Xing_Wan_Predicting Blood Donor_s Attrition
八年级英语文学作品赏析单选题40题
八年级英语文学作品赏析单选题40题1.In the novel "Oliver Twist", Oliver is known for being _____.A.cunningB.braveC.timidD.arrogant答案：B。
Oliver 在小说《雾都孤儿》中以勇敢著称。
选项A“cunning”意为狡猾的，不符合Oliver 的人物特点；选项C“timid”意为胆小的，也与Oliver 的形象不符；选项D“arrogant”意为傲慢的，同样不是Oliver 的特点。
2.The main character in "Pride and Prejudice", Elizabeth Bennet, is often described as _____.A.shyB.intelligentC.naiveD.snobbish答案：B。
《傲慢与偏见》中的女主角伊丽莎白·贝内特通常被描述为聪明。
选项A“shy”意为害羞的，不符合伊丽莎白的性格；选项C“naive”意为天真的，也不是她的特点；选项D“snobbish”意为势利的，与伊丽莎白的形象相悖。
3.In "Jane Eyre", Jane is characterized by her _____.A.vainnessB.passivityC.independenceD.cowardice答案：C。
在《《简·爱》中，简的特点是独立。
选项A“vainness”意为虚荣，简并不虚荣；选项B“passivity”意为被动，简不是被动的人；选项D“cowardice”意为胆小，简很勇敢，不是胆小之人。
4.The hero in "The Adventures of Tom Sawyer" is _____.zyB.cleverC.stupidD.cruel答案：B。
遗传学(第3版) 刘祖洞、乔守怡、吴燕华、 赵寿元 高等教育出版社 (2013-01)课后习题答案6
Chapter 6 Circulating Methylated DNA as Biomarkers for Cancer DetectionHongchuan Jin, Yanning Ma, Qi Shen andXian WangAdditional information is available at the end of the chapter/10.5772/514191. IntroductionIn addition to genetic alterations including deletion or point mutations, epigenetic changes such as DNA methylation play an important role in silencing tumor suppressor genes dur‐ing cancer development. By adding a methyl group from S-adenosyl-L-methionine to the cy‐tosine pyrimidine or adenine purine ring, DNA methylation is important to maintain genome structure and regulate gene expression. In mammalian adult tissues, DNA methyla‐tion occurs in CpG dinucleotides that often cluster in the genome as CpG islands in the 5’regulatory regions of the genes. Through recruiting transcriptional co-repressors including methyl-CpG-binding domain proteins (MBDs) and chromatin remodeling proteins like his‐tone deacetylases (HDACs) or impeding the binding of transcriptional activators, DNA methylation could suppress the transcription of many tumor suppressor genes critical to cancer initiation and progression [1-3].More and more results confirmed that cancer is a multi-stage process fuelled by many epige‐netic changes in addition to genetic changes in DNA sequence [4]. Chemical molecules like Trichostatin A (TSA) and 5-aza-2'-deoxycytidine (5-Aza-CdR) targeting epigenetic regula‐tors such as histone modifications and DNMTs (DNA methyltransferases) have been found to inhibit tumor growth both in vitro and in vivo. By reversing the epigenetic silencing of important tumor suppressor genes, an increasing number of epigenetic drugs such as 5-Aza-CdR, 5-Aza-CR and Vorinostat (SAHA) are currently investigated in the clinical trials for cancer treatment as a single drug or in combination with other epigenetic drugs or other ap‐proaches such as chemotherapy and showed very promising activities by offering signifi‐cant clinical benefits to cancer patients [5-13].© 2013 Jin et al.; licensee InTech. This is an open access article distributed under the terms of the CreativeCommons Attribution License (/licenses/by/3.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.As one of the major epigenetic changes to inactivate tumor suppressor genes critical to hu‐man cancer development, DNA methylation was recognized as the biomarker for cancer de‐tection or outcome prediction in addition to the identification of novel tumor suppressor genes. DNA mutations will occur randomly in any nucleotides of one particular gene and the comprehensive determination of DNA mutations is thus very difficult and time-consum‐ing. In contrast, aberrant DNA hypermethylation usually takes place in defined CpG Islands within the regulatory region of the genes and it is much more convenient to detect DNA methylation in a quantitatively manner. In addition, DNA methylation can be amplified and is thus easily detectable using PCR-based approaches even when the DNA concentration af‐ter sample extraction is relatively low. Due to such advantages over DNA mutation- or pro‐tein-based biomarkers, DNA methylation-based biomarkers have been intensively investigated in the recent years. A large body of research reports has proved the value of DNA methylations in the prognosis prediction and detection of various cancers. DNAs used for such methylation analyses are usually extracted from tumor tissues harvested after sur‐gical operation or biopsy, thus limiting its wide application as the biomarkers for the early detection or screening of human cancers. Recently, it has been reported that there are certain amount of circulating DNAs in the peripheral blood of cancer patients, providing an ideal source to identify novel biomarkers for non-invasive detection of cancers. Both genetic and epigenetic changes found in the genomic DNAs extracted from primary tumor cells could be detected in the circulating DNAs, indicating that the detection of methylated DNAs in the circulation represents a new direction to develop novel biomarkers for cancer detection or screening in a non-invasive manner.2. Cell free DNA in the circulationAccording to the origin of circulating tumor-related DNA, it could be grouped into circulat‐ing cell free DNA or DNA from cells in the blood such as circulating tumor cells (CTC) in cancer patients (Figure 1).In 1869, the Australian physician Thomas Ashworth observed CTCs in the blood of a cancer patient. Therefore, it was postulated that CTCs were responsible for the tumor metastases in distal sites and should have important prognostic and therapeutic implications [14-16].However, the number of CTCs is very small compared with blood cells. Usually around 1-10CTCs together with several million blood cells could be found in 1 ml of whole blood, mak‐ing the specific and sensitive detection of CTCs very difficult [17-18]. Until recently, technol‐ogies with the requisite sensitivity and reproducibility for CTC detection have been developed to precisely analyze its biological and clinical relevance. The US Food and Drug Administration (FDA) approved the test for determining CTC levels in patients with meta‐static breast cancer in 2004. Currently, it has been expanded to other cancer types such as advanced colorectal cancer and prostate cancer. Although CTCs-counting based test have proven its value in predicting prognosis and monitoring therapeutic effects, the number of CTCs per ml of blood limited its sensitivity greatly [19]. With the development of high-sen‐sitive PCR-based methods, the detection of gene mutations or epigenetic changes such asMethylation - From DNA, RNA and Histones to Diseases and Treatment138DNA methylation within small amount of CTCs could be the next generation of CTC-based test for cancer detection. However, the cost of such tests will be greatly exacerbated, thuslimiting its wide application in the clinic [20-22].Figure 1. Circulating tumor cells and cell free DNA. Circulating Tumor cells (CTC) escape from primary sites and spread into the vessel to form metastases in the distal organs with. Cell free DNAs (cf-DNAs) are released into the circulation from dead cancer cells or proliferating tumor cells. RBC: red blood cell; WBC: white blood cell.Although its origin and biological relevance remains unknown, circulating cell free DNA (cf-DNA) is supposed to be valuable source to identify cancer markers with ideal sensitivity and specificity for non-invasive detection of cancer [23-24]. Early in 1948, two French scientists Mandel and Metais firstly reported the presence of cf-DNAs in human plasma [25]. Such an important discovery has been unnoticed for a long time until cell-free circulating nucleic acid was found to promote the spread and metastasis of crown gall tumor in plants [26]. Subse‐quently, increased level of cf-DNAs was found in patients with various diseases such as lupus erythematosus and rheumatoid arthritis cancer [27-28]. In 1977, Leon et al. reported that higher level of circulating DNA in the plasma of cancer patients when compared to healthy con‐trols. Moreover, greater amounts of cf-DNA were found in the peripheral blood of cancer patients with tumor metastases and cf-DNA levels decreased dramatically after radiothera‐py while persistently high or increasing DNA concentrations were associated with a lack of response to treatment [29], clearly revealing the potential value of cf-DNA as biomarker for cancer detection. Following studies confirmed that cf-DNAs in the plasma contains genetic and epigenetic changes specific to DNAs within the tumor cells from primary tissues, indicat‐ing that tumor specific cf-DNAs are originated from tumor cells rather than lymphocytes reacting towards the disease [30-31]. For example, K-Ras mutation was found in cf-DNA from 17 out of 21 patients with pancreatic adenocarcinoma and mutations were similar in corre‐sponding plasma and tissues samples. Importantly, such DNA alterations were found inCirculating Methylated DNA as Biomarkers for Cancer Detection/10.5772/51419139patients with pancreatitis who were diagnosed as pancreatic cancer 5-14 months later, indi‐cating that release of tumor-specific DNA into the circulation is an early event in cancer development and cf-DNA could be used as the biomarkers for early cancer detection [32].Treatment resulted in disappearance of K-Ras mutations in plasma DNA in six of nine pa‐tients. Three patients with a persistently positive K-Ras gene mutation in plasma samples from patients before and after treatment showed early recurrence or progression and pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene, indicating the cf-DNA could be of value in monitoring disease progression or evaluating treatment response [31, 33].Through quantitatively analyzing plasma DNAs from patients with organ transplantation,Lo et al found that the majority of plasma DNAs was released from the hematopoietic sys‐tem. However, donor DNA could be detected in the plasma of recipients suffering from the graft rejection because of the large amount of cell death which promotes the release of donor DNAs into the peripheral blood of the recipients [34]. Therefore, it was postulated that cell-free tumor related DNA could originate from the apoptotic tumor cells since high-rate of apoptosis indeed occurs in primary and metastatic tumor tissues. However, cf-DNA quanti‐ties are significantly reduced in cancer patients after radiotherapy when a great number of tumor cells were believed to undergo apoptotic cell death and cf-DNAs in supernatants of cultured cancer cells increases with cell proliferation rather than apoptosis or necrosis, indi‐cating that proliferating tumor cells could actively release cf-DNA into the tumor microen‐vironment and circulation.In contrast to labile RNAs that were included into the actively secreted exosomes, the nature of cf-DNAs remains to be clarified. As negatively charged molecules, cf-DNA was bound by plasma proteins to escape from endonuclease-mediated degradation. Unfortunately, plasma proteins bound to cf-DNAs was not well characterized yet. Meanwhile, secreted exosomes could remodel microenviroments and promote tumor metastasis since RNAs within exo‐somes especially microRNA with high stability may influence gene expression in neighbor cells. The biological relevance of cf-DNAs remains unknown. DNA was believed to be more structural rather than functional. However, it was supposed that cf-DNA could play a role as vaccine in tumor microenvironment.3. Methods for the detection of methylated DNAIt is unclear so far whether serum or plasma is better for cf-DNA extraction. Although the DNA amount is significantly higher in the serum, the majority of the increase was due to the release of nuclear acids from destroyed blood cells during blood clotting [35]. In addition,the time gap between blooding drawing and DNA extraction as well as the methodologies used for DNA isolation contribute greatly to the amount of cf-DNA harvested. On an aver‐age, around 30 ng cf-DNA could be extracted from one ml of blood sample [36]. Therefore,in order to determine the quantity of potential cf-DNA-based biomarkers precisely and pro‐mote its wide application for cancer detection, it is very important to unify the source asMethylation - From DNA, RNA and Histones to Diseases and Treatment140well as the methodologies for cf-DNA extraction and use various internal controls to adjustpossible inter-laboratory variations.Figure 2. Schematic introductions of various methods for methylation analyses. MSP, BGS and COBRA are based on bisulfite-mediated conversion of unmethylated cytosines into uracils. CpG methylation could block DNA digestion by some restriction enzymes, making it possible to determine methylation status independent of bisulfite treatment by analyzing digestion products. Alternatively, DNA fragments containing methylated CpG sites could be enriched by an‐ti-methylcytosine antibody or methylation binding proteins. Advances in next generation genome sequencing tech‐nology led to the development of noel techniques such as SMRT which can specially analyze 5-methylcytosines with genome wide coverage.In general, the detection of DNA methylation could be bisulfite-dependent or -independent (Figure 2).The chemical reaction of sodium bisulfite with DNA could convert unmethylated cytosine of CpG into uracil or UpG but leave methylated cytosine of CpG unchanged. The following analyses such as methylation-and unmethylation specific polymerase chain reaction (M- and U-SP), bisulfite genome sequencing (BGS) or combined bisulfite restriction analysis (CO‐BRA) could determine the conversion of CpG sites of interest, thus reflecting their methyla‐tion status as methylated or unmethylated [37]. With varied resolution levels, different bisulfite-dependent DNA methylation analysis methods detect the conversion after bisulfite treatment of genomic DNA, which could have certain artificial effects such as incomplete conversion of unmethylated CpG into UpG, leading to high rate of false negative conclusion of DNA methylation status.Recently, some new modifications of cytosine in CpG dinucleotides have been discovered such as 5-hydoxymethylcytosine which was called the sixth base since 5-methylcytosine was named as the fifth base [38]. Generated from the oxidation of 5-methylcytosine by the Tet family of enzymes, 5-hydoxymethylcytosine was first found in bacteriophages and recentlyCirculating Methylated DNA as Biomarkers for Cancer Detection/10.5772/51419141shown to be abundant in human and mouse brains as well as in embryonic stem cells [39-40]. Although the exact relevance of 5-hydoxymethylcytosine in the genome is still not fully clarified, it has been found to regulate gene expression or promote DNA demethyla‐tion. The in vitro synthesized artificial oligonucleotides containing 5-hydoxymethylcyto‐sines can be converted into unmodified cytosines when introduced into mammalian cells,indicating that 5-hydoxymethylcytosine might be one of intermediate products during ac‐tive DNA demethylation [41]. Therefore, the increase of 5-hydoxymethylcytosine might re‐flect the demethylation of CpG dinucleotides. Unfortunately, 5-hydoxymethylcytosines,similar to 5-methylcytosines, appear to be resistant to bisulfite-mediated conversion and PCR could amplify DNA fragments containing 5-hydoxymethylcytosines or 5-methylcyto‐sines with similar efficiency [42-43]. Therefore, bisulfite-dependent methylation analyses could produce false positive results by counting 5-hydoxymethylcytosines into 5-methylcy‐tosines. In addition to 5-hydroxymethylcytosines, some forms of DNA modifications such as the seventh base, 5-formylcytosine and the eighth base, 5-carboxylcytosine, have been found in mammalian cells recently [44-47]. As the products of 5-hydoxymethylcytosine oxidation through TET hydroxylases, both 5-formylcytosine and 5-carboxylcytosine will be read as the uracil after bisulfite conversion, thus making it impossible for bisulfite-dependent analyses to distinguish unmodified cytosines from 5-formylcytosines and 5-carboxylcytosines.Bisulfite independent analyses such as MedIP (methylated DNA immunoprecipitation)could more or less detect DNA methylation specifically. In bisulfite independent analyses, 5-methylcytosines are differentiated from unmethylated cytosine by either enzyme digestion or affinity enrichment. DNA methylation analysis using restriction enzyme digestion is based on the property of some methylation-sensitive and -resistant restriction enzymes such as HpaII and MspI that target CCGG for digestion. HpaII fails to cut it once the second cyto‐sine was methylated while MspI-mediated digestion is not affected by DNA methylation,thus making it possible to determine the methylation status of CpG in the context of CCGG tetranucleotides by analyzing the products of DNAs digested by HpaII and MspI respective‐ly. As a primary method to analyze DNA methylation, it can only determine the methyla‐tion of CpG in the context of CCGG tetranucleotides and will overlook the majority of CpG dinucleotides in the genome.The development of monoclonal antibody specific to 5-methylcytosines revolutionized the analyses of DNA methylation [48-49]. Immunoprecipitated DNA by this antibody could be subject to DNA microarray or even deep sequencing to reveal novel sequences or sites con‐taining 5-methylcytosines [50]. This antibody specifically recognizes 5-methylcytosines but not 5-hydoxymethylcytosines. However, 5-methylcytosines could present not only in CpG dinucleotides but also in CHH or CHG trinucleotides, especially in plants, human embryon‐ic stem cells and probably cancer cells as well. CHH methylation indicates a 5-methylcyto‐sine followed by two nucleotides that may not be guanine and CHG methylation refers to a 5-methylcytosine preceding an adenine, thymine or cytosine base followed by guanine. Such non-CpG DNA methylations were enriched at transposons and repetitive regions, although the exact biological relevance remains unknown. However, antibody against 5-methylcyto‐Methylation - From DNA, RNA and Histones to Diseases and Treatment142sine may precipitate methylated CHH and CHG trinucleotide containing DNA fragments in addition to DNA sequences with methylated CpG sites.DNA methylation functions as the signal for DNA-interacting proteins to maintain genome structure or regulate gene expression. The proteins such as MBD1 (methyl-CpG binding do‐main protein 1), MeCP2 (methyl CpG binding protein 2) and MBD4 (methyl-CpG binding domain protein 4) bind methylated CpG specifically to regulate gene expression [51-52].Therefore, methyl-CpG binding domain could specifically enrich differentially methylated regions (DMRs) of physiological relevance [53]. Similar to MeDIP, MBD capture specifically enrich methylated CpG sites rather than hydroxymethlated CpG sites. The detailed analysis to compare MeDIP and MBD capture revealed that both enrichment techniques are sensitive enough to identify DMRs in human cancer cells. However, MeDIP enriched more methylat‐ed regions with low CpG densities while MBD capture favors regions of high CpG densities and identifies the greater proportion of CpG islands [49].Recently, the advance of next generation sequencing led to the development of several novel techniques, making it possible to quantitatively analyze DNA methylation at single nucleo‐tide resolution with genome wide coverage. Both the single molecule real time sequencing technology (SMRT) and the single-molecule nanopore DNA sequencing platform could dis‐criminate 5-methylcytosines from other DNA bases including 5-hydroxymethylcytosines even methyladenine independent of bisulfite conversion [54-55]. With many advantages such as less bias during template preparation, lower cost and better accuracy, such new techniques could offer more methods to detect DNA methylation with high specificity and sensitivity in addition to more potential DNA methylation based biomarkers for cancer de‐tection and screening.4. Potential DNA methylation biomarkers for cancer detectionIt has been questioned whether the methylated DNA in the circulation is sensitive to detect cancers early enough for curative resection. However, the development of sensitive detection methods confirmed the potential value of DNA methylation in cancer detection (Table 1).Most of DNA methylation biomarkers are well-known tumor suppressor genes silenced in primary tumor tissues. However, the biomarks do not have to be functional relevant. For ex‐ample, currently well-used biomarkers such as AFP (Alpha-Fetal Protein), PSA (Prostate-specific antigen) and CEA (Carcinoembryonic antigen) are not tumor suppressor genes with important biological functions. Profiling of methylated DNA in the circulation instead of primary tumor tissues with MeDIP or MBD capture or other methylation specific analyses methods would identify more potential biomarks rather than functional important tumor suppressor genes.Circulating Methylated DNA as Biomarkers for Cancer Detection/10.5772/51419143Cancer Markers Sensitivity Specificity Methods Ref.Bladder cancer CDKN2A (ARF) CDKN2A(INK4A)CDKN2A (INK4A)13/27 (48%)2/27 (7%)19/86 (22%)N/AN/A31/31 (100%)MSPMSPMSP[58][59]Breast cancer CDKN2A (INK4A)CDKN2A (INK4A)5/35 (14%)6/43 (14%)N/AN/AMS-AP-PCRMS-AP-PCR[56][57]Colorectal cancerMLH1CDKN2A (INK4A) CDKN2A(INK4A) CDKN2A (INK4A)ALX4CDH4NGFRRUNX3SEPT9TMEFF23/18 (17%)14/52 (27%)13/94 (11%)21/58 (36%)25/30 (83%)32/46 (70%)68/133 (51%)11/17 (65%)92/133 (69%)87/133 (65%)N/A44/44 (100%)N/AN/A36/52 (70%)17/17 (100%)150/179 (84%)10/10 (100%)154/179 (86%)123/179 (69%)MSPMSPMSPMSPMSPMSPMSPMSPMSPMSP[60][61][62][63][64][65][66][67][66]Esophageal cancer APCAPCCDKN2A (INK4A)13/52 (25%)2/32 (6%)7/38 (18%)54/54 (100%)54/54 (100%)N/AMSPMSPMSP[68][69]Gastric cancer CDH1CDKN2A (INK4A)CDKN2B (INK4B)DAPK1GSTP1Panel of five 31/54 (57%)28/54 (52%)30/54 (56%)26/54 (48%)18/54 (15%)45/54 (83%)30/30 (100%)30/30 (100%)30/30 (100%)30/30 (100%)30/30 (100%)30/30 (100%)MSPMSPMSPMSPMSPMSP[70]Head and neck cancer CDKN2A (INK4A)DAPK1MGMTPanel of threeDAPK18/95 (8%)3/95 (3%)14/95 (15%)21/95 (22%)N/AN/AN/AN/AN/AN/AMSPMSPMSPMSPMSP[71][72]Liver cancer CDKN2A (INK4A) CDKN2B(INK4B)13/22 (45%)4/25 (16%)48/48 (100%)35/35 (100%)MSPMSP[73][74]Lung cancer CDKN2A (INK4A)DAPK1GSTP1MGMTPanel of fourCDKN2A (INK4A)APC 3/22 (14%)4/22 (18%)1/22 (5%)4/22 (18%)11/22 (50%)N/A42/89 (47%)N/AN/AN/AN/AN/AN/A50/50 (100%)MSPMSPMSPMSPMSPMSPMSP[75][76][77]Methylation - From DNA, RNA and Histones to Diseases and Treatment 144Cancer Markers Sensitivity Specificity Methods Ref.CDKN2A (INK4A)CDKN2A (INK4A)77/105 (73%)12/35 (34%)N/A15/15 (100%)MSP MSP [78][79]Prostate cancer GSTP1GSTP123/33 (70%)25/69 (36%)22/22 (100%)31/31 (100%)MSP MSP[80][81]Table 1. Methylated DNA biomarkers in the literature.Most of the methods used for methylation biomarkers analyses are still bisulfite dependent.Few reports used MS-AP-PCR (methylation-sensitive arbitrarily primed PCR) which takes the advantage of methylation sensitive restriction endonucleases to distinguish methylated CpG from unmethylated form, although the sensitivity seems to be lower than MSP [56-57].Interestingly, combination of more than one methylated DNA as a methylation panel could great increase the sensitivity for cancer detection without significant reduction of specificity.Unfortunately, most of studies were performed in a retrospective manner. More prospective studies with large sample sizes will be warranted to compare different approaches especial‐ly bisulfite-independent methods in addition to confirm the value of DNA methylation for cancer detection.5. Conclusion and PerspectivesWith the development of the next generation genome sequencing as well as single molecular PCR, it became possible to analyze trace amount of DNAs including circulating cell-free DNA. Circulating tumor cells have been proven its value in prognosis predication even ear‐ly detection of various cancers. The analyses of methylated DNAs in the circulating will be the next promising epigenetic biomarkers for cancer detection. As one of the intermediate products of DNA demethylation, 5-hydroxymethlcytosines are resistant to bisulfite conver‐sion. Therefore, it should be carefully to interpret the data of methylation analyses based on bisulfite treatment due to potentially high rate of false positive results. Although some me‐thylated DNAs were found to valuable as a single biomarker for cancer detection, more po‐tential DNA methylations will be found after the wide application of SMRT and other sequencing platforms with high speed, depth and accuracy. DNA methylation signatures in‐cluding a panel of methylated DNAs will show the potential in the early diagnosis or screening and prognosis or therapy response prediction of many cancers. In addition, such DNA methylation biomarkers could be more sensitive and specific for cancer detection when combined with well-used biochemical biomarkers. However, unified methods with gold standards will be warranted to promote the development and clinical application of DNA methylation biomarkers.Circulating Methylated DNA as Biomarkers for Cancer Detection/10.5772/51419145AcknowledgementsThis work was supported by the National Natural Science Foundation of China (81071963;81071652), Program for Innovative Research Team in Science and technology of Zhejiang Province (2010R50046) and Program for Qianjiang Scholarship in Zhejiang Province (2011R10061; 2011R10073).Author detailsHongchuan Jin, Yanning Ma, Qi Shen and Xian Wang **Address all correspondence to: wangx118@Department of Medical Oncology, Laboratory of Cancer Epigenetics, Biomedical Research Center, Sir Runrun Shaw Hospital, Zhejiang University, ChinaReferences[1]Jones, P. A., & Baylin, S. B. (2007). The epigenomics of cancer. Cell , 128, 683-692.[2]Jones, P. A., & Baylin, S. B. (2002). The fundamental role of epigenetic events in can‐cer. 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益气活血法治疗中风的溯源与发展及新安医家的贡献
益气活血法治疗中风的溯源与发展及新安医家的贡献邵宁书1,杨文明2,3摘要中风作为四大顽症之一,在‘内经“首次提出后,便引起了历代医家的重视㊂以益气活血法为原则治疗中风,历来被认为是由清代医家王清任首次提出㊂但在近来研究中发现,益气活血法萌芽于‘内经“,并未广泛运用于中风治疗㊂隋唐时期有医家提出从气血论治中风,明清时期新安医家进一步认为气虚血瘀为中风成因,并选用益气活血药物治疗中风,其认识要早于清代医家王清任㊂益气活血法其后继续发展,并在当代治疗中风时广泛运用㊂关键词中风;新安医学;益气活血;溯源d o i:10.12102/j.i s s n.1672-1349.2024.04.001Tracing and Development of the Treatment of Stroke by Tonifying Qi and Promoting Blood Circulation and the Contribution of Xin'an DoctorsSHAO Ningshu,YANG WenmingFirst Affiliated Hospital of Anhui University of Chinese Medicine,Hefei230031,Anhui,ChinaCorresponding Author YANG Wenming,E-mail:******************Abstract As one of the four major stubborn diseases,stroke has attracted the attention of medical practitioners throughout history since it was first proposed in"the Neijing".The treatment of stroke based on the principle of tonifying Qi and promoting blood circulation has always been believed to have been first proposed by the Qing Dynasty physician Wang Qingren.However,recent research has found that the method of tonifying Qi and promoting blood circulation originated from"the Neijing"and has not been widely used in the treatment of stroke.During the Sui and Tang dynasties,some medical experts proposed to treat stroke based on the theory of Qi and blood.In the Ming and Qing dynasties,the Xin'an medical experts further believed that Qi deficiency and blood stasis were the causes of stroke,and chose to treat stroke with tonifying Qi and promoting blood circulation drugs,which was earlier than that of the Qing dynasty medical expert Wang Qingren.The method of tonifying Qi and promoting blood circulation continue to develop and is widely used in contemporary stroke treatment.Keywords stroke;Xin'an medicine;tonifying Qi and promoting blood circulation;traceability中风即脑卒中,与心脏病㊁癌症并列为人类三大死因之一㊂我国每5例死亡的城乡居民中就有2例源于心脑血管病,其死因高居死亡构成之首,而脑卒中又在我国成年人致死和致残疾病中居于首位,每年约有182万人死于脑血管疾病[1]㊂脑卒中居联合国192个成员国各种死因之首,所致伤残调整生命年约1.43亿基金项目国家中医药传承创新中心项目,编号:发改办社会 2022 366号;国家中医药管理局中医药循证能力建设项目(No.2019XZZX-NB001);安徽省高校协同创新项目(GXXT-2020-025)作者单位 1.安徽中医药大学第一附属医院(合肥230031);2.新安医学教育部重点实验室(合肥230038);3.合肥综合性国家科学中心大健康研究院-新安医学与中医药现代化研究所(合肥230012)通讯作者杨文明,E-mail:******************引用信息邵宁书,杨文明.益气活血法治疗中风的溯源与发展及新安医家的贡献[J].中西医结合心脑血管病杂志,2024,22(4):577-581.人年[2]㊂脑卒中临床有缺血性脑卒中和出血性脑卒中两大类型,以前者最为多见,约占所有脑卒中病人的80%,急性缺血性卒中病人入院之后通常采用抗血小板聚集[3-5]㊁促进侧支循环建立[6-8]㊁改善脑循环[9-11]㊁清除氧自由基[12-14]㊁营养脑细胞[15-17]等药物治疗㊂在时间窗内应用阿替普酶或尿激酶静脉或动脉溶栓或血管内取栓治疗[18],可以降低脑卒中病人致残率,甚至重新恢复正常的生活,但是溶栓对于发病时间的要求非常严格,所以大多数病人错过了有效时间窗,只有不足15%的脑卒中病人满足血管内治疗要求,错过有效时间窗者只得予以保守治疗㊂由于机械取栓方式㊁取栓次数㊁血栓性质㊁侧支循环状态等术中及术后因素会造成栓子逃逸或者开通血管再闭塞,加上血管内治疗对医疗条件及医师技术的要求比较高,这些都让血管内治疗存在许多亟待解决的困难㊂汪燕亭‘聊复集“记载: 中风者,其人表虚 ㊂中风的本质多为本虚标实,首次发病后常有宿根,大多数病人会反复发作,死亡的可能性也逐次递增,而西药长期用药的肝肾毒性㊁依赖性和副作用限制了临床的使用[19]㊂与西医相比较,中医在治疗中风上可充分发挥其 整体观念 辨证论治 的双重优势[20]㊂中医学从起源以来几千年间提出了诸多治疗中风的方法,直到从气血论治中风被大家所广泛采用并发展㊂从20世纪60年代起,医学界进一步探讨活血化瘀治疗中风,至20世纪70年代,一些中药注射液,如丹参注射液㊁水蛭注射液㊁复方红金注射液等用于治疗中风,并取得一定疗效[21]㊂在中医㊁中西医结合治疗中风或中风变证方面同样也取得了较好的疗效,崔涛[22]试验组运用中风膏联合双侧刺激治疗缺血性脑卒中导致的吞咽障碍,对照组仅用基础西药治疗,研究结果表明,试验组较对照组治疗效果更好㊁起效更快㊂郑文旭[23]使用疏肝活血解郁汤联合西药治疗中风后抑郁,对照组仅用西药氟西汀,治疗组加用疏肝活血解郁汤,结果显示,治疗组的中医证候评分㊁汉密尔顿抑郁量表评分㊁同型半胱氨酸(Hcy)及5-羟色胺(5-HT)水平明显低于对照组,表明运用中医或中西药联合治疗中风或中风变证弥补了单纯使用西药治疗的不足㊂益气活血法普遍认为是由王清任首次提出,并应用于临床,是目前中医治疗中风的主流治疗方法之一㊂此治疗方法起源为何,特别是新安医学作为一个既古老又现代的综合性学术流派,有上下800多年历史㊁800多位医家㊁800多部医著,在中风的治疗的长期临床实践中积累了丰富的经验,是否提出过类似的诊疗理论和方法,值得作一爬梳和比较研究㊂1萌芽于‘内经“唐宋之前,对中风病的认识多以 风邪侵表 立论,其源于‘内经“,‘素问“云: 百病之始生也,必先于皮毛㊂ 认为疾病的发生多是从皮肤毛发开始的,病邪侵入皮毛,而卫气代表人体防御系统,正气不足则邪气入里,外风袭人则出现中风,所中之风均为外邪,故人体卫气充足对于中风的治疗至关重要㊂人体卫气充足时,肌肉饱满㊁皮肤紧致㊁毛发茂盛㊁腠理致密,即使遇到风邪外袭体表,有卫气抵御外邪,也入里不深或仅停留于表;如果人体气虚,则形体瘦弱㊁肌肉消减㊁皮肤松弛㊁腠理不固㊁毛发稀疏,遇到邪气时,由于卫气不足,正气虚衰,无以与邪气抗衡,则病邪入里较深㊂邪气旺盛,滞留不去,则进一步传入经络,伤及脏腑,这时病人往往出现突然昏仆或肢体无力㊁半身不遂等中经络㊁中脏腑表现,正所谓: 卫气去 遇贼风则其入深,其病人也卒暴 ㊂脏腑位于人体的中央要位,所以说脏气盛衰可决定中风后病人的预后,脏气不足的病人往往症状较重,恢复也较慢,即如‘素问“所云: 定五脏之气,间甚之时,死生之期㊂ 总之,‘内经“时期认为中风主要是由于虚邪贼风入中,加之卫气本虚导致,持 外感所致内伤 的观点,还未提出血瘀也是导致中风发生的重要原因㊂直到‘金匮要略㊃惊悸吐衄下血胸满瘀血病脉证治“凡举 胸满 当汗出不出 烦满 等3种症状后,才明确提出 瘀血 一词,虽然并非用于中风病病因描述,但为后世确立益气活血法提供了思路[24]㊂2发轫于隋唐自隋唐开始,中风病的内因学说盛起,多数医家开始重视中风的气虚及血瘀病机㊂隋代巢元方提到 脾胃气弱,血气偏虚 为风邪所侵,故半身不遂也 ,即脾胃运化无力,则人体血气必然偏虚,容易受到风邪外侵,进而出现单侧肢体活动不能的表现,他指出气虚是病之本,是导致半身不遂的内在因素,病邪之所以能侵袭人体也是因为人体正气不足而不能与邪气抗争,为后世从气虚论治中风奠定了基础㊂唐朝王冰在‘玄珠经“中亦提到: 风病 五脏气绝也 由人元气素虚 ㊂中风病人出现张口不能闭合㊁双目紧闭㊁呼吸声如同打鼾㊁四肢瘫软㊁大小便失禁等 五脏气绝 的症状,是由于其元气素来不足㊂元气是以先天之精为基础,又有后天之气的培养,是人生存所需要的最根本㊁最重要的气,王冰认为中风病的病因就在于元气亏虚㊂金末元初时期李东垣云: 风邪直中血脉就会口歪眼斜 ,如果病人症状不止有口歪眼斜,还有风中六经之症,例如项背僵硬不适㊁头昏身重等,当予以小续命汤加减合疏风汤治疗,他还从病人的发病年龄出发,观察到中风的发生以本就体虚血滞的中高龄者居多, 气衰之际,或因忧喜愤怒伤其气者,多有此疾 ㊂其认为中风是以气病为根本原因,气不足时,或由于情志因素伤其气的,都会导致疾病发生㊂但也有体型肥胖之人发生中风, 是形盛气衰而如此 ㊂李东垣将 体虚 这一病机具体到了 气虚 方面,以益气法为主要治法,创制了治疗中风名方清阳汤㊂直到元朝的朱丹溪,才兼取众医家之长,将血瘀与气虚并列组合为两个引发中风的要素㊂朱丹溪认为 半身不遂,大率多痰 ,如果出现在左侧肢体多为 死血 (又有一说作 少血 ),如果出现在右侧肢体多由于 痰有热,并气虚 所致㊂血液的运行有赖于气的推动㊁温煦和固摄作用㊂所谓死血,即病邪日久而入络之瘀血;所谓少血,即由于气虚所致的缺血㊂瘀血与缺血,互为因果关系㊂瘀血阻滞经脉,则远端脉络空虚;血液不足,血行不畅则必然出现血瘀之象㊂朱丹溪认为中风半身不遂大多是由于血瘀所致,血瘀则脉络不能充盈,故出现缺血之症状㊂在廓清瘀血与中风关系的基础上,开创了从气虚血瘀论治中风的先河㊂之后的新安医家也正是从隋唐以降诸医家的理论中发展传承,提出以益气活血法治疗中风的理念㊂3形成于明清新安医学鼎盛于明清,众多的医家㊁宏富的医著必然将中风的各种治疗方法囊括其中,而益气活血法的完整提出和实践尤为重要㊂明代的新安医家汪机,以朱丹溪㊁李东垣为师并博采诸家之长,认为中风乃气虚为主,指出 脾胃不足,百病易生 ,脾胃乃后天之根本,脾土为万物之母,元气赖之以生,元气不足,气不生血,才是导致疾病产生的根本,所以在治疗中风之时,须考虑到正气的充盈是疾病治愈的关键,应当用益气之法;认为益气则活血,气道通畅则血脉通畅, 气运不利,血亦罕来 ㊂汪机观一六旬病人脉象云: 气血已衰,脉见浮洪弦虚 ,故予以人参㊁麦冬㊁白芍固护气阴,少量黄连㊁生姜等辛通苦降㊂此病案充分体现了益气之法,但对活血之法还着墨不多㊂完成益气活血法治疗中风理论阐述和临床实践的,是生活在同一时期的明代新安医家江瓘㊁孙一奎㊂江瓘在‘名医类案“中提到治疗某 一身俱麻 中风病患,认为 麻由虚而气不行 ,是故以乌药顺气散为主方,加施人参㊁白术㊁麦冬㊁川芎㊁当归诸药服之而愈㊂方中人参㊁白术大补元气以益气,川芎㊁当归活血行气,麦冬养阴,可见在治疗中风时,考虑到了病人为气虚血瘀,治疗上选用益气活血之品㊂这标志着新安医家益气活血理论在实际诊疗中得到应用,并取得理想的疗效㊂另一位新安医家孙一奎在‘赤水玄珠“中提到: 元气素虚,腠理疏豁 一遇风邪,莫之能御 ,邪气之所以能得以聚集而导致疾病的发生,都是源于正气的亏虚,认为中风多由于经脉瘀阻,气血不畅,故治疗中风的方法,初期应该益气,使得气旺调畅,若气虚猝倒,当用参芪汤补气,气不足则不能推动血行,血行不利,则会出现血瘀之症㊂故日久当活血,宜四物汤加桃仁㊁红花㊂如果纯用防风㊁天麻㊁羌活等祛风之类的外感祛风药物,很难治愈㊂若脉道通畅,气血得通,血随气行,周流不停,则病情可以好转向愈㊂明末清初的新安医家汪昂在‘医方集解“中提到以顺风匀气散治疗中风 邪不遂 ,认为中风系 气不匀 , 血脉不周 故半侧肢体活动不能㊂气虚与血瘀总是并见,血液运行于脉络之中,气虚且血液运行不畅会导致突然昏倒的症状㊂ 气匀则风顺 ,故该方以人参㊁白术㊁炙甘草补正气,全方共奏补气㊁行气㊁疏气之效,气匀则血脉也得以通畅㊂清初的新安医家程杏轩基本承袭了孙一奎的观点㊂久病气虚,致脏腑功能减退,故中风日久的病人会出现倦怠乏力,少气懒言,气虚无力推动血行,血液不能上荣于面部,故病人常出现面色淡白㊂所以他在‘医述“中亦认为: 若不顺气遂用乌㊁附,若不活血遂用羌活㊁防风,未能见其能治也 ,治疗中风初期应当治气,久病则当活血㊂与此同时,清初的医家王清任指出了中风突然跌仆的病因,阐述了气虚血瘀导致中风的病机㊂王清任发展中风非风论,否定风火气痰之论及真中类中之分,针对有的医家论治中风的病因从风㊁火㊁气㊁痰立论,选方用药遵循理气化痰㊁疏风清热之法,他在‘医林改错㊃半身不遂论叙“中指出中风初发时,并未出现诸如发热恶寒㊁身痛头疼等外感表证㊂认为如果是 风火湿痰,无论由外中,由内发,必归经络 ,而 气血若为风火痰湿阻滞 ,经络不通,则病人必诉疼痛不适,有身体疼痛者即应诊断为痹症,而非以半身不遂为主要表现的中风㊂王清任认为中风半身不遂多因气虚血瘀导致,所谓 气亏得半身不遂,所以跌仆 ㊂情志失调㊁饮食不节㊁劳累过度㊁耗伤元气,导致元气不足,推动㊁温煦功能衰减,无力推动血行,气血运行不畅致血瘀于脑脉㊂王清任肯定了李东垣的观点,指出元气亏损才是中风发生的根本原因, 元气绝则死矣 ㊂人体元气有十分,元气虚衰则经络空虚,十分元气亏空至五成,必有一侧肢体亏空,元气不足则血行无力,血行不畅则出现血瘀,一侧经脉失去血液滋养则出现为萎废不能用,就会出现中风偏瘫之象㊂元气在身体的分布如同湖水,当元气虚衰时,侧卧或者侧坐元气则会偏向低侧,而另一侧则出现元气偏枯㊁肢体活动不利㊂据此病机,王清任提出了益气化瘀治法,创制了补阳还五汤㊂气血盛衰对人体各项机能影响十分重要㊂王清任综合了朱丹溪的观点并结合了自身的认识,认为 元气藏于气管内,分布周身 ㊂在治疗中风时十分重视气道是否充盈㊁血行是否顺畅,治法以活血化瘀为本,加以补气益气,气推动血行,则血瘀自除㊂认为气有虚实㊁血有亏瘀,进一步发展了‘内经“ 血实宜决㊁气虚宜掣引 的观点,认为如果只益气而不活血,那么瘀血难去,新血不生,如果只活血,而不益气,则血行过度反而会耗伤正气,气不固摄血液,反而会导致血液行于脉外,出现出血的症状,所以在使用活血的药物时,还需加入益气之药,瘀血除而不伤正气㊂现代临床经验表明,补阳还五汤甚至对除中风外的其他疾病,如肿瘤㊁神经和循环系统以及代谢类疾病等也有很好的应用价值[24]㊂4鼎盛于当代新安王氏内科总结发扬了前医家的观点㊂王乐匋秉承孙一奎治疗中风病有关 中风皆因脉道不利,血气闭塞 的观点,宗新安医家之固本培元,认为气虚血瘀与中风的联系密不可分,益气活血是治疗中风的关键,脉络中气虚血运不畅,则会出现血脉瘀阻,瘀阻脑络则出现中风,病人常常表现为面色黝黑紫黯,舌下脉络瘀血,舌有瘀斑,脉涩,因此中风病气虚血瘀证不仅需要益气,气推动血行,更需要活血通络,使脉络通畅㊂王乐匋创立的邪正合治㊁益气活血的经验方 脑络欣通 ,常用的通络药物为活血化瘀和虫类搜剔㊂如用田三七,有瘀散瘀,有血止血,虚者能补;在补阳还五汤基础上予以创新,以蜈蚣代替地龙,取其既可通络又能息风之用㊂新安医家杨文明在治疗急性期气虚血瘀型中风时,认为应当既治标又治本,既益气又活血,疏通脑络以开窍,并拟脑络通方,全方由黄芪㊁赤芍㊁川芎㊁当归㊁地龙㊁熟大黄等组成㊂研究表明,脑络通方能够降低血液黏度,改善脑血流量,扩张血管,降低脑卒中后炎症反应以及减轻氧化应激对脑组织的损伤[25-26]㊂由于急性期病人正处于外邪与正气相争的阶段,邪气过盛时则会出现正气不足,正气虚则可导致邪气入里,症状加重,瘀阻脑络,血液运行不畅,故急性期病人常常表现出半身不遂㊁活动不利㊁言语含糊甚至言语不能㊁单侧肢体麻木等㊂方中黄芪大补元气,元气旺盛则可推动血行,血行顺畅,血瘀得化,脑络得通;全当归能活一身之血,既收通络之功又不伤血;川芎㊁白芍助全当归发挥活血祛瘀之效;熟大黄通便而不耗伤正气,推陈致新,使体内停滞瘀血得以散行㊂‘千金翼方“谓: 凡病皆由气血壅滞,不得宣通 ㊂认为可以采用针灸温通经脉,气血条畅则症状得以减轻㊂所以,杨文明教授主张中风早期辨证使用针灸疗法以疏通经络,调和阴阳,临床除了可选用水沟㊁内关㊁百会㊁三阴交㊁委中等治疗中风的主要穴位,结合病人症状特点应加用足三里㊁气海等以益气活血,通过针灸激发健侧大脑代偿功能,恢复肢体活动能力[27]㊂其他医家在治疗中风时一般也以益气活血为治疗原则和方法,并研究出一系列医院制剂或自拟方进行治疗,取得了一定的疗效㊂如周志梅等[28]以消栓肠溶胶囊治疗中风病人,结果显示治疗组较对照组的神经功能评分显著提高,美国国立卫生研究院卒中量表(NIHSS)评分明显降低,病人的活动及语言能力明显改善㊂刘春柳[29]用益气活血补偏汤免煎颗粒(由黄芪㊁当归㊁桃仁㊁红花㊁地龙㊁川芎㊁赤芍㊁甘松㊁天花粉㊁天冬㊁生龙骨㊁煅牡蛎㊁山萸肉组成)治疗缺血性脑卒中恢复期病人,取得较为满意的疗效,且治疗后病人的日常生活活动能力量表(ADL)㊁Fugl-Meyer运动功能(FMA)及NIHSS评分均有不同程度改善㊂王成[30]运用益气活血组方(由黄芪㊁白术㊁鸡血藤㊁太子参㊁赤芍㊁地龙㊁当归㊁川芎㊁桃仁㊁红花等组成)治疗缺血性脑卒中,相比较可见中药组临床疗效明显优于西药组,病人生活质量提高较对照组更为明显,可见该方治疗缺血性脑卒中效果较常规西药更有优势㊂鲁国志[31]研究发现,补气脉通汤(由人参㊁黄芪㊁桃仁㊁红花㊁当归㊁丹参㊁葛根㊁水蛭㊁全蝎㊁蜈蚣等药物组成)联合西药治疗脑卒中恢复期病人,收效好于单纯施以西药,此方对于改善病人预后具有重要价值㊂赵涛等[32]以益气活血㊁化瘀通络为治法,研制出脑心通胶囊,该药能补气活血㊁化瘀通络,从而使血脉通畅㊁脑络得通㊁髓海充养㊁气血调畅㊂由此可见,对于缺血性卒中恢复期病人,以益气活血法为代表的中药复方或成药均可不同程度地改善其临床症状和体征,提高病人的生活质量,改善病人预后㊂5小结作为中医治疗中风的主流治法,在益气活血法萌芽于‘黄帝内经“时期,发轫于隋唐,元代提出了由益气或活血法治疗中风的治疗原则,认为中风成因多为气虚或者血瘀,明清时期新安医家将气虚和血瘀致病的观点进一步发展完善,认为气虚血瘀同见于中风,而不是单独用补益元气或通调脉道的药物,在选方用药上补益元气与活血化瘀药物同施,并认为 精气内夺 则预后不良,而气不足不能运血则血液瘀阻,所以在治疗中风气虚血瘀证上益气活血必须共见㊂清代的王清任创立补阳还五汤,认识到了血瘀致病的广泛性,同样提出了气虚血瘀为中风发病的主要原因㊂明清时期的新安医家和王清任提出的益气活血法在当今仍被广泛运用,影响一系列医家临床实践并在此基础上进行治疗创新㊂表明位于江南的新安医家与北方的医家王清任,虽然处于不同时空地域,但对中风病的病因病机却有着完全相同的认识,并延习至今指导着当今医学的临床实践,说明古代医家在当时相对封闭㊁交通不便,罕有学术交流的环境下,在不同的时空区域内通过各自大量的临床实践,总结出中风病相同的病因病机,同时也说明中风气虚血瘀病机得到古代许多医家认可和验证㊂缺血性脑卒中以病程长㊁病势缓为特点,故而病人正易耗散,邪易留滞,容易出现标本虚实交错杂乱的气虚血瘀症状㊂因此,在选方用药上,应当以调达气血㊁补泻结合为治疗原则,益气活血以达到更好的治疗效果㊂近年来,中医药在治疗缺血性脑卒中应用广泛,在益气活血理论指导下的中医治疗方案临床疗效明显,且有较好应用前景,对提升脑卒中病人的临床疗效具有重要价值㊂参考文献:[1]WU S,WU B,LIU M,et al.Stroke in China:advances andchallenges in epidemiology,prevention,and management[J].Lancet Neurol,2019,18(4):394-405.[2]MA Q,LI R,LI R,et al.Temporal trend and attributable risk factorsof stroke burden in China,1990-2019:an analysis for the GlobalBurden of Disease Study2019[J].Lancet Public Health,2021,6(12):e897-e906.[3]DE STEFANO V,CAROBBIO A,DI LAZZARO V,et al.Benefit-riskprofile of cytoreductive drugs along with antiplatelet andantithrombotic therapy after transient ischemic attack or 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[19]ZERNA C,THOMALLA G,CAMPBELL B C V,et al.Currentpractice and future directions in the diagnosis and acutetreatment of ischaemic stroke[J].Lancet,2018,392(10154):1247-1256.[20]王建超,王育勤.中医药治疗中风后抑郁研究进展[J].中医药通报,2019,18(3):67-69.[21]张伯礼.百年中医史:1912-2015[M].上海:上海科学技术出版社,2016:454.[22]崔涛.中风膏联合重复经颅磁刺激治疗缺血性脑卒中后吞咽障碍的临床观察[D].兰州:甘肃中医药大学,2021.[23]郑文旭.疏肝活血解郁汤联合西药治疗中风后抑郁的疗效及对HAMD-24㊁NIHSS㊁ADL评分的影响[J].中医研究,2022,35(10):55-60.[24]任思思,宋丽娟,韩庆贤,等.从瘀血致病到益气活血之思想发展探析[J].山西大同大学学报(自然科学版),2021,37(6):71-74. [25]何望生,杨文明,汪瀚,等.脑络通颗粒改善痴呆型血管性认知功能障碍的临床研究[J].中医药临床杂志,2012,24(11):1045-1047.[26]何望生,杨文明,汪瀚,等.脑络通颗粒治疗痴呆型血管性认知功能障碍疗效观察[J].中医药临床杂志,2014,26(2):146-148. [27]张帅帅,杨文明.杨文明辨治脑梗死临证经验撷要[J].中医药临床杂志,2023,35(5):899-905.[28]周志梅,买雷,李艳红.消栓肠溶胶囊治疗脑梗死疗效及对患者NIHSS评分的影响[J].陕西中医,2019,40(6):696-699. [29]刘春柳.益气活血补偏汤治疗气虚血瘀型缺血性中风恢复期的临床疗效观察[D].南宁:广西中医药大学,2020.[30]王成.活血益气法对气虚血虚型缺血性脑卒中患者神经功能缺损的影响研究[J].中国现代药物应用,2021,15(1):218-220. [31]鲁国志.浅析中药汤剂干预缺血性中风恢复期之气虚血瘀证的临床疗效[J].智慧健康,2020,6(32):181-182.[32]赵涛,赵步长,贾力夫,等. 脑心同治 理论研究进展[J].中医临床研究,2015,7(27):8-10.(收稿日期:2023-12-08)(本文编辑邹丽)。
巫师3全代码(日常,工艺,材料,武器,套装)
日常应用：ShowAllFT(1) 打开全部快速旅行点就是路牌AllowFT(1) 允许你随地使用快速旅行，类似老滚ShowPins(1) 显示地图上所有？地点activateAllGlossaryCharacters() 解锁字典里所有的角色activateAllGlossaryBeastiary 解锁字典里所有的怪物staminaboy() Geralt耐力不减resurrect() 死掉了，打这个就复活了addmoney(9999999) 加钱(数量)addskillpoints() 添加技能点数（数值）addexp (1000) 增加经验值（数值）setlevel() 设置等级数levelup() 等级提升settattoo(1) 巫师2宿醉任务奖励蓝色纹身1打开、0关闭staminapony 蘿蔔（葡萄）无限体力shave 剃胡子setbeard(1) 长胡子winGwint(122) 昆特牌胜利？addgwintcards 快速添加全套牌工艺品符文AddAllThMaps 3个选派的所有藏宝图addbolts 添加全箭矢addcraft 添加全工艺品?未确认addsteelswords 添加全钢剑addsteelswords2 添加全钢剑2addwolfdlc 添加狼dlcaddsilverswords 添加全银剑addsilverswords2 添加全银剑2addcrossbows 添加全十字弓addarmor 添加全护甲addarmor2 添加全护甲2addpants 添加全裤子addboots 添加全鞋子addgloves 添加全手套addsets 添加全套装addbooks 添加全书籍addlore 添加知识addlore2 添加知识2addfood 添加全食物adddrinks 添加全酒精addtrophies 添加全战利品addmiscaddhorseitems 马的物品addupgrades 全剑部位镶嵌符文addcraftingingre 全打造矿物addCraftingItem 全打造材料图纸类learnallschematics 学会所有打造图纸addcraftedsteel 铁图纸addcraftedsilver 银图纸addcraftedsteelrelic 旧铁图纸addcraftedsilverrelic 旧银图纸addcraftedranged 围图纸addcraftedboots 鞋子图纸蓝图类addschematicsboots 获得鞋子蓝图addschematicspants 获得裤子蓝图addschematicsgloves 获得手套蓝图addschematicsarmor 获得盔甲蓝图addschematicscomponents 获得组件蓝图addschematicsupgrades 获得升级蓝图addschematicsbolts 获得螺栓蓝图药剂配方类addmutagens 所有突变药剂addmutageningredients 获得所有种类突变物addmutagenrecipes 学会所有煎药的配方addrecipesoils 学会所有剑油的配方addrecipesbombs 学会所有炸弹配方addrecipespotions 学会所有魔药配方addrecipespotions2 学会所有高级魔药配方addherbs 添加所有药草addkeys 所有钥匙addvaluables 所有贵重物additem('gwint_card_eredin_gold', 1) 添加物品（物品id）小技巧: 添加多数量物品时例如洗点药 additem('Clearing Potion',20) 这样就是20瓶一次添物品名区分大小写必须完全一致additemfood 所有食物additemalchemy 所有炼金术additemcrafting 所有艺术品additemleather 所有皮additemmetals 所有矿物additemrunesupgrades 所有符文additemmonstrous 所有怪物材料additemsprecious 所有贵重物品addjunk 所有垃圾addjunk2 所有垃圾2addquestitems 任务物品addquestitems2 任务物品2addquestitems3 任务物品3addtreasurehuntitems 宝物猎人物品addcharacterdecorations 个性装饰马鞍袋Horse Bag 1 马袋 30Horse Bag 2 马袋 70Horse Bag 3 马袋 100DLC1 Temerian HorseBag 暂未实装马眼罩Horse Blinder 1 惊慌减少Horse Blinder 2 惊慌减少Horse Blinder 3 惊慌减少DLC1 Temerian HorseBlinder 暂未实装马鞍Horse Saddle 3v3 70活力Horse Saddle 3v4 75活力Horse Saddle 4 80活力Horse Saddle 1 20活力Horse Saddle 1v2 25活力Horse Saddle 1v3 30活力Horse Saddle 1v4 35活力Horse Saddle 2 40活力Horse Saddle 2v4 45活力Horse Saddle 3 50活力Horse Saddle 3v2 55活力DLC1 Temerian HorseSaddle挂画装饰品代码(风景类)additem('mq7024_gen_painting_landscape_b') additem('mq7024_painting_prologue_village') additem('mq7024_palace_painting')additem('mq7024_gen_painting_landscape_c') additem('mq7024_painting_battlefield') additem('mq7024_gen_painting_landscape_a') additem('mq7024_painting_harbour')additem('mq7024_painting_stilllife') additem('q603_auctioned_painting')(人像类)additem('mq7024_gen_painting_portrait_a')additem('mq7024_painting_ciri_portrait')additem('mq7024_painting_emhyr_portrait')additem('q305_painting_of_hemmelfart')additem('mq7009_painting_pose1_grif') (裸体白狼——骑马) additem('mq7009_painting_pose2_grif') (裸体白狼——英雄) additem('mq7009_painting_pose3_grif') (裸体白狼——躺卧)Bang!炸药：additem('White Frost 3') 高等北风additem('Grapeshot 3') 高等蜂窝additem('Silver Dust Bomb 3') 高等月之尘(不能变形) additem('Samum 3') 高等樊风additem('Dragons Dream 3') 高等龙之梦additem('Devils Puffball 3') 高等恶魔之尘additem('Dancing Star 3') 高等舞动之星additem('Dwimeritium Bomb 3') 高等反魔法金属炸弹染料：additem('Dye Red',100) 红色护甲染剂additem('Dye Blue',100) 蓝色护甲染剂additem('Dye Gray',100) 灰色护甲染剂additem('Dye Black',100) 黑色护甲染剂additem('Dye White',100) 白色护甲染剂additem('Dye Green',100) 绿色护甲染剂additem('Dye Brown',100) 棕色护甲染剂additem('Dye Purple',100) 紫色护甲染剂additem('Dye Yellow',100) 黄色护甲染剂additem('Dye Pink',100) 粉红色护甲染剂additem('Dye Orange',100) 橘色护甲染剂additem('Dye Turquoise',100) 蓝绿色护甲染剂additem('Dye Default',100) 染色去除剂各种可获得的剑名称及代码：additem('Abarad') 冬之刃(非领主送的)additem('Addandeith') 艾丹·戴兹additem('Aerondight') 毛格林additem('Anathema') 咒逐additem('Angivare') 信鸽additem('Anth') 安司additem('Arainne') 艾林尼additem('Arbitrator') 仲裁者additem('Ardaenye') 阿德尼之剑additem('Ashrune') 灰符additem('Azurewrath') 阿祖烈之怒additem('Barbersurgeon') 理发医师additem('Beannshie') 女妖additem('Blackunicorn') 黑独角兽additem('Bladeofys') Y字之刃additem('Bloedeaedd') 布洛德·艾德additem('Bloodsword') 血剑additem('Breathofthenorth') 北方气息additem('Caerme') 凯而米additem('Caroline') 卡洛琳additem('Cheesecutter') 酪奶剑additem('Cleaver') 屠夫披肩additem('Dancer') 舞者additem('Daystar') 白昼之星additem('Deargdeith') 迪尔格戴斯additem('Deireadh') 戴尔瑞additem('Deithwen') 戴斯文additem('Devine') 代文additem('Dyaebl') 迪亚布罗additem('Fate') 命运additem('Forgottenvransword') 忘却的弗朗剑additem('Gloryofthenorth') 北方荣耀additem('Gwestog') 诡斯托格additem('Gwyhyr') 古威希尔additem('Gynvael') 吉纳维尔additem('Gynvaelaedd') 吉纳维尔·艾德additem('Harpy') 人面妖鸟additem('Harvall') 哈维尔剑additem('Havcaaren') 私袅additem('Headtaker') 人头猎人additem('Hjalmar_Short_Steel_Sword') 哈尔玛的钢剑additem('Inis') 伊尼斯additem('Karabela') 卡拉贝拉additem('Loathen') 洛森additem('Longclaw') 长爪additem('Lune') 月牙additem('Moonblade') 月刃additem('Mourner') 哀悼者additem('Maugrim') 银剑毛格林additem('Naevdeseidhe') 耐伏德·西迪additem('Negotiator') 谈判者additem('Princessxenthiasword') 杰西亚公主之剑additem('Reachofthedamned') 诅咒之地additem('Robustswordofdolblathanna') 高等多尔·布雷坦纳之剑additem('Roseofaelirenn') 夏拉韦玫瑰additem('Tlareg') 特拉雷格additem('Torlara') 托尔劳拉additem('Torzirael') 托尔吉薇艾儿additem('Theemmentaler') 钢剑奶酪剑additem('Ultimatum') 最后通牒additem('Virgin') 圣女additem('Vynbleidd') 希望additem('Weeper') 哀泣者additem('WitcherSilverWolf') 布雷伊德additem('Wolf') 狼additem('Zerrikanterment') 龙之剑additem('q402 Skellige sword 3') 冬之刃additem('Zireael Sword') 吉薇艾儿additem(‘q505 crafted sword’)吉薇艾儿(银，一级)additem(‘mq1058_cat_school_sword’)dlc里面猫派猎魔人送的剑，与白狼等级相关additem ('Olgierd Sabre') 卡拉神刀additem('PC Caretaker Shovel')独特武器：additem('Aerondight EP2') 湖女之剑-可跟角色升级的极品银剑(就是连击十下可以永久提升伤害，最佳是永远跟同等猎魔剑攻击一致或更高!)additem('q704 vampire silver sword') 坎塔娜(吸血鬼之剑)additem('Knights steel sword 3') 森特骑士钢剑additem('Zireael Phantom Sword') 希里的钢剑吉薇艾儿additem('Torzirael') 希里的银剑托尔吉薇艾儿additem('Concealment Kit') 看门人的铲子(盾牌)additem('sq701_geralt_shield')additem('sq701_ravix_shield')大赛奖励：additem('Geralt of Rivia Crossbow') 杰洛特的十字弓吸血鬼套(两套一红一黑)：Blood and Wine Vampire Set Item IDs红色additem('q704_vampire_mask') 面具additem('q704_vampire_armor') 胸additem('q704_vampire_gloves') 手additem('q704_vampire_pants') 裤additem('q704_vampire_boots') 鞋additem('q704 vampire steel sword') 钢剑黑色additem('q702_vampire_boots') 鞋additem('q702_vampire_pants') 裤additem('q702_vampire_gloves') 手additem('q702_vampire_armor') 胸additem('q702_vampire_mask') 面具additem('q702 vampire steel sword') 钢剑镜子大师全套奖励：additem('Devil Saddle')悲痛马衣，马永不惊慌，并随机混乱一名敌人additem ('Soltis Vodka') 无底酒瓶，无限烈酒additem (Cornucopia) 富饶之角，无限食物石之心超帅套装新月套：additem('Thief Armor') 新月盔甲additem('Thief Gloves') 新月手套additem('Thief Pants') 新月裤子additem('Thief Boots') 新月靴子森特骑士比武大赛套装：比骑士套、黄金套、师匠套属性更强，简直爆炸！additem('Knight Geralt A Armor 3')additem('Knight Geralt A Gloves 3')additem('Knight Geralt A Pants 3')additem('Knight Geralt A Boots 3')师匠套装代码：熊套：additem('Bear Pants 5')additem('Bear Boots 5')additem('Bear Gloves 5')additem('Bear Armor 4')additem('Bear School steel sword 4') additem('Bear School silver sword 4') additem('Bear School Crossbow') 十字弓猫套：additem('Lynx Pants 5')additem('Lynx Boots 5')additem('Lynx Gloves 5')additem('Lynx Armor 4')additem('Lynx School steel sword 4') additem('Lynx School silver sword 4') additem('Lynx School Crossbow') 十字弓狮鹫套：additem('Gryphon Pants 5')additem('Gryphon Boots 5')additem('Gryphon Gloves 5')additem('Gryphon Armor 4')additem('Gryphon School steel sword 4') additem('Gryphon School silver sword 4')狼套：additem('Wolf Pants 5')additem('Wolf Boots 5')additem('Wolf Gloves 5')additem('Wolf Armor 4')additem('Wolf School steel sword 4') additem('Wolf School silver sword 4')。
python心脏病预测案例
python心脏病预测案例以下是一个使用Python进行心脏病预测的案例：首先，我们需要准备一个心脏病数据集。
你可以从UCI机器学习库中获取一个叫做"heart.csv"的数据集，数据集包含了一些关于心脏病的指标和患病状态的信息。
接下来，我们需要导入必要的Python库和数据集：```import pandas as pdfrom sklearn.model_selection import train_test_splitfrom sklearn.ensemble import RandomForestClassifierfrom sklearn.metrics import accuracy_score# 导入数据集data = pd.read_csv('heart.csv')# 查看数据集的前几行print(data.head())```接下来，我们需要对数据集进行预处理，包括将目标变量和特征变量分开，并将数据集划分为训练集和测试集：```# 分割特征变量和目标变量X = data.drop('target', axis=1)y = data['target']# 将数据集划分为训练集和测试集X_train, X_test, y_train, y_test = train_test_split(X, y,test_size=0.2, random_state=42)```然后，我们可以使用随机森林分类器来训练模型并进行预测：```# 创建随机森林分类器对象rf = RandomForestClassifier()# 在训练集上拟合模型rf.fit(X_train, y_train)# 在测试集上进行预测y_pred = rf.predict(X_test)# 计算模型的准确率accuracy = accuracy_score(y_test, y_pred)print("模型的准确率: ", accuracy)```最后，我们可以将模型用于新的观测数据，并预测心脏病的发生情况：```# 创建一个新的观测数据new_data = [[63, 1, 3, 145, 233, 1, 0, 150, 0, 2.3, 0, 0, 1]]# 使用模型进行预测prediction = rf.predict(new_data)# 打印预测结果if prediction[0] == 0:print("该患者没有心脏病")else:print("该患者有心脏病")```通过以上步骤，我们可以使用Python进行心脏病的预测。
高中英语影视文化单选题30题
高中英语影视文化单选题30题1.In the movie "The Dark Knight", Batman is known for his bravery and intelligence. Which of the following is NOT a characteristic of Batman?A.StrongB.CunningC.CowardlyD.Determined答案：C。
解析：在电影《黑暗骑士》中，蝙蝠侠以勇敢、聪明和坚定著称。
选项A“Strong（强壮的）”，蝙蝠侠有强壮的体魄；选项B“Cunning 狡猾的）”，他在与反派的对抗中展现出机智；选项D“Determined（坚定的）”，他坚定地打击犯罪。
而选项C“Cowardly 胆小的）”与蝙蝠侠的形象完全不符。
2.In the TV series "Game of Thrones", Daenerys Targaryen is often associated with which of the following?A.CrueltypassionC.CowardiceD.Greed答案：B。
解析：在（《权力的游戏》中，丹妮莉丝·坦格利安经常被与同情心联系在一起。
她解放奴隶，展现出慈悲之心。
选项A“Cruelty（残忍）”不是她的主要特点；选项C“Cowardice（胆小）”不符合她的勇敢形象；选项D“Greed 贪婪）”也不准确。
3.In the movie "Forrest Gump", Forrest is characterized by his?A.ClevernessB.HonestyC.DeceitfulnessD.Arrogance答案：B。
解析：在电影《阿甘正传》中，阿甘以诚实著称。
选项A“Cleverness（ 聪明）”，阿甘不是特别聪明；选项C“Deceitfulness 欺骗）”与他的性格相悖；选项D“Arrogance（傲慢）”也不符合他的形象。
美剧Bostonlegal第一季结案陈词（中英文）
美剧Bostonlegal第一季结案陈词（中英文）Boston LegalHead CasesSeason 1，Episode 1在这一集中，黑人女孩参加全美巡演的面试，而且非常地演唱了歌曲―T omorrow‖，但被拒绝，因为她是黑人，和漫画中要求的肤色不符…下面是本集中客串牧师的演员Al Sharpton以一个黑人的立场在法庭发表观点…Denny Crane: Pull a rabbit out of your hat.Denny Crane: 从帽子里变出只兔子来（寓意另辟蹊径，出其不意，无中生有）原文：Reverend Al Sharpton: Could I be heard, your Honor? I heard about this matter. I would like to address this court on what I consider . . .Judge Rita Sharpley: I‘m sorry, R everend, but you have no standing here.Reverend Al Sharpton: I have standing as an American citizen speaking up on a civil rights violation.Judge Rita Sharpley: Reverend Sharpton, I will ask you to step down . . .Reverend Al Sharpton: I have standing as Bobby Kennedy had standing, . . .Judge Rita Sharpley: You have no standing in this meeting.Reverend Al Sharpton: . . . on the steps of the courthouse in Alabama!Judge Rita Sharpley: No one is denying this little girl an education, sir. She just can‘t p lay Annie.Reverend Al Sharpton: You may think this is a small matter.But this is no small matter. This child is being denied the right to play an American icon because she doesn‘t match the description. Those descriptions were crafted 50 years ago! We‘re supposed to be in a different day!Judge Rita Sharpley: Reverend . . .Reverend Al Sharpton: You talk about racial equality, how we‘re making progress. The problem with that progress is it‘s always a day away. Tomorrow, tomorrow—you love that!—because it‘s always a day away. I‘m here to stick out my chin today! Today! Give us an African-American Spider Man! Give us a black that can run faster than a speeding bullet and leap over tall buildings in a single bound! Not tomorrow—today! Today! The sun needs to come out today! Not tomorrow, your Honor! God Almighty! Give the American people a black Orphan Annie. It‘s just not good enough to say she doesn‘t look the part.Reverend Al Sharpton: That‘s what you call a rabbit, son. Denny Crane.译文：神父Al Sharpton: 请允许我发言，法官阁下，听说此事，我十分乐意在此表达我的观点…法官Rita Sharpley: 很抱歉，神父，您没有立场…神父Al Sharpton: 我以一个美国公民的身份在此评论公民权利的侵犯法官Rita Sharpley: Sharpton神父，请你退下神父Al Sharpton: 我站在此地，正如Bobby kennedy（肯尼迪家族成员，全家都主张人权）站在Alabama州法院的台阶上法官Rita Sharpley: 先生，没人在否认她的受教育权，她只是不能扮演Annie.神父Al Sharpton: 也许您认为这是小事，但它不是，这个孩子被拒绝了成为美国偶像的权利，那些作品已经过去了50年，今日的世界应有所不同法官Rita Sharpley: 神父. . .神父Al Sharpton: 您说种族平等取得了怎样的进展，但这种进展总是在说未来如何，―明天，明天，你们喜欢它‖ 因为它总是在今天之后，我要在今天疾呼，就在此时此刻，给予我们黑皮肤的蜘蛛侠吧，给我们一个比子弹还要快穿梭在高楼顶端的黑人英雄吧，不是明天，而是今天，今天，太阳要在今天升起，不是明天，法官阁下，全能的主啊，请赐予美国一个黑皮肤的孤儿Annie吧，说她不像角色，这个理由是站不住脚的。
关于黑神话悟空话题的英语阅读理解
关于黑神话悟空话题的英语阅读理解一、阅读理解原文。
Black Myth: Wukong is an upcoming action role - playing game that has captured the attention of gamers around the world. Developed by Game Science, it is set in a world inspired by Chinese mythology, with the main character being the well - known Monkey King, Sun Wukong.The game's trailers have shown stunning visuals, with detailed character models and beautiful landscapes. The combat system seems to be fast - paced and fluid, allowing players to perform a variety of acrobatic moves and powerful attacks as they battle against different enemies. One of the most impressive aspects is the way the developers have recreated the Monkey King's abilities. For example, his transformation skills are vividly presented, enabling him to change into different forms such as a bird or a fish to overcome obstacles or surprise opponents.The game also appears to have a rich story. It delves deep into thelore of Chinese mythology, not just focusing on the Monkey King's adventures but also exploring the relationships between different gods, demons, and mortals. This gives the game a sense of depth and authenticity that many players are looking forward to.However, developing such a game is not without challenges. The developers need to balance between staying true to the source material and making the game appealing to a global audience. They also have to deal with technical issues such as optimizing the game for different platforms to ensure smooth gameplay.Despite these challenges, the anticipation for Black Myth: Wukong continues to grow. It represents a new wave of games that draw inspirationfrom non - Western cultures, and it has the potential to introduce Chinese mythology to a whole new generation of gamers around the world.二、阅读理解题目。
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Sensitivity analysis
measures the importance of independent variable based on the change in modeling performance that occurs if this variable is not included in the model. The greater the performance decrease, the greater the ratio of importance.
SAS DM SAS EG Base SAS
Procedure
Data preprocessing
Dependent Variable
Target_dropout: code it as “1” if a donor did not return after his/her first donation
References
5. Schlumpf, K., Glynn, S., Schreiber, G., & Wright, D. (2008). Factors influencing donor return. TRANSFUSION, 48, 264-272. 6. Schreiber, G., Sanchez, A., Glynn, S., & Wright, D. (2003). Increasing blood availability by changing donation patterns. TRANSFUSION, 43, 590-597. 7. SPSS. SPSS PASW Modeler (formerly Clementine) User Manual. A Comprehensive Data Mining Toolkit, 2010. 8. Yu, P., Chung, K., Lin, C., Chan, J., & Lee, C. (2007). Predicting potential drop-out and future commitment for first-time donors based on first 1.5-year donation patterns: the case in Hong Kong Chinese donors. Vox Sanguinis, 93, 57–63.
Modeling
Popular classification methods
Logistic Regression; Decision Tree; ANN; SVM
Ensemble techniques Bagging ,Busting and Information fusion
Procedure
Results
Identify potential dropout by using data mining model Identify important independent variables or predictors Develop and deploy Detention strategies
Current situation of blood supply in the U.S. Prior survey based researches found some important factors (such as donation experience and convenient donation place) may influence donor’s decision to return A recent study on freshmen student attrition
RESEARCH QUESTIONS
What kind of blood donors is more likely to drop out? What are critical factors may lead to donor attrition?
Introduction
BRIEF LITERATURE REVIEW
used data mining techniques
DataSets
Donation Records
Disaster relief appeals and incentive info.
Possible survey data
Whole Dataset For Modeling
Methodology and Tools
Predicting Blood Donor’s Attrition with Data Mining Methods
Xing Wan
Introduction
Blood supply in the U.S. is always inadequate
Recruitment and retention of blood donor has become a top priority
CRISP-DM
Business Understanding Data Understanding Data Preparation Modeling Evaluation (10-fold cross-validation approach) Deployment
References
1. Cheng, E., Chany, C., & Chauz, M. (2010). Data Analysis for Healthcare: A Case Study in Blood Donation Center Analysis. Americas Conference on Information Systems. 2. Delen, D. (2010). A comparative analysis of machine learning techniques for student retention management. Decision Support Systems, 49, 498-506. 3. Masser, B., White, K., Hyde, M., & Terry, D. (2008). The Psychology of Blood Donation: Current Research and Future Directions. Transfusion Medicine Reviews, 22(3), 215-233. 4. Saltelli, A. ( 2002). Making best use of model evaluations to compute sensitivity indices, . Computer Physics Communications 145, 280-297.