Reverse causation between multiple sclerosis and psoriasis: a genetic correlation and Mendelian randomization study.

Observational studies have found a potential bidirectional positive association between multiple sclerosis and psoriasis, but these studies are susceptible to confounding factors. We examined the directionality of causation using Mendelian randomization and estimated the genetic correlation using the linkage disequilibrium score. We performed Mendelian randomization analysis using large-scale genome-wide association studies datasets from the International Multiple Sclerosis Genetics Consortium (IMSGC, 115,803 individuals of European ancestry) and FinnGen (252,323 individuals of European ancestry). We selected several Mendelian randomization methods including causal analysis using summary effect (CAUSE), inverse variance-weighted (IVW), and pleiotropy-robust methods. According to CAUSE and IVW the genetic liability to MS reduces the risk of psoriasis (CAUSE odds ratio [OR] 0.93, p = 0.045; IVW OR 0.93, p = 2.51 × 10-20), and vice versa (CAUSE OR 0.72, p = 0.001; IVW OR 0.71, p = 4.80 × 10-26). Pleiotropy-robust methods show the same results, with all p-values < 0.05. The linkage disequilibrium score showed no genetic correlation between psoriasis and MS (rg = - 0.071, p = 0.2852). In summary, there is genetic evidence that MS reduces the risk of psoriasis, and vice versa.

Coating 3D-Printed Bioceramics with Histatin Promotes Adhesion and Osteogenesis of Stem Cells.

Mesenchymal stem cell and 3D printing-based bone tissue engineering present a promising technique to repair large-volume bone defects. Its success is highly dependent on cell attachment, spreading, osteogenic differentiation, and in vivo survival of stem cells on 3D-printed scaffolds. In this study, we applied human salivary histatin-1 (Hst1) to enhance the interactions of human adipose-derived stem cells (hASCs) on 3D-printed ß-tricalcium phosphate (ß-TCP) bioceramic scaffolds. Fluorescent images showed that Hst1 significantly enhanced the adhesion of hASCs to both bioinert glass and 3D-printed ß-TCP scaffold. In addition, Hst1 was associated with significantly higher proliferation and osteogenic differentiation of hASCs on 3D-printed ß-TCP scaffolds. Moreover, coating 3D-printed ß-TCP scaffolds with histatin significantly promotes the survival of hASCs in vivo. The ERK and p38 but not JNK signaling was found to be involved in the superior adhesion of hASCs to ß-TCP scaffolds with the aid of Hst1. In conclusion, Hst1 could significantly promote the adhesion, spreading, osteogenic differentiation, and in vivo survival of hASCs on 3D-printed ß-TCP scaffolds, bearing a promising application in stem cell/3D printing-based constructs for bone tissue engineering.

The clinical value of serum xanthine oxidase levels in patients with acute ischemic stroke.

Xanthine oxidase (XO), a form of xanthine oxidoreductase, is widely distributed in various human tissues. As a major source for the generation of superoxide radicals, XO is involved in the induction of oxidative stress and inflammation during ischemic and hypoxic tissue injury. Therefore, we designed this study to identify the role of serum XO levels in acute ischemic stroke (AIS) pathogenesis. In this single-center prospective study, 328 consecutive patients with AIS for the first time were included, and 107 age- and sex-matched healthy controls from a community-based stroke screening population were also included. The serum levels of XO and several conventional stroke risk factors were assessed. Multivariate analysis was applied to evaluate the relationship between serum levels of XO and clinical outcomes, and nomogram models were developed to predict the onset, progression and prognosis of AIS. Compared with the healthy control group, the serum level of XO was significantly higher in the AIS group (P < 0.05) and was an independent risk factor for AIS (OR 8.68, 95% CI 4.62-14.33, P < 0.05). Patients with progressive stroke or a poor prognosis had a much higher serum level of XO than patients with stable stroke or a good prognosis (all P < 0.05). In addition, the serum level of XO was an independent risk factor for stroke progression (OR 1.98, 95% CI 1.12-3.50, P = 0.018) and a poor prognosis (OR 2.51, 95% CI 1.47-3.31, P = 0.001). The nomogram models including XO to predict the onset, progression and prognosis of AIS had good prediction and differentiation abilities. The findings of this study show that the serum level of XO on admission was an independent risk factor for AIS and had certain clinical predictive value for stroke progression and prognosis in patients with AIS.

Recent Advances in Animal Models, Diagnosis, and Treatment of Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a gradual degenerative jaw joint condition. Until recent years, TMJOA is still relatively unrecognized and ineffective to be treated. Appropriate animal models with reliable detection methods can help researchers understand the pathophysiology of TMJOA and find therapeutic options. In this study, we summarized common animal models of TMJOA created by chemical, surgical, mechanical, and genetical approaches. The relevant pathological symptoms and induction mechanisms were outlined. In addition, different pathological indicators, furthermore, emerging therapeutic regimens, such as intra-articular drug delivery and tissue engineering-based approaches to treat TMJOA based on these animal models, were summarized and updated. Understanding the physiology and pathogenesis of the TMJOA, together using various ways to diagnose the TMJOA, were elaborated, including imaging techniques, molecular techniques for detecting inflammatory cytokines, histochemical staining, and histomorphometry measures. A more reliable diagnosis will enable the development of new prevention and more effective treatment strategies and thereby improve the quality of life of TMJOA patients. Impact statement Temporomandibular joint osteoarthritis (TMJOA) affects 8 to 16 percent of the population worldwide. However, TMJOA is still relatively unrecognized and ineffective to be treated in the clinic. Appropriate animal models with reliable diagnostic methods can help researchers understand the pathophysiology of TMJOA and find therapeutic options. We herein summarized common animal models of TMJOA and various ways to diagnose the TMJOA. More importantly, emerging therapeutic regimens to treat TMJOA based on these animal models were summarized. With the aid of strategies listed, more effective treatment strategies will be developed and thereby improve the life quality of TMJOA patients.

si-PDGFRß-Loaded Exosomes Suppress the Progression of Glioma by Inhibiting the Oxidative Associated PI3K/Akt/EZH2 Signaling Pathway.

This study investigated the possibility of exosomes loaded with si-PDGFRß ability to suppress the progression of glioma. Common gliomas develop from neuroglial progenitor cells. Many variables affect the survival rate and occurrence of gliomas. Understanding oxidative stress processes and creating new, efficient treatments are crucial because oxidative stress is linked to the development of brain tumors. For this purpose, selected clinical samples were subjected to various tests like quantitative real-time PCR, Cignal Finder RTK signaling 7-pathway reporter array analysis, CCK-8 analysis, flow cytometry, and immunoblotting. Here, we demonstrated that PDGFRß expression was increased in glioma patients. Following that, cell-derived exosomes were extracted and collected and traced in vivo, and selected tissue samples were subjected to immunohistochemical analysis. The results indicated that the knockdown of PDGFRß (si-PDGFRß) inhibited the proliferation of glioma cells. Besides this, si-PDGFRß-loaded exosomes induced a similar antitumor effect in glioma cells. The anticancer effect of si-PDGFRß-loaded exosomes was mediated by the inactivation of the PI3K/Akt/EZH2 pathway. Finally, we verified that this exosome delivery system, si-PDGFRß-loaded exosomes, had robust targeting and no associated toxicity. In conclusion, the study confirmed that si-PDGFRß-loaded exosomes inhibit glioma progression via inactivating the PI3K/Akt/EZH2 signaling pathway.

Crosstalk Between the Gut and Brain: Importance of the Fecal Microbiota in Patient With Brain Tumors.

Background: Variations in the gut microbiota may affect the metabolism, inflammation and immune response of the host. Microbiota dysbiosis has been extensively investigated in neurological disorders and diseases of the central nervous system (CNS). However, the alterations of the gut microbiota in patients suffering from brain tumors and the associations of the gut microbiota with these diseases remain unknown. Herein, we investigate the alterations of the gut microbiota community in patients with brain tumors and the associations between the two and further explore microbial markers used for the diagnosis of brain tumors. Methods: In our study, we recruited 158 participants, consisting of 101 brain tumor patients (65 benign and 36 malignant cases) and 57 age- and sex-matched healthy controls (HCs). We characterized the gut microbial community by using 16S rRNA gene amplicon sequencing and investigated its correlations with clinical features. Results: The results showed remarkably less microbial ecosystem richness and evenness in patients with brain tumors than in HCs. The gut microbiota community structure underwent profound changes in the brain tumor group, including an increase in the abundances of pathogenic bacteria, such as Fusobacteriota and Proteobacteria and a reduction in the abundances of probiotic bacteria, such as Bifidobacterium or Lachnospira. Moreover, our study indicated more significant correlations and clustering of pathogens in the malignant brain tumor group. Furthermore, a biomarker panel was used to discriminate the brain tumor patients from the healthy controls (AUC: 0.77). Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation revealed an accumulation of harmful metabolites and disorders of the basic physiological pathways in the brain tumor group. Conclusions: Our study revealed that brain tumor patients may possess divergent host-microbe interactions from those of healthy controls, especially in malignant brain tumor patients. In addition, the intestinal flora may be involved in immune responses and metabolism in the microenvironment of brain tumors. All evidence, including the biomarker panel, suggests that the intestinal flora may be a useful diagnostic and predictive tool and an important preventive target for brain tumors.

The Potential Role of Hypoxia-Inducible Factor-1 in the Progression and Therapy of Central Nervous System Diseases.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimer protein composed of an oxygenregulated functional subunit, HIF-1α, and a structural subunit, HIF-1ß, belonging to the basic helixloop- helix family. Strict regulation of HIF-1 protein stability and subsequent transcriptional activity involves various molecular interactions and is primarily controlled by post-transcriptional modifications. Hypoxia, owing to impaired cerebral blood flow, has been implicated in a range of central nervous system (CNS) diseases by exerting a deleterious effect on brain function. As a master oxygen- sensitive transcription regulator, HIF-1 is responsible for upregulating a wide spectrum of target genes involved in glucose metabolism, angiogenesis, and erythropoiesis to generate the adaptive response to avoid, or at least minimize, hypoxic brain injury. However, prolonged, severe oxygen deprivation may directly contribute to the role-conversion of HIF-1, namely, from neuroprotection to the promotion of cell death. Currently, an increasing number of studies support the fact HIF-1 is involved in a variety of CNS-related diseases, such as intracranial atherosclerosis, stroke, and neurodegenerative diseases. This review article chiefly focuses on the effect of HIF-1 on the pathogenesis and mechanism of progression of numerous CNS-related disorders by mediating the expression of various downstream genes and extensive biological functional events and presents robust evidence that HIF-1 may represent a potential therapeutic target for CNS-related diseases.

Psychiatric traits and intracerebral hemorrhage: A Mendelian randomization study.

Background: Psychiatric traits have been associated with intracerebral hemorrhage (ICH) in observational studies, although their causal relationships remain uncertain. We used Mendelian randomization analyses to infer causality between psychiatric traits and ICH. Methods: We collected data from genome-wide association studies of ICH (n = 361,194) and eight psychiatric traits among Europeans, including mood swings (n = 451,619), major depressive disorder (n = 480,359), attention-deficit/hyperactivity disorder (n = 53,293), anxiety (n = 459,560), insomnia (n = 462,341), schizophrenia (n = 77,096), neuroticism (n = 374,323), and bipolar disorder (n = 51,710). We performed a series of bidirectional two-sample Mendelian randomization and related sensitivity analyses. A Bonferroni corrected threshold of p < 0.00625 (0.05/8) was considered to be significant, and p < 0.05 was considered suggestive of evidence for a potential association. Results: Mendelian randomization analyses revealed suggestive positive causality of mood swings on ICH (odds ratio = 1.006, 95% confidence interval = 1.001-1.012, p = 0.046), and the result was consistent after sensitivity analysis. However, major depressive disorder (p = 0.415), attention-deficit/hyperactivity disorder (p = 0.456), anxiety (p = 0.664), insomnia (p = 0.699), schizophrenia (p = 0.799), neuroticism (p = 0.140), and bipolar disorder (p = 0.443) are not significantly associated with the incidence of ICH. In the reverse Mendelian randomization analyses, no causal effects of ICH on mood swings (p = 0.565), major depressive disorder (p = 0.630), attention-deficit/hyperactivity disorder (p = 0.346), anxiety (p = 0.266), insomnia (p = 0.102), schizophrenia (p = 0.463), neuroticism (p = 0.261), or bipolar disorder (p = 0.985) were found. Conclusion: Our study revealed that mood swings are suggestively causal of ICH and increase the risk of ICH. These results suggest the clinical significance of controlling mood swings for ICH prevention.

Multimodal Monitoring in Large Hemispheric Infarction: Quantitative Electroencephalography Combined With Transcranial Doppler for Prognosis Prediction.

Background: We aimed to explore whether transcranial Doppler (TCD) combined with quantitative electroencephalography (QEEG) can improve prognosis evaluation in patients with a large hemispheric infarction (LHI) and to establish an accurate prognosis prediction model. Methods: We prospectively assessed 90-day mortality in patients with LHI. Brain function was monitored using TCD-QEEG at the bedside of the patient. Results: Of the 59 (55.3 ± 10.6 years; 17 men) enrolled patients, 37 (67.3%) patients died within 90 days. The Cox regression analyses revealed that the Glasgow Coma Scale (GCS) score ≤ 8 [hazard ratio (HR), 3.228; 95% CI, 1.335-7.801; p = 0.009], TCD-terminal internal carotid artery as the offending vessel (HR, 3.830; 95% CI, 1.301-11.271; p = 0.015), and QEEG-a (delta + theta)/(alpha + beta) ratio ≥ 3 (HR, 3.647; 95% CI, 1.170-11.373; p = 0.026) independently predicted survival duration. Combining these three factors yielded an area under the receiver operating characteristic curve of 0.905 and had better predictive accuracy than those of individual variables (p < 0.05). Conclusion: TCD and QEEG complement the GCS score to create a reliable multimodal method for monitoring prognosis in patients with LHI.

Nerve ultrasound evaluation of Guillain-Barré syndrome subtypes in northern China.

INTRODUCTION/AIMS: Ultrasound (US) studies have demonstrated patchy enlargement of spinal and peripheral nerves in Guillain-Barré syndrome (GBS). However, whether ultrasound yields useful information for early classification of GBS has not been established. We aimed to evaluate nerve ultrasound in patients with GBS in northern China and compare the sonographic characteristics between demyelinating and axonal subtypes. METHODS: Between November 2018 and October 2019, 38 hospitalized GBS patients within 3 wk of disease onset and 40 healthy controls were enrolled. Ultrasonographic cross-sectional areas (CSA) of the peripheral nerves, vagus nerve, and cervical nerve roots were prospectively recorded in GBS subtypes and controls. RESULTS: Ultrasonographic CSA exhibited significant enlargement in most patients' nerves compared with healthy controls, most prominent in cervical nerves. The CSA tended to be larger in acute inflammatory demyelinating polyneuropathy (AIDP) than in acute motor axonal neuropathy (AMAN)/acute motor and sensory axonal neuropathy (AMSAN), especially in cervical nerves (C5: 5.9 ± 1.6 mm2 vs. 7.0 ± 1.7 mm2 , p = .042; C6: 10.5 ± 1.8 mm2 vs. 12.0 ± 2.1 mm2 , p = .033). The chi-squared test revealed significant differences in nerve enlargement in C5 (p < .001), C6 (p < .001), the proximal median nerve (p < .001), and the vagus nerve (p = .003) between GBS and controls. The vagus nerve was larger in patients with autonomic dysfunction than in patients without it (2.3 ± 1.0 mm2 vs. 1.4 ± 0.5 mm2 , p = .003). DISCUSSION: The demyelinating subtype presented with more significant cervical nerve enlargement in GBS. Vagus nerve enlargement may be a useful marker for autonomic dysfunction.

Transcranial Doppler Combined With Quantitative Electroencephalography Brain Function Monitoring for Estimating the Prognosis of Patients With Posterior Circulation Cerebral Infarction.

Posterior circulation cerebral infarction (PCCI) can lead to deceased infratentorial cerebral blood flow (CBF) and metabolism. Neural activity is closely related to regional cerebral blood flow both spatially and temporally. Transcranial Doppler (TCD) combined with quantitative electroencephalography (QEEG) is a technique that evaluates neurovascular coupling and involves synergy between the metabolic and vascular systems. This study aimed to monitor brain function using TCD-QEEG and estimate the efficacy of TCD-QEEG for predicting the prognosis of patients with PCCI. We used a TCD-QEEG recording system to perform quantitative brain function monitoring; we recorded the related clinical variables simultaneously. The data were analyzed using a Cox proportional hazards regression model. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the cut-off for the diastolic flow velocity (VD) and (delta + theta)/(alpha + beta) ratio (DTABR). The area under the ROC curve (AUROC) was calculated to assess the predictive validity of the study variables. Forty patients (aged 63.7 ± 9.9 years; 30 men) were assessed. Mortality at 90 days was 40%. The TCD indicators of VD [hazard ratio (HR) 0.168, confidence interval (CI) 0.047-0.597, p = 0.006] and QEEG indicators of DTABR (HR 12.527, CI 1.637-95.846, p = 0.015) were the independent predictors of the clinical outcomes. The AUROC after combination of VD and DTABR was 0.896 and showed better predictive accuracy than the Glasgow Coma Scale score (0.75), VD (0.76), and DTABR (0.781; all p < 0.05). TCD-QEEG provides a good understanding of the coupling mechanisms in the brain and can improve our ability to predict the prognosis of patients with PCCI.

Monitoring of patients with brainstem hemorrhage: A simultaneous study of quantitative electroencephalography and transcranial Doppler.

OBJECTIVE: To explore whether quantitative electroencephalography (QEEG) and transcranial Doppler (TCD) can be used to evaluate patients with acute severe brainstem hemorrhage (ASBH). METHODS: We prospectively enrolled patients with ASBH and assessed their mortality at the 90-day follow-up. The patients' demographic data, serological data, and clinical factors were recorded. Quantitative brain function monitoring was performed using a TCD-QEEG recording system attached to the patient's bedside. RESULTS: Thirty-one patients (55.3 ± 10.6 years; 17 men) were studied. Mortality at 90 days was at 61.3%. There was no significant difference in TCD-related parameters between the survival group and the death group (p > 0.05). Among the QEEG-related indexes, only the (delta + theta)/(alpha + beta) ratio (DTABR) (odds ratio 11.555, 95%confidence interval 1.413-94.503, p = 0.022) was an independent predictor of clinical outcome; the area under the ROC curve of DTABR was 0.921, cut-off point was 3.88, sensitivity was 79%, and specificity was 100%. CONCLUSIONS: In patients with ASBH, QEEG can effectively inform the clinical prognosis regarding 90-day mortality, while TCD cannot. SIGNIFICANCE: QEEG shows promise for informing the mortality prognosis of patients with ASBH.