Vital Signs and Anthropomorphic Data

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专业英语

一、词汇（1）英译汉1.Web browser 浏览器2.Spreadsheet program 电子制表程序3.in nature 本质上，事实上4.be designed t o 目的是；被设计用于做5.software packages软件包6.formal communication 正式沟通rmal network 非正式的沟通8.word processor 文字处理软件；文字处理机9.secondary storage device 外存设备10.batch processing批处理11.physical sequenc 存储顺序12.tax rate 税率13.functional area 功能范围，功能区14.data dictionar数据字典15.data definition language 数据定义语言16.data manipulationlanguage 数据控制语言17.rubber band 橡皮圈18.account for 说明…原因19.Financial background财务状况20.job title 职别21.in contrast 相比之下22.on a small scale 小规模的23.human resources人力资源24.by any name 以任何名义25.decision making决策26.strategic decisionmaking 战略决策27.manage ment control 管理控制28.knowledge-level decision making 知识层决策29.operational control 运行管理30.unstructured decision 非结构化决策31.structured decision 结构化决策32.semistructured decision 半结构化决策33.concern with关于，关系到34.deal with 应付，处理（2）缩写词1.管理信息系统MIS2.信息系统C IS3.信息技术IT4.数据库管理系统DB MS5.结构化查询语言S OL6.事务处理系统TPS7.办公自动化系统O AS8.决策支持系统DSS9.知识工作系统KWS10.高层主管支持系统ESS二、翻译1.It is tempting to 一旦你学习如何使用文字处理软件、电子数据表和网页浏览器，你会认为自己已经掌握了所有解决业务问题所需的计算机知识。

标准分类(ICS和CCS)

Company organization and management in general Purchasing. Procurement. Management of stock Trade. Commercial function. Marketing Management of human resources Research and development Production. Production management Accountancy Other standards related to company organization and management Quality Quality in general Quality management and quality assurance Product and company certification. Conformity assessment Application of statistical methods Other standards related to quality Patents. Intellectual property Law. Administration Education Leisure. Tourism Transport Transport in general Road transport Transport by rail Transport by water Air transport Other forms of transport Postal services MATHEMATICS. NATURAL SCIENCES Mathematics Physics. Chemistry Astronomy. Geodesy. Geography Geology. Meteorology. Hydrology Biology. Botany. Zoology Microbiology Microbiology in general Medical microbiology Microbiology of water Food microbiology Other standards related to microbiology HEALTH CARE TECHNOLOGY Medical Sciences and health care facilities in general Medical equipment Medical equipment in general Anaesthetic, respiratory and reanimation equipment Transfusion, infusion and injection equipment Surgical instruments and materials Implants for surgery, prosthetics and orthotics

OECD439 重建皮肤模型体外刺激性检测

OECD/OCDE439 Adopted: 22 July 2010© OECD, (2010) You are free to use this material for personal, non-commercial purposes without seeking prior consent from the OECD, provided the source is duly mentioned. Any commercial use of this material is subject to written permission from the OECD.OECD GUIDELINE FOR THE TESTING OF CHEMICALSIn Vitro Skin Irritation: Reconstructed Human Epidermis Test MethodINTRODUCTION1. Skin irritation refers to the production of reversible damage to the skin following the application of a test chemical for up to 4 hours [as defined by the United Nations (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS)](1). This Test Guideline (TG) provides an in vitro procedure that may be used for the hazard identification of irritant chemicals (substances and mixtures) in accordance with UN GHS and EU CLP Category 2 (1) (2) (3). For member countries or regions that do not adopt the optional UN GHS Category 3 (mild irritants), this Test Guideline can also be used to identify non-classified chemicals, i.e. UN GHS and EU CLP “No Category”(1)(3). Depending on the regulatory framework and the classification system in use, this test method may be used to determine the skin irritancy of chemicals as a stand-alone replacement test for in vivo skin irritation testing, or as a partial replacement test, within a tiered testing strategy (4).2. The assessment of skin irritation has typically involved the use of laboratory animals [OECD TG 404; adopted in 1981 and revised in 1992 and 2002](4). In relation to animal welfare concerns, TG 404 was revised in 2002, allowing for the determination of skin corrosion/irritation by applying a tiered testing strategy, using validated in vitro or ex vivo test methods, thus avoiding pain and suffering of animals. Three validated in vitro test methods have been adopted as OECD TGs 430, 431 and 435 (5) (6) (7), to be used for the corrosivity part of the tiered testing strategy of TG 404 (4).3. This Test Guideline addresses the human health endpoint skin irritation. It is based on reconstructed human epidermis (RhE), which in its overall design (the use of human derived non-transformed epidermis keratinocytes as cell source and use of representative tissue and cytoarchitecture) closely mimics the biochemical and physiological properties of the upper parts of the human skin, i.e. the epidermis . This Test Guideline also includes a set of Performance Standards (PS)(Annex 2) for the assessment of similar and modified RhE-based test methods developed by EC-ECVAM (8), in accordance with the principles of Guidance Document No. 34 (9).4. There are three validated test methods that adhere to this Test Guideline. Prevalidation, optimisation and validation studies have been completed for an in vitro test method (10) (11) (12) (13) (14)(15) (16) (17) (18) (19) (20), using a RhE model, commercially available as EpiSkin™ (designated the Validated Reference Method – VRM). Two other commercially available in vitro skin irritation RhE test methods have shown similar results to the VRM according to PS-based validation (21), and these are the EpiDerm™ SIT (EPI-200) and the SkinEthic™ RHE test methods (22).5. Before a proposed similar or modified in vitro RhE test method other than the VRM, EpiDerm™ SIT (EPI-200) or SkinEthic™ RHE test methods can be used for regulatory purposes, its reliability, relevance (accuracy), and limitations for its proposed use should be determined in order to ensure that it can be regarded as similar to that of the VRM, in accordance with the requirements of the PS set out in this Test Guideline (Annex 2).439OECD/OCDE6. Definitions used are provided in Annex 1.INITIAL CONSIDERATIONS AND LIMITATIONS7. A limitation of the Test Guideline, as demonstrated by the validation study (16), is that it does not allow the classification of chemicals to the optional UN GHS Category 3 (mild irritants) (1). Thus, the regulatory framework in member countries will decide how this Test Guideline will be used. When used as a partial replacement test, follow-up in vivo testing may be required to fully characterize skin irritation potential (4). It is recognized that the use of human skin is subject to national and international ethical considerations and conditions.8. This Test Guideline addresses the in vitro skin irritation component of the tiered testing strategy of TG 404 on dermal corrosion/irritation (4). While this Test Guideline does not provide adequate information on skin corrosion, it should be noted that OECD TG 431 on skin corrosion is based on the same RhE test system, though using another protocol (6). This Test Guideline is based on RhE-models using human keratinocytes, which therefore represent in vitro the target organ of the species of interest. It moreover directly covers the initial step of the inflammatory cascade/mechanism of action (cell damage and tissue damage resulting in localised trauma) that occurs during irritation in vivo. A wide range of chemicals has been tested in the validation underlying this Test Guideline and the empirical database of the validation study amounted to 58 chemicals in total (16)(18)(23). The Test Guideline is applicable to solids, liquids, semi-solids and waxes. The liquids may be aqueous or non-aqueous; solids may be soluble or insoluble in water. Whenever possible, solids should be ground to a fine powder before application; no other pre-treatment of the sample is required. Gases and aerosols have not been assessed yet in a validation study (24). While it is conceivable that these can be tested using RhE technology, the current Test Guideline does not allow testing of gases and aerosols. It should also be noted that highly coloured chemicals may interfere with the cell viability measurements and need the use of adapted controls for corrections (see paragraphs 24-26).9. A single testing run composed of three replicate tissues should be sufficient for a test chemical when the classification is unequivocal. However, in cases of borderline results, such as non-concordant replicate measurements and/or mean percent viability equal to 50 ± 5%, a second run should be considered, as well as a third one in case of discordant results between the first two runs.PRINCIPLE OF THE TEST10. The test chemical is applied topically to a three-dimensional RhE model, comprised of non-transformed human-derived epidermal keratinocytes, which have been cultured to form a multilayered, highly differentiated model of the human epidermis. It consists of organized basal, spinous and granular layers, and a multilayered stratum corneum containing intercellular lamellar lipid layers representing main lipid classes analogous to those found in vivo.11. Chemical-induced skin irritation, manifested by erythema and oedema, is the result of a cascade of events beginning with penetration of the stratum corneum and damage to the underlying layers of keratinocytes. The dying keratinocytes release mediators that begin the inflammatory cascade which acts on the cells in the dermis, particularly the stromal and endothelial cells. It is the dilation and increased permeability of the endothelial cells that produce the observed erythema and oedema (24). The RhE-based test methods measure the initiating events in the cascade.12. Cell viability in RhE models is measured by enzymatic conversion of the vital dye MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Thiazolyl blue; CAS number 298-93-1], into a © OCDE, (2010) 2OECD/OCDE439 blue formazan salt that is quantitatively measured after extraction from tissues (25). Irritant chemicals areidentified by their ability to decrease cell viability below defined threshold levels (i.e.≤ 50%, for UN GHSCategory 2). Depending on the regulatory framework and applicability of the Test Guideline, chemicalsthat produce cell viabilities above the defined threshold level, may be considered non-irritants (i.e. > 50%,No Category).DEMONSTRATION OF PROFICIENCY13. Prior to routine use of any of the three validated test methods that adhere to this Test Guideline, laboratories should demonstrate technical proficiency, using the ten Proficiency Chemicals listed in Table1. For similar test methods developed under this Test Guideline or for modifications of any of the threevalidated test methods, the PS requirements described in Annex 2 of this Test Guideline should be metprior to using the test method for regulatory testing.14. As part of the proficiency exercise, it is recommended that the user verifies the barrier propertiesof the tissues after receipt as specified by the RhE model producer. This is particularly important if tissuesare shipped over long distance/time periods. Once a test method has been successfully established and proficiency in its use has been demonstrated, such verification will not be necessary on a routine basis. However, when using a test method routinely, it is recommended to continue to assess the barrier properties in regular intervals.The Proficiency Chemicals are a subset of the chemicals used in the validation study.2In vivo score in accordance with the OECD Test Guideline 404 (4).3Under this Test Guideline, the UN GHS optional Category 3 (mild irritants) (1) is considered as No Category.PROCEDURE3© OECD, (2010)439OECD/OCDE15. The following is a description of the components and procedures of a RhE test method for skin irritation assessment. A RhE model should be reconstructed, and can be in-house-prepared or obtained commercially. Standard Operating Procedures (SOPs) for the EpiSkin™, EpiDerm™ SIT (EPI-200) and SkinEthic™ RHE are available (26)(27)(28). Testing should be performed according to the following:R H E TEST METHOD COMPONENTSGeneral conditions16. Non-transformed human keratinocytes should be used to reconstruct the epithelium. Multiple layers of viable epithelial cells (basal layer, stratum spinosum, stratum granulosum) should be present under a functional stratum corneum. Stratum corneum should be multilayered containing the essential lipid profile to produce a functional barrier with robustness to resist rapid penetration of cytotoxic marker chemicals, e.g.sodium dodecyl sulphate (SDS) or Triton X-100. The barrier function should be demonstrated and may be assessed either by determination of the concentration at which a marker chemical reduces the viability of the tissues by 50% (IC50) after a fixed exposure time, or by determination of the exposure time required to reduce cell viability by 50% (ET50) upon application of the marker chemical at a specified, fixed concentration. The containment properties of the RhE model should prevent the passage of material around the stratum corneum to the viable tissue, which would lead to poor modelling of skin exposure. The RhE model should be free of contamination by bacteria, viruses, mycoplasma, or fungi. Functional conditionsViability17. The assay used for determining the magnitude of viability is the MTT-assay (25). The RhE model users should ensure that each batch of the RhE model used meets defined criteria for the negative control (NC). The optical density (OD) of the extraction solvent alone should be sufficiently small, i.e. OD<0.1. An acceptability range (upper and lower limit) for the negative control OD values (In the Skin Irritation Test Method conditions) are established by the RhE model developer/supplier, and the acceptability ranges for the 3 validated test methods are given in Table 2. It should be documented that the tissues treated with NC are stable in culture (provide similar viability measurements) for the duration of the test exposure period.Table 2:Acceptability ranges for negative control OD valuesBarrier function18. The stratum corneum and its lipid composition should be sufficient to resist the rapid penetration of cytotoxic marker chemicals, e.g. SDS or Triton X-100, as estimated by IC50 or ET50 (Table 3).© OCDE, (2010) 4OECD/OCDE439Morphology19. Histological examination of the RhE model should be performed demonstrating human epidermis-like structure (including multilayered stratum corneum).Reproducibility20. The results of the positive and negative controls of the test method should demonstrate reproducibility over time.Quality control (QC)21. The RhE model developer/supplier should ensure and demonstrate that each batch of the RhEmodel used meets defined production release criteria, among which those for viability (paragraph 17),barrier function (paragraph 18) and morphology (paragraph 19) are the most relevant. These data shouldbe provided to the test method users, so that they are able to include this information in the test report. An acceptability range (upper and lower limit) for the IC50 or the ET50 should be established by the RhE modeldeveloper/supplier (or investigator when using an in-house model). Only results produced with qualifiedtissues can be accepted for reliable prediction of irritation classification. As an example, the acceptabilityranges for the three validated test methods are given in Table 3.Table 3:Examples of QC batch release criteriaApplication of the Test and Control Chemicals22. At least three replicates should be used for each test chemical and for the controls in each run.For liquid as well as solid chemicals, sufficient amount of test chemical should be applied to uniformlycover the epidermis surface while avoiding an infinite dose, i.e.a minimum of 25 μL/cm2 or 25 mg/cm2should be used. For solid chemicals, the epidermis surface should be moistened with deionised or distilledwater before application, to improve contact between the test chemical and the epidermis surface.Whenever possible, solids should be tested as a fine powder. At the end of the exposure period, the testchemical should be carefully washed from the epidermis surface with aqueous buffer, or 0.9% NaCl. Depending on which of the three validated RhE test methods is used, the exposure period varies between15 and 60 minutes, and the incubation temperature between 20 and 37°C. These exposure periods and temperatures are optimized for each RhE test method and represent the different intrinsic properties of thetest methods, for details, see the Standard Operating Protocols (SOPs) for the test methods (26)(27)(28).5© OECD, (2010)439OECD/OCDE23. Concurrent NC and positive controls (PC) should be used in each run to demonstrate that viability (with the NC), barrier function and resulting tissue sensitivity (with the PC) of the tissues are within a defined historical acceptance range. The suggested PC chemical is 5% aqueous SDS. The suggested NC chemicals are water or phosphate buffered saline (PBS).Cell Viability Measurements24. The most important element of the test procedure is that viability measurements are not performed immediately after the exposure to the test chemicals, but after a sufficiently long post-treatment incubation period of the rinsed tissues in fresh medium. This period allows both for recovery from weak cytotoxic effects and for appearance of clear cytotoxic effects. The test optimisation phase (11) (12) (13) (14) (15) demonstrated that a 42 hours post-treatment incubation period was optimal.25. The MTT assay is a validated quantitative method which should be used to measure cell viability under this Test Guideline. It is compatible with use in a three-dimensional tissue construct. The tissue sample is placed in MTT solution of appropriate concentration (e.g.0.3 - 1 mg/mL) for 3 hours. The precipitated blue formazan product is then extracted from the tissue using a solvent (e.g.isopropanol, acidic isopropanol), and the concentration of formazan is measured by determining the OD at 570 nm using a filter band pass of maximum ± 30 nm.26.Optical properties of the test chemical or its chemical action on the MTT may interfere with the assay leading to a false estimate of viability (because the test chemical may prevent or reverse the colour generation as well as cause it). This may occur when a specific test chemical is not completely removed from the tissue by rinsing or when it penetrates the epidermis. If a test chemical acts directly on the MTT (MTT-reducer), is naturally coloured, or becomes coloured during tissue treatment, additional controls should be used to detect and correct for test chemical interference with the viability measurement technique. Detailed description of how to correct direct MTT reduction and interferences by colouring agents is available in the SOPs for the three validated test methods (26)(27)(28).Acceptability Criteria27. For each test method using valid RhE model batches (see paragraph 21), tissues treated with the NC should exhibit OD reflecting the quality of the tissues that followed shipment, receipt steps and all protocol processes. Control OD values should not be below historically established boundaries. Similarly, tissues treated with the PC, i.e.5% aqueous SDS, should reflect their ability to respond to an irritant chemical under the conditions of the test method (26) (27) (28). Associated and appropriate measures of variability between tissue replicates should be defined (e.g.if standard deviations (SD) are used they should be within the 1-sided 95% tolerance interval calculated from historical data; for the VRM SD < 18%).Interpretation of Results and Prediction Model28. The OD values obtained with each test chemical can be used to calculate the percentage of viability normalised to NC, which is set to 100%. The cut-off value of percentage cell viability distinguishing irritant from non-classified test chemicals and the statistical procedure(s) used to evaluate the results and identify irritant chemicals should be clearly defined, documented, and proven to be appropriate. The cut-off values for the prediction of irritation are given below:The test chemical is considered to be irritant to skin in accordance with UN GHS Category 2 ifthe tissue viability after exposure and post-treatment incubation is less than or equal (≤) to 50%.© OCDE, (2010) 6OECD/OCDE4397© OECD, (2010)Depending on the regulatory framework in member countries, the test chemical may be considered as non-irritant DATA AND REPORTINGto skin in accordance with UN GHS No Category if the tissue viabilityafter exposure and post-treatment incubation is more than (>) 50%.Data29. For each run, data from individual replicate tissues (e.g. OD values and calculated percentage cell viability data for each test chemical, including classification) should be reported in tabular form, including data from repeat experiments as appropriate. In addition means ± SD for each run should be reported. Observed interactions with MTT reagent and coloured test chemicals should be reported for each tested chemical.Test Report30.The test report should include the following information: Test and Control Chemicals:- C hemical name(s) such as CAS name and number, if known;- P urity and composition of the chemical (in percentage(s) by weight);-Physical-chemical properties relevant to the conduct of the study (e.g. physical state, stability,volatility, pH and water solubility if known);-Treatment of the test/control chemicals prior to testing, if applicable (e.g. warming,grinding);- S torage conditions;Justification of the RhE model and protocol used Test Conditions:- C ell system used;- C omplete supporting information for the specific RhE model used including its performance.This should include, but is not limited to;i) viabilityii) barrier functioniii) morphologyiv) reproducibility and predictivityv) Quality controls (QC) of the model- D etails of the test procedure used;- T est doses used, duration of exposure and post treatment incubation period;- D escription of any modifications of the test procedure;- R eference to historical data of the model. This should include, but is not limited to:i) acceptability of the QC data with reference to historical batch dataii) acceptability of the positive and negative control values with reference to positive andnegative control means and ranges439OECD/OCDE-D escription of evaluation criteria used including the justification for the selection of the cut-off point(s) for the prediction model;-Reference to historical control data;Results:-T abulation of data from individual test chemicals for each run and each replicatemeasurement;-I ndication of controls used for direct MTT-reducers and/or colouring test chemicals;-D escription of other effects observed;Discussion of the resultsConclusion© OCDE, (2010)8OECD/OCDE439LITERATURE1.UN (2009), United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS), Third revised edition, UN New York and Geneva. Available at:[/trans/danger/publi/ghs/ghs_rev03/03files_e.html]2.EC-ECVAM (2009), Statement on the “Performance under UN GHS of three in vitro assays forskin irritation testing and the adaptation of the Reference Chemicals and Defined Accuracy Values of theECVAM skin irritation Performance Standards”, issued by the ECVAM Scientific Advisory Committee(ESAC30), 9 April 2009. Available at: [http://ecvam.jrc.ec.europa.eu]3.EC (2008), REGULATION (EC) No 1272/2008 of the European Parliament and of the Councilof 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending andrepealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OfficialJournal of the European Union L353, 1-1355.4.OECD (2004), Acute Dermal Irritation/Corrosion, OECD Guideline for the Testing of Chemicals No. 404, OECD, Paris. Available at: [/env/testguidelines]5.OECD (2004), In Vitro Skin Corrosion: Transcutaneous Electrical Resistance (TER),OECDGuideline for the Testing of Chemicals No. 430, OECD, Paris. Available at:[/env/testguidelines]6.OECD (2004), In Vitro Skin Corrosion: Human Skin Model Test, OECD Guideline for theTesting of Chemicals No. 431, OECD, Paris. Available at: [/env/testguidelines]7.OECD (2006), In Vitro Membrane Barrier Test Method for Skin Corrosion, OECD Guideline forthe Testing of Chemicals No. 435, OECD, Paris. Available at: [/env/testguidelines]8.EC-ECVAM (2009), Performance Standards for in vitro skin irritation test methods based on Reconstructed human Epidermis (RhE)? Available at: [http://ecvam.jrc.ec.europa.eu]9.OECD (2005), Guidance Document on the Validation and International Acceptance of New orUpdated Test Methods for Hazard Assessment, OECD Series on Testing and Assessment No. 34, OECD,Paris. Available at: [/env/testguidelines]10.Fentem, J.H., Briggs, D., Chesné, C., Elliot, G.R., Harbell, J.W., Heylings, J.R., Portes, P.,Roguet, R., van de Sandt, J.J. M. and Botham, P. (2001), A prevalidation study on in vitro tests for acuteskin irritation, Results and evaluation by the Management Team, Toxicol. in Vitro 15, 57-93.11.Portes, P., Grandidier, M.-H., Cohen, C. and Roguet, R. (2002), Refinement of the EPISKINprotocol for the assessment of acute skin irritation of chemicals: follow-up to the ECVAM prevalidationstudy, Toxicol. in Vitro 16, 765–770.12.Kandárová, H., Liebsch, M., Genschow, E., Gerner, I., Traue, D., Slawik, B. and Spielmann, H. (2004), Optimisation of the EpiDerm test protocol for the upcoming ECVAM validation study on in vitroskin irritation tests, ALTEX 21, 107–114.13.Kandárová, H., Liebsch, M., Gerner, I., Schmidt, E., Genschow, E., Traue, D. and Spielmann, H. (2005), The EpiDerm test protocol for the upcoming ECVAM validation study on in vitro skin irritationtests – An assessment of the performance of the optimised test, ATLA 33, 351-367.9© OECD, (2010)439OECD/OCDE14.Cotovio, J., Grandidier, M.-H., Portes, P., Roguet, R. and Rubinsteen, G. (2005), The in vitro acute skin irritation of chemicals: optimisation of the EPISKIN prediction model within the framework of the ECVAM validation process, ATLA 33, 329-349.15.Zuang, V., Balls, M., Botham, P.A., Coquette, A., Corsini, E., Curren, R.D., Elliot, G.R., Fentem, J.H., Heylings, J.R., Liebsch, M., Medina, J., Roguet, R., van De Sandt, J.J.M., Wiemann, C. and Worth, A. (2002), Follow-up to the ECVAM prevalidation study on in vitro tests for acute skin irritation, The European Centre for the Validation of Alternative Methods Skin Irritation Task Force report 2, ATLA 30, 109-129.16.Spielmann, H., Hoffmann, S., Liebsch, M., Botham, P., Fentem, J., Eskes, C., Roguet, R., Cotovio, J., Cole, T., Worth, A., Heylings, J., Jones, P., Robles, C., Kandárová, H., Gamer, A., Remmele, M., Curren, R., Raabe, H., Cockshott, A., Gerner, I. and Zuang, V. (2007), The ECVAM international validation study on in vitro tests for acute skin irritation: Report on the validity of the EPISKIN and EpiDerm assays and on the skin integrity function test, ATLA 35, 559-601.17.Hoffmann, S. (2006), ECVAM skin irritation validation study phase II: Analysis of the primary endpoint MTT and the secondary endpoint IL1-α. Available at: [http://ecvam.jrc.ec.europa.eu]18.Eskes, C., Cole, T., Hoffmann, S., Worth, A., Cockshott, A., Gerner, I. and Zuang, V. (2007), The ECVAM international validation study on in vitro tests for acute skin irritation: selection of test chemicals, ATLA 35, 603-619.19.Cotovio, J., Grandidier, M.-H., Lelièvre, D., Roguet, R., Tinois-Tessonneaud, E. and Leclaire, J. (2007), In vitro acute skin irritancy of chemicals using the validated EPISKIN model in a tiered strategy - Results and performances with 184 cosmetic ingredients, AATEX, 14, 351-358.20.EC-ECVAM (2007), Statement on the validity of in vitro tests for skin irritation, issued by the ECVAM Scientific Advisory Committee (ESAC26), 27 April 2007. Available at: [http://ecvam.jrc.ec.europa.eu]21.EC-ECVAM (2007), Performance Standards for applying human skin models to in vitro skin irritation testing. Available at: [http://ecvam.jrc.ec.europa.eu]22.EC-ECVAM (2008), Statement on the scientific validity of in vitro tests for skin irritation testing, issued by the ECVAM Scientific Advisory Committee (ESAC29), 5 November 2008. Available at: [http://ecvam.jrc.ec.europa.eu]23.OECD (20xx), Explanatory background document to the OECD draft Test Guideline on in vitro skin irritation testing. To be published in OECD Series on Testing and Assessment, No. 1XX, OECD, Paris. Available at:24.Welss, T., Basketter, D.A. and Schröder, K.R. (2004), In vitro skin irritation: fact and future. State of the art review of mechanisms and models, Toxicol. in Vitro 18, 231-243.25.Mosmann, T. (1983), Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays, J. Immunol. Methods 65, 55-63.26.EpiSkin™ SOP, Version 1.8 (February 2009), ECVAM Skin Irritation Validation Study: Validation of the EpiSkin™ test method 15 min - 42 hours for the prediction of acute skin irritation of chemicals. Available at: [http://ecvam.jrc.ec.europa.eu]© OCDE, (2010)1027.EpiDerm™ SOP, Version 7.0 (Revised March 2009), Protocol for: In vitro EpiDerm™ skin irritation test (EPI-200-SIT), For use with MatTek Corporation's reconstructed human epidermal model EpiDerm (EPI-200). Available at: [http://ecvam.jrc.ec.europa.eu]28.SkinEthic™ RHE SOP, Version 2.0 (February 2009), SkinEthic skin irritation test-42bis test method for the prediction of acute skin irritation of chemicals: 42 minutes application + 42 hours post-incubation. Available at: [http://ecvam.jrc.ec.europa.eu]29.Harvell, J.D., Lamminstausta, K., and Maibach, H.I. (1995), Irritant contact dermatitis, In: Practical Contact Dermatitis, pp 7-18, (Ed. Guin J. D.). Mc Graw-Hill, New York.30.EC (2001), Commission Directive 2001/59/EC of 6 August 2001 adapting to technical progress for the 28th time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances, Official Journal of the European Union L225, 1-333.31.Basketter, D.A., York, M., McFadden, J.P. and Robinson, M.K. (2004), Determination of skin irritation potential in the human 4-h patch test. Contact Dermatitis 51, 1-4.32.Jirova, D., Liebsch, M., Basketter, D., Spiller, E., Kejlova, K., Bendova, H., Marriott, M. and Kandarova, H. (2007), Comparison of human skin irritation and photo-irritation patch test data with cellular in vitro assays and animal in vivo data, AATEX, 14, 359-365.33.Jírová, D., Basketter, D., Liebsch, M., Bendová, H., Kejlová, K., Marriott, M. and Kandárová, H. (2010), Comparison of human skin irritation patch test data with in vitro skin irritation assays and animal data, Contact Dermatitis, 62, 109-116.11。

新核心综合学术英语教程Unit4解析

Language Points
■ Words and Phrases:
• physician-assisted suicide 安乐死 • mean incidence 平均概率 • amount to 总计 • ALS=amyotrophic [eɪmaɪə'trɒfɪk] lateral sclerosis [sklə'roʊsɪs] 肌
Language Points
■ Sentences：
• 5. In the current study it was found that the pain factor remained at the 25% level, showing no significant differences between the 5-year period before and after implementation of the Euthanasia Act, albeit [ˌɔːl'biːɪt] that in recent years pain as a reason for a request seemed to decrease again. (Line 66-69)
Language Points
■ Sentences：
• 4. It should be noted that implementation of the Act took place after extended political and media discussion and therefore, may have been a formalization of an already existing practice rather than a turning point in attitudes. (Line 55-57)

数据挖掘_25,000 Records of Human Heights (in) and Weights (lbs)(人身高体重的25000条数据记录)

25,000 Records of Human Heights (in) and Weights (lbs)(人身高体重的25000条数据记录)数据摘要：Human Height and Weight are mostly hereditable, but lifestyles, diet, health and environmental factors also play a role in determining individual's physical characteristics. The dataset below contains 25,000 records of human heights and weights. These data were obtained in 1993 by a Growth Survey of 25,000 children from birth to 18 years of age recruited from Maternal and Child Health Centres (MCHC) and schools and were used to develop Hong Kong's current growth charts for weight, height, weight-for-age, weight-for-height and body mass index (BMI).中文关键词：数据挖掘,身高,体重,25000条,Maternal and Child Health Centres (MCHC),SOCR,英文关键词：Data mining,Heights (in),Weights (lbs),25000 records,Maternal and Child Health Centres (MCHC),SOCR,数据格式：TEXT数据用途：The data can be used for data mining and analysis.数据详细介绍：25,000 Records of Human Heights (in)and Weights (lbs)∙AbstractHuman Height and Weight are mostly hereditable, but lifestyles, diet, health and environmental factors also play a role in determining individual's physical characteristics. The dataset below contains 25,000 records of human heights and weights. These data were obtained in 1993 by a Growth Survey of 25,000 children from birth to 18 years of age recruited from Maternal and Child Health Centres (MCHC) and schools and were used to develop Hong Kong's current growth charts for weight, height, weight-for-age, weight-for-height and body mass index (BMI).∙Data DescriptionVariablesReference.Hung-Kwan So, Edmund AS Nelson, Albert M Li, Eric MC Wong, Joseph TF Lau, Georgia S Guldan, Kwok-Hang Mak, Youfa Wang, Tai-Fai Fok, and Rita YT Sung. (2008) Secular changes in height, weight and body mass index in Hong Kong Children. BMC Public Health.2008; 8: 320. doi: 10.1186/1471-2458-8-320. PMCID: PMC2572616Leung SS, Lau JT, Tse LY, Oppenheimer SJ. Weight-for-age and weight-for-height references for Hong Kong children from birth to 18 years. J Paediatr Child Health. 1996;32:103–109. doi:10.1111/j.1440-1754.1996.tb00904.x.Leung SS, Lau JT, Xu YY, Tse LY, Huen KF, Wong GW, Law WY, Yeung VT, Yeung WK, et al. Secular changes in standing height, sitting height and sexual maturation of Chinese–the Hong Kong Growth Study, 1993.Ann Hum Biol. 1996;23:297–306. doi: 10.1080/03014469600004532. 数据预览：点此下载完整数据集。

C.parvum全基因组序列

DOI: 10.1126/science.1094786, 441 (2004);304Science et al.Mitchell S. Abrahamsen,Cryptosporidium parvum Complete Genome Sequence of the Apicomplexan, (this information is current as of October 7, 2009 ):The following resources related to this article are available online at/cgi/content/full/304/5669/441version of this article at:including high-resolution figures, can be found in the online Updated information and services,/cgi/content/full/1094786/DC1 can be found at:Supporting Online Material/cgi/content/full/304/5669/441#otherarticles , 9 of which can be accessed for free: cites 25 articles This article 239 article(s) on the ISI Web of Science. cited by This article has been /cgi/content/full/304/5669/441#otherarticles 53 articles hosted by HighWire Press; see: cited by This article has been/cgi/collection/genetics Genetics: subject collections This article appears in the following/about/permissions.dtl in whole or in part can be found at: this article permission to reproduce of this article or about obtaining reprints Information about obtaining registered trademark of AAAS.is a Science 2004 by the American Association for the Advancement of Science; all rights reserved. The title Copyright American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the Science o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m3.R.Jackendoff,Foundations of Language:Brain,Gram-mar,Evolution(Oxford Univ.Press,Oxford,2003).4.Although for Frege(1),reference was established rela-tive to objects in the world,here we follow Jackendoff’s suggestion(3)that this is done relative to objects and the state of affairs as mentally represented.5.S.Zola-Morgan,L.R.Squire,in The Development andNeural Bases of Higher Cognitive Functions(New York Academy of Sciences,New York,1990),pp.434–456.6.N.Chomsky,Reﬂections on Language(Pantheon,New York,1975).7.J.Katz,Semantic Theory(Harper&Row,New York,1972).8.D.Sperber,D.Wilson,Relevance(Harvard Univ.Press,Cambridge,MA,1986).9.K.I.Forster,in Sentence Processing,W.E.Cooper,C.T.Walker,Eds.(Erlbaum,Hillsdale,NJ,1989),pp.27–85.10.H.H.Clark,Using Language(Cambridge Univ.Press,Cambridge,1996).11.Often word meanings can only be fully determined byinvokingworld knowledg e.For instance,the meaningof “ﬂat”in a“ﬂat road”implies the absence of holes.However,in the expression“aﬂat tire,”it indicates the presence of a hole.The meaningof“ﬁnish”in the phrase “Billﬁnished the book”implies that Bill completed readingthe book.However,the phrase“the g oatﬁn-ished the book”can only be interpreted as the goat eatingor destroyingthe book.The examples illustrate that word meaningis often underdetermined and nec-essarily intertwined with general world knowledge.In such cases,it is hard to see how the integration of lexical meaning and general world knowledge could be strictly separated(3,31).12.W.Marslen-Wilson,C.M.Brown,L.K.Tyler,Lang.Cognit.Process.3,1(1988).13.ERPs for30subjects were averaged time-locked to theonset of the critical words,with40items per condition.Sentences were presented word by word on the centerof a computer screen,with a stimulus onset asynchronyof600ms.While subjects were readingthe sentences,their EEG was recorded and ampliﬁed with a high-cut-off frequency of70Hz,a time constant of8s,and asamplingfrequency of200Hz.14.Materials and methods are available as supportingmaterial on Science Online.15.M.Kutas,S.A.Hillyard,Science207,203(1980).16.C.Brown,P.Hagoort,J.Cognit.Neurosci.5,34(1993).17.C.M.Brown,P.Hagoort,in Architectures and Mech-anisms for Language Processing,M.W.Crocker,M.Pickering,C.Clifton Jr.,Eds.(Cambridge Univ.Press,Cambridge,1999),pp.213–237.18.F.Varela et al.,Nature Rev.Neurosci.2,229(2001).19.We obtained TFRs of the single-trial EEG data by con-volvingcomplex Morlet wavelets with the EEG data andcomputingthe squared norm for the result of theconvolution.We used wavelets with a7-cycle width,with frequencies ranging from1to70Hz,in1-Hz steps.Power values thus obtained were expressed as a per-centage change relative to the power in a baselineinterval,which was taken from150to0ms before theonset of the critical word.This was done in order tonormalize for individual differences in EEG power anddifferences in baseline power between different fre-quency bands.Two relevant time-frequency compo-nents were identiﬁed:(i)a theta component,rangingfrom4to7Hz and from300to800ms after wordonset,and(ii)a gamma component,ranging from35to45Hz and from400to600ms after word onset.20.C.Tallon-Baudry,O.Bertrand,Trends Cognit.Sci.3,151(1999).tner et al.,Nature397,434(1999).22.M.Bastiaansen,P.Hagoort,Cortex39(2003).23.O.Jensen,C.D.Tesche,Eur.J.Neurosci.15,1395(2002).24.Whole brain T2*-weighted echo planar imaging bloodoxygen level–dependent(EPI-BOLD)fMRI data wereacquired with a Siemens Sonata1.5-T magnetic reso-nance scanner with interleaved slice ordering,a volumerepetition time of2.48s,an echo time of40ms,a90°ﬂip angle,31horizontal slices,a64ϫ64slice matrix,and isotropic voxel size of3.5ϫ3.5ϫ3.5mm.For thestructural magnetic resonance image,we used a high-resolution(isotropic voxels of1mm3)T1-weightedmagnetization-prepared rapid gradient-echo pulse se-quence.The fMRI data were preprocessed and analyzedby statistical parametric mappingwith SPM99software(http://www.ﬁ/spm99).25.S.E.Petersen et al.,Nature331,585(1988).26.B.T.Gold,R.L.Buckner,Neuron35,803(2002).27.E.Halgren et al.,J.Psychophysiol.88,1(1994).28.E.Halgren et al.,Neuroimage17,1101(2002).29.M.K.Tanenhaus et al.,Science268,1632(1995).30.J.J.A.van Berkum et al.,J.Cognit.Neurosci.11,657(1999).31.P.A.M.Seuren,Discourse Semantics(Basil Blackwell,Oxford,1985).32.We thank P.Indefrey,P.Fries,P.A.M.Seuren,and M.van Turennout for helpful discussions.Supported bythe Netherlands Organization for Scientiﬁc Research,grant no.400-56-384(P.H.).Supporting Online Material/cgi/content/full/1095455/DC1Materials and MethodsFig.S1References and Notes8January2004;accepted9March2004Published online18March2004;10.1126/science.1095455Include this information when citingthis paper.Complete Genome Sequence ofthe Apicomplexan,Cryptosporidium parvumMitchell S.Abrahamsen,1,2*†Thomas J.Templeton,3†Shinichiro Enomoto,1Juan E.Abrahante,1Guan Zhu,4 Cheryl ncto,1Mingqi Deng,1Chang Liu,1‡Giovanni Widmer,5Saul Tzipori,5GregoryA.Buck,6Ping Xu,6 Alan T.Bankier,7Paul H.Dear,7Bernard A.Konfortov,7 Helen F.Spriggs,7Lakshminarayan Iyer,8Vivek Anantharaman,8L.Aravind,8Vivek Kapur2,9The apicomplexan Cryptosporidium parvum is an intestinal parasite that affects healthy humans and animals,and causes an unrelenting infection in immuno-compromised individuals such as AIDS patients.We report the complete ge-nome sequence of C.parvum,type II isolate.Genome analysis identiﬁes ex-tremely streamlined metabolic pathways and a reliance on the host for nu-trients.In contrast to Plasmodium and Toxoplasma,the parasite lacks an api-coplast and its genome,and possesses a degenerate mitochondrion that has lost its genome.Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected.Elu-cidation of the core metabolism,including enzymes with high similarities to bacterial and plant counterparts,opens new avenues for drug development.Cryptosporidium parvum is a globally impor-tant intracellular pathogen of humans and animals.The duration of infection and patho-genesis of cryptosporidiosis depends on host immune status,ranging from a severe but self-limiting diarrhea in immunocompetent individuals to a life-threatening,prolonged infection in immunocompromised patients.Asubstantial degree of morbidity and mortalityis associated with infections in AIDS pa-tients.Despite intensive efforts over the past20years,there is currently no effective ther-apy for treating or preventing C.parvuminfection in humans.Cryptosporidium belongs to the phylumApicomplexa,whose members share a com-mon apical secretory apparatus mediating lo-comotion and tissue or cellular invasion.Many apicomplexans are of medical or vet-erinary importance,including Plasmodium,Babesia,Toxoplasma,Neosprora,Sarcocys-tis,Cyclospora,and Eimeria.The life cycle ofC.parvum is similar to that of other cyst-forming apicomplexans(e.g.,Eimeria and Tox-oplasma),resulting in the formation of oocysts1Department of Veterinary and Biomedical Science,College of Veterinary Medicine,2Biomedical Genom-ics Center,University of Minnesota,St.Paul,MN55108,USA.3Department of Microbiology and Immu-nology,Weill Medical College and Program in Immu-nology,Weill Graduate School of Medical Sciences ofCornell University,New York,NY10021,USA.4De-partment of Veterinary Pathobiology,College of Vet-erinary Medicine,Texas A&M University,College Sta-tion,TX77843,USA.5Division of Infectious Diseases,Tufts University School of Veterinary Medicine,NorthGrafton,MA01536,USA.6Center for the Study ofBiological Complexity and Department of Microbiol-ogy and Immunology,Virginia Commonwealth Uni-versity,Richmond,VA23198,USA.7MRC Laboratoryof Molecular Biology,Hills Road,Cambridge CB22QH,UK.8National Center for Biotechnology Infor-mation,National Library of Medicine,National Insti-tutes of Health,Bethesda,MD20894,USA.9Depart-ment of Microbiology,University of Minnesota,Min-neapolis,MN55455,USA.*To whom correspondence should be addressed.E-mail:abe@†These authors contributed equally to this work.‡Present address:Bioinformatics Division,Genetic Re-search,GlaxoSmithKline Pharmaceuticals,5MooreDrive,Research Triangle Park,NC27009,USA.R E P O R T S SCIENCE VOL30416APRIL2004441o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mthat are shed in the feces of infected hosts.C.parvum oocysts are highly resistant to environ-mental stresses,including chlorine treatment of community water supplies;hence,the parasite is an important water-and food-borne pathogen (1).The obligate intracellular nature of the par-asite ’s life cycle and the inability to culture the parasite continuously in vitro greatly impair researchers ’ability to obtain purified samples of the different developmental stages.The par-asite cannot be genetically manipulated,and transformation methodologies are currently un-available.To begin to address these limitations,we have obtained the complete C.parvum ge-nome sequence and its predicted protein com-plement.(This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the project accession AAEE00000000.The version described in this paper is the first version,AAEE01000000.)The random shotgun approach was used to obtain the complete DNA sequence (2)of the Iowa “type II ”isolate of C.parvum .This isolate readily transmits disease among numerous mammals,including humans.The resulting ge-nome sequence has roughly 13ϫgenome cov-erage containing five gaps and 9.1Mb of totalDNA sequence within eight chromosomes.The C.parvum genome is thus quite compact rela-tive to the 23-Mb,14-chromosome genome of Plasmodium falciparum (3);this size difference is predominantly the result of shorter intergenic regions,fewer introns,and a smaller number of genes (Table 1).Comparison of the assembled sequence of chromosome VI to that of the recently published sequence of chromosome VI (4)revealed that our assembly contains an ad-ditional 160kb of sequence and a single gap versus two,with the common sequences dis-playing a 99.993%sequence identity (2).The relative paucity of introns greatly simplified gene predictions and facilitated an-notation (2)of predicted open reading frames (ORFs).These analyses provided an estimate of 3807protein-encoding genes for the C.parvum genome,far fewer than the estimated 5300genes predicted for the Plasmodium genome (3).This difference is primarily due to the absence of an apicoplast and mitochondrial genome,as well as the pres-ence of fewer genes encoding metabolic functions and variant surface proteins,such as the P.falciparum var and rifin molecules (Table 2).An analysis of the encoded pro-tein sequences with the program SEG (5)shows that these protein-encoding genes are not enriched in low-complexity se-quences (34%)to the extent observed in the proteins from Plasmodium (70%).Our sequence analysis indicates that Cryptosporidium ,unlike Plasmodium and Toxoplasma ,lacks both mitochondrion and apicoplast genomes.The overall complete-ness of the genome sequence,together with the fact that similar DNA extraction proce-dures used to isolate total genomic DNA from C.parvum efficiently yielded mito-chondrion and apicoplast genomes from Ei-meria sp.and Toxoplasma (6,7),indicates that the absence of organellar genomes was unlikely to have been the result of method-ological error.These conclusions are con-sistent with the absence of nuclear genes for the DNA replication and translation machinery characteristic of mitochondria and apicoplasts,and with the lack of mito-chondrial or apicoplast targeting signals for tRNA synthetases.A number of putative mitochondrial pro-teins were identified,including components of a mitochondrial protein import apparatus,chaperones,uncoupling proteins,and solute translocators (table S1).However,the ge-nome does not encode any Krebs cycle en-zymes,nor the components constituting the mitochondrial complexes I to IV;this finding indicates that the parasite does not rely on complete oxidation and respiratory chains for synthesizing adenosine triphosphate (ATP).Similar to Plasmodium ,no orthologs for the ␥,␦,or εsubunits or the c subunit of the F 0proton channel were detected (whereas all subunits were found for a V-type ATPase).Cryptosporidium ,like Eimeria (8)and Plas-modium ,possesses a pyridine nucleotide tran-shydrogenase integral membrane protein that may couple reduced nicotinamide adenine dinucleotide (NADH)and reduced nico-tinamide adenine dinucleotide phosphate (NADPH)redox to proton translocation across the inner mitochondrial membrane.Unlike Plasmodium ,the parasite has two copies of the pyridine nucleotide transhydrogenase gene.Also present is a likely mitochondrial membrane –associated,cyanide-resistant alter-native oxidase (AOX )that catalyzes the reduction of molecular oxygen by ubiquinol to produce H 2O,but not superoxide or H 2O 2.Several genes were identified as involved in biogenesis of iron-sulfur [Fe-S]complexes with potential mitochondrial targeting signals (e.g.,nifS,nifU,frataxin,and ferredoxin),supporting the presence of a limited electron flux in the mitochondrial remnant (table S2).Our sequence analysis confirms the absence of a plastid genome (7)and,additionally,the loss of plastid-associated metabolic pathways including the type II fatty acid synthases (FASs)and isoprenoid synthetic enzymes thatTable 1.General features of the C.parvum genome and comparison with other single-celled eukaryotes.Values are derived from respective genome project summaries (3,26–28).ND,not determined.FeatureC.parvum P.falciparum S.pombe S.cerevisiae E.cuniculiSize (Mbp)9.122.912.512.5 2.5(G ϩC)content (%)3019.43638.347No.of genes 38075268492957701997Mean gene length (bp)excluding introns 1795228314261424ND Gene density (bp per gene)23824338252820881256Percent coding75.352.657.570.590Genes with introns (%)553.9435ND Intergenic regions (G ϩC)content %23.913.632.435.145Mean length (bp)5661694952515129RNAsNo.of tRNA genes 454317429944No.of 5S rRNA genes 6330100–2003No.of 5.8S ,18S ,and 28S rRNA units 57200–400100–20022Table parison between predicted C.parvum and P.falciparum proteins.FeatureC.parvum P.falciparum *Common †Total predicted proteins380752681883Mitochondrial targeted/encoded 17(0.45%)246(4.7%)15Apicoplast targeted/encoded 0581(11.0%)0var/rif/stevor ‡0236(4.5%)0Annotated as protease §50(1.3%)31(0.59%)27Annotated as transporter ࿣69(1.8%)34(0.65%)34Assigned EC function ¶167(4.4%)389(7.4%)113Hypothetical proteins925(24.3%)3208(60.9%)126*Values indicated for P.falciparum are as reported (3)with the exception of those for proteins annotated as protease or transporter.†TBLASTN hits (e Ͻ–5)between C.parvum and P.falciparum .‡As reported in (3).§Pre-dicted proteins annotated as “protease or peptidase”for C.parvum (CryptoGenome database,)and P.falciparum (PlasmoDB database,).࿣Predicted proteins annotated as “trans-porter,permease of P-type ATPase”for C.parvum (CryptoGenome)and P.falciparum (PlasmoDB).¶Bidirectional BLAST hit (e Ͻ–15)to orthologs with assigned Enzyme Commission (EC)numbers.Does not include EC assignment numbers for protein kinases or protein phosphatases (due to inconsistent annotation across genomes),or DNA polymerases or RNA polymerases,as a result of issues related to subunit inclusion.(For consistency,46proteins were excluded from the reported P.falciparum values.)R E P O R T S16APRIL 2004VOL 304SCIENCE 442 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o mare otherwise localized to the plastid in other apicomplexans.C.parvum fatty acid biosynthe-sis appears to be cytoplasmic,conducted by a large(8252amino acids)modular type I FAS (9)and possibly by another large enzyme that is related to the multidomain bacterial polyketide synthase(10).Comprehensive screening of the C.parvum genome sequence also did not detect orthologs of Plasmodium nuclear-encoded genes that contain apicoplast-targeting and transit sequences(11).C.parvum metabolism is greatly stream-lined relative to that of Plasmodium,and in certain ways it is reminiscent of that of another obligate eukaryotic parasite,the microsporidian Encephalitozoon.The degeneration of the mi-tochondrion and associated metabolic capabili-ties suggests that the parasite largely relies on glycolysis for energy production.The parasite is capable of uptake and catabolism of mono-sugars(e.g.,glucose and fructose)as well as synthesis,storage,and catabolism of polysac-charides such as trehalose and amylopectin. Like many anaerobic organisms,it economizes ATP through the use of pyrophosphate-dependent phosphofructokinases.The conver-sion of pyruvate to acetyl–coenzyme A(CoA) is catalyzed by an atypical pyruvate-NADPH oxidoreductase(Cp PNO)that contains an N-terminal pyruvate–ferredoxin oxidoreductase (PFO)domain fused with a C-terminal NADPH–cytochrome P450reductase domain (CPR).Such a PFO-CPR fusion has previously been observed only in the euglenozoan protist Euglena gracilis(12).Acetyl-CoA can be con-verted to malonyl-CoA,an important precursor for fatty acid and polyketide biosynthesis.Gly-colysis leads to several possible organic end products,including lactate,acetate,and ethanol. The production of acetate from acetyl-CoA may be economically beneficial to the parasite via coupling with ATP production.Ethanol is potentially produced via two in-dependent pathways:(i)from the combination of pyruvate decarboxylase and alcohol dehy-drogenase,or(ii)from acetyl-CoA by means of a bifunctional dehydrogenase(adhE)with ac-etaldehyde and alcohol dehydrogenase activi-ties;adhE first converts acetyl-CoA to acetal-dehyde and then reduces the latter to ethanol. AdhE predominantly occurs in bacteria but has recently been identified in several protozoans, including vertebrate gut parasites such as Enta-moeba and Giardia(13,14).Adjacent to the adhE gene resides a second gene encoding only the AdhE C-terminal Fe-dependent alcohol de-hydrogenase domain.This gene product may form a multisubunit complex with AdhE,or it may function as an alternative alcohol dehydro-genase that is specific to certain growth condi-tions.C.parvum has a glycerol3-phosphate dehydrogenase similar to those of plants,fungi, and the kinetoplastid Trypanosoma,but(unlike trypanosomes)the parasite lacks an ortholog of glycerol kinase and thus this pathway does not yield glycerol production.In addition to themodular fatty acid synthase(Cp FAS1)andpolyketide synthase homolog(Cp PKS1), C.parvum possesses several fatty acyl–CoA syn-thases and a fatty acyl elongase that may partici-pate in fatty acid metabolism.Further,enzymesfor the metabolism of complex lipids(e.g.,glyc-erolipid and inositol phosphate)were identified inthe genome.Fatty acids are apparently not anenergy source,because enzymes of the fatty acidoxidative pathway are absent,with the exceptionof a3-hydroxyacyl-CoA dehydrogenase.C.parvum purine metabolism is greatlysimplified,retaining only an adenosine ki-nase and enzymes catalyzing conversionsof adenosine5Ј-monophosphate(AMP)toinosine,xanthosine,and guanosine5Ј-monophosphates(IMP,XMP,and GMP).Among these enzymes,IMP dehydrogenase(IMPDH)is phylogenetically related toε-proteobacterial IMPDH and is strikinglydifferent from its counterparts in both thehost and other apicomplexans(15).In con-trast to other apicomplexans such as Toxo-plasma gondii and P.falciparum,no geneencoding hypoxanthine-xanthineguaninephosphoribosyltransferase(HXGPRT)is de-tected,in contrast to a previous report on theactivity of this enzyme in C.parvum sporo-zoites(16).The absence of HXGPRT sug-gests that the parasite may rely solely on asingle enzyme system including IMPDH toproduce GMP from AMP.In contrast to otherapicomplexans,the parasite appears to relyon adenosine for purine salvage,a modelsupported by the identification of an adeno-sine transporter.Unlike other apicomplexansand many parasitic protists that can synthe-size pyrimidines de novo,C.parvum relies onpyrimidine salvage and retains the ability forinterconversions among uridine and cytidine5Ј-monophosphates(UMP and CMP),theirdeoxy forms(dUMP and dCMP),and dAMP,as well as their corresponding di-and triphos-phonucleotides.The parasite has also largelyshed the ability to synthesize amino acids denovo,although it retains the ability to convertselect amino acids,and instead appears torely on amino acid uptake from the host bymeans of a set of at least11amino acidtransporters(table S2).Most of the Cryptosporidium core pro-cesses involved in DNA replication,repair,transcription,and translation conform to thebasic eukaryotic blueprint(2).The transcrip-tional apparatus resembles Plasmodium interms of basal transcription machinery.How-ever,a striking numerical difference is seenin the complements of two RNA bindingdomains,Sm and RRM,between P.falcipa-rum(17and71domains,respectively)and C.parvum(9and51domains).This reductionresults in part from the loss of conservedproteins belonging to the spliceosomal ma-chinery,including all genes encoding Smdomain proteins belonging to the U6spliceo-somal particle,which suggests that this par-ticle activity is degenerate or entirely lost.This reduction in spliceosomal machinery isconsistent with the reduced number of pre-dicted introns in Cryptosporidium(5%)rela-tive to Plasmodium(Ͼ50%).In addition,keycomponents of the small RNA–mediatedposttranscriptional gene silencing system aremissing,such as the RNA-dependent RNApolymerase,Argonaute,and Dicer orthologs;hence,RNA interference–related technolo-gies are unlikely to be of much value intargeted disruption of genes in C.parvum.Cryptosporidium invasion of columnarbrush border epithelial cells has been de-scribed as“intracellular,but extracytoplas-mic,”as the parasite resides on the surface ofthe intestinal epithelium but lies underneaththe host cell membrane.This niche may al-low the parasite to evade immune surveil-lance but take advantage of solute transportacross the host microvillus membrane or theextensively convoluted parasitophorous vac-uole.Indeed,Cryptosporidium has numerousgenes(table S2)encoding families of putativesugar transporters(up to9genes)and aminoacid transporters(11genes).This is in starkcontrast to Plasmodium,which has fewersugar transporters and only one putative ami-no acid transporter(GenBank identificationnumber23612372).As a first step toward identification ofmulti–drug-resistant pumps,the genome se-quence was analyzed for all occurrences ofgenes encoding multitransmembrane proteins.Notable are a set of four paralogous proteinsthat belong to the sbmA family(table S2)thatare involved in the transport of peptide antibi-otics in bacteria.A putative ortholog of thePlasmodium chloroquine resistance–linkedgene Pf CRT(17)was also identified,althoughthe parasite does not possess a food vacuole likethe one seen in Plasmodium.Unlike Plasmodium,C.parvum does notpossess extensive subtelomeric clusters of anti-genically variant proteins(exemplified by thelarge families of var and rif/stevor genes)thatare involved in immune evasion.In contrast,more than20genes were identified that encodemucin-like proteins(18,19)having hallmarksof extensive Thr or Ser stretches suggestive ofglycosylation and signal peptide sequences sug-gesting secretion(table S2).One notable exam-ple is an11,700–amino acid protein with anuninterrupted stretch of308Thr residues(cgd3_720).Although large families of secretedproteins analogous to the Plasmodium multi-gene families were not found,several smallermultigene clusters were observed that encodepredicted secreted proteins,with no detectablesimilarity to proteins from other organisms(Fig.1,A and B).Within this group,at leastfour distinct families appear to have emergedthrough gene expansions specific to the Cryp-R E P O R T S SCIENCE VOL30416APRIL2004443o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mtosporidium clade.These families —SKSR,MEDLE,WYLE,FGLN,and GGC —were named after well-conserved sequence motifs (table S2).Reverse transcription polymerase chain reaction (RT-PCR)expression analysis (20)of one cluster,a locus of seven adjacent CpLSP genes (Fig.1B),shows coexpression during the course of in vitro development (Fig.1C).An additional eight genes were identified that encode proteins having a periodic cysteine structure similar to the Cryptosporidium oocyst wall protein;these eight genes are similarly expressed during the onset of oocyst formation and likely participate in the formation of the coccidian rigid oocyst wall in both Cryptospo-ridium and Toxoplasma (21).Whereas the extracellular proteins described above are of apparent apicomplexan or lineage-specific in-vention,Cryptosporidium possesses many genesencodingsecretedproteinshavinglineage-specific multidomain architectures composed of animal-and bacterial-like extracellular adhe-sive domains (fig.S1).Lineage-specific expansions were ob-served for several proteases (table S2),in-cluding an aspartyl protease (six genes),a subtilisin-like protease,a cryptopain-like cys-teine protease (five genes),and a Plas-modium falcilysin-like (insulin degrading enzyme –like)protease (19genes).Nine of the Cryptosporidium falcilysin genes lack the Zn-chelating “HXXEH ”active site motif and are likely to be catalytically inactive copies that may have been reused for specific protein-protein interactions on the cell sur-face.In contrast to the Plasmodium falcilysin,the Cryptosporidium genes possess signal peptide sequences and are likely trafficked to a secretory pathway.The expansion of this family suggests either that the proteins have distinct cleavage specificities or that their diversity may be related to evasion of a host immune response.Completion of the C.parvum genome se-quence has highlighted the lack of conven-tional drug targets currently pursued for the control and treatment of other parasitic protists.On the basis of molecular and bio-chemical studies and drug screening of other apicomplexans,several putative Cryptospo-ridium metabolic pathways or enzymes have been erroneously proposed to be potential drug targets (22),including the apicoplast and its associated metabolic pathways,the shikimate pathway,the mannitol cycle,the electron transport chain,and HXGPRT.Nonetheless,complete genome sequence analysis identifies a number of classic and novel molecular candidates for drug explora-tion,including numerous plant-like and bacterial-like enzymes (tables S3and S4).Although the C.parvum genome lacks HXGPRT,a potent drug target in other api-complexans,it has only the single pathway dependent on IMPDH to convert AMP to GMP.The bacterial-type IMPDH may be a promising target because it differs substan-tially from that of eukaryotic enzymes (15).Because of the lack of de novo biosynthetic capacity for purines,pyrimidines,and amino acids,C.parvum relies solely on scavenge from the host via a series of transporters,which may be exploited for chemotherapy.C.parvum possesses a bacterial-type thymidine kinase,and the role of this enzyme in pyrim-idine metabolism and its drug target candida-cy should be pursued.The presence of an alternative oxidase,likely targeted to the remnant mitochondrion,gives promise to the study of salicylhydroxamic acid (SHAM),as-cofuranone,and their analogs as inhibitors of energy metabolism in the parasite (23).Cryptosporidium possesses at least 15“plant-like ”enzymes that are either absent in or highly divergent from those typically found in mammals (table S3).Within the glycolytic pathway,the plant-like PPi-PFK has been shown to be a potential target in other parasites including T.gondii ,and PEPCL and PGI ap-pear to be plant-type enzymes in C.parvum .Another example is a trehalose-6-phosphate synthase/phosphatase catalyzing trehalose bio-synthesis from glucose-6-phosphate and uridine diphosphate –glucose.Trehalose may serve as a sugar storage source or may function as an antidesiccant,antioxidant,or protein stability agent in oocysts,playing a role similar to that of mannitol in Eimeria oocysts (24).Orthologs of putative Eimeria mannitol synthesis enzymes were not found.However,two oxidoreductases (table S2)were identified in C.parvum ,one of which belongs to the same families as the plant mannose dehydrogenases (25)and the other to the plant cinnamyl alcohol dehydrogenases.In principle,these enzymes could synthesize protective polyol compounds,and the former enzyme could use host-derived mannose to syn-thesize mannitol.References and Notes1.D.G.Korich et al .,Appl.Environ.Microbiol.56,1423(1990).2.See supportingdata on Science Online.3.M.J.Gardner et al .,Nature 419,498(2002).4.A.T.Bankier et al .,Genome Res.13,1787(2003).5.J.C.Wootton,Comput.Chem.18,269(1994).Fig.1.(A )Schematic showing the chromosomal locations of clusters of potentially secreted proteins.Numbers of adjacent genes are indicated in paren-theses.Arrows indicate direc-tion of clusters containinguni-directional genes (encoded on the same strand);squares indi-cate clusters containingg enes encoded on both strands.Non-paralogous genes are indicated by solid gray squares or direc-tional triangles;SKSR (green triangles),FGLN (red trian-gles),and MEDLE (blue trian-gles)indicate three C.parvum –speciﬁc families of paralogous genes predominantly located at telomeres.Insl (yellow tri-angles)indicates an insulinase/falcilysin-like paralogous gene family.Cp LSP (white square)indicates the location of a clus-ter of adjacent large secreted proteins (table S2)that are cotranscriptionally regulated.Identiﬁed anchored telomeric repeat sequences are indicated by circles.(B )Schematic show-inga select locus containinga cluster of coexpressed large secreted proteins (Cp LSP).Genes and intergenic regions (regions between identiﬁed genes)are drawn to scale at the nucleotide level.The length of the intergenic re-gions is indicated above or be-low the locus.(C )Relative ex-pression levels of CpLSP (red lines)and,as a control,C.parvum Hedgehog-type HINT domain gene (blue line)duringin vitro development,as determined by semiquantitative RT-PCR usingg ene-speciﬁc primers correspondingto the seven adjacent g enes within the CpLSP locus as shown in (B).Expression levels from three independent time-course experiments are represented as the ratio of the expression of each gene to that of C.parvum 18S rRNA present in each of the infected samples (20).R E P O R T S16APRIL 2004VOL 304SCIENCE 444 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m。

EudraVigilance

agency of the European Union
© European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.
Table of contents
Executive summary ..................................................................................... 3 1. Background ............................................................................................. 4 2. Introduction ............................................................................................ 5 3. Objectives of the EudraVigilance access policy........................................ 5 4. EudraVigilance and medicinal products for human use............................ 5 5. Access to data held in EudraVigilance...................................................... 7
5.1. Stakeholder groups ............................................................................................ 7 5.2. Overview .......................................................................................................... 7 5.3. General principles .............................................................................................. 9 5.3.1. ICSR types ................................................................................................... 10 5.3.2. Primary and secondary report sources .............................................................. 10 5.3.3. Individual cases, ICSRs and classification rules .................................................. 10 5.3.4. Access to EudraVigilance data and access tools.................................................. 11 5.4. Access by stakeholder group.............................................................................. 11 5.4.1. Group I: Medicines regulatory authorities in the EEA, the European Commission and the Agency ............................................................................................................ 11 5.4.2. Group II: Healthcare professionals and the general public ................................... 12 5.4.3. Group III: Marketing authorisation holders and sponsors..................................... 14 5.4.4. Group IV: Research organisations .................................................................... 15

E2B(R3) 个例安全报告的电子传输问答

iii
日期 2017 年 6 月 1 日 E2B(R3) 问答
前言本问答文件为 E2B(R3) IG 的统一解释进行了澄清，应与 IG 一起对待。这将有助于在 ICH 地区实施问答个例安全报告（ICSRS）的电子传输。本问答文件的章节部分与 E2B(R3) IG 的结构相对应。鼓励制药公司、监管机构和供应商提交实施相关问题至 ICH E2B（R3）EWG / IWG；这些问题的答案由 ICH E2B（R3）EWG/IWG 按照 ICH 共识流程进行开发。在 E2B(R3)指南中未涉及的关于时间框架和具体区域要求的问题在针对各地区公布的指导文件中回答。包含在 IG 包中的文件内的“升级”或“降级”术语级的使用是指 E2B(R2) 和 E2B(R3)之间的技术转换。未来如果有问答文件的更新，将在 ICH 网站进行公布。
站提供 https:///obp/ui/#home
（R3）信息中使用国家代码。这包括“官方指定的”国家代码加上在“特别保
有一些类别，如“官方指定的代码”或“其他留”类别中的“欧盟”。
2016 年 6 月
代码类型”。ICH 只接受“官方指定的代码” “未指定”类别不应使用。“过渡性保留的”，“非明确保留的”和“以前使用
2014 年 11 月要区分大小写形式，没有相关指导。
有关区分大小写形式的更多信息，请参阅区域指南。
使用 HL7 nullFlavors 需要实施非常具体的业务支持 HL7 空白值，如 MSK（掩盖的）、NI（无信息）和 UNK（未知的）在实施规则来进行解析--不一定是 ICSR 文件验证的一中可能会有所不同。系统应设计为接收过程并利用在 ICH E2B（R3）IG 中定义的部分。ICSR 文件验证正在按照数据元素(数据空白值重新生成一条一致的信息。

A Survey on Wireless Body Area Networks

A survey on wireless body area networksBenoıˆt Latre ´•Bart Braem •Ingrid Moerman •Chris Blondia •Piet DemeesterPublished online:11November 2010ÓSpringer Science+Business Media,LLC 2010Abstract The increasing use of wireless networks and the constant miniaturization of electrical devices has empow-ered the development of Wireless Body Area Networks (WBANs).In these networks various sensors are attached on clothing or on the body or even implanted under the skin.The wireless nature of the network and the wide variety of sen-sors offer numerous new,practical and innovative applica-tions to improve health care and the Quality of Life.The sensors of a WBAN measure for example the heartbeat,the body temperature or record a prolonged ing a WBAN,the patient experiences a greater physical mobility and is no longer compelled to stay in the hospital.This paper offers a survey of the concept of Wireless Body Area Networks.First,we focus on some applications with special interest in patient monitoring.Then the communi-cation in a WBAN and its positioning between the different technologies is discussed.An overview of the current research on the physical layer,existing MAC and network protocols is given.Further,cross layer and quality of service is discussed.As WBANs are placed on the human body and often transport private data,security is also considered.An overview of current and past projects is given.Finally,the open research issues and challenges are pointed out.Keywords Wireless body area networks ÁRouting ÁMAC1IntroductionThe aging population in many developed countries and the rising costs of health care have triggered the introduction of novel technology-driven enhancements to current health care practices.For example,recent advances in electron-ics have enabled the development of small and intelligent (bio-)medical sensors which can be worn on or implanted in the human body.These sensors need to send their data to an external medical server where it can be analyzed and ing a wired connection for this purpose turns out to be too cumbersome and involves a high cost for deployment and maintenance.However,the use of a wireless interface enables an easier application and is more cost efﬁcient [1].The patient experiences a greater physical mobility and is no longer compelled to stay in a hospital.This process can be considered as the next step in enhancing the personal health care and in coping with the costs of the health care system.Where eHealth is deﬁned as the health care practice sup-ported by electronic processes and communication,the health care is now going a step further by becoming mobile.This is referred to as mHealth [2].In order to fully exploit the beneﬁts of wireless technologies in telemedicine and mHealth,a new type of wireless network emerges:a wire-less on-body network or a Wireless Body Area Network (WBAN).This term was ﬁrst coined by Van Dam et al.[3]and received the interest of several researchers [4–8].A Wireless Body Area Network consists of small,intelligent devices attached on or implanted in the body which are capable of establishing a wireless communica-tion link.These devices provide continuous health moni-toring and real-time feedback to the user or medical personnel.Furthermore,the measurements can be recorded over a longer period of time,improving the quality of the measured data [9].tre´(&)ÁI.Moerman ÁP.Demeester Department of Information Technology,Ghent University/IBBT,Gaston Crommenlaan 8,Box 201,9050Gent,Belgium e-mail:tre@intec.ugent.beB.Braem ÁC.BlondiaDepartment of Mathematics and Computer Science,University of Antwerp/IBBT,Middelheimlaan 1,2020Antwerp,Belgium e-mail:bart.braem@ua.ac.beWireless Netw (2011)17:1–18DOI 10.1007/s11276-010-0252-4Generally speaking,two types of devices can be dis-tinguished:sensors and actuators.The sensors are used to measure certain parameters of the human body,either externally or internally.Examples include measuring the heartbeat,body temperature or recording a prolonged electrocardiogram(ECG).The actuators(or actors)on the other hand take some speciﬁc actions according to the data they receive from the sensors or through interaction with the user,e.g.,an actuator equipped with a built-in reservoir and pump administers the correct dose of insulin to give to diabetics based on the glucose level measurements.Inter-action with the user or other persons is usually handled by a personal device,e.g.a PDA or a smart phone which acts as a sink for data of the wireless devices.In order to realize communication between these devi-ces,techniques from Wireless Sensor Networks(WSNs) and ad hoc networks could be used.However,because of the typical properties of a WBAN,current protocols designed for these networks are not always well suited to support a WBAN.The following illustrates the differences between a Wireless Sensor Network and a Wireless Body Area Network:•The devices used have limited energy resources avail-able as they have a very small form factor(often less than1cm3[10]).Furthermore,for most devices it is impossible to recharge or change the batteries althougha long lifetime of the device is wanted(up to severalyears or even decades for implanted devices).Hence, the energy resources and consequently the computa-tional power and available memory of such devices will be limited;•All devices are equally important and devices are only added when they are needed for an application(i.e.no redundant devices are available);•An extremely low transmit power per node is needed to minimize interference and to cope with health concerns[11];•The propagation of the waves takes place in or on a (very)lossy medium,the human body.As a result,the waves are attenuated considerably before they reach the receiver;•The devices are located on the human body that can be in motion.WBANs should therefore be robust against frequent changes in the network topology;•The data mostly consists of medical information.Hence,high reliability and low delay is required;•Stringent security mechanisms are required in order to ensure the strictly private and conﬁdential character of the medical data;•Andﬁnally the devices are often very heteroge-neous,may have very different demands or may requiredifferent resources of the network in terms of data rates, power consumption and reliability.When referring to a WBAN where each node comprises a biosensor or a medical device with sensing unit,some researchers use the name Body Area Sensor Network (BASN)or in short Body Sensor Network(BSN)instead of WBAN[12].These networks are very similar to each other and share the same challenges and properties.In the following,we will use the term WBAN which is also the one used by the IEEE[13].In this article we present a survey of the state of the art in Wireless Body Area Networks.Our aim is to provide a better understanding of the current research issues in this emergingﬁeld.The remainder of this paper is organized as follows.First,the patient monitoring application is dis-cussed in Sect.2.Next,the characteristics of the commu-nication and the positioning of WBANs amongst other wireless technologies is discussed in Sect.4.Section5 gives an overview of the properties of the physical layer and the issues of communicating near or in the body. Existing protocols for the MAC-layer and network layer are discussed in Sects.6and7,respectively.Section8 deals with cross-layer protocols available for WBANs.The Quality of Service(QoS)and possible security mechanisms are treated in Sects.9and10.An overview of existing projects is given in Sect.11.Finally,the open research issues are discussed in Sects.12and13concludes the paper.2Patient monitoringThe main cause of death in the world is CardioVascular Disease(CVD),representing30%of all global deaths. According to the World Health Organization,worldwide about17.5million people die of heart attacks or strokes each year;in2015,almost20million people will die from CVD.These deaths can often be prevented with proper health care[14].Worldwide,more than246million people suffer from diabetes,a number that is expected to rise to 380million by2025[15].Frequent monitoring enables proper dosing and reduces the risk of fainting and in later life blindness,loss of circulation and other complications [15].These two examples already illustrate the need for continuous monitoring and the usefulness of WBANs. Numerous other examples of diseases would beneﬁt from continuous or prolonged monitoring,such as hypertension, asthma,Alzheimer’s disease,Parkinson’s disease,renal failure,post-operative monitoring,stress-monitoring,pre-vention of sudden infant death syndrome,etc[9,16,17]. These applications can be considered as an indicator for thesize of the market for WBANs.The number of people suffering from diabetics or CVD and the percentage of people in the population age60years and older will grow in the future.Even without any further increase in world population by2025this would mean a very large number of potential customers.WBAN technology could provide the connectivity to support the elderly in managing their daily life and medical conditions[18].A WBAN allows continuous monitoring of the physiological parameters. Whether the patient is in the hospital,at home or on the move,the patient will no longer need to stay in bed,but will be able to move around freely.Furthermore,the data obtained during a large time interval in the patient’s natural environment offers a clearer view to the doctors than data obtained during short stays at the hospital[9].An example of a medical WBAN used for patient moni-toring is shown in Fig.1.Several sensors are placed in clothes,directly on the body or under the skin of a person and measure the temperature,blood pressure,heart rate,ECG, EEG,respiration rate,SpO2-levels,etc.Next to sensing devices,the patient has actuators which act as drug delivery systems.The medicine can be delivered on predetermined moments,triggered by an external source(i.e.a doctor who analyzes the data)or immediately when a sensor notices a problem.One example is the monitoring of the glucose level in the blood of diabetics.If the sensor monitors a sudden drop of glucose,a signal can be sent to the actuator in order to start the injection of insulin.Consequently,the patient will experience fewer nuisances from his disease.Another example of an actuator is a spinal cord stimulator implanted in the body for long-term pain relief[19].A WBAN can also be used to offer assistance to the disabled.For example,a paraplegic can be equipped with sensors determining the position of the legs or with sensors attached to the nerves[20].In addition,actuators posi-tioned on the legs can stimulate the muscles.Interaction between the data from the sensors and the actuators makes it possible to restore the ability to move.Another example is aid for the visually impaired.An artiﬁcial retina,con-sisting of a matrix of micro sensors,can be implanted into the eye beneath the surface of the retina.The artiﬁcial retina translates the electrical impulses into neurological signals.The input can be obtained locally from light sen-sitive sensors or by an external camera mounted on a pair of glasses[21].Another area of application can be found in the domain of public safety where the WBAN can be used byﬁre-ﬁghters,policemen or in a military environment[22].The WBAN monitors for example the level of toxics in the air and warns theﬁreﬁghters or soldiers if a life threatening level is detected.The introduction of a WBAN further enables to tune more effectively the training schedules of professional athletes.Next to purely medical applications,a WBAN can include appliances such as an MP3-player,head-mounted (computer)displays,a microphone,a camera,advanced human-computer interfaces such as a neural interface,etc [20].As such,the WBAN can also be used for gaming purposes and in virtual reality.This small overview already shows the myriad of pos-sibilities where WBANs are useful.The main characteristic of all these applications is that WBANs improve the user’s Quality of Life.3Taxonomy and requirementsThe applications described in the previous section indicate that a WBAN consists of several heterogeneous devices.In this section an overview of the different types of devices used in a WBAN will be given.Further the requirements and challenges are discussed.These include the wide var-iability of data rates,the restricted energy consumption,the need for QoS and reliability,ease-of-use by medical pro-fessionals and security and privacy issues.3.1Types of devices(Wireless)sensor node:A device that responds to and gathers data on physical stimuli,processes the data if necessary and reports this information wirelessly.It consists of several components:sensor hardware,a power unit,a processor,memory and a transmitter or transceiver[23].(Wireless)actuator node:A device that acts according to data received from the sensors or throughinteractionwith the user.The components of an actuator are similar to the sensor’s:actuator hardware(e.g.hardware for medicine administration,including a reservoir to hold the medicine),a power unit,a processor,memory and a receiver or transceiver.(Wireless)personal device(PD):A device that gathers all the information acquired by the sensors and actuators and informs the user(i.e.the patient,a nurse,a GP,etc.) via an external gateway,an actuator or a display/LEDS on the device.The components are a power unit,a (large)processor,memory and a transceiver.This device is also called a Body Control Unit(BCU)[4],body-gateway or a sink.In some implementations,a Personal Digital Assistant(PDA)or smart phone is used.Many different types of sensors and actuators are used in a WBAN.The main use of all these devices is to be found in the area of health applications.In the following,the termnodes refers to both the sensor as actuator nodes.The number of nodes in a WBAN is limited by nature of the network.It is expected that the number of nodes will be in the range of20–50[6,24].3.2Data ratesDue to the strong heterogeneity of the applications,data rates will vary strongly,ranging from simple data at a few kbit/s to video streams of several Mbit/s.Data can also be sent in bursts,which means that it is sent at higher rate during the bursts.The data rates for the different applications are given in in Table1and are calculated by means of the sampling rate,the range and the desired accuracy of the measure-ments[25,26].Overall,it can be seen that the application data rates are not high.However,if one has a WBAN with several of these devices(i.e.a dozen motion sensors,ECG, EMG,glucose monitoring,etc.)the aggregated data rate easily reaches a few Mbps,which is a higher than the raw bit rate of most existing low power radios.The reliability of the data transmission is provided in terms of the necessary bit error rate(BER)which is used as a measure for the number of lost packets.For a medical device,the reliability depends on the data rate.Low data rate devices can cope with a high BER(e.g.10-4),while devices with a higher data rate require a lower BER(e.g. 10-10).The required BER is also dependent on the criti-calness of the data.3.3EnergyEnergy consumption can be divided into three domains: sensing,(wireless)communication and data processing [23].The wireless communication is likely to be the most power consuming.The power available in the nodes is often restricted.The size of the battery used to store the needed energy is in most cases the largest contributor to the sensor device in terms of both dimensions and weight. Batteries are,as a consequence,kept small and energy consumption of the devices needs to be reduced.In some applications,a WBAN’s sensor/actuator node should operate while supporting a battery life time of months or even years without intervention.For example,a pacemaker or a glucose monitor would require a lifetime lasting more than5years.Especially for implanted devices,the lifetime is crucial.The need for replacement or recharging induces a cost and convenience penalty which is undesirable not only for implanted devices,but also for larger ones.The lifetime of a node for a given battery capacity can be enhanced by scavenging energy during the operation of the system.If the scavenged energy is larger than the average consumed energy,such systems could run eternally.How-ever,energy scavenging will only deliver small amounts of energy[5,28].A combination of lower energy consumption and energy scavenging is the optimal solution for achieving autonomous Wireless Body Area Networks.For a WBAN, energy scavenging from on-body sources such as body heat and body vibration seems very well suited.In the former,a thermo-electric generator(TEG)is used to transform the temperature difference between the environment and the human body into electrical energy[27].The latter uses for example the human gait as energy source[29].During communication the devices produce heat which is absorbed by the surrounding tissue and increases the temperature of the body.In order to limit this temperature rise and in addition to save the battery resources,the energy consumption should be restricted to a minimum. The amount of power absorbed by the tissue is expressed Table1Examples of medical WBAN applications[21,25,26,27] Application Data rate Bandwidth(Hz)Accuracy(bits) ECG(12leads)288kbps100–100012ECG(6leads)71kbps100–50012EMG320kbps0–10,00016EEG(12leads)43.2kbps0–15012 Blood saturation16bps0–18 Glucose monitoring1600bps0–5016 Temperature120bps0–18 Motion sensor35kbps0–50012 Cochlear implant100kbps––Artiﬁcial retina50-700kbps––Audio1Mbps––Voice50-100kbps––by the speciﬁc absorption rate(SAR).Since the device may be in close proximity to,or inside,a human body,the localized SAR could be quite large.The localized SAR into the body must be minimized and needs to comply with international and local SAR regulations.The regulation for transmitting near the human body is similar to the one for mobile phones,with strict transmit power requirements [11,30].3.4Quality of service and reliabilityProper QoS handling is an important part in the framework of risk management of medical applications.A crucial issue is the reliability of the transmission in order to guarantee that the monitored data is received correctly by the health care professionals.The reliability can be con-sidered either end-to-end or on a per link base.Examples of reliability include the guaranteed delivery of data(i.e. packet delivery ratio),in-order-delivery,…Moreover, messages should be delivered in reasonable time.The reliability of the network directly affects the quality of patient monitoring and in a worst case scenario it can be fatal when a life threatening event has gone undetected [31].3.5UsabilityIn most cases,a WBAN will be set up in a hospital by medical staff,not by ICT-engineers.Consequently,the network should be capable of conﬁguring and maintaining itself automatically,i.e.self-organization an self-mainte-nance should be supported.Whenever a node is put on the body and turned on,it should be able to join the network and set up routes without any external intervention.The self-organizing aspect also includes the problem of addressing the nodes.An address can be conﬁgured at manufacturing time(e.g.the MAC-address)or at setup time by the network itself.Further,the network should be quickly reconﬁgurable,for adding new services.When a route fails,a back up path should be set up.The devices may be scattered over and in the whole body.The exact location of a device will depend on the application,e.g.a heart sensor obviously must be placed in the neighborhood of the heart,a temperature sensor can be placed almost anywhere.Researchers seem to disagree on the ideal body location for some sensor nodes,i.e.motion sensors,as the interpretation of the measured data is not always the same[32].The network should not be regarded as a static one.The body may be in motion(e.g.walking, running,twisting,etc.)which induces channel fading and shadowing effects.The nodes should have a small form factor consistent with wearable and implanted applications.This will make WBANs invisible and unobtrusive.3.6Security and privacyThe communication of health related information between sensors in a WBAN and over the Internet to servers is strictly private and conﬁdential[33]and should be encrypted to protect the patient’s privacy.The medical staff collecting the data needs to be conﬁdent that the data is not tampered with and indeed originates from that patient.Further,it can not be expected that an average person or the medical staff is capable of setting up and managing authentication and authorization processes. Moreover the network should be accessible when the user is not capable of giving the password(e.g.to guarantee accessibility by paramedics in trauma situations).Security and privacy protection mechanisms use a signiﬁcant part of the available energy and should therefor be energy efﬁcient and lightweight.4Positioning WBANsThe development and research in the domain of WBANs is only at an early stage.As a consequence,the terminology is not always clearly deﬁned.In literature,protocols devel-oped for WBANs can span from communication between the sensors on the body to communication from a body node to a data center connected to the Internet.In order to have clear understanding,we propose the following deﬁ-nitions:intra-body communication and extra-body com-munication.An example is shown on Fig.2.The former controls the information handling on the body between the sensors or actuators and the personal device[34–37],the Fig.2Example of intra-body and extra-body communication in a WBANlatter ensures communication between the personal device and an external network[32,38–40].Doing so,the medical data from the patient at home can be consulted by a phy-sician or stored in a medical database.This segmentation is similar to the one deﬁned in[40]where a multi-tiered telemedicine system is presented.Tier1encompasses the intra-body communication,tier2the extra-body commu-nication between the personal device and the Internet and tier3represents the extra-body communication from the Internet to the medical server.The combination of intra-body and extra-body communication can be seen as an enabler for ubiquitous health care service provisioning.An example can be found in[41]where Utility Grid Com-puting is combined with a WBAN.Doing so,the data extracted from the WBAN is sent to the grid that provides access to appropriate computational services with highbandwidth and to a large collection of distributed time-varying resources.To date,development has been mainly focused on building the system architecture and service platform for extra-body communication.Much of these implementa-tions focus on the repackaging of traditional sensors(e.g. ECG,heart rate)with existing wireless devices.They consider a very limited WBAN consisting of only a few sensors that are directly and wirelessly connected to a personal device.Further they use transceivers with a large form factor and large antennas that are not adapted for use on a body.In Fig.3,a WBAN is compared with other types of wireless networks,such as Wireless Personal(WPAN), Wireless Local(WLAN),Wireless Metropolitan(WMAN) and Wide Area Networks(WAN)[42].A WBAN is operated close to the human body and its communication range will be restricted to a few meters,with typical values around1–2m.While a WBAN is devoted to intercon-nection of one person’s wearable devices,a WPAN is a network in the environment around the person.The com-munication range can reach up to10m for high data rate applications and up to several dozens of meters for low data rate applications.A WLAN has a typical communi-cation range up to hundreds of meters.Each type of net-work has its typical enabling technology,deﬁned by the IEEE.A WPAN uses IEEE802.15.1(Bluetooth)or IEEE 802.15.4(ZigBee),a WLAN uses IEEE802.11(WiFi)and a WMAN IEEE802.16(WiMax).The communication in a WAN can be established via satellite links.In several papers,Wireless Body Area Networks are considered as a special type of a Wireless Sensor Network or a Wireless Sensor and Actuator Network(WSAN)with its own requirements1.However,traditional sensor networks do not tackle the speciﬁc challenges associated with human body monitoring.The human body consists of a complicated internal environment that responds to and interacts with its external surroundings,but is in a way separate and self-contained.The human body environment not only has a smaller scale,but also requires a different type and fre-quency of monitoring,with different challenges than those faced by WSNs.The monitoring of medical data results in an increased demand for reliability.The ease of use of sensors placed on the body leads to a small form factor that includes the battery and antenna part,resulting in a higher need for energy efﬁciency.Sensor nodes can move with regard to each other,for example a sensor node placed on the wrist moves in relation to a sensor node attached to the hip.This requires mobility support.In brief,although challenges faced by WBANs are in many ways similar to WSNs,there are intrinsic differences between the two,requiring special attention.An overview of some of these differences is given in Table2.A schematic overview of the challenges in a WBAN and a comparison with WSNs and WLANs is given in Fig.4.5Physical layerThe characteristics of the physical layer are different for a WBAN compared to a regular sensor network or an ad-hoc network due to the proximity of the human body.Tests with TelosB motes(using the CC2420transceiver)showed lack of communications between nodes located on the chest and nodes located on the back of the patient[46]. This was accentuated when the transmit power was set to a minimum for energy savings reasons.Similar conclusions where drawn with a CC2420transceiver in[47]:when a person was sitting on a sofa,no communication was pos-sible between the chest and the ankle.Better results were obtained when the antenna was placed1cm abovethe Fig.3Positioning of a Wireless Body Area Network in the realm of wireless networks1In the following,we will not make a distinction between a WSAN and a WSN although they have signiﬁcant differences[43].body.As the devices get smaller and more ubiquitous,a direct connection to the personal device will no longer be possible and more complex network topologies will be needed.In this section,we will discuss the characteristics of the propagation of radio waves in a WBAN and other types of communication.5.1RF communicationSeveral researchers have been investigating the path loss along and inside the human body either using narrowband radio signals or Ultra Wide Band(UWB).All of them came to the conclusion that the radio signals experience great losses.Generally in wireless networks,it is known that the transmitted power drops off with d g where d represents the distance between the sender and the receiver and g the coefﬁcient of the path loss(aka propagation coefﬁcient)[48].In free space,g has a value of2.Other kinds of losses include fading of signals due to multi-path propagation.The propagation can be classiﬁed according to where it takes place:inside the body or along the body.5.1.1In the bodyThe propagation of electromagnetic(EM)waves in the human body has been investigated in[49,50].The body acts as a communication channel where losses are mainly due to absorption of power in the tissue,which is dissipated as heat.As the tissue is lossy and mostly consists of water, the EM-waves are attenuated considerably before they reach the receiver.In order to determine the amount of power lost due to heat dissipation,a standard measure of how much power is absorbed in tissue is used:the speciﬁc absorption rate(SAR).It is concluded that the path loss is very high and that,compared to the free space propaga-tion,an additional30–35dB at small distances is noticed.A simpliﬁed temperature increase prediction scheme based on SAR is presented in[50].It is argued that considering energy consumption is not enough and that the tissue is sensitive to temperature increase.The inﬂuence of a patient’s body shape and position on the radiation pattern from an implanted radio transmitter has been studied in [51].It is concluded that the difference between bodyTable2Schematic overview of differences between Wireless Sensor Networks and Wireless Body Area Networks,based on[45] Challenges Wireless sensor network Wireless body area networkScale Monitored environment(m/km)Human body(cm/m)Node number Many redundant nodes for wide area coverage Fewer,limited in spaceResult accuracy Through node redundancy Through node accuracy and robustnessNode tasks Node performs a dedicated task Node performs multiple tasksNode size Small is preferred,but not important Small is essentialNetwork topology Very likely to beﬁxed or static More variable due to body movementData rates Most often homogeneous Most often heterogeneousNode replacement Performed easily,nodes even disposable Replacement of implanted nodes difﬁcultNode lifetime Several years/months Several years/months,smaller battery capacityPower supply Accessible and likely to be replaced moreeasily and frequentlyInaccessible and difﬁcult to replaced in an implantable setting Power demand Likely to be large,energy supply easier Likely to be lower,energy supply more difﬁcultEnergy scavenging source Most likely solar and wind power Most likely motion(vibration)and thermal(body heat) Biocompatibility Not a consideration in most applications A must for implants and some external sensorsSecurity level Lower Higher,to protect patient informationImpact of data loss Likely to be compensated by redundant nodes More signiﬁcant,may require additional measures to ensure QoSand real-time data deliveryWireless technology Bluetooth,ZigBee,GPRS,WLAN,…Low power technologyrequired。

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