Random forest-based prediction of intracranial hypertension in patients with traumatic brain injury.

BACKGROUND: Treatment and prevention of intracranial hypertension (IH) to minimize secondary brain injury are central to the neurocritical care management of traumatic brain injury (TBI). Predicting the onset of IH in advance allows for a more aggressive prophylactic treatment. This study aimed to develop random forest (RF) models for predicting IH events in TBI patients. METHODS: We analyzed prospectively collected data from patients admitted to the intensive care unit with invasive intracranial pressure (ICP) monitoring. Patients with persistent ICP > 22 mmHg in the early postoperative period (first 6 h) were excluded to focus on IH events that had not yet occurred. ICP-related data from the initial 6 h were used to extract linear (ICP, cerebral perfusion pressure, pressure reactivity index, and cerebrospinal fluid compensatory reserve index) and nonlinear features (complexity of ICP and cerebral perfusion pressure). IH was defined as ICP > 22 mmHg for > 5 min, and severe IH (SIH) as ICP > 22 mmHg for > 1 h during the subsequent ICP monitoring period. RF models were then developed using baseline characteristics (age, sex, and initial Glasgow Coma Scale score) along with linear and nonlinear features. Fivefold cross-validation was performed to avoid overfitting. RESULTS: The study included 69 patients. Forty-three patients (62.3%) experienced an IH event, of whom 30 (43%) progressed to SIH. The median time to IH events was 9.83 h, and to SIH events, it was 11.22 h. The RF model showed acceptable performance in predicting IH with an area under the curve (AUC) of 0.76 and excellent performance in predicting SIH (AUC = 0.84). Cross-validation analysis confirmed the stability of the results. CONCLUSIONS: The presented RF model can forecast subsequent IH events, particularly severe ones, in TBI patients using ICP data from the early postoperative period. It provides researchers and clinicians with a potentially predictive pathway and framework that could help triage patients requiring more intensive neurological treatment at an early stage.

Natural products targeting cellular processes common in Parkinson's disease and multiple sclerosis.

The hallmarks of Parkinson's disease (PD) include the loss of dopaminergic neurons and formation of Lewy bodies, whereas multiple sclerosis (MS) is an autoimmune disorder with damaged myelin sheaths and axonal loss. Despite their distinct etiologies, mounting evidence in recent years suggests that neuroinflammation, oxidative stress, and infiltration of the blood-brain barrier (BBB) all play crucial roles in both diseases. It is also recognized that therapeutic advances against one neurodegenerative disorder are likely useful in targeting the other. As current drugs in clinical settings exhibit low efficacy and toxic side effects with long-term usages, the use of natural products (NPs) as treatment modalities has attracted growing attention. This mini-review summarizes the applications of natural compounds to targeting diverse cellular processes inherent in PD and MS, with the emphasis placed on their neuroprotective and immune-regulating potentials in cellular and animal models. By reviewing the many similarities between PD and MS and NPs according to their functions, it becomes evident that some NPs studied for one disease are likely repurposable for the other. A review from this perspective can provide insights into the search for and utilization of NPs in treating the similar cellular processes common in major neurodegenerative diseases.

Corrigendum: Natural products targeting cellular processes common in Parkinson's disease and multiple sclerosis.

[This corrects the article DOI: 10.3389/fneur.2023.1149963.].

Case report: Varicella-zoster virus infection triggering progressive encephalomyelitis with rigidity and myoclonus.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare neurological disease of unknown etiology, and most patients with PERM are positive for anti-glycine receptor (GlyR) antibody. In this case study, we report a clinical case of a varicella-zoster virus-infected patient who developed anti-GlyR antibody-positive PERM. He initially suffered from herpes zoster and gradually developed symptoms of impaired brainstem functions including hoarse voice and dysphagia, accompanied by paroxysmal sympathetic hyperactivity. The patient also suffered from severe spasms, which were easily triggered by external stimuli. Glycine receptor antibodies were then found to be positive in serum and cerebrospinal fluid, and the diagnosis of PERM was confirmed. Methylprednisolone and gamma globulin treatments were given, and spasms were improved after treatment. Unfortunately, the patient's family insisted on automatic discharge and the patient passed away several days later.

Nomogram for Early Prediction of Outcome in Coma Patients with Severe Traumatic Brain Injury Receiving Right Median Nerve Electrical Stimulation Treatment.

BACKGROUND: Accurate outcome prediction can serve to approach, quantify and categorize severe traumatic brain injury (TBI) coma patients for right median electrical stimulation (RMNS) treatment, which can support rehabilitation plans. As a proof of concept for individual risk prediction, we created a novel nomogram model combining amplitude-integrated electroencephalography (AEEG) and clinically relevant parameters. METHODS: This study retrospective collected and analyzed a total of 228 coma patients after severe TBI in two medical centers. According to the extended Glasgow Outcome Scale (GOSE), patients were divided into a good outcome (GOSE 3-8) or a poor outcome (GOSE 1-2) group. Their clinical and biochemical indicators, together with EEG features, were explored retrospectively. The risk factors connected to the outcome of coma patients receiving RMNS treatment were identified using Cox proportional hazards regression. The discriminative capability and calibration of the model to forecast outcome were assessed by C statistics, calibration plots, and Kaplan-Meier curves on a personalized nomogram forecasting model. RESULTS: The study included 228 patients who received RMNS treatment for long-term coma after a severe TBI. The median age was 40 years, and 57.8% (132 of 228) of the patients were male. 67.0% (77 of 115) of coma patients in the high-risk group experienced a poor outcome after one year and the comparative data merely was 30.1% (34 of 113) in low-risk group patients. The following variables were integrated into the forecasting of outcome using the backward stepwise selection of Akaike information criterion: age, Glasgow Coma Scale (GCS) at admission, EEG reactivity (normal, absence, or the stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs)), and AEEG background pattern (A mode, B mode, or C mode). The C statistics revealed that the nomograms' discriminative potential and calibration demonstrated good predictive ability (0.71). CONCLUSION: Our findings show that the nomogram model using AEEG parameters has the potential to predict outcomes in severe TBI coma patients receiving RMNS treatment. The model could classify patients into prognostic groups and worked well in internal validation.

Combining modified Graeb score and intracerebral hemorrhage score to predict poor outcome in patients with spontaneous intracerebral hemorrhage undergoing surgical treatment.

Objective: Spontaneous intracerebral hemorrhage (sICH) is a frequently encountered neurosurgical disease. The purpose of this study was to evaluate the relationship between modified Graeb Score (mGS) at admission and clinical outcomes of sICH and to investigate whether the combination of ICH score could improve the accuracy of outcome prediction. Methods: We retrospectively reviewed the medical records of 511 patients who underwent surgery for sICH between January 2017 and June 2021. Patient outcome was evaluated by the Glasgow Outcome Scale (GOS) score at 3 months following sICH, where a GOS score of 1-3 was defined as a poor prognosis. Univariate and multivariate logistic regression analyses were conducted to determine risk factors for unfavorable clinical outcomes. Receiver operating characteristic (ROC) curve analysis was performed to detect the optimal cutoff value of mGS for predicting clinical outcomes. An ICH score combining mGS was created, and the performance of the ICH score combining mGS was assessed for discriminative ability. Results: Multivariate analysis demonstrated that a higher mGS score was an independent predictor for poor prognosis (odds ratio [OR] 1.207, 95% confidence interval [CI], 1.130-1.290, p < 0.001). In ROC analysis, an optimal cutoff value of mGS to predict the clinical outcome at 3 months after sICH was 11 (p < 0.001). An increasing ICH-mGS score was associated with increased poor functional outcome. Combining ICH score with mGS resulted in an area under the curve (AUC) of 0.790, p < 0.001. Conclusion: mGS was an independent risk factor for poor outcome and it had an additive predictive value for outcome in patients with sICH. Compared with the ICH score and mGS alone, the ICH score combined with mGS revealed a significantly higher discriminative ability for predicting postoperative outcome.

The Value of the Correlation Coefficient Between the ICP Wave Amplitude and the Mean ICP Level (RAP) Combined With the Resistance to CSF Outflow (Rout) for Early Prediction of the Outcome Before Shunting in Posttraumatic Hydrocephalus.

Objective: To evaluate the value of the correlation coefficient between the ICP wave amplitude and the mean ICP level (RAP) and the resistance to CSF outflow (Rout) in predicting the outcome of patients with post-traumatic hydrocephalus (PTH) selected for shunting. Materials and Methods: As a training set, a total of 191 patients with PTH treated with VP shunting were retrospectively analyzed to evaluate the potential predictive value of Rout, collected from pre-therapeutic CSF infusion test, for a desirable recovery level (dRL), standing for the modified rankin scale (mRS) of 0-2. Eventually, there were 70 patients with PTH prospectively included as a validation set to evaluate the value of Rout-combined RAP as a predictor of dRL. We calculated Rout from a CSF infusion test and collected RAP during continuous external lumbar drainage (ELD). Maximum RAP (RAPmax) and its changes relative to the baseline (ΔRAPmax%) served as specific parameters of evaluation. Results: In the training set, Rout was proved to be a significant predictor of dRL to shunting, with the area under the curve (AUC) of 0.686 (p < 0.001) in receiver-operating characteristic (ROC) analysis. In the validation set, Rout alone did not present a significant value in the prediction of desirable recovery level (dRL). ΔRAPmax% after 1st or 2nd day of ELD both showed significance in predicting of dRL to shunting with the AUC of 0.773 (p < 0.001) and 0.786 (p < 0.001), respectively. Significantly, Rout increased the value of ΔRAPmax% in the prediction of dRL with the AUC of 0.879 (p < 0.001), combining with ΔRAPmax% after the 1st and 2nd days of ELD. RAPmax after the 1st and 2nd days of ELD showed a remarkable predictive value for non-dRL (Levels 3-6 in Modified Rankin Scale) with the AUC of 0.891 (p < 0.001) and 0.746 (p < 0.001). Conclusion: Both RAP and Rout can predict desirable recovery level (dRL) to shunting in patients with PTH in the early phases of treatment. A RAP-combined Rout is a better dRL predictor for a good outcome to shunting. These findings help the neurosurgeon predict the probability of dRL and facilitate the optimization of the individual treatment plan in the event of ineffective or unessential shunting.

Evaluation of Intracranial Hypertension in Traumatic Brain Injury Patient: A Noninvasive Approach Based on Cranial Computed Tomography Features.

BACKGROUND: Our purpose was to establish a noninvasive quantitative method for assessing intracranial pressure (ICP) levels in patients with traumatic brain injury (TBI) through investigating the Hounsfield unit (HU) features of computed tomography (CT) images. METHODS: In this retrospective study, 47 patients with a closed TBI were recruited. Hounsfield unit features from the last cranial CT and the initial ICP value were collected. Three models were established to predict intracranial hypertension with Hounsfield unit (HU model), midline shift (MLS model), and clinical expertise (CE model) features. RESULTS: The HU model had the highest ability to predict intracranial hypertension. In 34 patients with unilateral injury, the HU model displayed the highest performance. In three classifications of intracranial hypertension (ICP ≤ 22, 23-29, and ≥30 mmHg), the HU model achieved the highest F1 score. CONCLUSIONS: This radiological feature-based noninvasive quantitative approach showed better performance compared with conventional methods, such as the degree of midline shift and clinical expertise. The results show its potential in clinical practice and further research.

Intra-Abdominal Pressure Measurements in Neurocritical Patients.

Intra-abdominal pressure (IAP) is increasingly being recognized as an indispensable and significant physiological parameter in intensive care units (ICU). IAP has been measured in a variety of ways with the development of many techniques in recent years. The level of intra-abdominal pressure under normal conditions is generally equal to or less than 12 mmHg. Accordingly, abdominal hypertension (IAH) is defined as two consecutive IAP measurements higher than 12 mmHg within 4-6 h. When IAH deteriorates further with IAP higher than 20 mmHg along with organ dysfunction and/or failure, this clinical manifestation can be diagnosed as abdominal compartment syndrome (ACS). IAH and ACS are associated with gastrointestinal ischemia, acute renal failure, and lung injury, leading to severe morbidity and mortality. Elevated IAP and IAH may affect the cerebral venous return and outflow of the cerebrospinal fluid by increasing the intrathoracic pressure (ITP), ultimately leading to increased intracranial pressure (ICP). Therefore, it is essential to monitor IAP in critically ill patients. The reproducibility and accuracy of intra-bladder pressure (IBP) measurements in previous studies need to be further improved, although the indirect measurement of IAP is now a widely used technique. To address these limitations, we recently used a set of IAP monitoring systems with advantages of convenience, continuous monitoring, digital visualization, and long-term IAP recording and data storage in critically ill patients. This IAP monitoring system can detect intra-abdominal hypertension and potentially analyze clinical status in real time. The recorded IAP data and other physiological indicators, such as intracranial pressure, can be further used for correlation analysis to guide treatment and predict a patient's possible prognosis.

Circular RNA circ_0003204 inhibits proliferation, migration and tube formation of endothelial cell in atherosclerosis via miR-370-3p/TGFßR2/phosph-SMAD3 axis.

BACKGROUND: Circular RNAs (circRNAs) represent a class of non-coding RNAs (ncRNAs) which are widely expressed in mammals and tissue-specific, of which some could act as critical regulators in the atherogenesis of cerebrovascular disease. However, the underlying mechanisms by which circRNA regulates the ectopic phenotype of endothelial cells (ECs) in atherosclerosis remain largely elusive. METHODS: CCK-8, transwell, wound healing and Matrigel assays were used to assess cell viability, migration and tube formation. QRT-qPCR and Immunoblotting were used to examine targeted gene expression in different groups. The binding sites of miR-370-3p (miR-370) with TGFßR2 or hsa_circ_0003204 (circ_0003204) were predicted using a series of bioinformatic tools, and validated using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The localization of circ_0003204 and miR-370 in ECs were investigated by fluorescence in situ hybridization (FISH). Gene function and pathways were enriched through Metascape and gene set enrichment analysis (GSEA). The association of circ_0003204 and miR-370 in extracellular vesicles (EVs) with clinical characteristics of patients were investigated using multiple statistical analysis. RESULTS: Circ_0003204, mainly located in the cytoplasm of human aorta endothelial cells (HAECs), was upregulated in the ox-LDL-induced HAECs. Functionally, the ectopic expression of circ_0003204 inhibited proliferation, migration and tube formation of HAECs exposed to ox-LDL. Mechanically, circ_0003204 could promote protein expression of TGFßR2 and its downstream phosph-SMAD3 through sponging miR-370, and miR-370 targeted the 3' untranslated region (UTR) of TGFßR2. Furthermore, the expression of circ_0003204 in plasma EVs was upregulated in the patients with cerebral atherosclerosis, and represented a potential biomarker for diangnosis and prognosis of cerebrovascular atherogenesis. CONCLUSIONS: Circ_0003204 could act as a novel stimulator for ectopic endothelial inactivation in atherosclerosis and a potential biomarker for cerebral atherosclerosis.

Low free triiodothyronineis predicts worsen neurological outcome of patients with acute ischemic stroke: a retrospective study with bioinformatics analysis.

BACKGROUD: Patients with acute ischemic stroke (AIS) often experience low serum free triiodothyronine (FT3), but the association of low FT3 with stroke severity, subtype and prognosis has not yet been thoroughly studied, and the molecular events underlying these clinical observation were also unclear. METHODS: We retrospectively collected 221 cases of AIS and 182 non-AIS cases with detailed clinical data from our department. FT3 concentrations were measured on admission to predict functional outcome within 3 months using multivariable models adjusted for other risk factors. Receiver operating characteristic (ROC) curves were calculated to define the best cutoff value of FT3 of stroke severity, subtypes and neurological outcome. Gene set enrichment, pathway mapping and network analyses of deferentially expressed genes (DEGs) were performed. RESULTS: FT3 was significantly decreased in AIS patients with National Institutes of Health Stroke Scale (NIHSS) > 3 and 3-months modified Rankin Scale (mRS) > 2. The cut-off value of FT3 for NIHSS on admission was 4.30 pmol/L. Also, FT3 level was significantly lower in large artery atherosclerosis (LAA) group and cardioembolism (CE) group than that in small vessel occlusion (SVO). FT3 value served as an independent predictor for neurological outcomes for which the cut-off value of FT3 was 4.38 pmol/l. Gene ontology (GO) analysis showed that the biological function of DEGs was mainly enriched in multicellur organism, neuron differentiation and cellular response to hypoxia. The cellular components were involved in extracelluar region, exosome and matrix, and the molecular functions were transcriptional activator activity, DNA binding and nuclear hormone receptor binding. Signal pathways analysis was indicative of neuroactive ligand-receptor interaction, thyroid hormone signaling pathway, and protein digestion and absorption these DEGs were involved in. Six related gene were identified as hubs from the protein-protein interaction (PPI) networks. Three modules were selected from PPI, of which MMP4, ADRA2C and EIF3E were recognized as the seed genes. CONCLUSIONS: Low FT3 value on admission was associated with stroke severity, subtype and prognosis. In addition, DEGs identified from bioinformatics analysis are likely to be candidates for elucidating clinical outcomes with low FT3, and provide us with therapeutic targets for improving stroke prognosis.

Effects of interleukin-1 receptor-associated kinase 1 RNA interference in dendritic cells on inflammatory cytokine release and T-cell proliferation.

The present study aimed to reduce the expression of interleukin-1 receptor-associated kinase 1 (IRAK-1) in dendritic cells (DCs) by RNA interference (RNAi). Subsequently, its effects on the expression of costimulatory surface molecules, the release of inflammatory cytokines, and the proliferation of T cells during the activation process of DCs, were determined. RNAi was used to silence IRAK­1 gene expression in DCs, followed by lipopolysaccharide stimulation. Flow cytometry was then used to detect the expression levels of DC surface molecules, including cluster of differentiation (CD)86, major histocompatibility complex class II and CD40. Quantitative polymerase chain reaction was conducted to detect the mRNA expression levels of Toll­like receptor 4, IRAK­4, IRAK­1 and nuclear factor­κB (NF­κB) in DCs. In addition, ELISA was used to detect the release of the following inflammatory cytokines: Interleukin (IL)­10, IL­12 and tumor necrosis factor-α (TNF-α). The MTS assay was used to determine the effects of IRAK­1 RNAi on T­cell proliferation. Knockdown of IRAK­1 gene expression in DCs significantly reduced the expression levels of costimulatory surface molecules and intracellular NF­κB, decreased release of the proinflammatory cytokines IL­12 and TNF­α, increased release of the anti-inflammatory cytokine IL­10, and significantly reduced the proliferation of T cells. These results suggested that suppression of IRAK­1 gene expression may inhibit the differentiation and maturation of DCs via the downregulation of DC surface molecules, inhibition of intracellular signal transduction pathways, regulation of inflammatory cytokine release, and by reducing its promoting effects on T-cell proliferation.

Methionine enkephalin regulates microglia polarization and function.

Methionine enkephalin (MENK), an opioid peptide, is known to function as a regulator in the immune system. As microglia are considered the most important immune cells in the central nervous system (CNS), we aimed to assess the function of MENK on microglia polarization and tumoricidal responses. Initially, we chose the most optimal condition of 10-12M for 48h; however, MENK had no function on the viability and apoptosis of microglia under this treatment. However, MENK treatment markedly increased levels of M1-associated genes, such as CD86, CD40, IL-12, and TNF-α, but had no effect on M2 markers, including CD163, IL-10, and TGF-ß. Moreover, microglia in the MENK-treated group showed high phagocytosis capacity, which coincided with characteristics of M1 microglia. MENK stimulation also induced up-regulation of reactive oxygen species (ROS) expression, which contributed to maintaining homeostasis. We also detected NO production by measuring the end product nitrite, and found that MENK treatment increased expression of nitrite and inducible NO synthase (iNOS), but did not influence arginase-1 (Arg1) expression. Furthermore, treatment of microglia with MENK led to a significant increase in cytotoxicity against glioblastoma cells, indicating that MENK possessed anti-tumor ability. Overall, MENK treatment could induce microglia to an M1 phenotype, modulating Th1 responses in the immune system. Additionally, microglia treated with MENK had tumoricidal activity, which provides new insight into anti-tumor immunity.

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS.

Repulsive guidance molecule a (RGMa) is an axonal guidance molecule that has recently found to exert function in immune system. This study evaluated the function of RGMa in modulation of dendritic cells (DCs) function stimulated with Achyranthes bidentata polysaccharide (ABP) and lipopolysaccharide (LPS) using a RGMa-neutralizing antibody. Compared with the Control-IgG/ABP and Control-IgG/LPS groups, DCs in the Anti-RGMa/ABP and Anti-RGMa/LPS groups 1) showed small, round cells with a few cell processes and organelles, and many pinocytotic vesicles; 2) had decreased MHC II, CD86, CD80, and CD40 expression; 3) displayed the decreased IL-12p70, IL-1ß and TNF-α levels and increased IL-10 secretion; 4) had a high percentage of FITC-dextran uptake; and 5) displayed a reduced ability to drive T cell proliferation and reinforced T cell polarization toward a Th2 cytokine pattern. We conclude that DCs treated with RGMa-neutralizing antibodies present with tolerogenic and immunoregulatory characteristics, which provides new insights into further understanding of the function of RGMa.

A novel role for RGMa in modulation of bone marrow-derived dendritic cells maturation induced by lipopolysaccharide.

Repulsive guidance molecule a (RGMa) is known to mediate immune responses and has been indicated to modulates T cell activation and autoimmune diseases by dendritic cells (DCs), which hints its significant function in the latter cells. The aim of our study, therefore, was to evaluate the function of RGMa in DC maturation. We found that small interfering RNA (siRNA) successfully silenced the expression of RGMa in DCs. Even after LPS stimulation, RGMa-silenced DCs displayed an immature morphology, characterized by small, round cells with a few cell processes and organelles, and many pinocytotic vesicles. In the presence of LPS, RGMa siRNA transfection markedly reduced levels of CD80, CD86, CD40, and MHC II expression, as well as the secretion of IL-12p70 and TNF-α. With LPS treatment, RGMa siRNA-transfected DCs also showed increased levels of IL-10 and endocytosis. Moreover, in the presence of LPS, RGMa siRNA-transfected DCs displayed a low ability to induce T cell proliferation and differentiation, compared with negative control (NTi)-transfected or control DCs (p<0.05 for both). We conclude that after LPS stimulation, RGMa siRNA-transfected DCs show immunoregulatory and tolerogenic characteristics, which provides new insights into the immune system.

All-optical time-delay switch based on grating buildup time of two-wave mixing in a bacteriorhodopsin film.

We demonstrate time-delay switches using the first-order dynamic diffraction light of two-beam coupled light with wavelengths of 632.8, 650, 532, and 488 nm in a bacteriorhodopsin film. The optimal wavelengths are selected and the relationship between incident intensity and delay time is discussed. A switch delay time ranging from 3.52 to 12.5 s is presented by the 632.8 nm wavelength, while a delay time ranging from 1.24 to 10.6 s is demonstrated by the 488 nm wavelength. On the other hand, the wavelengths of 532 and 650 nm are not suitable for time-delay switches due to the large variation of first-order diffraction intensity for lower incident intensities.