本文關(guān)鍵詞： 低氧誘導(dǎo)因子-1α 心肌 缺血/再灌注損傷 缺血預(yù)處理 缺血后處理　出處：《山西醫(yī)科大學(xué)》2007年碩士論文　論文類型：學(xué)位論文

【摘要】： 研究背景: 缺氧在心肌缺血引起的病理生理變化中起著關(guān)鍵的作用,它可引起心肌細(xì)胞丟失,導(dǎo)致收縮功能障礙。心肌缺血后盡早對(duì)缺血區(qū)進(jìn)行再灌注是阻止心肌細(xì)胞死亡、恢復(fù)心肌功能的根本途徑,然而,再灌注本身又會(huì)加重心肌細(xì)胞損傷,即發(fā)生缺血/再灌注損傷。缺血預(yù)處理與缺血后處理是目前公認(rèn)的兩種能減輕缺血/再灌注損傷的心肌保護(hù)措施,但其機(jī)制十分復(fù)雜,尚未充分闡明。近年發(fā)現(xiàn)的低氧誘導(dǎo)因子-1α(HIF-1α)是一種在氧平衡調(diào)節(jié)中起關(guān)鍵作用的轉(zhuǎn)錄因子,它通過調(diào)節(jié)多種靶基因的表達(dá)介導(dǎo)細(xì)胞缺氧反應(yīng),從而保護(hù)組織免受缺血損傷。一些臨床及基礎(chǔ)研究發(fā)現(xiàn),HIF-1α可能是心肌缺血時(shí)首發(fā)的分子反應(yīng),提示它可能在缺血/再灌注損傷的內(nèi)源性保護(hù)機(jī)制中起關(guān)鍵的始動(dòng)作用;在缺血/再灌注以及缺氧/復(fù)氧的預(yù)處理過程中HIF-1α的蛋白表達(dá)量明顯增加,但它在缺血后處理過程中表達(dá)變化如何,以及它在預(yù)處理,特別是后處理過程中是否起保護(hù)作用等問題尚未見文獻(xiàn)報(bào)道。 目的: 1.觀察在心肌缺血/再灌注時(shí)給予缺血預(yù)處理及后處理后低氧誘導(dǎo)因子-1α的蛋白表達(dá)情況; 2.探討低氧誘導(dǎo)因子-1α的表達(dá)變化與缺血預(yù)處理及后處理的心肌保護(hù)效應(yīng)的關(guān)系。 方法: 選取健康雄性Wistar大鼠40只,隨機(jī)分為4組: ①偽手術(shù)組(sham,n=10):僅在左冠狀動(dòng)脈前降支(left anterior descending artery,LAD)下穿線,不結(jié)扎,持續(xù)225min; ②缺血/再灌注組(I/R,n=10):可逆性結(jié)扎LAD造成心肌缺血45min,再灌注3h; ③缺血預(yù)處理組(IP,n=10):給予3個(gè)循環(huán)的5min缺血/5min再灌注作為缺血預(yù)處理,隨后給予可逆性結(jié)扎LAD造成心肌缺血45min,再灌注3h; ④缺氧后處理組(PC,n=10):可逆性結(jié)扎LAD造成心肌缺血45min,隨即進(jìn)行3個(gè)循環(huán)的再灌注10g/缺血10s的缺血后適應(yīng),再行再灌注3h。 實(shí)驗(yàn)結(jié)束后用Even's blue和TTC雙染,測(cè)定心肌危險(xiǎn)區(qū)與梗塞區(qū)面積;利用免疫組織化學(xué)技術(shù)、Western蛋白免疫印跡檢測(cè)心肌HIF-1α的表達(dá):用DNA原位末端缺口標(biāo)記法并配合caspase-3的活性檢測(cè)對(duì)心肌細(xì)胞凋亡進(jìn)行檢測(cè);制備血清,檢測(cè)CK活性和MDA含量。 結(jié)果: 1.缺血/再灌注模型的建立 1.1心肌缺血/再灌注損傷對(duì)心肌梗塞面積的影響 危險(xiǎn)區(qū)面積占左心室面積的百分比(AAR/LV比值):在偽手術(shù)組與缺血/再灌注組之間無(wú)顯著性差異,各組動(dòng)物模型的缺血程度大體一致,具有可比性。 心肌梗塞面積占危險(xiǎn)區(qū)面積百分比(AN/AAR比值):缺血/再灌注(I/R)組與偽手術(shù)(sham)組相比明顯增高(44.17%±3.24%vs.3.36%±0.87%,P＜0.01)(表1,圖2,圖3)。 1.2心肌缺血/再灌注損傷對(duì)血清肌酸激酶(CK)活性的影響 實(shí)驗(yàn)采用CK活性作為評(píng)價(jià)心肌損傷的指標(biāo)。經(jīng)CK試劑盒檢測(cè)可見,缺血/再灌注(I/R)組與sham組相比,血清CK活性明顯增高(10.17±2.36 U/ml vs.0.037±0.01U/ml,P＜0.01),(表1,圖4)。 1.3心肌缺血/再灌注損傷對(duì)血清丙二醛(MDA)含量的影響 MDA含量可反應(yīng)機(jī)體內(nèi)脂質(zhì)過氧化的程度,同時(shí)間接地反應(yīng)出細(xì)胞損傷的程度。結(jié)果顯示:缺血/再灌注(I/R)組血清MDA含量明顯高于sham組(0.27±0.03 nmol/ml vs.0.04±0.01 nmol/ml,P＜0.01)(表1,圖5)。 1.4心肌缺血/再灌注損傷對(duì)細(xì)胞凋亡的影響 DNA原位末端缺口標(biāo)記法(TUNEL)心肌細(xì)胞凋亡檢測(cè)結(jié)果顯示:偽手術(shù)組(sham)大鼠心肌組織細(xì)胞凋亡指數(shù)為(1.45±0.41)%,缺血/再灌注組(I/R)心肌細(xì)胞凋亡指數(shù)明顯增高達(dá)到(17.68±2.44)%,I/R與sham兩組相比有統(tǒng)計(jì)學(xué)差異(P＜0.01)(圖6,圖7)。 由于TUNEL法檢測(cè)細(xì)胞凋亡具有敏感性高、但特異性較差的特點(diǎn),因此我們配合檢測(cè)了缺血/再灌注心肌組織的caspase-3比活性來(lái)共同說(shuō)明心肌細(xì)胞的凋亡情況。caspase-3檢測(cè)結(jié)果顯示:與sham組(1.00±0.14)相比,缺血/再灌注組caspase-3比活性明顯增高,達(dá)到2.22±0.39(P＜0.01)(圖8)。 以上結(jié)果均證明心肌缺血/再灌注模型建立成功。 2.缺血預(yù)處理和缺血后處理對(duì)心肌缺血/再灌注損傷的保護(hù)作用 2.1缺血預(yù)處理和缺血后處理對(duì)心肌梗塞面積的影響 危險(xiǎn)區(qū)面積占左心室面積的百分比(AAR/LV比值):在缺血/再灌注組、缺血預(yù)處理組和缺血后處理之間無(wú)顯著性差異,各組動(dòng)物模型的缺血程度大體一致,具有可比性(見表2,圖2,圖9a)。 心肌梗塞面積占危險(xiǎn)區(qū)面積百分比(AN/AAR比值):缺血預(yù)處理組(IP)的AN/AAR比值為(23.76±7.78)%,與缺血/再灌注組(44.17%±3.24%)相比明顯降低(P＜0.01);缺血后處理(PC)的AN/AAR比值為(19.79±2.42)%,與I/R組相比也明顯降低(P＜0.01);而IP與PC相比,則無(wú)統(tǒng)計(jì)學(xué)差異(表2,圖2,圖9b)。 2.2缺血預(yù)處理和缺血后處理對(duì)血清肌酸激酶(CK)活性的影響 缺血/再灌注組(I/R)血清肌酸激酶活性為10.17±2.36 U/ml,缺血預(yù)處理組(IP)血清肌酸激酶活性為7.84±0.87U/ml,與I/R組相比明顯降低(P＜0.05);缺血后處理(PC)組血清肌酸激酶活性(7.67±1.15U/ml)與I/R組相比也明顯降低(P＜0.05);而IP組與PC組相比,則無(wú)統(tǒng)計(jì)學(xué)差異(表3,圖10)。 2.3缺血預(yù)處理和缺血后處理對(duì)血清丙二醛(MDA)含量的影響 血清MDA含量在缺血預(yù)處理組(IP)組為0.16±0.02 nmol/ml,缺血后處理組(PC)為0.16±0.02 nmol/ml。IP、PC組與缺血/再灌注組(0.27±0.03 nmol/ml)相比,均顯著降低(P＜0.01);而IP組與PC組相比無(wú)統(tǒng)計(jì)學(xué)差異。(表3,圖11)。 2.4缺血預(yù)處理和缺血后處理對(duì)細(xì)胞凋亡的影響 DNA原位末端缺口標(biāo)記法(TUNEL)心肌細(xì)胞凋亡檢測(cè):缺血/再灌注組(I/R)心肌細(xì)胞凋亡指數(shù)為(17.68±2.44)%,預(yù)處理組(IP)及后處理組(PC)與I/R組相比心肌細(xì)胞的凋亡均顯著減少,其細(xì)胞凋亡指數(shù)分別降至(13.79±1.29)%和(11.34±1.54)%,P值均小于0.01(表4,圖12,圖13a)。IP組與PC組相比,未見統(tǒng)計(jì)學(xué)差異。 caspase-3比活性分析:caspase-3比活性在IP組為1.53±0.25,PC組為1.23±0.26,與I/R組(2.22±0.39)相比均顯著降低(P＜0.01)(表4,圖13b)。IP組與PC組相比無(wú)統(tǒng)計(jì)學(xué)差異。檢測(cè)結(jié)果提示,預(yù)處理及后處理均可抑制缺血/再灌注后心肌細(xì)胞的凋亡。其檢測(cè)結(jié)果與TUNEL法基本一致。 3.心肌組織HIF-1α蛋白表達(dá)量檢測(cè) 3.1心肌組織HIF-1α蛋白表達(dá)量的免疫組織化學(xué)檢測(cè) 偽手術(shù)(sham)組大鼠心肌組織僅有少量HIF-1α蛋白表達(dá),缺血/再灌注組(I/R)與sham組相比,其HIF-1α免疫組化染色積分光密度(IOD)顯著增強(qiáng)(8331.64±527.40 vs.2263.54±523.32,P＜0.01)。缺血預(yù)處理組(IP)和缺血后處理組(PC)與I/R組相比,它們的HIF-1αIOD均值明顯增強(qiáng),分別為9394.61±757.31和9847.20±940.66,均有統(tǒng)計(jì)學(xué)意義(P＜0.05和P＜0.01)(圖14,圖15)。免疫組化染色結(jié)果可見HIF-1α在細(xì)胞核與細(xì)胞漿內(nèi)均有表達(dá)。 3.2心肌組織HIF-1α蛋白表達(dá)量Western-blot測(cè)定 缺血/再灌注組(I/R)與sham組相比能明顯誘導(dǎo)HIF-1α蛋白的表達(dá)(1.70±0.34 vs.1.0±0.20,P＜0.01),而缺血預(yù)處理.(IP)和缺血后處理(PC)均可顯著增加I/R后心肌細(xì)胞的HIF-1α蛋白表達(dá)量,分別為(2.13±0.39)和(2.07±0.33),P值均小于0.05(圖16,圖17)。 4.HIF-1α蛋白表達(dá)量與反映心肌損傷各指標(biāo)(心肌梗塞面積、CK活性、MDA含量及caspase-3比活性)之間的相關(guān)性分析 采用SPSS 11.0軟件對(duì)各組心肌梗塞面積、CK活性、MDA含量及caspase-3比活性分別與HIF-1α表達(dá)量進(jìn)行相關(guān)分析,結(jié)果表明:心肌梗塞面積與HIF-1α蛋白表達(dá)量呈負(fù)相關(guān),其相關(guān)系數(shù)為r=-0.842,P＜0.01(見圖18);CK活性與HIF-1α蛋白表達(dá)量呈負(fù)相關(guān),r=-0.796,P＜0.01(見圖19);MDA含量與HIF-1α蛋白表達(dá)量呈負(fù)相關(guān),r=-0.839(見圖20);caspase-3比活性與HIF-1α蛋白表達(dá)量也呈負(fù)相關(guān),r=-0.84,P＜0.01(見圖21)。 結(jié)論: (1).缺血預(yù)處理和后處理對(duì)心肌缺血/再灌注損傷均具有保護(hù)作用,能明顯降低心梗面積、CK活性和MDA含量,并減少心肌細(xì)胞的凋亡。 (2).大鼠心肌在缺血/再灌注后,HIF-1α的蛋白表達(dá)量明顯增加,提示該因子是心肌細(xì)胞缺血時(shí)的重要分子反應(yīng)。 (3).心肌缺血預(yù)處理和后處理能使心肌缺血/再灌注后的HIF-1α蛋白表達(dá)量進(jìn)一步明顯增加,提示缺血預(yù)處理和后處理均有誘導(dǎo)心肌組織HIF-1α表達(dá)的效應(yīng)。 (4).缺血預(yù)處理及后處理所引起的HIF-1α蛋白表達(dá)量的增加與反映心肌損傷各指標(biāo)之間均有很高的負(fù)相關(guān)性,提示HIF-1α與缺血預(yù)處理以及后處理的心肌保護(hù)作用有密切關(guān)系。 (5).缺血預(yù)處理與后處理保護(hù)效應(yīng)的始動(dòng)機(jī)制可能是相同的。
[Abstract]:Research background:
Plays a key role in the pathophysiological changes caused by hypoxia in myocardial ischemia, it can cause myocardial cell loss, leading to systolic dysfunction after myocardial ischemia. Ischemia reperfusion as soon as possible to prevent the death of myocardial cells, the fundamental way, the recovery of myocardial function however, reperfusion itself may aggravate myocardial cell damage, which happened ischemia / reperfusion injury, ischemic preconditioning and ischemic postprocessing is currently recognized as the two kinds of protective measures can reduce ischemia / reperfusion injury of myocardium, but its mechanism is very complicated, have not yet been fully clarified. Hypoxia inducible factor found in recent years that -1 alpha (HIF-1 alpha) is a kind of play a key role in the regulation of oxygen balance the transcription factor, through the expression of multiple target genes mediated regulation of cell response to hypoxia, which protects tissues from ischemic injury. Some basic and clinical studies found that HIF-1 alpha may be myocardial ischemia When the first molecular reaction, suggesting that it may play a key role in the initiation of ischemia / reperfusion injury of the endogenous protective mechanisms in the pretreatment process; ischemia / reperfusion and hypoxia / reoxygenation in HIF-1 alpha protein expression was significantly increased, but its treatment after ischemia during expression, and it in the preprocessing, especially the postprocessing process whether the protection problem has not been reported.
Objective:
1. the protein expression of hypoxia inducible factor -1 alpha was observed after ischemic preconditioning and postconditioning in myocardial ischemia / reperfusion.
2. to investigate the relationship between the expression of hypoxia inducible factor -1 alpha and the myocardial protective effect of ischemic preconditioning and post-treatment.
Method:
40 healthy male Wistar rats were selected and divided into 4 groups randomly.
(1) the pseudo operation group (sham, n=10): only the left anterior descending branch of the coronary artery (left anterior descending artery, LAD) under the line, no ligation, continuous 225min;
(2) ischemia / reperfusion group (I/R, n=10): reversible ligation of LAD resulted in myocardial ischemia 45min, and reperfusion 3H;
(3) the ischemic preconditioning group (IP, n=10): 3 cycles of 5min ischemia /5min reperfusion were used as ischemic preconditioning, followed by reversible ligation of LAD, resulting in myocardial ischemia 45min and reperfusion 3H.
(4) hypoxic postconditioning group (PC, n=10): reversible ligation of LAD resulted in myocardial ischemia 45min, then 3 cycles of reperfusion, 10g/ ischemia, 10s ischemic postconditioning, and then reperfusion 3h..
After the end of the experiment by Even's blue and TTC double staining, the determination of the dangerous area and infarct size; using immunohistochemical technique, the expression of Western protein was detected by Western blot of myocardial HIF-1 alpha: DNA with TUNEL method and activity detection of Caspase-3 for detection of myocardial cell apoptosis; preparation of serum CK activity. And MDA were detected.
Result:
1. model of ischemia / reperfusion
The effect of 1.1 myocardial ischemia / reperfusion injury on the area of myocardial infarction
The percentage of the risk area occupied the ratio of the left ventricular area (AAR/LV ratio): there was no significant difference between the pseudo operative group and the ischemia-reperfusion group.
The area of myocardial infarction accounted for the percentage of the risk area (AN/AAR ratio): the ischemia / reperfusion (I/R) group was significantly higher than that of the pseudo operation (sham) group (44.17% + 3.24%vs.3.36% + 0.87%, P < 0.01) (Table 1, figure 2, figure 3).
The effect of 1.2 myocardial ischemia / reperfusion injury on the activity of serum creatine kinase (CK)
The activity of CK was used as an index to evaluate myocardial injury. CK kit test showed that the activity of serum CK in ischemia / reperfusion (I/R) group was significantly higher than that in sham group (10.17 + 2.36 U/ml vs.0.037 + 0.01U/ml, P < 0.01), (1, 4).
The effect of 1.3 myocardial ischemia / reperfusion injury on the content of serum malondialdehyde (MDA)
MDA content can reflect the extent of lipid peroxidation in the body, and indirectly reflect the extent of cell injury. The results showed that the serum MDA level in the ischemia / reperfusion (I/R) group was significantly higher than that in the sham group (0.27 + 0.03 nmol/ml vs.0.04 + 0.01 nmol/ml, P < 0.01) (table 1, figure 5).
The effect of 1.4 myocardial ischemia / reperfusion injury on cell apoptosis
DNA in situ nick end labeling (TUNEL) myocardial cell apoptosis test results show that: the sham operation group (sham) cell apoptosis index of myocardial tissue of rats was (1.45 + 0.41)%, ischemia / reperfusion group (I/R) myocardial apoptosis index was significantly increased to (17.68 + 2.44)%, I/R and sham two groups the difference was statistically significant (P < 0.01) (Figure 6, Figure 7).
The apoptotic cells were detected by TUNEL method has high sensitivity, but the specificity is low, so we detected with ischemia / reperfusion and myocardial perfusion caspase-3 activity showed together myocardial cells apoptosis and.Caspase-3 test results show that: the sham group (1 + 0.14) compared to the ischemia / reperfusion group caspase-3 activity significantly increased to 2.22 + 0.39 (P < 0.01) (Figure 8).
The above results all proved that the model of myocardial ischemia / reperfusion was established successfully.
2. protective effect of ischemic preconditioning and ischemic postconditioning on myocardial ischemia / reperfusion injury
2.1 the effect of ischemic preconditioning and ischemic postconditioning on the area of myocardial infarction
The percentage of the risk area occupied the percentage of the left ventricular area (AAR/LV ratio): there was no significant difference between the ischemic preconditioning group and the ischemic postconditioning group in the ischemia / reperfusion group. The degree of ischemia in each group was generally the same and comparable (see Table 2, Fig. 2, figure 9A).
Myocardial infarction area accounted for risk area percentage (AN/AAR ratio): ischemic preconditioning group (IP) AN/AAR ratio (23.76 + 7.78)%, and the ischemia / reperfusion group (44.17% + 3.24%) reduced significantly (P < 0.01); ischemic postprocessing (PC) AN/AAR ratio (19.79. 2.42)%, compared with the I/R group were significantly decreased (P < 0.01); and IP compared with PC, there was no significant difference (Table 2, figure 2, figure 9b).
2.2 effect of ischemic preconditioning and ischemic postconditioning on the activity of serum creatine kinase (CK)
Ischemia / reperfusion group (I/R) serum creatine kinase activity was 10.17 + 2.36 U/ml, ischemic preconditioning group (IP) and serum creatine kinase activity was 7.84 + 0.87U/ml, compared with the I/R group decreased significantly (P < 0.05); ischemic postprocessing (PC) serum creatine kinase activity (7.67 + 1.15U/ml) compared with the I/R group also decreased significantly (P < 0.05); and IP group compared with PC group, there was no significant difference (Table 3, figure 10).
2.3 effect of ischemic preconditioning and ischemic postconditioning on the content of serum malondialdehyde (MDA)
The serum MDA level in the ischemic preconditioning group (IP) group was 0.16 + 0.02 nmol/ml, and the ischemic postconditioning group (PC) was 0.16 + 0.02 nmol/ml.IP. Compared with the ischemia / reperfusion group (0.27 + 0.03 nmol/ml), the PC group decreased significantly (P < 0.01), while the IP group had no statistical difference compared with the PC group (tab 3, figure 11).
2.4 effect of ischemic preconditioning and ischemic postconditioning on cell apoptosis
DNA in situ nick end labeling (TUNEL) detection of myocardial cell apoptosis: the ischemia / reperfusion group (I/R) myocardial apoptosis index for (17.68 + 2.44)%, pretreatment group (IP) and postprocessing group (PC) compared with the I/R group myocardial apoptosis significantly decreased the apoptosis index respectively (13.79 + 1.29)% and (11.34 + 1.54)%, P values were less than 0.01 (Table 4, Figure 12, figure 13a) compared with.IP group and PC group, there was no statistical difference.
Analysis of specific activity of Caspase-3: caspase-3 activity in IP group was 1.53 + 0.25, 1.23 + 0.26 PC group, and I/R group (2.22 + 0.39) decreased significantly compared (P < 0.01) (Table 4, figure 13b).IP group and PC group compared with no significant difference. The results showed that pretreatment and postprocessing were inhibited after ischemia / reperfusion myocardial cells apoptosis. The results are consistent with the TUNEL method.
Detection of HIF-1 alpha protein expression in 3. myocardium
Immunohistochemical detection of the expression of HIF-1 alpha protein in 3.1 myocardium
Pseudo surgery (sham) in myocardial tissue of rats with only a small amount of HIF-1 protein expression, ischemia / reperfusion group (I/R) compared with sham group, the alpha HIF-1 immunohistochemical staining of the integral optical density (IOD) increased significantly (8331.64 + 527.40 vs.2263.54 + 523.32, P < 0.01). Ischemia preconditioning group (IP ischemia) and postprocessing group (PC) compared with I/R group, HIF-1 alpha IOD mean their obvious enhancement, were 9394.61 + 757.31 and 9847.20 + 940.66, there was statistically significant (P < 0.05 and P < 0.01) (Figure 14, Figure 15). The results of immunohistochemical staining showed HIF-1 expressed in alpha the nucleus and cytoplasm.
Determination of HIF-1 alpha protein expression by Western-blot in 3.2 myocardium
Ischemia / reperfusion group (I/R) was compared with the sham group could significantly induce HIF-1 alpha protein (1.70 + 0.34 vs.1.0 + 0.20, P < 0.01), and ischemic preconditioning. (IP) and ischemic postprocessing (PC) significantly increased HIF-1 protein expression in myocardial cells after I/R, respectively. (2.13 + 0.39) and (2.07 + 0.33), P values were less than 0.05 (Figure 16, Figure 17).
The correlation analysis between the expression of 4.HIF-1 alpha protein and the indexes of myocardial injury (myocardial infarction area, CK activity, MDA content and caspase-3 specific activity)
Using SPSS 11 software for each area of myocardial infarction, CK activity, MDA content and caspase-3 activity respectively with HIF-1 alpha expression by correlation analysis, the results show that the area of myocardial infarction and HIF-1 alpha protein expression was negatively correlated, the correlation coefficient is r=-0.842, P < 0.01 (see Figure 18); the activity of CK and HIF-1 alpha protein expression was negatively correlated with r=-0.796, P < 0.01 (see Figure 19); the content of MDA and HIF-1 protein expression was negatively correlated with r=-0.839 (see Figure 20); caspase-3 activity and HIF-1 protein expression was negatively correlated with r=-0.84, P < 0.01 (see Figure 21).
Conclusion:
(1) ischemic preconditioning and postconditioning have protective effects on myocardial ischemia / reperfusion injury, which can significantly reduce infarct size, CK activity and MDA content, and reduce cardiomyocyte apoptosis.
(2) after ischemia / reperfusion, the protein expression of HIF-1 alpha in the rat myocardium increased significantly, suggesting that the factor is an important molecular response to myocardial ischemia.
(3) myocardial ischemia preconditioning and postconditioning can further increase the expression of HIF-1 alpha protein after myocardial ischemia / reperfusion, suggesting that ischemic preconditioning and postconditioning can induce the expression of HIF-1 alpha in myocardium.
(4) the increase of HIF-1 alpha protein expression induced by ischemic preconditioning and postconditioning had a high negative correlation with all the indicators reflecting myocardial injury, suggesting that HIF-1 alpha is closely related to myocardial protection after ischemic preconditioning and postconditioning.
(5). The initial mechanism of ischemic preconditioning and postprocessing the protective effect may be the same.

【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2007
【分類號(hào)】：R363

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