• Title/Summary/Keyword: 치료 저항성

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Effects of the Eccentric Exercise Inuced Delayed Muscle Soreness on Proprioception, Muscle Strength and Muscle Fatigue (원심성 저항운동으로 유발한 지연성근육통이 고유수용성감각, 근력 및 근피로도에 미치는 영향)

  • Choi Kyu-Hwan;Nam Sang-Nam
    • The Journal of Korean Physical Therapy
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    • v.16 no.3
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    • pp.176-191
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    • 2004
  • The purpose of this study was to find the effects of the eccentric exercise induced delayed muscle soreness on proprioception, muscle strength, muscle fatigue, and muscle pain of the elbow flexor muscles. Thirty one healthy male subjects were participated in this study. Before resisted eccentric exercise of the elbow flexors and immediately and at 1, 3, 5, and 7 days post-exercise, pain threshold, proprioception, tension tracking, initial median frequency, and fatigue index were measured. Pain pressure threshold and visual analog scale (VAS) was used to measure muscle pain. Proprioception of the elbow joint was measured by using 3 dimension motion analysis system. Maximum isometric contraction was measured by using digital tensiometer. Electromyography and power spectrum analysis was used to measure initial median frequency (IMF) and fatigue index (FI). Immediately post-exercise, a significant decrease pain threshold was observed that continued to 5 days post-exercise. VAS score was significantly increased at 1 and 3 days post-exercise compared to that of immediately post-exercise. Maximum isometric contraction, IMF, tension tracking ability of the exercised elbow joint were significantly decreased at 1, 3, and 5 days post-exercise compared to that of pre-exercise. FI was significantly increased at 1 and 3 days post-exercise compared that of pre-exercise. Proprioception sense of exercised elbow joint was significantly decreased immediately and at 1, 3, and 5 days post-exercise compared to that of pre-exercise. Proprioception sense of the contralateral elbow joint was significantly decreased immediately post-exercise compared to that of pre-exercise. However, proprioception sense that was measured in close chain kinematic position was not significantly difference between pre-exercise and post-exercise. These results could be useful to determine the resume time for exercising and participating sports activities.

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Weaning Following a 60 Minutes Spontaneous Breathing Trial (1시간 자가호흡관찰에 의한 기계적 호흡치료로부터의 이탈)

  • Park, Keon-Uk;Won, Kyoung-Sook;Koh, Young-Min;Baik, Jae-Jung;Chung, Yeon-Tae
    • Tuberculosis and Respiratory Diseases
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    • v.42 no.3
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    • pp.361-369
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    • 1995
  • Background: A number of different weaning techniques can be employed such as spontaneous breathing trial, Intermittent mandatory ventilation(IMV) or Pressure support ventilation(PSV). However, the conclusive data indicating the superiority of one technique over another have not been published. Usually, a conventional spontaneous breathing trial is undertaken by supplying humidified $O_2$ through T-shaped adaptor connected to endotracheal tube or tracheostomy tube. In Korea, T-tube trial is not popular because the high-flow oxygen system is not always available. Also, the timing of extubation is not conclusive and depends on clinical experiences. It is known that to withdraw the endotracheal tube after weaning is far better than to go through any period. The tube produces varying degrees of resistance depending on its internal diameter and the flow rates encountered. The purpose of present study is to evaluate the effectiveness of weaning and extubation following a 60 minutes spontaneous breathing trial with simple oxygen supply through the endotracheal tube. Methods: We analyzed the result of weaning and extubation following a 60 minutes spontaneous breathing trial with simple oxygen supply through the endotracheal tube in 18 subjects from June, 1993 to June, 1994. They consisted of 9 males and 9 females. The duration of mechanical ventilation was from 38 hours to 341 hours(mean: $105.9{\pm}83.4$ hours). In all cases, the cause of ventilator dependency should be identified and precipitating factors should be corrected. The weaning trial was done when the patient became alert and arterial $O_2$ tension was adequate($PaO_2$ > 55mmHg) with an inspired oxygen fraction of 40%. We conducted a careful physical examination when the patient was breathing spontaneously through the endotracheal tube. Failure of weaning trial was signaled by cyanosis, sweating, paradoxical respiration, intercostal recession. Weaning failure was defined as the need for mechanical ventilation within 48 hours. Results: In 19 weaning trials of 18 patients, successful weaning and extubation was possible in 16/19(84.2 %). During the trial of spontaneous breathing for 60 minutes through the endotracheal tube, the patients who could wean developed slight increase in respiratory rates but significant changes of arterial blood gas values were not noted. But, the patients who failed weaning trial showed the marked increase in respiratory rates without significant changes of arterial blood gas values. Conclusion: The result of present study indicates that weaning from mechanical ventilation following a 60 minutes spontaneous breathing with $O_2$ supply through the endotracheal tube is a simple and effective method. Extubation can be done at the same time of successful weaning except for endobronchial toilet or airway protection.

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Allium hookeri Extract Improves Type 2 Diabetes Mellitus in C57BL/KSJ Db/db Obese Mouse via Regulation of Hepatic Lipogenesis and Glucose Metabolism (삼채 추출물의 인슐린 저항성 개선 효과 및 기전 탐색)

  • Kim, Ji-Soo;Heo, Jin-Sun;Choi, Jong-Won;Kim, Gun-Do;Sohn, Kie-Ho
    • Journal of Life Science
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    • v.25 no.10
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    • pp.1081-1090
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    • 2015
  • Diabetes has been one of major health risks in industrialized countries. Allium hookeri is a wild herb distributed in India and Myanmar. The root of the plant has been used as food and medicine in Southeast Asia. We investigated Allium hookeri extract improves type 2 diabetes mellitus in C57BL/KSJ db/db obese mouse. C57BL/KSJ db/db obese mouse arise out of Type 2 diabetes and we treated Allium hookeri methanol extract 400 mg/kg (AH 400), 800 mg/kg (AH 800), positive control group (thiazolidinedine;TZDs) were administered orally for 8weeks. AH treated group normalized lipid enzyme system (triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol) and serum glucose, HbA1c and plasma insulin level. AH treated group recovered β-cell damage by hyperglycemia and fatty liver disease. AH treated group significantly up regulated expression of Peroxisome proliferator-activated receptor gamma (PPAR-γ), pyruvate dehydrogenase kinase4 (PDK4), Sterol regulatory element-binding protein 1c (SREBP 1) and fork head box O1 (FOX 01) proteins in C57BL/KSJ db/db obese mouse liver. And we found that AH treated group decreased hepatic malondialdehyde formation in C57BL/KSJ db/db obese mouse liver. These results indicate that Allium hookeri methanol extract might be a potential anti-diabetic agent and could be useful in the treatment of type 2 diabetes mellitus.

Arginine Vasopressin Therapy of Vasodilatory Shock after Cardiac Surgery (심장 수술 후 혈관 확장성 쇼크가 발생한 환자에서 바소프레신 투여 요법)

  • Ahn, Young-Chan;Park, Chul-Hyun;Kim, Gun-Woo;Lee, Jae-Ik;Jun, Yang-Bin;Choi, Chang-Hyu;Hyun, Sung-Youl;Park, Kook-Yang
    • Journal of Chest Surgery
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    • v.39 no.12 s.269
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    • pp.913-919
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    • 2006
  • Background: Vasodilatory shock has been implicated in life-threatening complications after open heart surgery, where the systemic inflammatory reaction is attributed to the cardiopulmonary bypass(CPB). The secretion of arginine vasopressin(AVP) has been found to be defective in a variety of vasodilatory shock states and administration of AVP markedly improves vasomotor tone and blood pressure. So we reviewed our experience of AVP therapy in patients with vasodilatory shock following heart surgery using CPB. Material and Method: From January 2004 to July 2006, we reviewed the records of patients who received AVP therapy for vasodilatory shock following heart surgery using CPB. Vasodilatory shock was defined as a mean arterial pressure lower(MAP) than 70 mmHg, a cardiac index greater than 2.5 $L/min/m^2$, peripheral vascular resistance lower than 800 $dyn/s/cm^5$, and vasopressor requirements. The hemodynamic responses of patients who received AVP therapy for vasodilatory shock after cardiac surgery were analyzed retrospectively. Result: One hundred ninety nine open cardiac surgery patients were consecutively included in this study. Twenty two patients(11.1%) met criteria for vasodilatory shock. Despite the administration of high dose catecholamine vasopressor, all patients were hypotensive with a mean arterial pressure less than 70 mmHg. AVP therapy increased MAP from $53.3{\pm}7.4\;to\;82.0{\pm}12.0$ mmHg at 1 hour (p<0.001) and decreased other vasopressor requirements from $25{\pm}7\;to\;18{\pm}6$ at 1 hour(p<0.001) and individually maintained it for 12 hours. Conclusion: Our date suggest that AVP may be a safe and an effective vasopressor in patients with vasodilatory shock. In patients exhibiting vasodilatory shock after heart surgery, replacement of AVP increases blood pressure and reduces catecholamine vasopressor requirements.

The detection of collapsible airways contributing to airflow limitation (기류 제한에 영향을 미치는 허탈성 기도의 분석)

  • Kim, Yun Seong;Park, Byung Gyu;Lee, Kyong In;Son, Seok Man;Lee, Hyo Jin;Lee, Min Ki;Son, Choon Hee;Park, Soon Kew
    • Tuberculosis and Respiratory Diseases
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    • v.43 no.4
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    • pp.558-570
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    • 1996
  • Background : The detection of Collapsible airways has important therapeutic implications in chronic airway disease and bronchial asthma. The distinction of a purely collapsible airways disease from that of asthma is important because the treatment of the dormer may include the use of pursed lip breathing or nasal positive pressure ventilation whereas in the latter, pharmacologic approaches are used. One form of irreversible airflow limitation is collapsible airways, which has been shown to be a Component of asthma or to emphysema, it can be assessed by the volume difference between what exits the lung as determined by a spirometer and the volume compressed as measured by the plethysmography. Method : To investigate whether volume difference between slow and forced vital Capacity(SVC-FVC) by spirometry may be used as a surrogate index of airway collapse, we examined pulmonary function parameters before and after bronchodilator agent inhalation by spirometry and body plethysmography in 20 cases of patients with evidence of airflow limitation(chronic obstructive pulmonary disease 12 cases, stable bronchial asthma 7 cases, combined chronic obstructive pulmonary disease with asthma 1 case) and 20 cases of normal subjects without evidence of airflow limitation referred to the Pusan National University Hospital pulmonary function laboratory from January 1995 to July 1995 prospectively. Results : 1) Average and standard deviation of age, height, weight of patients with airflow limitation was $58.3{\pm}7.24$(yr), $166{\pm}8.0$(cm), $59.0{\pm}9.9$(kg) and those of normal subjects was $56.3{\pm}12.47$(yr), $165.9{\pm}6.9$(cm), $64.4{\pm}10.4$(kg), respectively. The differences of physical characteristics of both group were not significant statistically and male to female ratio was 14:6 in both groups. 2) The difference between slow vital capacity and forced vital capacity was $395{\pm}317ml$ in patients group and $154{\pm}176ml$ in normal group and there was statistically significance between two groups(p<0.05). Sensitivity and specificity were most higher when the cut-off value was 208ml. 3) After bronchodilator inhalation, reversible airway obstructions were shown in 16 cases of patients group, 7 cases of control group(p<0.05) by spirometry or body plethysmography d the differences of slow vital capacity and forced vital capacity in bronchodilator response group and nonresponse group were $300.4{\pm}306ml$, $144.7{\pm}180ml$ and this difference was statistically significant. 4) The difference between slow vital capacity and forced vital capacity before bronchodilator inhalation was correlated with airway resistance before bronchodilator(r=0.307 p=0.05), and the difference between slow vital capacity and forced vital capacity after bronchodilator was correlated with difference between slow vital capacity and forced vital capacity(r=0.559 p=0.0002), thoracic gas volume(r=0.488 p=0.002) before bronchodilator and airway resistance(r=0.583 p=0.0001), thoracic gas volume(r=0.375 p=0.0170) after bronchodilator, respectively. 5) The difference between slow vital capacity and forced vital capacity in smokers and nonsmokers was $257.5{\pm}303ml$, $277.5{\pm}276ml$, respectively and this difference did not reach statistical significance(p>0.05). Conclusion : The difference between slow vital capacity and forced vital capacity by spirometry may be useful for the detection of collapsible airway and may help decision making of therapeutic plans.

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EFFECTS OF MAXILLARY PROTRACTION ON THE DISPLACEMENT OF THE MAXILLA (상악골 전방 견인이 상악골체의 변위에 미치는 영향)

  • Ko, Jeong-Seok;Kim, Jong-Chul
    • The korean journal of orthodontics
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    • v.25 no.5 s.52
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    • pp.543-555
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    • 1995
  • In the orthopedic therapy, the biomechanical analysis of the appliance is necessary to get a desirable orthopedic effect. The purpose of this study was to investigate the desirable direction and application position of the protraction force. The protraction force of 500g was applied to the first premolar or to the first molar. The direction of force application was paralell or $20^{\circ}$ downward to the occlusal plane respectively. The stress distribution and the displacement within the maxilla was analyzed by a 3-dimensional finite element method. The findings obtained were as follows 1. Protraction forces caused a counterclockwise rotation of the maxilla. 2. The degree of maxillary rotation was less when the force was applied $20^{\circ}$ downward direction to the occlusal plane than when applied to the parallel direction. 3. The degree of rotation of maxilla was greater when the parallel force was applied to the 1st premolar than when applied to the first molar, whereas it was greater when force is applied $20^{\circ}$ downward than at the first premolar. In conclusion, the $20^{\circ}$ downward protraction from the first premolar induced the least counterclockwise rotation of the maxilla and was thought as the desirable direction and application position of the protraction force.

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소적백출산(消積白朮散)이 항암효과(抗癌效果) 및 Cisplatin부작용(副作用) 감소(減少)에 미치는 영향(影響)

  • Jo, Jong-Gwan
    • Journal of Haehwa Medicine
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    • v.4 no.2
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    • pp.255-272
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    • 1996
  • 소적백출산(消積白朮散)은 ${\ll}$화제국방(和劑局方)${\gg}$에 삼령백출산(蔘笭白朮散)에 정열해독약(淸熱解毒藥)인 와송(瓦松) 금은화(金銀花) 포공영(蒲公英)을 가미(加味)한 처방(處方)으로, 본방(本方)인 삼령백출산(蔘笭白朮散)은 비위허약(脾胃虛弱), 음식부진(飮食不振), 다곤소력(多困少力) 중만비대(中滿痺臺), 심정기천(心柾氣喘), 구토(嘔吐), 설사(泄瀉), 상한해수(傷寒咳嗽)를 치료목적(治療目的)으로 쓰여 온 이래(以來) 임상에서는 대편부실(大便不實), 구설(久泄), 옹달궤후(癰疸潰後) 불사식자(不思食者)를 치료(治療)하는데 다용(多用)되어 왔다. 종양(腫瘍)(Neoplasia)은 새로운 성장(成長)(New+ Glowth) 이라는 세포학적(細胞學的)으로 비정상세포(非正常細胞)의 과다증식(過多增殖)으로 인해 실질장기(實質臟器), 유강장기(有腔腸器), 및 골격(骨格), 피부조직(皮膚組織)에 비정상조직(非正常組織)을 형성(形成)하는 질환(疾患)이다. 현대적(現代的) 종양(腫瘍)과 유사(類似)한 한의학적(韓醫學的)인 병증(病症)은 ${\ll}$소문(素問)${\gg}$에서는 "궐산(厥疝), 복량(伏梁), 식적(息積)"으로 ${\ll}$영추(靈樞)${\gg}$에서는 "장담(腸覃), 석가"로 표시(表示)된 이후(以後)로 소원방(巢元方)은 징가, 식일, 석옹(石癰), 완저(緩疽), 석저(石疽) 등으로 표현(表現)하였다. 원인(原因)에 대(對)해서는 ${\ll}$내경(內經)${\gg}$에서는 허(虛)와 한기(寒氣), 한(寒) 열(熱)로 보았고, 그 외(外)의 학자(學者)들은 내허(內虛)와 기혈불순(氣血不順), 화(火), 한(寒), 기울(氣鬱), 음양불화(陰陽不和)등으로 보았다. 치료(治療)는 ${\ll}$내경(內經) 자법론(刺法論)${\gg}$에서 "정기재내(正氣在內) 사불가우(邪不可于)" 이라 하여 생명활동(生命活動)의 원동력(原動力)인 정기(正氣)의 역할(役割)을 강조(强調)하였고, ${\ll}$육원정기대론(六元正氣大論)${\gg}$에서는 "대적대취(大積大聚) 불가범야(不可犯也) 쇠기태반이지(衰其太半而止)"라 하여 공벌약(攻伐藥)을 과용(過用)하여 정기(正氣)를 손상(損傷)시켜서는 안된다고 하는 등 부정위주(扶正爲主), 거사위주(祛邪爲主) 혹은 부정거사(扶正祛邪) 겸용(兼用)의 방법(方法)이 혼용(混用)되고 있다. 현대(現代) 서양의학(西洋醫學)의 항암제(抗癌劑)는 치료효과(治療效果)는 우수(優秀)하지만 악심(惡心), 구토(嘔吐)를 비롯하여 골수억제효과(骨髓抑制效果)와 간(肝), 심(心), 신(腎), 폐(肺)의 손상(損傷)을 초래(招來)하는 등(等)의 부작용(副作用)을 나타내며, 빈번(頻繁)한 화학요법제(化學療法劑)의 투여(投與)로 인(因)한 암세포(癌細胞)의 약제저항성(藥劑抵抗性) 출현(出現)등이 항암제(抗癌劑)의 문제점(問題點)으로 제시(提示)되고 있다. 이에 저자(著者)는 비위기능(脾胃機能)을 강화(强化)시켜 정기형성(正氣形成)에 깊이 관여(關與)하는 삼령백출산(蔘笭白朮散)에 청열해독(淸熱解毒), 소종산결지제(消腫散結之劑)인 금은화(金銀花), 포공영(浦公英), 와송(瓦松)을 가미(加味)하여 암발생(癌發生) 백서(白鼠)에 투약(投藥)한 후(後) sarcoma 180암세포(癌細胞)에 대(對)한 생명연장효과(生命延長效果)와 항암제(劑)의 일종(一種)인 cis-platin을 이용(利用)하여 양방항암제(洋方抗癌劑)의 부작용(副作用)에 대(對)한 본(本) 방(方)의 효과(效果)를 실험(實驗)하여 관찰(觀察)하였던 바 다음과 같은 결론(結論)을 얻었다. 1. 소적백출산(消積白朮散)은 sarcoma 180 암세포(癌細胞) 이식종양(移植腫瘍)에 대(對)해 생명연장효과(生命延長效果)가 인정(認定)되었다. 2. 소적백출산(消積白朮散)은 치암제(治癌劑)인 cis-platin 치사독성(致死毒性)에 대(對)해 생존연장효과(生存延長效果)가 인정(認定)되었다. 3. 소적백출산(消積白朮散)은 cis-platin 현독성(腎毒性) 생쥐 및 흰쥐에 있어서 유의성(有意性) 있는 체중감소억제효과(體重減少抑制效果) 및 serum BUN 상승억제효과(上昇抑制效果)가 인정(認定)되었다. 4. 소적백출산(消積白朮散)은 cis-platin 현독성(賢毒性) 흰쥐에 대(對)해 유의성(有意性) 있는 serum creatinine 상승억제효과(上昇抑制效果)가 나타났으며, cis-platin의 혈액학적(血液學的) 부작용(副作用)인 RBC, WBC 감소(減少)에 대(對)해 감소억제효과(減少抑制效果)가 인정(認定)되었다. 5. 소적백출산(消積白朮散)은 cis-platin 현독성(腎毒性) 흰쥐에 대(對)해 뇨량감소억제(尿量減少抑制) 효과(效果) 및 ureanitrogen과 creatinine 배수감소억제효과가 관찰(觀察)되었다. 이상(以上)의 결과(結果)로부터 소적백출산(消積白朮散)은 악성종양치료(惡性腫瘍治療) 및 항암제(劑)의 부작용(副作用)을 경감(輕減)시키는 데 응용(應用)할 수 있을 것으로 사료(思料)된다.

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Batch and Fed-batch Fermentation for the Lovastatin Production by Cerulenin-resistant Aspergillus terreus Mutant (Cerulenin 저항성 Aspergillus terreus 변이주로부터 lovastatin 생산을 위한 회분식과 유가식 배양)

  • 문미경;전계택;정용섭
    • KSBB Journal
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    • v.16 no.1
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    • pp.87-94
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    • 2001
  • The biosynthesis of Lovastatin, a cholesterol lowering agent formed by the filamentous fungus, cerulenin-resistant Aspergillus terreus mutant was studied in shake flasks and bioreactors. The lovastatin production could be improved by fed-batch under the limited condition of carbon source. The relationship between the fungal morphology and the lovastatin production was also examined during the fed-batch cultures. The fed-batch studies in shake flasks were carried out to find the optimum glucose feeding method, and the pulsed feeding of glucose from 3 days onward at 24 hours intervals was found to be optimal to increase the lovastatin production and reduce the average pellet size. When the pH was controlled at around 5.8 during the whole fermentation period, the lovastatin concentration reached 384 mg/L, which is much higher than the values obtained pH-uncontrolled and pH 7.4. The optimal glucose feeding strategies was found that 30 g/L of glucose was added initially in batch mode, and then fed-batch was conducted by continuous addition of glucose solution(180 g/L) from 72 to 240 hr at a rate of 1.2 mL/hr at $28^{\circ}C$, pH 5.8, 400 rpm, and 1.0 vvm. The lovastatin concentration of 547 mg/L was obtained in 168 hr. It was about 1.5 times higher than the value of the batch fermentation.

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Arthroscopic Resection of Synovial Plica in Elbow (관절경을 이용한 주관절 활막 추벽의 제거)

  • Yoo, Yon-Sik
    • Clinics in Shoulder and Elbow
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    • v.10 no.1
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    • pp.50-58
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    • 2007
  • Purpose: To report our experience with nine cases of pathologic synovial plica on radiohumeral joint which symptom of painful snapping elbow was improved by arthroscopic resection. Materials and Methods: Between 1999 and 2004, 43 cases of elbow arthroscopy were performed by one surgeon. Eight patients with nine cases showed pathologic synovial plica in conjunction with snapping or posterolateral elbow pain. The mean age of eight patients (man: 7, woman: 1) was 29 years (range $16{\sim}56$ years). All patients had a trial of conservative treatment at least six months (range $6{\sim}16$ months). The diagnosis was confirmed before surgery in six cases and at the time of surgery in three cases. Pain, snapping, and subjective results were evaluated at least 12 months in the average(range $12{\sim}24$). Results: All patients showed a hypertropic lateral synovial plica with local synovitis. Seven of them had an associated lesion of chondromalacia on radial head. One of them was associated with radiocapitellar arthritis and had a wrapping over the radial head. Six patients experienced improved posterolateral pain at the end of study (VAS<1). However, the other two patients had occasional pain with activity. One of them persisted with mechanical symptoms, which was treated with additional arthroscopic procedure. Conclusion: Synovial plica in elbow should be considered as an important entity of common elbow disease, especially when pain in the lateral aspect of the elbow with a snapping sensation during motion is featured in patients. The arthroscopic resection seems to be safe and efficient in the short and long term treatment of plica in the elbow joint.

Anti-diabetic mechanism of melania snail (Semisulcospira libertina) protamex hydrolysates (다슬기 protamex 가수분해물(MPH)의 항당뇨 기작 연구)

  • Pyo, Sang-Eun;Choi, Jae-Suk;Kim, Mi-Ryung
    • Food Science and Preservation
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    • v.24 no.7
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    • pp.1007-1016
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    • 2017
  • Melania snail (Semisulcospira libertina) was traditionally used as the healthy food in Korea. It was generally known to improve liver function and heal a diabetes. The aim of this study was to elucidate the anti-diabetic mechanism of melanian snail hydrolysates treated with protamex (MPH) by investigating the inhibitory action on protein tyrosine phosphatase 1B (PTP1B), the improving effect on the insulin resistance in C2C12 myoblast and the protective effect for pancreatic beta-cell (INS-1) under the glucose toxicity. The melania snail hydrolysates treated with protamex (MPH), which showed the highest degree of hydrolysis (43%), and inhibited effectively PTP1B activity ($IC_{50}=15.42{\pm}1.1{\mu}g/mL$), of which inhibitory effect was higher than usolic acid, positive control ($IC_{50}=16.65{\mu}g/mL$). MPH increased the glucose uptake in C2C12 myoblast treated with palmitic acid. In addition, MPH increased insulin mRNA expression level by over 160% with enhanced cell viability in INS-1 cell under the high glucose concentration (30 mM). These results suggest that MHP may improve the diabetic symptom by the inhibiting the PTP1B activity, increasing the glucose uptake in muscle cell and protecting the pancreatic beta-cell from glucose toxicity.