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BACKGROUND: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. METHODS: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. RESULTS: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort. CONCLUSIONS: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.
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Clopidogrel , Citocromo P-450 CYP2C19 , Stents Farmacológicos , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Inibidores da Bomba de Prótons , Humanos , Clopidogrel/uso terapêutico , Clopidogrel/efeitos adversos , Clopidogrel/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/administração & dosagem , Masculino , Feminino , Stents Farmacológicos/efeitos adversos , Idoso , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Intervenção Coronária Percutânea/efeitos adversos , Citocromo P-450 CYP2C19/genética , Resultado do Tratamento , Sistema de Registros , População do Leste AsiáticoRESUMO
BACKGROUND: Artificial intelligence-based quantitative coronary angiography (AI-QCA) has been developed to provide a more objective and reproducible data about the severity of coronary artery stenosis and the dimensions of the vessel for intervention in real-time, overcoming the limitations of significant inter- and intraobserver variability, and time-consuming nature of on-site QCA, without requiring extra time and effort. Compared with the subjective nature of visually estimated conventional CAG guidance, AI-QCA guidance provides a more practical and standardized angiography-based approach. Although the advantage of intravascular imaging-guided PCI is increasingly recognized, their broader adoption is limited by clinical and economic barriers in many catheterization laboratories. METHODS: The FLASH (fully automated quantitative coronary angiography versus optical coherence tomography guidance for coronary stent implantation) trial is a randomized, investigator-initiated, multicenter, open-label, noninferiority trial comparing the AI-QCA-assisted PCI strategy with optical coherence tomography-guided PCI strategy in patients with significant coronary artery disease. All operators will utilize a novel, standardized AI-QCA software and PCI protocol in the AI-QCA-assisted group. A total of 400 patients will be randomized to either group at a 1:1 ratio. The primary endpoint is the minimal stent area (mm2), determined by the final OCT run after completion of PCI. Clinical follow-up and cost-effectiveness evaluations are planned at 1 month and 6 months for all patients enrolled in the study. RESULTS: Enrollment of a total of 400 patients from the 13 participating centers in South Korea will be completed in February 2024. Follow-up of the last enrolled patients will be completed in August 2024, and primary results will be available by late 2024. CONCLUSION: The FLASH is the first clinical trial to evaluate the feasibility of AI-QCA-assisted PCI, and will provide the clinical evidence on AI-QCA assistance in the field of coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT05388357.
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Angiografia Coronária , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Stents , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Angiografia Coronária/métodos , Intervenção Coronária Percutânea/métodos , Doença da Artéria Coronariana/cirurgia , Doença da Artéria Coronariana/diagnóstico por imagem , Inteligência Artificial , Feminino , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/cirurgia , Estenose Coronária/terapia , Estudos de Equivalência como Asunto , Masculino , Cirurgia Assistida por Computador/métodos , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgiaRESUMO
OBJECTIVES: We aimed to assess the diagnostic utility of an immunohistochemical panel including calcium-binding protein P, p53, Ki-67, and SMAD family member 4 and K-ras mutation for diagnosing pancreatic solid lesion specimens obtained by endoscopic ultrasound-guided fine-needle biopsy and to confirm their usefulness in histologically inconclusive cases. METHODS: Immunohistochemistry and peptide nucleic acid-clamping polymerase chain reaction for K-ras mutation were performed on 96 endoscopic ultrasound-guided fine-needle biopsy specimens. The diagnostic efficacy of each marker and the combination of markers was calculated. The diagnostic performances of these markers were evaluated in 27 endoscopic ultrasound-guided fine-needle biopsy specimens with histologically inconclusive diagnoses. A classification tree was constructed. RESULTS: K-ras mutation showed the highest accuracy and consistency. Positivity in more than two or three of the five markers showed high diagnostic accuracy (94.6 % and 93.6 %, respectively), and positivity for more than three markers showed the highest accuracy for inconclusive cases (92.0 %). A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 showed high diagnostic performance, with only two misclassifications in inconclusive cases. CONCLUSIONS: K-ras mutation detection via peptide nucleic acid-clamping polymerase chain reaction is a stable and accurate method for distinguishing between pancreatic ductal adenocarcinoma and non-pancreatic ductal adenocarcinoma lesions. A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 helps increase the diagnostic accuracy of cases that are histologically difficult to diagnose.
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Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Antígeno Ki-67 , Mutação , Neoplasias Pancreáticas , Proteína Smad4 , Humanos , Proteína Smad4/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Antígeno Ki-67/genética , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Reação em Cadeia da Polimerase/métodos , Adulto , Proteínas Proto-Oncogênicas p21(ras)/genética , Ácidos Nucleicos Peptídicos , Imuno-Histoquímica , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND AND AIMS: Training in interventional endoscopy is offered by nonaccredited advanced endoscopy fellowship programs (AEFPs). The number of these programs has increased dramatically with a concurrent increase in the breadth and complexity of interventional endoscopy procedures. Accreditation is governed by competency-based education, yet what constitutes a "high-quality" nonaccredited AEFP has not been defined. Using an evidence-based consensus process, we aimed to establish standards for AEFPs. METHODS: The RAND UCLA appropriateness method, a well-described modified Delphi process to develop quality indicators, was used. A task force established by the American Society for Gastrointestinal Endoscopy drafted potential quality indicators (structure, process, and outcome) in 6 categories: activity preceding training; structure of AEFPs; training in ERCP, EUS, and EMR; and luminal stent placement. Three rounds of iterative feedback from 20 experts were conducted. Round 0 involved discussion of project details. In round 1, experts independently ranked proposed quality indicators on a 9-point interval scale ranging from highly inappropriate (1) to highly appropriate (9). Next, proposed quality indicators were discussed and reworded in a group meeting followed by round 2, in which experts independently reranked proposed quality indicators and provided benchmarks (when applicable). The median score for each quality indicator was calculated. Mean absolute deviation from the median was calculated, and appropriateness of potential quality indicators was assessed using the BIOMED concerted action on appropriateness definition, P value method, and interpercentile range adjusted for symmetry definition. A quality indicator was deemed appropriate if the median score was ≥7 and met criteria for appropriateness using all 3 defined statistical methods. RESULTS: Of 89 proposed quality indicators, 37 statements met criteria as appropriate for a quality indicator (activity preceding training, 2; structure of AEFPs, 10; training in ERCP, 7; training in EUS, 8; training in EMR, 7; luminal stent placement, 3). Minimum thresholds were defined for 19 relevant quality indicators for number of trainers, procedures during fellowship, and procedures before assessment of competence. Among the final appropriate quality indicators were that all trainees should undergo qualitative and quantitative competence assessments using validated tools at least quarterly with documented feedback throughout the training period and that trainees should track outcomes and relevant quality metrics for specific procedures. CONCLUSIONS: This consensus process using validated methodology established standards for an AEFP in an effort to ensure adequate training in the most commonly taught interventional endoscopic procedures (ERCP, EUS, EMR, and luminal stent placement) during fellowship. An important component of an AEFP is the use of competency-based assessments that are compliant with the Accreditation Council for Graduate Medical Education's Next Accreditation System, with the goal of ensuring that trainees achieve specific milestones in their progression to achieving cognitive and technical competency.
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BACKGROUND: Coronary artery disease patients undergoing percutaneous coronary intervention (PCI) often exhibit reduced left ventricular ejection fraction (LVEF). However, the impact of LV dysfunction status in conjunction with platelet reactivity on clinical outcomes has not been previously investigated. METHODS: From the multicenter PTRG-DES (Platelet function and genoType-Related long-term prognosis in DES-treated patients) consortium, the patients were classified as preserved-EF (PEF: LVEF ≥ 50%) and reduced-EF (REF: LVEF< 5 0%) group by echocardiography. Platelet reactivity was measured using VerifyNow P2Y12 assay and high platelet reactivity (HPR) was defined as PRU ≥ 252. The major adverse cardiac and cerebrovascular events (MACCEs) were a composite of death, myocardial infarction, stent thrombosis and stroke at 5 years after PCI. Major bleeding was defined as Bleeding Academic Research Consortium bleeding types 3-5. RESULTS: A total of 13,160 patients from PTRG-DES, 9,319 (79.6%) patients with the results of both PRU and LVEF were analyzed. The incidence of MACCE and major bleeding was higher in REF group as compared with PEF group (MACCEs: hazard ratio [HR] 2.17, P < 0.001, 95% confidence interval [CI] 1.85-2.55; major bleeding: HR 1.78, P < 0.001, 95% CI 1.39-2.78). The highest rate of MACCEs was found in patients with REF and HPR, and the difference between the groups was statistically significant (HR 3.14 in REF(+)/HPR(+) vs. PEF(+)/HPR(-) group, P < 0.01, 95% CI 2.51-3.91). The frequency of major bleeding was not associated with the HPR in either group. CONCLUSION: LV dysfunction was associated with an increased incidence of MACCEs and major bleeding in patients who underwent PCI. The HPR status further exhibited significant increase of MACCEs in patients with LV dysfunction in a large, real-world registry. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734028.
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Stents Farmacológicos , Intervenção Coronária Percutânea , Disfunção Ventricular Esquerda , Humanos , Volume Sistólico , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Função Ventricular Esquerda , Hemorragia/etiologiaAssuntos
Drenagem , Endossonografia , Piloro , Stents , Ultrassonografia de Intervenção , Humanos , Drenagem/métodos , Drenagem/instrumentação , Endossonografia/métodos , Stents/efeitos adversos , Pancreatite Necrosante Aguda/cirurgia , Pancreatite Necrosante Aguda/terapia , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Despite evidence showing higher fatality rates in freight-related crashes, there has been limited exploration of their spatial distribution and factors associated with such distribution. This gap in the literature primarily stems from the focus of existing studies on micro-level factors predicting the frequency or severity of injuries in freight crashes. The present study delves into the factors contributing to freight crashes at the neighborhood level, particularly focusing on different types of freight crashes: collisions involving a freight vehicle and a passenger vehicle, crashes between freight vehicles, and freight vehicle-non-motorized crashes. METHOD: This study analyzes traffic crash data from the urbanized region of Seoul, collected between 2016 and 2019. To effectively deal with spatial autocorrelation and model different types of crashes in a unified framework, a Bayesian multivariate conditional autoregressive model was employed. RESULTS: Findings show substantial differences in the factors associated with various types of freight crashes. The predictors for crashes between freight vehicles diverge significantly from those for freight vehicle-non-motorized crashes. Crashes between freight vehicles are relatively more influenced by road network structure, while freight crashes involving non-motorized users are relatively more affected by the built environment and freight facilities than the other crash types examined. Freight vehicle-passenger vehicle crashes fall into an intermediate category, sharing most predictors with either of the other two types of freight crashes. CONCLUSIONS AND PRACTICAL APPLICATIONS: The findings of this study offer valuable lessons for transportation practitioners and policymakers. They can guide the formulation of effective land use policies and infrastructure planning, specifically designed to address the unique characteristics of different types of freight crashes.
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Acidentes de Trânsito , Ambiente Construído , Humanos , Teorema de Bayes , Meios de Transporte , Análise EspacialRESUMO
Despite considerable increases in road freight traffic and associated crashes over the past decade, our understanding of their spatial distribution remains limited. This is concerning because freight vehicle crashes often lead to fatal and severe injuries. This study focuses on Seoul, South Korea and contributes to the literature by investigating the patterns and sources of spatial inequity in freight crashes. Specifically, it examines whether socioeconomically disadvantaged neighborhoods experience a higher concentration of freight crashes. Using the Gelbach's decomposition technique, this study also aims to identify the factors contributing to differences in freight crashes between disadvantaged and less-disadvantaged neighborhoods and quantify their relative contributions. The regression results show that severe freight crashes are more prevalent in disadvantaged neighborhoods before adjusting for other factors-a pattern not observed in non-severe crashes. The decomposition analysis reveals that the observed disparities in severe freight crashes between disadvantaged and less-disadvantaged neighborhoods are fully explained by differences in several neighborhood characteristics, including local road density, truck traffic volume density, proximity to logistics terminals, and off-road bicycle lane density, between neighborhood types. Interestingly, differences in built environment characteristics between neighborhood types not only fail to explain but instead counteract the disparities in severe freight crashes. The findings of this study suggest detailed policy implications for mitigating freight crash occurrences and addressing related spatial inequities.
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Acidentes de Trânsito , Acidentes de Trânsito/estatística & dados numéricos , Humanos , Análise Espacial , Fatores Socioeconômicos , Ambiente Construído/estatística & dados numéricos , Características da Vizinhança , República da Coreia/epidemiologia , Seul , Características de Residência/estatística & dados numéricos , Populações Vulneráveis/estatística & dados numéricos , Planejamento AmbientalRESUMO
The outstanding development in contemporary medicine, highlighted by percutaneous coronary intervention (PCI), was achieved through the adoption of drug-eluting stents (DESs). Although DES is the established therapy for patients undergoing PCI for de novo coronary artery disease (CAD), their drawbacks include restenosis, stent thrombosis, and the requirement for dual antiplatelet therapy (DAPT) with an uncertain duration regarding its optimality. Drug-coated balloon (DCB) treatment leaves nothing behind on the vessel wall, providing the benefit of avoiding stent thrombosis and not necessitating obligatory extended DAPT. After optimizing coronary blood flow, DCB treatment delivers an anti-proliferative drug directly coated on a balloon. Although more evidence is needed for the application of DCB treatment in de novo coronary lesions, recent studies suggest the safety and effectiveness of DCB treatment for diverse conditions including small and large vessel diseases, complex lesions like bifurcation lesions or diffuse or multivessel diseases, chronic total occlusion lesions, acute myocardial infarctions, patients at high risk of bleeding, and beyond. Consequently, we will review the current therapeutic choices for managing de novo CAD using DCB and assess the evidence supporting their concurrent application. Additionally, it aims to discuss future important perspectives.
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The dense granule protein of Toxoplasma gondii, inhibitor of signal transducer and activator of transcription 1 (IST) is an inhibitor of signal transducer and activator of transcription 1 (STAT1) transcriptional activity that binds to STAT1 and regulates the expression of inflammatory molecules in host cells. A sterile inflammatory liver injury in pathological acute liver failures occurs when excessive innate immune function, such as the massive release of IFN-γ and TNF-α, is activated without infection. In relation to inflammatory liver injury, we hypothesized that Toxoplasma gondii inhibitor of STAT1 transcription (TgIST) can inhibit the inflammatory response induced by activating the STAT1/IRF-1 mechanism in liver inflammation. This study used IFN-γ and TNF-α as inflammatory inducers at the cellular level of murine hepatocytes (Hepa-1c1c7) to determine whether TgIST inhibits the STAT1/IRF-1 axis. In stable cells transfected with TgIST, STAT1 expression decreased with a decrease in interferon regulatory factor (IRF)-1 levels. Furthermore, STAT1 inhibition of TgIST resulted in lower levels of NF-κB and COX2, as well as significantly lower levels of class II transactivator (CIITA), iNOS, and chemokines (CLXCL9/10/11). TgIST also significantly reduced the expression of hepatocyte proapoptotic markers (Caspase3/8/9, P53, and BAX), which are linked to sterile inflammatory liver injury. TgIST also reduced the expression of adhesion (ICAM-1 and VCAM-1) and infiltration markers of programmed death-ligand 1 (PD-L1) induced by hepatocyte and tissue damage. TgIST restored the cell apoptosis induced by IFN-γ/TNF-α stimulation. These results suggest that TgIST can inhibit STAT1-mediated inflammatory and apoptotic responses in hepatocytes stimulated with proinflammatory cytokines.
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Toxoplasma , Fator de Necrose Tumoral alfa , Animais , Camundongos , Fator de Transcrição STAT1/genética , Hepatócitos , Transdução de SinaisRESUMO
It is uncertain when the head collar and collar spines of Isthmiophora hortensis (Digenea: Echinostomatidae), a zoonotic echinostome species in Far Eastern Asia, develop during its larval stages. In this study, the appearance of the head collar and collar spines was studied using light and scanning electron microscopy in cercariae and metacercariae experimentally obtained from freshwater snails (Lymnaea pervia) and tadpoles (Rana nigromaculata), respectively. The cercariae were shed from the snail on day 30 after exposure to laboratory-hatched miracidia. Metacercariae were obtained from the experimental tadpoles at 3, 6, 12, 15, 20, 24, 26, and 30 h after exposure to the cercariae. The head collar was already visible in the cercarial stage, although its degree of development was weak. However, collar spines did not appear in the cercarial stage and even in the early metacercarial stage less than 24 h postinfection in tadpoles. Collar spines became visible in the metacercariae when they grew older than 24 h. It was concluded that the head collar of I. hortensis developed early in the cercarial stage, but the development of collar spines did not occur until the worms became 24-h-old metacercariae in our experimental setting. Counting the number of collar spines was concluded as an unfeasible diagnostic method for I. hortensis cercariae when they are shed from the snail host.
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Echinostomatidae , Trematódeos , Animais , Larva , Cercárias , Ásia OrientalRESUMO
L-type voltage-gated calcium channels (L-VGCCs) are thought to be involved in epileptogenesis and acute excitotoxicity. However, little is known about the role of L-VGCCs in neuroinflammation or delayed neuronal death following excitotoxic insult. We examined the effects of repeated treatment with the L-VGCC blocker nimodipine on neuroinflammatory changes and delayed neuronal apoptosis in the dentate gyrus following trimethyltin (TMT)-induced convulsions. Male C57BL/6 N mice were administered TMT (2.6 mg/kg, i.p.), and the expression of the Cav1.2 and Cav1.3 subunits of L-VGCC were evaluated. The expression of both subunits was significantly decreased; however, the astroglial expression of Cav1.3 L-VGCC was significantly induced at 6 and 10 days after TMT treatment. Furthermore, astroglial Cav1.3 L-VGCCs colocalized with both the pro-inflammatory phenotype marker C3 and the anti-inflammatory phenotype marker S100A10 of astrocytes. Nimodipine (5 mg/kg, i.p. × 5 at 12-h intervals) did not significantly affect TMT-induced astroglial activation. However, nimodipine significantly attenuated the pro-inflammatory phenotype changes, while enhancing the anti-inflammatory phenotype changes in astrocytes after TMT treatment. Consistently, nimodipine reduced the levels of pro-inflammatory astrocytes-to-microglia mediators, while increasing the levels of anti-inflammatory astrocytes-to-microglia mediators. These effects were accompanied by an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), supporting our previous finding that p-ERK is a signaling factor that regulates astroglial phenotype changes. In addition, nimodipine significantly attenuated TMT-induced microglial activation and delayed apoptosis of dentate granule neurons. Our results suggest that L-VGCC blockade attenuates neuroinflammation and delayed neurotoxicity following TMT-induced convulsions through the regulation of astroglial phenotypic changes by promoting ERK signaling.
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Introduction: In this study, we aimed to comparatively analyse the indicators of availability to orphan drugs in South Korea, the United States of America, Europe Union, and Japan. Methods: For 169 drugs designated as orphan drugs in South Korea between 2012 and 2021, information on the drugs designated as orphan drugs from each jurisdiction was extracted by country. Then, the availability indicators (approval time, drug lag time, and designation gap) were analysed for the drugs approved in each jurisdiction. Results: The approval rate of drugs designated as orphan drugs were 11.22% and 6.31% in the USA and EU, respectively, which was lower than that of orphan drugs in South Korea and Japan. The highest number of approved drugs was in the USA (87 drugs), EU 27 drugs, Japan 22 drugs and Korea 21 drugs. Furthermore, the approval time significantly differed between South Korea and the other countries. South Korea had a significantly different drug lag time and designation gap compared with the USA and EU. Conclusion: Our findings show that to fundamentally improve the access to treatments for rare disease, a policy of regulatory science that can comprehensively support the early stages of research and development and commercialisation is needed.
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Background: Percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) for chronic total coronary occlusions (CTOs) improves clinical symptoms and quality of life. However, data on drug-coated balloon (DCB)-based PCI in CTO lesions are limited. Methods: A total of 200 patients were successfully treated for CTO lesions, either with DCB alone or in combination with DES (DCB-based PCI). They were compared with 661 patients who underwent second-generation DES implantation for CTO from the PTRG-DES registry (DES-only PCI). The endpoint was major adverse cardiovascular events (MACEs), which included a composite of cardiac death, myocardial infarction, stent or target lesion thrombosis, target vessel revascularization, and major bleeding at 2 years. Results: In the DCB-based PCI group, 49.0% of patients were treated with DCB only and 51.0% underwent the hybrid approach combining DCB with DES. Bailout stenting was performed in seven patients (3.5%). The DCB-based PCI group exhibited fewer stents (1.0; IQR: 0.0-1.0 and 2.0; IQR: 1.0-3.0, p < 0.001), shorter stent lengths (6.5 mm; IQR: 0.0-38.0 mm and 42.0 mm; IQR: 28.0-67.0 mm, p < 0.001), and lower usage of small stents with a diameter of 2.5 mm or less (9.8% and 36.5%, p < 0.001). Moreover, the DCB-based PCI group had a lower rate of MACEs than the DES-only PCI group (3.1% and 13.2%, p = 0.001) at 2-year follow-up. Conclusions: The DCB-based PCI approach significantly reduced the stent burden, particularly in the usage of small stent diameters, and resulted in a lower risk of MACEs compared to DES-only PCI in CTO lesions.
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OBJECTIVES: Data on side-branch (SB) ostial effect after drug-coated balloon (DCB) treatment in the context of de novo coronary bifurcation lesions are limited. We aimed to investigate the angiographic outcomes of SB ostium after DCB treatment compared with drug-eluting stents (DESs) implantation in the main vessel (MV) or optimal medical therapy (OMT) for the treatment of de novo coronary bifurcation lesions. METHODS: Serial angiographic changes in the SB ostium were compared between DCB, DES, and medication alone for MV treatment. Δ value was calculated by subtracting the follow-up value from the pre-procedure value. RESULTS: A total of 132 bifurcation lesions were included for analysis (44 lesions in DCB group; 38 lesions in DES group; 50 lesions in OMT group). The minimal lumen diameter (MLD) of SB ostium showed an increase at follow-up in the DCB group, whereas a decrease was observed in both the DES and OMT groups (ΔMLD: -0.16 ± 0.45 mm for DCB group vs. 0.50 ± 0.52 mm for DES group vs. 0.08 ± 0.38 mm for OMT group, p < 0.001). The diameter stenosis (DS) of SB ostium showed a marked decrease at follow-up in the DCB group, in contrast to an increase observed in both the DES and OMT groups (ΔDS: 8.01 ± 18.96% for DCB group vs. -18.68 ± 18.60% for DES group vs. -2.05 ± 14.58% for OMT group, p < 0.001). CONCLUSIONS: In de novo coronary bifurcation lesions, DCB treatment on the MV demonstrated favorable angiographic outcomes in the SB ostium at 6-9 month follow-up compared to DES implantation or OMT.
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Angioplastia Coronária com Balão , Angiografia Coronária , Stents Farmacológicos , Humanos , Stents Farmacológicos/efeitos adversos , Masculino , Feminino , Angiografia Coronária/métodos , Pessoa de Meia-Idade , Idoso , Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Resultado do Tratamento , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologiaRESUMO
Cellulose nanocrystal is a nanomaterial that has a large specific surface area, high surface energy, and high strength. As well, it is biocompatible, environmentally friendly, nontoxic, and can be extracted from biomass resources. Because of these features, cellulose nanocrystals can be used to improve the mechanical properties of polymer matrices with a shape memory effect and as a shape memory switch. In this study, a polytrimethylene ether glycol-based thermoplastic polyurethane (TPU)/cellulose nanocrystal (CNC) composite was prepared via an in-situ polymerization process to create a self-healing polymer matrix. Also, the effect of CNC doses in low concentrations (≤2â¯wt%) on the different properties of the resulting bio-nanocomposite was investigated. The results showed that the introduction of CNCs affects the hydrogen bonding within the polymer matrix and provides better thermal stability in the high temperature range than pure TPU. Furthermore, the samples with 0â¯wt%, 0.75â¯wt%, 1â¯wt%, and 2â¯wt% of CNC exhibited an increasing trend in tensile strength with values of 11.71â¯MPa, 18.95â¯MPa, 17.88â¯MPa, and 26.18â¯MPa, respectively, which indicates a remarkable improvement in mechanical strength. The shape memory behavior was also notably prominent in this polymer composite, where the composite containing 2â¯wt% of CNC showed the fastest recovery time (240â¯s) at 75⯰C with the highest shape retention. Moreover, their flow behavior and deformation capacity were examined through rheology tests. Besides, docking simulations were conducted in silico to assess the interaction of the TPU/CNC composite with the DNA gyrase enzyme. The interaction between CNC/TPU composite and DNA gyrase was meticulously analyzed across 10 distinct conformations, yielding docking scores ranging from -6.5â¯Kcal/mol to -5.3â¯Kcal/mol. Overall, the physico-mechanical properties of the TPU/CNC composites were substantially enhanced with the incorporation of nanofillers.
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OBJECTIVES: Currently, no approved stem cell-based therapies for preserving ovarian function during aging. To solve this problem, we developed a long-term treatment for human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs). We investigated whether the cells retained their ability to resist ovarian aging, which leads to delayed reproductive senescence. MATERIALS AND METHODS: In a middle-aged female model undergoing natural aging, we analyzed whether hESC-MPCs benefit the long-term maintenance of reproductive fecundity and ovarian reservoirs and how their transplantation regulates ovarian function. RESULTS: The number of primordial follicles and mice with regular estrous cycles were increased in perimenopausal mice who underwent multiple introductions of hESC-MPCs compared to age-matched controls. The estradiol levels in the hESC-MPCs group were restored to those in the young and adult groups. Embryonic development and live birth rates were higher in the hESC-MPC group than in the control group, suggesting that hESC-MPCs delayed ovarian senescence. In addition to their direct effects on the ovary, multiple-treatments with hESC-MPCs reduced ovarian fibrosis by downregulating inflammation and fibrosis-related genes via the suppression of myeloid-derived suppressor cells (MDSCs) produced in the bone marrow. CONCLUSIONS: Multiple introductions of hESC-MPCs could be a useful approach to prevent female reproductive senescence and that these cells are promising sources for cell therapy to postpone the ovarian aging and retain fecundity in perimenopausal women.
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Células-Tronco Embrionárias Humanas , Células-Tronco Mesenquimais , Adulto , Gravidez , Pessoa de Meia-Idade , Feminino , Humanos , Animais , Camundongos , Perimenopausa , Fertilidade , Envelhecimento , FibroseRESUMO
BACKGROUND: The liver fluke Clonorchis sinensis imports large amounts of glucose to generate energy and metabolic intermediates through glycolysis. We hypothesized that C. sinensis absorbs glucose through glucose transporters and identified four subtypes of glucose transporter (CsGTP) and one sodium glucose co-transporter (CsSGLT) in C. sinensis. METHODOLOGY/PRINCIPAL FINDINGS: Expressed sequence tags encoding CsGTPs were retrieved from the C. sinensis transcriptome database, and their full-length cDNA sequences were obtained by rapid amplification of cDNA ends (RACE). The tissue distribution of glucose transporters in C. sinensis adults was determined using immunohistochemical staining. Developmental expression was measured using RT-qPCR. The transport and distribution of glucose into living C. sinensis were monitored using confocal microscopy. Membrane topology and key functional residues of CsGTPs were homologous to their counterparts in animals and humans. CsGTP1, 2, and 4 were transcribed 2.4-5.5 times higher in the adults than metacercariae, while CsGTP3 was transcribed 2.1 times higher in the metacercariae than adults. CsSGLT transcription was 163.6 times higher in adults than in metacercariae. In adults, CsSGLT was most abundant in the tegument; CsGTP3 and CsSGLT were localized in the vitelline gland, uterine wall, eggs, mesenchymal tissue, and testes; CsGTP4 was found in sperm and mesenchymal tissue; and CsGTP1 was mainly in the sperm and testes. In C. sinensis adults, exogenous glucose is imported in a short time and is present mainly in the middle and posterior body, in which the somatic and reproductive organs are located. Of the exogenous glucose, 53.6% was imported through CsSGLT and 46.4% through CsGTPs. Exogenous glucose import was effectively inhibited by cytochalasin B and phlorizin. CONCLUSIONS/SIGNIFICANCE: We propose that CsSGLT cooperates with CsGTPs to import exogenous glucose from the environmental bile, transport glucose across mesenchymal tissue cells, and finally supply energy-demanding organs in C. sinensis adults. Studies on glucose transporters may pave the way for the development of new anthelmintic drugs.
Assuntos
Clonorchis sinensis , Proteínas Facilitadoras de Transporte de Glucose , Glucose , Proteínas de Transporte de Sódio-Glucose , Animais , Clonorchis sinensis/metabolismo , Clonorchis sinensis/genética , Glucose/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Proteínas de Transporte de Sódio-Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Clonorquíase/parasitologia , Transporte BiológicoRESUMO
Cellular senescence, a hallmark of aging, is pathogenically linked to the development of aging-related diseases. This study demonstrates that FRMD6, an upstream component of the Hippo/YAP signaling cascade, is a key regulator of senescence. Proteomic analysis revealed that FRMD6 is upregulated in senescent IMR90 fibroblasts under various senescence-inducing conditions. Silencing FRMD6 mitigated the senescence of IMR90 cells, suggesting its requirement in senescence. Conversely, the overexpression of FRMD6 alone induced senescence in cells and in lung tissue, establishing a causal link. The elevated FRMD6 levels correlated well with increased levels of the inhibitory phosphorylated YAP/TAZ. We identified cellular communication network factor 3 (CCN3), a key component of the senescence-associated secretory phenotype regulated by YAP, whose administration attenuated FRMD6-induced senescence in a dose-dependent manner. Mechanistically, FRMD6 interacted with and activated MST kinase, which led to YAP/TAZ inactivation. The expression of FRMD6 was regulated by the p53 and SMAD transcription factors in senescent cells. Accordingly, the expression of FRMD6 was upregulated by TGF-ß treatment that activates those transcription factors. In TGF-ß-treated IMR90 cells, FRMD6 mainly segregated with p21, a senescence marker, but rarely segregated with α-SMA, a myofibroblast marker, which suggests that FRMD6 has a role in directing cells towards senescence. Similarly, in TGF-ß-enriched environments, such as fibroblastic foci (FF) from patients with idiopathic pulmonary fibrosis, FRMD6 co-localized with p16 in FF lining cells, while it was rarely detected in α-SMA-positive myofibroblasts that are abundant in FF. In sum, this study identifies FRMD6 as a novel regulator of senescence and elucidates the contribution of the FRMD6-Hippo/YAP-CCN3 axis to senescence.
RESUMO
Concerns about dioxin-like compounds have increased; however, the monitoring of polychlorinated naphthalenes (PCNs) in food and the assessment of dietary intake remain limited. In this study, various foods were collected from Korean markets and analyzed for PCNs. Fishery products exhibited the highest mean concentration (48.0 pg/g ww) and toxic equivalent (TEQ) (0.0185 pg-TEQ/g ww). Agricultural products were the largest contributors (35.7%) to the total dietary intake of PCNTEQ, followed by livestock products (33.6%), fishery products (20.2%), and processed foods (10.5%). The mean intake of PCNTEQ for the Korean population was 0.901 pg-TEQ/day for males and 0.601 pg-TEQ/day for females. Generally, males and younger groups had higher daily intakes of PCNTEQ, but they did not exceed the tolerable weekly intakes. Nonetheless, it is important to manage potential health risks associated with PCNs and other dioxin-like compounds by identifying major food items contributing to PCN exposure and considering age and gender differences.