The alteration of serum bile acid profile among traumatic brain injury patients: a small-scale prospective study.

Traumatic brain injury is one of the major causes of morbidity and mortality worldwide. With the development of bile acids as a potential treatment, to identify the influence of traumatic brain injury on bile acid metabolism shows growing importance. This present study did a preliminary exploration of the bile acid profile alteration among traumatic brain injury patients. In total, 14 patients and 7 healthy volunteers were enrolled. The bile acid profile of the blood samples were detected by an Ultra-performance Liquid Chromatography Mass Spectrometer/Mass Spectrometer system. It was found that 6 bile acids were statistically decreased in traumatic brain injury patients comparing with healthy volunteers: glycocholic acid (median level 44.4 ng/ml vs 98.7 ng/ml, p = 0.003), taurocholic acid (median level 10.9 ng/ml vs 19.5 ng/ml, p = 0.006), glycoursodeoxycholic acid (median level 17.4 ng/ml vs 71.4 ng/ml, p = 0.001), ursodeoxycholic acid (median level <1 ng/ml vs 32.4 ng/ml, p = 0.002), taurochenodeoxycholic acid (median level <1 ng/ml vs 53.6 ng/ml, p = 0.003) and glycochenodeoxycholic acid (GCDCA, median level 160 ng/ml vs 364 ng/ml, p<0.001). In conclusion, traumatic brain injury events are able to induce bile acid metabolism alteration in plasma and might cause reduction in glycocholic, taurocholic, glycoursodeoxycholic, ursodeoxycholic, taurochenodeoxycholic and glycochenodeoxycholic acid levels.

Analysis of the efficacy and related factors of ventriculoperitoneal shunt for AIDS with cryptococcal meningitis.

Background: Cryptococcus neoformans is an opportunistic pathogen, which is more common in patients with AIDS. Increased intracranial pressure (ICP) is an important complication of cryptococcal meningitis (CM) and affects the therapeutic effect of CM. Objective: To evaluate the effect and treatment for the management of ventriculoperitoneal shunt (VPS) in the treatment of AIDS complicated with CM and to analyze the factors associated with VPS and the indices affecting the outcome of CM patients. Methods: A retrospective case study was conducted on patients with CM treated in the First Affiliated Hospital of Zhejiang University School of Medicine from 2011 to 2019. The Chi-square test was used for categorical variables and the Student's t-test was used for continuous variables. Multivariable analysis of baseline factors related to VPS placement was performed with stepwise logistic regression analysis, factors associated with the outcome of these patients were studied by Cox regression analysis, and Kaplan-Meier survival curves were constructed to assess the outcome of patients. Results: There were 96 patients with AIDS complicated with CM. VPS had a great effect on the patients, especially those with ICP > 350 mmH2O. The outcome, including the mortality rate and modified Rankin scale (MRS) score of these patients, significantly improved after the placement of VPS. The karnofsky performance status (KPS) scores of patients whose ICP > 350 mmH2O improved from 39.3 ± 21.3 at baseline to 88.7 ± 26.9 at 3 months after VPS, better than those without VPS. Multivariable analysis showed that visual impairment (OR, 0.026; 95% CI, 0.001, 0.567; P = 0.021) and ICP > 350 mmH2O (OR, 0.026; 95% CI, 0.002, 0.293; P = 0.003) were related elements with the placement of shunt, and KPS score (HR, 0.968; 95% CI, 0.943, 0.993; P = 0.013) and ICP > 350 mmH2O (HR, 2.801; 95% CI, 1.035, 7.580; P = 0.043) were indices of the outcome of AIDS patients with CM. For patients with ICP > 350 mmHg, Kaplan-Meier analysis showed that the 3-year outcome of patients with VPS was better than that of patients without VPS (P = 0.0067). Conclusion: VPS was associated with better 3-year survival rates, and postshunt placement complications like infections were rare. The identification of factors related to VPS in the initial diagnosis of CM can contribute to more active management and improve the outcome.

Exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation after traumatic brain injury.

Exosomes derived from bone marrow mesenchymal stem cells can inhibit neuroinflammation through regulating microglial phenotypes and promoting nerve injury repair. However, the underlying molecular mechanism remains unclear. In this study, we investigated the mechanism by which exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation. Our in vitro co-culture experiments showed that bone marrow mesenchymal stem cells and their exosomes promoted the polarization of activated BV2 microglia to their anti-inflammatory phenotype, inhibited the expression of proinflammatory cytokines, and increased the expression of anti-inflammatory cytokines. Our in vivo experiments showed that tail vein injection of exosomes reduced cell apoptosis in cortical tissue of mouse models of traumatic brain injury, inhibited neuroinflammation, and promoted the transformation of microglia to the anti-inflammatory phenotype. We screened some microRNAs related to neuroinflammation using microRNA sequencing and found that microRNA-181b seemed to be actively involved in the process. Finally, we regulated the expression of miR181b in the brain tissue of mouse models of traumatic brain injury using lentiviral transfection. We found that miR181b overexpression effectively reduced apoptosis and neuroinflamatory response after traumatic brain injury and promoted the transformation of microglia to the anti-inflammatory phenotype. The interleukin 10/STAT3 pathway was activated during this process. These findings suggest that the inhibitory effects of exosomes derived from bone marrow mesenchymal stem cells on neuroinflamation after traumatic brain injury may be realized by the action of miR181b on the interleukin 10/STAT3 pathway.

Traumatic Brain Injury Induces Gastrointestinal Dysfunction and Dysbiosis of Gut Microbiota Accompanied by Alterations of Bile Acid Profile.

Gastrointestinal dysfunction is a common peripheral organ complication after traumatic brain injury (TBI), yet the underlying mechanism remains unknown. TBI has been demonstrated to cause gut microbiota dysbiosis in animal models, although the impacts of gut microbiota dysbiosis on gastrointestinal dysfunction were not examined. Bile acids are key metabolites between gut microbiota and host interactions. Therefore, the aim of this study was to investigate the mechanistic links between them by detecting the alterations of gut microbiota and bile acid profile after TBI. For that, we established TBI in mice using a lateral fluid percussion injury model. Gut microbiota was examined by 16S rRNA sequencing, and bile acids were profiled by ultra-performance liquid chromatography-tandem mass spectrometry. Our results showed that TBI caused intestinal inflammation and gut barrier impairment. Alterations of gut microbiota and bile acid profile were observed. The diversity of gut microbiota experienced a time dependent change from 1 h to 7 days post-injury. Levels of bile acids in feces and plasma were decreased after TBI, and the decrease was more significant in secondary bile acids, which may contribute to intestinal inflammation. Specific bacterial taxa such as Staphylococcus and Lachnospiraceae that may contribute to the bile acid metabolic changes were identifed. In conclusion, our study suggested that TBI-induced gut microbiota dysbiosis may contribute to gastrointestinal dysfunction via altering bile acid profile. Gut microbiota may be a potential treatment target for TBI-induced gastrointestinal dysfunction.

A comparison of demographic, epidemiological and clinical characteristics of hospital influenza-related viral pneumonia patients.

BACKGROUND: Through the comparison of the demographic, epidemiological, and clinical characteristics of hospital human influenza (influenza A (H1N1) pdm09, H3N2, and B)-related and hospitalized avian-origin influenza A (H7N9)-related viral pneumonia patients, find the different between them. METHODS: A retrospective study was conducted in hospitalized influenza-related viral pneumonia patients. RESULTS: Human influenza A-related patients in the 35-49-year-old group were more than those with B pneumonia patients (p = 0.027), and relatively less in the ≥ 65-year-old group than B pneumonia patients (p = 0.079). The proportion of comorbid condition to human influenza A pneumonia was 58%, lower than B pneumonia and H7N9 pneumonia patients (78% vs. 77.8%; p = 0.013). The proportion of invasive mechanical ventilation (IMV), lymphocytopenia, elevated lactate dehydrogenase to hospitalized human influenza A-related viral pneumonia patients was higher than B pneumonia patients (p < 0.05), but lower than H7N9 pneumonia patients (p < 0.05). In the multivariate analysis, pulmonary consolidation (odds ratio (OR): 13.67; 95% confidence interval (CI) 1.54-121.12; p = 0.019) and positive bacterial culture (sputum) (OR: 7.71; 95% CI 2.48-24.03; p < 0.001) were independently associated with IMV, while shock (OR: 13.16; 95% CI 2.06-84.07; p = 0.006), white blood cell count > 10,000/mm3 (OR: 7.22; 95% CI 1.47-35.58; p = 0.015) and positive bacterial culture(blood or sputum) (OR: 6.27; 95% CI 1.36-28.85; p = 0.018) were independently associated with death in the three types hospitalized influenza-related viral pneumonia patients. CONCLUSIONS: Hospital influenza B-related viral pneumonia mainly affects the elderly and people with underlying diseases, while human influenza A pneumonia mainly affects the young adults; however, the mortality was similar. The hospitalized human influenza A-related viral pneumonia patients was severer than B pneumonia patients, but milder than H7N9 pneumonia patients. Pulmonary consolidation and positive bacterial culture (sputum) were independently associated with IMV, while shock, white blood cell count > 10,000/mm3, and positive bacterial culture (blood or sputum) were independently associated with death to three types hospitalized influenza-related viral pneumonia patients.

A Retrospective Clinical Analysis of the Serum Bile Acid Alteration Caused by Traumatic Brain Injury.

Traumatic brain injury (TBI) can cause damage to peripheral organ systems, such as digestive organ system, and alterations of gut microbiota in addition to brain injury. Our previous study found that TBI induced gastrointestinal dysfunction accompanied by alterations of bile acid metabolism. Bile acid and its receptors have been reported to play important roles in various neurological diseases. To further examine the changes of bile acid metabolism in TBI patients, we performed a retrospective clinical analysis. In this study, 177 patients were included, and the results showed that TBI patients had more frequent antibiotic use compared with a control group. Regression analysis identified TBI as an independent factor for reduction of serum bile acid level (B = -1.762, p = 0.006), even with antibiotic use taken into a regression model. Sub-group regression analysis of TBI patients showed that antibiotic use was negatively associated with bile acid level, while creatinine and triglyceride were positively associated with bile acid level. In conclusion, these data indicated that TBI could greatly reduce serum bile acid. This study provided preliminary but novel clinical evidence of TBI interfering with bile acid metabolism, and further studies with large sample sizes are needed to validate these findings in the future.

Mechanism of ARPP21 antagonistic intron miR-128 on neurological function repair after stroke.

OBJECTIVE: Stroke is a cerebrovascular disorder that often causes neurological function defects. ARPP21 is a conserved host gene of miR-128 controlling neurodevelopmental functions. This study investigated the mechanism of ARPP21 antagonistic intron miR-128 on neurological function repair after stroke. METHODS: Expressions of ARPP21 and miR-128 in stroke patients were detected. The mouse neurons and astrocytes were cultured in vitro and treated with oxygen-glucose deprivation (OGD). The OGD-treated cells were transfected with pc-ARPP21 and miR-128 mimic. The proliferation of astrocytes, and the apoptosis of neurons and astrocytes were detected, and inflammatory factors of astrocytes were measured. The binding relationship between miR-128 and CREB1 was verified. The rat model of middle cerebral artery occlusion (MCAO) was established. ARPP21 expression in model rats was detected. The effects of pc-ARPP21 on neuron injury, brain edema volume, and cerebral infarct in rats were observed. RESULTS: ARPP21 expression was downregulated and miR-128 expression was upregulated in stroke patients. pc-ARPP21 facilitated the proliferation of astrocytes and inhibited apoptosis of neurons and astrocytes, and reduced inflammation of astrocytes. miR-128 mimic could reverse these effects of pc-ARPP21 on neurons and astrocytes. miR-128 targeted CREB1 and reduced BDNF secretion. In vitro experiments confirmed that ARPP21 expression was decreased in MCAO rats, and pc-ARPP21 promoted neurological function repair after stroke. CONCLUSION: ARPP21 upregulated CREB1 and BDNF expressions by antagonizing miR-128, thus inhibiting neuronal apoptosis and promoting neurological function repair after stroke. This study may offer a novel target for the management of stroke.

Inhibition of miR-19a-3p decreases cerebral ischemia/reperfusion injury by targeting IGFBP3 in vivo and in vitro.

BACKGROUND: Inflammation and apoptosis are considered to be two main factors affecting ischemic brain injury and the subsequent reperfusion damage. MiR-19a-3p has been reported to be a possible novel biomarker in ischemic stroke. However, the function and molecular mechanisms of miR-19a-3p remain unclear in cerebral ischemia/reperfusion (I/R) injury. METHODS: The I/R injury model was established in vivo by middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and in vitro by oxygen-glucose deprivation and reperfusion (OGD/R) induced SH-SY5Y cells. The expression of miR-19a-3p was determined by reverse transcription quantitative PCR. The infarction volumes, Neurological deficit scores, apoptosis, cell viability, pro-inflammatory cytokines and apoptosis were evaluated using Longa score, Bederson score, TTC, TUNEL staining, CCK-8, ELISA, flow cytometry assays. Luciferase reporter assay was utilized to validate the target gene of miR-19a-3p. RESULTS: We first found miR-19a-3p was significantly up-regulated in rat I/R brain tissues and OGD/R induced SH-SY5Y cells. Using the in vivo and in vitro I/R injury model, we further demonstrated that miR-19a-3p inhibitor exerted protective role against injury to cerebral I/R, which was reflected by reduced infarct volume, improved neurological outcomes, increased cell viability, inhibited inflammation and apoptosis. Mechanistically, miR-19a-3p binds to 3'UTR region of IGFBP3 mRNA. Inhibition of miR-19a-3p caused the increased expression of IGFBP3 in OGD/R induced SH-SY5Y cells. Furthermore, we showed that IGFBP3 overexpression imitated, while knockdown reversed the protective effects of miR-19a-3p inhibitor against OGD/R-induced injury. CONCLUSIONS: In summary, our findings showed miR-19a-3p regulated I/R-induced inflammation and apoptosis through targeting IGFBP3, which might provide a potential therapeutic target for cerebral I/R injury.

Template-specific fidelity of DNA replication with high-order neighbor effects: A first-passage approach.

DNA replication fidelity is a critical issue in molecular biology. Biochemical experiments have provided key insights on the mechanism of fidelity control by DNA polymerases in the past decades, whereas systematic theoretical studies on this issue began only recently. Because of the underlying difficulties of mathematical treatment, comprehensive surveys on the template-specific replication kinetics are still rare. Here we propose a first-passage approach to address this problem, in particular the positional fidelity, for complicated processes with high-order neighbor effects. Under biologically relevant conditions, we derived approximate analytical expressions of the positional fidelity which show intuitively how some key kinetic pathways are coordinated to guarantee the high fidelity, as well as the high velocity, of the replication processes. It is also shown that the fidelity at any template position is dominantly determined by the nearest-neighbor template sequences, which is consistent with the idea that replication mutations are randomly distributed in the genome.

Ginkgolide B promotes the proliferation and differentiation of neural stem cells following cerebral ischemia/reperfusion injury, both in vivo and in vitro.

Neural stem cells have great potential for the development of novel therapies for nervous system diseases. However, the proliferation of endogenous neural stem cells following brain ischemia is insufficient for central nervous system self-repair. Ginkgolide B has a robust neuroprotective effect. In this study, we investigated the cell and molecular mechanisms underlying the neuroprotective effect of ginkgolide B on focal cerebral ischemia/reperfusion injury in vitro and in vivo. Neural stem cells were treated with 20, 40 and 60 mg/L ginkgolide B in vitro. Immunofluorescence staining was used to assess cellular expression of neuron-specific enolase, glial fibrillary acid protein and suppressor of cytokine signaling 2. After treatment with 40 and 60 mg/L ginkgolide B, cells were large, with long processes. Moreover, the proportions of neuron-specific enolase-, glial fibrillary acid protein- and suppressor of cytokine signaling 2-positive cells increased. A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion. Six hours after ischemia, ginkgolide B (20 mg/kg) was intraperitoneally injected, once a day. Zea Longa's method was used to assess neurological function. Immunohistochemistry was performed to evaluate the proportion of nestin-, neuron-specific enolase- and glial fibrillary acid protein-positive cells. Real-time quantitative polymerase chain reaction was used to measure mRNA expression of brain-derived neurotrophic factor and epidermal growth factor. Western blot assay was used to analyze the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2. Ginkgolide B decreased the neurological deficit score, increased the proportion of nestin-, neuron-specific enolase- and glial fibrillary acid protein-positive cells, increased the mRNA expression of brain-derived neurotrophic factor and epidermal growth factor, and increased the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2 in the ischemic penumbra. Together, the in vivo and in vitro findings suggest that ginkgolide B improves neurological function by promoting the proliferation and differentiation of neural stem cells in rats with cerebral ischemia/reperfusion injury.

Relationship of the angle between the A1 and A2 segments of the anterior cerebral artery with formation and rupture of anterior communicating artery aneurysm.

PURPOSE: To measure the angle between A1 and A2 segments of the anterior cerebral artery and analyze the relationship of this angle with the formation and rupture of anterior communicating artery aneurysm (ACoAA). METHODS: Patients with ACoAA (n=64) and with non-ACoAA (n=187) randomly chosen were included. The A1-A2 segment angles were measured using multislice spiral computed tomography angiography. The angular dimensions and differences were recorded and compared between the ACoAA and non-ACoAA groups and the ruptured (n=23) and unruptured group (n=41). The A1 segment morphology was divided into predominant and balanced type. The ACoAA aneurysm protrusion direction was divided into five types. RESULTS: The incidence of ACoAA was significantly higher in patients with A1 predominance compared to A1 balance (p<0.05). The mean A1-A2 segment angle was significantly smaller in the ACoAA group compared with the non-ACoAA group (p<0.001). There was no significant difference in mean A1-A2 segment angle between ruptured and unruptured groups. There was no significant relationship between aneurysm protrusion rupture and direction. CONCLUSIONS: The formation of ACoAA is more likely when there is A1 segment predominance in the anterior cerebral artery. The A1-A2 angle can help predict the formation of ACoAA but not useful for rupture predicting.