LMP2 deficiency causes abnormal metabolism, oxidative stress, neuroinflammation, myelin loss and neurobehavioral dysfunctions.

BACKGROUND: Substantial evidence suggests that immunoproteasome is implicated in the various neurological diseases such as stroke, multiple sclerosis and neurodegenerative diseases. However, whether the immunoproteasome itself deficiency causes brain disease is still unclear. Therefore, the aim of this study was to explore the contribution of the immunoproteasome subunit low molecular weight protein 2 (LMP2) in neurobehavioral functions. METHODS: Male LMP2 gene completed knockout (LMP2-KO) and littermate wild type (WT) Sprague-Dawley (SD) rats aged 12-month-old were used for neurobehavioral testing and detection of proteins expression by western blotting and immunofluorescence. A battery of neurobehavioral test tools including Morris water maze (MWM), open field maze, elevated plus maze were used to evaluate the neurobehavioral changes in rats. Evans blue (EB) assay, Luxol fast blue (LFB) and Dihydroethidium (DHE) staining were applied to explore the blood-brain barrier (BBB) integrity, brain myelin damage and brain intracellular reactive oxygen species (ROS) levels, respectively. RESULTS: We firstly found that LMP2 gene deletion did not cause significantly difference in rats' daily feeding activity, growth and development as well as blood routine, but it led to metabolic abnormalities including higher levels of low-density lipoprotein cholesterol, uric acid and blood glucose in the LMP2-KO rats. Compared with the WT rats, LMP2-KO rats displayed obviously cognitive impairment and decreased exploratory activities, increased anxiety-like behavior and without strong effects on gross locomotor abilities. Furthermore, multiple myelin loss, increased BBB leakage, downregulation of tight junction proteins ZO-1, claudin-5 and occluding, and enhanced amyloid-ß protein deposition were observed in brain regions of LMP2-KO rats. In addition, LMP2 deficiency significantly enhanced oxidative stress with elevated levels of ROS, caused the reactivation of astrocytes and microglials and markedly upregulated protein expression levels of interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), IL-6 and tumor necrosis factor-α (TNF-α) compared to the WT rats, respectively. CONCLUSION: These findings highlight LMP2 gene global deletion causes significant neurobehavioral dysfunctions. All these factors including metabolic abnormalities, multiple myelin loss, elevated levels of ROS, increased BBB leakage and enhanced amyloid-ß protein deposition maybe work together and eventually led to chronic oxidative stress and neuroinflammation response in the brain regions of LMP2-KO rats, which contributed to the initial and progress of cognitive impairment.

Immunoproteasome modulates NLRP3 inflammasome-mediated neuroinflammation under cerebral ischaemia and reperfusion conditions.

Compelling evidence showed that both nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasomes and the immunoproteasome participate in neuroinflammatory responses in cerebral ischaemia injury. Moreover, inhibition of either NLRP3 inflammasomes or the immunoproteasome attenuates both neuroinflammation and neurological deterioration during ischaemic stroke. However, the underlying mechanism between the immunoproteasome and NLRP3 inflammasomes under ischaemic stroke conditions remains to be established. In this study, using both in vitro and in vivo ischaemic models, we demonstrated that the immunoproteasome inhibition reduced the expressions of NLRP3 inflammasome-associated proteins, including NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1 and mature cytokines (interleukin [IL]-1ß and IL-18). It also downregulated the levels of nuclear factor (NF)-κB and pyroptotic- and apoptotic-related proteins, and improved cell viability. In addition, inhibition of NF-κB by the small molecule inhibitor Bay-11-7082 led to lower levels of NLRP3 inflammasomes and cleaved caspase-1 proteins in BV2 cells after oxygen-glucose deprivation and reoxygenation. Together, these findings suggest that the immunoproteasome may be responsible for inducing the expression and activation of NLRP3 inflammasomes via the NF-κB pathway. Therapeutic interventions that target activation of the immunoproteasome/NF-κB/NLRP3 inflammasome pathway may provide novel prospects for the future treatment of ischaemic stroke.

Antifungal Strategy in Patients with Invasive Fungal Disease Associated with Hematological Malignancies Based on Risk Stratification.

Patients with hematological malignancies (HM) often develop the invasive fungal disease (IFD), causing important morbidity/mortality. While treatment guidelines are available, risk stratification models for optimizing antifungal therapy strategies are few. Clinical records from 458 HM patients with IFD were retrospectively analyzed. Following Chinese treatment guidelines, patients received empirical (n = 239) or diagnostic-driven therapy (n = 219). The effectiveness rate was 87.9% for the empirical and 81.7% for the diagnostic-driven therapy groups (P ≥ 0.05). The incidence of adverse reactions was 18.4% and 16.9%, respectively (P ≥ 0.05). All risk factors of IFD in HM patients were estimated in the univariate analyses and multivariate analyses by the chi-square test and logistic regression model. Duration ≥14 days (OR = 18.340, P=0.011), relapsed/refractory disease (OR = 11.670, P=0.005), IFD history (OR = 5.270, P=0.021), and diabetes (OR = 3.120, P=0.035) were significantly associated with IFD in the multivariate analysis. Patients with more than 3 of these factors have a significant difference in effective rates between the empirical (85.7%) and diagnostic-driven (41.6%) therapy (P=0.008). Empirical and diagnostic-driven therapy effective rates were 80.6% and 70.9% in the patients with two risk factors (P > 0.05) and 85.1% and 85.4% in the patients with one risk factor (P > 0.05). Thus, there was no significant difference in effectiveness in patients with one or two risk factors. The abovementioned risk stratification can guide clinical antifungal therapy. The patients with 3 or more risk factors benefit from empirical therapy.

Inhibition of immunoproteasome promotes angiogenesis via enhancing hypoxia-inducible factor-1α abundance in rats following focal cerebral ischaemia.

Angiogenesis after ischemic stroke contributes to the restoration of blood supply in the ischemic zone. Strategies to improve angiogenesis may facilitate the function recovery after stroke. Growing evidence shows that proteasome inhibitors enhance angioneurogenesis and induces a long-term neuroprotection after cerebral ischemia in rodents' models. We have previously reported that inhibition of the immunoproteasome subunit low molecular mass peptide 2 (LMP2) offers a strong neuroprotection in ischemic stroke rats. However, there are no data available to show the relationship between immunoproteasome and angiogenesis under ischemia stroke context. In this study, we identified that inhibition of immunoproteasome LMP2 was able to enhance angiogenesis and facilitate neurological functional recovery in rats after focal cerebral ischemia/reperfusion. In vitro, oxygen-glucose deprivation and reperfusion (OGD/R) significantly enhanced the expression of immunoproteasome LMP2 and proteasome activities in primary culture astrocytes, but these beneficial effects were abolished by knockdown of LMP2 with siRNA transfection. Along with this, protein abundance of HIF-1α was significantly increased by inhibition LMP2 in vivo and in vitro and was associated with angiogenesis and cell fates. However, these beneficial effects were partly abolished by HIF-1α inhibitor 2-methoxyestradiol (2ME). Taken together; this study highlights an important role for inhibition of LMP2 in promoting angiogenesis events in ischemic stroke, and point to HIF-1α as a key mediator of this response, suggesting that immunoproteasome inhibitors may be a promising strategy for stroke treatment.

Anterior Borderzone Angle for Hemodynamic Collateral Metric in Patients with Symptomatic Middle Cerebral Artery Stenosis.

BACKGROUND AND AIMS: We aimed to introduce a parameter of anterior borderzone angle (ABZA) to quantitatively evaluate the ACA-MCA leptomeningeal collaterals for middle cerebral artery stenosis (MCAS). METHODS: Two hundred seventy-five patients with 50-100% MCAS and 100 controls were included. The 95% reference range of ABZA was obtained from the controls. ABZAtrans was defined as "ABZA/the 95% upper limit." Relationships between ABZA and MCAS, -ABZAtrans and the TICI grade, the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral grade were analyzed. An ABZA grade model for the ACA leptomeningeal collaterals was tentatively developed. RESULTS: The 95% reference range of ABZA was 0.0º-23.0º. ABZA was significantly associated with MCAS by a function of the fourth power (R2 = 0.723, p < 0.001), and could predict hemodynamic MCAS (≥70%) with an AUC of 0.928 (95% CI 0.903-0.953). ABZAtrans was negatively correlated with the TICI grade (rho = -0.752, p < 0.001) and positively with the ASITN/SIR grade (rho = 0.921, p < 0.001). The ABZA grade was created by rounding -ABZAtrans to a nearest integer, and was closely associated with the ASITN/SIR grade (rho = 0.894, p < 0.001). CONCLUSIONS: ABZA can be used as a hemodynamic parameter to quantitatively evaluate ACA leptomeningeal collaterals.

Plasma Immunoproteasome Predicts Early Hemorrhagic Transformation in Acute Ischemic Stroke Patients.

BACKGROUND AND PURPOSE: Currently, blood biomarkers associated with an increased hemorrhagic transformation (HT) risk remain uncertain. We aimed to determine the significance of immunoproteasome as predictors of early HT in acute ischemic stroke patients. METHODS: This study enrolled 316 patients with ischemic stroke. HT was assessed by computed tomography examination performed on day 5 ± 2 after stroke onset or immediately in case of clinical deterioration (CD). Plasma immunoproteasome subunits low molecular mass peptide 2 (LMP2), multicatalytic endopeptidase complex-like 1 (MECL-1), LMP7, interleukin-1ß (IL1ß), and high-sensitivity C-reactive protein (Hs-CRP) were measured with quantitative sandwich enzyme-linked immunosorbent assay kits. Factors associated with HT were analyzed using a multivariate logistic regression analysis. RESULTS: There were 42 (13.3%, 42 of 316) patients who experienced HT. Compared with those patients without HT, plasma LMP2, MECL-1, LMP7, IL1ß, and Hs-CRP concentrations on admission were significantly increased in patients with subsequent HT (P < .001). These protein concentrations increased with hemorrhage severity. Patients with CD caused by HT had the highest levels of LMP2 (1679.5 [1394.6-136.6] pg/mL), MECL-1 (992.5 [849.7-1075.8] pg/mL), LMP7 (822.6 [748.6-1009.5] pg/mL), IL1ß (113.2 [90.6-194.5] pg/mL), and Hs-CRP (30.0 [12.8-75.6] mg/L) (P < .05). Logistic regression analysis showed cardioembolism, LMP2, MECL-1, and LMP7 as independent predictors of HT (P < .05). Receiver operating characteristic curve analysis demonstrated LMP2 ≥ 988.3 pg/mL, MECL-1 ≥ 584.7 pg/mL, and LMP7 ≥ 509.0 pg/mL as independent factors associated with HT (P < .001). CONCLUSION: Evaluation of plasma levels of immunoproteasome could be helpful in the early prediction of HT in acute ischemic stroke patients.

Safety and efficacy of simultaneous bilateral carotid angioplasty and stenting.

In this study, we aimed to evaluate the safety and feasibility of simultaneous bilateral carotid artery stenting (BCAS) compared with staged BCAS in patients with bilateral atherosclerotic carotid stenosis (BCS). From January 2004 to March 2012, 68 patients who underwent BCAS were identified from the Nanjing Stroke Registry Program. Of these patients, 42 (61.8 %) underwent simultaneous BCAS (simultaneous group), and 26 (38.2 %) underwent staged BCAS (staged group). We compared demographic data, major vascular risk factors, procedural parameters, and 30 day outcomes between the simultaneous and staged groups. No significant differences were detected in baseline data between the groups. Patients in the simultaneous group had a lower post-operative systolic pressure compared with the staged group (119.1 ± 16.1 vs. 130.2 ± 17.5 mmHg, P = 0.009). Technical success was 100 % of patients in the simultaneous group and 98.1 % in the staged group. Hemodynamic depression was observed in 57.4 % of procedures, with no significant difference between groups in the rate of HD. Four (5.9 %) patients had neurological complications within 30 days, including two cases of hyperperfusion syndrome in the simultaneous group, and two ischemic events in the staged group. There was no significant difference in the 30 day complication rate between the simultaneous and staged groups (4.8 vs. 7.7 %, P = 0.633). Simultaneous BCAS may be safe and feasible for most patients with BCS, with a similar 30 day complication rate to staged BCAS. Multicenter randomized control studies with larger sample sizes are warranted to further explore the safety and efficacy of simultaneous BCAS.

Development and Validation of a Risk Predictive Model for Small Intracranial Aneurysms in Adults Over a Five-Year Period.

Objective The optimal management of a small intracranial aneurysm (sIA) remains a challenge due to the lack of a size-specific risk predictive model for aneurysm rupture. We aimed to develop and validate a nomogram-based risk predictive model for sIA. Methods A total of 382 patients harboring 215 ruptured and 167 unruptured small intracranial aneurysms (uSIAs) (≤ 7 mm) were recruited and divided into training and validation cohorts. Risk factors for the construction of a nomogram were selected from clinical and aneurysmal features by least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. The nomogram for risk of rupture was evaluated in both the training and validation cohorts for discrimination, calibration, and clinical usefulness. Results Hyperlipidemia (odds ratio (OR)=2.74, 95% confidence interval (CI)=1.322~5.956, P=0.008), the presence of a daughter dome (OR=3.068, 95%CI=1.311~7.598, P=0.012), larger size-to-neck ratio (SN) (OR=1.807, 95%CI=1.131~3.063, P=0.021) and size ratio (SR) (OR=2.221, 95%CI=1.262~4.025, P=0.007) were selected as independent risk factors for sIA rupture and used for construction of nomogram. Internal validation by bootstrap sampling showed the Concordance index (C index) of 0.756 for the nomogram. The calibration by the Hosmer-Lemeshow test showed a P value of 0.847, indicating the model was well-fitted. Additionally, decision curve analysis (DCA) demonstrated that the predictive model has good clinical usefulness, providing net benefits across a range of threshold probabilities, thus supporting its application in clinical decision-making. Conclusion The risk prediction model can reliably predict the risk of sIA rupture, which may provide an important reference for optimizing the therapeutic strategy.

Association of immune cell traits with Parkinson's disease: a Mendelian randomization study.

Background: Immunity and neuroinflammation play crucial roles in the pathogenesis of Parkinson's disease (PD). Nonetheless, prior investigations into the correlation between immune inflammation and PD have produced varying results. Identifying specific immune cell phenotypes that are truly associated with PD is challenging, and the causal relationship between immune cells and PD remains elusive. Methods: This study conducted a comprehensive two-sample Mendelian randomization (MR) analysis, employing five distinct analytical approaches, to clarify the causal connection between immune cell characteristics and the risk of PD. Utilizing GWAS data, we investigated the causal relationship between 731 immune cell traits and PD. These immune cell phenotypes encompass absolute cell (AC) counts, median fluorescence intensity (MFI), and relative cell (RC) counts for B cells, cDCs, mature stage T cells, monocytes, myeloid cells, TBNK (T cells, B cells, and natural killer cells), and Tregs, as well as the logistic parameter (MP) for cDCs and TBNK. Results: The inverse variance weighted (IVW) analysis indicated that Myeloid DCs (p = 0.004), HVEM expression on CD45RA- CD4+ T cells (p = 0.007), CD62L- CD86+ Myeloid DCs (p = 0.015), and HLA DR expression on monocytes (p = 0.019) were associated with a reduced risk of PD. CD14+ CD16+ monocytes (p = 0.005), HLA DR+ NK cells within CD3- lymphocytes (p = 0.023), and CD28 expression on activated & secreting Tregs (p = 0.032) were associated with an increased risk of PD. Conclusion: This study establishes a causal link between immune cell phenotype and the pathogenesis of PD, identifying several specific immune cell characteristics associated with PD. This could inspire researchers to delve into the pathogenesis of PD at the cellular subtype level, and aid in the identification of potential pharmacological protein targets for PD.

Investigating the shared genetic architecture between frailty and insomnia.

Background: The epidemiological association between frailty and insomnia is well established, yet the presence of a common genetic etiology is still uncertain. Further exploration is needed to ascertain the causal relationship between frailty and insomnia. Methods: Utilizing data obtained from genome-wide association studies (GWAS) summaries, we utilized the linkage disequilibrium score regression (LDSC) to determine the genetic correlation existing between frailty and insomnia. The determination of causality was achieved through the application of two-sample Mendelian randomization. We investigated the enrichment of single nucleotide polymorphism (SNP) at various tissue types utilizing stratified LD score regression (S-LDSC) and multimarker analysis of genome annotation (MAGMA). Common risk SNPs were identified using Multi-Trait Analysis of GWAS (MTAG) and Cross-Phenotype Association (CPASSOC). We further investigated the expression profiles of risk genes in tissues using Summary-data-based Mendelian randomization(SMR) based on pooled data, to explore potential functional genes. Results: Our findings indicated a significant genetic correlation between frailty and insomnia, highlighting SNPs sharing risk (rs34290943, rs10865954), with a pronounced correlation in the localized genomic region 3p21.31. Partitioned genetic analysis revealed 24 functional elements significantly associated with both frailty and insomnia. Furthermore, mendelian randomization revealed a causal connection between frailty and insomnia. The genetic correlation between frailty and insomnia showed enrichment in 11 brain regions (S-LDSC) and 9 brain regions (MAGMA), where four functional genes (RMB6, MST1R, RF123, and FAM212A) were identified. Conclusion: This study suggests the existence of a genetic correlation and common risk genes between frailty and insomnia, contributing to a deeper comprehension of their pathogenesis and assists in identifying potential therapeutic targets.

Endovascular stenting for atherosclerotic subclavian artery stenosis in patients with other craniocervical artery stenosis.

Atherosclerotic subclavian artery stenosis (SAS) accompanied with other craniocervical artery stenosis (OCAS) is not uncommon in practice. We sought to investigate the safety and efficacy of endovascular stenting for SAS in patients with OCAS. Between January 2004 and February 2012, 71 consecutive atherosclerotic SAS patients who underwent primary stenting in our medical center were included. The enrolled patients were divided into combined-SAS group (n = 51) and solitary-SAS group (n = 20) depending on the presence or absence of OCAS. Data of demographics, procedure, and the followed-up were retrieved and analyzed. The technical success rate was 95.8%; the clinical success rate was 90.1%. There was no catheter-related major stroke or death. The immediate outcomes had no statistical difference between groups. During a mean of 27 ± 20 months (range 2-88 months) followed-up, 7 (10.3%) restenosis and 12 (17.6%) clinical events were identified. The primary patency rate was 95.3, 84.9 and 84.9% at 12, 24 months, and final followed-up respectively, which had no statistical difference between groups (odds ratio (OR), 2.60; 95% confidence interval (CI), 0.54-12.53; P = 0.232). The overall clinical event-free survival rate was 93.5, 86.2 and 54.6%, respectively, where the result of combined-SAS group was inferior to that of the solitary-SAS group (OR, 3.34; 95% CI, 1.02-11.00; P = 0.047). Endovascular stenting was safe and feasible for atherosclerotic SAS in patients with OCAS, although the combined OCAS may have a significant influence on the long-term outcome. Further studies are warrant to investigate the effects of revascularization for multiple craniocervical artery stenoses on the cerebral hemodynamics and long-term outcomes.

Evaluation of ferritin and TfR level in plasma neural-derived exosomes as potential markers of Parkinson's disease.

Introduction: Early diagnosis of Parkinson's disease (PD) remains challenging. It has been suggested that abnormal brain iron metabolism leads to excessive iron accumulation in PD, although the mechanism of iron deposition is not yet fully understood. Ferritin and transferrin receptor (TfR) are involved in iron metabolism, and the exosome pathway is one mechanism by which ferritin is transported and regulated. While the blood of healthy animals contains a plentiful supply of TfR-positive exosomes, no studies have examined ferritin and TfR in plasma neural-derived exosomes. Methods: Plasma exosomes were obtained from 43 patients with PD and 34 healthy controls. Neural-derived exosomes were isolated with anti-human L1CAM antibody immunoabsorption. Transmission electron microscopy and western blotting were used to identify the exosomes. ELISAs were used to quantify ferritin and TfR levels in plasma neural-derived exosomes of patients with PD and controls. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of ferritin and TfR. Independent predictors of the disease were identified using logistic regression models. Results: Neural-derived exosomes exhibited the typical exosomal morphology and expressed the specific exosome marker CD63. Ferritin and TfR levels in plasma neural-derived exosomes were significantly higher in patients with PD than controls (406.46 ± 241.86 vs. 245.62 ± 165.47 ng/µg, P = 0.001 and 1728.94 ± 766.71 vs. 1153.92 ± 539.30 ng/µg, P < 0.001, respectively). There were significant positive correlations between ferritin and TfR levels in plasma neural-derived exosomes in control group, PD group and all the individuals (rs = 0.744, 0.700, and 0.752, respectively). The level of TfR was independently associated with the disease (adjusted odds ratio 1.002; 95% CI 1.000-1.003). ROC performances of ferritin, TfR, and their combination were moderate (0.730, 0.812, and 0.808, respectively). However, no relationship was found between the biomarkers and disease progression. Conclusion: It is hypothesized that ferritin and TfR in plasma neural-derived exosomes may be potential biomarkers for PD, and that they may participate in the mechanism of excessive iron deposition in PD.

Optimizing intra-arterial hypothermia scheme for acute ischemic stroke in an MCAO/R rat model.

Hypothermia is a promising neuroprotective treatment. This study aims to explore and optimize the intervention scheme of intra-arterial hypothermia (IAH) in a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model. The MCAO/R model was established with a thread that could be retracted 2 h after occlusion. Cold normal saline was injected into the internal carotid artery (ICA) through a microcatheter in different infusion conditions. Grouping followed an orthogonal design (L9[34]) based on three critical factors closely associated with IAH: perfusate temperature (4, 10, 15 °C), infusion flow rate (1/3, 1/2, 2/3 blood flow rate of ICA), and duration (10, 20, 30 min), resulting in 9 subgroups (H1, H2 to H9). A myriad of indexes were monitored, such as vital signs, blood parameters, changes in local ischemic brain tissue temperature (Tb), ipsilateral jugular venous bulb temperature (Tjvb), and the core temperature of the anus (Tcore). After 24 h and 72 h of cerebral ischemia, cerebral infarction volume, cerebral water content, and neurological function were assessed to explore the optimal IAH conditions. The results revealed that the three critical factors were independent predictors for cerebral infarction volume, cerebral water content, and neurological function. The optimal perfusion conditions were 4 °C, 2/3 RICA (0.50 ml/min) for 20 min, and there was a significant correlation between Tb and Tjvb (R = 0.994, P < 0.001). The vital signs, blood routine tests and biochemical indexes showed no significant abnormal changes. These findings revealed that IAH was safe and feasible with the optimized scheme in an MCAO/R rat model.

Corrigendum: Evaluation of ferritin and TfR level in plasma neural-derived exosomes as potential markers of Parkinson's disease.

[This corrects the article DOI: 10.3389/fnagi.2023.1216905.].

Bridging the Skills Gap: Evaluating an AI-Assisted Provider Platform to Support Care Providers with Empathetic Delivery of Protocolized Therapy.

Despite the high prevalence and burden of mental health conditions, there is a global shortage of mental health providers. Artificial Intelligence (AI) methods have been proposed as a way to address this shortage, by supporting providers with less extensive training as they deliver care. To this end, we developed the AI-Assisted Provider Platform (A2P2), a text-based virtual therapy interface that includes a response suggestion feature, which supports providers in delivering protocolized therapies empathetically. We studied providers with and without expertise in mental health treatment delivering a therapy session using the platform with (intervention) and without (control) AI-assistance features. Upon evaluation, the AI-assisted system significantly decreased response times by 29.34% (p=0.002), tripled empathic response accuracy (p=0.0001), and increased goal recommendation accuracy by 66.67% (p=0.001) across both user groups compared to the control. Both groups rated the system as having excellent usability.

Caring burden and associated factors of care providers for senile dementia patients in an urban-rural fringe of Fuzhou City, China.

BACKGROUND AND AIMS: Dementia is a serious disease that places undue burden on family care providers. This study aimed to investigate caring burden and associated factors of care providers for dementia patients in an urban-rural fringe area in China. METHODS: A total of 197 dementia patients ≥65 years of age were identified from July-November 2007 in 22 villages of Gushan Town, Fuzhou City, China, and 152 care providers of the patients were recruited and analyzed. The Care Provider Burden Inventory was used to evaluate the main burdens including overall burden and time-dependent, developmental, physical, emotional and social burdens. Factors associating with caring burden were analyzed. RESULTS: The prevalence rate of dementia was 7.3% (197/2696) in study area. Four factors significantly increased overall care providers' burden score: daily hours of caring time, payment source for patients' medical expense, care providers' religion and care providers' role awareness (adjusted-R2 0.617). Patients with significantly impaired function of daily living (higher ADL scores) resulted in a higher caregivers' time-dependent burden. Increasing hour of caring per day increased care providers' time-dependent, physical and developmental burden. Care providers' view of their role awareness as obligation increased score of time-dependent, developmental, physical and emotional burdens. Patient with physical disability significantly increased developmental, physical, emotional and social burdens. CONCLUSION: The main influence factors of the caring burden of care providers' for dementia patients were length of daily caring hours, source of care receivers' medical expenses, patient with physical disability and care providers' role awareness (i.e., obligated vs willing).

Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFß/Smad Signaling.

OBJECTIVES: Chronic cerebral hypoperfusion induces white matter ischemic injury and cognitive impairment, whereas the mechanism remains unclear. Immunoproteasomes have been implicated in the pathogenesis of acute ischemia stroke and multiple sclerosis. However, the expression and role of immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be clarified. METHODS: Chronic white matter ischemic injury mice models were induced by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. Cognitive function, white matter integrity, and potential pathways were assessed after BCAS. RESULTS: The present study found that chronic cerebral hypoperfusion following BCAS induced cerebral white matter demyelination and cognitive impairment, accompanied with elevated expression of the immunoproteasomes LMP2 and LMP7, activation of astrocytes and microglia, and increased production of inflammatory cytokines (e.g., interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-ß1 (TGFß1), and insulin-like growth factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome inhibitor PR957 significantly mitigated the histological damage of the white matter, suppressed inflammatory response, and paralleled by an improvement of cognitive function. Furthermore, treatment of PR957 significantly upregulated the level of TGFß1, the total expression level, and the phosphorylation level of Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFß/Smad signaling in the sham-operated (BCAS-nonoperated) mice. CONCLUSIONS: The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFß/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.

MicroRNA-513b-5p targets COL1A1 and COL1A2 associated with the formation and rupture of intracranial aneurysm.

Collagen-type I alpha 1 chain (COL1A1) and COL1A2 are abnormally expressed in intracranial aneurysm (IA), but their mechanism of action remains unclear. This study was performed to investigate the mechanism of COL1A1 and COL1A2 affecting the occurrence and rupture of IA. Quantitative real-time polymerase chain reaction was used to measure the expression of hsa-miR-513b-5p, COL1A1, COL1A2, TNF-α, IL-6, MMP2, MMP3, MMP9 and TIMP4 in patients with ruptured IA (RA) (n = 100), patients with un-ruptured IA (UA) (n = 100), and controls (n = 100). Then, human vascular smooth muscle cells (HASMCs) were cultured, and dual luciferase reporter assay was performed to analyse the targeting relationship between miR-513b-5p and COL1A1 or COL1A2. The effects of the miR-513b-5p mimic and inhibitor on the proliferation, apoptosis, and death of HASMC and the RIP1-RIP3-MLKL and matrix metalloproteinase pathways were also explored. The effect of silencing and over-expression of COL1A1 and COL1A2 on the role of miR-513b-5p were also evaluated. Finally, the effects of TNF-α on miR-513b-5p targeting COL1A1 and COL1A2 were tested. Compared with those in the control group, the serum mRNA levels of miR-513b-5p, IL-6 and TIMP4 were significantly decreased in the RA and UA groups, but COL1A1, COL1A2, TNF-α, IL-1ß, MMP2, MMP3 and MMP9 were significantly increased (p < 0.05). Compared with those in the UA group, the expression of COL1A1, COL1A2, TNF-α, IL-1ß and MMP9 was significantly up-regulated in the RA group (p < 0.05). Results from the luciferase reporter assay showed that COL1A1 and COL1A were the direct targets of miR-513b-5p. Further studies demonstrated that miR-513b-5p targeted COL1A1/2 to regulate the RIP1-RIP3-MLKL and MMP pathways, thereby enhancing cell death and apoptosis. Over-expression of COL1A1 or COL1A2, rather than silencing COL1A1/2, could improve the inhibitory effect of miR-513b-5p on cell activity by regulating the RIP1-RIP3-MLKL and MMP pathways. Furthermore, over-expression of miR-513b-5p and/or silencing COL1A1/2 inhibited the TNF-α-induced cell proliferation and enhanced the TNF-α-induced cell death and apoptosis. The mechanism may be related to the inhibition of collagen I and TIMP4 expression and promotion of the expression of RIP1, p-RIP1, p-RIP3, p-MLKL, MMP2 and MMP9. MiR-513b-5p targeted the inhibition of COL1A1/2 expression and affected HASMC viability and extracellular mechanism remodelling by regulating the RIP1-RIP3-MLKL and MMP pathways. This process might be involved in the formation and rupture of IA.

Subarachnoid Hemorrhage Following Ischemic Stroke Caused by Atrial Myxoma.

Subarachnoid hemorrhage (SAH) is a rare neurological complication of cardiac myxoma and is associated with poor outcomes. Previous reports have shown that myxoma-associated SAH was contributed by rupture of myxomatous intracerebral aneurysm. Here, we present an unusual case of angiographic-negative SAH in a young patient with left atrial myxoma.  A 28-year-old male was admitted for SAH. He had a history of magnetic resonance imaging (MRI)-confirmed ischemic stroke one year ago. The digital subtraction angiography (DSA) performed on next day revealed no intracerebral aneurysm or vascular malformation. Transthoracic echocardiography (TTE) showed a left atrial mass measuring 5.09 * 3.34 cm, indicating a diagnosis of atrial myxoma, which was confirmed by pathological examination. The cardiac tumor was excised and the patient's symptoms improved completely. No intracerebral aneurysm was found by brain computed tomographic angiography (CTA) performed on day 24 after onset and one year after discharge. The patient remained asymptomatic during the one-year following-up. The result suggests that SAH may be more commonly associated with cardiac myxoma than previously expected. And, mechanisms other than rupture of myxomatous intracerebral aneurysm involve in SAH associated with cardiac myxoma. Prolonged length of following-up using novel imaging technique should be applied to identify and monitor the change of source bleeding.

Effects of creative expression program on the event-related potential and task reaction time of elderly with mild cognitive impairment.

OBJECTIVES: This study aimed to evaluate the effects of a 16-week creative expression intervention program (CrExp) on the event-related potential (ERP) and task reaction time in older individuals with mild cognitive impairment (MCI). METHODS: This study is a randomized controlled clinical trial conducted in the Memory Center of Fujian Provincial hospital. Thirty-six MCI patients were randomly distributed into two groups. One group underwent a 16-week creative expression program (CrExp, n = 18) and the other performed as a control group (CG, n = 18) by general social activities. The amplitude and latency of ERP-P300 from the central (Cz), parietal (Pz), frontal (Fz) cortices and task reaction time (RT) were assessed at baseline, post-interventi on, and 24-week follow-up. RESULTS: The CrExp group showed greater differences than CG of P300 latency in Cz (F = 4.37, P = 0.015), Pz (F = 2.78, P = 0.009), Fz (F = 6.45, P = 0.031) brain area after 16 weeks of intervention and in Fz (F = 3.23, P = 0.028), Cz (F = 3.79, P = 0.024), and Pz (F = 5.60, P = 0.036) at 24 weeks follow-up. Also, we analyzed the task reaction time between two groups and found that a shorten reaction time at post-intervention (F = 4.47, P = 0.011) and 24 weeks follow-up (F = 3.12, P = 0.007) in the CrExp group. However, there was no difference in P300 amplitude in either brain area between the two groups. CONCLUSION: The electrophysiological results of the creative expression cognitive therapy group were more obvious than those of the general cognitive therapy group, and the latency and task reaction time may be considered as supported parameters in diagnosing the effects during non-drug therapy intervention in clinical practice.