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INTRODUCTION: Incarcerated individuals exhibit higher suicide rates compared to the general population. Investigating risk factors aids in developing effective public policies and interventions. The goal of this study was to assess and analyze factors predicting both suicidal thoughts and suicide attempts in a population of male incarcerated individuals who engage in the use of multiple psychoactive substances. METHODS: A cross-sectional observational study was conducted. A total of 174 male individuals deprived of liberty participated in the study, all of whom were serving a closed regime sentence during the data collection steps. Participants were assessed with the following instruments: the "Addiction Severity Index" (ASI-6) and the "Barratt Impulsiveness Scale" (BIS-11). RESULTS: Amongst our sample, prevalences of 36.7% in suicidal ideation and of 16.0% in suicide attempts were found. Impulsivity (OR = 1.098, 95% CI: 1.008 - 1.197), social support (OR = 0.281, 95% CI: 0.085 - 0.925), witnessing someone being killed or beaten (OR = 5.173, 95% CI: 2.143 - 12.486), cigarette use (OR = 3.309, 95% CI: 1.063 - 10.293), and cocaine use (OR = 2.678, 95% CI: 1.040 - 6.897) were also found to be associated with suicidal ideation. No significant associations were found between drug use and suicide attempts. CONCLUSION: A high prevalence of suicidal behaviors was observed in the study's sample, with findings demonstrating that impulsivity moderately differentiates the groups 'with' and 'without' suicidal ideation. Traumatic life events and substance use were also associated with suicide ideation, while social support was established as a protective factor for it.
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Introduction: Functional magnetic resonance imaging (fMRI) can be used to assess language and memory function as part of pre-surgical decision making in refractory epilepsy. Although language paradigms are well established, memory paradigms are not widely used in clinical practice due to a lack of evidence for robust and reliable methods. Here, we aim to investigate the clinical utility of the Home Town Walk (HTW) paradigm for personalized treatment decisions in medial temporal lobe epilepsy. Methods: A cohort of 123 consecutive patients having HTW-fMRI as part of routine MRI scans over a 7.5 year period were included in this retrospective study. Of these, 111 patients underwent repeated HTW-fMRI in two scanning sessions one to three days apart. fMRI analysis was performed at the time of the scans using clinically approved software and retrospectively validated using FSL. We assessed the test-retest within subject reliability of activations within the posterior parahippocampal gyri (pPHG) at the individual subject level. Results and discussion: Activations within the pPHG region were observed for 101 patients (91%) in at least one of the fMRI sessions and for 88 patients (79%) in both fMRI sessions, with 82 patients showing overlapping unilateral or bilateral activations and 8 further patients showing overlapping activations in one of the hemispheres but not the other. Reproducibility was evaluated using metrics based on the concordance ratios for size (Rsize) and location (Roverlap) within the pPHG region, as well as the lateralization index (LI) metric to reflect the asymmetry of hemispheric activations, which is of crucial relevance to inform surgery. Test-retest reliability of visuospatial memory LIs, assessed by an intra-class correlation coefficient (ICC) yielded a value of 0.76, indicating excellent between session stability of memory lateralization. Conclusion: The HTW-fMRI paradigm shows reproducible activations in the medial temporal lobes of individual epilepsy patients sufficient to consistently lateralize visuospatial memory function, demonstrating the clinical utility of HTW memory fMRI and its potential for application in the pre-surgical assessment of people with temporal lobe epilepsy.
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BACKGROUND: Iron (Fe) supplementation is a critical component of anemia therapy for patients with chronic kidney disease (CKD). However, serum Fe, ferritin, and transferrin saturation, used to guide Fe replacement, are far from optimal, as they can be influenced by malnutrition and inflammation. Currently, there is a trend of increasing Fe supplementation to target high ferritin levels, although the long-term risk has been overlooked. METHODS: We prospectively enrolled 28 patients with CKD on hemodialysis with high serum ferritin (> 1000 ng/ml) and tested the effects of 1-year deferoxamine treatment, accompanied by withdrawal of Fe administration, on laboratory parameters (Fe status, inflammatory and CKD-MBD markers), heart, liver, and iliac crest Fe deposition (quantitative magnetic resonance imaging [MRI]), and bone biopsy (histomorphometry and counting of the number of Fe positive cells in the bone marrow). RESULTS: MRI parameters showed that none of the patients had heart iron overload, but they all presented iron overload in the liver and bone marrow, which was confirmed by bone histology. After therapy, ferritin levels decreased, although neither hemoglobin levels nor erythropoietin dose was changed. A significant decrease in hepcidin and FGF-23 levels was observed. Fe accumulation was improved in the liver and bone marrow, reaching normal values only in the bone marrow. No significant changes in turnover, mineralization or volume were observed. CONCLUSIONS: Our data suggest that treatment with deferoxamine was safe and could improve Fe accumulation, as measured by MRI and histomorphometry. Whether MRI is considered a standard tool for investigating bone marrow Fe accumulation requires further investigation. Registry and the registration number of clinical trial: ReBEC (Registro Brasileiro de Ensaios Clinicos) under the identification RBR-3rnskcj available at: https://ensaiosclinicos.gov.br/pesquisador.
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Medula Óssea , Desferroxamina , Ferritinas , Sobrecarga de Ferro , Ferro , Fígado , Diálise Renal , Humanos , Masculino , Feminino , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/metabolismo , Medula Óssea/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Ferritinas/sangue , Ferritinas/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/diagnóstico por imagem , Pessoa de Meia-Idade , Desferroxamina/uso terapêutico , Desferroxamina/administração & dosagem , Ferro/metabolismo , Idoso , Imageamento por Ressonância Magnética , Estudos Prospectivos , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/sangue , Fator de Crescimento de Fibroblastos 23 , Hepcidinas/metabolismoRESUMO
BACKGROUND: The COVID-19 pandemic has resulted in great incertitude and overwhelming changes in healthcare that have had a direct impact on antibiotic prescription. However, the influence of this pandemic on antibiotic consumption in patients undergoing surgery has not yet been analysed. The goal of this study was to analyse antimicrobial consumption and prescription in the same period of 2019 (pre-COVID-19), 2020 (beginning of the COVID-19 pandemic) and 2021 (established COVID-19) according to the DDD system in surgical patients at a tertiary-level hospital. METHODS: A prospectively maintained database was analysed. All patients who underwent elective or emergency gastrointestinal surgery during the same period (2019, 2020 and 2021) were included. Those who received at least 1 of the 10 most frequently prescribed antimicrobials during those periods were analysed. RESULTS: A total of 2975 patients were included in this study. In 2020, the number of procedures performed decreased significantly (653 versus 1154 and 1168 in 2020 versus 2019 and 2021, respectively; Pâ=â0.005). Of all patients who underwent surgery during these periods, 45.08% received at least one of the antimicrobials studied (45.8% in 2020 versus 22.9% and 22.97% in 2019 and 2021, respectively; Pâ=â0.005). Of these, 22.97% of the patients received a combination of these antimicrobials, with ceftriaxone/metronidazole being the most frequent. Hepato-Pancreato-Biliary and Liver Transplant, Emergency Surgery and Colorectal Surgery units had higher antibiotic consumption. CONCLUSIONS: The COVID-19 pandemic has resulted in a significant decrease in surgical activity and higher post-operative antimicrobial prescription compared with previous and subsequent years.
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OBJECTIVE: US Hispanics have several health disparities, greater tobacco/nicotine-related illnesses, lower access to smoking cessation, and lower rates of cessation. Understanding cultural constructs linked to tobacco/nicotine use may provide a greater understanding of future cultural adaptations of cessation interventions. This study used a multidimensional acculturation framework, with cultural practices, identity, and values, to test links between measures of acculturation stress, multidimensional acculturation (language-based enculturation and acculturation, cultural identity, familism), and tobacco/nicotine use, and interactions with gender. DESIGN: Participants were 391 adult Latin American immigrants (69% women); 12% self-reported tobacco/nicotine use in the past six months. RESULTS: Path analysis showed acculturative stress, ß = .16, and acculturation, ß = .20, were positively related to tobacco/nicotine use. Enculturation, familism, and Hispanic cultural identity were not related to tobacco/nicotine use. There were no significant acculturation by enculturation or gender interactions, but women were less likely to use tobacco/nicotine than men, ß = -.36. CONCLUSION: Findings suggest that tobacco/nicotine cessation interventions for Latino immigrants may be enhanced with an emphasis on the mitigation of acculturative stress, attention to the adoption of US cultural practices, and gender. Future research should examine specific sources of acculturative stress or social norms related to tobacco/nicotine use.
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OBJECTIVE: To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. METHODS: A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. RESULTS: Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. CONCLUSION: In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population.
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BACKGROUND: Metabolic syndrome (MetS) in adolescence is a risk factor for future cardiovascular disease. The chronic inflammation associated with MetS can be attenuated by the anti-inflammatory effect of polyphenols. We aimed to evaluate total urinary polyphenols as a biomarker of anti-inflammatory diets and their effect on MetS in adolescents. METHODS: In this retrospective analysis of a longitudinal cohort study, the relationship between total polyphenol excretion (TPE) in urine, the inflammatory potential of the diet measured through the Children's Dietary Inflammatory Index (C-DII), and the presence of metabolic syndrome was evaluated. The study population consisted of adolescents enrolled in the SI! Program for Secondary Schools trial, who had completed all the study forms and provided urine samples at baseline and at the two-year follow-up. Multivariate linear regression and multinominal logistic regression models were generated to evaluate the relationship of changes in TPE with changes in the C-DII score and changes in MetS status, respectively. An analysis of the ROC curve was performed to assess the potential of TPE as a biomarker of an anti-inflammatory diet. RESULTS: This study included 662 adolescents, 51.2% were males, and 48.8% were females, with a mean age of 12 (0.38) years at baseline. The relationship between changes in TPE and changes in the C-DII score was stratified by sex with a p-value <0.001 for the interaction. TPE and C-DII were inversely associated in males (-0.13 mg GAE/g creatinine [-0.26; -0.01] per 1-SD increase, p-value = 0.037). In addition, an increase in changes in TPE levels were associated with a reversal in MetS status in all adolescents (1.30 [1.27; 1.34] per 1-SD increase, p-value<0.001). The ROC curve showed that urinary TPE levels can predict dietary inflammatory potential with an AUC = 0.793 (0.725; 0.863) in males. CONCLUSION: Polyphenols excreted in urine are a potential biomarker of anti-inflammatory diets in males and are associated with a reversal of MetS status in adolescents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03504059, https://clinicaltrials.gov/study/NCT03504059.
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Biomarcadores , Dieta , Síndrome Metabólica , Polifenóis , Humanos , Masculino , Feminino , Polifenóis/administração & dosagem , Polifenóis/urina , Adolescente , Biomarcadores/urina , Síndrome Metabólica/urina , Estudos Longitudinais , Estudos Retrospectivos , Dieta/métodos , Inflamação/urina , Criança , Anti-Inflamatórios/administração & dosagemRESUMO
Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997-2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.
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Biomarcadores , Vírus Linfotrópico T Tipo 1 Humano , Interleucina-10 , Carga Viral , Humanos , Feminino , Masculino , Brasil/epidemiologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Interleucina-10/sangue , Biomarcadores/sangue , Pessoa de Meia-Idade , Adulto , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/sangue , Infecções por HTLV-I/diagnóstico , Provírus , Estudos de Coortes , Paraparesia Espástica Tropical/sangue , Paraparesia Espástica Tropical/imunologia , Paraparesia Espástica Tropical/virologia , IncidênciaRESUMO
Introduction: Tobacco consumption and its impact on health remain high worldwide. Additionally, it is a contentious issue generating significant controversy. Twitter has proven to be a useful platform for evaluating public health topics related to population health behaviors, and tobacco consumption. Objective: The objective of this study is to analyze the content of tweets related to tobacco. Moreover, geolocation data will be considered to understand regional differences. Methods: Tweets published between 2018 and 2022, in both English and Spanish, containing the keyword "tobacco," were analyzed. A total of 56,926 tweets were obtained. The tweets were classified into different categories. 550 tweets were manually analyzed, and an automated and computerized classification was performed for the remaining and largest subset of tweets. Results: The analysis yielded 30,812 classifiable tweets. Healthcare professionals were the most frequent contributors to the topic (50.2%), with the most common theme being general information about the toxic effects of tobacco. 57.9% of the tweets discussed the harmful effects of tobacco on health, with fear being the predominant emotion. The largest number of tweets were located in America. Conclusions: Our study revealed a substantial number of tweets highlighting the health risks and negative perceptions of tobacco consumption. Africa showed the lowest percentage of tweets discussing the health risks associated with tobacco, coinciding with the continent having the least developed anti-tobacco policies. Healthcare professionals emerged as the most prominent users discussing the topic, which is encouraging as they play a crucial role in disseminating accurate and scientific health information.
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Mídias Sociais , Uso de Tabaco , Humanos , Mídias Sociais/estatística & dados numéricos , Uso de Tabaco/epidemiologiaRESUMO
With the objective of gaining insight into the modulation of the reduction potential of the Ni(II/I) couple, we have synthesized two mononuclear nickel(II) complexes, NiLen (H2Len = N,N'-bis(3-methoxysalicylidene)-1,2-diamino-2-methylpropane) and NiLpn (H2Lpn = N,N'-bis(3-methoxysalicylidene)-1,3-diamino-2,2-dimethylpropane) of two N2O4 donor ligands and recorded their cyclic voltammograms. Both the nickel complexes show reversible reduction processes for the Ni(II/I) couple in acetonitrile solution but the reduction potential of NiLpn (E1/2 = -1.883 V) is 188 mV more positive than that of NiLen (E1/2 = -2.071 V). In the presence of redox inactive metal ions (Li+, Na+, K+, Mg2+, Ca2+ and Ba2+), the reduction potentials are shifted by 49-331 mV and 99-435 mV towards positive values compared to NiLen and NiLpn, respectively. The shift increases with the decrease of the pKa of the respective aqua-complexes of the metal ion but is poorly co-linear; however, better linearity is found when the shift of the mono- and bi-positive metal ion aqua complexes is plotted separately. Spectrophotometric titrations of these two nickel complexes with the guest metal ions in acetonitrile showed a well-anchored isosbestic point in all cases, confirming the adduct formation of NiLen and NiLpn with the metal ions. Structural analysis of single crystals, [(NiLen)Li(H2O)2]·ClO4 (1), [(NiLpn)Li(H2O)]·ClO4 (2), [(NiLpn)2Na]·BF4 (3) and [(NiLpn)2Ba(H2O)(ClO4)]·ClO4 (4), also corroborates the heterometallic adduct formation. The orbital energies of the optimised heterometallic adducts from which electron transfers originated were calculated in order to explain the observed reduction process. A strong linear connection between the calculated orbital energies and the experimental E1/2 values was observed. According to MEP and 2D vector field plots, the largest shift for divalent metal ions is most likely caused by the local electric field that they impose in addition to Lewis acidity.
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Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN's tumor-supporting role might also be metabolic-independent. Materials and Methods: In the present study, we show that FASN inactivation by specific small interfering RNA (siRNA) promoted the downregulation of the S-phase kinase associated-protein kinase 2 (SKP2) and the consequent induction of p27KIP1 in HCC cell lines. Results: Expression levels of FASN and SKP2 directly correlated in human HCC specimens and predicted a dismal outcome. In addition, forced overexpression of SKP2 rendered HCC cells resistant to the treatment with the FASN inhibitor C75. Furthermore, FASN deletion was paralleled by SKP2 downregulation and p27KIP1 induction in the AKT-driven HCC preclinical mouse model. Moreover, forced overexpression of an SKP2 dominant negative form or a p27KIP1 non-phosphorylatable (p27KIP1-T187A) construct completely abolished AKT-dependent hepatocarcinogenesis in vitro and in vivo. Conclusions: In conclusion, the present data indicate that SKP2 is a critical downstream effector of FASN and AKT-dependent hepatocarcinogenesis in liver cancer, envisaging the possibility of effectively targeting FASN-positive liver tumors with SKP2 inhibitors or p27KIP1 activators.
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Carcinoma Hepatocelular , Inibidor de Quinase Dependente de Ciclina p27 , Neoplasias Hepáticas , Proteínas Quinases Associadas a Fase S , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Ácido Graxo Sintases/metabolismo , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Graxo Sintase Tipo I/genética , Regulação para Baixo , MasculinoRESUMO
BACKGROUND: Early cutaneous squamous cell carcinomas (cSCCs) generally show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits associated with tumor relapse, metastasis, and poor survival. Currently, the mechanisms involved in cSCC progression are unclear, and the established markers are suboptimal for accurately predicting the clinical course of the disease. METHODS: Using a mouse model of cSCC progression, expression microarray analysis, immunofluorescence and flow cytometry assays, we have identified a prognostic biomarker of tumor relapse, which has been evaluated in a cohort of cSCC patient samples. Phosphoproteomic analysis have revealed signaling pathways induced in epithelial plastic cancer cells that promote epithelial-mesenchymal plasticity (EMP) and tumor progression. These pathways have been validated by genetic and pharmacological inhibition assays. RESULTS: We show that the emergence of epithelial cancer cells expressing integrin αV (ITGAV) promotes cSCC progression to a mesenchymal state. Consistently, ITGAV expression allows the identification of patients at risk of cSCC relapse above the currently employed clinical histopathological parameters. We also demonstrate that activation of insulin-like growth factor-1 receptor (IGF1R) pathway in epithelial cancer cells is necessary to induce EMP and mesenchymal state acquisition in response to tumor microenvironment-derived factors, while promoting ITGAV expression. Likewise, ITGAV knockdown in epithelial plastic cancer cells also blocks EMP acquisition, generating epithelial tumors. CONCLUSIONS: Our results demonstrate that ITGAV is a prognostic biomarker of relapse in cSCCs that would allow improved patient stratification. ITGAV also collaborates with IGF1R to induce EMP in epithelial cancer cells and promotes cSCC progression, revealing a potential therapeutic strategy to block the generation of advanced mesenchymal cSCCs.
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Transição Epitelial-Mesenquimal , Receptor IGF Tipo 1 , Transdução de Sinais , Neoplasias Cutâneas , Animais , Humanos , Camundongos , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/genética , Linhagem Celular Tumoral , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/genética , Prognóstico , Microambiente Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genéticaRESUMO
Muscle weakness is a common symptom in CKD patients, and the pathway by which secondary hyperparathyroidism (SHPT) affects muscle function is unknown. Osteopontin (OPN), a bone matrix protein stimulated by PTH and phosphate, has been associated with inflammatory muscle diseases. In this observational and prospective cohort study, we evaluated 30 patients with severe SHPT (39 ± 12 yr; 18 women), before and 6 mo after parathyroidectomy (PTx). We examined the relationships among CKD-mineral and bone disorder parameters; myokine and inflammatory cytokine levels; and changes in resting energy expenditure (REE), muscle function, BMD, and muscle-related proteins. At baseline, the patients showed low gene expression of muscle turnover markers and irisin, as well as high protein expression of OPN, transforming growth factor beta (TGF-ß), and fibroblast growth factor 21. Six months after PTx, REE and muscle mass had not changed, but physical performance, muscle strength, and bone mass improved, more so in patients undergoing total PTx. Also, there were reductions in the protein expression of OPN (11 vs 3%, p=.01) and TGF-ß (21 vs 7%, p=.002) in muscle, together with a significant increase in irisin muscular levels (30 vs 35 pg/mg, p=.02). The gain in bone mass and the increase in irisin levels correlated with a reduction in PTH. The levels of interleukin (IL)-1ß, tumor necrosis factor alpha, and IL-17 (markers of myositis) were also lower after PTx. Our data suggest that SHPT plays a role in CKD-induced muscle dysfunction, indirectly, via release of bone-specific proteins, which is partially reverted with PTx.
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Maternal breast milk plays a key role in providing newborns with passive immunity and stimulating the maturation of an infant's immune system, protecting them from many diseases. It is known that diet can influence the immune system of lactating mothers and the composition of their breast milk. The aim of this study was to establish if a supplementation during the gestation and lactation of Lewis rats with extra virgin olive oil (EVOO), due to the high proportion of antioxidant components in its composition, has an impact on the mother's immune system and on the breast milk's immune composition. For this, 10 mL/kg of either EVOO, refined oil (control oil) or water (REF group) were orally administered once a day to rats during gestation and lactation periods. Immunoglobulin (Ig) concentrations and gene expressions of immune molecules were quantified in several compartments of the mothers. The EVOO group showed higher IgA levels in both the breast milk and the mammary glands than the REF group. In addition, the gene expression of IgA in mammary glands was also boosted by EVOO consumption. Overall, EVOO supplementation during gestation and lactation is safe and does not negatively affect the mother's immune system while improving breast milk immune composition by increasing the presence of IgA, which could be critical for an offspring's immune health.
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Lactação , Azeite de Oliva , Ratos Endogâmicos Lew , Animais , Feminino , Gravidez , Ratos , Fenômenos Fisiológicos da Nutrição Materna , Imunoglobulina A/metabolismo , Imunoglobulina A/análise , Sistema Imunitário/efeitos dos fármacos , Suplementos Nutricionais , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/metabolismo , Leite/química , Leite/imunologia , Leite Humano/química , Leite Humano/imunologiaRESUMO
BACKGROUND: Clinical and ultrasound experience has revealed that after soft tissue injections of the lateral cheek, the filler may displace from the zygoma to the caudal temporal area. OBJECTIVE: To obtain more data to provide insight into product distribution when soft tissue fillers are injected in the zygomatic region. METHODS: Two hundred patients were examined with facial ultrasound imaging of the zygomatic and temporal region. Inclusion criteria were simply a positive response on the screening questionnaire as to whether or not they had filler injections placed in their lateral cheek. Control injections were also performed to the zygomatic regions of a body donor and in 10 patients ultrasound-guided. RESULTS: A correlation was found between the layers in which filler was detected on the zygoma and where it was ultimately found in the temples. Four different redistribution patterns were observed: (1) migration of filler within the superficial muscular aponeurotic system (SMAS) on the zygoma into the superficial temporal fascia. Migration of filler from the lateral suborbicularis oculi fat to (2) the deep interfacial plane of the temple or (3) to the superficial temporal fat pad; (4) migration from the supraperiosteal layer of the zygoma to the superficial temporal fat pad. Body donor and patients: filler deposits injected on the zygoma were witnessed to shift during injection into the caudal part of the temple. CONCLUSION: Soft tissue filler aliquots may be redistributed into the temples after injections of the lateral side of the zygomatic arch. The displacement follows a distinct pattern depending on the initial layer of injection.
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Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9-12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9-12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT-qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9-12 alleles using nanopore long-sequencing. Using the Kruskal-Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9-12 and identifying which of them has developed cancer.
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Alelos , Proteína BRCA1 , Síndrome Hereditária de Câncer de Mama e Ovário , Humanos , Proteína BRCA1/genética , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Pessoa de Meia-Idade , Predisposição Genética para Doença , Adulto , Efeito Fundador , Éxons/genética , Neoplasias da Mama/genética , Heterozigoto , Mutação , México , Neoplasias Ovarianas/genética , Relevância ClínicaRESUMO
Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.
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Antígeno B7-H1 , Carcinoma de Células Escamosas , Plasticidade Celular , Transição Epitelial-Mesenquimal , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Cutâneas , Animais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Camundongos , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Imunoterapia/métodos , Transição Epitelial-Mesenquimal/imunologia , Plasticidade Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/imunologia , Receptores Virais/metabolismo , Receptores Virais/genética , Antígeno B7-1/metabolismo , Receptores Imunológicos/metabolismoRESUMO
BACKGROUND: The low prevalence of rare diseases poses a significant challenge in advancing their understanding. This study aims to delineate the clinical and genetic characteristics of patients with rare eye diseases (RED) enrolled in the Spanish Rare Diseases Patient Registry. METHODS: A total of 864 patients from the registry database were included. Diseases were categorized into inherited retinal dystrophies (n=688); anterior segment diseases (n=48); congenital malformations (n=27); and syndromic diseases with ocular involvement including muscular (n=46), neurological (n=34), or metabolic (n=13); inflammatory diseases (n=4); and tumors (n=4). Data on visual acuity (VA) and/or visual field (VF), symptoms and signs, concurrent diseases in syndromic cases, age of onset and at diagnosis, affected genes, disability rating, inability to work and dependency grade recognition were collected. RESULTS: A mean diagnostic delay of 7 years from symptom onset was observed. Commonly reported symptoms included photophobia, night blindness, and progressive vision loss (≥57% of patients). Cataract was the most prevalent secondary disease (46%), with pseudophakia being the most common ocular surgery (26%). Hearing loss and cardiovascular diseases were the most prevalent concurrent systemic diseases (≥13%). Certificates of disability, incapacity for work, and dependency were held by 87%, 42%, and 19% of patients, respectively. Among the 719 patients with available VA data, 193 (27%) were blind, and 188 (26%) had moderate to severe visual impairment. Over half of the patients (54%) exhibited VF defects, and 216 (25%) had concentric contraction ≤5° or abolished VF. Most had genetic diseases with autosomal recessive (55%), autosomal dominant (30%), X-linked (9%), and mitochondrial (6%) patterns. One patient had mutations in both recessive USH2A and dominant RHO genes simultaneously. Of the 656 patients (75.7%) who underwent genetic testing, only 461 (70.3%) received a positive result (pathogenic or likely pathogenic mutations explaining the phenotype). We found 62 new gene variants related to RED not previously reported in databases of genetic variants related to specific phenotypes. CONCLUSIONS: This study delineates the clinical and genotypic profiles of RED in Spain. Genetic diseases, particularly retinal disorders, predominate, but a significant proportion of affected patients remain genetically undiagnosed, hindering potential gene therapy endeavors. Despite notable improvements in reducing diagnosis delays, it is still remarkable. RED frequently lead to disability and blindness among young populations.
Assuntos
Oftalmopatias , Doenças Raras , Sistema de Registros , Humanos , Masculino , Feminino , Oftalmopatias/genética , Oftalmopatias/epidemiologia , Espanha/epidemiologia , Adulto , Doenças Raras/genética , Pessoa de Meia-Idade , Adolescente , Criança , Adulto Jovem , Pré-Escolar , Idoso , Lactente , Acuidade Visual/fisiologia , Distrofias Retinianas/genética , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/diagnósticoRESUMO
EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n = 9) to IFS (n = 1) or lipofibromatosis-like tumors (LFT-like) (n = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (n = 1) to a predominantly myxoid spindle cell lesion (n = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored EGFR-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFR kinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase-related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.