本文選題：慢性血栓栓塞性肺動脈高壓 + 鐵代謝　； 參考：《北京協(xié)和醫(yī)學院》2015年博士論文

【摘要】：一、研究背景慢性血栓栓塞性肺動脈高壓(Chronic thromboembolic pulmonary hypertension, CTEPH)在肺動脈高壓分類中屬于第四大類。急性肺血栓栓塞癥(Acute pulmonary thromboembolism, APE)患者5年內(nèi)發(fā)生CTEPH的累積發(fā)病率約為0.4%-5.1%。這一部分患者發(fā)生CTEPH的病理生理機制目前不明確。CTEPH的病理特征為肺動脈內(nèi)不能消融的血栓繼發(fā)纖維化、機化。既往有多項研究顯示：1、鐵代謝紊亂與血栓性疾病密切相關。2、病理研究顯示CTEPH患者的非阻塞血管的遠端動脈也發(fā)生了與特發(fā)性肺動脈高壓(pulmonary arterial hypertension, PAH)相同的叢狀病變�；蛲蛔兪翘匕l(fā)性PAH及可遺傳性PAH的重要發(fā)病機制,目前已發(fā)現(xiàn)多個基因突變與PAH發(fā)病有關,CTEPH患者是否存在PAH相關的基因突變目前尚不清楚。3、差異蛋白質組學研究是明確疾病發(fā)病機制、尋找疾病特異的蛋白質分子的良好方法。4、及早發(fā)現(xiàn)CTEPH的存在并給予積極治療有望改善患者預后。因此本課題從鐵代謝、基因突變和蛋白質組學三個方面探討CTEPH可能的發(fā)病機制；并以心肺運動試驗評估APE后不同疾病狀態(tài)患者的表現(xiàn),以尋找預測CTEPH的敏感因子。二、研究內(nèi)容第一部分鐵代謝在CTEPH發(fā)病過程中作用的研究1、研究目的通過比較CTEPH患者和急性PE事件后痊愈的患者鐵代謝情況,明確鐵代謝是否與CTEPH有關。2、研究方法2.1研究對象：2013年4月至2014年3月在阜外醫(yī)院肺血管病科住院的明確診斷的CTEPH患者和慢性PE患者。2.2實驗室檢測：收集空腹血漿,檢測血漿自由鐵濃度、鐵蛋白、可溶性轉鐵蛋白受體(sTfR)、hepcidin-25、腫瘤壞死因子-α (TNF-α)、白介素-6(IL-6)、丙二醛(MDA)水平。2.3統(tǒng)計學分析：連續(xù)數(shù)據(jù)兩組間比較采用student's t檢驗或Mann-Whitney U檢驗；分類變量的兩組間比較采用卡方檢驗。非結合鐵離子濃度與hepcidin-25、 sTfR,鐵蛋白、sTfR/鐵蛋白比值、TNF-α,IL-6、MDA間的相關關系采用Spearman相關系數(shù)表示。hepcidin-25濃度與上述各檢測指標的關系采用Spearman相關系數(shù)表示。Logistic回歸模型分析CTEPH與上述各檢測指標的關系。3、研究結果血漿非結合鐵離子濃度在CTEPH組與慢性PE對照組無明顯差別。兩組間hepcidin-25、sTfR、TNF-α、MDA水平也無顯著差別。CTEPH組的IL-6顯著高于對照組。hepcidin-25水平與sTfR濃度呈負相關(Spearman's r=-0.438, p 0.001); hepcidin-25水平與鐵蛋白呈正相關(Spearman'sr=0.503, p0.001).血漿非結合鐵離子濃度與hepcidin-25、sTfR、鐵蛋白、sTfR/鐵蛋白比值、TNF-β、 IL-6、MDA均無顯著相關(見表1-3).單變量logistic回歸分析顯示,非結合鐵離子濃度、sTfR、鐵蛋白、sTfR/鐵蛋白比值、TNF-α、IL-6、MDA均與CTEPH發(fā)病無明顯關系。4、第一部分研究結論鐵代謝水平與CTEPH發(fā)病無明確相關。CTEPH患者和慢性PE患者的機體sTfR水平及鐵蛋白水平均在正常范圍。第二部分CTEPH患者的基因突變研究1、研究目的通過比較CTEPH患者和有PE病史而無PAH的患者的基因變異情況,目的是明確PAH相關的基因突變是否參與了CTEPH的發(fā)病。2、研究方法2.1研究對象：49名CTEPH患者和17名有PE病史而無PH的對照組患者。2.2基因突變檢測：收集血液標本,提取全基因組DNA。直接測序并與參考序列比對檢測PAH相關的基因：BMPR2、ACVRL1、ENG、SMAD9、CAV1、KCNK3、CBLN2。多重連接探針擴增(MLPA)方法檢測片段重排突變。點突變對基因功能的影響以PolyPhen-2軟件進行預測。2.3兩組間的基因突變頻率比較采用Fisher's檢驗。采用卡方檢驗明確基因型分布是否服從Hardy-Weinberg平衡定律。3、研究結果共66個樣本進行了基因變異的分析,包括49名CTEPH患者及17名PE后無PAH的患者。CBLN2的CDS1因技術原因PCR擴增失敗。共發(fā)現(xiàn)40個基因突變位點,包括31個點突變和9個片段重排。13個位點很可能造成功能破壞,2個突變位點可能造成破壞,2個突變位點為良性突變。3名研究對象有多處的點突變。CTEPH患者的PAH相關基因的非同義突變比率大于對照組(CTEPH組25/49(51%)vs.對照組3/17(18%),p=0.022)。共發(fā)現(xiàn)12個在dbSNP數(shù)據(jù)庫中已有記錄的單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)。比較了兩組間的基因型及等位基因頻率后,發(fā)現(xiàn)SNP rs3739817和SNP rs55805125與CTEPH有關。4、第二部分研究結論中國漢族CTEPH患者中較高的PAH致病基因的突變頻率可能與CTEPH發(fā)病有關。第三部分CTEPH患者的蛋白質組學研究1、研究目的從CTEPH患者的肺動脈內(nèi)膜切除組織中進行差異蛋白質對比,以尋求發(fā)病過程中的“特異蛋白質分子”或“特異的信號轉導通路”。2、研究方法2.1實驗分組：1)CTEPH患者行肺動脈血栓內(nèi)膜切除術中取得的增生內(nèi)膜組織提取蛋白質的等份混合物；2)培養(yǎng)的人肺動脈內(nèi)皮細胞、人肺動脈平滑肌細胞、人肺成纖維細胞,收集并鑒定后提取蛋白質的等份混合物。2.2兩組蛋白質混合物以高效液相色譜(high-performance liquid chromatography, HPLC)分離后作色質聯(lián)用進一步分離、鑒定。2.3兩次均分離鑒定到的蛋白質在兩組間比較,取得病變組織特異表達的蛋白質譜作進一步的G0和KEGG生物信息學分析。3、研究結果組織特異性的蛋白質為679個。由特異表達蛋白質的生物學過程富集結果顯示,特異表達蛋白質主要參與了損傷反應、免疫反應、炎癥反應、補體激活及血液凝固等生物過程。特異表達蛋白質主要構成細胞外基質、血小板、分泌顆粒、脂蛋白復合體以及囊泡等細胞組分。特異表達蛋白質主要發(fā)揮了與糖類結合、酶抑制劑激活以及與鈣離子結合等功能。富集于補體及凝血通路、系統(tǒng)性紅斑狼瘡通路、ECM與受體結合通路、細胞粘附分子通路、Fc epsilon RI信號通路、白細胞跨內(nèi)皮遷移通路、朊病毒疾病通路(CCL5,補體C1qa, C1QB, C1QC, C6, C7, C8A, C8B, C8G)、病毒性心肌炎、Fc gamma R介導的胞吞通路等信號通路。4、第三部分研究結論此部分CTEPH患者肺動脈血栓內(nèi)膜的蛋白質組學研究得到679個病變組織特異的蛋白質。特異表達蛋白質主要參與了損傷反應、免疫反應、炎癥反應、補體激活及血液凝固等生物過程。富集于補體及凝血通路、系統(tǒng)性紅斑狼瘡通路、ECM與受體結合通路、細胞粘附分子通路、Fc epsilon RI信號通路、白細胞跨內(nèi)皮遷移通路等信號通路。第四部分心肺運動試驗在預測CTEPH中的作用1、研究目的在這部分研究中,我們評估了APE存活者三種不同的預后狀態(tài),以期發(fā)現(xiàn)敏感的心肺運動試驗的疾病監(jiān)測指標。2、研究方法2.1研究對象：自2011年1月至2014年5月間連續(xù)入選符合標準的,在我科住院的66名CTEPH患者、44名慢性PE患者、15名PE痊愈患者。慢性PE, PE痊愈患者以及3例CTEPH來自2011年1月起始的中國肺栓塞注冊登記研究(2011BA11B17).36名健康成年人作為對照組。2.2心肺運動試驗：在醫(yī)生監(jiān)督下進行癥狀限制的功率遞增式直立踏車運動試驗。先進行3分鐘靜息數(shù)據(jù)采集后開始3分鐘的無負荷踏車運動,繼之3分鐘的持續(xù)功率遞增直至最大耐受量。氣體交換采用逐次呼吸測量系統(tǒng)：功率遞增幅度的選擇根據(jù)對患者病史包括日常運動量和運動強度、體格檢查和肺功能狀況綜合決定。遞增方案：CTEPH組、CPE組為10～15 W/min,對照組為10～30 W/min。2.3統(tǒng)計分析：連續(xù)數(shù)據(jù)組間比較采用方差分析；分類變量的組間比較采用卡方檢驗。Pearson或Spearman相關分析臨床數(shù)據(jù)與VE/VC02斜率、VD/VTphy、最低點VE/VCO2比值。多變量線性回歸分析明確CPET中的獨立預測CTEPH的指標。受試者工作曲線(receiver operator characteristic curve, ROC)分析預測效力。以ROC曲線的最佳截點分類待測數(shù)據(jù),應用單變量和多變量logistic回歸分析建立預測模型。3、研究結果CTEPH患者的最低點VE/VC02比值比慢性PE組和PE痊愈組明顯增高(43.4L/min vs 29.9 L/min vs 27.1 L/min, p0.005); VE/VC02斜率(48.4 L/min/L/min vs 29.9 L/min/L/min vs 28.0 L/min/L/min, p0.005)及攝氧效率平臺(OUEP) (37.1 L/min vs 27.0 L/min vs 25.2 L/min, p0.005)也顯著高于慢性PE組和PE痊愈組。Logistic回歸分析顯示,最低點VE/VC02比值≥34.35 L/min是預測CTEPH的最強因子(OR 159.0,95% CI 36.0-702.3, p0.001)。慢性PE組的最低點VE/VC02比值較對照組高(29.9 L/min vs 26.5 L/min, p0.05),但最低點VE/VC02比值在痊愈組和對照組無差別。在多元線性回歸分析中,基于肺通氣／灌注顯像評價的血管阻塞率(PVO)是慢性PE組和痊愈組的通氣效率指標的獨立預測因子。4、第四部分研究結論4.1CTEPH患者的通氣效率降低；4.2最低點VE/VC02比值是預測CTEPH的最佳指標；4.3通氣效率隨急性PE恢復而改善。三、結論1、鐵代謝水平與CTEPH發(fā)病無明確相關。CTEPH患者和慢性肺栓塞患者的機體sTfR水平及鐵蛋白水平均在正常范圍。2、中國漢族CTEPH患者中較高的PAH致病基因的突變頻率可能與CTEPH發(fā)病有關。3、CTEPH患者肺動脈血栓內(nèi)膜切除的組織特異表達蛋白質主要參與了損傷反應、免疫反應、炎癥反應、補體激活及血液凝固等生物過程。富集于補體及凝血通路、系統(tǒng)性紅斑狼瘡通路、ECM與受體結合通路、細胞粘附分子通路、Fc epsilonRI信號通路、白細胞跨內(nèi)皮遷移通路等信號通路。4、心肺運動試驗是評估肺栓塞預后的良好方法,最低點VE/VC02比值是預測CTEPH的最佳指標。
[Abstract]:1. Background chronic thromboembolic pulmonary hypertension (Chronic thromboembolic pulmonary hypertension, CTEPH) is of fourth major categories in the classification of pulmonary hypertension. The cumulative incidence of CTEPH in patients with acute pulmonary thromboembolism (Acute pulmonary thromboembolism, APE) within 5 years is about 0.4%-5.1%. in this part of the patients. The pathophysiological mechanism of PH is not clearly defined as the pathological features of.CTEPH in the pulmonary artery that can not be melted with secondary fibrosis and machine. 1, a number of previous studies have shown that iron metabolic disorders are closely related to thrombotic diseases and.2. Pathological studies show that the distal arteries of the non blocking vessels of the CTEPH patients also occur with the idiopathic pulmonary hypertension Pulmonary arterial hypertension (PAH) is the same plexiform lesion. Gene mutation is an important pathogenesis of idiopathic PAH and hereditary PAH. Multiple gene mutations have been found to be associated with the pathogenesis of PAH. The existence of PAH related gene mutations in CTEPH patients is not yet clear of.3. Differential proteomics research is a clear disease pathogenesis. .4, a good method for searching for disease specific protein molecules, and early detection of the presence of CTEPH and active treatment are expected to improve the prognosis of the patients. Therefore, this subject studies the possible pathogenesis of CTEPH from three aspects of iron metabolism, gene mutation and proteomics, and the assessment of patients with different disease status after APE by cardiopulmonary exercise test. To find a sensitive factor for predicting CTEPH. Two, Part 1 of the study, Part 1, study of the role of iron metabolism in the pathogenesis of CTEPH. The purpose of this study was to determine whether iron metabolism was associated with CTEPH.2 by comparing the iron metabolism in patients with CTEPH and acute PE events, and method 2.1: April 2013 to March 2014. A clear diagnosis of CTEPH patients and chronic PE patients in the Fuwai Hospital of the Fuwai Hospital: collecting fasting plasma, detecting plasma free iron concentration, ferritin, soluble transferrin receptor (sTfR), hepcidin-25, tumor necrosis factor - alpha (TNF- alpha), interleukins -6 (IL-6), and malondialdehyde (MDA) level:.2.3 statistics analysis: The two groups of continuous data were compared with student's t test or Mann-Whitney U test; the two groups of classified variables were compared with chi square test. The correlation between the concentration of non binding iron ions and hepcidin-25, sTfR, ferritin, sTfR/ ferritin ratio, TNF- a, IL-6, MDA was carried out by Spearman correlation coefficient to indicate the.Hepcidin-25 concentration and the above tests. The relationship between measurement index and Spearman correlation coefficient was used to express.Logistic regression model to analyze the relationship between CTEPH and the above indexes.3. The results of the study showed no significant difference between the concentration of non binding iron ions in the CTEPH group and the chronic PE control group. There was no significant difference between the two groups of hepcidin-25, sTfR, TNF- alpha and MDA, and the IL-6 significantly higher than that of the.CTEPH group was higher than that of the pair. The level of.Hepcidin-25 was negatively correlated with the concentration of sTfR (Spearman's r=-0.438, P 0.001); hepcidin-25 level was positively correlated with ferritin (Spearman'sr=0.503, p0.001). There was no significant correlation between the concentration of non binding iron ions in plasma and hepcidin-25, sTfR, ferritin, sTfR/ ferritin ratio, TNF- beta, etc. (see table 1-3). The analysis showed that the concentration of non binding iron ions, sTfR, ferritin, sTfR/ ferritin ratio, TNF- a, IL-6, MDA were not significantly related to the pathogenesis of CTEPH.4. The first part of the study concluded that the level of iron metabolism was not clearly related to the pathogenesis of CTEPH and the sTfR level and the level of ferritin in the patients with.CTEPH and chronic PE were in the normal range. Second part CTEPH. Gene mutation study 1, the purpose of the study was to compare the genetic variation of CTEPH patients and patients with a history of PE without PAH. The purpose of the study was to determine whether PAH related mutations were involved in the pathogenesis of.2 in CTEPH. Study methods 2.1 subjects: 49 CTEPH patients and 17 patients with PE history without PH control group, the.2.2 gene mutation test. Test: collect the blood samples, extract the whole genome DNA. direct sequencing and compare with the reference sequence to detect PAH related genes: BMPR2, ACVRL1, ENG, SMAD9, CAV1, KCNK3, CBLN2. multiple connection probe amplification (MLPA) method for detecting fragment rearrangement mutation. The effect of point mutation on gene function is used to predict the genes between two groups of.2.3. The mutation frequency was compared with the Fisher's test. A chi square test was used to determine whether the genotype distribution was subject to the Hardy-Weinberg equilibrium law.3. The results of the study were analyzed in 66 samples, including 49 CTEPH patients and 17 PE without PAH for.CBLN2 CDS1 due to the failure of PCR amplification. A total of 40 gene mutations were found. Points, including 31 point mutations and 9 fragment rearrangements,.13 sites are likely to cause functional damage, 2 mutation sites may cause damage, 2 mutation sites are benign.3 names, and there are multiple point mutations in.CTEPH patients with PAH related genes more non synonymous mutations than the control group (CTEPH group 25/49 (51%) vs. control group 3/17 (18%), p= 0.022). A total of 12 single nucleotide polymorphisms (single nucleotide polymorphism, SNP), which were recorded in the dbSNP database, were found. After comparing the genotype and allele frequencies between the two groups, the SNP rs3739817 and SNP rs55805125 were found to be associated with CTEPH.4. The second part studies the higher pathogenic genes in the Chinese Han patients. The mutation frequency may be associated with the incidence of CTEPH. Third part of the proteomics study in partial CTEPH patients 1. The purpose of the study was to compare protein contrast in the pulmonary endarterectomy tissues of patients with CTEPH in order to seek "specific protein molecules" or "specific signal transduction pathways" in the pathogenesis of.2, and the study method 2.1 group. 1) an equal mixture of proteins extracted from the intima tissue of the CTEPH patients during the endarterectomy of pulmonary artery thrombosis; 2) the cultured human pulmonary artery endothelial cells, human pulmonary artery smooth muscle cells, human lung fibroblasts, and after collecting and identifying the equivalent mixture of protein.2.2 two groups of protein mixtures for high performance liquid chromatography After the high-performance liquid chromatography (HPLC) separation, the color composition was further separated, and the protein identified by the.2.3 two times was compared between the two groups. The protein mass specific expressed by the pathological tissue was obtained for further G0 and KEGG bioinformatics analysis.3, and the results of the study were 679 of the specific proteins. Biological process enrichment results show that specific protein mainly participates in biological processes such as injury reaction, immune response, inflammatory reaction, complement activation and blood coagulation. Specific proteins mainly consist of extracellular matrix, platelets, secretory particles, lipoprotein complexes and vesicles. The proteins expressed mainly in combination with carbohydrates, activation of enzyme inhibitors and binding with calcium ions. Enriched in complement and coagulation pathways, systemic lupus erythematosus pathway, ECM and receptor binding pathway, cell adhesion molecule pathway, Fc epsilon RI signaling pathway, white fine cell transendothelial pathway, prion disease pathway (CCL5, supplementation) C1qa, C1QB, C1QC, C6, C7, C8A, C8B, C8G), viral myocarditis, and Fc gamma R mediated endocytosis pathway and other signaling pathways. The third part studies the proteomic study of the pulmonary artery intima of the pulmonary artery of the patients. The specific protein is mainly involved in the damage response and immunization. Biological processes such as reaction, inflammatory response, complement activation and blood coagulation. Enrichment in complement and coagulation pathways, systemic lupus erythematosus pathway, ECM and receptor binding pathway, cell adhesion molecular pathway, Fc epsilon RI signaling pathway, and leucocyte transendothelial migration pathway. The fourth part cardiopulmonary exercise test in predicting CTEPH 1, in this part of the study, we evaluated three different prognostic states of APE survivors in order to find the disease monitoring index of the sensitive cardiopulmonary exercise test.2. Methods 2.1 research subjects: 66 CTEPH patients hospitalized in our department from January 2011 to May 2014 and 44 chronic PE patients hospitalized in our department. 15 PE patients, chronic PE, PE healers, and 3 cases of CTEPH from the January 2011 Chinese pulmonary embolism registration study (2011BA11B17).36 healthy adults as the control group.2.2 cardiopulmonary exercise test: a power incremental treadmill exercise test under the supervision of a doctor under the supervision of a doctor. An advanced line of 3 minutes resting The 3 minute load free treadmill started after the data collection, followed by a 3 minute continuous power increase to the maximum tolerance. Gas exchange using a successive respiratory measurement system: the choice of power increasing amplitude was based on the patient's medical history including daily movement and exercise intensity, physical examination and lung function status. An incremental scheme: CT The EPH group, CPE group was 10~15 W/min, and the control group was 10~30 W/min.2.3 statistical analysis: the continuous data group was compared with the analysis of variance; the group comparison of the classified variables used the chi square test.Pearson or Spearman correlation analysis clinical data with the VE/VC02 slope, VD/VTphy, and the lowest VE/ VCO2 ratio. Multivariate linear regression analysis made clear CPET in the CPET. Receiver operator characteristic curve (ROC) was used to predict the effectiveness of CTEPH independently. The optimal section of the ROC curve was used to classify the data, and the single variable and multivariable logistic regression analysis was used to establish the prediction model.3. The results of the study results of the lowest VE/VC02 ratio of the CTEPH patients were better than those of the chronic PE group and the recovery. The group was significantly higher (43.4L/min vs 29.9 L/min vs 27.1 L/min, P0.005), VE/VC02 slope (48.4 L/min/L/min vs 29.9 L/min/L/min vs 28 L/min/L/min, 37.1) and oxygen uptake efficiency platform (37.1) was also significantly higher than that of the chronic group and the recovery group. The VC02 ratio of more than 34.35 L/min was the strongest factor for predicting CTEPH (OR 159.0,95% CI 36.0-702.3, p0.001). The lowest VE/VC02 ratio of the chronic PE group was higher than that of the control group (29.9 L/min vs 26.5), but there was no difference between the recovery group and the control group. The rate of vascular obstruction rate (PVO) was an independent predictor of the ventilation efficiency index in the chronic PE group and the healing group. The fourth part of the study concluded that the ventilation efficiency of the 4.1CTEPH patients was reduced; the 4.2 lowest VE/VC02 ratio was the best indicator of the prediction of CTEPH; the 4.3 ventilation efficiency was improved with the acute PE recovery. Three, conclusion 1, the iron metabolism level and CTEPH pathogenesis. The level of sTfR and ferritin in the patients with.CTEPH and chronic pulmonary embolism were in a normal range of.2. The mutation frequency of the higher PAH pathogenic gene in Chinese Han CTEPH patients may be associated with the pathogenesis of CTEPH, and the tissue specific protein expressed in the patients with pulmonary artery thrombosis in CTEPH patients is mainly involved in the injury reaction. Biological processes such as immune response, inflammatory response, complement activation and blood coagulation, enrichment in complement and coagulation pathways, systemic lupus erythematosus pathways, ECM and receptor binding pathways, cell adhesion molecules pathway, Fc epsilonRI signaling pathway, leucocyte transendothelial migration pathway,.4, cardiopulmonary exercise test is a good prognosis assessment of pulmonary embolism Good method, the lowest VE/VC02 ratio is the best indicator for predicting CTEPH.

【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R544.1

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