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PURPOSE: The prevalence of homologous recombination repair gene mutations (HRRm) in patients with metastatic castration-resistant prostate cancer (mCRPC) in Latin America and the Caribbean (LAC) is unknown. Prevalence of homologous Recombination repair (HRR) gene mutatiOns in patientS with metastatic castration resistant ProstatE Cancer in LaTin America (PROSPECT) aimed to determine this prevalence and to describe the demographic and clinical characteristics of the participants. MATERIALS AND METHODS: This was a prospective, cross-sectional, multicenter study across 11 cancer centers in seven LAC countries. After informed consent, all eligible participants underwent genomic testing by provided blood samples for germline HRR testing; they also provided PC tissue blocks if available for somatic HRR testing. RESULTS: Between April 2021 and April 2022, 387 patients (median age, 70 years [49-89], 94.3% Eastern Cooperative Oncology Group 0-1) with mCRPC were enrolled in the study. Almost 40% of them had a family history of cancer, and the overall time from their initial PC and mCRPC diagnosis was 3 years and 1 year, respectively. The overall prevalence of germline HRRm was 4.2%. The mutations detected included the genes CHEK2 (n = 4, 1%), ATM (n = 3, 0.8%), BRCA2 (n = 3, 0.8%), BRIP1 (n = 2, 0.5%), RAD51B (n = 2, 0.5%), BRCA1 (n = 1, 0.3%), and MRE11 (n = 1, 0.3%). The prevalence of somatic HRRm could not be assessed because of high HRR testing failure rates (79%, 199/251) associated with insufficient DNA, absence of tumor cells, and poor-quality DNA. CONCLUSION: Despite the study's limitations, to our knowledge, PROSPECT was the first attempt to describe the prevalence of HRRm in patients with PC from LAC. Notably, the germline HRRm prevalence in this study was inferior to that observed in North American and European populations. The somatic HRR testing barriers identified are being addressed by several projects to improve access to HRR testing and biomarker-based therapies in LAC.
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Mutación , Neoplasias de la Próstata Resistentes a la Castración , Reparación del ADN por Recombinación , Humanos , Masculino , Anciano , Estudios Prospectivos , Persona de Mediana Edad , Estudios Transversales , América Latina/epidemiología , Anciano de 80 o más Años , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/epidemiología , Neoplasias de la Próstata Resistentes a la Castración/patología , Reparación del ADN por Recombinación/genética , PrevalenciaRESUMEN
OBJECTIVE: To identify factors influencing the availability and sales of healthy food and drinks in a café located in a hospital setting in a rural area. METHODS: Three online and 1 in-person group model building workshops were conducted with hospital staff members to develop a causal loop diagram. RESULTS: Four areas in the causal loop diagram were identified, 5 teams were created to implement 15 identified action ideas, and an action registry was created to track their progress. By May 2023, 4 actions were active, 6 inactive, 4 completed, and 1 abandoned. CONCLUSIONS AND IMPLICATIONS: The group model building process identified factors and actions to improve the healthiness of the hospital's café and motivated staff members to act for change. However, progress was limited by staff turnover, recruitment, and inadequate participation from decision-makers. Better leadership and support by senior management can ensure that long-term objectives are achieved and healthier hospital food environments are sustained.
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Servicio de Alimentación en Hospital , Análisis de Sistemas , Humanos , Promoción de la Salud/métodosRESUMEN
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1ß production. Although these are gain-of-function variants characterized by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4 A. The constitutively active NLRP3-inflammasome of CAPS is responsive to the selective NLRP3 inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-κB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1ß production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1ß-dependent inflammatory episodes through immunometabolism modulation.
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Síndromes Periódicos Asociados a Criopirina , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Interleucina-18 , Síndromes Periódicos Asociados a Criopirina/genética , Sulfonamidas/farmacología , Interleucina-1beta/metabolismoRESUMEN
Mucopolysaccharidosis type II (MPS II) is an inborn error of the metabolism resulting from several possible mutations in the gene coding for iduronate-2-sulfatase (IDS), which leads to a great clinical heterogeneity presented by these patients. Many studies demonstrate the involvement of oxidative stress in the pathogenesis of inborn errors of metabolism, and mitochondrial dysfunction and oxidative stress can be related since most of reactive oxygen species come from mitochondria. Cellular models have been used to study different diseases and are useful in biochemical research to investigate them in a new promising way. The aim of this study is to develop a heterozygous cellular model for MPS II and analyze parameters of oxidative stress and mitochondrial dysfunction and investigate the in vitro effect of genistein and coenzyme Q10 on these parameters for a better understanding of the pathophysiology of this disease. The HP18 cells (heterozygous c.261_266del6/c.259_261del3) showed almost null results in the activity of the IDS enzyme and presented accumulation of glycosaminoglycans (GAGs), allowing the characterization of this knockout cellular model by MPS II gene editing. An increase in the production of reactive species was demonstrated (p < .05 compared with WT vehicle group) and genistein at concentrations of 25 and 50 µm decreased in vitro its production (p < .05 compared with HP18 vehicle group), but there was no effect of coenzyme Q10 in this parameter. There was a tendency for lysosomal pH change in HP18 cells in comparison to WT group and none of the antioxidants tested demonstrated any effect on this parameter. There was no increase in the activity of the antioxidant enzymes superoxide dismutase and catalase and oxidative damage to DNA in HP18 cells in comparison to WT group and neither genistein nor coenzyme q10 had any effect on these parameters. Regarding mitochondrial membrane potential, genistein induced mitochondrial depolarization in both concentrations tested (p < .05 compared with HP18 vehicle group and compared with WT vehicle group) and incubation with coenzyme Q10 demonstrated no effect on this parameter. In conclusion, it is hypothesized that our cellular model could be compared with a milder MPS II phenotype, given that the accumulation of GAGs in lysosomes is not as expressive as another cellular model for MPS II presented in the literature. Therefore, it is reasonable to expect that there is no mitochondrial depolarization and no DNA damage, since there is less lysosomal impairment, as well as less redox imbalance.
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Iduronato Sulfatasa , Enfermedades Mitocondriales , Mucopolisacaridosis II , Ubiquinona/análogos & derivados , Humanos , Mucopolisacaridosis II/tratamiento farmacológico , Mucopolisacaridosis II/genética , Genisteína/farmacología , Potencial de la Membrana Mitocondrial , Estrés Oxidativo , Iduronato Sulfatasa/metabolismo , Iduronato Sulfatasa/farmacología , Antioxidantes/farmacología , Antioxidantes/metabolismoRESUMEN
Introduction: Food environments are a key determinant of food intake and diet-related health. This paper describes the development of an iterative, adaptive, context-specific framework for health-enabling food environments embedded in cocreation theory. Methods: A 3-stage multimethod framework for the coproduction and prototyping of public health interventions was followed in an iterative manner during the development of the framework. These 3 stages were (1) evidence review, including systematic review, consultation with experts, and observation of current work; (2) codesign of the framework prototype with multiple stakeholders; and (3) coproduction through refinement of the prototype through stakeholder workshops and expert reviews with incorporation of researcher notes and workshop evaluation. We use the term prototype during the development phase and the term framework to report on the final product. Results: COACH (CO-creation and evaluation of food environments to Advance Community Health) is a process framework that describes what best practice application of cocreation in health-enabling food retail environments should involve. COACH consists of 10 interdependent factors within a 4-phase continuous quality improvement cycle. The 4 phases of the cycle are engagement and governance establishment, communication and policy alignment, codesign and implementation, and monitoring and evaluation. Conclusions: Utilizing cocreation theory represents an innovative step in research and practice to improve the healthiness of food retail environments. COACH provides a specific, unique, and comprehensive guide to the utilization of cocreation to improve the healthiness of food environments in practice.
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Phenylketonuria (PKU) is the most common inherited metabolic disorders caused by severe deficiency or absence of phenylalanine hydroxylase activity that converts phenylalanine (Phe) to tyrosine. PKU patients were treated with a Phe restricted diet supplemented with a special formula containing l-carnitine (L-car), well-known antioxidant compound. The lack of treatment can cause neurological and cognitive impairment, as severe mental retardation, neuronal cell loss and synaptic density reduction. Although Phe has been widely demonstrated to be involved in PKU neurotoxicity, the mechanisms responsible for the CNS injury are still not fully known. In this work, we evaluated markers of neurodegeneration, namely BDNF (brain-derived neurotrophic factor), PAI-1 total (Plasminogen activator inhibitor-1 total), Cathepsin D, PDGF AB/BB (platelet-derived growth factor), and NCAM (neuronal adhesion molecule) in plasma of PKU patients at early and late diagnosis and under treatment. We found decreased Phe levels and increased L-car concentrations in PKU patients treated with L-car compared to the other groups, indicating that the proposed treatment was effective. Furthermore, we found increased BDNF levels in the patients under treatment compared to patients at early diagnosis, and a positive correlation between BDNF and L-car and a negative correlation between BDNF and Phe. Our results may indicate that in PKU patients treated with L-car there is an attempt to adjust neuronal plasticity and recover the damage suffered, reflecting a compensatory response to brain injury.
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Carnitina , Fenilcetonurias , Humanos , Factor Neurotrófico Derivado del Encéfalo , Fenilcetonurias/tratamiento farmacológico , Suplementos Dietéticos , Antioxidantes , Fenilalanina , BecaplerminaRESUMEN
Objetivo: Conocer la relación entre mortalidad y nivel de fragilidad mediante los índices de fragilidad-valoración geriátrica integral (IF-VGI) a los 12 meses de seguimiento en adultos mayores. Materiales y métodos: Estudio descriptivo, observacional y prospectivo, con muestreo no probabilístico. Se incluyeron pacientes mayores de 60 años del Servicio de Geriatría. Se utilizaron los IF-VGI, y se diagnosticó la fragilidad si la puntuación era mayor o igual a 0,2 en los diferentes niveles de atención: unidad de agudos, hospital de día, consulta externa y consulta domiciliaria; se realizó un seguimiento de 12 meses después de su evaluación por vía telefónica. En caso de fallecimiento, se corroboró el suceso y la causa en el Sistema Informático Nacional de Defunciones (SINADEF) del Ministerio de Salud del Perú. Se excluyeron los pacientes que fallecieron por complicaciones de coronavirus. Para determinar la asociación entre IF-VGI y mortalidad se utilizaron las pruebas ji al cuadrado y t de Student, tanto para las variables cualitativas y cuantitativas, respectivamente. Resultados: Se incluyeron 241 sujetos, con una edad media de 85,08 años. De esta población, 222 (92,12 %) tenían fragilidad con un IF mayor-igual a 0,2. De ellos, 82 presentaron fragilidad leve (IF entre 0,2-0,36); 59, fragilidad moderada (IF entre 0,4-0,52), y 54, fragilidad severa (IF mayor 0,56). En el seguimiento de la población reevaluada a los 12 meses, 28 (11,61 %) fallecieron en este periodo. De los fallecidos, 23 (82,14 %) registraron un IF mayor igual a 0,56. Al analizar la asociación entre la mortalidad y el IF-VGI, se encontró que, a mayor índice de fragilidad, mayor mortalidad, con diferencias muy significativas (p = 0,001). No hubo asociación entre edad y mortalidad (p = 0,95). Conclusiones: El IF-VGI es una herramienta útil para predecir la mortalidad en los pacientes frágiles, según su severidad, a los 12 meses de seguimiento.
Objective: To determine the relationship between mortality and level of frailty using the Frailty Index-Comprehensive Geriatric Assessment (FI-CGA) among older adults at a 12-month follow-up. Materials and methods: A descriptive, observational and prospective study with non-probabilistic sampling conducted with patients over 60 years of age from the Geriatrics Service. Using the FI-CGA, frailty was diagnosed if the score was greater than or equal to 0.2 at the different levels of care: acute care unit, day hospital, outpatient clinic and house call. Moreover, a follow-up was conducted 12 months following their telephone consultation. In case of death, the event and cause were confirmed in the Sistema Informático Nacional de Defunciones (SINADEF, National Death Computer System) of the Ministry of Health of Peru. Patients who died from coronavirus complications were excluded. To determine the association between FI-CGA and mortality, chi-square and Student's t tests were used for the qualitative and quantitative variables, respectively. Results: A total of 241 subjects with an average age of 85.08 years were included in the research. Out of this population, 222 (92.12 %) were classed as frail (FI-CGA score ≥ 0.2), among which 82 were considered mildly frail (0.2-0.36), 59 moderately frail (0.4-0.52) and 54 severely frail (> 0.56). At the 12-month follow-up, 28 (11.61 %) older adults had died during that period. Out of the deceased, 23 (82.14 %) had a FI-CGA score greater than or equal to 0.56. When analyzing the association between mortality and the FI-CGA, it was found that the higher the FI, the higher the mortality, with very significant differences (p = 0.001). There was no association between age and mortality (p = 0.95). Conclusions: The FI-CGA is a useful tool to predict mortality in frail patients, according to their severity, at a 12-month follow-up.
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Mucopolysaccharidosis type II (MPS II) is a disorder caused by a deficient activity of iduronate-2-sulfatase, a lysosomal enzyme responsible for degrading glycosaminoglycans (GAGs). The abnormal storage of GAGs within lysosomes disrupts cellular homeostasis and leads to a severe symptomatology. Patients present neuropsychiatric impairment characterized by mental retardation and impaired cognition. The aim of this study was to quantify four neurodegeneration biomarkers in plasma: brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF-AA), neural cell adhesion molecule (NCAM) and cathepsin-D, as well as to identify possible correlations with urinary GAGs in seven patients undergoing treatment with ERT (Elaprase® 0.5 mg/kg of body weight). Patients with both severe and attenuated forms of MPS II showed signs of neurodegeneration in neuroimaging exams. Patients have a decrease in BDNF and PDGF-AA concentrations, and an increase in NCAM level compared to controls. No alterations in cathepsin-D concentration were seen. GAGs levels were higher in patients than in controls, but no significant correlations between GAGs and biomarkers were observed. These results evidence that patients have neurodegeneration and that monitoring these biomarkers might be useful for assessing this process. To this date, this is the first work to analyze these plasmatic markers of neurodegeneration in patients.
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Mucopolisacaridosis II , Humanos , Mucopolisacaridosis II/complicaciones , Mucopolisacaridosis II/tratamiento farmacológico , Mucopolisacaridosis II/diagnóstico , Factor Neurotrófico Derivado del Encéfalo/uso terapéutico , Terapia de Reemplazo Enzimático , Glicosaminoglicanos/metabolismo , Glicosaminoglicanos/uso terapéutico , Biomarcadores , Moléculas de Adhesión de Célula Nerviosa/uso terapéuticoRESUMEN
BACKGROUND: Animal models of acute respiratory distress syndrome (ARDS) do not completely resemble human ARDS, struggling translational research. We aimed to characterize a porcine model of ARDS induced by pneumonia-the most common risk factor in humans-and analyze the additional effect of ventilator-induced lung injury (VILI). METHODS: Bronchoscopy-guided instillation of a multidrug-resistant Pseudomonas aeruginosa strain was performed in ten healthy pigs. In six animals (pneumonia-with-VILI group), pulmonary damage was further increased by VILI applied 3 h before instillation and until ARDS was diagnosed by PaO2/FiO2 < 150 mmHg. Four animals (pneumonia-without-VILI group) were protectively ventilated 3 h before inoculum and thereafter. Gas exchange, respiratory mechanics, hemodynamics, microbiological studies and inflammatory markers were analyzed during the 96-h experiment. During necropsy, lobar samples were also analyzed. RESULTS: All animals from pneumonia-with-VILI group reached Berlin criteria for ARDS diagnosis until the end of experiment. The mean duration under ARDS diagnosis was 46.8 ± 7.7 h; the lowest PaO2/FiO2 was 83 ± 5.45 mmHg. The group of pigs that were not subjected to VILI did not meet ARDS criteria, even when presenting with bilateral pneumonia. Animals developing ARDS presented hemodynamic instability as well as severe hypercapnia despite high-minute ventilation. Unlike the pneumonia-without-VILI group, the ARDS animals presented lower static compliance (p = 0.011) and increased pulmonary permeability (p = 0.013). The highest burden of P. aeruginosa was found at pneumonia diagnosis in all animals, as well as a high inflammatory response shown by a release of interleukin (IL)-6 and IL-8. At histological examination, only animals comprising the pneumonia-with-VILI group presented signs consistent with diffuse alveolar damage. CONCLUSIONS: In conclusion, we established an accurate pulmonary sepsis-induced ARDS model.
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Neumonía , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Inducida por Ventilación Mecánica , Humanos , Porcinos , Animales , Síndrome de Dificultad Respiratoria/diagnóstico , Pulmón/patología , Neumonía/complicaciones , Lesión Pulmonar Inducida por Ventilación Mecánica/complicaciones , Lesión Pulmonar Inducida por Ventilación Mecánica/patología , Mecánica Respiratoria , Respiración Artificial/efectos adversosRESUMEN
Research into the co-creation of healthy food retail is in its early stages. One way to advance co-creation research is to explore and understand how co-creation was applied in developing, implementing, and evaluating a heath-enabling initiative in a supermarket in regional Victoria, Australia. A case study design was used to explore and understand how co-creation was applied in the Eat Well, Feel Good Ballarat project. Six documents and reports related to the Eat Well, Feel Good Ballarat project were analyzed with findings from the focus groups and interviews. Motivations to develop or implement health-enabling supermarket initiatives differed among the participants. Participants considered that initial negotiations were insufficient to keep the momentum going and to propose the value to the retailers to scale up the project. Presenting community-identified needs to the supermarket helped gain the retailer's attention, whilst the co-design process helped the implementation. Showcasing the project to the community through media exposure kept the supermarket interested. Retailers' time constraints and staff turnover were considered significant barriers to partnership building. This case study contributes insights into applying co-creation to health-enabling strategies in food retail outlets using two co-creation frameworks.
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Abastecimiento de Alimentos , Supermercados , Humanos , Victoria , Alimentos , Mercadotecnía , ComercioRESUMEN
Maple syrup urine disease (MSUD) is caused by a deficiency in the activity of the branched-chain α-ketoacid dehydrogenase (BCKD) complex, promoting the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their respective α-keto acids. MSUD is an autosomal recessive hereditary metabolic disorder characterized by ketoacidosis, ataxia, coma, and mental and psychomotor retardation. The mechanisms involved in the brain damage caused by MSUD are not fully understood. Early diagnosis and treatment, as well as proper control of metabolic decompensation crises, are crucial for patients' survival and for a better prognosis. The recommended treatment consists of a high-calorie diet with restricted protein intake and specific formulas containing essential amino acids, except those accumulated in MSUD. This treatment will be maintained throughout life, being adjusted according to the patients' nutritional needs and BCAA concentration. Because dietary treatment may not be sufficient to prevent neurological damage in MSUD patients, other therapeutic strategies have been studied, including liver transplantation. With transplantation, it is possible to obtain an increase of about 10% of the normal BCKD in the body, an amount sufficient to maintain amino acid homeostasis and reduce metabolic decompensation crises. However, the experience related to this practice is very limited when considering the shortage of liver for transplantation and the risks related to the surgical procedure and immunosuppression. Thus, the purpose of this review is to survey the benefits, risks, and challenges of liver transplantation in the treatment of MSUD.
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Trasplante de Hígado , Enfermedad de la Orina de Jarabe de Arce , Humanos , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Aminoácidos de Cadena Ramificada , Leucina , DietaRESUMEN
OBJECTIVE: To describe participants' lived experience of co-creating and implementing initiatives to improve children's health. DESIGN: This manuscript reports an embedded case study design, which aims to describe participants' lived experiences of co-creating community-based initiatives. Information was gathered from an online survey and two focus groups. The two transcribed discussions from the focus groups were analysed using a 6-step phenomenological process. SETTING: Mansfield, Australia, population 4787, is one of ten local government areas (LGA) participating in the Reflexive Evidence and Systems Interventions to Prevent Obesity and Non-communicable Disease (RESPOND) project. PARTICIPANTS: Participants were purposively selected from established community groups previously engaged by RESPOND using a co-creation approach. The recruitment for the focus groups was a convenient sampling from participants that provided their email addresses in the online survey. RESULTS: Eleven participants completed the online survey. A total of ten participants attended the two focus groups of 1-h duration: five participants in each. Participants reported feeling empowered to create unique, locally relevant and readily adaptable community-wide change. They were supported by a strong partnership that mobilised funding for a part-time health promotion employee. Strengthened social connections were an unexpected though highly valued outcome. CONCLUSION: Co-creation processes may assist stakeholders in delivering prevention strategies in ways that are empowering for them, responsive to the changing needs of the community, strengthen organisational partnerships and enhance community participation, social inclusion and engagement.
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Salud Infantil , Promoción de la Salud , Niño , Humanos , Australia/epidemiología , Obesidad , Participación de la ComunidadRESUMEN
Societies often respond to a crisis by attributing blame to some groups while constructing others as victims and heroes. While it has received scant sociological attention, 'panic buying' is a critical indicator of such public sentiment at the onset of a crisis, and thus a crucial site for analysis. This article traces dynamics of blame in news media representations of an extreme period of panic buying during COVID-19 in Australia. Analysis reveals that lower socio-economic and ethnically diverse consumers were blamed disproportionately. Unlike wealthier consumers who bulk-bought online, shoppers filling trollies in-store were depicted as selfish and shameful, described using dehumanising language, and portrayed as 'villains' who threatened social order. Supermarkets were cast simultaneously as 'victims' of consumer aggression and 'heroes' for their moral leadership, trustworthiness and problem-solving. This portrayal misunderstands the socio-emotional drivers of panic buying, exacerbates stigma towards already disadvantaged groups, and veils the corporate profiteering that encourages stockpiling.
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Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L-carnitine (L-car) deficiency, compound that has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro- and anti-inflammatory cytokines, as well as the L-car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L-car levels in the patients under treatment. Inverse correlation between Phe versus L-car and nitrate plus nitrite versus L-car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)-1ß, interferons (IFN)-gamma, IL-2, tumor necrosis factor (TNF)-alpha, IL-8 and IL-6 in the patients at late diagnosis compared to controls, and IL-8 in the patients at early diagnosis and treatment compared to controls. Increased IL-2, TNF-alpha, IL-6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL-6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN-gamma and L-car in treated patients. Otherwise, it was observed that there were increased IL-4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8-isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro-oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L-car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.
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Citocinas , Fenilcetonurias , Recién Nacido , Humanos , Fenilalanina , Diagnóstico Tardío , Interleucina-2 , Interleucina-6 , Interleucina-8 , Carnitina/farmacología , Fenilcetonurias/diagnóstico , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/orina , Factor de Necrosis Tumoral alfaRESUMEN
INTRODUCTION: Co-creation of healthy food retail comprises the systematic collaboration between retailers, academics and other stakeholders to improve the healthiness of food retail environments. Research into the co-creation of healthy food retail is in its early stages. Knowledge of the roles and motivations of stakeholders in intervention design, implementation and evaluation can inform successful co-creation initiatives. This study presents academic experiences of stakeholder roles and motivations in the co-creation of healthy food retail environments. METHODS: Purposive sampling of academics with research experience in the co-creation of healthy food retail initiatives. Semi-structured interviews conducted between October and December 2021 gathered participants' experiences of multi-stakeholder collaborative research. Thematic analysis identified enablers, barriers, motivations, lessons and considerations for future co-creation of healthy food retail. RESULTS: Nine interviewees provided diverse views and applications of co-creation research in food retail environments. Ten themes were grouped into three overarching areas: (i) identification of stakeholders required for changes to healthier food retail; (ii) motivations and interactions, which included the intrinsic desire to build healthier communities along with recognition of their work; and (iii) barriers and enablers included adequate resourcing, effective and trusting working relationships and open communications. CONCLUSION: This study provides insights that could help future co-creation in healthy food retail environments. Trusting and respectful relationships and reciprocal acknowledgement between stakeholders are key practices in the co-creation process. These constructs should be considered in developing and testing a model that helps to systematically co-create healthy food retail initiatives that ensure all parties meet their needs while also delivering research outcomes.
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Alimentos , Mercadotecnía , Humanos , Abastecimiento de Alimentos , Estado de Salud , MotivaciónRESUMEN
Lysosomal acid lipase deficiency (LALD) is an inborn error of metabolism that lacks satisfactory treatment, which leads to the development of severe hepatic and cardiac complications and may even lead to death. In this sense, knowledge of the mechanisms involved in the pathophysiology of this disorder becomes essential to allow the search for new therapeutic strategies. There are no studies in the literature investigating the role of reactive species and inflammatory processes in the pathophysiology of this disorder. Therefore, the aim of this work was to investigate parameters of oxidative and inflammatory stress in LALD patients. In this work, we obtained results that demonstrate that LALD patients are susceptible to oxidative stress caused by an increase in the production of free radicals, observed by the increase of 2-7-dihydrodichlorofluorescein. The decrease in sulfhydryl content reflects oxidative damage to proteins, as well as a decrease in antioxidant defenses. Likewise, the increase in urinary levels of di-tyrosine observed also demonstrates oxidative damage to proteins. Furthermore, the determination of chitotriosidase activity in the plasma of patients with LALD was significantly higher, suggesting a pro-inflammatory state. An increase in plasma oxysterol levels was observed in patients with LALD, indicating an important relationship between this disease and cholesterol metabolism and oxidative stress. Also, we observed in LALD patients increased levels of nitrate production. The positive correlation found between oxysterol levels and activity of chitotriosidase in these patients indicates a possible link between the production of reactive species and inflammation. In addition, an increase in lipid profile biomarkers such as total and low-density lipoprotein cholesterol were demonstrated in the patients, which reinforces the involvement of cholesterol metabolism. Thus, we can assume that, in LALD, oxidative and nitrosative damage, in addition to inflammatory process, play an important role in its evolution and future clinical manifestations. In this way, we can suggest that the study of the potential benefit of the use of antioxidant and anti-inflammatory substances as an adjuvant tool in the treatment will be important, which should be associated with the already recommended therapy.
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Antioxidantes , Estrés Oxidativo , Humanos , Colesterol , Lípidos , Enfermedad de WolmanRESUMEN
Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.
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Enfermedad de Niemann-Pick Tipo C , Humanos , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/metabolismo , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Daño del ADNRESUMEN
Mucopolysaccharidosis type IV A (MPS IVA) is an inborn error of the metabolism (IEM) caused by a deficiency of the enzyme N-acetylgalactosamine 6-sulfate sulfatase (GALNS). Since 2014, enzyme replacement therapy (ERT) is the recommended treatment for these patients. It is known that the inflammatory response is closely related to antioxidant defenses and oxidative stress, and literature shows involvement of oxidative stress in the pathogenesis of IEM. The aim of this study is to investigate the mechanisms of oxidative/nitrative stress and inflammation in patients with MPS IVA under long-term ERT. In the present work we investigate parameters of oxidative/nitrative stress in plasma and urine of MPS IVA patients under long-term ERT and controls, such as plasmatic nitrate/nitrite levels using the LDH Method, urinary di-tyrosine levels by fluorometric method, plasmatic content of sulfhydryl groups, urinary oxidized guanine species by ELISA kit and the plasmatic total antioxidant status. We next evaluated the plasmatic pro and anti-inflammatory cytokines concentration (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α) and the expression of factors and enzymes Nrf-2, NF-κß and HO-1, main mediators between inflammation and oxidative stress. In concern to the oxidative/nitrative stress parameters, there was no significant difference between the groups MPS IVA patients under long-term ERT and controls, showing that there is no overproducing of RNS, no protein damage, no DNA/RNA oxidative damage and no modification in the non-enzymatic antioxidant capacity of a tissue to prevent the damage associated to free radical processes in these patients. It was also verified no significant difference between the MPS IVA patients under long-term ERT and controls groups regarding the production of proinflammatory cytokines. About anti-inflammatory cytokines, IL 10 was shown to be elevated in MPS IVA patients under long-term ERT in comparison to the control group. We next evaluated the genic expression of Nrf-2, NF-κß and HO-1and there was no significant difference between the MPS IVA patients under long-term ERT and control groups. In conclusion, MPS IVA patients under long term ERT are not in an inflammatory state and there is no alteration in genic expression in the genes analyzed which are involved in oxidative stress and inflammatory pathways. It is,however, important to consider that absence of imbalance of antioxidant defenses in MPS IVA patients under long term ERT is so far preliminary it is supported by methodologies that are not highly sensitive nor very accurate. Further experiments in future using state-of-the-art methodologies will corroborate these findings. Nevertheless, our results demonstrated the protective effect of the treatment in relation to the parameters studied and the importance of starting treatment in the early stages of the disease.
Asunto(s)
Condroitinsulfatasas , Mucopolisacaridosis IV , Humanos , Mucopolisacaridosis IV/tratamiento farmacológico , Mucopolisacaridosis IV/genética , Terapia de Reemplazo Enzimático/métodos , Antioxidantes/farmacología , Estrés Oxidativo , Citocinas/metabolismo , Inflamación , Condroitinsulfatasas/genética , Condroitinsulfatasas/metabolismo , Condroitinsulfatasas/uso terapéuticoRESUMEN
Niemann-Pick type C1 (NPC1) is a fatal inherited disease, caused by pathogenic variants in NPC1 gene, which leads to intracellular accumulation of non-esterified cholesterol and glycosphingolipids. This accumulation leads to a wide range of clinical manifestations, including neurological and cognitive impairment as well as psychiatric disorders. The pathophysiology of cerebral damage involves loss of Purkinje cells, synaptic disturbance, and demyelination. Miglustat, a reversible inhibitor of glucosylceramide synthase, is an approved treatment for NPC1 and can slow neurological damage. The aim of this study was to assess the levels of peripheric neurodegeneration biomarkers of NPC1 patients, namely brain-derived neurotrophic factor (BDNF), platelet-derived growth factors (PDGF-AA and PDGF-AB/BB), neural cell adhesion molecule (NCAM), PAI-1 Total and Cathepsin-D, as well as the levels of cholestane-3ß,5α,6ß-triol (3ß,5α,6ß-triol), a biomarker for NPC1. Molecular analysis of the NPC1 patients under study was performed by next generation sequencing (NGS) in cultured fibroblasts. We observed that NPC1 patients treated with miglustat have a significant decrease in PAI-1 total and PDGF-AA concentrations, and no alteration in BDNF, NCAM, PDGF-AB/BB and Cathepsin D. We also found that NPC1 patients treated with miglustat have normalized levels of 3ß,5α,6ß-triol. The molecular analysis showed four described mutations, and for two patients was not possible to identify the second mutated allele. Our results indicate that the decrease of PAI-1 and PDGF-AA in NPC1 patients could be involved in the pathophysiology of this disease. This is the first work to analyze those plasmatic markers of neurodegenerative processes in NPC1 patients.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Enfermedad de Niemann-Pick Tipo C , Humanos , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/patología , Inhibidor 1 de Activador Plasminogénico , Factor de Crecimiento Derivado de Plaquetas , Biomarcadores , BecaplerminaRESUMEN
OBJECTIVE: To analyse factors involved in the decision to optimise biologics in juvenile idiopathic arthritis. METHODS: A "discrete-choice" methodology was used. In a nominal group meeting, factors which may influence physicians' decisions to optimise biological dose were identified, together with decision nodes. 1000Minds® was used to create multiple fictitious clinical scenarios based on the factors identified, and to deploy surveys that were sent to a panel of experts. These experts decided for each item which of two clinical scenarios prompted them to optimise the dose of biologic. A conjoint analysis was carried out, and the partial-value functions and the weights of relative importance calculated. RESULTS: In the nominal group, three decision nodes were identified: (1) time to decide; (2) to maintain/reduce or prolong interval; (3) what drug to reduce. The factors elicited were different for each node and included patient and drug attributes. The presence of macrophage activation syndrome (MAS), systemic involvement, or subclinical inflammation made the decision easier (highest weights). The presence of joints of difficult control and year of debut influenced the decision in some but not all, and in different directions. Immunogenicity, adherence, and concomitant treatments were also aspects taken into account. CONCLUSIONS: The decision to optimise the dose of biological therapy in children and youngster can be divided into several nodes, and the factors, both patient and therapy-related, leading to the decision can be detailed. These decisions taken by experts may be transported to practice, study designs, and guidelines.