Probing twisted intramolecular charge transfer of pyrene derivatives as organic emitters in OLEDs.

Intramolecular charge transfer (ICT) plays a critical role in determining the photophysical properties of organic molecules, including their luminescence efficiencies. Twisted intramolecular charge transfer (TICT) is a process in which structural change accompanies ICT. Herein, we used time-resolved spectroscopy to study TICT in pyrene derivatives that are promising blue organic light emitting diode (OLED) emitter candidates; these derivatives show strong solvent-dependent charge-transfer (CT) behavior with unique fluorescence properties, increased fluorescence intensity in polar solvent. Slight structural changes that do not affect excited state dynamics were observed in nonpolar solvents, while polar solvents were found to affect excited state dynamics and CT characteristics, which affect their unusual fluorescence behavior. The TICT behavior of these pyrene derivatives can be modulated through structural modification. Our study provides valuable guidelines for the control of optical properties, including the luminescence efficiencies of OLED emitters that show TICT characteristics.

Early clinical experience of using the Surpass Evolve flow diverter in the treatment of intracranial aneurysms.

PURPOSE: Here, we presented our early experience with flow diversion procedures using the Surpass Evolve flow diverter (SE, Stryker) and reported the feasibility and safety profile compared to those of a control group treated with other types of flow diverters. METHODS: We included 31 and 53 consecutive flow diversion procedures performed using the SE and other commercial flow diverters, respectively, to treat intracranial aneurysms at our institution. We used two commercial flow diversion systems in the comparison group: the pipeline embolization device and Surpass Streamline. RESULTS: In the SE group, technical failures occurred in three (9.7%) cases, due to either incomplete wall apposition (n = 1, 3.2%) or stent migration (n = 2, 6.5%). Major complications occurred in four (12.9%) cases: delayed rupture of the target aneurysm (n = 1, 3.2%), major ischemic stroke (n = 1, 3.2%), sudden death from an unidentified cause (n = 1, 3.2%), and parent artery occlusion with stent thrombosis (n = 1, 3.2%). Balloon angioplasty was performed in eight (25.8%) cases. On post-procedure MRI, a DWI-positive lesion was detected in three (9.7%) cases. After multivariate adjustment, the SE group was independently associated with less procedural time of ≥ 90 min (adjusted OR, 0.09; 95% CI, 0.03-0.29; p < 0.001), balloon angioplasty (adjusted OR, 0.22; 95% CI, 0.07-0.75; p = 0.015), and DWI-positive lesions (adjusted OR, 0.04; 95% CI, 0.01-0.19; p < 0.001). CONCLUSION: The SE is safe and easy to deploy.

Improvement of Biological Effects of Root-Filling Materials for Primary Teeth by Incorporating Sodium Iodide.

Therapeutic iodoform (CHI3) is commonly used as a root-filling material for primary teeth; however, the side effects of iodoform-containing materials, including early root resorption, have been reported. To overcome this problem, a water-soluble iodide (NaI)-incorporated root-filling material was developed. Calcium hydroxide, silicone oil, and NaI were incorporated in different weight proportions (30:30:X), and the resulting material was denoted DX (D5~D30), indicating the NaI content. As a control, iodoform instead of NaI was incorporated at a ratio of 30:30:30, and the material was denoted I30. The physicochemical (flow, film thickness, radiopacity, viscosity, water absorption, solubility, and ion releases) and biological (cytotoxicity, TRAP, ARS, and analysis of osteoclastic markers) properties were determined. The amount of iodine, sodium, and calcium ion releases and the pH were higher in D30 than I30, and the highest level of unknown extracted molecules was detected in I30. In the cell viability test, all groups except 100% D30 showed no cytotoxicity. In the 50% nontoxic extract, D30 showed decreased osteoclast formation compared with I30. In summary, NaI-incorporated materials showed adequate physicochemical properties and low osteoclast formation compared to their iodoform-counterpart. Thus, NaI-incorporated materials may be used as a substitute for iodoform-counterparts in root-filling materials after further (pre)clinical investigation.

Gamma Knife Radiosurgery for Incidental, Symptomatic Unruptured, and Ruptured Brain Arteriovenous Malformations.

BACKGROUND: This study was performed to investigate clinical characteristics and outcome after gamma knife radiosurgery (GKS) in patients with incidental, symptomatic unruptured, or ruptured arteriovenous malformations (AVMs). METHODS: A total of 491 patients with brain AVMs treated with GKS from June 2002 to September 2017 were retrospectively reviewed. All patients were classified into the incidental (n = 105), symptomatic unruptured (n = 216), or ruptured AVM (n = 170) groups. RESULTS: The mean age at diagnosis of incidental, symptomatic unruptured, and ruptured AVMs was 40.3, 36.7, and 27.6 years, respectively. The mean nidus volume was 3.9, 5.7, and 2.4 cm3, respectively. Deep venous drainage was identified in 34, 54, and 76% patients, respectively. There were no significant differences in obliteration rates after GKS between the 3 groups (64.8, 61.1, and 65.9%, respectively) after a mean follow-up period of 60.5 months; however, patients with incidental AVM had a significantly lower post-GKS hemorrhage rate than patients with symptomatic unruptured or ruptured AVMs (annual hemorrhage rate of 1.07, 2.87, and 2.69%; p = 0.028 and p = 0.049, respectively). CONCLUSIONS: There is a significant difference in clinical and anatomical characteristics between incidental, symptomatic unruptured, and ruptured AVMs. The obliteration rate after GKS is not significantly different between the 3 groups. Meanwhile, an older age at diagnosis and lower hemorrhage rate after GKS in incidental AVMs suggest that they have a more indolent natural course with a lower life-long risk of hemorrhage.

Vitrification for cryopreservation of 2D and 3D stem cells culture using high concentration of cryoprotective agents.

BACKGROUND: Vitrification is the most promising technology for successful cryopreservation of living organisms without ice crystal formation. However, high concentrations (up to ~ 6-8 M) of cryoprotective agents (CPAs) used in stem cell induce osmotic and metabolic injuries. Moreover, the application of conventional slow-freezing methods to cultures of 3-D organoids of stem cells in various studies, is limited by their size. RESULTS: In this study, we evaluated the effect of high concentrations of CPAs including cytotoxicity and characterized human mesenchymal stem cell (MSC) at single cell level. The cell viability, cellular damage, and apoptotic mechanisms as well as the proliferation capacity and multipotency of cells subjected to vitrification were similar to those in the slow-freezing group. Furthermore, we identified the possibility of vitrification of size-controlled 3-D spheroids for cryopreservation of organoid with high survivability. CONCLUSIONS: Our results demonstrate successful vitrification of both single cell and spheroid using high concentration of CPAs in vitro without cytotoxicity.

Clinical Role of Microembolic Signals in Adult Moyamoya Disease With Ischemic Stroke.

Background and Purpose- Hemodynamic compromise has been implicated in moyamoya disease (MMD) with transient ischemic attacks or ischemic stroke. However, increasing evidence supports the notion that artery-to-artery embolism may also contribute to ischemic events based on microembolic signal (MES) monitoring. Methods- A total of 48 patients aged between 20 and 60 years with newly diagnosed MMD were enrolled and angiographically classified according to the Suzuki staging system. For detection of MESs, transcranial Doppler was performed at the middle cerebral artery bilaterally for a 30-minute period. Mean flow velocities in the middle cerebral artery were also evaluated and categorized into low (<40 cm/s), normal (40-80 cm/s), and high (>80 cm/s). Clinical characteristics, cerebral angiography findings, recent ischemic events within 3 months, and antiplatelet medication were correlated with transcranial Doppler findings. Results- MESs were detected in 11 of the 48 patients (23%), with a frequency of 11 of 89 (12%) examined hemispheres. The mean number of MESs was 2 (range, 1-6). Six of the 11 hemispheres (55%) presented with ischemic strokes or transient ischemic attacks, and 2 (18%) presented with hemorrhagic strokes. The presence of MESs was associated with recent ischemic events ( P=0.024) and high mean flow velocities ( P=0.016), which was usually observed in Suzuki stage I and II (early-stage MMD). After controlling for age, sex, and antiplatelet medication, both recent ischemic events (odds ratio, 6.294; 95% CI, 1.345-29.457; P=0.019) and high mean flow velocities (odds ratio, 6.172; 95% CI, 1.235-31.25; P=0.027) were found to be independent predictors of MESs. Conclusions- MESs were observed in patients with high mean flow velocities, particularly early-stage MMD, and clinically associated with recent ischemic events. A randomized controlled study is necessary to determine the efficacy of antiplatelet agents in the treatment of MES-positive MMD.

Gamma Knife Radiosurgery for ARUBA-Eligible Patients with Unruptured Brain Arteriovenous Malformations.

BACKGROUND: A randomized trial of unruptured brain arteriovenous malformations (ARUBA) reported superior outcomes in conservative management compared to interventional treatment. There were numerous limitations to the study. This study aimed to investigate the efficacy of gamma knife radiosurgery (GKS) for patients with brain arteriovenous malformations (AVMs) by comparing its outcomes to those of the ARUBA study. METHODS: We retrospectively reviewed ARUBA-eligible patients treated with GKS from June 2002 to September 2017 and compared against those in the ARUBA study. AVM obliteration and hemorrhage rates, and clinical outcomes following GKS were also evaluated. RESULTS: The ARUBA-eligible cohort comprised 264 patients. The Spetzler-Martin grade was Grade I to II in 52.7% and III to IV in 47.3% of the patients. The mean AVM nidus volume, marginal dose, and follow-up period were 4.8 cm³, 20.8 Gy, and 55.5 months, respectively. AVM obliteration was achieved in 62.1%. The annual hemorrhage rate after GKS was 3.4%. A stroke or death occurred in 14.0%. The overall stroke or death rate of the ARUBA-eligible cohort was significantly lower than that of the interventional arm of the ARUBA study (P < 0.001) and did not significantly differ from that of the medical arm in the ARUBA study (P = 0.601). CONCLUSION: GKS was shown to achieve a favorable outcome with low procedure-related morbidity in majority of the ARUBA-eligible patients. The outcome after GKS in our patients was not inferior to that of medical care alone in the ARUBA study. It is suggested that GKS is rather superior to medical care considering the short follow-up duration of the ARUBA study.

Cav-1 (Caveolin-1) and Arterial Remodeling in Adult Moyamoya Disease.

Background and Purpose- Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease characterized by progressive stenosis and negative remodeling of the distal internal carotid artery (ICA). We hypothesized that cav-1 (caveolin-1)-a protein that controls the regulation of endothelial vesicular trafficking and signal transduction-is associated with negative remodeling in MMD. Methods- We prospectively recruited 77 consecutive patients with MMD diagnosed via conventional angiography. Seventeen patients with intracranial atherosclerotic stroke and no RNF213 mutation served as controls. The outer distal ICA diameters were examined using high-resolution magnetic resonance imaging. We evaluated whether the degree of negative remodeling in the patients with MMD was associated with RNF213 polymorphism, cav-1 levels, or various clinical and vascular risk factors. We also investigated whether the derived factor was associated with negative remodeling at the cellular level using the tube formation and apoptosis assays. Results- The serum cav-1 level was lower in the patients with MMD than in the controls (0.47±0.29 versus 0.86±0.68 ng/mL; P=0.034). The mean ICA diameter was 2.48±0.98 mm for the 126 affected distal ICAs in patients with MMD and 3.84±0.42 mm for the asymptomatic ICAs in the controls ( P<0.001). After adjusting for confounders, cav-1 levels (coefficient, 1.018; P<0.001) were independently associated with the distal ICA diameter in patients with MMD. In vitro analysis showed that cav-1 downregulation suppressed angiogenesis in the endothelial cells and induced apoptosis in the smooth muscle cells. Conclusions- Our findings suggest that cav-1 may play a major role in negative arterial remodeling in MMD.

Infarct Pattern and Collateral Status in Adult Moyamoya Disease: A Multimodal Magnetic Resonance Imaging Study.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals, called moyamoya vessels. Although hemodynamic studies have been applied in MMD patients, the mechanisms of stroke in MMD are still unclear. The present study evaluated the infarct pattern and collateral status using multimodal magnetic resonance imaging in MMD patients. METHODS: Adult MMD patients with acute ischemic stroke were prospectively recruited, and infarct pattern on diffusion-weighted imaging was evaluated. A collateral flow map, derived from magnetic resonance perfusion-weighted imaging data, was generated through automatic postprocessing, and collateral status was assigned into 3 grades. Transcranial Doppler monitoring was performed to detect microembolic signals in selected patients. RESULTS: A total of 67 hemispheres (31 patients with bilateral and 5 patients with unilateral MMD) were analyzed. Most patients (83.7%) showed embolic pattern and rarely deep (9.3%) or hemodynamic infarct pattern (7.0%) on diffusion-weighted imaging. Most cases (86%) showed good collateral status, and few patients with acute infarcts of embolic pattern showed poor collateral status (n=7). One third (31.6%) of patients who underwent transcranial Doppler monitoring showed microembolic signals. CONCLUSIONS: In the studied population of adult MMD patients, embolic phenomenon played an important role in ischemic stroke. Therapeutic strategies against thromboembolism, as well as collateral enhancing strategies targeting improvement of hemodynamic status or increased washout of emboli, are warranted.

Reactivation of the inactive X chromosome and post-transcriptional reprogramming of Xist in iPSCs.

Direct reprogramming of somatic cells to pluripotent stem cells entails the obliteration of somatic cell memory and the reestablishment of epigenetic events. Induced pluripotent stem cells (iPSCs) have been created by reprogramming somatic cells through the transduction of reprogramming factors. During cell reprogramming, female somatic cells must overcome at least one more barrier than male somatic cells in order to enter a pluripotent state, as they must reactivate an inactive X chromosome (Xi). In this study, we investigated whether the sex of somatic cells affects reprogramming efficiency, differentiation potential and the post-transcriptional processing of Xist RNA after reprogramming. There were no differences between male and female iPSCs with respect to reprogramming efficiency or their differentiation potential in vivo. However, reactivating Xi took longer than reactivating pluripotency-related genes. We also found that direct reprogramming leads to gender-appropriate post-transcriptional reprogramming - like male embryonic stem cells (ESCs), male iPSCs expressed only the long Xist isoform, whereas female iPSCs, like female ESCs, expressed both the long and short isoforms.

Preventive Effect of Clazosentan against Cerebral Vasospasm after Clipping Surgery for Aneurysmal Subarachnoid Hemorrhage in Japanese and Korean Patients.

BACKGROUND: Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH. METHODS: The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared. RESULTS: Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003). CONCLUSION: These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.

Early rebleeding of intracranial dural arteriovenous fistulas after an intracranial hemorrhage.

BACKGROUND: The aim of this study was to evaluate the clinical and angiographic characteristics of dural arteriovenous fistulas (DAVF) presenting with intracranial hemorrhage (ICH), with a focus on early rebleeding according to the initial hemorrhage type. METHOD: The clinical and radiologic features of 21 dAVFs that presented with intracranial hemorrhage were retrospectively reviewed. The hemorrhage type was classified as pure intraparenchymal hemorrhage (pIPH) and subarachnoid or subdural hemorrhage with IPH (non-pIPH). RESULTS: There were 13 patients with pIPH and 8 with non-pIPH. The median follow-up period was 30 months (range, 1-116 months), and the median interval from hemorrhage to treatment was 4 days (range, 0-72 days). Rebleeding occurred in 8 (38.1%) of 21 patients. Four (50%) of eight patients with non-pIPH suffered from early rebleeding within 3 days, while there was no early rebleeding in patients with pIPH. There was a significantly higher rate of early rebleeding in the non-pIPH group (p = 0.012). Angiographically, venous ectasia (p = 0.005) and direct cortical venous drainage (dCVD) (p = 0.008) showed a significantly higher proportion in the non-pIPH group than in the pIPH group. CONCLUSIONS: DAVFs with ICH is likely to rebleed after the first hemorrhage. Thus, early treatment can be needed in all DAVFs with ICH. In addition, DAVFs that presenting with non-pIPH and containing venous ectasia or dCVD on initial angiography may have a higher risk of early rebleeding. Therefore, cautious attention and urgent treatment are necessary for these patients.

Genetic variations of MTHFR gene and their association with preterm birth in Korean women.

BACKGROUND AND OBJECTIVE: The MTHFR gene encodes the methylenetetrahydrofolate reductase known to be involved in the homocysteine-methionine pathway. It has been reported that the deficiency of MTHFR activity may cause hyperhomocysteinemia which results in adverse pregnancy outcomes. Previous studies reported a correlation between the MTHFR gene polymorphisms (677 T/C and 1298 A/C) and lower MTHFR activity and its association with preterm birth in various populations. Since these results were conflicting, we analyzed the genetic association of MTHFR gene 677 T/C and 1298 A/C polymorphisms with preterm birth in Korean women. MATERIALS AND METHODS: The subjects for case-control study were collected a total of 226 Korean women (98 preterm-birth patients and 128 controls). Genotype frequency differences between the case and the control were assessed using chi-square tests. Mann-Whitney t-test was used to estimate the effects of 1298 A/C genotype on clinicopathological characteristics (systolic blood pressure, diastolic blood pressure, birth weight, and gestational age at delivery) in preterm-birth patients. RESULTS: Our results showed that the MTHFR 677 C/T polymorphism was significantly associated with preterm-birth patients in the analysis of genotype frequency (P=0.044) and the over-dominant model (OR=0.54; 95% CI, 0.320-0.920; P=0.023). The recessive model showed a marginal trend toward significance (OR=0.47; 95% CI, 0.220-1.010; P=0.046). The 1298 A/C polymorphism was also associated with reduced preterm-birth risk in the recessive model (P=0.032). In the correlation analysis, the 1298 C allele was significantly associated with increasing of gestational age at delivery in preterm-birth patients (P=0.034). CONCLUSIONS: Our findings suggested that the MTHFR gene 677 C/T and 1298 A/C polymorphisms might have protective effects for preterm birth in the Korean women.

Clinical Features of Superficially Located Brain Arteriovenous Malformations with Transdural Arterial Communication.

BACKGROUND: Contrary to deeply located brain arteriovenous malformations (AVMs), superficially located AVMs are more likely to have transdural arterial communications (TACs). However, the clinical and radiologic characteristics of patients presenting with AVMs and TACs are poorly understood. The purpose of this study is to determine whether clinicoradiological features of cerebral AVMs differ according to TAC. METHODS: Between 2002 and 2012, 438 consecutive patients with a brain AVM were treated in our hospital. Among them were 124 patients with superficially located brain AVMs who met the inclusion and exclusion criteria of our study. We retrospectively reviewed the clinicoradiological features of their TACs to explore the variation in characteristics. RESULTS: Thirty-two of the 124 patients with a superficially located AVM (25.8%) had TAC. Radiologic findings of brain AVM images with TAC showed that TAC occurred significantly more frequently among larger AVMs (with vs. without TAC, 11.2 vs. 4.0 ml) and among diffuse AVMs (56.3 vs. 28.3%, p = 0.004). Clinical findings indicate that TAC was associated with chronic headache (43.8 vs. 12.0%, p < 0.001) and older age (43.1 vs. 36.6 years, p = 0.037). CONCLUSIONS: Brain AVM with TAC seems to be accompanied by distinctive clinical features, such as chronic headache and older age. Larger size and diffuseness of the AVM were also associated with TAC. Findings from this study and the prognostic significance of TAC should be further explored in a large prospective study.

Examination of endothelial cell-induced epidermal regeneration in a mice-based chimney wound model.

As wound contraction in the cutaneous layer occurs rapidly in mice, mechanical means are typically used to deliberately expose the wound to properly investigate healing by secondary intention. Previously, silicon rings and splinting models were attempted to analyze histological recovery but prevention of surrounding epidermal cell migration and subsequent closure was minimal. Here, we developed an ideal chimney wound model to evaluate epidermal regeneration in murine under hESC-EC transplantation through histological analysis encompassing the three phases of regeneration: migration, proliferation, and remodeling. Human embryonic stem cell derived endothelial cells (hESC-EC) were transplanted due to possessing a well-known therapeutic effect in angiogenesis which also enhances epidermal repair to depict the process of regeneration. Following a standard 1 mm biopsy punch, a chimney manufactured by modifying a 1.7 mL microtube was simply inserted into the excisional wound to complete the modeling process. Under this model, the excisional wound remained fully exposed for 14 days and even after 4 weeks, only a thin transparent layer of epidermal tissue covered the wound site. This approach is able to more accurately depict epidermal repair in relation to histology while also being a user-friendly and cost-effective way to mimic human recovery in rodents and evaluate epithelial repair induced by a form of therapy.

Morphological risk factors for the rupture of anterior communicating artery aneurysms: the significance of fenestration.

INTRODUCTION: The purpose of this study was to evaluate morphological factors associated with rupture in anterior communicating artery (AcomA) aneurysms and to investigate the significance of AcomA fenestration as a risk factor for aneurysm rupture. METHODS: The clinical and radiologic findings of 255 patients with AcomA aneurysms treated with coil embolization between January 2005 and March 2014 were retrospectively reviewed. We performed univariate and multivariate analyses to evaluate the associations between morphological variables and rupture status. RESULTS: The number of patients with AcomA fenestration was 17 out of 255 (6.6 %). There were no statistically significant differences between the fenestration group and non-fenestration group in clinical and morphological characteristics. Multivariate logistic regression tests showed that superior direction of aneurysm dome (OR 2.802, p = 0.023), presence of a bleb (OR 5.998, p < 0.001), high aspect ratio (OR 3.138, p = 0.009), size greater than 7 mm (OR 3.356, p = 0.013), and AcomA fenestration (OR 4.135, p = 0.026) were significantly associated with AcomA aneurysm rupture. CONCLUSIONS: The results of this study demonstrated that a fenestrated AcomA is associated with risk of aneurysm rupture. Therefore, AcomA fenestration can be considered as an important morphological risk factor for rupture, along with other known risk factors such as the direction of aneurysm dome, a bleb, high aspect ratio, and size.

Safety and efficacy of antiplatelet response assay and drug adjustment in coil embolization: a propensity score analysis.

INTRODUCTION: The purpose of this study was to explore the safety and efficacy of an antiplatelet response assay and drug adjustment to prevent delayed thromboembolic events after stent-assisted coil embolization. METHODS: A total of 370 patients were enrolled in this study between December 2005 and July 2014. Of these, 124 patients were placed into the drug resistance test (DRT) group with drug adjustment according to response to an antiplatelet agent, and 246 patients comprised the control group with a standard antiplatelet regimen. The response to the antiplatelet agent was evaluated with the VerifyNow Rapid Platelet Function Assay. Propensity score matching analysis was performed with one-to-multiple matching. RESULTS: Among 370 patients, delayed thromboembolic events occurred in 28 (7.6 %) patients including 25 (10.2 %) in the control group and three (2.4 %) in the DRT group. Antiplatelet response test (p = 0.012), diabetes mellitus (DM) (p = 0.014), and hypertension (HTN) (p < 0.001) were associated with delayed infarction in multivariate analysis. In propensity score matching analysis, 331 patients were matched (control group (n = 229) vs. DRT group (n = 103)), and antiplatelet response (hazard ratio 0.247, 95 % confidence interval 0.070-0.868, p = 0.029) was correlated with delayed infarction. Conversely, the two groups were not significantly different with regard to total (p = 0.368) or major hemorrhagic complications (p = 0.108). CONCLUSION: Antiplatelet drug adjustment according to the results of an antiplatelet response assay might be associated with a decreased risk of delayed thromboembolic infarction compared with the standard antiplatelet regimen.

Determinants of Basal Collaterals in Moyamoya Disease: Clinical and Genetic Factors.

BACKGROUND/AIMS: To enable the diagnosis of moyamoya disease (MMD), detection of distal internal carotid artery stenosis and hazy network of basal collaterals (BCs) are required. This study aimed at evaluating the factors that could determine the degree of BCs in patients with angiographically confirmed MMD. METHODS: We analyzed 146 consecutive patients with MMD (age 26.2 ± 19.6, range 1-75). The degree of BCs (%) was measured based on conventional angiography. Factors associated with the degree of BCs, including clinico-radiological and genetic factors (p.Arg4810Lys variant), were analyzed. RESULTS: The degree of BCs varied among MMD patients and significantly decreased with an increase in the age of diagnosis of MMD (coefficient -1.55; p < 0.001). Although the degree of BC development depends on the MMD stage (Suzuki stage), it is less prominent in adult-onset (>18 years) MMD compared to childhood MMD. The presence of p.Arg4810Lys variant, types of MMD (bilateral vs. unilateral) and stroke (ischemic, hemorrhagic, or asymptomatic), shrinkage (outer diameter) of intracranial vessels, external carotid collateral status, and cortical neovascularization were not associated with the degree of BCs. CONCLUSION: Although prominent BCs are required for diagnosis of MMD, BCs are decreased with aging, suggesting that angiogenic capacity is altered in adult onset MMD compared to childhood MMD.

Whole genome sequencing of an ethnic Pathan (Pakhtun) from the north-west of Pakistan.

BACKGROUND: Pakistan covers a key geographic area in human history, being both part of the Indus River region that acted as one of the cradles of civilization and as a link between Western Eurasia and Eastern Asia. This region is inhabited by a number of distinct ethnic groups, the largest being the Punjabi, Pathan (Pakhtuns), Sindhi, and Baloch. RESULTS: We analyzed the first ethnic male Pathan genome by sequencing it to 29.7-fold coverage using the Illumina HiSeq2000 platform. A total of 3.8 million single nucleotide variations (SNVs) and 0.5 million small indels were identified by comparing with the human reference genome. Among the SNVs, 129,441 were novel, and 10,315 nonsynonymous SNVs were found in 5,344 genes. SNVs were annotated for health consequences and high risk diseases, as well as possible influences on drug efficacy. We confirmed that the Pathan genome presented here is representative of this ethnic group by comparing it to a panel of Central Asians from the HGDP-CEPH panels typed for ~650 k SNPs. The mtDNA (H2) and Y haplogroup (L1) of this individual were also typical of his geographic region of origin. Finally, we reconstruct the demographic history by PSMC, which highlights a recent increase in effective population size compatible with admixture between European and Asian lineages expected in this geographic region. CONCLUSIONS: We present a whole-genome sequence and analyses of an ethnic Pathan from the north-west province of Pakistan. It is a useful resource to understand genetic variation and human migration across the whole Asian continent.

Neural stem cells differentiated from iPS cells spontaneously regain pluripotency.

Differentiated somatic cells can be reprogrammed into pluripotent stem cells by transduction of exogenous reprogramming factors. After induced pluripotent stem (iPS) cells are established, exogenous genes are silenced. In the pluripotent state, retroviral genes integrated in the host genome are kept inactive through epigenetic transcriptional regulation. In this study, we tried to determine whether exogenous genes remain silenced or are reactivated upon loss of pluripotency or on differentiation using an in vitro system. We induced differentiation of iPS cells into neural stem cells (NSCs) in vitro; the NSCs appeared morphologically indistinguishable from brain-derived NSCs and stained positive for the NSC markers Nestin and Sox2. These iPS cell-derived NSCs (iPS-NSCs) were also capable of differentiating into all three neural subtypes. Interestingly, iPS-NSCs spontaneously formed aggregates on long-term culture and showed reactivation of the Oct4-GFP marker, which was followed by the formation of embryonic stem cell-like colonies. The spontaneously reverted green fluorescent protein (GFP)-positive (iPS-NSC-GFP(+) ) cells expressed high levels of pluripotency markers (Oct4 and Nanog) and formed germline chimeras, indicating that iPS-NSC-GFP(+) cells had the same pluripotency as the original iPS cells. The reactivation of silenced exogenous genes was tightly correlated with the downregulation of DNA methyltransferases (Dnmts) during differentiation of iPS cells. This phenomenon was not observed in doxycycline-inducible iPS cells, where the reactivation of exogenous genes could be induced only by doxycycline treatment. These results indicate that pluripotency can be regained through reactivation of exogenous genes, which is associated with dynamic change of Dnmt levels during differentiation of iPS cells.