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1.
Nat Immunol ; 23(5): 781-790, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35383307

RESUMO

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.


Assuntos
COVID-19 , SARS-CoV-2 , Linfócitos T CD8-Positivos , Humanos , Fenótipo , Receptores de Antígenos de Linfócitos T/genética , Glicoproteína da Espícula de Coronavírus/genética , Vacinas Sintéticas , Vacinas de mRNA
2.
Proc Natl Acad Sci U S A ; 119(11): e2121609119, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35259016

RESUMO

SignificanceNeurodegenerative diseases are poorly understood and difficult to treat. One common hallmark is lysosomal dysfunction leading to the accumulation of aggregates and other undegradable materials, which cause damage to brain resident cells. Lysosomes are acidic organelles responsible for breaking down biomolecules and recycling their constitutive parts. In this work, we find that the antiinflammatory and neuroprotective compound, discovered via a phenotypic screen, imparts its beneficial effects by targeting the lysosome and restoring its function. This is established using a genome-wide CRISPRi target identification screen and then confirmed using a variety of lysosome-targeted studies. The resulting small molecule from this study represents a potential treatment for neurodegenerative diseases as well as a research tool for the study of lysosomes in disease.


Assuntos
Anti-Inflamatórios/farmacologia , Lisossomos/efeitos dos fármacos , Doenças Neurodegenerativas/metabolismo , Animais , Anti-Inflamatórios/química , Biomarcadores , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , Perfilação da Expressão Gênica , Humanos , Camundongos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Smad/agonistas
3.
Sensors (Basel) ; 24(12)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38931713

RESUMO

The rapid advancements in Artificial Intelligence of Things (AIoT) are pivotal for the healthcare sector, especially as the world approaches an aging society which will be reached by 2050. This paper presents an innovative AIoT-enabled data fusion system implemented at the CMUH Respiratory Intensive Care Unit (RICU) to address the high incidence of medical errors in ICUs, which are among the top three causes of mortality in healthcare facilities. ICU patients are particularly vulnerable to medical errors due to the complexity of their conditions and the critical nature of their care. We introduce a four-layer AIoT architecture designed to manage and deliver both real-time and non-real-time medical data within the CMUH-RICU. Our system demonstrates the capability to handle 22 TB of medical data annually with an average delay of 1.72 ms and a bandwidth of 65.66 Mbps. Additionally, we ensure the uninterrupted operation of the CMUH-RICU with a three-node streaming cluster (called Kafka), provided a failed node is repaired within 9 h, assuming a one-year node lifespan. A case study is presented where the AI application of acute respiratory distress syndrome (ARDS), leveraging our AIoT data fusion approach, significantly improved the medical diagnosis rate from 52.2% to 93.3% and reduced mortality from 56.5% to 39.5%. The results underscore the potential of AIoT in enhancing patient outcomes and operational efficiency in the ICU setting.


Assuntos
Inteligência Artificial , Unidades de Terapia Intensiva , Humanos , Síndrome do Desconforto Respiratório/terapia
4.
Europace ; 25(12)2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-38042981

RESUMO

AIMS: This study aimed to investigate the effectiveness of closed-loop stimulation (CLS) pacing compared with the traditional DDD mode in patients with chronotropic incompetence (CI) using bicycle-based cardiopulmonary exercise testing (CPET). METHODS AND RESULTS: This single-centre, randomized crossover trial involved 40 patients with CI. Patients were randomized to receive either DDD-CLS or DDD mode pacing for 2 months, followed by a crossover to the alternative mode for an additional 2 months. Bicycling-based CPET was conducted at the 3- and 5-month follow-up visits to assess exercise capacity. Other cardiopulmonary exercise outcome measures and health-related quality of life (QoL) were also assessed. DDD-CLS mode pacing significantly improved exercise capacity, resulting in a peak oxygen uptake (14.8 ± 4.0 vs. 12.0 ± 3.6 mL/kg/min, P < 0.001) and oxygen uptake at the ventilatory threshold (10.0 ± 2.2 vs. 8.7 ± 1.8 mL/kg/min, P < 0.001) higher than those of the DDD mode. However, there were no significant differences in other cardiopulmonary exercise outcome measures such as ventilatory efficiency of carbon dioxide production slope, oxygen uptake efficiency slope, and end-tidal carbon dioxide between the two modes. Patients in the DDD-CLS group reported a better QoL, and 97.5% expressed a preference for the DDD-CLS mode. CONCLUSION: DDD-CLS mode pacing demonstrated improved exercise capacity and QoL in patients with CI, highlighting its potential as an effective pacing strategy for this patient population.


Assuntos
Estimulação Cardíaca Artificial , Qualidade de Vida , Humanos , Estimulação Cardíaca Artificial/métodos , Dióxido de Carbono , Ciclismo , Tolerância ao Exercício , Estudos Cross-Over , Teste de Esforço , Oxigênio , Frequência Cardíaca/fisiologia
5.
Indian Pacing Electrophysiol J ; 23(4): 110-115, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37044211

RESUMO

BACKGROUND: High-power short-duration (HPSD) and cryoballoon ablation (CBA) has been used for pulmonary vein isolation (PVI). OBJECTIVE: We aimed to compare the efficacy of PVI between CBA and HPSD ablation in patients with paroxysmal atrial fibrillation (PAF). METHODS: We retrospectively analyzed 251 consecutive PAF patients from January 2018 to July 2020. Of them, 124 patients (mean age 57.2 ± 10.1 year) received HPSD and 127 patients (mean age 59.6 ± 9.4 year) received CBA. In HPSD group, the radiofrequency energy was set as 50 W/10 s at anterior wall and 40 W/10 s at posterior wall. In CBA group, 28 mm s generation cryoballoon was used for PVI according the guidelines. RESULTS: There was no significant difference in baseline characteristics between these 2 groups. The time to achieve PVI was significantly shorter in cryoballoon ablation group than in HPSD group (20.6 ± 1.7 min vs 51.8 ± 36.3, P = 0.001). The 6-month overall recurrence for atrial tachyarrhythmias was not significantly different between the two groups (HPSD:14.50% vs CBA:11.0%, P = 0.40). There were different types of recurrent atrial tachyarrhythmia between these 2 groups. Recurrence as atrial flutter was significantly more common in CBA group compared to HPSD group (57.1% vs 12.5%, P = 0.04). CONCLUSION: In PAF patients, CBA and HPSD had a favourable and comparable outcome. The recurrence pattern was different between CBA and HPSD groups.

6.
J Biomed Sci ; 29(1): 9, 2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35130876

RESUMO

BACKGROUND: K1 capsular polysaccharide (CPS)-associated Klebsiella pneumoniae is the primary cause of pyogenic liver abscesses (PLA) in Asia. Patients with PLA often have serious complications, ultimately leading to a mortality of ~ 5%. This K1 CPS has been reported as a promising target for development of glycoconjugate vaccines against K. pneumoniae infection. The pyruvylation and O-acetylation modifications on the K1 CPS are essential to the immune response induced by the CPS. To date, however, obtaining the fragments of K1 CPS that contain the pyruvylation and O-acetylation for generating glycoconjugate vaccines still remains a challenge. METHODS: We analyzed the digested CPS products with NMR spectroscopy and mass spectrometry to reveal a bacteriophage-derived polysaccharide depolymerase specific to K1 CPS. The biochemical and biophysical properties of the enzyme were characterized and its crystal structures containing bound CPS products were determined. We also performed site-directed mutagenesis, enzyme kinetic analysis, phage absorption and infectivity studies, and treatment of the K. pneumoniae-infected mice with the wild-type and mutant enzymes. RESULTS: We found a bacteriophage-derived polysaccharide lyase that depolymerizes the K1 CPS into fragments of 1-3 repeating trisaccharide units with the retention of the pyruvylation and O-acetylation, and thus the important antigenic determinants of intact K1 CPS. We also determined the 1.46-Å-resolution, product-bound crystal structure of the enzyme, revealing two distinct carbohydrate-binding sites in a trimeric ß-helix architecture, which provide the first direct evidence for a second, non-catalytic, carbohydrate-binding site in bacteriophage-derived polysaccharide depolymerases. We demonstrate the tight interaction between the pyruvate moiety of K1 CPS and the enzyme in this second carbohydrate-binding site to be crucial to CPS depolymerization of the enzyme as well as phage absorption and infectivity. We also demonstrate that the enzyme is capable of protecting mice from K1 K. pneumoniae infection, even against a high challenge dose. CONCLUSIONS: Our results provide insights into how the enzyme recognizes and depolymerizes the K1 CPS, and demonstrate the potential use of the protein not only as a therapeutic agent against K. pneumoniae, but also as a tool to prepare structurally-defined oligosaccharides for the generation of glycoconjugate vaccines against infections caused by this organism.


Assuntos
Bacteriófagos , Infecções por Klebsiella , Liases , Animais , Cápsulas Bacterianas/genética , Bacteriófagos/genética , Humanos , Cinética , Klebsiella pneumoniae , Camundongos
7.
Neural Plast ; 2022: 3593262, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35529454

RESUMO

Background: Various forms of theta-burst stimulation (TBS) such as intermittent TBS (iTBS) and continuous TBS (cTBS) have been introduced as novel facilitation/suppression schemes during repetitive transcranial magnetic stimulation (rTMS), demonstrating a better efficacy than conventional paradigms. Herein, we extended the rTMS-TBS schemes to electrical stimulation of high-definition montage (HD-TBS) and investigated its neural effects on the human brain. Methods: In a within-subject design, fifteen right-handed healthy adults randomly participated in 10 min and 2 mA HD-TBS sessions: unilateral (Uni)-iTBS, bilateral (Bi)-cTBS/iTBS, and sham stimulation over primary motor cortex regions. A 20-channel near-infrared spectroscopy (NIRS) system was covered on the bilateral prefrontal cortex (PFC), sensory motor cortex (SMC), and parietal lobe (PL) for observing cerebral hemodynamic responses in the resting-state and during fast finger-tapping tasks at pre-, during, and poststimulation. Interhemispheric correlation coefficient (IHCC) and wavelet phase coherence (WPCO) from resting-state NIRS and concentration of oxyhemoglobin during fast finger-tapping tasks were explored to reflect the symmetry between the two hemispheres and cortical activity, respectively. Results: The IHCC and WPCO of NIRS data in the SMC region under Bi-cTBS/iTBS showed relatively small values at low-frequency bands III (0.06-0.15 Hz) and IV (0.02-0.06), indicating a significant desynchronization in both time and frequency domains. In addition, the SMC activation induced by fast finger-tapping exercise was significantly greater during Uni-iTBS as well as during and post Bi-cTBS/iTBS sessions. Conclusions: It appears that a 10 min and 2 mA Bi-cTBS/iTBS applied over two hemispheres within the primary motor cortex region could effectively modulate the interhemispheric synchronization and cortical activation in the SMC of healthy subjects. Our study demonstrated that bilateral HD-TBS approaches is an effective noninvasive brain stimulation scheme which could be a novel therapeutic for inducing effects of neuromodulation on various neurological disorders caused by ischemic stroke or traumatic brain injuries.


Assuntos
Lobo Parietal , Estimulação Magnética Transcraniana , Adulto , Estimulação Elétrica , Potencial Evocado Motor/fisiologia , Voluntários Saudáveis , Humanos , Córtex Pré-Frontal/fisiologia , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos
8.
Sensors (Basel) ; 22(5)2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35271134

RESUMO

Venous needle dislodgement (VND) is a major healthcare safety concern in patients undergoing hemodialysis. Although VND is uncommon, it can be life-threatening. The main objective of this study was to implement a real-time multi-bed monitoring system for VND by combining a novel leakage-detection device and IoMT (Internet of Medical Things) technology. The core of the system, the Acusense IoMT platform, consisted of a novel leakage-detection patch comprised of multiple concentric rings to detect blood leakage and quantify the leaked volume. The performance of the leakage-detection system was evaluated on a prosthetic arm and clinical study. Patients with a high risk of blood leakage were recruited as candidates. The system was set up in a hospital, and the subjects were monitored for 2 months. During the pre-clinical simulation experiment, the system could detect blood leakage volumes from 0.3 to 0.9 mL. During the test of the IoMT system, the overall success rate of tests was 100%, with no lost data packets. A total of 701 dialysis sessions were analyzed, and the accuracy and sensitivity were 99.7% and 90.9%, respectively. Evaluation questionnaires showed that the use of the system after training changed attitudes and reduced worry of the nursing staff. Our results show the feasibility of using a novel detector combined with an IoMT system to automatically monitor multi-bed blood leakage. The innovative concentric-circle design could more precisely control the warning blood-leakage threshold in any direction to achieve clinical cost-effectiveness. The system reduced the load on medical staff and improved patient safety. In the future, it could also be applied to home hemodialysis for telemedicine during the era of COVID-19.


Assuntos
Membros Artificiais , COVID-19 , Braço , Humanos , Internet , Diálise Renal/efeitos adversos , SARS-CoV-2
9.
Int J Mol Sci ; 23(18)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36142225

RESUMO

Various infarct sizes induced by middle cerebral artery occlusion (MCAO) generate inconsistent outcomes for stroke preclinical study. Monitoring cerebral hemodynamics may help to verify the outcome of MCAO. The aim of this study was to investigate the changes in brain tissue optical properties by frequency-domain near-infrared spectroscopy (FD-NIRS), and establish the relationship between cerebral hemodynamics and infarct variation in MCAO model. The rats were undergone transient MCAO using intraluminal filament. The optical properties and hemodynamics were measured by placing the FD-NIRS probes on the scalp of the head before, during, and at various time-courses after MCAO. Bimodal infarction severities were observed after the same 90-min MCAO condition. Significant decreases in concentrations of oxygenated hemoglobin ([HbO]) and total hemoglobin ([HbT]), tissue oxygenation saturation (StO2), absorption coefficient (µa) at 830 nm, and reduced scattering coefficient (µs') at both 690 and 830 nm were detected during the occlusion in the severe infarction but not the mild one. Of note, the significant increases in [HbO], [HbT], StO2, and µa at both 690 and 830 nm were found on day 3; and increases in µs' at both 690 and 830 nm were found on day 2 and day 3 after MCAO, respectively. The interhemispheric correlation coefficient (IHCC) was computed from low-frequency hemodynamic oscillation of both hemispheres. Lower IHCCs standing for interhemispheric desynchronizations were found in both mild and severe infarction during occlusion, and only in severe infarction after reperfusion. Our finding supports that sequential FD-NIRS parameters may associated with the severity of the infarction in MCAO model, and the consequent pathologies such as vascular dysfunction and brain edema. Further study is required to validate the potential use of FD-NIRS as a monitor for MCAO verification.


Assuntos
Infarto da Artéria Cerebral Média , Acidente Vascular Cerebral , Animais , Modelos Animais de Doenças , Hemodinâmica , Infarto da Artéria Cerebral Média/patologia , Oxiemoglobinas , Ratos , Acidente Vascular Cerebral/patologia
10.
J Cardiovasc Electrophysiol ; 32(3): 758-765, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33448496

RESUMO

INTRODUCTION: A drug provocation test (DPT) is important for the diagnosis of Brugada syndrome (BrS). The link, however, between dynamic changes of electrocardiography (ECG) features after DPT and unstable ventricular arrhythmia (VA) in BrS remains unknown. METHODS: Between 2014 and 2019, we assessed 27 patients with BrS (median age: 37.0 [interquartile range, IQR: 22.0-51.0] years; 25 men), including 9 (33.3%) with a history of unstable VA and 18 (66.7%) without. All patients in the study presented with Brugada-like ECG features before DPT. The ECG parameters and dynamic changes (∆) in 12-lead ECGs recorded from the second, third, and fourth intercostal spaces (ICS) before and at 1, 6, 12, 18, and 24 h after DPT (oral flecainide 400 mg) were analyzed. RESULTS: The total amplitude of V1 at the third ICS 18 and 24 h after DPT was significantly lower in patients with a history of unstable VA than in those without. Patients with BrS and unstable VAs had a significantly larger ∆ amplitude of V1 at the second ICS 12 h after DPT than in those without unstable VAs (0.28 [0.18-0.41] mV vs. 0.08 [0.01-0.15] mV, p = .01). A multivariate analysis revealed that the amplitude of V1 at the third ICS 18 and 24 h after DPT and the ∆ amplitude of V1 at the second ICS 12 h after DPT were associated with a history of unstable VA. CONCLUSION: Nonuniform changes and spatiotemporal differences in precordial ECG features after DPT were observed in patients with BrS and these may be surrogate markers for risk stratification.


Assuntos
Síndrome de Brugada , Flecainida , Adulto , Síndrome de Brugada/diagnóstico , Eletrocardiografia , Flecainida/efeitos adversos , Humanos , Masculino
11.
Bull Math Biol ; 83(3): 19, 2021 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-33452931

RESUMO

Mathematical equations are often used to model biological processes. However, for many systems, determining analytically the underlying equations is highly challenging due to the complexity and unknown factors involved in the biological processes. In this work, we present a numerical procedure to discover dynamical physical laws behind biological data. The method utilizes deep learning methods based on neural networks, particularly residual networks. It is also based on recently developed mathematical tools of flow-map learning for dynamical systems. We demonstrate that with the proposed method, one can accurately construct numerical biological models for unknown governing equations behind measurement data. Moreover, the deep learning model can also incorporate unknown parameters in the biological process. A successfully trained deep neural network model can then be used as a predictive tool to produce system predictions of different settings and allows one to conduct detailed analysis of the underlying biological process. In this paper, we use three biological models-SEIR model, Morris-Lecar model and the Hodgkin-Huxley model-to show the capability of our proposed method.


Assuntos
Aprendizado Profundo , Modelos Biológicos , Conceitos Matemáticos , Redes Neurais de Computação
12.
Int J Med Sci ; 18(12): 2521-2531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104083

RESUMO

Developing treatment strategies for triple-negative breast cancer (TNBC) has become an important clinical challenge. Currently, taxane-based chemotherapy is one of the standard treatments for TNBC. However, determining the key factor of taxane-resistance is urgently in need for clinical treatment for breast cancer. We used GEO data to generate paclitaxel resistance in two basal-like TNBC cell lines (SUM149 and MDA-MB-468). Seventy-one common upregulated differentially expressed genes (DEGs) and 11 downregulated DEGs were found to be related to paclitaxel resistance. By constructing protein-protein interactions, 28 hub proteins with a degree cutoff criterion of ≥1 were found. Nine hub genes (COL4A6, COL4A5, IL6, PDGFA, LPAR1, FYB, IL20, IL18R1 and INHBA) are involved in important signaling pathways. We found that upregulated PDGFA and downregulated COL4A6 were significantly associated with an insensitive response to neoadjuvant paclitaxel-based therapy. A Kaplan-Meier plot was created to check the prognostic values of 11 hub DEGs in terms of recurrence-free survival. High expressions of PDGFA and LAMB3 were correlated with poor recurrence-free survival, while low levels of FYB, IL18R1, and RASGRP1 indicated poorer relapse-free survival. Our results suggest that PDGFA, COL4A6, LPAR1, FYB, COL4A5, and RASGRP1 might be candidate target genes for taxane-based therapy in basal-like TNBC.


Assuntos
Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/epidemiologia , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/terapia , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Heterogeneidade Genética , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/prevenção & controle , Paclitaxel/uso terapêutico , Mapas de Interação de Proteínas/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima
13.
J Formos Med Assoc ; 120(1 Pt 2): 542-550, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32669233

RESUMO

BACKGROUND/PURPOSE: Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. METHODS: In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5 mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). RESULTS: Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7 ± 10.10 years; mean duration of MS was 5.4 ± 4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts <0.2 × 103/uL over the study period. One patient developed second degree AV block after first-dosing. Serious AEs were observed in 11 patients (15.9%; mild-to-moderate). No newly developed macular oedema was detected. The ARR was 0.3 ± 0.74 in fingolimod-treated patients and 66.7% of patients were relapse-free. The mean (SD) change from baseline in expanded disability status scale score was -0.30 ± 1.353. CONCLUSION: Fingolimod 0.5 mg/day treatment with an average of 2 years of exposure was associated with a manageable safety profile, and maintained/improved effectiveness in RRMS patients from Taiwan.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Esclerose Múltipla , Adulto , Cloridrato de Fingolimode/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos Retrospectivos , Taiwan
14.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069531

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective therapies for AD, which is an urgent problem to solve. Evodiamine, one of the main bioactive ingredients of Evodia rutaecarpa, has been reported to ameliorate blood-brain barrier (BBB) permeability and improve cognitive impairment in ischemia and AD mouse models. However, whether evodiamine alleviates tauopathy remains unclear. This study aimed to examine whether evodiamine ameliorates tau phosphorylation and cognitive deficits in AD models. METHODS: A protein phosphatase 2A inhibitor, okadaic acid (OA), was used to induce tau phosphorylation to mimic AD-like models in neuronal cells. Protein expression and cell apoptosis were detected using Western blotting and flow cytometry, respectively. Spatial memory/cognition was assessed using water maze, passive avoidance tests, and magnetic resonance imaging assay in OA-induced mice models, and brain slices were evaluated further by immunohistochemistry. RESULTS: The results showed that evodiamine significantly reduced the expression of phosphor-tau, and further decreased tau aggregation and neuronal cell death in response to OA treatment. This inhibition was found to be via the inhibition of glycogen synthase kinase 3ß, cyclin-dependent kinase 5, and mitogen-activated protein kinase pathways. In vivo results indicated that evodiamine treatment ameliorated learning and memory impairments in mice, whereas Western blotting and immunohistochemical analysis of the mouse brain also confirmed the neuroprotective effects of evodiamine. CONCLUSIONS: Evodiamine can decrease the neurotoxicity of tau aggregation and exhibit a neuroprotective effect. Our results demonstrate that evodiamine has a therapeutic potential for AD treatment.


Assuntos
Quinazolinas/farmacologia , Tauopatias/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ácido Okadáico/efeitos adversos , Ácido Okadáico/farmacologia , Fosforilação , Quinazolinas/metabolismo , Memória Espacial/efeitos dos fármacos , Proteínas tau/efeitos dos fármacos , Proteínas tau/metabolismo
15.
Ann Rheum Dis ; 79(5): 646-656, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32205337

RESUMO

OBJECTIVES: Emerging evidence suggests that the microbiome plays an important role in the pathogenesis of osteoarthritis (OA). We aimed to test the two-hit model of OA pathogenesis and potentiation in which one 'hit' is provided by an adverse gut microbiome that activates innate immunity; the other 'hit' is underlying joint damage. METHODS: Medical history, faecal and blood samples were collected from human healthy controls (OA-METS-, n=4), knee OA without metabolic syndrome (OA+METS-, n=7) and knee OA with metabolic syndrome (OA+METS+, n=9). Each group of human faecal samples, whose microbial composition was identified by 16S rRNA sequencing, was pooled and transplanted into germ-free mice 2 weeks prior to meniscal/ligamentous injury (MLI) (n≥6 per group). Eight weeks after MLI, mice were evaluated for histological OA severity and synovitis, systemic inflammation and gut permeability. RESULTS: Histological OA severity following MLI was minimal in germ-free mice. Compared with the other groups, transplantation with the OA+METS+ microbiome was associated with higher mean systemic concentrations of inflammatory biomarkers (interleukin-1ß, interleukin-6 and macrophage inflammatory protein-1α), higher gut permeability and worse OA severity. A greater abundance of Fusobacterium and Faecalibaterium and lesser abundance of Ruminococcaceae in transplanted mice were consistently correlated with OA severity and systemic biomarkers concentrations. CONCLUSION: The study clearly establishes a direct gut microbiome-OA connection that sets the stage for a new means of exploring OA pathogenesis and potentially new OA therapeutics. Alterations of Fusobacterium, Faecalibaterium and Ruminococcaceae suggest a role of these particular microbes in exacerbating OA.


Assuntos
Transplante de Microbiota Fecal/métodos , Microbioma Gastrointestinal , Síndrome Metabólica/complicações , Osteoartrite do Joelho/terapia , Animais , Biomarcadores/análise , Biópsia por Agulha , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Meniscos Tibiais/patologia , Meniscos Tibiais/cirurgia , Síndrome Metabólica/patologia , Camundongos Endogâmicos C57BL , Análise Multivariada , Osteoartrite do Joelho/patologia , Distribuição Aleatória , Valores de Referência , Análise de Regressão , Medição de Risco
16.
J Cardiovasc Electrophysiol ; 31(6): 1436-1447, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32227530

RESUMO

INTRODUCTION: Accurate identification of slow conducting regions in patients with scar-related atrial tachycardia (AT) is difficult using conventional electrogram annotation for cardiac electroanatomic mapping (EAM). Estimating delays between neighboring mapping sites is a potential option for activation map computation. We describe our initial experience with CARTO 3 Coherent Mapping (Biosense Webster Inc,) in the ablation of complex ATs. METHODS: Twenty patients (58 ± 10 y/o, 15 males) with complex ATs were included. We created three-dimensional EAMs using CARTO 3 system with CONFIDENSE and a high-resolution mapping catheter (Biosense Webster Inc). Local activation time and coherent maps were used to aid in the identification of conduction isthmus (CI) and focal origin sites. System-defined slow or nonconducting zones and CI, defined by concealed entrainment (postpacing interval < 20 ms), CV < 0.3 m/s and local fractionated electrograms were evaluated. RESULTS: Twenty-six complex ATs were mapped (mean: 1.3 ± 0.7 maps/pt; 4 focal, 22 isthmus-dependent). Coherent mapping was better in identifying CI/breakout sites where ablation terminated the tachycardia (96.2% vs 69.2%; P = .010) and identified significantly more CI (mean/chamber 2.0 ± 1.1 vs 1.0 ± 0.7; P < .001) with narrower width (19.8 ± 10.5 vs 43.0 ± 23.9 mm; P < .001) than conventional mapping. Ablation at origin and CI sites was successful in 25 (96.2%) with long-term recurrence in 25%. CONCLUSIONS: Coherent mapping with conduction velocity vectors derived from adjacent mapping sites significantly improved the identification of CI sites in scar-related ATs with isthmus-dependent re-entry better than conventional mapping. It may be used in conjunction with conventional mapping strategies to facilitate recognition of slow conduction areas and critical sites that are important targets of ablation.


Assuntos
Potenciais de Ação , Cicatriz/complicações , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca , Taquicardia Supraventricular/diagnóstico , Idoso , Algoritmos , Ablação por Cateter , Cicatriz/diagnóstico , Feminino , Sistema de Condução Cardíaco/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Taquicardia Supraventricular/etiologia , Taquicardia Supraventricular/fisiopatologia , Taquicardia Supraventricular/cirurgia , Fatores de Tempo , Resultado do Tratamento
17.
BMC Pregnancy Childbirth ; 20(1): 558, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967640

RESUMO

BACKGROUND: Peters anomaly is a rare form of anterior segment ocular dysgenesis, the antenatal image of Peters anomaly had not been reported. We herein showcased a discordant finding of Peters anomaly in a monozygotic twin complicated with twin-twin transfusion syndrome (TTTS) and exhibited its antenatal sonographic images, CASE PRESENTATION: A 38-year-old gravida 2 para 1 pregnant woman visited our clinic at the gestational age of 18 weeks where TTTS stage III was diagnosed and the following laser therapy was done successfully. Ten days after the surgery, the follow-up ultrasound detected the opacity of both fetal eyeballs in the donor twin and thus congenital cataract was suspected initially. Then magnetic resonance imaging (MRI) examination was arranged at the gestational age of 23 weeks, and no central nervous system or other anomaly was found. At the 29 weeks of gestation, the opacity of both fetal eyeballs of the donor twin did not clear. The pregnancy resulted in cesarean section at the gestational age of 37 weeks indicated by malpresentation where two male live births were born. Examination under anesthesia was arranged for donor twin after delivery and Peters anomaly was diagnosed based on central corneal opacity with iridocorneal and corneolenticular adhesions. CONCLUSIONS: The prenatal image of Peters anomaly may present as the opacity of the fetal eyeballs similar to congenital cataract. Some cases of the Peters anomaly had been reported with a genetic abnormality, but since our case presented discordant presentation in monozygotic twin pregnancy where both twins are supposed to share the same genetic make-up, therefore other factors that are epigenetic may be held accountable. Nevertheless, a genetic origin of the anomaly in our case cannot be excluded.


Assuntos
Segmento Anterior do Olho/anormalidades , Opacidade da Córnea/complicações , Doenças em Gêmeos/complicações , Anormalidades do Olho/complicações , Transfusão Feto-Fetal/complicações , Gêmeos Monozigóticos , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez
18.
Sensors (Basel) ; 20(11)2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526837

RESUMO

Nowadays, user identification plays a more and more important role for authorized machine access and remote personal data usage. For reasons of privacy and convenience, biometrics-based user identification, such as iris, fingerprint, and face ID, has become mainstream methods in our daily lives. However, most of the biometric methods can be easily imitated or artificially cracked. New types of biometrics, such as electrocardiography (ECG), are based on physiological signals rather than traditional biological traits. Recently, compressive sensing (CS) technology that combines both sampling and compression has been widely applied to reduce the power of data acquisition and transmission. However, prior CS-based frameworks suffer from high reconstruction overhead and cannot directly align compressed ECG signals. In this paper, in order to solve the above two problems, we propose a compressed alignment-aided compressive analysis (CA-CA) algorithm for ECG-based biometric user identification. With CA-CA, it can avoid reconstruction and extract information directly from CS-based compressed ECG signals to reduce overall complexity and power. Besides, CA-CA can also align the compressed ECG signals in the eigenspace-domain, which can further enhance the precision of identifications and reduce the total training time. The experimental result shows that our proposed algorithm has a 94.16% accuracy based on a public database of 22 people.


Assuntos
Identificação Biométrica , Compressão de Dados , Eletrocardiografia , Algoritmos , Humanos
19.
Sensors (Basel) ; 20(20)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053827

RESUMO

This work presents a fall detection system that is worn on the head, where the acceleration and posture are stable such that everyday movement can be identified without disturbing the wearer. Falling movements are recognized by comparing the acceleration and orientation of a wearer's head using prespecified thresholds. The proposed system consists of a triaxial accelerometer, gyroscope, and magnetometer; as such, a Madgwick's filter is adopted to improve the accuracy of the estimation of orientation. Moreover, with its integrated Wi-Fi module, the proposed system can notify an emergency contact in a timely manner to provide help for the falling person. Based on experimental results concerning falling movements and activities of daily living, the proposed system achieved a sensitivity of 96.67% in fall detection, with a specificity of 98.27%, and, therefore, is suitable for detecting falling movements in daily life.


Assuntos
Acidentes por Quedas , Atividades Cotidianas , Algoritmos , Dispositivos Eletrônicos Vestíveis , Aceleração , Humanos , Movimento
20.
Neuromodulation ; 23(3): 399-406, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31840383

RESUMO

OBJECTIVE: To investigate whether indicators of cortical excitability are good biomarkers of seizure controllability in temporal lobe epilepsy (TLE). MATERIALS AND METHODS: Three groups of subjects were recruited: those with poorly controlled (PC) TLE (N = 41), well-controlled (WC) TLE (N = 71), and healthy controls (N = 44). Short- and long-latency recovery curves were obtained by paired-pulse transcranial magnetic stimulation. Linear mixed effect models were used to study the effects of group, interstimulus interval (ISI), and antiepileptic drugs on long-interval intracortical inhibition (LICI) and short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). RESULTS: The mixed effect model that did not incorporate antiepileptic drugs showed that group and ISI were significant factors for LICI and SICI/ICF. LICI in the healthy control group was greater than in the two epilepsy groups, and the difference was significant at ISIs of 50, 150, and 200 msec. In contrast, SICI/ICF in the PC group was greater than in the healthy control and WC groups, and the difference was significant at an ISI of 15 msec. However, due to large variance, it was difficult to identify a cutoff value with both good sensitivity and good specificity. Incorporating the information of antiepileptic drugs to the mixed effect model did not change the overall results. CONCLUSIONS: Although LICI and SICI/ICF parameters were significantly different at the group level, they may not be suitable biomarkers for the controllability of TLE at the subject level.


Assuntos
Excitabilidade Cortical , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Convulsões/fisiopatologia , Estimulação Magnética Transcraniana/métodos , Adulto , Anticonvulsivantes/uso terapêutico , Córtex Cerebral/fisiopatologia , Excitabilidade Cortical/efeitos dos fármacos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/prevenção & controle , Resultado do Tratamento
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