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BACKGROUND: Food insecurity is a heightened concern among economically disadvantaged youth, and it may contribute to the atypical body mass index (BMI) patterns frequently observed in this group. Self-efficacy seems to intervene in the negative impacts of contextual restraints. This study investigated the relationship between food insecurity, self-efficacy, and BMI trajectory among economically disadvantaged Taiwanese youth. METHODS: We utilized three-wave longitudinal data from the Taiwan Database of Children and Youth in Poverty. The Food Insecurity Score (FIS) assessed food insecurity with a 4-item scale measuring reduced meal frequency, hunger, skipping meals, and economic constraints. Moreover, the General Self-Efficacy Scale (GSES) assessed self-efficacy, showcasing the ability to handle stress effectively and envision success scenarios, contributing to positive outcomes. By employing latent growth modeling, we were able to delineate the impacts of baseline food insecurity and self-efficacy on initial BMI and its subsequent growth trajectory. RESULTS: Elevated baseline FIS significantly predicted higher initial BMI (coefficient = 0.420, p = 0.042). Baseline GSES was negatively associated with initial BMI (coefficient = -0.093, p < 0.001) but positively predicted the BMI growth rate (coefficient = 0.023, p = 0.011). CONCLUSION: Enhancing self-efficacy may be an effective multidisciplinary intervention to address psychosocial and socioeconomic factors when tackling weight problems in vulnerable youth groups.
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The mechanisms accounting for the functional changes of α- and ß-cells over the course of type 1 diabetes (T1D) development are largely unknown. Permitted by our established technology of high spatiotemporal resolution imaging of cytosolic Ca2+ ([Ca2+]c) dynamics on fresh pancreas tissue slices, we tracked the [Ca2+]c dynamic changes, as the assessment of function, in islet α- and ß-cells of female nonobese diabetic (NOD) mice during the development of spontaneous diabetes. We showed that, during the phases of islet inflammation, 8 mmol/L glucose-induced synchronized short [Ca2+]c events in ß-cells were diminished, whereas long [Ca2+]c events were gradually more triggerable at substimulatory 4 and 6 mmol/L glucose. In the islet destruction phase, the synchronized short [Ca2+]c events in a subset of ß-cells resumed at high glucose condition, while the long [Ca2+]c events were significantly elevated already at substimulatory glucose concentrations. In the α-cells, the glucose sensitivity of the [Ca2+]c events persisted throughout the course of T1D development. At the late islet destruction phase, the α-cell [Ca2+]c events exhibited patterns of synchronicity. Our work has uncovered windows of functional recovery in ß-cells and potential α-cells functional synchronization in NOD mice over the course of T1D development. ARTICLE HIGHLIGHTS: In NOD mice ß-cells, 8 mmol/L glucose-induced synchronized short [Ca2+]c events diminish in the early phases of islet inflammation, and long Ca2+ events became more sensitive to substimulatory 4 and 6 mmol/L glucose. In the late islet destruction phase, the synchronized short [Ca2+]c events in a subset of ß-cells resumed at 8 mmol/L glucose, while the long Ca2+ events were significantly elevated at substimulatory glucose concentrations. In the α-cells, the glucose sensitivity of the [Ca2+]c events persisted throughout the course of type 1 diabetes development. α-Cell [Ca2+]c events occasionally synchronize in the islets with severe ß-cell destruction.
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Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Camundongos , Animais , Feminino , Camundongos Endogâmicos NOD , Cálcio , Glucose/farmacologia , InflamaçãoRESUMO
BACKGROUND: The echocardiographic parameter E/e' has been associated with cardiovascular (CV) events. However, few studies have analyzed multiple associated CV outcomes using E/e' in a diverse population of both inpatients and outpatients with and without cardiac diseases and risk factors. METHODS: Medical records of 75,393 patients without atrial fibrillation (AF) with first available E/e' were retrieved from our hospital database. Patients with mitral valve disease were excluded, and the remainder were studied in protocol 1 (70,819 patients). Patients with hypertension, diabetes mellitus, hyperlipidemia, CV diseases, prior CV events, CV surgeries, and left ventricular ejection fraction <50% or missing left ventricular ejection fraction were further excluded, and the remaining patients were studied in protocol 2 (14,665 patients). The study outcomes are major adverse CV events (MACE), which included myocardial infarction (MI), AF, ischemic and hemorrhagic stroke (IHS), hospitalization for heart failure (HHF), and cardiac death. The primary outcomes were MACE and each of the MACE components. RESULTS: At the end of maximal 5-year follow-up (median 22.18 months with interquartile range 7.20-49.08 months for MACE in protocol 1 and 23.46 months with interquartile range 8.15-49.02 months for MACE in protocol 2), compared with an E/e' value of <8, an intermediate value of E/e' 8 to 15 and a high value of E/e' >15 were significantly associated with MACE, MI, AF, IHS, HHF, and cardiac death in protocol 1 (all P < .0001). In protocol 2, an intermediate E/e' value of 8 to 15 and a high value of E/e' >15 were significantly associated with MACE, MI, AF, IHS, HHF, and CV death (all P < .05), except an intermediate value E/e' 8 to 15 was not associated with AF. CONCLUSIONS: In a diverse population of inpatients and outpatients with and without cardiac diseases and risk factors, the echocardiographic parameter E/e' was associated with CV events and is a useful marker of risk.
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Fibrilação Atrial , Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Volume Sistólico , Função Ventricular Esquerda , Pacientes Internados , Pacientes Ambulatoriais , Ecocardiografia/efeitos adversos , Fatores de Risco , Infarto do Miocárdio/complicações , Morte , PrognósticoRESUMO
Background: The safety and efficacy of dual antiplatelet therapy (DAPT) in medically treated acute myocardial infarction (AMI) patients with baseline thrombocytopenia (platelet count < 150 × 103/uL) are unclear. Methods: In this multi-institute retrospective cohort study, we included 468 patients with medically treated AMI with baseline thrombocytopenia and separated them into single antiplatelet therapy (SAPT) and DAPT groups according to the discharge anti-thrombotic strategy. The primary outcome was net clinical adverse events (NACEs), defined as a composite of death, ischemic events (myocardial infarction, ischemic stroke, and transient ischemic attack), and major bleeding within 30 days. Results: There were 168 patients in the SAPT group (100 taking aspirin and 68 taking clopidogrel) and 300 in the DAPT group. A primary outcome occurred in 35 (24.11 per 100 patient-months) patients in the SAPT group and 39 (14.26 per 100 patient-months) patients in the DAPT group [adjusted hazard ratio (HR): 0.67; 95% confidence interval (CI): 0.40-1.10; p = 0.1145]. Kaplan-Meier curves showed favorable results in the DAPT group (log-rank p = 0.0243). Bleeding events occurred in 18 (10.71 per 100 patient-months) patients in the SAPT group and 18 (6.40 per 100 patient-months) patients in the DAPT group (adjusted HR: 0.66; 95% CI: 0.32-1.36; p = 0.2573). Conclusions: DAPT versus SAPT as discharge anti-thrombotic strategy in thrombocytopenic patients with medically treated AMI did not significantly improve NACEs at 30 days. However, there was a trend towards favorable outcomes in the DAPT group. These results should be interpreted carefully with respect to the relatively limited trial population and study design.
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Recently, drug-resistant bacterial infections, especially ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), have become a critical health issue worldwide, highlighting the emerging need for novel antibacterial agents. In this study, silver nanoparticles were extracted from silver-containing mesoporous bioactive glass (MBG-Ag) using four different matrixes, including water, phosphate buffer saline (PBS), tryptic soy broth (TSB), and taurine (Tau). The inductively coupled plasma-mass spectrometer (ICP-MS) results demonstrated that the silver concentration of Tau-Ag was the highest among the four matrixes. The Tau-Ag was also observed to have 87.35% silver ions in its X-ray photoelectron spectrometer (XPS) spectra. The micrograph of transmission electron microscope (TEM) displayed a uniform distribution of silver nanoparticles, which was confined in a smaller size compared to that in TSB-Ag. Moreover, the peak shifts observed in the Fourier-transform infrared spectrometer (FTIR) spectrum implied that the -SO32- and -NH groups in taurine may interact with silver. A low cytotoxicity was noted for Tau-Ag, with approximately 70% of cells surviving at 0.63 mg/mL. Compared to the other three matrix-induced silver agents, Tau-Ag represented a better antibacterial effect against methicillin-resistant Staphylococcus aureus, with a minimum inhibitory concentration (MIC) value of 0.63 mg/mL and a postponed growth of 0.31 mg/mL observed. Further antibacterial examinations illustrated the presence of remarkable antibacterial activities against vancomycin-resistant Enterococcus feacium, carbapenem-resistant Klebsiella pneumoniae, carbapenem-resistant Acinetobacter baumannii, and carbapenem-resistant Pseudomonas aeruginosa. Given our observations and multiple bioactive functions of taurine (prevent patients from inflammation and oxidative-stress injuries), we anticipate that taurine matrix-induced silver ions would be a biomedical material with a high potential for combatting drug-resistant ESKAPE pathogens.
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Cholinergic innervation in the pancreas controls both the release of digestive enzymes to support the intestinal digestion and absorption, as well as insulin release to promote nutrient use in the cells of the body. The effects of muscarinic receptor stimulation are described in detail for endocrine beta cells and exocrine acinar cells separately. Here we describe morphological and functional criteria to separate these two cell types in situ in tissue slices and simultaneously measure their response to ACh stimulation on cytosolic Ca2+ oscillations [Ca2+]c in stimulatory glucose conditions. Our results show that both cell types respond to glucose directly in the concentration range compatible with the glucose transporters they express. The physiological ACh concentration increases the frequency of glucose stimulated [Ca2+]c oscillations in both cell types and synchronizes [Ca2+]c oscillations in acinar cells. The supraphysiological ACh concentration further increases the oscillation frequency on the level of individual beta cells, inhibits the synchronization between these cells, and abolishes oscillatory activity in acinar cells. We discuss possible mechanisms leading to the observed phenomena.
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Acetilcolina/farmacologia , Células Acinares/metabolismo , Sinalização do Cálcio , Citosol/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Citosol/efeitos dos fármacos , Feminino , Glucose/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Receptores Muscarínicos/metabolismo , Fatores de TempoRESUMO
In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.
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Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cobre/química , Nitrilas/química , Quinolonas/síntese química , Quinolonas/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Animais , Catálise , DNA Topoisomerases Tipo I/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Simulação de Acoplamento Molecular , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Patients with active peptic ulcer (PU) were excluded from direct oral anticoagulant (DOAC) trials for stroke prevention in patients with atrial fibrillation (AF). This study evaluated the safety and effectiveness of DOACs in AF patients with active, inactive and no peptic ulcer (PU). Methods: This study accessed electronic medical records from January 1, 2009 to May 31, 2019 at a multi-center healthcare provider in Taiwan and involved 2,955 AF patients who had undergone esophagogastroduodenoscopy ≤ 1 year before anticoagulation. Subjects were classified into 3 groups: active (n = 237), inactive (n = 828) and no-PU (n = 1,890) groups. We compared the risks of major bleeding, gastrointestinal bleeding, and ischemic stroke/systemic embolism (IS/SE) between DOACs and warfarin among the 3 groups. Results: In the active PU group, there were no significant differences in the risks of major bleeding [hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.08-4.98, p = 0.676], gastrointestinal bleeding (HR = 0.65, 95% CI 0.08-4.98, p = 0.676) and IS/SE (HR = 2.58; 95% CI 0.53-12.70, p = 0.243) between DOAC and warfarin (as the reference). In the inactive PU group, there were no significant differences in the risks of major bleeding (HR = 0.36, 95% CI 0.09-1.39, p = 0.138), gastrointestinal bleeding (HR = 0.21, 95% CI 0.02-1.80, p = 0.153), and IS/SE (HR = 1.04, 95% CI 0.39-2.82, p = 0.934) between DOAC and warfarin (as the reference). In the no-PU group, DOACs were associated with lower risk of major bleeding (HR = 0.26, 95% CI 0.12-0.53, p < 0.001), gastrointestinal bleeding (HR = 0.25, 95% CI 0.01-0.59, p = 0.002), and similar risk of IS/SE (HR = 0.92, 95% CI 0.55-1.54, p = 0.757) compared to warfarin. Conclusions: DOACs were as effective as warfarin in preventing IS/SE irrespective of PU status and safer than warfarin in reducing major bleeding in the no-PU group. In patients with active or inactive PUs, DOAC and warfarin were not significantly different in their effects on major bleeding or gastrointestinal bleeding.
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PURPOSE: We introduce a novel technique for closed chamber iridodialysis repair. MATERIALS AND METHODS: We use a 2.8-mm paracentesis knife to penetrate into the anterior chamber and create interrupted incisions in the sclera. The wounds are 1.5 mm distant from the limbus, at consistent 2.8-mm intervals along the dialysis area. After injecting viscocohesive ophthalmic viscosurgical device through a side port to relieve the synechia and to push the iris toward the incisions, the iris is then grasped by Kelman forceps through the sclera, dragged carefully, and incarcerated. After adjusting the tension of the iris according to the pupil shape, the sclera and the incarcerated iris tissue were sutured together with 10-0 nylon. RESULTS: The technique was effective in six patients with traumatic iridodialysis. CONCLUSION: Our surgical technique repairs the iris, restores the shape of pupil, as well as avoids creating a large incision in the limbus in patients suffering from iridodialysis.
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Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Rim/fisiopatologia , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Idoso , Fibrilação Atrial/complicações , Feminino , Humanos , Rim/efeitos dos fármacos , Testes de Função Renal , Masculino , Acidente Vascular Cerebral/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Off-label dosing non-vitamin K antagonist oral anticoagulants (NOACs) are commonly prescribed for Asian patients with atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to investigate the associations between inappropriate dosing of NOACs and clinical outcomes. METHODS: We used medical data from a multicenter health care system in Taiwan, which included 2068, 5135, 2589, 1483, and 2342 AF patients taking dabigatran, rivaroxaban, apixaban, edoxaban, and warfarin, respectively. The risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding in patients treated with underdosing or overdosing NOACs were compared to those of on-label dosing NOACs and warfarin. RESULTS: About 27% and 5% of AF patients were treated with underdosing and overdosing NOACs, respectively. Compared to on-label dosing, underdosing NOACs were associated with a significantly higher risk of IS/SE (adjusted hazard ratio [aHR] 1.59; 95% confidence interval [CI] 1.25-2.02; P <.001), whereas overdosing NOACs were associated with a significantly higher risk of major bleeding (aHR 2.01; 95% CI 1.13-3.56; P = .017). Compared to warfarin, the 4 on-label dosing NOACs were associated with a comparable risk of IS/SE and a significantly lower risk of major bleeding, whereas underdosing NOACs were associated with a higher risk of IS/SE (aHR 1.46; P = .012). CONCLUSION: About 3 in 10 Asian AF patients were treated with off-label dosing NOACs in daily practice. Compared to on-label dosing, underdosing was associated with a higher risk of IS/SE, whereas overdosing was associated with a higher risk of major bleeding. Thus, even for Asian AF patients at higher risk for bleeding, NOACs still should be prescribed at the dosing based on clinical trial criteria and guideline recommendations.
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Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Uso Off-Label/estatística & dados numéricos , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Idoso , Fibrilação Atrial/complicações , Feminino , Humanos , Incidência , Masculino , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Taiwan/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: Studies specifically examining the association between glycated hemoglobin A1c (HbA1c) levels and ischemic stroke/systemic thromboembolism (IS/SE) risk in atrial fibrillation (AF) patients are limited. Here, we investigated the association between HbA1c levels and the risk of IS/SE, as well as major bleeding, among AF patients with or without oral anticoagulants (OACs). We also compared the effectiveness and safety of warfarin and direct oral anticoagulants (DOACs) in different HbA1c categories. METHODS: We utilized medical data from a multi-center healthcare provider in Taiwan, which included 34,036 AF patients with serum HbA1c data available within 3 months after AF being diagnosed. Patients were divided into seven study groups according to their HbA1c levels: < 5.4%, 5.4%-5.6%, 5.7%-5.9%, 6.0%-6.4%, 6.5%-6.9%, 7.0%-7.9%, and ≥ 8.0%. The risks of IS/SE and major bleeding were compared among the groups after adjusting for baseline stroke and bleeding risk factors. RESULTS: Compared with the patients with HbA1c level < 5.4%, IS/SE risk significantly increased at HbA1c levels higher than 6.5% [adjusted hazard ratio (HR): 1.20, 95% confidence interval (CI): 1.00-1.43 for HbA1c level 6.5%-6.9%; 1.32, (95% CI 1.11-1.57) for HbA1c level 7.0%-7.9%; and 1.48 (95% CI 1.25-1.76) for HbA1c level ≥ 8.0%]. These results were generally consistent in AF patients without OACs (n = 24,931). However, among 9105 patients receiving OACs, IS/SE risk was not higher for patients having higher HbA1c levels. The risk of major bleeding was comparable across all HbA1c categories. Compared with warfarin, DOACs were associated with lower risks of IS/SE (adjusted HR: 0.61, 95% CI 0.49-0.75) and major bleeding (adjusted HR: 0.30, 95% CI 0.21-0.42) without interactions across different HbA1c categories (all P interactions > 0.05). CONCLUSION: For AF patients, IS/SE risk significantly increased once HbA1c levels exceeded 6.5%, and OACs may attenuate these associations. Compared with warfarin, DOACs were more effective and safer across broad HbA1c categories. Therefore, in addition to prescribing DOACs when indicated, more aggressive glycemic control to achieve an HbA1c level < 6.5% may be considered for eligible AF patients and should be tested in further prospective studies.
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Anticoagulantes/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Diabetes Mellitus/sangue , Inibidores do Fator Xa/efeitos adversos , Hemoglobinas Glicadas/análise , Hemorragia/induzido quimicamente , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/prevenção & controle , Varfarina/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Biomarcadores/sangue , Bases de Dados Factuais , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Inibidores do Fator Xa/administração & dosagem , Feminino , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Taiwan/epidemiologia , Tromboembolia/sangue , Tromboembolia/diagnóstico , Tromboembolia/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Varfarina/administração & dosagemRESUMO
BACKGROUND: Generally, a person with dementia may be unable to make decisions by themselves and professionals may decide what is best for them. Unfortunately, in most cases, professionals assist a person with dementia to make decisions without clear explanation or consent. Whether a person with dementia possesses dignity in routine care is an important issue. RESEARCH OBJECTIVES: The purpose of this study was to explore the lived experience of the healthcare professionals in providing dignified dementia care in Taiwan. RESEARCH DESIGN: A qualitative, hermeneutic-phenomenological approach was conducted. PARTICIPANTS: Participants were enrolled by purpose sampling. Researchers performed in-depth interviews to reveal the essential ingredient of dignity within dementia care in Taiwan. A total of 20 cases were enrolled to achieve data saturation. ETHICAL CONSIDERATIONS: This study was approved by the institutional review board. Before conducting the interview, interviewees provided informed consent. FINDINGS: There were three themes and six categories that were addressed and constructed; within the themes, 23 Guidelines for Taiwan Dignified Dementia Care and 12 Principles for Dignified Dementia Care in Taiwan were developed. DISCUSSION: From the data relating to dignity in dementia care, we can develop a more independent and dignified care environment to improve the quality of life of person with dementia in Taiwan. CONCLUSION: The results indicated that dignity within dementia care was constructed by the lived experience of the healthcare professionals, as well as affected by the culture of the organizations and society at the same time.
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Demência/enfermagem , Pessoalidade , Demência/psicologia , Feminino , Hermenêutica , Humanos , Masculino , Pesquisa Qualitativa , TaiwanRESUMO
BACKGROUND: Reducing hospital readmissions for stroke remains a significant challenge to improve outcomes and decrease healthcare costs. METHODS: We analyzed 10,034 adult patients with ischemic stroke, presented within 24 hours of onset from a hospital-based stroke registry. The risk factors for early return to hospital after discharge were analyzed using multivariate logistic regression and classification and regression tree (CART) analyses. RESULTS: Among the study population, 277 (2.8%) had 3-day Emergency Department (ED) reattendance, 534 (5.3%) had 14-day readmission, and 932 (9.3%) had 30-day readmission. Multivariate logistic regression revealed that age, nasogastric tube feeding, indwelling urinary catheter, healthcare utilization behaviour, and stroke severity were major and common risk factors for an early return to the hospital after discharge. CART analysis identified nasogastric tube feeding and length of stay for 72-hour ED reattendance, Barthel Index (BI) score, total length of stay in the Year Preceding the index admission (YLOS), indwelling urinary catheter, and age for 14-day readmission, and nasogastric tube feeding, BI score, YLOS, and number of inpatient visits in the year preceding the index admission for 30-day readmission as important factors to classify the patients into subgroups. CONCLUSION: Although CART analysis did not improve the prediction of an early return to the hospital after stroke compared with logistic regression models, decision rules generated by CART can easily be interpreted and applied in clinical practice.
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Isquemia Encefálica/epidemiologia , Alta do Paciente/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Adulto , Idoso , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7q11.23) are neurodevelopmental disorders caused by the deletion and duplication, respectively, of ~ 25 protein-coding genes on chromosome 7q11.23. The general transcription factor 2I (GTF2I, protein TFII-I) is one of these proteins and has been implicated in the neurodevelopmental phenotypes of WS and Dup7q11.23. Here, we investigated the effect of copy number alterations in Gtf2i on neuronal maturation and intracellular calcium entry mechanisms known to be associated with this process. Mice with a single copy of Gtf2i (Gtf2i+/Del) had increased axonal outgrowth and increased TRPC3-mediated calcium entry upon carbachol stimulation. In contrast, mice with 3 copies of Gtf2i (Gtf2i+/Dup) had decreases in axon outgrowth and in TRPC3-mediated calcium entry. The underlying mechanism was that TFII-I did not affect TRPC3 protein expression, while it regulated TRPC3 membrane translocation. Together, our results provide novel functional insight into the cellular mechanisms that underlie neuronal maturation in the context of the 7q11.23 disorders.
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Neurônios/metabolismo , Canais de Cátion TRPC/metabolismo , Fatores de Transcrição TFII/metabolismo , Animais , Axônios/metabolismo , Cálcio/metabolismo , Membrana Celular/metabolismo , Aberrações Cromossômicas , Modelos Animais de Doenças , Camundongos , Neuritos/metabolismo , Fenótipo , Fatores de TempoRESUMO
Leptomeningeal carcinomatosis (LC) is an uncommon presentation of acute lymphoblastic leukemia (ALL), and it is a devastating and life-threatening complication. The disease affects all levels of the central nervous system, and most patients present with different multifocal neurological symptoms. This case was a 34-year-old male who had acute bilateral blindness secondary to recurrent ALL with meningeal infiltration. Diagnosis of LC is made based on the clinical symptoms and the test results including cranial and spinal magnetic resonance imaging and cerebrospinal fluid (CSF) survey. The differential diagnosis of meningeal enhancement and early treatment are also important for prognosis. This case had a good visual recovery after treatment.
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A genuine understanding of human exocrine pancreas biology and pathobiology has been hampered by a lack of suitable preparations and reliance on rodent models employing dispersed acini preparations. We have developed an organotypic slice preparation of the normal portions of human pancreas obtained from cancer resections. The preparation was assessed for physiologic and pathologic responses to the cholinergic agonist carbachol (Cch) and cholecystokinin (CCK-8), including 1) amylase secretion, 2) exocytosis, 3) intracellular Ca2+ responses, 4) cytoplasmic autophagic vacuole formation, and 5) protease activation. Cch and CCK-8 both dose-dependently stimulated secretory responses from human pancreas slices similar to those previously observed in dispersed rodent acini. Confocal microscopy imaging showed that these responses were accounted for by efficient apical exocytosis at physiologic doses of both agonists and by apical blockade and redirection of exocytosis to the basolateral plasma membrane at supramaximal doses. The secretory responses and exocytotic events evoked by CCK-8 were mediated by CCK-A and not CCK-B receptors. Physiologic agonist doses evoked oscillatory Ca2+ increases across the acini. Supraphysiologic doses induced formation of cytoplasmic autophagic vacuoles and activation of proteases (trypsin, chymotrypsin). Maximal atropine pretreatment that completely blocked all the Cch-evoked responses did not affect any of the CCK-8-evoked responses, indicating that rather than acting on the nerves within the pancreas slice, CCK cellular actions directly affected human acinar cells. Human pancreas slices represent excellent preparations to examine pancreatic cell biology and pathobiology and could help screen for potential treatments for human pancreatitis.
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Exocitose , Técnicas de Preparação Histocitológica/métodos , Modelos Biológicos , Pâncreas Exócrino/metabolismo , Pancreatite/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas Exócrino/patologia , Pancreatite/patologiaAssuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Olho/patologia , Linfoma/tratamento farmacológico , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Idoso , Encéfalo/patologia , Neoplasias do Sistema Nervoso Central/patologia , Evolução Fatal , Humanos , Injeções Intravítreas , Linfoma/patologia , Imageamento por Ressonância Magnética , MasculinoRESUMO
Hepatocellular carcinoma (HCC) relies on angiogenesis for growth and metastasis. Leukocyte cell-derived chemotaxin 2 (LECT2) is a cytokine and preferentially expressed in the liver. Previous studies have found that LECT2 targets to both immune and tumor cells to suppress HCC development and vascular invasion. Although LECT2 did not affect HCC cells growth in vitro, it still suppressed HCC xenografts growth in immune-deficient mice, suggesting other cells such as stroma cells may also be targeted by LECT2. Here, we sought to determine the role of LECT2 in tumor angiogenesis in HCC patients. We found that LECT2 expression inhibited tumor growth via angiogenesis in the HCC xenograft model. Specifically, we demonstrated that recombinant human LECT2 protein selectively suppressed vascular endothelial growth factor (VEGF)165-induced endothelial cell proliferation, migration, and tube formation in vitro and in vivo. Mechanistically, LECT2 reduced VEGF receptor 2 tyrosine phosphorylation and its downstream extracellular signal-regulated kinase and AKT phosphorylation. Furthermore, LECT2 gene expression correlated negatively with angiogenesis in HCC patients. Taken together, our findings demonstrate that LECT2 inhibits VEGF165-induced HCC angiogenesis through directly binding to VEGFR2 and has broad applications in treating VEGF-mediated solid tumors.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Neoplasias Hepáticas/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear. Here, we found that erythropoietin-producing hepatocellular receptor A4 (EphA4), which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the extracellular signal-regulated kinase (ERK) pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV(-) tonsils but not in EBV(+) PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV(+) and EBV(-) DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV(+) PTLD and DLBCL.