Showing papers by "Young Hoon Kim published in 2014"

Quantitative Assessment of Pancreatic Fat by Using Unenhanced CT: Pathologic Correlation and Clinical Implications

Abstract: CT attenuation indexes are well correlated with histologically measured pancreatic fat, and they are significantly associated with impaired glucose metabolism.

Differentiation of Acute Osteoporotic and Malignant Compression Fractures of the Spine: Use of Additive Qualitative and Quantitative Axial Diffusion-weighted MR Imaging to Conventional MR Imaging at 3.0 T

Abstract: Our study showed that diagnostic accuracy in the differentiation of acute osteoporotic from malignant compression fracture was improved by adding qualitative and quantitative axial diffusion-weighted imaging with a high b value to conventional MR imaging at 3.0 T.

Abstract LB-100: Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor

Abstract: Introduction: Activating mutations of EGFR are well known as oncogenic driver mutations in lung adenocarcinoma. Currently, EGFR TKIs including Gefitinib and Erlotinib are used as the first line therapy in NSCLC patients harboring EGFR activating mutations. However, drug resistance caused by T790M mutation limits the efficacy of these 1st generation EGFR TKIs. Currently, some of the next generation EGFR TKIs are under investigation for the treatment of lung cancer patients having T790M mutation. In our current presentation, to obtain HM61713, an EGFR mutant selective inhibitor, as a clinical candidate and the evaluation of HM61713 for mutant EGFR cancer model will be introduced. Method: Novel analogues were designed and synthesized to find active compounds for the T790M mutation as well as EGFR activating mutations with good selectivity over wild- type EGFR. Finally, HM61713 was selected as a clinical candidate through multi-optimization processes including both in vitro and in vivo pharmacologcal studies. Results: HM61713 was designed as an irreversible kinase inhibitor having a Michael acceptor, which covalently binds to a cysteine residue near the kinase domain of mutant the EGFR. In a cell wash out test, HM61713 inhibited phospho-EGFR for a long duration with a half-life of over 24 hours. From in vitro study, HM61713 showed potent activities for H1975 (L858-T790M) and HCC827 (exon 19 del.) with GI50 values of 9.2 nM and 10 nM, respectively. Instead, it showed low potency for H358 (wild type EGFR NSCLC) with GI50 of 2,225 nM. In xenograft studies using H1975 and HCC827, HM61713 resulted in good efficacy without showing any side effects. Conclusion: HM61713 showed excellent in vitro and in vivo activities for H1975 harboring L858R-T790M mutation as well as HCC827 having exon 19 deletion mutation with selectivity over wild-type EGFR. Currently, HM61713 is undergoing phase I study (NCT01588145) for NSCLC patients after the failure of 1st generation EGFR TKIs in Korea. Citation Format: Kwang-Ok Lee, Mi Young Cha, Mira Kim, Ji Yeon Song, Jae-Ho Lee, Young Hoon Kim, Young-Mi Lee, Kwee Hyun Suh, Jeewoong Son. Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-100. doi:10.1158/1538-7445.AM2014-LB-100

Comprehensive Variant Screening of the UGT Gene Family

Abstract: Purpose UGT1A1, UGT2B7, and UGT2B15 are well-known pharmacogenes that belong to the uridine diphosphate glucuronyltransferase gene family. For personalized drug treatment, it is important to study differences in the frequency of core markers across various ethnic groups. Accordingly, we screened single nucleotide polymorphisms (SNPs) of these three genes and analyzed differences in their frequency among five ethnic groups, as well as attempted to predict the function of novel SNPs. Materials and methods We directly sequenced 288 subjects consisting of 96 Korean, 48 Japanese, 48 Han Chinese, 48 African American, and 48 European American subjects. Subsequently, we analyzed genetic variability, linkage disequilibrium (LD) structures and ethnic differences for each gene. We also conducted in silico analysis to predict the function of novel SNPs. Results A total of 87 SNPs were detected, with seven pharmacogenetic core SNPs and 31 novel SNPs. We observed that the frequencies of UGT1A1 *6 (rs4148323), UGT1A1 *60 (rs4124874), UGT1A1 *93 (rs10929302), UGT2B7 *2 (rs7439366), a part of UGT2B7 *3 (rs12233719), and UGT2B15 *2 (rs1902023) were different between Asian and other ethnic groups. Additional in silico analysis results showed that two novel promoter SNPs of UGT1A1 -690G>A and -689A>C were found to potentially change transcription factor binding sites. Moreover, 673G>A (UGT2B7), 2552T>C, and 23269C>T (both SNPs from UGT2B15) changed amino acid properties, which could cause structural deformation. Conclusion Findings from the present study would be valuable for further studies on pharmacogenetic studies of personalized medicine and drug response.

Assessment of Factors Affecting the Difficulty of Caudal Epidural Injections in Adults Using Ultrasound

Abstract: BACKGROUND: In unaided caudal epidural block (CEB), incorrect needle insertion has been reported to occur in 15% to 38% of attempts.

Does extracorporeal shock wave introduce alteration of microenvironment in cell therapy for chronic spinal cord injury

Abstract: Study Design.Animal experimental study.Objective.To present experimental evidence for cell therapy for spinal cord injury (SCI).Summary of Background Data.In chronic SCI, the efficacy of cell engraftment has been known to be low due to its distinct pathology. Alteration of microenvironment was tried

Long-term Effects of Delayed Graft Function on Pancreas Graft Survival After Pancreas Transplantation.

Abstract: BACKGROUND Compared with the impact of delayed graft function (DGF) after renal transplantation, DGF after pancreas transplantation has not been fully evaluated. METHODS We retrospectively verified the impact of DGF on long-term pancreas graft survival in surgically successful cases. Pancreas graft failure was defined by the recipient's return to exogenous insulin administration. RESULTS Between May 2004 and April 2013, we performed 135 technically successful primary pancreas transplantations. Delayed graft function was defined as a total cumulative insulin requirement of 19 UI or greater within postoperative 7 days. Of the 135 recipients in our study cohort, 47 (34.8%) developed DGF after the pancreas transplantation. By multivariate analysis, DGF was found to be associated with a donor age of 30 years or older (odds ratio, 3.4; 95% confidence interval, 1.50-7.69; P=0.003) and the increased ratio of body mass index in a recipient to a donor (odds ratio, 26.1; 95% confidence interval, 2.53-270.0; P=0.006). There was a trend toward higher acute rejection (P=0.622) and mortality (P=0.49) rates in recipients with versus without DGF, although this did not reach statistical significance. Delayed graft function was found to be associated with a greater risk of overall pancreas graft failure (P=0.016) and death-censored graft failure (P=0.037). CONCLUSION Delayed graft function after pancreas transplantation was found to be associated with a greater risk of overall pancreas graft failure and death-censored graft failure.

Spinal cord compression by B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma in a patient seropositive for human immunodeficiency virus: a case report

Abstract: Introduction Although non-Hodgkin’s lymphoma is one of the most common and frequently fatal of the acquired immune deficiency syndrome-defining illnesses, survival has improved significantly since the introduction of antiretroviral therapy. Patients with spinal cord compression resulting from non-Hodgkin’s lymphoma present with clinically acute or rapidly progressive neurologic deficits. The purpose of this case report is to present a case of a patient seropositive for human immunodeficiency virus with spinal cord compression due to B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma.

Spinopelvic Alignment by Different Surgical Methods in the Treatment of Degenerative Sagittal Imbalance of the Lumbar Spine.

Abstract: Study Design: Retrospective comparative study Objective: To compare pedicle subtraction osteotomy (PSO) and iliac fixation (ILF) without osteotomy as methods of correcting lumbar spine deformities due to degenerative sagittal imbalance (DSI) through the evaluation of the changes in spinopelvic alignment. Summary of Background Data: Many papers have reported the surgical results after PSO and ILF for patients with fixed adult deformities. However, little is known about the difference between PSO and ILF corrections of spinopelvic alignment in adults with DSI. Methods: DSI patients who had undergone PSO or ILF with a minimum of 2-year follow-up (FU) were retrospectively studied in PSO (n=30) or ILF (n=25) groups. Lumbar lordosis (LL), thoracic kyphosis (TK), and sagittal vertical axis (SVA) were measured as spinal parameters and pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT) were used as measurements of pelvic parameters. Clinical outcomes were evaluated using a visual analogue scale (VAS) and Oswestry Disability Index (ODI) scores.

Neural Changes Associated with Emotion Processing in Children Experiencing Peer Rejection: A Functional MRI Study

Abstract: This study was performed to investigate differences between children who did and did not experience peer rejection in psychological state through surveys and in emotion processing during an interpersonal stress challenge task to reflect naturalistic interpersonal face-to-face relationships. A total of 20 right-handed children, 10 to 12 yr of age, completed self-rating questionnaires inquiring about peer rejection in school, depression, and anxiety. They then underwent an interpersonal stress challenge task simulating conditions of emotional stress, in reaction to positive, negative and neutral facial expression stimuli, using interpersonal feedbacks, and functional magnetic resonance imaging (FMRI) for an analysis of neural correlates during the task. Ten were the peer-rejection group, whereas the remainder were the control group. Based on the behavioral results, the peer-rejection group exhibited elevated levels of depression, state anxiety, trait anxiety and social anxiety as compared to the control group. The FMRI results revealed that the peer-rejection group exhibited greater and remarkably more extensive activation of brain regions encompassing the amygdala, orbitofrontal cortex and ventrolateral prefrontal cortex in response to negative feedback stimuli of emotional faces. The different brain reactivities characterizing emotion processing during interpersonal relationships may be present between children who do and do not experience peer rejection.

Is it real adjacent segment pathology by stress concentration after limited fusion in degenerative lumbar scoliosis

Abstract: STUDY DESIGN A retrospective comparative study. OBJECTIVE To investigate adjacent segment pathology (ASP) after limited lumbar fusion in the treatment of degenerative lumbar scoliosis (DLS). SUMMARY OF BACKGROUND DATA The assessment of appropriate surgical techniques for DLS remains one of the most controversial topics in spinal surgery. So far, there has been no study specifically addressing why ASP shows different patterns with respect to different fusion levels after instrumented lumbar fusion for DLS. METHODS Fifty-nine patients were enrolled and divided into 2 groups with respect to the proximal fusion level: group I consisted of 29 patients who underwent fusion below the proximal neutral vertebrae, and group II consisted of 30 patients who underwent fusion to the proximal neutral vertebrae. Clinical and radiological assessments were performed with an average of 59.4 months of follow-up. The number of radiological findings for ASP was determined on the basis of a 7-point scale that gave 1 point for each radiological finding. The 2 groups were analyzed according to radiological ASP (RASP). The Oswestry Disability Index and visual analogue scale scores were recorded prospectively. RESULTS Overall, RASP developed in 16 (27.1%) patients. In group I, 12 (41.4%) of 29 patients, and in group II, 4 (13.3%) of 30 patients showed RASP. Group I yielded an average of 4.5 points, and group II, 1.8 points. RASP scores were much higher in group I than in group II, with statistical significance (P = 0.000). In group I, 4 patients underwent revision surgery, but in group II, only 1 patient did so. CONCLUSION RASP displayed variance according to different fusion levels. RASP in group I showed similar patterns to the natural progression of DLS. It is suggested that fusion be included at least at the proximal neutral vertebrae to reduce RASP although RASP with different patterns is unavoidable. LEVEL OF EVIDENCE 4.

Articulation error of children with adenoid hypertrophy

Abstract: PURPOSE Adenoid hypertrophy is a physical alteration that may affect speech, and a speech disorder can have other negative effects on a child's life. Airway obstruction leads to constricted oral breathing and causes postural alterations of several oro-facial structures, including the mouth, tongue, and hyoid bone. The postural modifications may affect several aspects of speech production. METHODS In this study, we compared articulation errors in 19 children with adenoid hypertrophy (subject group) to those of 33 children with functional articulation disorders independent of anatomical problems (control group). RESULTS The mean age of the subject group was significantly higher (P=0.016). Substitution was more frequent in the subject group (P=0.003; odds ratio [OR], 1.80; 95% confidence interval [CI], 1.23-2.62), while omission was less frequent (P<0.001; OR, 0.43; 95% CI, 0.27-0.67). Articulation errors were significantly less frequent in the palatal affricative in the subject group (P=0.047; OR, 0.25; 95% CI, 0.07-0.92). The number of articulation errors in other consonants was not different between the two groups. Nasalization and aspiration were significantly more frequent in the subject group (P=0.007 and 0.014; OR, 14.77 and 0.014; 95% CI, [1.62-135.04] and NA, respectively). Otherwise, there were no differences between the two groups. CONCLUSION We identified the characteristics of articulation errors in children with adenoid hypertrophy, but our data did not show the relationship between adenoid hypertrophy and oral motor function that has been observed in previous studies. The association between adenoid hypertrophy and oral motor function remains doubtful.

Effects of simultaneous iliac artery angioplasty on graft and patient survival after living-donor kidney transplantation.

Abstract: BACKGROUND Renal transplant candidates with extended indications, such as older age and advanced atherosclerosis, are currently accepted onto the waiting list. METHODS We retrospectively evaluated the clinical outcomes of simultaneous kidney transplantation and angioplasty compared with transplantation alone. RESULTS We included 748 patients who underwent living-donor kidney transplant because of end-stage renal disease during a 5-year period, consisting of 27 kidney transplants with simultaneous angioplasty and 721 without additional vascular procedures. As candidates for simultaneous angioplasty and transplant, we considered patients with TransAtlantic Inter-Society Consensus type A and B aorto-iliac disease. We compared transplant outcomes in patients who did or did not receive simultaneous angioplasty. Although simultaneous iliac artery angioplasty was significantly related to recipient age, diabetes mellitus, hypertension, and coronary artery disease, it was not associated with graft (uncensored, P=0.937; death censored, P=0.981) or patient (P=0.804) survival during the follow-up period. In addition, simultaneous angioplasty was not associated with a higher risk of delayed graft function (P=0.099) or a longer hospital stay (P=0.790). There was no significant difference in mortality due to a cardiovascular event between the two groups (P=0.199). CONCLUSIONS Simultaneous iliac artery angioplasty and kidney transplantation in carefully selected patients can be performed safely with equivalent graft and patient survival to transplantation alone.

Synthesis of Vinyl Sulfone-tethered Proline Derivatives as Highly Selective Cathepsin S Inhibitors

Abstract: Cathepsin S (CatS), a cysteine protease belonging to the papain family, has been proposed as an attractive therapeutic target for asthma and autoimmune diseases due to the fact that CatS is closely implicated in the process of antigen presentation. Indeed, it has been reported that inhibition of CatS decreases chronic inflammatory pain in a collageninduced arthritis (CIA) model of rheumatoid arthritis. Thus, there is a growing interest among medicinal chemists to identify CatS inhibitors. Morpholineurea-leucine homophenylalanine vinyl sulfone 1 (LHVS, Figure 1) has been previously identified as a potent CatS inhibitor but limited selectivity for members of the cathepsin family. A number of selective CatS inhibitors have been reported as potential therapeutic agents, including cyanopeptide-, pyrrolopyrimidine-, aminopyrimidine-, cyanopyrazolidine-based inhibitors. Although some CatS inhibitors are currently being evaluated in clinical trials, potent and selective CatS inhibitors are still required. With respect to development of selective CatS inhibitors, we recently reported novel selective cathepsin S inhibitors based on a proline scaffold. Following up on this work, we herein report the synthesis of a series of proline analogues with vinyl sulfone group, which is a key functional group of LHVS. We evaluated these novel compounds for their in vitro CatS inhibitory activity to investigate a structure-activity relationship (SAR). The general synthetic procedure for preparing 4-sulfonyl substituted proline-derived analogues is summarized in Scheme 1. Mesylation of the commercially available proline analogue 2 was performed under Mitsunobu condition and subsequent nucleophilic substitution by a thiol afforded the thioether 4, which was converted to sulfone 5 by mCPBA oxidation. After deprotection of tert-Boc, acid chloride or

Fate of Osteophytes and Sclerosis in Fused Segments After Lumbar Fusion

Abstract: Study design Retrospective cohort study. Objective To investigate the fate of sclerosis and anterior osteophytes in the fused segments after instrumented lumbar fusion for degenerative lumbar disorders. Summary of background data Sclerosis and osteophytosis are well-known radiographical findings, but little is known of their significance with regard to spontaneous resorption after spine fusion. Methods Thirty patients (9 males, 21 females; 60 vertebra; mean age of 66.9 yr [45-86 yr]) were divided into a posterolateral fusion group (n = 14, 28 vertebrae) and a posterior lumbar interbody fusion group (n = 16, 32 vertebrae). Using serial radiographs obtained preoperatively; postoperatively at 3, 6, 12, and 24 months; and last follow-up, sclerotic areas of each involved vertebra were mapped and osteophyte lengths were measured. Results Sclerosis and osteophytes decreased with time for the instrumented fusion. The decrease in sclerotic areas and osteophytes length was observed as early as 3 months postoperatively, and the significant changes between each time point were noted in initial 3- and 6-month intervals. In terms of the type of surgery, similar changes were noted in the posterolateral fusion and posterior lumbar interbody fusion groups. Conclusion Resorption of osteophytes and sclerosis after instrumented spine fusion were observed. Significant resorption was noted at 3 and 6 months postoperatively. As well, most graft bone would be incorporated in postoperative 6 months. Resorption of osteophytes and sclerosis after instrumented spine fusion could be helpful to confirm the successful union. Level of evidence 4.

Ultrasound-guided pudendal nerve pulsed radiofrequency in patients with refractory pudendal neuralgia -Three cases report-

Abstract: Received: June 16, 2014. Revised: July 11, 2014. Accepted: July 31, 2014. Corresponding author: Dong Eon Moon, M.D., Department of Anesthesiology and Pain Medicine, The Catholic University of Korea, Seoul St.Mary's Hospital, 505, Banpo-dong, Seocho-gu, Seoul 137-040, Korea. Tel: 82-2-2258-2236, Fax: 82-2-537-1951, E-mail: demoon@catholic.ac.kr Pudendal neuralgia is characterized by severe sharp pain along the innervation area of pudendal nerve, which may be worsened when sitting position. Successful pudendal nerve block is crucial to the diagnosis of pudendal neuralgia. Although fluoroscopy-guided pudendal nerve blocks have traditionally been performed, recently ultrasound-guided pudendal nerve blocks were reported. For the long term effect of nerve block, pulsed radiofrequency was performed under fluoroscopic guidance in some reports. We report our successful experiences of three cases using ultrasound-guided pulsed radiofrequency. (Anesth Pain Med 2014; 9: 250-253)

Computed tomographic colonography is valuable for post-treatment evaluation and screening of hidden colorectal cancer in patients with cryptogenic pyogenic liver abscess.

Abstract: Background/Aims: It has been demonstrated that cryptogenic pyogenic liver abscess (PLA) is associated with colonic mucosal defect, especially colorectal cancer (C

Immune-stimulatory Effects of Fomes fomentarius Extract in Murine Macrophages

Abstract: 본 연구에서는 아직 까지 연구되지 않은 말굽버섯의 면역증강 효과를 설치류 대식세포에서 검증하였다. 연구결과에 따르면 말굽버섯 메탄올 추출물(FFE)의 처리에 의해 대식세포의 산화질소의 생성이 농도 의존적으로 증가되었다. 산화질소의 생성이 증가된 이유는 산호질소의 생성을 유도하는 효소인 iNOS의 발현이 FFE에 의해 증가되었기 때문이었다. FFE는 면역반응에 중요한 cytokine인 TNF- ${\alpha}$ , IL- $1{\beta}$ , IL-6의 생성도 농도 의존적으로 증가 시켰다. 이 같은 FFE의 면역증강 활성은 면역활성을 중계하는 세포 신호전달분자 중 NF- ${\kappa}B$ 와 MAP Kinases의 활성증가에 의한 것임을 확인 할 수 있었다. 본 연구 결과는 말굽버섯의 임상적 적용에 중요한 자료로 활용될 것이며, 만일 말굽버섯으로부터 분리한 단일성분에서 면역증강활성을 검증 하게 된다면 새로운 식 의약소재로서의 가치를 인정 받을 수 있을 것으로 생각된다. 【In this study, we demonstrated whether the extract of Fomes fomentarius (FFE; FF extract) could be used to stimulate macrophages (RAW 264.7 cells). All four doses of FFE (5, 10, 20, and $40{\mu}g/mL$ ) had no significant cytotoxicity during the entire experimental period. FFE potently increased the production of nitric oxide (NO). Consistent with these observations, inducible NO synthase levels were increased by FFE in a dose-dependent manner. Moreover, FFE increased the production of tumor necrosis factor- ${\alpha}$ , interleukin (IL)- $1{\beta}$ , and IL-6 in the same cells. These stimulating effects of FFE were found to be caused by the stimulation of phosphorylation of $I{\kappa}B{\alpha}$ and MAP kinases (p38, ERK, and JNK). These results suggest that FFE may be used as new agents for wide application in the immune study of mushroom.】

Spinal interventions under ultrasound guidance

Abstract: Injection therapies play important roles in the management of spinal pain and it has been preferred that they be performed under the guidance of computed tomography or fluoroscopy. Recently, several ultrasound-guided techniques for alleviating spinal pain have been introduced due to visualization of the inner structures, portability, and lack of radiation exposure. For the cervical spine, ultrasound-guided procedures including the nerve root block, facet joint injection, and medial branch block have shown successful results, and for the lumbar spine, so do the interventions including the interlaminar epidural block, nerve root block, facet joint injection, and medial branch block. However, ultrasonographically guided procedures have some limitations in that they cannot completely avoid unintentional intravascular injection and identify the spread pattern of injected solution underneath the bony structures. New and untried techniques to overcome these limitations are expected. This paper reviews a variety of techniques under ultrasound guidance that have been reported for injection therapy in the cervical and lumbar spine.

Epigenetic Mechanisms of Early Adverse Experience in the Development of Depression

Abstract: Epigenetic Mechanisms of Early Adverse Experience in the Development of Depression Mi Kyoung Seo, PhD, Jung Goo Lee, MD, PhD, Sung Woo Park, PhD, Bong Ju Lee, MD, PhD, Jun Hyung Baek, MD and Young Hoon Kim, MD, PhD Paik Institute for Clinical Research, Inje University, Busan, Department of Psychiatry, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Department of Health Sciences and Technology, Graduate School of Inje University, Busan, Korea

Efficacy of Venlafaxine Hydrochloride Extended Release for the Treatment of Perimenopausal Depressive Women with Vasomotor Symptoms: Open-Label Observation Study

Abstract: ObjectivezzDuring the transition to menopause, various symptoms including vasomotor symptoms and depressed mood lead to low quality of life. We investigated the effect of low-dose venlafaxine hydrochloride extended release on depressed mood and vasomotor symptoms of perimenopausal women. Methodszz33 perimenopausal women fulfilling Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for a depressive episode were enrolled between January 2014 and May 2014. Subjects were prescribed 37.5 mg/day or 75 mg/day venlafaxine hydrochloride according to clinician’s judgement, and the dosages were maintained for 8 weeks. Depressed mood and other psychological difficulties were evaluated by using Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAMA), Clinical Global Impression-Severity. Climacteric symptoms including vasomotor symptoms were evaluated by using Greene Climacteric Scale (GCS). For statistical analysis, paired t-test was used. ResultszzSignificant decreases in HAMD, HAMA, GCS scores were observed after 2 weeks of treatment and the trends continued until the end of the study. The scores of HAMD significantly decreased, 28 of them reached remission (HAMD ≤7). The scores on vasomotor symptoms of GCS after 8 week treatment significantly decreased compared to baseline (13.1±5.0, p<0.01). ConclusionzzThese results suggest that venlafaxine hydrochloride is effective and tolerable treatment option for vasomotor symptoms and depressed mood in perimenopausal women. To validate our results, furthur studies with double-blind, placebo controlled will be needed. Korean J Psychopharmacol 2014;25(4):186-191

Head circumference alone at birth, is it practical?

Abstract: Head circumference (HC) measurement is an important physical examination of infants because an abnormality of HC can indicate an underlying congenital, genetic, or acquired neurologic problem. An abnormality of HC is determined by brain size, including any malformations and space occupying lesions, cerebrospinal fluid and blood volume, presence of subdural fluid and thickness of skull bones and overlying tissue scalp. The HC measurement, herein referred to as the occipital frontal circumference (OFC), extends from the most prominent part of the glabella to the most prominent posterior area of the occiput. The OFC can be affected by thick hair and cranial bone deformations or hypertrophies. Ethnicity and growth stature must also be considered when evaluating the OFC. Relative macrocephaly indicates that the OFC plots within 2.0 standard deviations (SDs) of the mean but plots disproportionately above that for stature1). Macrocephaly may be due to megalencephaly, hydrocephalus, cranial hyperostosis, or other conditions. Macrocephaly is relatively frequent at birth and is a common cause for genetic consultation. For practical purposes, +2 SD is reasonable as a threshold for considering further investigation and counseling, but many normal infants will also be included if HC alone is used as the diagnostic criterion. Benign macrocephaly of infancy is a common problem in pediatric neurology practice2). Therefore, measurement of HC is an important diagnostic tool for discovering intracranial expansive conditions in infants. A limited number of studies regarding macrocephaly at birth have been performed in Korea. Jeong et al.3) used ultrasonography to investigate the characteristics and significance of macrocephaly at birth in Korean infants and Jeong et al's study is the first study to investigate macrocephaly based on the 2007 Korean National Growth Charts. This study showed that macrocephaly was twice as prevalent in boys as in girls and that height at birth correlated with OFC. The majority of patients had no remarkable abnormality on ultrasonography. Some patients were diagnosed with germinal matrix hemorrhage (GMH) and an enlarged subarachnoid space. GMH without intraventricular hemorrhage (IVH) usually disappears within a year4). Full-term infants with subarachnoid space enlargement have normal development, a normal neurologic examination, and usually do not require surgical intervention. This study identified an enlarged subarachnoid space in 6.7% of the patients. The majority of patients with isolated macrocephaly have few neurological symptoms or physical abnormalities and show normal development or intelligence or both5). Neverthless, macrocephaly is a common reason for a medical genetics referral as there are many genetic conditions associated with it. According to the Online Mendelian Inheritance in Man (OMIM) Database, 225 syndromes are associated with macrocephaly. The degree of severity of the macrocephaly is an important predictor of prognosis. The finding of mild macrocephaly (<+2.5 SD), even in the presence of subtle signs, such as enlarged subarachnoid spaces or frontal bossing, carries a good prognosis6). Nonsyndromic macrocephaly is not associated with any other prominent physical trait or major malformation. Minor craniofacial changes can be present but those are due to the secondary effects of the enlarged cranial vault. These changes include a prominent or high forehead and a dolichocephalic head shape7). Increased width of the cranial base can at times produce mild hypertelorism and down slanting palpebral fissures. Syndromic macrocephaly is diagnosed when significant abnormalities are associated with generalized brain enlargement. Megalencephaly causing macrocephaly is considered a disorder of neuronal and glial proliferation. Syndromic macrocephaly may be associated with minor or major brain anomalies. Although macrocephaly rarely results from chromosomal anomalies, it has recently been described in patients with chromosomal microdeletion syndromes7). Patients with syndromic macrocephaly, who may frequently suffer from mental retardation, must be differentiated from patients with nonsyndromic macrocephaly, which has a good prognosis. Therefore, studies suggest considering karyotyping and microarray-based comparative genomic hybridization in macrocephalic patients without a definitive diagnosis7). In syndromic macrocephaly, significant abnormalities are associated with the generalized brain enlargement. Syndromic macrocephaly should be distinguished from other genetic syndromes in which macrocephaly is a clinically predominant finding. The nongenetic macrocephalies are due to secondary effects of environmental events such as those related to neonatal IVH or infection. Benign extracerebral fluid collections are a relatively common cause of nongenetic macrocephalies. However, routine measurements of HC are of value mainly for early detection of hydrocephalic conditions and, to a certain degree, intracranial cysts during the first 10 months of life. Increased HC as a initial symptom seems important only for infants with hydrocephalus and patients with cysts8). For intracranial tumors and other expansive conditions, increased HC is very rarely the initial symptom that causes suspicion and leads to diagnosis. Instead, other symptoms, such as vomiting, irritability, drowsiness, or headache, are more common as the initial symptoms. In Norway, measurements of HC are performed at regular intervals during the first year of life. Serial OFC measurements and clinical follow-up are necessary to accurately determine the course of macrocephaly. Routine measurements of HC during the first year of life mainly detect infants with hydrocephalus or cysts; other expansive conditions yield other symptoms8). In a neonate suspected of having macrocephaly, consideration should be given to detailed ultrasonography, magnetic resonance imaging (MRI), family history, and genetic counseling, including karyotyping and more detailed genetic testing. Radiologic findings of macrocephaly at birth are often benign. However, a benign ultrasonography finding does not guarantee that there will be benign long-term neurological and neurophysiological outcomes. Ultrasonography is the initial procedure recommended since it accurately evaluates ventricular size, extraaxial fluid, and congenital malformations6). Primary megalencephaly (PMG) is defined as an HC above the 98th percentile that most likely is due to brain enlargement and is not secondary to disease. PMG at birth is a risk factor for low intelligence level8). The macrocephaly observed in autism becomes manifest around 1-3 years of age and is typically not present at birth9). Most children with phosphate tensin homolog (PTEN) mutations are macrocephalic10). The conditions associated with macrocephaly in combination with generalized somatic overgrowth include the syndromes of Sotos, Weaver, Beckwith-Wiedemann and others7). Relative macrocephaly may be present in Fragile X syndrome7). Of all the leukodystrophies, Alexander disease and Canavan disease are most clearly associated with macrocephaly. Macrocephaly is present in the neonate in glutaric aciduria, type 1, an inborn error of metabolism associated with neuronal or glial dysfunction11). Physical examination and history alone may identify a syndromic disorder. If there is no neurological dysfunction, a brain imaging study may not be needed, and the possibility of PMG should be considered. When developmental concerns exist, a brain MRI is usually performed. In the absence of an informative MRI phenotype, tests such as chromosome study, array-comparative genomic hybridisation and fragile X molecular screening are often performed7). Metabolic screening with urine organic acids analysis and blood acylcarnitine profile may also be considered. Lysosomal enzyme screening is indicated if the clinical picture suggests a storage disorder. An MRI phenotype showing a predominant leukodystrophy warrants specific diagnostic testing such as enzyme or gene analysis. In conclusion, serial measurements of OFC are important in the evaluation of conditions with macrocephaly. Because identification of macrocephaly can lead to correct syndrome identification, the careful assessment of the OFC remains a crucial part of pediatric neurologic evaluation.

A novel TSC2 mutation in a Korean patient with tuberous sclerosis complex.

Abstract: A 20-month-old girl presented with five seizures since the previous day. She experienced her first seizure at 10 months of age. In the past month, she began having recurrent seizures, with a frequency of about one every 4–5 days. She showed a normal pattern of development. Otherwise, past medical and family history were unremarkable. On examination, she had one hypomelanotic macule and three café-au-lait spots. Brain MRI revealed multifocal cortical tubers and multiple subependymal nodules along the right lateral ventricle (Fig. 1). And EEG revealed intermittent spike and slow waves on the right temporal area during interictal period (Fig. 2). We performed a chest radiography, echocardiogram, renal sonogram and ophthalmic examination, which all showed no abnormalities. According to the clinical diagnostic criteria for tuberous sclerosis complex (TSC) [1], she was diagnosed with definite TSC. Subsequently, vigabatrin was prescribed (1,000 mg/day) and she did not develop additional seizure. We performed PCR sequencing of 23 exons on TSC1, 41 exons on TSC2 and their exon–intron boundaries and identified a novel heterozygous missense mutation (c.3379C[T: R1127 W) on exon 29 of the TSC2 (Fig. 3a). This variant has not been reported in dbSNP137 (http:// www.ncbi.nlm.nih.gov/SNP/, build 137), the 1,000 Genomes Project (http://www.1000genomes.org/, April 2012 release), nor 54 databases of normal Korean genomes (http://tiara.gmi.ac.kr/ and http://opengenome.net/index. php/Korean). Variant conservation was observed with phastCons and phyloP scores, which are part of the MutationTaster program [2]. MutationTaster calculates these scores based on pre-computed values from UCSC. The values from phastCons are calculated from multiple genome sequences of 46 different species and scaled to a range of 0–1: values close to 1 indicate that the nucleotide is likely highly conserved. PhastCons values are estimated from each aligned column and flanking columns. In contrast, phyloP estimates each column separately without considering the effects of flanking columns. PhyloP values range from -14 to ?6, where positive scores indicate conserved sites and negative scores indicate fast-evolving sites. According to the phastCons and phyloP scores (1 and 1.547, respectively), this mutation occurs in a conserved region (Fig. 3b). Subsequently, we applied in silico methods, such as SIFT [3], PolyPhen-2 [4] and MutationTaster [2]. These methods predict where a single amino-acid substitution affects protein function, and thus is a disease-causing mutation. SIFT defines a mutation as deleterious if the substitution has a score\\0.05 while PolyPhen-2 predicts it to be probably damaging if the probability score of the substitution is [0.85. Using MutationTaster, a probability H.-J. Hu and Y.-J. Chung contributed equally for this paper.