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Duchenne muscular dystrophy (DMD), a rare pediatric disease, presents numerous challenges when designing clinical trials, mainly due to the scarcity of available trial participants and the heterogeneity of disease progression. A quantitative clinical trial simulator (CTS) has been developed based on previously published five disease progression models describing each of the longitudinal changes in the velocity at which individuals can complete specified timed functional tests, frequently used as clinical trial efficacy endpoints (supine-stand, 4-stair climb, and 10 m walk/run test or 30-foot walk/run test), as well as each of the longitudinal changes in forced vital capacity and North Star Ambulatory Assessment total score. The model-based CTS allows researchers to optimize the selection of numerous trial parameters for designing trials for the five functional measures commonly used as endpoints in DMD clinical trials. This case report serves as a demonstration of the tool's functionality while providing an easy-to-follow guide for users to reference when preparing simulations of their own design. Two case studies, using input selection based on previous DMD clinical trials, provide realistic examples of how the tool can help optimize clinical trial design without the risk of decreasing statistical significance. This optimization allows researchers to mitigate the risk of designing trials that may be longer, larger, or more inclusive/exclusive than necessary., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: This study aimed to advance the MetaLAB algorithm and verify its performance with multicenter data to effectively detect major adverse drug reactions (ADRs), including drug-induced liver injury., Methods: Based on MetaLAB, we created an optimal scenario for detecting ADRs by considering demographic and clinical records. MetaLAB-HOI was developed to identify ADR signals using common model-based multicenter electronic health record (EHR) data from the clinical health outcomes of interest (HOI) template and design for drug-exposed and nonexposed groups. In this study, we calculated the odds ratio of 101 drugs for HOI in Konyang University Hospital, Seoul National University Hospital, Chungbuk National University Hospital, and Seoul National University Bundang Hospital., Results: The overlapping drugs in four medical centers are amlodipine, aspirin, bisoprolol, carvedilol, clopidogrel, clozapine, digoxin, diltiazem, methotrexate, and rosuvastatin. We developed MetaLAB-HOI, an algorithm that can detect ADRs more efficiently using EHR. We compared the detection results of four medical centers, with drug-induced liver injuries as representative ADRs., Conclusions: MetaLAB-HOI's strength lies in fully utilizing the patient's clinical information, such as prescription, procedure, and laboratory results, to detect ADR signals. Considering changes in the patient's condition over time, we created an algorithm based on a scenario that accounted for each drug exposure and onset period supervised by specialists for HOI. We determined that when a template capable of detecting ADR based on clinical evidence is developed and manualized, it can be applied in medical centers for new drugs with insufficient data., (© 2023 John Wiley & Sons Ltd.)

Purpose: Quetiapine is a drug used to treat schizophrenia, bipolar disorder, and major depressive disorder. However, it can cause mild or severe hepatic adverse events and rarely fatal liver damage. This study was aimed at investigating hepatic toxicity caused by quetiapine use by analyzing the information captured from hospital electronic health records by using the Observational Medical Outcomes Partnership common data model (CDM)., Methods: This was a retrospective observational study involving a nested case-control method. A CDM based on an electronic health record database from five hospitals between January 2009 and May 2020 was used. We analyzed the status of quetiapine use, adverse events, and hepatic impairment., Results: The numbers of patients with non-serious and severe hepatic adverse reactions were 2566 (5.05%) and 835 (1.64%) out of 50 766 patients, respectively. After adjusting for covariates, the odds ratio of hepatic adverse events was 2.35 (95% CI: 2.03-2.72), and the odds ratio of severe hepatic adverse events was 1.76 (95% CI: 1.16-2.66)., Conclusion: Our findings suggest that quetiapine should be cautiously used, and hepatic function should be monitored in patients using quetiapine because it can cause mild or severe hepatic adverse events, complications, and in rare cases, fatal liver damage., (© 2023 John Wiley & Sons Ltd.)

Aims: Few studies have reported data on the optimal timing of left ventricular (LV) unloading during venoarterial extracorporeal membrane oxygenation (VA-ECMO) for cardiac arrest or shock. This study evaluated the feasibility of an early LV unloading strategy compared with a conventional strategy in VA-ECMO., Methods and Results: Between December 2018 and August 2022, 60 patients at two institutions were randomized in a 1:1 ratio to receive early (n = 30) or conventional (n = 30) LV unloading strategies. The early LV unloading strategy was defined as LV unloading performed at the time of VA-ECMO insertion. LV unloading was performed using a percutaneous transseptal left atrial cannulation via the femoral vein incorporated into the ECMO venous circuit. The early and conventional LV unloading groups included 29 (96.7%) and 23 (76.7%) patients, respectively (median time from VA-ECMO insertion to LV unloading: 48.4 h, interquartile range 47.8-96.5 h). The groups showed no significant differences in the rate of VA-ECMO weaning as the primary endpoint (70.0% vs. 76.7%; relative risk 0.91; 95% confidence interval 0.67-1.24; p = 0.386) and survival to discharge (53.3% vs. 50.0%, p = 0.796). However, the pulmonary congestion score index at 48 h after LV unloading was significantly improved only in the early LV unloading group (2.0 ± 0.7 vs. 1.7 ± 0.6 at baseline vs. at 48 h; p = 0.008)., Conclusions: Compared with the conventional approach, early LV unloading did not improve the VA-ECMO weaning rate, despite the rapid improvement in pulmonary congestion. Therefore, the results of this study do not support the application of this strategy after VA-ECMO insertion., (© 2023 European Society of Cardiology.)

Although regulatory agencies encourage inclusion of imaging biomarkers in clinical trials for Duchenne muscular dystrophy (DMD), industry receives minimal guidance on how to use these biomarkers most beneficially in trials. This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease-drug-trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6-minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual-level data collected for 10 years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed-effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation-based diagnostics and fivefold cross-validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: HLA-B*58:01 is a well-known risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs). However, only a minority of HLA-B*58:01 carriers suffer SCARs after taking allopurinol. The aim of this study was to investigate subsidiary genetic markers that could identify those at further increased risk of developing allopurinol-induced drug reaction with eosinophilia and systemic symptoms (DRESS) in subjects with HLA-B*58:01., Methods: Subjects with B*58:01 were enrolled (21 allopurinol-induced DRESS and 52 allopurinol-tolerant control). HLA-A, -B, -C and -DRB1 alleles were compared. Comparison of risk between HLAs and allopurinol-induced SCAR in separate populations was performed to support the results. Kruskal-Wallis test, Pearson's chi-square test, Fisher's exact test and binary logistic regression were used to analyze the risk of SCAR development., Results: Frequencies of A*24:02 (71.4 vs. 17.3%, p < 0.001, odds ratio [OR] = 12.0; 95% confidence interval [CI], 3.6-39.2) were significantly higher in B*58:01 (+) DRESS than B*58:01 (+) tolerant controls. In addition, DRB1*13:02 further increased the risk of DRESS. The phenotype frequency of A*24:02/DRB1*13:02 was significantly higher in the B*58:01 (+) DRESS group than in the B*58:01 (+) tolerant controls (52.4% vs. 5.8%, p < 0.001, OR, 66.0; 95% CI, 6.1-716.2). In 2782 allopurinol user cohort, the overall prevalence of DRESS was 0.22%, which increased to 1.62% and 2.86% in the presence of B*58:01 and B*58:01/A*24:02, respectively., Conclusion: The additional secondary screening with A*24:02 and DRB1*13:02 alleles may identify those at further increased risk of allopurinol-induced DRESS in B*58:01 carriers., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Several type B adverse drug reactions (ADRs), especially severe cutaneous adverse reactions (SCARs), are associated with particular human leukocyte antigen (HLA) genotypes. However, pre-stored HLA information obtained from other clinical workups has not been used to prevent ADRs. We aimed to simulate the preemptive use of pre-stored HLA information in electronic medical records to evaluate whether this information can prevent ADRs., Methods: We analyzed the incidence and the risk of ADRs for selected HLA alleles ( HLA-B*57:01 , HLA-B*58:01 , HLA-A*31:01 , HLA-B*15:02 , HLA-B*15:11 , HLA-B*13:01 , HLA-B*59:01 , and HLA-A*32:01 ) and seven drugs (abacavir, allopurinol, carbamazepine, oxcarbazepine, dapsone, methazolamide, and vancomycin) using pre-stored HLA information of transplant patients based on the Pharmacogenomics Knowledge Base guidelines and experts' consensus., Results: Among 11,988 HLA-tested transplant patients, 4092 (34.1%) had high-risk HLA alleles, 4583 (38.2%) were prescribed risk drugs, and 580 (4.8%) experienced type B ADRs. Patients with HLA-B*58:01 had a significantly higher incidence of type B ADR and SCARs associated with allopurinol use than that of patients without HLA-B*58:01 (17.2% vs. 11.9%, odds ratio [OR] 1.53 [95% confidence interval {CI} 1.09-2.13], p  = 0.001, 2.3% versus 0.3%, OR 7.13 [95% CI 2.19-22.69], p  < 0.001). Higher risks of type B ADR and SCARs were observed in patients taking carbamazepine or oxcarbazepine if they had one of HLA-A*31:01 , HLA-B*15:02 , or HLA-B*15:11 alleles. Vancomycin and dapsone use in HLA-A*32:01 and HLA-B*13:01 carriers, respectively, showed trends toward increased risk of type B ADRs., Conclusion: Utilization of pre-stored HLA data can prevent type B ADRs including SCARs by screening high-risk patients., Competing Interests: The authors have declared no conflicts of interest., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

The trifluoromethyl group is a prominent motif in biologically active compounds and therefore of great interest for the labeling with the positron emitter fluorine-18 for positron emission tomography (PET) imaging. Multiple labeling strategies have been explored in the past; however, most of them suffer from low molar activity due to precursor degradation. In this study, the potential of 1-(difluoromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium triflate as precursor for the synthesis of the [ 18 F]trifluoromethylation building block [ 18 F]fluoroform with high molar activity was investigated. The triazolium precursor was reacted under various conditions with [ 18 F]fluoride, providing [ 18 F]fluoroform with radiochemical yields (RCY) and molar activities (A m ) comparable and even superior with already existing methods. Highest molar activities (A m  = 153 ± 14 GBq/μmol, dc, EOS) were observed for the automated procedure on the Neptis® perform module. Due to its easy handling and good RCY and A m in the [ 18 F]fluoroform synthesis, the triazolium precursor is a valuable alternative to already known precursors., (© 2021 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

Background and Purpose: We aimed to assess the accuracy of magnetic resonance angiography (MRA) in the differentiation of small aneurysms versus infundibular dilations (IDs) at the internal carotid artery-posterior communicating artery (ICA-PComA) junction, emphasizing the role of MRA axial source images., Methods: This retrospective study consisted of 83 focal arterial protrusions at ICA-PComA junction in 76 patients who underwent both MRA and digital subtraction angiography (DSA)/3-dimensional rotational angiography (3DRA). The diagnostic performance of MRA for differential diagnosis of aneurysm from ID was calculated using DSA/3DRA interpretation as the standard of reference. In addition, long-axis diameter, short-axis diameter, long-axis diameter/short-axis diameter (L/S) ratio, and angle of lesion (angle of the long-axis of lesion with respect to the x-axis) measured on MRA source images were compared between aneurysms and IDs., Results: Sensitivity, specificity, and accuracy of MRA for distinguishing aneurysms from IDs were 74.4% (57.9-87.0%) to 76.9% (60.7-88.9%), 93.2% (81.3-98.6%) to 95.5% (84.5-99.4%), and 85.5% (76.1-92.3%), respectively. Significant differences were found for the long-axis diameter (P < .001), short-axis diameter (P < .001), L/S ratio (P < .05), and angle of the lesion (P < .001) on MRA axial source images between aneurysms and IDs. The angle of the lesion had the highest discriminatory ability (area under the curve = .966 [.902-.994]) to differentiate aneurysms from IDs. An angle of lesion >60° was 89.7% (75.8-97.1%) sensitive and 100% (92.0-100.0%) specific for diagnosis of aneurysm., Conclusions: MRA is a useful imaging modality for distinguishing between aneurysm and ID at the ICA-PComA junction. Furthermore, geometric parameters on MRA axial source images can provide added value in their differentiation., (© 2021 American Society of Neuroimaging.)

Background: Increased strain of the iliotibial band (ITB) is a plausible contributing factor for the development of iliotibial band syndrome (ITBS). Although several studies have found relationships between the strain of the ITB and kinematic factors during running, the associations of the ITB strain with knee alignment and sex, which are considered intrinsic factors, are not well understood., Objective: To clarify the sex differences in the ITB strain between genu varum and normal knee alignments in different postures., Design: Observational cross-sectional study., Setting: Laboratory research within a university., Participants: Forty-four healthy recreational athletes (21 men and 23 women) volunteered for this study and were divided into four groups by sex and knee alignment: men with genu varum alignment, men with normal knee alignment, women with genu varum alignment, and women with normal knee alignment., Methods: An ultrasound real-time elastography (RTE) unit was used for distal ITB strain measurements in weight bearing and for different non-weight-bearing: neutral, knee flexion, hip adduction, and hip adduction with knee flexion. Gender information and the intercondylar distance data were collected to divide the participants into two groups., Main Outcome Measurements: Main Outcome was the ITB strain (strain ratio) measured by the RTE., Results: There were no significant differences in neutral and hip adduction postures among the four groups. However, during weight-bearing, the women's genu varum group (6.91 ± 1.69; Mean ± SD) exhibited greater strain than both the men's normal group (3.50 ± 1.04, P = .005) and the women's normal group (4.42 ± 1.42, P = .048). In addition, there were significant positive correlations between the intercondylar distance and the ITB strain during weight-bearing (r = 0.315, P = .037)., Conclusions: The women's genu varum group exhibited a higher ITB strain during weight-bearing, which may be related to the high incidence of ITBS in women athletes. Furthermore, the changes in alignment and muscle activities during weight-bearing could influence the strain of the ITB., Level of Evidence: III., (© 2019 American Academy of Physical Medicine and Rehabilitation.)

Background: Anal sphincter needle electromyography (EMG) is a useful tool to evaluate various neurologic lesions. However, landmark-based needle placement has risks of missing the intended target including risk of bowel penetration. Ultrasound guidance has been widely used to enhance needle placement for various interventional procedures, but it has not been previously reported for use in anal sphincter EMG., Objective: To demonstrate the accuracy of ultrasound-guided needle insertion into the external anal sphincter (EAS)., Design: Observational study., Setting: Tertiary care university hospital., Participants: A single live male participant and six fresh cadavers., Methods: A preliminary study was conducted in a single live male participant to investigate the utility of ultrasonography imaging for the EAS and proper transducer location. After this preliminary study, 12 sides of the EAS in six fresh cadavers were assessed. A hooked fine wire was inserted into the EAS under ultrasound guidance., Main Outcome Measures: Accuracy of needle placement was assessed after cadaver dissection., Results: The EAS was easily identified with ultrasound in preliminary and cadaver studies. The needle tips were located in the EAS in 11 of 12 cadavers., Conclusions: Ultrasound-guided needle EMG of the EAS is convenient and accurate in cadavers and may be useful in clinical practice. Further studies comparing ultrasound-guided and landmark-guided needle EMG of the EAS in live patients will be needed., (© 2018 American Academy of Physical Medicine and Rehabilitation.)

Purpose: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but serious condition that systematically damages various internal organs through T-cell-mediated immunological drug reactions. We aimed to investigate whether clinical manifestations of DRESS syndrome differ according to culprit drugs., Methods: We retrospectively analyzed data from 123 patients with probable/definite DRESS syndrome based on the RegiSCAR criteria (January 2011 to July 2016). The data were obtained from the Korean Severe Cutaneous Adverse Reaction Registry. Causality was assessed using the World Health Organization-Uppsala Monitoring Centre criteria. The culprit drugs were categorized as allopurinol, carbamazepine, anti-tuberculosis drug, vancomycin, cephalosporins, dapsone, and nonsteroidal anti-inflammatory drugs., Results: Differences were observed among culprit drugs regarding the frequencies of hepatitis (P < 0.01), renal dysfunction (P < 0.0001), lymphadenopathy (P < 0.01), and atypical lymphocyte (P < 0.01). Latency period differed among culprit drugs (P < 0.0001), being shorter in vancomycin and cephalosporin. In terms of clinical severity, admission duration (P < 0.01) and treatment duration (P < 0.05) differed among culprit drugs, being longer in vancomycin and anti-tuberculosis drugs, respectively., Conclusions: Based on the findings, clinical manifestations, including latency period and clinical severity, may differ according to culprit drugs in DRESS syndrome., (© 2019 John Wiley & Sons, Ltd.)

Background: The carotid artery must be avoided during stellate ganglion block. However, information on optimal neck position during the ultrasound-guided approach is limited., Objective: To investigate the relation between the target area of the procedure and the carotid artery in different neck positions., Design: Observational study., Setting: Tertiary university., Participants: A total of 30 sides of the neck from 18 healthy participants were included., Methods: An ultrasound transducer was placed at the level of the anterior tubercle of C6 with a short-axis view for measuring the distance from the tip of the C6 anterior tubercle to the margin of the carotid artery. The participants were first examined through ultrasonography in 3 different rotational neck positions (neutral, semicontralateral rotation, and full-contralateral rotation), in the supine position. After changing to the lateral decubitus position, the measurement was performed again in the same 3 neck positions., Main Outcome Measures: The C6 anterior tubercle to carotid distance was measured with ultrasound., Results: The C6 anterior tubercle to carotid distance was the longest with full-contralateral neck rotation (P < .05). The distance was longer in the semicontralateral neck rotation compared with the neutral neck position (P < .05). Supine or decubitus positions did not affect the distance., Conclusions: We suggest that the full-contralateral neck rotation posture in either the supine or decubitus position is most beneficial for avoiding damage to the carotid artery during the ultrasound-guided stellate ganglion block., Level of Evidence: Not applicable., (© 2018 American Academy of Physical Medicine and Rehabilitation.)

Since the first description of Guillain-Barré syndrome (GBS) 100 years ago, the concept of this syndrome has changed remarkably. The purpose of our study was to identify and characterize the most-cited articles that have contributed to advancing the understanding of GBS. Based on the database of Journal Citation Reports, we selected 554 journals that were considered as potential sources of reports on studies related to clinical neurology and general medicine. The Web of Science search tools were used to identify the most-cited articles relevant to GBS or other variants in the selected journals. Of the selected articles, 18 were review articles and the remainder were original articles or included only a few case series. Among the original articles, 13 described basic research associated with immunological pathogenesis involving anti-ganglioside antibodies. Most of the original studies (42/64, 66%) published after 1990 evaluated anti-ganglioside antibodies that mediated axonal GBS or Miller Fisher syndrome, with only a small number of the papers involving electrodiagnostic medicine (n = 4). Our bibliometric analysis has yielded a detailed list of the top-100 cited articles in the field of GBS., (© 2016 Peripheral Nerve Society.)

Objective: Peroxiredoxin 6 plays important and complex roles in the process of inflammation, but its role in the development of rheumatoid arthritis (RA) remains unclear. We undertook this study to investigate the roles and mechanisms of peroxiredoxin 6 in the development of collagen antibody-induced arthritis (CAIA) and antigen-induced arthritis (AIA) in peroxiredoxin 6-overexpressing transgenic mice, in peroxiredoxin 6-transfected RAW 264.7 cells, in macrophages isolated from peroxiredoxin 6-overexpressing transgenic mice, and in synoviocytes from arthritis patients., Methods: CAIA and AIA were induced using standard methods. Peroxiredoxin 6-transfected RAW 264.7 cells, macrophages isolated from peroxiredoxin 6-overexpressing transgenic mice, and synoviocytes from arthritis patients were used to study proinflammatory responses and mechanisms. Clinical scores and histopathologic changes were determined in peroxiredoxin 6-overexpressing transgenic mice and wild-type (WT) mice with CAIA or AIA. Generation of nitric oxide (NO), expression of inducible NO synthase and cyclooxygenase 2, and activity of NF-κB and activator protein 1 (AP-1) were determined in cultured macrophages and synoviocytes as well as in joint tissue from mice by Western blotting, electrophoretic mobility shift assay, and immunohistochemical analysis., Results: Development of CAIA and AIA and proinflammatory responses were more exacerbated in peroxiredoxin 6-overexpressing transgenic mice than in WT mice. Overexpression of peroxiredoxin 6 increased lipopolysaccharide-induced inflammatory responses in RAW 264.7 cells, in macrophages isolated from peroxiredoxin 6-overexpressing transgenic mice, and in synoviocytes from arthritis patients, and this was accompanied by up-regulation of the JNK pathway. Moreover, a JNK inhibitor completely blocked RA development and proinflammatory responses., Conclusion: Our findings suggest that overexpression of peroxiredoxin 6 might promote development of RA through NF-κB and AP-1 activity via the JNK pathway., (© 2015, American College of Rheumatology.)

Background and Purpose: cAMP as a second messenger stimulates expression of microphthalmia-associated transcription factor (MITF) or the tyrosinase gene in UVB-induced skin pigmentation. Diphenylmethylene hydrazinecarbothioamide (QNT 3-80) inhibits α-melanocyte-stimulating hormone (α-MSH)-induced melanin production in B16 murine melanoma cells but its molecular basis remains to be defined. Here, we investigated the mechanism underlying the amelioration of skin hyperpigmentation by QNT 3-80., Experimental Approach: We used melanocyte cultures with raised levels of cAMP and UVB-irradiated dorsal skin of guinea pigs for pigmentation assays. Immunoprecipitation, kemptide phosphorylation, fluorescence analysis and docking simulation were applied to elucidate a molecular mechanism of QNT 3-80., Key Results: QNT 3-80 inhibited melanin production in melanocyte cultures with elevated levels of cAMP, including those from human foreskin. This compound also ameliorated hyperpigmentation in vivo in UVB-irradiated dorsal skin of guinea pigs. As a mechanism, QNT 3-80 directly antagonized cAMP binding to the regulatory subunit of PKA, nullified the dissociation and activation of inactive PKA holoenzyme in melanocytes and fitted into the cAMP-binding site on the crystal structure of human PKA under the most energetically favourable simulation. QNT 3-80 consequently inhibited cAMP- or UVB-induced phosphorylation (activation) of cAMP-responsive element-binding protein in vitro and in vivo, thus down-regulating expression of genes for MITF or tyrosinase in the melanogenic process., Conclusions and Implications: Our data suggested that QNT 3-80 could contribute significantly to the treatment of skin disorders with hyperpigmented patches with the cAMP-binding site of PKA as its molecular target., (© 2015 The British Pharmacological Society.)

We have developed a new precursor, 3,17β-O-bis(methoxymethyl)-16β-O-p-nitrobenzenesulfonylestriol (14c) of 16α-[(18) F]fluoroestradiol ([(18) F]FES). Although we could not selectively protect the C17 alcohol in the presence of the C16 alcohol, we were able to prepare and chromatographically isolate the desired C16 TBDMS, C17,C3-dimethoxymethyl (diMOM) protected estriol derivative and convert into the ultimate fluorination precursor. The MOM protective group proved to be more quickly removed than the cyclic sulfate group. The di-MOM protective precursor at the C3 and C17 alcohols instead of a cyclic sulfate group shortened hydrolysis time. We prepared three different sulfonate precursors at C16 alcohol. After checking their reactivity in the [(18) F]fluorination step and considering the stability of the precursors, we obtained the best results with nosylate precursor 14c., (Copyright © 2013 John Wiley & Sons, Ltd.)

A new isoflavone glycitein 7-O-beta-d-glucoside 4''-O-methylate (CGLM) has been isolated recently from Cordyceps militaris grown on germinated soybean extract and has antioxidant activity. In the present study, CGLM was investigated for its suppression of airway mucous hyper-secretion in epidermal growth factor (EGF)-treated human lung mucoepidermoid cells. NCI-H292 cells were treated with CGLM for 1 h, followed by EGF treatment for 24 h. The decrease in cyclooxygenase-2 (COX-2) production was correlated with reduced levels of protein and mRNA of inducible matrix metalloproteinase 9 (MMP-9) and also MUC5AC gene expression. CGLM directly inhibited down-regulated NF-κB activity, and significantly inhibited the phosphorylation of p38 and ERK1/2 (p42/p44) in NCI-H292 cells. These results suggest that CGLM protects NCI-H292 cells from EGF-induced damage by down-regulation of COX-2, MMP-9 and MUC5AC gene expression, mediated via blocking the NF-kappa-B and p38/ERK MAPK pathways., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: The role of (18)F-fluorodeocyglucose positron emission tomography (PET)/computed tomography (CT) in only PET/CT-positive lymph nodes (LNs) is not well elucidated yet. This study was conducted to evaluate the diagnostic value of only PET/CT-positive LNs without correlating positive findings on conventional imaging modalities (CT, magnetic resonance imaging [MRI], and ultrasound [US]) in patients with head and neck squamous cell carcinoma (HNSCC)., Study Design: Case series with chart review., Setting: Hallym University School of Medicine., Subjects and Methods: From January 2006 to September 2009, 114 patients with HNSCC who underwent CT, MRI, US, and PET/CT before definitive surgery with neck dissection were reviewed. All imaging tests were interpreted on imaging-based nodal classification and were compared with histopathological findings., Results: Only PET/CT-positive LNs were found at 48 nodal levels in 33 patients. Thirteen of 48 (27%) nodal levels were true-positive (TP), and 35 of 48 (73%) were false-positive (FP). Fourteen nodal levels were included on N+ necks, and 34 were included on N0 necks. In N0 necks, the FP rate was significantly higher than the TP rate (28 vs 6, P = .034). Eleven only PET/CT-positive nodal levels in 10 patients were found on the contralateral neck side, and FP was significantly more prevalent than TP (8 vs 3, P = .041). No significant difference was observed for mean standardized uptake value and LN sizes between TP and FP., Conclusion: Only PET/CT-positive LNs can frequently be found and do not predict LN metastasis, because a high percentage of results were FP. Our results suggest that only PET/CT-positive LNs should be considered negative, especially in N0 and contralateral necks.

Garlic is widely used as a spice. Garlic extracts exert anticancer and antiinflammatory effects, but its antiobesity efficacy studies have produced conflicting results. The antiobesity effects of thiacremonone, a sulfur compound isolated from garlic, was evaluated in obese db/db mice. Thiacremonone was orally administrated to mice for 3 weeks. The thiacremonone-treated db/db mice showed a loss of body weight and decrease in blood triglyceride and glucose levels compared with the control mice. Histological analysis further revealed that thiacremonone significantly decreased lipid accumulation in the fatty livers of treated db/db mice. It was observed that GLUT-4 expression and glucose uptake were up-regulated by thiacremonone in 3T3-L1 adipocytes. Thiacremonone treatment also suppressed expression levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), which are involved in lipid metabolism, in the liver of db/db mice. In addition, thiacremonone enhanced peroxisome proliferator-activated receptor γ (PPARγ) expression in the fatty liver. Taken together, these results suggest that thiacremonone may play a vital role in improving the management of obesity and related metabolic syndromes via inhibition of lipid accumulation., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background and Purpose: In Parkinson's disease, the dopaminergic neurones in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is not completely understood, neuronal apoptosis and neuroinflammation are thought to be key contributors. We have recently established that MMP-3 plays crucial roles in dopaminergic cell death and microglial activation., Experimental Approach: We tested the effects of 7-hydroxy-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) on expression of MMP-3 and inflammatory molecules and dopaminergic cell death in vitro and in an animal model of Parkinson's disease, and Parkinson's disease-related motor deficits. The pharmacokinetic profile of PTIQ was also evaluated., Key Results: PTIQ effectively suppressed the production of MMP-3 induced in response to cellular stress in the dopaminergic CATH.a cell line and prevented the resulting cell death. In BV-2 microglial cells activated with lipopolysaccharide, PTIQ down-regulated expression of MMP-3 along with IL-1β, TNF-α and cyclooxygenase-2 and blocked nuclear translocation of NF-κB. In the mouse model of Parkinson's disease ,induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), PTIQ attenuated the associated motor deficits, prevented neurodegeneration and suppressed microglial activation in the substantia nigra. Pharmacokinetic analysis showed it was relatively stable against liver microsomal enzymes, did not inhibit the cytochrome p450 isozymes or the hERG ion channel, exhibited no cytotoxicity on liver cells or lethality when administered at 1000 mg kg(-1) and entered the brain rather rapidly yielding a 28% brain:plasma ratio after i.p. injection., Conclusions and Implications: These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Objective: This study investigated whether preoperative (18)fluorine-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scanning improved the diagnosis of retropharyngeal lymph node (RPLN) metastasis in patients with head and neck squamous cell carcinoma (HNSCC) relative to conventional imaging alone., Study Design: Case series with chart review., Setting: University hospital cancer center., Subjects and Methods: Sixty-three patients with HNSCC underwent RPLN dissection in accordance with our indications and were subsequently divided into two groups: CT/magnetic resonance imaging (MRI) only (group A, n = 33) and CT/MRI with PET-CT (group B, n = 30). The preoperative radiological findings of each group were compared with the RPLN histopathologic findings, which served as the standard of reference., Results: RPLN metastasis was confirmed histopathologically in 17 of 63 patients (27.0%): eight from group A and nine from group B. With the additional use of PET-CT in group B, the sensitivity (88.9%), specificity (85.7%), and accuracy (86.7%) were higher than the respective values in group A (62.5%, 60.0%, and 60.6%). The positive and negative predictive values for group B (72.7% and 94.7%, respectively) were also higher than those for group A (33.3% and 83.3%, respectively). False-positive results were obtained in 10 patients from group A and three patients from B; false-negative findings occurred in three patients from group A and one patient from group B. The predictive power of the radiological findings was statistically significant in group B (P = 0.0017), with an odds ratio of 47.987 (95% confidence interval, 4.3-535.0)., Conclusion: (18)F-FDG PET-CT, when used in combination with CT/MRI, increases diagnostic efficacy in the detection of RPLN metastases and may therefore be useful in screening high-risk patients.

Inhibition of HBsAg release against hepatitis B virus (HBV) was investigated in an aqueous extract prepared from the aerial parts (stems and leaves) of Agrimonia eupatoria. The inhibitory effect on HBsAg secretion was footed using aqueous extracts of Agrimonia eupatoria at four different temperatures (37 degrees C 45 degrees C, 55 degrees C and 60 degrees C), and the extract prepared at 60 degrees C was found to have the greatest effect. The inhibitory activity of Agrimonia eupatoria extracts on HBsAg secretion varied over the growing season and was the highest at mid-July. This inhibitory activity was also shown with the aqueous extracts of two other species of the genus Agrimonia: A. pilosa and A. coreana pilosella. These results suggest that some plants of the genus Agrimonia contain potential antiviral activity against HBV., ((c) 2005 John Wiley & Sons, Ltd.)

The presence of hepatitis B virus x (HBx) antigen/antibody is known to correlate with the well-established serological markers of ongoing viral replication in the chronic phase of HBV infection, and strongly suggests that the level and duration of HBx expression may influence the outcome of the chronic infection. In this research, we developed a polymerase chain reaction enzyme-linked immunosorbent assay (PCR-ELISA) method for the detection of HBx gene expression. We also investigated its relationship to the progress of the disease in HBV-related patients. Peripheral blood mononuclear cells (PBMCs) were purely isolated, and reverse transcription-PCR (RT-PCR) was performed for improved sensitivity. The PCR products were determined by ELISA, and we investigated the relationship of the proposed method to the clinical status of the patients. The PCR-ELISA used in this work was found to be at least 100 times more sensitive than the conventional PCR method, and even 8,000-fold diluted PCR products could be detected. The HBx concentrations significantly differed among control subjects (0.36+/-0.09, [P<0.01] and patients with chronic hepatitis (1.13+/-0.34 [P<0.01 compared to control]), liver cirrhosis (LC; 1.37+/-0.28 [P<0.01 compared to control]), and hepatocellular carcinoma (HCC; 1.48+/-0.95 [P<0.01 compared to control]). These findings suggest that monitoring of HBx could be useful for early diagnosis and prognosis in patients with chronic HBV infection, LC, and HCC.