroid carcinoma. Patients with IHT and hypothyroidism were older than euthyroid patients (p < 0.001).  IHT and hypothyroid patients had a statistically significant higher body mass index (BMI) than euthyroid women (p=0.001 for hypothyroid women, p = 0.035 for IHT). Hypothyroid  and IHT women were more likely to have had a previous lower segment caesarean section  (p=0.043,  and 0.006 respectively). Type 1 diabetes and gestational diabetes  p = 0.012) were more common associated comorbidities in hypothyroid pregnancies. Offspring of patients with IHT had a higher birth weight than those born to euthyroid patients (p=0.009). Patients with hyperthyroidism were found to have a significantly increased risk of early preterm delivery before 34 weeks of gestation and were also more likely to have suspected intrauterine growth restriction and low mean birth weight. We report no significant differences in past history of obstetric loss, antenatal complications, mode of delivery, gestational age at delivery and postpartum haemorrhage rates across thyroid categories. CONCLUSIONS: Available evidence suggests that thyroid dysfunction is more likely in the setting of older age, and higher body mass index. Moreover, it impacts on neonatal birth weight, rates of early preterm delivery and intrauterine growth restriction.

Estudio WAKE de vida real en pacientes con narcolepsia con cataplejía tratados con pitolisant no respondedores a tratamientos previos / Real-life WAKE study in narcolepsy patients with cataplexy treated with pitolisant and unresponsive to previous treatments

Introducción: La narcolepsia de tipo 1 es una enfermedad incapacitante que requiere tratamiento continuo, que no siempre es eficaz. El pitolisant es un nuevo fármaco con un mecanismo de acción diferente que ofrece una nueva opción de tratamiento. El objetivo del estudio fue analizar la efectividad y la seguridad del pitolisant en pacientes con narcolepsia de tipo 1 que no hubieran respondido o tolerado previamente los tratamientos habituales. Pacientes y métodos: Estudio observacional descriptivo multicéntrico de vida real que incluyó a pacientes diagnosticados de narcolepsia de tipo 1 no respondedores a tratamientos previos que iniciaron tratamiento con pitolisant. El estudio evaluó tres momentos: el inicio del tratamiento, la estabilización del tratamiento con pitolisant y los tres meses posteriores. Resultados: En 32 pacientes incluidos (media de edad, 44 años; 37,5% de mujeres), la media de la escala de somnolencia de Epworth se redujo de 17,1 a 13,5; un 47,8% de los pacientes mejoró subjetivamente de su cataplejía; un 65% de los pacientes mejoró su impresión clínica global a criterio médico y a criterio del paciente; y se redujo la media de medicamentos consumidos de 2,0 a 1,4. El efecto adverso más frecuente fue el insomnio, en un 43,8% de los pacientes. De los 32 pacientes, 23 mantuvieron el tratamiento durante los tres meses de seguimiento. Conclusiones: En pacientes con narcolepsia de tipo 1 que no responden a o no toleran los tratamientos disponibles, el pitolisant puede mejorar su situación clínica y reducir su consumo de medicamentos. Son necesarios estudios de mayor nivel de evidencia para confirmar estos resultados.(AU)

INTRODUCTION: Type 1 narcolepsy is a disabling disease that requires continuous treatment, which is not always effective. Pitolisant is a new drug with a different mechanism of action that offers a new treatment option. The objective of the study was to analyse the effectiveness and safety of pitolisant in patients with type 1 narcolepsy that did not respond to or tolerate previous standard treatments. PATIENTS AND METHODS: Real-life multicentre descriptive observational study that included patients diagnosed with type 1 narcolepsy who did not respond to or tolerate previous treatments and started treatment with pitolisant. The study evaluated three different moments: the start of treatment, the stabilization of treatment with pitolisant and the three months after. RESULTS: In 32 patients included (mean age, 44 years; 37.5% women) the mean of the Epworth Sleepiness Scale was reduced from 17.1 to 13.5; 47.8% of the patients improved from their cataplexy; 65% of the patients improved their clinical global impression at the physician’s and at the patient’s discretion and the mean number of medications consumed was reduced from 2.0 to 1.4. The most frequent adverse effect was insomnia in 43.8% of patients. Of the 32 patients, 23 continued with the treatment during the 3-month follow-up period. CONCLUSIONS: In patients with type I narcolepsy who do not respond to or do not tolerate the available treatments, pitolisant can improve their clinical situation and reduce their medication consumption. Studies with a higher level of evidence are needed to confirm these results.(AU)

[Real-life WAKE study in narcolepsy patients with cataplexy treated with pitolisant and unresponsive to previous treatments]. / Estudio WAKE de vida real en pacientes con narcolepsia con cataplejía tratados con pitolisant no respondedores a tratamientos previos.

INTRODUCTION: Type 1 narcolepsy is a disabling disease that requires continuous treatment, which is not always effective. Pitolisant is a new drug with a different mechanism of action that offers a new treatment option. The objective of the study was to analyse the effectiveness and safety of pitolisant in patients with type 1 narcolepsy that did not respond to or tolerate previous standard treatments. PATIENTS AND METHODS: Real-life multicentre descriptive observational study that included patients diagnosed with type 1 narcolepsy who did not respond to or tolerate previous treatments and started treatment with pitolisant. The study evaluated three different moments: the start of treatment, the stabilization of treatment with pitolisant and the three months after. RESULTS: In 32 patients included (mean age, 44 years; 37.5% women) the mean of the Epworth Sleepiness Scale was reduced from 17.1 to 13.5; 47.8% of the patients improved from their cataplexy; 65% of the patients improved their clinical global impression at the physician's and at the patient's discretion and the mean number of medications consumed was reduced from 2.0 to 1.4. The most frequent adverse effect was insomnia in 43.8% of patients. Of the 32 patients, 23 continued with the treatment during the 3-month follow-up period. CONCLUSIONS: In patients with type I narcolepsy who do not respond to or do not tolerate the available treatments, pitolisant can improve their clinical situation and reduce their medication consumption. Studies with a higher level of evidence are needed to confirm these results.

TITLE: Estudio WAKE de vida real en pacientes con narcolepsia con cataplejía tratados con pitolisant no respondedores a tratamientos previos.Introducción. La narcolepsia de tipo 1 es una enfermedad incapacitante que requiere tratamiento continuo, que no siempre es eficaz. El pitolisant es un nuevo fármaco con un mecanismo de acción diferente que ofrece una nueva opción de tratamiento. El objetivo del estudio fue analizar la efectividad y la seguridad del pitolisant en pacientes con narcolepsia de tipo 1 que no hubieran respondido o tolerado previamente los tratamientos habituales. Pacientes y métodos. Estudio observacional descriptivo multicéntrico de vida real que incluyó a pacientes diagnosticados de narcolepsia de tipo 1 no respondedores a tratamientos previos que iniciaron tratamiento con pitolisant. El estudio evaluó tres momentos: el inicio del tratamiento, la estabilización del tratamiento con pitolisant y los tres meses posteriores. Resultados. En 32 pacientes incluidos (media de edad, 44 años; 37,5% de mujeres), la media de la escala de somnolencia de Epworth se redujo de 17,1 a 13,5; un 47,8% de los pacientes mejoró subjetivamente de su cataplejía; un 65% de los pacientes mejoró su impresión clínica global a criterio médico y a criterio del paciente; y se redujo la media de medicamentos consumidos de 2,0 a 1,4. El efecto adverso más frecuente fue el insomnio, en un 43,8% de los pacientes. De los 32 pacientes, 23 mantuvieron el tratamiento durante los tres meses de seguimiento. Conclusiones. En pacientes con narcolepsia de tipo 1 que no responden a o no toleran los tratamientos disponibles, el pitolisant puede mejorar su situación clínica y reducir su consumo de medicamentos. Son necesarios estudios de mayor nivel de evidencia para confirmar estos resultados.

Modelling the interplay of SARS-CoV-2 variants in the United Kingdom.

Many COVID-19 vaccines are proving to be highly effective to prevent severe disease and to diminish infections. Their uneven geographical distribution favors the appearance of new variants of concern, as the highly transmissible Delta variant, affecting particularly non-vaccinated people. It is important to device reliable models to analyze the spread of the different variants. A key factor is to consider the effects of vaccination as well as other measures used to contain the pandemic like social behaviour. The stochastic geographical model presented here, fulfills these requirements. It is based on an extended compartmental model that includes various strains and vaccination strategies, allowing to study the emergence and dynamics of the new COVID-19 variants. The model conveniently separates the parameters related to the disease from the ones related to social behavior and mobility restrictions. We applied the model to the United Kingdom by using available data to fit the recurrence of the currently prevalent variants. Our computer simulations allow to describe the appearance of periodic waves and the features that determine the prevalence of certain variants. They also provide useful predictions to help planning future vaccination boosters. We stress that the model could be applied to any other country of interest.

Antisenescence effect of REAC biomodulation to counteract the evolution of myelodysplastic syndrome.

About 30 percent of patients diagnosed with myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML). The senescence of bone marrow?derived mesenchymal stem cells (BMSCs) seems to be one of the determining factors in inducing this drift. Research is continuously looking for new methodologies and technologies that can use bioelectric signals to act on senescence and cell differentiation towards the phenotype of interest. The Radio Electric Asymmetric Conveyer (REAC) technology, aimed at reorganizing the endogenous bioelectric activity, has already shown to be able to determine direct cell reprogramming effects and counteract the senescence mechanisms in stem cells. Aim of the present study was to prove if the anti-senescence results previously obtained in different kind of stem cells with the REAC Tissue optimization - regenerative (TO-RGN) treatment, could also be observed in BMSCs, evaluating cell viability, telomerase activity, p19ARF, P21, P53, and hTERT gene expression. The results show that the REAC TO-RGN treatment may be a useful tool to counteract the BMSCs senescence which can be the basis of AML drift. Nevertheless, further clinical studies on humans are needed to confirm this hypothesis.

Are intravitreal injections essential during the COVID-19 pandemic? Global preferred practice patterns and practical recommendations.

Tertiary outpatient ophthalmology clinics are high-risk environments for COVID-19 transmission, especially retina clinics, where regular follow-up is needed for elderly patients with multiple comorbidities. Intravitreal injection therapy (IVT) for chronic macular diseases, is one of the most common procedures performed, associated with a significant burden of care because of the vigorous treatment regimen associated with multiple investigations. While minimizing the risk of COVID-19 infection transmission is a priority, this must be balanced against the continued provision of sight-saving ophthalmic care to patients at risk of permanent vision loss. This review aims to give evidence-based guidelines on managing IVT during the COVID-19 pandemic in common macular diseases such as age-related macular degeneration, diabetic macula edema and retinal vascular disease and to report on how the COVID-19 pandemic has affected IVT practices worldwide.To illustrate some real-world examples, 18 participants in the International Retina Collaborative, from 15 countries and across four continents, were surveyed regarding pre- and during- COVID-19 pandemic IVT practices in tertiary ophthalmic centers. The majority of centers reported a reduction in the number of appointments to reduce the risk of the spread of COVID-19 with varying changes to their IVT regimen to treat various macula diseases. Due to the constantly evolving nature of the COVID-19 pandemic, and the uncertainty about the normal resumption of health services, we suggest that new solutions for eye healthcare provision, like telemedicine, may be adopted in the future when we consider new long-term adaptations required to cope with the COVID-19 pandemic.

Embolic stroke of undetermined source: beyond atrial fibrillation.

INTRODUCTION: Embolic stroke of undetermined source (ESUS) accounts for 25% of all cerebral infarcts; only 30% are associated with paroxysmal atrial fibrillation (AF). Various biochemical, electrocardiographic, and echocardiographic findings may suggest left atrial damage and increased risk of embolism in the absence of clinically documented AF or atrial flutter. In this review, we analyse the available evidence on atrial cardiopathy or atrial disease, its involvement in ESUS, and its identification through electrocardiographic, echocardiographic, and serum markers and its possible therapeutic implications. DEVELOPMENT: A systematic search was conducted on MEDLINE (PubMed) using the following MeSH terms: MeSH [ESUS]+[atrial cardiopathy]+[atrial fibrillation]+[interatrial block]+[treatment]. We selected what we considered to be the most useful original prospective or retrospective studies and systematic reviews. We then read the full texts of the articles and checked the references cited in each article. We analyse epidemiological and demographic variables of patients with ESUS, as well as recent evidence related to presentation and prognosis and factors associated with recurrence and mortality. We review the contribution of atrial cardiopathy diagnosis prior to the detection of AF and the clinical, electrocardiographic, and echocardiographic variables and the biochemical markers associated with its development and its potential contribution to cerebral embolism. CONCLUSIONS: The systematic search of biochemical and electrocardiographic, and echocardiographic alterations can be useful to identify ESUS patients at higher risk of recurrence.

Infarto cerebral embólico de origen no determinado: más allá de la fibrilación auricular / Embolic stroke of undetermined source: Beyond atrial fibrillation

Introducción: El infarto cerebral embólico de origen no determinado (ESUS por sus siglas en inglés) representa el 25% de todos los infartos cerebrales y solo el 30% se asocia con fibrilación auricular (FA) paroxística. Existen diferentes hallazgos bioquímicos, electro y ecocardiográficos que sugieren daño auricular izquierdo y aumento del riesgo de embolismo en ausencia de FA o flutterauricular clínicamente documentados. En la presente revisión analizamos la evidencia disponible sobre cardiopatía atrial o enfermedad auricular, su implicación en el ESUS y su identificación mediante marcadores electrocardiográficos, ecocardiográficos y séricos y sus posibles implicaciones terapéuticas. Desarrollo: Se realizó una búsqueda sistematizada a través de la fuente de información MEDLINE (PubMed), utilizando una estrategia diseñada con términos MeSH [ESUS] + [atrial cardiopathy] + [atrial fibrillation] + [interatrial block] + [treatment]. Se seleccionaron las publicaciones originales de estudios prospectivos, retrospectivos y de revisión consideradas como las más útiles. Se procedió a la lectura del texto completo y la bibliografía aportada en cada artículo. Se incluyeron los factores epidemiológicos y demográficos de los pacientes ESUS, así como la evidencia reciente relacionada con su forma de presentación, pronóstico y factores asociados con recurrencia y mortalidad. Se revisó la contribución de la presencia de cardiopatía auricular previo a la documentación de FA y las variables clínicas, electro y ecocardiográficas, así como los marcadores bioquímicos asociados con su desarrollo y su contribución como fuente potencial de embolismo cerebral. Conclusiones: La búsqueda sistemática de alteraciones bioquímicas, electro y ecocardiográficas pueden ser de utilidad para identificar pacientes ESUS con mayor riesgo de recurrencia. (AU)

Introduction: Embolic stroke of undetermined source (ESUS) accounts for 25% of all cerebral infarcts; only 30% are associated with paroxysmal atrial fibrillation (AF). Various biochemical, electrocardiographic, and echocardiographic findings may suggest left atrial damage and increased risk of embolism in the absence of clinically documented AF or atrial flutter. In this review, we analyse the available evidence on atrial cardiopathy or atrial disease, its involvement in ESUS, and its identification through electrocardiographic, echocardiographic, and serum markers and its possible therapeutic implications. Development: A systematic search was conducted on MEDLINE (PubMed) using the following MeSH terms: MeSH [ESUS] + [atrial cardiopathy] + [atrial fibrillation] + [interatrial block] + [treatment]. We selected what we considered to be the most useful original prospective or retrospective studies and systematic reviews. We then read the full texts of the articles and checked the references cited in each article. We analyse epidemiological and demographic variables of patients with ESUS, as well as recent evidence related to presentation and prognosis and factors associated with recurrence and mortality. We review the contribution of atrial cardiopathy diagnosis prior to the detection of AF and the clinical, electrocardiographic, and echocardiographic variables and the biochemical markers associated with its development and its potential contribution to cerebral embolism. Conclusions: The systematic search of biochemical and electrocardiographic, and echocardiographic alterations can be useful to identify ESUS patients at higher risk of recurrence. (AU)

Strategies for COVID-19 vaccination under a shortage scenario: a geo-stochastic modelling approach.

In a world being hit by waves of COVID-19, vaccination is a light on the horizon. However, the roll-out of vaccination strategies and their influence on the pandemic are still open questions. In order to compare the effect of various strategies proposed by the World Health Organization and other authorities, a previously developed SEIRS stochastic model of geographical spreading of the virus is extended by adding a compartment for vaccinated people. The parameters of the model were fitted to describe the pandemic evolution in Argentina, Mexico and Spain to analyze the effect of the proposed vaccination strategies. The mobility parameters allow to simulate different social behaviors (e.g. lock-down interventions). Schemes in which vaccines are applied homogeneously in all the country, or limited to the most densely-populated areas, are simulated and compared. The second strategy is found to be more effective. Moreover, under the current global shortage of vaccines, it should be remarked that immunization is enhanced when mobility is reduced. Additionally, repetition of vaccination campaigns should be timed considering the immunity lapse of the vaccinated (and recovered) people. Finally, the model is extended to include the effect of isolation of detected positive cases, shown to be important to reduce infections.

Endocrine disruptor chlorpyrifos promotes migration, invasion, and stemness phenotype in 3D cultures of breast cancer cells and induces a wide range of pathways involved in cancer progression.

Organophosphorus chlorpyrifos (CPF) is currently considered an endocrine disruptor (ED), as it can imitate hormone actions both in vitro and in vivo. We recently reported that CPF induces migration and invasion in 2D cultures and changes the expression of key molecular markers involved in epithelial mesenchymal transition in MCF-7 and MDA-MB-231 cell lines. In this study, we investigated whether CPF could behave as a predisposing factor for tumors to become more metastatic and aggressive using 3D culture models. In MCF-7 cells, 0.05 µM CPF induced an increase in the number and size of mammospheres via estrogen receptor alpha (ERα) and c-SRC. Furthermore, 0.05 µM CPF increased the area of spheroids generated from MCF-7 cells, induced invasion using both Matrigel® and type 1 collagen matrices, and increased cell migration capacity via ERα in this 3D model. In turn, 50 µM CPF increased cell migration capacity and invasion using type 1 collagen matrix. In monolayers, CPF increased the phosphorylation and membrane translocation of c-SRC at both concentrations assayed. CPF at 0.05 µM boosted p-AKT, p-GSK-3ß and p-P38. While p-AKT rose in a ERα-dependent way, p-GSK-3ß was dependent on ERα- and c-SRC, and p-P38 was only dependent on c-SRC. On the other hand, the increase in p-AKT and p-P38 induced by 50 µM CPF was dependent on the c-SRC pathway. We also observed that 0.05 µM CPF increased IGF-1R and IRS-1 expression and that 50 µM CPF induced IGF-1Rß phosphorylation. In the MDA-MB-231 cell line, 0.05 and 50 µM CPF increased p-c-SRC. Finally, p-AKT and p-GSK-3ß were also induced by CPF at 0.05 and 50 µM, and an increase in p-P38 was observed at 50 µM. Taken together, these data provide support for the notion that CPF may represent a risk factor for breast cancer development and progression.

Contenido onírico en diferentes trastornos del sueño: síndrome de apnea e hipopnea del sueño, insomnio primario, trastorno de la conducta del sueño REM idiopático y narcolepsia de tipo 1 / Dream content in different sleep disorders: sleep apnoea and hypopnoea syndrome, primary insomnia, idiopathic REM sleep behaviour disorder and narcolepsy type 1

Objetivo: Determinar si existen diferencias en el contenido onírico en diferentes trastornos del sueño y describir sus características. Pacientes y métodos: Estudiamos cuatro trastornos del sueño: síndrome de apnea e hipopnea del sueño (SAHS), insomnio primario (IP), trastorno de conducta del sueño REM idiopático (TCSRI) y narcolepsia de tipo 1. Se solicitó a cada paciente que llenara un diario de sus sueños durante dos semanas. El contenido de los diarios fue transcrito y analizado en longitud, contenido mental, complejidad y amenaza. Los resultados se compararon para establecer diferencias. Resultados: Se estudió a 89 pacientes: 23 con SAHS sin presión positiva continua de la vía aérea (CPAP) que tuvieron la mayor cantidad de sueños con participación en amenazas (32,5%); 19 con SAHS tratados con CPAP que tuvieron la mayor cantidad de sueños con objetos (64,8%), elementos descriptivos (38%) y de más alta complejidad (9,5%); 22 con insomnio primario con la mayor cantidad de sueños con eventos amenazantes al ámbito social (57,7%); 12 con TCSRI que tuvieron en sus sueños la más alta cantidad de fracasos (14%) y menor complejidad (71,7%), y 13 con narcolepsia de tipo 1 que tuvieron la mayor cantidad de sueños relacionados con actividades (84,3%) y amenazas hacia la vida (41,4 %). Estas diferencias fueron estadísticamente significativas (p < 0,05). Conclusiones: Los distintos trastornos del sueño sí se asocian a contenidos oníricos diferentes que traducirían distintos procesos neurológicos subyacentes. Estos hallazgos deberían replicarse en estudios que analicen más pacientes y añadan un grupo control sin trastornos del sueño.(AU)

Aim: The aim of this study is to determine whether there are any differences in the dream content in different sleep disorders and to describe their characteristics. Patients and methods: We studied four sleep disorders: sleep apnoea and hypopnoea syndrome (SAHS), primary insomnia (PI), idiopathic REM sleep behaviour disorder (IRBD) and narcolepsy type I. Each patient was asked to keep a dream diary for two weeks. The content of the diaries was transcribed and analysed for length, mental content, complexity and threat. The results were compared to establish differences. Results: Eighty-nine patients were studied: 23 with SAHS without continuous positive airway pressure (CPAP) who had the highest number of dreams involving threats (32.5%); 19 with SAHS treated with CPAP who had the highest number of dreams involving objects (64.8%), descriptive elements (38%) and higher complexity (9.5%); 22 with primary insomnia who had the highest number of dreams with threatening events in the social sphere (57.7%); 12 with IRBD who had the highest number of dreams with failures (14%) and lower complexity (71.7%); and 13 with narcolepsy type I who had the highest number of dreams related to activities (84.3%) and threats to life (41.4%) These differences were statistically significant (p <0.05). Conclusions: Different sleep disorders are associated with different dream contents, which would be translating different underlying neurological processes. These findings should be replicated in studies that analyse more patients and add a control group without sleep disorders.(AU)

Chlorpyrifos subthreshold exposure induces epithelial-mesenchymal transition in breast cancer cells.

Chlorpyrifos (CPF) is one of the most frequently used pesticide in extensive agriculture around the world and can be incorporated by humans and animals with possible consequences on health. The effects of this pesticide on carcinogenesis are not clear and there is no consensus concerning the risks of this compound. In previous work, we demonstrated that CPF induces proliferation of breast cancer cells both in vivo and in vitro. In this work we investigate whether CPF promotes the epithelial-mesenchymal transition (EMT) in breast cancer cells. Herein, we demonstrate that 50 µM CFP induces invasion in MCF-7 and MDA-MB-231 cells. In addition, 0.05 and 50 µM CPF increases migration in both cell lines. In MCF-7 cells, 0.05 and 50 µM CPF increase the metalloprotease MMP2 expression and decrease E-Cadherin and ß-Catenin expression diminishing their membrane location. Furthermore, 50 µM CPF induces Vimentin expression and Slug nuclear translocation in MCF-7 cells. 0.05 and 50 µM CPF increase MMP2 gelatinolytic activity and expression, decrease ß-Catenin expression and increase Vimentin expression in MDA-MB-231 cells. Inhibition of the oncoprotein c-Src reverses all the effects induced by CPF in MDA-MB-231 but not in MCF-7 indicating that c-Src is a kinase with a crucial role in the cells which grow in an estrogen-independent way. In MCF-7 cells both c-Src and estrogen receptor alpha must be blocked to completly inhibit the CPF-mediated effects. Our results show for the first time that the exposure to subthreshold concentrations of CPF promotes the modulation of EMT-molecular markers and pathways. These results, together with the ubiquitous distribution of the pesticide CPF, make it of utmost importance to take measures to minimize the risk of exposure to this compound.

A physico-chemical study on amphiphilic cyclodextrin/liposomes nanoassemblies with drug carrier potential.

In this paper, two medusa-like ACyDs, modified at the primary rim bearing four (ACyD4) and eight carbons (ACyD8) acyl chain length, and one bouquet-like CyD, modified at primary side with thiohexyl and at secondary one with oligoethylene moiety (SC6OH), were investigated for their ability to assemble in nanostructures or to form hybrid dipalmitoylphosphatidylcholine (DPPC)/ACyDs systems. The lipophilicity of these molecules and the different preparation methods used in this study (thin layer evaporation and nanoprecipitation method) significantly affect the aggregation behaviour in aqueous medium. Except for the shortest medusa-like ACyD4, the other ACyDs formed stable nanoaggregates for at least 45 days. The effect of ACyDs on the thermotropic behaviour of DPPC liposomes was also studied by differential scanning calorimetry analysis, thus elucidating their interaction with liposomes to afford hybrid liposome/ACyDs systems. The medusa-like ACyD4 cannot be used to realize nanosystems because it quickly aggregates or it induces a complete destabilization of the liposomes. At the highest concentration investigated (0.01 molar fraction), both ACyD8 and SC6OH interacted with DPPC liposomes, forming ACyD/DPPC or SC6OH/DPPC hybrid vesicular carriers.

Embolic stroke of undetermined source: Beyond atrial fibrillation. / Infarto cerebral embólico de origen no determinado: más allá de la fibrilación auricular.

INTRODUCTION: Embolic stroke of undetermined source (ESUS) accounts for 25% of all cerebral infarcts; only 30% are associated with paroxysmal atrial fibrillation (AF). Various biochemical, electrocardiographic, and echocardiographic findings may suggest left atrial damage and increased risk of embolism in the absence of clinically documented AF or atrial flutter. In this review, we analyse the available evidence on atrial cardiopathy or atrial disease, its involvement in ESUS, and its identification through electrocardiographic, echocardiographic, and serum markers and its possible therapeutic implications. DEVELOPMENT: A systematic search was conducted on MEDLINE (PubMed) using the following MeSH terms: MeSH [ESUS]+[atrial cardiopathy]+[atrial fibrillation]+[interatrial block]+[treatment]. We selected what we considered to be the most useful original prospective or retrospective studies and systematic reviews. We then read the full texts of the articles and checked the references cited in each article. We analyse epidemiological and demographic variables of patients with ESUS, as well as recent evidence related to presentation and prognosis and factors associated with recurrence and mortality. We review the contribution of atrial cardiopathy diagnosis prior to the detection of AF and the clinical, electrocardiographic, and echocardiographic variables and the biochemical markers associated with its development and its potential contribution to cerebral embolism. CONCLUSIONS: The systematic search of biochemical and electrocardiographic, and echocardiographic alterations can be useful to identify ESUS patients at higher risk of recurrence.

Stem cells and physical energies: can we really drive stem cell fate?

Adult stem cells are undifferentiated elements able to self-renew or differentiate to maintain tissue integrity. Within this context, stem cells are able to divide in a symmetric fashion, feature characterising all the somatic cells, or in an asymmetric way, which leads daughter cells to different fates. It is worth highlighting that cell polarity have a critical role in regulating stem cell asymmetric division and the proper control of cell division depends on different proteins involved in cell development, differentiation and maintenance of tissue homeostasis. Moreover, the interaction between cells and the extracellular matrix are crucial in influencing cell behavior, included in terms of mechanical properties as cytoskeleton plasticity and remodelling, and membrane tension. Finally, the activation of specific transcriptional program and epigenetic modifications contributes to cell fate determination, through modulation of cellular signalling cascades. It is well known that physical and mechanical stimuli are able to influence biological systems, and in this context, the effects of electromagnetic fields (EMFs) have already shown a considerable role, even though there is a lack of knowledge and much remains to be done around this topic. In this review, we summarize the historical background of EMFs applications and the main molecular mechanism involved in cellular remodelling, with particular attention to cytoskeleton elasticity and cell polarity, required for driving stem cell behavior.

Effects of the pesticide chlorpyrifos on breast cancer disease. Implication of epigenetic mechanisms.

Chlorpyrifos (CPF) is an organophosphorus pesticide used for agricultural pest control all over the world. We have previously demonstrated that environmental concentrations of this pesticide alter mammary gland histological structure and hormonal balance in rats chronically exposed. In this work, we analyzed the effects of CPF on mammary tumors development. Our results demonstrated that CPF increases tumor incidence and reduces latency of NMU-induced mammary tumors. Although no changes were observed in tumor growth rate, we found a reduced steroid hormone receptor expression in the tumors of animals exposed to the pesticide. Moreover, we analyzed the role of epigenetic mechanisms in CPF effects. Our results indicated that CPF alters HDAC1 mRNA expression in mammary gland, although no changes were observed in DNA methylation. In summary, we demonstrate that the exposure to CPF promotes mammary tumors development with a reduced steroid receptors expression. It has also been found that CPF affects HDAC1 mRNA levels in mammary tissue pointing that CPF may act as a breast cancer risk factor.

Las Competencias de Salud Global para Estudiantes de Enfermería: Percepciones de Docentes en América Latina / Global Health Competencies among Nursing Students: Perceptions of Teachers in Latin America / As Competências de Saúde Global para Estudantes de Enfermagem: Percepções de Docentes na América Latina

Resumen: Objetivo: El propósito de este estudio fue describir las percepciones de docentes de enfermería de habla hispana en América Latina, sobre las competencias relacionadas a la salud global que deben mostrar los estudiantes de enfermería del pregrado. Métodos: Este estudio descriptivo fue basado en una muestra de docentes de escuelas de enfermería miembros de la Asociación Latinoamericana de Escuelas y Facultades de Enfermería (ALADEFE) y de la Asociación de Escuelas de la Zona Centro Sur de México, las cuales recibieron un correo electrónico con una liga para responder una encuesta electrónica por Survey Monkey©. La encuesta incluyó una lista de 30 competencias en salud global dividida en seis dimensiones. Los docentes indicaron en una escala Likert de 4 puntos la relevancia de cada competencia para la educación de enfermería en el nivel de pregrado (1 = Completamente en desacuerdo; 2 = En desacuerdo; 3 = De acuerdo; 4 = Completamente de acuerdo). Resultados: En total, 110 profesores de nueve países respondieron a la encuesta. El promedio de cada ítem fue entre 3.0 - 4.0, esto indica que los profesores estuvieron de acuerdo en que todas las competencias son relevantes para la formación de estudiantes de enfermería a nivel de pregrado. Conclusiones: Los resultados de este estudio sugirieron que estas competencias deben ser incluidas en los currículos de enfermería a nivel de pregrado, para formar a los estudiantes en su labor como enfermeras y enfermeros en un mundo globalizado y prepararlos para contribuir a la Cobertura y el Acceso Universal a la Salud (Salud Universal).

Abstract: Objective: To describe the perceptions of Spanish-speaking nursing teachers in Latin America on the global health competences which, undergraduate nursing students should demonstrate. Methods: This descriptive study was based on a sample of teachers of nursing schools belonging to the Latin American Association of Nursing Schools and Faculties, and the Association of Schools of the Center-South Zone in Mexico. These institutions received an invitation via e-mail to respond to a survey through the Survey Monkey© platform. The survey included a list of 30 Global Health competencies grouped in 6 dimensions. Teachers indicated through a 4-point Likert scale their perception on the relevance to undergraduate nursing education of each of these competencies (1 = total disagreement, 2 = disagreement, 3 = agreement, 4 = total agreement). Results: In total, 110 professors of 9 countries responded to the survey. The average score per item was 3.0 - 4.0 suggesting that the teachers agreed that all competencies are relevant to the formation of undergraduate nursing students. Conclusions: These results suggested that these competencies should be part of the objectives of undergraduate nursing curricula in order to prepare the students to contribute to the Coverage and Access to Universal Health agenda.

Resumo: Objetivo: O propósito deste estudo foi descrever as percepções de docentes de enfermagem de fala hispana na América Latina, sobre as competências relacionadas à saúde global que devem mostrar os estudantes de enfermagem de graduação. Métodos: Este estudo descritivo foi baseado em uma amostra de docentes de escolas de enfermagem membros da Associação Latino-americana de Escolas e Faculdades de Enfermagem (ALADEFE) e da Associação de Escolas da Zona Centro Sul do México, as quais receberam um e-mail electrónico com um link para responder uma enquete electrónica por Survey Monkey©. A enquete incluiu uma lista de 30 competências em saúde global dividida em seis dimensões. Os docentes indicaram em uma escala Likert de 4 pontos a relevância de cada competência para a educação de enfermagem no nível de graduação (1 = Completamente em discordância; 2 = Em discordância; 3 = Em concordância; 4 = Completamente em concordância). Resultados: Em total, 110 professores de nove países responderam à enquete. A média de cada item foi entre 3.0-4.0, isto indica que os professores concordaram em que todas as competências são relevantes para a formação de estudantes de enfermagem a nível de graduação. Conclusões: Os resultados deste estudo sugeriram que estas competências devem ser incluídas nos currículos de enfermagem a nível de graduação, para formar aos estudantes em seu labor como enfermeiras e enfermeiros em um mundo globalizado e prepará-los para contribuir à Cobertura e o Acesso Universal à Saúde (Saúde Universal).