Response rate in cardiac resynchronization therapy patients implanted with a left ventricular quadripolar lead and the MultiPoint™ pacing feature early activated. QUARTO III.

BACKGROUND: Although cardiac resynchronization therapy (CRT) is beneficial in most heart failure patients, up to 40% do not respond to CRT. It has been suggested that multipoint left ventricle pacing (MPP) would increase the response rate. AIM: To assess the CRT response rate at 6 months in patients implanted with a CRT device with the MPP feature activated early after the implant. METHODS: This was a multicentre, prospective, open-label and non-randomized study. The primary endpoint was response to biventricular pacing defined as >15% relative reduction in left ventricular end-systolic volume (LVESV) comparing echocardiography measurements performed at baseline and 6 months by a core laboratory. Among secondary endpoints the combined endpoint of mortality or all-cause hospitalizations was evaluated. Primary study endpoint and clinical outcomes were compared to a Quarto II control cohort. RESULTS: Totally, 105 patients were included. The response rate was 64.6% (97.5% lower confidence bound 53%). Mean relative reduction in LVESV was 25.3%, and mean absolute increase in LVEF was 9.4%. The subjects with device programmed using anatomical approach showed a trend towards higher responder rate than those using the electrical approach (72% vs. 61.1%, p = 0.32). Finally, the combined incidence of mortality and or all-cause hospitalizations at 6 month was 12.4%. CONCLUSIONS: Early activation of MPP was not associated to an advantage increasing echocardiography responders to CRT at 6 months of follow-up. Nevertheless, patients programmed using widest pacing cathodes had a numerically higher responder rate. Finally, early activation of MPP was associated to a low incidence of clinical endpoints at 6 months of follow-up.

Roles of early events in the modifications undergone by bovine corneal endothelial cells during wound healing.

A mechanical injury in bovine corneal endothelial (BCE) cells in culture induces: (1) a fast calcium wave (FCW); (2) slow increases in cytosolic sodium and calcium, critical for the healing process, and (3) a rise in the apoptotic rate with respect to quiescent cells. In order to investigate the nature of the stimuli that determine the ionic changes and apoptotic response, we performed here studies on a non-injury model of tissue restitution in BCE monolayers. For this, we employed cell cultures grown to confluence in the presence of a Parafilm strip. We observed that, previously to strip removal, most of the border cells had already developed the slow ionic modifications, while in the scratch wounds these changes gradually occur after several hours of healing. This finding suggests that, in BCE cells, the presence of a free edge is sufficient to trigger ionic modifications necessary for wound healing and to elicit an augmented apoptotic response. The apoptotic index of the migrating cells in the Parafilm model (PF) was determined to be approximately two-fold the one of scratch wounds, a result that, in agreement with our previous observations, we attributed to the absence of the FCW in the PF experiments. The findings of this work further contribute to the understanding of epithelial wound healing, a crucial adaptive, and homeostatic response.

A mathematical model of wound healing in bovine corneal endothelium.

We developed a mathematical model to describe healing processes in bovine corneal endothelial (BCE) cells in culture, triggered by mechanical wounds with parallel edges. Previous findings from our laboratory show that, in these cases, BCE monolayers exhibit an approximately constant healing velocity. Also, that caspase-dependent apoptosis occurs, with the fraction of apoptotic cells increasing with the distance traveled by the healing edge. In addition, in this study we report the novel findings that, for wound scratch assays performed preserving the basal extracellular matrix: i) the healing cells increase their en face surface area in a characteristic fashion, and ii) the average length of the segments of the cell columns actively participating in the healing process increases linearly with time. These latter observations preclude the utilization of standard traveling wave formalisms to model wound healing in BCE cells. Instead, we developed and studied a simple phenomenological model based on a plausible formula for the spreading dynamics of the individual healing cells, that incorporates original evidence about the process in BCE cells. The model can be simulated to: i) obtain an approximately constant healing velocity; ii) reproduce the profile of the healing cell areas, and iii) obtain approximately linear time dependences of the mean cell area and average length of the front active segments per column. In view of its accuracy to account for the experimental observations, the model can also be acceptably employed to quantify the appearance of apoptotic cells during BCE wound healing. The strategy utilized here could offer a novel formal framework to represent modifications undergone by some epithelial cell lines during wound healing.

Rezago en desarrollo infantil temprano en México: un análisis de la desigualdad.

OBJETIVO: Estimar la desigualdad en el rezago de desarrollo infantil temprano (DIT) en la niñez de 24 a 59 meses. Material y métodos. Se evaluó el DIT mediante el índice de desarrollo infantil temprano 2030. Se estimaron los factores asociados con el rezago de DIT y su índice de concentración (IC), además de su descomposición para estimar la desigualdad entre los factores. RESULTADOS: La desigualdad se concentró más en la niñez con menor nivel de bienestar (IC= -0.09, p<0.01), con peores niveles en estados con marginación muy alta (-0.28, valor-p <0.01) y muy baja (-0.15, valor- p= 0.03). Los factores que más contribuyen a esta desigualdad son falta de acceso a libros y de apoyo al aprendizaje, además de residencia en municipios de alta marginación. Conclusión. Las políticas públicas deben enfocarse en priorizar a la niñez en riesgo de no lograr su máximo DIT, facilitar el acceso a oportunidades de aprendizaje y a libros infantiles.

Adolescent use of outpatient health services in Mexico: their health needs and associated factors.

OBJECTIVE: To estimate adolescent use of outpatient services, identifying their health needs and associated socioeconomic factors. MATERIALS AND METHODS: Using data from Ensanut 2018-2019, adolescents (ages 10-19) with health needs and those receiving care from health personnel (users) were identified. Needs were analyzed by sex and socioeconomic status (SES). Logistic models were used to assess the factors associated with the use of health care and choice of provider. RESULTS: 6% of adolescents reported health needs, of whom 64% used outpatient services. Respiratory and gastrointestinal infections were the principal health needs prompting use of services overall. However, by SES, motivations centered on pregnancy for the poor and accidental injuries for the wealthy. One in three adolescents with health needs, particularly the poorest, received no care. Living with a partner and having health insurance were the main predictors of use. Greater schooling among household heads and higher SES correlated with the use of private services. CONCLUSIONS: Despite being aware of their health needs, adolescents are the group that uses health services the least in Mexico. Promoting preventative and timely treatment for this population would encourage youths to seek care more often.

Mediator effect of caregiver burden on the association between disability and quality of life among older adults.

OBJECTIVE: To estimate the association of disability and qual-ity of life considering the potential mediating role of caregiver burden among a sample of older Mexican adults and their caregivers. MATERIALS AND METHODS: Cross-sectional study with 93 dyads (elderly/caregivers) conducted in 2018 in five localities (urban and rural) of the State of Mexico. The quality of life (QoL) was determined using the WHOQoL (WHO Quality of Life) instrument. Disability was measured by assessing the basic activities of daily living (BADL), and the caregiver burden was evaluated by the Zarit Burden Interview (ZBI). RESULTS: The results showed that BADL disability is associated with a lower QoL (total effect: -14.3; 95%CI: -20.2,-8.4) and that a significant proportion of this associa-tion can be attributable to caregiver burden (25.0%; 95%CI: 17.9,43.2). CONCLUSIONS: Our findings show the need for designing effective interventions that prevent or ameliorate the adverse effects of caregiver burden.

Exploratory Machine Learning Modeling of Adaptive and Maladaptive Personality Traits from Passively Sensed Behavior.

Continuous passive sensing of daily behavior from mobile devices has the potential to identify behavioral patterns associated with different aspects of human characteristics. This paper presents novel analytic approaches to extract and understand these behavioral patterns and their impact on predicting adaptive and maladaptive personality traits. Our machine learning analysis extends previous research by showing that both adaptive and maladaptive traits are associated with passively sensed behavior providing initial evidence for the utility of this type of data to study personality and its pathology. The analysis also suggests directions for future confirmatory studies into the underlying behavior patterns that link adaptive and maladaptive variants consistent with contemporary models of personality pathology.

Acute Nonruptured Expansion of Extracranial Carotid Artery Aneurysm. An Infrequent Clinical Presentation.

The extracranial carotid artery aneurysms are a rare disease, representing a low percentage of peripheral aneurysms (0.4-4%). Their main symptoms are derived from cerebral events and local compression, with rupture being rare. We report the case of a 79-year-old woman who presented with a right Common Carotid Artery aneurysm with pain and local symptoms. The expansion of the aneurysm is documented with images and the surgical treatment consisting of bypass from Common Carotid artery to Internal Carotid artery with Dacron prosthesis and reimplantation of External Carotid artery is described and discussed. To the best of our knowledge, this is the first case of expansion directly documented in the literature.

Dido3-dependent SFPQ recruitment maintains efficiency in mammalian alternative splicing.

Alternative splicing is facilitated by accessory proteins that guide spliceosome subunits to the primary transcript. Many of these splicing factors recognize the RNA polymerase II tail, but SFPQ is a notable exception even though essential for mammalian RNA processing. This study reveals a novel role for Dido3, one of three Dido gene products, in alternative splicing. Binding of the Dido3 amino terminus to histones and to the polymerase jaw domain was previously reported, and here we show interaction between its carboxy terminus and SFPQ. We generated a mutant that eliminates Dido3 but preserves other Dido gene products, mimicking reduced Dido3 levels in myeloid neoplasms. Dido mutation suppressed SFPQ binding to RNA and increased skipping for a large group of exons. Exons bearing recognition sequences for alternative splicing factors were nonetheless included more efficiently. Reduced SFPQ recruitment may thus account for increased skipping of SFPQ-dependent exons, but could also generate a splicing factor surplus that becomes available to competing splice sites. Taken together, our data indicate that Dido3 is an adaptor that controls SFPQ utilization in RNA splicing. Distributing splicing factor recruitment over parallel pathways provides mammals with a simple mechanism to regulate exon usage while maintaining RNA splicing efficiency.

Signaling pathways in cytoskeletal responses to plasma membrane depolarization in corneal endothelial cells.

In previous work, we reported that plasma membrane potential depolarization (PMPD) provokes cortical F-actin remodeling in bovine corneal endothelial (BCE) cells in culture, which eventually leads to the appearance of intercellular gaps. In kidney epithelial cells it has been shown that PMPD determines an extracellular-signal-regulated kinase (ERK)/Rho-dependent increase in diphosphorylated myosin light chain (ppMLC). The present study investigated the signaling pathways involved in the response of BCE cells to PMPD. Differently to renal epithelial cells, we observed that PMPD leads to a decrease in monophosphorylated MLC (pMLC) without affecting diphosphorylated MLC. Also, that the pMLC reduction is a consequence of cyclic adenosine 3',5'-monophosphate (cAMP)/protein kinase A (PKA) activation. In addition, we found evidence that the cAMP increase mostly depends on soluble adenylyl cyclase activity. Inhibition of this enzyme reduces the effect of PMPD on the cAMP rise, F-actin remodeling, and pMLC decrease. No changes in phosho-ERK were observed, although we could determine that RhoA undergoes activation. Our results suggested that active RhoA is not involved in the intercellular gap formation. Overall, the findings of this study support the view that, differently to renal epithelial cells, in BCE cells PMPD determines cytoskeletal reorganization via activation of the cAMP/PKA pathway.

Correction to: Gender inequality in the health workforce in the midst of achieving universal health coverage in Mexico.

An amendment to this paper has been published and can be accessed via the original article.

Gender inequality in the health workforce in the midst of achieving universal health coverage in Mexico.

BACKGROUND: The third Sustainable Development Goal aims to ensure healthy lives and to promote well-being for all at all ages. The health system plays a key role in achieving these goals and must have sufficient human resources in order to provide care to the population according to their needs and expectations. METHODS: This paper explores the issues of unemployment, underemployment, and labor wastage in physicians and nurses in Mexico, all of which serve as barriers to achieving universal health coverage. We conducted a descriptive, observational, and longitudinal study to analyze the rates of employment, underemployment, unemployment, and labor wastage during the period 2005-2017 by gender. We used data from the National Occupation and Employment Survey. Calculating the average annual rates (AAR) for the period, we describe trends of the calculated rates. In addition, for 2017, we calculated health workforce densities for each of the 32 Mexican states and estimated the gaps with respect to the threshold of 4.45 health workers per 1000 inhabitants, as proposed in the Global Strategy on Human Resources for Health. RESULTS: The AAR of employed female physicians was lower than men, and the AARs of qualitative underemployment, unemployment, and labor wastage for female physicians are higher than those of men. Female nurses, however, had a higher AAR in employment than male nurses and a lower AAR of qualitative underemployment and unemployment rates. Both female physicians and nurses showed a higher AAR in labor wastage rates than men. The density of health workers per 1000 inhabitants employed in the health sector was 4.20, and the estimated deficit of workers needed to match the threshold proposed in the Global Strategy is 70 161 workers distributed among the 16 states that do not reach the threshold. CONCLUSIONS: We provide evidence of the existence of gender gaps among physicians and nurses in the labor market with evident disadvantages for female physicians, particularly in labor wastage. In addition, our results suggest that the lack of physicians and nurses working in the health sector contributes to the inability to reach the health worker density threshold proposed by the Global Strategy.

Preparation and Evaluation of Mebendazole Microemulsion for Intranasal Delivery: an Alternative Approach for Glioblastoma Treatment.

Although mebendazole (MBZ) has demonstrated antitumor activity in glioblastoma models, the drug has low aqueous solubility and therefore is poorly absorbed. Considering that other strategies are needed to improve its bioavailability, the current study was aimed to develop and evaluate novel microemulsions of MBZ (MBZ-NaH ME) for intranasal administration. MBZ raw materials were characterized by FTIR, DSC, and XDP. Subsequently, the raw material that contained mainly polymorph C was selected to prepare microemulsions. Two different oleic acid (OA) systems were selected. Formulation A was composed of OA and docosahexaenoic acid (3:1% w/w), while formulation B was composed of OA and Labrafil M2125 (1:1% w/w). Sodium hyaluronate (NaH) at 0.1% was selected as a mucoadhesive agent. MBZ MEs showed a particle size of 209 nm and 145 nm, respectively, and the pH was suitable for nasal formulations (4.5-6.5). Formulation B, which showed the best solubility and rheological behavior, was selected for intranasal evaluation. The nasal toxicity study revealed no damage in the epithelium. Furthermore, formulation B improved significantly the median survival time in the orthotopic C6 rat model compared to the control group. Moreover, NIRF signal intensity revealed a decrease in tumor growth in the treated group with MBZ-MaH ME, which was confirmed by histologic examinations. Results suggest that the intranasal administration of mebendazole-loaded microemulsion might be appropriated for glioblastoma treatment. Graphical abstract.

Nuclear transfer nTreg model reveals fate-determining TCR-ß and novel peripheral nTreg precursors.

To study the development and function of "natural-arising" T regulatory (nTreg) cells, we developed a novel nTreg model on pure nonobese diabetic background using epigenetic reprogramming via somatic cell nuclear transfer. On RAG1-deficient background, we found that monoclonal FoxP3(+)CD4(+)Treg cells developed in the thymus in the absence of other T cells. Adoptive transfer experiments revealed that the thymic niche is not a limiting factor in nTreg development. In addition, we showed that the T-cell receptor (TCR) ß-chain of our nTreg model was not only sufficient to bias T-cell development toward the CD4 lineage, but we also demonstrated that this TCR ß-chain was able to provide stronger TCR signals. This TCR-ß-driven mechanism would thus unify former per se contradicting hypotheses of TCR-dependent and -independent nTreg development. Strikingly, peripheral FoxP3(-)CD4(+)T cells expressing the same TCR as this somatic cell nuclear transfer nTreg model had a reduced capability to differentiate into Th1 cells but were poised to differentiate better into induced nTreg cells, both in vitro and in vivo, representing a novel peripheral precursor subset of nTreg cells to which we refer to as pre-nTreg cells.

Lung cancer in Mexico: findings from the Global Burden of Disease Study, 1990-2016.

OBJECTIVE: To show lung cancer (LC) mortality and disability-adjusted life years (DALYs) in Mexico. MATERIALS AND METHODS: With the visualization tools at the Global Burden of Disease Study website, we analyzed LC mortality and disability-adjusted life years (DALYs) by state, sex, socio- demographic index (SDI), age, and risk factors between 1990 and 2016. RESULTS: Mortality rate decreased from 13.9 to 9.1 per 100 000 between 1990 and 2016. This reduction is greater among men. However, deaths by LC rose from 5 478 to 8 470. DALYs rate also decreased. Northern states with higher SDI face a larger burden from LC but exhibited greater reductions compared with southern, less developed states. The burden of LC is concentrated among older population. Smoking is the main risk factor for LC. CONCLUSIONS: The burden by LC has decreased but is differential between states. LC threatens financially both the health system and individuals, since an important fraction of the population is not protected.

OBJETIVO: Mostrar la mortalidad y los años de vida saluda- bles (Avisas) perdidos por cáncer de pulmón (CP) en México. MATERIAL Y MÉTODOS: Con la herramienta de visualización del estudio de la Carga Global de la Enfermedad, se analizó mortalidad y Avisas por CP según diferentes criterios entre 1990 y 2016. RESULTADOS: La tasa de mortalidad disminuyó de 13.9 a 9.1 por 100 000. Dicha reducción fue mayor entre hombres. Las muertes por CP crecieron de 5 478 a 8 470. La tasa de Avisas se redujo. La carga del CP se concentra en grupos de edad avanzada. Los estados del norte, con mayor nivel sociodemográfico, enfrentan mayor carga, pero presen- taron mayores reducciones comparados con estados menos desarrollados. Fumar es el principal factor de riesgo para CP. CONCLUSIONES: La carga por CP ha disminuido pero es diferencial entre estados. El CP amenaza financieramente el sistema de salud y la población, pues una fracción importante no está protegida.

Boosting heterologous protein production yield by adjusting global nitrogen and carbon metabolic regulatory networks in Bacillus subtilis.

Bacillus subtilis is extensively applied as a microorganism for the high-level production of heterologous proteins. Traditional strategies for increasing the productivity of this microbial cell factory generally focused on the targeted modification of rate-limiting components or steps. However, the longstanding problems of limited productivity of the expression host, metabolic burden and non-optimal nutrient intake, have not yet been completely solved to achieve significant production-strain improvements. To tackle this problem, we systematically rewired the regulatory networks of the global nitrogen and carbon metabolism by random mutagenesis of the pleiotropic transcriptional regulators CodY and CcpA, to allow for optimal nutrient intake, translating into significantly higher heterologous protein production yields. Using a ß-galactosidase expression and screening system and consecutive rounds of mutagenesis, we identified mutant variants of both CodY and CcpA that in conjunction increased production levels up to 290%. RNA-Seq and electrophoretic mobility shift assay (EMSA) showed that amino acid substitutions within the DNA-binding domains altered the overall binding specificity and regulatory activity of the two transcription factors. Consequently, fine-tuning of the central metabolic pathways allowed for enhanced protein production levels. The improved cell factory capacity was further demonstrated by the successfully increased overexpression of GFP, xylanase and a peptidase in the double mutant strain.

Epithelial Fluid Transport is Due to Electro-osmosis (80%), Plus Osmosis (20%).

Epithelial fluid transport, an important physiological process shrouded in a long-standing enigma, may finally be moving closer to a solution. We propose that, for the corneal endothelium, relative proportions for the driving forces for fluid transport are 80% of paracellular electro-osmosis, and 20% classical transcellular osmosis. These operate in a cyclical process with a period of 9.2 s, which is dictated by the decrease and exhaustion of cellular Na+. Paracellular electro-osmosis is sketched here, and partially discussed as much as the subject still allows; transcellular osmosis is presented at length.

Fast calcium wave inhibits excessive apoptosis during epithelial wound healing.

Successful wound closure is mainly the result of two cellular processes: migration and proliferation. Apoptosis has also been suggested to play a role in the mechanisms of wound healing. The fast calcium wave (FCW), triggered immediately after a wound is produced, has been proposed to be involved in determining healing responses in epithelia. We have explored the effects of the reversible inhibition of FCW on the apoptotic and proliferative responses of healing bovine corneal endothelial (BCE) cells in culture. The most important findings of this study are that caspase-dependent apoptosis occurs during the healing process, that the amount of apoptosis has a linear dependence on the migrated distance, and that FCW inhibition greatly increases the apoptotic index. We have further been able to establish that FCW plays a role in the control of cell proliferation during BCE wound healing. These results indicate that one of the main roles of the wave is to inhibit an excessive apoptotic response of the healing migrating cells. This property might represent a basic mechanism to allow sufficient migration and proliferation of the healing cells to assure proper restitution of the injured tissue.

Characterization of the myoepithelial cells in the major salivary glands of the fruit bat Artibeus jamaicensis.

Bats constitute one of the most numerous mammalian species. Bats have a wide range of dietary habits and include carnivorous, haematophagous, insectivorous, frugivorous and nectivorous species. The salivary glands of these species have been of particular research interest due to their structural variability among chiropterans with different types of diets. Myoepithelial cells (MECs), which support and facilitate the expulsion of saliva from the secretory portions of salivary glands, are very important for their function; however, this cell type has not been extensively studied in the salivary glands of bats. In this study, we characterized the MECs in the major salivary glands of the fruit bat Artibeus jamaicensis. Herein, we describe the morphology of the parotid, submandibular and sublingual glands of A. jamaicensis at the light- and electro-microscopic level and the distribution of MECs in these glands, as defined by their expression of smooth-muscle markers such as α-smooth muscle actin (SMAα) and desmin, and of epithelial cell markers, such as KRT14. We found that the anatomical locations of the major salivary glands in this bat species are similar to those of humans, except that the bat sublingual gland appears to be unique, extending to join the contralateral homologous gland. Morphologically, the parotid gland has the characteristics of a mixed-secretory gland, whereas the submandibular and sublingual glands were identified as mucous-secretory glands. MECs positive for SMAα, KRT14 and desmin were found in all of the structural components of the three glands, except in their excretory ducts. Desmin is expressed at a lower level in the parotid gland than in the other glands. Our results suggest that the major salivary glands of A. jamaicensis, although anatomically and structurally similar to those of humans, play different physiological roles that can be attributed to the dietary habits of this species.

Secretion of biologically active human interleukin 22 (IL-22) by Lactococcus lactis.

Interleukin-22 (IL-22) participates in the modulation of innate immunity and inflammation. This cytokine has important therapeutic potential, such as with ulcerative colitis, liver and lung injury, and infection, in different animal models. We generated a Lactococcus lactis strain that secretes human IL-22 under the regulation of the nisin-inducible promoter. Identification and secretion of this cytokine was demonstrated using western blots of culture supernatants from IL-22-expressing bacteria. The recombinant IL-22 protein produced by L. lactis was biologically active as determined by its ability to induce IL-10 secretion when co-cultured with a colon epithelial cell line in vitro. We consider this novel strain a promising live vaccine for various therapeutic applications.