A diagnostic model for Parkinson's disease based on circadian rhythm-related genes.

BACKGROUND: Circadian rhythm (CR) disturbance is intricately associated with Parkinson's disease (PD). However, the involvement of CR-related mechanisms in the pathogenesis and progression of PD remains elusive. METHODS: A total of 141 PD patients and 113 healthy participants completed CR-related clinical examinations in this study. To further investigate the CR-related mechanisms in PD, we obtained datasets (GSE7621, GSE20141, GSE20292) from the Gene Expression Omnibus database to identify differentially expressed genes between PD patients and healthy controls and further selected CR-related genes (CRRGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) followed by logistic algorithms were employed to identify the hub genes and construct a diagnostic model. The predictive performance was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses in the training set and external validation sets. Finally, RT‒qPCR and Western blotting were conducted to verify the expression of these hub genes in blood samples. In addition, Pearson correlation analysis was utilized to validate the association between expression of hub genes and circadian rhythm function. RESULTS: Our clinical observational study revealed that even early-stage PD patients exhibited a higher likelihood of experiencing sleep disturbances, nocturnal hypertension, reverse-dipper blood pressure, and reduced heart rate variability compared to healthy controls. Furthermore, 4 CR-related hub genes (AGTR1, CALR, BRM14, and XPA) were identified and subsequently incorporated as candidate biomarkers to construct a diagnostic model. The model showed satisfactory diagnostic performance in the training set (AUC = 0.941), an external validation set GSE20295 (AUC = 0.842), and our clinical centre set (AUC = 0.805). Additionally, the up-regulation of CALR, BRM14 and the down-regulation of AGTR1, XPA were associated with circadian rhythm disruption. CONCLUSION: CR disturbance seems to occur in the early stage of PD. The diagnostic model based on CR-related genes demonstrated robust diagnostic efficacy, offering novel insights for future clinical diagnosis of PD and providing a foundation for further exploration into the role of CR-related mechanisms in the progression of PD.

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

BACKGROUND: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. METHODS: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. RESULTS: A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 159 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). CONCLUSIONS: In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).

The Role of Circadian Rhythms in Stroke: A Narrative Review.

Stroke, a debilitating condition often leading to long-term disability, poses a substantial global concern and formidable challenge. The increasing incidence of stroke has drawn the attention of medical researchers and neurologists worldwide. Circadian rhythms have emerged as pivotal factors influencing stroke's onset, pathogenesis, treatment, and outcomes. To gain deeper insights into stroke, it is imperative to explore the intricate connection between circadian rhythms and stroke, spanning from molecular mechanisms to pathophysiological processes. Despite existing studies linking circadian rhythm to stroke onset, there remains a paucity of comprehensive reviews exploring its role in pathogenesis, treatment, and prognosis. This review undertakes a narrative analysis of studies investigating the relationship between circadian variation and stroke onset. It delves into the roles of various physiological factors, including blood pressure, coagulation profiles, blood cells, catecholamines, cortisol, and the timing of antihypertensive medication, which contribute to variations in circadian-related stroke risk. At a molecular level, the review elucidates the involvement of melatonin, circadian genes, and glial cells in the pathophysiology. Furthermore, it provides insights into the diverse factors influencing stroke treatment and outcomes within the context of circadian variation. The review underscores the importance of considering circadian rhythms when determining the timing of stroke interventions, emphasizing the necessity for personalized stroke management strategies that incorporate circadian rhythms. It offers valuable insights into potential molecular targets and highlights areas that require further exploration to enhance our understanding of the underlying pathophysiology. In comparison to the published literature, this manuscript distinguishes itself through its coverage of circadian rhythms' impact on stroke across the entire clinical spectrum. It presents a unique synthesis of epidemiological, clinical, molecular, and cellular evidence, underscoring their collective significance.

Bidirectional association between hypothyroidism and myasthenia gravis: a Mendelian randomized study.

OBJECTIVES: Although observational studies have suggested a link between hypothyroidism and myasthenia gravis (MG), a causal relationship has not been established. We aimed to investigate the causal association using a two-sample Mendelian randomization (MR) study. METHODS: Using summary statistics from genome-wide association studies involving 494,577 and 38,243 individuals, single-nucleotide polymorphisms exhibiting no linkage disequilibrium (r2 ≤ 0.001) and displaying significant differences (p ≤ 5 × 10-8) were selected for hypothyroidism and MG. To assess the potential causality relationship between hypothyroidism and MG, MR analysis was conducted using inverse variance weighted (IVW), weighted median method, and MR-Egger. The MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test were employed to examine sensitivity analyses. In addition, validation datasets were used to validate the relevant results. RESULTS: Genetic liability to hypothyroidism was positively associated with MG (IVW, OR: 1.36, 95% CI: 1.17-1.58, p = 7.53 × 10-05; weighted median, OR: 1.19, 95% CI: 0.70-2.02, p = 0.522; MR-Egger, OR: 1.19, 95% CI: 0.98-1.45, p = 0.080). Among the three MR methods, the correlation between hypothyroidism and MG genetic prediction was consistent. The independent validation set (IVW, OR: 466.47, 95% CI: 4.70 -46,285.95, p = 0.01) further supported this. Additionally, bidirectional studies showed that using IVW, there was no reverse causality (OR: 1.104, 95%CI: 0.96-1.27, p = 0.170). DISCUSSION: This MR study showed that hypothyroidism can increase the risk of MG. Further investigation into the underlying mechanisms of this potential causality is warranted to offer novel therapeutic options for MG in the future.

Boosting N2 Conversion into NH3 over Ru Catalysts via Modulating the Ru-Promoter Interface.

Promoters are indispensable components of Ru-based catalysts to promote N2 activation in ammonia (NH3) synthesis. The rational addition and regulation of promoters play a critical role in affecting the NH3 synthesis rate. In this work, we report a simple method by altering the loading sequence of Ba and Ru species to modulate the Ru-promoter interface, thus significantly boosting the NH3 synthesis rate. The Ba-Ru/GC BM catalyst via the prior loading of Ba rather than Ru over graphitic carbon (GC) exhibits a high NH3 synthesis rate of 18.7 mmol gcat-1 h-1 at 400 °C and 1 MPa, which is 2.5 times that of the Ru-Ba/GC BM catalyst via the conventional prior loading of Ru rather than Ba on GC. Our studies reveal that the prior loading of Ba benefits the high dispersion of the basic Ba promoter over an electron-withdrawing GC support, and then Ba species serve as structural promoters to stabilize Ru with small particle sizes, which exposes more active sites for N2 activation. Additionally, the intimate Ba and Ru interface enables facile electron donation from Ba to Ru sites, thus accelerating N2 dissociation to realize efficient NH3 synthesis. This work provides a simple approach to modulating the Ru-promoter interface and maximizing promoter utilization to enhance NH3 synthesis performance.

A Diagnostic Model for Parkinson's Disease Based on Anoikis-Related Genes.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, and its pathological mechanisms are thought to be closely linked to apoptosis. Anoikis, a specific type of apoptosis, has recently been suggested to play a role in the progression of Parkinson's disease; however, the underlying mechanisms are not well understood. To explore the potential mechanisms involved in PD, we selected genes from the GSE28894 dataset and compared their expression in PD patients and healthy controls to identify differentially expressed genes (DEGs), and selected anoikis-related genes (ANRGs) from the DEGs. Furthermore, the least absolute shrinkage and selection operator (LASSO) regression approach and multivariate logistic regression highlighted five key genes-GSK3B, PCNA, CDC42, DAPK2, and SRC-as biomarker candidates. Subsequently, we developed a nomogram model incorporating these 5 genes along with age and sex to predict and diagnose PD. To evaluate the model's coherence, clinical applicability, and distinguishability, we utilized receiver operating characteristic (ROC) curves, the C-index, and calibration curves and validated it in both the GSE20295 dataset and our center's external clinical data. In addition, we confirmed the differential expression of the 5 model genes in human blood samples through qRT-PCR and Western blotting. Our constructed anoikis-related PD diagnostic model exhibits satisfactory predictive accuracy and offers novel insights into both diagnosis and treatment strategies for Parkinson's disease while facilitating its implementation in clinical practice.

A Risk Score for Predicting the Necessity of Surgical Necrosectomy in the Treatment of Infected Necrotizing Pancreatitis.

BACKGROUND: For infected necrotizing pancreatitis (INP), percutaneous catheter drainage (PCD) is now widely acknowledged as the initial intervention in a step-up approach, followed, if necessary, by minimally invasive necrosectomy or even open pancreatic necrosectomy. However, an overemphasis on PCD may cause a patient's condition to deteriorate, leading to missed surgical opportunities or even death. This study aimed to develop a simple and convenient scoring tool for assessing the need for surgery in INP patients who received PCD procedures. METHODS: In an observational study conducted between April 2015 and December 2020, PCD was utilized as the initial step to treat 143 consecutive INP patients. A surgical necrosectomy was performed when the patient failed to respond. Risk factors of PCD failure (i.e., need for surgical necrosectomy) were identified by multivariate logistic regression models. An integer-based risk scoring tool was developed using the ß coefficients derived from the logistic regression model. RESULTS: In 62 (43.4%) patients, PCD was successful, while the remaining 81 (56.6%) individuals required subsequent surgical necrosectomy. In the multivariate model, organ failure, percentage of pancreatic necrosis, extrapancreatic necrosis volume, and mean CT density of extrapancreatic necrosis volume were associated with a need for surgical necrosectomy. A predictive scoring tool based on these four factors demonstrated an area under the receiver operating characteristic curve (AUC) of 0.893. Under the scoring tool, a total score of 4 or more indicates a high possibility of surgical necrosectomy being required (at least 80%). Using the coordinates of the receiver operating characteristic curve (ROC), the sensitivity and specificity at this threshold are 0.802 and 0.903, respectively. CONCLUSIONS: A risk score model integrating organ failure, percentage of pancreatic necrosis, extrapancreatic necrosis volume, and mean CT density of extrapancreatic necrosis volume can identify INP patients at high risk for necrosectomy. The straightforward risk assessment tool assists clinicians in stratifying INP patients and making more judicious medical decisions.

Development of gene model combined with machine learning technology to predict for advanced atherosclerotic plaques.

BACKGROUND: Atherosclerosis, as a major cause of stroke, is responsible for a quarter of deaths worldwide. In particular, rupture of late-stage plaques in large vessels such as the carotid artery can lead to serious cardiovascular disease. The aim of our study was to establish a genetic model combined with machining leaning techniques to screen out gene signatures and predict for advanced atherosclerosis plaques. METHODS: The microarray dataset GSE28829 and GSE43292 which were publicly obtained from the Gene Expression Omnibus database were utilized to screen for potential predictive genes. Differentially expressed genes (DEGs) were identified by using the "limma" R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) analyses of these DEGs were performed by Metascape. Later, Random Forest (RF) algorithm was applied to further screen out top-30 genes which contribute the most. The expression data of top 30-DEGs were converted into a "Gene Score". Finally, we developed a model based on artificial neural network (ANN) to predict advanced atherosclerotic plaques. The model later was validated in an independent test dataset GSE104140. RESULTS: A total of 176 DEGs were identified in the training datasets. GO and KEGG enrichment analysis revealed that these genes were enriched in leukocyte-mediated immune response, cytokine- cytokine interactions, and immunoinflammatory signaling. Further, top-30 genes (including 25 upregulated and 5 downregulated DEGs) were screened as predictors by RF algorithm. The predictive model was developed with a significantly predictive value (AUC = 0.913) in the training datasets, and was validated with an independent dataset GSE104140 (AUC = 0.827). CONCLUSION: In present study, our prediction model was established and showed satisfactory predictive power in both training and test datasets. In addition, this is the first study adopted bioinformatics methods combined with machine learning techniques (RF and ANN) to explore and predict for the advanced atherosclerotic plaques. However, further investigations were needed to verify the screened DEGs and predictive effectiveness of this model.

Identifying the potential role of serum miR-20a as a biomarker for olfactory dysfunction in patients with Parkinson's disease.

INTRODUCTION: Olfactory dysfunction (OD), one of the most common non-motor symptoms in Parkinson's disease (PD), is a cardinal prodromal symptom that can appear years before the onset of motor symptoms. Ongoing studies have demonstrated that microRNAs (miRNAs) are suitable biomarkers for PD, while there is a lack of robust miRNAs that can serve as markers for OD in PD. METHODS: The concordantly differentially expressed miRNAs (DE miRNAs) in the damaged olfactory system were first identified in 2 OD-related Gene Expression Omnibus (GEO) datasets. Then, they were verified in another PD-related GEO dataset and only one miRNA (miR-20a) was found to be significantly altered. Serum levels of miR-20a were further measured by qPCR in 79 PD patients with OD (PD-OD), 52 PD patients without OD (PD-NOD), and 52 healthy controls (HC). Objective measure of OD was defined by 16-item Sniffin' Sticks odor identification test. All the participants underwent a demographic and comprehensive PD-related clinical assessment. RESULTS: Our results proved that miR-20a was significantly downregulated in PD-OD compared with PD-NOD and the area under curve (AUC) for OD detection by miR-20a was 0.803 (95% confidence interval, 0.724-0.883). In addition, PD-OD had higher scores of Movement Disorder Society-Unified Parkinson's Disease Rating Scale (UPDRS) II, Hoehn and Yahr stage (H-Y), Non-Motor Symptoms Scale (NMSS) 3, NMSS 5, NMSS 9, Hamilton Rating Scale for Depression (HAMD), Hamilton Anxiety Scale (HAMA), Activity of Daily Living (ADL), and lower scores of Mini-Mental State Examination (MMSE) and 39-item PD Quality of Life Questionnaire (PDQ-39) than PD-NOD. Binary regression model further presented that lower expressions of miR-20a and poorer cognitive function acted as promoting factors in the development of OD. CONCLUSION: Our results suggest that miR-20a could be a novel biomarker for OD in PD and PD-OD patients tend to have higher disease stage, poorer motor aspects of experiences of daily living, worse cognitive scores, and inferior quality of life, and were more likely to have mental disorders. Cognitive function, in particular, is strongly associated with OD in PD patients.

Protective Effects of Querectin against MPP+-Induced Dopaminergic Neurons Injury via the Nrf2 Signaling Pathway.

BACKGROUND: Parkinson's disease (PD) is a common selective and progressive neurodegenerative disorder of nigrostriatal dopaminergic (DA) neurons. Quercetin is a bioflavonoid with antioxidant, anti-inflammatory, anti-aging and anti-cancer properties. However, the exact mechanism by which quercetin exerts its protective effect on DAergic neurons remains unclear. PURPOSE: To investigate the underlying molecular mechanism of quercetin's protective effect on DA neurons using 1-methyl-4-phenylpyridinium (MPP+)-induced PD ferroptosis model in vitro. METHODS: MPP+ was used to induce cytotoxicity in SH-SY5Y/primary neurons. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The expression levels of ferroptosis-related proteins (NCOA4, SLC7A11, Nrf2, and GPX4) were determined by Western blotting. Malondialdehyde (MDA), iron, and GPX4 levels were assesed using corresponding assay kits. Lipid peroxidation was assessed by C11-BODIPY staining. RESULTS: In the MPP+-induced ferroptosis model of SH-SY5Y cells, the expressions of SLC7A11 and GPX4 were inhibited, and the expression of NCOA4 protein was increased, causing the overproduction of MDA and lipid peroxidation. Quercetin can reduce the above changes caused by MPP+, that is, reduce the protein expression of NCOA4 in SH-SY5Y cells, increase SLC7A11 and GPX4 partially inhibited by MPP+, and reduce MDA overproduction and lipid peroxidation to protect DA neurons. Nrf2 inhibitor ML385 could inhibit quercetin-induced increase of GPX4 and SLC7A11 protein expression, indicating that the protective effect of quercetin was mediated through Nrf2. CONCLUSIONS: The results of this study suggest that quercetin regulates ferroptosis through Nrf2-dependent signaling pathways, thereby inhibiting MPP+-induced neurotoxicity in SH-SY5Y/primary neurons.

Parkinson's disease patients combined with constipation tend to have higher serum expression of microRNA 29c, prominent neuropsychiatric disorders, possible RBD conversion, and a substandard quality of life.

INTRODUCTION: The symptom of constipation has been confirmed as an early diagnose criteria for Parkinson's disease (PD). Furthermore, evidences suggest that pathogenesis of PD initiates in gut, rather than brain. If so, identifying biomarkers for constipation in PD might have potentials to assist early diagnosis and initial treatment. METHOD: We first identified that microRNA 29c (miR-29c) was dysregulated both in PD and constipation patients through bioinformatics analysis. Then, serological analysis of the expression of miR-29c in 67 PD patients with constipation (PD-C), 51 PD patients without constipation (PD-NC), and 50 healthy controls (HC) was carried out by qPCR. Demographic and clinical features were also compared. Patients in PD-C group were further classified into two groups: those with prodromal stage constipation (PD-C-Pro) (n = 36) and those with clinical stage constipation (PD-C-Clinic) (n = 31), to explore their different characteristics. RESULTS: The levels of miR-29c in PD-C group were higher than that in PD-NC group, both higher than HC group. PD-C-Pro group's miR-29c levels were statistically higher compared with PD-C-Clinic group's. What is more, PD-C group had higher scores of MDS-UPDRS-I, NMSS, NMSS3, NMSS4, NMSS6, NMSS9, SCOPA-AUT, HAMD, HAMA, RBDSQ, CSS, and PACQOL compared with PD-NC party. Relative to the PD-C-Clinic, patients in PD-C-Pro group had higher MDS-UPDRS-I, NMSS, NMSS3, HAMD, and HAMA scores, and were more likely to have RBD. CONCLUSION: Our results indicated that miR-29c seems to be an underlying cause for developing constipation in patients with PD and PD-C identifies a group of patients with more severe non-motor impairment, prominent neuropsychiatric disorders, and possible RBD conversion as well as a substandard quality of life. We further confirmed that there is a close relationship between symptoms representing the same pathological origin, especially constipation and RBD.

The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer.

Background: Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood. Methods: SIX1 expression was determined using immunohistochemistry in PC tissues and cell lines. Glucose consumption, lactate production, and ATP assays were used to detect the function of SIX1. PC cells and NK cells were cocultured to study the effect of SIX1 overexpression in PC cells on NK cell function. Chromatin immunoprecipitation (ChIP) assays were used to study the relationship between SIX1 and lactate dehydrogenase A (LDHA). A series of in vitro and in vivo assays were further applied to elucidate the important role of the SIX1/LDHA axis in metabolism and NK cell dysfunction in PC. Results: SIX1 was significantly upregulated in PC tissue; SIX1 overexpression promoted the glycolysis capacity of PANC-1 and CFPAC-1 cells and resulted in NK cell dysfunction after the NK cells had been cultured with PC cells. LDHA inhibitor partially restored the promotion of PC caused by SIX1 overexpression. According to ChIP assays, SIX1 directly binds to the LDHA promoter region. Moreover, LDHA inhibitor and lactate transporter blocker treatment promoted the function of NK cells cocultured with PC cells. In vivo experiments yielded the same results. Conclusion: The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC.

Parkinson's Disease Gene Biomarkers Screened by the LASSO and SVM Algorithms.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder. Various evidence has revealed the possible penetration of peripheral immune cells in the substantia nigra, which may be essential for PD. Our study uses machine learning (ML) to screen for potential PD genetic biomarkers. Gene expression profiles were screened from the Gene Expression Omnibus (GEO). Differential expression genes (DEGs) were selected for the enrichment analysis. A protein-protein interaction (PPI) network was built with the STRING database (Search Tool for the Retrieval of Interacting Genes), and two ML approaches, namely least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE), were employed to identify candidate genes. The external validation dataset further tested the expression degree and diagnostic value of candidate biomarkers. To assess the validity of the diagnosis, we determined the receiver operating characteristic (ROC) curve. A convolution tool was employed to evaluate the composition of immune cells by CIBERSORT, and we performed correlation analyses on the basis of the training dataset. Twenty-seven DEGs were screened in the PD and control samples. Our results from the enrichment analysis showed a close association with inflammatory and immune-associated diseases. Both the LASSO and SVM algorithms screened eight and six characteristic genes. AGTR1, GBE1, TPBG, and HSPA6 are overlapping hub genes strongly related to PD. Our results of the area under the ROC (AUC), including AGTR1 (AUC = 0.933), GBE1 (AUC = 0.967), TPBG (AUC = 0.767), and HSPA6 (AUC = 0.633), suggested that these genes have good diagnostic value, and these genes were significantly associated with the degree of immune cell infiltration. AGTR1, GBE1, TPBG, and HSPA6 were identified as potential biomarkers in the diagnosis of PD and provide a novel viewpoint for further study on PD immune mechanism and therapy.

Association between plasma trimethylamine-N-oxide and cognitive impairment in patients with transient ischemic attack.

BACKGROUND: There is increasing evidence for the association of trimethylamine-N-oxide (TMAO) with cognitive impairment after minor stroke or transient ischemic attack (TIA). However, how TMAO affects cognitive function in TIA patients has seldom been studied. METHODS: A total of 310 TIA participants were retrospectively collected from our stroke register between January 2020 and July 2021. Plasma TMAO was measured by liquid chromatography‒mass spectrometry at baseline. Cognitive performance was assessed by neuropsychological evaluation at 3 months after TIA onset. RESULTS: A total of 310 patients were included (mean age, 74 years; male, 160 [51.6%]; mean ABCD2 score, 2.6). TMAO was positively associated with cognitive impairment after TIA (aOR, 1.423; 95% CI, 1.125-2.561). The highest quartile of TMAO was related to an almost 2-fold increased risk of cognitive decline compared to the lowest quartile. Furthermore, executive and memory function were more susceptible to impairment after TIA in groups with higher levels of TMAO. Mediation analysis revealed that the overall mediated effect was-0.347 (p < 0.001), and the intermediary effect of CRP was-0.108. CONCLUSION: Plasma TMAO at baseline was independently associated with cognitive impairment at the 3-month follow-up after TIA. In addition, the inflammatory marker CRP may serve as an important mediator in this relationship. Our study may provide some insights into anti-inflammatory therapy to improve the cognitive trajectory of TIA patients with high TMAO levels.

Bibliometric analysis of research trends in stem cell therapy for knee osteoarthritis over the period 2001-2021.

Stem cell therapy is a promising treatment for knee osteoarthritis, but few bibliometric studies have been performed on the subject. Bibliometric analysis is helpful for identifying the most influential studies in a specific field and can evaluate the global research trends in stem cell therapy for knee osteoarthritis. The Web of Science Core Collection was searched for publications from 2001 to 2021. Publication performance was analyzed using several bibliometric parameters, including VOSviewer, to identify the research landscape of trends in topics, and CiteSpace was investigated to identify the keywords that have the strongest citation bursts. From 2001 to 2021, in total, 1,345 publications explored the research on stem cells in knee osteoarthritis. The United States contributed the largest number of publications and at the top list of international collaborations. Tokyo Medical and Dental University ranked first among institutions in the overall number of articles and citations. The journal of Osteoarthritis and Cartilage had the largest number of publications. Sekiya Ichiro was the most cited author, with 32 articles. The keywords with the most frequent occurrence were "osteoarthritis," "mesenchymal stem cells," and "cartilage," in descending order of frequency. "fibroblast growth factor" and "extracellular vesicle" were the first and last searched theme terms, respectively. The number of publications on stem cells for knee osteoarthritis stays growing. Cartilage repair and paracrine function are current research hotspots for the stem cell therapy mechanism. Stem cell therapy has gradually advanced from basic research to the clinical application stage.

The mechanism underlying ICAM-1 and E-selectin-mediated hypertriglyceridemic pancreatitis-associated lung injury.

PURPOSE: To investigate the possible mechanism by which adhesion molecules ICAM-1 and E-selectin mediate hypertriglyceridemic pancreatitis (HTGP)-associated lung injury. METHODS: C57BL/6 mice were randomly divided into five groups: control group (Con), severe acute pancreatitis group (SAP), HTGP group (HTGP), A-205804 group (A-205804), and apocynin group (Apo). Serum biochemical markers related to pancreatitis, such as inflammatory cytokines, amylase and lipase, were measured by enzyme-linked immunosorbent assay (ELISA) kits. Hematoxylin and eosin (HE) staining was used to analyze the histopathology changes in the pancreas and lung, and myeloperoxidase (MPO) activity in lung was detected by immunohistochemistry (IHC). Molecules related to NF-κB signaling pathway and adhesion molecules were assessed by western blotting (WB), IHC and immunofluorescence staining. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) in lung tissues and serum were measured with reagent kits, respectively. RESULTS: The severity of pancreatitis and lung injury in HTGP group was more severe than that in SAP group, and the expression levels of adhesion molecules ICAM-1 and E-selectin in lung tissues of HTGP mice were significantly increased. After HTGP mice were treated with adhesion molecule inhibitor A-205804, the expression of ICAM-1 and E-selectin in A-205804 group significantly decreased, and the lung injury was alleviated. The HTGP group had higher levels of oxidative stress and NF-κB pathway-related protein p-p65 expression compared with the SAP group. Apocynin treatment resulted in suppression of p-p65, ICAM-1, and E-selectin expression. CONCLUSION: In HTGP, hypertriglyceridemia may exacerbate pancreatitis-related lung injury by regulating oxidative stress and activating the NF-κB proinflammatory pathway to upregulate ICAM-1 and E-selectin levels.

The difference in red blood cell distribution width from before to after thrombolysis as a prognostic factor in acute ischemic stroke patients: A 2-year follow-up.

Purpose: The aim of our study was to determine whether delta red blood cell distribution (ΔRDW) improves neurological outcomes in acute ischemic stroke (AIS) patients 2 years after intravenous thrombolysis (IVT) therapy. Methods: AIS patients who received IVT between January 2013 and December 2019 were retrospectively analyzed. In accordance with their mRS scores, the patients were divided into two groups. A binary logistic regression analysis was conducted to determine the influencing factors of adverse functional outcomes. It was decided to evaluate the variables' the predictive ability by using the area under the receiver operating characteristic. For the poor neurological recovery risk model, features were selected using the LASSO regression model. We also developed a predictive model based on logistic regression analysis, which combined the features selected in the minimum absolute contraction and selection operator regression models. An evaluation of the discrimination, calibration, and clinical applicability of the predictive model was conducted using the C index, calibration chart, and decision curve analysis. Internal validation was evaluated via bootstrapping. Results: Binary logistic regression analysis showed that ΔRDW was an independent influencing factor for poor neurofunctional outcomes. The most appropriate ΔRDW cut-off value for predicting the recovery of poor neurological outcomes was 18.9% (sensitivity: 89.9%, specificity: 78.6%, p < 0.001). The predictive factors included in the nomogram were age, the occurrence of CHD, stroke, AF, ΔRDW, NIHSS score at onset, interval time from onset to IVT, and whether there were indwelling urine catheters and gastric tubes. The model has not only a good discrimination ability, which was indicated by an overall C index of 0.891 (95% confidence interval: 0.829-0.953), but also a considerable calibration ability. Decision curve analysis showed that the nomogram of adverse neurological outcomes recovery was useful in the clinical practice when intervention was implemented above the threshold of 1% possibility of adverse neurological outcomes recovery. Conclusion: In patients with AIS after thrombolysis, the ΔRDW is a potential influencing factor that can be readily used to predict the likelihood of poor neurological function recovery.

Prognostic Model and Nomogram Construction and Validation With an Autophagy-Related Gene Signature in Low-Grade Gliomas.

Background : Autophagy plays a vital role in cancer development. However, the prognostic value of autophagy-related genes (ARGs) in low-grade gliomas (LGG) is unclear. This research aimed to investigate whether ARGs correlated with overall survival (OS) in LGG patients. Methods: RNA-sequencing data were obtained from The Cancer Genome Atlas (TCGA) TARGET GTEx database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of ARGs were performed by the "clusterprofile" R package. Cox regression with the wald χ2 test was employed to identify prognostic significant ARGs. Next, the receiver operator characteristic curves were established to evaluate the feasibility of risk score ( riskscore = h 0 ( t ) exp ( ∑ j = 1 n Coef j × X j ) ) and other clinical risk factors to predict prognosis. A nomogram was constructed. Correlations between clinical features and ARGs were further verified by a t-test or Kruskal-Wallis test. In addition, the correlations between autophagy and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA) and tumor immune estimation resource database. Last, the prediction model was verified by LGG data downloaded from the Chinese Glioma Genome Atlas (CGGA) database. Results: Overall, 35 DE-ARGs were identified. Functional enrichment analysis showed that these genes were mainly related to oxidative stress and regulation of autophagy. Nine ARGs (BAX, BIRC5, CFLAR, DIRAS3, GRID2, MAPK9, MYC, PTK6, and TP53) were significantly associated with OS. Age (Hazard ratio (HR) = 1.063, 95% CI: 1.046-1.080), grade (HR = 3.412, 95% CI: 2.164-5.379), histological type (HR = 0.556, 95% CI: 0.346-0.893), and risk score (HR = 1.135, 95% CI: 1.104-1.167) were independent prognostic risk factors (all p < 0.05). In addition, BIRC5, CFLAR, DIRAS3, TP53, and risk scores were found to correlate significantly with age and tumor grade (all p < 0.05). Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group (all p < 0.05). A prognostic nomogram was constructed to predict 1-, 3-, and 5-year survival, and the prognostic value of sorted ARGs were verified in the CGGA database and clinical samples. Conclusion: Our findings suggest that the 9 DE-ARGs' risk score model could serve as diagnostic and prognostic biomarkers. The prognostic nomograms could be useful for individualized survival prediction and improved treatment strategies.

The influence of unexpected early termination of intravenous rt-PA treatment on clinical outcome in acute ischemic stroke patients.

INTRODUCTION: This study aimed to explore the impact of unexpected early termination during intravenous thrombolysis on clinical prognosis in patients with acute ischemic stroke (AIS). METHODS: Patients who received intravenous thrombolysis were divided into an early termination group and a normal treatment group. The causes of unexpected termination were analyzed, and the prognosis was compared between the groups. RESULTS: The main causes of early termination of thrombolytic therapy included subjective wishes of family members (11.8%, 4) and persistently elevated blood pressure (14.7%, 5). The effective rate of thrombolytic therapy in the early termination group was significantly lower than that in the normal treatment group (P < 0.05). The rate of early neurological deterioration in the early termination group was significantly higher than that in the normal treatment group (P < 0.05). There was no significant difference in the incidence of symptomatic intracranial hemorrhage after thrombolysis between the two groups (P > 0.05). The average mRS score of the early termination group was significantly higher than that of the normal treatment group (P < 0.05). Multivariate analysis indicated that early termination of thrombolytic therapy and cumulative dosage of rt-PA before termination were the main factors affecting the 3-month prognosis. CONCLUSION: Subjective wishes of family members and persistently elevated blood pressure may be the main causes of early termination of thrombolysis, and the 3-month prognosis of patients could be adversely affected by early termination of thrombolytic therapy and cumulative dosage of rt-PA. Certain measures, such as popularizing thrombolytic health education and optimizing blood pressure management before and during thrombolysis, may be helpful for the normal operation of intravenous thrombolysis.

Targeting gut-brain axis through scalp-abdominal electroacupuncture in Parkinson's disease.

BACKGROUND: Evidence suggests that the pathogenesis of Parkinson's disease (PD) is initiated in the gut rather than in the brain. Thus, targeting the gut in early stages may have the potential to halt disease progression and alleviate symptoms. Various acupuncture techniques have been used to treat patients with PD and have shown promising results. However, previous acupuncture techniques focused on the brain and motor symptoms. We aimed to determine if targeting PD patients' gut-brain axis through electroacupuncture could be an effective, safe, and low-cost therapeutic option for management of non-motor and motor symptoms. METHODS: Thirty patients with mild to moderate PD were randomised into an intervention (n = 15) and a control group (n = 15). The intervention group received electroacupuncture twice a week for 30 min based on conventional drug treatment for 8 weeks. Conventional drug treatment was continued in the control group. The primary outcomes were changes in the score of clinical scales including the Non-motor Symptom Rating Scale (NMSS), PD Sleep Scale (PDSS), Bristol Stool Function Scale (BSFS), and Patient Associated Constipation and Quality of Life Scale (PAC-QOL). The secondary outcomes were the Unified PD Rating Scale (UPDRS) and Modified Hoehn-Yahr Staging Scale scores. Stool samples from the intervention group were collected before and after the procedure and were sent for gene sequencing. Adverse effects and personal impressions of the patients were noted during the course of the trial. RESULT: An 8-week course of scalp-abdominal electroacupuncture treatment was effective in improving the NMSS, PDSS, and UPDRS scores in patients with PD. Further, there was statistical significance in the two subdomains of NMSS, namely sleep/fatigue and miscellaneous, further implying the efficacy of acupuncture on sleep disturbance. However, although the current acupuncture treatment was gut targeted, it had no effect on BSFS or PAC-QOL. Apart from improved UPDRS motor scores and activities of daily living scores, acupuncture had no significant impact on scores of mentation, behaviour, mood, and therapy complications. Acupuncture did not alter the Hoehn and Yahr stage. Significant alterations in gut bacterial composition were detected in nine taxa at the genus level. The relative abundances of the genera Bacteroides and Parasutterella were significantly increased after the intervention, whereas the abundances of the genera Dialister, Hungatella, Barnesiella, Megasphaera, Allisonella, Intestinimon, and Moryella were significantly lower. CONCLUSION: An 8-week scalp-abdominal electroacupuncture treatment may be a complementary and alternative vehicle for PD patients. We detected nine taxa at the genus level which were significantly altered after treatment, emphasising the role of the gut-brain axis in the process.