Allelic heterogeneity in <i>NCF2</i> associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations

Kim-Howard, Xana,Sun, Celi,Molineros, Julio E.,Maiti, Amit K.,Chandru, Hema,Adler, Adam,Wiley, Graham B.,Kaufman, Kenneth M.,Kottyan, Leah,Guthridge, Joel M.,Rasmussen, Astrid,Kelly, Jennifer,Sá Oxford University Press 2014 Human Molecular Genetics Vol.23 No.6

<P>Recent reports have associated <I>NCF2</I>, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within <I>NCF2</I>, we assessed 145 SNPs in and around the <I>NCF2</I> gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (<I>P</I><SUB>EA</SUB> = 1.01 × 10<SUP>−54</SUP>, <I>P</I><SUB>HS</SUB> = 3.68 × 10<SUP>−10</SUP>, <I>P</I><SUB>AA</SUB> = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (<I>P</I><SUB>AA</SUB> = 1.49 × 10<SUP>−9</SUP>), and rs13306575 in HS and KR (<I>P</I><SUB>HS</SUB> = 7.04 × 10<SUP>−7</SUP>, <I>P</I><SUB>KR</SUB> = 3.30 × 10<SUP>−3</SUP>). In KR, a 3-SNP haplotype was significantly associated (<I>P</I> = 4.20 × 10<SUP>−7</SUP>), implying that SLE predisposing variants were tagged. Significant SNP–SNP interaction (<I>P</I> = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting <I>in vivo</I> enhancer function. Our results not only establish allelic heterogeneity within <I>NCF2</I> associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance (‘missing heritability’) of complex diseases like SLE.</P>

The role of microneedle patch test in the diagnosis of atopic dermatitis

( Howard Chu ),( Ji Hye Kim ),( Seo Hyeong Kim ),( Hyeran Kim ),( Min Kyung Lee ),( Chang Ook Park ),( Kwang Hoon Lee ) 대한피부과학회 2017 대한피부과학회 학술발표대회집 Vol.69 No.2

Background: Atopic dermatitis (AD) is a disease well-known to be associated with sensitization to housedust mite, and atopy patch test has been used evaluate the elicitation of atopic skin reactions. Microneedle patches allow the increased penetration of allergens with constant and controlled depth and amount. Objectives: To evaluate the efficacy of the microneedle patch test in the diagnosis of sensitization to housedust mite in AD Methods: Atopic patch tests were performed by using Dermatophagoides farinae(D. farinae)-loaded microneedle patch and Finn chamber patch test in patients with AD, allergic rhinitis and normal subjects, and the results were compared and analyzed Results: No significant difference was observed between the positivity rate of microneedle patch and finn chamber patch in patients with AD. The positivity rate was significantly lower in patients with allergic rhinitis. No serious complications occurred. Conclusion: Microneedle patch may be a useful tool for atopy patch test confirming the elicitation of skin reactions after the exposure to housedust mite in AD. The amount of D. farinae required in microneedle patch is less than the amount used in Finn chamber, in which microneedle patch can be suggested as more efficient method for atopy patch test.

A case of bullous pemphigoid induced by clobazam

( Howard Chu ),( Jae Won Lee ),( Dongyun Shin ),( Hee Ju Kim ),( Min Geol Lee ),( Daesuk Kim ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.1

Bullous pemphigoid (BP) is an acquired autoimmunebullous dermatosis resulting in subepidermal blistering. Although usually idiopathic, certain medications are known to be associated, which is referred as drug-induced BP. Herein, we report a novel case of a patient who developed BP after taking clobazam, an anticonvulsant agent. A 50-year-old female presented with a 1cm-sized tense yellowish bulla and few 3mm-sized vesicles on her right shin. When she was six, she started to havedevelopmental delay on her left face and arm. Also, she has a prolonged history of recurrent episodes of seizures since she was 30 years old, and had continuously taken anti-epileptic medications since then. Her seizures were relatively well-controlled until May, 2014, when she arrived at the emergency room with another episode of seizure, and clobazam was added. After taking clobazam for about a month, she visited our dermatology clinic with the skin lesions described above. Biopsy was done and it revealed subepidermal blister containing eosinophils and neutrophils. Although the result for direct immunofluorescence was negative, her clinical features and histological results were highly suggestive of BP. This adverse reaction of clobazam has never been reported before.Further studies are required to clearly determine this drug as the causative agent, yet cautions should be taken before starting treatment with clobazam.

Pharmacokinetics, Safety, and Tolerability of Tedizolid Phosphate After Single-dose Administration in Healthy Korean Male Subjects

Kim, Yun,Kim, Anhye,Lee, SeungHwan,Choi, Sung-Hak,Lee, Dae Young,Song, Ji-Su,Lee, Howard,Jang, In-Jin,Yu, Kyung-Sang Elsevier 2017 Clinical therapeutics Vol.39 No.9

<P><B>Abstract</B></P> <P><B>Purpose</B></P> <P>Tedizolid phosphate is a next-generation oxazolidinone prodrug that is transformed into the active moiety tedizolid. Its indication is acute bacterial skin and skin structure infections caused by gram-positive species, including methicillin-resistant <I>Staphylococcus aureus</I>. Although tedizolid phosphate has been marketed in Korea, no data on the pharmacokinetic (PK) properties or tolerability of tedizolid phosphate in Korean subjects are available. This study was designed to evaluate the PK properties, oral bioavailability, and tolerability with a single-dose oral and intravenous administration of tedizolid phosphate in healthy Korean male subjects.</P> <P><B>Methods</B></P> <P>A block-randomized, double-blind, placebo-controlled, single-dose study was conducted in 3 groups (200, 400, and 600 mg; 10 subjects in each group). In the second part of the study, subjects from the 200-mg group received administration orally and intravenously (1-hour infusion) via 2-way crossover for the evaluation of absolute bioavailability. There was a 7-day washout period between treatments in the absolute bioavailability part of the study. Serial blood samples for PK analysis were collected for up to 72 hours. Tolerability was assessed by analysis of adverse events.</P> <P><B>Findings</B></P> <P>Thirty healthy Korean subjects completed the study and were included in the PK and tolerability analyses. Tedizolid phosphate was rapidly converted into tedizolid. After a single oral dose, the T<SUB>max</SUB> of tedizolid was observed to be 1.5 to 2.5 hours, and the plasma concentration–time curve of tedizolid showed a 2-phase elimination pattern, with a half-life of ~11 hours. Dose-dependent increases were observed in the AUC<SUB>last</SUB> value (29,441–78,062 μg · h/L) and in the C<SUB>max value (</SUB>2679–6980 μg/L) with the administration of tedizolid phosphate 200 to 600 mg PO. The absolute bioavailability of tedizolid was 95.2% (90% CI, 92.7%–97.8%) in the 200-mg administration group. There were no serious adverse events or clinically significant changes in the tolerability assessment.</P> <P><B>Implications</B></P> <P>Tedizolid phosphate at doses of up to 600 mg was well-tolerated in these healthy Korean male subjects. Tedizolid shows dose linearity with oral administration, and no dose adjustment of tedizolid phosphate 200 mg would be needed when switching administration routes. ClinicalTrials.gov identifier: NCT02097043.</P>

The association of Malassezia, barrier disruption, and immune dysregulation in the pathogenesis of red face syndrome of atopic dermatitis

( Howard Chu ),( Ji Hye Kim ),( Seo Hyeong Kim ),( Kwang Hoon Lee ),( Chang Ook Park ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.2

Background: Red face syndrome is a chronic symptom seen in patients with atopic dermatitis (AD), which can be a therapeutic challenge. Studies have suggested the possibility of involvement of Malassezia furfur (M. furfur) in the pathogenesis, yet the underlying mechanism remains unclear. Objectives: To identify the immune reactions induced by M. furfur and the association with barrier disruption in the development of red face syndrome in AD . Methods: Keratinocytes were co-cultured with M. furfur and treated with IL-4 and the expressions of VEGF and VEGFR were analyzed. Staphylococcus epidermidis was also co-cultured as control. The same procedures were performed with endothelial cells and the expressions of VEGFR, TFG-β, and TNF-α were analyzed. To observe the inhibitory effect of ceramide, M. furfur was cultured after treatment with ceramide. Results: The expressions of VEGF, VEGFR, IL-31, and IL-33 were highest in keratinocytes co-cultured with M. furfur and treated with IL-4. For endothelial cells, the expressions of VEGFR, TGF-β, TNF-α and IL-1β were also highest when co-cultured with M. furfur and treated with IL-4. The growth of M. furfur was inhibited when cultured in media treated with ceramide. Conclusion: M. furfur has a crucial role of inducing red face syndrome in AD under the circumstances of Th2 milieu and barrier disruption that cause the increase of VEGF, TGF-β, TNF-α and IL-1β which induce inflammation, angiogenesis, and tissue remodeling.

A Case of “Sinking Skin Flap Syndrome” in Vegetative State Patient

Howard Kim,양회생,이근수 대한신경손상학회 2020 Korean Journal of Neurotrauma Vol.16 No.2

Sinking skin flap syndrome is defned by a series of neurological symptoms with skindepression at the site of cranial defect. We experienced neurological improvement ina patient with markedly sunken craniectomy site afer ventriculoperitoneal shunt (V-Pshunt) clamping operation. A 17-year old female patient was in vegetative state and spasticquadriplegia afer traumatic brain injury. She was suffered from frequent vomiting. Toevaluate central nervous system problem we checked brain computed tomography whichshowed that right frontotemporoparietal craniectomy area was markedly sunken and midlinewas shifing to the lef. Afer V-P shunt clamping operation, craniectomy site was elevatedand midline shifing was improved. Vomiting was disappeared. Coma Recovery Scale-revised(CRS-R) score was improved from 3 to 6

Intramuscular Hematoma Following Radial Extracorporeal Shockwave Therapy for Chronic Neurogenic Heterotopic Ossification: A Case Report

Howard Kim,전지환,이동열,천지홍,조윤경,이성훈,강은영 대한재활의학회 2017 Annals of Rehabilitation Medicine Vol.41 No.3

Extracorporeal shockwave therapy (ESWT) has been reported to be a safe and effective method for decreasing pain and relieving range of motion (ROM) limitations caused by neurogenic heterotopic ossification (NHO), though there has been no report that it might cause hematoma if applied to NHO. We hereby report a case of massive hematoma after ESWT, specifically the radial shockwave therapy (RSWT) device at both hips in a 49-year-old female patient with NHO. She had developed NHO after extensive subarachnoid hemorrhage. We had applied RSWT according to the previous report. The pain and the ROM limitations were gradually improved. Six weeks later, she reported pain and ROM limitations on the right hip. From a medial aspect, swelling and bruising of the right thigh could be seen. Magnetic resonance imaging and ultrasonography suggested a large hematoma between right hip adductor muscles. The symptoms disappeared after conservative treatment for one month, and subsequent follow-up imaging studies demonstrated resolution of the hematoma.

New tablet formulation of tacrolimus with smaller interindividual variability may become a better treatment option than the conventional capsule formulation in organ transplant patients

Kim, Yu Kyong,Kim, Anhye,Park, Shin Jung,Lee, Howard Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P>To evaluate the pharmacokinetic (PK) and tolerability profiles of a new tablet formulation of tacrolimus and its interindividual variability (IIV) in the systemic exposure, and to compare them with those of the conventional capsule formulation, a randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in 47 healthy males. The capsule or tablet formulation of tacrolimus was orally administered, and serial blood samples were collected up to 96 hours after dosing. Whole-blood tacrolimus concentration was determined using liquid chromatography–tandem mass spectrometry. The maximum whole-blood tacrolimus concentration (C<SUB>max</SUB>) and the area under the whole-blood tacrolimus concentration–time curve from 0 hour to the last quantifiable concentration (AUC<SUB>last</SUB>) were compared between the two formulations. The similarity factor (f<SUB>2</SUB>) of the in vitro dissolution profiles was calculated. The geometric mean ratio (90% confidence interval) of tablet to capsule was 0.9680 (0.8873–1.0560) and 1.0322 (0.9359–1.1385) for C<SUB>max</SUB> and AUC<SUB>last</SUB>, respectively. The IIV of C<SUB>max</SUB> and AUC<SUB>last</SUB> of the tablet was smaller than the capsule. The f<SUB>2</SUB> values were >50 in all media. Both formulations were well tolerated. Thus, the tablet formulation of tacrolimus has smaller IIV in the systemic exposure than capsule, while having comparable PK and tolerability profiles, which may render it as a better treatment option for organ transplant patients.</P>

Two cases of blaschkitis

( Howard Chu ),( Jae Won Lee ),( Dongyun Shin ),( Hee Ju Kim ),( Min Geol Lee ),( Dae Suk Kim ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.1

Blaschkitis is a rare, recurrent dermatitis that consists of linearly distributed pruritic papules along the Blaschko lines. Since the first description in 1990, several reports have been made. The histologic finding initially described was spongiotic dermatitis, yet findings of interface dermatitis have been reported recently. We also present two cases of blaschkitis where interface dermatitis was revealed histologically. A 26-year-old male visited our dermatology clinic with slightly pruritic linear figurative irregular-shaped erythematous scaly patches on right trunk for 6 months. A skin biopsy was done, which revealed lichenoid dermatitis with hyperkeratosis. The patient was treated with topical steroid only, and slight improvements were observed. Another 14-year-old male came to our clinic with non-pruritic linear irregular shaped scaly erythematous plaques that have been persistent for 2 months on his trunk. Biopsy was also done, with the findings of interface dermatitis. The patient was treated with topical steroid and low dose systemic steroid. His symptoms improved more dramatically and both patients are under regular follow-up. The generally accepted histologic feature of blaschkitis is spongiotic dermatitis, but in accordance with few recent reports, the current cases show interface dermatitis as the histologic finding.

Failure mode and effects analysis drastically reduced potential risks in clinical trial conduct

Lee, Howard,Lee, Heechan,Baik, Jungmi,Kim, Hyunjung,Kim, Rachel Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P><B>Background</B></P><P>Failure mode and effects analysis (FMEA) is a risk management tool to proactively identify and assess the causes and effects of potential failures in a system, thereby preventing them from happening. The objective of this study was to evaluate effectiveness of FMEA applied to an academic clinical trial center in a tertiary care setting.</P><P><B>Methods</B></P><P>A multidisciplinary FMEA focus group at the Seoul National University Hospital Clinical Trials Center selected 6 core clinical trial processes, for which potential failure modes were identified and their risk priority number (RPN) was assessed. Remedial action plans for high-risk failure modes (RPN >160) were devised and a follow-up RPN scoring was conducted a year later.</P><P><B>Results</B></P><P>A total of 114 failure modes were identified with an RPN score ranging 3–378, which was mainly driven by the severity score. Fourteen failure modes were of high risk, 11 of which were addressed by remedial actions. Rescoring showed a dramatic improvement attributed to reduction in the occurrence and detection scores by >3 and >2 points, respectively.</P><P><B>Conclusions</B></P><P>FMEA is a powerful tool to improve quality in clinical trials. The Seoul National University Hospital Clinical Trials Center is expanding its FMEA capability to other core clinical trial processes.</P>