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ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu Guizhi Decoction (CGD) has a long history of use in China for the treatment of influenza, which involves the use of a variety of aromatic herbs. Our previous studies have found that the contents of aromatic constituents in CGD affected the efficacy of treatment of influenza-infected mice, suggesting a clue that essential oil from CGD may play a relatively important role in ameliorating influenza induced pneumonia. AIM OF THE STUDY: To evaluate the anti-influenza potential of essential oil derived from Chaihu Guizhi Decoction (CGD-EO), to characterize and predict the key active components in CGD-EO, and to explore the mechanism of action of CGD-EO. MATERIALS AND METHODS: CGD-EO was obtained by steam distillation, and the components of the essential oil were characterized by gas chromatography-mass spectrometry (GC-MS) in conjunction with the retention index. The constituents absorbed into the blood of mice treated with CGD-EO were analyzed by headspace solid phase microextraction gas chromatography/mass spectrometry (HS-SPME-GC/MS). The potential anti-influenza active constituents and their possible action pathway were predicted by simulation using a network pharmacology approach. The protective effect of CGD-EO and its major components on H1N1/PR8-infected cells was determined using the CCK8 assay kit. Mice infected with influenza A virus H1N1/PR8 were administered different doses of CGD-EO orally and the body weights and lung weights were recorded. Mice with varying degrees of H1N1/PR8 infection were administered CGD-EO orally, and their daily weight, water consumption, and clinical indicators were recorded. Necropsies were conducted on days 3 and 5, during which lung weights were measured and lung tissues were preserved. Furthermore, the mRNA expression of the H1N1/PR8 virus and inflammatory factors in lung tissue was analyzed using RT-qPCR. RESULTS: (E)-cinnamaldehyde was the most abundant compound in the CGD-EO. The results of serum medicinal chemistry combined with network pharmacological analysis indicated that (E)-cinnamaldehyde and 3-phenyl-2-propenal may be potential active components of the CGD-EO anti-influenza, and may be involved in the NF-κB signalling pathway. In vitro studies have demonstrated that both CGD-EO and cinnamaldehyde exert a protective effect on MDCK cells infected with H1N1/PR8. In a 0.5 TCID50 H1N1/PR8-induced influenza model, mice treated with CGD-EO at a dose of 63.50 µg/kg exhibited a reduction in lung index, pathological lung lesions, and H1N1/PR8 viral gene levels. In addition, CGD-EO treatment was found to regulate the levels of inflammatory cytokines, including IL-6, TNF-α, and IFN-γ. Moreover, following three days of administration, an upregulation of NF-κB mRNA levels in mouse lung tissue was observed in response to CGD-EO treatment. CONCLUSIONS: The findings of our study indicate CGD-EO exerts a protective effect against H1N1-induced cytopathic lesions in vitro and is capable of alleviating H1N1-induced pneumonitis in mice. Moreover, it appears to be more efficacious in the treatment of mild symptoms of H1N1 infection. Studies have demonstrated that CGD-EO has antiviral potential to attenuate influenza-induced lung injury by modulating inflammatory cytokines and NF-κB signalling pathways during the early stages of influenza infection. It is possible that (E)-cinnamaldehyde is a potential active ingredient in the anti-influenza efficacy of CGD-EO.

Asunto(s)

Antivirales , Medicamentos Herbarios Chinos , Aceites Volátiles , Infecciones por Orthomyxoviridae , Animales , Aceites Volátiles/farmacología , Medicamentos Herbarios Chinos/farmacología , Ratones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Antivirales/farmacología , Ratones Endogámicos BALB C , Neumonía Viral/tratamiento farmacológico , Masculino , Células de Riñón Canino Madin Darby , Perros , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Pulmón/metabolismo , Humanos , Femenino , Neumonía/tratamiento farmacológico , Neumonía/virología , Neumonía/metabolismo

RESUMEN

BACKGROUND: Hand function assessment heavily relies on specific task scenarios, making it challenging to ensure validity and reliability. In addition, the wide range of assessment tools, limited and expensive data recording, and analysis systems further aggravate the issue. However, smartphones provide a promising opportunity to address these challenges. Thus, the built-in, high-efficiency sensors in smartphones can be used as effective tools for hand function assessment. OBJECTIVE: This review aims to evaluate existing studies on hand function evaluation using smartphones. METHODS: An information specialist searched 8 databases on June 8, 2023. The search criteria included two major concepts: (1) smartphone or mobile phone or mHealth and (2) hand function or function assessment. Searches were limited to human studies in the English language and excluded conference proceedings and trial register records. Two reviewers independently screened all studies, with a third reviewer involved in resolving discrepancies. The included studies were rated according to the Mixed Methods Appraisal Tool. One reviewer extracted data on publication, demographics, hand function types, sensors used for hand function assessment, and statistical or machine learning (ML) methods. Accuracy was checked by another reviewer. The data were synthesized and tabulated based on each of the research questions. RESULTS: In total, 46 studies were included. Overall, 11 types of hand dysfunction-related problems were identified, such as Parkinson disease, wrist injury, stroke, and hand injury, and 6 types of hand dysfunctions were found, namely an abnormal range of motion, tremors, bradykinesia, the decline of fine motor skills, hypokinesia, and nonspecific dysfunction related to hand arthritis. Among all built-in smartphone sensors, the accelerometer was the most used, followed by the smartphone camera. Most studies used statistical methods for data processing, whereas ML algorithms were applied for disease detection, disease severity evaluation, disease prediction, and feature aggregation. CONCLUSIONS: This systematic review highlights the potential of smartphone-based hand function assessment. The review suggests that a smartphone is a promising tool for hand function evaluation. ML is a conducive method to classify levels of hand dysfunction. Future research could (1) explore a gold standard for smartphone-based hand function assessment and (2) take advantage of smartphones' multiple built-in sensors to assess hand function comprehensively, focus on developing ML methods for processing collected smartphone data, and focus on real-time assessment during rehabilitation training. The limitations of the research are 2-fold. First, the nascent nature of smartphone-based hand function assessment led to limited relevant literature, affecting the evidence's completeness and comprehensiveness. This can hinder supporting viewpoints and drawing conclusions. Second, literature quality varies due to the exploratory nature of the topic, with potential inconsistencies and a lack of high-quality reference studies and meta-analyses.

Asunto(s)

Mano , Teléfono Inteligente , Humanos , Mano/fisiopatología , Mano/fisiología , Masculino , Femenino , Enfermedad de Parkinson/fisiopatología , Telemedicina/instrumentación , Anciano

RESUMEN

Phytochemical study on the stems and leaves of Artocarpus tonkinensis led to the isolation of a new 2-arylbenzofuran, artocartone (1), as well as seven known 2-arylbenzofurans (2-8). The chemical structure of 1 was established by means of comprehensive spectroscopic analyses and the known compounds were determined by comparing their MS and NMR data with those reported data in literature. The antiproliferative activities of all isolates 1-8 against five human cancer cell lines: HL-60, SMMC-7721, A-375, MCF-7 and SW480 in vitro were evaluated. As a result, compounds 1- 8 displayed notable antiproliferative activities against various human cancer cell lines with IC50 values in the range of 0.28 ± 0.05-26.89 ± 0.18 µM.

RESUMEN

To understand the current saturation of emergency nurses' risk perception and its influencing factors, and to explore the correlation between emergency nurses' risk perception and nurse's safety behavior. This study is a cross-sectional study. From January 2024 to February 2024 using the questionnaire star online survey method. The convenience sampling method was used to survey nurses in the emergency departments of 5 hospitals in China. Male and female emergency nurses (n = 189) from China were included in the final sample. Nursing risk perception questionnaire and nurses safety behavior scale were used for evaluation. The collected data were comprehensively analyzed using various statistical methods, including descriptive analysis, 2 independent samples t-test mean comparison, 1-way analysis of variance for differences, multiple linear regression analysis to identify influencing factors, and Pearson correlation analyze correlations. All analyses were performed using SPSS version 26.0, and P < .05 was considered statistically significant (2-sided). The emergency nurses score was (87.08 ±â€…20.18) on the risk perception scale, scoring rate 62.2%. The results of multiple regression showed that age, marital status, education level, professional title, monthly income level, and safety behaviors were the main factors influencing the risk perception of emergency nurses (P < .05). The results of correlation analysis showed a positive correlation between the dimensions of nurses' risk perception and safety behaviors (R = 0.636, P < .01). Age, marriage, education level, years of work experience, professional title, duties. engagement type, monthly income level, participation in teaching work, safety training, and no adverse events were the influencing factors of risk perception. The research results emphasize that risk perception of emergency nurses has a positive prediction effect on safe behavior. It is suggested that nursing managers should optimize nursing workflow and human resource allocation, strategically add occupational risk training to vocational training, and strengthen nurses' safety behaviors.

Asunto(s)

Enfermería de Urgencia , Humanos , Femenino , Masculino , China , Estudios Transversales , Adulto , Encuestas y Cuestionarios , Actitud del Personal de Salud , Percepción , Personal de Enfermería en Hospital/psicología , Persona de Mediana Edad , Servicio de Urgencia en Hospital , Adulto Joven

RESUMEN

A phytochemical study on the stems and leaves of Cratoxylum cochinchinense (Lour.) Blume resulted in the isolation and characterisation of a new polyprenylated xanthone, cratocochinone (1), as well as seven known analogues, fuscaxanthone K (2), pruniflorone Q (3), 1,3,5,8-tetrahy-droxy- 2-(3-methybut-2-enyl)-4-(3,7-dimethylocta-2,6-dienyl) xanthone (4), cochinensoxanthone (5), cratoxylum-xanthone B (6), cochinchinone I (7) and cochinchinone K (8). The chemical structure of 1 was determined by comprehensive spectral analyses. The known compounds 2 - 8 were identified by comparing their experimental spectroscopic data with those reported data in the literature. The anti-inflammatory and anti-HIV effects of all isolates 1-8 were evaluated. As a result, compounds 1-8 showed remarkable inhibitory effects against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells showing IC50 values ranging from 0.68 ± 0.06 to 10.27 ± 0.18 µM. Meanwhile, compounds 1-8 displayed notable anti-HIV-1 reverse transcriptase (RT) effects with EC50 values ranging from 0.19 to 10.72 µM.

RESUMEN

Sudden cardiac death (SCD) is responsible for a high percentage of cardiovascular fatalities, with ventricular arrhythmias being the most common cause. Despite numerous clinically available antiarrhythmic drugs (AADs), AADs retain some undesirable arrhythmic effects, and their inappropriate use can lead to severe adverse reactions. The exploration of new therapeutic options against arrhythmias with fewer unreceptive effects is of utmost importance. The ethanolic extracts of seven Cupressaceae species, namely, Chamaecyparis obtusa, Juniperus chinensis (L.) Ant., Sabina chinensis (L.) Ant. cv. Kaizuca, Platycladus orientalis (L.) Franco, Juniperus sabina L., Fokienia hodginsii, and Juniperus chinensis 'Pyramidalis' were investigated for their pharmacological effects on barium chloride (BaCl2)-induced arrhythmia using normal II lead electrocardiogram (ECG) measurements in a mouse model. According to the ECG profiles, pretreatment with C. obtusa, P. orientalis, and J. sabina extracts provoked dose-dependent protection against BaCl2-induced arrhythmia, while pretreatment with the other four species and amiodarone did not exert cardioprotective effects. The treatment effects were confirmed using a rat model. The therapeutic effects of C. obtusa, P. orientalis, and J. sabina extracts on the M2 and M3 receptors but not the M1 receptor were mediated by the inhibition of the M2 receptor blocker (methoctramine tetrahydrochloride), M3 antagonist (4-DAMP), or M1 receptor blocker (pirenzepine dihydrochloride). This first-line evidence illustrates that certain Cupressaceae species possess active antiarrhythmic components. The first line of key findings revealed that active components of certain Cupressaceae species have cardioprotective effects, suggesting that these innovative phytochemicals have promising potential for preventing the occurrence of cardiac arrhythmia and reducing sudden cardiac death.

RESUMEN

BACKGROUND: Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition. METHODS: A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition. RESULTS: Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (PFDR = 0.012) and amyloid biomarkers (PFDR < 0.05), as well as cognitive scores (PFDR < 0.05) and hippocampal volume (PFDR = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2. CONCLUSIONS: MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology.

Asunto(s)

Enfermedad de Alzheimer , Depresión , Glicoproteínas de Membrana , Receptores Inmunológicos , Humanos , Femenino , Masculino , Glicoproteínas de Membrana/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Depresión/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Cognición/fisiología , Anciano de 80 o más Años , Estudios de Cohortes , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Persona de Mediana Edad

RESUMEN

This study aims to develop an ensemble learning (EL) method based on magnetic resonance (MR) radiomic features to preoperatively differentiate intracranial extraventricular ependymoma (IEE) from glioblastoma (GBM). This retrospective study enrolled patients with histopathologically confirmed IEE and GBM from June 2016 to June 2021. Radiomics features were extracted from T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) sequence images, and classification models were constructed using EL methods and logistic regression (LR). The efficiency of the models was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. The combined EL model, based on clinical parameters and radiomic features from T1WI and T2WI images, demonstrated good discriminative ability, achieving an area under the receiver operating characteristics curve (AUC) of 0.96 (95% CI 0.94-0.98), a specificity of 0.84, an accuracy of 0.92, and a sensitivity of 0.95 in the training set, and an AUC of 0.89 (95% CI 0.83-0.94), a specificity of 0.83, an accuracy of 0.81, and a sensitivity of 0.74 in the validation set. The discriminative efficacy of the EL model was significantly higher than that of the LR model. Favorable calibration performance and clinical applicability for the EL model were observed. The EL model combining preoperative MR-based tumor radiomics and clinical data showed high accuracy and sensitivity in differentiating IEE from GBM preoperatively, which may potentially assist in clinical management of these brain tumors.

RESUMEN

BACKGROUND: Endobronchial metastases (EBMs) are tumours that metastasise from a malignant tumour outside the lungs to the central and subsegmental bronchi, and are visible under a bronchofibrescope. Most EBMs are formed by direct invasion or metastasis of intrathoracic malignant tumours, such as lung cancer, oesophageal cancer or mediastinum tumours. Renal cell carcinoma (RCC), accounting for 2% to 3% of all tumours, is a common malignant tumour of the urinary system. Renal clear cell carcinoma (RCCC) constitutes the predominant pathological subtype of RCC, comprising approximately 70% to 80% of all RCC cases. RCCC can spread and metastasise through arterial, venous and lymphatic circulation to almost all organs of the body. Moreover, lung, bone, liver, brain and local recurrence are the most common metastatic neoplasms of RCCC. However, EBM from RCCC has a low complication rate and is often misdiagnosed as primary lung cancer. CASE SUMMARY: A 71-year-old male patient who had undergone radical left nephrectomy 7 years prior due to RCCC was referred to our hospital due to a 1-mo history of productive cough. The results of an enhanced chest CT scan indicated the presence of a soft tissue nodule in the upper lobe of the left lung, and flexible bronchoscopy revealed a hypervascular lesion in the bronchus of the left lung's superior lobe. Therefore, the patient underwent thoracoscopic left superior lobe wedge resection, and pathology confirmed EBM from the RCCC. CONCLUSION: EBM from RCCC has a low incidence and no characteristic clinical manifestations in the early stage. If a bronchial tumour is found in a patient with RCCC, the possibility of bronchial metastatic cancer should be considered.

RESUMEN

The morphology is a crucial indicator for diagnosing a low-energy, low-brightness particle beam. However, conventional positron beam diagnosis, based on the pixel scanning principle, is limited by physical constraints, such as the resolution of detector pixels. Here, we have presented a novel slow positron diagnosis method using compressive sampling. With a 100 × 100 pixel-sized mask, for example, the positron beam morphology can be significantly reconstructed with a peak signal-to-noise ratio of ∼40 dB, even at half the sampling rate compared to pixel scanning. It explores a promising approach for positron beam diagnosis with an ultra-high resolution and fast sampling rates.

RESUMEN

This study explored the effect of Tianma Gouteng Decoction on oxidative stress induced by angiotensin Ⅱ(AngⅡ) in vascular smooth muscle cell(VSMC) and its molecular mechanism. Primary rat VSMC were cultured using tissue block method, and VSMC were identified by α-actin immunofluorescence staining. AngⅡ at a concentration of 1×10~(-6) mol·L~(-1) was used as the stimulating factor, and Sprague Dawley(SD) rats were orally administered with Tianma Gouteng Decoction to prepare drug serum. Rat VSMC were divided into normal group, model group, Chinese medicine group, and inhibitor(3-methyladenine, 3-MA) group. Cell counting kit-8(CCK-8) assay was used to detect cell proliferation activity. Bromodeoxyuridine(BrdU) flow cytometry was used to detect cell cycle. Transwell assay was used to detect cell migration ability. Enzyme-linked immunosorbent assay(ELISA) was used to detect the activity of superoxide dismutase(SOD), catalase(CAT), and malondialdehyde(MDA) in VSMC. The intracellular reactive oxygen species(ROS) fluorescence intensity was detected using DCFH-DA fluorescent probe. Western blot was used to detect the expression of PTEN-induced putative kinase 1(PINK1), Parkin, p62, and microtubule-associated protein 1A/1B-light chain 3(LC3-Ⅱ) proteins in VSMC. The results showed that Tianma Gouteng Decoction-containing serum at a concentration of 8% could significantly inhibit VSMC growth after 48 hours of intervention. Compared with the normal group, the model group showed significantly increased cell proliferation activity and migration, significantly decreased levels of SOD and CAT, significantly increased levels of MDA, significantly enhanced ROS fluorescence intensity, significantly decreased expression of PINK1, Parkin, and LC3-Ⅱ proteins, and significantly increased expression of p62 protein. Compared with the model group, the Chinese medicine group showed significantly reduced cell proliferation activity and migration, significantly increased levels of SOD and CAT, significantly decreased levels of MDA, significantly weakened ROS fluorescence intensity, significantly increased expression of PINK1, Parkin, and LC3-Ⅱ proteins, and significantly decreased expression of p62 protein. Compared with the Chinese medicine group, the addition of the mitochondrial autophagy inhibitor 3-MA could block the intervention of Tianma Gouteng Decoction-containing serum on VSMC proliferation, migration, mitochondrial autophagy, and oxidative stress levels, with statistically significant differences. In summary, Tianma Gouteng Decoction has good antioxidant activity and can inhibit cell proliferation and migration. Its mechanism of action may be related to the activation of the mitochondrial autophagy PINK1/Parkin signaling pathway.

Asunto(s)

Angiotensina II , Proliferación Celular , Medicamentos Herbarios Chinos , Músculo Liso Vascular , Estrés Oxidativo , Proteínas Quinasas , Ratas Sprague-Dawley , Ubiquitina-Proteína Ligasas , Animales , Medicamentos Herbarios Chinos/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Masculino , Proliferación Celular/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Movimiento Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células Cultivadas , Superóxido Dismutasa/metabolismo

RESUMEN

BACKGROUND: Paragonimiasis, primarily caused by Paragonimus westermani and P. skrjabini in China, is a common food-borne parasitic zoonosis. However, the national distribution of Paragonimus spp. infection and its associated environmental determinants remain poorly understood. In this paper, we summarize the infection of P. westermani and P. skrjabini and describe key biogeographical characteristics of the endemic areas in China. METHODS: Data on Paragonimus infection in humans and animal hosts were extracted from eight electronic databases, including CNKI, CWFD, Chongqing VIP, SinoMed, Medline, Embase, PubMed, and Web of Science. A random-effects meta-analysis model was used to estimate the pooled prevalence. All survey locations were georeferenced and plotted on China map, and scatter plots were used to illustrate the biogeographical characteristics of regions reporting Paragonimus infection. RESULTS: A total of 28,948 cases of human paragonimiasis have been documented, with 2,401 cases reported after 2010. Among the 11,443 cases with reported ages, 88.05% were children or adolescents. The pooled prevalence of P. skrjabini is 0.45% (95% CI: 0.27-0.66%) in snails, 31.10% (95% CI: 24.77-37.80%) in the second intermediate host, and 20.31% (95% CI: 9.69-33.38%) in animal reservoirs. For P. westermani, the pooled prevalence is 0.06% (95% CI: 0.01-0.13%) in snails, 52.07% (95% CI: 43.56-60.52%) in the second intermediate host, and 21.40% (95% CI: 7.82-38.99%) in animal reservoirs. Paragonimus are primarily distributed in regions with low altitude, high temperature, and high precipitation. In northeastern China, only P. westermani infections have been documented, while in more southern areas, infections of both P. westermani and P. skrjabini have been reported. CONCLUSIONS: Paragonimiasis remains prevalent in China, particularly among children and adolescents. Variations exist in the intermediate hosts and geographical distribution of P. westermani and P. skrjabini. Additionally, altitude, temperature, and precipitation may influence the distribution of Paragonimus.

Asunto(s)

Paragonimiasis , Paragonimus , Animales , Paragonimiasis/epidemiología , Paragonimiasis/parasitología , Humanos , China/epidemiología , Paragonimus/aislamiento & purificación , Paragonimus/clasificación , Paragonimus/genética , Zoonosis/parasitología , Zoonosis/epidemiología , Prevalencia , Niño

RESUMEN

Objective: To preliminarily explore the risk factors for post-infectious bronchiolitis obliterans (PIBO) complicating adenovirus pneumonia (ADVP) in children through a meta-analysis. Methods: A systematic search was conducted on three English-language databases (PubMed, Web of Science and The National Library of Medicine) and two Chinese-language databases (China National Knowledge Infrastructure and the Wanfang Database) between database inception and 1 January 2023. Data analysis was conducted using Stata 15.1 software. Results: A total of 10 articles, reporting 14 risk factors, were included in the analysis, with 8 risk factors taken into consideration. Through the meta-analysis, 5 risk factors were identified for PIBO complicating ADVP in paediatric patients: hypoxaemia [odds ratio (OR) = 9.37, 95% CI: 4.22, 20.77, p < 0.001], persistent wheezing (OR = 4.65, 95% CI: 2.20, 9.82, p < 0.001), mechanical ventilation (OR = 3.87, 95% CI: 2.37, 6.33, p < 0.001), length of hospital stay (LoHS) (OR = 1.25, 95% CI: 1.09, 1.43, p < 0.001) and fever duration (OR = 1.08, 95% CI: 1.02, 1.14, p = 0.009). Conclusion: Existing evidence suggests that hypoxaemia, persistent wheezing, mechanical ventilation, LoHS and fever duration are risk factors for PIBO complicating ADVP in children. These findings underscore the need for enhanced assessment and management in clinical practice. This study may provide such a clinical prediction model from the identified 5 risk factors for PIBO and offer valuable insights for preventing bronchiolitis obliterans in children with ADVP.

RESUMEN

Among the HDACs family, histone deacetylase 6 (HDAC6) has attracted extensive attention due to its unique structure and biological functions. Numerous studies have shown that compared with broad-spectrum HDACs inhibitors, selective HDAC6 inhibitors exert ideal efficacy in tumor treatment with insignificant toxic and side effects, demonstrating promising clinical application prospect. Herein, we carried out rational drug design by integrating a deep learning model, molecular docking, and molecular dynamics simulation technology to construct a virtual screening process. The designed derivatives with 5-phenyl-1H-indole fragment as Cap showed desirable cytotoxicity to the various tumor cell lines, all of which were within 15 µM (ranging from 0.35 to 14.87 µM), among which compound 5i had the best antiproliferative activities against HL-60 (IC50 = 0.35 ± 0.07 µM) and arrested HL-60 cells in the G0/G1 phase. In addition, 5i exhibited better isotype selective inhibitory activities due to the potent potency against HDAC6 (IC50 = 5.16 ± 0.25 nM) and the reduced inhibitory activities against HDAC1 (selective index ≈ 124), which was further verified by immunoblotting results. Moreover, the representative binding conformation of 5i on HDAC6 was revealed and the key residues contributing 5i's binding were also identified via decomposition free-energy analysis. The discovery of lead compound 5i also indicates that virtual screening is still a beneficial tool in drug discovery and can provide more molecular skeletons with research potential for drug design, which is worthy of widespread application.

Asunto(s)

Diseño de Fármacos , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Indoles , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Indoles/farmacología , Indoles/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Interfaz Usuario-Computador

RESUMEN

Introduction: This study aimed to investigate the cognitive profile and prospective cognitive changes in non-demented adults with elevated Modified Dementia Risk Scores (MDRS), while also exploring the potential relationship between these associations and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology and neuroinflammation. Methods: Within the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, 994 participants without dementia were assessed on MDRS, CSF biomarkers and cognition. We examined the associations of the MDRS with CSF biomarkers and cognitive scores using linear regressions. Causal mediation analyses were conducted to analyze the associations among MDRS, brain pathologies, and cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate the mediation effects and to investigate the longitudinal association between MDRS and cognitive decline. Results: The results revealed that higher MDRS were linked to poorer cognitive performance (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and increases in CSF levels of phosphorylated tau (P-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), total tau (T-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), P-tau/Aß42 ratio (Model 1: PFDR = 0.023; Model 2: PFDR = 0.028), T-tau/Aß42 ratio (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and soluble triggering receptor expressed on myeloid cells 2 (sTrem2, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) in the CABLE study. The impact of MDRS on cognition was partially mediated by neuroinflammation and tau pathology. These mediation effects were replicated in the ADNI study. Baseline MDRS were significantly associated with future cognitive decline, as indicated by lower scores on the Mini-Mental State Examination (MMSE, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), ADNI composite memory score (ADNI-MEM, Model 1: PFDR = 0.005; Model 2: PFDR < 0.001), ADNI composite executive function score (ADNI-EF, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), and higher score on the Alzheimer's Disease Assessment Scale (ADAS13, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001). Discussion: The findings of this study revealed significant associations between MDRS and cognitive decline, suggesting a potential role of tau pathology and neuroinflammation in the link between MDRS and poorer cognitive performance in individuals without dementia. Consequently, the MDRS holds promise as a tool for targeted preventive interventions in individuals at high risk of cognitive impairment.

RESUMEN

2,2',4,4'-Tetrabromodiphenyl ether (PBDE-47), being the most prevalent congener of polybrominated diphenyl ethers (PBDEs), has been found to accumulate greatly in the environment and induce spermatogenesis dysfunction. However, the specific underlying factors and mechanisms have not been elucidated. Herein, male Sprague-Dawley (SD) rats were exposed to corn oil, 10 mg/kg body weight (bw) PBDE-47 or 20 mg/kg bw PBDE-47 by gavage for 30 days. PBDE-47 exposure led to blood-testis barrier (BTB) integrity disruption and aberrant spermatogenesis. Given that Sertoli cells are the main toxicant target, to explore the potential mechanism involved, we performed RNA sequencing (RNA-seq) in Sertoli cells, and the differentially expressed genes were shown to be enriched in ferroptosis and lysosomal pathways. We subsequently demonstrated that ferroptosis was obviously increased in testes and Sertoli cells upon exposure to PBDE-47, and the junctional function of Sertoli cells was restored after treatment with the ferroptosis inhibitor ferrostatin-1. Since glutathione peroxidase 4 (GPX4) was dramatically reduced in PBDE-47-exposed testes and Sertoli cells and considering the RNA-sequencing results, we examined the activity of chaperone-mediated autophagy (CMA) and verified that the expression of LAMP2a and HSC70 was upregulated significantly after PBDE-47 exposure. Notably, Lamp2a knockdown not only inhibited ferroptosis by suppressing GPX4 degradation but also restored the impaired junctional function induced by PBDE-47. These collective findings strongly indicate that PBDE-47 induces Sertoli cell ferroptosis through CMA-mediated GPX4 degradation, resulting in decreased BTB-associated protein expression and eventually leading to BTB integrity disruption and spermatogenesis dysfunction.

Asunto(s)

Barrera Hematotesticular , Ferroptosis , Éteres Difenilos Halogenados , Animales , Masculino , Ratas , Barrera Hematotesticular/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Éteres Difenilos Halogenados/toxicidad , Ratas Sprague-Dawley , Células de Sertoli/efectos de los fármacos , Células de Sertoli/metabolismo , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos

RESUMEN

IMPORTANCE: Intra-arterial therapies(IATs) are promising options for unresectable hepatocellular carcinoma(HCC). Stratifying the prognostic risk before administering IAT is important for clinical decision-making and for designing future clinical trials. OBJECTIVE: To develop and validate a machine learning(ML)-based decision support model(MLDSM) for recommending IAT modalities for unresectable HCC. DESIGN, SETTING, AND PARTICIPANTS: Between October 2014 and October 2022, a total of 2,959 patients with HCC who underwent initial IATs were enroled retrospectively from 13 tertiary hospitals. These patients were divided into the training cohort (n = 1700), validation cohort (n = 428), and test cohort (n = 200). MAIN OUTCOMES AND MEASURES: Thirty-two clinical variables were input, and five supervised ML algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBM) and Random Forest (RF), were compared using the areas under the receiver operating characteristic curve (AUC) with the DeLong test. RESULTS: A total of 1856 patients were assigned to the IAT alone Group(I-A), and 1103 patients were assigned to the IAT combination Group(I-C). The 12-month death rates were 31.9% (352/1103) in the I-A group and 50.4% (936/1856) in the I-C group. For the test cohort, in the I-C group, the CatBoost model achieved the best discrimination when 30 variables were input, with an AUC of 0.776 (95% confidence intervals [CI], 0.833-0.868). In the I-A group, the LGBM model achieved the best discrimination when 24 variables were input, with an AUC of 0.776 (95% CI, 0.833-0.868). According to the decision trees, BCLC grade, local therapy, and diameter as top three variables were used to guide clinical decisions between IAT modalities. CONCLUSIONS AND RELEVANCE: The MLDSM can accurately stratify prognostic risk for HCC patients who received IATs, thus helping physicians to make decisions about IAT and providing guidance for surveillance strategies in clinical practice.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , Aprendizaje Automático , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Técnicas de Apoyo para la Decisión , Toma de Decisiones Clínicas , Pronóstico , Quimioembolización Terapéutica/métodos

RESUMEN

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson's (STAB1, KCNA10), Alzheimer's (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson's. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.

Asunto(s)

Encéfalo , Secuenciación del Exoma , Hierro , Humanos , Hierro/metabolismo , Encéfalo/metabolismo , Masculino , Femenino , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Persona de Mediana Edad , Predisposición Genética a la Enfermedad/genética , Anciano , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Adulto , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo

RESUMEN

BACKGROUND: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. METHODS: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. FINDINGS: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10-31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. CONCLUSIONS: Our findings highlight the importance of causal genes for VV and provide new directions for treatment.

Asunto(s)

Secuenciación del Exoma , Exoma , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Várices , Humanos , Várices/genética , Femenino , Masculino , Exoma/genética , Polimorfismo de Nucleótido Simple , Enzimas Convertidoras de Endotelina/genética , Persona de Mediana Edad , Variación Genética , Adulto , Canales Iónicos

RESUMEN

OBJECTIVES: To investigate the application of endoscopic retrograde cholangiopancreatography (ERCP) in children and the risk factors for post-ERCP pancreatitis (PEP). METHODS: A retrospective analysis was conducted on the clinical data of 66 children, aged ≤16 years, who underwent ERCP for pancreaticobiliary diseases at the Gastrointestinal Endoscopy Center of the Second Affiliated Hospital of Kunming Medical University from September 2013 to September 2023. The incidence rate of PEP and the risk factors for the development of PEP were analyzed. RESULTS: A total of 78 ERCP procedures were performed on 66 children, with 5 diagnostic ERCPs, 69 therapeutic ERCPs, and 4 failed procedures. The success rate of ERCP operations was 95% (74/78). There were 17 cases of PEP in total, with an incidence rate of 22%. In the PEP group, the proportion of children with normal preoperative bilirubin and the proportion of guidewire insertion into the pancreatic duct during surgery were higher than in the non-PEP group (P<0.05). The multivariate logistic regression analysis showed that guidewire insertion into the pancreatic duct was an independent risk factor for PEP (P<0.05). CONCLUSIONS: With the increasing application of ERCP in children with pancreaticobiliary diseases, it is important to select an appropriate intubation technique during surgery to avoid blindly entering the guidewire into the pancreatic duct and reduce the occurrence of PEP.

Asunto(s)

Colangiopancreatografia Retrógrada Endoscópica , Pancreatitis , Humanos , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Niño , Masculino , Pancreatitis/etiología , Pancreatitis/prevención & control , Femenino , Factores de Riesgo , Estudios Retrospectivos , Preescolar , Adolescente , Modelos Logísticos , Lactante