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Ginsengenin derivatives synthesized from 20(R)-panaxotriol: Synthesis, characterization, and antitumor activity targeting HIF-1 pathway

  • Guo, Hong-Yan;Xing, Yue;Sun, Yu-Qiao;Liu, Can;Xu, Qian;Shang, Fan-Fan;Zhang, Run-Hui;Jin, Xue-Jun;Chen, Fener;Lee, Jung Joon;Kang, Dongzhou;Shen, Qing-Kun;Quan, Zhe-Shan
    • Journal of Ginseng Research
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    • v.46 no.6
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    • pp.738-749
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    • 2022
  • Background: Ginseng possesses antitumor effects, and ginsenosides are considered to be one of its main active chemical components. Ginsenosides can further be hydrolyzed to generate secondary saponins, and 20(R)-panaxotriol is an important sapogenin of ginsenosides. We aimed to synthesize a new ginsengenin derivative from 20(R)-panaxotriol and investigate its antitumor activity in vivo and in vitro. Methods: Here, 20(R)-panaxotriol was selected as a precursor and was modified into its derivatives. The new products were characterized by 1H-NMR, 13C-NMR and HR-MS and evaluated by molecular docking, MTT, luciferase reporter assay, western blotting, immunofluorescent staining, colony formation assay, EdU labeling and immunofluorescence, apoptosis assay, cells migration assay, transwell assay and in vivo antitumor activity assay. Results: The derivative with the best antitumor activity was identified as 6,12-dihydroxy-4,4,8,10,14-pentamethyl-17-(2,6,6-trimethyltetrahydro-2H-pyran-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(tert-butoxycarbonyl)glycinate (A11). The focus of this research was on the antitumor activity of the derivatives. The efficacy of the derivative A11 (IC50 < 0.3 µM) was more than 100 times higher than that of 20(R)- panaxotriol (IC50 > 30 µM). In addition, A11 inhibited the protein expression and nuclear accumulation of the hypoxia-inducible factor HIF-1α in HeLa cells under hypoxic conditions in a dose-dependent manner. Moreover, A11 dose-dependently inhibited the proliferation, migration, and invasion of HeLa cells, while promoting their apoptosis. Notably, the inhibition by A11 was more significant than that by 20(R)-panaxotriol (p < 0.01) in vivo. Conclusion: To our knowledge, this is the first study to report the production of derivative A11 from 20(R)-panaxotriol and its superior antitumor activity compared to its precursor. Moreover, derivative A11 can be used to further study and develop novel antitumor drugs.

Comparison of Clinical and Radiologic Findings Between Perforated and Non-Perforated Choledochal Cysts in Children

  • Yu Jin Kim;Soo-Hyun Kim;So-Young Yoo;Ji Hye Kim;Soo-Min Jung;Sanghoon Lee;Jeong-Meen Seo;Sung-Hoon Moon;Tae Yeon Jeon
    • Korean Journal of Radiology
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    • v.23 no.2
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    • pp.271-279
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    • 2022
  • Objective: To compare the clinical and radiologic findings between perforated and non-perforated choledochal cysts in children. Materials and Methods: Fourteen patients (mean age ± standard deviation, 1.7 ± 1.2 years) with perforated choledochal cysts (perforated group) and 204 patients (3.6 ± 3.8 years) with non-perforated choledochal cysts (non-perforated group) were included between 2000 and 2019. All patients underwent choledochal cyst excision after ultrasound, CT, or MR cholangiopancreatography. Relevant data including demographics, clinical symptoms, laboratory findings, imaging findings, and outcomes were analyzed. Statistical differences were compared using the Mann-Whitney U test and Fisher's exact test. Results: Choledochal cyst perforation occurred only in children under the age of 4 years. Acute symptoms, including fever (p < 0.001), were more common in the perforated group than in the non-perforated group. High levels of white blood cells (p = 0.004), C-reactive protein (p < 0.001), and serum amylase (p = 0.002), and low levels of albumin (p < 0.001) were significantly associated with the perforated group. All 14 patients with perforated choledochal cysts had ascites, whereas only 16% (33/204) of patients in the non-perforated group had ascites (p < 0.001). In the subgroup of patients who had ascites, a large amount of ascites (p = 0.001), increase in the amount of ascites in a short time (p < 0.001), complex ascites (p < 0.001), and perihepatic pseudocysts (p < 0.001) were more common in the perforated group than in the non-perforated group. Conclusion: Children with perforated choledochal cysts have characteristic clinical and radiologic findings compared to those with non-perforated choledochal cysts. In young children with choledochal cysts, perforation should be differentiated in cases with acute symptoms, laboratory abnormalities, and characteristic ascites findings.

Seedling Emergence of Dry -seeded Rice under Different Sowing Depths and Irrigation Regimes (건답직파에서 파종심도와 관개조건에 따른 벼 품종들의 출아특성)

  • 이변우;명을재
    • KOREAN JOURNAL OF CROP SCIENCE
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    • v.40 no.1
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    • pp.59-68
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    • 1995
  • Investigated were the relationships between plumule elongation characteristics and seedling emergence of 46 varieties including native, improved and red rice varieties of Korea, and varieties from U.S.A., Italy, India, Japan under 1, 3, and 5cm deep sowing with irrigated and non-irrigated condition. Experiments were carried out in paddy field of sandy loam. There was heavy shower of 19.2mm on the next day of seeding and thereafter, clear and dry weather continued during the experiment period. Soil temperature averaged over 30 days after seeding was $16.4^{\circ}C$ at 3cm depth. Soil hardness increased linearly up to 2.5kg /$cm^2$ on the 14th day after seeding, on which date irrigated plot was irrigated through furrow, and up to 4kg / $cm^2$ on the 28th day in non-irrigated plot. Soil hardness dropped near to 0kg /$cm^2$ after irrigation and developed up to 2.5kg /$cm^2$ again by 28 days after seeding. Seedling emergence was higher in irrigated plots than non-irrigated plots at all seeding depths. Korean improved varieties were substantially lower in seedling emergence under non-irrigated condition of 1 cm deep sowing than those under irrigated condition. This poor seedling emergence resulted mainly from delayed emergence by exposing them to greater soil strength. Percent seedling emergence under irrigated and non-irrigated condition showed signifi-cant correlations at 3 and 5 cm deep sowing. Korean improved varieties belonged to the group of poor seedling emergence, and I taliconaverneco, Chinsura Boro and Weld Pally to best group under both irrigation conditions at 3 and 5cm deep sowing. Seedling emergence showed highly signifi-cant positive correlation with the plumule length of mesocotyl + 1st internode + incomplete leaf and of mesocotyl+coleoptile. Among the characters constituting plumule length, incomplete leaf length showed greatest positive correlation followed by coleoptile and mesocotyl under irrigated condition at 3 and 5 cm deep sowing, and highest correlation with mesocotyllength followed by first internode and incomplete leaf under non-irrigated condition. Days to 50% seedling emergence at 1 cm deep sowing with irrigation showed great varietal variation of 10 to 30 days, and showed high significant negative correlations with percent seedling emergence under both irrigation conditions except for 1 cm deep sowing with irrigation, Days to seedling emergence revealed sig-nificant negative correlations with plumule characters except 2nd internode, showing highest cor-relation with incomplete leaf length.

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Index Cases in Pediatric Surgery - a National Survey by the Korean Association of Pediatric Surgeons, 2000 - (소아외과의 지수 질환 - 대한소아외과학회 정회원을 대상으로 한 2000년도 전국 조사 -)

  • Lee, M.D.;Kim, S.Y.;Kim, W.K.;Kim, I.K.;Kim, S.C.;Kim, S.K.;Kim, J.E.;Kim, J.C.;Kim, H.H.;Park, K.W.;Park, W.H.;Seo, J.M.;Song, Y.T.;Oh, S.M.;Yoo, S.Y.;Lee, D.S.;Lee, S.K.;Lee, S.C.;Chung, S.Y.;Chung, S.U.;Jung., E.S.;Jung, P.M.;Cho, M.H.
    • Advances in pediatric surgery
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    • v.7 no.2
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    • pp.147-156
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    • 2001
  • Membership qualifications and recognition of the subspecialty training programs by the Korean Association of Pediatric Surgeons(KAPS) have been determined by criteria based on the number of neonatal and total pediatric surgical cases registered, since 1989 (Index cases). The numbers are based on a survey of the 14 founding members of the society by Jung et al. in 1987. The current survey is to review the present status of the index cases from 1997 to 1999 among 36 members of the KAPS. Two surveys were undertaken for this study. In the first survey, cases were collected by the registration form, composed of neonatal(N), important pediatric surgical cases (I), tumor and other similar operations(T) and other common pediatric surgical cases(O). Thirty members responded. and the result was discussed at the Topic Discussion section of the 15th Annual Congress of KAPS, 2000. The second survey analyzed additive data, proposed during discussion at the Congress. Twenty-three members responded. This report is the analysis of the both surveys. The average numbers of the cases/year/surgeon of N, I, T, O and total were 19.5, 51.8, 9.5, 77.1 and 356.5. respectively. The number of index cases(N+I+T)/year/surgeon was 80.8. The ratio of (N+I+T)/total cases was 0.3. Seventeen of 30 members have more than 20 cases of N per year. Twelve members have more than 150 cases, and 13 do more than 100 cases of I per year. Fourteen members have more than 10 cases of T per year. Nineteen and 10 members experienced more than 150 and 100 of index cases(N+I+T) per year. A new list of the index cases and coding system are proposed for the future regular update.

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한국인 좌심실 비대증 환자들에서 파브리병 선별검사의 의의

  • Park, Hyeong-Du;Jo, Seong-Yun;Lee, Su-Yeon;Jeon, Eun-Seok;Park, Seung-U;Lee, Sang-Hun;Lee, Sang-Cheol;Choe, Jin-O;Park, Seong-Ji;Jang, Seong-A;Kim, Hyeong-Gwan;Gi, Chang-Seok;Kim, Jong-Won;Jin, Dong-Gyu
    • Journal of The Korean Society of Inherited Metabolic disease
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    • v.14 no.2
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    • pp.135-141
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    • 2014
  • Objectives: Fabry disease (FD) is a lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide (Gb3) in tissues due to a deficiency in the enzyme ${\alpha}$-galactosidase A. Hypertrophic cardiomyopathy is one of the chronic complications of FD. We tried to evaluate the prevalence of Fabry disease in the Korean patients with left ventricular hypertrophy (LVH). Methods: A total of 257 patients with LVH were recruited and they were 172 males (mean 56 years, range 30-81 years) and 84 females (mean 66 years, range 45-85 years). Urinary Gb3 was used to screen FD by high performance liquid chromatography-tandem mass spectrometry. Confirmatory tests were done by alpha-galactosidaseA activity using fluorometric assay and by GLA mutation analysis using sequencing. Results: Four patients were screening positive by urinary Gb3 analysis (cutoff, 25 ug/mmol creatinine). But, one female patient was diagnosed with FD confirmed by enzyme analysis in leukocytes as well as by genetic analysis (1/257 patients, 0.4%). She showed 54.3 ug/mmoL creatinine of Gb3 and 15.5 nmole/hr/mg protein (reference range, $55.2{\pm}12.7nmole/hr/mg$ protein) of alphagalactosidase A activity. And she had a heterozygous GLA mutation of c.796G>A (p.D266N). Her daughter was found to be a carrier for FD confirmed by GLA mutation analysis. Asymptomatic carrier showed 25.5ug/mmol creatinine of Gb3 and 42.5 nmole/hr/mg protein (reference range, $55.2{\pm}12.7nmole/hr/mg$ protein) of alpha-galactosidase A activity. Conclusions: The prevalence of FD in Koran patients with LVH was detected as 0.4%. Although the prevalence seems to be low, screening studies are of great importance for detecting hidden cases as well as for identifying other effected family members.

Effect of rbST Administrations at Artificial Insemination on Conception and Parturition Rates in Hanwoo (한우 인공수정시 rbST 투여가 수태 및 분만율에 미치는 영향)

  • Han M. H.;Choi S. H.;Choi Y. H.;Kim H. J.;Cho S. R.;Choi C.Y.;Ryu I. S.;Son D. S.;Yeon S. H.;Woo J. S.;Kweon U. G.;Yoon K. Y.;Chang B. S.
    • Journal of Embryo Transfer
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    • v.20 no.2
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    • pp.177-184
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    • 2005
  • This study was conducted to investigate the effects of recombinant bovine somatotropin (rbST) injection on conception and parturition rates in normal or repeat breeding Hanwoo. We treated 462 cows containing 79 repeat-breeding cows of multiparous and allocating 5 treatment groups. Treatment 1 (T1) was injection of 2ml saline (for pseudo treatment), T2 was one injection of rbST 250mg into the tailhead region at the estrus, T3 was twice injection of rbST 250mg both at the time of insemination and again 10 to 14 day later, T4 was once injection of rbST 500mg at insemination and T5 was twice injection of 500mg rbST both at the time of insemination and again 10 to 14day later respectively. In rbST treated groups, timed artificial inseminations (TAI) were performed fellowing estrus synchronization. 100 us GnRH was injected into the scapula region on Day 0, 25mg $PGF_2{\alpha}$ was injected on Day 7 for degeneration of corpus luteum (CL) and 100ug GnRH was injected for inducing the synchronization. The results are as fellows; When normal Hanwoo were inseminated once with rbST administration, the pregnancy rate of T2 $(67.5\pm18.48\%)$ were higher than control $(52.4\pm9.72\%)$, while the pregnancy rate of T4 $(63.3\pm5.77\%)$ were significantly higher (p.<0.05) than control $(39.3\pm12.89\%)$ in repeat breeder Hanwoo. The parturition rates of normal Hanwoo were no differences among the treatments but were significant different in repeat breeder Hanwoo (p<0.05). When the estrous was induced by Ovsynch and inseminated once with rbST administration, the pregnancy rates of T2 was $12.5\%$ higher than control in normal Hanwoo, T4 $(80.0\%)$ was highest among the treatments (p<0.05) in repeat breeder Hanwoo. When normal Hanwoo were inseminated once with rbST administration, the pregnant period was $282.7\~284.8$ days and the body weight was $25.1\~25.9kg$, there were no difference among the treatments. The ratio of sex was almost same without T4 (male vs. female=18:9). In repeat breeder Hanwoo, pregnant period was 280.4~289.3 day and body weight was $23.0\~26.6kg$, it had no difference among the treatments. The sex ratio were similar to normal Hanwoo except T4 (M : F=2 : 8). In conclusion, the pregnancy and parturition rate by once insemination could be improved by the administration of rbST 250mg in normal Hanwoo or 500mg in repeat breeder Hawoo.

A Study for the Norms of Audiometric Tests in Koreans (정상한국인의 청력검사치에 관한 연구)

  • 오혜경;서장수;이근해;김희남;김영명;권영화;서옥기
    • Proceedings of the KOR-BRONCHOESO Conference
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    • 1981.05a
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    • pp.38.1-38
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    • 1981
  • Currently in the otologic field, there are various methods of special audiometric examinations, such as, tone decay, SISI, and impedance audiometry and only a few studies has been done in these fields sporadically in Korea. The purpose of this paper is to establish norms of various special audiometric tests, so we have performed the special audiometric tests on 100 male medical students in good physical condition and the follow results were obtained. 1. All cases showed over 90% of PB scores. The mean and its 2 S.D. were 98$\pm$4.9% in the right ear and 97$\pm$5.6% in the left ear. 2. The mean and its 2 S.D. of MCL(most comfortable level) were 45$\pm$15.4 dB in the right ear and 46$\pm$17.9 dB in the left ear, and its range was 12$\pm$12.2 dB in the right ear and 13$\pm$12.6 dB in the left ear. 3. The mean and its 2 S.D. of UCL (uncomfortable level) were 102$\pm$7.9 dB in the right ear and 102$\pm$7.9 dB in the left ear and about an half in cases showed over 106 dB of UCL. 4. In 95% of cases, SISIs(short increment sensitivity index) at 1, 000 Hz and 4000 Hz was below 45% in the right ear in both frequencies and below 55% and 75% in the left ear, respectively. 5. In 95% of cases, tone decays at 2, 000 Hz and 4, 000 Hz was below 10 dB in both ears. 6. The difference between SRT and PTA (speech reception threshold minus pure tone average) was 4$\pm$9.2 dB in the right ear and 4$\pm$10.0 dB in the left ear. 7. The dynamic range(uncomfortable level minus speech reception threshold) was 98$\pm$13.5 dB in the right ear and 99$\pm$13.5 dB in the left ear. We had trouble in estimating the dynamic range in about an half in cases, in which we couldn't estimate the UCL with our conventional audiometry. 8. The results of impedance audiometric tests were as follow: A. In the tympanogram, all cases were of A type with one exception of B type in the left ear. The mean and its 2 S.D. of its peak level were 22.8$\pm$32.94mm $H_2O$ in the right ear and 23.9$\pm$29. 81mm $H_2O$ in the left ear. B. The mean and its 2 S.D. of the compliance were 0.6$\pm$0.54cc in the right ear and 0.6$\pm$0.53cc in the left ear. C. The results of stapedial reflex: a. The mean and its 2 S.D. of the controlateral stapedial reflex at 500Hz, 1, 000Hz, 2, 000Hz, 4, 000Hz were 99$\pm$17.7 dB, 87$\pm$14.4 dB, 79$\pm$13.7 dB, 77$\pm$20.0 dB in the right ear and 99$\pm$15.9 dB, 88$\pm$13.9 dB, 79$\pm$13.7 dB, 77$\pm$21.3 dB in the left ear. Depending on the tested frequencies, the stapedial reflex wasn't generated in 6 cases in the right ear and 11 cases in the left ear. b. The mean and its 2 S.D. of the ipsilateral stapedial reflex at 1, 000Hz, and 2, 000Hz were 89$\pm$16.3 dB, 82$\pm$15.9 dB in the right ear and 89$\pm$18.0 dB, 83$\pm$18.9 dB in the left ear. Depending on the tested frequencies, the stapedial reflex wans't generated in 1 case in the right ear and 2 cases in the left ear. 9. Eustachian tube function using with impedance audiometry was malfunctioned in21 cases depending on the tested pressure and the range of peak level of tympanogram was 14$\pm$26.9mm $H_2O$(tested pressure:+250mm $H_2O$), 8$\pm$21.9mm $H_2O$ (tested pressure:-250mm $H_2O$) in the right ear and 11 cases depending on the tested pressure and the range of the peak level of tympanogram was 12$\pm$22.5mm $H_2O$ (tested pressure: +250 mm $H_2O$, 9$\pm$17.3mm $H_2O$(tested pressure: -250mm $H_2O$) in the left ear.

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Immune-modulation Effect of Ulmus macrocarpa Hance Water Extract on Balb/c Mice (왕느릅나무 껍질 열수 추출물의 마우스에서의 in vivo 면역조절 효과)

  • Lee, Inhwan;Kwon, Da Hye;Lee, Sun Hee;Lee, Sung Do;Kim, Deok Won;Lee, Jong-Hwan;Hyun, Sook Kyung;Kang, Kyung-Hwa;Kim, CheolMin;Kim, Byoung Woo;Hwang, Hye Jin;Chung, Kyung Tae
    • Journal of Life Science
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    • v.24 no.10
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    • pp.1151-1156
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    • 2014
  • Traditional medicinal plants are widely used to treat many diseases, such as inflammation, infections, and even cancer. Ulmus macrocarpa Hance, a Chinese elm species, is distributed in Korea, China, and Japan. The stem bark is widely employed in Korean traditional medicine to treat dermatitis, mastitis, and edema. The aim of this study was to investigate whether water extract of U. macrocarpa Hance bark (Ulmus cortex) has a immune-modulating function in a mouse model. Three different concentrations (30 mg/kg, 100 mg/kg, and 300 mg/kg) of Ulmus cortex water extract (UCWE) were orally administered to mice for 14 days, and their immune responses were analyzed. Cytokines, such as interleukin (IL)-2, IL-12, and IFN-${\gamma}$, increased in the blood of UCWE-fed groups when compared with a control group. In contrast, the IL-4 level did not change in any of the UCWE-fed groups Cell-mediated cytotoxicity was also assayed using lymphokine-activated killer cells (LAK). LAK showed greater cytotoxicity in the UCWE-fed groups than LAK in the control group. Internal organ indices, such as liver, kidney, spleen, and thymus, were similar in all the groups, including the control group, indicating that UCWE may have been nontoxic in the experimental animals. These data suggest that UCWE has an immune-modulating function in a mouse model.

Effect of exercise and energy restriction on blood pattern in obese children (운동과 에너지 제한이 비만아동의 혈액 성상에 미치는 영향)

  • 이성숙;오승호
    • Korean Journal of Human Ecology
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    • v.4 no.1
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    • pp.68-78
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    • 2001
  • The purpose of this study was to examine the effect of exercise and diet control program on blood pattern in obese children. The subjects of this study were five obese boys aged from 8 to 12 participating in the control period(C) for 3 days, exercise period(E) for one week, and exercise+energy restriction period(EER) for another one week, consecutively. The intensity of the exercise was 60~70% of HRmax and the energy was restricted at 493kcal/day. Daily mean total energy intake was 2,152${\pm}$138kcal. 1,861${\pm}$138kca1, and 1,368${\pm}$87kcal for the period C, E and EER, respectively. Body weight of after the program was significantly decreased from 48.94$\pm$5.11kg to 45.94${\pm}$4.74kg(P<0.01). And skinfold thickness. %fat. lean body mass, body mass index were significantly decreased(p<0.01). Blood sugar concentration was not significantly affected by weight loss, but alkaline phosphatase activity was significantly decreased. Concentrations of total lipid, LDL-cholesterol, triglyceride, phospholipid were not significantly decreased. But concentrations of HDL-cholesterol, %HDL-cholesterol, free fatty acid were significantly increased and concentration of VLDL-cholesterol, atherogenic index were significantly decreased. The results of this study showed that the obese children had a tendency to decrease coronary heart disease risk in the respect of plasma HDL-cholesterol and VLDL-cholesterol concentration by the exercise plus energy restriction program. Thus if we apply the lower intensity or duration of exercise for them this program might be more effective on the obese children.

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Relationship between Helicobacter pylori infection and iron-deficiency anemia in infants and children (영유아에서 Helicobacter pylori 감염과 철결핍성 빈혈과의 관계 연구)

  • Son, Meong Hi;Yeom, Jung Suk;Park, Ji Suk;Park, Eun Sil;Seo, Ji Hyun;Lim, Jae Young;Park, Chan Hoo;Woo, Hyang Ok;Youn, Hee Shang
    • Clinical and Experimental Pediatrics
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    • v.52 no.5
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    • pp.544-548
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    • 2009
  • Purpose : To elucidate a potential association between Helicobacter pylori (HP) infection and iron-deficiency anemia (IDA) in infants and children in terms of the other factors related to iron utilization and storage although the association of ferritin was previously studied. Methods : We evaluated 135 infants (aged 6-24 months) admitted at Gyeongsang National University Hospital from 2000 to 2006. Western blot assays using the HP CagA antigen (120 kD) were conducted to identify infections. The concentrations of six parameters were measured: hemoglobin (Hb), serum ferritin, soluble serum transferrin receptors, interleukin-6, prohepcidin, and C-reactive protein. In addition, the infants were classified into IDA, anemia from inflammation (AI), unclassified anemia (UCA), and normal groups on the basis of Hb and ferritin concentrations. Results : In the IDA group (n=20), seven infants were infected with HP, with the other infants showing no evidence of infection. The mean Hb levels in the IDA group were significantly lower in HP-infected infants than those uninfected (7.1 vs. 8.2 g/dL, respectively); the mean ferritin levels were also significantly lower in the infected infants (3.2 vs. $6.8{\mu}g/L$). The other four parameters did not differ significantly among the IDA infants. No correlations were found between the six parameters and HP infection status in the other groups. Conclusion : There were no significant differences in the HP infection rates among the study groups. However, in the IDA group, the HP-infected infants had significantly lower serum ferritin and Hb levels than the HP-negative infants (P<0.05).