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Ji-Hyun Kang,1,2,&ast; Jin-Hyuk Jeong,1,&ast; Yong-Bin Kwon,1 Young-Jin Kim,1 Dae Hwan Shin,1 Yun-Sang Park,3 Soonsil Hyun,1 Dong-Wook Kim,4 Chun-Woong Park1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2School of Pharmacy, Institute of New Drug Development, and Respiratory Drug Development Research Institute, Jeonbuk National University, Jeonju, Republic of Korea; 3Research & Development Center, P2K Bio, Cheongju, Republic of Korea; 4College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Chun-Woong Park, College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea, Tel +82-43-261-3330, Fax +82-43-268-2732, Email cwpark@cbnu.ac.kr Dong-Wook Kim, College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea, Tel +82-63-229-7130, Fax +82-63-850-7309, Email pharmengin@gmail.comPurpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers.Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract.Results: The nano-micelles, with a particle size of < 100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (Cmax) and AUC0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h.Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.Keywords: insulin, polyethylene glycol, cell-penetrating peptide, aerodynamic properties, mucus penetration

Hong-Goo Lee,*,1 Yun-Sang Park,*,1 Jin-Hyuk Jeong,1 Yong-Bin Kwon,1 Dae Hwan Shin,1 Ju-Young Kim,2 Yun-Seok Rhee,3 Eun-Seok Park,4 Dong-Wook Kim,5 Chun-Woong Park11College of Pharmacy, Chungbuk National University, Cheongju 28160, South Korea; 2College of Pharmacy, Woosuk University, Wanju 55338, South Korea; 3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, South Korea; 4School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; 5Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28530, South Korea*These authors contributed equally to this workIntroduction: In this study, a dual release bi-layer tablet containing Fesoterodine fumarate (Fst) 5 mg and Mirabegron (Mrb) 50 mg was prepared to investigate the different release behavior of each drug in bilayer tablet. The bilayer tablet was prepared based on monolayer-tablet formulation of each drug.Methods: The optimized bi-layer tablet showed an in vitro dissolution profile similar to commercial reference tablets Toviaz and Betmiga, based on a satisfactory similarity factor. Drug-release kinetics of each drug in the bilayer tablet were evaluated based on dissolution profiles. Drug-release behavior was evaluated by observing the surface of each layer by scanning electron microscopy and measuring the changes in weight and volume of the tablet during dissolution. Drug transfer between each layer was also investigated by Fourier -transform infrared spectroscopic imaging by observing the cross-section of the bilayer tablet cut vertically during dissolution.Results: The release of Fst was well suited for the Higuchi model, and the release of Mrb was well suited for the Hixson-crowell model. Compared with dissolution rate of each monolayer tablet, that of Fst in the bilayer tablet was slightly reduced (5%), but the dissolution rate of Mrb in bilayer tablet was dramatically decreased (20%). Also, a drug-release study confirmed that polymer swelling was dominant in Fst layer compared with polymer erosion, and degradation was dominant in MRB layer. Fourier-transform infrared imaging and 3-D image reconstruction showed that drug transfer in the bilayer tablet correlates with the results of drug-release behavior.Conclusion: These findings are expected to provide scientific insights in the development of a dual-release bilayer drug-delivery system for Fst and Mrb.Keywords: mirabegron, fesoterodine fumarate, swelling property, erosion property, bilayer tablet, FT-IR imaging

Jinse Park,1 Si-Eun Kim,1 Eun-Joo Kim,2 Byung In Lee,1 Jee Hyang Jeong,3 Hae Ri Na,4 Seong Hye Choi,5 Do-Young Kang,6 Kyung Won Park71Department of Neurology, Haueundae Paik Hospital, Inje University, Busan, South Korea; 2Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, South Korea; 3Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea; 4Department of Neurology, Bobath Memorial Hospital, Seongnam, South Korea; 5Department of Neurology, Inha University School of Medicine, Incheon, South Korea; 6Department of Nuclear Medicine, College of Medicine, Dong-A University, Busan, South Korea; 7Department of Neurology, Cognitive Disorders and Dementia Center, Dong-A University College of Medicine and Institute of Convergence Bio-Health, Busan, South KoreaPurpose: We assessed the effect of home-based cognitive intervention (HCI) on cognitive function along with brain metabolism by 18F-FDG PET in patients with amnestic MCI (aMCI).Patients and methods: Fifty-seven patients with aMCI from three hospitals were randomized (30 HCI, 27 control). For 12 weeks, subjects received HCI. Thirty-two subjects (15 HCI, 17 control) underwent brain 18-F-FDG-PET imaging at baseline and at 12 and 24 weeks.Results: The HCI group showed significant improvement in the scores of the Controlled Oral Word Association Test (COWAT) 12 and at 24 weeks. Significant brain metabolic changes by 18F-FDG PET were not observed.Conclusion: The current study suggests that HCI was effective in improving general cognition along with frontal executive function in patients with aMCI.Keywords: mild cognitive impairment, cognitive training, brain PET

Chanyoung Song,1,* Hathaichanok Phuengkham,1,* Sun-Young Kim,1 Min Sang Lee,2 Ji Hoon Jeong,2 Sung Jae Shin,3 Yong Taik Lim1 1SKKU Advanced Institute of Nanotechnology, School of Chemical Engineering, 2Department of Pharmacy, Sungkyunkwan University, Suwon, 3Department of Microbiology and Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: In this study, we suggest a designer vaccine adjuvant that can mimic the drainage of pathogens into lymph nodes and activate innate immune response in lymph nodes. By the amination of multivalent carboxyl groups in poly-(γ-glutamic acid) (γ-PGA) nanomicelles, the size was reduced for rapid entry into lymphatic vessels, and the immunologically inert nanomicelles were turned into potential activators of inflammasomes. Aminated γ-PGA nanomicelles (aPNMs) induced NLRP3 inflammasome activation and the subsequent release of proinflammatory IL-1β. The NLRP3-dependent inflammasome induction mechanism was confirmed through enzyme (cathepsin B and caspase-1) inhibitors and NLRP3 knockout mice model. After the aPNMs were combined with a clinically evaluated TLR3 agonist, polyinosinic–polycytidylic acid sodium salt (aPNM-IC), they triggered multiple arms of the innate immune response, including the secretion of pro-inflammatory cytokines by both inflammasomes and an inflammasome-independent pathway and the included type I interferons. Keywords: vaccine adjuvant, nanoparticles, innate immunity, antigen-presenting cells, lymphatic vessel, type I interferon

Jung Eun Lee,1,* Koung Li Kim,2,* Danbi Kim,2 Yeongju Yeo,2 Hyounkoo Han,3 Myung Goo Kim,1,4 Sun Hwa Kim,4 Hyuncheol Kim,3,5 Ji Hoon Jeong,1,4 Wonhee Suh2 1School of Pharmacy, Sungkyunkwan University, Suwon, 2College of Pharmacy, Chung-Ang University, Seoul, 3Department of Chemical and Biomolecular Engineering, Sogang University, 4Center for Theragnosis Biomedical Research Institute, Korea Institute of Science and Technology (KIST), 5Department of Biomedical Engineering, Sogang University, Seoul, Korea *These authors contributed equally to this work Abstract: Pathological angiogenesis is one of the major symptoms of severe ocular diseases, including corneal neovascularization. The blockade of vascular endothelial growth factor (VEGF) action has been recognized as an efficient strategy for treating corneal neovascularization. In this study, we aimed to investigate whether nanoparticle-based delivery of apatinib, a novel and selective inhibitor of VEGF receptor 2, inhibits VEGF-mediated angiogenesis and suppresses experimental corneal neovascularization. Water-insoluble apatinib was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro angiogenesis assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles potently inhibited VEGF-induced tube formation, scratch wounding migration, and proliferation of human endothelial cells. In a rat model of alkali burn injury-induced corneal neovascularization, a subconjunctival injection of Apa-HSA-PEG nanoparticles induced a significant decrease in neovascularization compared to that observed with an injection of free apatinib solution or phosphate-buffered saline. An in vivo distribution study using HSA-PEG nanoparticles loaded with fluorescent hydrophobic model drugs revealed the presence of a substantial number of nanoparticles in the corneal stroma within 24 h after injection. These in vitro and in vivo results demonstrate that apatinib-loaded nanoparticles may be promising for the prevention and treatment of corneal neovascularization-related ocular disorders. Keywords: apatinib, corneal neovascularization, nanoparticle, vascular endothelial growth factor

Seong Soo An,1,* Sun Ah Park,2,* Eva Bagyinszky,1 Sun Oh Bae,1 Yoon-Jeong Kim,2 Ji Young Im,2 Kyung Won Park,3 Kee Hyung Park,4 Eun-Joo Kim,5 Jee Hyang Jeong,6 Jong Hun Kim,7 Hyun Jeong Han,8 Seong Hye Choi,9 SangYun Kim10 1Department of Bionano Technology, Gachon University, Seongnam-si, 2Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, 3Department of Neurology, Dong-A University College of Medicine and Institute of Convergence Bio-Health, Busan, 4Department of Neurology, Gachon University Gil Medical Center, Incheon, 5Department of Neurology, Pusan National University Hospital, Busan, 6Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, 7Department of Neurology, Ilsan Hospital, National Health Insurance Corporation, 8Department of Neurology, Myongii Hospital, Goyang, 9Department of Neurology, Inha University School of Medicine, Incheon, 10Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea *These authors contributed equally to this work Abstract: Early-onset Alzheimer’s disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer’s disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer’s disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16-17), PSEN1 (exons 3-12), and PSEN2 (exons 3-12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE ε4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history in Korean EOAD population. Keywords: Alzheimer’s disease, mutation, presenilin, apolipoprotein-E, sequencing, early onset Alzheimer’s disease, genetics

Ji Hoon Jeong,1,* Hong Khanh Nguyen,2,* Jung Eun Lee,1 Wonhee Suh2 1School of Pharmacy, Sungkyunkwan University, Suwon, 2College of Pharmacy, Chung-Ang University, Seoul, Korea *These authors contributed equally to this work Abstract: Apatinib, a novel and selective inhibitor of vascular endothelial growth factor (VEGF) receptor 2, has been demonstrated recently to exhibit anticancer efficacy by inhibiting the VEGF signaling pathway. Given the importance of VEGF in retinal vascular leakage, the present study was designed to investigate whether apatinib-loaded polymeric nanoparticles inhibit VEGF-mediated retinal vascular hyperpermeability and block diabetes-induced retinal vascular leakage. For the delivery of water-insoluble apatinib, the drug was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro paracellular permeability and transendothelial electric resistance assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles significantly inhibited VEGF-induced endothelial hyperpermeability in human retinal microvascular endothelial cells. In addition, they substantially reduced the VEGF-induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes. In vivo intravitreal injection of Apa-HSA-PEG nanoparticles in mice blocked VEGF-induced retinal vascular leakage. These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood–retinal barrier. In vivo experiments with streptozotocin-induced diabetic mice showed that an intravitreal injection of Apa-HSA-PEG nanoparticles substantially inhibited diabetes-induced retinal vascular leakage. These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders. Keywords: permeability, retinal vascular endothelial cells, vascular endothelial growth factor

Jae Hoon Jeong,1 Jeong Kyu Lee,1,2 Dong Ik Lee,1 Yeoun Sook Chun,1 Bo Youn Cho2 1Department of Ophthalmology, College of Medicine, Chung-Ang University 2Thyroid Center, Chung-Ang University Hospital, Seoul, Korea Objective: To report the physiological monitoring of intraocular pressure (IOP) during the postoperative periods after orbital decompression surgery and ascertain the correlation between the clinical factors and IOP changes.Methods: The medical records of 113 orbits from 60 patients who underwent orbital decompression surgery were reviewed retrospectively. IOP measurement during the postoperative periods was classified based on the postoperative day: week 1 (1–7 days), month 1 (8–41 days), month 2 (42–70 days), month 3 (71–97 days), month 4 (98–126 days), and final (after 127 days). The mean postoperative follow-up was 286.5 days for orbits with at least 6 months of follow-up. Univariate and multivariate linear regression analyses were performed to assess the correlation between the IOP reduction percentage and clinical factors.Results: The mean IOP increased from 16.9 to 18.6 mmHg (10.1%) at postoperative week 1 and decreased to 14.4 mmHg (14.5%) after 2 months. Minimal little changes were observed postoperatively in the IOP after 2 months. Preoperative IOP had a significant positive effect on the reduction percentage both at postoperative week 1 (β=2.51, P=0.001) and after 2 months (β=1.07, P=0.029), and the spherical equivalent showed a positive correlation with the reduction level at postoperative week 1 (β=1.71, P=0.021).Conclusion: Surgical decompression caused a significant reduction in the IOP in thyroid-associated orbitopathy, and the amount of reduction was closely related to preoperative IOP; however, it may also cause a transient elevation in the IOP during the early postoperative phase in highly myopic eyes. Keywords: Graves’ ophthalmopathy, intraocular pressure, myopia, physiologic monitoring, postoperative periods, surgical decompression

Jong-Hyun Jeong,1 Won-Myong Bahk,1 Young Sup Woo,1 Kyung-Uk Lee,1 Do Hoon Kim,2 Moon-Doo Kim,3 Won Kim,4 Jong-Chul Yang,5 Kwang Heun Lee6 1Department of Psychiatry, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 2Department of Psychiatry, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon, 3Department of Psychiatry, Jeju National University Hospital, Jeju, 4Department of Psychiatry, Stress Research Institute, Seoul Paik Hospital, College of Medicine, Inje University, Seoul, 5Department of Psychiatry, Chonbuk National University Medical School, Jeonju, 6Department of Psychiatry, College of Medicine, Dongguk University, Gyeongju, South Korea Objectives: The primary aim of this non-inferiority study was to investigate the clinical effectiveness and safety of generic escitalopram (Lexacure®) versus branded escitalopram (Lexapro®) for patients with major depressive disorder (MDD).Methods: The present study included 158 patients, who were randomized (1:1) to receive a flexible dose of generic escitalopram (n=78) or branded escitalopram (n=80) over a 6-week single-blind treatment period. The clinical benefits in the two groups were evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS), the 17-item Hamilton Depression Rating Scale (HDRS), the Clinical Global Impressions-Severity scale (CGI-S), and the Clinical Global Impressions-Improvement scale (CGI-I) at baseline, week 1, week 2, week 4, and week 6. The frequency of adverse events (AEs) was also assessed to determine safety at each follow-up visit.Results: During the 6-week study period, 30 patients (38.5%) from the generic escitalopram group and 28 patients (30.0%) from the branded escitalopram group dropped out of the study (P=0.727). The MADRS, HDRS, CGI-S, and CGI-I scores significantly decreased in both groups, and there were no significant differences between the groups. At week 6, 28 patients (57.1%) in the generic escitalopram group and 35 patients (67.3%) in the branded escitalopram group had responded to treatment (as indicated by a ≥50% decrease from the baseline MADRS score; P=0.126), and the remission rates (MADRS score: ≤10) were 42.9% (n=21) in generic escitalopram group and 53.8% (n=28) in the branded escitalopram group (P=0.135). The most frequently reported AEs were nausea (17.9%), sleepiness/somnolence (7.7%), weight gain (3.8%), and dry mouth (2.6%) in the generic escitalopram group and nausea (20.0%), sleepiness/somnolence (3.8%), weight gain (2.5%), and dry mouth (2.5%) in the branded escitalopram group.Conclusion: The present non-inferiority study demonstrated that generic escitalopram is a safe and an effective initial treatment for patients with MDD and may also be considered as an additional therapeutic option for this population. Keywords: depression, branded escitalopram, Lexapro®, generic escitalopram, Lexacure®

Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH) nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX) was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp) using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH) nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.Keywords: docetaxel, polyaspartic acid, drug delivery systems, antitumor, pH-sensitive

Jong-Hyun Jeong,1 Jeong Goo Lee,2,3 Moon-Doo Kim,4 Inki Sohn,5 Se-Hoon Shim,6 Hee Ryung Wang,1 Young Sup Woo,1 Duk-In Jon,7 Jeong Seok Seo,8 Young-Chul Shin,9 Kyung Joon Min,10 Bo-Hyun Yoon,11 Won-Myong Bahk1 1Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, 2Department of Psychiatry, Haeundae Paik Hospital, College of Medicine, Paik Institute for Clinical Research, Inje University, 3Department of Health Science and Technology, Graduate School of Inje University, Busan, 4Department of Psychiatry, Jeju National University Hospital, Jeju, 5Department of Psychiatry, Keyo Hospital, Keyo Medical Foundation, Uiwang, 6Department of Psychiatry, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, 7Department of Psychiatry, Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, 8Department of Psychiatry, Konkuk University Chungju Hospital, School of Medicine, Konkuk University, Chungju, 9Department of Psychiatry, Kangbuk Samsung Hospital, School of Medicine, Sungkyunkwan University, Seoul, 10Department of Psychiatry, Chung-Ang University Hospital, College of Medicine, Chung-Ang University, Seoul, 11Department of Psychiatry, Naju National Hospital, Naju, Korea Abstract: Our goal was to compare the recommendations of the Korean Medication Algorithm Project for Bipolar Disorder 2014 (KMAP-BP 2014) with other recently published guidelines for the treatment of bipolar disorder. We reviewed a total of four recently published global treatment guidelines and compared each treatment recommendation of the KMAP-BP 2014 with those in other guidelines. For the initial treatment of mania, there were no significant differences across treatment guidelines. All recommended mood stabilizer (MS) or atypical antipsychotic (AAP) monotherapy or the combination of an MS with an AAP as a first-line treatment strategy for mania. However, the KMAP-BP 2014 did not prefer monotherapy with MS or AAP for dysphoric/psychotic mania. Aripiprazole, olanzapine, quetiapine, and risperidone were the first-line AAPs in nearly all of the phases of bipolar disorder across the guidelines. Most guidelines advocated newer AAPs as first-line treatment options in all phases, and lamotrigine in depressive and maintenance phases. Lithium and valproic acid were commonly used as MSs in all phases of bipolar disorder. As research evidence accumulated over time, recommendations of newer AAPs – such as asenapine, paliperidone, lurasidone, and long-acting injectable risperidone – became prominent. This comparison identifies that the treatment recommendations of the KMAP-BP 2014 are similar to those of other treatment guidelines and reflect current changes in prescription patterns for bipolar disorder based on accumulated research data. Further studies are needed to address several issues identified in our review. Keywords: bipolar disorder, pharmacotherapy, treatment algorithm, guideline comparison, KMAP-2014

Young Sup Woo,1 Jung Goo Lee,2,3 Jong-Hyun Jeong,1 Moon-Doo Kim,4 Inki Sohn,5 Se-Hoon Shim,6 Duk-In Jon,7 Jeong Seok Seo,8 Young-Chul Shin,9 Kyung Joon Min,10 Bo-Hyun Yoon,11 Won-Myong Bahk1 1Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, South Korea; 2Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, South Korea;3Paik Institute for Clinical Research, Inje Univeristy, Busan, South Korea; 4Department of Psychiatry, Jeju National University Hospital, Jeju, South Korea; 5Department of Psychiatry, Keyo Hospital, Keyo Medical Foundation, Uiwang, South Korea; 6Department of Psychiatry, Soonchunhyang University Cheonan Hospital, Soonchunhyang University, Cheonan, South Korea; 7Department of Psychiatry, Sacred Heart Hospital, Hallym University, Anyang, South Korea; 8Department of Psychiatry, School of Medicine, Konkuk University, Chungju, South Korea; 9Department of Psychiatry, Kangbuk Samsung Hospital, School of Medicine, Sungkyunkwan University, Seoul, South Korea; 10Department of Psychiatry, College of Medicine, Chung-Ang University, Seoul, South Korea; 11Department of Psychiatry, Naju National Hospital, Naju, South Korea Objective: To constitute the third revision of the guidelines for the treatment of bipolar disorder issued by the Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP 2014). Methods: A 56-item questionnaire was used to obtain the consensus of experts regarding pharmacological treatment strategies for the various phases of bipolar disorder and for special populations. The review committee included 110 Korean psychiatrists and 38 experts for child and adolescent psychiatry. Of the committee members, 64 general psychiatrists and 23 child and adolescent psychiatrists responded to the survey. Results: The treatment of choice (TOC) for euphoric, mixed, and psychotic mania was the combination of a mood stabilizer (MS) and an atypical antipsychotic (AAP); the TOC for acute mild depression was monotherapy with MS or AAP; and the TOC for moderate or severe depression was MS plus AAP/antidepressant. The first-line maintenance treatment following mania or depression was MS monotherapy or MS plus AAP; the first-line treatment after mania was AAP monotherapy; and the first-line treatment after depression was lamotrigine (LTG) monotherapy, LTG plus MS/AAP, or MS plus AAP plus LTG. The first-line treatment strategy for mania in children and adolescents was MS plus AAP or AAP monotherapy. For geriatric bipolar patients, the TOC for mania was AAP/MS monotherapy, and the TOC for depression was AAP plus MS or AAP monotherapy. Conclusion: The expert consensus in the KMAP-BP 2014 differed from that in previous publications; most notably, the preference for AAP was increased in the treatment of acute mania, depression, and maintenance treatment. There was increased expert preference for the use of AAP and LTG. The major limitation of the present study is that it was based on the consensus of Korean experts rather than on experimental evidence. Keywords: pharmacological treatment, treatment guideline, expert consensus

Hae Kook Lee, Jong-Hyun Jeong, Na-Young Kim, Min-hyeon Park, Tae-Won Kim, Ho-Jun Seo, Hyun-Kook Lim, Seung-Chul Hong, Jin-Hee Han Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea Objectives: Attention-deficit hyperactivity disorder (ADHD) is characterized by inattentive and impulsive behavior. Many ADHD patients reportedly have cognitive dysfunction and sleep problems, including longer sleep latency, lower sleep efficiency, and shorter total sleep time. The purpose of this study was to examine neurocognitive functions and nocturnal sleep parameters in patients with ADHD, using a cognitive function test and actigraphy.Methods: Subjects included 37 male patients with ADHD and 32 controls (7–12 years of age). For each participant, we determined intelligence quotient (IQ) and administered the Matching Familiar Figures Test (MFFT) and 72-hour actigraphy. The relationships between sleep parameters and cognitive functions were assessed.Results: ADHD patients significantly differed from controls in several cognitive functions and sleep variables. In the MFFT, response error rate (P

Sang Gon Lee,1,* Jae Han Jeong,1,* Kyung Min Lee,1 Kyu Ho Jeong,1 Huisuk Yang,2 Miroo Kim,2 Hyungil Jung,2 Sangkil Lee,3 Young Wook Choi11College of Pharmacy, Chung-Ang University, Seoul, South Korea; 2Department of Biotechnology, Yonsei University, Seoul, South Korea; 3College of Pharmacy, Keimyung University, Daegu, South Korea *These authors contributed equally to this workAbstract: Nanostructured lipid carriers (NLCs) were employed to formulate a lipophilic drug into hydrophilic polymeric microneedles (MNs). Hyaluronic acid (HA) was selected as a hydrophilic and bioerodible polymer to fabricate MNs, and nile red (NR) was used as a model lipophilic molecule. NR-loaded NLCs were consolidated into the HA-based MNs to prepare NLC-loaded MNs (NLC-MNs). A dispersion of NLCs was prepared by high-pressure homogenization after dissolving NR in Labrafil and mixing with melted Compritol, resulting in 268 nm NLCs with a polydispersity index of 0.273. The NLC dispersion showed a controlled release of NR over 24 hours, following Hixson–Crowell's cube root law. After mixing the NLC dispersion with the HA solution, the drawing lithography method was used to fabricate NLC-MNs. The length, base diameter, and tip diameter of the NLC-MNs were approximately 350, 380, and 30 µm, respectively. Fluorescence microscopic imaging of the NLC-MNs helped confirm that the NR-loaded NLCs were distributed evenly throughout the MNs. In a skin permeation study performed using a Franz diffusion cell with minipig dorsal skin, approximately 70% of NR was localized in the skin after 24-hour application of NLC-MNs. Confocal laser scanning microscopy (z-series) of the skin at different depths showed strong fluorescence intensity in the epidermal layer, which appeared to spread out radially with the passage of time. This study indicated that incorporation of drug-loaded NLCs into MNs could represent a promising strategy for controlled dermal delivery of lipophilic drugs.Keywords: polymeric microneedles, nanostructured lipid carriers, dermal delivery, controlled release, hyaluronic acid

Jong-Hyun Jeong,1 Won-Myong Bahk,1 Young Sup Woo,1 Ho-Jun Seo,1 Seung-Chul Hong,1 Duk-In Jon,2 Kyung Joon Min,3 Bo-Hyun Yoon41Department of Psychiatry, College of Medicine, The Catholic of University of Korea, Seoul, 2Department of Psychiatry, College of Medicine, Hallym University, Anyang, 3Department of Neuropsychiatry, College of Medicine, Chung-Ang University, Seoul, 4Naju National Hospital, Naju, KoreaPurpose: To evaluate and compare the therapeutic efficacy of quetiapine in bipolar I and II depression patients in the clinical setting.Patients and methods: This was an 8-week, multicenter, open-label, observational study for bipolar depression. The dosage of quetiapine was flexible, and concomitant medications were permitted on clinician's judgments. A total of 1097 patients were enrolled, and 764 bipolar depression patients who exhibited good therapeutic compliance (>75% compliance rate) were analyzed.Results: Clinical Global Impression – Bipolar scale and Montgomery–Asberg Depression Rating Scale scores were significantly improved at weeks four and eight compared with the baseline scores. At the end of the 8-week study, the response rate was 58.9%, and the remission rate was 42.1%. However, there were no significant differences in the response and remission rates between bipolar I and II disorder (BD-I and BD-II) patients (response rate 60.1% versus 56.3%; remission rate 44.5% versus 37.0%). Montgomery–Asberg Depression Rating Scale score at baseline (β = 0.612, P < 0.001), duration of current episode (β = −0.152, P = 0.001), and presence of remission on previous episode (β = 0.111, P = 0.012) were significantly associated with improvements in depressive symptoms. Fatigue (16.0%), somnolence (14.9%), and manic/hypomanic switching (0.6% at week four, 0.3% at week eight) were observed throughout the study period.Conclusion: The results of this study suggest that quetiapine improves depressive symptoms in BD-I and BD-II patients with a minimal incidence of manic switching. The therapeutic efficacy of quetiapine increased with time. Quetiapine could be an effective and safe modality for the treatment of BD-I and BD-II.Keywords: bipolar depression, quetiapine, therapeutic efficacy, observational study

The structure of the toroidal rotation profile with mixed heating by neutral beam injection (NBI) and electron cyclotron resonance heating (ECH) has been investigated in KSTAR L-mode plasmas. ECH with varying resonance layer positions was used for heating a mix control. The experimental results show that ECH causes a counter-current rotation increment both for off-axis and on-axis ECH heating. For L-mode plasmas, off-axis ECH produces larger counter-current rotation than on-axis ECH. Analysis of ion heat and momentum transport for the ECH L-mode plasmas shows that the electron temperature gradient is the main reason for the degradation of ion heat confinement and also the main driving force for the non-diffusive momentum flux. As a possible mechanism for the counter-current intrinsic torque with ECH, the transition of the turbulence mode from ion temperature gradient (ITG) to the trapped electron mode (TEM) with the resulting sign change of turbulence driven residual stress is suggested. A linear gyro-kinetic analysis shows the ITG → TEM transition occurs in a localized region during ECH injection, and the trend of TEM excitation is consistent with the observed macroscopic trend of the toroidal rotation.

The fourth KSTAR campaign in 2011 concentrated on active edge-localized mode (ELM) control by various methods such as non-axisymmetric magnetic perturbations, supersonic molecular beam injection (SMBI), vertical jogs of the plasma column and edge electron heating. The segmented in-vessel control coil (IVCC) system is capable of applying n2 perturbed field with different phasing among top, middle and bottom coils. Application of an n=1 perturbed field showed a desirable ELM suppression result. Fast vertical jogs of the plasma column achieved ELM pace-making and ELMs locked to 50Hz vertical jogs were observed with a high probability of phase locking. A newly installed SMBI system was used for ELM control and the state of mitigated ELMs was sustained by the optimized repetitive SMBI pulse for a few tens of ELM periods. A change in ELM behaviour was seen due to edge electron heating although the effect of ECH launch needs supplementary analyses. The ECEI images of suppressed/mitigated ELM states showed apparent differences when compared with natural ELMy states. Further analyses are ongoing to explain the observed ELM control results. © 2012 IAEA, Vienna.

Syndecan-1 (SDC-1), a transmembrane heparin sulphate proteoglycan predominantly expressed on epithelial cells, also exists in a soluble form through ectodomain shedding. SDC-1 expression and shedding may be modulated in the inflammatory milieu of primary Sjögren's syndrome (SS). We investigated SDC-1 expression in minor salivary glands (MSGs) and analysed the association between salivary or plasma levels of SDC-1 and clinical parameters in SS. We measured salivary and plasma SDC-1 levels via an enzyme-linked immunosorbent assay and assessed the salivary flow rates (SFRs) in 70 patients with SS and 35 healthy subjects. Disease activity indices, serological markers, salivary gland scintigraphy, and MSG biopsy were evaluated in patients with SS. SDC-1 expression was upregulated on ductal epithelial cells in inflamed salivary glands. Salivary SDC-1 levels in patients significantly exceeded those in healthy subjects [median (interquartile range) 49.0 (20.7–79.1) vs 3.7 (1.7–6.3) ng/mL, p < 0.001] and inversely correlated with SFRs (r = −0.358, p = 0.032) and ejection fractions of the parotid (r = −0.363, p = 0.027) and submandibular (r = −0.485, p = 0.002) glands in salivary gland scintigraphy. Plasma SDC-1 levels were significantly correlated with the EULAR Sjögren's Syndrome Disease Activity Index (r = 0.507, p < 0.001) and EULAR Sjögren's Syndrome Patient Reported Index (r = 0.267, p = 0.033). Focus scores were correlated with salivary SDC-1 levels (r = 0.551, p = 0.004). Salivary and plasma SDC-1 levels may constitute potential biomarkers for salivary gland function and disease activity, respectively, in SS. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The prophylactic coadministration of anticholinergics during dissociative sedation has been considered necessary to mitigate ketamine-associated hypersalivation. Given recent conflicting conclusions regarding adjunctive atropine, we compared the incidence of hypersalivation, degree of secretion, and related side effects with atropine or placebo as an adjunct to intravenous (IV) ketamine sedation for children. METHODS: This controlled trial randomized children, 1 to 10 years old, requiring ketamine sedation in a tertiary emergency department to receive 0.01 mg/kg of atropine or placebo, along with IV ketamine (2 mg/kg). A nurse rated preprocedure and postprocedure salivation on a 100-mm visual analog scale and recorded the frequency and nature of airway complications and interventions for hypersalivation. RESULTS: During 27 months, 140 patients were enrolled. Baseline characteristics did not differ between the 2 groups (P > .05). Secretion was significantly less in the atropine vs placebo group (mean visual analog scale score ± SD, 21.2 ± 13.1 [preprocedure] to 16.5 ± 9.9 [postprocedure] vs 22.4 ± 13.5 [preprocedure] to 27.0 ± 15.9 [postprocedure], respectively; P < .05). Visual analog scale scores greater than 50 were assigned to 7 (9.7%) of 72 and 1 (1.5%) of 68 patients in the placebo and atropine groups, respectively; these patients needed only medical procedures such as suction or airway repositioning. Heart rate was significantly higher in the atropine group compared with the placebo group (P < .05). There were no significant differences between the groups in terms of other adverse events. CONCLUSION: Atropine as an adjunct to IV ketamine sedation in children significantly reduced hypersalivation, without providing a clinical benefit. [ABSTRACT FROM AUTHOR]

Background: Most studies report high survivorship rates for TKAs, however, we observed higher than anticipated rates of dislocation and femoral component loosening after implanting a Columbus posterior stabilized prosthesis.Questions/purpose: We therefore determined (1) the incidence of dislocation and aseptic loosening that occurred after implantation of posterior stabilized high-flexion prostheses in TKAs, (2) the causative factors of dislocation and aseptic femoral component loosening when comparing two designs of prostheses, and (3) the mechanisms of dislocation.Methods: We retrospectively reviewed 319 patients who underwent 384 TKAs from May 2007 to July 2008. These patients had been assigned alternately to receive a Scorpio posterior stabilized knee prosthesis (Group I, 158 patients, 187 knees) or a Columbus posterior stabilized knee prosthesis (Group II, 161 patients, 197 knees). We followed the patients with clinical and radiographic evaluations for a minimum of 24 months (mean, 26 months; range, 24-38 months). Ten retrieved prostheses were examined visually.Results: Ten dislocations (5.1%; 10 of 197 knees) and seven aseptic loosenings of femoral components (3.6%; seven of 197 knees) occurred in Group II at a mean of 10.9 months postoperatively. However, no dislocation or loosening occurred in patients in Group I. Most dislocations were associated with varus flexion or flexion rotation movements during normal daily activities. The cam jump distance at 90º flexion for the Columbus prosthesis was lower than for the Scorpio prosthesis.Conclusions: We observed a high rate of early failure during short-term followup after implantation of a Columbus posterior stabilized prosthesis. It appears that early failures of the Columbus design were related to a different cam-post design attributable to a low jump distance during knee flexion. We no longer recommend using this device.Level Of Evidence: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

PURPOSE: Most patients with tongue cancer require surgical resection of the tongue to varying degrees. As a result, quality of life, which is strongly related to speech, chewing, and swallowing, can deteriorate severely from extensive surgical treatment of tongue cancer. In addition to surgery, adjuvant therapy may affect the severity of functional impairment. Therefore, the influence of postoperative radiotherapy on functional outcome after partial glossectomy with free flap reconstruction was evaluated in patients with early oral tongue cancer. PATIENTS AND METHODS: Functional outcome was measured and charts of 31 patients with oral tongue cancer who were surgically treated at Yonsei Head and Neck Cancer Clinic from 2003 through 2008 were reviewed. Only patients who underwent partial glossectomy and reconstruction with radial forearm free flap and did not develop recurrence were included. Speech integrity was evaluated with diadochokinetic testing by a professional speech therapist. Tongue mobility was checked by measurements of upward distance, protrusion distance, and lateral deviation distance. Swallowing capacity was evaluated with the M.D. Anderson Dysphagia Inventory. RESULTS: Diadochokinetic rates of the surgery-only and postoperative radiotherapy groups were 27.8 and 23.9, respectively, which was statistically different. Swallowing capacity was significantly superior in the surgery-only group. Tongue mobility was not statistically different between the 2 groups. CONCLUSIONS: Functional outcome of speech and swallowing is negatively influenced by postoperative radiotherapy. [ABSTRACT FROM AUTHOR]

Inflammatory pseudotumor is a rare benign lesion mimicking malignancy both clinically and radiologically. An accurate diagnosis is still difficult and is based on the histological examination. Since inflammatory pseudotumor is exceptionally rare in the colon, this unexpected lesion can be mistaken for malignancy. We report the first case of inflammatory pseudotumor in the colon that showed (18)F-fluorodeoxyglucose (FDG) uptake and acted as the lead point causing colocolic intussusception. [ABSTRACT FROM AUTHOR]