RNF213 variant and autophagic impairment: A pivotal link to endothelial dysfunction in moyamoya disease.

Moyamoya disease (MMD) is closely associated with the Ring Finger Protein 213 (RNF213), a susceptibility gene for MMD. However, its biological function remains unclear. We aimed to elucidate the role of RNF213 in the damage incurred by human endothelial cells under oxygen-glucose deprivation (OGD). We analyzed autophagy in peripheral blood mononuclear cells (PBMCs) derived from patients carrying either RNF213 wildtype (WT) or variant (p.R4810K). Subsequently, human umbilical vein endothelial cells (HUVECs) were transfected with RNF213 WT (HUVECWT) or p.R4810K (HUVECR4810K) and exposed to OGD for 2 h. Immunoblotting was used to analyze autophagy marker proteins, and endothelial function was analyzed by tube formation assay. Autophagic vesicles were observed using transmission electron microscopy. Post-OGD exposure, we administered rapamycin and cilostazol as potential autophagy inducers. The RNF213 variant group during post-OGD exposure (vs. pre-OGD) showed autophagy inhibition, increased protein expression of SQSTM1/p62 (p < 0.0001) and LC3-II (p = 0.0039), and impaired endothelial function (p = 0.0252). HUVECR4810K during post-OGD exposure (versus pre-OGD) showed a remarkable increase in autophagic vesicles. Administration of rapamycin and cilostazol notably restored the function of HUVECR4810K and autophagy. Our findings support the pivotal role of autophagy impaired by the RNF213 variant in MMD-induced endothelial cell dysfunction.

Transdural Revascularization by Multiple Burrhole After Erythropoietin in Stroke Patients With Cerebral Hypoperfusion: A Randomized Controlled Trial.

BACKGROUND: In patients with acute symptomatic stroke, reinforcement of transdural angiogenesis using multiple burr hole (MBH) procedures after EPO (erythropoietin) treatment has rarely been addressed. We aimed to investigate the efficacy and safety of cranial MBH procedures under local anesthesia for augmenting transdural revascularization after EPO treatment in patients with stroke with perfusion impairments. METHODS: This prospective, randomized, blinded-end point trial recruited patients with acute ischemic stroke with a perfusion impairment of grade ≥2 within 14 days of symptom onset, steno-occlusive mechanisms on imaging examinations, and absence of transdural collaterals on transfemoral cerebral angiography. Patients were randomly assigned to receive MBH + EPO or MBH alone. The primary and secondary outcomes were revascularization success (trans-hemispheric and trans-burr hole) at 6 months and adverse events, respectively. RESULTS: We evaluated 42 of the 44 targeted patients, with 2 patients lost to follow-up. The combined and MBH-only (n=21 each) groups showed no differences in demographic characteristics and baseline perfusion parameters. Significantly, more cases of trans-hemispheric (19/21 [90.5%] versus 12/21 [57.1%]) and trans-burr hole (42/58 [72.4%] versus 30/58 [51.7%]) revascularization and significant improvements in perfusion parameters were observed in the combined group relative to the MBH-only group. No differences in treatment-related complications were observed between groups. Even after adjustment for potential covariates, EPO usage was an independent factor of successful hemispheric revascularization in this study (odds ratio, 6.41 [95% CI, 1.08-38.02]). CONCLUSIONS: The combination of MBH and EPO is safe and feasible for reinforcing transdural revascularization in acute steno-occlusive patients with perfusion impairments. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02603406.

A novel global ischemia-reperfusion rat model with asymmetric brain damage simulating post-cardiac arrest brain injury.

BACKGROUND: Post-cardiac arrest brain injury (PCABI) is a major cause of disability and death in patients with post-cardiac arrest syndrome (PCAS). However, there have been no suitable animal models with characteristic behaviors and cerebral damage adequately mimicking clinical PCABI. NEW METHOD: We established a chimeric model by increasing transient middle cerebral artery occlusion-mediated ipsilateral hemisphere damage in the 4-vessel occlusion (4VO) model, thereby inducing global forebrain asymmetric hemisphere ischemia. Severity of brain damage was then evaluated by behavioral and histological approaches. Neuroprotection was assessed by performing targeted temperature management (TTM) for two hours. RESULTS: Comatose behaviors were observed in both groups. Compared to the 4VO group, the chimeric group exhibited a higher neurological deficit score (NDS) (70.5 ± 17.6 vs. 139.5 ± 16.8, p = 0.0002), decreased brain cell viability (88.6 ± 18.0% vs. 5.7 ± 2.7%, p < 0.0001), and increased inflammation in the cortex (10.3 ± 1.6% vs. 16.9 ± 1.1%, p = 0.0061). After TTM neuroprotection, the chimeric-TTM group showed improvement in NDS (139.5 ± 16.8 vs. 0.0 ± 0.0, p < 0.0001), cortex and hippocampus cell viability (5.7 ± 2.7% vs. 72.8 ± 10.0%, p < 0.0001; and 2.5 ± 1.5% vs. 75.5 ± 10.3%, p < 0.0001, respectively) and inflammation (16.9 ± 1.1% vs. 11.0 ± 2.3%, p = 0.190; and 30.9 ± 1.7% vs. 16.6 ± 1.2%, p < 0.0001, respectively) compared to the chimeric group. COMPARISON WITH EXISTING METHOD: Unlike the extensive brain damage found in clinical PCAS settings, the existing 4VO models showed only global forebrain damage involving CA1 lesions on both hippocampi. Our model induced global forebrain and additional asymmetric hemisphere ischemic damages, which resulted in simulating PCABI-specific clinical manifestations than conventional models. CONCLUSIONS: Our model adequately simulates clinical PCABI and reflects appropriate neuroprotective effects of TTM.

Genome-Wide Analysis Identifies NURR1-Controlled Network of New Synapse Formation and Cell Cycle Arrest in Human Neural Stem Cells.

Nuclear receptor-related 1 (Nurr1) protein has been identified as an obligatory transcription factor in midbrain dopaminergic neurogenesis, but the global set of human NURR1 target genes remains unexplored. Here, we identified direct gene targets of NURR1 by analyzing genome-wide differential expression of NURR1 together with NURR1 consensus sites in three human neural stem cell (hNSC) lines. Microarray data were validated by quantitative PCR in hNSCs and mouse embryonic brains and through comparison to published human data, including genome-wide association study hits and the BioGPS gene expression atlas. Our analysis identified ~40 NURR1 direct target genes, many of them involved in essential protein modules such as synapse formation, neuronal cell migration during brain development, and cell cycle progression and DNA replication. Specifically, expression of genes related to synapse formation and neuronal cell migration correlated tightly with NURR1 expression, whereas cell cycle progression correlated negatively with it, precisely recapitulating midbrain dopaminergic development. Overall, this systematic examination of NURR1-controlled regulatory networks provides important insights into this protein's biological functions in dopamine-based neurogenesis.

Cranial burr hole with erythropoietin administration induces reverse arteriogenesis from the enriched extracranium.

It is challenging to revitalize ischemic penumbra after an acute stroke with intracranial perfusion insufficiency. To evaluate whether cranial burr hole and erythropoietin (EPO) generate effective revascularization, we investigated the efficacy of the augmentation method for reverse arteriogenesis from the healthy extracranial milieu. An intracranial perfusion insufficiency was created through bilateral internal carotid artery ligation (bICAL) in Sprague-Dawley rats. We administered recombinant human EPO (5000 U/kg) or saline intraperitoneally for 3 days after bICAL. Mechanical barrier disruption (MBD) was performed through a cranial burr hole with small dural cracks in the right hemisphere. The ipsilateral hemisphere with MBD grossly showed vascular networks between the extra- and intra-cranial spaces 2 weeks after the MBD procedure. It also showed significantly increased vessels in the intracranial vasculature adjacent to the MBD region (p = 0.0006). The levels of pro-angiogenic and inflammatory factors with prominent markers of vessel permeability were also significantly increased (MBD-only vs. control; Tnf-α, p = 0.0007; Vegf, p = 0.0206). In the EPO-administered group, such elevations in inflammation were significantly mitigated (combined vs. MBD-only; Tnf-α, p = 0.0008). The ipsilateral hemisphere with MBD-EPO (vs. MBD-only) showed significantly increased vessels (RECA-1, p = 0.0182) and their maturation (RECA-1/α-SMA, p = 0.0046), with upregulation of tumor growth factor-ß1 (Tgf-ß1, p = 0.037) and matrix metalloproteinase-2 (Mmp-2, p = 0.0488). These findings were completely blocked by minocycline (MIC) administration during in vivo (Tgf-ß1, p = 0.0009; Mmp-2, p < 0.0001) and in vitro experiments (tube formation, p < 0.0001). Our data suggest that the MBD procedure (for angiogenic routes) and EPO administration (for an arteriogenic booster) are complimentary and can facilitate successfully "reverse arteriogenesis" in subjects with intracranial perfusion insufficiency.

[Development of the Developmental Support Competency Scale for Nurses Caring for Preterm Infants].

PURPOSE: Developmental care has been recognized as a very important component for the development and health promotion of preterm infants. However, research on how to assess developmental nursing competency has not been studied as expected. This study was done to develop and evaluate a new scale to measure nursing competency for developmental support of preterm infants. METHODS: Concept analysis was done with using the Hybrid model of Schwartz-Barcott and Kim (2000), from which a preliminary new scale (30 items) was developed. To test the validity and reliability of the new scale being developed, data were collected from 122 NICU nurses at 4 hospitals in 3 cities in the Republic of Korea, from December, 2014 to March, 2015. RESULTS: The final version of the Developmental Support Competency Scale for Nurses (DSCS-N) caring for premature infants was a 4-point Likert type scale, consisting of 19 items, and categorized as 6 factors, explaining 62.5% of the total variance. Each of the factors were named as follows; 'environmental support' (4 items), 'parental support' (3 items), 'interaction' (3 items), 'critical thinking' (3 items), 'professional development' (3 items), and 'partnership' (3 items). The Cronbach's α coefficient for the scale was .83 and the reliability of the subscales ranged from .60~.76. CONCLUSION: The psychometric evaluation of the new scale demonstrated an acceptable validity and reliability. Findings indicate that the DSCS-N can be used as the tool to test the effect of educational programs for nurses and contribute to advance developmental care for preterm infants.

Case management for medical aid beneficiaries in Korea: findings from case-control study.

PURPOSE: This study was to evaluate effects of case management provided for 7 months for medical aid in Korea. METHODS: This study was a retrospective comparative study using secondary data analysis. Data from two pre-existing survey were reanalyzed. The data were collected through door to-door interviews using the structured questionnaire. For the medical service use, claims data from the Korea National Health Insurance Corporation was used. Subjects were 73 in the intervention group and 118 in the control group. RESULTS: There was no significant change in the intervention group in self-care ability (p = .296), medication adherence (p = .194) or quality of life (p = .903) compared to those of the control group. For hospital visiting days, it appeared to decrease in the intervention group (p = .038) but with no significant difference from that of the control group (p = .157). Neither were there significant differences in medical expenditures (p = .605). CONCLUSION: Although the effect of case management in this study appeared extremely limited, the short intervention period and characteristics of the medical aid beneficiaries and the limit of controlling only the demand side were discussed as factors to be considered. Nurses have been carrying out professional roles in case management in Korea. However more efforts are needed to develop case management as an area for nursing specialization.

TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling.

We recently reported that hNSCs (human neural stem cells) have the interesting characteristic of migration towards an intracranial glioma. However, the molecules and mechanisms responsible for tumour tropism are unclear. In the present study, we used microarray and proteomics analyses to identify a novel chemoattractant molecule, TIMP-1 (tissue inhibitor of metalloproteinase-1), secreted from human brain tumour tissues. We demonstrate that TIMP-1 significantly enhances hNSC adhesion and migration in a cell culture system. These effects were critically dependent on CD63, as shRNA-mediated ablation of CD63 expression attenuated the response. TIMP-1 significantly increased the number of FAs (focal adhesions) and cytoskeletal reorganization for cell migration in hNSCs, whereas knockdown of CD63 resulted in decreased hNSC spreading, FAs and migration, even after TIMP-1 treatment. In addition, TIMP-1 binding to CD63 activated ß1 integrin-mediated signalling through Akt and FAK phosphorylation, leading to pattern changes in distribution of vinculin and F-actin (filamentous actin). Furthermore, inactivation of ß1 integrin by use of a blocking antibody or inhibition of PI3K (phosphoinositide 3-kinase) signalling impaired the migration of hNSCs towards TIMP-1. Collectively, our results underline TIMP-1 as a novel and effective key regulator of CD63 and ß1 integrin-mediated signalling, which regulates hNSC adhesion and migration.

[Analysis of relationships between parenting stress, maternal depression, and behavioral problems in children at risk for Attention Deficit Hyperactive Disorder].

PURPOSE: In this study differences in behavioral problems between children at risk for Attention Deficit Hyperactive Disorder (ADHD) and normally developing children were identified. Further, relationships between parental stress, depression, and child behavioral problems according to ADHD symptoms were explored. METHODS: Participants were 222 elementary school children and their parents. The ADHD risk group was determined by the Korean-ADHD Rating Scale. Data were collected using the Korean-ADHD Rating Scale, Korean version of Child Behavior CheckList (K-CBCL), Parenting Stress Index, and Beck Depression Inventory. Data were analyzed using t-test, Pearson correlation coefficients, and regression analysis. RESULTS: 1) The ADHD risk group showed higher levels of behavioral problems, parenting stress, and maternal depression than the normal group. 2) There were significant relationships between ADHD scores and parenting stress (r=.66), maternal depression (r=.35), internal behavioral problems (r=.47), and external problems (r=.55), but, ADHD risk scores were negatively correlated with social competence (r=-.40). 3) The regression analysis revealed that ADHD levels affected the child's internal behavioral problems, mediated by maternal depression (beta=.29, p<.001). CONCLUSION: The study results show that higher risk scores for ADHD indicate a significant effect for behavioral problems. Also, parenting stress and depression influence child's behavioral problems. These results suggest that identification of children at risk for ADHD and development of parental education programs would contribute to the prevention of behavioral problems and aggravation of the ADHD symptoms.