加罗法洛文稿
On the determination of CP violating Majorana phases
(5)
or of the products of Jγk . For three generations, there are nine of such invariants Jγk but the unitarity of U makes all of them have the same imaginary component including the sign Im [Jγk ] = J = c1 c2 c2 3 s1 s2 s3 sin δ. (6)
The phase δ can be determined once one knows J and the mixing angles. Recently there have been many studies [5] where extracting J from the long-baseline three-flavour neutrino oscillations experiments is discussed. Existing 2 neutrino anomalies imply [6] three different scales of neutrino mass squared differences δm2 ≡ (m2 j − mk ):
On the determination of CP violating Majorana phases
M K Samal∗
Institute of Physics, Sachivalaya Marg, Bhubaneswar 751 005, India. The determination of CP violating phases in the Majorana neutrino mixing matrix using phenomenological constraints from neutrino oscillations, neutrinoless double beta decay, (µ− , e+ ) conversion and few other processes is discussed. We give the expressions for the phases in terms of the mixing angles and masses consistent with the recent data from Kamiokande.
ch06
OPTOELECTRONICS
OPTOELECTRONICS
12
Prof. Wei-I Lee
Photovoltaic Device Principles
Solar Cell Structure Design
photogenerated EHP near device surface disappear by recombination due to surface defects Eg of Si ~ 1.1 eV threshold
OPTOELECTRONICS
9
Prof. Wei-I Lee
Photovoltaic Device Principles
Schematic of a Typical Single Junction Si Solar Cell
consider a Si pn junction with a very thin and more heavily doped n region with finger electrodes and thin antireflection (AR) coating on the surface
OPTOELECTRONICS
4
Prof. Wei-I Lee
Solar Energy
Solar Energy
at earth’s surface, average solar energy ~ 4 x 1024 J/year or ~ 5 x 1020 J/hr global energy consumption in 2001 ~ 4 x 1020 J/year
total current :
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Slovenské vzory dělení slov as pro změnu
Slovenskévzory dˇe leníslov:ˇc as pro zmˇe nu?Petr SojkaMasarykova univerzita v Brnˇe,Fakulta informatikyBotanická68a,60200BrnoEmail:sojka@fi.muni.czAbstrakt:Dˇe leníslov neboli algoritmickásegmentace velkémnožinyˇr e-tˇe zc˚u nˇe jakého jazyka je problémˇc astˇe jšínežby se na prvnípohled zdálo.Pro volnˇešiˇr itelnéslovenskédˇe leníslov zatím existuje pouzeˇr ešenívy-cházejícíz definice slabiky ve slovenštinˇe,bez rozsáhlého pokrytívýjimek.Z více nežmiliónu shromáždˇe ných a rozdˇe lených slov se podaˇr ilo vyge-nerovat programem P AT G EN novévolnˇešiˇr itelnévzory,kterése s nepra-videlnostmi jazyka vyrovnávajílépe neždosud dostupnéˇr ešení.Výsledekje použitelnýnejen v distribucích T E Xu,ale i v dalších systémech jako na-pˇríklad O PEN O .Použitéa diskutovanétechniky bootstrappingu,stratifikace a generovánívzor˚u jsou použitelnépˇr iˇr ešeníširokého spektradalších…segmentaˇc ních“aplikací.Klíˇc ováslova:dˇe leníslov,segmentace,P AT G EN,pˇr ebíjejícívzory,bootstrapping, stratifikace1MotivaceDˇe leníslov je v jádru všech aplikacípro zpracovánítext˚u.Na kvalitˇe použitého algoritmu dˇe leníslov závisímnožstvíruˇc nípráce pˇr iˇrádkovém zlomu sazby. Stáleˇc astˇe jšíjsou aplikace,kdy kontrola zlomu se neprovádív˚u bec:databázovépublikování,dávkovézpracováníXML dat m˚uže sloužit jako pˇríklad.O to vˇe tšíje poptávka po kvalitním dˇe leníslov.Obvyklépožadavky na algoritmus dˇe leníslov jsou tyto:rychlost:pˇr i optimalizaci zlomu celého odstavce naráz je potˇr eba najít dˇe lenívšech slov v odstavci.pˇr esnost:algoritmus neoznaˇcíchybnˇešvy slov pro rozdˇe lení.úplnost:algoritmus najde všechna možnádˇe leníslov.rozšiˇr itelnost:algoritmus umožníuživatelem specifikovanévýjimky–napˇrí-klad slova cizího jazyka dle pravidel dˇe lenítohoto jazyka.adaptivita:jelikožseživéjazyky vyvíjejí(nedávnáreforma pravopisu v Nˇe-mecku),je potˇr ebnénemít algoritmus…zadrátovaný“a draze optimalizo-vanýtak,že pˇr i zmˇe nˇe jazyka se musízaˇcínatúplnˇe znova.68Petr Sojkaparametrizovatelnost:algoritmus umožníjinéchovánídle charakteru použití(vúzkých sloupcích napˇríklad umožníjen dva znaky na novémˇrádku místo obvykležádaných tˇrí).minimálnípamˇe t’ovénároky:aplikace typu zalomenízpráv na displeji mobil-ního telefonu je tˇr eba navrhovat s minimálními pamˇe t’ovými,a tedy energe-tickými nároky.Základním problémem tedy je vytvoˇr it algoritmus pro zvolenýjazyk,kterýv maximálnímíˇr e splˇn uje výše uvedenépožadavky.Tentoˇc lánek popisuje pˇrístup ˇr ešenítohoto problému pro slovenštinu a krátce diskutuje výsledek ve formˇe nových vzor˚u dˇe leníslov pro slovenštinu.2Stávajícístav slovenského dˇe leníslovUživatelésázecího systému T E X používajípˇr i sazbˇe výsledky dizertaˇc nípráce[16]Knuthova studenta Franka Lianga.Liang navrhl na jazyku nezávislýpopis dˇe leníslov,kterýsplˇn uje vˇe tšinu výše uvedených požadavk˚u.Dále im-plementoval program P AT G EN[17],kterýumožˇn uje tento popis generovat ze slovníku jižrozdˇe lených slov.Brzy po rozšíˇr eníT E Xu doˇCeskoslovenska zaˇc ala být otázka dˇe leníaktuálnía vznikly prvníverze slovenských aˇc eských vzor˚u dˇe lení[14,15].Obˇe byly psány ruˇc nˇe,bez použitíprogramu P AT G EN.Ruˇc nˇe psanápravidla zachycujízákladnícharakteristiky dˇe lení,tedy napˇríklad slabiˇc nýprincip,definujíco je to slabika. U etymologického pˇrístupu k dˇe leníslov,kterýje respektován v britskéangliˇc tinˇe a standardizován nakladatelstvím Oxford Universitzy Press,však je témˇeˇr každéslovo výjimkou a proto jeˇc astˇe jšígenerovánívzor˚u ze slovníku.Vˇe tšina jazyk˚u však oba pˇrístupy kombinuje,ctíse zejména zlom našvech složených slov oproti slabiˇc nému principu.Hranice mezi cítˇe ním složeného slova dle jeho etymologie však m˚uže být diskutabilní:máme dˇe lit slabiˇc nˇe ro-zumˇc i…etymologicky“a konzervativnˇe roz-um?Pro detailnívysvˇe tleníprincipu pˇr ebíjejících vzor˚u odkazujeme na[13,pˇrí-loha H]a naˇc lánky[2,22,3].Zjednodušenˇeˇr eˇc eno,vzory specifikujíkontextovápravidla,kterámezi sebou soutˇežío každou mezipísmennou pozici ve slovˇe, a urˇc ují,zda na nídˇe litˇc i ne.Pravidla specifikujína základˇe r˚u znˇeširokého kontextu výjimky,výjimky z výjimek,....Vzájemnˇe se pˇr ebíjejí–m˚uže existovat nˇe kolikúrovnípriorit vynuceníˇc i potlaˇc enídˇe leníslova.Vítˇe zí…nejsilnˇe jší“pra-vidlo(s nejvyššíprioritou)pro každou pozici ve slovˇe:k pozici se m˚uže vyjádˇr it pravidlo v každéúrovni.Stávajícíverze slovenských vzor˚u dˇe leníexistuje ve verzi2.0z24.4.1992 (soubor skhyph.tex):\patterns{%samohl\’asky a1\’a1\"a1e1...%dvojice spoluhl\’asokSlovenskévzory dˇe leníslov:ˇc as pro zmˇe nu?692b1b2b1c2b1\v c2b1d2b1\v d...%6spoluhl\’asok3c4v4r4n3g4n3\v s4k4v4r4k3n3\v s4k4v4\’r4k3n%koncovka-n\’yk4\v c3n\’y.k4\v c3n\’eho.k4\v c3n\’emu.k4\v c3nom.%slovn\’e z\’aklady 5alkoholauto4rkauto4rs5b4lah5b4ledn 5b4lesk...%koncovky4b4s4\v t.8c4h.8d4z.8d4\v z.4c4ht4.4j4s4\v t.4lt.4m4p4r....%cudzie slov\’a akci3a2akv\’ari3u2m gymn\’azi3umle2u3k\’emiat2ri3u2mfkli3e2nt}Z komentáˇr˚u ve vzorech je vidˇe t,jakým zp˚u sobem vzory vznikaly.Po rozge-nerovánívzor˚u popisujících slabiku jako sekvenci pˇríslušného poˇc tu souhlásek a samohlásek se vzory autorka snažila zachytit slabiˇc névýjimky na zaˇcátku a konci slov a pˇr i dˇe lenícizích slov.Lze si ale tˇežko pˇr edstavit,že by se tímto zp˚u sobem podaˇr ilo zachytit nˇe kolik milión˚u slovních tvar˚u,kteréve slovenštinˇe existují. Našvech pˇr edpon a složených slov jsou mnohévýjimky,kteréjdou proti základ-nímu slabiˇc nému principu.Tˇe ch jsou ale tisíce,ˇc i desetitisíce,a jen s enormním úsilím by se daly vypsat všechny.Proˇc eštinu byly sepsány Hallerem[10],pro slovenštinu však patrnˇe takovýsoupis neexistuje.Na archívu CTAN lze nalézt vzory vytváˇr enéjak ruˇc nˇe výše popsaným zp˚u sobem,tak automaticky z jižrozdˇe leného slovníku slov daného jazyka.Tento postup máz hlediska požadavk˚u vytˇc ených vúvoduˇc lánku mnohévýhody oproti ruˇc nˇe vytvoˇr enéverzi.Pˇrístupy se takédajíkombinovat:k ruˇc nˇe zadanémnožinˇe základních vzor˚u se dogenerujívzory pro výjimky.Nebo naopak ex post nalezenévýjimky se dajík jižvygenerovaným vzor˚u m pˇr idat jako slova–vzory s nejvyššíprioritou(úrovní),tedy rozum jako.r8o8z9u8m..3Generovánívzor˚u ze slovníku rozdˇe lených slov Problematice generovánívzor˚u na semináˇr i S L T jižbyl vˇe novánˇc lánek[1],proto zopakujeme jen hlavníprincipy a laskavéhoˇc tenáˇr e odkážeme dále na dalšíˇc lánky vˇe novanététo a pˇríbuznéproblematice[11,25,20,21].Generováníprobíháve fázích,kterése nazývajíúrovnˇe(anglicky levels). V lichýchúrovních se generujípokrývacívzory,tedy vzory,kterédle kontextu znak˚u vynucujídˇe lení,v sudýchúrovních se dˇe lenídle kontextu zakazuje.70Petr SojkaGenerovanévzory se kumulují,a výslednéchováníurˇc uje výslednámnožina vzor˚u vygenerovanáve všechúrovních.U vˇe tšiny generovaných vzor˚u pro dˇe leníslov v užívaných jazycích staˇcíˇc tyˇr iúrovnˇe,ale pro pˇr ehlednost,ale takénedostatekˇc asu vzory optimalizovat,je v ruˇc nˇe chystaných vzorechúrovnímnohem více–souˇc asnéslovenskévzory jich majínapˇríklad osm.Technologie pˇr ebíjejících vzor˚u je natolik obecná,že jejípoužitíje možnépro vˇe tšinu segmentaˇc ních problém˚u.Jako pˇríklad m˚uže sloužit problematika segmentaceˇr etˇe zce thajských znak˚u na slova–v thajském textu nejsou slova oddˇe lena mezerami[23].4Bootstrapping a stratifikaceV rámci bakaláˇr sképráce[18]se podaˇr ilo shromáždit z r˚u zných zdroj˚u1 témˇeˇr milión slovenských slov.Dnešnívýpoˇc etníkapacity umožˇn ujígenerovat vzory dˇe leníi z takto rozsáhlých slovník˚u v dobách desítek minut.ˇCasovˇe nejnároˇc nˇe jšíoperaci–rozdˇe leníslovníku slov pravidly daného jazyka–lze dˇe lat pomocípˇr edchozíverze vzor˚u a místa dˇe leníslov…pouze“zkontrolovat.Jelikožvšak i tato kontrola jeˇc asovˇe nároˇc ná,lze parametry generovánívhodnou heuristikou volit tak,že vygenerovaných vzor˚u nepokrytých slov je právˇe tolik, kolik je reálnéjich v rozumnédobˇe ruˇc nˇe zkontrolovat.To znaˇc nˇe urychluje vývoj nových vzor˚u technikou bootstrappingu.Tabulka1.Výsledky jednéiterace bootstrappingu slovenského dˇe leníze slov-níku822878slovúroveˇn dobˇr ešpatnˇe chybí#vzor˚u velikost1Bohužel výslednou množinu slov nelze volnˇešíˇr it.Volnˇe pˇrístupnýseznam slov by umožnil ještˇe mnohemflexibilnˇe jšívytváˇr enívariant dˇe licích vzor˚u optimalizovaných pro konkrétníprojekty.Slovenskévzory dˇe leníslov:ˇc as pro zmˇe nu?71 ještˇe v tomto stoletíjedno celéˇcísloˇc asopisu TUG BOAT.Patrnˇe z d˚u vodu zpˇe tnékompatibility nejsou tyto vzory nahrazeny kvalitnˇe jšími,byt’kompatibilita je pˇr i pˇr idánívýjimek do vzor˚u ve formátu stejnˇe porušena.Dnešnívýpoˇc etnítech-nika jižumožˇn ujeˇc etnéexperimenty a generováníopakovat s r˚u znými parame-try.Vhodnými heuristikami nastaveníprah˚u akceptace adept˚u vzor˚u v jednotli-výchúrovních generováníse lze dostat na mnohem kvalitativnˇe vyššíparametry vzor˚u,nežkterédocílil pˇr ed témˇeˇrˇc tvrtstoletím Liang.Typicky je možnéza cenu mírného zvýšenívelikosti vzor˚u docílit stoprocentního pokrytíuˇcícímnožiny, nebo naopak pˇr i zadánívelikostních omezenína velikost vzor˚u lze maximalizo-vat pokrytí.A to vše s nulovou chybovostía stejnými konstantními výpoˇc etními nároky pˇr i aplikaci vzor˚u.Jinakˇr eˇc eno,poˇc et instrukcína nalezenídˇe licíchšv˚u slova je ohraniˇc en shora konstantou,nezávisle na tom,z jak velkého slovníku vzory generujeme.Dalšítechnikou,kteráse dápˇr i generovánívzor˚u použít,je stratifikace.Tato technika spoˇcíváv tom,že se snažíme minimalizovat množinu slov k uˇc ení, anižbychom ale pˇr išli o funkˇc nost vzor˚u na výjimkách.Máme-li napˇríklad slovník generovanýmorfologickým analyzátorem,tedy známe od každého slovního tvaru slovnízáklad,staˇcído slovníku slov zahrnout náhodnˇe pouze pár slovních tvar˚u od jednoho lemmatu.Dˇe leníkoncovek se zgeneralizuje,nebot’koncovkovémnožiny se neustále opakujía uˇcícíalgoritmus bude mít dostatek uˇcících pˇríklad˚u,aby se pravidelnosti dˇe leníkonc˚u slov nauˇc il.Naopak se nesmív seznamu uˇcících slov zapomenout na negace a pˇr edpony.Dˇe leníza prvníslabikou slov zaˇcínajících na na-naj-,pre-pred-apod.je nutno nahlížet jako na výjimky.5Shrnutí:ˇc as pro zmˇe nu?Bylo vytvoˇr eno nˇe kolik variant nových vzor˚u dˇe lenípro slovenštinu.Vzory jsou pro testováník dispozici ve FTP archívu CSTUGu v adresáˇr i cstug/sojka/skhyp. Po nezbytnéfázi testovánípˇr edpokládáme jejich zaˇr azenído bˇežných T E Xových distribucía projektu O PEN O a budoušíˇr eny bez omezujících licenˇc-ních podmínek.Jelikožzmˇe na vzor˚u dˇe lenípravdˇe podobnˇe zp˚u sobízmˇe nu zalomeníjižvytvoˇr ených dokument˚u,je tˇr eba být v pˇrípadˇe rozšíˇr eného požadavku na zpˇe tnou kompatibilitu obezˇr etný.Jelikožna zálohováníúplných zdroj˚u vˇc etnˇe zdroj˚u potˇr ebných na generováníformátu se obvykle zapomíná,pˇr i požadavku zpˇe tnékompatibility je tˇr eba zvážit všechna pro i proti a novévzory si tˇr eba zavést jako novýjazyk(\language)spolu se starými.Jsme pˇr esvˇe dˇc ení,žeˇc as pro zmˇe nu po více neždekádˇe používánísouˇc asných vzor˚u nastal a kvalita nových vzor˚u je dostateˇc ným argumentem pro zavedenízmˇe ny.Po téjižostatnˇe nˇe kolik let volajítakéuživateléO PEN O a dalších sázecích systém˚u, kteˇrídosud používajístarévzory dˇe lení.72Petr SojkaReference1.David Antoša Petr Sojka.Generovánívzor˚u dˇe leníslov v UNICODE.V Kasprzak aSojka[12],strany23–32.2.David Antoša Petr Sojka.Pattern Generation Revisited.V Pepping[19],strany7–17.3.David Antoša Petr Sojka.Generovánívzor˚u pomocíknihovny P AT L IB a programuOP AT G EN.Zpravodaj C S TUG,12(1):3–12,2002.4.Barbara Beeton.Hyphenation exception log.TUGboat,5(1):15,kvˇe ten1984.5.Barbara Beeton.Hyphenation exception log.TUGboat,6(3):121,listopad1985.6.Barbara Beeton.Hyphenation exception log.TUGboat,7(3):146–147,ˇríjen1986.7.Barbara Beeton.Hyphenation exception log.TUGboat,10(3):336–341,listopad1989.8.Barbara Beeton.Hyphenation exception log.TUGboat,13(4):452–457,prosinec1992.9.Pat Hall a Durgesh D Rao,editoˇr i.Proceedings of EACL2003Workshop onComputational Linguistics for South Asian Languages–Expanding Synergies with Europe,duben2003.10.JiˇríHaller.Jak se dˇe líslova.StátnípedagogickénakladatelstvíPraha,1956.11.Yannis Haralambous.A Small Tutorial on the Multilingual Features of PATGEN2.dostupnéna CTAN jako info/patgen2.tutorial,leden1994.12.Jan Kasprzak a Petr Sojka,editoˇr i.SLT2001,Brno,Czech Republic,únor2001.Konvoj.13.Donald E.Knuth.The T E Xbook,volume A of Computers and Typesetting.Addison-Wes-ley,Reading,MA,USA,1986.14.Jana Chlebíková.Ako rozdˇe lit’(slovo)ˇCeskoslovensko.Zpravodaj C S TUG,1(4):10–13,1991.dislav Lhotka.ˇCeskédˇe lenípro T E X.Zpravodaj C S TUG,1(4):10–13,1991.16.Franklin M.Liang.Word Hy-phen-a-tion by Com-put-er.PhD thesis,Department ofComputer Science,Stanford University,USA,srpen1983.17.Franklin M.Liang a Peter Breitenlohner.PAT tern GEN eration program for the T E X82hyphenator.dokumentace programu PATGEN verze2.3z distribuce web2c na CTAN, 1999.18.Ján Lieskovský.Systém pro práci se seznamy slov.Bakaláˇr skápráce,Masarykovauniverzita v Brnˇe,Fakulta informatiky,2003.19.Simon Pepping,editor.EuroT E X2001,Kerkrade,The Netherlands,záˇrí2001.NTG.20.Petr Sojka.Notes on Compound Word Hyphenation in T E X.TUGboat,16(3):290–297,1995.21.Petr Sojka.Hyphenation on Demand.TUGboat,20(3):241–247,1999.22.Petr peting Patterns for Language Engineering.V Sojka et al.[24],strany157–162.23.Petr Sojka a David Antoš.Context Sensitive Pattern Based Segmentation:A ThaiChallenge.V Hall a Rao[9].24.Petr Sojka,Ivan Kopeˇc ek,a Karel Pala,editoˇr i.Proceedings of the Third InternationalWorkshop on Text,Speech and Dialogue—TSD2000,Lecture Notes in Artificial Intelligence LNCS/LNAI1902,Brno,záˇrí2000.Springer-Verlag.25.Petr Sojka a PavelŠeveˇc ek.Hyphenation in T E X–Quo Vadis?TUGboat,16(3):280–289,1995.。
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课件2
9
Algoritmo
Data un’approssimazione iniziale x0 , si ha: xk+1 = xk f (xk ) f (xk )
Si va avanti nel calcolo delle approssimazioni xk+1 no a che lo scarto |xk+1 xk | diventa minore di una certa tolleranza toll (si segue lo stesso ragionamento fatto per il metodo del punto sso).
4
Implementazione in FORTRAN
Alla stessa maniera con cui usiamo xk e xkp1, avremo scartok e scartokp1, gli scarti alla iterata precedente e alla nuova iterata, rispettivamente. Introduciamo altre due nuove variabili che rappresentano un’approssimazione di M , che chiamiamo asint1 e asint2. asint1 = scartokp1/scartok = rapporto tra due scarti successivi asint2 = abs(dfun(xkp1)) = valore assoluto della derivata prima della funzione fun in xkp1 - nel programma bisogna aggiungere una function che calcola il valore della derivata prima di fun, che chiamiamo dfun . Il ciclo do while diventa:
法国06药理会
10th Annual meeting of French Society of Pharmacology,73rd Annual meeting of Society of Physiology,27th pharmacovigilance meeting,54th APNET Seminar and 4th CHU CIC meeting (Corum Montpellier 10–12April 2006)1Training does not reverse the impairment of pulmonary artery relaxation in hypoxia-induced pulmonary hypertensive rats:involvement of L-arginine bioavailabilityL Goret a ,S Tanguy a ,I Guiraud b ,M Dauzat c ,P Obert a a Faculte´des Sciences,Je2426Laboratoire de Physiologie Cardiovasculaire A´l’Exercice,Avignon;b Faculte ´de Me ´decine,Laboratoire d’Histologie,embryologie,cytoge ´ne ´-tique,Nıˆmes;c Faculte ´de Me ´decine,Ea2992,dynamique des Incohe ´rences Cardiovasculaires A ´l’Exercice,Nıˆmes Introduction:Hypoxia-induced pulmonary hypertension is associated with deleterious effects on the nitric oxide mediated endothelium-dependent pulmonary artery relaxation.We previously demonstrated that pulmonary artery relaxation was not improved by exercise training in pulmonary hypertensive rats.This study was designed to test whether an hypoxia-related alteration in L-arginine bioavailability is involved in the impairment in nitric oxide-induced vasorelaxation.Methods:40male Wistar rats were randomly assigned to 4groups:normotensive sedentary,normotensive trained,pulmonary hypertensive sedentary,pulmonary hypertensive trained.Pulmonary hypertension was obtained by chronic exposure to hypobaric hypoxia (PIO 2»90mmHg,alti-tude »4000m).Endothelium-dependent vasorelaxation to acetylcholine (10)8–10)4M)with or without L-arginine (10)3M)and/or nitro-L-arginine methylester (5.10)6M)was assessed on isolated pulmonary artery rings.Results:There was a significant impairment of maximal relaxation to acetylcholine in both sedentary and trained pulmonary hypertensive rats.However,although it has no effect in pulmonary hypertensive sedentary rats,the acute L-arginine supplementation led to a significant improvement of acetylcholine-induced vasorelaxation in pulmonary hypertensive trained rats to the level obtained in normotensive sedentary rats.Conclusion:Our results clearly suggest that the potential beneficial effect of exercise on nitric oxide-mediated pulmonary artery vasorelaxation is partly blunted by deleterious effects of hypoxia on L-arginine bioavailability.Therefore we can postulate that combinated L-arginine supplementation and exercise training may have beneficial effects on hypoxia-induced pulmonary hypertension.2Electrophysiological effects of the association of Droperidol and OndansetronJ Weissenburger a ,B Charbit b ,E Fligeil a ,P Jaillon a ,C Funck-Brentano b a Laboratoire de Pharmacologie,Hoˆpital Saint-Antoine –Universite´Pierre et Marie Curie,Paris;b Centre d’Investigation Clinique,Ho ˆpital Saint-Antoine –Universite´Pierre et Marie Curie,Paris Introduction:Droperidol (DRO)and ondansetron (OND)have both been reported to prolong QT interval through HERG blockade.These two antiemetics are frequently combined in patients at high risk of postoperative vomiting.This study assessed cardiac electrophysiological effects of this association.Methods:Purkinje fibres were excised from Rabbit hearts and exposed to increasing doses (0.01,0.1,1&10l M)of DRO (n =7)or OND (n =8)at 30min intervals at 36.5°C.Other fibres were exposed to a constant DRO concentration (0.1l M)together with the same increasing doses of OND (n =6).Action potential driven at 1Hz were recorded using conventional intracellular glass microelectrode.Data are presented as mean ±parison between experiments used a Kruskal-Wallis test.Results:DRO increased action potential duration measured at 90%repolarization (APD90)from the first DRO dose (0.01l M:27±5ms,P <0.02)while the third dose was necessary for OND (1l M:60±10ms,P <0.01).The maximal effect was a lengthening of 426±175ms at 1l M of DRO and of 205±36ms at 10l M of OND.When OND was added to DRO,the maximal increase was similar:216±53ms at 10l M.Early after depolarization occurred in 6DRO experiments and 1OND experiment.Conclusion:Both OND and DRO prolong action potential duration in Purkinje fibres,DRO being more potent than OND on a molar bination of OND and DRO exhibits an additive effect on action potential duration.This might favor arrhythmia during combination therapy in clinical practice.3Improvement of carotid diameter and functional properties with perindopril 8mg but not with perindopril 4mg in diabetic hypertensive patients :a pressure-independent effectP Boutouyrie a ,AI Tropeano a ,B Pannier b ,R Joannides c ,E Balkestein d ,H Struijker-Boudier d ,C Thuilliez c ,SLaurent a a Service de Pharmacologie,Hoˆpital Europe ´en Georges Pompidou,Paris;b Service de Cardiologie,Manhe `s,Fleury Me´rogis;c Service de Pharmacologie,Chu –Hopitaux de Rouen,Rouen;d Service de Pharmacologie,University Of Medecine,Maastricht,NETHERLANDSBackground and objective:Hypertension and diabetes are associated with an increased of carotid internal diameter and arterial stiffness.ACE inhibitors (ACEI)reduce arterial stiffness and improve arterial distensibility.These reductions under treatment could be related to the decrease in blood pressure.However,taking into account the predominant role of the renin-angiotensin system in arterial remodeling,we hypothesized that carotid diameter and carotid distensibility would be improved by a pressure-independent pharmacological effect of ACEI,mainly in diabetic hypertensive patients who have predominant arterial stiffening and carotid dilatation.Methods:After a placebo run-in period,57essential hypertensive patients with type 2diabetes (age 63±7)were randomized to 6months of double-blind treatment with either Perindopril 4mg or Perindopril 8mg.Patients were allocated to an ACEI as first step and a diuretic (DIU)as second step.All patients had a preserved renal function (creatinin clearance 60mL/min).Common carotid diameter,carotid cross-sectional distensibility and elastic modulus were determined with a high resolution echotracking system (Walltrack)and aplanation tonometry at baseline and after treatment.For comparison of serial changes in BP and arterial parameters,repeated-measures ANOVA (period,group)was performed to detect treatment differences.The effects of relevant variables on the study endpoints were analyzed by use of a multivariate analysis.Results:The reduction in BP was significantly more important with Perindopril 8mg (from 154±18/88±9to 139±18/80±10mmHg)than Perindopril 4mg (from 156±15/87±9to 148±15/82±9mmHg,P >0.05).However,ambulatory blood pressure showed no difference in the hypotensive effects of the two doses in 28patients.ACEI decreased carotid diameter with Perindopril 8mg ()3.6%)but not with Perindopril 4mg (3.6%,P <0.01).Moreover,carotid distensibility and elastic modulus were improved with Perindopril 8mg but not with Perindopril 4mg,with a significant treatment-period interaction (P <0.05).These differences remained significant after adjustment to BP changes.Conclusion:Despite adjustment to BP changes,and similar ambulatory BP reduction in the two groups,Perindopril 8mg but not Perindopril 4mg improved carotid distensibility and diameter in diabetic hypertensive patients after 6month.These results suggest that Perindopril improves carotid diameter and distensibility independently of the blood pressure changes.4Effect of chronic hypoxia on the expression and functional role of gap junctions in rat intrapulmonary arteriesC Guibert a ,M Lafargue a ,A Moothoocarpen a ,R Marthan a ,JP Savineau a a Laboratoire de Physiologie Cellulaire Respiratoire,Inserm E356,BordeauxIntroduction:Since the activity and the number of gap junctions are linked to cellular proliferation and variation of vascular reactivity,such intercellular communications may participate to the hyperreactivity and the increase in the proliferation to serotonin (5)HT)observed following hypoxia-induced pulmonary hypertension.In the present study,we focused on the expression of connexins,and their role in the reactivity to 5)HT in small intrapulmonary arteries from normoxic and chronic hypoxic rats.Methods:Vessels from normoxic (N)rats were compared to vessels from rats exposed to 3weeks of hypobaric chronic hypoxia (CH).To determine the expression of connexins 37,40and 43,immuno-fluorescent labelling and western blot experiments were performed in confluent smooth muscle cells (SMC)and vessels,respectively.Isometric contraction to 5-HT was measured in an organ bath system and confluent SMC were loaded with indo-1to record intracellular calcium signal to 5-HT.N indicates the number of vessels or slides of confluent SMC.Results:Immunofluorescent labelling demonstrated the presence of connexins 40and 43unlike 37in N confluent SMC.Western blot analyses on whole vessels showed the presence of connexins 37,40and 43in N and CH vessels suggesting the presence of connexins 37in endothelial cells (n =5).Normalisation of the expression of connexins against the expression of b -actin indicated no differences in the amount of connexins 37,40and 43in CH versus N.The amount of b -actin was not changed following hypoxia-induced pulmonary hypertension.Isometric contraction to increasing concentrations of 5-HT (0.01–100l M),in normoxic vessels,was decreased after one hour incubation with 300l M Gap 27,a specific peptide blocker of connexins 37and 43(n =9).Inversely,the same pretreatment with 300l M Gap 27did not affect the calcium response to 10l M 5-HT in N confluent SMC (n =5).Conclusion:All together,connexins 37,40and 43were equally expressed in N and CH vessels.In confluent SMC,the expression of connexin 37was absent suggesting the importance of this connexin in intercellular junctions between endothelial cells.Moreover,the effects of Gap 27suggest (1)the importance of connexins 37and 43in endothelial and/or myoendothelial junctions and (2)the functional role of these endothelium-dependent connexins in the contraction to 5-HT in N rats.From these results,we can speculate that gap junctions may participate to the hyperreactivity to 5-HT in hypoxia-induced pulmonary hypertension.5Hypoxia differentially regulates vesiculation of human endothelial progenitor cells and mature endothelial cellsC Labrande a ,B Guillet a ,JL Codaccioni b ,F Sabatier c ,F Dignat-George c ,P Pisano a a Laboratoire dePharmacodynamie,Faculte de Pharmacie,Marseille;b Service d’Anesthe´sie,Ho ˆpital de la Timone,Marseille;cLaboratoire d’He´matologie,Hopital de la Conception,Marseille Introduction:An increasing number of studies provide evidence that exogenous hematopoietic stem cell application improves functional outcome after ischemic brain lesions.Although hypoxic preconditioning was shown to enhance neovascularization efficacy of human endothelial progenitor cells (EPCs)transplanted into the ischemied hindlimb of rats,the exact effects of hypoxia on EPCs phenotype and vesiculation are not fully characterized.We therefore present here preliminary results showing the effect of different techniques of hypoxia on the vesiculation of human EPCs and mature endothelial cells (HUVECs).Methods:HUVECs and EPCs were incubated for 24hours in growth factor free-medium with 1%of fetal bovin serum,in presence of cobalt chloride (CoCl2,150l M:chemical hypoxia)or in oxygen free-atmosphere with bubbled-medium (5%CO2,10%H2/N2:drastic hypoxia)or in 1.5%oxygen-atmosphere without bubbled-medium (1.5%O2,5%CO2and 94.5%N2:soft hypoxia)or in normoxic conditions (21%O2,5%CO2and 74%N2).Cell viability was estimated by LDH release and MTT reduction.Endothelial microparticles (EMP)release (number of EMP/1000cells)was estimated by annexin-V labelling analyzed by flow cytometry.Results:HUVECs viability (expressed as %of normoxic conditions)was significantly altered by chemical hypoxia (MTT:79±11%and LDH:11±7%)and by drastic hypoxia (MTT:73±14%and LDH:21±18%).In the same way,EPCs viability was significantly altered by chemical hypoxia (MTT:82±7%and LDH:8±5%)and by drastic hypoxia (MTT:64±10%and LDH:23±19%).Surprisingly,soft hypoxia seemed to protect HUVECs (MTT:102±8%and LDH:-20±8%)as well as EPCs (105±11%and LDH:)4±8%).Chemical and drastic hypoxia induced a significant increase of the number of EMP released by HUVECs (respectively 3709±653and 3507±978)and by EPCs (respectively 15295±8408and 14508±6756)compared to normoxic conditions (HUVECs:2504±844and EPCs:5630±2626).In a different way,soft hypoxia significantly decreased the number of EPM released by HUVECs 44±602)whereas it seemed to increase the release of EMP by EPCs (11478±3302%).Conclusion:Our results indicate that the effect of hypoxia on HUVECs and PECs viability and vesiculation depend on the hypoxia modalities.However,further research is needed to explore the functional properties of EMP released.6The anchoring protein SAP97reduces the mobility of Kv1.5channels in CHO cells and cardiac myocytesJ Abi Char a ,C Pouzet b ,A Coulombe a ,S Hatem a a Faculte´de Me ´decine,Inserm-Upmc,Paris;b Faculte ´de Me´decine,Groupe Hospitalier Bichat –Claude Bernard,Paris Introduction:Localization of ion channels in discrete plasma membrane domains is critical for cell function.Excitatory synapses of neurons and gap junctions of the myocardium are the best examples of this phenomenon.However,little information is available on the regulation of ion channel expression in the plasma membrane,owing mainly to the difficulty of studying membrane proteins with conventional immunocytochemical and imaging approaches.Methods:Here,using the fluorescence recovery after photobleaching (FRAP)approach,we examined the mobility of Kv 1.5channels in CHO cells and neonatal rat cardiac myocytes expressing GFP-tagged Kv1.5channels.Immunocytochemistry was used to study the expression of endogenous proteins.Currents were recorded with the patch clamp technique.The expression of endogenous proteins was studied by means of immunocytochemistry.Results:In CHO cells,Kv1.5channels were evenly distributed and highly mobile:the fraction of mobile channels was 88.0±1.8%and the apparent diffusion constant was 0.086±0.011l m 2/s,n =18.When co-expressed with the membrane-associated guanylate kinase protein SAP97,the channels formed plaque-like clusters in the plasma membrane and became poorly mobile (the mobile fraction and apparent diffusion constant became respectively 42.6±3.0%and 0.032±0.003l m 2/s,n =35).This effect was suppressed by colchicine,which disrupts the cytoskeleton.The sustained outward current was markedly increased in cardiac myocytes over expressing GFP-Kv1.5channels attesting of their functionality (30fold the endogenous Kv1.5current).Channels were highly mobile when clustered at the bottom of the cell whereas they were immobile when linearly organized in membrane at the cell periphery.The immunostaining of endogenous SAP97predominanted also at the myocyte periphery.Conclusion:The mobility of Kv1.5channels depends on their clustering and interaction with an anchoring protein,possibly explaining the presence of distinct pools of channels in cardiac myocytes.As in neuron,regulation of cardiac channel mobility could play an important role in their replacement and recruitment of in specializeddomains.+ DRO (0.1 µM )I n c r e a s e i n A P D 90 (m s )Fundamental &Clinical Pharmacology 20(2006)145–234doi:10.1111/j.1472-8206.2006.00409.xÓ2006Blackwell Publishing Fundamental &Clinical Pharmacology 20(2006)145–2341457Hyaluronan induces migration though RHAMM-mediated activation of Rac-andPI3K-dependent pathway in rat vascular smooth muscle cellsY Goue¨ffic a,C Guilluy a,P Gue´rin a,P Pacaud a,G Loirand a a U-533,L’Institut du Thorax,Nantes Introduction:Atherosclerosis and restenosis are characterized by marked changes in the content and distribution of hyaluronan,an important glycoaminoglycan constituent of the extra cellular matrix. Hyaluronan is known to regulate cellular events such as proliferation and locomotion through binding to at least two cell surface receptors:CD44and the receptor for hyaluronan-mediated motility(RHAMM). However,the relative contribution of these receptors and the intracellular signaling pathways involved in hyaluronan-mediated effects in vascular smooth muscle cells remains unknown.Methods:In this study we identified the receptors and the signaling pathways involved in hyaluronan-mediated effects in rat aortic smooth muscle cells in culture.Results:Hyaluronan(0.1to5mg/ml)stimulated the actin cytoskeleton organization,leading to actin stressfiber and lamelipodia formation,and dose-dependently induced vascular smooth muscle cell migration,analyzed by both scratch test and Boyden chamber assay.Hyaluronan had no effect on vascular smooth muscle cell proliferation.Time-course analysis of Rho protein activity by pull-down assay indicated that hyaluronan induced sequential activation of RhoA and Rac.Hyaluronan rapidly(10min)and transiently activated RhoA,and induced delayed(1–6h)but maintained Rac activation.The RhoA inhibitor Tat-C3(10l g/ml),the Rho kinase inhibitor Y-27632(10l M)and blocking anti-CD44antibody have no effect on HA-induced vascular smooth muscle cell migration.In contrast,hyaluronan-induced VSMC migration was reduced by89±4%by the non-selective Rho protein inhibitor simvastatin(10l M), by96±1%by the Rac inhibitor LT-toxin(1l g/ml)and by84±1%by the PI3K inhibitor LY294002 (25l M)(n=5).To further assess the respective role of CD44and RHAMM in hyaluronan effects,we selectively knockdown CD44and RHAMM in vascular smooth muscle cell by small interfering RNA.CD44 knockdown did not alter hyaluronan-induced vascular smooth muscle cell migration but inhibited hyaluronan-mediated RhoA activation.In contrast,small interfering RNA-mediated RHAMM gene silencing inhibited both hyaluronan-induced vascular smooth muscle cell migration and Rac activation. Conclusion:Our results demonstrate that hyaluronan activates two independent signaling pathways in vascular smooth muscle cells and that,although hyaluronan binding to CD44induced transient RhoA activation,hyaluronan-induced migration exclusively depends on Rac-and PI3K-dependent signaling pathway downstream to RHAMM activation.8Infection is associated with an overexpression of pro-apoptotic proteins that is reversed by ADRB3stimulation:an In Vitro approach in human myometriumF Lirussi a,Z Rakotoniaina a,F Goirand a,P Guerard a,M Dumas a,P Sagot b,MJ Leroy b,M Breuiller-Fouche c, M Bardou a a LPPCE Faculte´de Me´decine,Dijon;b De´partement d’Obste´trique,CHU du Bocage,Dijon;c INSERM U427,Hoˆpital Saint Vincent de Paul,Paris,FranceIntroduction:Pre-term delivery remains the main cause of perinatal morbidity and mortality.Infection is one of the leading causes of preterm labour(PTL).Recent data have suggested that apoptotic pathways may play a role in triggering PTL.This study was aimed to assess,In Vitro,the consequences of lipopolysaccharide(LPS)induced inflammation on human myometrium and to evaluate the ability of ADRB3agonists to interfere with this process.Material&Methods:Myometrium biopsies were obtained from pregnant women delivered by caesarean section.Myometrium samples were placed in a24-well plate and leaved to stabilize at37°C for48h and were thereafter incubated with LPS at three different concentrations(50ng/ml,1l g/ml,10l g/ml)or the vehicle for8h,24h,or48h.The level of expression of apoptosis proteins(cleaved caspase-3CC-3,Bax, Bcl-2)was assessed by western blot(WB)and immunostaining(IS)experiments.In a second set of experiments myometrial samples were incubated for48h with LPS(10l g/ml)and SAR59119A(10)7to 10)5M),an ADRB3agonist,We performed similar IS and WB experiments in two myometrial samples obtained from women with confirmed chorioamniotitis.Results:Compared with controls,LPS stimulation was associated with a significant increase in CC-3and Bax and a decrease in the antiapoptotic protein Bcl-2,with a time and dose relationship.The same level of CC-3 expression was observed in IS of samples obtained from infected women.We defined that the optimal conditions of LPS-stimulation to reproduce the clinical situation were10l g/ml for48h Compared with LPS alone, treatment with SR59119A was associated with a decrease of Bax and an increase of Bcl-2expression(cf.table).Bax(n=3)Bcl-2(n=3) Control14999±1055335189±5162 LPS53505±225489201±1356 LPS+SR59119A0.1l M23831±740412199±1199 LPS+SR59119A1l M31134±905424198±2243 LPS+SR59119A10l M60287±12954Level of Bax and Bcl-2expression assessed by western blot experiments.Results are expressed as(mean±s.e.m)in Arbitrary Density Unit.Conclusion:This study suggests that inflammation,in a validated In Vitro model of human myometrial infection,is associated with an over expression of pro-apoptotic protein that is reversed by ADRB3 stimulation.This result,with our previous works,strengthens the potential clinical interest of ADRB3 agonists in the management of preterm labour.9Time course of ventilatory acclimatization to hypoxia in a model of transgenic anemic miceF Favret a,JL Macarlupu´b,A Buvry a,OE Morel a,F Leo´n-Velarde b,JP Richalet a a Ea2363‘‘Re´ponses Cellulaires et Fonctionnelles A´l’Hypoxie’’,Universite´Paris13,Bobigny;b Departamento de Ciencias Biolo´gicas Y Fisiolo´gicas,laboratorio de Transporte de Oxı´geno/Iia,Universidad Cayetano Heredia,Lima,PERU Introduction:Exposure to hypoxia induces polycythemia secondary to an increase in erythropoietin release,allowing to increase oxygen carrying capacity to maintain O2delivery.To survive at high altitude, anemic transgenic mice need to develop other adaptation mechanisms to maintain oxygen delivery,such as a higher ventilatory acclimatisation to hypoxia.This study focuses on the time course and effect of acute and chronic hypoxia on the ventilatory response in the erythropoietin SV-40T antigen mouse(Epo-TAg h) with a reduction in Epo expression resulting in anemia.Methods:Epo-Tag h and Wild Type mice were exposed to different FIO2(8%to21%)to characterise hypoxic ventilatory response.Acclimatisation to hypoxia(14days)was achieved in both groups using a hypobaric chamber(PB=450mmHg,equ.4200meters).Ventilation was measured at day1,day5and day14.After the physiological measurements,the heart was rapidly removed and weighed(left and right ventricle). Results:Hemoglobin concentration(g/dl)was lower in Epo-TAg h than in Wild type mice in normoxia (6.9±0.3vs.17.1±0.3,P<0.05).Acclimatisation to hypoxia induced an increase in hemoglobin in Wild Type but not in Epo-TAg h mice(19.2±0.4vs.7.3±0.4).Ventilation in normoxia in Epo-TAg h mice was greater than in Wild Type,and the difference was due to a higher tidal volume.Hypoxic ventilatory response was higher in Epo-TAg h mice at every FIO2suggesting a higher chemosensitivity.However ventilation declined only in Epo-TAg h at FIO28%.Epo-TAg h mice increased their ventilation with acclimatisation,mainly through a greater tidal volume at every FIO2.Non-acclimatised Epo-TAg h mice showed an hypertrophied heart but did not develop right ventricular hypertrophy secondary to acclimatisation to hypoxia. Conclusion:We show that anemia in Epo-TAg h mice is partially compensated by a hyperventilation in normoxia and probably a higher cardiac output as suggested by heart hypertrophy.Epo-TAg h mice survive to chronic hypoxia through a greater ventilatory acclimatisation probably due to the higher chemosensitivity.10Alteration of the diaphragm contractility in piglet and its recovery after acute hypercapniaS Jaber a,B Jung a,M Sebbane a,M Ramonatxo b,J Mercier b,X Capdevila c,JJ Eledjam a,S Matecki d a Service de Re´animation,Hopital Saint-Eloi,Montpellier;b Faculte´de Me´decine,Institut de Biologie,Montpellier;c Service de Re´animation,Hopital Lapeyronie,Montpellier;d Faculte´de Me´decine,Hopital Arnaud de Villeneuve,Montpellier Introduction:The effects of hypercapnic acidosis on the diaphragm and its recovery to normocapnia have been poorly studied.Thus our aim was to study diaphragmatic contractility facing acute variations of PaCO2and evaluated the contractile function at60minutes after normocapnia recovery.Methods:Eight anaesthetized and ventilated piglets were acutely and shortly exposed tofive consecutive ranges of PaCO2(40,50,70,90and110mmHg).Then CO2insufflation was stopped.Diaphragmatic contractility was assessed by measuring transdiaphragmatic pressure(Pdi)variation obtained after bilateral transjugulary phrenic pacing at increased frequencies(20–120Hz).Results:For each level of PaCO2,force-frequency curves were obtained in in vivo by phrenic nerve pacing.Mean(±SEM)Pdi decreased significantly from42±3to30±3cm H2O(P<0.01)between the first(40mmHg)and thefifth stage of capnia(116mmHg)at the supramaximal frequency of stimulation (120Hz).The observed alteration of the contractile force was proportional to the level of capnia(r=0.78, P<0.01).Normocapnia recuperation allowed a partial recovery of the diaphragmatic contractile force (80%of the initial value)at sixty minutes after CO2insufflation interruption.Conclusion:A short exposure to respiratory acidosis may impair diaphragmatic contractility propor-tionally to the degree of hypercapnia and this impairment is only partially(80%of the initial value) reversed at60min following exposure.11Chaotic dynamics of ventilatoryflow in humans during sleepMN Fiamma a,M Wysocki b,E Konofal c,I Arnulf c,M Zelter d,JP Derenne e,T Similowski e,C Straus f;a Upres Ea 2397,Faculte´de Me´decine Pitie´-Salpeˆtrie`re,University Pierre et Marie Curie,Paris b Service de Pneumologie, Groupe Hospitalier Pitie-Salpetriere,Paris;c Fe´de´ration des Pathologies du Sommeil,Groupe Hospitalier Pitie-Salpetriere,Paris;d Explorations Fonctionnelles Respiratoires et Upres Ea2397,Groupe Hospitalier Pitie-Salpetriere,Paris;e Service de Pneumologie et Upres Ea2397,Groupe Hospitalier Pitie-Salpetriere,Paris;f Explorations Fonctionnelles Respiratoires,Groupe Hospitalier Pitie-Salpetriere,ParisIntroduction:Although seemingly periodic,the ventilatoryflow of awake humans follows a chaotic trajectory.This does not means that this oscillatory phenomenon would be random or stochastic but that it depends on deterministic processes,without any period however.The chaos that characterizes the ventilatoryflow may originate either in the mechanical properties of the peripheral ventilatory apparatus or,most probably,in the central pattern generator that controls ventilation.The degree of chaos in the ventilatoryflow may then provide a new approach to study the human control of breathing.To further investigate this issue we analyzed the ventilatoryflow of humans,when their control of breathing was naturally modified by sleep.Methods:Six healthy volunteers(5men and1woman,25–26years)participated in the study.The ventilatoryflow was reconstructed from the signal recorded with a thoracic and abdominal inductance plethysmograph.Sleep stages were assessed by EEG.Recordings were performed during wakefulness,light (stages I–II),deep slow wave sleep(stages III-IV)and rapid eye movement sleep(REM).The chaotic behavior of theflow was assessed with the noise titration method.If chaos was confirmed,the degree of chaos was assessed with the Lyapunov exponents,its complexity with the correlation dimension,and its unpredictability with the Kolmogorov-Sinai entropy.Results:The ventilatoryflow followed a chaotic trajectory,during wakefulness and during all sleep stages.The correlation dimension,the largest Lyapunov exponent(bit/iteration)and the Kolmogorov-Sinai entropy(bit/iteration)did not differ between wakefulness,either in the evening(respectively 3.103±0.216,0.285±0.047,0.339±0.073)or in the morning(respectively 3.095±0.230, 0.264±0.090,0.314±0.133),and REM(respectively 3.125±0.152,0.288±0.037,0.348±0.050).They were significantly higher(ANOVA,P<0.016)during wakefulness and during REM than in light(respectively 1.768±0.207,0.216±0.065,0.244±0.089)and deep slow-wave sleep (respectively2.125±0.303,0.163±0.027,0.163±0.027).In light sleep,the correlation dimension was significantly smaller than in deep slow wave sleep(P<0.05)and than in REM(3.125±0.152) (P<0.0001).Conclusion:The trajectory of the ventilatoryflow remains chaotic during sleep.The chaotic structure of the ventilatoryflow is similar during wake and REM sleep.However,the degree of chaos,its complexity and its unpredictability decrease during slow wave sleep.The results suggest also that the complexity of he flow may not be simply related to the depth of sleep.12A model of lung diffusionS Glenet a,C de Bisschop b,R Dridi c,H Gue´nard a a Service de Pneumologie,Centre Hospitalier Universitaire, Bordeaux;b Faculte´de Sport,Laphap,Poitiers;c Service de Pneumologie,Faculte´de Me´decine Ibn El Jazzar,Sousse, TUNISIAIntroduction:The usual model describing the lung transfer of a gas is that of Roughton and Forster (1957):1/TL=1/Dm+1/(h x.Vc).In which the transfer of a gas x is a function of two conductances, that for the alveolo-capillary membrane,Dm,the other for the blood h x.Vc where h x is the rate of reaction of a gas x with haemoglobin and Vc the amount of blood within the lung capillaries assuming that the haemoglobin concentration is normal.The criticism which can be made to this model is that, Dm depends on Vc,as if there was no capillary behind the membrane,the membrane conductance would be nil.Methods:We hypothesized that the surface of exchange S of the membrane is related to the capillary volume.In afirst attempt:Vc=K.S.If lung capillaries are considered to form a sheet of blood,K is the thickness of this sheet.If l is the thickness of the membrane,setting c=K.l,1/c=(TLNO/TLCO-A).B, with A=d NO.a NO.Coefficients d and a are diffusivity and solubility respectively.TLNO/TLCO ratio is then inversely proportional to the thickness of the membrane and of the pulmonary capillary bed.Coefficient A without unit is about2.Coefficient B is6.2x107cm2taking into account a The experimental protocols were devised as to illustrate the sensitivity of the TLNO/TLCO ratio to alterations in the thickness of either the alveolo-capillary membrane or the blood sheet.TLNO and TLCO were measured with a commercially available device(Hypair’compact Medisoft,Belgique).Results:In18subjects in the sitting position,the TLNO/TLCO ratio decreased from 4.9±0.6to 4.2±0.5when alveolar volume decreases from7.4±1.4to 4.8±0.5L.Vc did not changed significantly(from113to105ml),suggesting that the thickness of the membrane increase by32%, without appreciable change in the thickness of the blood sheet.In50subjects the TLNO/TLCO ratio was measured while the subjects breathed freely or during continuous negative pressure()13hPa)at the same alveolar volume.The TLNO/TLCO ratios decreased from4.88±0.32to4.71±0.25respectively, suggesting an increase in the thickness of the blood sheet of6%in the negative pressure breathing condition.Conclusion:The present model seems to give some more insight in the analysis of the diffusion of gases in the lung however further works should be made to validate the assumptions made in the model.Ó2006Blackwell Publishing Fundamental&Clinical Pharmacology20(2006)145–234 146Abstracts。
CP and T Violation in Neutrino Oscillations and Invariance of Jarlskog's Determinant to Mat
CP and T Violation in Neutrino Oscillations and Invariance of Jarlskog’s Determinant to r Effects
arXiv:hep-ph/9912435v1 21 Dec 1999
2
trix, Mν is in general, an arbitrary 3x3 matrix. The Hermitian square of the neutrino † mass matrix, Mν Mν , may be diagonalised to find its eigenvalues, and its eigenvectors form the columns of the lepton mixing matrix, U. It is well-known that under these circumstances, neutrinos propagating in vacuum undergo flavour oscillations, and furthermore, in general, these result in CP - and T -violating asymmetries. The CP - and T -violating asymmetries in the transition probabilities are given (for arbitrary mixing matrix) by the universal function P (να → νβ ) − P (ν α → νβ ) = P (να → νβ ) − P (νβ → να ) = 16J sin (∆12 L/2) sin (∆23 L/2) sin (∆31 L/2)
LANGUAGES
U LRICH F RANK T OWARDS A S TANDARDIZATION OF O BJECT-O RIENTED M ODELLINGL ANGUAGES?Mai 1997Arbeitsberichte des Instituts für Wirtschaftsinformatik Nr. 3U LRICH F RANK T OWARDS A S TANDARDIZATION OF O BJECT-O RIENTED M ODELLINGL ANGUAGES?Mai 1997Arbeitsberichte des Instituts für Wirtschaftsinformatik Nr. 3Die Arbeitsberichte des Instituts für Wirtschaftsinfor-matik dienen der Darstellung vorläufiger Ergebnisse, die i.d.R. noch für spätere Veröffentlichungen überar-beitet werden. Die Autoren sind deshalb für kritische Hinweise dankbar.The "Arbeitsberichte des Instituts für Wirtschaftsin-formatik" comprise preliminary results which will usually be revised for subsequent publications. Criti-cal comments would be appreciated by the authors.Alle Rechte vorbehalten. Insbesondere die der Über-setzung, des Nachdruckes, des V ortrags, der Entnah-me von Abbildungen und Tabellen - auch bei nur auszugsweiser Verwertung.All rights reserved. No part of this report may be re-produced by any means, or translated.Arbeitsberichte des Instituts für WirtschaftsinformatikHerausgegeben von / Edited by:Prof. Dr. Ulrich FrankProf. Dr. J. Felix Hampe Prof. Dr. Stefan KleinBezugsquelle / Source of Supply:Institut für Wirtschaftsinformatik Universität Koblenz-Landau Rheinau 156075 Koblenz Tel.:0261-9119-480Fax:0261-9119-487Email:iwi@uni-koblenz.deWWW:http://www.uni-koblenz.de/~iwiAnschrift der Verfasser/Address of the authors:Prof. Dr. Ulrich FrankInstitut für Wirtschaftsinformatik Universität Koblenz-Landau Rheinau 1D-56075 Koblenz©IWI 1997AbstractObject-oriented modelling is used in a growing number of commercial software development projects. However, the plethora of approaches and corresponding CASE tools still prevents corporate users to migrate to object-oriented software development methods. Against this background the recent efforts of the Object Management Group (OMG) to standardize object-oriented modelling languages seem to promise substantial benefits: Not only will a standard allow to easily port a model from one CASE tool to another, it will also protect investment in training. In addition, it is a prerequisite for standardized business object models which - in the long run - may substantially improve the economics of developing and maintaining corporate information systems. Nevertheless there are objections against a standardization at present time: It is questionable, whether the state of the art in object-oriented modelling is mature enough to allow for standardization. Furthermore standardization holds the risk to discourage further innovations.In order to analyze the state of the art, this report will first give an overview of previous ap-proaches to object-oriented modelling. To get an idea of the present state of the art, the essen-tial characteristics of the modelling languages currently under review at the OMG are briefly characterized - together with an additional approach that recently has gained remarkable atten-tion. This will lead to a number of research challenges still to overcome. Finally the report of-fers a subtly differentiated answer to the question whether or not it is time for standardizing object-oriented modelling languages.1.MotivationDuring the last decade, object-oriented software development has been adopted in the academ-ic world with remarkable enthusiasm. This is different with corporate software development: Although there is a tremendous marketing push caused by vendors, consultants, and specialist journals, many companies are hesitating to introduce object-oriented methods1. This is for comprehensible reasons: At present time, there are still serious inhibitors of object-oriented software development to overcome. There is lack of mature technology. While there are ob-ject-oriented programming languages that come with reliable compilers - sometimes embed-ded in rather convenient environments, today’s object-oriented database management systems are usually not suited to replace relational database management systems within corporate in-formation systems. Furthermore there is lack of competence. In order to exploit the benefits offered by the object-oriented paradigm, and to avoid its pitfalls, it is necessary for the devel-opers to gain a deep understanding of the essential concepts. It is certainly not too daring to assume that most software developers do not have these skills today. From a managerial point of view it is risky to provide for the training that is required to develop these skills: Not only that training is expensive, and its success is hard to predict, furthermore there is still lack of standards. This is the case for object-oriented programming languages and database manage-ment systems, as well as for specialized development methods. For this reason protection of investments, both in professional training and in technology (CASE, compilers, etc.), is usual-ly not satisfactory.Although many companies are still hesitating to introduce object-oriented methods and tech-nologies, there is no doubt that the future (that is at least the next ten years) of corporate soft-ware development will be more and more object-oriented - simply because there is no alterna-tive paradigm of similar relevance. In other words: The already big market for object-oriented concepts, training, and technologies can still be expected to grow at a fast pace. However, in order to encourage corporate investments, it is not sufficient to develop mature technologies. In addition it is crucial to provide reliable standards that foster interoperability and reusability, and protect investments at the same time. Only recently it became apparent that the various di-alects of object-oriented modelling will eventually be replaced by an industry standard mod-elling language. On the one hand, three of the best known authors of modelling methods de-cided to merge their efforts into one company in order to consolidate their methods into one "unified method" ([Rum96b]). On the other hand, the "Object Management Group" (OMG) is-sued a request for proposals for object analysis and design ([OMG96]). The submissions were due at January, 17th, 1997. The review process can be expected not to be completed before the end of 1997. The OMG’s request for proposal was the cause for writing this report which will focus on the following questions:•What is/could be subject of standardization in the area of object-oriented modelling?•What are the prospects and risks that are related to standardization?•What is the OMG’s intention?•What are the characteristics of the official proposals to the OMG?1. To our knowledge there has not been a single representative study on an international scale. A recentlyconducted empirical study ([Sch97]) indicates that less than 10% of the german insurance companiesuse object-oriented software development methods.•Is the current state of the art mature enough to allow for standardization?This paper is intended to be followed by a later report ([FrPr97]) which will compare two mod-elling languages, the UML ([Rat97a] .. [Rat97j]) that has been proposed to the OMG, and the OML [FiHe96].2.Object-Oriented Modelling: Need for Standardization?During the last 10 years a remarkable number of approaches to support object-oriented soft-ware development on a conceptual level have been published. The majority of them evolved in an academic setting. Unfortunately, most of them are not documented in a comprehensive way. Furthermore the differences between some approaches seem to be marginal. For this rea-son, it would not make much sense to consider all of the approaches we have encountered. In-stead we will give an overview that is restricted to a few characteristics. With the increasing popularity of object-oriented software development, object-oriented modelling has gained more and more commercial attention - resulting in a growing market for specialized services and tools. Against this background - a new paradigm, attractive both from an academic and a commercial point of view - it is not surprising that there is remarkable diversity in concepts and terminology. In order to discuss the benefits and risks of standardization we will define essential subjects of object-oriented modelling - such as method, model, metamodel, etc. 2.1Overview of Previous Object-Oriented Modelling MethodsObject-oriented software development in general, object-oriented modelling in particular has been a rather popular topic both for conferences and specialized journals. This may indicate a vivid period of research - or simply the usual hyper-activity caused by the emergence of a new research paradigm (or at least what seems to be a new paradigm). To give an impression of the amount of research, we have gathered more than 40 approaches which focus on various aspects of object-oriented analysis and design. The following list is compiled from a previous survey ([Fra93]) and additional sources ([Big97], [Obj97]). It is not meant to be complete. Missing information about the name of an approach or about its tool support means that there was no information available. It does not necessarily imply that a name or tool does not exist.Author/Institution Name Refs Type ofPub.Tool SupportAckroyd/Daum[AcDa91]A Alabisco[Ala88]CBerard[Ber93]TBailin[Bai89]ABooch[Boo94]T Y Buhr[Bu84]TCherry PAMELA 2[Che87]RCoad/Y ourdon OOA/OOD[CoYo91],[CoYo90]TTYColeman Fusion[Col94]T YAuthor/Institution Name Refs Type ofPub.Tool SupportCunningham/Beck[CuBe86]CDesfray Object Engi-neering[Des94]TEdwards Ptech[Edw89]T Y Embley et al.[EmKu92]TESA HOOD[ESA89]MFelsinger[Fel87]RFerstl/Sinz SOM[FeSi91],[FeSi90]AAYFiresmith[Fir92]TGoldberg/Rubin OBA[GoRu92]A Y Graham[Gra91]THalladay/Wiebel[HaWi93]THenderson-Sellers/Edwards[HeEd94],[Hen92]T TIBM[IBM90]RJacobson et al.OOSE[JaCh92]T Y Johnson/Foote[JoFo85]AKadie[Kad86]RKappel/Schrefl[KaSc91]ALee/Carver[LeCa91]ALiskov/Guttag[LiGu86]TMartin/Odell[MaOd92],[MaOd95]T TMasiero/Germano[MaGe88]A McGregor/Sykes[McSy92]T Meyer[Mey88]T Mullin[Mul89]T Nielsen[Nie88]R Odell[Ode92]A Page et al.[PaBe89]C Rajlich/Silva[RaSi87]R Robinson[Rob92]T2.2TerminologyOne of the shady sides of object-oriented software technology is the lack of a common, and consistent terminology. This fact may be contributed to various reasons:•The specialized research is still in a rather early stage.•There are many players - with different backgrounds and motives - who influence the evolv-ing terminology: software-engineers, computer scientists, consultants, tool vendors, etc.•There is an "inherent" ambiguity that results from the different levels of abstraction that are characteristic for the various phases of software development - resulting in subtle termino-logical traps that everybody in the field knows: Sometimes somebody, who is talking about an "object", actually means a "class", within another context he may think of a particular instance ...The definition of a sound terminology is certainly one of the key contributions to be expected from a modelling approach. For this - and for some other reasons - we do not have to discuss the whole range of terminological problems at this point. However, we do need a number of terms to categorize the approaches to be evaluated: method, methodology, model, metamodel,modelling language, etc.. Since they are essential terms not only of computer science but of science and philosophy in general, we do not intend to provide a comprehensive definition. In-stead, we will briefly describe the interpretations we favour within the context of this working paper.A method in general is a systematic approach that helps with solving a class of problems. TheAuthor/Institution Name Refs Type of Pub.Tool SupportRumbaugh et al.OMT[Rum91]T YSeidewitz/Stark [SeSt87]A Shlaer/Mellor [ShMe92], [ShMe88]T T YVelho/Carapuca SOM [VeCa92]C Walden/Nerson BON[WaNe95]T YWasserman et al.[WaPi90]A Wirfs-Brock/Wilkerson[WiWi90]TT TextbookA Article in a Journal or Reader M ManualR Research Report C Conference PaperFig. 1:Overview of past approaches to object-oriented modellingterm "systematic" is to express that usually a class of problems is divided into classes of sub-problems, together with techniques, or methods to solve them ([Lor84]). Furthermore a meth-od includes a more or less rigid temporal order of the various problem solving activities togeth-er with the required skills and resources. In general, it is a key characteristic of scientific work to apply, to review and to revise methods. A software development method is a method that is supposed to support the systematic development of a class of software.The term methodology in contrast denotes a study or a theory of methods in the sense that it includes a set of methods together with guidelines or principles to evaluate, select, apply, and develop them ([Mit84]). Many authors use "methodology" to denote a method. The methodol-ogy that is focusing on scientific methods in general, or within a particular discipline, is also called epistemology, or theory of science.A model in general is a description of an existing or potential domain, where domain denotes either a part of the "real", perceivable world, an intellectual construction, or a mixture of both. It is essential for this description that it is an abstraction of the related domain. Certain aspects of the domain are not taken into account on purpose. For this reason a model allows to concen-trate on relevant aspects, thereby helping to simplify the analysis of a complex matter. Rele-vance depends on the particular purpose a model is to serve - such as analysis, description, ex-planation, understanding, design. In the context of software development we call a model con-ceptual if it is focusing on relevant concepts of the application domain, neglecting implemen-tation-related issues. A concept is a notion, an idea that allows to identify and describe classes or categories of real world entities by defining their essential features. According to Mylopou-los and Levesque ([MyLe84], p. 11), a conceptual model should provide "... descriptions of a world enterprise/slice of reality which correspond directly and naturally to our own conceptu-alizations of the object of these descriptions.” Notice that this does not exclude models of tech-nical systems, such as machines, processors, etc. Hence, a concept is an abstraction of a set of particular occurrences. In other words: Whether or not a model is regarded as being conceptual will also depend on the intention of its creators - and the perception of the observers. Usually, but not necessarily, a conceptual model includes a graphical representation.A description requires the existence of a language. While in principle any language, in partic-ular a natural language, can be used to describe a model, there are languages that were espe-cially introduced for the purpose of describing models. We call these languages modelling lan-guages. A language may be formalized or not. There may be various representations - such as text or graphics - to express propositions of a language. Modelling languages that are used for software development usually come with a graphical notation. Languages of that kind should be suited to fulfil the requirements of conceptual modelling (focus on "natural" concepts). At the same time they should allow for a straightforward transformation to a programming lan-guage. Object-Oriented modelling is an attempt to provide modelling languages which fulfil these divergent requirements.A metalanguage is a language that serves to speak about a language, like its symbols, syntax and semantics. One inherent source of ambiguity in natural languages is the lack of a rigid sep-aration of meta- and object language. In order to avoid ambiguity, formal languages require a clear separation of meta- and object level. That does not mean, however, that a formal language and its corresponding metalanguage need to be different in terms of their symbols or their syn-tax. Defining a language with a formal metalanguage promises a number of benefits. A meta-language that is used to specify a number of object-level languages helps to integrate these lan-guages: Information represented in the various object-level languages can be exchanged by re-ferring to concepts defined in the common metalanguage - as long as the involved languages have those concepts in common. Furthermore a metalanguage can help with reusability and flexibility: Software that operates on a particular metalanguage, can be used to generate soft-ware that operates on the object-level language (like a compiler compiler, or Meta CASE, see for instance [EbSü96]). A metalanguage may be described by yet another metalanguage which is sometimes called meta metalanguage, and so forth. A meta metalanguage provides the same advantages for handling metalanguages as a metalanguage does for object-level languages.A metamodel is a model representing a metalanguage of a class of modelling languages. It serves to describe the symbols, syntax, and semantics of these modelling languages in a more or less rigid way. Depending on the metalanguage it is based on a metamodel may be formal or not. A metamodel may also include instructions or recommendations of how to render a model for the viewer, in other words: the notation of the modelling language. A metamodel may be rendered in the same notation as its subordinated models. The benefits provided by metamodels or meta metamodels correspond to those of metalanguages and meta metalan-guages respectively.A modelling method is a method that supports the construction and use of a class of models. It will usually include some sort of metamodel or metalanguage that, however, does not have to be formalized. Furthermore it may include some of the following aspects (this list is not meant to be complete):•more or less detailed decomposition into subproblems together with problem solving activ-ities•temporal/causal order of problem solving activities•profiles of roles required to perform those activities•information required, together with heuristics to gather it•documents/models to be produced•criteria or even metrics to evaluate models•further support for project management•examples of how to apply the method•generic models for certain domains that can be reused and modifiedA modelling methodology is a study or a theory about modelling methods within a certain area. Its subject is a set of modelling methods together with criteria/principles to use, analyze, and revise them. Computer science in general could be regarded as a modelling methodology, since one of its essential research goals is to provide appropriate abstractions for a class of problems - together with solutions to these problems.Fig. 2 shows a semantic net that illustrates the terminology. It is not intended to provide a com-plete and precise definition.2.3Subjects, Benefits, and Pitfalls of StandardizationWhile conventions and standards have played an important role in information technology for long, standards have gained a still increasing attention in the nineties. It is remarkable that to-day’s information managers are not only interested in suitable standards. Instead they are con-Fig. 2:Concepts within object-oriented modellingMethodMethodologyNotation Language Model Metalanguage MetamodelModellingLanguageProblem Heuristics ModellingMethodology ModellingMethodDomain Natural Language Level of Formalization Technique Processis a Artificial Language is acharacterized byrequiresserves to express serves to describe is adescribes/definesserves asserves to expressrepresents includes +++++includes+includesis a includesincludes includes should help with solving +is subject of ++is subject ofis a+++more than one possible serves ascentrating more than ever on the question which attempt will finally make it as the one and only global standard for a certain area - thereby almost paralyzing their ability to make deci-sions. We believe that this is both for economic and psychological reasons. The emergence of microcomputers and so called industry standards (which are sometimes in fact proprietary specifications) have demonstrated the tremendous impact of scale economies on the produc-tion costs per unit of hardware, and especially of software. This experience seems to have fos-tered a wide spread believe that in the end only one standard within a particular scope will sur-vive. Not only vendors, but also (organizational) buyers are obviously impressed (not to say "obsessed") with this "the winner takes it all" mentality. From an economic point of view it makes a big difference, whether a "standard" results from a dominating proprietary technolo-gy, or whether it is "open" in the sense that its specification may - in principle - be accessed, and used by everybody. The specification of open standards has been the business of national or international standardization bodies for long. There have also been standardization initia-tives which were organized by the industry itself, mainly for two reasons: to speed up the standardization process and to gain better control over it. Before we will have a look at one particular initiative that is of outstanding importance within the area of object-oriented tech-nologies, namely the OMG, we will first analyze what could be subject of standardization in the area of object-oriented modelling.Standardizing a (Modelling) MethodologyA methodology in the sense of how we introduced the term is by no means a subject suitable for standardization. It is common sense that a theory should be permanently evaluated against the domain it has been introduced for - and revised if necessary. This epistemological process would be compromised by "standard theories". Standardizing a study would be equally bizarre. There is, however, no doubt that a common terminology is rather important for the evolution of methodologies as well.Standardizing a (Modelling) MethodSimilar to methodology it is not obvious, why it would make sense to standardize "a systematic approach that helps with solving a class of problems". Instead it seems to be more appropriate that anybody, who has to solve a problem, may try the available methods and finally take the one that suits him best. From an academic point of view such a standardization seems to be bizarre: Scientific progress relies heavily on permanent reviews and - eventually - modifica-tions of existing methods. Freezing a method by standardizing it would contradict this process. However, while this is certainly true from an epistemological point of view, things tend to be more subtle in practice. For one, we have to take into account that defining and prescribing sta-ble methods - with more or less rigour - is an essential prerequisite of professional collabora-tive work ([Wei79], pp. 15). Organizing allows for task specific training, and is a prerequisite for core management functions such as planning and control. Does that mean, however, that there is need to standardize business processes? There is certainly a clear objection against standardizing the organisation of processes: Organizing its business should be part of the core competencies of almost any company, and therefore it is an essential part of its competitive-ness. On the other hand we currently witness a tendency toward standard business processes, promoted by technologies such as integrated business software, or workflow management sys-tems. Reorganising business processes by applying certain standard patterns facilitates the ef-ficient introduction of corresponding software. The question of the appropriate level of stand-ardization within business processes is a complex matter that we cannot analyze here in depth.There is, however, another motivation for standardizing methods: Defining steps and guide-lines for documenting their results may help with reconstructing a business process. Thereby customers may get an idea of the efficiency of a process and how the process contributes to the overall quality of a product or service. For the companies that apply the method it may help with increasing the awareness of organizational efficiency and thereby fostering more efficient processes. Recent examples of efforts to standardize methods or processes are ISO 9000 ([KeJa96], [Sch94]) and the "V-Modell" (a process model for software development, defined by the German forces "Bundeswehr" [BrDr93]). Notice that standard methods such as ISO 9000 or the "V-Modell" define a temporal order of documents and their corresponding (mod-elling) languages (which may be structured forms of the natural language) rather than provid-ing a precise definition of the involved tasks and how to perform them.We can summarize that standardizing a software development method in every detail is cer-tainly no option. A method’s potential depends on the problem it is used for, the skills and at-titude of the method users, the available resources, etc. For this reason it is hard to imagine that there could be one best (object-oriented modelling) method at a point in time. Furthermore you have to take into account that methods will (and should) evolve over time. At last it would cer-tainly be too expensive to enforce a detailed standard method, since that would cause expenses for monitoring which nobody could afford. Therefore it is definitely no good idea to standard-ize a method. However, in order to foster comparability, quality, and professional training, it can make sense to standardize the documents (models) that should be produced within a meth-od - which in turn will certainly have an impact on the methods that use these documents. Standardizing a (Modelling) LanguageThe notion of a language implies the idea of conventions which may be more or less rigid. Oth-erwise a language could not be used for the purpose of communication. Standardizing a lan-guage implies its formalization which in turn requires a formal metalanguage. It is evident that the metalanguage itself has to be precisely defined, too. In order to avoid a regressum ad in-finitum there has to be at one point a reference to already existing well defined languages and concepts - like a logical calculus or standardized types/classes.What are the benefits of standardizing modelling languages used within the process of soft-ware development? The potential benefits are obvious: Standardized modelling languages will allow for better protection of investments in technologies that depend on those languages. This is also the case for investments into training. Standardized modelling language will also im-prove the chance for exchanging models and interoperability in general, or - in other words -for system integration. Furthermore standardized modelling languages will foster reusability of existing models, for instance of generic or reference models developed for certain problem areas or domains. A modelling language will usually include a graphical notation which, how-ever, does not have to be part of a standard: From a logical point of view the notation is irrel-evant, since it does not contain any formal semantics. Nevertheless a common notation will facilitate the communication between all people using the modelling language. Therefore it might be reasonable to enhance a standard with recommendations for a notation.Despite its potential benefits, standardizing modelling languages faces a severe challenge: What are the requirements a modelling language should fulfil in order to be useful within a longer time frame? We will analyze this question later (see 4.3, [FrPr97]). One thing, however, is for sure: There is no easy answer to it. This leads to another question we will also look at later in this report: Is it already the time to standardize object-oriented modelling languages?。
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加罗法洛的刑法思想巴伦〃拉斐尔〃加罗法洛，是意大利法学家、犯罪学家，犯罪人类学的代表人物，现代犯罪学的创始人之一。
加罗法洛与其老师龙勃罗梭、师兄菲利共同创立了犯罪实证学派，且三人都是实证主义犯罪学派的主要代表人物，因此被后人称为“犯罪学三圣”（holy three of criminology）。
在其代表著作《犯罪学》中，他首次提出了自然犯罪的概念，该书的出版标志着犯罪学从法学中独立出来，成为一门独立学科。
1、历史背景1.1 犯罪率的激增19世纪中后期，随着自有资本主义向垄断资本主义过度，大量人口涌入城市，失业、贫困导致犯罪率上升。
1.2 个人主义弊端的显现个人主义要求保障最大限度的个人的自由，个人依靠自身的聪明才智获取所需的生活资料。
而导致的直接问题就是，自由的竞争，自由的发展就会导致生产资料过于集中，而能力较弱的人就会面临着严峻的生存考验。
同时伴随着贫富差距的拉大，导致社会矛盾层出不穷，这都是个人主义的弊端，也是导致犯罪率上升的主要原因。
2、理论背景2.1孔德的实证主义孔德是实证主义的创始人。
孔德的实证主义基本原则是：哲学应当以实证主义自然科学作为基础，以可以观察和试验的事实和基础为内容，摒弃神学和思辨形而上学所研究的那些所谓的绝对的、最终的却又无法证明的抽象本质。
核心就是一试征得知识来代替神学的和形而上学的思辨概念。
孔德认为，我们的每一种观点、知识的获得，都要经历三种不同的阶段：即神学阶段（虚构阶段）、形而上学阶段（抽象阶段）、科学阶段（实证阶段）。
在实证阶段，人们借助于推理和观察，以便发现现象之间的不变的内在的联系。
把一切事物的研究和解释都局限于现象世界的范围，不去探讨那些玄妙的、虚幻的世界，对世界和事务采用实证的科学的态度，这就是实证阶段。
孔德把按照实证主义建立起来的关于社会现象的理论称为社会学，其任务是研究和发现社会中不变的规律。
社会现象和自然现象一样服从不变的规律。
孔德的这些思想，对实证主义学派起到了方法论的指导作用。
在加罗法洛研究犯罪学的过程中，他之所以将自然犯与法定犯相区别，就是因为他认为可以对这类犯罪进行实证研究，从而可以对犯罪进行更好的研究和防治。
2.2达尔文的生物进化论达尔文在1859年发表了《物种起源》，这在人类的发展史上起了划时代的巨大作用。
达尔文创立了以自然选择为核心的生物进化论，认为生物的进化是一个自然选择，适者生存的过程，自然选择是生物进化的主要动因。
达尔文的生物进化论不仅对生物学的发展起了很大作用，而且，在人们的思想上也引起了一场变革。
人们开始把这种适用于生物学的理论应用到社会学中。
同样，实证主义犯罪学派也不例外，龙勃罗梭的生来犯罪人论和隔代遗传理论就深受进化论的影响。
加罗法洛的有关道德感的来源和发展过程、自然犯罪人的产生以及对他们所应采取的措施的论述，都可以看出所受到的达尔文的理论的影响。
2.3斯宾塞的社会有机体理论以及伦理学思想斯宾塞是19世纪下半期英国实证主义的代表人物，他同孔德都认为可以像研究自然现象一样研究社会现象。
斯宾塞社会学的最大的特色就在于利用生物学的概念，特别是利用进化论来解释社会现象，是社会学生物学化，这点突出地表现在他的社会有机体理论上。
加罗法洛的观点与斯宾塞大致相同，他认为，社会是一个完美和谐的有机体,按照物竞天择，适者生存的法则不断前进。
每个人生而有之的利他情感维系着社会的存在，文明发展到现代阶段，欧洲民族的正常分子都具有基本的利他情感，实施自然犯罪的是那些利他情感部分丧失或者全部缺失、退化或者薄弱的人实施的。
同时，斯宾塞又是进化论伦理学的主要代表人物。
实际上，进化论伦理学与社会有机体理论紧密相连，坚持生物进化论到社会进化论的自然主义原则，把人类道德生活现象的最终说明诉诸“社会有机体”的进化过程。
斯宾塞的伦理学主要是依靠实证主义哲学的方法论和生物进化论的科学基础而完成的。
他提出的利己主义与利他主义之间的关系以及伦理学的两个范畴——正义与仁慈，对加罗法洛产生了重大影响，加罗法洛在论述这些观点时，大量引用了斯宾塞的观点。
3、对古典学派（旧派）的批判3.1从行为刑法到行为人刑法旧派的刑法理论可以总结为一种行为刑法的理论，即一种将犯罪与刑罚均建立在行为基础之上的刑法理论，他强调表现欲外部的行为及其实害-：刑事责任的基础是表现于外部的犯罪人的行为，没有对社会现实有害的客观行为就没有犯罪；处罚犯罪人必须以这些客观行为及其实害行为为依据，以免熬成认定犯罪的困难和恣意擅断；刑罚的量定应与客观行为及其实害相适应，即以报应主义（康德、黑格尔）或者心理强制说（贝卡利亚、费尔巴哈）为理论内核的一般预防的罪行均衡论。
从价值取向上来看，这种理论以反对封建专制刑法为己任，其理论内容的建构，在个人人权保障与保护社会免受犯罪侵害的二元对立的价值冲突中，无疑是一种倾向于个人权利保障的价值偏一选择。
这种理论理解的行为与行为人都是抽象的、大写的，而不是受体制、社会制约的个性。
集中注意犯罪的名称、定义及法理学分析，而把一定背景下形成的犯罪人格抛在一边。
这种抽象化的理解，使得其所构建的刑法理论难以针对犯罪人的特殊之处采取有针对性的犯罪预防措施。
泛犯罪人化。
19实际后半期，犯罪率的激增，而按照旧派理论，由于泛罪化而导致了泛罪人化。
一方面，社会矛盾激增导致犯罪率上升，另一方面，在行为主义、报应主义以及一般预防的立场下，面对犯罪率上升，只能采取犯罪化、加大打击力度这种手段，导致泛罪人化这种弊端。
而这种情况下，监狱的“染缸”培养了一批惯犯、累犯。
加罗法洛的犯罪学思想，其首要任务就是回应社会对秩序的渴求。
因此加罗法洛选择了一条与旧派完全不同的道路，即将刑法打击的重点集中在真正需要刑罚惩罚的犯罪人，即自然犯上面；对自然泛之外的法定犯，则实行非犯罪化、非犯罪人化。
3.2 道义责任与自由意志旧派强调犯罪人的道义责任，认为犯罪人在自由意志的支配下，选择实施犯罪行为，从道义上应当承担刑罚后果。
加罗法洛反对意志自由的理论假设，他认为只有在一定的情况下，行为人才有思考和感觉的权利。
因为，自由意志经常受到个人意志的内在或外在情况的影响，它通常是相对的，而且具有多变性的特征，经常可能把犯罪行为的应罚性降低到无足轻重和难以感觉的最低限度。
所以，道义责任只能为犯罪提供避难场所。
4.自然犯与法定犯4.1 什么是犯罪人旧派：触犯了刑法规定的人就是犯罪人。
加罗法洛认为：旧派忽视了罪犯的人格，把其视做抽象的一般人，这种观点是一种恶性循环，不能满足社会学研究的需要。
龙勃罗梭：天生犯罪人论。
加罗法洛认为：从人类学的角度寻求犯罪人特征的努力在当时并不成功，并且进一步的研究能够成功也是未知的。
而从观相学的角度已经获得的材料并不准确，具有很大的主观随意性。
从生理异常到心理异常加罗法洛也想在罪犯与非罪犯之间寻找某种区别，但在区别的标志上显然不同于龙勃罗梭，我们可以归纳为从生理异常到道德异常这样的一个发展轨迹。
（陈兴良，《刑法的启蒙》。
法律出版社1998年版，第236页。
）加罗法洛认为犯罪人是道德异常的人，认为，犯罪人的那种怜悯和正直的道德感的缺乏，即犯罪的倾向和素质具有先天的和遗产的性质。
赋予了天生犯罪人以道德异常的内涵。
龙勃罗梭的困境犯罪的概念是犯罪人概念的前提和基础。
旧派认为犯罪就是违反刑法法规的行为。
但龙勃罗梭在研究犯罪原因时，只承认犯罪的人类学的原因。
而这样的话，对于那些并无生理异常但是按照刑法规定构成犯罪从而并成为犯罪人的人，又该如何解释其犯罪原因呢？1、如果接受犯罪的刑法定义，那么他的天生犯罪人理论比如与立法、司法实践不相符合，从而必须修正自己的犯罪人与犯罪原因理论2、如果维持天生犯罪人理论，则必须绕开犯罪的刑法定义，自己给出一个全新的犯罪概念，而这又不符合当时刑事立法的实际。
龙勃罗梭实际上采取了接受犯罪的刑法定义，同时修正自己的犯罪原因与犯罪人理论的策略来避免理论上的尴尬。
4.2自然犯加罗法洛的对策：区分自然犯与法定犯加罗法洛认为犯罪是一种即对社会有害又侵害了一种或两种最基本怜悯和正直情感的行为，犯罪则必然是这种情感部分或全部缺失、退化或者薄弱的人。
（自然犯）也就是说，他认为只有自然犯是真正的犯罪，而其它犯罪不是真正的犯罪，不应该由刑法进行调整。
4.3 法定犯那些被加罗法洛排除在犯罪之外的但是按照刑法的规定依然是犯罪的东西，被加罗法洛以及后来的研究人员称之为“法定犯罪”，实施了“法定犯罪”的人即为法定犯。
这些行为不是真正的犯罪行为，法定犯也不是真正的犯罪人。
法定犯包括：a威胁一个政府组织为代表的国家的行为。
b无政治目标的攻击社会权利的行为。
c可能侵害公共和平、公民的政治权利、宗教信仰或导致公共礼仪受到侵害的行为。
d与某个国家中地方性或特别立法相抵触的行为。
总结：法定犯是没有道德异常的正常人，之所以犯罪在于违反了法律，行为人不表现为任何道德低下。
4.4 自然犯与法定犯的判定标准加罗法洛认为，自然犯与法定犯的区别在于是否具有道德异常。
道德异常是什么？是指对怜悯和正直这两种道德情感部分或者全部的缺失、退化或者薄弱；同时这种道德异常具有先天和遗传的性质。
如何判断道德异常？判断行为人是否存在道德异常的标尺在于其是否实施了能够彰显其道德异常的行为，行为成了判断犯罪人危险性的外在的、直观的的标尺（征表主义）。
4.5 区分的意义自然犯与法定犯有各自不同的犯罪原因，需要采取不同的对策。
a自然犯：由于道德异常是天生的，因此对其规制应将重点放在防止自然犯再次犯罪上。
b法定犯：由于法定犯不存在道德异常，其具有不确定性，因此对其规制的重点应放在预防其犯罪之上。
二元犯罪违法控制体系加罗法洛构建了一个刑法典与违法法典并存的二元犯罪违法控制体系。
别分规定对自然犯与法定犯的处罚方式。
5.犯罪处遇观5.1 犯罪对策a完全消除，剥夺犯罪与社会的一切往来。
b部分消除，把罪犯与其不适应的特殊环境隔离开。
c赔偿，强迫罪犯赔偿其犯罪所导致的物质上和精神上的损失。
5.2 对不同种类犯罪人的对策1、谋杀犯2、暴力犯3、缺乏正直感罪犯4、色情犯6、国际刑法加罗法洛的目标是建立一个国际刑法典。
为了达到这个目的，因此他必须为自己所说的国际刑法典寻求一个广泛的基础，以使该法典能够为不同国家所接受。
因此，加罗法洛必须努力的寻求各种不同社会类型中道的情感的最大公约数。
从社会学以及伦理学的角度来说，这个想法具有正当性。
如法国涂尔干认为：社会成员平均具有的信仰和情感的综合，构成了他们自身明确的生活体系。
如果一种行为触犯了强烈而又明确的集体意识，那么这种行为就是犯罪。
（法，涂尔干，《社会分工论》，渠东译，三联书店2000年版，第42页）6. 局限性6.1 自然犯罪与法定犯罪的区别是难以成立的犯罪分类理论a两者的区分存在重大的方法论上的缺陷。