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BACKGROUND: A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. MATERIALS AND METHODS: Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. RESULTS: Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (nâ =â 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. CONCLUSION: EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Quimioterapia de Consolidação , Citarabina , Etoposídeo , Humanos , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Etoposídeo/efeitos adversos , Feminino , Masculino , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Idoso , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Quimioterapia de Consolidação/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Resultado do Tratamento , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidadeRESUMO
BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).
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Transtorno do Espectro Autista/tratamento farmacológico , Ocitocina/administração & dosagem , Comportamento Social , Administração Intranasal , Adolescente , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Ocitocina/efeitos adversos , Ocitocina/uso terapêutico , Habilidades Sociais , Falha de TratamentoRESUMO
BACKGROUND: Parkinson's disease (PD) is a common and costly progressive neurodegenerative disease of unclear etiology. A disease-modifying approach that can directly stop or slow its progression remains a major unmet need in the treatment of PD. A clinical pharmacology-based drug repositioning strategy is a useful approach for identifying new drugs for PD. METHODS: We analyzed claims data obtained from the National Health Insurance Service (NHIS), which covers a significant portion of the South Korean population, to investigate the association between antihistamines, a class of drugs commonly used to treat allergic symptoms by blocking H1 receptor, and PD in a real-world setting. Additionally, we validated this model using various animal models of PD such as the 6-hydroxydopmaine (6-OHDA), α-synuclein preformed fibrils (PFF) injection, and Caenorhabditis elegans (C. elegans) models. Finally, whole transcriptome data and Ingenuity Pathway Analysis (IPA) were used to elucidate drug mechanism pathways. RESULTS: We identified fexofenadine as the most promising candidate using National Health Insurance claims data in the real world. In several animal models, including the 6-OHDA, PFF injection, and C. elegans models, fexofenadine ameliorated PD-related pathologies. RNA-seq analysis and the subsequent experiments suggested that fexofenadine is effective in PD via inhibition of peripheral immune cell infiltration into the brain. CONCLUSION: Fexofenadine shows promise for the treatment of PD, identified through clinical data and validated in diverse animal models. This combined clinical and preclinical approach offers valuable insights for developing novel PD therapeutics.
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Doenças Neurodegenerativas , Doença de Parkinson , Terfenadina/análogos & derivados , Animais , Doença de Parkinson/patologia , Caenorhabditis elegans/metabolismo , Doenças Neurodegenerativas/metabolismo , Oxidopamina , Modelos Animais de Doenças , alfa-Sinucleína/metabolismo , Neurônios DopaminérgicosRESUMO
BACKGROUND: Risk stratification in multiple myeloma (MM) patients is crucial, and molecular genetic studies play a significant role in achieving this objective. Enrichment of plasma cells for next-generation sequencing (NGS) analysis has been employed to enhance detection sensitivity. However, these methods often come with limitations, such as high costs and low throughput. In this study, we explore the use of an error-corrected ultrasensitive NGS assay called positional indexing sequencing (PiSeq-MM). This assay can detect somatic mutations in MM patients without relying on plasma cell enrichment. METHOD: Diagnostic bone marrow aspirates (BMAs) and blood samples from 14 MM patients were used for exploratory and validation sets. RESULTS: PiSeq-MM successfully detected somatic mutations in all BMAs, outperforming conventional NGS using plasma cells. It also identified 38 low-frequency mutations that were missed by conventional NGS, enhancing detection sensitivity below the 5% analytical threshold. When tested in an actual clinical environment, plasma cell enrichment failed in most BMAs (14/16), but the PiSeq-MM enabled mutation detection in all BMAs. There was concordance between PiSeq-MM using BMAs and ctDNA analysis in paired blood samples. CONCLUSION: This research provides valuable insights into the genetic landscape of MM and highlights the advantages of error-corrected NGS for detecting low-frequency mutations. Although the current standard method for mutation analysis is plasma cell-enriched BMAs, total BMA or ctDNA testing with error correction is a viable alternative when plasma cell enrichment is not feasible.
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Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of paternal genes on chromosome 15. The Aberrant Behavior Checklist (ABC) is a standardized rating scale for assessing problematic behaviors in persons with developmental disabilities. Our study aims to describe ABC scores in youth with PWS and track their change over time. The analysis included 69 patients. Mean ABC scores were compared in four age groups (5-8, 9-12, 13-16, and 17-22 years). A statistically significant difference was found only in the Irritability subscale, with lower scores in the 5-8 age group compared to the 9-12 age group. For change over time, scores for Irritability, Lethargy, Stereotypic Behavior, Hyperactivity subscales, and Total score were likely to decrease after age 12. Irritability subscale scores of males were predicted to increase more than those of females between ages of 5 and 12 . The Lethargy score in the nondeletion group had a greater reduction than the deletion group in the 12-20 year range. This study highlights the need for systematic collection and characterization of behavioral data given the burden of maladaptive behaviors that often persist for a lifetime.
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AIMS: This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with haematologic malignancy, identify factors affecting methotrexate PK, and propose an optimal dosage regimen for the Korean population. METHODS: Data were retrospectively collected from 188 patients with acute leukaemia or non-Hodgkin's lymphoma who were admitted to Severance Hospital during the period from November 2005 to January 2016. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. RESULTS: A two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.09 L for central volume of distribution ( V 1 ), 17.65 L for peripheral volume of distribution ( V 2 ), 12.89 L/h for clearance (CL) and 0.655 L/h for inter-compartmental clearance in a 50 kg patient. Covariate analyses showed that, at the weight of 50 kg, CL decreased by 0.11 L/h for each 1-year increase in age above 14 years old and decreased 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (= V 1 + V 2 ) was 0.85 L/kg, which was similar to those in the Western or Chinese populations. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. CONCLUSIONS: The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with haematologic malignancy.
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Neoplasias Hematológicas , Metotrexato , Humanos , Adolescente , Metotrexato/uso terapêutico , Metotrexato/farmacocinética , Estudos Retrospectivos , Neoplasias Hematológicas/tratamento farmacológico , República da Coreia , Modelos BiológicosRESUMO
BACKGROUND: Thyroid cancer overdiagnosis is a major public health issue in South Korea, which has the highest incidence rate. The accessibility of information through the Internet, particularly on YouTube, could potentially impact excessive screening. This study aimed to analyze the content of thyroid cancer-related YouTube videos, particularly those from 2016 onwards, to evaluate the potential spread of misinformation. METHODS: A total of 326 videos for analysis were collected using a video search protocol with the keyword "thyroid cancer" on YouTube. This study classified the selected YouTube videos as either provided by medical professionals or not and used topic clustering with LDA (latent dirichlet allocation), sentiment analysis with KoBERT (Korean bidirectional encoder representations from transformers), and reliability evaluation to analyze the content. The proportion of mentions of poor prognosis for thyroid cancer and the categorization of advertising content was also analyzed. RESULTS: Videos by medical professionals were categorized into 7 topics, with "Thyroid cancer is not a 'Good cancer'" being the most common. The number of videos opposing excessive thyroid cancer screening decreased gradually yearly. Videos advocating screening received more favorable comments from viewers than videos opposing excessive thyroid cancer screening. Patient experience videos were categorized into 6 topics, with the "Treatment process and after-treatment" being the most common. CONCLUSION: This study found that a significant proportion of videos uploaded by medical professionals on thyroid cancer endorse the practice, potentially leading to excessive treatments. The study highlights the need for medical professionals to provide high-quality and unbiased information on social media platforms to prevent the spread of medical misinformation and the need for criteria to judge the content and quality of online health information.
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Médicos , Mídias Sociais , Neoplasias da Glândula Tireoide , Humanos , Disseminação de Informação/métodos , Detecção Precoce de Câncer , Reprodutibilidade dos Testes , Sobrediagnóstico , República da Coreia , Neoplasias da Glândula Tireoide/diagnóstico , Gravação em VídeoRESUMO
OBJECTIVES: This study aimed to determine the overall oral health statuses of patients with fixed orthodontic appliance and clear aligner, as well as their oral hygiene management behaviours and satisfaction. METHODS: We selected 40 participants (20 each with fixed orthodontic devices and clear aligners) who visited a dental clinic. We conducted a survey to determine the oral hygiene management behaviours of the subjects and their satisfaction with their orthodontic treatment. Three measurements were also conducted at 4-week intervals to determine the oral health statuses of the subjects. RESULTS: The Löe and Silness gingival index of patients with fixed orthodontic appliances indicated moderate gingivitis (1.1 ± 0.3), and those with clear aligners had mild gingivitis (0.6 ± 0.4) (p < 0.001). The modified O'Leary index also indicated that the degree of dental plaque deposition in the oral cavity was lower in patients treated with a clear aligner (43.0 ± 18.2 points) than in those treated with a fixed orthodontic (28.1 ± 10.9 points) (p = 0.004). Regarding oral hygiene management, the fixed orthodontic group received scaling more frequently (p = 0.006), received more oral health education (p < 0.001) and had a longer brushing time (p = 0.008) than the clear aligner group. No significant difference was observed in satisfaction between the fixed orthodontic appliance and the clear aligner. CONCLUSIONS: Regarding the oral health status by orthodontic appliance type, the clear aligner group had the advantages of reduction in dental plaque attachment and gingival health. The fixed orthodontic group exhibited better oral hygiene management behaviours. Satisfaction with orthodontic treatment was found to be similar for the two device types.
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Diatoms have long been used as living biological indicators for the assessment of water quality in lakes and rivers worldwide. While this approach benefits from the great diversity of these unicellular algae, established protocols are time-consuming and require specialized equipment. Here, this work 3D prints diatom-laden hydrogels that can be used as a simple multiplex bio-indicator for water assessment. The hydrogel-based living materials are created with the help of a desktop extrusion-based printer using a suspension of diatoms, cellulose nanocrystals (CNC) and alginate as bio-ink constituents. Rheology and mechanical tests are employed to establish optimum bio-ink formulations, whereas cell culture experiments are utilized to evaluate the proliferation of the entrapped diatoms in the presence of selected water contaminants. Bioprinting of diatom-laden hydrogels is shown to be an enticing approach to generate living materials that can serve as low-cost bio-indicators for water quality assessment.
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Bioimpressão , Diatomáceas , Bioimpressão/métodos , Qualidade da Água , Hidrogéis/química , Reologia , Impressão Tridimensional , Engenharia Tecidual/métodos , Alicerces Teciduais/química , TintaRESUMO
Efficient foraging by plant roots relies on the ability to sense multiple physical and chemical cues in soil and to reorient growth accordingly (tropism). Root tropisms range from sensing gravity (gravitropism), light (phototropism), water (hydrotropism), touch (thigmotropism), and more. Electrotropism, also known as galvanotropism, is the phenomenon of aligning growth with external electric fields and currents. Although root electrotropism has been observed in a few species since the end of the 19th century, its molecular and physical mechanisms remain elusive, limiting its comparison with the more well-defined sensing pathways in plants. Here, we provide a quantitative and molecular characterization of root electrotropism in the model system Arabidopsis (Arabidopsis thaliana), showing that it does not depend on an asymmetric distribution of the plant hormone auxin, but instead requires the biosynthesis of a second hormone, cytokinin. We also show that the dose-response kinetics of the early steps of root electrotropism follows a power law analogous to the one observed in some physiological reactions in animals. Future studies involving more extensive molecular and quantitative characterization of root electrotropism would represent a step toward a better understanding of signal integration in plants and would also serve as an independent outgroup for comparative analysis of electroreception in animals and fungi.
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Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Citocininas/biossíntese , Eletricidade , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Tropismo/efeitos dos fármacos , Arabidopsis/genética , Citocininas/genética , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Variação Genética , Genótipo , Raízes de Plantas/genéticaRESUMO
ABSTRACT: Autism spectrum disorder (ASD) is characterized by impaired social communication in conjunction with patterned behaviors. Often associated with emotional dysregulation, irritability, aggression, depression, and suicidality, ASD youth frequently present to the emergency department for behavioral and mental health evaluation. Psychiatric comorbidities, agitation, and depression are commonly encountered. During these visits, practitioners must thoughtfully consider organic etiologies for presenting symptoms, formulate plans to address risk of agitation, and understand how to effectively formulate disposition options in this patient population.
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Transtorno do Espectro Autista , Transtorno Autístico , Adolescente , Humanos , Criança , Transtorno do Espectro Autista/terapia , Transtorno do Espectro Autista/complicações , Transtorno Autístico/complicações , Transtorno Autístico/terapia , Serviço Hospitalar de Emergência , Comorbidade , Humor IrritávelRESUMO
This study sought to examine the association between male-to-female physical, psychological, and sexual violence and controlling behaviors of male partners. Further, the moderating effect of insecure attachment style on this association was examined in the context of South Korea. Existing national data collected from a representative Korean sample of 2,000 unmarried men was utilized. Findings indicated controlling behaviors among men were positively and negatively associated with psychological and physical violence, respectively, and no association was observed with sexual violence against female partners. Anxious attachment moderated the relationship between control over partner and psychological abuse. The avoidant attachment was identified as a quasi and pure moderator for the associations between control over the partner and physical and sexual violence, respectively.
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Violência por Parceiro Íntimo , Delitos Sexuais , Masculino , Humanos , Feminino , Comportamento Sexual/psicologia , Parceiros Sexuais/psicologia , Delitos Sexuais/psicologia , Violência , República da Coreia , Violência por Parceiro Íntimo/psicologiaRESUMO
AIM: To develop more effective and long-lasting antiobesity and antidiabetic therapeutics by employing novel chemical modifications of glucagon-like peptide-1 receptor (GLP-1R) agonists. METHODS: We constructed novel unimolecular dual agonists of GLP-1R and glucagon receptor prepared by linking sEx-4 and native glucagon (GCG) via lysine or triazole [sEx4-GCG(K) and sEx4-GCG(T), respectively] and evaluated their antiobesity and antidiabetic efficacy in the diabetic and obese mouse model. RESULTS: Both sEx4-GCG(K) and sEx4-GCG(T) showed the beneficial metabolic effects of GLP-1 and glucagon: they promoted weight loss and ameliorated insulin resistance and hepatic steatosis. They also increased thermogenesis in brown adipose tissue, and lipolysis and ß-oxidation in white adipose tissue, with concomitant suppression of lipogenesis. Furthermore, both dual agonists activated the 5'-AMP-activated protein kinase signalling pathway and prevented palmitate-induced oxidative stress in skeletal muscle cells. CONCLUSION: Through their complementary dual agonism, sEx4-GCG(T) and sEx4-GCG(K) induce more marked weight loss and metabolic improvements than conventional agonists, and could be developed as novel therapeutic agents for the treatment of obesity and associated metabolic disorders in humans.
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Receptor do Peptídeo Semelhante ao Glucagon 1 , Glucagon , Animais , Glucagon/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Camundongos , Receptores de Glucagon/metabolismo , TermogêneseRESUMO
OBJECTIVE: Violence and aggressive behaviors among youth are a leading cause of Emergency Department (ED) mental health (MH) encounters. A consistent method is needed for public health research, to identify ED encounters associated with aggression. The aim of this study was to develop such a screening procedure. DATA SOURCES: Electronic records and administrative claims data related to MH related ED encounters at one of Pediatric Health Information System (PHIS) Children's Hospitals in the United States from January 1, 2019 to December 31, 2019. STUDY DESIGN: The authors selected a combination of ICD-10 codes to screen MH ED encounters for aggression; and then conducted a chart review to compare characteristics of groups that screened positive vs. screened negative, and groups with confirmed vs. without confirmed aggression. DATA EXTRACTION METHOD: Unique ED encounters associated with a MH related ICD-10 code from a one-year period at the study institution were extracted (n = 3092 MH ED encounters). Encounters with any aggression-associated codes were identified as "screen-positive" (N = 349). From the remaining "screen-negative" encounters, 352 unique encounters were randomly selected as a comparison group. Both groups were chart reviewed to investigate the accuracy of the screening method. MAIN FINDING: Chart review confirmed aggression in 287 of 349 screen-positive and 48 of 352 select screen-negative, chart-reviewed encounters. Additional codes were added, with a goal of finding the combination of codes with the highest accuracy. The resulting screen had sensitivity, specificity, positive and negative predictive values of 0.901, 0.817, 0.818, and 0.864, respectively. PRINCIPAL CONCLUSIONS: This paper presents a screening method for identifying ED encounters related to aggression. A replication study will be necessary to validate the method prior to applying to large claims data. If validated, it will support future research on this important population.
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Serviço Hospitalar de Emergência , Classificação Internacional de Doenças , Adolescente , Agressão , Criança , Hospitais Pediátricos , Humanos , Programas de Rastreamento , Estudos Retrospectivos , Estados UnidosRESUMO
PURPOSE: The purpose of this study is to identify and compare the unmet needs of adolescents and young adults (AYAs) with cancer by age and gender. DESIGN AND METHODS: This is a mixed-methods study to analyze textual data from blog posts on AYAs' unmet needs. Themes were identified using a qualitative descriptive method with content analysis, and a quantitative method was used to compare themes by age and gender. RESULTS: The findings from blog posts of 100 AYAs showed that AYAs with cancer expressed somewhat different needs by age and gender. Young adults (26-39 years) with cancer tended to describe significantly more feelings of fear (p = .043) and parenting needs (p < .001) and significantly fewer educational needs (p < .001) than did emerging adults (18-25 years) with cancer. Female AYAs with cancer described significantly more feelings of guilt (p = .020), sexual needs (p = .003), fertility issues (p = .023), and social needs (p = .013) than did male AYAs with cancer. There were no statistically significant differences in the remaining themes between age and gender groups, although how they described unmet needs differed qualitatively. CONCLUSIONS: AYAs with cancer have various unmet needs and their unmet needs were different by age and gender. PRACTICE IMPLICATIONS: Nurses should proactively provide integrated systematic screening by offering a safe, non-judgmental environment to encourage AYAs to express their needs across their cancer journey. Nurses also should respond with developmentally appropriate support, resources, and referrals based on these expressed needs.
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Neoplasias , Mídias Sociais , Adolescente , Feminino , Humanos , Masculino , Neoplasias/terapia , Projetos de Pesquisa , Adulto JovemRESUMO
Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general.
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Estresse do Retículo Endoplasmático , Doenças Neurodegenerativas , Animais , Autofagia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Humanos , Doenças Neurodegenerativas/metabolismo , Resposta a Proteínas não DobradasRESUMO
The presence of protein inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), in the brain is the main feature of Parkinson's disease (PD). Recent evidence that the prion-like propagation of α-synuclein (α-syn), as a major component of LBs and LNs, plays an important role in the progression of PD has gained much attention, although the molecular mechanism remains unclear. In this study, we evaluated whether neuronal ApoE regulates the cell-to-cell transmission of α-syn and explored its molecular mechanism using in vitro and in vivo model systems. We demonstrate that neuronal ApoE deficiency attenuates both α-syn uptake and release by downregulating LRP-1 and LDLR expression and enhancing chaperone-mediated autophagy activity, respectively, thereby contributing to α-syn propagation. In addition, we observed that α-syn propagation was attenuated in ApoE knockout mice injected with pre-formed mouse α-syn fibrils. This study will help our understanding of the molecular mechanisms underlying α-syn propagation.
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Apolipoproteínas E/metabolismo , Doença de Parkinson , alfa-Sinucleína/metabolismo , Animais , Apolipoproteínas E/genética , Corpos de Lewy/metabolismo , Camundongos , Neurônios/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/genéticaRESUMO
Renal fibrosis, the final pathway of chronic kidney disease, is caused by genetic and epigenetic mechanisms. Although DNA methylation has drawn attention as a developing mechanism of renal fibrosis, its contribution to renal fibrosis has not been clarified. To address this issue, the effect of zebularine, a DNA methyltransferase inhibitor, on renal inflammation and fibrosis in the murine unilateral ureteral obstruction (UUO) model was analyzed. Zebularine significantly attenuated renal tubulointerstitial fibrosis and inflammation. Zebularine decreased trichrome, α-smooth muscle actin, collagen IV, and transforming growth factor-ß1 staining by 56.2%. 21.3%, 30.3%, and 29.9%, respectively, at 3 days, and by 54.6%, 41.9%, 45.9%, and 61.7%, respectively, at 7 days after UUO. Zebularine downregulated mRNA expression levels of matrix metalloproteinase (MMP)-2, MMP-9, fibronectin, and Snail1 by 48.6%. 71.4%, 31.8%, and 42.4%, respectively, at 7 days after UUO. Zebularine also suppressed the activation of nuclear factor-κB (NF-κB) and the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6, by 69.8%, 74.9%, and 69.6%, respectively, in obstructed kidneys. Furthermore, inhibiting DNA methyltransferase buttressed the nuclear expression of nuclear factor (erythroid-derived 2)-like factor 2, which upregulated downstream effectors such as catalase (1.838-fold increase at 7 days, p < 0.01), superoxide dismutase 1 (1.494-fold increase at 7 days, p < 0.05), and NAD(P)H: quinone oxidoreduate-1 (1.376-fold increase at 7 days, p < 0.05) in obstructed kidneys. Collectively, these findings suggest that inhibiting DNA methylation restores the disrupted balance between pro-inflammatory and anti-inflammatory pathways to alleviate renal inflammation and fibrosis. Therefore, these results highlight the possibility of DNA methyltransferases as therapeutic targets for treating renal inflammation and fibrosis.
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Nefrite , Insuficiência Renal Crônica , Obstrução Ureteral , Camundongos , Animais , Fibrose , Nefrite/patologia , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/genética , Inflamação/patologia , Insuficiência Renal Crônica/complicações , Metilases de Modificação do DNA , DNA/uso terapêuticoRESUMO
The prevalence of Gambling Disorder among Koreans suggests that it is relatively higher than other countries. This study explored gambling-related crimes and related mental health care needs of those with Gambling Disorder on a case-by-case basis. Participants (n = 6) included men attending Gamblers Anonymous in South Korea with gambling debts and histories of illegal acts. Thematic analysis of qualitative interviews identified themes: (1) Meaning of Gambling Disorder in life, (2) Initiation of illegal acts stemming from Gambling Disorder, and (3) Life after addiction, efforts for recovery, and mental health care needs. Gambling Disorder destroyed lives and created criminal victims thereby threatening familial and community health.
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Comportamento Aditivo , Jogo de Azar , Crime/psicologia , Comportamento Criminoso , Jogo de Azar/epidemiologia , Jogo de Azar/psicologia , Pessoal de Saúde , Humanos , MasculinoRESUMO
BACKGROUND: For chronic disease management, self-management strategies are essential to achieve sustained improvement. OBJECTIVE: Our study evaluated the efficacy of health coaching and a self-management strategy-based electronic program on self-management strategies for patients with osteoporosis, chronic respiratory disease, or arthritis. DESIGN: Three-arm randomized controlled trial, pilot study PARTICIPANTS: Fifty-four participants INTERVENTIONS: The first intervention group (n = 53) received a self-management strategy-based electronic program and 12 weeks of health coaching (20 sessions). The second intervention group received the information and communications technology (ICT) program; the control group received usual care and an educational booklet about self-management of chronic diseases. MAIN MEASURES: The primary outcome was the difference in the change of the mean of self-management strategy scores. Secondary outcomes included depression (PHQ-9), physical activity (Godin Leisure Exercise Questionnaire), and health habit maintenance (transtheoretical model) after 12 weeks in the program. KEY RESULTS: The combination of health coaching and ICT was superior to control group (change 18.5 vs. - 2.6, adjusted difference = 24.5, p < 0.001); however, the ICT alone group was not superior to the control group (change 8.0 vs. - 2.6, adjusted difference = 8.0, p = 0.156). As a result of evaluating the change in the percentage of people with positive stage changes in the transtheoretical model of health habits, regular exercise (p = 0.008), a balanced diet (p = 0.005), helping others (p = 0.001), and living with loved ones (p = 0.038) showed significant differences. There was no significant difference in the changes in percentage of patients with depressive symptoms in comparison with control group; however, there was in comparison with control group among groups (p = 0.033). Compared to the control group, the proportion of patients who achieved an exercise amount of 12.5 MET or higher was significantly higher (p = 0.028) in the health coaching and ICT group. CONCLUSIONS: The combination of ICT + health coaching led to improvement in self-management as well as in increasing exercise, and several healthy behaviors. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03294057.