Association between time to treatment and functional outcomes according to the Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score in endovascular stroke therapy.

BACKGROUND AND PURPOSE: The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion-weighted magnetic resonance imaging (DWI-MRI) and whether ischaemic core size affects this rate remain to be investigated. METHODS: This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI-MRI that was categorized into three groups: small [Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS)] (8-10), moderate (5-7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0-2). The interaction between onset-to-groin puncture time (OTP) and DWI-ASPECTS categories regarding functional outcomes was investigated. RESULTS: Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI-ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction  = 0.06). Every 60-min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity  = 0.15). CONCLUSIONS: Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI-ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.

Cycling of Dexmedetomidine May Prevent Delirium After Liver Transplantation.

BACKGROUND: Dexmedetomidine is useful for managing delirium. However, few studies have discussed the effect of dexmedetomidine on delirium after liver transplantation. Moreover, the studies have focused on treatment rather than prevention of delirium. This study found that dexmedetomidine cycling may prevent delirium by restoration of the circadian rhythm. METHODS: Of 38 patients who underwent liver transplantation between April 2013 and July 2016, 37 were retrospectively analyzed, except for 1 case of early mortality. The patients were divided into two groups, with 24 receiving dexmedetomidine for more than 3 days with cycling, and 13 receiving dexmedetomidine without cycling or for less than 3 days. Cycling was intended to restore circadian rhythm with high doses of dexmedetomidine at night and low doses during the day, while the patients remained intubated. After extubation, dexmedetomidine infusion was continued at night and discontinued during the day. The patients who used dexmedetomidine without cycling or for less than 3 days received dexmedetomidine without regard to circadian rhythm. RESULTS: Of the 24 patients who received dexmedetomidine for more than 3 days with cycling, 3 (12.5%) had delirium. In contrast, of the 12 patients who received dexmedetomidine without regard to circadian rhythm and the 1 who received dexmedetomidine cycling for less than 3 days, 6 (46.2%) had delirium (P = .042). Patients with hepatitis C showed higher prevalence of delirium (P = .022). CONCLUSION: Dexmedetomidine use for more than 3 days with cycling is useful for prevention of delirium after liver transplantation.

Association Study of 60 Candidate Genes with Antipsychotic-induced Weight Gain in Schizophrenia Patients.

INTRODUCTION: This study aimed to investigate the association of multiple candidate genes with weight gain and appetite change during antipsychotic treatment. METHODS: A total of 233 single nucleotide polymorphisms (SNPs) within 60 candidate genes were genotyped. BMI changes for up to 8 weeks in 84 schizophrenia patients receiving antipsychotic medication were analyzed using a linear mixed model. In addition, we assessed appetite change during antipsychotic treatment in a different group of 46 schizophrenia patients using the Drug-Related Eating Behavior Questionnaire. RESULTS: No SNP showed a statistically significant association with BMI or appetite change after correction for multiple testing. We observed trends of association (P<0.05) between 19 SNPs of 11 genes and weight gain, and between 7 SNPs of 5 genes and appetite change. In particular, rs696217 in GHRL showed suggestive evidence of association with not only weight gain (P=0.001) but also appetite change (P=0.042). Patients carrying the GG genotype of rs696217 exhibited higher increase in both BMI and appetite compared to patients carrying the GT/TT genotype. DISCUSSION: Our findings suggested the involvement of a GHRL polymorphism in weight gain, which was specifically mediated by appetite change, during antipsychotic treatment in schizophrenia patients.

Temporal variability of glucocorticoid receptor activity is functionally important for the therapeutic action of fluoxetine in the hippocampus.

Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity.

Activation of OCT4 enhances ex vivo expansion of human cord blood hematopoietic stem and progenitor cells by regulating HOXB4 expression.

Although hematopoietic stem cells (HSC) are the best characterized and the most clinically used adult stem cells, efforts are still needed to understand how to best ex vivo expand these cells. Here we present our unexpected finding that OCT4 is involved in the enhancement of cytokine-induced expansion capabilities of human cord blood (CB) HSC. Activation of OCT4 by Oct4-activating compound 1 (OAC1) in CB CD34(+) cells enhanced ex vivo expansion of HSC, as determined by a rigorously defined set of markers for human HSC, and in vivo short-term and long-term repopulating ability in NSG mice. Limiting dilution analysis revealed that OAC1 treatment resulted in 3.5-fold increase in the number of SCID repopulating cells (SRCs) compared with that in day 0 uncultured CD34(+) cells and 6.3-fold increase compared with that in cells treated with control vehicle. Hematopoietic progenitor cells, as assessed by in vitro colony formation, were also enhanced. Furthermore, we showed that OAC1 treatment led to OCT4-mediated upregulation of HOXB4. Consistently, siRNA-mediated knockdown of HOXB4 expression suppressed effects of OAC1 on ex vivo expansion of HSC. Our study has identified the OCT4-HOXB4 axis in ex vivo expansion of human CB HSC.

Relationship between serum vitamin D concentrations and clinical outcome of community-acquired pneumonia.

SETTING: Hospitalised patients with community-acquired pneumonia (CAP) in a tertiary referral hospital in South Korea. OBJECTIVE: To determine the burden of vitamin D deficiency in patients hospitalised with CAP and to investigate whether vitamin D deficiency affected clinical outcomes. DESIGN: Serum 25-hydroxyvitamin D (25[OH]D) levels were measured at admission; vitamin D deficiency was defined as 25(OH)D <20 ng/ml. Data were retrospectively analysed for incidence of vitamin D deficiency. The primary outcome was the relationship between serum vitamin D concentration and 28-day all-cause mortality in CAP. RESULTS: The mean age was 68.1 years (standard deviation [SD] ± 14.6), and the mean pneumonia severity index was 98.0 (± SD 28.6). Of the 797 patients (males 66.0%), 641 (80.4%) had vitamin D deficiency. Overall mean serum 25(OH)D level was 14.0 ± 7.4 ng/ml. The 28-day all-cause mortality rate in vitamin D-deficient patients was significantly higher than in non-deficient patients (8.3% vs. 2.6%, P = 0.01), and serum vitamin D level was negatively associated with risk of 28-day mortality in CAP after adjustment for pneumonia severity index and serum lactate levels (OR 0.94, 95%CI 0.90-0.99, P < 0.01). CONCLUSION: The prevalence of vitamin D deficiency was ~80% in patients hospitalised with CAP. Vitamin D deficiency was also a significant predictor of increased 28-day all-cause mortality.

Aspirin decreases systemic exposure to clopidogrel through modulation of P-glycoprotein but does not alter its antithrombotic activity.

Decreased oral clopidogrel absorption caused by induction of intestinal permeability glycoprotein (P-gp) expression after aspirin administration was observed in rats. This study evaluated the effect of aspirin coadministration on the pharmacokinetics/pharmacodynamics of clopidogrel in humans. A single 75-mg dose of clopidogrel was orally administered before and after 2 and 4 weeks of once-daily 100-mg aspirin administration in 18 healthy volunteers who were recruited based on CYP2C19 and PON1 genotypes. Plasma concentrations of clopidogrel and its active metabolite, H4, and relative platelet inhibition (RPI) were determined. The P-gp microRNA miR-27a increased by up to 7.67-fold (P = 0.004) and the clopidogrel area under the concentration-time curve (AUC) decreased by 14% (P > 0.05), but the AUC of H4 remained unchanged and RPI increased by up to 15% (P = 0.002) after aspirin administration. These findings indicate low-dose aspirin coadministration may decrease clopidogrel bioavailability but does not decrease its efficacy.

Apparent treatment-resistant hypertension among elderly Korean hypertensives: an insight from the HIT registry.

The aim of this study was to determine the clinical characteristics of patients with resistant hypertension (RH) and predictors among elderly Korean hypertensives. This prospective, multi-center, observational study evaluated 2439 elderly hypertensive patients between December 2008 and November 2011, who visited secondary hypertension clinics for high blood pressure (BP). Patients were categorized as resistant if their BP was ≥140/90 mm Hg and if they reported using antihypertensive medications from three different drug classes, including a diuretic or drugs from ≥4 antihypertensive drug classes, regardless of BP. Characteristics of patients with RH were compared with those of patients who were controlled with one or two antihypertensive medications after 6-month antihypertensive treatment. In comparison with 837 patients with non-RH, 404 patients with RH were more likely to be aware of their status of high BP before enrollment and have a high baseline systolic BP ≥160 mm Hg, microalbuminuria, high body mass index (BMI) ≥24 kg m(-2) and diabetes mellitus (DM). In drug-naive patients, awareness of hypertension at baseline was the only independent predictor for RH. In elderly Korean hypertensives, BMI (≥24 kg m(-2)), baseline systolic BP (≥160 mm Hg), microalbuminuria, DM and awareness of hypertension showed an association with RH.

Deep subcortical infarct burden in relation to apolipoprotein B/AI ratio in patients with intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE: Pre-existing brain infarct (PBI), frequently seen on magnetic resonance imaging and usually silent, is recognized as a risk factor for future stroke. Increased apolipoprotein B (apoB)/apoAI ratio is known to be a risk predictor of ischaemic stroke and is associated with intracranial atherosclerotic stenosis (ICAS). However, little is known about the association of apoB/apoAI ratio with PBI. METHODS: A total of 522 statin-/fibrate-naïve Korean patients, who experienced acute ischaemic stroke, were categorized into three groups: ICAS (n=254), extracranial (n=51), and no cerebral atherosclerotic stenosis (n=217). We explored the association between apoB/apoAI ratio and PBI lesions according to atherosclerosis type (ICAS, ECAS, and NCAS), PBI location (deep subcortical [ds-PBI] versus hemispheric [h-PBI]), and symptomatic PBI (s-PBI) which was relevant to a prior clinical stroke event. RESULTS: Pre-existing brain infarct(+) patients showed a higher apoB/apoAI ratio than PBI(-) patients (0.81 ± 0.28 vs. 0.72 ± 0.23, P<0.001). In ICAS group, patients with higher apoB/apoAI ratio quartiles had more PBIs, ds-PBIs, and s-PBIs (P=0.020, P=0.025, and P=0.001, respectively). With multivariable analyses, the highest apoB/apoAI ratio quartile was associated with PBI (OR, 2.56; 95% CI, 1.39-4.73), ds-PBI (2.48; 1.33-4.62), and advanced (≥ 3) ds-PBIs (2.68; 1.27-5.63) in ICAS group, but not with h-PBI. s-PBI had a dose-response relationship with apoB/apoAI ratio quartiles (6.18; 1.31-29.13 for the second; 5.34; 1.06-26.83 for the third; and 12.17; 2.50-59.19 for the fourth quartile), when referenced to the first quartile. CONCLUSION: ApoB/apoAI ratio is associated with asymptomatic deep subcortical ischaemic burden as well as with symptomatic lesion in patients with ICAS.

Pharmacodynamic comparison of two formulations of Acarbose 100-mg tablets.

WHAT IS KNOWN AND OBJECTIVE: Acarbose, an α-glycosidase inhibitor, is used to treat diabetic patients. Pharmacokinetic evaluation of acarbose is difficult because <2% is absorbed systemically. The current investigation evaluated the bioequivalence of two formulations of acarbose through pharmacodynamic comparison. METHODS: This investigation consisted of a pilot study and a main study. The pilot study had an open, single-dose, single-sequence design. Subjects received placebo and then two tablets of reference formulation (Glucobay(®) 100 mg tablet; Bayer Healthcare) on two consecutive days with sucrose. The main study was an open, randomized, two-period, two-sequence crossover study. Subjects randomly received placebo and two tablets of either test formulation (generic acarbose 100-mg tablet) or reference formulation with sucrose on two consecutive days in the first period. In the second period, placebo and alternative formulation were administered. Serial blood samples for pharmacodynamic assessment were taken after each administration. The maximum serum glucose concentration (G(max)) and the area under the serum glucose concentration-time profile (AUC(gluc)) were determined and compared. RESULTS AND DISCUSSION: Five subjects completed the pilot study. The AUC(gluc) from dosing until 1 h post-dose (AUC(gluc,1 h)) was significantly different between the placebo and acarbose. A total of 33 subjects completed the main study. The mean differences in G(max) (ΔG(max)) and AUC(gluc,1 h) (ΔAUC(gluc,1 h)) for the reference formulation compared with placebo were 22·0 ± 18·3 mg/dL and 928·2 ± 756·0 mg min/dL, respectively. The corresponding values for the test formulation were 23·3 ± 21·2 mg/dL and 923·0 ± 991·4 0 mg min/dL, respectively. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for ΔG(max) and ΔAUC(gluc, 1 h) were 1·06 and 1·00, respectively, and the 90% confidence intervals (CIs) corresponding values were 0·79-1·39 and 0·64-1·36, respectively. WHAT IS NEW AND CONCLUSION: The 90% CIs of GMRs for the pharmacodynamic parameters chosen for bioequivalence evaluation of two formulations of acarbose did not meet the commonly accepted regulatory criteria for bioequivalence (0·80-1·25).

Comparison of 90-day case-fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis.

BACKGROUND: It has not been clarified whether the disparity in ischemic stroke outcome between populations is caused by ethnic and geographic differences or by variations in case mix. Propensity score matching (PSM) analysis can overcome some analytical problems but is rarely used in stroke outcome research. This study was to compare the ischemic stroke case-fatality between two PSM cohorts of Sweden and Korea. METHODS: Prognostic variables related to baseline characteristics and stroke care were included in our PSM model. Then, we selected 7675 Swedish and 1220 Korean patients with ischemic stroke from each stroke registers and performed one-to-one matching based on propensity scores of each patient. RESULTS: After PSM, all measured variables were well balanced in 1163 matched subjects, and the 90-day case-fatality was identical 6.2% (HR 0.997, 95%CI 0.905-1.099) in Sweden and Korea. CONCLUSIONS: No difference is found in the 90-day case-fatality in propensity score-matched Swedish and Korean patients with ischemic stroke.

Effect of cilnidipine vs losartan on cerebral blood flow in hypertensive patients with a history of ischemic stroke: a randomized controlled trial.

OBJECTIVES: The aim of this study was to compare the effects of antihypertensive agents on cerebral blood flow (CBF) in hypertensive patients with previous ischemic stroke. MATERIALS AND METHODS: In this double-blind, multi-center, non-inferiority trial, 196 patients were randomized to cilnidipine 10-20 mg or losartan 50-100 mg once daily for 4 weeks. Baseline and follow-up CBF as measured by single photon emission computed tomography were obtained in 167. The primary endpoint was the global CBF change. The secondary endpoints were the CBF change in the hemisphere ipsilateral to the index stroke, non-impairment of global CBF and blood pressure (BP) reduction. RESULTS: Global CBF increased significantly in the cilnidipine arm (9.0 +/- 29.6%, P = 0.0071) and the losartan arm (11.4 +/- 31.4%, P = 0.0012), and these changes were not different between the two groups (P = 0.607). However, the estimated difference in percentage global CBF change between the two groups was -2.43% (97.5% CI, -13.06% to 8.21%), which crossed the predetermined non-inferiority margin of -8.6%. Ipsilesional hemispheric CBF change, non-impairment of global CBF and BP reduction were similar in the two groups. CONCLUSIONS: This trial failed to prove the non-inferiority of cilnidipine to losartan regarding global CBF change. Both the treatments, however, increase the global CBF despite BP lowering.

Synthesis and electrochemical studies of nano-scale carbon-coated LiFePO4 electrodes for Li-ion batteries.

Regardless of high capacity and stability during lithium extraction, LiFePO4 materials have difficulty in the applications for high electrical density because of low electrical conductivities. In order to optimize this problem, we synthesized carbon coated LiFePO4 by adding humic acid using solid state reaction method. We characterized the synthesized compounds via the crystallinity, the valence states of Fe ions, and their shapes. We found the carbon coating using X-ray photoelectron spectroscopy (XPS) and transmission electron microscope (TEM). We also found that the iron ion is substituted from 3+ to 2+ through XPS measurement. We showed that the carbon coating increased the electrochemical behavior by measuring the charge-discharge characteristics.

Mechanical properties of bovine articular cartilage under microscale indentation loading from atomic force microscopy.

Atomic force microscopy (AFM) techniques have been increasingly used for investigating the mechanical properties of articular cartilage. According to the previous studies reporting the microscale Young's modulus under AFM indentation tests, the Hertz contact model has been employed with a sharp conical tip indenter. However, the non-linear microscale behaviour of articular cartilage could not be resolved by the standardized Hertz analysis using small and sharp atomic force microscope tips. Therefore, the objective of this study was to evaluate the microscale Young's modulus of articular cartilage more accurately through a non-Hertzian approach with a spherical tip of 5 microm diameter, and to characterize its microscale mechanical behaviour. This methodology adopted in the present study was proved by the consistent values between the microscale (2 per cent, about 9.3 kPa; 3 per cent, about 17.5kPa) and macroscale (2 per cent, about 8.3kPa; 3 per cent, about 18.3kPa) Young's moduli for 2 per cent and 3 per cent agarose gel (n = 100). Therefore, the microscale Young's modulus evaluated in this study is representative of more accurate measurements of cartilage stiffness at the 600 nm deformation level and corresponds to approximately 30.9 kPa (n = 100). Furthermore, on this level of the microscale deformation, articular cartilage showed depth-dependent and frequency-independent behaviour under AFM indentation loading. These findings reveal the microscale mechanical behaviour of articular cartilage more accurately and can be employed further to design microscale structures of chondrocyte-seeded scaffolds and tissue-engineered cartilage by evaluating their microscale properties.

Specific hippocampal choline decrease in an animal model of depression.

A decreased level of the hippocampal choline signal was found in patients with depression in previous proton magnetic resonance spectroscopy ((1)H-MRS) studies. The objective of this study is to compare choline levels before and after the forced swimming test (FST), an animal model of depression typically used for assessing antidepressant activity. (1)H-MRS spectra were obtained from both the left and right hippocampus. After the FST, rats showed a significant decrease of the choline/creatine (Cho/Cr, p = 0.037) and choline/N-acetylaspartate (Cho/NAA, p = 0.048) ratios in the left hippocampus, but not in the right hippocampus. This finding was analogous to results from patients with depression. It suggests that decreased Cho/Cr and Cho/NAA ratios in the left hippocampal regions might be considered to be biomarkers in rats with depression.

The relationship between body fat mass and erectile dysfunction in Korean men: Hallym Aging Study.

The aim of this study was to assess the relationship between body fat mass (BFM) and erectile dysfunction (ED) in Korean men. This study was a cross-sectional study using data on 208 men (the mean age=67.4+/-8.2). ED was diagnosed by the International Index of Erectile Function (IIEF)-5 and body fat percentage (BF%) was quantified with bioelectrical impedance. BF% was divided into quintiles (quintile 1: < or =20.5%, quintile 2: 20.6-23.2%, quintile 3: 23.3-25.8%, quintile 4: 25.9-28.8%, quintile 5: > or =28.9%). Using subjects with quintile 3 of BF% as reference, the adjusted odds ratios of subjects with the lowest quintile of BF% and with the highest quintile were 9.29 (95% CI: 2.29-37.72) and 4.99 (95% CI: 1.37-18.09), respectively. This study showed that BFM and ED had a U-shaped relationship in Korean men. These findings suggest that not only obesity but also a low BFM may be a risk factor of ED in Asians.

CD34, RAB20, PU.1 and GFI1 mRNA expression in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) with hypocellular bone marrow (BM) is often difficult to distinguish from aplastic anemia (AA). Furthermore, the diagnosis of MDS with low blast counts and normal karyotype may be problematic. These issues highlight the need for a reliable marker for the diagnosis of MDS. This study was conducted to determine if changes of mRNA expression in any of the four selected genes would be useful markers for differentiation of hypoplastic MDS from AA, and MDS from benign disease, as well as to investigate whether mRNA expressions differ between MDS risk subgroups. Thirty-five patients diagnosed with MDS, 27 patients with AA and 17 patients with benign diseases were included. The CD34, RAB20, PU.1 and GFI1 mRNA levels were measured by real-time RT-PCR. The CD34 mRNA expressions in hypoplastic MDS were higher than those found in AA. PU.1 and GFI1 mRNA expressions were significantly lower in MDS with low blast counts and normal karyotype than those of benign disease. High-risk MDS showed higher CD34 expressions than those of low-risk MDS. This study suggests that measurement of CD34 and GFI1 mRNA expressions could be useful as a diagnostic and prognostic marker for MDS.

Impact of neurological and medical complications on 3-month outcomes in acute ischaemic stroke.

OBJECTIVE: To evaluate the impact of neurological and medical complications on 3-month outcomes in acute ischaemic stroke patients. METHODS: We prospectively investigated complications for all the consecutive acute ischaemic stroke patients admitted within 7 days from onset in four university hospitals during a 1-year period. Baseline data and 3-month outcomes were collected. Poor outcome was defined as a modified Rankin Scale score 3-6. RESULTS: A total of 1 254 patients were recruited: 264 (21.1%) and 303 (24.2%) patients experienced one or more neurological and medical complications, respectively. The most common complications were ischaemic stroke progression (17.1%) and pneumonia (12.0%). Of 1 233 patients with available 3-month outcomes, 34.9% had a poor outcome. Multivariate analysis revealed that neurological (odds ratio, 95% confidence interval; 5.47, 3.63-8.24) and medical (3.47, 2.30-5.23) complications were independent predictors of the poor outcome. For the individual complications, ischaemic stroke progression (7.48, 4.73-11.84), symptomatic hemorrhagic transformation (3.57, 1.33-9.54), pneumonia (4.44, 2.20-8.99), extracranial bleeding (4.45, 1.88-10.53), and urinary tract infection (2.72, 1.32-5.60) were independently associated with the poor outcome. CONCLUSION: Outcome after ischaemic stroke is adversely influenced by complications, especially ischaemic stroke progression, symptomatic hemorrhagic transformation, pneumonia, extracranial bleeding, and urinary tract infection. Interventions to prevent those complications might improve ischaemic stroke outcome.