Molecular insights into the early stage of glomerular injury in IgA nephropathy using single-cell RNA sequencing.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and defined by the presence of IgA-containing immune complexes in the mesangium that induce an inflammation leading to glomerulonephritis. Since we poorly understand early mechanisms of glomerular injury in IgAN we performed single-cell RNA sequencing (scRNA-seq) analysis of glomerulus-associated cells using SMARTseq2-technology at the early stage of IgAN in grouped ddY-mice. Cell-specific molecular signatures unraveled a key role of endothelial cells in the early pathogenesis of IgAN, especially in the recruitment and infiltration of immune cells. Mesangial and podocyte cells demonstrated less molecular changes. Several intra-glomerular paracrine pathways were detected, such as mesangial cell-derived Slit3 potentially activating Robo-receptors in podocyte/endothelial cells. Surprisingly, proximal tubular cells were strongly affected at the early stage and potential glomerulo-tubular cell-cell crosstalk pathways were identified. Importantly, many of the cellular transcriptomic signatures identified in this well-established mouse model were also detected in published bulk transcriptomic data in human IgAN. Moreover, we validated the functionality of key cell-cell crosstalk pathways using cell culture models, such as the effect of the Slit-Robo signalling axis. Thus, our study provides important novel molecular insights into the pathogenesis of early IgAN-associated glomerulopathy.

Retinoic acid receptor responder1 promotes development of glomerular diseases via the Nuclear Factor-κB signaling pathway.

Inflammatory pathways are activated in most glomerular diseases but molecular mechanisms driving them in kidney tissue are poorly known. We identified retinoic acid receptor responder 1 (Rarres1) as a highly podocyte-enriched protein in healthy kidneys. Studies in podocyte-specific knockout animals indicated that Rarres1 was not needed for the normal development or maintenance of the glomerulus filtration barrier and did not modulate the outcome of kidney disease in a model of glomerulonephritis. Interestingly, we detected an induction of Rarres1 expression in glomerular and peritubular capillary endothelial cells in IgA and diabetic kidney disease, as well as in ANCA-associated vasculitis. Analysis of publicly available RNA data sets showed that the induction of Rarres1 expression was a common molecular mechanism in chronic kidney diseases. A conditional knock-in mouse line, overexpressing Rarres1 specifically in endothelial cells, did not show any obvious kidney phenotype. However, the overexpression promoted the progression of kidney damage in a model of glomerulonephritis. In line with this, conditional knock-out mice, lacking Rarres1 in endothelial cells, were partially protected in the disease model. Mechanistically, Rarres1 promoted inflammation and fibrosis via transcription factor Nuclear Factor-κB signaling pathway by activating receptor tyrosine kinase Axl. Thus, induction of Rarres1 expression in endothelial cells is a prevalent molecular mechanism in human glomerulopathies and this seems to have a pathogenic role in driving inflammation and fibrosis via the Nuclear Factor-κB signaling pathway.

Novel insights into the disease transcriptome of human diabetic glomeruli and tubulointerstitium.

BACKGROUND: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease, affecting ∼30% of the rapidly growing diabetic population, and strongly associated with cardiovascular risk. Despite this, the molecular mechanisms of disease remain unknown. METHODS: RNA sequencing (RNAseq) was performed on paired, micro-dissected glomerular and tubulointerstitial tissue from patients diagnosed with DN [n = 19, 15 males, median (range) age: 61 (30-85) years, chronic kidney disease stages 1-4] and living kidney donors [n = 20, 12 males, median (range) age: 56 (30-70) years]. RESULTS: Principal component analysis showed a clear separation between glomeruli and tubulointerstitium transcriptomes. Differential expression analysis identified 1550 and 4530 differentially expressed genes, respectively (adjusted P < 0.01). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses highlighted activation of inflammation and extracellular matrix (ECM) organization pathways in glomeruli, and immune and apoptosis pathways in tubulointerstitium of DN patients. Specific gene modules were associated with renal function in weighted gene co-expression network analysis. Increased messengerRNA (mRNA) expression of renal damage markers lipocalin 2 (LCN) and hepatitis A virus cellular receptor1 (HAVCR1) in the tubulointerstitial fraction was observed alongside higher urinary concentrations of the corresponding proteins neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in DN patients. CONCLUSIONS: Here we present the first RNAseq experiment performed on paired glomerular and tubulointerstitial samples from DN patients. We show that prominent disease-specific changes occur in both compartments, including relevant cellular processes such as reorganization of ECM and inflammation (glomeruli) as well as apoptosis (tubulointerstitium). The results emphasize the potential of utilizing high-throughput transcriptomics to decipher disease pathways and treatment targets in this high-risk patient population.

GPRC5b Modulates Inflammatory Response in Glomerular Diseases via NF-κB Pathway.

BACKGROUND: Inflammatory processes play an important role in the pathogenesis of glomerulopathies. Finding novel ways to suppress glomerular inflammation may offer a new way to stop disease progression. However, the molecular mechanisms that initiate and drive inflammation in the glomerulus are still poorly understood. METHODS: We performed large-scale gene expression profiling of glomerulus-associated G protein-coupled receptors (GPCRs) to identify new potential therapeutic targets for glomerulopathies. The expression of Gprc5b in disease was analyzed using quantitative PCR and immunofluorescence, and by analyzing published microarray data sets. In vivo studies were carried out in a podocyte-specific Gprc5b knockout mouse line. Mechanistic studies were performed in cultured human podocytes. RESULTS: We identified an orphan GPCR, Gprc5b, as a novel gene highly enriched in podocytes that was significantly upregulated in common human glomerulopathies, including diabetic nephropathy, IgA nephropathy, and lupus nephritis. Similar upregulation of Gprc5b was detected in LPS-induced nephropathy in mice. Studies in podocyte-specific Gprc5b knockout mice showed that Gprc5b was not essential for normal development of the glomerular filtration barrier. However, knockout mice were partially protected from LPS-induced proteinuria and recruitment of inflammatory cells. Mechanistically, RNA sequencing in Gprc5b knockouts mice and experiments in cultured human podocytes showed that Gpr5cb regulated inflammatory response in podocytes via NF-κB signaling. CONCLUSIONS: GPRC5b is a novel podocyte-specific receptor that regulates inflammatory response in the glomerulus by modulating the NF-κB signaling pathway. Upregulation of Gprc5b in human glomerulopathies suggests that it may play a role in their pathogenesis.

Leptin Induces Oxidative Stress Through Activation of NADPH Oxidase in Renal Tubular Cells: Antioxidant Effect of L-Carnitine.

Leptin is a protein involved in the regulation of food intake and in the immune and inflammatory responses, among other functions. Evidences demonstrate that obesity is directly associated with high levels of leptin, suggesting that leptin may directly link obesity with the elevated cardiovascular and renal risk associated with increased body weight. Adverse effects of leptin include oxidative stress mediated by activation of NADPH oxidase. The aim of this study was to evaluate the effect of L-carnitine (LC) in rat renal epithelial cells (NRK-52E) exposed to leptin in order to generate a state of oxidative stress characteristic of obesity. Leptin increased superoxide anion (O2 (•) -) generation from NADPH oxidase (via PI3 K/Akt pathway), NOX2 expression and nitrotyrosine levels. On the other hand, NOX4 expression and hydrogen peroxide (H2 O2 ) levels diminished after leptin treatment. Furthermore, the expression of antioxidant enzymes, catalase, and superoxide dismutase, was altered by leptin, and an increase in the mRNA expression of pro-inflammatory factors was also found in leptin-treated cells. LC restored all changes induced by leptin to those levels found in untreated cells. In conclusion, stimulation of NRK-52E cells with leptin induced a state of oxidative stress and inflammation that could be reversed by preincubation with LC. Interestingly, LC induced an upregulation of NOX4 and restored the release of its product, hydrogen peroxide, which suggests a protective role of NOX4 against leptin-induced renal damage. J. Cell. Biochem. 117: 2281-2288, 2016. © 2016 Wiley Periodicals, Inc.

The renoprotective effect of L-carnitine in hypertensive rats is mediated by modulation of oxidative stress-related gene expression.

PURPOSE: Arterial hypertension is associated with a high production of reactive oxygen species and a decrease in the antioxidant defense systems. Based on the lack of toxicity of L-carnitine (LC) and previous studies reporting beneficial effects of this compound in experimental models of hypertension, the aim of this work was to test the hypothesis that LC might protect the kidney against hypertension-induced oxidative damage, as well as to investigate the mechanisms involved in this effect. To this end, specific activities and protein/mRNA expression of the antioxidant enzymes (glutathione peroxidase, glutathione reductase, and superoxide dismutase), and those of NADPH oxidase (the main responsible for superoxide anion production in renal tissue) have been measured in renal cortex homogenates from NG-nitro-L-arginine methyl ester (L-NAME)-treated rats and control normotensive rats. In addition, components of the renin-angiotensin system (RAS) and redox-sensitive transcription factors (NF-κB, Nrf2, and PPARα) have also been evaluated. METHODS: Male Wistar rats aged 6-8 weeks were divided into four groups of six animals each: (1) control, normotensive Wistar rats (with free access to tap water); (2) Wistar rats subjected to treatment with 25 mg of L-NAME/kg body weight/day dissolved in the drinking water, in order to develop L-NAME-induced hypertension; (3) Wistar rats subjected to treatment with 400 mg of LC/kg body weight/day (also dissolved in the drinking water); and (4) L-NAME-treated rats subjected to simultaneous treatment with LC at the indicated doses. RESULTS: The beneficial effect of LC supplementation on oxidative damage in the renal cortex of hypertensive rats reversed hypertension-associated renal function damage and produced an upregulation of both antioxidant enzymes and eNOS, and with a downregulation of both NADPH oxidase and RAS components. LC improves the oxidative stress response through a specific modulation of NF-κB, Nrf2, and PPARα transcription factors. Thus, the low production of superoxide anions, subsequent to NADPH oxidase inhibition, might act by increasing the expression of Nrf2 and PPARα and by decreasing that of NF-κB, which, in turn, would enhance the antioxidant defense systems. CONCLUSIONS: Our results might support the use of LC to prevent hypertension-induced renal damage.

Soluble Klotho protects against glomerular injury through regulation of ER stress response.

αKlotho (Klotho) has well established renoprotective effects; however, the molecular pathways mediating its glomerular protection remain incompletely understood. Recent studies have reported that Klotho is expressed in podocytes and protects glomeruli through auto- and paracrine effects. Here, we examined renal expression of Klotho in detail and explored its protective effects in podocyte-specific Klotho knockout mice, and by overexpressing human Klotho in podocytes and hepatocytes. We demonstrate that Klotho is not significantly expressed in podocytes, and transgenic mice with either a targeted deletion or overexpression of Klotho in podocytes lack a glomerular phenotype and have no altered susceptibility to glomerular injury. In contrast, mice with hepatocyte-specific overexpression of Klotho have high circulating levels of soluble Klotho, and when challenged with nephrotoxic serum have less albuminuria and less severe kidney injury compared to wildtype mice. RNA-seq analysis suggests an adaptive response to increased endoplasmic reticulum stress as a putative mechanism of action. To evaluate the clinical relevance of our findings, the results were validated in patients with diabetic nephropathy, and in precision cut kidney slices from human nephrectomies. Together, our data reveal that the glomeruloprotective effects of Klotho is mediated via endocrine actions, which increases its therapeutic potential for patients with glomerular diseases.

Adaptation and validation of the Screening Questionnaire for Family Abuse of the Elderly in the sociocultural context of Colombia.

In Colombia, like many countries in the world, due to the increase in population of elderly people, mistreatment has increased, which has physical, psychological and social consequences for the individual and major repercussions on society. The detection of abuse is a complex task, among other aspects, due to the concealment of victims and the lack of valid, reliable detection instruments that are in keeping with the sociocultural context. Professionals responsible for dealing with these situations must have an instrument that allows early detection. The objective of this study was to adapt and validate the Family Abuse Screening Questionnaire for Elderly People in Colombia. A cross-sectional study with mixed methods was carried out in two stages from 2017 to 2018. In the first stage, linguistic and semantic adaptation was carried out using translation, synthesis, back translation, expert analysis and pilot testing with 30 abused and non-abused elderly people. In the second stage, the validity and reliability of the questionnaire were obtained by means of an exploratory factor analysis and Cronbach's Alpha, using STATA 13. In the results, we provided a Socially and Culturally Adapted Family Abuse Screening Questionnaire for elderly people in Colombia with a Cronbach's Alpha of 0.82, sensitivity value of 86.9% (p < 0.05) and a specificity value of 84% (p < 0.05), detecting abuse with 4 or more positive responses to abuse. The application of the screening questionnaire by health and social services professionals will prevent further damage to social and physical health in the elderly people in Colombia, as well as reduce the costs of care in institutions.

Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes.

Molecular characterization of the individual cell types in human kidney as well as model organisms are critical in defining organ function and understanding translational aspects of biomedical research. Previous studies have uncovered gene expression profiles of several kidney glomerular cell types, however, important cells, including mesangial (MCs) and glomerular parietal epithelial cells (PECs), are missing or incompletely described, and a systematic comparison between mouse and human kidney is lacking. To this end, we use Smart-seq2 to profile 4332 individual glomerulus-associated cells isolated from human living donor renal biopsies and mouse kidney. The analysis reveals genetic programs for all four glomerular cell types (podocytes, glomerular endothelial cells, MCs and PECs) as well as rare glomerulus-associated macula densa cells. Importantly, we detect heterogeneity in glomerulus-associated Pdgfrb-expressing cells, including bona fide intraglomerular MCs with the functionally active phagocytic molecular machinery, as well as a unique mural cell type located in the central stalk region of the glomerulus tuft. Furthermore, we observe remarkable species differences in the individual gene expression profiles of defined glomerular cell types that highlight translational challenges in the field and provide a guide to design translational studies.

Crime Victimization and Suicidal Ideation Among Colombian College Students: The Role of Depressive Symptoms, Familism, and Social Support.

Crime victimization is one of the most pressing public health concerns in Latin America. Young people in the region are at particularly high risk of victimization. The present study examined exposure to crime victimization as a risk factor for depressive symptoms and suicidal ideation, and the protective effects of familism and social support in a community sample of Colombian college students. Data (N = 424) came from the Juventud Project (The Emergent Adults Project), a cross-sectional study of college students, 18 to 29 years old (M = 20.8, SD = 2.5; 63% female; 75.5% lived with their families), attending an urban public university in Southern Colombia. Data were collected between March and June of 2014 through anonymous, self-administered surveys. Conditional process analysis was used to test a model in which crime victimization was directly and indirectly associated with suicidal ideation via depressive symptoms, with familism and social support as moderators of this association while controlling for gender, age, and socioeconomic status. Overall, 58.9% of participants reported at least one crime victimization event in the past year. The most common types of victimization were being robbed without the threat of harm (29.8%) and being robbed with a weapon (24.8%). Male participants reported more instances of crime victimization than female participants. Levels of depressive symptoms that could be clinically significant were reported by 30.2% of participants, and suicidal ideation was reported by 31% of participants. The association between crime victimization and suicidal ideation was fully mediated by depressive symptoms. Social support, but not familism, moderated this association; social support weakened the link between depressive symptoms and suicidal ideation. Findings suggest that crime victimization may be a significant risk for depressive symptoms and suicidal ideation among college students in Colombia, and that social support may protect from the harmful mental health effects of crime victimization.

Mechanism of Vascular Toxicity in Rats Subjected to Treatment with a Tyrosine Kinase Inhibitor.

Sunitinib (Su) is a tyrosine kinase inhibitor with antiangiogenic and antineoplastic effects that is recommended therapy for renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Arterial hypertension is one of the adverse effects observed in the treatment with Su. The aim of this work was to deepen our understanding of the underlying mechanisms involved in the development of this side effect. Studies on endothelial function, vascular remodeling and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) system were carried out in thoracic aortas from rats treated with Su for three weeks. Animals subjected to Su treatment presented with increased blood pressure and reduced endothelium-dependent vasodilation, the latter being reverted by NADPH oxidase blockade. Furthermore, vascular remodeling and stronger Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1α1), were observed in aortas from treated animals. These results were accompanied by a significant elevation in superoxide anion production and the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), which was also prevented by NOX inhibition. Furthermore, a decrease in nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activation was observed in aortas from Su-treated animals. All these results indicate that endothelial dysfunction secondary to changes in vascular remodeling and oxidative stress might be responsible for the typical arterial hypertension that develops following treatment with Su.

Inactivation of mediator complex protein 22 in podocytes results in intracellular vacuole formation, podocyte loss and premature death.

Podocytes are critical for the maintenance of kidney ultrafiltration barrier and play a key role in the progression of glomerular diseases. Although mediator complex proteins have been shown to be important for many physiological and pathological processes, their role in kidney tissue has not been studied. In this study, we identified a mediator complex protein 22 (Med22) as a renal podocyte cell-enriched molecule. Podocyte-specific Med22 knockout mouse showed that Med22 was not needed for normal podocyte maturation. However, it was critical for the maintenance of podocyte health as the mice developed progressive glomerular disease and died due to renal failure. Detailed morphological analyses showed that Med22-deficiency in podocytes resulted in intracellular vacuole formation followed by podocyte loss. Moreover, Med22-deficiency in younger mice promoted the progression of glomerular disease, suggesting Med22-mediated processes may have a role in the development of glomerulopathies. This study shows for the first time that mediator complex has a critical role in kidney physiology.

Coro2b, a podocyte protein downregulated in human diabetic nephropathy, is involved in the development of protamine sulphate-induced foot process effacement.

Podocytes have an important role in the pathogenesis of diabetic nephropathy (DN). Podocyte foot process effacement, mediated largely by the actin-based cytoskeleton of foot processes, is commonly detected in DN and is believed to be a key pathogenic event in the development of proteinuria. In this study, we identified coronin 2b (Coro2b), a member of known actin-regulating proteins, the coronins, as a highly podocyte-enriched molecule located at the cytoplasmic side of the apical plasma membrane. Studies in human renal biopsies show that glomerular Coro2b expression is significantly down-regulated in patients with DN. Studies in knockout mice indicate that Coro2b is not required for the development or maintenance of the glomerular filtration barrier. Moreover, inactivation of Coro2b specifically in podocytes does not affect the outcome of nephropathy in a streptozotocin-induced diabetes model. However, Coro2b seems to modulate the reorganization of foot processes under pathological conditions as Coro2b knockout podocytes are partially protected from protamine sulfate perfusion-induced foot process effacement. Taken together, our study suggests a role for Coro2b in the pathogenesis of glomerulopathies. Further studies regarding the involvement of Coro2b in podocyte health and diseases are warranted.

FYVE domain-containing protein ZFYVE28 regulates EGFR-signaling in podocytes but is not critical for the function of filtration barrier in mice.

The kidney ultrafiltration barrier is formed of endothelial cells, the glomerular basement membrane and podocytes. Podocytes have a central role in normal physiology and disease pathogenesis of the glomerulus. Signaling through epidermal growth factor receptor (EGFR) in podocytes mediates development of many glomerular disease processes. In this work, we have identified zinc finger FYVE-type containing 28 (ZFYVE28) as a novel highly podocyte-enriched gene. We localize ZFYVE28 in podocyte foot processes in adult kidney. During glomerulogenesis, Zfyve28 is first expressed at the early capillary loop glomerulus. In cultured podocytes, we show that overexpression of ZFYVE28 promotes EGF-signaling, possibly by up-regulating EGFR expression and by modulating its localization. To study the role of ZFYVE28 in vivo, we generated both conventional and podocyte-specific knockout mouse lines. Kidneys developed normally in ZFYVE28-deficient mice. In adult mice, the absence of ZFYVE28 did not affect the maintenance of the filtration barrier. Moreover, ZFYVE28-deficiency did not affect the outcome of glomerular damage induced by injection of nephrotoxic serum. Taken together, we have identified Zfyve28 as a new molecular component of podocyte foot processes and show that it mediates EGF-signaling in podocytes. However, ZFYVE28 is not essential for the development or maintenance of the glomerulus filtration barrier.

Cooperación Internacional: Un desafío en la Educación Superior Pública y Regional

R E S U M E N El artículo tiene por objetivo el analizar la cooperación internacional, desde el convenio entre la Universidad de Atacama UDA-Chile y la Universidad de Nariño UDENAR-Colombia, las dos instituciones son de educación superior públicas y regionales. El estudio fue cualitativo - descriptivo, los participantes fueron I3 entre docentes, administrativos y estudiantes pertenecientes a las dos universidades. Sus edades fluctúan entre los 21 y 59 años, hombres y mujeres, nacidos en Chile o Colombia. Se utilizó como técnicas de recolección de información el análisis documental y un cuestionario con preguntas abiertas. Los resultados muestran una valoración positiva del convenio puesto que se ha manejado desde las tres funciones sustantivas universitarias: docencia, investigación e interacción social; en este mismo sentido se hace fuerte los aprendizajes adquiridos por cada participante y la necesidad de profundizar en investigación. Se concluye que la internacionalización tiene muchos beneficios desde el intercambio cultural, el prestigio internacional y los aprendizajes, así como la transdisiciplinariedad del convenio, que a través del pensamiento crítico construyendo espacios de diálogo de saberes no fragmentado en disciplinas, sino unido por un interés genuino por el conocimiento.

The article aims to analyze international cooperation, from the agreement between the University of Atacama UDA-Chile and the University of Nariño UDENAR-Colombia, the two institutions are public and regional higher education. The study was qualitative - descriptive, the participants were I3 among teachers, administrators and students belonging to the two universities. Their ages fluctuate between 21 and 59 years, men and women, born in Chile or Colombia. Documentary analysis and a questionnaire with open questions were adapted as data collection techniques. The results show a positive assessment of the agreement since it has been managed from the three substantive university functions: teaching, research and social interaction; In it, the learning acquired by each participant and the need to deepen the investigation become strong. It is concluded that internationalization has many benefits from cultural exchange, international prestige and learning, as well as the transdisciplinarity of the agreement, which through critical thinking, building spaces for dialogue of knowledge not fragmented into disciplines, but united by genuine interest for knowledge.

O artigo tem como objetivo analisar a cooperação internacional, a partir do convênio entre a Universidade de Atacama UDA-Chile e a Universidade de Nariño UDENAR-Colômbia, as duas instituições são públicas e de ensino superior regional. O estudo foi qualitativo - descritivo, os participantes foram I3 entre professores, administradores e alunos pertencentes às duas universidades. Suas idades oscilam entre 2I e 59 anos, homens e mulheres, nascidos no Chile ou na Colômbia. A análise documental e um questionário com questões abertas foram utilizados como técnicas de coleta de dados. Os resultados mostram uma avaliação positiva do convênio, uma vez que tem sido gerido a partir das três funções substantivas da universidade: ensino, pesquisa e interação social; Nesse mesmo sentido, torna-se forte o aprendizado adquirido por cada participante e a necessidade de aprofundar a pesquisa. Conclui-se que a internacionalização traz muitos benefícios pelo intercâmbio cultural, prestígio internacional e aprendizado, bem como a transdisciplinaridade do convênio, que por meio do pensamento crítico, constrói espaços de diálogo de saberes não fragmentados em disciplinas, mas unidos pelo interesse genuíno.

Prevalencia de subtipos de cáncer de mama y su asociación con factores reproductivos / Prevalence of breast cancer subtypes and their association with reproductive factors

Introducción: Los factores reproductivos se asocian con cáncer de mama. Actualmente se estudia el comportamiento según subtipos moleculares. Objetivo: Establecer la prevalencia de estos subtipos y su asociación con factores reproductivos en mujeres atendidas en centros del nororiente colombiano. Método: Estudio observacional de corte transversal, en mujeres con cáncer de mama subtipos luminales y HER2 durante 2012-2021. Se indagaron variables sociodemográficas, factores reproductivos y estadio tumoral. Resultados: En total, 347 pacientes cumplieron criterios de elegibilidad, correspondiendo a luminal A el 49,8% (intervalo de confianza del 95% [IC95%]: 44,5-55,1), a luminal B el 29,1% (IC95%: 24,3-33,9) y a HER2 el 15,5% (IC95%: 11,7-19,4). Las mujeres con tumores de mama luminal B tenían más riesgo de tener estadios localmente avanzados (odds ratio [OR]: 1,83; IC95%: 1,11-3,01; p = 0,02). Agrupando los subtipos luminales frente a HER2 se encontró que el 40,72% de las pacientes con subtipos luminales no habían lactado, frente al 69,71% con HER2 (diferencia estadísticamente significativa a favor de luminal A; OR: 1,91; IC95%: 1,02-3,53; p = 0,041). Conclusiones: La prevalencia de tumores luminales es del 84,5%. Existe asociación diferencial entre el antecedente de lactancia materna y la aparición de subtipos luminales, es decir, las mujeres que no lactaron se corresponden con mayor frecuencia con HER2. No se estableció asociación con otros factores estudiados.

Introduction: Stimulus-estrogenic factors are associated with breast cancer. Currently, the behavior according to molecular subtypes is being studied. Objective: To establish the prevalence of these subtypes and their association with reproductive factors in women attended in centers in northeastern Colombia. Method: Observational cross-sectional study in women with breast cancer subtypes luminal and HER2 during 2012 -2021. Sociodemographic variables, stimulus-estrogenic factors and tumor stage were investigated. Results: In total, 347 patients met eligibility criteria, corresponding to luminal A 49.8% (95% confidence interval [95%CI]: 44.5-55.1), luminal B 29.1% (95%CI: 24.3-33.9) and HER2 15.5% (95%CI: 11.7-19.4). Women with luminal B breast tumors were at higher risk of having locally advanced stages (odds ratio [OR]: 1.83; 95%CI: 1.11-3.01; p = 0.02). Grouping the luminal subtypes versus HER2 showed that 40.72% of patients with luminal subtypes had not lactated, compared to 69.71% HER2 (statistically significant difference in favor of luminal A; OR: 1.91; 95%CI: 1.02-3.53; p = 0.041). Conclusions: The prevalence of luminal tumors is 84.5%. There is a differential association between the history of breastfeeding and the appearance of luminal subtypes, i.e., women who did not breastfeed are more likely to have HER2. No association was established with other factors studied.

l-Carnitine ameliorates the oxidative stress response to angiotensin II by modulating NADPH oxidase through a reduction in protein kinase c activity and NF-κB translocation to the nucleus.

l-Carnitine (LC) exerts beneficial effects in arterial hypertension due, in part, to its antioxidant capacity. We investigated the signalling pathways involved in the effect of LC on angiotensin II (Ang II)-induced NADPH oxidase activation in NRK-52E cells. Ang II increased the generation of superoxide anion from NADPH oxidase, as well as the amount of hydrogen peroxide and nitrotyrosine. Co-incubation with LC managed to prevent these alterations and also reverted the changes in NADPH oxidase expression triggered by Ang II. Cell signalling studies evidenced that LC did not modify Ang II-induced phosphorylation of Akt, p38 MAPK or ERK1/2. On the other hand, a significant decrease in PKC activity, and inhibition of nuclear factor kappa B (NF-kB) translocation, were attributable to LC incubation. In conclusion, LC counteracts the pro-oxidative response to Ang II by modulating NADPH oxidase enzyme via reducing the activity of PKC and the translocation of NF-kB to the nucleus.

Inflammatory and fibrotic processes are involved in the cardiotoxic effect of sunitinib: Protective role of L-carnitine.

Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-κB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment.

Evaluación de Pensamiento Crítico en estudiantes de Trabajo Social de la región de Atacama-Chile / Evaluation of critical thinking in Social Work students of the Atacama Region-Chile / Avaliação do Pensamento Crítico no Trabalho Social estudantes da região do Atacama - Chile

RESUMEN El pensamiento crítico es un conjunto de habilidades que permiten al ser humano mejorar su pensamiento, autorregularse y tomar decisiones a partir de lo que piensa y cree. La presente investigación es cuantitativa de tipo descriptivo, con el objetivo de evaluar el pensamiento crítico en 119 estudiantes de Trabajo Social de una universidad estatal al norte de Chile, de los cuales el 19% eran hombres y el 8I% mujeres, con un rango de edad entre los 18 a 31 años. Los resultados señalan que 27% de los estudiantes tienen un pensamiento crítico muy alto, 25% nivel medio, 23% nivel bajo, 18% nivel alto y 7% nivel muy bajo. Igualmente, se destaca que los estudiantes de mayor edad, procedentes de instituciones educativas públicas e hijos de padres con niveles de formación de postgrado tienen mejor pensamiento crítico. En este sentido, es imprescindible implementar en la educación superior programas y metodologías que estimulen en el estudiante el desarrollo de habilidades de pensamiento crítico, así como la adquisición de una postura reflexiva para la resolución de problemas académicos y sociales.

ABSTRACT Critical thinking is a set of skills that allow human beings to improve their thinking, self-regulate and make decisions based on what they think and believe. The present research is quantitative of descriptive type, with the objective of evaluating critical thinking in 119 students of Social Work of a state university in the north of Chile, of which 19% were men and 81% women, with a range of age between 18 and 31 years. The results indicate that 27% of students have very high critical thinking, 25% average level, 23% low level, 18% high level and 7% very low level. It also highlights that older students from public educational institutions and children of parents with postgraduate education levels have better critical thinking. In this sense, it is essential to implement in higher education programs and methodologies that stimulate in the student the development of critical thinking skills, as well as the acquisition of a reflective posture for the resolution of academic and social problems.

RESUMO O pensamento crítico é um conjunto de habilidades que permitem aos seres humanos melhorar seu pensamento, auto-regulamentar e tomar decisões baseadas no que eles pensam e acreditam. A presente pesquisa é quantitativa e descritiva, com o objetivo de avaliar o pensamento crítico em 119 estudantes de Serviço Social de uma universidade estadual do norte do Chile, dos quais I9% eram homens e 8I% mulheres, com uma faixa etária entre 18 e 31 anos. Os resultados mostram que 27% dos alunos têm um nível muito alto de pensamento crítico, 25% um nível médio, 23% um nível baixo, 18% um nível alto e 7% um nível muito baixo. Da mesma forma, destaca-se que os alunos mais velhos, provenientes de instituições públicas de ensino e filhos de pais com níveis de formação de pós-graduação, têm um melhor pensamento crítico. Neste sentido, é essencial implementar programas e metodologias no ensino superior que estimulem o desenvolvimento de habilidades de pensamento crítico nos estudantes, assim como a aquisição de uma postura reflexiva para a resolução de problemas acadêmicos e sociais

Depresión y ansiedad prenatal: una revisión de la literatura / Prenatal Depression and Anxiety: a Literature Review / Depressão e ansiedade pré-natal: uma revisão da literatura

Introducción. Las mujeres con depresión y ansiedad prenatal pueden sufrir problemas en su funcionamiento social, retraimiento emocional y excesiva preocupación por su habilidad futura para ejercer el rol materno. Objetivo. Identificar y describir los hallazgos reportados sobre los factores de riesgo para el desarrollo de depresión y ansiedad prenatal, las consecuencias para la madre y su descendencia, las explicaciones teóricas que abordan su génesis, mantenimiento y las estrategias de atención en salud. Metodología. Se realizó una revisión de la literatura en las bases de datos y fuentes de información: Pub Med, EBSCO Host, Scielo, Redalyc y Google Scholar, de artículos publicados entre 1995 y 2015, empleando los términos "depression during pregnancy", "antenatal anxiety", "perinatal mental health", y "prenatal anxiety" entre otros, se seleccionaron artículos que reportaran el riesgos e impactos en la salud de la madre y su descendencia, explicaciones teóricas sobre génesis y mantenimiento de la depresión y ansiedad. Resultados. El principal factor de riesgo identificado es una historia previa de ansiedad y/o depresión; entre los efectos negativos para la salud del bebe se destacan restricción en el crecimiento fetal, bajo peso al nacer, parto prematuro y a futuro problemas emocionales y conductuales del niño. Las estrategias de acción comprenden el diseño de guías y protocolos de atención clínica que permiten identificar las mujeres en riesgo y las que ya presentan una sintomatología media o severa. Conclusiones. Los anteriores resultados ponen en evidencia la necesidad de implementar estrategias de acción que permitan la identificación temprana de poblaciones en riesgo. Cómo citar. Mojica-Perilla M, Redondo-Rodríguez S, Osma-Zambrano SE. Depresión y ansiedad prenatal: una revisión de la literatura. MedUNAB. 2019;22(2):200-212. doi: 10.29375/01237047.2820

Introduction. Women with prenatal depression and anxiety may suffer issues in their social performance, emotional withdrawal and excessive worrying about their future ability to be mothers. Objective. To identify and describe the findings that literatura reports on risk factors for developing prenatal depression and anxiety, the consequences for the mother and child, theoretical explanations that cover origin and treatment, and health care strategies. Methodology. We performed a literature review on articles published between 1995 and 2015 on the PubMed, EBSCO Host, Scielo, Redalyc and Google Scholar databases and sources of information. The terms, "depression during pregnancy," "antenatal anxiety," "perinatal mental health," and "prenatal anxiety," among others, were used. Moreover, we selected articles that reported risks and impacts on the mother and child's health, theoretical explanations on its origin and treatments for depression and anxiety. Results. The main identified risk factor is a previous history of anxiety and/or depression at some point in life. A restriction to prenatal development, a low birth weight and premature labor all stand out as some of the negative effects on the baby's health. Going forward, emotional and behavioral issues in the child stand out. Action strategies consist of designing clinical care guides and protocols that allow identifying women who are at risk and women who already present a moderate or severe symptomatology. Conclusions. The above results bring to light the need to implement action strategies that allow identifying populations at risk early. Cómo citar. Mojica-Perilla M, Redondo-Rodríguez S, Osma-Zambrano SE. Depresión y ansiedad prenatal: una revisión de la literatura. MedUNAB. 2019;22(2):200-212. doi: 10.29375/01237047.2820

Introdução. Mulheres com depressão e ansiedade pré-natal podem sofrer problemas em seu funcionamento social, retraimento emocional e preocupação excessiva com sua capacidade futura de exercer o papel materno. Objetivo. Identificar e descrever os achados que a literatura relata sobre os fatores de risco para o desenvolvimento de depressão e ansiedade pré-natal, as consequências para a mãe e seus filhos, as explicações teóricas que abordam sua gênese e manutenção, e as estratégias de cuidado em saúde. Metodologia. Foi realizada uma revisão de literatura nas bases de dados e fontes de informação PubMed, EBSCO Host, Scielo, Redalyc e Google Scholar de artigos publicados entre 1995 e 2015. Foram utilizados os termos "depression during pregnancy", "antenatal anxiety", "perinatal mental health" e "prenatal anxiety" entre outros. Foram selecionados artigos que relataram riscos e impactos na saúde da mãe e seus filhos, explicações teóricas sobre a gênese e a manutenção da depressão e ansiedade. Resultados. O principal fator de risco identificado é uma história prévia de ansiedade e/ou depressão em algum momento da vida. Dentre os efeitos negativos à saúde do bebê, destacam-se a restrição ao crescimento fetal, baixo peso ao nascer e parto prematuro. No futuro destacam-se os problemas emocionais e comportamentais da criança. As estratégias de ação incluem o desenho de diretrizes e protocolos de atenção clínica que permitam identificar as mulheres em risco e aquelas que já possuem uma sintomatologia média ou grave. Conclusões. Os resultados anteriores evidenciam a necessidade de implementar estratégias de ação que permitam a identificação precoce de populações em risco. Cómo citar. Mojica-Perilla M, Redondo-Rodríguez S, Osma-Zambrano SE. Depresión y ansiedad prenatal: una revisión de la literatura. MedUNAB. 2019;22(2):200-212. doi: 10.29375/01237047.2820