Gravastars and bifurcation in quasistationary accretion

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中医西医英语作文

Traditional Chinese Medicine TCM and Western Medicine are two distinct systems of healthcare that have evolved over time to address the health needs of humanity.Both systems have their unique approaches,methodologies,and philosophies that define their practice.Historical BackgroundTCM has a history that dates back over2,000years,deeply rooted in Chinese culture and philosophy.It is based on the concept of Qi vital energy,the balance of Yin and Yang, and the Five Elements theory.TCM includes practices such as acupuncture,herbal medicine,massage Tui Na,and dietary therapy.Western Medicine,on the other hand,has its roots in ancient Greece and has evolved significantly with the advent of modern science.It is characterized by evidencebased practices,the use of pharmaceuticals,surgical procedures,and technological advancements in diagnostics and treatment.Philosophical DifferencesTCM operates on a holistic approach,treating the body as an integrated whole where the mind and spirit are as important as the physical body.It emphasizes the prevention of disease and the maintenance of health through balance and harmony.Western Medicine tends to focus on a more reductionist approach,treating specific symptoms and diseases with targeted interventions.It often employs a specialized and compartmentalized view of the body,with different medical professionals addressing different aspects of health.Diagnostic MethodsIn TCM,diagnosis often involves observing,listening,smelling,asking,and palpating to understand the patients condition.This includes the examination of the tongue and pulse, which are believed to reflect the state of the bodys energy and overall health.Western Medicine relies heavily on technological tools for diagnosis,such as blood tests, imaging studies Xrays,MRIs,CT scans,and other laboratory tests to identify diseases and abnormalities.Treatment ModalitiesTCM treatment modalities are diverse and may include herbal remedies,acupuncture, cupping,and lifestyle adjustments.The goal is to restore balance and promote the bodys natural healing processes.Western treatments are often more invasive and may include surgery,medication, radiation therapy,and other medical interventions.The focus is on treating the disease or condition directly.PatientPractitioner RelationshipIn TCM,the relationship between the practitioner and the patient is often more personal and longterm,with a focus on understanding the patients lifestyle,emotions,and environment.Western Medicine tends to have a more transactional relationship,with patients visiting different specialists for various health concerns and often having shorter,more focused interactions.Efficacy and IntegrationBoth TCM and Western Medicine have their strengths and weaknesses.Some patients find relief from chronic conditions through TCM,while others may require the precision and targeted treatments offered by Western Medicine.There is a growing interest in integrating both systems to provide a more comprehensive approach to healthcare.ConclusionUnderstanding the differences between TCM and Western Medicine can help individuals make informed decisions about their health and wellbeing.As both systems continue to evolve,there is potential for greater collaboration and mutual respect,leading to improved health outcomes for patients worldwide.。

Phytotoxicity and Volatile Monoterpenes of Laris and Artemisia iwayomogi Used as Korean Herbal Injin

J. Ecol. Field Biol. 32 (1): 9～12, 2009Phytotoxicity and Volatile Monoterpenes of Leaves from Artemisia capillarisand Artemisia iwayomogi Used as Korean Herbal InjinYun, Kyeong WonDepartment of Oriental Medicine Resources, Sunchon National University, Suncheon 540-742, KoreaABSTRACT : Artemisia capillaris and Artemisia iwayomogi are weeds used as medicinal plants in Korea under the name ”Injin“. I collected leaves of A. capillaris and A. iwayomogi , examined them for phytotoxic effects from volatile substances and determined the composition of monoterpenes in the leaves. The effects of volatile substances from each species on seed germination and radicle elongation in each of the two Artemisia species were assessed. The volatile substances of A. capillaris did not negatively affect the seed germination of A. ca-pillaris , but they did inhibit radicle elongation. Rates of seed germination of A. iwayomogi decreased when the seeds were exposed to high concentration of A. capillaris volatile substances. The inhibition of seed germination and radicle elongation by volatile substances from both Artemisia species was stronger for A. iwayomogi than for A. capillaris . I identified the monoterpenoids from the leaves with a gas chromatograph-mass spectrometer (GC-MS). The main constituents of A. capillaris were acenaphthylene (37.91%), β-pinene (12.08%), 4-carene (10.61%) and γ-curcumene (9.92%), while those of A. iwayomogi were germacrene-δ (32.15%), borneol (21.24%), camphor (20.45%) and trans-caryophyllene (7.75%).Key words : Artemisia capillaris , Artemisia iwayomogi , Monoterpene, Phytotoxicity* Corresponding author; Phone: +82-61-750-3664, e-mail: ykw@sunchon.ac.krINTRODUCTIONArtemisia species are known to be a rich source of volatile compounds with a variety of biological activities, and it has been suggested that Artemisia exhibits strong allelopathic properties (Rice 1984). Members of this genus have a characteristic scent or taste, and are of botanical and pharmaceutical interest (Kordali et al. 2006). Though Artemisia capillaris and A. iwayomogi are weeds, they have been used in traditional medicine, under the name "Injin". Artemisia capillaris is a common perennial herb and has been cul-tivated in Korea for the treatment of hepatitis. A. capillaris has been shown to have an antifungal effect (Choi et al. 2005) and an allelopathic effect (Kil 1999). Artemisia iwayomogi is an unique shrub of the genus in Korea. It inhibits hepatotoxicity and liver cirrhosis (Song et al. 2001).Volatile monoterpenes exhibit a greater diversity of compounds than any of the other volatile terpenoid compounds. The biological activity of volatile compounds is dependent on the synergistic or additive effects of the constituent types present at different concen-trations. Volatile components from aromatic plants can cause a number of positive or negative interactions (Vokou et al. 2003). The volatile constituents that play a prominent role as plant protection agents are being explored for their insecticidal, pesticidal, and her-bicidal properties (Singh et al. 2002). Volatile compounds iden-tified from Artemisia plants have been implicated as phytotoxic and are responsible in part for the allelopathic activity of these species (Rice 1984). The aim of the study was to assess the phytotoxic effect of volatile substances and the volatile monoterpene constituents in A. capillaris and A. iwayomogi .MATERIALS AND METHODSPlant MaterialAerial parts of A. capillaris and A. iwayomogi were collected from a cultivated population in the Jinan Medicinal Herbs Experi-ment Station, Jeollabuk-do Agricultural Research & Extension Ser-vices (35°46'15"N, 127°22'40"E), in Korea, on June 23, 2007. The fresh plant materials were taken, sealed in a plastic bag, trans-ported to the laboratory and then used immediately for experiments. Seeds of the two Artemisia plants were collected from the Jinan Medicinal Herbs Experiment Station in the fall of 2006. Phytotoxic Effects of Volatile Substances from A. capillaris and A. iwayomogiTo assess the phytotoxic activity of volatile substances from the two Artemisia species on germination and radicle elongation, 50 seeds of the test plants were placed in a 1.8 L glass chamber on filter paper that was layered on moist, absorbent cotton. Fresh leaves of the two Artemisia species were cut into 1-cm pieces, and differentKyeong Won Yun J. Ecol. Field Biol. 32 (1) 10quantities of the cut Artemisia leaves (fresh masses of 5, 10, 15, 20, 25, or 30 g) were placed in a glass beaker within the chamber. The glass chambers were then covered with vinyl wrap and placed in a growth chamber that was maintained at 25℃during the day (14 h) and 18℃at night (10 h). The experiment was terminated after four days, when seed germination had ceased, and seed germi-nation and radicle elongation were recorded. Seed germination rates and radicle elongation rates relative to control (RGR and RER) were calculated following Kil and Yun (1992) as (seed germination rate in treatment group) / (seed germination rate in control group)×100 and (average radicle elongation in treated seedlings)/(ave-rage radicle elongation in control seedlings)×100.Analysis of MonoterpenoidsFresh leaves of the two species of Artemisia plants were ground in a mortar with pure sand and extracted with 50 mL of pentane. After extraction, extracts from fresh leaves were concentrated to 8～10 mL or 0.5～1.0 mL under nitrogen gas. Each sample was analyzed by injection of a 1 μL aliquot onto a Gas Chromato-graphy-Mass Spectrophotometer (HP 5890II-5972MS) with a flame ionization detector. Monoterpenoids were separated on a fused silica capillary column packed with HP5 (id, 0.25 mm, 30 m long) with oven temperature programmed from 37℃for five minutes, increa-sing to 180℃at a rate of 5℃/min, and then at 20℃/min to 320℃. The individual peaks were identified by comparison with the spectral data in the internal spectral library of the instrument (Wiley library ver. 7.0) and by retention times, based on references. Be-cause of the complexity of the chromatograms, a limited number of peaks were examined. The concentration of peaks at selected reten-tion times were estimated from peak area using the internal standard curve of tetradecane (Kim et al. 2006).Statistical AnalysisA randomized complete block design with four replications was applied in all the experiments. Each experiment was repeated three times. Statistical analysis was performed with the software program SPSS (Version 10.0).Comparisons between treatments were made at the 0.05 level using Duncan’s multiple-range test.RESULTS AND DISCUSSIONPhytotoxic Effects of Volatile Substances from Artemisia ca-pillaris and Artemisia iwayomogi on Each of the Two Artemisia plantsBiologically active compounds from higher plants are now known to be important components of a plant’s interaction with its environ-ment. Plant-produced compounds can act as phytotoxins if they are found to inhibit or halt growth of other organisms. In this case the interaction between plants is known as allelopathy (Beninger and Hall 2005). Seed germination in the two Artemisia species was influenced by the volatile substances from both Artemisia plants. In cases where the relative germination/elongation ratio is more than 100%, the plant compound has stimulated germination or elonga-tion. Conversely, when the value is less than 100%, inhibition of germination or growth has occurred. Seed germination in A. ca-pillaris was stimulated, rather than inhibited, by volatile substances from A. capillaris(i.e., from conspecifics), but A. iwayomogi was inhibited by concentrations of volatile substances of A. capillaris (i.e., from heterospecifics) that exceeded 25 g/1.8 L. Seed germina-tion of A. capillaris and A. iwayomogi were both inhibited by con-centrations of volatile substances of A. iwayomogi that exceeded 15 g/1.8 L (Fig. 1). Volatile substances from the two Artemisia spe-cies also affected radicle elongation in both Artemisia species (Fig.2). Seed germination and radicle elongation of A. iwayomogi were dramatically inhibited by high concentrations of volatile substances from A. capillaris and A. iwayomogi. Perennial species in the genus Artemisia expend considerable energy to produce terpenoids that protect them from other organisms (Reid 1964). Aqueous extracts and volatile substances from Artemisia princeps var. orientalis affected seed germination and seedling growth depending on the concentra-tions of the extract and volatile substances and the species tested (Kil and Yun 1992, Yun et al. 1993). Plants of the genusArtemisiaFig. 1. Relative germination ratios of Artemisia capillaris and A. iwa-yomogi treated at different concentrations of volatile substancesfrom the two Artemisia plants. Bars topped by different lettersare significantly different according to Duncan's multiple-range test (p≤0.05)。

周围性面瘫中医康复护理的研究进展

2022年第8卷第10期Vol.8，No.10，2022中西医结合护理Chinese Journal of Integrative NursingOPEN ACCESS http ：//周围性面瘫中医康复护理的研究进展任梅1，刘丽1，耿庆文2（1.北京中医药大学东直门医院针灸科，北京，100700；2.北京中医药大学东直门医院，北京，100700）摘要：本文总结了近年来中医康复护理在周围性面瘫中应用现状，对周围性面瘫临床表现、治疗方法、中医护理措施等进行阐述，以期为今后周围性面瘫的临床护理实践及科研提供参考。

关键词：周围性面瘫；疼痛；中医护理；康复护理中图分类号：R 473.5文献标志码：A文章编号：2709-1961（2022）10-0055-05Research progress of Traditional ChineseMedicine nursing in rehabilitation ofperipheral facial paralysisREN Mei 1，LIU Li 1，GENG Qingwen 2（1.Department of Acupuncture ，Dongzhimen Hospital Beijing University of Chinese Medicine ，Beijing ，100700；2.Dongzhimen Hospital Beijing University of Chinese Medicine ，Beijing ，100700）ABSTRACT ：This paper reviewed the literature on the intervention of Traditional Chinese Medi⁃cine nursing in the rehabilitation of facial paralysis in recent five years ，and summarized the etiolo⁃gy analysis ，treatment methods ，Traditional Chinese Medicine nursing strategies ，etc.，so as to provide references for clinical nursing practice and scientific research of peripheral facial paralysis in the future.KEY WORDS ：peripheral facial paralysis ；pain ；Traditional Chinese Medicine nursing ；rehabilitation nursing周围性面瘫是指发生在面神经核及核以下部位损伤导致的面神经麻痹，致同侧面神经所支配的上、下面部表情肌瘫痪，临床表现为睑裂增宽、鼻唇沟及额纹变浅或消失、口角歪斜、鼓腮漏气等，支配味觉及泪腺分泌的纤维受损时，可伴舌前2/3味觉障碍、泪液分泌障碍。

OxfordTextbookof...

Matthew Smallman-Raynor and Andrew Cliff,Atlas of Epidemic Britain:A Twentieth-Century Picture.Oxford,Oxford University Press,2012,xþ207pages,£125hardcover.This book,as its title implies,maps infectious disease data in the twentieth century,largely within England,Scotland,and Wales,but occasionally straying into a wider geographical area and into the twenty-ﬁrst century.The focus is largely on infectious epidemics in humans.The authors make the slightly ambitious claim that this might be considered a continuation of Charles Creighton’s classic History of Epidemics in Britain(2vols.,Cambridge,1891e4).In the present work,after a slightly congested opening chapter(contain-ing a lot of the basic ideas and terminology),chapter2surveys epidemic mortality in the British Isles and Europe over the twen-tieth century,highlighting a threefold division into emerging diseases(e.g.,inﬂuenza,pneumonia,respiratory infections,polio-myelitis),retreating diseases(e.g.,anthrax,diphtheria,typhoid), and secularly varying emerging/retreating diseases(e.g.,malaria, brucellosis).Chapter3concentrates on the extinction of the‘old plagues’,speciﬁcally bubonic and pneumonic plague,malaria, smallpox,cholera and typhus fever in the period up to1945.The focus of the two chapters that follow is on common infections up to1945,speciﬁcally the four major epidemic in-fections of childhood(diphtheria,scarlet fever,measles,whooping cough)(chapter4),and inﬂuenza,typhoid,parathyroid,dysentery, and poliomyelitis(chapter5),emphasizing the importance of im-munization and public health measures such as closure of schools, and improvement in sewage treatment,in control of these in-fections.Chapter6deals with infections during the two world wars, in particular tuberculosis,meningococcal meningitis,sexually transmitted infections(syphilis,gonorrhoea),and viral hepatitis; curiously,despite large-scale rural e urban migration,there was no marked change in infectious disease rates anywhere.After1945Britain saw dramatic reductions in prevalence of many bacterial(chapter7)and viral(chapter8)infectious diseases as a result of mass immunization campaigns and wide availability of antibiotics and antiviral agents,both of which depended in turn very largely on the establishment of the UK National Health Service.Chapter9deals with the‘new plagues’of HIV/AIDS,Legionnaires’disease,new-variant Creutzfeldt-Jakob disease,methicillin-resistant staphylococcus aureus(MRSA),and a few others,including some old friends(e.g.,falciparum malaria).Chapter10is an oddity,detailing the work of research in general practice,through detailed examination of the work of four such general practitioners working in isolation,Drs Will Pickles,Edgar Hope-Simpson,Peter Higgins,and James Mackenzie,and the work of the Royal College of General Practitioners in organizing multi-practice studies,as exempliﬁed in the Epidemic Observation Unit established by Dr G.I.Watson.This chapter discusses the valuable work of these individuals and groups in furthering understanding of the epidemiology,speciﬁcally the spatio e temporal dynamics,of inﬂuenza and other common infections.Aﬁnal chapter(11)brieﬂy brings us up to date,examining epidemics in the twenty-ﬁrst century.Among the most signiﬁcant of these was inspired by the measles e mumps e rubella vaccine scare that was generated by an article(subsequently withdrawn) supposedly demonstrating a link with autism[A.J.Wakeﬁeld et al., Lancet351(1998),637e641].There followed a predictable increase in cases of mumps and measles,only very recently brought under control.Arguably of more public health concern is the re-emergence of tuberculosis,rates of which in the UK are among the highest in western Europe,and particularly of the emergence of antibiotic-resistant strains.This chapter also deals with certain animal epidemics,in particular the2001foot-and-mouth and bluetongue disease outbreaks,and related animal e human epi-demics,in particular the avian inﬂuenza(H5N1)epidemic of 2005e2007[M.D.de Jong et al.NEJM352(2005):686e691;G.J.Smith et al.,PNAS103(2006)16936e16941],although in a volume focused on Britain the authors cannot discuss this last epidemic with the necessary focus on the parallel spread in infected fowl in the Middle East and Asia.Would I recommend you to buy it?In chapter8and a few other places results of statistical analysis are presented and it is not clear whether these represent analysis of the authors,or some other publication.Unfortunately details of the particular modelsﬁtted are lacking.The predominant focus on epidemic events in Britain handicaps the treatment of certain topics,in particular those of chapter11.Despite these shortcomings,and the quite high price there is much that is commendable in the book.The book is handsomely illustrated,and clearly much care has gone into preparation of the graphs andﬁgures.I suspect many readers will ﬁnd chapters7e9,11dealing with the post-1945period particu-larly interesting,but there is much of interest in other chapters, particularly chapter10.Each chapter comes with a conclusion highlighting links with succeeding chapters.This book would be very helpful for historians,geographers,epidemiologists,and physicians and others working in public health who want an overview of this important area.Mark P.Little Radiation Epidemiology Branch,National Cancer Institute,USA /10.1016/j.jhg.2014.05.004Andrew Cliff and Matthew Smallman-Raynor,Oxford Textbook of Infectious Disease Control:A Geographical Analysis from Medieval Quarantine to Global Eradication.Oxford,Oxford University Press, 2013,ixþ193pages,£85hardcover.This book,as its title implies,is concerned with measures for controlling spread of infectious disease epidemics,and its geographical focus and historical breadth make its content relevant to historical geographers.Chapter1deals with various historical examples,in particular the moderately sophisticated control mea-sures used in various city-states in Italy(also in Ragusa e modern day Dubrovnik)between the fourteenth and eighteenth centuries. These were largely based on quarantine and isolation,which for the unfortunate traveller to one of these places could mean conﬁne-ment in one of the lazzaretti,an appalling and frequently lethal experience.A slight oddity is the introduction of the susceptible-infectious-recovered(SIR)model(R.M.Anderson and R.May,In-fectious Diseases of Humans:Dynamics and Control,Oxford:OUP (1991)),in a very non-technical way;the authors claim this pro-vides insights into the spread and control of epidemics:however why this should be the case is not made really clear here,although it is treated at somewhat greater length much later in the book,in chapter6.Chapter2deals with the issues of disease classiﬁcation and surveillance.Modern disease classiﬁcation starts with the work of William Farr and Marc d’Espine,following the International Sta-tistical Congress in Brussels in1853.Disease surveillance goes back to Roman times at least,but in its modern form began with the Bills of Mortality for London which appeared from1532and were annually published from1606.Mortality and morbidity counts became steadily more sophisticated,national and international in scope,culminating in the establishment of the World Health Or-ganization(WHO)in1948.The chapter documents the remarkableReviews/Journal of Historical Geography45(2014)120e141 130achievements of the disease monitoring and parallel immunization programs of the WHO,notably the eradication of smallpox and the near eradication of poliomyelitis.The critical need here is for rapidly updated morbidity registers,something easily achieved with the internet.Chapter3continues the theme of chapter1(which it should really have immediately followed,if not been amalgamated with), considering quarantine and isolation measures,predominantly in the nineteenth and twentieth centuries in the USA and UK.The effectiveness of these inherently geographical control measures has sadly been reduced by technological progress in transport and the consequently dramatically reduced journey times(which are now frequently shorter than the incubation times of most infections). The good news of technological progress,in the form of in-terruptions in transmission provided by vaccination,is the theme of chapter4.Both human data(smallpox,poliomyelitis,measles)and animal data(equine inﬂuenza)are covered in some detail;there is brief coverage of vaccination strategies,in particular the apparently successful trial of ring vaccination to eliminate equine inﬂuenza in Australia.Chapter5,entitled‘Eradication’,rather confusingly deals with a lot of the same material again,with speciﬁc focus on WHO global eradication campaigns.In particular,the largely successful WHO smallpox and poliomyelitis eradication campaigns are dealt with at some length,again.Failures in WHO eradication programmes with respect to malaria,yellow fever and yaws,are also discussed;the failures of the malarial eradication programme are treated at some length.Such failures may be a result of(i)a lack of biological or technical feasibility(yellow fever,yaws,malaria),(ii)lack of detailed economic analyses to justify or support the eradication effort(yellow fever,yaws)and(iii)lack of broad-based societal and political support(yellow fever,yaws,malaria)(B.Aylward et al.Am J Publ Health90(2000)1515e1520).The possibility of such a global eradication programme is discussed for measles.Theﬁnal chapter6is in some ways the most substantial chapter, and for me the most interesting one as it attempts a novel spatial approach to various modeling and public health issues.Starting out with the standard deﬁnition and implications of the basic repro-duction number R0,a fundamentally aspatial variable,the authors go on to consider a spatial analogue of this,in fulﬁlment of their aim in their subtitle of providing a geographical analysis.The authors apply both concepts to a variety of human datasets.They alsoﬁt an SIR model(as loosely deﬁned in chapter1,and unfortunately no more technical details are given here)and their Swash-Backwash model to a number of human datasets.Just how they do this is not explained here,although at least for the SIR model such details are given elsewhere(A.D.Cliff et al,Measles:An Historical Geography of a Major Human Viral Disease from Global Expansion to Local Retreat,1840e1990,Oxford,Blackwell(1993)).Would I recommend you to buy it?As noted above,there is considerable redundancy between chapters4and5,and arguably chapters1and3should have been combined also.Much of the material in this book(particularly chapters5and6)overlaps with a previous book by these and other authors(A.D.Cliff et al,Emergence and Re-Emergence:Infectious Diseases:A Geographical Analysis.New York,OUP(2009)).The lack of technical details in chapter6is also a major shortcoming.On the other hand the book itself is very handsome,with beautifully clear and well-chosen pictures and graphs that generally reinforce the points being made in the text. On the whole,however,rather than recommending this book, I would direct interested historical geographers to the authors’2009book.Mark P.Little Radiation Epidemiology Branch,National Cancer Institute,USA /10.1016/j.jhg.2014.05.003Nick Megoran and Sevara Sharapova(Eds),Central Asia in Interna-tional Relations:The Legacies of Halford Mackinder,London,Hurst, 2013,xviþ331pages,£45hardcover.Since their appearance in1904,the geopolitical ideas of Halford Mackinder in relation to Central Asia have attracted both admiring praise and dismissive criticism,inﬂuencing the larger academic and political debate over the future of that region.Mackinder’s vision of the Central Asian steppes as the‘pivot’or‘heartland’of the Eurasian landmass,destined to determine the world’s balance of power,has showed an impressive resilience andﬂexibility in international strategic discourses,inspiring the foreign policy of great powers like Germany and the United States throughout the twentieth century.The end of the Cold War in1991d and the sudden disin-tegration of the Communist bloc and emergence of new,fragile independent states in the former Soviet Union d again put Mack-inder’s vision at the centre of debates in international relations.In an attempt to understand the often confusing foreign policies of these emergent states,many geopolitical analysts and strategic experts have looked again at Mackinder’s original view of the Eurasian heartland,using this concept as a viable guideline for understanding the diplomatic or military actions of these Central Asian countries.The recent war in Afghanistan against Al-Qaida and the Taliban has reinforced such a tendency,providing further stimuli for the theoretical and practical adoption of Mackinder’s ideas in international politics.Mackinder’s ideas are,however,far more complex and problematic than is generally acknowledged, and their direct impact in Central Asia is also somewhat confused and contradictory,as is clearly shown by this excellent collection of interdisciplinary essays edited by Nick Megoran and Sevara Sharapova.Inspired by an international symposium held in Tashkent in 2004,the collection in fact encapsulates all the most recent scholarship on Mackinder’s geopolitical theories produced both in the West and in the former Soviet Union,providing a fresh and comprehensive overview of their persistent relevance to interna-tional affairs.The main intent of the editors,as is noted in the lengthy introduction to the volume,is to consider‘how useful the pivot/heartland thesis is in understanding contemporary Central Asia’and to discuss‘a number of other intellectual puzzles’about Mackinder’s geopolitical thought that have generally been over-looked by previous academic studies on the subject(p.4e5).Such questions include:How did Mackinder’s ideas travel to Central Asia in the post-Cold War era,inﬂuencing the foreign policy debates of local states like Uzbekistan and Tajikistan?What level of popularity do they enjoy in post-Soviet Russia,and to what extent are they revised or manipulated by nationalist intellectuals in support of a more aggressive defence of Russian strategic interests?Have Anglo-American strategists really learned the right lessons from Mack-inder,or have they instead downplayed some key aspects of his thought,committing their countries to aﬂawed political course in Central Asia?These are only some of the interesting questions addressed by the various contributors to the volume,and,although their individual responses are not always entirely convincing or satisfactory,their common critical approach to Mackinder’sReviews/Journal of Historical Geography45(2014)120e141131。

沙利度胺的传说

The International Journal of Biochemistry&Cell Biology39(2007)1489–1499ReviewThe thalidomide sagaMagda Melchert a,∗,Alan List ba Mofﬁtt Cancer Center and Research Institute,12902Magnolia Drive,SRB-4,Tampa,FL33612,USAb12902Magnolia Drive,SRB-4,Tampa,FL33612,USAAvailable online30January2007AbstractOver the past50years,thalidomide has been a target of active investigation in both malignant and inﬂammatory conditions. Although initially developed for its sedative properties,decades of investigation have identiﬁed a multitude of biological effects that led to its classiﬁcation as an immunomodulatory drug(IMiD).In addition to suppression of tumor necrosis factor-alpha(TNF-␣), thalidomide effects the generation and elaboration of a cascade of pro-inﬂammatory cytokines that activate cytotoxic T-cells even in the absence of co-stimulatory signals.Furthermore,vascular endothelial growth factor(VEGF)and betaﬁbroblast growth factor (bFGF)secretion and cellular response are suppressed by thalidomide,thus antagonizing neoangiogenesis and altering the bone marrow stromal microenvironment in hematologic malignancies.The thalidomide analogs,lenalidomide(CC-5013;Revlimid)and CC-4047(Actimid),have enhanced potency as inhibitors of TNF-␣and other inﬂammatory cytokines,as well as greater capacity to promote T-cell activation and suppress angiogenesis.Both thalidomide and lenalidomide are effective in the treatment of multiple myeloma and myelodysplastic syndromes for which the Food and Drug Administration granted recent approval.Nonetheless,each of these IMiDs remains the subject of active investigation in solid tumors,hematologic malignancies,and other inﬂammatory conditions.This review will explore the pharmacokinetic and biologic effects of thalidomide and its progeny compounds.©2007Elsevier Ltd.All rights reserved.Keywords:Thalidomide;Immunomodulatory agent;Angiogenesis;Lenalidomide;CC-4047Contents1.Introduction (1490)2.Pharmacokinetic properties (1490)3.Pharmacodynamic effects (1491)3.1.Immunomodulation (1491)3.2.T-cell activation (1492)3.3.Angiogenesis (1492)3.4.Bone marrow microenvironment (1493)3.5.Anti-tumor and apoptotic mechanisms (1493)4.Role of IMiDs in cancer therapy (1493)4.1.Multiple myeloma (1493)4.2.Myelodysplastic syndromes (1493)5.Conclusion (1496)References (1496)∗Corresponding author.Tel.:+18137453163;fax:+18137453071.E-mail addresses:Melcheme@mofﬁ(M.Melchert),ListAF@mofﬁ(A.List).1357-2725/$–see front matter©2007Elsevier Ltd.All rights reserved.doi:10.1016/j.biocel.2007.01.0221490M.Melchert,A.List/The International Journal of Biochemistry&Cell Biology39(2007)1489–14991.IntroductionThalidomide(Thalomid TM,Celgene Corp,Warren, NJ)is a synthetic glutamic acid derivative which was ini-tially developed in the early1950s as an anticonvulsant for the treatment of epilepsy.Following a lack of sufﬁ-cient efﬁcacy as an anti-epileptic,it was eventually mar-keted as a sleep aid and was also widely used as an anti-emetic during pregnancy(Randall,1990).Prior to its use in gravid women,the teratogenic effects of thalidomide in animals or humans were unknown.However,by1962, two published reports by William McBride in Australia and Widukind Lenz in Germany emerged describing limb and bowel malformations in children born to moth-ers who were exposed to thalidomide during pregnancy (Lenz,1962;McBride,1961).Use of this agent dur-ing theﬁrst trimester of gestation led to alarming rates of phocomelia,defects in long bones,absence of auri-cles,cleft lip,and cardiac and gastrointestinal anomalies. While thalidomide had not received approval by the Food and Drug Administration(FDA)in the United States (US)at this time due to concerns of neurotoxicity,the widespread international use of this drug as a sedative was eventually halted during the early1960s.The pharmacological effects of thalidomide extended beyond its neurosedative effects,and for that reason, it was subsequently investigated in a number of der-matologic,rheumatologic,and malignant diseases.In 1965,theﬁrst report of clinical activity in erythema nodosum leprosum(ENL)was serendipitously discov-ered by a dermatologist from Israel,Jacob Sheskin (Sheskin,1965).Thalidomide was found to be effec-tive in reducing fevers,night sweats,and improving skin lesions in a patient with ENL.However,it was not until1998that thalidomideﬁrst received approval by the FDA for the treatment of ENL(Pearson&Vedagiri, 1969;Sheskin,1965;Waters,1971).More recently, thalidomide was approved for the treatment of multi-ple myeloma in May2006,and has reported efﬁcacy in a wide spectrum of malignant and non-malignant dis-eases.Access to this agent in the US is restricted,and requires participation in the System for Thalidomide Education and Prescription Safety(STEPS)program to prevent adverse outcomes related to teratogenicity (Zeldis,Williams,Thomas,&Elsaved,1999).Thalidomide and its analogs are immunomodula-tory drugs(IMiDs)that exhibit a multitude of biologic effects on cytokine and cell-mediated responses.These effects are largely responsible for the clinical efﬁcacy seen in conditions such as lupus erythematosis,apt-hous ulcers that occur in human immunodeﬁciency virus and Behcet’s disease,ENL,graft versus host dis-ease,and cancer(Hamuryudan et al.,1998;Jacobson et al.,1997;Kumar,Witzig,&Rajkumar,2004;Parker et al.,1995;Pearson&Vedagiri,1969).Thalidomide is the most widely studied of the IMiDs;however, the newer structural analogs,CC-5013(lenalidomide, Revlimid TM,Celgene Corp.,Warren,NJ)and CC-4047 (Actimid TM),promise even greater activity for clinical development.These two analogs of thalidomide were developed in the mid-1990s with enhanced potency and a relatively favorable toxicity proﬁle.This review will summarize the pharmacokinetic and biologic properties of thalidomide and its derivatives.2.Pharmacokinetic propertiesThalidomide(␣[N=Phthalimido]glutarimide)con-tains a glutarimide moiety with a single chiral center and is formulated as a racemic mixture of two active enantiomers,S(−)and R(+)(see Fig.1).Initially,the S(−)isoform was thought to be the enantiomer pri-marily responsible for the teratogenic effects and the R(−)isoform for the sedative properties.Puriﬁcation of the R(−)enantiomer was attempted in order to optimize its clinical application,but was eventually not found to be technically feasible secondary to the rapid interconversion of isomers under physiologic con-ditions.Furthermore,both forms were found to be teratogenic in the New Zealand rabbit model,and thus it remains a racemic mixture(Eriksson,Bjorkman,Roth,& Fig.1.Adapted with permission from Macmillan Publishers Ltd:Nature Reviews Cancer,2004(Bartlett et al.,2004);(a)the chemical structure of thalidomide;(b)alteration of the structure of thalidomideby adding an amino(NH2−)group at the4position of the phthaloyl ring to generate the IMiDs CC-5013and CC-4047.For CC-5013,one of the carbonyls(C O)of the4-amino-substituted phthaloyl ring has been removed.M.Melchert,A.List/The International Journal of Biochemistry&Cell Biology39(2007)1489–14991491Hoglund,2000;Fabro,Smith,&Williams,1967).Poor water solubility led to the development of thalidomide exclusively as an oral agent,with peak plasma con-centrations of the drug detected at3–6h(Chen et al., 1989).Upon ingestion,thalidomide undergoes sponta-neous non-enzymatic hydrolytic cleavage into more than 12different metabolites.Thalidomide and its metabo-lites are quickly eliminated in the urine,with a mean elimination half-life of approximately5h.The pharma-cokinetic properties of thalidomide in the presence of renal or hepatic dysfunction are largely unknown.Dos-ing with thalidomide is disease-dependent,with daily oral schedules of50–800mg,demonstrating efﬁcacy in a variety of disease processes.Over the last decade,second-generation IMiD com-pounds have been developed by chemical modiﬁcation of the structural backbone of thalidomide in order to enhance immunomodulatory potency and minimize the dose-limiting neurotoxic effects.Both lenalidomide and CC-4047are4-amino-gultaramide derivatives of thalidomide in which an amino group was added to the fourth carbon of the phthaloyl ring of the parent com-pound(see Fig.1)(Bartlett,Dredge,&Dalgleish,2004; Teo et al.,2003).Both agents also exist as a racemic mixture of the active S(−)and R(+)forms.Like thalido-mide,they are both administered in daily oral dosing every21–28days of monthly cycles.Renal elimination predominates,and caution is recommended in dosing of patients with impaired creatinine clearance.The ter-minal half-life of lenalidomide and CC-4047after oral administration are reported as3and7h,respectively (Bartlett et al.,2004;Schey et al.,2004).In contrast to thalidomide in which somnolence,constipation,and peripheral neuropathy are common dose-limiting toxic-ities,both lenalidomide and CC-4047lack signiﬁcant neurosedative toxicity.Dose-limiting neutropenia and thrombocytopenia are the most common toxic sequelae, while venous thromboembolism has been reported with use of all three agents.3.Pharmacodynamic effects3.1.ImmunomodulationThalidomide and its derivatives are potent immunomodulators with biologic effects on both cytokine stimulation and cell-mediated immunity(see Fig.2).One of the key mediators responsible for the anti-inﬂammatory responses seen with the use of IMiD agents is tumor necrosis factor-alpha(TNF-␣). Thalidomide enhances degradation of TNF-␣mRNA, thus suppressing this pro-inﬂammatory cytokinerelease Fig.2.Reproduced with permission from Journal of Clinical Oncol-ogy,2004(Kumar et al.,2004).Proposed mechanism of action of thalidomide in cancer illustrated using myeloma as an example. Thalidomide inhibits angiogenesis,enhances effects of the immune system,inhibits binding of tumor cells to stroma,and inhibits various cytokines.Thaliomide may also have direct effects on the tumor.NK: natural killer;TNF:tumor necrosis factor;IL-6:interleukin-6;VEGF: vascular endothelial growth factor;NF-kB:nuclear factor kappa B. from endotoxin-stimulated monocytes and macrophages (Moreira et al.,1993).The effect on TNF-␣is felt to be largely responsible for the clinical beneﬁt seen in patients with inﬂammatory conditions such as ENL,who have high endogenous TNF-␣production that is suppressed following thalidomide treatment (Sampaio et al.,1993).In addition,both lenalidomide and CC-4047have up to a50,000-fold higher potency than thalidomide as inhibitors of cytokine generation, including suppression of endotoxin-induced TNF-␣secretion(Bartlett et al.,2004;Corral et al.,1999a). Activation of the transcription factor nuclear factor kappa B(NF-kB),a key regulator of TNF-␣and inter-leukin(IL)-8production,is blocked after thalidomide exposure through inhibition of the inhibitor of kappa B (IkB)kinase(Keifer,Guttridge,Ashburner,&Baldwin, 2001).However,the cellular response to IMiD agents is quite complex and lineage and ligand speciﬁc,with evidence that TNF-␣generation is actually enhanced in the setting of T-cell activation.This is demonstrable in1492M.Melchert,A.List/The International Journal of Biochemistry&Cell Biology39(2007)1489–1499vitro with upregulation of TNF-␣production by CD4+ and CD8+T-lymphocytes stimulated by anti-CD3 (Marriott et al.,2002).Furthermore,an increase in TNF-␣serum concentration has been reported upon exposure to IMiD agents in early-phase trials involving solid tumors and inﬂammatory dermatologic diseases such as toxic epidermal necrolysis(Bartlett et al.,2004; Wolkenstein et al.,1998).While the biologic effects of TNF-␣modulation by the IMiD agents may be central to the therapeutic bene-ﬁts seen in a variety of inﬂammatory conditions,there are several other cytokines that are similarly affected by this class of agents that may play a signiﬁcant role in immune modulation.Generation of pro-inﬂammatory enzymes and cytokines,such as cyclooxygenase-2(COX-2), interleukin-1beta(IL-1␤),transforming growth fac-tor(TGF)-␤,and IL-6are suppressed upon exposure to IMiDs,and contribute to the activation of the T-cell receptor(TCR),particularly in the T H1subset (Bartlett et al.,2004;Corral et al.,1999a;Musto,2004). Analogous to TNF-␣modulation,IL-12secretion is sup-pressed by IMiDs when monocytes are stimulated by lipopolysaccharide and is enhanced in the setting of T-cell stimulation(Corral et al.,1999a,1999b).Expansion of both T-cells and NK-cells is promoted by IL-12secre-tion and thus IMiD agents have the potential to be useful adjuncts in the development of cancer vaccines and other immunotherapuetic approaches(Trinchieri,1998).Fur-thermore,IL-12stimulates interferon-␥(IFN-␥)produc-tion and both cytokines have demonstrable anti-tumor activity and anti-angiogenic-activity(Beatty&Paterson, 2001;Qin&Blankenstein,2000;Trinchieri,1998). 3.2.T-cell activationThe immune response to foreign antigens is a highly regulated process requiring the presentation of major histocompatability(MHC)-bound peptides on antigen presenting cells(APCs)to the TCR.Acces-sory molecules,such as B7on APC and CD28on the T-cell surface,provide secondary signals that are vital to the promotion of T-cell responsiveness.These interactions lead to the subsequent activation and pro-liferation of T-cells followed by a cascade of cytokine and cellular responses.Thalidomide and its deriva-tives are able to enhance the CD8+T-cell response in the absence of these secondary co-stimulatory sig-nals(Haslett,Corral,Albert,&Kaplan,1998;Mueller, Jenkins,&Schwartz,1989).In vitro data of primary human T-cells suggest that thalidomide enhances IL-2 mediated T-cell proliferation and IFN-␥production via the TCR complex.The effect of thalidomide on T-cell expansion is dose-dependent and occurs even at low lev-els of CD3stimulation.Furthermore,thalidomide affects the balance between T-helper(Th)-1and-2subsets at least in part through cytokine modulation of IL-4,IL-5,and IFN-␥(McHugh et al.,1995).In the presence of thalidomide,mitogen-and antigen-stimulated human peripheral blood mononuclear cells preferentially induce the Th-2subtype,which corresponds with maximum enhancement of IL-4production.Thalidomide derivatives are also potent co-stimulators of T-cells that enhance activation of CD8+ T-cells in vitro(Stirling,2001).Upon exposure to CMV and inﬂuenza virus matrix proteins,both CC-5013and thalidomide were shown to enhance CD8+cytokine production and cytotoxic activity(Haslett,Hanekom, Muller,&Kaplan,2003).CC-4047has demonstrated durable,tumor-speciﬁc Th-1type immunity in mice tumor xenograft models(Dredge,Marriott,Todryk et al.,2002).These preclinical investigations have suggested a potential role for the use of IMiD agents in the development of tumor vaccine adjuncts and as modulators of immune response in the setting of defective CD4+mediated immunity such as HIV and graft versus host disease.3.3.AngiogenesisIn the early1990s,thalidomide wasﬁrst reported to exhibit potent anti-angiogenic properties that were thought to contribute to the teratogenic effects of limb bud malformations observed in offspring of thalidomide exposed gravid mothers(D’Amato,Loughnan,Flynn, &Folkman,1994).Eventually,the effect of IMiDs on vasculogenesis was recognized as a mechanism of poten-tial clinical beneﬁt in the treatment of malignancies in which neoangiogenesis is a conserved feature of the malignant phenotype.Vascular endothelial growth fac-tor(VEGF)and betaﬁbroblast growth factor(bFGF)are potent stromal mitogens that are produced in excess in a variety of malignancies,including multiple myeloma and myeloid disorders.Paracrine and autocrine secre-tion of VEGF causes proliferation of multiple myeloma cell lines and has also been shown to promote self-renewal of leukemia progenitors(Bellamy et al.,2001; Gupta et al.,2001).Secretion of both VEGF and bFGF from tumor and bone marrow stromal cells is sup-pressed upon exposure to IMiDs,resulting in reduced endothelial cell migration and adhesion(D’Amato et al.,1994;Dredge,Marriott,Macdonald et al.,2002; Lentzsch et al.,2003).Both thalidomide and CC-4047 have been shown to suppress the induction of VEGF in co-cultures of multiple myeloma cell lines and boneM.Melchert,A.List/The International Journal of Biochemistry&Cell Biology39(2007)1489–14991493marrow stromal cells(Gupta et al.,2001).Additionally, thalidomide inhibits bFGF-induced angiogenesis in vivo using a rabbit cornea micropocket assay(D’Amato et al.,1994).In murine lymphoma and rectal carcinoma cell line xenografts,IMiDs decrease tumor microvessel formation(Dredge,Marriott,Macdonald et al.,2002; Lentzsch et al.,2003).The latter anti-angiogenic effect is independent of TNF-␣suppression or endothelial cell proliferation,and appears to be dose-or concentration-dependent.Furthermore,lenalidomide has been shown to attenuate AKT-dependent phosphorylation,resulting in a reduction of bFGF-induced endothelial cell migra-tion(Dredge,Marriott,Macdonald et al.,2002;Dredge et al.,2005).3.4.Bone marrow microenvironmentThe pro-inﬂammatory responses within the bone marrow microenvironment are thought to play a sup-portive or tumor nurturing role in many hematologic diseases,including multiple myeloma and myeloid dis-orders.TNF-␣induces expression of IL-6secretion by bone marrow stromal cells and is markedly upregulated upon adhesion of multiple myeloma cells to bone mar-row stromal cells(Gupta et al.,2001;Witzig,1999). The adhesion molecules,ICAM-1,LFA-1,and VCAM-1,are similarly affected in the bone marrow milieu (Miyamoto et al.,1995).IL-6promotes the prolifera-tion of multiple myeloma cell lines and inhibits Fas-and dexamethasone-induced apoptosis in vitro.Both thalidomide and CC-4047decrease upregulation of IL-6in co-cultures of bone marrow stromal and multiple myeloma cells,suggesting an additional mechanism of therapeutic beneﬁt in multiple myeloma.Lenalido-mide induces activation of cell adhesion molecules and increases␤1integrin-mediated adhesion to extracel-lular matrix proteinﬁbronectin(Dredge et al.,2005; Miyamoto et al.,1995).3.5.Anti-tumor and apoptotic mechanismsIndependent of the immune-modulating activities, IMiDs have direct anti-proliferative activity in hema-tologic malignancies.The IMiDs,as a class,induce concentration-dependent inhibition of proliferation in multiple myeloma cell lines and primary myeloma cells that are resistant to standard chemotherapy(Lentzsch et al.,2003).Effects on apoptosis are evident at multiple levels of death receptor signaling,including potentia-tion of TNF-related apoptosis-inducing ligand(TRAIL), inhibition of apoptosis protein-2,increased sensitivity to Fas induction,and upregulation of caspase-8activa-tion(Keifer et al.,2001;Mitsiades et al.,2002).G0/G1 cell cycle arrest or apoptosis in leukemia cell lines and other hematologic malignancies occurs with lenalido-mide exposure and is mediated,at least in part,by A-dependent mechanisms(Dredge et al.,2005).Further-more,lenalidomide has preferential anti-proliferative activity against a5q mutant cell line(MUTZ-1)with corresponding induction of expression of genes encoded at the5q locus(Gandhi et al.,2004).These preclinical ﬁndings have been conﬁrmed in clinical trials involving patients with myelodysplastic syndromes(MDS).4.Role of IMiDs in cancer therapyThalidomide and its analogs have therapeutic potential in a wide spectrum of diseases given their multifaceted pharmacologic effects.The known immunomodulatory and anti-angiogenic properties of IMiDs provided the impetus to investigate these agents in the treatment of both hematologic malignancies and in solid tumors.Numerous early-phase trials in solid tumors have shown activity in prostate cancer,breast cancer,Kaposi’s sarcoma,renal cell cancer,melanoma, neuroendocrine tumors,hepatocellular carcinoma,lung cancer,and gliomas(Kumar et al.,2004).Response rates have been promising in some;however,further studies are needed to elucidate the true magnitude of thera-peutic beneﬁt in solid tumors.In addition,the IMiDs are attractive agents for the treatment of both myeloid and lymphoid malignancies with reported activity in non-Hodgkin’s lymphoma,acute myeloid leukemia,and myeloﬁbrosis with myeloid metaplasia(Kumar et al., 2004).However,the earliest focus of clinical investiga-tions involved multiple myeloma and MDS and thus will be discussed in further detail.4.1.Multiple myelomaThe use of IMiDs in the treatment of multiple myeloma has recently emerged as the standard of care following multiple reports of efﬁcacy in both front-line therapy and in relapsed or refractory dis-ease(Glasmacher et al.,2006;Rajkumar,Blood,Vesole, Fonseca,&Greipp,2006;Singhal et al.,1999;Tosi, Zamagni,&Cellini,2004).In May2006,thalidomide was approved by the US FDA for the treatment of newly diagnosed multiple myeloma in combination with dex-amethasone.The approval was based on a phase III multicenter trial performed by the Eastern Coopera-tive Oncology Group(ECOG)in which patients were randomized to four cycles of dexamethasone40mg on days1–4,9–12,17–20of28-day cycles either1494M.Melchert,A.List/The International Journal of Biochemistry&Cell Biology39(2007)1489–1499Table1Summary of MM-009and MM-010,phase III trials of CC-5013in multiple myelomaMM-009MM-010North American trial International trialCC-5013+Dex Dex alone CC-5013+Dex Dex alone TTP(weeks)60.120.753.420.6 Overall RR(%)61.222.85821.7CR(%)26.5 4.113.6 4.0 Dex:dexamethasone;TTP:time to progression;RR:response rate;CR:complete response.alone or with200mg daily of thalidomide(Table1) (Rajkumar et al.,2006).Paraprotein responses in serum and urine monoclonal protein levels were observed in63%of patients treated on the combination arm compared to41%of patient receiving dexamethasone alone(p=.0017).Toxicities were signiﬁcant,with17% of patients developing deep venous thrombosis which prompted the recommendation for anticoagulation dur-ing combination therapy.Other adverse events included rash,bradycardia,and neuropathy.As a consequence,the thalidomide/dexamethasone combination is a common induction regimen for use as initial therapy in multiple myeloma and prior to autologous transplant.Thalidomide has also enjoyed success in the salvage setting,with multiple phase I and II trials demon-strating efﬁcacy either alone with response rates of 25–35%,or in combination with dexamethasone with response rates of50–60%(Glasmacher et al.,2006; Tosi et al.,2004).Combination chemotherapy trials with thalidomide have yielded variable rates of suc-cess in relapsed and refractory disease when applied in conjunction with dexamethasone,cisplatin,adriam-cyin,cyclophosphamide,etoposide,clarithramycin,and melphalan(Coleman et al.,2002;Kyriakou et al.,2005; Lee et al.,2003;Srkalovic,Elson,Trebisky,Karam, &Hussein,2002).Finally,thalidomide has also shown beneﬁt in the maintenance setting.The Intergroupe Fran-cophone du Myelome(IFM)recently reported the results of trial involving597patients who were randomized after autologous stem cell transplantation to three of the treatment strategies,i.e.,either(A)no maintenance, (B)pamidronate maintenance,or(C)thalidomide and pamidronate maintenance treatment until disease pro-gression(Attal et al.,2006).A complete or very good partial response was achieved in55%of patients in arm A,57%in arm B,and67%in arm C(p=0.03).The 3-year post-randomization probability of event-free sur-vival was improved with the thalidomide combination maintenance with36%of patients in arm A,37%in arm B,and52%in arm C remaining without evidence of disease progression(p<.009).The4-year probabil-ity of survival from the date of diagnosis was improved in the thalidomide/pamidronate maintenance arm(77% versus74%versus87%;p<.04).The initial dose of thalidomide was400mg daily,with39%of patients dis-continuing treatment secondary to adverse effects at a median of8months.Thus,while toxicities remain sub-stantial,thalidomide is an effective agent in the treatment of myeloma in all stages of the disease.Of particular importance,maintenance therapy with thalidomide in this trial did not increase the risk of thromboembolic complications,suggesting that thrombogenic potential may be highest when thalidomide is administered dur-ing induction therapy when tumor burden is high or when combined with agents that have intrinsic thrombogenic potential.Lenalidomide was subsequently approved by the FDA in June2006for combination treatment with dex-amethasone for relapsed or refractory multiple myeloma. Based on encouraging data from several phase I and II trials,two phase III randomized,multicenter trials (MM-009,US and MM-010,Europe)were initiated comparing lenalidomide and dexamethasone combi-nation treatment with dexamethasone and placebo in patients with multiple myeloma who had received at least one prior therapy(Weber et al.,2006).Interim results were reported at the American Society of Clinical Oncology Meeting in2006.Lenalidomide was adminis-tered in a daily25mg dose for21days in combination with dexamethasone pulse dose treatment of40mg on days1–4,9–12,and17–20in a28-day cycle.Major reductions in serum paraprotein concentration were reported in51–53%of the lenalidomide/dexamethasone group and were statistically superior to those seen in patients receiving dexamethasone alone(OR 5.5 [3.9,9.1];p<.0001).The median time to progression (TTP)in MM-009compared favorably:37weeks in the lenalidomide/dexamethasone arm versus19.9weeks for dexamethasone alone(HR=0.356[0.257,0.494]; p>.0001).Toxicities were manageable;however,grade 3/4neutropenia and thrombocytopenia were experienced in27%and17%of patients,respectively,with a7.8% incidence of deep vein thrombosis.Importantly,the adverse events commonly seen with thalidomide,such asM.Melchert,A.List/The International Journal of Biochemistry&Cell Biology39(2007)1489–14991495neuropathy,constipation,and sedation,were infrequent in these trials.Other toxicities include included rash, gastrointestinal symptoms,myalgias,and pulmonary embolism.Among patients receiving the lenalidomide combination in the MM-009study,thrombo-embolic events were reported in20of87patients(23%)who received concomitant recombinant erythropoietin ther-apy and in4of83patients who did not receive erythropoietin(5%)(Knight,DeLap,&Zeldis,2006). In the group that received placebo and dexametha-sone,thrombosis occurred in5of67patients(7%) who received concomitant erythropoietin and in1of 103patients(1%)who did not receive erythropoietin. Multivariate analysis of both studies combined showed an independent correlation between the development thrombotic events and treatment with the combination of lenalidomide and high-dose dexamethasone or treatment with concomitant erythropoietin.Of particular interest, thrombotic events were not reported among23patients who received aspirin or salicylates during theﬁrst month of treatment,as compared with52of668patients who did not receive aspirin or salicylates.A recent study showed a reduction in the thrombosis rate with the administration of aspirin in myeloma patients receiving a combination of thalidomide and anthracycline,sug-gesting that thrombotic risk with the IMiDs may be reduced when used in combination therapy by avoid-ance of recombinant erythropoietins that have inherent thrombotic potential,or prophylaxis with aspirin or alter-nate strategies(Baz et al.,2005).The latter approach is a subject of current investigation in an ECOG study.Dis-tribution of lenalidomide,like its parent compound,is also highly regulated given concerns for possible ter-atogenic effects.All patients prescribed this drug must participate in the Rev-Assist program prior to receiving medication.A phase I,dose-escalation study of CC-4047in multiple myeloma has also been reported with demon-strated safety and efﬁcacy(Schey et al.,2004).The drug was well tolerated,with the main dose-limiting toxic-ities being neutropenia and venous thrombosis with a maximum tolerated dose of2mg/day.A25%or more reduction in paraprotein was seen in67%of patients,and 54%achieved greater than a50%reduction.In support of T-cell activation as possible mechanistic role,increased serum IL-2receptor and IL-12levels were detected in patients receiving CC-4047.4.2.Myelodysplastic syndromesIMiDs were initially targeted as potential agents for the treatment of MDS based on their immunomodula-tory and anti-angiogenic features.Theﬁrst report of the use of thalidomide in MDS involved a trial of83 patients and included biologic correlates designed to assess angiogenic and inﬂammatory responses(Raza et al.,2001).Thalidomide was initiated at100mg daily and titrated upwards to a dose of400mg daily as tolerated. At12weeks of treatment,only61%of patients were able to complete the planned course of treatment sec-ondary to dose-limiting toxicities.Only13%of patients experienced a major erythroid response,and platelet or neutrophil improvements were uncommon.How-ever,erythroid responses were durable,with a median duration of306days.Thalidomide has since been inves-tigated in multiple trials at doses of200–1000mg daily in the treatment of both low-and high-risk MDS,with either hematologic improvement or partial responses reported in approximately20–60%of patients(Bouscary et al.,2005;Moreno-Aspitia et al.,2006;Zorat et al.,2001).At these doses,tolerance of thalidomide is discouraging,with a high frequency of dose-limiting fatigue,constipation,neuropathy,and sedation.For this reason,enthusiasm for development of thalidomide in the treatment of MDS has been tempered.In contrast,lenalidomide has shown remarkable activ-ity in the treatment of MDS with toxicities that compare favorably to thalidomide.The initial report on the safety and efﬁcacy of lenalidomide in MDS included 43patients with symptomatic anemia who had either failed treatment with erythropoietin(EPO)or were poor candidates for beneﬁt from EPO therapy(frequent transfusions(>2per month)and/or high endogenous ery-thropoietin serum concentration(>500mU/ml))(List et al.,2005).Patients were randomized to one of three dos-ing schedules:25mg daily,10mg daily,or10mg/day for21of ing the International Work-ing Group(IWG)criteria,56%of patients experienced durable erythroid responses and20of32patients who previously required RBC support became transfusion independent.Furthermore,10of12patients with an isolated interstitial deletion of chromosome5(5q31.1) experienced an erythroid response compared to57%of patients with a normal karyotype or12%of patients with other chromosomal abnormalities.Patients with 5q31.1had particular beneﬁt with a longer duration of transfusion independence.Both cytogenetic responses and decreased medullary myeloblast percentage were noted in patients responding to lenalidomide,and were more pronounced in patients with chromosome5q31.1 deletion.The dose-limiting toxicities were related to myelosuppression,with grade3or greater neutrope-nia(58%)and thrombocytopenia(50%)necessitating dose reductions or treatment interruption in47–77%of。

211126693_天麻在我国保健食品中的应用

段昊，周亚西，周士琦，等. 天麻在我国保健食品中的应用[J]. 食品工业科技，2023，44（9）：403−412. doi: 10.13386/j.issn1002-0306.2022050051DUAN Hao, ZHOU Yaxi, ZHOU Shiqi, et al. Application of Gastrodia elata in Functional Food in China[J]. Science and Technology of Food Industry, 2023, 44(9): 403−412. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2022050051· 专题综述 ·天麻在我国保健食品中的应用段　昊，周亚西，周士琦，闫文杰*（北京联合大学生物化学工程学院，生物活性物质与功能食品北京市重点实验室，北京 100023）摘　要：天麻是一种食药兼备的植物。

在中医领域常用于治疗眩晕、头痛、半身不遂等。

现代医学研究发现天麻在改善心脑血管健康、抗癫痫、改善高血压等方面具有良好的效果。

天麻在保健食品中常用于改善睡眠类功能声称的产品。

随着现代药理研究的不断深入，天麻发挥功能的主要活性成分和作用机理被不断揭示并进一步完善，扩大了天麻在保健食品领域的功能声称应用范围，以及发展前景与价值。

本文阐述了天麻原料在我国作为保健食品原料的合规性使用依据，汇总并分析了已获批使用天麻及其提取物作为保健食品原料的产品应用现状，综述了天麻的安全性评价以及相关的保健功能。

以期为天麻原料在我国保健食品中的合规性使用、研究开发和临床应用提供参考依据。

关键词：天麻，合规性依据，保健功能，应用现状本文网刊:中图分类号：TS218；TS219 文献标识码：A 文章编号：1002−0306（2023）09−0403−10DOI: 10.13386/j.issn1002-0306.2022050051Application of Gastrodia elata in Functional Food in ChinaDUAN Hao ，ZHOU Yaxi ，ZHOU Shiqi ，YAN Wenjie *（Beijing Key Laboratory of Bioactive Substances and Functional Food, College of Biochemical Engineering,Beijing Union University, Beijing 100023, China ）Abstract ：Gastrodia elata is a plant with both food and medicine. In the field of traditional Chinese medicine, it is often used to treat dizziness, headache, hemiplegia, etc. Modern medical research has found that Gastrodia elata has good effects in improving cardiovascular and cerebrovascular health, anti epilepsy, and improving hypertension. Gastrodia elata is often used in functional food to improve sleep. With the deepening of modern pharmacological research, the main active ingredients and action mechanism of gastrodia elata have been revealed and further improved, which has expanded the application range, development prospect and value of functional claims of Gastrodia elata in the field of health food. This paper expounded the basis for the compliance use of Gastrodia elata raw materials as functional food raw materials in China, summarized and analyzed the application status of Gastrodia elata and its extracts as functional food raw materials,and summarized the safety evaluation and related health functions of Gastrodia elata . In order to provide reference for the compliant use, research and development and clinical application of Gastrodia elata raw materials in functional food in China.Key words ： Gastrodia elata ；compliance basis ；health care function ；application status天麻在我国是一种食药兼备的植物，主要用于改善头晕目眩，缓解癫痫抽搐等。

民族的文化英语介绍作文

Ethnic culture is a rich tapestry woven from the threads of history,tradition,and the unique experiences of a community.It is the collective expression of a groups identity, values,and beliefs,which are passed down from generation to generation.Here is an introduction to ethnic culture in English,highlighting its various aspects:nguage:Language is the most direct expression of ethnic culture.It is not only a means of communication but also a carrier of a groups history,folklore,and wisdom. Each language has its own unique grammar,vocabulary,and expressions that reflect the cultural nuances of its speakers.2.Traditions and Customs:Traditions are the practices and customs that have been preserved over time.They include festivals,ceremonies,and rituals that are specific to a culture.These traditions often serve to strengthen community bonds and preserve cultural heritage.3.Arts:The arts are a vibrant part of ethnic culture,encompassing music,dance,theater, and visual arts.Each form of art is influenced by the history,religion,and social structure of the culture,offering a window into the soul of the community.4.Cuisine:Food is a fundamental aspect of culture,reflecting the availability of local ingredients,climate,and historical influences.Ethnic cuisine is a blend of flavors, techniques,and ingredients that have been developed over centuries and are often tied to specific celebrations or daily life.5.Religion and Belief Systems:Religion plays a central role in many ethnic cultures, influencing moral codes,rituals,and community life.Belief systems,whether they are part of an organized religion or more personal spiritual practices,shape the worldview and ethics of a community.6.Clothing and Adornment:Traditional clothing and adornments are not just functional they are also a form of cultural expression.They can signify social status,age,gender, and even marital status within a community.The materials,colors,and designs used in clothing often have symbolic meanings.7.Architecture:The architecture of a culture is a testament to its history and aesthetic sensibilities.From the grand structures of ancient civilizations to the vernacular architecture of rural communities,buildings reflect the social organization,religious beliefs,and artistic styles of a culture.8.Literature:The written word is a critical component of ethnic culture.Literature,including poetry,prose,and oral traditions,captures the stories,myths,and historical accounts that form the collective memory of a people.9.Folklore and Mythology:Folklore and mythology are the stories,legends,and myths that have been passed down through generations.They often serve to explain the natural world,provide moral lessons,and entertain.10.Social Structure and Family Values:The social structure of an ethnic group defines the relationships among its members and the roles they play within the community. Family values are integral to this structure,emphasizing the importance of kinship, respect for elders,and the raising of children.Ethnic culture is dynamic and evolves over time,influenced by interactions with other cultures,technological advancements,and societal changes.However,the core elements that define a cultures identity remain,providing a sense of continuity and belonging for its members.Preserving and promoting ethnic culture is essential for fostering understanding,respect,and appreciation among diverse communities.。

The Renaissance英国文学文艺复兴时期总结

The RenaissanceThis is a greatest and most advanced revolution in the human history. This is the age the giants are needed and produced.------F. Engles<1> Brief introduction▪Renaissance in European history, refers to the period between 14th century to 17th century. It started in Italy and ended in England and Spain.▪“Renaissance” means “revival”, the revival of interest in Ancient Greek and Roman culture and getting rid of conservatism in feudalist Europe and introducing new ideas that express the interests of the rising bourgeoisie.▪Renaissance sprang first in Italy (Florence and Venice) with the flowering of paintings, sculpture and architecture, and gradually spread all over Europe;▪Renaissance originally indicated a revival of classical arts and science (ancient Greek and Roman culture) after the dark ages of medieval obscurantism.During the period of Renaissance:1. the Roman Catholic Church was shaken,2. old sciences revived and new sciences emerged,3. national languages and cultures took shape,4. art and literature flourishedBrief introduction▪There arose an interest in the manuscripts surviving from ancient Greece and Rome. Classical learning and philosophy were enthusiastically studied.▪The intellectual wisdom of ancient Greece and Rome encouraged a rebirth of human spirit，a realization of human potential for development and creation．▪Never before in human history were men and women so eager to create and discover something new．In Italy a group of artists，scientists，politicians，and writers created the most brilliant page of culture and science in Renaissance Europe．Examples:①Copernicus (哥白尼) asserted that the earth was not the center of the universe；②The passionate Petrarch produced sonnets that influenced Shakespeare and many others；③Boccaccio(卜伽邱) wrote tales of eternal charm: The Decameron；④Marco Polo (马可波罗) made journeys into the remote kingdom of China；⑤Michelangelo（米开朗琪罗），Leonardo da Vinci (达芬奇)，Raphael (拉斐尔)，and Titian (提香) createdpaintings and sculptures that are invaluable treasures of the world．<2>Essence and features▪Essence: It is the reflection of the rise of bourgeoisie in the sphere of cultural life.（另版本）：Renaissance, in essence, is a historical period in which the European humanist thinkers and scholars made attempts to:to get rid of conservatism in Feudalist Europe;to introduce new ideas that expressed the interests of the rising bourgeoisie,to lift the restrictions in all areas placed by the Roman church authorities.Briefly it is the reflection of the rise of bourgeoisie inthe sphere of cultural life.▪Features: there are two striking features①A thirsting curiosity for the classical literature.②The keen interest in the activities of humanity.<3>Renaissance and HumanismRenaissance: the term originally indicated a revival of classical arts and science after the dark ages of medieval obscurantism. Indeed, a great number of the works of classical authors were translated into English during the 16th century.Humanism：The progressive thinkers of the humanists held their chief interest not in ecclesiastical knowledge, but in man, his environment and doings and bravely fought for the emancipation of man from the tyranny of the church and religious dogmas.Humanism is the key-note of the Renaissance. It reflected the new outlook of the rising bourgeois class;<4>HumanismHumanism is the essence of the Renaissance. It sprang from the endeavor to restore a reverence for the Greek and Roman civilization based on the conception that man is the measure of all things.Contrary to the subordination of individuals to the feudal rules and the sacrifice of earthly life for a future life in the medieval society, Renaissance humanists found in the classics a justification to exalt human nature and came to see that human beings were glorious creatures capable of individual development for perfection.By emphasizing the dignity of human beings and the importance of the present life, they voiced their beliefs that man did not only have the right to enjoy life, but had the ability to perfect himself and to perform wonders.<5>Features of humanism in RenaissanceEmphasizing the power, value and dignity of the human being and holding that human beings are glorious creatures The core of Renaissance thought is the greatness of man/giants. This is best summarized in the lines of Shakespeare’s HamletWhat a piece of work is man; how noble in reason; how infinite in faculty, in form and moving how express and admirable; in action how like and angel; in apprehension how like a god! The beauty of the world, the paragon of animals.人是一件多么了不起的杰作！多么高贵的理性！多么伟大的力量！多么优美的仪表！多么文雅的举动！在行为上多么像一个天使！在智慧上多么想一个天神！宇宙的精华！万物的灵长！▪1. Emphasizing secular happiness and individualism against the medieval ideas of asceticism;▪2.shifting man’s interest from Christianity to humanity, from religion to philoso phy, from beauty and greatness of God to the beauty of human body in all its joys and pains.▪3. Applying Aristotle’s theory, Humanist literature mainly use realistic style and take literature as the mirror or miniature of the society.<6>Influence and English RenaissanceInfluences:1.These Italians, and many others, helped to make Italy the center of the Renaissance movement in Europe.2.The movement changed the medieval Western Europe into a modern one．3.The intellectual wisdom of ancient Greece and Rome encouraged a rebirth of human spirit，a realization of human potential for development and creationEnglish Renaissance:Oxford Reformers: the Oxford reformers, scholars and humanists introduced classical literature to England. Education was revitalized and literature became more popular.This was England’s Golden Age in literature. There appeared many English literary giants such as Shakespeare, Spenser, Johnson, Sidney, Marlowe, Bacon and Donne.English RenaissanceContents●I.TheSixteenthCentury England ●II. Renaissance in England ●III. The main artistic styles●IV. William Shakespeare●V. Francis BaconI. The Sixteenth Century England1. Enclosure Movement2. The establishment of absolute monarchy3. Religious reformation4. International situation5. Cultural preparati●The background of the humanism in Europe●The introduction of printing led to an enlarged reading public and a commercial market for literature;●The great economic and political changes led to the rise of democracy;●The spirit of nationalism;●The growing of "new science” etc.Characteristics of the Elizabethan Age1. An age of comparative religious tolerance;2. An age of comparative social contentment;3. An age of dreams, of adventures, of unbounded enthusiasm;4. An age of intellectual liberty, of growing intelligence and comfort among all classes and of unbounded patriotism.II. Renaissance in England▪The time: mainly from the reign of Henry VIII, Edward, Mary and then to Queen Elizabeth and Jacobean Eraa. Beginning: the last years of the 15-th century---first half of the 16-th centuryb. Flourishing: the Elizabethan Age (1558-1603)c. Declining: the period of James I (1603-1625) early 17-th centuryThe flowering of English literatureThe second half of the 16th century, “a nest of singing birds”The early period:imitation and assimilation, translated works, poetry and poetic drama were the most outstanding literary forms. ▪Sonnet: an exact form of poetry in 14 lines of iambic pentameter intricately rhymed.▪Blank verse: iambic pentameter unrhymedThe latter period:Drama— the real mainstream of the English Renaissanceyears 1587-93. they were all of humble birth and struggled for a livelihood by writing. Through hard work, they revised old plays and wrote new ones. They made rapid progress in dramatic techniques because they has close contact with the actors and audiences. They were looked down upon by the gentlemen and suspected by the government. It was their industrious works that furnished the Elizabethan stage.Christopher MarloweWilliam ShakespeareIII. The main artistic stylesThe artistic styles as lyric poetry, narrative poetry, drama are maturized; new styles which characterized the modern literature such as sonnets, short stories and novels were produced.translation:Ovid’s Metamorphoses, Homer’s Iliad, Montaigne’s Essays▪travel books:More’s Utopia▪poetry: Edmund Spenser▪drama: “University Wits”, Marlowe, Shakespeare▪essay: Francis BaconForerunner of utopian socialism▪An imaginative travel narrative written in the form of conversation between More and Hythloday, a returned voyager describing an ideal state governed by reason.▪The subject is the search for the best possible form of government: Utopia---a community of property---a pure, pre-Marx form of communism.The Sheph erd’s Calendar 《牧人日历》: 12 pastoral poems and eclogues, one for each month, put into the mouths of speakers distinguishing themselves as shepherds, really representing Spenser and his friends.▪Amoretti《爱情小诗》:a series of 88 sonnets in honor of his lover Elizabeth. All except one was written in the Spenserian sonnet.▪Epithlamion 《婚后曲》: marriage hymns to celebrate his marriage with Elizabeth.The Faerie Queene《仙后》:▪The blending of religious and historical allegory with chivalric romance: a long poem planned 12 books. 12 knights for the qualities of the chivalric virtues--- the six completed books are holiness, temperance, chastity, friendship, justice and courtesy.Fairy Queen—Queen Elizabeth, the knights as a whole --- England, the evil figures—enemies.Themes of the poem :●nationalism( celebration of Queen Elizabeth)●humanism (strong opposition to Roman Catholicism),●Puritanism (moral teaching)Spenserian stanza:it is a nine-line stanza with the first 8 lines iambic pentameter and the ninth, iambic hexameter 六步格的诗rhyming abab,bcbc,c which is the typical verse in The Faerie Queene.For its rare beauty, this verse form was much used by many later poets, esp. imitated by the romantic poets of the 19th century.Spenser’s position in English Literature:the publica tion of “The Shepherd’s Calendar” marks the budding of Renaissance flower in the northern island of England.The language he used was modern English which has distinguished itself from the Middle English of Chaucer's day. Spenserian stanza: a model of poetic art among the Renaissance English poets.“the poet’s poet”, the first master to make the Modern English the natural music of his poetic effusion and held his position as a model of poetic art. His influence can be traced in the works of Milton, Shelley and Keats.Life: short but riotous⏹Major works:➢Tamburlaine the Great:《帖木耳》•A drama in a blank verse•About the rise and fall of Tamburlaine the Mongol conqueror on the 14th century central Asia.•A tragedy about a man who thinks he can but actually can not control his own fate.•By depicting a great hero with high ambition and sheer brutal force, the author voiced the supreme desire of the man of the Renaissance for infinite power and authority.•➢The Jew of Malta:《马耳他的犹太人》•A study of the lust for wealth, which centers around Barabas the Jew, an old money lender, whose only philosophy is the art of gaining advantage.•Suggestive of Shylock in Shakespeare’s The Merchant of Venice.•A tragic result: typically greedy of riches and gold, which is another feature shared by those in Renaissance England. •➢The History of Doctor Faustus 《浮士德博士》•Refer to compare with Goethe’s Faust•The Faust myth in 16th century Germany: the myth of men seeking great earthly power from demons at the cost of their immortal soul.•The conventional view: Dr. Faustus is a morality play that vindicates humility, faith and obedience to the law of God. •The new view: Dr. Faustus celebrates the human passion for knowledge, power and happiness, and also reveals man’s frustration in realizing the high aspiration in a hostile moral order.⏹Social significance and literary achievement1.showing the spirit of the rising bourgeoisie. Its eager curiosity for knowledge, power and gold.The praise of individuality freed from the restraints of medieval dogmas and the conviction of the boundless possibility of human efforts in conquering the universe.The heroes are mainly individualists. Their individualistic ambition often brings ruin to the world and to themselves.…soul of the Age!The applause! Delight! The wonder of our stage! Triumph, my Britain, thou hast one to show To whom all scenes of Europe homage owe. He was not of an age, but for all time!William Shakespeare1. Brief Introduction2. Shakespeare’s dramaFour periods of his literary career Categories of his drama 3. the artistic features of his plays4. Shakespeare’s place and contribution5. Shakespeare’s sonnetsWhat to be at least known about ShakespeareLife: birthplace, birth date, death date, important time in his life and career●His major works: 37 plays(10histories, 10 comedies, 10 tragedies), 2 long narrative poems, 154 sonnets.Plays to be read: great comedies & 4 great tragedies●Writing features in each of four periodsI. Brief IntroductionA dramatist “not of an age, but of all time” by Ben Jonhson, not of Engla nd, but of the world.●Not only a master of English language but also a genius of character portrayal and plot construction●A “poet of reality” for his idea that literature should reflect nature and reality.●37 plays, 154 sonnets and 2 long poems.II. Shak espeare’s dramaFour Periods of Shakespeare’s Literary careerFour major phrases represent respectively his early, mature, flourishing and late periods.1. Period of early experiment and apprenticeship (1590-1594)Background:A. it was in the middle of the highly thriving Elizabethan Age.B. The thoughts of humanism and the ideas of man’s emancipation, freedom of love was rapidly spread.C. Shakespeare was a young man full of astonishing versatility and wonderful talent and the great interest in the political questions of his time.Features:A. the writer made experiments in a number of dramatic forms: the historical plays, comedy, the revenge tragedy and the romantic tragedy.B. this period is distinctively marked by youthfulness and exuberance of imagination, by extravagance of witty language or speech, and by the final and frequent use of blank verse. In his hand, blank verse developed into a happy vehicle to express all kinds of thoughts and emotions (thus shaking off the rigidity of rimed and mechanic lines) .2. Period of maturity (1595-1600)Features:A. a period of “great comedies” and mature historical plays and sonnets.B. a sweet and joyful time when the writer portrays successfully a magnificent panorama of the manifold pursuit of people in real life.C. a great shift in characterization. A notable gallery of heroines in the comedies and vivid characters in historical plays is presented: Portia, Posalynd, Voila, Beatrice, Sir John Falstaff.3. Period of gloom and depression (1601-1607)Background:A. the aggravation of the social situation: the rising of peasants, the corruption, the tension between bourgeoisie and the feudal lands.B. the change of mood in the playwright: gloomy and indignantFeatures:A. a period of “great tragedies” and “dark comedies”B. the writer gave a scathing exposition of the somber pictures and scenes of murder, lust, treachery, ingratitude and crime.C. a higher level of crafts is reached: more intricate plotting, intense inner conflict, meticulous depiction of human mind.4. Period of calm and reconciliation (1608-1612)Background:A. the fall and collapse of absolute monarchB. the retirement of the playwright back into the tranquil countrysideFeatures:A. some serenity and optimism, instead of the beginning lightness and the middle somber violence reigned.B. romantic dramas and comedies were the main form.C. moral teaching and supernatural forces were relied on to restore the rightful honor and position. These plays all show a falling off from his previous works.Categories of his dramacomedies histories tragedies romances？？Comedy is a light form of drama aiming primarily to amuse and ending happily. It often deals with people in their human state, restrained and ridiculous by their limitations, faults, bodily functions.Four Great ComdiesThe Merchant of VeniceA Midsummer Night’s DreamAs you Like itTwelfth NightComedies of the First PeriodThe keynote of his comedies:●to portray people just freed from the feudal fetters, sing of youth, love and ideas of happiness.●The heroes and heroines fight against destiny and mould their fate according to their own free will. Thus becomethe sons and daughters of Renaissance.●The victory of humanist ideal is inevitable. The general spirit of these plays is optimistic.The Merchant of Venice•The double plot: one is about the Bassanio’s winning of a bride by undergoing a test; the other is about the demanding of a pound of human flesh by Shylock.•The traditional theme is to praise the friendship between Antonio and Bassanio, to idealize Portia as a heroine of great beauty, wit and loyalty and to expose the insatiable greed and brutality of the Jew.•The new one is to regard the play as a satire of the Christian hypocrisy and their false standards of friendship and love, their cunning ways of pursuing worldliness and unreasoning prejudice against Jews.Portia: a rich heiress of Belmont in Shakespeare's comedy The Merchant of Venice.●1. Portia is a woman of Renaissance—beautiful, prudent, cultured, courteous and capable of rising to an emergency. She is one of Shakespear’s ideal women.●2. the young heroes in Shakespeare's comedies are always independent in character and take their own path of life.History plays aim to present some historical age or character, and may be either a comedy or a tragedy.●His histories include two tetralogies (四部曲)and two other plays. Characterizes two centuries of English history from Richard III to Henry VIII (1377-1547)●There is only one ideal king---Henry V who represents the aspiration for national unity under a powerful and efficient monarchy.The image of Henry V:Henry V is the symbol of Shakespear’s ideal kingship. He represents the upsurging patriotism of the time. In depicting Henry V as a prince and as a man, Shakespeare looks deep into the personality of his hero and shows a profound understanding of the politics and social life of the time.Theme: Shakespeare’s historical plays describe the decaying of the old feudal society an d the rising of the new forces. His historical plays sum up the necessity for national unity under a mighty and just sovereign. The idea is anti-feudal inIt is concerned with the harshness and injustice of life. They are often serious plays with sad endings.●Often the hero’s tragedy is due to a weakness in his or her character which brings self-destruction. A weakness such as the excessive pride of Faustus, the overweening ambition of Macbeth, or the uncontrolled jealousy of Othello.●In S hakespeare’s plays, he saw sharp contradictions between his lofty humanistic ideals and the evil social forces. Background for Shakespeare’s tragediesHe began to observe life with penetration, to expose mercilessly the contradiction of the Elizabethan society. The economical and social crisis which began at the end of the reign of Queen Elizabeth continued right up to the English Revolution.The bourgeoisie intended to break up the yoke of absolute monarchy and struggled for free development.It was in this atmosphere of general unrest that he created his great tragedies.Four Great Tragedies All analyzing the human wickedness.●Hamlet: the hero’s weakness makes him vulnerable in fighting against the outward evil.●Othello shows how an outward evil make s use of the hero’s weakness and causes his fall.●King Lear demonstrates how man’s mistake sets free the evils of treachery, hypocrisy, flattery, selfishness and distrust.●Macbeth reveals how the outward evil stirs up the wickedness in man and destroys him.Hamlet“Hamlet” is considered the summit of Shakespeare's art.Hamlet is a man of genius, highly accomplished and educated, a man of profound perception and sparkling wit. He is a scholar, soldier and statesman all combined. His image reflects the versatility of the man of Renaissance.Hamlet’s melancholy is not the negative, over-subtle and fruitless kind, it is the result of his penetrating mind. It expresses, in away, the crisis of humanism at the end of the 16th and the beginning of the 17th century.III. the artistic features of his plays1. Characterization: By using comparison and contrasts, he depicts a group of individuals with strong and distinct personalities.The melancholy of Hamlet, the wickedness of Claudius and Iago, the honesty of Othello, ambition of Macbeth and the beauty and wit of Portia.2. Psycho-analytical study: He reveals the intricate inner workings of the character’s minds through the full use of soliloquies(独白).3. Structure:⏹His plays usu. have more than one plot. Through contrast and parallel, the major and minor plots are woven intoan organic whole.⏹the device of a play within the play also plays an important part.4. Language: Shakespeare is a master of the English language, with a large vocabulary of 16000 English words. More important are the figurative speeches such as analogy and metaphor.5. style: realistic style. The reader may be impressed by the typical speech modes —the question in Hamlet, the ambiguities in Macbeth, the exclamations and very simple but also very basic questions in King Lear.IV. Shakespeare’s place and contributionOne of the founder of realism in world literature. Living in the historical period of the transition from feudalism to capitalism, he paints a panorama of the decline of the old feudal nobility and the rise of new bourgeoisie.Amazing prolificacy. In 22years, nearly 40 plays, no two of which evoke the same feeling or image among the audience, a master of every forms of drama.Skilled in many poetic forms. The songs, sonnets, couplets, esp. at home with blank verse, which became a vehicle of utterance to all the possible sentiments of his characters.A great master of English language. He has an amazing wealth of vocabulary and idiom. He is known to have used 16,000 different words. His coinage of new words and distortion of the meaning of the old ones also create striking effects on the reader.He was universally regarded are the summit of English Renaissance. His influence on later writers is immeasurable. Almost all English writers after him have been influenced by him either in artistic point view, in literary form or in language.SonnetDefinition:▪A sonnet is a fourteen-line poem in iambic pentameter with a carefully patterned rhyme scheme.Origin:▪A form of lyrical poetry was originated in Italy. “sonnet” was derived from Provencal (普罗旺斯语) “Sonet”. It was once a short popular poetry used for singing in the medieval age.▪Italian poet Petrarch was the major representatives of the poets who used this poetic form. He wrote altogether 375 sonnets, dedicated to his lover. That is the Petrarchan sonnet.▪Sonnet was introduced into England by Thomas Wyatt . It flourished in the 1590s and reach its peak of popularity with the surge of Renaissance in England.Two types of sonnetThe Italian, or Petrarchan sonnet :Petrarchan Sonnet▪The Italian form, in some ways the simpler of the two, Its fourteen lines break into an octave （八行诗）(or octet), which usually rhymes abba,abba, and a sestet （六行诗节）, which may rhyme cdecde or cdcdcd, or any of the multiple variations possible using only two or three rhyme-sounds.▪It usually projects and develops a subject in the octave, then executes a turn at the beginning of the sestet, which means that the sestet must in some way release the tension built up in the octave.▪Example: see Wyatt's "Farewell Love and all thy laws for ever."Farewell, LoveSir Thomas Wyatt (1503~1542)Farwell, Love, and all thy laws forever,Thy baited hooks shall tangle me no more;Senec and Plato call me from thy lore,To perfect wealth my wit for to endeavor,In blind error then I did persever,Thy sharp repulse, that prickth aye so sore,Hath taought me to set in trifles no storeAnd’ scape forth since liberty is leverTherefore farewell, go trouble younger hearts, And in me claim no more authorityWith idle youth go use thy property,And therein spend thy many brittle darts,For hitherto though I have lost all my time,Me lusteth no longer rotten boughs to climb.别了，爱，以及你所有的法则，你上饵的钩子不再能把我缠绞，塞内克与柏拉图叫我离开你那套，并尽我才智把完美的财富获得。

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a rXiv:as tr o-ph/612492v118Dec26Gravastars and bifurcation in quasistationary accretion Edward Malec and Krzysztof Roszkowski M.Smoluchowski Institute of Physics,Jagiellonian University,Reymonta 4,30-059Krak´o w,Poland We investigate the newtonian stationary accretion of a polytropic perfect ﬂuid onto a central body with a hard surface.The selfgravitation of the ﬂuid and its interaction with luminosity is included in the model.We ﬁnd that for a given luminosity,asymptotic mass and temperature of the ﬂuid there exist two solutions with diﬀerent cores.Keywords :gravastars,nonuniqueness of solutions,stationary accretion 1.Introduction The question we want to address in this paper is the following inverse problem :having a complete set of data describing a compact body immersed in a spherically symmetric accreting ﬂuid,ﬁnd the mass of the central body.We assume that we know the total mass,luminosity,asymptotic temperature,the equation of state of the accreting gas and the gravitational potential at the surface of the core.The fundamental question is whether observers can distinguish between gravas-tars [1]versus black holes as engines of luminous accreting systems (see a controversy in [2,3]).While we do not address this problem here,we show a related ambiguity in a simple newtonian model.2.The Shakura model The ﬁrst investigation of stationary accretion of spherically symmetric ﬂuids,includ-ing luminosity close to the Eddington limit,was provided by Shakura [4].It was later extended to models including the gas pressure,its selfgravity and relativistic eﬀects [5–8].In the following we will denote the areal velocity by U (r,t )=∂t R (where t iscomoving time and R the areal radius),the local,Eddington and total luminosities by L (R ),L E and L 0,quasilocal mass by m (R )and total by M ,pressure by p ,the baryonic mass density by ̺(the polytropic equation of state will be p =K̺Γ,1<Γ≤5/3)and the gravitational potential by φ(R).The radius of the centralbody is R 0while its “modiﬁed radius”is deﬁned by ˜R 0=GM/|φ(R 0)|.Under theassumption that at the outer boundary of the ﬂuid the following holds true:U 2∞≪Gm(R ∞)R 2−1R 2,(3)12∂R˙M=0,(4) L0−L(R)=˙M a2∞Γ−1−U2L E ,y=M∗R∗,and obtain the total luminosity:L0=φ0χ∞G2π2M35−3Γ(5−3Γ)/2(Γ−1).(6)χ∞is approximately the inverse of the volume of the gas located outside the sonic point.In sake of brevity we will useβ=αφ0χ∞Gπ2M25−3Γ(5−3Γ)/2(Γ−1)to obtain Eq.(6)in a form using the relative luminosity:x=β(1−y)[y−x exp(−xγ)]2.(7)3.BifurcationFor the relative luminosity,fulﬁlling Eq.(7)we proved the following theorem: (i)For the functional F(x,y)=x−β(1−y)[y−x exp(−xγ)]2there exists a criticalpoint x=a,y=b such that F(a,b)=0and∂y F(a,b)=0with0<a<b<1 and a=4β(1−b)3,b=[2+a exp(−aγ)]/3.(ii)For any0<x<a there exist two solutions y(x)+−bifurcating from(a,b).They are locally approximated by:y+−=b± (a−x)[b+a exp(−aγ)(1−2aγ)]3 checked numerically that the performed simpliﬁcation causes errors of the order of 10−3(see[9]for details).The analysis of Eq.(7)shows that there exist two diﬀerent solutions,having the same total luminosity and total mass,but diﬀerent masses of the core objects.One can also conclude that for suﬃciently largeβthe maximal relative luminosity a can get close to1,i.e.,the total luminosity approaches the Eddington limit.As the two solution branches bifurcate from the point(a,b),there is no much diﬀerence between the central masses of bright objects(see[9,10]for plots).How-ever,when luminosity is small(L0≪L E),this diﬀerence can become arbitrarily large.This can be understood intuitively,because the radiation is small for test ﬂuids(since the layer of gas is thin),or when the central object is light(therefore weakly attracting surrounding gas).The results obtained here are consistent with relativistic analysis neglecting interaction between the gas and the radiation[11,12].AcknowledgmentsThis paper has been partially supported by the MNII grant1P03B01229.References[1]P.O.Mazur and E.Mottola,Proc.Nat.Acad.Sci.101,p.9545(2004).[2]M.Abramowicz,W.Klu´z niak and sota,Astron.Astrophys.396,p.L31(2002).[3] A.E.Broderick and R.Narayan,Astrophys.J.638,p.L21(2006).[4]N.I.Shakura,Astr.Zh.18,p.441(1974).[5]T.Okuda and S.Sakashita,Astroph.Space Sc.52,p.350(1977).[6]K.S.Thorne,R.A.Flammang and A.N.˙Zytkow,MNRAS194,p.475(1981).[7]L.Rezzolla and ler,Class.Quant.Grav.11,p.1815(1994).[8]M.G.Park and ler,Astrophys.J.371,p.708(1991).[9]J.Karkowski, E.Malec andK.Roszkowski,Luminosity,selfgravitation and nonuniqueness of stationary accre-tion,Submitted to Astrophys.J.,/ps/astro-ph/0611393,(2006).[10] E.Malec and K.Roszkowski,Nonuniqueness of stationary accretion in the Shakuramodel,in Proceedings of the XXIX Spanish Relativity Meeting(ERE2006):Ein-stein’s Legacy:From the Theoretical Paradise to Astrophysical Observations,(Palma de Mallorca,Spain,2006).[11]J.Karkowski,B.Kinasiewicz,P.Mach,E.Malec and Z.´Swierczy´n ski,Phys.Rev.D73,p.021503(R)(2006).[12] B.Kinasiewicz,P.Mach and E.Malec,Selfgravitation in a general-relativistic ac-cretion of steadyﬂuids,in Proceedings the42Karpacz Winter School of Theoretical Physics,(Ladek Zdroj,Poland,2006).。