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Perfusion of porous scaffolds transports cells to the surface to yield cellular constructs for 3D models of disease and for tissue engineering applications. While ceramic scaffolds mimic the structure and composition of trabecular bone, their opacity and tortuous pores limit the penetration of light into the interior. Scaffolds that are both perfusable and amenable to fluorescence microscopy are therefore needed to visualize the spatiotemporal dynamics of cells in the bone microenvironment. In this study, a hybrid injection molding approach was designed to enable rapid prototyping of collector arrays with variable configurations that are amenable to longitudinal imaging of attached human mesenchymal stem cells (hMSCs) using fluorescence microscopy. Cylindrical collectors were arranged in an array that is permeable to perfusion in the xy-plane and to light in the z-direction for imaging from below. The effects of the collector radius, number, and spacing on the collection efficiency of perfused hMSCs was simulated using computational fluid dynamics (CFD) and measured experimentally using fluorescence microscopy. The effect of collector diameter on simulated and experimental cell collection efficiencies followed a trend similar to that predicted by interception theory corrected for intermolecular and hydrodynamic forces for the arrays with constant collector spacing. In contrast, arrays designed with constant collector number yielded collection efficiencies that poorly fit the trend with collector radius predicted by interception theory. CFD simulations of collection efficiency agreed with experimental measurements within a factor of two. These findings highlight the utility of CFD simulations and hybrid injection molding for rapid prototyping of collector arrays to optimize the longitudinal imaging of cells without the need for expensive and time-consuming tooling.
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The growth of two-dimensional (2D) van der Waals (vdW) magnetic materials presents attractive opportunities for exploring new physical phenomena and valuable applications. Among these materials, Fe3GeTe2(FGT) exhibits a variety of remarkable properties and has garnered significant attention. Herein, we have for the first time created a nanomesh structure-a honeycomb-like array of hexagonal nanopores-with the zigzag pore-edge atomic structure on thin FGT flakes with and without oxidation of the pore edges. It is revealed that the magnitude of ferromagnetism (FM) significantly increases in both samples compared with bulk flakes without nanomeshes. Critical temperature annealing results in the formation of zigzag pore edges and interpore zigzag-edge nanoribbons. We unveil that the non-oxide (O) termination of the Fe dangling bonds on these zigzag edges enhances FM behavior, while O-termination suppresses this FM by introducing antiferromagnetic behavior (AFM) through edge O-Fe coupling. FGT nanomeshes hold promise for the creation of strong FM and their effective application in magnetic and spintronic systems. .
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Objective: To investigate the factors affecting primary patency time in arteriovenous graft (AVG) patients receiving percutaneous transluminal balloon angioplasty (PTA). Methods: Hemodialysis patients who underwent AVG placement at the First Affiliated Hospital of Chongqing Medical University between February 2018 and December 2021 were included. The factors including age, gender, total duration of AVG use, site of stenosis, degree of stenosis, length of stenosis, residual stenosis, and presence of thrombosis were analyzed, and influencing factors of primary patency time in AVG were determined using a multiple linear regression model. Results: A total of 101 patients who underwent 331 PTA treatments were enrolled, including 35 males and 66 females. The median age of patients undergoing PTA for the first time was 61 (51, 68) years, and the primary patency time after PTA was 5 (3, 10) months. The patients were followed up for (38.5±15.3) months. Multivariable linear regression analysis revealed that severe stenosis at the venous anastomosis and reflux veins (ß=-2.773, 95%CI:-5.440--0.105, P=0.042), female (ß=-2.247, 95%CI:-3.853--0.642, P=0.006), and previous multiple PTA treatments (ß=-0.516, 95%CI:-0.978--0.054, P=0.029) were risk factors for a shorter primary patency time after PTA. Conclusion: Severity of stenosis at the venous anastomosis and reflux veins of the AVG, female, and a history of multiple previous PTA treatments are associated with a shorter primary patency time in AVG patients.
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Angioplastia de Balón , Derivación Arteriovenosa Quirúrgica , Diálisis Renal , Grado de Desobstrucción Vascular , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Oclusión de Injerto Vascular , Factores de Riesgo , Constricción PatológicaRESUMEN
TIAM Rac1 associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging, remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmarks expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor images analysis were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus-mPFC circuits, leading to age-related spatial memory impairment.
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Thrombocytopenia is one of the common complications of cirrhotic patients, which can induce an increasing bleeding risk and closely correlate with bleeding following invasive procedures. Consequently, how to respond to thrombocytopenia is crucial for improving the prognosis of patients with cirrhosis. This article reviews the main mechanisms of cirrhosis concurrent with thrombocytopenia, as well as the corresponding clinical management strategies.
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Cirrosis Hepática , Trombocitopenia , Humanos , Trombocitopenia/terapia , Trombocitopenia/etiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/terapiaRESUMEN
Objective: To construct a diabetes foot prediction model for adult patients with type 2 diabetes based on retrospective cohort study using data from a regional health data platform. Methods: Using Yinzhou Health Information Platform of Ningbo, adult patients with newly diagnosed type 2 diabetes from January 1, 2015 to December 31, 2022 were included in this study and divided randomly the train and test sets according to the ratio of 7â¶3. LASSO regression model and bidirectional stepwise regression model were used to identify risk factors, and model comparisons were conducted with net reclassification index, integrated discrimination improvement and concordance index. Univariate and multivariate Cox proportional hazard regression models were constructed, and a nomogram plot was drawn. Area under the curve (AUC) was calculated as a discriminant evaluation indicator for model validation test its calibration ability, and calibration curves were drawn to test its calibration ability. Results: No significant difference existed between LASSO regression model and bidirectional stepwise regression model, but the better bidirectional stepwise regression model was selected as the final model. The risk factors included age of onset, gender, hemoglobin A1c, estimated glomerular filtration rate, taking angiotensin receptor blocker and smoking history. AUC values (95%CI) of risk outcome prediction at year 5 and 7 were 0.700 (0.650-0.749) and 0.715(0.668-0.762) for the train set and 0.738 (0.667-0.801) and 0.723 (0.663-0.783) for the test set, respectively. The calibration curves were close to the ideal curve, and the model discrimination and calibration powers were both good. Conclusions: This study established a convenient prediction model for diabetic foot and classified the risk levels. The model has strong interpretability, good discrimination power, and satisfactory calibration and can be used to predict the incidence of diabetes foot in adult patients with type 2 diabetes to provide a basis for self-assessment and clinical prediction of diabetic foot disease risk.
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Diabetes Mellitus Tipo 2 , Pie Diabético , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Pie Diabético/epidemiología , Estudios Retrospectivos , Incidencia , Factores de Riesgo , Masculino , Femenino , Modelos de Riesgos Proporcionales , Nomogramas , Persona de Mediana Edad , Hemoglobina Glucada/análisis , AdultoRESUMEN
BACKGROUND: Dendritic spine dysfunction is a key feature of Alzheimer's disease (AD) pathogenesis. Human T-cell lymphoma invasion and metastasis 2 (TIAM2) is expressed in two isoforms, the full length (TIAM2L) and a short transcript (TIAM2S). Compared to TIAM2L protein, which is undetectable, TIAM2S protein is abundant in human brain tissue, especially the hippocampus, and can promote neurite outgrowth in our previous findings. However, whether enhanced hippocampal TIAM2S expression can alleviate cognitive deficits in Alzheimer's disease model mice remains unclear. METHODS: We crossbred 3xTg-AD with TIAM2S mice to generate an AD mouse model that carries the human TIAM2S gene (3xTg-AD/TIAM2S mice). The Morris water maze and object location tests assessed hippocampus-dependent spatial memory. Lentiviral-driven shRNA or cDNA approaches were used to manipulate hippocampal TIAM2S expression. Golgi staining and Sholl analysis were utilized to measure neuronal dendrites and dendritic spines in the mouse hippocampi. RESULTS: Compared to 3xTg-AD mice, 3xTg-AD/TIAM2S mice displayed improved cognitive functions. According to the hippocampus is one of the earliest affected brain regions by AD, we further injected TIAM2S shRNA or TIAM2S cDNA into mouse hippocampi to confirm whether manipulating hippocampal TIAM2S expression could affect AD-related cognitive functions. The results showed that the reduced hippocampal TIAM2S expression in 3xTg-AD/TIAM2S mice abolished the memory improvement effect, whereas increased hippocampal TIAM2S levels alleviated cognitive deficits in 3xTg-AD mice. Furthermore, we found that TIAM2S-mediated memory improvement was achieved by regulating dendritic plasticity. CONCLUSIONS: These results will provide new insights into connecting TIAM2S with AD and support the notion that TIAM2S should be investigated as potential AD therapeutic targets.
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Objective: To evaluate the efficacy and safety of CD30 antibody-drug conjugates (ADC) brentuximab vedotin (BV) combined with chemotherapy in children with refractory or relapsed classic Hodgkin's lymphoma (R/R cHL). Methods: Clinical data (including age, gender, B symptoms, clinical stage, previous treatment, etc.) of the 10 R/R cHL children diagnosed and treated at Beijing Children's Hospital Affiliated to Capital Medical University from October 2021 to August 2023 were analyzed retrospectively. According to the different intensity of chemotherapy drugs, the dose of BV applied in the same course of treatment was 1.8 mg/kg for BV applied once every 3 weeks, and 1.2 mg/kg for BV applied once every 2 weeks. All 10 patients received at least 2 cycles of BV combined with chemotherapy and were evaluated every 2 cycles. The patients were followed up until May 31, 2024. The infusion reactions and adverse reactions after treatment were recorded. Results: In all 10 patients, there were 7 males and 3 females, the age ranged from 5.3-16.9 years, and there were 6 cases of refractory and 4 cases of relapsed. There were 6 cases of nodular sclerosis type, 2 cases of mixed cell type, 1 case of lymphocyte-rich type, and 1 case of lymphodepletion type. There were 5 cases of stage â £ and 5 cases of stage â ¢. Previous treatment was mainly chemotherapy, 4 cases received radiotherapy and 1 case received programmed cell death protein 1 (PD-1) antibody therapy. The follow-up time ranged from 9 to 27 months. A total of 43 courses with 49 doses of BV alone or combined with chemotherapy were recorded, and the number of courses was 2 to 10 times. All 10 children responded to the treatment, and 9 achieved complete remission. BV infusion was successfully completed in all cases. A total of 28 cases of grade 3 or above adverse events were recorded, mainly myelosuppression, all of which were related to chemotherapy and did not affect sequential treatment. Conclusion: Brentuximab vedotin has demonstrated efficacy and a tolerable safety profile in the treatment of refractory and relapsed CD30-positive Hodgkin's lymphoma in children.
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Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotina , Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Femenino , Masculino , Niño , Adolescente , Estudios Retrospectivos , Preescolar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento , Inmunoconjugados/administración & dosificaciónRESUMEN
Stereotactic Body Radiation Therapy for lung tumors near the chest wall often causes significant chest wall pain (CWP), negatively impacting patients' quality of life. The mechanisms behind SBRT-induced CWP remain unclear and may involve multiple factors. We investigated the potential crosstalk between radiation-activated osteoclasts and sensory neurons, focusing on osteoclast-derived factors in CWP. Using the murine pre-osteoclast cell line Raw264.7, we induced differentiation with RANKL, followed by 10Gy gamma-irradiation. Conditioned media from these irradiated osteoclasts was used to treat sensory neuronal cultures from mouse dorsal root ganglia. Neuronal cultures were also directly exposed to 10Gy radiation, with and without osteoclast co-culture. Analysis of osteoclast markers and pain-associated neuropeptides was conducted using RT-qPCR and histochemical staining. Osteoclast differentiation and activity were inhibited using Osteoprotegerin and risedronate. Results showed that high-dose radiation significantly increased osteoclast size, resorption pit size, and activity biomarkers. Neurons treated with CM from irradiated osteoclasts showed increased expression of pain-associated neuropeptides CGRP and Substance P, which was mitigated by osteoprotegerin and risedronate. This study suggests that high-dose radiation enhances osteoclast activity, upregulating pain-associated neuropeptides in sensory neurons, and that inhibitors like osteoprotegerin and risedronate may offer therapeutic strategies for managing radiation-induced pain.
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Echinococcosis is a common zoonotic disease in livestock; the type with the highest incidence is cystic echinococcosis (CE). In clinical management, patients with CE of the liver in which the cyst wall is calcified have been found to have better prognoses than those without calcification. In this study, we collected calcified and uncalcified cyst wall tissue from patients with hepatic CE and observed significant changes in the expression of 2336 messenger ribonucleic acids (mRNAs), 178 long noncoding RNAs (lncRNAs), 210 microRNAs (miRNAs), and 33 circular RNAs (circRNAs) using high-throughput sequencing (HTS). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of differentially expressed RNAs (DERNAs: DEmRNAs, DElncRNAs, DEmiRNAs, and DEcircRNAs) were performed to explore these RNAs' potential biological functions and signaling pathways. Ultimately, the results of hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining confirmed the correlation between calcification and apoptosis of the cyst wall. In summary, this study was an initial exploration of the molecular-biological mechanism underlying spontaneous calcification of the hydatid cyst wall, and it provides a theoretical basis for exploring new targets for drug treatment in CE.
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Biología Computacional , Humanos , Calcinosis/genética , Calcinosis/parasitología , Transcriptoma , Equinococosis/parasitología , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Masculino , MicroARNs/genética , Equinococosis Hepática/parasitología , Adulto , Femenino , Persona de Mediana Edad , ARN Circular/genéticaRESUMEN
BACKGROUND: Relationships of fish-shellfish consumption, cognitive health and mortality from Alzheimer's disease (AD) among US adults aged 60 years and older have not been adequately studied. OBJECTIVES: To determine the relationship of fish-shellfish consumption, cognitive health and mortality from AD in US adults aged 60 years and older. DESIGN, SETTING AND PARTICIPANTS: The data of this cross-sectional study of US adults aged 60 years and older were from the National Nutrition and Health Examination Survey (NHANES) datasets. Frequency of fish-shellfish consumption, its association with subjective cognitive decline (SCD) and AD mortality of these participants between 1999 and 2018 and cognitive assessment scores between 2011 and 2014 were analyzed. MEASUREMENTS AND RESULTS: US adults aged 60 years and older consumed fish-shellfish 1.2 times/week and had a blood Hg of 1.63 ug/L on average between 1999 and 2018. Participants aged 60 years and older in the highest quartile of fish-shellfish consumption (~3 times/week) had significantly higher cognitive assessment scores than those in the lowest quartile (rare or no fish-shellfish consumption). Adults in the highest quartile of fish-shellfish consumption had a 30% lower risk (odds ratio 0.7, 95%CI 0.57-0.87) of SCD, and 44% lower risk (hazard ratio 0.56, 95%CI 0.35-0.9) of AD mortality than those in the lowest quartile. CONCLUSION: Increased fish-shellfish consumption was associated with improved scores of cognitive assessment and reduced risks of SCD and AD mortality.
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Enfermedad de Alzheimer , Encuestas Nutricionales , Mariscos , Humanos , Enfermedad de Alzheimer/mortalidad , Anciano , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Estados Unidos/epidemiología , Cognición/fisiología , Alimentos Marinos , Peces , Animales , Disfunción Cognitiva/mortalidad , Disfunción Cognitiva/epidemiología , Dieta , Anciano de 80 o más AñosRESUMEN
Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.
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Dasatinib , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , China , Dasatinib/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Pirimidinas/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , /uso terapéuticoRESUMEN
AIM: To assess whether adults with diabetes on oral hypoglycaemic agents undergoing general endotracheal anaesthesia during nine common surgical procedures who are glucagon-like peptide-1 receptor agonist (GLP1-RA) users, compared with non-users, are at increased risk of six peri- and post-procedure complications. MATERIALS AND METHODS: A retrospective observational cohort analysis of over 130 million deidentified US adults with diabetes (defined as being on oral hypoglycaemic agents) from a nationally representative electronic health dataset between 1 January 2015 and 1 April 2023 was analysed. Cohorts were matched by high-dimensionality propensity scoring. We compared the odds of six peri- and postoperative complications in GLP1-RA users and non-users. A sensitivity analysis compared these odds in GLP1-RA users to non-users with diabetes and obesity. We measured the odds of (a) a composite outcome of postoperative decelerated gastric emptying, including antiemetic use, ileus within 7 days post-procedure, gastroparesis diagnosis, gastric emptying study; (b) postoperative aspiration or pneumonitis; (c) severe respiratory failure; (d) postoperative hypoglycaemia; (e) inpatient mortality; and (f) 30-day mortality. RESULTS: Among 13 361 adults with diabetes, 16.5% were treated with a GLP1-RA. In the high-dimensionality propensity score-matched cohort, GLP1-RA users had a lower risk of peri- and postoperative complications for decelerated gastric emptying and antiemetic use compared with non-users. The risk of ileus within 7 days, aspiration/pneumonitis, hypoglycaemia and 30-day mortality were not different. A sensitivity analysis showed similar findings in patients with diabetes and obesity. CONCLUSION: No increased risk of peri- and postoperative complications in GLP1-RA users undergoing surgery with general endotracheal anaesthesia was identified.
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Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Persona de Mediana Edad , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Anciano , Adulto , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Factores de Riesgo , Complicaciones Intraoperatorias/inducido químicamente , Complicaciones Intraoperatorias/epidemiología , Estudios de Cohortes , Agonistas Receptor de Péptidos Similares al GlucagónAsunto(s)
Hepatitis B Crónica , Hepatitis B , Complicaciones Infecciosas del Embarazo , Embarazo , Femenino , Humanos , Hepatitis B Crónica/prevención & control , Hepatitis B Crónica/tratamiento farmacológico , Antivirales/uso terapéutico , Virus de la Hepatitis B , Hepatitis B/tratamiento farmacológico , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Complicaciones Infecciosas del Embarazo/prevención & control , Complicaciones Infecciosas del Embarazo/tratamiento farmacológicoRESUMEN
Prediabetes is an intermediate state of glucose homeostasis whereby plasma glucose concentrations are above normal but below the threshold of diagnosis for diabetes. Over the last several decades, criteria for prediabetes have changed as the cut points for normal glucose concentration and diagnosis of diabetes have shifted. Global consensus does not exist for prediabetes criteria; as a result, the clinical course and risk for type 2 diabetes vary. At present, we can identify individuals with prediabetes based on three glycemic tests (hemoglobin A1c, fasting plasma glucose, and 2-h plasma glucose during an oral glucose tolerance test). The majority of individuals diagnosed with prediabetes meet only one of these criteria. Meeting one, two, or all glycemic criteria changes risk for type 2 diabetes, but this information is not widely known and does not currently guide intervention strategies for individuals with prediabetes. This review summarizes current epidemiology, prognosis, and intervention strategies for individuals diagnosed with prediabetes and suggests a call for more precise risk stratification of individuals with prediabetes as elevated (one prediabetes criterion), high risk (two prediabetes criteria), and very high risk (three prediabetes criteria). In addition, the roles of oral glucose tolerance testing and continuous glucose monitoring in the diagnostic criteria for prediabetes need reassessment. Finally, we must reframe our goals for prediabetes and prioritize intensive interventions for those at high and very high risk for type 2 diabetes.
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Glucemia , Diabetes Mellitus Tipo 2 , Prueba de Tolerancia a la Glucosa , Estado Prediabético , Humanos , Estado Prediabético/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Medición de Riesgo , Glucemia/metabolismo , Glucemia/análisis , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Factores de Riesgo , PronósticoRESUMEN
OBJECTIVE: To investigate the effect of asiaticoside on blood pressure and relaxation of thoracic aorta in rats and explore the underlying mechanism. METHODS: SD rats treated with 50 and 100 mg/kg asiaticoside by daily gavage for 2 weeks were monitored for systolic blood pressure changes, and histological changes of the thoracic aorta were evaluated using HE staining. In isolated rat endothelium-intact and endothelium-denuded thoracic aorta rings, the effects of asiaticoside on relaxation of the aortic rings were tested at baseline and following norepinephrine (NE)- and KCl-induced constriction. The vascular relaxation effect of asiaticoside was further observed in NE-stimulated endothelium-intact rat aortic rings pretreated with L-nitroarginine methyl ester, indomethacin, zinc protoporphyrin â ¨, tetraethyl ammonium chloride, glibenclamide, barium chloride, Iberiotoxin, 4-aminopyridine, or TASK-1-IN-1. The aortic rings were treated with KCl and NE followed by increasing concentrations of CaCl2 to investigate the effect of asiaticoside on vasoconstriction induced by external calcium influx and internal calcium release. RESULTS: Asiaticoside at 50 and 100 mg/kg significantly lowered systolic blood pressure in rats without affecting the thoracic aorta histomorphology. While not obviously affecting resting aortic rings with intact endothelium, asiaticoside at 100 mg/kg induced significant relaxation of the rings constricted by KCl and NE, but its effects differed between endothelium-intact and endothelium-denuded rings. In endothelium-intact aortic rings pretreated with indomethacin, ZnPP â ¨, barium chloride, glyburide, TASK-1-IN-1 and 4-aminopyridine, asiaticoside did not produce significant effect on NE-induced vasoconstriction, and tetraethylammonium, Iberiotoxin and L-nitroarginine methyl ester all inhibited the relaxation effect of asiaticoside. In KCland NE-treated rings, asiaticoside obviously inhibited CaCl2-induced vascular contraction. CONCLUSION: Asiaticoside induces thoracic aorta relaxation by mediating high-conductance calcium-activated potassium channel opening, promoting nitric oxide release from endothelial cells and regulating Ca2+ influx and outflow, thereby reducing systolic blood pressure in rats.
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Aorta Torácica , Compuestos de Bario , Cloruros , Triterpenos , Vasodilatación , Ratas , Animales , Presión Sanguínea , Células Endoteliales , Calcio , Cloruro de Calcio/farmacología , Nitroarginina/farmacología , Ratas Sprague-Dawley , 4-Aminopiridina/farmacología , Indometacina/farmacología , Ésteres/farmacología , Endotelio Vascular , Relación Dosis-Respuesta a DrogaRESUMEN
Objective: To investigate the effects of Porphyromonas gingivalis derived outer membrane vesicles (Pg OMV) on osteoclast differentiation of macrophages and its underlying mechanisms. Methods: The morphology and the size distribution of Pg OMV were analyzed by transmission electron microscopy and nanoparticle tracing analysis, respectively. The osteoclast precursors were treated with 1, 3 and 10 mg/L Pg OMV (1, 3 and 10 mg/L OMV treatment group) or phosphate buffer solution (PBS)(control group). The formation of osteoclasts was analyzed by tartrate-resistant acid phosphase (TRAP) staining and F-actin staining and real-time quantitative PCR (RT-qPCR) were used to detect the expression of Fos and matrix metallopeptidase 9 (MMP9). Polymyxin B (PMB) was used to block lipopolysaccharide (LPS) and then Pg OMV was used to treat osteoclast precursor (PMB-OMV treatment group), and OMV treatment group was used as control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The effect of Pg OMV on the expression of Toll-like receptor (TLR) 2 and TLR4 in preosteoclasts was detected by Western blotting. The osteoclast precursors were pretreated with 10, 50, 100 and 200 µmol/L C29, an inhibitor of TLR2, and then treated with Pg OMV(OMV+10, 50, 100 and 200 µmol/L C29 treatment group) and OMV treatment group without C29 pretreatment was control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The osteoclast precursor cells were treated with OMV (OMV treatment group) and OMV incubated with PMB (PMB-OMV treatment group) and the expression of TLR2 in osteoclast precursor was detected by Western blotting. Results: Pg OMV showed classical vesicular structures, and the average particle size of Pg OMV were 179.2 nm. A large number of actin rings were observed in the 3 and 10 mg/L OMV treatment groups. The percentages of TRAP-positive osteoclast area in 3 mg/L OMV treatment group [(22.6±2.1)%] and 10 mg/L OMV treatment group [(32.0±2.3)%] were significantly increased compared with control group [(4.9±0.5)%] (P<0.001). Compared with the control group (1.000±0.029), the mRNA relative expression of Fos in 3 mg/L OMV treatment group (1.491±0.114) and 10 mg/L OMV treatment group (1.726±0.254) was significantly increased (P=0.013, P=0.001). Compared with the control group (1.007±0.148), the mRNA relative expression of MMP9 in the group of 10 mg/L OMV (2.232±0.097) was significantly increased (P<0.001). Actin ring formation was less in PMB-OMV treatment groups than in OMV treatment groups. The proportion of TRAP-positive osteoclasts area [(14.8±3.8)%] in PMB-OMV treatment group was significantly lower than OMV treatment group [(31.5±6.7) %] (P=0.004). The relative expression of TLR2 in OMV treatment group (1.359±0.134) was significantly higher than that in the control group (1.000±0.000) (t=4.62, P=0.044). Compared with the OMV treatment group [(29.4±1.7)%], 50, 100 and 200 µmol/L C29 significantly decreased the formation of osteoclasts [(24.0±1.7)%, (18.5±2.1)%, (9.1±1.3) %] (P=0.026, P<0.001, P<0.001). TLR2 protein expression in PMB-OMV group (0.780±0.046) was significantly lower than that in OMV group (1.000±0.000)(t=8.32, P=0.001). Conclusions: Pg OMV can promote osteoclast differentiation by carrying LPS, TLR2 plays an important role in Pg OMV mediated osteoclast differentiation.
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Lipopolisacáridos , Osteoclastos , Lipopolisacáridos/farmacología , Porphyromonas gingivalis/química , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Actinas/metabolismo , Actinas/farmacología , Metaloproteinasa 9 de la Matriz/metabolismo , ARN Mensajero/metabolismo , Diferenciación CelularRESUMEN
STUDY QUESTION: Do embryos with longer telomere length (TL) at the blastocyst stage have a higher capacity to survive after frozen-thawed embryo transfer (FET)? SUMMARY ANSWER: Digitally estimated TL using low-pass whole genome sequencing (WGS) data from the preimplantation genetic testing for aneuploidy (PGT-A) process demonstrates that blastocyst TL is the most essential factor associated with likelihood of implantation. WHAT IS KNOWN ALREADY: The lifetime TL is established in the early cleavage cycles following fertilization through a recombination-based lengthening mechanism and starts erosion beyond the blastocyst stage. In addition, a telomerase-mediated slow erosion of TL in human fetuses has been observed from a gestational age of 6-11 weeks. Finally, an abnormal shortening of telomeres is likely involved in embryo loss during early development. STUDY DESIGN SIZE DURATION: Blastocyst samples were obtained from patients who underwent PGT-A and FET in an IVF center from March 2015 to May 2018. Digitally estimated mitochondrial copy number (mtCN) and TL were used to study associations with the implantation potential of each embryo. PARTICIPANTS/MATERIALS SETTING AND METHODS: In total, 965 blastocysts from 232 cycles (164 patients) were available to investigate the biological and clinical relevance of TL. A WGS-based workflow was applied to determine the ploidy of each embryo. Data from low-pass WGS-PGT-A were used to estimate the mtCN and TL for each embryo. Single-variant and multi-variant logistic regression, decision tree, and random forest models were applied to study various factors in association with the implantation potential of each embryo. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 965 blastocysts originally available, only 216 underwent FET. While mtCN from the transferred embryos is significantly associated with the ploidy call of each embryo, mtCN has no role in impacting IVF outcomes after an embryo transfer in these women. The results indicate that mtCN is a marker of embryo aneuploidy. On the other hand, digitally estimated TL is the most prominent univariant factor and showed a significant positive association with pregnancy outcomes (P < 0.01, odds ratio 79.1). We combined several maternal and embryo parameters to study the joint effects on successful implantation. The machine learning models, namely decision tree and random forest, were trained and yielded classification accuracy of 0.82 and 0.91, respectively. Taken together, these results support the vital role of TL in governing implantation potential, perhaps through the ability to control embryo survival after transfer. LIMITATIONS REASONS FOR CAUTION: The small sample size limits our study as only 216 blastocysts were transferred. The number was further reduced to 153 blastocysts, where pregnancy outcomes could be accurately traced. The other limitation of this study is that all data were collected from a single IVF center. The uniform and controlled operation of IVF cycles in a single center may cause selection bias. WIDER IMPLICATIONS OF THE FINDINGS: We present novel findings to show that digitally estimated TL at the blastocyst stage is a predictor of pregnancy capacity after a FET cycle. As elective single-embryo transfer has become the mainstream direction in reproductive medicine, prioritizing embryos based on their implantation potential is crucial for clinical infertility treatment in order to reduce twin pregnancy rate and the time to pregnancy in an IVF center. The AI-powered, random forest prediction model established in this study thus provides a way to improve clinical practice and optimize the chances for people with fertility problems to achieve parenthood. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from the National Science and Technology Council, Taiwan (MOST 108-2321-B-006-013 -). There were no competing interests. TRIAL REGISTRATION NUMBER: N/A.
RESUMEN
Cross sections of the 54Fe(n,p)54Mn, 54Fe(n,α)51Cr, 56Fe(n,p)56Mn and 204Pb (n,2n)203Pb reactions induced by D-T neutrons were obtained with activation method and γ-ray spectrometry technique. Experimental values measured in this work are consistent with most of the previous literature data. These reactions cross sections were theoretically calculated by using the TALYS-1.96 and EMPIRE-3.2.3 codes from threshold up to 20 MeV, and significant discrepancies were found between calculated results and experiment data. In addition, experimental values are compared with evaluated nuclear data of the CENDL-3.2, ENDF/B-VIII.0, JENDL-5, BROND-3.1 and JEFF-3.3 libraries, and significant difference was found for the 54Fe(n,α)51Cr reaction in ENDF/B-VIII.0 library but not for other reactions.