Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

Montelukast alleviates inflammation in experimental autoimmune encephalomyelitis by altering Th17 differentiation in a mouse model.

Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4+ T cells expressed CysLTR1 in MS lesions. Among T-cell subsets, Th17 cells had the highest expression of CysLTR1, and blocking CysLTR1 signalling abrogated their development in vitro. Inhibition of CysLTR1 by montelukast suppressed EAE development in both a prophylactic and therapeutic manner and inhibited myelin loss in EAE mice. Similarly, the in vivo results showed that montelukast inhibited Th17 response in EAE mice and that Th17 cells treated with montelukast had reduced encephalitogenic in adoptive EAE. Our findings strongly suggest that targeting Th17 response by inhibiting CysLTR1 signalling could be a promising therapeutic strategy for the treatment of MS and CNS inflammatory diseases.

Effectiveness of Needs-oriented Hospital Discharge Planning for Caregivers of Patients With Schizophrenia.

Hospital discharge planning for clients with schizophrenia reduces client rehospitalization rates and improves their medication adherence. The effectiveness of caregiver participation in hospital discharge planning has seldom been explored. The purpose of this study was to examine the effectiveness of caregiver participation in hospital discharge planning for clients with schizophrenia in reducing caregiver burden and improving health status. A quasi-experimental research design was adopted. The research location was in a psychiatric hospital in Northern Taiwan. The target population was caregivers of inpatients with schizophrenia. Nurses served as care coordinators and provided six-step hospital discharge planning services to caregivers. Structured questionnaires were employed to measure caregiver burden and health status. Intervention effect was tested using analysis of covariance in which outcome measure at pretest and selected demographic variables were treated as covariates. A total of 114 caregivers completed pretest and posttest evaluations, with 57 people in each group. A significant difference was found between the experimental and the control group regarding the caregiver burden and health status (P<0.001) The caregiver burden and health status of the experimental group improved more significantly compared with the control group. The caregiver-involved discharge planning process developed in this study effectively reduced the burden placed on caregivers and improved their health status. Mental health nurses can serve as the main care coordinators for assessment, planning, referral and provision of the required services. Caregiver-involved hospital discharge planning should become part of the routine care process.

Risk factors for early cardiovascular mortality in patients with bipolar disorder.

AIM: We attempted to determine risk factors, particularly pathophysiological changes, for early cardiovascular mortality in bipolar disorder (BD). METHODS: A total of 5416 inpatients with bipolar I disorder were retrospectively followed through record linkage for cause of death. A total of 35 patients dying from cardiovascular disease (CVD; ICD 9: 401-443) before the age of 65 years were identified. Two living BD patients and two mentally healthy adults were matched with each deceased patient as control subjects according to age (±2 years), sex, and date (±3 years) of the final/index admission or the date of general health screening. Data were obtained through medical record reviews. RESULTS: Eighty percent of CVD deaths occurred within 10 years following the index admission. Conditional logistic regression revealed that the variables most strongly associated with CVD mortality were the leukocyte count and heart rate on the first day of the index hospitalization, as the deceased BD patients were compared with the living BD controls. Systolic pressure on the first day of the index hospitalization can be substituted for heart rate as another risk factor for CVD mortality. CONCLUSION: It is suggested that systemic inflammation and sympathetic overactivity during the acute phase of BD may be risk factors for early CVD mortality.

[The Effects of a Biosensing Game on the Physical Health-Related Fitness of Chronic Schizophrenic Patients].

BACKGROUND: Being overweight is a common problem among chronic schizophrenic patients. However, these patients lack related exercise interventions that are both effective and convenient. PURPOSE: To explore the effects of a biosensing game intervention on the health-related fitness of chronic schizophrenic patients. METHODS: Two rehabilitation wards at a psychiatric hospital in New Taipei City were selected as the study sites. Simple random sampling was used to recruit participants. Participants in the experimental group received a 12-week biosensing game intervention, while participants in the control group received routine nursing care only. The study instruments included a demographic data sheet and anthropometric measurements. In addition, health-related fitness variables including cardiovascular endurance, muscular endurance, flexibility, and body composition (e.g., body mass index (BMI), waist-hip ratio, and body fat) were used as outcome indicators. RESULTS: A total of 35 patients participated in the experimental group and 35 patients participated in the control group. The results showed that the mean differences between the pre-test and post-test values for body weight (t=6.07, p<.01), BMI (t=5.79, p<.01), and waist-hip ratio (t=2.87, p<.05) differed significantly, with the experimental group performing better than the control group on all three indicators. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The results indicate that this 12-week intervention holds the potential to help chronic schizophrenic patients improve their health-related fitness, especially in terms of body weight, BMI, and waist-hip ratio. This study may be used as a reference for the promotion of health-related fitness programs in psychiatric institutes in the future.

Engineered extracellular vesicles encapsulated Bryostatin-1 as therapy for neuroinflammation.

Targeted and effective drug delivery to central nervous system (CNS) lesions is a major challenge in the treatment of multiple sclerosis (MS). Extracellular vesicles (EVs) have great promise as a drug delivery nanosystem given their unique characteristics, including a strong cargo-loading capacity, low immunogenicity, high biocompatibility, inherent stability, high delivery efficiency, ease of manipulation, and blood-brain barrier (BBB) penetration. Clinical applications are, however, limited by their insufficient targeting capability and "dilution effects" upon systemic administration. Neural stem cells (NSCs) provide an abundant source of EVs because of their remarkable capacity for self-renewal. Here, we developed a novel therapeutic strategy for local delivery and treatment using EVPs, which are derived from NSCs with the expression of the CNS lesion targeting ligand-PDGFRα. Furthermore, we used EVPs as a targeting carrier for encapsulating Bryostatin-1 (Bryo-1), a natural compound with remarkable anti-inflammation ability. Our data showed that Bryo-1 delivered by EVPs was more stable and concentrated in the CNS than native Bryo-1. Systemic injection of a low dosage (1 × 108 particles) of EVPs + Bryo-1, versus only EVPs or Bryo-1 administration, significantly ameliorated clinical disease development, decreased the infiltration of pro-inflammatory cells, blocked myelin loss and astrogliosis, protected BBB integrity, and altered microglia pro-inflammatory phenotype in the CNS of EAE mice. Taken as a whole, our study showed that engineered EVs have a CNS targeting capacity, and it provides potentially powerful therapeutic effects for the treatment of various neuroinflammatory diseases.

Targeting central nervous system extracellular vesicles enhanced triiodothyronine remyelination effect on experimental autoimmune encephalomyelitis.

The lack of targeted and high-efficiency drug delivery to the central nervous system (CNS) nidus is the main problem in the treatment of demyelinating disease. Extracellular vesicles (EVs) possess great promise as a drug delivery vector given their advanced features. However, clinical applications are limited because of their inadequate targeting ability and the "dilution effects" after systemic administration. Neural stem cells (NSCs) supply a plentiful source of EVs on account of their extraordinary capacity for self-renewal. Here, we have developed a novel therapeutic system using EVs from modified NSCs with high expressed ligand PDGF-A (EVPs) and achieve local delivery. It has been demonstrated that EVPs greatly enhance the target capability on oligodendrocyte lineage. Moreover, EVPs are used for embedding triiodothyronine (T3), a thyroid hormone that is critical for oligodendrocyte development but has serious side effects when systemically administered. Our results demonstrated that systemic injection of EVPs + T3, versus EVPs or T3 administration individually, markedly alleviated disease development, enhanced oligodendrocyte survival, inhibited myelin damage, and promoted myelin regeneration in the lesions of experimental autoimmune encephalomyelitis mice. Taken together, our findings showed that engineered EVPs possess a remarkable CNS lesion targeting potential that offers a potent therapeutic strategy for CNS demyelinating diseases as well as neuroinflammation.

Encapsulation of bryostatin-1 by targeted exosomes enhances remyelination and neuroprotection effects in the cuprizone-induced demyelinating animal model of multiple sclerosis.

Demyelination is a critical neurological disease, and there is still a lack of effective treatment methods. In the past two decades, stem cells have emerged as a novel therapeutic effector for neural regeneration. However, owing to the existence of the blood-brain barrier (BBB) and the complex microenvironment, targeted therapy still faces multiple challenges. Targeted exosome carriers for drug delivery may be considered a promising therapeutic method. Exosomes were isolated from mice neural stem cells. To develop targeting exosomes, we generated a lentivirus armed PDGFRα ligand that could anchor the membrane. Exosome targeting tests were carried out in vitro and in vivo. The modified exosomes showed an apparent ability to target OPCs in the lesion area. Next, the exosomes were loaded with Bryostatin-1 (Bryo), and the cuprizone-fed mice were administered with the targeting exosomes. The data show that Bryo exhibits a powerful therapeutic effect compared with Bryo alone after exosome encapsulation. Specifically, this novel exosome-based targeting delivery of Bryo significantly improves the protection ability of the myelin sheath and promotes remyelination. Moreover, it blocks astrogliosis and axon damage, and also has an inhibitory effect on pro-inflammatory microglia. The results of this investigation provide a straightforward strategy to produce targeting exosomes and indicate a potential therapeutic approach for demyelinating disease.

Gastric cancer cell-derived extracellular vesicles disrupt endothelial integrity and promote metastasis.

The endothelium is the critical barrier that controls transendothelial communications. Blood vessels in cancer tissue are poorly developed and highly permeable. However, it is poorly understood how circulating cancer cells released through these "leaky" vessels break the intact vasculature of remote organs to metastasize. We investigated the roles of cancer cell-derived extracellular vesicles (CEVs) in regulating cancer metastasis by analyzing samples from gastric cancer patients, performing in vitro experiments, and studying mouse models. We made several novel observations. First, the rate of metastasis was closely associated with plasma levels of CEVs in patients with gastric cancer. Second, cultured endothelial cells endocytosed CEVs, resulting in cytoskeletal rearrangement, low expression of the junction proteins cadherin and CD31, and forming large intercellular gaps to allow the transendothelial migration of cancer cells. The dynamin inhibitor Dynasore prevented these CEV-induced changes of endothelial cells by blocking CEVs endocytosis. Third, CEVs disrupted the endothelial barrier of cancer-bearing mice to promote cancer metastasis. Finally, lactadherin promoted the clearance of circulating CEVs to reduce metastasis. These results demonstrate the essential role of CEVs in promoting the metastasis of gastric cancer.

The Role of miR-23b in Cancer and Autoimmune Disease.

Short-stranded miRNAs are single-stranded RNA molecules involved in the regulation of gene expression. miRNAs are involved in a variety of cellular physiological processes, including cell proliferation, differentiation, and apoptosis. miR-23b have been identified to act both as oncogenes and as tumor suppressors. In addition, miR-23b is related to inflammation resistance to various autoimmune diseases and restrained inflammatory cell migration. The characterization of the specific alterations in the patterns of miR-23b expression in cancer and autoimmune disease has great potential for identifying biomarkers for early disease diagnosis, as well as for potential therapeutic intervention in various diseases. In this review, we summarize the ever-expanding role of miR-23b and its target genes in different models and offer insight into how this multifunctional miRNA modulates tumor cell proliferation and apoptosis or inflammatory cell activation, differentiation, and migration.

Role of Extracellular Vesicles in Autoimmune Pathogenesis.

Autoimmune diseases are conditions that emerge from abnormal immune responses to natural parts of the body. Extracellular vesicles (EVs) are membranous structures found in almost all types of cells. Because EVs often transport "cargo" between cells, their ability to crosstalk may be an important communication pathway within the body. The pathophysiological role of EVs is increasingly recognized in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Type 1 diabetes, and autoimmune thyroid disease. EVs are considered as biomarkers of these diseases. This article outlines existing knowledge on the biogenesis of EVs, their role as messegers in cellular communication and the function in T/B cell differentiation and maturation, and focusing on their potential application in autoimmune diseases.

Robot-assisted Percutaneous Cannulated Screw Fixation of Femoral Neck Fractures: Preliminary Clinical Results.

OBJECTIVE: To assess the clinical efficacy of TiRobot-assisted percutaneous cannulated screw fixation in the treatment of femoral neck fractures. METHODS: From September 2015 to July 2017, 26 patients with unilateral femoral neck fractures were treated with TiRobot-assisted percutaneous cannulated screw fixation. The femoral necks were fixed using three cannulated screws with robot assistance applying the following procedure: image acquisition, path planning, and needle and screw placement. The results of the treatment, including operation duration, frequency of fluoroscopy use, implant placement accuracy, intraoperative bleeding, total drilling, surgical complications, fracture healing time, fracture healing rate, and Harris scores at the last follow-up, were recorded and compared with 23 similar patients who underwent conventional manual positioning surgery. RESULTS: A total of 147 cannulated screws were placed in all patients. The TiRobot group had shorter operation duration (62.6 ± 8.7 min vs 72.4 ± 10.3 min) and fracture healing time (5.1 ± 2.4 months vs 5.9 ± 2.8 months) than the conventional group (P > 0.05). The robot group had significantly less use of fluoroscopy (26.5 ± 7.4 times vs 51.3 ± 9.4 times), intraoperative bleeding (8.2 ± 5.3 mL vs 36.4 ± 12.5 mL), and total drilling (9.4 ± 4.2 times vs 18.3 ± 9.1 times) than the conventional group (all P < 0.05). The screw parallelism was significantly improved (24.0 ± 0.6 points vs 21.5 ± 1.2 points) and the neck-width coverage (72.0 ± 6.7 mm2 vs 53.8 ± 10.4 mm2 ) was significantly enlarged compared to the conventional group (P < 0.05). Only three guiding needles were used to penetrate the femoral head during manual insertion in the TiRobot group, which was significantly lower than that in the conventional group (3/78, 3.8% vs 9/69, 13.0%; P < 0.05). Other complications such as wound infection, vascular or nerve injury, screw loosening, and secondary screw displacement, did not occur in the two groups. There was no significant difference between the two groups in fracture healing rate (88.4% vs 82.6%) and Harris scores at the last follow up (88.2 ± 3.6 points vs 87.3 ± 4.7 points; P > 0.05). CONCLUSION: TiRobot-assisted percutaneous cannulated screw fixation of femoral neck fractures is advantageous over conventional surgery with manual positioning due to easier manipulation, more accurate screw insertion, less invasion, and less radiation exposure, suggesting that it is a better method to stabilize femoral neck fractures.

Risk factors for early circulatory mortality in patients with schizophrenia.

Patients with schizophrenia have higher mortality and shortened life expectancy than the general population, and cardiovascular disease (CVD) accounts for up to 50% cases of early mortality in schizophrenia. We determined risk factors, particularly pathophysiological changes, for early circulatory mortality in schizophrenia. In this multi-institutional, nested, case-control study, we enrolled consecutive inpatients with schizophrenia admitted to three psychiatric hospitals in the northern Taiwan. Seventy-nine patients who died of CVD before 65 years of age were identified as cases through record linkage, and 158 controls were randomly selected in a 2:1 ratio through risk-set density sampling, after matching for age (±2 years), sex, and index admission (±3 years). Data were obtained through medical record reviews. At the time of death, the mean age of the patients was 47.5 years (standard deviation = 10.3). Conditional logistic regression revealed that the duration of antipsychotic treatment was significantly associated with a lower risk of early circulatory mortality, and leukocyte counts at index hospitalization were significantly associated with a higher risk. Systemic inflammation may be a risk factor for early circulatory mortality in schizophrenia, but antipsychotic treatment, in particular typical antipsychotic treatment, could be a protective factor.

Occurrence, profiles, and ecological risks of polybrominated diphenyl ethers in mangrove sediments of Shantou, China.

Surface sediments were collected from three mangrove wetlands (Yifeng Xi, Shuanghan, and Su'ai Wan) in Shantou coastal zone of South China to investigate spatial distributions of polybrominated diphenyl ethers (PBDEs). The results demonstrate that PBDEs were detected in all the samples, indicating their widespread occurrence in coastal sediments of the studied area. Σ9PBDEs (defined as the sum of nine targeted PBDE congeners except BDE-209) and BDE-209 are in the range of 2.3 to 11.5 and 16.7 to 58.2 ng/g, respectively. BDE-209 is the dominant PBDE congener in all sediment samples. The sediment concentrations of ∑9PBDEs and BDE-209 among the three wetlands decrease in the order of Su'ai Wan > Shuanghan > Yifeng Xi. The concentrations of ∑9PBDEs are higher in mangrove sediments than in mudflats, but no obvious regularity can be found on the correlation between mangrove species and PBDE levels in sediments. The contents of total organic carbon are moderately correlated with BDE-209 concentrations in sediments but not with ∑9PBDE concentrations. The samples collected from different locations show slightly different composition profiles except BDE-209, with BDE-100 and BDE-47 being the pre-dominated congeners. The mudflats exhibit higher abundances of tri- to hexa-substituted congeners than the mangrove sediments. Ecological risk assessment demonstrates that the surface sediments from Shantou may pose a potential ecological risk of exposure to sediment-dwelling organisms.