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Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.
Assuntos
Músculo Liso Vascular , Ligante RANK , Receptores Acoplados a Proteínas G , Calcificação Vascular , Ligante RANK/metabolismo , Ligante RANK/genética , Animais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Ratos , Humanos , Masculino , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Osteoprotegerina/metabolismo , Osteoprotegerina/genética , Hormônio Paratireóideo/metabolismo , Células Cultivadas , Ratos Sprague-DawleyRESUMO
The molecular complexity displayed in acute myeloid leukemia (AML) hinders patient stratification and treatment decisions. Previous studies support the utility of using specific gene panels for this purpose. Focusing on two salient features of AML, the production of reactive oxygen species (ROS) by NADPH oxidases (NOX) and metabolism, we aimed to identify a gene panel that could improve patient stratification. A pairwise comparison of AML versus healthy gene expression revealed the downregulation of four members of the NOX2 complex including CYBB (coding for NOX2) in AML patients. We analyzed the expression of 941 genes related to metabolism and found 28 genes with expression correlated to CYBB. This panel of 29 genes (29G) effectively divides AML samples according to their prognostic group. The robustness of 29G was confirmed by 6 AML cohort datasets with a total of 1821 patients (overall accuracies of 85%, 78%, 80%, 75%, 59% and 83%). An expression index (EI) was developed according to the expression of the selected discriminatory genes. Overall Survival (OS) was higher for low 29G expression index patients than for the high 29G expression index group, which was confirmed in three different datasets with a total of 1069 patients. Moreover, 29G can dissect intermediate-prognosis patients in four clusters with different OS, which could improve the current AML stratification scheme. In summary, we have found a gene signature (29G) that can be used for AML classification and for OS prediction. Our results confirm NOX and metabolism as suitable therapeutic targets in AML.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , PrognósticoRESUMO
OBJECTIVES: The estimates of biological variation (BV) have traditionally been determined using direct methods, which present limitations. In response to this issue, two papers have been published addressing these limitations by employing indirect methods. Here, we present a new procedure, based on indirect methods that analyses data collected within a multicenter pilot study. Using this method, we obtain CVI estimates and calculate confidence intervals (CI), using the EFLM-BVD CVI estimates as gold standard for comparison. METHODS: Data were collected over a 18-month period for 7 measurands, from 3 Spanish hospitals; inclusion criteria: patients 18-75 years with more than two determinations. For each measurand, four different strategies were carried out based on the coefficient of variation ratio (rCoeV) and based on the use of the bootstrap method (OS1, RS2 and RS3). RS2 and RS3 use symmetry reference change value (RCV) to clean database. RESULTS: RS2 and RS3 had the best correlation for the CVI estimates with respect to EFLM-BVD. RS2 used the symmetric RCV value without eliminating outliers, while RS3 combined RCV and outliers. When using the rCoeV and OS1 strategies, an overestimation of the CVI value was obtained. CONCLUSIONS: Our study presents a new strategy for obtaining robust CVI estimates using an indirect method together with the value of symmetric RCV to select the target population. The CVI estimates obtained show a good correlation with those published in the EFLM-BVD database. Furthermore, our strategy can resolve some of the limitations encountered when using direct methods such as calculating confidence intervals.
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Mineração de Dados , Bases de Dados Factuais , Humanos , Projetos Piloto , Valores de ReferênciaRESUMO
The objective of this cross-sectional study was to evaluate the frequency, impact, and management of sexual dysfunction associated with commonly prescribed antidepressants available in psychiatry outpatient clinics in Spain. We recruited 2163 adult patients who had undergone treatment with antidepressants for at least 8 weeks and had a history of normal sexual functioning before the prescription of the antidepressant, except for mildly impaired libido. We used the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX) for evaluating the frequency and tolerance of sexual dysfunction and whether this side effect was spontaneously reported. Overall, 79% patients showed sexual dysfunction, as indicated by a total score ≥ 3 on the PRSexDQ-SALSEX; 64% showed moderate-severe sexual dysfunction, with no differences between men and women on these outcomes. In the multivariate logistic regression analysis, treatment with a serotonergic antidepressant and having a severe clinical state of psychiatric illness were the factors associated with the highest likelihood of presenting with sexual dysfunction. Sexual dysfunction was spontaneously reported by 838 (41%) of the 2066 evaluable patients for this outcome. Among patients with sexual dysfunction, this condition was poorly tolerated by 22% of the patients, with these frequencies being significantly higher in men than in women. The most frequently used strategies employed by the psychiatrists in our study for dealing with sexual dysfunction were switching to another antidepressant (34%) and waiting for spontaneous resolution (33%). In conclusion, our results indicate that despite being a well-known, long-standing side effect of antidepressants, sexual dysfunction continues to be extremely common in patients receiving antidepressants, especially serotonergic ones, potentially jeopardizing treatment success in a substantial proportion of patients. There are important sex differences in the reporting and tolerance of sexual dysfunction that require further investigation.
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Antidepressivos/efeitos adversos , Transtornos Mentais/complicações , Disfunções Sexuais Fisiológicas/induzido quimicamente , Disfunções Sexuais Psicogênicas/induzido quimicamente , Adulto , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Treatment-emergent sexual dysfunction (TESD) is one of the most frequent and persistent adverse effects of antidepressant medication. Sexual dysfunction (SD) secondary to SSRIs occurs in >60% of sexually active patients and >80% of healthy volunteers, with this causing treatment discontinuation in >35% of patients. However, this factor is rarely addressed in routine examinations, and only 15-30% of these events are spontaneously reported. A strategy of switching to a different non-serotonergic antidepressant could involve a risk of relapse or clinical worsening due to a lack of serotonergic activity. Vortioxetine appears to have less impact on sexual function due to its multimodal mechanism of action. No studies have been published on the effectiveness of switching to vortioxetine in patients with poorly tolerated long-term antidepressant-related SD in naturalistic settings. STUDY OBJECTIVES: To determine the effectiveness of switching to vortioxetine due to SD in a routine clinical practice setting. METHODOLOGY: observational pragmatic and naturalistic study to determine the effectiveness of the switch to vortioxetine (mean dosage 13.11 ± 4.03) in 74 patients aged 43.1 ± 12.65 (54% males) at risk of discontinuing treatment due to sexual dysfunction. The PRSexDQ*- SALSEX scale (* Psychotropic-Related Sexual Dysfunction Questionnaire) was applied at two moments: baseline visit and after 3 months of follow-up. RESULTS: global Sexual Dysfunction (SD) measured with the SALSEX scale decreased significantly between the baseline visit (10.32; SD 2.73) and the follow-up visit (3.78; SD 3.68), p < 0.001. There was a significant improvement (p < 0.001) at the endpoint including decreased libido, delay of orgasm, anorgasmia and arousal difficulties in both sexes. After switching to vortioxetine, 83.81% of patients experienced an improvement in sexual function (43.2% felt greatly improved). Most patients (83.3%) who switched to vortioxetine continued treatment after the follow-up visit. A total of 58.1% of patients showed an improvement in depressive symptoms from the baseline visit. CONCLUSION: switching to vortioxetine is an effective and reliable strategy to treat patients with poorly tolerated previous antidepressant-related sexual dysfunction in real-life clinical settings.
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HJ-Biplot analysis is a multivariate graphic representation that collects data covariation structure between variables and individuals to represent them in a low-dimensional space with the highest quality in the same reference system. Consequently, it is a promising technique for evaluating dietary exposure to polyphenols and accurately characterizing female nutrition. Herein, we hypothesized that polyphenol intake defines specific clusters with dietary impacts, which can be assessed using HJ-Biplot, based on a cross-sectional study in Argentina. The study included 275 healthy postpartum women who provided information about their food frequency intake and other conditions, which were then used to evaluate polyphenolic intake using the Phenol-Explorer database. Outcomes were established using HJ-Biplot for clustering and ANOVA to compare their impact on diet quality indicators. Two HJ-Biplot models were run (for intakes >20 mg/d and 5â¼20 mg/d, respectively) to identify three clusters per model with excellent statistical fitness to explain the data. Thus, specific polyphenolic clusters with potentially bioactive and safe compounds were defined despite significant interindividual variability. In fact, women with the lowest polyphenolic intake exhibited worse dietary quality, body fat, and physical activity. As a result, HJ-Biplot proved to be an effective technique for clustering women based on their dietary intake of these compounds. Furthermore, cluster membership improved the intake of antioxidants, water, fiber, and healthy fats. Additionally, women with formal jobs and a higher educational level showed a better diet. Dietary polyphenols are critical during postpartum because they exert beneficial effects on women and breastfed infants.
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The aim of this paper is to analyze the main coping strategies used by frontline teams during the first days of the COVID pandemic confinement in Spain. This information could be necessary in order to carry out training programs that allow a better handling of future emergency situations, as well as acting more effectively and with less negative emotional impact. A questionnaire was used to identify different psychological profiles for coping, and in turn, other relevant variables were analyzed. The most used strategies by health professionals were problem solving, desiderative thinking and social support. Emotional expression and social support were used more by women. Significantly different behaviors were found in desiderative thinking (lower in people of 35-50 years old, and social support, higher in people 35 years old). The symptoms most commonly experienced by medical personnel were: sleep disorders, anxiety, tension, depressive symptoms, gastrointestinal symptoms and general somatic muscular symptoms. A relationship could be determined between the age/gender of the workers and the participants' overall assessment of their ability to cope with the COVID-19 stress situation they had experienced (men 50 years old and women between 35 and 50 years old, who felt able or very able to cope with the stress caused by the health emergency. However, women <35 years old and >50 years old believed they were able to cope poorly with the circumstances. The advantage of specific training plans in order to help with some stress symptoms could be suggested, aimed at the acquisition of tools based on problem solving, and emotional management in stressful and emergency situations.
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COVID-19 , Sintomas Inexplicáveis , Masculino , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , RNA Viral , SARS-CoV-2 , Adaptação Psicológica , Pessoal de SaúdeRESUMO
Diagnosis and classification of gliomas mostly relies on histopathology and a few genetic markers. Here we interrogated microarray gene expression profiles (GEP) of 268 diffuse astrocytic gliomas-33 diffuse astrocytomas (DA), 52 anaplastic astrocytomas (AA) and 183 primary glioblastoma (GBM)-based on multivariate analysis, to identify discriminatory GEP that might support precise histopathological tumor stratification, particularly among inconclusive cases with II-III grade diagnosed, which have different prognosis and treatment strategies. Microarrays based GEP was analyzed on 155 diffuse astrocytic gliomas (discovery cohort) and validated in another 113 tumors (validation set) via sequential univariate analysis (pairwise comparison) for discriminatory gene selection, followed by nonnegative matrix factorization and canonical biplot for identification of discriminatory GEP among the distinct histological tumor subtypes. GEP data analysis identified a set of 27 genes capable of differentiating among distinct subtypes of gliomas that might support current histological classification. DA + AA showed similar molecular profiles with only a few discriminatory genes overexpressed (FSTL5 and SFRP2) and underexpressed (XIST, TOP2A and SHOX2) in DA vs AA and GBM. Compared to DA + AA, GBM displayed underexpression of ETNPPL, SH3GL2, GABRG2, SPX, DPP10, GABRB2 and CNTN3 and overexpression of CHI3L1, IGFBP3, COL1A1 and VEGFA, among other differentially expressed genes.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Análise Discriminante , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais , SoftwareRESUMO
BACKGROUND: The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial. METHODS: We investigated the RNA gene expression profile of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), murine doble minute 4 (MDM4), and platelet derived growth factor receptor alpha (PDGFRA) in 83 primary GBM tumors vs. 42 normal brain tissue samples. Interphase FISH (iFISH) analysis for the four genes, together with analysis of intragenic deletions in EGFR and PDGFRA, were evaluated in parallel at the DNA level. As validation cohort, publicly available RNA gene expression data on 293 samples from 10 different GBM patient series were also studied. RESULTS: At the RNA level, CDK4 was the most frequently overexpressed gene (90%) followed by EGFR (58%) and PDGFRA (58%). Chromosome 7 copy number alterations, i.e., trisomy (49%) and polysomy (44%), showed no clear association with EGFR gene expression levels. In turn, intragenic EGFR deletions were found in 39 patients (47%), including EGFRvIII (46%) in association with EGFRvIVa (4%), EGFRvII (2%) or other EGFR deletions (3%) and PDGFRA deletion of exons 8-9 was found in only two tumors (2%). CONCLUSIONS: Overall, none of the gene expression profiles and/or intragenic EGFR deletions showed a significant impact on overall survival of GBM supporting the notion that other still unraveled features of the disease might play a more relevant prognostic role in GBM.
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This study examined whether methadone (hereinafter referred to as MTD) maintenance treatment (MMT) is correlated with sexual dysfunction (SD) in heroin-dependent men. This was conducted to determine the prevalence of sexual dysfunction and if there is a relationship between duration and dose among men on MMT and its impact on the quality of life. The study combined a retrospective and a cross-sectional survey based on the Kinsey Scale, TECVASP, and PRSexDQ-SALSEX clinical interviews of 85 patients who are currently engaged in MMT. Sexual dysfunction in all five PRSexDQ-SALSEX domains (lack of libido, delay in orgasm, inability to orgasm, erectile dysfunction, and tolerance or acceptance of changes in sexual function) was associated with dose and long-term use of heroin. All dimensions of SD were affected by the MTD intake. From the analysis of our sample, we may conclude that dose of MTD and overall score of SD were directly associated. However, no evidence was found to prove that treatment duration and severity of SD were linked. It is notable that only one tenth of the patients spontaneously reported their symptoms of the sexual sphere, but up to a third considered leaving the MMT for this reason.
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BACKGROUND: One of the most important concepts within Cognitive Social Theory as framed by Bandura is the perceived self-efficacy; this concept became widespread in 1981 when Mathias Jerusalem and Ralf Schwarzer, using 10 items, established a one-dimensional and universal construct of this scale. The main purpose of this study is to show that the General Self-Efficacy Scale (GSE) is not a one-dimensional and universal construct, as is currently assumed. METHOD: The data from 19,719 people from 26 countries were analyzed. In order to identify and understand invariance we applied seven multivariate statistical techniques. RESULTS: The findings suggest the existence of a multidimensional structure and differential item functioning by country. Insofar as there is differential item functioning by country and it is not possible to universalize it, and there are several items on the scale that statistically constitute additional factors. The results confirm that the self-efficacy construct is neither universal nor unidimensional. CONCLUSIONS: A psychometric instrument must be valued and used with great care; the one in question is being used in a generalized way.