Clinical Significance of Classification of Graves` Disease According to the Characteristics of TSH receptor Antibodies

(Won Bae Kim),(Hyun Kyung Chung),(Young Joo Park),(Do Joon Park),(Hong Kyu Lee),(Bo Youn Cho) 대한내과학회 2001 The Korean Journal of Internal Medicine Vol.16 No.3

N/A Background:It has been widely accepted that the epitope (s) and/or functional characteristics of thyrotropin receptor antibodies (TSHRAb) from Graves` patients are heterogenous among patients. However, the clinical significance of such heterogeneity has not been systematically evaluatedyet. We were to elucidate and find the clinical significance of heterogeneity for TSH receptor antibodies in Graves` disease. Methods:We measured stimulating TSHRAb (TSAb) activities using CHO-hTSHR cells, FRTL-5 cells and chimeric receptor expressing cells (Mc1+2 and Mc2), specific blocking TSHRAb (TSBAb) activities using Mc2 cells and TBII activities using porcine thyroid membrane in 136 patients with untreated hyperthyroid Graves` disease. Results: Based on various TSHRAb activities from each patient, the patients could be categorized into 7 subgroups by cluster analysis; 1) Group 1 (n=41) was characterized by moderate TSAb activities bothin CHO-hTSHR cells and in FRTL-5 cells, typical TSAb epitope, rare blocking antibodies and high TBII activities. 2) Group 2 (n=16) was characterized by the presence of blocking TSHRAb in most patients, albeit the other characteristics were the same as those in Group 1. 3) Group 3 (n=19) patients had low TSAb activities bothin CHO-hTSHR cells and in FRTL-5 cells, seldom had blocking TSHRAb, but they had high TBII activities. 4) Group 4 (n=30) could be categorized as `mild disease` group, as they had low activities in all kinds of TSHRAb assay and had low antim icrosomal antibody activities. 5) Group 5 (n=14) was characterized by moderate TSAb activities with atypical epitope (s), rare blocking TSHRAb and moderate TBII activities. 6) Group 6 (n=10) patients had veryhigh TSAb activities with typical epitopes, seldom blocking TSHRAb and low TBII activities. 7) Group 7 (n=6) was characterized by very high TSAb activities with atypical epitopes and high TBII activities. Pretreatment serum thyroid hormone level was low only in group 4 patients compared to the other 6 groups (p<0.05). The size of goiter was significantly larger in those in group 1 and group 3 (p<0.05) compared to the other 5 groups. The prevalence of clinically significant ophthalmopathy was higher in group 2 patients than the other 6 groups (50%vs.27.5%,p=0.06). Among 6 kinds of TSHRAb activities, only the blocking TSHRAb activity was significantly associated with the presence of ophthalmopathy in multivariate analysis. Conclusion:These results suggest that the differences inepitopes for TSAb or the presence of blocking TSHRAb is not a major factor in determining the degree of thyrotoxicosis in Graves` disease. Although the pathogenic mechanism is not clearyet, we suggest that patients with ophthalmopathy have different TSHRAb repertoire from those without ophthalmopathy in Graves` disease.

體重 및 無脂肪體重과 背筋力과의 相關에 관한 硏究

曺容善,黃甫淵 漢陽大學校 體育科學硏究所 1986 體育科學 Vol.6 No.6

The Purpose of this study was to investigate the influence of percent of Body Fat on Back Muscle Strength 150 Subjects(50=Physical Education department Students, (=P.E.D.S.), 50=General Students(=G.S), 50=Excellent Players (=E.P)) were Selected to measure the percent of Body fat at the Subscapular and Thigh with a skinfolder. Percent of Body fat was then Calculated with Sloan & Wire's formula and Brozek, et als formula. The Back Muscle Strength was Calculated through investigating the difference between the percent of Body fat and Static Back muscle Strength among the 3 groups. The results of this study are as follows: 1) The difference of Mean of Percent of Body fat, (1) There are significant differences among the 3 groups. (P<0.05, G.S., E.P., P.E.D.S.) (2) There is a Significant difference between G.S. and P.E.D.S. (P<0.01, G.S., P.E.D.S.) (3) There is no Significant difference between the P.E.D.S. and E.P. (P>0.05) (4) There is a Significant difference between the G.S. and E.P. (P <0.05, G.S., E.P.) :2) The difference of Means of Back Muscle Strength, (1) There are significant differences among the 3 groups (P<0.01, E.P., P.E.D.S., G.S.) (2) There is a significant difference between the G.S. and P.E.D.S. (P<0.01, P.E.D.S., G.S.) (3) There is a significant difference between the P. E. D. S. and E.P. (P<0.01, P.E.D.S., E.P.) (4) There is a high significant difference between the G.S. and E.P. (P<0.01, G.S., E.P.) 3) The correlation between the Back Muscle Strength and Weight, (1) There is no correlation in the G.S. (r=0.10) (2) There is a little correlation in the P.E.D.S. (r=0.23) (3) There is a high significant correlation in the E.P. (r=0.91) 4) The correlation between the Back Muscle Strength and Lean Body Weight (1) There is a small Negative Correlation in the G.S. (r=-0.22) (2) There is a negation Correlation in the P.E.D.S. (r=-0.32) (3) There is a significant positive correlation in the E.P. (r=0. 55)

식품생물 산업기술의 새로운 미래를 선도하는 나노기술

김종태,김철진,조용진,전보연 한국산업식품공학회 2004 산업 식품공학 Vol.8 No.1

Nanotechnology represents a new frontier in science and technology with long term goal and benefits. Nowdays, nanotechnology is producing many revolutions and applications such as quantum computing, surface and materials modification, novel swparation and sensing technologies, and human biomedical replacements. These new techniques are being introduced in food and cio filed. In this review, the status and trends related to nanocomposites, nanoparticles, nanoyubes, delivery vehicles and biosafely were reviwed. The situation of funding of nanotechnology research in USA, Japan and Korea is also summarized.

甲狀腺炎과 Lithium 治療에 의한 甲狀腺機能低下症

鄭道彦,禹鍾仁,李定均,趙普衍,高昌舜,金勇一 大韓神經精神醫學會 1982 신경정신의학 Vol.21 No.2

A case of a female Manic Depressive Illness patient with goitrous hypothyroidism is presented. After ten and half months of lithium maintenance therapy starting during her first psychiatric admission, she was admitted again due to acute recurrent manic episode. On admission, she complained of easy fatigability and cold intolerance, and thyroid gland was palpable and enlarged in moderate degree. Thyroid function test revealed markedly increased TSH and moderately decreased thyroxine levels. TRH stimulation test showed an exaggerated response. Needle biopsy specimen revealed chronic lymphocytic and immune complex thyroiditis. However, antithyroglobulin and antimicrosomal antibodies were negative. In pretreatment thyroid evaluation on her first admission, neither goiter nor thyroid function abnormality was detectable and no signs of underlying thyroid disease or hereditary predisposition to hypothyroidism were present. Within three weeks of discontinuation of lithium, goiter was no more palpable and within five weeks, thyroid function test returned to normal range. The possibility that patients with underlying thyroiditis may be particularly susceptible to a rapid onset of lithium-induced hypothyroidism is discussed.

2.9% 과산화수소를 함유한 부착형 미백제의 임상적 효능과 안정성에 관한 연구

박은숙,성소래,홍성태,김지은,이소영,황수연,이신재,진보형,손호현,조병훈 大韓齒科保存學會 2006 Restorative Dentistry & Endodontics Vol.31 No.4

2.9%의 과산화수소를 함유한 시험용 부착형 미백제(Medison dental whitening strip, Samsung medical Co.,Anyang,Korea)를 실험군 피험자 23명, 시험용 미백제에서 과산화수소를 제외한 동일한 제재를 대조약으로 대조군 피험자 24명에게 매일 1시간 30분씩, 2주간 적용하여 임상적 효능과 안전성을 평가하였다. 미백 효과는 Shade Vision, Chroma Mete 및 Vitapan classical shade guide를 이용하여 색변화를 측정하여 다음과 같은 결론을 얻었다. 1. 실험군에서의 전체 치아의 색변화량(ΔE^(*))은 세 가지 측정법에서 모두 대조군에 비해 통계적으로 유의한 차이를 보였고 (p < 0.05). 쉽게 인지할 수 있는 정도였다. 2. 색변화는 색좌표 상에서 명도의 증가와 녹색조 및 청색조로의 변화에 의해 얻어졌다. 3. 치아별로는 어두운 견치의 색변화량이 가장 컸고, 측절치, 중절치 순으로 감소하였다. 4. 47명의 피험자 중 5명이 경도의 과민증을 경험하였으나 곧 완화되었다, 치은염증지수와 전기치수검사 결과 시험 전후에 차이가 없어 안전성을 확인하였다. This study evaluated the effectiveness and safety of an experimental bleaching strip (Medison dental whitening strip, Samsung medical Co., Anyang, Korea) containing 2.9% hydrogen peroxide. Twenty-three volunteers used the bleaching strips for one and a half hour daily for 2 weeks. As control group, the same strips in which hydrogen peroxide was not included were used by 24 volunteers with the same protocol. The shade chang (ΔE^(*), color differnce) of twelve anterior teeth was measured using Shade Vision (X-Rite Inc., S. W. Grandville, MI, USA), Chroma Meter (Minota Co., Ltd. Osaka, Japan) and Vitapan classical shade guide (Vita Zahnfabrik, Germany). The shade change of overall teeth in the experimental group was significantly greater than that in the control group (p < 0.05) and was easily perceivable. The change resulted from the increase of lightness (CIE L^(*) value) and the decrease of redness (CIE a^(*) value) and yellowness (CIE b^(*) value). The shade change of individual tooth was greatest in canine, can smallest in central incisor. The safety of the bleaching strip was also confirmed. 〔J Kor Acad Cons Dent 31(4):269-281, 2006〕

일차성 갑상선기능 저하증 환자에서 사람 TSH 수용체 항체를 발현하는 Chinese Hamster Ovary ( CHO ) 세포를 이용한 갑상선 자극차단 항체 활성의 측정

조보연,김원배,박도준 대한내분비학회 1997 Endocrinology and metabolism Vol.12 No.1

Background: The Chinese hamster ovary cells transfected with human TSH receptor cDNA (hTSHR-CHO), expressing functional human TSH receptors, are known to be more sensitive in detection of thyroid stimulating antibodies than FRTL-5 cells. There has been no report on the usefulness of these cells to measure thyroid stimulation blocking antibody(TSBAb) activity which is frequently found in patients with primary myxedema, Methods: We established the optimal assay condition of measurement of TSBAb using hTSHR- CHO cells, and simultaneously measured TSBAb activities with FRTL-5 cells and with hTSHR- CHO cells in 49 patients with primary myxedema, compared them with their thyrotropin binding inhibitor immunoglobulin(TBII) activities. Results: 1) hTSHR-CHO cells specifically bound bTSH and were stimulated by bTSH in terms of cyclic AMP generation in a dose dependent manner. 2) Myxedema IgG suppressed TSH-stimulated cAMP production of hTSHR-CHO cells in a dose dependent manner reaching plateau at the concentration of I g/L. Normal pooled IgG has no suppressive action at the concentration of less than 1 g/L, but caused significant suppression at the concentration of greater than 1g/L. 3) TSBAb activities measured by hTSHR-CHO cells in 49 patients with primary myxedema were as follows: Four of 25 TBII-negative cases(16%) and 22 of 24 TBII-positive cases(92%) had TSBAb activities. Most of TSBAb positive patients(95%), especially in TBII positive cases, showed very high activities of more than 90%. 4) TSBAb activities measured by hTSHR-CHO cells and those by FRTL-5 cells were both positive in 24 patients(49%), both negative in 18 patients(37%), and were discrepant in 7 patients(14%). The TSBAb activities measured with hTSHR-CHO cells and those measured with FRTL-5 cells were significantly correlated(r=0.71, p$lt; 0.01). 5) Forty five percent of patients with primary myxedema had all of 3 kinds of activities(TBII, hTSHR-CHO cell TSBAb, FRTL-5 cell TSBAb), 37% of them had none of 3 activities and 18% of them had 1 or 2 kinds of activities only. Conclusion: The usefulness of hTSHR-CHO cells in measurements of TSBAb activities were confirmed. The TSBAb activities of most patients with primary myxedema measured by hTSHR- CHO cells were concordant with those measured by FRTL-5 cells. However, a small subset of patients(18%) had discrepant results in assays of TSH receptor antibodies according to the differences in TSH receptors(rat, human and porcine) used in assay. Such discrepancy may be explained by heterogeneity in epitopes for blocking TSH receptor antibodies. (J Kor Soc Endocrinol 12:18-32, 1997)

Chinese Hamster Ovary 세포에 발현시킨 유전자재조합 사람 갑상선자극호르몬 수용체를 이용한 갑상선자극호르몬 수용체 항체 측정

조보연,이홍규,김원배,고창순,고경수,정재훈,이가희 대한내분비학회 1995 Endocrinology and metabolism Vol.10 No.4

Thyroid stimulating antibody which results in the development of hyperthyroidism and goiter in Graves' patients used to be measured by using rat thyroid cells, FRTL-5. However, this assay has disadvantages: decreased sensitivity due to differences in species, and fastidious culture conditions for FRTL-5 cells. Thus, we recently created stably transfected Chinese hamster ovary(CHO) cells containing the human TSH receptor(hTSHR-CHO) and developed optimal conditions for the measurement of thyroid stimulating antibody using hTSHR-CHO cells. In this study, to evaluate the clinical relevance of thyroid stimulating antibody measurement using hTSHR-CHO cells, we measured thyroid stimulating antibody activities of IgGs from Graves' disease and other thyroid disease using hTSHR-CHO cells, and compared to those of thyroid stimulating antibody assays using FRTL-5 cells. 1) The cut off value of positive thyroid stimulating antibody activity measured in hTSHR-CHO cells was 145%(above the mean +2SD) which was lower than 165% in FRTL-5 cells. The intra-assay and inter-assay variances were 3.9% to 9.0% and 12.7% to 1.6%, respectively. 2) Thyroid stimulating antibody activity was detected in 90% of patients with untreated Graves' disease when patients initially presented. Further, in patients seen initially but already under therapy, 75% had positive values if they were hyperthyroid but only 43% had IgGs with activity if they were euthyroid. Patients in clinical remission after therapy showed positive values in 23% of cases. Only 2 of 25 patients with Hashimoto's thyroiditis showed weak thyroid stimulating antibody activity, none of 18 patients with nodular nontoxie goiter, 1 of 15 patients with primary myxedema, and 2 of 33 control patients with no thyroid disease. Thus, the detection frequency and specificity of the assay with hTSHR-CHO cells was excellent for this type bioassay. 3) The detection frequency of thyroid stimulating antibody activity by hTSHR-CHO cells assay system(90%) was higher than that by FRTL-5 cells assay system(66%) in untreated Graves' patients. Those two activities were positively correlated with each other(r=0.52, p$lt;0.001). However, some IgGs showed discrepancy of the thyroid stimulating antibody activity measured in hTSHR-CHO cells and in FRTL-5 cells; 56 of 87 patients were positive in both cells system, 8 of 87 were negative in both cells system, 1 of 87 was only positive in FRTL-5 cells and 22 of 87 were only positive in hTSHR-CHO cell system. Thus, 73%(22/30) of IgGs showing negative values of thyroid stimulating antibody activities in FRTL-5 cells were detected its activities in hTSHR-CHO cells system. In summary, thyroid stimulating antibody assay with hTSHR-CHO cells exhibited so excellent sensitivity and specificity that this technique should be used for clinical practice as well as basic research(J Kor Soc Endocrinol 10: 347-361, 1995).

자가면역성 갑상선 질환에서 TSH 수용체 자가항체의 이질적 특성

조보연,김원배,김광원,이문규,이명식,민용기,정재훈,김경아 대한내분비학회 1997 Endocrinology and metabolism Vol.12 No.2

Background: It has been known that most of thyroid stimulating antibodies(TSAbs) may interact with epitopes near N-terminal, and thyroid stimulation blocking antibodies(TSBAbs) near C-terminal on the extracellular domain of TSH receptor. However, many authors have reported different results about epitopes reacting with TSH receptor autoantibody(TRAb). TSBAbs inhibit thyroid stimulation of TSH and TSAbs at the receptor level. However, it has been reported that there are some TSBAbs which bind to the other sites, not TSH receptor, or block post-reeeptor process. These findings raise the possibility that TRAbs may be heterogeneous according to the mechanism of action. In order to investigate the heterogeneity of TRAb, we undertook immuno- precipitation using synthetic peptides of TSH receptor and measured TRAb activities by FRTL-5 cells and chimeric CHO cells. Methods: We studied 102 patients with autoimmune thyroid disease(Graves disease 32, Hashimotos thyroiditis 29, atrophic thyroiditis 41) and 35 healthy persons. Three synthetic peptide fragments of TSH receptor were used to perform immunoprecipitation with serum or IgG of patients and healthy persons, TSAb and TSBAb activities were measured by FRTL-5 cells and CHO cells transfected with wild-type and 2 mutant TSH receptor cDNA(Mc2, Mc1+2). Mc2 and Mcl+2 were rnade to substitute amino acid residues of 90-165, 8-165 of the TSH receptor with corresponding residues of LH/CG receptor, respectively. Results: Two out of 10 IgGs extracted from Graves disease and 2 out of 9 IgGs from atrophic thyroiditis had specific bidings over 0.84% in immunoprecipitation with peptide I(amino acid residue 35-50). Four out of 18 IgGs from Graves disease, 9 out of 41 IgGs from atrophic thyroiditis, and 6 out of 14 IgGs from Hashimotos thyroiditis had specific bidings over 0.84% in immunoprecipitation with peptide II(amino acid residue 317-332). Only 2 out of 10 IgGs from Graves disease had specific bidings over 0.84% in immunoprecipitation with peptide III(amino acid residue 341-358). When 10 IgGs extracted from Graves disease were reacted with wild-type, Mc2, and Mcl+2 CHO cells, 7 IgGs in wild-type and 4 IgGs in Mc2 had positive for TSAb activities. In 10 IgGs from atrophic thyroiditis, 5 in wild-type, 5 in Mc2, and 3 in Mcl+2 CHO cells had positive for TSBAb activities. In Hashimoto's thyroiditis, only 1 with hyperthyroidism had positive for TSAb activity in wild-type and 1 with hypothyroidism had positive for TSBAb activities in both of wild-type and Mc2 CHO cells. Therefore, patients with Graves disease were divided into at least 3 groups according to the TSAb activities measured by wild-type, Mc2, Mcl+ 2 CHO cells and TBII activities. And patients with atrophic thyroiditis were divided into at least 4 groups according to the TBII activities, TSBAb activities by wild-type, Mc2, Mcl+2 CHO cells and FRTL-5 cells. Conclusion: From these results, epitopes of TSH receptor reacting with TSAb or TSBAb in autoimmune thyroid disease may be scattered in the TSH receptor, although epitopes of TSAb tend to be near N-terminal and those of TSBAb near C-terminal. Graves disease or atrophic thyroiditis were divided into 3 or 4 groups according to the TBII and TRAb activities. Therefore, TRAb detected in autoimmune thyroid disease may be heterogenous. (J Kor Soc Endocrinol 12:176-193, 1997)

사람 갑상선자극호르몬 수용체를 발현하는 Chinese Hamster Ovary 세포를 이용한 갑상선자극항체 활성의 측정 : 측정 조건의 최적화 Optimization of Assay Condition

송영기,조보연,이홍규,김원배,고창순,오연상,이가희 대한내분비학회 1995 Endocrinology and metabolism Vol.10 No.4

We investigated the optimal condition of thyroid stimulating antibody(TSAb) assay using Chinese hamster ovary cells transfected with cDNA of human TSH receptor(TSHr-CHO) stably expressing functional TSH receptors. The extracellular cAMP responses of TSHr-CHO cells to the stimulation of bTSH or Graves' IgG were observed in three different incubation media. Stimulation indices of extracellular cAMP were higher when sucrose containing NaCl-free isotonic Hank's balanced salt solution(HBSS)(media A)was used as incubation media than those of NaCl-free hypotonic HBSS(media B) or those of NaCl containing isotonic HBSS(media C). The incubation of TSHr-CHO cells in media B caused marked increase in the basal cAMP level without concomittant fold-increase in the stimulated cAMP level at various doses of bTSH and Graves' IgG. Decreasing the stimulation indices of extracellular cAMP, use of media B failed to detect TSAb activities in two TSAb-positive Graves' IgG tested. In case of media C, extracellular cAMP responses are poor at 0.001 and 0.1U/L of bTSH and at all doses of Graves' IgG tested(0.5, 1, 5g/L). The incubation of TSHr-CHO cells in media B caused significant increase in the number of trypan blue-stained, nonviable cells(5.7+-1.5, 7.6+-1.9 and 8.5+-1.6% at 1, 2 and 3h of incubation, respectively; p<0.01) comparing to those incubated in media A or media C(about 2-3% in both media). Those decrease in the viability of TSHr-CHO cells when incubated in hypotonic incubation media may explain the decrease in the stimulation index of extracellular cAMP with the use of media B in contrast to the case of FRTL-5 cells. TSAb assay of 87 consecutive fresh Graves' patients with TSHr-CHO cells using media A detected TSAb activities in 90%(78 patients) of them, and moreover TSAb activities showed significant positive correlation with the pre-treatment serum T_3 and free T_4 levels of those patients. We conclude that TSAb assay with TSHr-CHO cells is a sensitive and physiologically relevant assay system to measure TSAb activities merely through measurements of extracellular cAMP provided that the cells are incubated in NaCl-free isotonic incubation media(J Kor Soc Endocrinol 10: 333-346, 1995).

그레이브스병에서 사람 TSH 수용체 발현 Chinese Hamster Ovary 세포 ( hTSHR-CHO ) 와 FRTL-5 세포로 측정한 갑상선자극항체 활성의 차이 및 임상상과의 관계

송영기,조보연,김원배,고창순,오연상,박혜영,이홍규 대한내분비학회 1996 Endocrinology and metabolism Vol.11 No.1

Background : Thyroid stimulating antibodies result in the development of hyperthyroidism and goiter in Graves disease. However, thyroid stimulating antibody activities do not correlate with the clinical features in many patients with Graves disease. The purpose of this study is to address this discrepancy between thyroid stimulating antibody activities and clinical features of Graves patients. Methods: We measured thyroid stimulating antibody activities simultaneously using human TSH receptor transfected Chinese hamster(hTSHR-CHO) cells and rat thyroid(FRTL-5) cells in 57 untreated patients with Graves disease, and compared their activities with clinical features including thyroid hormone levels. Results : The detection rate of thyroid stimulating antibody measured by hTSHR-CHO cells was 90% in 57 untreated Graves patients and it was higher than that measured by FRTL-5 cells. Thyroid stimulating antibody activity by hTSHR-CHO cells was significantly correlated with that by FRTL-5 cells(r=0.5, p$lt;0.001), however, 18 of 57(32%) patients showed marked discrepancy of thyroid stimulating antibody activity between in hTSHR-CHO and FRTL-5 systems. Thyroid stimulating antibody activity measured by hTSHR-CHO cells was significantly correlated with serum total T3, free T4 levels, and goiter size but not 99mTc-thyroid uptake. On the other hand, thyroid stimulating antibody activity measured by FRTL-5 cells was significantly correlated with goiter size and 99mTc-thyroid uptake but not thyroid hormone levels. The difference between function and goiter size with respect to thyroid stimulating antibody measurement in two cells system is, nevertheless, particularly evident in the free T4/goiter ratio in patients with high hTSHR-CHO and low FRTL-5 cell assay values. Conclusion: These findings suggest that thyroid stimulating antibodies in Graves disease are heterogeneous population in terms of responses to different origin of cells. Further, thyroid stimulating antibody activities measured by FRTL-5 cells tend to correlate better with goiter size and Tc-thyroid uptake, whereas thyroid stimulating antibody activities measured by hTSH-CHO cells correlate better with thyroid hormone levels(J Kor Soc Endocrinol 11:18-29, 1996).