Role of Enlarged Perivascular Space in the Temporal Lobe in Cerebral Amyloidosis.

OBJECTIVE: Although growing evidence suggests that perivascular space (PVS) serves as a clearance route for amyloid and tau, the association between enlarged PVS (EPVS) and Alzheimer disease is highly inconsistent across studies. As the conventional visual rating systems for EPVS were insufficient to predict amyloid/tau/neurodegeneration (A/T/N) status, we developed a new rating scale for EPVS located in the temporal lobe (T-EPVS). METHODS: EPVS located in the basal ganglia (BG-EPVS), centrum semiovale (CS-EPVS), and T-EPVS was visually rated in 272 individuals (healthy controls, n = 96; mild cognitive impairment, n = 106; dementia, n = 70) who underwent structural magnetic resonance imaging (MRI) and dual positron emission tomography scans (18 F-flortaucipir and 18 F-florbetaben). T-EPVS and BG-EPVS were defined as high degree when the counts in any hemisphere were >10, and the CS-EPVS cutoff was >20. Logistic regression models were constructed to investigate whether the regional EPVS burden was predictive of A/T/N status. The derived models were externally validated in a temporal validation cohort (n = 195) that underwent MRI studies using a different scanner. RESULTS: Compared with those with low-degree T-EPVS (23/136, 16.9%), individuals with high-degree T-EPVS/CS-EPVS but low-degree BG-EPVS were more likely to exhibit amyloid positivity (46/56, 82.1%). High-degree T-EPVS burden (odds ratio [OR] = 7.251, 95% confidence interval [CI] = 3.296-15.952) and low-degree BG-EPVS (OR = 0.241, 95% CI = 0.109-0.530) were predictive of amyloid positivity. Although high-degree T-EPVS was associated with tau positivity, the association was no longer significant after adjusting for amyloid and neurodegeneration status. INTERPRETATION: Investigating the burden and topographic distribution of EPVS including T-EPVS may be useful for predicting amyloid status, indicating that impaired perivascular drainage may contribute to cerebral amyloidosis. ANN NEUROL 2023;93:965-978.

Screening and genetic engineering of marine-derived Aspergillus terreus for high-efficient production of lovastatin.

BACKGROUND: Lovastatin has widespread applications thanks to its multiple pharmacological effects. Fermentation by filamentous fungi represents the major way of lovastatin production. However, the current lovastatin productivity by fungal fermentation is limited and needs to be improved. RESULTS: In this study, the lovastatin-producing strains of Aspergillus terreus from marine environment were screened, and their lovastatin productions were further improved by genetic engineering. Five strains of A. terreus were isolated from various marine environments. Their secondary metabolites were profiled by metabolomics analysis using Ultra Performance Liquid Chromatography-Mass spectrometry (UPLC-MS) with Global Natural Products Social Molecular Networking (GNPS), revealing that the production of secondary metabolites was variable among different strains. Remarkably, the strain of A. terreus MJ106 could principally biosynthesize the target drug lovastatin, which was confirmed by High Performance Liquid Chromatography (HPLC) and gene expression analysis. By one-factor experiment, lactose was found to be the best carbon source for A. terreus MJ106 to produce lovastatin. To improve the lovastatin titer in A. terreus MJ106, genetic engineering was applied to this strain. Firstly, a series of strong promoters was identified by transcriptomic and green fluorescent protein reporter analysis. Then, three selected strong promoters were used to overexpress the transcription factor gene lovE encoding the major transactivator for lov gene cluster expression. The results revealed that compared to A. terreus MJ106, all lovE over-expression mutants exhibited significantly more production of lovastatin and higher gene expression. One of them, LovE-b19, showed the highest lovastatin productivity at a titer of 1512 mg/L, which represents the highest production level reported in A. terreus. CONCLUSION: Our data suggested that combination of strain screen and genetic engineering represents a powerful tool for improving the productivity of fungal secondary metabolites, which could be adopted for large-scale production of lovastatin in marine-derived A. terreus.

16S rRNA seq-identified Corynebacterium promotes pyroptosis to aggravate diabetic foot ulcer.

BACKGROUND: Diabetic foot ulcer (DFU) is one of the main chronic complications caused by diabetes, leading to amputation in severe cases. Bacterial infection affects the wound healing in DFU. METHODS: DFU patients who met the criteria were selected, and the clinical data were recorded in detail. The pus exudate from the patient's foot wound and venous blood were collected for biochemical analysis. The distribution of bacterial flora in pus exudates of patients was analyzed by 16S rRNA sequencing, and the correlation between DFU and pathogenic variables, pyroptosis and immunity was analyzed by statistical analysis. Then, the effects of key bacteria on the inflammation, proliferation, apoptosis, and pyroptosis of polymorphonuclear leukocytes were investigated by ELISA, CCK-8, flow cytometry, RT-qPCR and western blot. RESULTS: Clinical data analysis showed that Wagner score was positively correlated with the level of inflammatory factors, and there was high CD3+, CD4+, and low CD8+ levels in DFU patients with high Wagner score. Through alpha, beta diversity analysis and species composition analysis, Corynebacterium accounted for a large proportion in DFU. Logistics regression model and Person correlation analysis demonstrated that mixed bacterial infections could aggravate foot ulcer, and the number of bacteria was closely related to inflammatory factors PCT, PRT, immune cells CD8+, and pyroptosis-related proteins GSDMD and NLRP3. Through in vitro experiments, Corynebacterium inhibited cell proliferation, promoted inflammation (TNF-α, PCT, CRP), apoptosis and pyroptosis (IL-1ß, LDH, IL-18, GSDMD, NLRP3, and caspase-3). CONCLUSION: Mixed bacterial infections exacerbate DFU progression with a high predominance of Corynebacterium, and Corynebacterium promotes inflammation, apoptosis and pyroptosis to inhibit DFU healing.

Natural compound So-2 suppresses triple-negative breast cancer through inducing ferroptosis via downregulating transcription factor E2F7.

Triple-negative breast cancer (TNBC), accounting for about 15∼18% of all breast cancers, is notorious for its poor prognosis, high rate of relapse and short overall survival. Because of lacking effective therapeutic targets or drugs, treatment of TNBC in clinical encounters great obstacle. Siegesbeckiaorientalis L. have been used as a traditional Chinese medicine "Xi-Xian-Cao" for centuries with multiple medicinal benefits including cancerous treatment. We have reported the isolation of twenty-seven germacranolides including So-2 from the aerial parts of S. orientalis with potent cytotoxicity against breast cancer cells. The studyaims to verified the anti-TNBC function of the natural compound So-2 both in vitro and vivo and uncover the underlying mechanism. The results showed that So-2 caused cell cycle arrest and suppress TNBC cell proliferation and migration. Also, So-2 was first identified to be a bona fide ferroptosis inducer in TNBC cells. So-2 effectively suppressed tumor growth of TNBC by using an orthotopic transplantation tumor model. We also characterized the oncogenic role of the transcription factor E2F7 in TNBC. E2F7 was demonstrated to be involved in the ferroptosis-inducing and tumor suppression effect of So-2. Altogether, So-2 exhibits inhibitory effect on TNBC both in vitro and vivo by inducing TNBC ferroptosis via downregulating the expression of E2F7. These findings provide valuable insight into the pathogenesis of TNBC. The natural compound So-2, isolated from Chinese traditional medicine, might be a prospective drug candidate in TNBC therapy.

Effect of Amyloid on Cognitive Performance in Parkinson's Disease and Dementia with Lewy Bodies.

BACKGROUND: Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs). OBJECTIVE: The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis. RESULTS: In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B = -2.03; P = 0.010) and memory functions (B = -1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group. CONCLUSIONS: Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society.

Effects of Dihydropyridines on the Motor and Cognitive Outcomes of Patients with Parkinson's Disease.

BACKGROUND: Dihydropyridines (DHPs) may have neuroprotective effects against Parkinson's disease (PD). OBJECTIVE: This study investigated the effects of DHPs on nigrostriatal dopaminergic denervation and longitudinal motor and cognitive outcomes in PD. METHODS: We classified 476 patients with drug-naive PD who had undergone dopamine transporter imaging into three groups. They were selected according to a prior diagnosis of hypertension and use of DHPs and were matched using propensity scores: patients without hypertension (HTN-; n = 50) and patients with hypertension treated without DHP (HTN+/DHP-; n = 50) or with DHP (HTN+/DHP+; n = 50). Multiple linear regression and linear mixed model analyses were performed to determine intergroup differences in baseline dopamine transporter availability and longitudinal changes in the levodopa-equivalent dose, respectively. Using Kaplan-Meier analyses, we compared the risks of levodopa-induced dyskinesia, wearing off, and dementia-free survival during the 5.06 years of the mean follow-up period. The Cox regression model determined the independent effects of DHPs on dementia conversion. RESULTS: Dopamine transporter availability in all striatal subregions was comparable between the HTN-, HTN+/DHP-, and HTN+/DHP+ groups. The risks of levodopa-induced dyskinesia and wearing off, as well as longitudinal changes in the levodopa-equivalent dose, did not differ between the groups. The HTN+/DHP+ group had a lower risk of developing dementia than the HTN+/DHP- (Bonferroni-corrected Plog-rank  = 0.036) group. The use of DHP was independently associated with a lower risk of dementia conversion after controlling for other antihypertensive drugs and confounding factors (hazard ratio, 0.242; 95% confidence interval, 0.087-0.668; P = 0.006). CONCLUSIONS: DHPs may be associated with better long-term cognitive outcomes in hypertensive patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Metallothionein Family Proteins as Regulators of Zinc Ions Synergistically Enhance the Anticancer Effect of Cannabidiol in Human Colorectal Cancer Cells.

Cannabidiol (CBD) is a chemical obtained from Cannabis sativa; it has therapeutic effects on anxiety and cognition and anti-inflammatory properties. Although pharmacological applications of CBD in many types of tumors have recently been reported, the mechanism of action of CBD is not yet fully understood. In this study, we perform an mRNA-seq analysis to identify the target genes of CBD after determining the cytotoxic concentrations of CBD using an MTT assay. CBD treatment regulated the expression of genes related to DNA repair and cell division, with metallothionein (MT) family genes being identified as having highly increased expression levels induced by CBD. It was also found that the expression levels of MT family genes were decreased in colorectal cancer tissues compared to those in normal tissues, indicating that the downregulation of MT family genes might be highly associated with colorectal tumor progression. A qPCR experiment revealed that the expression levels of MT family genes were increased by CBD. Moreover, MT family genes were regulated by CBD or crude extract but not by other cannabinoids, suggesting that the expression of MT family genes was specifically induced by CBD. A synergistic effect between CBD and MT gene transfection or zinc ion treatment was found. In conclusion, MT family genes as novel target genes could synergistically increase the anticancer activity of CBD by regulating the zinc ions in human colorectal cancer cells.

Knockout of FosB gene changes drug sensitivity and invasion activity via the regulation of Bcl-2, E-cadherin, ß-catenin, and vimentin expression.

Our previous research suggested the presence of a novel SETDB1-mediated FosB pathway that could be responsible for the regulation of cell proliferation and invasiveness during anticancer treatments. In this study, we prepared FosB knock-out (FosB-KO) A549 human lung cancer cells using the CRISPR/Cas9 system and examined the physiological and molecular changes that caused. Annexin V and TUNEL assays showed that FosB-KO clones were less sensitive to doxorubicin treatment compared to the control A549 cells. Bcl2 expression and mitochondrial membrane potential were also both markedly increased in FosB-KO clones, which suggests the involvement of Bcl2 in the doxorubicin mediated increase in cell viability demonstrated the FosB-KO clones. Moreover, we identified changes in the migration and transforming activities of the FosB-KO clones that coincided with changes in the expression levels of E-cadherin, ß-catenin, and Vimentin. RT-PCR and qPCR analysis showed that the expressions of Bcl2, E-cadherin, ß-catenin, and Vimentin were regulated at the transcriptional level. Importantly, FosB overexpression in FosB-KO clones restored the expression of Bcl2, Akt, E-cad, ß-catenin, and Vimentin, suggesting that those proteins were tightly regulated by FosB. These data suggest that the FosB gene critically regulates both drug sensitivity and invasion related genes, and does so in a manner coordinated with the function of SETDB1. Therefore, we propose that the FosB gene regulates both drug sensitivity and invasion activity related genes, and also shows coordinated function with SETDB1 for the regulation of target proteins.

Knockout of SETDB1 gene using the CRISPR/cas-9 system increases migration and transforming activities via complex regulations of E-cadherin, ß-catenin, STAT3, and Akt.

SETDB1 HMTase participates in various cellular processes via epigenetic transcriptional regulation. SETDB1 expression is downregulated by anticancer drug treatment in cancer cells, but we still need to verify the functional significance on SETDB1 downregulation. CRISPR/cas9 is a useful technology for doing a knockout (KO) of a target gene. It is widely used to examine the function of genes. In this study, we prepared SETDB1-KO from A549 human lung cancer cells using the CRISPR/Cas9 system, and we compared molecular changes between the A549 cells and the SETDB1-KO cells. The SETDB1-KO cell proliferation rate was slightly decreased as compared to the A549 cells, but there was no large difference in sensitivity with doxorubicin treatment. Instead, the migration activity and transforming activity were dramatically increased in SETDB-KO cells. Using a western blot analysis and an immunostaining experiment, we confirmed that SETDB1-KO downregulates the expression of E-cadherin and ß-catenin. A qPCR and an RT-PCR analysis suggested that SETDB1 transcriptionally regulates E-cadherin and ß-catenin. Moreover, E-cadherin expression was also detected in the cytoplasmic region of SETDB1-KO cells, indicating that functional localization of E-cadherin might be changed in SETDB1-KO cells. On the other hand, total levels of STAT3 and Akt were increased in the SETDB1-KO cells, but activation of STAT3 (pSTAT3) was not induced in doxorubicin-treated SETDB1-KO cells. SETDB1 overexpression into SETDB1-KO cells restores the expression of E-cadherin, ß-catenin, STAT3, and Akt, suggesting that those proteins are tightly regulated by SETDB1. Collectively, we suggest that complex regulations on E-cadherin, ß-catenin, STAT3, and Akt are correlated with the increased migration and transforming activity of SETDB1-KO cells.

Volume change in amygdala enlargement as a prognostic factor in patients with temporal lobe epilepsy: A longitudinal study.

OBJECTIVE: Considering the clinical heterogeneity of temporal lobe epilepsy with amygdala enlargement (TLE-AE), identifying distinct prognostic subgroups of TLE-AE has clinical implications. Until now, baseline volume of the enlarged amygdala (EAV) has consistently failed to predict prognosis in TLE-AE. Based on studies suggesting that patients responsive to antiepileptic drugs (AEDs) exhibit remission of AE on follow-up imaging, we investigated whether reduction rate of EAV is predictive of long-term prognosis in TLE-AE. METHODS: Sixty-one consecutive patients with two separate magnetic resonance imaging (MRI) scans were enrolled. To utilize longitudinally measured biomarkers in prediction, the period beyond the first MRI acquisition was split into two periods: the "observation window" (period between the two MRIs) and "prediction window" (follow-up period beyond the second MRI). Patients were classified according to their AED responsiveness during the observation window, and AED-responsive patients were further subdivided by initial seizure frequency: (a) AED-responsive patients presenting with low-frequency seizures (<5 seizures/3 mo; Group A, n = 25), (b) high-frequency seizures (≥5 seizures/3 mo; Group B, n = 23), and (c) patients with poor initial treatment response (Group C, n = 13). Multivariate logistic regression models were constructed for identification of prognostic factors. Along with factors obtained at baseline, factors derived from the observation window (annual percentage change of EAV [APCEAV] and initial AED responsiveness) were also considered as potential predictors. RESULTS: Favorable initial treatment response and faster volume reduction rate (APCEAV ≤ -5.0%/y) were identified as factors predictive of achieving overall seizure freedom. Among the AED-responsive patients, Group A (low-frequency seizures) showed slower remission of AE and higher rate of seizure recurrence, whereas Group B (high-frequency seizures) exhibited faster remission of AE and lower rate of seizure recurrence. SIGNIFICANCE: Faster recuperation of AE in patients with initial high-frequency seizures may be indicative of seizure-induced changes. As volume reduction rate serves as a prognostic marker in TLE-AE, short-term MRI follow-up may be useful in prognostication.

Non-vitamin K oral anticoagulants as first-line regimen for acute ischemic stroke with non-valvular atrial fibrillation.

PURPOSE: There are various patterns in determining the choice of the first-line antithrombotic agent for acute stroke with non-valvular atrial fibrillation. We investigated the efficacy and safety of non-vitamin K oral anticoagulants as first-line antithrombotics for patients with acute stroke and non-valvular atrial fibrillation. MATERIALS AND METHODS: Patients with non-valvular atrial fibrillation and ischemic stroke or transient ischemic attack within 24 h from stroke onset were included. On the basis of the first regimen used and the regimen within 7 days after admission, the study population was divided into three groups: 1) antiplatelet switched to warfarin (A-W), 2) antiplatelet switched to NOAC (A-N), and 3) NOAC only (N only). We compared the occurrence of early neurologic deterioration, symptomatic intracranial hemorrhage, systemic bleeding, and poor functional outcome at 90 days. RESULTS: Of 314 included patients, 164, 53, and 97 were classified into the A-W, A-N, and N only groups, respectively. Early neurologic deterioration was most frequently observed in the A-W group (9.1%), followed by the A-N (5.7%) and N only (1.0%) groups (p = 0.017). Multivariable analysis adjusting for potential confounders demonstrated that the N only group was independently associated with a lower rate of early neurologic deterioration (odds ratio [OR] 0.104, 95% CI 0.013-0.831) or poor functional outcome at 90 days (OR 0.450, 95% CI 0.215-0.940) than the A-W group. However, the rate of symptomatic intracranial hemorrhage or any systemic bleeding event did not differ among the groups. CONCLUSION: Using non-vitamin K oral anticoagulants as the first-line regimen for acute ischemic stroke may help prevent early neurologic deterioration without increasing the bleeding risk.

Incorporation of Pt Nanoparticles on the Surface of TeO2-Branched Porous Si Nanowire Structures for Enhanced Room-Temperature Gas Sensing.

A new gas sensor working in room temperature, which is compatible with silicon fabrication technology is presented. Porous silicon nanowires (NWs) were synthesized by metal-assisted chemical etching method and then TeO2 NWs branches were attached to their stem by thermal evaporation of Te powders in the presence of air. Afterwards TeO2 branched porous Si NWs were functionalized by Pt via sputtering followed by low temperature thermal annealing. Scanning electron microscopy, transmission electron microscopy and energy-dispersive X-ray spectroscopy collectively confirmed successful formation of TeO2 branched porous Si NWs functionalized by Pt nanoparticles. Their gas sensing properties in the presence of CO, C6H6 and C7H8 were tested at room temperature, for Si wafer, pristine porous Si NWs, pristine TeO2 branched porous Si NWs, and Pt functionalized TeO2 branched porous Si NWs sensors. Pt functionalized TeO2 branched porous Si NWs have higher responses to all tested gases than the other sensors. The origin of high response is discussed in detail. This new room temperature gas sensor can open a new aperture for development of gas sensors with minimum energy consumption which are compatible with silicon fabrication technology.

SETDB1-mediated FosB regulation via ERK2 is associated with an increase in cell invasiveness during anticancer drug treatment of A549 human lung cancer cells.

We have determined a functional link to the inverse expression of SETDB1 and FosB following anticancer drug treatment. Doxorubicin treatment caused decreased SETDB1 expression and FosB overexpression both at the mRNA and protein levels. The decreased HMTase activity of SETDB1 coincided with altered occupancy across the promoter region of the FosB gene. SETDB1 overexpression decreased the luciferase reporter activity containing the FosB promoter region, but siSETDB1 increased the luciferase reporter activity, suggesting that SETDB1 directly and negatively regulated FosB expression. In addition, MEK inhibitor (PD98059) blocked the SETDB1 regulation of the FosB promoter activity via ERK2 activation during doxorubicin treatment. A microscopic analysis reveals that FosB expression was observed in living cells in spite of doxorubicin treatment. Ectopic FosB/ΔFosB expression increased the number of colonies and the migration of A549 cells compared to that in control. These results suggest that the ERK2-SETDB1-FosB signaling pathway might have an anti-therapeutic regulatory mechanism that increases the transformation and migration activity of cancer cells during anticancer drug treatment.

Porous Si nanowires for highly selective room-temperature NO2 gas sensing.

We report the room-temperature sensing characteristics of Si nanowires (NWs) fabricated from p-Si wafers by a metal-assisted chemical etching method, which is a facile and low-cost method. X-ray diffraction was used to the the study crystallinity and phase formation of Si NWs, and product morphology was examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). After confirmation of Si NW formation via the SEM and TEM micrographs, sensing tests were carried out at room temperature, and it was found that the Si NW sensor prepared from Si wafers with a resistivity of 0.001-0.003 Ω.cm had the highest response to NO2 gas (Rg/Ra = 1.86 for 50 ppm NO2), with a fast response (15 s) and recovery (30 s) time. Furthermore, the sensor responses to SO2, toluene, benzene, H2, and ethanol were nearly negligible, demonstrating the excellent selectivity to NO2 gas. The gas-sensing mechanism is discussed in detail. The present sensor can operate at room temperature, and is compatible with the microelectronic fabrication process, demonstrating its promise for next-generation Si-based electronics fused with functional chemical sensors.

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden.

Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00-0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI-visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer's and subcortical vascular cognitive impairment.

Fluoroscopic removal of retrievable self-expandable metal stents in patients with malignant oesophageal strictures: Experience with a non-endoscopic removal system.

OBJECTIVES: To evaluate clinical outcomes of fluoroscopic removal of retrievable self-expandable metal stents (SEMSs) for malignant oesophageal strictures, to compare clinical outcomes of three different removal techniques, and to identify predictive factors of successful removal by the standard technique (primary technical success). METHODS: A total of 137 stents were removed from 128 patients with malignant oesophageal strictures. Primary overall technical success and removal-related complications were evaluated. Logistic regression models were constructed to identify predictive factors of primary technical success. RESULTS: Primary technical success rate was 78.8 % (108/137). Complications occurred in six (4.4 %) cases. Stent location in the upper oesophagus (P=0.004), stricture length over 8 cm (P=0.030), and proximal granulation tissue (P<0.001) were negative predictive factors of primary technical success. If granulation tissue was present at the proximal end, eversion technique was more frequently required (P=0.002). CONCLUSIONS: Fluoroscopic removal of retrievable SEMSs for malignant oesophageal strictures using three different removal techniques appeared to be safe and easy. The standard technique is safe and effective in the majority of patients. The presence of proximal granulation tissue, stent location in the upper oesophagus, and stricture length over 8 cm were negative predictive factors for primary technical success by standard extraction and may require a modified removal technique. KEY POINTS: • Fluoroscopic retrievable SEMS removal is safe and effective. • Standard removal technique by traction is effective in the majority of patients. • Three negative predictive factors of primary technical success were identified. • Caution should be exercised during the removal in those situations. • Eversion technique is effective in cases of proximal granulation tissue.

Tracking Cognitive Decline in Amnestic Mild Cognitive Impairment and Early-Stage Alzheimer Dementia: Mini-Mental State Examination versus Neuropsychological Battery.

BACKGROUND/AIMS: Although the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SOB), and neuropsychological batteries are widely used for evaluating cognitive function, it remains elusive which instrument best reflects the longitudinal disease progression in amnestic mild cognitive impairment (aMCI) and probable Alzheimer disease (AD). We investigated whether changes in these three instruments over time correlate with loss of cortical gray matter volume (cGMV). METHODS: We retrospectively investigated 204 patients (aMCI, n = 114; AD, n = 90) who had undergone MMSE, CDR-SOB, the dementia version of the Seoul Neuropsychological Screening Battery (SNSB-D), and 3-dimensional T1-weighted magnetic resonance images at least twice. We investigated the partial correlation between annual decline in test scores and percent change of cGMV. RESULTS: In aMCI patients, changes in the SNSB-D total score (r = 0.340, p < 0.001) and CDR-SOB (r = 0.222, p = 0.020), but not MMSE, showed a correlation with cGMV loss, with the SNSB-D total score showing the strongest correlation. In AD patients, decline in all three test scores correlated significantly with cGMV loss, with MMSE exhibiting the strongest correlation (r = 0.464, p < 0.001). CONCLUSION: In aMCI patients, neuropsychological battery, though time-consuming, was the most adequate tool in tracking disease progression. In AD patients, however, MMSE may be the most effective longitudinal monitoring tool when considering cost-effectiveness.

Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers.

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers.

Design and synthesis of amorphous SiOx structures generated by Sn quantum dots: growth mechanism and luminescent origin.

SiOx structures with different diameters of a few hundreds of nanometers and/or a few micrometers are prepared using applied thermal evaporation. Subsequently, Sn quantum dot-based SiOx architectures are synthesized via the continuous steps of the carbothermal reduction of SnO2, substitution of Sn(4+) for In(3+), thermal oxidation of Si, Sn sublimation, interfacial reaction, and diffusion reaction consistent with corresponding phase equilibriums. Several crystalline and spherical-shaped Sn quantum dots with diameters between 2 and 7 nm are observed in the amorphous SiOx structures. The morphological evolution, including hollow Sn (or SnOx) sphere and wire-like, worm-like, tube-like, and flower-like SiOx, occurs stepwise on the Si substrate upon increasing the given process energies. The optical characteristics based on confocal measurements reveal the as-synthesized SiOx structures, irrespective of whether crystallinity is formed, which all have visible-range emissions originating from the numerous different-sized and -shaped Sn quantum dots permeating into the SiOx matrix. In addition, photoluminescence emissions ranging between ultraviolet and red regions are in agreement with confocal measurements. The origins of the morphology- and luminescence-controlled amorphous SiOx with Sn quantum dots are also discussed.

Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

OBJECTIVES: To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. MATERIALS: Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). METHOD: The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. RESULTS: Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. CONCLUSION: Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners.