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Boala cardiaca ischemica

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Boala cardiaca ischemicaDr. Neguțescu Sorina, Medic Rezident –Medicina de Familie

 

Rezumat: Boala cardiaca ischemica este o afeciune datorata unui aport insuficient de sange si implicit, oxigen intr-o portiune a miocardului. Ea apare cand exista un dezechilibru intre fluxul sanguin coronarian si necesitatile miocarice, produs prin modificari in circulatia coronariana. Cea mai frecventa cauza a ischemiei cardiace este reprezentata de leziunea aterosclerotica a unei artere coronare, ceea ce duce la scaderea fluxului sanguin si hipoperfuzia teritoriului miocardic adiacent arterei respective.

Abstract: Ischemic heart disease is a condition in which there is an inadequate blood and oxygen supply to a portion of the myocardium. It occures when there is an imbalance between the coronary blood supply and the myocardial demand. The most commun cause  of myocardial ischemia is an atherosclerotic lesion of a coronary artery, which leads to a decrease of the blood flow and the hypoperfusion of the myocardial teritory supplied by that artery.

 

Boala cardiaca ischemica prezinta atat forme acute, cat si forme cronice (angina pectorala veche, infarctul miocardic vechi, cardiomiopartia ischemica).

Factori de risc: Boala cardiaca ischemica cauzeaza mai multe decese si dizabilitati decat orice alta boala existenta pe glob la ora actuala. Principalii factori de risc sunt reprezentanti de o dieta bogata in grasimi si glucide; fumatul si stilul de viata sedentar. Obezitatea, rezistenta la insulina si diabetul zaharat de tip II sunt de asemena factori de risc importanti in aparitia acestui tip de afectiune.

Etiopatogenie: cauzele bolii cardiace ischemice pot fi de origine aterosclerotica sau non-aterosclerotica.

  • Ateroscleroza coronariana cu diversele sale tipuri morfologice  reprezinta cauza a peste 90% din totalul evenimentelor coronariene acute sau cronice (1). Leziunile aterosclerotice sunt localizate pe coronarele epicardiace, putand fi unice sau multiple; difuze sau limitate; concentrice sau excentrice; complicate sau necomplicate; semnificative, nesemnificative sau critice, in functie de criteriile de evaluare folosite.
  • Cauzele non-aterosclerotice ce reduc sau intrerup fluxul sanguin coronarian, producand un tablou de boala cardiaca ischemica sunt urmatoarele: embolii (trombus, vegetatii, calciu); anomalii congenitale (origine anormala din aorta sau din trunchiul arterei pulmonare; fistule coronariene); desectie; spasm, traumatism (penetrant, nepenetrant, chirugical, cateterism); tulburari metabolice (homocistinurie; boala Fabry; amiloidoza); compresie externa; tromboza primara (policitemia vera; trombocitoza; siclemie, leucoza, hipercoagulabilitate); arterite (poliarterita nodoasa; LES; sifilis; boala Kawasaki, boala Buerger; boala Takayasu); dezechilibru intre nevoile miocardice de oxigen si aport (stenoza aortica; hipertensiunea arteriala sistemica; tireotoxicoza); boala vaselor coronare mici (cardiomiopatia hipertrofica; amiloid, diabet zaharat),etc.

Clasificarea cardiopatiei ischemice conform Societatii de Cardiologie si Federatiei de Cardiologie:

  1. Oprirea cardiaca primara;
  2. Angina pectorala
    • Angina de efort: angina de novo; angina de efort stabila si angina de efort agravata
    • Angina spontana
  3. Infarctul miocardic
  4. Insuficienta cardiaca in cardiopatia ischemica
  5. Aritmiile cardiace presupuse sau dovedite de origine ischemica

Principalele sindroame coronariene intalnite in practica sunt reprezenate de:
- Infarctul miocardic acut cu supradenivelare de segment ST;
- Angina pectorala instabila/ Infarctul miocardic fara denivelare de segment ST;
- Angina pectorala stabila, cronica;
- Angina varianta Prinzmetal;

Infarctul miocardic acut cu supradenivelare de segment ST: se poate evientia pe baza diagnosticului patogenic (reprezentat de necroza coagulata si necroza contractata in banda, rezultata prin moartea miocitelor ca urmare a ischemiei prelungite) si diagnosticul clinic rezultat din asocierea datelor anamnestice cu semnele de necroza miocardica evidentiate in testele imagistice, electrocardiografice si biochimice specifice.

Anamneza constituie un criteriu de baza in stabilirea diagnosticului de infarct miocardic acut. Prodromul se prezinta ca un disconfort toracic, asemanator unei angine pectorale, care apare in repaus sau la eforturi mici. Alte simptome sunt reprezentate de anxietate, dispnee, fatigabilitate.

Durerea in infarctul miocardic acut este localizata retrosternal cu extensie precordiala, in majoritatea cazurilor, sau retroxifoidian, epigastric in cazul infarctelor cu localizare inferioara. Ea iradiaza spre umarul si membrul superior stang sau in anumite cazuri spre mandibula, interscapilovertebral, epigastric, etc. Durerea  este de intensitate foarte mare, rareori de intensitatate medie sau absenta; are caracter de strivire, constrictie, apasare si dureaza cateva zeci de minute sau ore, urmand sa dispara la aproximativ 24 de ore, cand se instaleaza necroza cardiaca. Ea  nu cedeaza la administrarea de nitroglicerina sau alti nitrati si este de obicei asociata cu efortul fizic deosebit, stresul psihic sau interventiile chirurgicale.

Alte simptome ce pot aparea in infarctul miocardic acut sunt reprezentate de dispnee sau polipnee, sincope  si semne neurologice de focar, palpitatii, fatigabilitate cu sau fara durere, febra moderata in primele 2-5 zile de la debut.(2)

Investigatiile: o ECG in  12-15 derivatii trebuie efectuta cat mai curand pentru a estima progresia sau regresia sindromului sub tratament. Fiecare tip de infarct, in functie de localizare, prezinta modificari- ECG specificice. Pentru stabilirea diagnosticului un rol extrem de important il au markerii de necroza cardiaca: cresterea nivelului izoenzimei CPK-MB transeaza diagnosticul. AST si LDH cresc de asemenea, dar au o dinamica mai lenta, avand rol in diagnosticul retrospectiv al IMA. Troponinele cardiace (troponina T si troponina I) cresc la aproximativ 6-8 ore.

Tratamentul imediat consta in administrarea de morfina, oxigen, nitroglicerina si aspirina, la care se asociaza terapia de reperfuzie cardiaca, care se poate face in 3 moduri: terapia trombolitica, angioplastia coronariana percutanata sau by-pass-ul aorto-coronarian de urgenta.(3)

Angina pectorala instabila/ infarctul miocardic fara denivelare de ST: reprezinta un sindrom coronarian acut cu manifestarile clinice de angina pectorala sau echivalentul  unui disconfort toracic de tip ischmic la care se asociaza unul din urmatoarele criterii:

  • Apare in repaus sau la exercitii fizice minime si dureaza mai mult de 20 de minute, daca nu se administreaza nitroglicerina,
  • Este severa si este descrisa ca o durere franca sau cu debut recent (sub 1 luna);
  • Are caracteristici de tip crescendo- mai severa, prelungita si mai frecventa decat crizele recurente de angina pectorala.

Din punct de vedere morfopatologic se diferentiaza de angina stabila prin fisuri sau rupturi aparute la nivelul placilor de aterom. Modificarile electrocardiografice si biologice specifice evidentiaza ischemia cardiaca, fara a obiectiva necroza cardiaca

In ceea ce priveste tratamentul, un rol important il au terapia anti-trombotica cu administrarea de antiagregante plachetare (doze mici de asipirina), reducerea nivelurilor de colesterol (statine si asigurarea unei diete sarace in grasimi si bogata in fibre), imbunatatirea performantei ventriculului stang prin adminstrarea de inhibitori de enzima de conversie si renuntarea definitiva la fumat.

Angina pectorala stabila se prezinta ca o durere sau disconfort retrosternal sau in teritoriile toracice adiacente, cu iradiere predominant spre umarul si bratul stang. Aceasta are caracteristici bine definite: durata de aproximativ 3- 15 minute, este declansata de efort sau emotie si cedeaza la repaus sau administrarea de nitroglicerina.

Din punct de vedere morfopatologic se evidentiaza stenoza uneia sau a mai multor artere coronare, datorata aterosclerozei. Placile ateromatoase pot fi placi “moi” care au risc crescut de evolutie spre sindroamele coronariene acute si placile fibroase, lungi, care realizeaza stenoze concentrice severe. Alte modificari morfologice necaracteristice sunt reprezentate de calcificari difuze ale placilor de aterom, ocluzii vasculare coronariene; vase de neoformatie intimale sau infiltrate intimale in adventice.

Diagnosticul pozitiv se stabileste pe baza  anamnezei, a coronorografiei si a examenului ECG care evidentiaza leziuni de ischemie in repaus, in criza sau in timpul testelor de provocare.

Boala cardiaca ischemicaAngina varianta sau angina Prinzmetal este o forma de angina pectorala datorata spasmului coronarian localizat, ce determina reducerea drastica si tranzitorie a diametrului unei artere epicardiace si prezinta modificari ECG secundare ischemiei cardiace. Ea se poate asocia cu infarct miocardic acut, aritmii severe si moarte subita. Tipic pentru acest tip de angina este durerea, care este de durata si intensitate mai mare decat durerea din angina pectorala; aparare in repaus, nu este legata de efort sau de factori emotionali; are un “orar fix”, aparand intre miezul noptii si ora 8 dimineata in episoade de 2-3 pana la 30-60 de minute si este calmata de administrarea de nitroglicerina. Durerea se poate asocia cu aritmii, sincopa, migrena sau sindrom Raynaud si este intalnita frecvent la persoane tinere, de sex feminin.

Diagnosticul se stabileste pe baza criteriilor anamnestice, caracterul pasager al modificarilor ECG si usoara crestere a enzimelor cardiace.

In conditiile unor coronare normale, prognosticul este relativ bun, iar tratamentul prelungit cu blocanti ai canalelor de calciu imbunatatesc prognosticul pe termen lung(3).

 

Bibliografie:

  1. Fauci AS, Brawnwald E, Kasper D, Hauser SL, Longo DL, Jamson JL, Loscalzo J, Harrison’s Principlals of Internal Medicine; 17th edition; 2008, 1514
  2. Cozlea L, Semiologia aparatului cardiovascular, 2006, 149-185
  3. Matei D, Esentialul in medicina de familie, 2007; 269-275

 


ESOFAGITA EOZINOFILICA- O AFECTIUNE EMERGENTA

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ESOFAGITA EOZINOFILICA- O AFECTIUNE EMERGENTADr. Claudia Vasiliu, medic specialist
gastroenterolog

 

Eozinofilia esofagiana a fost descrisa in asociere cu gastroenterita eozinofilica, o afectiune rara, care poate determina o serie de simptome ca malabsorbtie, dismotilitate si ascita, in functie de stratul peretelui tubului digestiv afectat. Atunci cand eozinofilia gastrointestinala este limitata la esofag, este acompaniata de simptome caracteristice si sunt excluse alte cauze de eozinofilie, termenul folosit este de esofagita eozinofilica.

Esofagita eozinofilica reprezinta o afectiune cronica, mediata immunologic a esofagului, caracterizata din punct de vedere clinic prin simptome  legate de disfunctia esofagiana  iar din punct de vedere histologic de inflamatia predominant eozinofilica. Este important sa facem diferenta intre esofagita eozinofilica , un diagnostic clinicopatologic, si eozinofilia esofagiana in absenta simptomelor caracteristice, situatie intalnita in multiple afectiuni, ca boala de reflux gastroesofagian, vasculite, hipersensibilitate la medicamente.

Esofagul, care in conditii normale este lipsit de eozinofile, este un organ immunologic activ, capabil sa recruteze eozinofile ca raspuns la o varietate de stimuli.Astfel, s-a observat o tendinta sezoniera a esofagitei eozinofilice, sugerand rolul unor aeroalergeni. Pe modele experimentale , unii alergeni obisnuiti in locuinte, ca praful , acarienii si mucegaiul au indus eozinofilie esofagiana. Jumatate din pacientii adulti cu esofagita eozinofilica au o alergie alimentara la cel putin un aliment, cel mai frecvent implicate fiind alergia la alune(38%), ou(27%) si soia(23%).

Cel putin o treime din adulti si peste 40% din copiii cu esofagita eozinofilica asociaza o afectiune alergica. Cele mai puternice asocieri sunt cu astmul bronsic(14-70% din cazuri) si cu rinita alergica(40-75%). Mai multe studii au raportat cel putin jumatate  din pacientii cu esofagita eozinofilica ca avand un istoric de atopie.

Prevalenta esofagitei eozinofilice este in crestere, lucru dovedit de studii desfasurate in SUA, Olanda, Danemarca, in parte datorita expunerii crescute la alergeni secundar poluarii si folosirii excesive a aditivilor alimentari, in parte accesibilitatii si utilizarii tot mai frecvente a endoscopiei si sensibilizarii specialistilor.

Dovezi recente sugereaza ca patogenia esofagitei eozinofilice este imuna, Th2 mediata, cu niveluri crescute de mastocite esofagiene, IL-5, TGF-ᵦ1, IgE si celule pozitive pentru FcᵋRI. Disfunctia esofagiana este secundara unui proces de remodelarea esofagiana,dirijat de citokina Il-5, identificata in biopsiile pacientilor. Locusul genetic implicat in predispozitia pentru aceasta afectiune pare a fi 5q22. Gena pentru limfopoietina timica stromala(TLSP), o citokina implicata in diferentierea celulelor Th2 s-a demonstrat a fi un locus de susceptibilitate pentru esofagita eozinofilica. Se sugereaza ca eozinofilele de la nivelul esofagului exprima HLA-DR, putand actiona ca si celule prezentatoare de antigen.

Esofagita eozinofilica afecteaza predominant sexul masculin( raport barbati : femei 3: 1) si are doua varfuri de varsta(copilaria si decadele 3 si 4 de viata).Boala poate apare la orice varsta si poate afecta orice rasa sau orice grup etnic, desi multe studii au aratat o predominanta la populatia alba non-hispanica. Examenul clinic obiectiv este nespecific si neremarcabil.

La adulti simptomele sunt oarecum stereotipice si includ disfagie, durere toracica, impactarea bolului alimentar si durere in etajul abdominal superior. Pacientii mai pot acuza anorexie, satietate precoce, varsaturi, globus si simptome similare bolii de reflux dar refractare la tratamentul medicamentos si chirurgical uzual al BRGE. Nou-nascutii si sugarii prezinta dificultati de alimentatie, iar copiii de varsta scolara se prezinta cu varsaturi sau durere. La adolescenti simptomul predominant este disfagia.

Cel mai frecvent simptom de prezentare este disfagia pentru solide. La pacientii cu disfagie examinati in clinicile de endoscopie s-a observat o prevalenta de pana la 15%. Durerea toracica este al doilea simptom ca frecventa la adulti cu esofagita eozinofilica.Impactarea alimentelor impunand indepartarea endoscopica a bolusului apare la cel putin o treime din pacientii adulti. Pacientii dezvolta mecanisme de evitare sau minimalizare a simptomelor, ca evitarea alimentelor  texturate si voluminoase(carne, painea),a bauturilor acidulate si alcoolui, taierea alimentelor in bucatele, mestecatul excesiv, consumul de lichide in timpul mesei.

Un subgrup de pacienti au simptome tipice de esofagita eozinofilica la prezentare dar raspund clinic si au ameliorare histologica la tratamentul cu IPP, in ciuda excluderii unei boli de reflux. Termenii utilizati sunt  eozinofilie esofagiana responsiva la IPP si esofagita eozinofilica responsiva la IPP. Explicatii posibile sunt vindecarea barierei epiteliale lezate, prevenind o activare imuna suplimentara, reducerea longevitatii eozinofilelor, proprietati anti-inflamatorii inerente ale IPP sau teste diagnostice nefiabile.

Din punct de vedere paraclinic,pacientii prezinta eozinofilie in sangele periferic, aproape jumatate dintre ei avand nivele de peste 300-350/mmc. Eozinofilia periferica scade dupa tratamentul cu steroizi topici si se coreleaza cu numarul de eozinofile tisulare. Numarul total de IgE este crescut la peste 50% din pacientii cu esofagita eozinofilica(›114 kU/l), dar nu sunt predictive pentru raspunsul terapeutic, fara a scadea dupa 2 saptamani de tratament cu budesonid.

Asocierea tulburarilor de motilitate cu esofagita eozinofilica este controversata, unele studii demonstrand anomalii, precum contractii de amplitudine inalta, presurizare esofagiana crescuta si unde de contractie cu pattern dezordonat, iar altele relevand motilitate normala. Manometria si pH metria esofagiana la copiii cu esofagita eozinofilica au evidentiat o corelatie intre peristaltismul ineficace si disfagie la acesti copii fata de lotul de control.

Endoscopia digestiva superioara cu prelevare de biopsii ramane singura metoda de diagnostic sigura pentru esofagita eozinofilica. Anomaliile esofagiene observate la acesti pacienti includ inele esofagiene fixe(denumite si corugate sau trahealizare), inele esofagiene tranzitorii(numite si pliuri feline sau felinizare), exudate de culoare albicioasa, santuri longitudinale, edem, ingustare esofagiana difuza, esofag cu calibru redus, fragilitate a mucoasei cu laceratii esofagiene induse de pasajul endoscopului , dand esofagului un aspect de hartie creponata in formele severe. Nici unul din aceste aspecte endoscopice nu este patognomonic, fiind gasite si in alte afectiuni esofagiene.

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A, Esofag normal. B, santuri longitudinale. C, Placi mucoase albe. D, Trahealiyare sau inele esofagiene. E, esofag cu calibru ingustat cu laceratie a mucoasei postendoscopie.

Radiografia cu bariu poate identifica o serie de anomalii anatomice si ale mucoasei in esofagita eozinofilica si oferi informatii despre lungimea si diametrul stricturilor esofagiene complicate. Sensibilitatea acesteia ca test diagnostic este scazuta, nefiind recomandata de rutina.

Pentru o evaluare patologica adecvata se impune prelevarea de 2-4 biopsii din esofagul proximal si din cel distal. Valoarea prag pentru diagnosticul histologic al esofagitei eozinofilice este de 15 eozinofile/camp microscopic( asa numita „peak value” – obtinuta din aria cu cea mai mare densitate de eozinofile). La pacientii simptomatici(cu disfagie inexplicabila) si aspect endoscopic normal si la cei asimptomatici dar cu anomalii endoscopice, ar trebui obtinute biopsii din antru si duoden, pentru a exclude alte cauze de eozinofilie esofagiana.

Intr-un studiu, din 222 pacienti cu disfagie, 15% aveau dovezi histologice de esofagita eozinofilica. Aproape 10% din pacientii cu aspect endoscopic normal au avut dovezi histologice de esofagita eozinofilica. In ceea ce priveste numarul optim de biopsii necesar pentru cresterea acuratetii diagnostice , un studiu a aratat o crestere a sensibilitatii diagnostice la 84% pentru 2 biopsii, 97% pentru 3 biopsii si 100% in cazul a 6 specimene de biopsie.

In afara pragului de › 15 eozinofile/cpm, s-au constatat si alte modificari histopatologice(tabel 1). Chiar in absenta atingerii acestui prag, unele aspecte histologice pot sugera diagnosticul. Prezenta granulelor eozinofilice extracelulare, reprezentate de depozite extracelulare de granule proteice(incluzand peroxidaza eozinofilica, proteina bazica majora si neurotoxina derivata din eozinofile), microabcesele cu eozinofile si startificarea de suprafata a eozinofilelor sunt aspecte mai frecvent asociate cu esofagita eozinofilica decat cu BRGE. Un studiu pe pacienti pediatrici a aratat ca hiperplazia celulelor epiteliale bazale si granulele eozinofilice extracelulare sunt corelate cu simptomatologia.

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Aspecte histologice . A, Esofag normal. B, esofagita eozinofilica. C,esofagita eozinofilica cu stratificare la suprafata a eozinofilelor . D,esofagita eozinofilica, microabscese.

Aspecte histologice in esofagita eozinofilica

eozinofilie mucosala
Microabcese cu eozinofile
Stratificare superficial a eozinofilelor
Granule eozinofilice extra celulare
Descuamare epiteliala
Hiperplazie strat bazal
Spatii intercelulare largite
Fibroza/scleroza subepiteliala – fibroza in lamina propria
Mastocitoza si degranularea mastocitelor
Limfocite CD8+ si limfocite B
Alungirea crestelor papilare

Fibroza laminei propria este observata pe majoritatea biopsiilor la pacienti cu esofagita eozinofilica, atat adulti cat si copii, si raspunde putin la tratament topic cu steroizi sau cu anticorpi anti IL-5(mepolizumab). Pe biopsiile acestor pacienti se observa un numar crescut de mastocite si celule purtatoare de IgG , comparativ cu cei cu boala de reflux. Pacientii cu esofagita eozinofilica au deasemenea un numar crescut de limfocite T regulatorii intraepiteliale.

Complicatiile bolii includ : impactarea alimentelor, stricturi esofagiene, esofag cu calibru ingustat si perforatia esofagiana. Prevalenta impactarii alimentare la acesti pacienti variaza intre 30% si 55% pe loturi mari de pacienti. Dintre pacientii care s-au prezentat la medic pentru impactare alimentelor, 11% pana la 55% s-au dovedit a avea esofagita eozinofilica. Stricturile esofagiene se pot dezvolta la pana la o treime din pacienti, iar esofagul cu calibru redus la cca 10%.

Exista 3 directii de tratament: dietetic, medicamentos si endoscopic. Excluderea din dieta a unor alergeni reprezinta un tratament eficient al esofagitei eozinofilice atat la adulti cat si la copii. De regula sunt excluse alimente de tipul soia, grau, oua, alune, fructe de mare, lapte de vaca. Tratamentul dietetic duce la diminuarea simptomatologiei si intr-o masura mai mica la  ameliorarea aspectului endoscopic si histologic.

Un studiu observational efectuat pe 98 de pacienti pediatrici a demonstrat efectul benefic a 3 abordari dietetice: dieta elementala, excluderea din dieta a diferiti antigeni(de tipul celor de mai sus) sau excluderea din dieta a unor alimente pe baza testelor cutanate la alergeni, desi ameliorarea histologica procentul a fost mai mare la cei cu dieta elementala( 96%, fata de 81% si respectiv 65%).

Un alt studiu care a inrolat 50 de pacienti adulti cu excluderea a 6 alimente din dieta timp de 6 saptamani a evidentiat atat un raspuns clinic(diminuarea disfagiei) la 94% din acestia, cat si o ameliorare a aspectului endoscopic( la 78%) si histologica(la 74%). Testele cutanate la diversi alergeni au identificat doar 13% din trigger-ii alimentari. Dieta poate fi asadar o optiune terapeutica la pacientii motivati.

Medicamentele utilizate in tratamentul actual al esofagitei eozinofilice sunt fluticason propionat(Flovent), budesonid si inhibitorii de pompa de protoni(omeprazol, esomeprazol, pantoprazol). Desi steroizii administrati oral sunt eficace in tratamentul esofagitei eozinofilice, efectele lor adverse sistemice le limiteaza folosirea.

Fluticason reduce numarul de eozinofile de la nivelul esofagului si amelioreaza disfagia. Este administrat cu ajutorul unui inhalator fara spacer, de 2 ori pe zi, pacientii trebuind sa evite sa manance sau sa bea timp de 2 ore dupa tratament. Ameliorarea disfagiei se produce  in cateva zile sau saptamani, dar majoritatea pacientilor dezvolta simptome recurente la oprirea tratamentului. Un efect advers al acestui medicament este candidoza orofaringiana. Steroizii sistemici pot fi utilizati in situatii de urgenta, ca disfagie severa, spitalizare si scadere ponderala. Exista unele dovezi privind reversia fibrozei esofagiene sub tratament cu budesonid.

Doze steroizi topici

Fluticasona Adulti :440-880 ug x2/zi, copii : 88-440 ug x2-4/zi
Budesonid(suspensie vascoasa) Adulti si copii peste 10 ani:2 mg/zi; copii sub 10 ani: 1 mg/zi

Doza recomandata de IPP pentru eliminarea eozinofiliei esofagiene induse de boala de reflux este 20-40 mg 1-2x/zi, si de 1mg/kgc/doza, de 2 ori pe zi, la copii, timp de 8-12 saptamani la adulti(in functie de pacient si de IPP ales). Aceste medicamente nu trateaza inflamatia eozinofilica, asocierea fluticasonei sau a unui alt steroid fiind frecvent necesara. IPP sunt utili ca si co-terapie la pacientii cu esofagita eozinofilica deoarece amelioreaza simptomele secundare bolii de reflux, cu care poate coexista.

Tratamentul cu cromolyn de sodium, montelukast si imunosupresoare(azatioprina sau 6-mercaptopurina) nu este recomandat, datorita lipsei de beneficii clinice si histologice si potentialelor efecte adverse.Agentii biologici necesita evaluare prin studii suplimentare, iar testele privind efectele terapiei anti-IL-5 sunt in curs de desfasurare.

Tratamentul endoscopic consta in dilatatii esofagiene, prin intinderea stricturilor sau ruperea stricturilor sau inelelor, permitand astfel pasajul liber al alimentelor. Dilatatia poate ameliora imediat si pe termen lung disfagia la pacientii cu stricturi esofagiene de grad inalt. Complicatiile dilatatiei endoscopice apar mai frecvent la pacienti tineri si la cei ce necesita mai multe sedinte de dilatatie, la pacienti cu stricturi in 1/3 superioara a esofagului si la cei la care strictura nu poate fi traversata cu endoscopul inainte de dilatatie.

Unii pacienti dezvolta fisuri ale mucoasei esofagului care pot duce la aparitia durerii toracice severe postdilatatie. Perforatia esofagiana este o complicatie rara dar de temut a dilatatiei deoarece duce la mediastinita, cu mortalitate ridicata. Rata perforatiilor este sub 1%,  iar durerea toracica apare in procent de aproximativ 5%. Tratamentul endoscopic trebuie aplicat numai in cazul esecului terapiei medicamentoase si de catre un specialist cu experienta in efectuarea dilatatiilor.

 

Referinte

1.Furuta GT, Liacouras CA, Collins MH et al. – Eosinophilic esophagitis in children and adults : a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology 2007;133:1342-1363
2.Spergel JM, BOOK WM, Mays E, Song L et al. – Variation in prevalence, diagnostic criteria and initial management options for eosinophilic gastrointestinal disease in United States. J Pediatr Gastroenterology Nutr. 2011;52:300-306.
3.Dellon ES, Gibbs WB, Fritchie KJ, Rubinas TC et al. Clinical, endoscopic and histologic findings distinguish eosinophilic esophagitis from gastroesophagel reflux disease. Clin Gastroenterol Hepatol. 2009;7:1305-1313 quiz 1261
4.Mishra A, Hogan SP, Brandt EB et al. IL-5 promotes eosinophil trafficking to the esophagus.J Immunol 2002;168:2464-2469.
5. Kirsch A, Bokhary A, Marcon MA et al. Activated mucosal mast cells differentiate eosinophilic allergic esophagitis from gastroesophageal reflux disease. J Pediatric Gastroenterol Nutrition 2007;45:22-31.
6.Tantibhaedhyangkul U, Tatevian N,Gilger MA et al. Increased esophageal regulatory T cells and eosinophils characteristics in children with eosinophilic esophagitis and gastroesophageal reflux disease. Ann Clin Lab Sci. 2009;39:99-107.
7. Sherill JD, Gao PS, Stucke EM, Blanchard C, Collins MH et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J Allergy Clin Immunol. 2010;126:160-165.
8.Straumann A, Conus S, Grzonka P, Kita H, et al.Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut. 2010;59:21-30
9. Vicario M, Blanchard C, Stringer KF et al. Local B cells and IgE production in the esophageal mucosa in eosinophilic esophagitis. Gut 2010;59:12-20.
10.Mukkada VA, Haas A, Maune NC, Capocelli KE, et al. Feeding dysfunction in children with eosinophilic gastrointestinal diseases. Pediatrics. 2010;126:e672-677.
11.Kapel RC, Miller JK, Torres C, Aksoy S, et al. Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups. Gastroenterology. 2008;134:1316-1321
12.Dalby K, Nielsen RG, Kruse-Andersen S, Fenger C, et al. Eosinophilic oesophagitis in infants and children in the region of southern Denmark: a prospective study of prevalence and clinical presentation. J Pediatr Gastroenterol Nutr. 2010;51:280-282
13.Mackenzie SH, Go M, Chadwick B, Thomas K, et al. Eosinophilic oesophagitis in patients presenting with dysphagia”a prospective analysis. Aliment Pharmacol Ther. 2008;28:1140-1146
14.Straumann A. The natural history and complications of eosinophilic esophagitis. Gastrointest Endosc Clin N Am. 2008;18:99-118ix
15.Peterson KA, Thomas KL, Hilden K, et al. Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis. Dig Dis Sci. 2010;55:1313-1319
16.Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Dig Dis Sci. 2009;54:2312-2317
17.Aceves SS, Ackerman SJ. Relationships between eosinophilic inflammation, tissue remodeling, and fibrosis in eosinophilic esophagitis. Immunol Allergy Clin North Am. 2009;29:197-211xiii-xiv
18.Aceves SS, Newbury RO, Chen D, Mueller J, et al. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy. 2010;65:109-116
19.Schoepfer AM, Gonsalves N, Bussmann C, et al. Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am J Gastroenterol. 2010;105:1062-1070
20.Baxi S, Gupta SK, Swigonski N, Fitzgerald JF. Clinical presentation of patients with eosinophilic inflammation of the esophagus. Gastrointest Endosc. 2006;64:473-478
21.Yantiss RK, Odze RD. Optimal approach to obtaining mucosal biopsies for assessment of inflammatory disorders of the gastrointestinal tract. Am J Gastroenterol. 2009;104:774-783
22.Steiner SJ, Kernek KM, Fitzgerald JF. Severity of basal cell hyperplasia differs in reflux versus eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2006;42:506-509
23. Mishra A. Et al. Mechanism of eosinophilic esophagitis. Immunol Allergy Clin North Am. 2009;29:29-40viii
24.Nurko S, Rosen R, Furuta GT. Esophageal dysmotility in children with eosinophilic esophagitis: a study using prolonged esophageal manometry. Am J Gastroenterol. 2009;104:3050-3057
25.Blanchard C, Wang N, Rothenberg ME. Eosinophilic esophagitis: pathogenesis, genetics, and therapy. J Allergy Clin Immunol. 2006;118:1054-1059
26.Almansa C, Krishna M, Buchner AM, Ghabril MS, et al. Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults. Am J Gastroenterol. 2009;104:828-833
27.Moawad FJ, Veerappan GR, Lake JM, Maydonovitch CL, et al. Correlation between eosinophilic oesophagitis and aeroallergens. Aliment Pharmacol Ther. 2010;31:509-515
28.Roy-Ghanta S, Larosa DF, Katzka DA. Atopic characteristics of adult patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2008;6:531-535
29.Erwin EA, James HR, Gutekunst HM, Russo JM, et al. Serum 34.IgE measurement and detection of food allergy in pediatric patients with eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2010;104:496-502
30.Veerappan GR, Perry JL, Duncan TJ, Baker TP, et al. Prevalence of eosinophilic esophagitis in an adult population undergoing upper endoscopy: a prospective study. Clin Gastroenterol Hepatol. 2009;7:420-426e1-2
31.Straumann A, Conus S, Degen L, Felder S, et al. Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology. 2010;139:1526-1537e1
32.Patel AJ, Fuentebella J, Gernez Y, Nguyen T, et al. Increased HLA-DR expression on tissue eosinophils in eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2010;51:290-294
33.Penfield JD, Lang DM, Goldblum JR, Lopez R, Falk GW. The role of allergy evaluation in adults with eosinophilic esophagitis. J Clin Gastroenterol. 2010;44:22-27
34.Dalby K, Nielsen RG, Kruse-Andersen S, et al. Eosinophilic oesophagitis in infants and children in the region of southern Denmark: a prospective study of prevalence and clinical presentation. J Pediatr Gastroenterol Nutr. 2010;51:280-282
35.Straumann A, Bussmann C, Conus S, Beglinger C, . Anti-TNF-alpha (infliximab) therapy for severe adult eosinophilic esophagitis. J Allergy Clin Immunol. 2008;122:425-427
36.Kerlin P, Jones D, Remedios M, Campbell C. Prevalence of eosinophilic esophagitis in adults with food bolus obstruction of the esophagus. J Clin Gastroenterol. 2007;41:356-361
37.Arora AS, Perrault J, Smyrk TC. Topical corticosteroid treatment of dysphagia due to eosinophilic esophagitis in adults. Mayo Clin Proc. 2003;78:830-835
38.Jung KW, Gundersen N, Kopacova J, et al. Occurrence of and risk factors for complications after endoscopic dilation in eosinophilic esophagitis. Gastrointest Endosc. 2011;73:15-21

 

DR. MĂDĂLINA CARAIVAN: „Când ne confruntăm cu un caz complicat, e bine să colaborăm cu colegii de alte specialităţi, pentru o abordare cât mai cuprinzătoare”

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DR. MĂDĂLINA CARAIVAN: „Când ne confruntăm cu un caz complicat, e bine să colaborăm cu colegii de alte specialităţi, pentru o abordare cât mai cuprinzătoare”Am aflat de la dr. Mădălina Caraivan, specialist dermatologie-venerologie la LaurusMedical, care sunt cele mai frecvente afecțiuni dermatologice cu care românii se prezintă la medic, care este evoluția acestor afecțiuni în țara noastră, ce descoperiri există în domeniul bolilor dermato-venerice și cum pot fi gestionate eficient două afecțiuni din ce în ce mai răspândite astăzi: psoriazisul și dermatita atopică.


G: De ce ați ales această specialitate și care sunt plusurile și minusurile profesiei dumneavoastră?

În anul 6 de medicină, când am început stagiul de dermatologie, făcusem deja cunoştinţă cu majoritatea specialităţilor. Eram atrasă de chirurgia generală, însă conştientizam sacrificiile pe care le impune. Cochetam cu unele specialităţi medicale, însă aici îmi lipsea partea intervenţională. Voiam să îmi folosesc şi creierul, şi mâinile. Şi atunci, a început modulul de dermatologie şi mi-am primit răspunsul: dermatologia îmbină tratamentul medical şi intervenţiile de mică chirurgie, necesitând şi abilităţi deductive remarcabile, deoarece afecţiunile cutanate sunt o sabie cu dublu tăiş: diagnosticul pare la îndemână deoarece leziunile sunt vizibile la simpla examinare; pe de altă parte, numeroase afecţiuni pot avea manifestări similare, încât diagnosticul diferenţial devine o provocare.

 

G: Cum apreciați evoluția afecțiunilor dermatologice în România acum, față de începutul carierei dumneavoastră?

Deşi mă despart doar câţiva ani de începutul carierei, am observat deja unele tendinţe. Adresabilitatea oamenilor este în creştere, deoarece accesul la informaţie de calitate este mult mai bun. De exemplu, campaniile de conştientizare a pericolelor pe care le presupune expunerea exagerată la soare contribuie la creşterea numărului de prezentări în perioada respectivă. Şi aici mă refer la persoane care vin “doar pentru un control al aluniţelor”. Oameni sănătoşi, asimptomatici, care însă au început deja să implementeze în rutina lor principiile medicinei profilactice. În plus, senzaţia mea e că majoritatea afecţiunilor dermatologice sunt diagnosticate mai din timp.

 

G: Care a fost cel mai complicat caz pe care l-ați întâlnit în cariera dumneavoastră și cum l-ați gestionat?

Am întâlnit multe situaţii complicate de-a lungul timpului, şi din raţiuni de comorbidităţi, şi din motive socio-economice. Un astfel de pacient a fost o doamnă care suferea de psoriazis extins, refractar la tratament (inclusiv la terapii biologice, care fuseseră încercate, cu răspuns nesatisfăcător). Lucrurile erau suplimentar complicate de asocierea cu hepatita autoimună, anemie şi trombocitopenie. În plus, explicabil în circumstanţele date, starea psihică a pacientei mele nu era cea mai bună, alternând între anxietate, tristeţe, resemnare, revoltă. Cred că, în astfel de situaţii, e bine să cerem ajutor, să colaborăm în mod real cu colegii de alte specialităţi, pentru o  abordare cât mai cuprinzătoare.

 

G: Cu ce afecțiuni dermatologice vin cel mai des pacienții la dumneavoastră?

Se spune că bolile comune sunt frecvente, iar cele rare sunt… rare. Într-adevăr, cel mai des văd pacienţi care suferă de afecţiuni comune: acnee, tumori benigne ale pielii (veruci, keratoze, nevi, angioame etc), leziuni premaligne şi cancere cutanate, eczeme, urticarie, boli venerice etc

 

G: Care sunt cele mai frecvente afecțiuni dermato-venerice în rândul bărbaților români? Dar al femeilor?

O parte însemnată din pacientura de sex masculin se prezintă pentru afecţiuni care implică regiunea genitală; nu e vorba numai de infecţii cu transmitere sexuală, ci şi alte afecţiuni, de exemplu balanitele iritative sau alergice de contact.

Femeile vin frecvent în încercarea de a rezolva probleme cum sunt acneea vulgară, rozaceea, hiperpigmentările.

 

G: Ce ne puteți spune despre bolile de piele autoimune, care sunt cele mai frecvente afecțiuni de acest tip, în ce cazuri apar etc.?

În afecţiunile autoimune dermatologice, substratul patogenic este o funcţionare anormală a sistemului imunitar, care se manifestă prin atacarea unor structuri proprii de la nivelul pielii. Exemple ilustrative sunt: lupusul eritematos, vitiligo, psoriazisul, alopecia areata, pemfigoidul şi pemfigusul, dermatita herpetiformă etc.

Pentru declanşarea acestor afecţiuni, în general e nevoie de un factor declanşator (ex: agenţi infecţioşi, toxine, unele alimente) a cărui acţiune trebuie să se exercite pe un teren predispus genetic.

 

G: În ultima perioadă, s-a constatat o creștere a incidenței psoriazisului. În plus, acesta a început să apară la vârste din ce în ce mai mici. Care sunt cauzele?

Este posibil ca modificările stilului de viaţă să inducă o expunere mai pregnantă la factori declanşatori (stres psihogen, toxine din fumul de ţigară, alcool, anumite medicamente, infecţii etc).

Însă întotdeauna când observăm o creştere a incidenţei unei afecţiuni se pune întrebarea: este o creştere reală sau se datorează modificărilor survenite în procesul de diagnosticare ca urmare a progresului mijloacelor de diagnostic şi a creşterii adresabilităţii la medic? Ambele mecanisme ar putea fi implicate.

 

G: Știm că nu există încă un tratament pentru psoriazis. Cum poate fi ținută totuși sub control această afecțiune?

Deşi nu există tratament curativ pentru psoriazis, în general boala poate fi ţinută sub control prin evitarea factorilor declanşatori alături de aderarea la un regim de tratament care constă în aplicarea de topice pe zonele afectate. În situaţiile în care răspunsul la tratament local este insuficient, pasul următor sunt tratamentele sistemice (fototerapia, imunosupresoarele, agenţii biologici). Foarte importantă este depistarea unor eventuale boli asociate (ex: hipertensiunea arterială, dezechilibre metabolice) care trebuie corectate, deoarece pot contribui la întreţinerea inflamaţiei.

 

G: Care sunt cele mai mari probleme cu care se confruntă pacienții cu psoriazis, din experiența dumneavoastră, și cum pot fi gestionate?

Aproximativ 10% din cei afectaţi pot dezvolta artrită psoriazică, ce poate evolua către deformare articulară şi dizabilitate. Afectarea unghială poate asocia durere, distrucția lamei unghiale şi aspect inestetic. Afectarea extracutanată este indicaţie de terapie sistemică.

În plus, la pacienţii cu psoriazis s-a remarcat un risc relativ crescut de boală cardiacă ischemică, atac vascular cerebral, hipertensiune, dislipidemie, prin existenţa comorbidităților dar şi prin impactul psihologic al bolii cronice asupra comportamentului individului afectat.

Chiar dacă boala se limitează la piele, calitatea vieţii poate fi profund afectată, din cauza caracterului vizibil al leziunilor, cu impact asupra stimei de sine, modificarea imaginii corporale, stigmatizare, uneori privare de suport social.

 

G: O altă afecțiune din ce în ce mai des întânită astăzi este dermatita atopică. De ce apare această afecțiune și care sunt categoriile de oameni cele mai afectate?

Ca şi psoriazisul, dermatita atopică este o afecţiune cronică, inflamatorie, ce evoluează cu exacerbări şi remisiuni şi care se manifestă pe un teren genetic predispus, având ca substrat o disfuncţie a sistemului imunitar. Termenul “atopie” se referă la un grup de afecţiuni ce include, alături de dermatita atopică, astmul bronşic şi rinita alergică. Un rol important în apariţia bolii e jucat de filaggrine şi implicarea lor în afectarea funcţiei de barieră cutanată.

Deşi dermatita atopică poate apărea la orice vârstă, cel mai frecvent debutul se produce în copilărie, ambele sexe fiind afectate. Copiii care au un părinte atopic au un risc mai mare de apariţie a bolii, iar dacă ambii părinţii sunt afectaţi, riscul este maxim.

 

G: Ce rol au modificările din mediu în declanșarea acestei afecțiuni?

Expunerea la anumite condiţii de mediu (climat uscat, extreme termice) poate favoriza debutul sau exacerbările dermatitei atopice. Traiul în mediu urban este şi el considerat un factor agravant, favorizând expunerea la iritanţi (praf, poluanţi atmosferici) sau alergeni.

Lunile de vară se asociază de regulă cu ameliorarea dermatitei, parţial datorită expunerii la ultraviolete care, în cantitate moderată, pot fi benefice.

 

G: Care sunt cele mai eficiente tratamente la ora actuală pentru dermatita atopică?

Deşi nu s-a descoperit încă un tratament curativ pentru dermatita atopică, există opţiuni terapeutice care pot controla inflamaţia, în majoritatea cazurilor optându-se iniţial pentru tratament topic: folosit corect, acesta are avantajul de a fi eficient, cu un foarte bun profil de siguranţă. Cazurile rezistente pot beneficia de fototerapie sau tratament sistemic.

 

G: Cât de importante sunt stilul de viață și alimentația în tratamentul bolilor de piele?

Există afecţiuni ale pielii unde relaţia dintre dietă şi manifestările cutanate este evidentă, de exemplu dermatita herpetiformă sau unele forme de urticarie. Dincolo de acestea, majoritatea bolilor de piele, de la acnee până la psoriazis, dermatită atopică sau cancere cutanate, pot beneficia de un stil de viaţă cât mai sănătos, care include o alimentaţie echilibrată.

 

G: Vorbiți-ne puțin și despre descoperirile importante recente în dermatologie…

Voi aminti doar câteva progrese relativ recente: vismodegibul este primul tratament cu administrare orală pentru carcinomul bazocelular avansat; keratozele actinice beneficiază în prezent şi de tratamentul topic cu ingenol mebutat; brimonidina, condiţionată sub formă de gel, este un agent eficient pentru reducerea eritemului din rozacee; tratamentul melanomului s-a diversificat, fiind în uz sau în studiu agenţi care blochează CTLA-4 (ipilimumab), PD-1 (pembrolizumab), agenţi care ţintesc proteine BRAF (vemurafenib, dabrafenib) sau proteine MEK (trametinib) etc.

 

G: Cum stă România la capitolul programe de sănătate pentru bolile dermatologice? Ar fi nevoie de mai mult ajutor din partea Ministerului Sănătății pe această zonă, de măsuri/programe speciale?

Programele finanţate de la buget permit accesul pacienţilor la tratamente performante, dar costisitoare, cum sunt terapiile biologice. Infliximabul, adalimumambul şi etanerceptul sunt exemple de astfel de tratamente. Sprijinul provenit din partea Ministerului Sănătăţii este esenţial, fiind în prezent direcţionat către pacienţii cu psoriazis, însă există şi alte afecţiuni dermatologice care ar putea beneficia de programele de sănătate.

 

Text: Bianca Bădescu

 

DR. SIMONA CARNICIU: ”Momentul iniţierii terapiei insulinice trebuie ales cu întelepciune, în scopul de a prezerva funcţia β-celulară pancreatică

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DR. SIMONA CARNICIU: ”Momentul iniţierii terapiei insulinice trebuie ales cu întelepciune, în scopul de a prezerva funcţia β-celulară pancreaticăDr. Simona Carniciu, medic specialist în diabet, nutriţie şi boli metabolice la Centrul de Diabet “Ion Pavel” (Institutul Paulescu) și secretar executiv al Asociaţiei Medicale Romane, ne-a vorbit despre soluțiile care ar trebui adoptate în cazul pacienților cu prediabet, despre provocările cu care se confruntă medicii în tratarea bolnavilor cu diabet de tip 2, dar și despre un studiu clinic unic la noi în țară prin care se investighează eficiența chirurgiei bariatrice în controlul și remisia diabetului, realizat de Institutul Paulescu în colaborare cu Spitalul Ponderas.

 

G: În urma studiului PREDATORR s-a constatat că sunt aproape 2 milioane de români care suferă de diabet, un număr foarte mare am putea spune. Dumnevoastră cum ați primit aceste rezultate și de ce considerați că s-a ajuns la acest procent ridicat (11,6%) de diabetici la noi în țară?

Da, am luat la cunoştinţă aceste cifre, încă de la Congresul Naţional de Diabet din luna mai 2014, când doamna Prof. Maria Moţa a prezentat rezultatele acestui studiu! Acest fapt poate fi explicat prin faptul că ţara noastră se află în curs de dezvoltare, astfel modernizarea/industrializarea societăţii noastre, dar şi în general, au adus de la sine accesul facil la alimente, în special cele hipercalorice, bogate în lipide şi zaharuri rafinate, iar sedentarismul adăugat acestui stil alimentar, a facilitat dezechilibrarea balanţei energetice a organismului uman, aportul caloric fiind mult crescut faţă de consumul energetic.

Acest stil de viaţă a dus la creşterea numărului de persoane obeze şi supraponderale (66% conform studiului PREDATORR), cât şi la scăderea vârstei de apariţie a diabetului zaharat de tip 2 (30, 20 şi chiar 10-15 ani, în cazuri restrânse). Patologia metabolică include obezitatea, sindromul metabolic, diabetul de tip 2 şi boală vasculară periferică care au ca element comun „expansiunea ţesutului adipos”.

 

G: Pe lângă cei 2 milioane de diabetici, s-a constatat că există și 3 milioane de români cu prediabet. Ce se  poate face pentru aceștia din urmă, ce soluții vedeți pentru ei?

Diabetul este un sindrom complex, de afectare a întregului metabolism, glucidic, proteic, lipidic, iar scăderea numărului de celule β-pancreatice (secretoare de insulina) începe cu mult timp înainte de apariţia clinică a diabetului de tip 2. În momentul diagnosticării, între 50-70% dintre aceste celule sunt distruse, proces ireversibil, de altfel. Stadiul de prediabet, este unul precursor apariţiei hiperglicemiei clinice, dar deja discutăm de o toleranţă alterată la glicemie.

Încă din stadiul de prediabet, putem preveni instalarea diabetului zaharat de tip 2 prin schimbarea stilului de viaţă, un consum mai mare de legume şi fructe şi un consum mai redus de carne grasă şi zaharuri rafinate. Mai important decât începerea prevenţiei în acest moment, este conştientizarea şi adoptarea unui stil de viaţă sănătos, echilibrat, încă de la vârste tinere, pentru a proteja şi stopa distrugerea celulelor secretoare de insulină.

O altă abordare foarte importantă, este scăderea excesului ponderal, astfel scăderea presiunii biochimice crescute a organismului. Interesant de menţionat şi de luat în considerare în această abordare este rezultatul ultimelor studii, susţinute şi de subiectul tezei mele de doctorat, acela că nu cantitatea de ţesut adipos, ci distribuţia lui contribuie la apariţia modificărilor metabolice. Distribuţia adipozităţii predominant în zona superioară a corpului (obezitatea androidă) conduce la mai multe tulburări faţă de distribuţia predominant în zona inferioară (obezitatea ginoidă).

 

G: Am înțeles că dintre persoanele cu diabet zaharat participante la studiu, 21% au fost cazuri nou depistate. Încă mai sunt, se pare, multe persoane care trăiesc cu diabet fără să fie conștiente că îl au.  Din ce cauză se întâmplă acest lucru?

Diabetul este un sindrom “şiret”, în sensul că, aşa cum am menţionat mai sus, apariţia hiperglicemiei este tardivă în evoluţia lui, a simptomelor clinice şi mai târzie, iar populaţia, nefiind conştientă de acest lucru, de multe ori neglijează controalele medicale perioadice, care ar trebui efectuate annual, cel puţin după vârsta de 30 de ani. Tot din acest motiv şi prezentarea la medic este tardivă, multe din cazuri adoptând o dietă nespecializată, care duce la o alterare suplimentară a funcţiei şi masei β-celulare.

Informarea medicilor de familie, cât şi a altor specialităţi este o problemă care ar trebui abordată cu intensitate mai mare, mai ales în privinţa stadiilor intermediare de diabet, cele ale toleranţei alterate la insulină. Chiar şi o glicemie între 100-126 mg/dl, în contextul prezenţei altor factori de risc (genetice, dislipidemie, sedentarism, hipertensiune arterială, supraponderabilitate/obezitate) ar trebui să ridice medicului un semn de întrebare şi să stabilească atitudinea terapeutică corespunzătoare (trimiterea pacientului către centrele specializate sau efectuarea unui test oral de toleranţă la glucoză).

 

G: Se întâmplă să vină la Institutul de Diabet bolnavi cu schema de tratament nepotrivită dată de alți medici? Și dacă da, cât de des și care sunt cauzele acestei probleme?

Se întâmplă, nu des, iar acest lucru ne bucură! Informarea şi educaţia medicală în domeniul nostru este destul de intensă. Cauzele acestei probleme vin din faptul că pacientul nu este suficient de compliant sau, probabil, medicul nu îl abordează corespunzător. Stabilirea unei relaţii medic-pacient corespunzătoare este foarte importantă, precum şi timpul potrivit evaluării pacientului în scopul identificării terapiei potrivite, individual. Prof. C. Ionescu-Tîrgovişte, spune mereu că în toată practica să nu a întâlnit două cazuri de diabet identice, astfel individualizarea, personalizarea este extrem de importantă!

 

G: Care sunt cele mai mari probleme cu care vă confruntați în tratarea bolnavilor cu diabet de tip 2?

Schimbarea stilului de viaţă este un pas important şi de multe ori, greu de îndeplinit. Aderenţa la dietă corespunzătoare şi la tratament depinde de gradul de implicare atât a medicului, cât şi a asistentei, a pacientului, dar și de educaţie. În anumite cazuri, este necesară şi intervenţia unui psiholog, în abordarea cazurilor mai dificile. Cele mai mari probleme în practică, pot spune că au rezultat din problemele psihologice ale pacienţilor, de câteva ori întâmpinând persoane cu agresivitate crescută şi un comportament revendicativ. Dar, cu răbdare şi calm, chiar şi acestea se pot rezolva.

 

G: De ce ar trebui să țină cont medicul atunci când decide trecerea unui bolnav cu diabet de tip 2 pe insulină? Și ce măsuri de siguranță ar trebui luate pentru bolnav?

Depinde de stadiul diabetului. În prima fază, la debut, în cazuri cu hiperglicemii mult crescute, simptomatologie evidentă şi/sau asocierea cu factori de risc, iniţierea insulinoterapiei este necesară, permanent sau temporar, în funcţie de complianţa pacientului şi de evoluţia bolii.

În celelalte cazuri, trebuie ales cu înţelepciune momentul iniţierii terapiei insulinice, în scopul de a prezerva masa/funcţia β-celulara pancreatică. Depinde de profilul glicemic, de asocierea factorilor de risc şi a comorbidităților, dar cea mai importantă este durata de evoluţie a diabetului de tip 2. La o durată de 10 ani şi peste, funcţia β-pancreatica poate fi foarte scăzută, iar atunci singura terapie eficienţa este insulinoterapia, asociată sau nu cu antidiabetice orale.

Ca şi măsuri de siguranţă pentru pacient, trebuie avut în vedere o bună educare a acestuia, în scopul dietei, a automonitorizării şi a ajustării dozelor.

 

G: Cât de eficiente sunt terapiile naturiste pentru cotrolul diabetului și reducerea glicemiei?

Depinde de terapia naturistă. Dar sunt eficiente, în primele stadii ale bolii, când încă funcţia secretorie a pancreasului este suficientă. Pentru aceasta este nevoie de produse concentrate şi bine echilibrate. Chiar în cadrul Centrului de Diabet, în multe cazuri, acolo unde ne permite profilul pacientului, iniţiem dieta plus un produs naturist, dar foarte eficient, după studiul cazurilor noastre, aproape la fel de eficient ca şi unul dintre cele mai utilizate medicamente.

 

G: Tendința în lume, nu doar la noi în țară, este de înmulțire a cazurilor de diabet și boli metabolice. Pentru că oamenii nu mai au de multe ori nici timpul nici resursele necesare adoptării unui stil de viață sănătos. Cum vedeți viitorul, ce este de făcut?

Sunt optimistă asupra viitorului, am văzut o implicare cât mai intensă a populaţiei şi a mass-mediei în promovarea stilului de viaţă sănătos, dar şi nu numai. La Asociaţia Medicală Romană, unde îndeplinesc funcţia de secretar executiv, avem în desfăşurare un Program Naţional de Prevenţie a Bolilor Metabolice şi Cardiovasculare. În contextul economic viitor, sunt iar optimistă că mai multe fonduri vor susţine astfel de proiecte ale unor ONG-uri.

 

G: De curând ați demarat împreună cu spitalul Ponderas un studiu care dorește să demonstreze eficiența chirurgiei bariatrice în controlul și remisia diabetului. De la ce a plecat această idee?

Ideea a plecat de la concluziile diverselor studii naţionale şi internaţionale, cât şi observarea acestor rezultate la pacienţi, anume că insulinorezistenţa asociată cu apariţia diabetului de tip 2, la pacienţii obezi operaţi prin chirurgie metabolică, dispare în câteva zile sau luni. Determinismul genetic al acesteia nu ar putea să-i permită remisia sau chiar dispariţia, odată cu dispariţia obezităţii. Probabil mecanismul de acţiune al chirurgiei metabolice este scăderea presiunii biochimice crescute din sistemul energetic. Rămâne de văzut ce rezultate vom avea, ţinând cont că acest studiu este unul destul de complex, cu multe investigaţii, greu acesibile în afara domeniului cercetării.

 

G: Cum decurge proiectul în prezent?

Proiectul decurge conform programării iniţiale, am identificat pacienţii eligibili, am făcut primele investigaţii pentru a-i elimina eventual pe aceia care nu îndeplinesc criteriile de eligibilitate, urmând randomizarea lor în cele două grupuri: 20 care vor fi operaţi prin chirurgie metabolică şi 20 care vor fi abordaţi prin metode convenţionale, dar cu o dietă personalizată. Această etapă va avea loc în luna ianuarie 2015, după care se va începe faza de tratament.

 

G: Există riscuri pe termen lung ale chirurgiei bariatrice?

Efectele acestei operaţii pe termen lung pot fi: neuropatii datorate malnutriţiei, hernii, stenoze ale anastomozelor sau complicaţii emoţionale. O complicaţie severă este hipoglicemia, cu valori de până la 30 mg/dl şi până la 14 ani de urmărire. Un alt risc, este câştigul ponderal după o anumită perioadă de la operaţie, vârful scăderii ponderale aflându-se la 2 ani de la intervenţie, iar un procent mic, 5-7% vor recâştiga în greutate în decurs de 5 ani, aceasta fiind datorată lipsei de revenire la controalele prestabilite şi alţi factori individuali.

 

G: Există vreo descoperire recentă în  diabetologie care merită menționată?

Domeniul diabetologiei este în continuă cercetare, atât în domeniul terapiei, cât şi a cauzei lui.

Aş putea menţiona studiul identificării scorurilor de risc în diabet, în scopul stabilirii precoce a momentului debutului distrucției masei/funcţiei β-celulare, de către echipa din care fac parte, coordonata de Prof. C. Ionescu-Tîrgovişte. În acest sens s-au publicat câteva articole în reviste de specialitate.

 

G: Este ceva ce nu v-am întrebat și doriți să adăugați?

Aş dori să subliniez necesitatea schimbării/ajustării terapiei pacienţilor cu diabet zaharat în contextul actual al creşterii alarmante a prevalenţei lui, dar şi a obezităţii. Abordarea pacientului diabetic este necesar să fie una multi şi chiar interdisciplinară, iar comunicarea între medici şi prioritizarea prevenţiei ar trebui să fie prioritatea lor, dar şi a instituţiilor non-guvernamentale şi guvernamentale responsabile.

 

Text: Bianca Bădescu

PARTICULARITES IN THE MANAGEMENT OF ACUTE CORONARY SYNDROMES IN THE ELDERLY

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Dr.Cristian Romeo Revnic*,Dr.Bogdan Paltineanu**,Dr.Catalina Pena***,Dr.Speranta Prada***,Dr.Flory Revnic***,Dr.Gabriel Prada****
*Ambroise Pare` Hospital,University of Medicine,ParisVI,France
**UMF Tg.Mures
***NIGG”Ana Aslan”
****UMF”Carol Davila”

Rezumat
Este cunoscut faptul ca boala cardiaca reprezinta principala cauza a mortalitatii in intreaga lume atat in radul barbatilor cat si a femeilor peste varta de 65 de ani, de aceea exista o mare preocupare cu privire la masurile preventive si la strategiile de tratament in scopul reducerii ratei crescute a morbiditatii si mortalitatii din cauza bolilor cardiovasculare .Aceasta lucrare reprezinta o trecere in revista a datelor din literatura privind particularitatile bolii coronariene la varstnici si abordarile terapeutice si consideratiile care trebuiesc luate in calcul cand avem de aface cu pacient varstnic cu sinrom coronarian acut(ACS).
Cuvinte cheie: varstnici ,boala arterelor coronare,(CAD),sinrom coronarian acut,(ACS), infarctul miocardic acut(AMI),revascularizarea,tromboliza.

 

Abstract
It is known that cardiovascular disease(CV) is the leading cause of death in the whole world in both men and women after 65 years of age ,therefore it is a great concern on preventive and treatment strategies to slow down the high rate of morbidity and mortality from CV. This article is a review of the literature data on particularities of coronary artery disease in elderly people and therapeutic approaches and considerations that must be taken when dealing with an elderly patient with acute coronary syndromes(ACS).
Key words: Elderly,coronary artery disease(CAD),acute coronary syndromes(ACS),Acute myocardial infarction(AMI),revascularisation,trombolysis

 

Introduction
According with The World Health Organization,the age of 60 years is used to define elderly ,whereas the rest of classifications consider the age of 65 years and the patients older than 75 years are frail elderly.[1].
The prevalence and severity of CAD increases with age in both men and women. A significant number of people older than the age of 60 years have significant CAD with increasing prevalence of left main or triple-vessel disease.[2].
Evidence of myocardial infarction (MI), abnormal echocardiogram, carotid intimal thickness, or abnormal ankle-brachial index have been detected in 22 percent of women and 33 percent of men aged 65 to 70 years and 43 percent of women and 45 percent of men older than age 85 years. In addition, aging is associated to increased arterial stiffness and increased pulse pressure. There is an increase in fibrinogen, coagulation factors, platelet activity, increase in the levels of plasminogen activator inhibitor, resulting in impaired fibrinolysis. Inflammatory cytokines, endothelial dysfunction potentiate the development of atherosclerosis.[3].

Acute coronary syndromes(ACS)
At least 60 percent of hospital admissions for acute myocardial infarction (AMI) occur in
people older than 65 years, and this accounts for approximately 85 percent of deaths caused by AMI. With increasing age, the gender composition of patients presenting with AMI changes from predominantly men in the middle age, to an equal number of men and women and a majority of women in patients older than 80 years of age.

Mortality is higher in older women than in older men with AMI, as are adverse outcomes with thrombolytics, and glycoprotein (GP) IIb/IIIa inhibitors.[4].
As age increases, there are more patients with functional limitation, heart failure, prior coronary disease, renal insufficiency and patients with prior revascularization. Fewer older patients present with chest pain or ST elevation on ECG within 6 hours of symptom onset.

Thrombolysis
Most randomized clinical trials of thrombolysis have enrolled few patients older than 75 years of age. In a study of 14,341 of Medicare patients older than 65 years with ST elevation MI or left bundle bunch block, treated with thrombolytics there was a significant reduction of mortality at one year, but with 1.5 rate of intracranial hemorrhage.
The Fibrinolytics Therapy Trialists´ found a 15% percent reduction in mortality in patients older than 65 years, and there were 34 lives saved per 1000 patients. This result was more effective than in younger patients in whom 11 lives were saved per 1000 patients. Some studies that include patients up to 75 years of age have demonstrated that fibrinolytic, antiplatelet, and antithrombin therapy is associated with a survival advantage compared with placebo that may be similar to than that seen in younger patients.

The Global Utilization of Streptokinase and Tissue plasminogen activator for Ocluded coronary arteries-I (GUSTO I) found a significant absolute reduction in mortality with thrombolysis, specially with plasminogen activator in patients 65 to 85 years of age.
In patients older than 85 there was a beneficial trend with streptokinase. Finally, in a registry of Swedish Hearts Intensive Care Admissions, in a group of 6,891 patients 75 years and older, fibrolytic therapy was associated with a 13% relative reduction in the composite of mortality and cerebral bleeding complications at one year.

Complication of minor and major bleeding, intracranial bleeding and transfusion rates are higher in older patients compared with younger patients with all agents and some subgroups may not have an overall benefit from use of thrombolytics.
Those with high risk for ICH include patients older than 75 years, women, African Americans, small size, prior stroke, systolic blood pressure >160 mm Hg.
Fibrin-specific agents such as tissue plasminogen activator are also associated with increased stroke risk caused by ICH in the older than 75 year age group. Improper dosing of antiplatelet, antithrombin agents or combinations with low-molecular-weight heparins or GP IIB/IIIa inhibitors increase as well the risk of bleeding. Even with dose adjustments, however, the risk of bleeding appears increased in older patients.

Antithrombotic agents
Trial data shows that aspirin reduces mortality in patients older than 70 years and is recommended for routine administration to older patients with acute MI, although older patients have been less likely to receive aspirin than younger patients in routine clinical practice. The addition of clopidogrel to aspirin reduces major events, with similar absolute reductions in patients younger and older than 65 years.
In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), a chinese megatrial with almost 46,000 MI patients, with 11,934 patients older than 70, in which half of the patients were treated with clopidogrel and the other half with placebo, there was a 9% reduction in the composite end point of death, reinfarction and stroke without an increase in serious bleeding. It also showed a significant reduction in mortality in the patients treated with clopidogrel[5].

Patients were treated with 75 mg. of clopidogrel without the 300 milligrams loading dose. Low- dose of aspirin (< 100mg.) should be used when combined with clopidogrel. Prasugrel is not recomended in patients over 75 years and there is not enough information on the safety about ticagrelor. GP IIb/IIIa inhibitors appear efficacious in older patients but in patients over age 75 years when given in combination with thrombolytics there is an increased risk of bleeding. Bleeding is about two fold greater in older patients undergoing PCI who receive GP IIb/IIIa inhibitors compared with patients who do not, with intracranial bleeding as the most common site of fatal bleeds.

Antiplatelet and antithrombin agents have narrow therapeutic windows dosing should bebased on weight and renal function. Prospective observational analyses have shown that more than 40 percent of patients with acute coronary syndromes receiving unfractionated heparin, low-molecular-weight heparin, or GP IIb/IIIa inhibitors receive at least one dose in excess of guidelines. Factors associated with excess dosing were older age, female sex, renal insufficiency, low body weight, diabetes mellitus, and congestive HF.
Bleeding increased relative to the degree of excess dose and to the number of agents administered in excess.

Mortality is higher and length of hospital stay is longer in patients administered excess dosing and there is a close relation between bleeding and mortality. Women had twofold
higher rates of major bleeding than men and are three times more likely to receive excess GP IIb/IIIa doses than men. Approximately 25 percent of the bleeding risk was attributable to excess dosing in women versus 4.4 percent in men.

A randomized, controlled clinical trial for treatment of acute MI with PCI with eptifibatide administration has also reported increased bleeding resulting from lack of dose adjustment for reduced renal function [6] .
Fondaparinux and bivalirudin have shown less risk of bleeding in patients with ST-elevation MI (STEMI) and non-STEMI, including the elderly.
Primary angioplasty in experienced centers is associated with improved outcomes
compared with thrombolytic strategies in elderly patients with STEMI. Even when mortality is reduced with primary PCI compared with thrombolytic therapy, in-hospital mortality of patients older than the age of 75 years is estimated to be fivefold higher than patients younger than 75 years, and 1-year mortality is 7-fold greater. Achieving revascularization within 90 minutes is less likely in older patients with delays in diagnosis and/or transport to experienced centers.
Acute procedural success rates are also somewhat lower than in younger MI populations, there are increased risk of bleeding, complications including those at the access site, increased transfusion requirements and contrast-mediated renal dysfunction. However, PCI is preferred to fibrinolysis as a reperfusion option for elderly patients who experience STEMI.
The Global use of strategies to open Occluded Coronary Arteries (GUSTO) IIb trial[7]. was one of the first to report that PCI is superior to fibrinolysis among all age groups, and in particular that this strategy has the greatest benefit in the elderly, when all age groups are compared (Angioplasty Substudy Investigators, 1997).
The National Registry of Myocardial Infarction (NRMI)-2, evaluated 38,787 patients in which the treatment was performed within 12 hours of onset symptoms with either an intravenous thrombolytic agent or PCI.
Of these,10,2% were treated with streptokinase or anistreplase, 77,1% were treated with alteplase and 12,7% underwent primary PCI. In patients with STEMI who were aged 75 years, this study demonstrated that there was a lower risk of the combined end points of death and nonfatal stroke with primary PCI than with fibrinolysis, owing primarily to a higher rate of intracranial bleeding (2.5%) observed in the fibrinolysis group [8].

In the Senior Primary Angioplasty in Myocardial Infarction (Senior PAMI) study, PCI was superior to thrombolytic therapy from ages 65 to 79 with no advantage of primary PCI over thrombolysis in those older than 80 years of age[9] .
In the observational setting, the Global Registry of Acute Coronary Events (GRACE) [10].showed lower adjusted in-hospital mortality (or 0.62, 95% Ci 0.39–0.96) for primary PCI compared with fibrinolysis among 2,975 patients with STEMI who were aged ≥70 years [11].
The Tratamiento del Infarto Agudo del Miocardio en Ancianos (TRIANA) compared primary PCI and fibrinolysis in very old patients (mean age 81). It enrolled 266 patients, 134 allocated to PCI and 132 to fibrinolysis, both groups were well balanced in baseline characteristics, and it demonstrated that recurrent ischemia was less common in PCI-treated patients (0.8 vs. 9.7%,P< 0,001). No differences were found in major bleeds. A pooled analysis with two previous reperfusion trials performed in older patients showed an advantage of PCI over fibrinolysis in reducing death, re-infarction, or stroke at 30 days [12]. Finally, in a metaanalysis of 22 randomized trials (n= 6,763) evaluating the effects of primary PCI versus fibrinolysis, de Boer et al [13]., showed a mortality reduction favoring primary PCI in all age strata, as well as reductions in the risk of repeat MI and stroke. Regarding non STEMI, it is the most frequent manifestation of CAD and represents the largest group of patients undergoing PCI. Despite the advances in medical and interventional treatments, the mortality and morbidity remain high and equivalent to patients with STEMI after the initial month.

The ultimate goals of angiography and revascularization are mainly twofold: symptom relief, and improvement of prognosis in the short and long term. Different trials have shown that an invasive strategy reduces ischaemic endpoints mainly by reducing severe recurrent ischaemia and the clinical need for revascularization. The most recent metaanalysis of 3 randomized trials with a follow up of 5 years, showed a 19 % relative reduction in non fatal MI and death. This difference was mainly driven by reduction in MI. In these trials between 12,5% to 18,8% of the patients were over 75 years old, most of them in the high risk group, in whom the invasive therapy had the greatest effect. [14].

Drug eluting versus bare metal stents
Randomized controlled trials and pooled analyses of randomized trials in which drug eluting stents (DES) and bare metal stents (BMS) have been compared demonstrate similar acute and intermediate survival and MI outcomes among nonelderly patients.

Elderly patients enrolled in these trials has been small and no dedicated randomized comparison trial of DES to BMS has been performed among patients aged >65 years. In a study of 71,965 elderly patients (mean age 75 years) undergoing PCI, in those in whom DES were used, there was lower adjusted mortality (HR 0.83, 95% Ci 0.81–0.86) than contemporary controls undergoing BMS implantation. [15].DES-treated patients were also less likely than controls to undergo revascularization procedures within 2 years after PCI

Conclusion
Primary angioplasty in experienced centers is associated with improved outcomes compared with thrombolytic strategies in elderly patients with STEMI. Even when mortality is reduced with primary PCI compared with thrombolytic therapy, in-hospital mortality of patients older than the age of 75 years is estimated to be fivefold higher than patients younger than 75 years, and 1-year mortality is 7-fold greater .
One of the main future objective is being placed on preventive strategies for CAD in older patients and improving the quality of care using current therapies that were not designed for the elderly.
Increased investigation at both the basic level and clinical level is necessary to identify therapies that will benefit older patients on the basis of both the pathophysiology of age-related CV disease and the frequent presence of comorbid diseases.

References
1.Centers for Disease Control and Prevention: MMWR Series on Public Health and Aging. MMWR 2003; 52:101-106.
2.Lakatta EG. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part III: Cellular and molecular clues to heart and arterial aging. Circulation 2003; 107:490-497.
3.Willerson J. Systemic and local inflammation in patients with unstable atherosclerotic plaques. Prog Cardiovasc Dis 2002; 44:469-478. Review
4.Alexander K P, Chen A Y, Newby L K et al. Decline in GP 2b3a inhibitor overdosing with site-specific feedback in CRUSADE [abstract 3527]. Circulation 2007; 116 (Suppl. II),798–799.
5.COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative Group: Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005; 366: 1607-1621
6.Kirtane A, Piazza G, Murphy S et al: TIMI Study Group: Correlates of bleeding events among moderate- to high-risk patients undergoing percutaneous coronary intervention and treated with eptifibatide. Observations from the PROTECT-TIMI-30 Trial. J Am Coll Cardiol 2006; 47:2374-2379
7.An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction. The GUSTO Investigators N Engl J Med 1993; 329:673-682.
8.Tiefenbrunn A J, Chandra, N C, French, W J et al. Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) in patients with acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 1998; 31: 1240–1245.
9.Grines C L SENIOR PAMI: a prospective randomized trial of primary angioplasty and thrombolytic therapy in elderly patients with acute myocardial infarction.Presented at the 17th Annual Transcatheter Cardiovascular Therapeutics Symposium, October 16–21, 2005
10.Mehta R H, Sadiq I, Goldberg R J et al. For the GRACE Investigators. Effectiveness of primary percutaneous Coronary intervention compared with that of thrombolytic therapy in elderly patients with acute myocardial infarction. Am Heart J 2004; 147: 253–259
11.Mehta R H, Sadiq I, Goldberg R J et al. For the GRACE Investigators. Effectiveness of primary percutaneous Coronary intervention compared with that of thrombolytic therapy in elderly patients with acute myocardial infarction. Am Heart J 2004; 147:253–259.
12.Bueno H, Bertriu A, Heras M. et al. Primary angioplasty vs. fibrinolysis in very old patients with acute myocardial infarction: TRIANA (Tratamiento del Infarto Agudo de miocardio en Ancianos) Eur Heart J 2010; 32: 51-60.
13.de Boer S P, Westerhout C M, Simes R J et al. for the PCAT-2 Trialists Collaborators Group.Mortality and morbidity reduction by primary percutaneous coronary intervention is independent of the patient’s age. JACC Cardiovasc Interv 2010; 3: 324–331.
14.Fox K A, Clayton T C, Damman P, et al. Long term outcome of a routine versus selective invasive strategy in patients with non ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol 2010; 55:2435-2445.
15.Douglas P S, Brennnan J M, Anstrom K J, et al. Clinical effectiveness of coronary stents in elderly persons: results from 262,700 Medicare patients in the American College of Cardiology–National Cardiovascular Data Registry. J Am Coll Cardiol 2009; 53:1629–1641.

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NEW INSIGHTS IN ALZHEIMER`S DISEASE CELLULAR AND MOLECULAR MECHANISMS-THE ROLE OF LIPID RAFTS

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Dr.Flory Revnic*,Dr.Bogdan Paltineanu**,Dr.Catalina Pena*,Dr.Speranta Prada*,Dr.Cristian Romeo Revnic***,Dr.Gabriel Prada****
*NIGG”Ana Aslan”
**UMF Tg.Mures
***Ambroise Pare`Hospital,University of Medicine,ParisVI,France


Rezumat
Boala Alzheimer(AD) este o patologie legata de varsta care afecteaza mai mult de 37 milioane de persoane rezultand in neurodegenerarea structurii si functiei creierului uman.Anual sunt diagnosticate 5 milioane de noi cazuri de AD,la fiecare 7 secunde fiind raportat un nou caz.Pana in momentul de fata,nu exista nici o terapie curenta care sa stopeze ori sa reverseze aceasta patologie.Acest articol este o trecere in revista a datelor recente din literatura de specialitate privind mecanismele biopatologice ale AD cu privire la rolul platformelor mobile lipidice si modificarile acestora in AD.
Cuvinte cheie:Boala Alzheimer(AD),42 amino acidul amilioid βA,(Aβ 42) proteina precursoare a amiloidului(APP),platforme mobile de lipide de membrana

 

Abstract
Alzheimer`s disease(AD) is an age related disorder affecting more than 37 million of people resulting in a progressive neurodegeneration of human brain structure and function .Annualy 5 million new cases of AD are diagnosed,a new case being reported every 7 seconds. So far,there is no a current therapy that can stop or reverse this desease.This article is a review of recent literature data on biopathological mechanisms of AD regarding the role of lipid rafts and their changes in AD.
Key words:Alzheimer`s disease(AD), 42 amino acid amiloid beta A,(Aβ42)amyloid precursor protein(APP),Lipid rafts

 

Introduction
Lipid rafts definition
Lipid rafts are regions of membranes with a distinct, characteristic structural composition and that appear to act as platforms to colocalize proteins involved in intracellular signaling pathways.[1] The organization of membranes into such microdomains recognizes that, far from being randomly arranged,lipids may actually be highly organized within different parts of the membrane, and that this organization influences the way that membrane proteins are distributed [2]. Rafts are particularly rich in sphingolipids and cholesterol, and the side chains of the phospholipids present are usually highly enriched in saturated fatty acids compared with the surrounding nonraft regions of the membrane. Enrichment of phospholipids with saturated fatty acids allows for the close packing of lipids within rafts because [1] sphingolipids also contain saturated fatty acid side chains, and[2] cholesterol and saturated fatty acids are able to pack closely. As a result of the presence of cholesterol and saturated fatty acids, lipid rafts are more ordered and less fluid than the surrounding membrane. Cytoplasmic proteins that are covalently modified by saturated fatty acids (palmitoyl or myristoyl moieties) and cell surface proteins that are attached via a glycosyl phosphatidylinositol anchor are highly concentrated within lipid rafts. Many proteins involved in signal transduction,such as Src family kinases, G proteins, growth factor receptors,mitogen-activated protein kinase (MAPK),3 and protein kinaseC are predominantly found in lipid rafts, which appear to act as signaling platforms by bringing together (i.e., colocalizing)various signaling components, facilitating their interaction [3].
According to Kay Simons et al[4], AD is associated with neurodegeneration involving accumulation of extracellular amyloid aggregates (also known as senile plaques) (SP) of small, toxic, and highly amyloidogenic 42 amino acid amyloid beta (Aβ42) peptides and intracellular neurofibrillary tangles (NFTs) of hyper-phosphorylated tau (p-tau) protein . The accumulation of Aβ42 as diffuse plaques triggers the inflammatory responses due to microglial activation with release of pro-inflammatorycytokines and the most affected brain areas are the neo-cortex and hippocampus.
In addition, perturbations in the equilibrium between kinases and phosphatases resulting in hyperphosphorylation of tau protein that results in neuronal degeneration and neuronal loss [5].

 

Lipid rafts in biopathological mechanisms of AD
Lipid rafts are small nanodomains (10–200 m),heterogeneous, highly dynamic of which there are millions in a single cell [4,6]. Recently they have gained considerable attention as these membrane-embedded clusters of phospholipid-sphingolipid- and cholesterol-enriched,integral and peripheral membrane proteins are instrumental in the processing of APP holoprotein and hence the amyloidogenic process itself [7]. Sometimes small rafts can be stabilized to form larger platforms through protein–protein and protein–lipid interactions” [6]. The long, saturated acyl chains of sphingolipids allow tight packing hence their juxtaposition with the kinked, unsaturated acyl chains of bulk membrane phospholipids leads to phase separation. The cholesterol molecules can act as“spacers,” filling any gaps in sphingolipid packing [8].The researchers [6] pointed out the importance of lipid rafts in protein sorting and segregation with glycosylphosphatidylinositol(GPI)-anchored proteins, being preferentially localized in lipid rafts.
Also,other lipid modifications of proteins have been described, such as palmitoylation and myristoylation which may influence raft localization [6]. In describing membrane lipid clusters as moving platforms, or rafts perhaps the most important finding was that proteins could be segregated being selectively included or excluded from the rafts.
In this way, raft localization can serve to facilitate or obstruct protein interactions or act as a protein scaffold while allowing diffusion [9].

 

Lipid raft components and their changes in AD


Raft localization of APP and secretases
It has been emphasized that all of the enzymatic machinery responsible for the generation of Aβ42, and subsequent SP formation, are plasma membrane-resident secretases with modifier/accelerator/accessory proteins that are involved in the catabolic processing of the membrane-bound βAPP. Beside the β secretase, presenilins are transmembrane proteins localized predominantly in the endoplasmic reticulum (ER) and Golgi apparatus.[4]
The accelerator proteins include nicastrin, aph-1, pen-2,sortilin, TSPAN membrane proteins, and others [5] interact with PS-1 and PS-2 to form a large enzymatic complex known as Gamma secretase that cleaves APP to generate Aβ [10].
They also interact with antiapoptotic Bcl-2 through human FK506-binding protein 38, thus it may regulate the apoptotic cell death [11]. Generation of Aβ42 :Aβ is cleaved out of the APP through the sequential action of the β secretase and the PS-containing gamma secretase complex “amyloidogenic pathway”.
In the alternative,“non-amyloidogenic pathway”, APP is first cleaved by the Alpha -secretase, members of the ADAM (a disintegrin and metalloprotease) family of zinc metalloproteases, within the Aβ sequence thus precluding production of intact Aβ peptides [12].

 

Cellular mechanisms of Aβ oligomer-mediated neurotoxicity
Cellular prion protein (PrPC) signaling in AD. The key event driving AD pathogenesis is the accumulation of the 40–43 residue Aβ peptides in the brain [13].The peptides, particularly Aβ1–42, are aggregation prone,self-assembling to form a heterogeneous mixture of solubleoligomers, protofibrils and fibrils.
Only levels of the soluble,fibrillar oligomers were found to be elevated significantly in AD brains, where their levels correlate strongly withAD onset-severity, and are therefore proposed to be the major neurotoxic species in AD [14].
Consequent deleterious effects include neurotoxicity, memory impairments,inhibition of long-term potentiation (LTP), loss of dendritic spines and synaptic dysfunction [15]. The cellular mechanisms of A _ oligomer-mediated neurotoxicity are,however, poorly defined [16].The cellular prion protein (PrPC) was identified as a high-affinity receptor for Aβ _ oligomers [17]. PrPC is a GPI anchored cell surface glycoprotein.
It is a neuroprotective and plays important roles in limitation of excessive N-methyl-d-aspartate (NMDA) receptor activity which mightcause neuronal damage, neuronal oxidative stress defense,and metal ion homeostasis in the brain [18]. It also loweredAβ _ production through the inhibition of β secretase [19].However, fibrillar Aβ oligomers, but not monomers or fibrils, bound tightly to PrPC[17,20] and the presence of PrPC in hippocampal slices was shown to be responsible for the fibrillar Aβ oligomer-mediated inhibition of LTP [17]and the manifestation of memory impairments in an AD mouse model [15].
Recent studies have identified PrPC as a critical modulator of the AD-related synaptic dysfunction and cognitive impairments caused by Aβ oligomers[21]. Rushworth et al. [16] revealed details of the molecular and cellular mechanisms underpinning the PrPC-fibrillarAβ oligomer interaction and the resulting downstream cellular events.Fibrillar A _ oligomers cointernalised with PrPC from the cell surface and then trafficked to endosomes and lysosomes through low-density lipoprotein receptor-1 (LRP1)which is highly expressed in neuronal cells. It is a trans-membrane protein that facilitates the clathrin-mediatedendocytosis of PrPC[22] and has also been implicated in the neuronal uptake of Aβ oligomers [23].
The researchers[16] indicated that LRP1 functions as a transmembrane coreceptor that is involved in the Aβ oligomers-PrPC interaction and is required for their internalization, and cytotoxicity of the Aβ oligomers. It has been revealed [24] that PrPC also mediates the transcytosis of monomeric Aβ40 across the blood-brain barrier (BBB). The ability of fibrillar Aβ_oligomers to stimulate the endocytosis of PrPC, thus lowering its cell surface expression, impaired the ability of PrPC to inhibit β secretase, hence increasing the amyloidogenic processing of APP [16]. Thus, PrPC is no longer protective but contributes to Aβ oligomer neurotoxicity and furtherAβ production in a toxic, positive feedback loop. In addition, PrPC was required for the downstream cytotoxicity of the fibrillar Aβ oligomers through the activation of amember of the Src family kinases (SFK), Fyn kinase.
The latter is implicated in multiple pathways that underlie AD[25], including mediating the toxicity of Aβ oligomers and linking Aβ to tau toxicity [26], NMDA receptor phosphorylation and cell surface distribution, dendritic spine loss and lactate dehydrogenase [24]. PrPc together with the data on β secretase regulation provides a unifying molecular mechanism explaining the interplay between toxic Aβ species, NMDA receptor-mediated toxicity and copper homeostasis in pathogenesis of AD [27].
Interestingly, theinteraction of PrPCwith _-secretase [19] and the interac-tion of PrPCwith LRP1 [22] are both dependent upon thepolybasic N-terminal sequence (KKRP) of PrPC. This same region is also the crucial determinant of PrPC-mediated A _oligomer binding and toxicity. Surface plasmon resonance studies showed that deletion of the N-terminus blocked the toxicity of natural Aβ oligomers [28]. Thus, this region appears to be critical to a number of functions of PrPC,although its role in protective functions raises questions,would be a viable approach for the treatment of AD? [16].Rushworth et al. [16] found that not only the binding of the oligomers to PrPCbut also the downstream signaling mechanisms is dependent on the integrity of the raft microdomains, disruption of the rafts caused a signif-icant (80%) reduction in Aβ oligomer binding to the cells and prevented the activation of Fyn kinase.

The importance of using well-defined oligomer con-formations for biological activity potentially explain thediscrepancies in results showing a lack of PrPC-dependence of Aβ oligomer toxicity, as different studies have employed distinct, often poorly characterized Aβ oligomer prepara-tions or unnatural APP constructs which may not lead to the generation of biologically relevant Aβ oligomers [13]. As the conformation of fibrillar A β oligomers is a critical deter-minant of their PrPC-mediated binding and subsequent toxicity so, disrupting the conformation of Aβ oligomers could also be a potential therapeutic approach for AD [12].

Tau is a microtubule-associated protein that stabilizes neuronal microtubules under normal physiological conditions, however in AD, Aβ induces tau phosphorylation that can result in the generation of aberrant aggregates that are toxic to neurons [29]. Mutations in tau give rise to NFTs but not plaques and mutations in APP or in the probable APP proteases give rise to both plaques and tangles indicates that amyloid pathology occurs upstream of tau pathology[11].Aβ accumulation can be affected by numerous factors including increased rates of its production and/or impaired clearance. There are numerous proteases in the brain that participate in Aβ degradation and clearance including cathepsins, gelatinases, endopeptidases, aminopeptidase,neprilysin, serine protease, and insulin-degrading enzyme(IDE) [30]. Genetic linkage studies have also linked AD and plasma Aβ 42 levels to chromosome 10q, which harbors the IDE gene. IDE has been observed in human cerebrospinal fluid (CSF); and its activity levels and m-RNA are decreased in AD brain tissue and is associated with increased Aβ levels[31].

 

Conclusion
Although the function of APP remains to be fully elucidated, understanding APP trafficking and processing would also provide new insights into the regulatory mechanism of the amyloidogenic pathway.
The processing of APP involves numerous steps, including APP sorting, transport,internalization and sequential proteolysis [32].
Newly synthesized APP in ER is sorted through the trans-Golgi-network (TGN), trafficked to the cell surface membrane,and internalized via its NPTY motif near the C terminus of APP into endosome/TGN for recycling or into lysosome for degradation [33]. Altered routing of APP trafficking and distribution in neurons might lead to the amyloidogenic pathway, which is implicated in the pathology of AD.
Hence, the intracellular distribution and transport of APPare critical for Aβ production [34].
Sortilin is important in neuronal functions and shares genetic similarity with other Vps10p family members, such as SorLA, SORCS1and SORCS2 [35].
SorLA is down-regulated but sortilin is up-regulated in AD [36].
SorLA is reported to retain APPin Golgi, this can lead to decreasing Ab production. Mean-while, sortilin is associated with APP via head-to-head (the extracellular domain) and tail-to-tail (the intracellular domain) interactions; it regulates APP lysosomal and lipid raft trafficking through FLVHRY motif, and may promote lysosome-dependent degradation of APP [34].
They found that lack of the FLVHRY motif reduces APP lysosomal targeting and increases APP distribution in lipid rafts in cotransfected HEK293 cells, and in sortilin knockout mice[34].
Other, membrane-integral or -peripheral associated modulators of Aβ42 peptide generation such as TSPAN 12 further contributes to the kinetics of formation, cleavage,processing, and speciation of APP [37].
The participation of a membrane-spanning triggering receptor expressed in myeloid cells 2 protein supports a role for yet another plasma membrane-integral glycoprotein in phagocytosis and the clearance of Aβ42 peptides before they aggregate into SP [38]. Hence, depending on the processing pathways and biological signals utilized, the plasma membrane can be the source of both beneficial and detrimental signals to further modulate amyloidogenic, inflammatory or neurotrophic aspects of the AD process [5].

 

References
[1]. Schley PD, Brindley DN, Field CJ. (n-3) PUFA alter raft lipid composition and decrease epidermal growth factor receptor levels in lipid rafts of human breast cancer cells. J. Nutr. 2007;548–553.
[2]. Pike LJ. Lipid rafts: bringing order to chaos. J Lipid Res. 2003;44:655–67.3]. Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev MolCell Biol. 2000;1:31–41.
[3] Kai Simons , Julio L. Sampaio Membrane organization and lipid rafts Cold Spring Harb Perspect Biol 2011;1-17
[4] Hanuman T, Allam AR, Kiran KR, Sivaprasad A, Suresh BC, GedelaS. Alzheimer’s disease care and management: role of informationtechnology. Bioinformation 2 2007:91– [6] Pike LJ. The challenge of lipid rafts. J Lipid Res2009;50(Suppl.):S323–8.
[5] Kosicek M, Hecimovic S. Phospholipids and Alzheimer’s disease:alterations, mechanisms and potential biomarkers. Int J Mol Sci2013;14:1310–22.
[6]Brown DA, London E. Structure and function of sphingolipid-andcholesterol-rich membrane rafts. J Biol Chem 2000;275:17221–4.
[7]Lingwood D, Simons K. Lipid rafts as a membrane-organizing princi-ple. Science 2009;327:46–50.
[8]Verdile G, Gandy SE, Martins RN. The role of presenilin and itsinteracting proteins in the biogenesis of Alzheimer’s beta amyloid.Neurochem Res 2007;32:609–23
[9] Wang HQ, Nakaya Y, Du Z, Yamane T, Shirane M, Kudo T, et al. Inter-action of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2. Hum Mol Genet 2005;14:1889–902
[10] Kessels HW, Nguyen LN, Nabavi S, Malinow R. The prion protein as areceptor for amyloid-beta. Nature 2010;466:E3–4.[
[11] Hardy J. The amyloid hypothesis for Alzheimer’s disease: a criticalreappraisal. J Neurochem 2009;110:1129–34
[12] Tomic JL, Pensalfini A, Head E, Glabe CG. Soluble fibrillar oligomerlevels are elevated in Alzheimer’s disease brain and correlate withcognitive dysfunction. Neurobiol Dis 2009;35:352–8.
[13] Gimbel DA, Nygaard HB, Coffey EE, Gunther EC, Laurén J, Gimbel ZA,et al. Memory impairment in transgenic Alzheimer mice requirescellular prion protein. J Neurosci 2010;30:6367–74.
[14] Rushworth JV, Griffiths HH, Watt NT, Hooper NM. Prion protein-mediated toxicity of amyloid- _ oligomers requires lipid rafts andthe transmembrane LRP1. J Biol Chem 2013;2:1–32.
[15] Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cel-lular prion protein mediates impairment of synaptic plasticity byamyloid-beta oligomers. Nature 2009;457:1128–32.
[16] Youa H, Tsutsuib S, Hameeda S, Kannanayakalb TJ, Chena L, Xiac P,et al. A _ neurotoxicity depends on interactions between copper ions,prion protein, and N-methyl-d-aspartate receptors. Proc Natl AcadSci USA 2012;109:1737–42.
[17] Griffiths HH, Whitehouse IJ, Baybutt H, Brown D, Kellett KAB, JacksonCD, et al. Prion protein interacts with BACE1 protein and differentiallyregulates its activity toward wild type and Swedish mutant amyloidprecursor protein. J Biol Chem 2011;286:33489–500.
[18] Chen S, Yadav SP, Surewicz WK. Interaction between humanprion protein and amyloid- _ (A _) oligomers. J Biol Chem2010;285:26377–83.
[19] Kudo W, Lee1 HP, Zou1 WQ, Wang X, Perry G, Zhu X, et al. Cellu-lar prion protein is essential for oligomeric amyloid-beta-inducedneuronal cell death. Hum Mol Genet 2012;21:1138–44
[20] Taylor DR, Hooper NM. The low-density lipoprotein receptor-relatedprotein 1 (LRP1) mediates the endocytosis of the cellular prion pro-tein. Biochem J 2007;402:17–[23] Kanekiyo T, Zhang J, Liu Q, Liu C, Zhang L, Bu G. Heparan sulphateproteoglycan and the low-density lipoprotein receptor-related pro-tein 1 constitute major pathways for neuronal amyloid-beta uptake.J Neurosci 2011;31:1644–51.
[21] Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, VortmeyerA, et al. Alzheimer amyloid-beta oligomer bound to postsynap-tic prion protein activates Fyn to impair neurons. Nat Neurosci2012;15:1227–35.
[22] Haass C, Mandelkow E. Fyn-tau-amyloid: a toxic triad. Cell2010;142:356–8.
[23] Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, et al. Amyloid-beta/Fyn induced synaptic, network, and cognitive impairmentsdepend on Tau levels in multiple mouse models of Alzheimer’s dis-ease. J Neurosci 2011;31:700–11.
[24] Rushworth JV, Hooper NM. Lipid rafts: linking Alzheimer’s amyloid- _ production, aggregation, and toxicity at neuronal membranes. IntJ Alzheimers Dis 2011, 603052.
[25] Watt NT, Taylor DR, Kerrigan TL, Griffiths HH, Rushworth JV, White-house IJ, et al. Prion protein facilitates uptake of zinc into neuronalcells. Nat Commun 2012;3:1134
[26] Broersen K, Rousseau F, Schymkowitz J. The culprit behind amyloidbeta peptide related neurotoxicity in Alzheimer’s disease: oligomersize or conformation? Alzheimers Res Ther 2010;2:12–26.
[27] Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau proteinin both physiological and pathological conditions. Physiol Rev2004;84:361–84
[28] Saido T. Alzheimer’s disease as proteolytic disorders: anabolismand catabolism of beta-amyloid. Neurobiol Aging 1998;19:S69–75
[29] Edland SD. Insulin-degrading enzyme, apolipoprotein E, andAlzheimer’s disease. J Mol Neurosci 2004;23:213–7.
[30] Thinakaran G, Koo EH. Amyloid precursor protein trafficking,processing, and function. J Biol Chem 2008;283:29615–9.
[31] Yang M, Virassamy B, Vijayaraj SL, Lim Y, Saadipour K, Wang YJ, et al.The intracellular domain of sortilin interacts with amyloid precursorprotein and regulates its lysosomal and lipid raft trafficking. PLoSONE 2013;8(5):e63049.
[32] Lorenzen A, Samosh J, Vandewark K, Anborgh PH, Seah C, MagalhaesAC, et al. Rapid and direct transport of cell surface APP to the lysosomedefines a novel selective pathway. Mol Brain 2010;3:11.
[33] Finan GM, Okada H, Kim TW. BACE1 retrograde trafficking isuniquely regulated by the cytoplasmic domain of sortilin. J Biol Chem2011;286:12602–16.
[34] Pallesen LT, Vaegter CB. Sortilin and SorLA regulate neuronalsorting of trophic and dementia-linked proteins. Mol Neurobiol2012;45:379–87.
[35] Singaraja RR. TREM2: a new risk factor for Alzheimer’s disease.Clin Genet 2013, http://dx.doi.org/10.1111/cge.12108

MANAGEMENT OF OESOPHAGEAL CANCER

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Dr.Bogdan Paltineanu
UMF Tg.Mures


Rezumat
Aceas articol este o trecere in revista a datelor din literatura de specialitate privind managementul evaluarii cancerului esofagian si gastric si stadializarea.Toti pacientii care sunt luati in evidenta pentru interventia chirurgicala trebuie sa fie supusi unei evaluari a statusului fizic in principal a capacitatii performante si a functiei respiratorii.Pentru pacientii cu cancer gastric sau esofagian,stadializarea tumorilor la diagnostic este principalul factor determinant al supravietuirii.Implicarea ganglionilor limfatici este cel mai important si singurul factor,urmat de stadiul T.La pacientii cu cancer esofagian ,prezenta nodulilor implicati reduce supravietuirea la 5 ani de la 60-80% la 25%.
Cuvinte cheie:cancer esofagian,stadiu tumoral,ganglioni limfatici

 

Abstract
This article is a review of the literature data on management of oesophageal gastric cancer assesement and staging. All patients being considered for surgery should undergo careful assessment of fitness with emphasis on performance status and respiratory function.For patients with gastric or oesophageal cancer, tumour stage at diagnosis is the main determinant of survival. Lymph node involvement is the most important single factor, followed by T stage.In patients with oesophageal cancer, the presence of involved nodes reduces five year survival from 60-80% to approximately 25%.
Key words:oesophageal cancer,tumor stage,lymph node

 

Introduction
For patients with gastric or oesophageal cancer, tumour stage at diagnosis is the main determinant of survival. Lymph node involvement is the most important single factor, followed by T stage.In patients with oesophageal cancer, the presence of involved nodes reduces five year survival from 60-80% to approximately 25%.
The presence of more than four involved nodes or M1a node involvement is associated with significantly reduced survival, although it does not necessarily preclude long term survival following resection[1]. Long term survival is not seen in patients with junctional cancers who have cervical nodal disease or nodal metastases in three body compartments (neck, mediastinum and abdomen)[2].In patients with gastric cancer both the number of involved nodes and the ratio of involved to uninvolved nodes significantly influence long term outcome.[3,4].
T stage is the most significant factor in node negative cases.[5].In patients with oesophageal cancer preoperative identification of lymph node involvement by EUS is associated with a poor prognosis.[6].Selected patients with T4 gastric cancer in the absence of extensive lymph node involvement can have long term survival (five years and over) following surgical resection[7,8].
The patients most likely to benefit from curative treatment are those without distant metastases and with limited lymph node involvement. Long term survival is possible in highly selected patients with more advanced disease but the majority of patients in this category will survive for less than two years following resection.
Oesophageal cancer should undergo careful preoperative staging to enable targeting of potentially curative treatment to those likely to benefit.
B Patients with oesophageal cancer who have distant metastases or patients with oesophageal cancer who have metastatic lymph nodes in three compartments(neck, mediastinum and abdomen) on preoperative staging are not candidates for curative treatment.
C When M1a nodal involvement in oesophageal cancer, or extensive lymphadenopathy in any cancer, is identified on preoperative staging, the anticipated poor prognosis should be carefully considered when discussing treatment options.
Where there is clear evidence of incurable disease following staging, attempts at resection should be avoided.

 

Tumor stage and quality of life
There is no evidence directly addressing the influence of tumour stage on quality of life in patients with oesophageal cancer. Surgery results in a reduction in quality of life which only returns to preoperative levels in patients surviving more than two years. In these patients quality of life improves after three to four months and approaches preoperative levels at around nine months.[9].
D The possibility of reduction in quality of life after surgery should be considered when discussing treatment options, particularly when preoperative staging suggests that surgery would be unlikely to be curative.

 

Assessement of preoperative fitness
Of all patients with oesophageal cancer who are surgically assessed, over half (57%) are rejected for surgery because they are considered insufficiently fit.[10]. In those who have surgery, respiratory (20-41%) and cardiac (11-16%) complications are the major causes of postoperative mortality.[2,10]. Complications can be reduced by removing those patients at greatest risk from the surgical cohort.[11]. This is most frequently achieved by exercising clinical judgement and there is evidence that this is predictive of in-hospital mortality.[10]. The more objective POSSUM (physiological and operative severity score for the enumeration of mortality and morbidity) scoring system is also predictive of in-hospital death. Both POSSUM and ASA grade(American Society of Anesthesiologists) independently predicted medical complications.[10].
Scoring systems for risk prediction specifically for patients with oesophageal cancer have been developed. Use of a composite scoring system based on general performance status as well as cardiac, hepatic and respiratory function has been shown to reduce postoperative mortality from 9.4% to 1.6% but the system relied on subjective judgement and appeared cumbersome.[11].
A simpler but unvalidated scoring system based on age, spirometry and performance status predicted an incrementally increasing risk of respiratory and cardiac complications although it did not predict postoperative mortality.[12].
A Japanese study found no association between preoperative cardiac or hepatic dysfunction and the development of postoperative complications, but respiratory dysfunction, FVC (forced vital capacity) <80% or FEV1 (forced expiratory volume in first one second)<70%, did predict complications.[13].156 Another Japanese study did not find routine pulmonary function tests useful but found that expired gas analysis during exercise predicted cardiopulmonary complications.[14]. This measure of cardiopulmonary reserve is not routinely available. In an American study of high-risk surgical patients, symptom-limited stair climbing predicted postoperative complications.[15].
The role of dynamic testing of cardiac function has not been addressed in patients with oesophageal cancers.
B All patients being considered for surgery should undergo careful assessment of fitness
with emphasis on performance status and respiratory function.
5.4 pathological Staging of resected specimens SAGOC illustrated the variability in the reporting of the pathology of resection specimens from patients with oesophageal and gastric carcinomas[2].
Accurate completion of pathology reports is essential to ensure accurate pathological staging (for comparison with clinical staging), to inform assessment of prognosis, to indicate the completeness and adequacy of resection and to assist in audit.

 

Important pathological parameters
Resection specimens need to be dissected carefully for accurate tumour staging. Tumour stage correlates with prognosis . The Royal College of Pathologists (RCP), in its standards and minimum data sets has identified important parameters.[16].The RCP standards also give information on the ideal preparation and dissection methods for resection specimens and the information which should be recorded for each resection.
The following parameters have been identified as important in the RCP standards:
Oesophageal, and junctional type I and II cancers – extent within the wall, longitudinal margins, vascular invasion and total number of lymph nodes and number and sites in which there is metastatic tumour. The latter is important to identify M1 nodes as these are associated with a poor prognosis.[2,3,16].

Resection specimens of oesophageal and gastric cancer resections should be reported according to, or supplemented by, the Royal College of Pathologists’ minimum data sets.

 

Assessement and staging
Management of oesophageal and gastric cancer
Treatment principles
The choice of treatment for patients with oesophageal or gastric cancer depends on the stage of the disease, and on the condition and wishes of the patient. Patients with resectable lesions may be unfit for surgery or potentially curative chemoradiotherapy by virtue of significant comorbid disease . The patient’s preoperative status and comorbidity are strong predictors of outcome. The management of all patients should be discussed in an appropriate multidisciplinary meeting (MDM) where all staging and other relevant information is available to all members of the team. Patients should be informed of the treatment options available (surgery, chemotherapy or radiotherapy), and these should be evaluated in terms of risks and benefits.[9].
The management of all patients who are diagnosed with gastric or oesophageal cancer, should be discussed within a multidisciplinary forum.
Stress associated with the diagnosis and treatment of cancer can cause significant psychological morbidity. There is some evidence that providing emotional, spiritual and practical support may have a positive effect on patients’ well-being.[17]. Giving better information and taking time to explain and understand patients’ concerns can result in decreased psychological distress for patients and have a positive impact on patients’ quality of life.[18].
Obtaining support from national and local support groups can improve a patient’s ability to cope and information relating to these support services should be made readily available.[19].

 

Conclusion
Health professionals providing care and treatment for patients with oesophageal or gastric cancer should seek appropriate training in communication skills.
D Information relating to local and national support services should be made available to both patients and carers.
Patients should be given clear information relating to the potential risks and benefits of treatment.

 

References
1. Tachibana M, Dhar DK, Kinugasa S, Kotoh T, Shibakita M, Ohno S, et al. Esophageal cancer with distant lymph node metastasis: prognostic significance of metastatic lymph node ratio. J Clin Gastroenterol 2000;31(4):318-22
2. Lerut T, Nafteux P, Moons J, Coosemans W, Decker G, De Leyn P, et al. Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: impact on staging, disease-free survival, and outcome: a plea for adaptation of TNM classification in upper-half esophageal carcinoma. Ann Surg 2004;240(6):962-72.
3. Kim JY, Bae HS. A controlled clinical study of serosa-invasive gastric carcinoma patients who underwent surgery plus intraperitoneal hyperthermo-chemo-perfusion (IHCP). Gastric Cancer 2001;4(1):27-33.
4. Y u CC, D. A. Levison, et al. Pathological prognostic factors in the second British Stomach Cancer Group trial of adjuvant therapy in resectable gastric cancer. Br J Cancer 1995;71(5):1106-10.
5. Kooby DA, Suriawinata A, Klimstra DS, Brennan MF, Karpeh MS. Biologic predictors of survival in node-negative gastric cancer. Ann Surg 2003;237(6):828-35; discussion 35-7.
6. Pfau PR, Ginsberg GG, Lew RJ, Brensinger CM, Kochman ML. EUS predictors of long-term survival in esophageal carcinoma. Gastrointest Endosc 2001;53(4):463-9.
7. Dhar DK, Kubota H, Tachibana M, Kinugasa S, Masunaga R, Shibakita M, et al. Prognosis of T4 gastric carcinoma patients: an appraisal of aggressive surgical treatment. J Surg Oncol 2001;76(4):278-82.
8. 0 Saito H, Tsujitani S, Maeda Y, Fukuda K, Yamaguchi K, Ikeguchi M, et al.Combined resection of invaded organs in patients with T4 gastric carcinoma. Gastric Cancer 2001;4(4):206-11.
9. Blazeby JM, Farndon JR, Donovan J, Alderson D. A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer 2000;88(8):1781-7.
10. McCulloch P, Ward J, Tekkis PP. Mortality and morbidity in gastrooesophageal cancer surgery: Initial results of ASCOT multicentre prospective cohort study. BMJ 2003;327(7425):1192-6.
11. Bartels H, Stein HJ, Siewert JR. Preo153 McCulloch P, Ward J, Tekkis PP. Mortality and morbidity in gastrooesophageal cancer surgery: Initial results of ASCOT multicentre
prospective cohort study. BMJ 2003;327(7425):1192-6.
12. Ferguson MK, Durkin AE. Preoperative prediction of the risk of pulmonary complications after esophagectomy for cancer. J Thorac Cardiovasc Surg 2002;123(4):661-9.
13. Nagamatsu Y, Shima I, Yamana H, Fujita H, Shirouzu K, Ishitake T. Preoperative evaluation of cardiopulmonary reserve with the use of expired gas analysis during exercise testing in patients with squamous cell carcinoma of the thoracic esophagus. J Thorac Cardiovasc Surg 2001;121(6):1064-8.
14. Girish M, Trayner E, Jr., Dammann O, Pinto-Plata V, Celli B. Symptomlimited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery. Chest 2001;120(4):1147-51.
15. Gauss A, Rohm HJ, Schauffelen A, Vogel T, Mohl U, Straehle A, et al. Electrocardiographic exercise stress testing for cardiac risk assessment in patients undergoing noncardiac surgery. Anesthesiology 2001;94(1):38-46.
16. The Royal College of Pathologists. Standards and datasets for reporting cancers.[cited 06 April 2006]. Available from url: http://www.rcpath. org/index.asp?PageID=254
17. Fallowfield L, Ratcliffe D, Jenkins V, Saul J. Psychiatric morbidity and its recognition by doctors in patients with cancer. Br J Cancer 2001;84(8):1011-5.
18. Patient-centred care. In: Department of Health. Guidance on Commissioning Cancer Services: Improving Outcomes in Upper Gastro-intestinal Cancers: The Manual. London: Department of Health;2001. [cited 06 January 2006]. Available from url : http://www.dh.gov.uk/assetRoot/04/08/02/78/04080278.pdf
19. Jenkins V, Fallowfield L, Saul J. Information needs of patients with cancer: results from a large study in UK cancer centres. Br J Cancer 2001;84(1):48-51


MANAGEMENT OF ACCIDENTAL EXPOSURE TO EBOLA VIRUS IN BIOSAFETLY LEVEL(BSL4)- LABORATORES

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Emil Ionita
Dr.Ion Cantacuzino

 
Rezumat
Virusul Ebola este un pathogen zoonotic,care determina febra hemoragica la om.Speciile Zaire ebola virus(ZEBOV)si Sudan ebola virus(SEBOV) ca si Bundibugyo ebola virus,un membru prototip propus al unei noi specii, au cauzat epidemii in randul populatiei umane in Africa cu o rata a mortalitatii intre 25-90%.Acest articol este o trecere in revista a datelor din literatura de specialitate cu privire la managementul in cazul unei expuneri accidentale cauzata de contaminarea cu virusul Ebola datorata intepaturii cu acul unei seringi in cursul experimentelor pe animale la un laborator de cercetare din Hamburg 2009.
Cuvinte cheie:Virusul Zair ebola(ZEBOV),virusul ebola Sudan(SEBOV),virusul ebola Bundibugyo,febra hemoragica

 

Abstract
Ebola virus is a zoonotic pathogen causing hemorrhagic fever in humans. The species Zaire ebolavirus (ZEBOV)and Sudan ebolavirus (SEBOV), as well as Bundibugyo
ebolavirus, a proposed prototype member of a new species, have caused epidemics among humans in Africa with case fatality rates ranging from 25% to 90%.
This article is a review of the literature data on management in a case of accidental exposure to Ebola virus due to needlestick injury during an animal experiment in the biosafety level 4 laboratory in Hamburg 2009.
Key words:Zaire ebola virus(ZEBOV), Sudan ebola virus(SEBOV),hemorrhagic fever

 

Introduction
Ebola virus is a zoonotic pathogen causing hemorrhagic fever in humans. The species Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV), as well as Bundibugyo ebolavirus, a proposed prototype member of a new species, have caused epidemics among humans in Africa with case fatality rates ranging from 25% to 90%.
The virus is transmitted from human to human by infectious body fluids, often in hospital settings [1–4]. Neither a vaccine, an effective treatment, nor a postexposure prophylaxis (PEP) for humans is currently available. For these reasons, experiments with Ebola virus have to be performed in biosafety level (BSL)-4 laboratories. Despite high standards of protection in these laboratories,laboratory workers are still at risk of contracting Ebola hemorrhagic fever, in particular during animal experimentation.
In the scientific literature are documented three laboratory accidents with Ebola virus: 1 case was fatal [5],1 case was symptomatic and survived [6], and in 1 case,there was no evidence that the accident resulted in infection [7].

In this paper the scientists [1], have reported a case report on the management of a laboratory accident with Ebola virus that occurred in the BSL-4 facility at the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany in 2009.
A woman virologist who was working in the BSL-4 laboratory pricked herself in the finger during a mouse experiment on 12 March 2009. The syringe contained ZEBOV from culture supernatant that had been concentrated by ultracentrifugation and mixed 1:1 with incomplete Freund’s adjuvant for immunization of mice. The material was injected into the animal before the accident happened.
When the laboratory worker tried to recap the needle, it penetrated the cap laterally and subsequently all 3 gloves. The puncture site on the skin was visible, but it did not bleed. The wound was disinfected after leaving the laboratory. Overnight, reverse-transcription polymerase chain reaction (RT-PCR) analysis revealed that the ultracentrifuged material, before mixing with Freund’s adjuvant, contained 2.6 3 1010 copies/mL ZEBOV. Traces of material in the syringe (about 2 lL) were recovered and tested as well: it contained 1.4 3 108 copies/mL. The effect of incomplete Freund’s adjuvant on Ebola virus was retrospectively tested by immunofocus assay. Mixing cell culture supernatant with adjuvant reduced the virus titer 4.4-fold. Thus,Ebola virus mixed with incomplete Freund’s adjuvant essentially retains its infectivity.

The syringe contained Zaire ebolavirus (ZEBOV) mixed with Freund’s adjuvant.
Neither an approved treatment nor a postexposure prophylaxis (PEP) exists for Ebola hemorrhagic fever.
Following a risk–benefit assessment, it was recommended the exposed person take an experimental vaccine that had shown PEP efficacy in ZEBOV-infected nonhuman primates (NHPs) [12]. The vaccine, which had not been used previously in humans, was a live-attenuated recombinant vesicular stomatitis virus (recVSV) expressing the glycoprotein of ZEBOV. A single dose of 5 3 107 plaque-forming units was injected 48 hours after the accident. The vaccinee developed fever 12 hours later and recVSV viremia was detectable by polymerase chain reaction (PCR) for 2 days. Otherwise, the person remained healthy, and ZEBOV RNA, except for the glycoprotein gene expressed in the vaccine, was never detected in serum and peripheral blood mononuclear cells during the 3-week observation period.

An infectious disease specialist at the University Medical Center Hamburg saw the patient immediately after the accident.
It was decided to consult colleagues from Canada and the United States to explore possibilities for PEP and treatment. The first teleconference was held in the evening of 12 March; a second one on 13 March. Filovirus experts from the Laboratory of Virology, National Institutes of Health, Hamilton, Montana; the Boston University School of Medicine; the Public Health Agency of Canada, Winnipeg, Canada; the Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia; the US Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, and the University of Texas Medical Branch, Galveston, Texas, participated in the consultations.
Various possibilities for PEP and treatment, which had previously been tested in nonhuman primates (NHPs), were discussed, including recombinant nematode anticoagulant protein c2 (rNAPc2) [8], recombinant human activated protein C [9], siRNA (unpublished at the time of accident) [10], interferon (L. Hensley, unpublished data), immune therapy with neutralizing antibodies [11, 12], and experimental vaccines [13–18].
The expert panel eventually recommended postexposure vaccination with live-attenuated recombinant vesicular stomatitis virus (recVSV) expressing the glycoprotein of ZEBOV (VSVDG/ZEBOVGP) for the following reasons: (1) VSVDG/ZEBOVGP has shown PEP efficacy in NHP [12]; (2) it is well tolerated in immunocompromized NHPs [14]; (3) a similar vaccine shows PEP efficacy against Marburg virus [16] and SEBOV [19]; (4) at the time of the accident, unpublished data indicated PEP effect (33% survival) of the recVSV-based Marburg virus vaccine, even 48 hours postinfection [15]; and (5) recVSV vectors show good safety profile in NHPs as long as the vector is not inoculated directly into the central nervous system [20]. Immediately following the first teleconference, the VSVDG/ZEBOVGP vaccine was shipped from Winnipeg, Canada, to Hamburg. An emergency clearance from customs was obtained in advance.
ZEBOV infection is associated with 80–90% case fatality rate [20];9. 1 of 3 documented needlestick injuries with Ebola virus had a fatal outcome [5–7].
The risk of ZEBOV infection and fatal outcome due to the accidental exposure was considered to be low, but real. A hypothetical risk of life-threatening adverse effects due to the experimental vaccine was considered acceptable in view of the anticipated benefit and the risk of ZEBOV infection. In addition, overwhelming recVSV replication was expected to be amenable to treatment with ribavirin and type I interferon, both of which strongly inhibit VSV replication in vitro and in vivo [21–25].
Members of the Institutional Ethics Committee of the University Medical Center, who were available for evaluation of the planned interventions, also shared these views. As a result, the patient was recommended to take the experimental vaccine.
A PEP and treatment protocol with informed consent was drafted and signed by the patient. The patient voluntarily agreed on being hospitalized on 13 March. The responsible public health authorities, infectious disease specialists, and virologists considered the risk of virus transmission during the incubation period extremely low, as available epidemiological evidence indicates that Ebola virus is spread by ill or deceased patients through direct contact with infectious body fluids [1–3]. It was agreed that surveillance on a regular infectious disease ward in a single room with anteroom and negative pressure is appropriate. Standard barrier nursing precautions were implemented (gown, gloves, N95 mask, eye protection). It was also taken into account that this level of isolation is less stressful to the patient and the hospital staff.
A maximum incubation period of 21 days was assumed and,therefore, surveillance was foreseen for this period of time. Daily monitoring during this period included (1) body temperature; (2) D-dimer level, which is an early marker of Ebola hemorrhagic fever in NHPs [8] and is increased in humans with Ebola hemorrhagic fever [26]; (3) hematology and blood chemistry; and (4) Ebola virus in plasma and peripheral blood mononuclear cells (PBMCs) using real-time RT-PCR [27, 28]. PBMCs were tested because the virus was detected in these cells in asymptomatic Ebola virus infections [29]. Fever, a rise in the D-dimer level, or the detection of Ebola virus RNA by RT-PCR were defined as independent indications of Ebola virus infection.
If any of these showed a positive indication, the patient would have to be transferred to the Biocontainment Patient Care Unit (BPCU) of the University Medical Center . Isolation in the BPCU was required twice during the observation period for the reasons given below. The BPCU was located in a separate building and included a single patient room with 2 airlocks. It had an independent ventilation system and was maintained under negative pressure. Exhaust air underwent high efficiency particulate air (HEPA) filtration. Staff was specifically trained and dressed in biosafety suits equipped with HEPA filters.
A disinfectant shower enabled transfer of specimens out of the unit for laboratory analysis. All waste was treated in an autoclave.
Personal protective equipment was decontaminated in the disinfectant shower before leaving the unit. Routine laboratory investigations were performed by the Clinical Chemistry Department without special precautions, as soon as a negative PCR result for a parallel sample had been communicated. If PCR results were not available in a timely manner, point of care diagnostics was performed within the BPCU.
If an Ebola virus infection would have been diagnosed in the patient, the expert panel recommended treatment with rNAPc2, an inhibitor of factor VIIa/tissue factor that has shown some therapeutic potential in NHPs infected with Ebola virus [7] and already undergone phase II studies for other medical conditions [30]. ARCA Biopharma generously released a batch of rNAPc2 on 13 March, which arrived in Hamburg on 15 March. In addition, Ebola virus–specific small interfering RNA (siRNA) preparations were provided by Tekmira Pharamaceuticals and arrived in Hamburg on 14 March. This siRNA had shown PEP effects in NHPs (unpublished at the time of accident) [10].
The VSVDG/ZEBOVGP vaccine was administered on 14 March, 48 hours after the accident: a single dose of 2.5 mL reason for this interference was not known, it was recommended not to use drugs with effects on the clotting system and the inflammatory response, including rNAPc2, in combination with the recVSV vaccine.
The next day (day 3 after the accident), the patient developed fever and myalgia . The symptoms were not treated. As it could not be decided if the fever was an adverse effect of the vaccine or a sign of an Ebola virus infection,the patient was transferred to the BPCU. The ZEBOV GP genespecific real-time RT-PCR [29] and a VSV-specific specific realtime RT-PCR (primer VSV-F1 GACCTTGTATCCTTGAAAGCC,primer VSV-R1 CATTTGTGTTCTGCCCACTC,and probe FAM-GCTTCCAGAACCAGCGCAGATGACAAABBQ)were positive with plasma samples from days 3 and 4. The cycle threshold (Ct) values were high: VSV RT-PCR day 3: Ct 34;day 4 morning: Ct 32; day 4 evening: Ct 34; ZEBOV GP RT-PCRday 3: Ct 31; day 4 morning: Ct 33; day 4 evening: Ct 35. (Note: The Ct is the PCR cycle at which the sample reaches the detection level. The higher the Ct, the lower the amount of virus RNA in the sample. A Ct above 30 indicates low viremia, around 103–104 genome copies/mL plasma.) The Ebola virus–specific L gene PCR [28] was negative, indicating that the signals from VSV and ZEBOV GP RT-PCR originated from low-level viremia of the recVSV rather than from ZEBOV replication. All 3 PCR assays remained negative during the rest of the observation period. The temperature returned to normal in the evening of day 3. Blood chemistry, coagulation, and hematology parameters were in the normal range. As no disease developed and fever and positive PCR signals could not be attributed to Ebola virus infection, the public health authorities released the patient from BPCU.
On day 7, surveillance was continued on the regular infectious disease ward as described above. A slow increase in the D-dimer level starting day 9 led again to the decision to transfer the patient to the BPCU on day 11.
However, as no signs or symptoms developed, and other laboratory parameters remained normal—except for a slight elevation of the fibrinogen level—and all PCR assays remained negative, it was decided to retransfer the patient to the regular infectious disease ward on day 14. The elevation of the D-dimer level, as measured by Siemens Innovance assay, persisted. However, it could not be confirmed by 2 other D-dimer assays (Triage and bioMe´rieux Vidas), and the exact cause of this elevation has not been determined.
No signs of thrombosis were detected by physical examination and Doppler sonography. The remaining clinical course was uneventful and the patient was discharged from hospital on day 21.

 

CONCLUSIONS
A key beneficial factor in the medical management of this accidental exposure to Ebola virus has been the immediate communication with the scientific community. Several ad hoc teleconferences were held, complemented by extensive e-mail communication, to support decision making of the team in Hamburg. Within a few hours after the accident, the way forward was defined based on the knowledge of leading experts in the field. Unpublished data were shared and investigational vaccines and drugs were provided in a completely unbureaucratic way [31].
One may ask why the team in Hamburg chose this ad hoc procedure and not activated a defined operational plan to manage the patient. The Bernhard Nocht Institute followed a general operational plan for the management of accidental laboratory exposures, which included agreements with the Infectious Diseases Unit at the University Medical Center. Both virologists and clinicians in Hamburg had been aware of experimental treatment options as published in the literature.
Finally, the question remains whether the patient had been infected with Ebola virus or not.
Investigation of the patient’s serum samples revealed high IgG titers to VSV and robust IgG titers to Ebola virus GP.
No further serological evidence could be obtained that would support an Ebola virus infection (unpublished data).
The serological data suggest that the patient was either not infected with Ebola virus, which is considered more likely, or that the vaccine reduced virus replication to an extent that the development of a proper humoral immune response to the virus was prevented. The Ebola virus GP antibody titers are most likely a result of the vaccination.

 

References
1. Stephan Gunther,1 Heinz Feldmann,2 Thomas W. Geisbert,3 Lisa E. Hensley,4 Pierre E. Rollin,5 Stuart T. Nichol,5Ute Stroher,6 Harvey Artsob,6 Clarence J. Peters,7 Thomas G. Ksiazek,8 Stephan Becker,9 Janter Meulen,10Stephan Olschlager,1 Jonas Schmidt-Chanasit,1 Hinrich Sudeck,11 Gerd D. Burchard,12 and Stefan Schmiedel12 Management of Accidental Exposure to Ebola Virus in the Biosafety Level 4 Laboratory, Hamburg, Germany Accidental Exposure to Ebola Virus d JID 2011:204 (Suppl 3) d S785
2. Dowell SF, Mukunu R, Ksiazek TG, Khan AS, Rollin PE, Peters CJ.Transmission of Ebola hemorrhagic fever: a study of risk factors in family members, Kikwit, Democratic Republic of the Congo, 1995.Commission de Lutte contre les Epidemies a Kikwit. J Infect Dis 1999;179(Suppl 1):S87–91.
3. Francesconi P, Yoti Z, Declich S, et al. Ebola hemorrhagic fever transmission and risk factors of contacts, Uganda. Emerg Infect Dis 2003; 9:1430–7.
4. Bausch DG, Towner JS, Dowell SF, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis 2007;196(Suppl 2):S142–7.
5. Anonymous. Russian scientist dies after Ebola lab accident. Science 2004; 304:1225b.
6. Emond RT, Evans B, Bowen ET, Lloyd G. A case of Ebola virus infection. Br Med J 1977; 2:541–4.
7. Kortepeter MG, Martin JW, Rusnak JM, et al. Managing potential laboratory exposure to Ebola virus by using a patient biocontainment care unit. Emerg Infect Dis 2008; 14:881–7.
8. Geisbert TW, Hensley LE, Jahrling PB, et al. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor:a study in rhesus monkeys. Lancet 2003; 362:1953–8.
9. Hensley LE, Stevens EL, Yan SB, et al. Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever.J Infect Dis 2007; 196(Suppl 2):S390–9.
10. Geisbert TW, Lee AC, Robbins M, et al. Postexposure protection of nonhuman primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet 2010; 375:1896–905.
11. Jahrling PB, Geisbert JB, Swearengen JR, Larsen T, Geisbert TW. Ebola hemorrhagic fever: evaluation of passive immunotherapy in nonhuman primates. J Infect Dis 2007; 196(Suppl 2):S400–3.
12. Oswald WB, Geisbert TW, Davis KJ, et al. Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys. PLoS Pathog 2007; 3:e9.
13. Feldmann H, Jones SM, Daddario-DiCaprio KM, et al. Effective post-exposure treatment of Ebola infection. PLoS Pathog 2007; 3:e2.
14. Geisbert TW, Daddario-Dicaprio KM, Lewis MG, et al. Vesicular stomatitis virus-based Ebola vaccine is well tolerated and protects immunocompromised nonhuman primates. PLoS Pathog 2008; 4:e1000225.
15. Geisbert TW, Hensley LE, Geisbert JB, et al. Postexposure treatment of Marburg virus infection. Emerg Infect Dis 2010; 16:1119–22.
16. Daddario-DiCaprio KM, Geisbert TW, Stroher U, et al. Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in nonhuman primates: an efficacy assessment. Lancet 2006; 367:1399–404.
17. Sullivan NJ, Sanchez A, Rollin PE, Yang ZY, Nabel GJ. Development of a preventive vaccine for Ebola virus infection in primates. Nature 2000;408:605–9.
18. Sullivan NJ, Geisbert TW, Geisbert JB, et al. Accelerated vaccination for Ebola virus haemorrhagic fever in nonhuman primates. Nature 2003;424:681–4.
19. Geisbert TW, Daddario-DiCaprio KM, Williams KJ, et al. Recombinant vesicular stomatitis virus vector mediates postexposure protection against Sudan Ebola hemorrhagic fever in nonhuman primates. J Virol 2008; 82:5664–8.
20. Johnson JE, Nasar F, Coleman JW, et al. Neurovirulence properties of recombinant vesicular stomatitis virus vectors in nonhuman primates.Virology 2007; 360:36–49.
21. Khan AS, Tshioko FK, Heymann DL, et al. The reemergence of Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995. Commission de Lutte contre les Epidemies a Kikwit. J Infect Dis 1999; 179(Suppl 1):S76–86.
22. Sidwell RW, Huffman JH, Khare GP, Allen LB,Witkowski JT, Robins RK. Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science 1972; 177:705–6.
23. Huffman JH, Sidwell RW, Khare GP,Witkowski JT, Allen LB, Robins RK. In vitro effect of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) on deoxyribonucleic acid and ribonucleic acid viruses. Antimicrob Agents Chemother 1973; 3:235–41.
24. Wyde PR, Wilson SZ, Sun CS, Knight V. Interferon aerosol suppression of vesicular stomatitis virus replication in the lungs of infected mice. Antimicrob Agents Chemother 1984; 26:450–4.
25. Gresser I, Tovey MG, Bourali-Maury C. Efficacy of exogenous interferon treatment initiated after onset of multiplication of vesicular stomatitis virus in the brains of mice. J Gen Virol 1975; 27:395–8.
26. Repik P, Flamand A, Bishop DH. Effect of interferon upon the primary and secondary transcription of vesicular stomatitis and influenza viruses. J Virol 1974; 14:1169–78.
27. Rollin PE, Bausch DG, Sanchez A. Blood chemistry measurements and D-dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. J Infect Dis 2007; 196(Suppl 2):S364–71.
28. Panning M, Laue T, Olschlager S, et al. Diagnostic reverse-transcription polymerase chain reaction kit for filoviruses based on the strain collections of all European biosafety level 4 laboratories. J Infect Dis 2007;196(Suppl 2):S199–204.
29. Gibb TR, Norwood DA Jr., Woollen N, Henchal EA. Development and evaluation of a fluorogenic 5# nuclease assay to detect and differentiate between Ebola virus subtypes Zaire and Sudan. J Clin Microbiol 2001;39:4125–30.
30. Leroy EM, Baize S, Volchkov VE, et al. Human asymptomatic Ebola infection and strong inflammatory response. Lancet 2000; 355:2210–5.

Culisele travaliului de doliu

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PSIHOLOG  GEANINA BERBECARU

 

Rezumat

Atunci cand vorbim despre pierderea prin deces a unei persoane semnificative din viata noastra vorbim despre o rana. O rana a sufletului inaccesibila vazului dar cu un impact profund asupra tuturor aspectelor vietii. Astfel, ea este profund (re)simtita si poate genera reactii perturbatoare fiziologice, emotionale, cognitive, comportamentale si relationale. Pune la grea incercare atat intelegerea sensului vietii cat si folosirea resurselor pentru a merge mai departe. Furnizarea unor aspecte teoretice privind definirea traumei psihice, a etapelor si a efectelor ei creeaza o cale de acces in culisele travaliului de doliu.

 

The backstage of the mourning process

Abstract

When we talk about the death of a significant person in our life we talk about a wound. A wound of the soul, unseen, but with  a deep impact in all aspects of our existence. Therefore, this wound is profoundly felt and can generate disturbing physiological, emotional, cognitive, behavioral and relational reactions. It poses a great challenge in both the understanding of the meaning of life and the using of our resources in order to carry on. By providing theoretical aspects in defining psychical trauma, its stages and effects, a pathway is created to access the backstage of the mourning process.

De-a lungul timpului au fost identificate o serie de stadii generale, inevitabile prin care fiinta umana trece dupa pierderea unei persoane semnificative, si anume: negare si izolare, furie, targuire, depresie, acceptare. Oamenii traiesc si isi manifesta durerea in moduri diferite si experimenteaza o gama larga de sentimente si stari precum tristetea, regretul, frustrarea, furia, neputinta, vina, anxietatea, singuratatea, nefericirea, neajutorarea, senzatia de gol sufletesc – toate fiind reactii specifice, normale in contextul pierderii.

Experienta traumatica (2) presupune la modul fundamental existenta urmatoarelor elemente:

  • Un eveniment cu caracter traumatic, trairea, experimentarea evenimentului traumatic, consecinte pe termen scurt ale traumei si consecinte pe termen lung.
  • Modelul evolutiv al traumatizarii psihice:

- situatie traumatica
- reactie traumatica
- proces traumatic

Trauma psihica este definita ca  o experienta vitala de discrepanta intre factorii situationali amenintatori si capacitatile individuale de stapanire, care este insotita de sentimente de neajutorare si abandonare lipsita de aparare si care duce astfel la o prabusire de durata a intelegerii de sine si de lume. (3).
Persoana traieste o anumita situatie traumatica in particularitatea ei istorica si individuala, astfel ca incercarile persoanei de a o depasi sunt profund dependente de aceasta experienta individuala. Semnificatia data evenimentului respectiv, caracteristicile persoanei, momentul aparitiei evenimentului, tipul, numarul si caracteristicile persoanelor prezente in timpul evenimentului vor da nuante aparte situatiei traumatice cu care se confrunta persoana. De aceea, intotdeauna situatiile traumatizante vor fi diferite de la individ la individ, chiar daca evenimentul traumatizant va fi acelasi. (1)
Reactia post-expozitorie trece prin mai multe faze care au o varianta normala si una patologica. Reactia normala este denumita stress response, varianta patologica reprezinta reactia traumatica in sens mai ingust:
• Faza expozitorie peri-traumatica – raspunsul normal este format din tipete, teama doliu, si reactie de manie. Starea patologica a experientei este desemnata ca inundare cu impresii coplesitoare. Persoana afectata este cuprinsa de o reactie nemijlocita si se afla adesea inca mult timp dupa aceea intr-o stare de panica, respectiv, epuizare, care ia fiinta din reactiile emotionale care escaladeaza.
• Faza (respectiv starea) de negare. Cei afectati se apara impotriva amintirii situatiei traumatice. Varianta patologica: comportament extrem de evitare, eventual sustinut de folosirea de droguri si medicamente pentru a nu fi obligat sa traiasca durerea sufleteasca.
• Faza (respectiv starea) de invazie a gandurilor sau imaginilor mnezice. Varianta patologica: trairi cu ganduri si imagini mnezice ale traumei care se tot impun.
• Faza (respectiv starea) de perlaborare. Aici, cei afectati se confrunta cu evenimentele traumatice si cu reactia lor personala.
• Concluzie relativa (completion). Un criteriu este capacitatea de a-si putea reaminti situatia traumatica in cele mai importante parti ale sale, fara a trebui sa se gandeasca la aceasta compulsiv. (3)

In faza de debut a doliului  toate trairile au un caracter acut, intens care se poate intinde pe o durata de aproximativ 6 luni. Treptat, intensitatea trairilor scade si pe masura ce se proceseaza implicatiile pierderii se realizeaza trecerea catre etapa acceptarii si vindecarii. Perioada de timp estimata face referire doar la etapa in care toate starile sunt traite la o intensitate coplesitoare si nu la intregul proces al doliului, care este unul de durata. In situatiile in care nu se reuseste tranzitia catre etapa de integrare a pierderii si vindecare a ranii vorbim despre un doliu complicat. Specificitatea lui consta in faptul ca trairile nu scad in intensitate si se mentin pe o perioada de timp mai mare de 6 luni. Vorbim practic de un blocaj in etapa de debut a procesului. Astfel, genereaza o serie de reactii si comportamente precum:
- reactii emotionale disproportionate declansate de stimuli aparent lipsiti de importanta;
- trairi de intensitate foarte mare la accesarea experientei pierderii;
- preocupare excesiva legata de tematica pierderii suferite;
- prezenta unor schimbari majore in modul de a trai;
- prezenta unor stari depresive si scaderea stimei de sine;
- prezenta unor tendinte auto-distructive;

Acesti indicatori ai doliului complicat pot fi mai bine intelesi printr-o detaliere a  reactiile specifice traumei/ranii psihice in toate planurile existentei umane:
In sfera fiziologica: amortirea responsivitatii generale (fizica sau psihica), nivel de excitare foarte crescut (arousal sporit)– reactii exagerate si imediate la stimulii obisnuiti, insomnie, plans, lipsa apetitului ce duce la scaderea greutatii corporale, manifestari neurovegetative: palpitatii, tahicardie, hiperhidroza, paloare, scaderea sistemului imunitar (de unde frecventa crescuta a diverselor boli) etc.
• In sfera emotiilor (aici sunt cele mai puternice reactii): stare de soc, temeri, groaza, diverse anxietati, depresie, disperare, neputinta, neajutorare, melancolie, regret, durere, singuratate, tristete, furie, ura, vinovatie, dezaprobare, neimplinire si gol existential;
• In sfera cognitiilor: amintiri, flash-back-uri, ruminatii, ganduri culpabilizatoare, catastrofizante, negative, cosmaruri, tendinta de a uita, de a reprima, de a nega pentru a nu mai simti durerea, depersonalizare, derealizare, scindare, ideatii suicidare. Foarte semnificativ este faptul ca trauma produce o puternica zguduire a sistemului de valori si de credinte ale persoanei despre sine, altii si despre lume; ea duce la o zdruncinare durabila a intelegerii de sine si a lumii, mai mult sau mai putin cuprinzatoare. Este afectata imaginea si stima de sine, precum si capacitatea de a-si imagina vreun viitor.
• In sfera comportamentala: persoana se poate izola de ceilalti, poate deveni agresiva, pretentioasa, cicalitoare, haotica, poate renunta la unele activitati, la viata sociala, poate apela la abuz de alcool, droguri, tutun sau poate sa se suprasolicite profesional sau familial pentru a nu mai avea timp si putere sa simta durerea. Chiar si tentativele suicidare si suicidele sunt des intalnite. (1)

Un model ilustrativ  pentru procesul traumatic este propus de catre psihologul german Franz Ruppert  care pune accentul pe scindarea psihicului in trei parti (instante): partea sanatoasa, partea traumatizata/ranita si partea supravietuitoare.
Partea sanatoasa: are vitalitate, forta de a confrunta realitatea; are capacitatea de a regla emotiile si de a crea relatii securizante: cauta si gaseste solutii/raspunsuri adaptative.
Partea ranita: contine toata suferinta  si durerea traumei,este neputincioasa, invizibila si se activeaza in mod imprevizibil doar in prezenta unor anumiti stimuli.
Partea supravietuitoare: are unicul scop de protectie (pazeste rana) – tine durerea departe pentru a preveni repetarea suferintei; creeaza iluzii si astfel iau nastere mecanismele de aparare. Acestea sunt prezente atata timp cat rana ”este deschisa”.

In practica, interventia terapeutica vizeaza reconectarea partilor fragmentate. Partea sanatoasa reprezinta temelia pe care se va realiza reconstructia. Va fi stimulata si intarita in permanenta pentru a surmonta obstacolele create de partea supravietuitoare si pentru a sustine contactul cu suferinta. Printre efectele dorite sa se obtina ca urmare a acestui demers se afla:
- capacitatea de a investi energie  si emotie in activitatile curente;
- recapatarea capacitatii de a trai placerea;
- aducerea aminte a pierderii cu impact emotional just, adecvat;
- prezenta spontaneitatii si a simtului ludic;
- capacitatea de a putea observa ”castiguri” aparute din suferinta;
- dorinta de a experimenta lucruri noi;
- gestionare optima a emotiilor si a gandurilor;
- prezenta unor perspective pozitive de viitor.

In cadrul asistarii psihologice de specialitate a persoanele care se confrunta cu un doliul complicat (si nu numai) alegerea celor mai potrivite metode si tehnici de interventie terapeutica vor tine intotdeauna cont de contextul experientei personale a celui asistat si de o serie de principii printre care: respectarea suferintei, respectarea ritmului si acceptarea neconditionata,  cu scopul de a stimula si facilita procesul de vindecare si integrare a pierderii.

 

Concluzii

Ranile sufletului, la fel ca toate ranile fizice, au nevoie de atentie si ingrijire adecvata astfel incat procesul de vindecare sa fie cat mai lin.
Atunci cand viata capata iar sens si speranta isi face simtita prezenta, cand bucuria e din nou traita si, mai ales cand s-a realizat adaptarea la noua identitate care s-a creat in contextul pierderii, se poate spune ca doliul a fost integrat.
O credinta care mi-a fost insuflata in timpul formarii mele profesionale este aceea ca traumele psihice reprezinta mult mai mult decat ocazii de durere sufleteasca si suferinta emotionala. Trauma psihica este o importanta sursa de invatare si de evolutie personala.


Bibliografie

(7) Bowlby, J. (2011). O baza de siguranta. Aplicatii clinice ale teoriei atasamentului. Bucuresti: Editura Trei.

(3)  Fischer, G. si  Riedesser, P.  (2007). Tratat de Psihotraumatologie. Editia a II-a revizuita si adaugita. Bucuresti: Editura Trei. (p. 90; pp. 103-104)

(6)  Goleman, D.  (2001). Inteligenta emotionala. Bucuresti: Editura Curtea Veche.

(2) Nedelcea, C. (2012). Psihoterapia experientiala in lucrul cu emotiile. Contributii si repere. Bucuresti: Editura SPER.  (p.12)

(4) Ruppert, F. (2012). Trauma, atasament, constelatii familiale. Psihoterapia traumei. Bucuresti: Editura Trei.

(1) Vasile, D. (2012). Trauma familiala si resursele compensatorii. Editia a II-a revizuita. Bucuresti: Editura SPER. (pp.16-17; 23-25)

(5)  Vrasti, R. (2012). Ghid practic de interventie in criza. www.vrasti.org

SCORUL APGAR – MAI ESTE VALABIL DUPA 60 DE ANI?

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Dr. Adriana Dan

Medic primar neonatologie

Sef sectie

Spitalul Universitar de Urgenta Bucuresti

 

Rezumat
Scorul Apgar  a fost descris in anul 1952 de Virginia Apgar, medic anestezist la Columbia University Presbyterian Hospital New York, ca un mijloc de apreciere a efectelor asupra fatului a tipului de anestezie administrata mamei si a devenit  apoi o metoda universal folosita, rapida si standardizata, de evaluare a starii clinice a nou nascutului imediat dupa nastere;  el sta la baza deciziei de reanimare si evalueaza ulterior eficienta reanimarii nou nascutului. Desi  scorul Apgar nu a fost conceput ca un factor  de predictie a evolutiei postnatale, in timp, datorita asocierii relativ frecvente intre scorurile mici si unele complicatii perinatale, numeroase studii au incercat sa demonstreze existenta unei corelatii intre valorile mici ale scorului Apgar (<7), durata persistentei acestora si mortalitatea sau morbiditatea infantila.
Daca in ceea ce priveste prognosticul neurologic pe termen mediu si lung al nou nascutilor, scorul Apgar singur nu s-a dovedit a fi un bun predictor, cercetarile au aratat ca exista o legatura stransa intre valorile sale mici si persistente si mortalitatea neonatala precoce si tardiva.

 

Abstract
The Apgar score was developed in 1952 by Virginia Apgar, an anestesiologist at Columbia University Presbyterian Hospital New York, as a mean to evaluate the effects of maternal type of anesthesia on fetus and became, afterwards, an universal, quick and standardized method  to assess the clinical status of the newborn immediatly after delivery; Apgar score’s value determines the need for ressuscitation and evaluates the effectiveness of ressuscitation. Although Apgar score was not intended for prediction of outcome beyond the neonatal period, since low scores correlate with perinatal adversities, multiple studies have examined the relation between the value of Apgar score, the duration of low (<7)  scores and infant mortality and morbidity.
If, regarding the neurological medium and long term outcomes , the Apgar score alone could not be considered as a reliable predictor, studies showed that there is a strong relation between the duration of low scores and neonatal and postneonatal mortality.

 

Introducere
Scorul Apgar  reprezinta un sistem simplu, standardizat, folosit de mai mult de 60 de ani, in intreaga lume, pentru evaluarea starii clinice a nou nascutului imediat dupa nastere. Dr. Virginia Apgar a inclus in componenta scorului care ii poarta numele,  in 1952, cinci criterii clinice, obiective, usor de apreciat, care sa nu fie influentate de ingrijirile medicale acordate: coloratie, respiratie, frecventa cardiaca, tonus, reflexe; fiecare dintre aceste componente se noteaza cu 0,1 sau 2 si suma lor cuantifica pe o scara de la 1 la 10 starea nou nascutului la momentul respectiv (traditional evaluarea se efectueaza la 1 si 5 minute de la nastere si poate fi repetata si mai tarziu – la 10, 15 si 20 de minute, daca scorul ramane mic).

SIMPTOME 0 PUNCTE 1 PUNCT 2 PUNCTE
culoarea pielii palid-cianotic cianoza periferica roz
respiratie (tipat) absent(a) gasping bun(a), eficient(a)
frecventa cardiaca <60/1 <100/min >100/min
tonus muscular flasc generalizat membre in semiflexie bun, membre in flexie
reflexe (reactie la stimuli) Absent Slab  (grimasa la apirat) bun,  plans viguros

In interpretarea scorului Apgar, valorile egale sau mai mari de 8 sunt considerate normale, 7 corespunde apneei tranzitorii (denumita si hipoxie prinatala usoara sau de gradul I), valorile 4,5,6 caracterizeaza hipoxia perinatala medie sau gradul II, iar valorile de 3 sau mai putin desemneaza hipoxia perinatala severa sau gradul III (numita de unii autori asfixie). (1).

In ultimii ani s-au ridicat suspiciuni cu privire la utilitatea scorului Apgar. Acest lucru se datoreaza pe de o parte faptului ca studiile au aratat ca el nu poate fi folosit pentru prognosticul neurologic pe termen lung al nou nascutilor si, pe de alta parte, pentru ca a fost utilizat incorect, in unele situatii, ca singur element de diagnostic al asfixiei neonatale (2). In plus, mult  timp scorul Apgar la 1 minut a fost considerat a sta la baza deciziei de reanimare a nou nascutului;  normele actuale, acceptate si utilizate pe plan international in ceea ce priveste timpii  si mijloacele reanimarii neonatale, statueaza ca resuscitarea nou nascutului trebuie sa inceapa inainte de 1 minut, imediat ce se observa ca nou nascutul nu este capabil sa respire eficient pentru a isi asigura o frecventa cardiaca adecvata.  Fiziopatologia a demonstrat ca un proces patologic avand ca efect asfixia nou nascutului poate incepe inca din utero si, de aceea, a astepta 1 minut pentru a evalua nou nascutul si a incepe reanimarea, creste riscul afectarii cerebrale si aparitiei sechelelor neurologice. (3)

Scorul Apgar se acorda tuturor nou nascutilor, indiferent de greutatea la nastere sau varsta gestationala. Dar, deoarece unele dintre elementele luate in considerare pentru calculul scorului Apgar, precum tonusul, culoarea si reactivitatea, sunt dependente partial de maturitatea fiziologica a nou nascutului, prematurii au scoruri Apgar mai mici, fara sa sufere neaparat de hipoxie. La un minut de viata scorul Apgar este de 0-3 la aproximativ 57% din totalul prematurilor sub 1500g si numai 5% din totalul nou nascutilor cu greutate peste 3000g. Numai 4%dintre copiii cu greutate mica la nastere au scorul 9 sau 10, in timp ce in cazul nou nascutilor la termen acest scor se intalneste la peste 50%. (1). Alti factori care influenteaza valoarea scorului Apgar sunt: depresia respiratorie data de anestezicele administrate mamei, traumatismul obstetrical, anomaliile congenitale, infectiile, hipoxia, hipovolemia. (2).

Articolul de fata isi propune sa fie o revizuire a valabilitatii si utilitatii scorului Apgar in prezent, la mai mult de jumatate de secol de la crearea lui, in conditiile in care dezvoltarea medicinei si cercetarii medicale in aceasta perioada au condus la progrese semnificative ale ratei de supravietuire a nou nascutilor foarte mici/imaturi, iar normele de reanimare neonatala s-au ajustat continuu.

 

Material si metoda
Am efectuat un studiu retrospectiv in maternitatea Spitalului Universitar de Urgenta Bucuresti pe un numar de 3468 nou nascuti vii internati in departamentul nostru in anul 2014. Structura lotului analizat a fost format din 3101 nou nascuti la termen (89,5%) si 367 de prematuri (10,5%). Pe grade de prematuritate repartitia acestora a fost urmatoarea:
- prematuri gradul I (2000-2500g) -   209 (56,9%)
- prematuri gradul II (1500g-200g) -    91 (24,79%)
- prematuri gradul III (1000-1500g) –  46 (13,35%)
- prematuri gradul IV (sub 1000g)  –    21  (5,72%)

Din totalul nou nascutilor, 996 (28,7%) au fost nascuti natural si  2472 (71,3%) prin operatie cezariana.

Am analizat foile de observatie ale nou nascutilor si am notat scorul Apgar la 1 si 5 minute pentru fiecare pacient si am incercat sa gasim o corelatie intre acesta si varsta de gestatie, tipul de nastere (vaginala vs operatie cezariana) si mortalitatea neonatala.

 

Rezultate
Din totalul nou nascutilor un numar de 156 (4,5%) au prezentat hipoxie perinatala medie (scor Apgar 4,5,6) la 1 si/sau 5 minute si un numar de 54 (1,5%) au prezentat hipoxie perinatala severa (gradul III) avand scor Apgar ≤3. Pe sexe, repartitia a fost cvasi-egala, cu usoara predominenta a afectarii la sexul masculin – 55, 7% baieti si 44,3% fete, in primul caz si 53,7% baieti si 46,3 fete in  celalalt caz.

Raportat la vasta de gestatie, au fost  69 (44,2%) hipoxii perinatale usoare/medii la nou nascutii la termen si 87 (55,7%) la prematuri. Hipoxia perinatala severa s-a intalnit la 8 (14,3%) nou nascuti la termen si 48 (85,7%) prematuri.

In functie de modalitatea de desfasurare a nasterilor repartitia cazurilor cu hipoxie a fost: 114 cazuri  (54,3%) la nou nascuti extrasi din operatie cezariana  (90 de hipoxii gradul I – 78,9% si II si 23 hipoxii gradul III – 21,1%) si 96 (45,7%) la nou nascutii nascuti pe cale vaginala (66 hipoxii de gradul I – 68,7% si II si 30 de hipoxii gradul III – 31,3%).

Mortalitatea neonatala in lotul studiat a fost de 1,03% (36 de decese din totalul de 3468 nou nascuti vii). Este important de remarcat ca dintre acestia 31 au fost prematuri (dupa varsta de gestatie), corespunzator deci la un procent de 86,1% prematuri si 5 (13,9%) nou nascuti la termen. In functie de gradul de prematuritate, situatia deceselor se prezinta in felul urmator:
- prematuri gradul I –     3/209 (1,43%)
- prematuri gradul II –    3/91 (3,29%)
- prematuri gradul III – 15/46 (32,6%)
- prematuri gradul IV – 10/21 (47,6%)

Cu exceptia a doua cazuri, un nou nascut macrosom, la termen si un prematur gradul I, toti nou nascutii decedati au suferit de hipoxie perinatala medie sau severa (94,4%).

Din totalul de decese, numarul de nou nascuti cu scor Apgar ≤ 3 la 1 minut a fost de 25/36 de cazuri (69,4%), Apgar 4,5,6 – 9/36 cazuri (25%) si Apgar ≥7 – 2 /36 cazuri (5,6%)

Luand in considerare valoarea scorului Apgar la 5 minute, nou nascutii care au decedat au avut : scor Apgar ≤3 -13/36 cazuri (36,1%), scor Apgar 4, 5,6 -  17/36 cazuri (47,2%) si scor Apgar ≥ 7 – 6/36 nou nascuti (16,6%).

Din totalul de 156  de cazuri cu diagnostic de hipoxie perinatala medie (Apgar < 6) la 1 sau 5 minute s-au inregistrat  9 (5,7%) decese, 7 la prematuri  (77%) si 2 la nou nascutii la termen (22,3%). In ceea ce priveste hipoxia perinatala severa (Apgar <3) la 1 sau 5 minute, din totalul de 54 de cazuri, cifrele au indicat un numar de 25  (46,2%) decese, toate la prematuri.

Analiza  scorului  Apgar in functie de  varsta de gestatie la decedati arata urmatoarele date:

Varsta gestatie Hipoxie perinatala medie    (la 1 sau 5 minute) Hipoxie perinatala severa (la 1 sau 5 minute) Fara hipoxie Nn decedati
24-26 SG 2 8 (80%) 0 10
27-30 SG 4 11 (73,3%) 0 15
30-34 SG 1 2 0 3
34-36 SG 1 1 1 3
≥36 SG 2 2 1 5
TOTAL 10 24 2 36

De remarcat in tabelul de mai sus este ca, in cazul nou nascutilor cu varste de gestatie foarte mici, hipoxia perinatala in corelatie cu imaturitatea accentuata sunt factori ce afecteaza considerabil supravietuirea acestora.

Analiza scorului Apgar in functie de greutate la decedati este ilustrata in tabelul de mai jos:

GREUTATE Hipoxie perinatala medie    (la 1 sau 5 minute) Hipoxie perinatala severa (la 1 sau 5 minute) Fara hipoxie NN decedati
<1000g 3 12 (80%) 0 15
1000-1500g 2 9 (81,8%) 0 11
1500-2000g 2 1 0 3
2000-2500g 2 2 1 5
≥2500g 1 0 1 2
TOTAL 10 25 2 36

Datele arata ca nou nascutii cu greutate mica la nastere sunt mai numerosi decat cei cu varste de gestatie sub 30 de saptamani, ceea ce inseamna ca o suferinta fetala prenatala a determinat si o intarziere de crestere intrauterina, care poate sa fi influentat si scorul Apgar, dar in mod sigur a contribuit la cresterea numarului de decese la aceasta categorie de nou nascuti.

Varsta medie la care a survenit decesul la nou nascutii cu hipoxie perinatala medie a fost de 308 ore si a celor cu hipoxie perinatala severa de 109 ore.

 

Discutii
In tarile dezvoltate din punct de vedere economic, aproximativ 1% din nou nascuti au scoruri Apgar <7 la 5 minute (SUA 1,4 % si 0,7% Danemarca). Prevalente crescute ale scorului Apgar <7 sunt raportate in tarile in curs de dezvoltare, ceea ce demonstreaza ca distibutia scorului Apgar in populatie poate fi influentata de nivelul ingrijirilor medicale disponibile,  situatia economica, nutritia. (4). In clinica noastra hipoxiiile perinatale medii au fost in procent de 4.5%, iar cele severe au fost in procent de 1,5%.

Inca din perioada in care a fost definit, Virginia Apgar a semnalat o relatie invers proportionala  intre „nota la nastere” si mortalitatea neonatala. Dintre cele 2 scoruri, la 1 si la 5 minute, cel de la 5 minute, pare sa fie un mai bun predictor pentru supravietuirea nou nascutilor (5), respectiv pentru mortalitatea neonatala si postneonatala, atat pentru nou nascutii la termen cat si prematuri. (3). Un studiu pe 150 000 de nou nascuti efectuat in SUA a raportat o relatie de inversa proportionalitate intre valoarea Apgarului la 1 si 5 minute si incidenta deceselor neonatale (5). In studiul nostru se confirma acest lucru, dar scorul la 1 minut pare sa reflecte mai bine corelatia cu mortalitatea neonatala precoce.

In general mortalitatea neonatala este in jur de 50% la nou nascutii cu scor 0 sau 1 la 5 minute. Decedeaza in perioada neonatala aproximativ 80% din copiii cu greutatea sub 1800g si cu scor Apgar 0-3 la 5 minute si numai 15% dintre cei cu greutatea peste 2500g si cu acelasi scor. Majoritatea deceselor apar in primele 2 zile de viata. (1).

Nasterile premature au  de 10-20 ori mai mare riscul de a avea scoruri Apgar la 5 minute <7, comparativ cu nasterile la termen; atat rata deceselor neonatale cat si a celor post-neonatale este in scadere pe masura ce scorul Apgar este in crestere. Intre nasterile cu un scor Apgar foarte mic (1-3), mortalitatea neonatala ramane ridicata pana la VG ≥37 saptamani de gestatie; daca scorul Apgar este ≥7, mortalitatea neonatala scade progresiv, in functie de varsta de gestatie. (2). Aceeasi distributie se pastreaza si in ceea ce priveste mortalitatea postneonatala, sugerand ca scorul Apgar mic nu este strict corelat cu prematuritatea.  Intr-un alt studiu (5) s-a demonstrat ca valoarea medie a scorului Apgar la 5 minute s-a corelat cu varsta gestationala a nou nascutilor prematuri (scorul mediu la 26-27 saptamani a fost de 6,6±2,1, fata de 8,7±0,8 la 34-36 saptamani de gestatie). Indiferent de varsta de gestatie, incidenta deceselor  neonatale a fost cea mai mare  pentru scoruri Apgar ≤3.  Asa cum reiese din tabele, si in analiza noastra se confirma ca varsta de gestatie si greutatea mica asociate cu hipoxia perinatala severa sunt direct proportionale cu mortalitatea.

Este de mentionat insa ca, in ceea ce priveste nou nascutii prematuri, valori scazute ale unor componente ale scorului Apgar (reactivitatea, tonusul muscular, efortul respirator) reflecta mai mult imaturitarea fiziologica decat injuria hipoxica (6). De aceea, gradul de corelatie dintre scorul Apgar mic si potentiali markeri ai afectarii cerebrale este mai slaba la prematur fata de nou nascutul la termen; un procent mare de prematuri au scor Apgar mic, fara evidenta acidozei in sangele cordonului ombilical. Riscul relativ al modificarilor clinice patologice asociate scorului Apgar mic in primele ore de viata par sa fie in scadere, concordant cu scaderea varstei de gestatie. Nou nascutii prematuri au risc crescut de a dezvolta complicatii postnatale indiferent de scorul Apgar. La acestia, dintre componentele scorului Apgar, efortul respirator, tonusul muscular, si activitatea reflexa se coreleaza bine una cu alta; frecventa cardiaca se coreleaza mai putin si coloratia, cel mai putin (6).

Analiza comparativa a valorilor scorului Apgar cu valorile pH-ului din cordonul ombilical la copiii cu hipoxie perinatala a demonstrat ca Apgarul la 5 minute este un predictor mai bun de 8 ori pentru mortalitatea neonatala comparativ cu pH ul < 7 din cordon (5).  Acidemia a fost demonstrata la aproximativ 38% din nou nascutii la termen cu scor Apgar la 5 minute < 7. Atunci cand apare, acidemia poate fi un indicator pentru aparitia encefalopatiei hipoxic ischemice (EHI), care la randul ei conduce la deficiente neurologice tardive. Intr-un studiu recent prevalenta EHI a fost de 70%, 14% si 0% la nou nascuti la termen, fara alte patologii, cu IA la 5 minute 0-3, 4-6 si respectiv, 7-10. EHI severa se asociaza in proportie de 75% cu mortalitatea infantila (5).

Este foarte important sa facem diferenta intre hipoxia perinatala gradul 3 (Apgar 0-3) si asfixe, care implica hipoxemie si hipercarbie fetala, precum si acidoza metabolica, date care nu concorda intotdeauna. Un scor Apgar de 0-3 la 5 minute este asociat cu un risc crescut de paralizie cerebrala la nou nascutii la termen, dar cresterea este numai de la 0,3% la 1% (7). Scorul Apgar singur nu poate afirma ca hipoxia e cauza paraliziei cerebrale. Un nou nascut la termen cu un Apgar de 0-3 la 5 minute al carui scor la 10 minute s-a imbunatatit la 4 sau mai mult are sanse de 99% sa nu aiba paralizie cerebrala la 7 ani de viata. Si, invers, 75% din copiii cu paralizie cerebrala au avut scor Apgar normal la nastere.

Studii recente, care au utilizat pulsoximetria pentru evaluarea tranzitiei nou nascutului la viata extrauterina, au aratat ca un nou nascut sanatos, la termen, isi realizeaza o saturatie stabila > 90% numai dupa cateva minute  (intre 2 si 10 minute) de la clamparea cordonului ombilical (8), ceea ce ridica semne de intrebare asupra relevantei scorului Apgar la 1 minut.

In 2010 Asociatia Americana de Pediatrie (AAP), in ghidurile sale de resuscitare a emis recomandarea obtinerii unei saturatii tinta de 60-65% la 1 minut, 65-70% la 2 minute, 70-75% la 3 minute , 75-80% la 4 minute, 80-85% la 5 minute si 85-95% la 10 minute. In acelasi an, International Liaison Commitee on Resuscitation (ILCOR) a modificat ghidurile de reanimare neonatala explicand ca „pentru nou nascutii la termen care sunt reanimati cu presiune intermitent pozitiva, concentratia de oxigen administrata de 100% nu confera nici un beneficiu fata de reanimarea cu aer atmosferic si conduce la cresterea duratei pana la aparitia primei respiratii sau a primului tipat”(8).

Intr-un studiu recent care a analizat concentratiile de oxigen indicate in reanimarea prematurului, comparatia intre doua loturi de nou nascuti  cu varsta de gestatie sub 32 saptamani care au primit unii  FiO2>50% , iar altii FiO2 < 50%,  a condus la concluzia ca nou nascutii reanimati cu concentratii mari de oxigen au avut o mortalitate mai mare, desi rata bronhodisplaziei pulmonare sau a hemoragiei intraventriculare a fost similara la ambele grupuri. De aceea, autorii au concluzionat ca prematurii cu VG < 32 saptamani  trebuie ventilati initial cu FiO2 de 20-30%, ulterior, ajustandu-se crescator, la nevoie, in functie de valorile saturatiei in oxigen masurate preductal si frecventa cardiaca (8). Aceste noi descoperiri cu privire la toxicitatea oxigenului, in special pentru prematuri, determina prudenta si judiciozitate in decizia si modul initierii reanimarii nou nascutului, lucru rezolvat in trecut rapid prin calcularea scorului Apgar.

 

Concluzii
Scorul Apgar este o metoda simpla, standardizata, rapida si universal acceptata pentru evaluarea nou nascutului la nastere, ceea ce il face sa fie foarte agreat de catre clinicieni. Valoarea lui insa a  diminuat in ultimii ani din cauza scaderii importantei lui in reanimare si intrucat pentru nou nascutul prematur are numai valoare orientativa, fiind influentat de imaturitatea fiziologica a acestuia, precum si de tipul de ingrijiri medicale acordate. Si alti factori externi modifica acuratetea scorului Apgar. In ceea ce priveste valoarea lui predictiva, aceasta se rezuma la riscul crescut pe care scorurile mici si persistente il au in corelatie cu mortalitatea neonatala precoce.

 

Bibliografie:

  1. Iulian Lupea – Tratat de Neonatologie, Ed. Medicala Universitara Iuliu Hatieganu, Cluj Napoca, 1999
  2. Fei Li, Ting Wu, Xiaoping Lei, Hao Zhang, Meng Mao, Jung Zhang – The Apgar Score and Infant Mortality, published July 29, 2013, DOI: 10.371/journal.pone.0069072
  3. Avroy A. Fanaroff, Richard J. Martin – Neonatal-Perinatal Medicine, Ed. Mosby, 1997
  4. Vera Ehrenstein – Association of Apgar scores with death and neurologic disability, Clinical Epidemiology 2009:I 45-53
  5. Brian M. Casey, M.D., Donald McIntire, Ph.D. and Kenneth  J.leveno, M.D. – The Continuing Value of the Apgar Score for the Assessment of Newborn Infants, The New England Journal of Medicine, February 15, 2001
  6. Hegyi T, Carbone T, Anwar M, Ostfeld B, Hiatt M, Koons A, Pinto-Martin J, Paneth N – The Apgar Score and its components in the preterm infant, Pediatrics, 1998, January, 77-81
  7. Committee on Fetus and Newborn, American Academy of Pediatrics and Committee on Obstetric Practice, American College of Obstetricians and Gynecologists – Use and Abuse of the Apgar Score, Pediatrics 1996;98;141
  8. Vento Maximo, Oxygen supplementation in the neonatal period: changing the paradigm;  Neonatology  – 2014; 105:323-331

Tratamentul bolii parodontale-dilema sau certitudine?

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Dr.Madalina Gabriela Teodorescu

 

Rezumat

Parodontitele marginale cronice sunt afectiuni dentare intalnite la aproximativ 50-60% din populatia planetei, de aceea aceasta afectiune necesita o atentie deosebita din partea personalului medical si pentru fiecare pacient in parte trebuie gasite cele mai bune metode de prevenire si stopare in evolutie a acesteia.

De cele mai multe ori, cauza principala o reprezinta placa bacteriana, fiind influentata si de alti factori locali(carii, tartru, igiena deficitara), dar si de alti factori de natura sistemica(diabet,stari fiziologice, SIDA etc). In evolutia bolii parodontale sunt multe stadii, dar debutul este inflamatia gingivala(gingivita) si poate duce pana la pierderi importante de os alveolar.

Metodele de tratament sunt variate, dar nici una nu reuseste sa restabileasca situatia dinaintea primului stadiu al aparitiei acestei afectiuni, ci doar sa o stopeze din evolutie. Prima atitudine terapeutica trebuie sa vizeze in primul rand dezinfectia cu substante antiseptice a focarelor infectioase si chiuretajul subgingivale a pungilor parodontale.

In stadiile mai avansate, terapia de electie este terapia chirurgicala de eradicare a plagii infectate si cu rol de imbunatatire a troficitatii tisulare dar si a structurii osoase. Cea mai des practicata este operatia cu lambou care combina inlaturarea chirurgicala a osului afectat cu materialele cu rol biostimulant de aditie de os introduse mai ales in zonele cu resorbtii verticale alveolare.

De cele mai multe ori, pentru a stabiliza dintii cu mobilitate 2 si 3, se poate combina tehnica chirurgicala cu imobilizarea dintilor cu ajutorul lucrarilor protetice si eventual cu devitalizarea dintilor parodontotici, fapt ce favorizeaza cresterea vascularizatiei in parodontiu. Din observatiile noastre, studiind evolutia dupa interventia chirurgicala, gingia chiar daca este repozitionata coronar, de multe ori coboara la aproximativ o luna dupa operatie, deci pentru un efect fizionomic maxim, se poate adauga grefa gingivala autogena sau obtinuta pe cale artificiala din colagen.

 

Abstract

Parodontopathies are encountered in approximatively 50-60% of the world population and represent a medical scourge of dentists time. This is why this disease aimed finding the best solutions for prevention and assistance.

The parodontium that has undergone severe bacterial plaque aggression of local (tartar, deficient bucal hygene) or general factors (diabetes,pregnancy,infectuos diseases, AIDS) will develop parodontal diseases.

The process of this disease have many stages and it begins with a gingival inflammation and can evaluate until bone loss and dental mobility.

The methods of treatment are various, but none until now will repair and institute the situation before first inflammation.  They only stop in process this disease. The first step is the septic one- the curettage of the focus and a very careful disinfection with septic fluids. When the bone distruction is to big, is inducing in the cleaned focus a recondensation of the alveolar bone with os-minerale.

This is especially important when surgery is considered, wich mainly aims at removing the cronic focus and attempts at inducing biological phenomena capable of improving the trophicity of the local tissues as well as of improving the condition of the bone structure. This methodology combines local treatment of the biodystrophic focus with the mineral bone biostimulants wich are introduces by surgical methods in the interalveolar septa.

To stabilize dental mobility grade 2 and 3, we can combine surgical methods with immobilization with crowns. From our studies, we observe that after a mounth after surgical step, gum doesen’t remain at the level we want. That’s why, for a maximum  estetic effect, we can complete with  gingival-graft.

 

Parodontopatia marginala cronica este una din principalele cauze a pierderii dintilor, mai exact a 2-a dupa caria dentara, afectand aproximativ 50-60% din populatia globului, fiind intalnita foarte des in randul pacientilor, chiar si a celor tineri.

Simptomatologia este prezenta inca de la inceput, afectiunea debutand cu inflamatia gingiei insotita de sangerare gingivala care netrata la timp poate dezvolta fenomene de osteite si resorbtii vericale si creare de pungi parodontale, urmate de retractia mucoasei gingivale care urmeaza suportul osos cu dezgolirea radacinilor  si aparitia fenomenelor de mobilitate dentara. In stadiile foarte avansate, dintele va avea o mobilitate in toate planurile,radiologic sesizabil un suport osos pe cel mult o treime din lungimea radacinilor cu afectarea furcatiei dintilor pluriradiculari si pungi parodontale mai adanci de 5 mm.

Caracterul afectarii parodontale poate fi urmarit inca din primele stadii, gingia pierzand aspectul de “gravura punctata” si culoarea roz-deschis, devenind lucioasa, rosie-volacee, tumefiata si sangeranda la atingere, uneori aparand chiar fenomene de hiperplazie gingivala.

In functie de gradul de afectare parodontala, poate aparea mobilitatea dentara:

-gradul 1-cand excursia extremitatii incizale sau ocluzale a coroanei nu depaseste 1 mm

-gradul 2, cand in acelasi plan depaseste 1 mm

-gradul 3-cand dintele este mobil si in sens vertical

Circumstantele etiologice in parodontopatiile marginale cornice sunt:

1)Factori locali  -direct cauzali-placa bacteriana

-favorizanti: tartrul dentar, trauma ocluzala, cariile dentare,edentatia, anomaliile dento-maxilare, parafunctii, obiceiuri vicioase

2)Factori sistemici- diabet, boli hematologice sistemice (leucemii, trombocitopenii,anemii), SIDA, avitaminoza C.

In urma multor studii, se releva ca boala parodontala poate aparea  si in cadrul unor stari fiziologice:la pubertate, in timpul sarcinii, in timpul ciclului menstrual, la menopauza sau chiar in timpul administrarii unor medicamente pe cale generala: medicatia contraceptiva, hidantoina(la bolnavii epileptici) sau antagonistii de calciu(in special nifedipin).

Boala parodontala este consecinta unei resorbtii osoase, care afecteaza atat componenta minerala cat si cea organica a osului alveolar ca urmare a agresiunii microbiene in prezenta unor factori locali si generali favorizanti. De aceea, o alta afectiune sistemica strans legata de parodontopatia marginala cronica este osteoporoza, caracterizata prin fragilitatea masei osoase reduse prin demineralizare si implicit  o scadere a nivelului de calciu si vitamina D. Intr-un studiu efectuat de Dr. Grigore Osipov-Sinesti pe un lot de 74 de pacienti parodontopati, s-a demonstrate ca aproximativ  doua treimi (48 pacienti), aveau o calcemie  totala sub limita fiziologica, ajungand sub 6 mg% si doar 3 cazuri din 74, avand o calcemie peste 11mg%.

Bacteriile patogene in parodontitele marginale sunt in special bacilli gram negativi anaerobi printre care un rol major il joaca: Actinobacillus Actinomycetemcomitans(preponderent in parodontitele agresive), drept urmare o buna antibioterapie atat pe cale generala, cat si p e cale locala o realizeaza tetraciclina, antibioticele din grupa penicilinelor, cat si a chimioterapicelor cum este Metronidazolul.

Mijloacele de tratament sunt multiple, insa nu exista o metoda de tratament care sa restabileasca in totalitate functiile initiale ale aparatului dento-maxilar , acestea fiind efectuate mai mult in scop profilactic si de stopare in evolutie a afectarii ligamentelor periodontale si resorbtiei osoase.

S-a constatat eficacitatea vaccinurilor parodontale de anihilare a bacteriilor si cu rol in stimularea formarii de anticorpi (Cantastim, Imudon,Polidin) , insa eficacitatea lor este dovedita mai mult pe durata tratamentului si in urma unor studii s-a demonstrat ca doar la jumatate din subiectii examinati s-a observat o stopare in evolutie a parodontopatiei si asta datorita dificultatii de a prepara un vaccin foarte eficient, intrucat in etiopatologia bolii nu a putut fi incriminat in mod cert un singur microorganism, ci o asociatie de bacterii ce concureaza impreuna la realizarea leziunilor distructive complexe.

O alta modalitate de stopare in evolutie este bioterapia de reactivare cu extracte tisulare de origine animala sau vegetala, care se bazeaza pe existenta in citoplasma celulelor tinere a unor activatori biologici asemanatori hormonilor.

De asemenea s-a observat o stransa legatura intre pulpa dentara si parodontiul marginal,deoarece intre cele doua exista o serie de corelatii fiziopatologice. In parodontopatiile marginale cronice, pulpa dentara prezinta frecvent fenomene de degenerescenta reticulara, care pot fi explicate prin alterarea dinamicii vasculare, provocata de imbolnavirea parodontala. Efectul benefic al extirparii pulpei radiculare este atribuit intreruperii sursei de excitatii patogene si intensificarii vascularizatiei parodontale. Dupa realizarea extirparii pulpei dentare, s-a constatat reducerea procesului inflamator si a mobilitatii dentare in 78% din cazuri.

Pentru dintii cu mobilitate 1 si 2, se poate opta pentru imobilizarea lor cu atele de imobilizare din materiale compozite dispuse pe fata linguala sau palatinala a dintilor in zona dintre colet si cingulum pentru a nu interfera cu ocluzia, cu anse de sarme din otel inoxidabil sau wipla(folosite din ce in ce mai rar datorita faptului ca sunt inestetice) sau cel mai frecvent se imobilizeaza cu ajutorul lucrarilor protetice, evitandu-se lucrarile din material iritante pentru gingie cum ar fi acrilatul sau lucrarile metalice Nichel-Crom datorita iritatiei gingivale care o exercita mai ales la persoanele alergice.
Cea mai frecventa si eficienta metoda de stopare a evolutiei acestei boli este operatia cu lambou asociata sau nu cu terapie de aditie de os liofilizat  sau obtinut pe cale artificiala in cazul in care exista resorbtii verticale (nu doar orizontala)  cu regenerare tisulara ghidata cu membrane, cel mai des folosite fiind cele resorbabile din colagen. Grefele osoase autogene pot fi prelevate din cavitatea bucala din tuberozitatea maxilara sau zona retromolara mandibulara sau din alte zone cum ar fi osul iliac. Osul artificial este cel mai des folosit in augmentarea osoasa este obtinut din cristale de hidroxiapatita sau biovitroceramica si se prezinta sub forma de granule, care se amesteca cu ser fizilogic pentru a adera mai usor la structura osoasa. Dupa 4-5 luni de la operatie, se poate realiza o radiografie, care in 70% din cazuri indica o osificare a granulelor de os in special in zonele cu lipse verticale osoase. Reusita operatiei, depinde bineinteles de igiena locala a pacientului si de respectarea indicatiilor post-chirurgicale. Scopul acestei interventii, este ca prin decolarea unui fragment de mucoasa si periost de pe osul alveolar subiacent prin intermediul a cateva incizii, sa se asigure un acces bun la nivelul radacinilor, de curatare si “raclare” a osului moale infectat si a mucosei, eliminare a pungilor parodontale interdentare si eliminare a continutului bacterian si de realizare a unei dezinfectii riguroase a suprafetelor radiculare si de incercare de crestere a nivelului suportului osos alveolar atat cat este posibil in cazul in care se completeaza cu terapie de aditie de os. Fara o “curatare” elaborata a tesuturilor afectate de microorganisme, toate celelalte tehnici nu pot stopa in evolutie traiectul microbian de distructie tisulara si oasoasa.

In cazul in care atrofia osoasa se insoteste de retractile gingivala marcata, se poate recurge la mai multe variante de “reasezare” a ei cat mai aproape de nivelul  coletului dentar: prin repozitionare coronara cu ajutorul tractiunii suturii sau prin gingivoplastie. Se poate preleva grefa de gingie autogena de la pacient de pe bolta palatina sau  se poate folosi un material sintetic(ex: Gingigraft) de reconstructie gingivala.

Pe un lot de 30 de pacienti parodontopati aflati in diverse stadii ale evolutiei acestei afectiuni, tratati in clinica noastra (Dentlclinica), am observat urmatoarele:

-fara o metoda ajutatoare de augmentare a inaltimii gingiei(aditie de gingie din alte zone ale cavitatii bucale), pe durata vindecarii gingia revine la nivelul premergator operatiei, deoarece suportul osos neoformat din granule de os artificial sau autogen nu este suficient de stabil ca sa confere mucoasei gingivale suportul necesar pentru a ramane la un nivel mai coronar

-dintii cu mobilitate de gradul 2, la cateva luni dupa interventie ajung la o mobilitate de grad 1, iar daca acest lucru este combinat cu terapia de depulpare a dintilor mobili pot ajunge la 40% din pacienti chiar la mobilitate 0

-de cele mai multe ori, in stadiile avansate, pentru o cat mai buna imbunatatire a gradului de mobilitate, e indicat sa se combine terapia chirurgicala cu imobilizarea dintilor cu ajutorul operatiilor cu lambou

-recuperarea coloratiei normale a gingiei dupa aproximativ o luna

-in cazul folosirii membranelor neresorbabile ramforsate cu titan in detrimentul celor resorbabile,vindecarea este mult mai dificila.

 

Concluzii

Afectiunile parodontale sunt inatlnite foarte des in randul pacientilor si netratate din primele stadia ale evolutiei lor pot duce la consecinte ireversibile ale aparatului dento-maxilar, la tulburari de estetice si chiar de fonatie. Fiind o afectiune de natura bacteriana, tratamentul trebuie sa fie complex si de inlaturare a cauzelor care au stat la baza producerii ei dar si de stopare a evolutiei in functie de stadiul in care se afla pacientul care se prezinta la medic.

 

Bibliografie

  1. Dumitriu H.T.- Parodontologie editia a IV, Editura Viata medicala romaneasca, 2006
  2. Osipov-Sinesti G.-Parodontopatia esentiala  conceptie originala,de interpretare si de tratament prin biostimulatori de omoimplante din “os-minerale”, Editura Medicala, 1976
  3. Osipov-Sinesti G.- Metodologie parodontologica stiintifica si practica, Editura Medicala, 1976
  4. Osipov-Sinesti G.- Periodontal diseases, Bucharest, 1985

Sindromul de oboseala vizuala la calculator

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Dr.Madalina Totir

Spitalul Universitar de Urgenta Bucuresti, Reteaua de Sanatate Privata Regina Maria

 

Rezumat: Majoritatea adultilor au acum locuri de munca ce necesita folosirea prelungita a device-urilor electronice, in plus folosirea lor s-a extins din ce in ce mai mult si in timpul liber  prin utilizarea smartphone-urilor, tabletelor, laptopurilor, consolelor de jocuri video astfel ca tot mai multe persoane se prezinta la medicul oftalmolog cu diverse acuze oculare. In acest articol vor fi prezentate mecanismele etiopatogenice care determina aparitia sindromului de oboseala vizuala la calculator dar si metodele de preventie si tratament ale acestuia.

Abstract: The adult majority has now jobs that include prolonged use of electronic devices and also their use extended more and more in private time by utilizing smartphones, tablets, laptops or video games resulting in an increased number of persons that present to the ophthalmologist with varied ocular complains. In this article there are presented etiopathogenesis mechanism that determine computer vision syndrome and also the possibilities of treatment and prevention.

 

Computerul a devenit o parte necesara, indispensabila a vietii noastre cotidiene atat la serviciu cat si acasa astfel ca in ultimii ani a crescut foarte mult perioada petrecuta in fata dispozitivelor digitale (precum desktop computer, laptop, tablet, TV, console de joc sau smartphone-uri) ajungandu-se la o expunere medie de aproximativ 6-9 ore pe zi.

Sindromul de oboseala vizuala la calculator reprezinta o afectiune ce apare ca urmare a focalizarii privirii pe un monitor pentru perioade de timp indelungate, mai mult de 3 ore pe zi, fara intrerupere.

Acuzele vizuale pot fi vederea incetosata, diplopia, oboseala oculara, fotofobia, cefaleea, senzatia de ochi uscat asociate cu manifestari generale precum oboseala generalizata, dar si probleme musculoscheletale precum dureri cervicale, scapulohumerale. [1]

Sindromul de oboseala vizuala la calculator apare mai frecvent la adultii sub 55 ani si de obicei mai frecvent la femei decat la barbati si simptomele sunt corelate cu numarul de ore petrecute in fata calculatorului si cu instalarea lor de obicei dupa ora 3pm.

Aceste simptome sunt determinate in special prin doua componente, respectiv: tulburari ale acomodatiei si sindromul de ochi uscat.

Acomodatia reprezinta un mecanism fiziologic ce permite ochiului sa isi ajusteze puterea dioptrica, absolut necesar vederii clare a obiectelor aflate la apropiere in care sunt implicati muschiul ciliar, cristalinul si zonula Zinn astfel ca pentru razele venite de la obiectele apropiate se produce contractia muschiului ciliar ce produce relaxarea fibrelor zonulei Zinn si bombarea cristalinului, mecanism care permite proiectarea corecta a imaginii obiectelor apropiate pe retina. Cristalinul se poate bomba mai mult sau mai putin, in functie de distanta la care privim, cu ajutorul unor muschilor ciliari. In schimb daca privim un obiect aflat la o distanta mai mare de 6 metri, muschiul ciliar se relaxeaza si ochiul se odihneste.

In momentul in care mecanismul este suprasolicitat (in conditiile lucrului prelungit la calculator, viciilor de refractie necorectatate sau stresului) apar tulburari ale acomodatiei si anume astenopia acomodativa si spasmul acomodativ.

  • Astenopia acomodativa este determinata de ineficienta mentinerii efortului acomodativ constant corespunzator varstei si se manifesta prin vedere neclara la apropiere, oboseala oculara, durere intraoculara, cefalee. [2]
  • Spasmul acomodativ (pseudomiopia) este dat de o contractie exagerata a muschiului ciliar avand ca rezultat o acomodatie continua atat la apropiere cat si la distanta, care se manifesta cu vedere incetosata la distanta si cefalee cu caracter migrenos.

Sindromul de ochi uscat poate fi de asemenea parte componenta oboselii vizuale la calculator. Este o afectiune destul de frecventa, subdiagnosticata reprezentata de deficienta in umectarea si lubrefierea suprafetei oculare ce determina o permanenta senzatie de iritare oculara.

Sindromul de ochi uscat poate aparea si la persoane care nu folosesc calculatorul in cadrul unor afectiuni oftalmologice sau generale.

Simptomele frecvente sunt senzatia de arsura, de corp strain, intepaturi, iritatie, inrosirea ochilor.

Filmul lacrimal prezinta 3 straturi: extern cu structura lipidica care impiedica evaporarea, stratul mijlociu apos cu rol antibacterian, antialergenic si in oxigenarea corneei si stratul intern mucos care adera la suprafata corneana.

Filmul lacrimal este repartizat uniform pe toata suprafata oculara de catre pleoape prin mecanismul clipitului, astfel ca uscaciunea suprafetei oculare la cei care folosesc calculatorul perioade lungi poate fi explicate printr-o reducere a ratei de clipit care creste perioada in care suprafata oculara este expusa evaporarii pana la urmatorul clipit; in acest moment exista metode prin care se realizeaza inregistrarea ratei de clipit (scaderea ratei de clipit apare ca mecanism fiziologic in timpul folosirii calculatorului sau altor video terminale [3]) pentru a o corela cu aparitia si intensitatea simptomelor sindromului de uscat.

Un alt lucru pe care trebuie sa-l stim este ca majoritatea electronicelor moderne – tableta, computer, telefon, TV – emit lumina albastra.

Noile cercetari arata ca expunerea cronica la lumina albastra poate duce la afectiuni oftalmologice precum aparitia cataractei si a degenerescentei maculare legate de varsta.

Degenerescenta maculara legata de varsta reprezinta principala cauza de scadere a vederii la populatia peste 55-60 ani si  afecteaza regiunea centrala retinei, macula. Implicatiile pe termen lung ale expunerii prelungite la lumina albastra sunt inca incomplet elucidate dar studiile elaborate pana in prezent arata ca supraexpunerea (radiatia cu lungimea de unda  intre 400-450nm este cea mai daunatoare) poate cauza leziuni retiniene prin absorbtia acestei lumini de catre pigmentii maculari (luteina si zeaxantina) provocand o alterare a mecanismelor protectoare si facand celulele retiniene susceptibile la degenerare si moarte celulara si determinand aparitia de leziuni severe, ireversibile precum degenerescenta maculara legata de varsta. [4,5]

Banda de lumina albastra-turcoaz cu lungime de unda in jurul valorii de 470nm este implicata in ritmul circadian, procesele cognitive si reflexul pupilar [6,7]

Pana la aparitia iluminatului artificial, soarele era sursa principala de lumina, astfel ca oamenii isi petreceau serile intr-o lumina slaba sau chiar intuneric. Producția de melatonină (hormonul care regleaza ritmul circadian) este inhibată de lumină (în special de lumina albastră, cu lungimi de undă cuprinse între 460 și 480 nm). Producția de melatonină devine maximă la miezul nopții, scăzând treptat în a doua jumătate a nopții.

Expunerea la lumina albastra produce efecte benefice pe timpul zilei precum cresterea atentiei, a timpului de reactie si a dispozitiei.

La persoanele care folosesc noaptea dispozitive ce emit lumina albastra poate aparea suprimarea secretiei de melatonina prin stimularea anumitor celule retiniene ce contin fotopigmentul melanopsina, astfel lucrul la calculator seara poate altera ritmul somn-veghe. Recomandarile sunt sa evitam folosirea device-urilor electronice cu 2-3 ore inainte de a merge la culcare, iar pentru cei care lucreaza in ture de noapte sa foloseasca lentile de protectie care blocheaza lumina albastra.

Numarul de dispozitive electronice a crescut foarte mult in ultimii ani, de asemenea a crescut numarul orelor petrecute in fata lor cu toate acestea foarte multe persoane nu stiu sau nu au incercat niciodata sa reduca disconfortul ocular aparut prin folosirea lor prelungita.

Recomandarea pentru persoanele care lucreaza la calculator este sa consulte un medic specialist oftalmolog care dupa un consult oftalmologic complet sa ofere informatii si solutii pentru scaderea efectelor oculare aparute ca urmare a efortului vizual prelungit la calculator.

Consultul oftalmologic include istoricul pacientului (simptomele experimentate, afectiuni generale, tratamente medicamentoase sau factori ambientali care pot contribui la acest sindrom), determinarea acuitatii vizuale, determinarea refractiei oculare(cu sau fara cicloplegie in functie de varsta pacientului), determinarea presiunii intraoculare si examenul fundului de ochi, teste pentru diagnosticul sindromului de ochi uscat (test Schirmer – evalueaza secretia lacrimala dpdv cantitativ, testul de rupere a filmului lacrimal – evalueaza secretia lacrimala dpdv calitativ).

Solutiile care pot fi aplicate pentru preventia sau tratamentul acestui sindrom sunt variate[8]:
1. Ochelarii cu protectie pentru calculator amelioreaza frecvent simptomele; se folosesc lentile cu filtru antireflex ce elimina reflexiile deranjante de pe suprafata lentilei si imbunatatirea contrastului, filtre Office care filtreaza componenta albastra a radiatiei si imbunatatesc confortul vizual
- pentru persoanele care prezinta vicii de refractie precum astigmatism, hipermetropie, prezbiopie este nevoie de prescriptia adecvata a corectiei optice in functie de distanta la care este pozitionat dispozitivul electronic
- pentru persoanele care nu prezinta vicii de refractie si nu necesita corectie optica se pot prescrie lentile cu filtre de protectie fara dioptrii
Un studiu publicat in 2014 in Revista Espanola de Salud Publica [9] arata ca persoanele care poarta lentile de contact si folosesc computerul prezinta mai frecvent simtome oculare si vizuale cu o prevalenta de 17-95% fata de o prevalenta de 9,9-57,5% la cei care nu poarta lentile de contact si conform aceluiasi studiu cei care poarta lentile de contact  prezinta de 4 ori mai frecvent simptome asociate sindromului de ochi uscat. Dintre lentilele de contact se pare ca cele din silicon hidrogel ofera cel mai bun confort.

2. Imbunatatirea posturii si factorilor ergonomici
- pozitie cu spatele drept pe un scaun de birou confortabil, cu inaltime setata astfel incat picioarele sa atinga solul usor
- ecranul computerului sa fie la 15-20 grade sub nivelul ochilor si sa fie protejat de luminile de pe tavan sau de ferestre fiind nevoie sa scadem iluminatul interior cand folosim computerul pentru ca monitorul sa fie cea mai puternica lumina din incapere

3. Display-ul trebuie sa fie relativ mare (desktop computer-ul sa aiba o diagonala de 19 inch)  si sa selectam cea mai mare resolutie, contrast – varianta alb-negru este cea mai buna , ajustarea dimensiunii textului  pentru a fi confortabil cititului

4. Respectarea pauzelor de efort vizual prin indepartarea privirii de pe monitor si privit la o distanta mai mare de 6 metri lucru care relaxeaza musculatura intraoculara (REGULA 20:20:20 – la fiecare 20 minute, pauza de 20 secunde de privit un obiect aflat la o distanta de peste 20 picioare)

5. Clipitul mai des, cu inchiderea completa  a pleoapelor asigurand astfel lubrefierea corecta a intregii suprafete oculare, precum  si aportul adecvat de lichide amelioreaza simptomele  ochiului uscat.

Factorii de mediu, precum temperatura ambientala si umiditatea sunt importanti si trebuie monitorizati pentru controlul acestor simptome; in cazul in care toate aceste masuri nu sunt suficiente pot fi prescrise de catre medicul oftalmolog lacrimi artificiale cu rolul de a lubrefia suprafata  oculara si a elimina disconfortul creat de uscaciunea oculara (lacrimile artificiale care nu trebuie confundate cu preparatele vasoconstrictoare care diminueaza roseata dar nu amelioreaza uscaciunea)

 

Concluzii

In ultimii ani tehnologia a evoluat foarte mult si se pare ca vom fi nevoiti sa folosim device-urile electronice tot mai mult si in conditiile in care laptopurile sau tabletele devin tot mai mici trebuie sa invatam cum sa ne protejam ochii si sa ne dezvoltam obiceiuri sanatoase la folosirea lor. Pentru a preveni aparitia simptomelor de oboseala vizuala la calculator dar si pentru a putea determina si preveni posibilele efecte pe termen lung ale folosirii prelungite a dispozitivelor electronice este nevoie de mai multe studii. De asemenea sa nu uitam ca examenul oftalmologic este obligatoriu si ca anumite simptome oculare ce se intalnesc si in sindromul de oboseala vizuala la calculator pot reprezenta de fapt o afectiune oftalmologica ce poate fi depistata doar de catre medicul specialist.

 

Bibliografie:
1. Ophthalmic Physiol Opt. 2011 Sep;31(5):502-15. Computer vision syndrome: a review of ocular causes and potential treatments.
Rosenfield M1.
2. http://emedicine.medscape.com/article/1199429-clinical
3. Arch Ophthalmol. 1995;113(2):155-158  – Effects of Ocular Surface Area and Blink Rate on Tear Dynamics
Kazuo Tsubota, MD; Katsu Nakamori, PhD;
4. Acta Ophthalmol Scand. 2006 Feb;84(1):4-15. Age-related maculopathy and the impact of blue light hazard.
Algvere PV1, Marshall J, Seregard S.
5. Arch Ophthalmol. 1992 Jan;110(1):99-104.The long-term effects of visible light on the eye.
Taylor HR1, West S, Muñoz B, Rosenthal FS, Bressler SB, Bressler NM
6. J Clin Endocrinol Metab. 2005 Mar;90(3):1311-6. Epub 2004 Dec 7.
High sensitivity of human melatonin, alertness, thermoregulation, and heart rate to short wavelength light.
Cajochen C1, Münch M, Kobialka S, Kräuchi K, Steiner R, Oelhafen P, Orgül S, Wirz-Justice A.
7. J Clin Endocrinol Metab. 2003 Sep;88(9):4502-5.
High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light.
Lockley SW1, Brainard GC, Czeisler CA.
8. Surv Ophthalmol. 2005 May-Jun;50(3):253-62. Computer vision syndrome: a review.
Blehm C1, Vishnu S, Khattak A, Mitra S, Yee RW.
9. Rev. Esp. Salud Publica vol.88 no.2 Madrid mar.-abr. 2014
Ocular and Visual Alterations in Computer Workers Contact Lens Wearers: Scoping Review

ABORDAREA DIAGNOSTICA SI TERAPEUTICA A PACIENTILOR CU POLIARTRITA REUMATOIDA SI BOLI INFLAMATORII INTESTINALE – ASOCIERI INEDITE

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Dr.Amalia Calinoiu, Dr.Picus A, Dr. Bibirus N, Dr. Vizitiu A,
Dr. Lupu D, Dr. Schiopu O, Dr. Bach J.

Clinica Medicala I –  Spitalul Universitar de Urgenta Bucuresti


Bolile autoimune sunt caracterizate printr-un raspuns imun anormal al organismului impotriva anumitor substante sau tesuturi, care in mod normal sunt prezente la nivelul organismului (autoimunitate). Acest raspuns poate fi indreptat spre anumite organe ( ex. Tiroidite) sau pot avea rasunet asupra mai multor tesuturi diferite.

Tratamentul afectiunilor autoimune consta, in principal, in terapii imunosupresoare, menite sa limiteze amplitudinea raspunsulului imun. Etiologia bolilor autoimune este necunoscuta. Una dintre teoriile vehiculate este ca anumite microorganisme (bacterii sau virusuri) sau medicamente pot produce schimbari in organism care genereaza confuzie in randul sistemului imun. Acest fenomen este mai frecvent intalnit in cazul indivizilor purtatori de anumite gene susceptibile pentru patologii autoimune.

 

ABSTRACT

Autoimmune diseases arise from an abnormal immune response of the body against some substances and tissues that are normally present in the body (autoimmunity). This may be restricted to certain organs (e.g. thyroid) or involve a particular tissue in different places.

The treatment of autoimmune diseases is typically with immunosuppression—medication that decreases the immune response. The exact cause of autoimmune disorders is unknown. One theory is that some microorganisms (such as bacteria or viruses) or drugs may trigger changes that confuse the immune system. This may happen more often in people who have genes that make them more prone to autoimmune disorders.

Poliartrita reumatoida (PR) este o artropatie cronica, cu caracter progresiv, distructiv si deformant, insotita de multiple manifestari sistemice.

Aceasta patologie constituie reumatismul inflamator cel mai frecvent, avand o prevalenta de aproximativ 1% in populatia generala, putandu-se estima un minim de 200.000 bolnavi in Romania. Incidenta anuala a bolii este de 0,5 cazuri noi/1000 locuitori pentru femei si 0,2 cazuri noi/1000 locuitori pentru  barbati, observandu-se o predispozitie crescuta in defavoarea sexului feminin [1,2].

Poliartrita reumatoida este o maladie autoimuna a tesutului conjunctiv, idiopatica, caracterizata prin sinovita eroziva simetrica (insotita de leziuni articulare severe) si afectare polisistemica. Majoritatea pacientilor prezinta o evolutie cronica fluctuanta a bolii, care fara tratament conduce la distructie articulara progresiva, ireversibila, cu deformari articulare permanente, insotite de deficit functional si afectarea semnificativa a calitatii vietii [3].

Pentru diagnosticul poliartritei reumatoide se folosesc criteriile ACR [4]:

1) redoare matinala: la nivelul articulatiilor, cu durata de minim o ora

2) artrita a cel putin 3 zone articulare: minim 3 zone articulare prezentand simultan tumefactie de tesuturi moi sau acumulare de lichid sinovial. Cele 14 zone articulare cel mai posibil afectate sunt: articulatiile interfalangiene proximale (IFP), metacarpofalangiene (MCF), radiocubitocarpiene (RCC), articulatia cotului, articulatia genunchiului, tibiotarsiene (TT), metatarsofalangiene (MTF)

3) artrita a articulatiilor mainilor: cel putin o zona articulara tumefiata, la nivelul RCC, MCF, IFP;

4) artrite simetrice: afectarea simultana bilateral a acelorasi arii articulare. Se accepta afectarea bilaterala a IFP, MCF, MTF fara simetrie absoluta;

5) noduli reumatoizi: noduli subcutanati, dispusi deasupra proeminentelor osoase, suprafetelor de extensie sau regiunilor juxtaarticulare

6) factor reumatoid (FR) seric: evidentierea unei cantitati crescute de FR seric

7) modificari radiologice: leziuni tipice pentru PR evidentiate pe radiografia posteroanterioara de maini cu RCC. Aceste leziuni tipice sunt: eroziuni sau osteoporoza

Criteriile 1-4 trebuie sa fie prezentate pe o perioada de minim 6 saptamani.

Pentru diagnosticul PR este necesara prezenta a minim 4 din cele 7 criterii [5].

Pentru fiecare caz de PR este necesara stabilirea unui plan individual de tratament, care va fi discutat in detaliu cu pacientul.

Momentul aplicarii si agresivitatea programului de tratament necesita aprecierea corecta a prognosticului bolii. Un prognostic nefavorabil este in gene­ral determinat de: varsta tanara la debut, un titru inalt al factorilor reumatoizi, titrul mare al reactantilor de faza acuta (PCR sau VSH), numarul mare de articulatii tumefiate, status functional alterat (apreciat prin HAQ), prezenta manifestarilor extraarticulare (inclusiv a nodulilor reumatoizi) [6,7].

Boala Crohn este o boala inflamatorie cronica localizata la nivelul peretelui tractului digestiv, putand afecta orice segment de la esofag pana la anus, cu predilectie pentru portiunea distala a intestinului subtire (ileita terminala) si colon, caracterizata prin leziuni inflamatorii ulcerative transmurale ce pot duce la complicatii de tipul stricturilor sau fistulelor [9].  Aceasta patologie este boala adultului tanar (15 – 30 ani), insa poate fi intalnita si la varste mai inaintate, avand incidenta egala la femei si barbat [10].

Etiologia bolii Crohn este idiopatica. Au fost propuse ca si cauze genetice, infectioase, tulburarile imunolgice, insa niciuna nu a fost demonstrata cert [11,12].

Principalele manifestari ale bolii Crohn sunt :

-  accentuarea tranzitului intestinal – scaune moi, de cateva ori pe zi – persistenta saptamani-luni (diaree cronica neinfectioasa)

-  dureri abdominale recurente

-  rectoragii

-  febra persistenta

-  alterarea starii generale

-  artralgii – frecvent lombalgii

-  scadere in greutate

Severitatea diareei si extinderea bolii inflamatorii intestinale pot necesita spitalizare de urgenta; uneori simptomatologia poate mima alte urgente chirurgicale, cum ar fi apendicita acuta sau  ocluzia intestinala, dar de cele mai multe ori, pacientii se interneaza pentru stabilirea etiologiei unei diareei prelungite sau a unui sindrom febril persistent,

Cel mai frecvent, boala Crohn are o evolutie cronica cu atenuari si recaderi, cu remisiuni de durata saptamanilor, lunilor sau anilor, intercalate de exacerbari severe.

Diagnosticul pozitiv este sugerat de simptomatologia caracteristica, completat de prezenta sindromului biologic inflamator (cresterea VSH, fibrinogenului, proteina C reactiva), eventual anemie si confirmat de endoscopia digestiva (interesare difuza, discontinua a mucoasei, cu ulceratii liniare si profunde; cu evidentierea histopatologica a infiltratului inflamator in fragmentele prelevate bioptic). Examinarea radiologica cu bariu a tubului digestiv poate fi utila in aprecierea intinderii si existentei complicatiilor bolii (fistule). Explorarile imagistice moderne (tomografie computerizata, rezonanta magnetica) pot ajuta, de asemenea, la diagnosticarea complicatiilor bolii Crohn (abcese, fistule) [13,14].

Diagnosticul diferential se realizeaza cu alte afectiuni digestive cu simptomatologie asemanatoare [15]:

-  dizenteria (coproculturi pozitive)

-  amoebiza

-  colita ischemica

-  colita peudomembranosa

-  angiodisplazia

-  cancerul de colon

-  rectocolita ulcero-hemoragica (boala inflamatorie cronica, strict localizata la nivelul colonului terminal si rectului, cu afectarea intregii mucoase colice si ulceratii intinse dar superficiale – evidentiate la colonoscopie)

Ca si complicatii ale bolii Crohn putem nota [16]:

  • abcese parietale si perianale
  • fistule: entero-enterice, entero-vezicale, entero-vaginale, entero-cutanate, cu complicatii infectioase determinate de continutul septic al intestinului (infectii urinare recidivante, infectii genitale, putand duce si la sepsis)
  • aderente ale anselor intestinale de vecinatate cu dezvoltarea de mase tumorale cu fenomene obstructive
  • dilatatie toxica a colonului (megacolonul toxic) – incidenta scazuta – cu pericol iminent de perforatie
  • anemia
  • malnutritia
  • cancerul de colon – rar – incidenta creste dupa 10 ani de boala activa

Tratamentul bolii Crohn este, in principal, medicamentos, procedeele chirurgicale fiind, de obicei, rezervate pentru complicatii (fistule, abcese, ocluzii).
Medicamentele utilizate se adreseaza in special substratului inflamator (terapii antiinflamatorii: sulfasalzina, corticoterapia, dar si terapii imunosupresoare: azatioprina, mercaptopurina, metotrexat, ciclosporina) [18]. Fiind un tratament de lunga durata si cu efecte adverse importante, necesita o atenta monitorizare clinica si paraclinica.
Pot fi utile si medicamentele antispatice, sedativele si uneori terapii antibiotice, doar la indicatia medicului curant. Recent, se utilizeaza noi terapii – anticorpi monoclonali impotriva citokinelor proinflamatorii – cu rezultate promitatoare [18].

Prognosticul bolii Crohn este variabil, in functie de intinderea procesului inflamator, prezenta complicatiilor, tratamentul urmat, si nu in ultimul rand, de complianta pacientului, fiind o boala cronica ce necesita periodic investigatii medicale, urmarire atenta si competenta [19].

 

CAZ CLINIC

Pacienta in varsta de 53 ani, se prezinta la medic acuzand epigastralgii de aproximativ o luna, neinfluentate de aportul alimentar, putin ameliorate de antialgice, scadere ponderala involuntara (4-5 kg in 2 luni) si inapetenta.

Pacienta este nefumatoare, neaga consumul de bauturi alcoolice sau substante toxice si provine din mediul rural. Din antecedentele heredo-colaterale, retinem mama hipertensiva, fara alt istoric familial de patologii autoimune. Ca si antecedente personale fiziologice, notam 1 nastere pe cale naturala si menopauza instalata natural in 2013.

Pacienta a fost diagnosticata cu poliartrita reumatoida la varsta de 20 ani prin criterii clinice, biologice (FR+, Ac anti-CCP+) si imagistice (leziuni erozive radiologice). Initial, pacienta a primit tratament cu Metotrexat, iar in prezent urmeaza tratament cu Rituximab de aproximativ 8 ani. Pentru puseele de activitate ale bolii, pacienta a urmat cure repetate cu AINS si corticoterapie.

La examenul clinic, observam o pacienta subponderala (IMC=18 kg/m2), cu tumefactii si deformari la nivelul mainilor bilateral, insa fara articulatii dureroase la momentul examinarii. Examenul clinic pulmonar, cardiac si digestiv este in limite normale (AV= 90 bpm ritmice, TA= 130/70 mmHg).

Pe baza acestor informatii, emitem ca si supozitii de diagnostic urmatoarele afectiuni:

-  Dureri abdominale in contextul tratamentului cu Rituximab

-  Gastrita indusa de AINS

-  Ulcer gastric/duodenal

-  Neoplasm gastric

-  Litiaza biliara

-  Sindrom dispeptic

In urma examenelor de laborator constatam sindrom inflamator (CRP=69,1 mg/l, VSH=43 mm/1h, Fib=427 mg/dl), anemie hipocroma microcitara moderata (Hgb=10,1 g/dl, MCV=64,7 fL, MCH=20,2 pg) cu feritina=20 microg/L si hiposideremie (Fe=9 microg/dl), trombocitoza (PLT=536.000/microL).

Se urmareste investigarea etiologiei sindromului anemic. Ecografia abdominala releva ficatul moderat difuz hiperecogen, colecist de dimensiuni normale cu pereti de grosime normala si continut transonic si microlitiaza renala stanga. Se propune pacientei efectuarea EDS, insa pacienta nu poate inghiti endoscopul.

Din aceste motive, se efectueaza CT abdomino-pelvin care evidentiaza ingrosare parietala circumferentiala a ceco-ascendentului cu densificarea grasimii adiacente, adenopatii iliace comune drepte, celiace si aortico-renale stangi, hemangiom hepatic (9mm) in segmentul VII si usoara hiperplazie suprarenaliana stanga. Se ridica astfel suspiciunea unui proces proliferativ la nivelul colonului drept.

In continuare, pacienta este supusa unei colonoscopii, care evidentiaza plaja ulcerata la nivelul cecului si portiunii initiale a colonului ascendant, valva ileo-cecala edematiata si ulcerata si stenoza si ulceratie intinsa la nivelul ileonului terminal.

Se recolteaza biopsii de la nivelul ulceratiei colonice, buletinul anatomo-patologic relevand metaplazie intestinala la nivelul epiteliului luminal si al criptelor (granulocite neutrofile in membrana bazala si in lumene, granulocite eozinofile parcelar in periferie) dilacerate de tesut de granulatie cu abundente granulocite. Acest aspect este sugestiv pentru  boala CROHN.

Ca si particularitati ale cazului clinic prezentat, putem nota simptomatologia pacientei putin sugestiva pentru boala Crohn, existenta a doua patologii autoimune diferite la o pacienta fara antecedente familiale de boli autoimune. De asemenea, debutul PR la varsta tanara si a bolii Crohn la varsta matura reprezinta o caracteristica inedita a acestor afectiuni.

 

BIBLIOGRAFIE

  1. Gabriel S. Epidemiology of the rheumatic diseases. In: Ruddy S, Harris E, Sledge C, editors. Kelley’s  Textbook of Rheumatology. Vol 1.6 ed Philadelphia, Pennsylvania: W. B. Suanders Company; 2001. p. 321-33
  2. Vanhoof J, Declerck K, Geusens P. Prevalence of rheumatic diseases in a rheumatological outpatient practice. Ann Rheum Dis 2002; 61: 435-5
  3. Ionescu R Esentialul in Reumatologie. Editura Amaltea.2006.p. 214
  4. Symmons DPM (1995) Disease assessment indices: activity, damage and severity. Baillière’s Clin Rheumatol 9:267–285
  5. Frank C. Arnett, MD, Steven M. Edworthy, MD, Daniel A. Bloch, PhD, Dennis J. Mcshane, MD, James F. Fries, MD, Norman S. Cooper, MD, Louis A. Healey, MD, Stephen R. Kaplan, MD, Matthew H. Liang, MD MPH, Harvinder S. Luthra, MD, Thomas A. Medsger Jr, MD, Donald M. Mitchell, MD, David H. Neustadt, MD, Robert S. Pinals, MD, Jane G. Schaller, MD, John T. Sharp, MD , Ronald L. Wilder, MD PhD , Gene G. Hunder, MD. The american rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis & Rheumatism Volume 31 Issue 3, Pages 315 – 324.
  6. Schenkier, S. & Golbus, J. Treatment of rheumatoid arthritis. New thoughts on the classic pyramid approach. Postgrad. Med. 91, 285–286 (1992)
  7. Wilske, K. R. & Healey, L. A. Challenging the therapeutic pyramid: a new look at treatment strategies for rheumatoid arthritis. J. Rheumatol. 25, 4–7 (1990).
  8. B Combe, R Landewe, C Lukas, H D Bolosiu, F Breedveld, M Dougados, P Emery, G Ferraccioli, J M W Hazes, L Klareskog, K Machold, E Martin-Mola, H Nielsen, A Silman, J Smolen, H Yazici . EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:34-45 doi:10.1136/ard.2005.044354
  9. Kornbluth A, Sachar DB, Salomon P. Crohn’s disease. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. Vol 2. 6th. Philadelphia, Pa: WB Saunders Co; 1998:1708-34.
  10. Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. Nov 2007;133(5):1670-89.
  11. Thoreson R, Cullen JJ. Pathophysiology of inflammatory bowel disease: an overview. Surg Clin North Am. Jun 2007;87(3):575-85.
  12. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. May 2004;126(6):1504-17
  13. Craig O, O’Neill S, O’Neill F, McLaughlin P, McGarrigle A, McWilliams S, et al. Diagnostic accuracy of computed tomography using lower doses of radiation for patients with Crohn’s disease. Clin Gastroenterol Hepatol. Aug 2012;10(8):886-92
  14. Panés J, Bouzas R, Chaparro M, García-Sánchez V, Gisbert JP, Martínez de Guereñu B, et al. Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn’s disease. Aliment Pharmacol Ther. Jul 2011;34(2):125-45
  15. Friedman S, Blumberg RS. Inflammatory bowel disease. In: Braunwald E, Fauci AS, Kasper DS, et al, eds. Harrison’s Principles of Internal Medicine. Vol 2. 15th ed. New York, NY: McGraw-Hill Professional Publishing; 2001:1679-91.
  16. Wilkins T, Jarvis K, Patel J. Diagnosis and management of Crohn’s disease. Am Fam Physician. Dec 15 2011;84(12):1365-75
  17. Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. Apr 2011;106(4):644-59
  18. Garcia JC, Persky SE, Bonis PA, Topazian M. Abscesses in Crohn’s disease: outcome of medical versus surgical treatment. J Clin Gastroenterol. May-Jun 2001;32(5):409-12
  19. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn’s disease in Olmsted County, Minnesota, 1940-1993: outcome, survival. Gastroenterology. Jun 1998;114(6):1161-8

Convulsiile febrile la copii

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Dr. Veronica Crisan, medic specialist Pediatrie, Spitalul Clinic de Urgenta pentru Copii „ Grigore Alexandrescu” Bucuresti

 

Rezumat

Convulsiile febrile reprezinta cea mai frecventa problema a neurologiei pediatrice. Conform statisticilor din toata lumea, un procent cuprins intre 2-5% dintre copiii sub 5 ani fac cel putin o data in viata un episod de convulsii febrile.

Convulsiile febrile sunt crize de tip epileptic, care se produc in asociere cu febra, dar in absenta unei infectii a sistemului nervos ( meningite, encefalite), in perioada de varsta de 3 luni-5 ani. [1]

Diagnosticul de convulsie febrila se pune dupa o anamneza riguroasa si un examen clinic si neurologic atent.

Desi simptomatologia este extrem de dramatica pentru parinti, prognosticul este de cele mai multe ori unul favorabil.

 

Abstract

Febrile seizures are the most common pediatric neurology problem. Worldwide, a percentage between 2-5% of children under 5 years old has at least once an episode of febrile seizures.

Febrile seizures are epileptic type seizures, occurring in association with fever, but in the absence of an infection of the nervous system (meningitis, encephalitis) during the 3 months to 5 years period. [1]

The diagnosis of febrile seizure comes after a thorough anamnesis and a careful clinical and neurological examination.

Although, for parents, the symptoms are very dramatic, the prognosis is, most of the times, favorable.

Etiopatogenie

Principalii factori implicati in declansarea convulsiilor febrile sunt:

1)      Febra – in proportie de 90 % febra este declansata de infectii acute ale cailor respiratorii (rinofaringite, otite, pneumonii), dar poate aparea si in cazul gastroenterocolitelor sau infectiilor urinare.[2] Convulsiile febrile mai pot aparea si in momentul ascensionarii febrile aparute la cei vaccinati  impotriva rujeolei, rubeolei si oreionului.

2)      Varsta – apar rar sub 6 luni si dupa 5 ani si au frecventa maxima intre 1 an si jumatate si 2 ani [1]

3)      Factorii genetici – majoritatea studiilor indica un mecanism de transmitere ereditara de tip autosomal dominant (AD). S-a identificat gena pentru convulsiile febrile  pe cromozomul 19p si pe cromozomul 8q13-q21[2], dar cercetarile au aratat ca si gena de pe cromozomul 5q14-q15 este implicata in predispozitia pentru convulsiile  febrile. [3]

Tabloul clinic

Convulsiile febrile se impart in:

1)      Convulsii febrile simple:

-          Sunt cele mai frecvente

-          Apar de obicei intre 6 luni si 5 ani

-          Sunt, de obicei, unice in 24 de ore

-          Au o durata redusa ( sub 15 minute)

-          Sunt bilaterale; de obicei, de tip convulsii tonico-clonice generalizate, sau numai clonice sau hipotone

-          Apar la copii anteriori normali, fara anomalii la examenul neurologic si fara retard psihomotor

-          Apar la cresterea brusca a temperaturii peste 38,5  grade Celsius

-          nu  sunt urmate de deficit postcritic

2)      Convulsiile febrile complexe (complicate) – oricare dintre criteriile:

-          Apar, de obicei, inaintea varstei de 1 an

-          se repeta, de obicei, in decursul unei zile

-          au o durata mai mare de 15 minute

-          sunt, de obicei, unilaterale

-          apar la copii cu dezvoltare psihomotorie anormala anterior crizei

-          sunt urmate de deficit postcritic[1]

 

O alta categorie definita in practica pediatrica este statusul epileptic febril (SEF), care se defineste ca fiind o criza epileptica clonica, mai rar tonico-clonica, generalizata sau unilaterala, cu durata de peste 30 de minute, asociata cu febra sau o serie de crize epileptice subintrante cu aceleasi caractere si aceeasi durata, indepedent de cauza febrei si de statusul neuropsihic precedent. [2]

Diagnosticul pozitiv

Diagnosticul de convulsii febrile se stabileste pe baza datelor anamnestice, a examenului clinic si a investigatiilor paraclinice.

Anamneza are un  rol foarte important. Medicul specialist pediatru impreuna cu medicul specialist neurolog vor pune intrebari tintite mamei sau celor care au fost de fata atunci cand s-a produs manifestarea de tip epileptic: cand a aparut criza convulsiva, cat a durat, daca s–a asociat sau nu cu pierderea starii de constienta, daca au aparut manifestarile postcritice, daca o noua criza convulsiva s-a repetat in aceiasi zi. [4]

Se vor intreba apartinatorii date despre afectiunea febrila si, foarte important, date despre dezvoltarea neuropsihica a copilului si despre antecedentele personale.

Examenul obiectiv al copilului  se va face cu mare atentie si se va insista pe semnele neurologice de focar si pe semnele de iritatie meningeana, pentru a elimina o serie de alte afectiuni.

Evaluarea paraclinica

In cazul convulsiilor febrile simple nu este nevoie de investigatii complexe, ci doar cele legate de afectiunea acuta ce a declansat ascensiunea febrila responsabila de aparitia convulsiilor febrile (cum ar fi hemoleucograma, probe inflamatorii, exudat faringian sau  sumarul de urina).

In cazul convulsiilor febrile complexe sunt necesare unele investigatii amanuntite pentru excluderea unei infectii a sistemului nervos central – meningita sau encefalita.

Se recomanda efectuarea punctiei lombare daca episodul de convulsii febrile a aparut la un sugar cu varsta sub 6 luni sau daca exista cea mai mica suspiciune clinica de meningita.

Daca a fost luata decizia de efectuare a punctiei lombare atunci trebuie efectuata si hemocultura pentru a spori sansele determinarii bacteriene. Datele statistice recente au aratat ca au crescut cazurile de convulsii febrile in randul copiilor nevaccinati – mai ales in cazul celor neimunizati impotriva haemophillus influenzae sau streptococul pneumonie. De aceea punctia lombara poate fi o optiune in cazul celor nevaccinati sau in cazul celor cu un status imun incert.[5]

Exista o alta categorie de pacienti care se prezinta pentru un episod de convulsii febrile, dar care au primit deja tratament antibiotic. Studiile au aratat ca si in aceste cazuri este recomandata punctia lombara deoarece un putem sti sigur daca antibioticul administrat a putut influenta manifestarile sau chiar evolutia meningitei bacteriene. Acest lucru depinde de doza administrata, de calea de administrare, de trecerea acestuia la nivelul lichidului cefalorahidian. [5] In concluzie, punctia lombara ramane o optiune si in cazul celor ce au primit tratament antibiotic anterior manifestarii convulsive.

Electroencefalograma nu se recomanda, de rutina, in cazul convulsiilor febrile simple;  studiile efectuate in intreaga lume au confirmat acest lucru. Aceasta investigatie poate fi efectuata, daca medicul neurolog considera necesar, in cazul convulsiilor febrile complexe sau in cazul unor copii ce au prezentat o serie de anomalii neurologice inainte de aparitia crizei.

Investigatiile neuroimagistice cum ar fi rezonanta magnetica nucleara (RMN)  sau computer tomograful (CT) nu sunt indicate. Daca sunt folosite pot evidentia leziuni cum ar fi displazia sau, in foarte rare cazuri, o formatiune tumorala sau un abces. Punand in balanta riscurile (iradierea pacientului sau complicatiile sedarii pentru efectuarea RMN –ului) si beneficiile, s-a ajuns la concluzia ca aceste investigatii nu sunt necesare.

Diagnosticul diferential

Diagnosticul diferential se va face cu:

1)      sincopa anoxica(crize anoxic-ischemice) provocate de cresterea brusca a temperaturii corporale

2)      convulsiile simptomatice din afectiunile acute febrile ale sistemului nervos central (meningite, encefalite, asociate cu modificari ale lichidului cefalorahidian)

3)      crize epileptice precipitate sau relevate de febra

4)      frisonul si delirul febril

5)      spasmul hohotului de plans [1]

Tratament

  1. 1. Tratamentul acut

Desi este un moment difícil pentru cel, sau cei, care se afla langa sugarul sau copilul  aflat in convulsii febrile este foarte important sa se actioneze rapid pentru oprirea manifestarii convulsive. Copilul trebuie pus in pozitie laterala (intr-o zona sigura,  unde acesta nu se poate lovi) cu eliberarea cailor respiratorii si asigurarea unei circulatii corespunzatoare. Dupa asezarea copilului in pozitia de siguranta se va suna la ambulanta si se va nota ora la care s-au declansat convulsiile febrile. Se vor initia masurile de scadere a temperaturii folosind antitermicele: ibuprofen (10 mg/kg corp), acetaminofen – paracetamol (10-15 mg/kg corp) sau metamizol (algocalmin).

In cazul copiilor care au mai trecut printr-un astfel de episod , parintii sunt instruiti sa administreze diazepamul intrarectal in doza corespunzatoare greutatii copilului.

Criza trebuie oprita cat mai repede pentru a evita producerea leziunilor cerebrale secundare anoxiei. In momentul in care ambulanta ajunge la pacient, de cele mai multe ori acesta nu  mai convulsioneaza; copilul va fi preluat si dus la o unitate spitaliceasca. Daca, in schimb, in momentul ajungerii la pacient acesta continua sa convulsioneze medicul il va plasa in pozitia de siguranta, aplica oxigenoterapia apoi va administra diazepam intrarectal 0,5 mg/kg corp. Daca crizele nu se opresc se va administra o noua  doza de diazepam 0,3 – 0,5 mg/kg dupa 5-15 minute de la prima doza. Dupa incetarea crizei convulsive acesta va fi transportat la spital unde va fi preluat de medicul specialist pediatru.

O meta-analiza a aratat ca lorazepamul este la fel de eficient ca si diazepamul, are mai putine efecte adverse si o nevoie mult mai scazuta de a administra alte medicamente antiepileptice. Un alt studiu a aratat ca midazolamul administrat pe cale bucala este mult mai eficient decat diazepamul intrarectal ( in cazul in care nu se poate obtine abordul venos).[7]

 

  1. 2. Tratamentul profilactic :

a)      Tratament intermitent

Consta in administrarea medicamentelor atunci cand copilul este bolnav si febril. Se vor administra antipiretice la temperaturi ce depasesc 38 de grade Celsius si diazepam  0,2 – 0,5 mg/kg corp/zi, per os, pe perioada cat copilul prezinta febra si inca doua zile dupa ce febra a incetat.

Daca in acesta perioada copilul prezinta un episod de convulsii febrile se va administra diazepam intrarectal: 0,5 mg/kg si  va fi transportat la spital.

b)      Tratamentul continuu

Acest tratament va fi administrat de medicul specialist de neurologie pediatrica doar in anumite cazuri cum ar fi:

-          Copii cu risc mare de a face convulsii febrile (mai mult de  3 episoade in 6 luni sau mai mult de 4 episoade intr-un an)

-          La cei care fac convulsii febrile complexe

-          La cei cu recurente frecvente

-          La cei cu dezvoltare psihomotorie anormala

-          La cei care necesita de fiecare data terapie medicamentoasa pentru oprirea episodului convulsivant.

Exista o serie de efecte adverse ale tratamentului cum ar fi iritabilitate, agitatie, deprivarea functiilor cognitive, foarte rar putand determina insuficienta pancreatica sau hepatica.

Tratamentul se va face cu fenobarbital -3-5 mg/kg-corp/zi sau acid valproic 20-30 mg/kg-corp/zi.

Evolutie si prognostic

 

Prognosticul este unul bun. Dezvoltarea neurologica si mentala la pacientii cu convulsii febrile ramane normala la marea majoritate a pacientilor care au avut o dezvoltare neurologica normala anterior convulsiilor.

Riscul de recurenta apare la o treime dintre copii ce au avut un episod de convulsii febrile, procentul de recurenta fiind cu atat mai mare cu cat varsta copilului este mai mica.  [2]

Riscul de recurenta este mai mare:

-           in cazul celor cu istoric familial de convulsii febrile (frati, parinti)

-          la cei la care convulsia febrila s-a declansat la temperaturi ce depasesc cu putin 38 de grade

-           la cei cu convulsii febrile complexe

-           la cei cu durata mare a crizei convulsive

-           la cei care au facut primul episod la mai putin de 15 luni.

In cazul celor cu convulsii febrile complexe exista riscul unor deficite neurologice si cognitive. In cazul celor dezvoltati normal din punct de vedere neurologic anterior, riscul este foarte scazut, dar pot aparea dificultati la invaltare, sindrom hiperkinetic sau semne neurologice minore sau chiar si hemiplegie, diplegie sau coreoatetoza.

 

Material si metoda

 

Am realizat un studiu retrospectiv al cazurilor de convulsii febrile internate in Spitalul Clinic de Urgenta pentru Copii „Grigore Alexandrescu” Bucuresti. Intervalul de culegere a datelor a fost 1 ianuarie – 31 Decembrie 2014.

In ceea ce priveste grupa de varsta, pana intr-un an au fost doar 4 cazuri internate cu acest diagnostic. Pe grupa de varsta 1-5 ani au fost internati 164 de pacienti, dintre care 94 au fost baieti (57,3%) si 70 fete (42,7%), confirmand statisticile din lumea intreaga in care procentul celor de sex masculin este usor crescut fata de cel al sexului feminin.

Dintre pacientii inclusi in studiul nostru au fost 141 de cazuri la care diagnosticul a fost de convulsii febrile primul episod, 21 de pacienti care s-au internat cu convulsii febrile recurente iar 4 s-au prezentat la spital in stare de rau convulsiv fiind internati de urgenta in sectia de terapie intensiva. Doar unul dintre cazurile care s-au prezentat in stare de rau convulsiv era cunoscut cu o afectiune neurologica grava.

Ca si in cazul frecventei, in cazul sexului masculin au fost mai multe cazuri ce s-au prezentat cu convulsii febrile recurente (14 cazuri), fata de sexul feminin unde au fost doar 7 cazuri. Se pare ca si in cazul severitatii crizei convulsive sexul masculin conduce din punct de vedere statistic: sunt trei cazuri care s-au prezentat in stare de rau convulsiv, in timp ce doar o fata a fost internata cu acest diagnostic.

Ca si afectiune de baza ce a declansat ascensiunea febrila au fost 161 de cazuri de infectii acute de cai respiratorii (rinofaringite acute, faringite acute si otite acute), 5 cazuri de pneumonie acuta si 1 caz de enterocolita acuta.

 

Concluzii

 

  1. Convulsiile febrile nu sunt crize epileptice.
  2. Apar cel mai frecvent intre 1,5 – 2 ani.
  3. Desi sunt foarte infricosatoare pentru apartinatori, de cele mai multe ori, nu au efecte in ceea ce priveste dezvoltarea neurologica.
  4. Convulsiile febrile apar, de obicei, in prima zi de boala, uneori fiind primul simptom al afectiunii curente – cele mai frecvente fiind infectii ale cailor respiratorii superioare.
  5. Cea mai frecventa manifestare este cea de convulsii tonico-clonice; durata medie este de aproximativ 2-3 minute.
  6. In cazul aparitiei convulsiilor febrile copilul trebuie asezat in pozitia de siguranta, sa se administreze tratament antipiretic si sa mearga de urgenta la spital.
  7. Copilul cu convulsii febrile va fi consultat de medicul pediatru pentru a determina cauza febrei si a exclude alte diagnostice posibile, cum ar fi meningita si encefalita.
  8. In general, convulsiile febrile simple nu necesita evaluare ulterioara sau investigatii speciale cum ar fi electroencefalograma, hemocultura sau punctie lombara.
  9. Copii ce au trecut printr-un episod de convulsii febrile prezinta riscul de a avea un nou episod; parintii trebuie sa fie foarte atenti la orice modificare in starea copilului (lipsa apetitului, somnolenta, scaune modificate) si sa administreze medicatia antipiretica imediat ce copii au febra.

10.  La aparitia unui nou episod de convulsii febrile parintii vor actiona de urgenta prin administrarea diazepamului (Desitin-ului) intrarectal, in functie de greutatea corporala.

11.  Epilepsia apare mult mai frecvent la copii ce au avut antecedent de convulsii febrile dar, totusi, riscul ca un copil sa dezvolte epilesie dupa un episod de convulsii febrile simple este foarte putin crescut fata de cei care nu au avut niciodata convulsii febrile. [6]

 

Bibliografie

  1. Tratat de Pediatrie-editia 1, Editura Medicala, Bucuresti, 2001, Sub redactia: Prof.Dr. Eugen Pascal Ciofu, Dr. Carmen Ciofu
  2. Tratat de Pediatrie, Editia I-a, Constantin N. Iordache, Editura “Gr. T. Popa”, U.M.F. Iasi, 2011
  3. Significant evidence for linkage of febrile seizures to chromosome 5q14–q15 – Junko Nakayama & others, Oxford Journals, 1999
  4. Algoritm de diagnostic si tratament in pediatrie, Valeriu Popescu, Editura Amaltea, 2003
  5. Febrile seizures: guideline for the neurodiagnostic evaluation of the child with a simple febrile seizure. Subcommittee on Febrile Seizures, American Academy of Pediatrics. Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics. 2011 Feb;127(2):389-94.
  6. Patient information: Febrile seizures (Beyond the Basics), Marvin A Fishman, MD, UpToDate
  7. Pediatric Febrile Seizures, Robert J Baumann, MD Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine , Medscape, Updated June 2014

Evaluari de laborator in ateroscleroza

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Rezumat:

LDL modificate sunt  imunogene, determinand  atat un raspuns imun mediat tumoral, cat si un raspuns imun celular. Ambele  tipuri de raspuns imun sunt pro-inflamatorii si pot determina  mentinerea  procesului inflamator cronic din cursul aterosclerozei.  Raspunsurile imune mediate de celulele T fata de prezenta lipoproteinelor de densitate joasa (LDL) modificate pot fi directionate catre peptidele asociate complexului major de histocompatibilitate clasa II (MHC-II), iar  raspunsul mediat de celulele B (umoral) apare fata de o varietate de grupari reziduale lizil (din aminoacidul lizina),  fosfolipide modificate si  lipoproteine de joasa densitate  oxidate care se asociaza cu  glicoproteine.  Concentratii semnificative de LDL modificate sunt in peretele vascular, in timp ce in plasma sunt concentratii mici de LDL modificate ( oxidative). Privind corelarea statistica slaba a LDL plasmatice modificate cu factori de risc cardiovascular CV, comparative cu NO care coreleaza puternic cu factori de risc CV, s-a aratat ca nu este posibila o asociere intre modificarea cu 1U/l a concentratiei plasmatice  a  LDL modificate oxidative si  riscul cardiovascular. Pe de alta parte, panelul cu parametrii masurabili in cazul persoanelor cu risc cardiovascular crescut, s-a modificat si el, datorita administrarii tratamentelor cu statine si prevalentei crescute a persoanelor cu obezitate, astfel ca atentia s-a concentrat asupra pacientilor in cazul carora valorile LDL-c sunt intr-o mai mica masura, indicatori ai riscului cardiovascular. Panelul de determinari mentionat mai sus include proteina C reactiva, fosfolipaza A2 asociata lipoproteinelor, concentratia particulelor de LDL, apolipoproteina B si subfractiile de HDL-c. Determinarea cu acuratete a afectarii “tesutului” vascular de catre ateroscleroza este dificila, dat fiind complexitatea  unor evaluari  pe care le presupune cum sunt angiografia si  evaluarea manifestarilor clinice. Determinari  de mai mica acuratete pot fi cauzate de:  faptul ca ateroscleroza evolueaza de o maniera discontinua si formarea epitopilor (antigenici) este variabila; epitopii in relatie cu oxidarea, pot fi localizati si pe  tesuturi, altele decat peretele vascular; leziunile aterosclerotice din stadii diferite ale bolii se caracterizeaza prin niveluri diferite de LDL modificate; heterogenitatea mare a speciilor imunogene de LDL modificate; anticorpii care se masoara reprezinta o “balanta” intre anticorpii formati si cei “consumati”, ceea ce depinde in final de functia sistemului imun la un moment dat. Eroarea subliniata in cercetarile recente care includ determinarea serica a LDL modificate in vederea evaluarii aterosclerozei, se refera la selectia unor subiecti sanatosi, expusi unor niveluri scazute de LDL oxidate, in vederea comparatiei cu  pacienti cu risc cardiovascular inalt, in cazul carora nivelurile corespunzatoare de LDL oxidate sunt  mai mari.  Astfel de studii trebuie sa  selecteze subiecti, care din punct de vedere clinic. au profiluri  similare de risc cardiovascular.

 

Abstract: Modified low density lipoproteins LDL are immunogenic as they induce both  humoral and cellular mediated immune responses that are pro-inflammatory and maintaining chronic inflammation of atherosclerosis. T cell mediated immune responses to modified LDL can be directed to major histocompatibility complex MHC class II associated peptides, whereas the B cell mediated response appears to  a variety of lysil groups, modified phospholipids and oxidized LDL associated with glycoproteins. Levels of modified LDL in the wall plaque content are considerably higher than plasma concentrations of modified LDL. Regarding weak correlations of plasma modified LDL with cardiovascular risk factors, it was shown that for example, a 1U/l change of oxLDL did not allow an attributable cardiovascular risk. By contrast, nitric oxide strongly correlates with cardiovascular risk factors. On the other hand, treatment with lipid lowering drugs and obesity shifted the risk profile toward patients in whom LDL-c values indicate less the risk for cardiac events. The above panel includes C reactive protein, phospholipase A2 associated with lipoproteins, concentrations of LDL particles, apolipoprotein B and HDL subfractions. Accurate determinations of severity and   extent of atherosclerosis in a patient are difficult due to complexity of evaluations such as angiography and assessments of clinical manifestations. Less accurate determinations may be due to the following factors: atherosclerosis progresses in a discontinuous fashion and formation of epitopes varies also. Oxidation specific epitopes may be generated in tissues other than the vessel wall; atherosclerotic lesions in different stages of the disease, contain various amounts of modified LDL; heterogeneity of molecular species of modified LDL; antibodies that are measured in serum, in fact point to a balance between antibodies formation and consumption, which is related to the immune function at a certain point in time. An error occurring  in researches that evaluate plasma modified LDL in view of atherosclerosis assessment, is the assumption that controls, namely healthy subjects exposed to low levels of, for instance, plasma oxidized LDL could have comparable cardiovascular risk profiles with those of patients with diabetes end-stage renal disease and coronary disease and in whom plasma concentrations of oxidized LDL are higher. Recruiting healthy subjects for comparing levels of modified LDL is an error and selection of patients should aim at including persons with clinically similar risk profiles in study-groups.

 

Exista un volum amplu de studii si cercetari  care descriu relatia complexa dintre lipoproteinele de joasa densitate modificate (oxidative) si stadiile aterosclerozei.  LDL modificate sunt  imunogene, inducand  atat un raspuns imun mediat umoral cat si un raspuns imun mediat celular. Ambele  tipuri de raspuns imun sunt pro-inflamatorii si determina  mentinerea   procesului inflamator cronic din cursul  aterosclerozei. Raspunsurile imune mediate de celulele T fata de prezenta lipoproteinelor de densitate joasa (LDL) modificate pot fi directionate catre peptidele asociate complexului major de histocompatibilitate clasa II (MHC-II), iar  raspunsul imun mediat de celulele B (umoral) apare fata de o varietate de grupari reziduale lizil (din aminoacidul lizina),  fosfolipide modificate si  lipoproteine de joasa densitate  oxidate care se asociaza cu  glicoproteine /1,2,3/. Epitopii antigenici derivati  de la LDL oxidate pot determina si activarea limfocitelor T reglatorii. In conditiile unor expresii crescute  ale compusilor complexului major de histocompatibilitate se activeaza celulele endoteliale, macrofagele  si celulele musculare netede din peretele vascular, iar liganzii receptorilor Toll-like, induc eliberarea de TNF-alfa, IL-6 si MCP-1 (proteina chemoatractanta de monocite). Cercetarile mai recente efectuate de Holvoet (2010) au aratat ca LDL oxidate pot induce receptorii Toll-like -2 si -4 si  factorul-1 care regleaza interferonul si prin aceasta inducere determina  inflamatie. De asemenea, in macrofagele activate se sintetizeaza fosfolipaza A(2) pro-inflamatorie cu rol in  lipoliza straturilor fosfolipidice din lipoproteinele de joasa densitate/1/.

LDL modificate (oxidative) induc sinteza compusilor de adezivitate celulara (VCAM-1- “vascular cell adhesion molecule-1”, ICAM-1- “intercellular adhesion molecule-1”si L-selectin) pe suprafata celulelor endoteliale. Neutrofilele si monocitele “migreaza” spre endoteliu, compusii de adezivitate facilitand  patrunderea acestor cellule in peretele vascular. Ulterior, VCAM-1, ICAM-1 si L-selectin de pe suprafata endoteliala “se transfera” in ser, deci in cazul pacientilor cu boala coronariana, concentratiile serice ale compusilor de mai sus, apar crescute, fiind astfel posibil ca acestia  sa fie considerati biomarkeri plasmatici de disfunctie endoteliala. Speciile reactive de oxigen (anionul superoxide) generate  de neutrofilele localizate de acesta data, chiar in peretele vascular,  pot  oxida LDL. Exceptand neutrofilele infiltrate in peretele vascular, s-a demonstrat si prezenta altor surse de generare a anionului superoxide, de exemplu:

  • cellulele endoteliale izolate de la animale de laborator hipercolesterolemice, pot produce intensiv anion superoxide.
  • tot in model experimental, cellule musculare netede din peretele vascular care au fost isolate de la sobolani hipertensiv genereaza superoxide prin activarea NADH/NADPH oxidaza localizata in membrane lor celulara.
  • sintetaza de oxid nitric constitutive, din cellulele endoteliale cultivate, poate genera superoxide dupa adaugarea LDL in mediul de cultura.

Anionul superoxide si speciile reactive radicalice pot oxida oxidul nitric cu formare de peroxinitrit si alti produsi de reactie care lezeaza endoteliul si nu permit activarea guanilil-ciclazei. Studiile nu au fost foarte clare  cu precizarea asupra  producerii de oxid nitric de catre endoteliul vascular disfunctional, in conditii de hipercolesterolemie, considerandu-se ca aceasta sinteza de oxid nitric este fie crescuta, fie diminuata semnificativ /4/.

Concentratiile semnificative de LDL modificate se localizeaza in peretele vascular, in timp  ce in plasma aceste  concentratii sunt mici  /2/. In ceea ce priveste  corelarea statistica slaba a LDL plasmatice modificate cu factori de risc cardiovascular CV, comparative cu oxidul nitric NO care coreleaza puternic cu factori de risc CV/5/, in cercetarile sale Guxen a aratat ca nu este posibila  o asociere  intre modificarea cu 1U/l a concentratiei plasmatice  a  LDL oxidate si  riscul cardiovascular/5,6/.  Argumentarea pe baza de date, a asocierii dintre lipoproteinele de joasa densitate plasmatice modificate si ateroscleroza, este criticata pe baza unei serii de argumente /7,8/. Pe de alta parte, panelul cu parametrii masurabili in cazul persoanelor cu risc cardiovascular crescut, s-a modificat si el, datorita administrarii tratamentelor cu statine si prevalentei crescute a obezitatii (in populatia nord-americana), astfel ca  atentia s-a concentrat asupra pacientilor cu valori ale LDL-c care nu indica risc cardiovascular. Panelul de determinari mentionat mai sus, care presupune   utilizarea de tehnici avansate, include:

proteina C reactiva;

fosfolipaza A (2) asociata lipoproteinelor;

concentratia particulelor de LDL-c;

concentratia de apolipoproteina B;

subfractiile de HDL-c /9/.

La pacientii cu fenotip de hipercolesterolemie  severa apar niveluri extreme de crescute ale LDL-c. Din punct de vedere genetic aceasta dislipidemie  (ereditara) este autosomala- dominanta si cauzata de mutatii ale genelor care codifica receptorul pentru LDL, apolipoproteina B si proproteina- convertaza-subtilisin-kexin, tipul 9 (PCSK9). In cazul altor pacienti, nu genele de mai sus determina  hipercolesterolemia severa, ci modificari epigenetice, poligenice , modificari (genetice) dobandite sau mutatii ale unor gene neidentificate inca. Consecintele clinice, indifferent de determinarea genetica sunt aceleasi, deci atat identificarea acestor pacienti cat si screening-ul  membrilor familiilor lor, sunt necesare. Screening-ul genetic nu trebuie efectuat pentru stabilirea diagnosticului sau a tratamentului. Tratamentul acestei hipercolesterolemii   include  administrarea mai multor hipolipemiante precum si afereza lipoproteinelor de joasa densitate. Procedura se utilizeaza in cazul pacientilor cu boala coronariana si LDL-c mai mare de 200mg/dl si in cazul subiectilor cu LDL-c mai mare de 300mg/dl, fara manifestari clinice. Inhibitorii de PCSK9 sunt testati in prezent in trialuri clinice si ar putea scadea nivelurile LDL-c cu inca 70% aditional reducerii determinate de hipolipeminatele pe care un pacient le tolereaza maxim,  in general, considerandu-se ca acesti inhibitori  pot scadea concentratiile LDL-c  cu mai putin de70% in cazul majoritatii pacientilor cu fenotip  hipercolesterolemic /10/.

Cu aproximativ doua decade in urma,  J Witzum a argumentat  faptul ca  asocierea dintre lipoproteinele de joasa densitate plasmatice modificate (oxidative)   si prezenta si extinderea aterosclerozei este slaba. Argumentele s-au dovedit corecte , astfel incat volumul de date semnificative statistic privind corelarea acestui parametru oxidativ cu patologia cardiovasculara  si factorii de risc ai acesteia, ramane limitat. In mod current, determinarea cu acuratete a afectarii “tesutului” vascular de catre ateroscleroza este dificila, dat fiind  complexitatea evaluarilor  pe care le presupune (angiografie, manifestari clinice). Determinari de mai mica acuratete  pot fi cauzate de :

  • faptul ca ateroscleroza evolueaza de o maniera discontinua si formarea epitopilor (antigenici) este variabila.
  • epitopii reprezentati de specii moleculare in relatie cu oxidarea, pot sa fie localizati si pe alte tesuturi, nu numai in peretele vascular;
  • leziunile aterosclerotice din stadii diferite ale bolii se caracterizeaza prin niveluri diferite de LDL modificate;
  • heterogenitatea mare a speciilor imunogene de LDL modificate, pentru care se incearca determinari in  ser;
  • anticorpii care se masoara reprezinta o “balanta” intre anticorpii formati si cei “consumati”, ceea ce depinde in final de functia sistemului imun la un moment dat /7/.

14 dintre studiile clinice mentionate in articolul publicat de  Maiolino, in 2013 au aratat corelatii pozitive intre concentratii plasmatice ale lipoproteinelor modificate (oxidative)  si aparitia de crize cardiace,  8 studii clinice mentionate de acelasi autor aratand dimpotriva, absenta corelatiilor de mai sus. Este lesne de inteles ca cele 14 studii nu pot oferi un volum suficient de rezultate robuste statistic. O remarca importanta este si faptul ca 3 dintre cele 8 studii care au evidentiat absenta corelatiilor positive dintre cei doi parametri specificati, au inclus persoane sanatoase. A considera ca profilul de risc cardiovascular al persoanelor sanatoase cu concentratii plasmatice  mici ale lipoproteinelor de joasa densitate modificate, este comparabil cu profilul de risc cardiovascular crescut al persoanelor cu boala renala in stadiu terminal, diabet, boala cronariana si concentratii plasmatice mai mari de LDL modificate, reprezinta o eroare subliniata de autor.  De asemenea, auto-anticorpii fata de MDA-LDL  si Cu-LDL si lipoproteinele oxidate plasmatice in cazul persoanelor sanatoase, nu au fost predictivi pentru evolutia aterosclerozei carotidiene si nici pentru aparitia de crize cardiace. Nivelurile lipoproteinelor plasmatice oxidate au fost predictive pentru aparitia de crize cardiace numai in analiza statistica multivariabila, in care valorile nu au fost ajustate pentru componentele sindromului metabolic /8/.

Eroarea includerii in cercetari a unor esantioane populationale mici este subliniata de asemenea in articolul publicat de Maiolino. Numarul mic de pacienti nu permite evidentierea valida din punct de vedere statistic, a rolului lipoproteinelor de joasa densitate plasmatice modificate. O alta greseala este stabilirea unui rezultat neadecvat, de urmarit in studiul respectiv. De exemplu, aparitia restenozei coronariene este mult prea frecvent aleasa ca rezultat care se urmareste in 75% din  astfel de studii, comparative cu alte complicatii cardiovasculare. Deci, niveluri plasmatice mai mari ale lipoproteinele de densitate joasa plasmatice modificate (oxidative)  apar mai ales in cazurile  pacientilor cu risc cardiovascular inalt,  diabetici, cu boala renala avansata si boala coronariana. Acestei limitari a domeniului de determinari ale LDL plasmatice modificate,  i se adauga si necoroborarea cu studii observationale,  in care   rezultatele determinarilor de  LDL plasmatice modificate sunt si ele contradictorii /8/.

Exista  surse de erori si in cercetarile care au utilizat modele experimentale  pentru a explica posibile mecanisme imunologice si biochimice in  ateroscleroza, rezultatele acestor cercetari  fiind de asemenea contradictorii. In astfel de studii, prin inginerie genetica s-a indus  animalelor de laborator utilizate, fie o expresie crescuta a lipooxigenazei-15 din peretele vascular, fie un deficit de receptori pentru LDL modificate, fie inactivarea genelor associate cu stresul oxidative. La soareci de laborator, prin inducerea pierderii activitatii genelor care codifica receptorii scavenger macrofagici SR-A si CD-36 (glicoproteina) pentru LDL oxidate, s-a obtinut o extindere mai mica a aterosclerozei. Rezultatele nu s-au confirmat prin inducerea unei pierderi duble de activitate a genelor /8/. Prin urmare, limitarile unor astfel de cercetari sunt legate de consecinte mai putin controlabile ale manipularii genetice (de exemplu, stergerea unor gene) si heterogenitatea  animalelor de laborator.

 

Kit-uri de reactivi pentru determinarea LDL plasmatice modificate

Caracteristicile celor trei teste de determinare in plasma,  a lipoproteinelor de densitate joasa modificate oxidativ in acord cu descrierea lor din kit-ul specific. de reactivi
OxLDL-4E6 OXLDL-DLH3 OxPL/apoB
Anul in care testul de determinare a fost descris 1995 1995 1996
Anticorp Monoclonal 4E6 DLH3/FOH1a EO6
Epitop (antigenic) Aldehida-lizina pe apoB Fosfolipide oxidate Fosfatidil-colina-fosfolipide oxidate
Proba biologica Plasma LDL izolat Plasma
Metoda de detectie Absorbtie la  450nm Absorbtie la 405nm Chemiluminiscenta
Exprimare in unitati de masura U/L ng/µg proteina LDL Unitati de luminiscenta relative
Standardizat Nu Nu Nu
Calibrare Se utilizeaza standard de LDL oxidate Se utilizeaza  standard de LDL oxidate Unitati de luminiscenta relative
Coeficient de variatie 4.0% – 8.3% 4.7% – 7.7% 6% – 10%
Stabilitatea probelor de ser congelate 6 luni Nu >5 ani
Randament crescut Da Nu Nu
Kit-uri disponibile comercial pentru utilizare in cercetare stiintifica Da (Mercodia) Da (Kyowa Medex MX kit) Nu
Corelatia cu LDL-colesterol Da Nu Nu
Corelatia cu Lp(a) ? Da Da

Tabel din: Miller YI and Tsimikas S. in Clinical Lipidology, A Companion to Brunewald’s Heart Disease, edited by Christie Ballantyne, 2009 p.104.

 

Bibliografie selective:

  1. Hulsmans M, Holvoet P. The vicious circle between oxidative stress and inflammation in atherosclerosis. J.Cell. Mol. Med., 2010, Vol. 14, no. 1-2, p 70-78.
  2. Alexander E. Fraley and Sotirios Tsimikas Clinical applications of circulating oxidized low-density lipoprotein biomarkers in cardiovascular disease Curr Opin Lipidol 17:502–509.
  3. Berger JS, Rockman CB, Guyer KE and Lopez LR. Proatherogenic Oxidized Low-Density Lipoprotein/2-Glycoprotein I Complexes in Arterial and Venous Disease http://dx.doi.org/10.1155/2014/234316
  4. RO Cannon http://www.clinchem.org/content/44/8/1809.long

 

  1. ukessays.com /essays/sciences/endothelial-function-as-a-surrogate-marker-of-cardiovasculardisease.php Endothelial function as a surrogate marker of cardiovascular disease.
  2. Guxen M, Fitó M,Martínez-González MA, Salas-Salvadó J, Estruch R, Vinyoles E, Fiol M, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Lapetra J, Ros E, Vila J and Covas MI Hypertensive Status and Lipoprotein Oxidation in an Elderly Population at High Cardiovascular Risk.  American J of Hypertension  2009, vol 22, no1, 68-73 Nature Publishing Group.
  3. Maiolino G, Rossito G, Caielli P, Bisogni V, Rossi GP and Lorenzo AC. The role of oxidized low density lipoproteins in atherosclerosis: the myths and the facts. http://dx.doi.org/10.1155/2013/714653
  4. Palinski W and Witzum JL Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis. J of Internal Medicine, 2000, 247, 371-380.
  5. Davidson MH, Ballantyne CM, Jacobson TA, Bittner VA, Braun LT, Brown WV, Cromwell WC, Goldberg RB, McKenney JM, Remaley AT, Sniderman AD, Toth PP, Tsimikas S, Ziajka PE, Maki KC, Diklin MR Clinical utility of inflammatory markers and advanced lipoprotein testing:advice from an expert panel of lipid specialists. J Clin Lipidol. 2011, 5, 338-67.
  6. Sniderman AD, Tsimikas S, Fazio S  The severe hypercholesterolemia type: clinical diagnosis, management and emerging therapies. J Am Coll Cardiol. 2014, 63(19), 1935-47.

Cristina Ionescu, CSIII, biolog, INGG “Ana Aslan”, Bucuresti

Prof Daniela Gradinaru, UMF Carol Davila-Facultatea de Farmacie, Bucuresti

DERMATITA SEBOREICA

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Oana Andreia Coman*, Ana-Mihaela Ungureanu**

*, ** Spitalul Clinic de Boli Infectioase “Dr. Victor Babes”, Clinica Dermatovenerologie, Bucuresti

*UMF “Carol Davila”, Facultatea de Medicina, Bucuresti

Rezumat:

Dermatita seboreica (DS) este o afectiune inflamatorie cronica care afecteaza mai frecvent fata si scalpul. DS apare atat la adulti cat si la copii, cu afectare preponderenta a sexului masculin. Etiologia bolii nu este pe deplin intelesa, insa exista citati cativa factori implicati in dezvoltarea dermatitei seboreice. Aspectul histopatologic al dermatitei seboreice este similar cu cel al psoriazisului, iar uneori doar timpul clarifica exact tipul afectiunii. Tratamentul trebuie sa fie non-agresiv, iar majoritatea pacientilor raspund la tratamentul topic care consta in: sampoane,  creme, lotiuni antifungice, dermatocorticoizi cu potenta joasa sau medie, geluri cu metronidazol. Terapia sistemica este rezervata cazurilor severe si consta in administrarea orala de antifungice din clasa imidazolilor, isotretinoin sau corticosteroizi.

Summary:

Seborrheic dermatitis (SD) is a chronic inflammatory disease that affects more frequently the face and scalp. DS occurs in both adults and children, men are more often affected than women. The etiology of the disease is not fully understood, but there are several factors involved in the development of seborrheic dermatitis. The histology of seborrheic dermatitis is similar to psoriasis, sometimes only time will tell what disease will evolve. The treatment must be non-aggressive, and almost all patients can be treated successfully with topical therapy: antifungal shampoos, creams, lotions, low to medium potency topical corticosteroids, metronidazole gel. Systemic therapy is reserved for severe cases and consists of oral imidazoles, isotretinoin or corticosteroids.

 

Dermatita seboreica (DS) este o dermatoza cu evolutie cronica care apare in zonele seboreice la persoane cu teren predispus.

Afecteaza in special adultul, avand incidenta maxima intre 18 si 40 ani, dar se intalneste si la nou-nascut. Sexul masculin este interesat preponderent.1

Din punct de vedere clinic, DS a adultului se prezinta sub forma unor placarde eritematoase, bine delimitate, uneori pruriginoase, acoperite de scuame grase alb-galbui, de grosime variata. Leziunile se localizeaza in regiunile bogate in glande sebacee:

- la nivelul scalpului poate debuta sub forma unei descuamari furfuracee difuze (matreata sau Pitiriazis capitis) care evolueaza in timp spre aspectul tipic de placi eritemato-scuamoase ce se extind si dincolo de liziera, pe frunte, retro si periauricular, precum si in conductul auditiv, complicandu-se cu otita externa. De asemenea, leziunile se pot extinde latero-cervical.

- la nivelul fetei ocupa zona mediala a sprancenelor si regiunea intersprancenoasa, santurile nazogeniene si barbia, precum si marginea libera a pleoapelor (blefarita seboreica).

- la nivelul toracelui, interscapular si mai ales presternal realizeaza placarde circinate, policiclice (eczematidele figurate mediotoracice Brocq).

Mai pot fi afectate pliurile de flexie, in special cele axilare si inghinale. De asemenea, la nivelul glandului pot aparea leziuni abia perceptibile sub forma unui eritem discret insotit de o descuamare fina, ce trec frecvent neobservate.

DS a nou-nascutului apare in primele 3 luni de viata la nivelul extremitatii cefalice, in regiunea parietala si a fontanelei anterioare, in partile mediane ale fetei, precum si la nivelul pliurilor mari. Evolutia este lenta, favorabila, cu resorbtie spontana in 1 – 2 luni. Extensia si generalizarea leziunilor realizeaza o complicatie severa – eritrodermia descuamativa Leiner-Moussous.

Etiopatogenia DS nu este complet elucidata. Se considera ca seboreea reprezinta un factor predispozant important, aflata sub influenta hormonilor androgeni si probabil determinata genetic. Desi s-au observat cazuri familiale, nu a putut fi stabilit un mod de transmitere.2 Terenul seboreic este susceptibil la diferiti agenti externi: Pityrosporum ovale ( levura lipofila, saprofita, cu rol important in producerea si intretinerea DS prin mecanism imunologic si proinflamator), agenti microbieni, factori alimentari (deficit de zinc, regim hipercaloric, alcoolism cronic), stressul emotional si oboseala, umiditatea crescuta, infectia HIV prin imunosupresia ce favorizeaza dezvoltarea exagerata a levurilor.3,4 De asemenea, anumite afectiuni interne (obezitate, pancreatita) si neurologice (sindroame extrapiramidale, psihoze organice) favorizeaza aparitia DS.5 Sunt si unele medicamente incriminate in agravarea DS, cum ar fi neurolepticele.

Aspectul histopatologic al dermatitei seboreice nu este foarte caracteristic. La nivelul epidermului se observa usoara acantoza, hiperkeratoza, parakeratoza, spongioza, iar acumularea sebumului in stratul cornos se traduce clinic prin prezenta scuamelor grase. In derm apare edem si infiltrat inflamator limfocitar perivascular.

Diagnosticul diferential se face cu: psoriazis (uneori doar timpul clarifica tipul afectiunii), dermatita de contact, otomicoza (cand leziunile sunt intraauriculare), dermatita atopica (in cazul DS infantile, insa dermatita atopica debuteaza mai tarziu, este mult mai pruriginoasa si, de cele mai multe ori, se deceleaza un istoric familial sau personal de atopie), pitiriazis rozat (atunci cand leziunile sunt extinse), sindrom Sézary si eruptie postmedicamentoasa (suspiciunea ultimelor doua se ridica in cazul eritrodermiei seboreice).

In ceea ce priveste evolutia si prognosticul, DS este o afectiune cronica, aceasta se tine sub control (nu se vindeca) si, de asemenea, sunt citate cazuri de overlap cu psoriazis.

Tratamentul DS

Datorita faptului ca DS este o afectiune cu evolutie cronica, uneori constitutionala, ea va necesita tratament de atac, continuat obligatoriu cu unul de intretinere, pe perioade lungi de timp (chiar de ani de zile).

Deoarece nu exista un tratament etiopatogenic al acestei afectiuni, tratamentul DS se bazeaza pe inlaturarea factorilor favorizanti amintiti anterior (combaterea seboreei cu o medicatie reductoare sau cu retinoizi aromatici, reducerea colonizarii cu Pityrosporum ovale cu ajutorul medicatiei antifungice, combaterea stressului prin sedative sau anxiolitice, tratarea adecvata  a  afectiunilor interne si neurologice).

Tratamentul igieno-dietetic consta in asigurarea unui ritm regulat de viata, cu ore suficiente de odihna si somn. Dieta trebuie sa fie echilibrata, cu continut corespunzator de zinc si fara alcool. In ceea ce priveste climatul, evitarea umiditatii excesive si expunerea la soare in timpul verii au efect favorabil asupra leziunilor pielii glabre, in special. Este importanta, de asemenea, evitarea folosirii cosmeticelor grase care modifica natura lipidelor de suprafata si echilibrul florei cutanate. Seboreea se va controla prin spalarea pielii glabre cu sapun moale, nealcalin (ex. sapun cu zinc pirition 2%) si a pielii capului cu sampoane ale caror componente au actiune antiseboreica (care vor fi prezentate in cele ce urmeaza).

Tratamentul simptomatic cuprinde combaterea inflamatiei si a pruritului – medicatia corticosteroida si inlaturarea scuamelor – medicatia keratolitica.

Tratamentul complicatiilor se refera in special la combaterea suprainfectiilor microbiene – medicatia antibiotica.

In esenta, tratamentul DS combina medicatia antifungica cu actiune asupra Pityrosporum ovale, medicatia reductoare, keratolitica si antiinflamatoare. In majoritatea cazurilor este suficient tratamentul local. Totusi pentru formele severe, generalizate, rezistente, este necesara asocierea unui tratament sistemic.

I. In ceea ce priveste tratamentul local, trebuie sa se tina cont de faptul ca DS nu tolereaza excipientii grasi. De aceea se vor folosi preparate sub forma de sampoane, lotiuni sau spray-uri pentru pielea capului si sub forma de crema, lotiuni sau spray-uri pentru pielea glabra.

  1. 1. Tratamentul antifungic

S-a observat ca actiunea cea mai eficienta impotriva Pityrosporum ovale o au derivatii imidazolici si in special ketoconazolul si bifonazolul. De asemenea rezultate favorabile ofera si unele antifungice neimidazolice ca ciclopiroxolamina si pirocton-olamina.6

a).- Ketoconazolul derivat imidazolic de sinteza, are o mare afinitate pentru keratina, fiind principalul antifungic cu actiune asupra Pityrosporum ovale. S-a demonstrat ca persista in concentratie ridicata in keratina stratului cornos si a firului de par. Actiunea sa antifungica este determinata de inhibarea specifica a sintezei ergosterolului, principalul sterol al membranei fungice, indispensabil cresterii celulare si stabilitatii membranare. De asemenea, prezinta un efect antiinflamator prin scaderea sintezei leucotrienei B4, ca urmare a inhibarii lipooxigenazei. Pentru pielea capului este preparat sub forma de sampon 2% (flacon de 60 ml), indicandu-se spalarea de 2 ori pe saptamana timp de o luna, apoi odata pe saptamana timp indelungat. Se mentine 5 minute inainte de clatire.

Pentru leziunile de pe fata si corp se foloseste ketoconazol sub forma de crema 2% (tub de 15 g) ce se aplica o data pe zi pe toata perioada prezentei leziunilor si cateva zile dupa disparitia acestora (aproximativ 2 – 4 saptamani in total). Se va continua, ca tratament de intretinere, de 1 – 2 ori pe saptamana.

Ketoconazolul are o foarte buna toleranta cutanata, rareori aparand reactii alergice sau iritative, de obicei la unul din componenti (sulfit de sodiu sau propilenglicol).

b).- Bifonazolul este comercializat sub forma de crema, solutie, gel 1%. Se aplica o data pe zi, timp de 2 – 4 saptamani.

c).- Ciclopiroxolamina 1%  se gaseste sub forma de crema in tuburi de 15 g. Se aplica de 2 ori pe zi, continuandu-se 1 – 2 saptamani de la disparitia leziunilor.

2.  Tratamentul reductor normalizeaza keratinizarea si secretia sebacee si diminueaza procesul inflamator cronic;  unele reductoare au si efect antifungic moderat (gudroanele). Principalele reductoare utilizate in tratamentul DS sunt: calomelul, precipitatul alb de mercur, sulful precipitat, gudroanele (ihtiol, coaltar, gudron de huila, ulei de cad). Acestea pot fi prescrise in preparate magistrale asociind agenti keratolitici (acid salicilic, rezorcina) si dermatocorticoizi. Mai jos sunt prezentate cateva exemple. 9

 

Rp.    Sulf precipitat

Calomel sau precipitat alb de mercur                 aa      1,5g

Acid salicilic                                                       0,3g

Hidrocortizon acetat                                           40g

D.S. ext. 1 data pe zi pentru fata si corp

 

 

Rp.    Acid salicilic                                              0,25g

Acid boric                                                 0,3g

Sulf precipitat                                          0,5g

Hidrocortizon acetat                                20g

Cutaden                                                   10g

D.S. ext.pentru corp 1 data pe zi

 

Rp.    Sulf precipitat                        0,5g

Acid salicilic                           0,7g

Precipitat alb de mercur                   aa 1g

Oleum cadinii

Oleum parafina                      2 ml

Triamcinolon crema               20g

D.S. ext. o data pe zi, pentru corp.

 

3. Tratamentul keratolitic in DS asociaza acidul salicilic cu rezorcina in solutie alcoolica pentru inlaturarea scuamelor din pielea capului si in creme pentru fata si corp (de obicei in combinatie cu reductoare, ca mai sus).

 

Rp.    Acid salicilic        aa      2g

Rezorcina

Alcool 700 ad      200 ml

D.S. ext. de 2 ori pe zi, pentru pielea capului.

 

4. Tratamentul antiinflamator si antipruriginos are la baza dermatocorticoizii. Pentru fata se folosesc cei de clasa 1: hidrocortizon acetat 1%, iar pentru corp si pielea capului cei de clasa a 2-a, de preferat nefluorinati (Triamcinolon acetonid 0,1%) si a 3-a, Mometazona furoat 0,1%, Metilprednisolon aceponat 0,1%, Hidrocortizon butirat 0,1%, Fluticazona propionat 0,05%.         Pentru a evita efectele adverse si de rebound, se recomanda utilizarea pe perioade scurte, eventual cu intermitenta si cu micsorare progresiva a ritmului de aplicare.

Hidrocortizonul acetat este folosit si in blefarita seboreica, eventual in asociere cu un antibiotic, dupa recomandarea oftalmologului.

5. Tratamentul cu metronidazol gel

Metronidazolul este un antibiotic sintetic, nitro-imidazol, care actioneaza prin distrugerea ADN-ului si prevenirea sintezei acizilor nucleici  la nivelul microorganismelor patogene anaerobe. Pe langa efectul antimicrobian, are efect antiinflamator prin inhibarea chemotaxiei leucocitelor.  De asemenea, previne eliberarea de mediatori inflamatori ai neutrofilelor. Exista cateva studii in care s-a folosit metronidazol gel in tratamentul dermatitei seboreice. Autorii acestor studii au concluzionat ca metronidazol gel 1% a fost eficient in tratamentul dermatitei seboreice faciale.7,8

6. Tratamentul complicatiilor se refera in special la suprainfectiile bacteriene si consta in administrarea de topice antibacteriene.

Diverse preparate comercializate sub forma de lotiuni, creme sau sampoane contin substante care combina efectele medicatiilor prezentate (antifungic, antiseboreic, reductor, keratolitic si antiinflamator), cum ar fi preparatul Skincap si alte sampoane.

a).- Preparatul Skincap – spray (flacon de 100 ml), crema (tub de 50g), sampon (flacon de 150 ml) – are ca substanta activa zinc piritionul (0,2% in spray si crema si 0,5% in sampon). Acesta are atat actiune antiseboreica cat si antifungica fata de Pityrosporum ovale si antibacteriana fata de streptococ si stafilococ, este antipruriginos si keratolitic. Se aplica de 2 ori pe zi, timp de aproximativ 2 – 4 saptamani, recomandandu-se continuarea inca o saptamana dupa incetarea simptomelor. Samponul se utilizeaza pentru spalarea pielii capului o data pe saptamana si este recomandat si ca tratament de intretinere. Pentru DS a pielii capului se pot folosi urmatoarele preparate:.

b)  - Samponul Kelual  DS (flacon 100 ml) formula sa contine doi activi microbieni complementari, ciclopiroxolamina si zinc piritionul. Se aplica pe parul umed, se lasa sa actioneze 3 minute, dupa care se clateste din abundenta.

c) – Samponul Sebomax Control (flacon 125 ml) contine octopirox si acid undecilenic. Se foloseste de 2-3 ori pe saptamana.

d) – Samponul Kertyol (flacon 125 ml), contine acid salicilic cu efect keratolitic si agenti tensioactivi cu actiune antifungica si antiinflamatorie. Se foloseste de 2 ori pe saptamana timp de 6 saptamani, mentinandu-se 3 minute inainte de clatire.

e) – Samponul Selegel (flacon 125 ml) contine disulfura de seleniu 1%. Se recomanda in formele de debut, cu descuamare furfuracee difuza a pielii capului. Se foloseste cu acelasi ritm de administrare, eventual in asociere cu lotiunea Kelual zinc.

f) – Samponul Selsun flacoane 120 ml, contine sulfura de seleniu 2,5%, cu efect antiseboreic si keratolitic. Se aplica de 2 ori pe saptamana timp de 2 saptamani, apoi o data pe saptamana. Se clateste dupa 3 minute.

g) – Samponul Novophane DS, flacoane 125 ml, contine agenti antifungici (octopirox 1%, zinc pirition 0,5%), agent keratolitic (acid salicilic 0,5%), agent keratoreductor si agenti de calmare si hidratare. In perioada de atac se utilizeaza de 2-3 ori pe saptamana, iar in perioada de intretinere se utilizeaza de 1-2 ori pe saptamana.

h) – Samponul Node D.S. (flacon 150 ml) contine climbazol, zinc pirition, piroctonolamina, cu efect antifungic, ihtiol, ulei de cad, acid salicilic, cu efect keratolitic, reductor, antiinflamator. Se foloseste pentru spalarea pielii capului de 3 – 4 ori pe saptamana ca tratament de intretinere, mentinanduase 3 minute inainte de clatire.

II. Tratamentul sistemic

Pentru formele severe de DS este necesar un tratament sistemic cu itraconazol 200-400 mg pe zi timp de 2 saptamani, ca terapie de atac, urmat de administrarea  a 200mg/zi, 5-7 zile pe luna, timp de 6 luni. Dupa priza orala zilnica de itraconazol timp de 14 zile, concentratia cutanata este se mentine o perioada mai lunga de timp.  De aceasta remanenta se poate profita prin administrarea intermitenta a itraconazolului in cazurile frecvent recidivante.

Pentru formele profuze sau cele asociate cu hiperplazie sebacee a fetei se mai recomanda retinoizii (isotretinoin 0,5 mg/kg/zi timp de 4 luni, sub supraveghere biologica corespunzatoare) care regleaza productia de sebum si implicit diminua colonizarea cu Pityrosporum ovale.

In sfarsit, se mai poate folosi PUVA-terapia pentu leziunile de pe pielea capului, pielea glabra a fetei si a toracelui anterior (leziunile de foliculita pitirosporica de pe toracele posterior nu raspund si pot fi chiar agravate).

In cazul suprainfectiei bacteriene se recomanda asocierea unui antibiotic de tip tetraciclina 1 g pe zi sau doxiciclina 100 mg pe zi, timp de 3 – 4 saptamani.

In DS cu tendinta la extensie se mai pot folosi corticosteroizi in doze moderate (20 – 30 mg prednison pe zi) si in cure scurte.

Tratamentul blefaritei seboreice

Tratamentul blefaritei seboreice se face, de obicei, impreuna cu oftalmologii. Se administreaza corticosteroizi topici cu potenta joasa (atentie la glaucom, rozaceea indusa de steroizi), antibiotice topice, creme cu imidazol si spalarea ochilor cu sampon.

 

 

Tratamentul DS a nou-nascutului

Are la baza mentinerea uscata a pielii si reducerea inflamatiei. Este necesar sa se corecteze tulburarile digestive si sa se asigure o dieta echilibrata. Se vor evita topicele grase si spalarea cu sapun alcalin care va fi inlocuit cu galbenus de ou sau cel mult cu un sapun slab acid.

In formele usoare este suficient un tratament local.

Pentru corp se folosesc comprese sau bai cu solutii slab antiseptice (KMnO4 1%) urmate de aplicatii de coloranti tip eozina 1% si dermatocorticoizi de clasa 1 (hidrocortizon acetat) in cure scurte, in asociere cu antifungice de tip imidazoli (ketoconazol) sau anticandidozice (nistatin sau fenticonazol) si cu antibacteriene, in caz de suprainfectie bacteriana. Scuamocrustele de la nivelul pielii capului se indeparteaza cu ulei de masline continand acid salicilic 1-3% apoi se aplica solutii de coloranti, dermatocorticoizi, eventual si antibiotice.

In formele cu leziuni intinse se asociaza tratamentul sistemic care cuprinde: antihistaminice pentru combaterea pruritului, antibiotice in functie de antibiograma; in caz de infectie secundara se poate completa cu o cura scurta de corticosteroizi (0,5 mg prednison/kg/zi).

In concluzie, DS este o afectiune cronica ce necesita tratament indelungat. Acesta trebuie adaptat in functie de intensitate, extensia si localizarea leziunilor si de raspunsul acestora la tratamentele anterioare. In formele de debut, in care matreata domina tabloul clinic, sunt indicate sampoane cu actiune asupra Pityrosporum ovale – ketoconazol, zinc pirition, sulfura de seleniu, gudroane.

In formele acute, cu placi eritemato-scuamoase la nivelul pielii capului, fetei si trunchiului, se adauga asocieri de topice antiseboreice, antifungice, dermatocorticoizi si eventual antibacteriene. Pentru cazurile severe, extensive, rezistente, se asociaza tratamentul sistemic cu itraconazol oral, corticoizi si eventual antibiotice.

Bibliografie

1.Gupta AK, Bluhm R. Seborrheic dermatitis. J Eur Acad Dermatol Venerol 2004;18: 13–26

2. Schwartz RA, Janusz CA, Janniger CK. Seborrheic dermatitis: an overview. Am Fam Phys 2006;74: 125–30.

3. Prohic A. Distribution of Malassezia species in seborrhoeic dermatitis: correlation with patients’ cellular immune status. Mycoses 2009;53: 344–349.

4. Kieffer M, Berbrant IM, Faergemann JF et al. Immune reactions to

Pityrosporum ovale in adult patients with atopic and seborrheic dermatitis.

J Am Acad Dermatol 1990;22: 739–742.

5. Cowley NC, Farr PM, Shuster S. The permissive effect of sebum in seborrhoeic dermatitis: an explanation of the rash in neurological disorders.

Br J Dermatol 1990;122:71–76.

6. Ortonne JP, Lacour JP, Vietta A, Le Fichoux Y. Comparative study of

ketoconazole 2% foaming gel and betamethasone dipropionate 0.05% lotion in the treatment of seborrhoeic dermatits in adults. Dermatology 1992;184:275–280.

7. Koca R, Altinyazar HC, Esturk E. Is topical metronidazole effective in seborrheic dermatitis? A double blind study. Int J Dermatol 2003;42:632-5.

8. Quan LT. Metronidazole. In:Wolverton SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders Co; 2001.p. 484-6.

9. Diaconu J.D., Coman O.A., Benea V. Tratat de terapeutica dermato-venerologica, Editura Viata Medicala Romaneasca,  Bucuresti, 2002.

MANAGEMENTUL TERAPEUTIC IN INTOXICATIILE ACUTE

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Dr. Calinoiu Amalia, Dr. Picus A,

Dr. Vizitiu A, Dr. Lupu D,

Dr. Schiopu O, Dr. Bach J.

Clinica Medicala I- SUUB

Abstract

Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short space of time, in usually less than 24 hours. Toxic substances include any chemical substance capable of producing structural and functional alterations of any cells, that clinically induce the alteration of vital status, reversible or not, potentially lethal and with a rapid progression.

 

Rezumat

Intoxicatia acuta reprezinta manifestarile ce apar in urma patrunderii in organism a substantei toxice in doza relativ mare, o singura data sau de mai multe ori intr-un interval de 24 de ore. Substantele toxice reprezinta orice compus chimic capabil sa produca alterari structurale si functionale, la diferite niveluri de organizare a materiei vii, alterari care se exprima pe plan clinic printr-o stare patologica,  care poate sa fie reversibila sau nu, avand uneori caracter letal, instalata in general brusc, este bine conturata si evolueaza rapid. (1)

In tarile dezvoltate sunt mai frecvente intoxicatiile cu medicamente (analgezice, antidepresive, sedative hipnotice, stimulante, droguri, medicamente cardiovasculare), in timp ce in tarile in curs de dezvoltare se intalnesc mai frecvent intoxicatii cu substante agricole (pesticide, ciuperci otravitoare), sau produse industriale (alcool metilic, produse petroliere), menajere (soda caustica, detergenti, solventi). (2)

Intoxicatiile medicamentoase apar datorita unor erori ale pacientului prin depasirea zilnica a dozei recomandate sau asocierea cu alte medicamente cu actiune sinergica, erori ale farmacistului (nedescifrarea corecta a prescriptiei, confuzia de substante), erori ale medicului (prescrierea unor doze mai mari, nerespectarea posibilelor interactiuni medicamentoase cu alte prescriptii ). (1)

Etapele sunt:

  1. Stabilizarea pacientului:
  • functii vitale: hemodinamica , ventilatie corespunzatoare;
  • examene “screening” pentru identificarea masurii de prevenire a agravarii starii intoxicatului
  1. Evaluarea completa a pacientului:
  • istoric: substanta toxica, doza, timpul scurs, prezenta simptomatologiei;
  • examen fizic;
  • teste de laborator: uzuale si specifice
  1. Masuri de scadere a absorbtiei toxicului prin : decontaminare – piele, ochi; varsatura, spalatura gastrica, carbune activat, purgative osmotice.
  2. Masuri pentru cresterea eliminarii toxicului: modificari ale pH – ului (plasmatic si urinar), diureza fortata, hemodializa, hemoperfuzia, carbune activat in doze repetate, exsangvinotransfuzia, plasmafereza, hiperoxibarism.
  3. Folosirea antidotului specific in 5% din intoxicatii:
  • Naloxona 0,4-2 mg i.v.à 10mg + glucoza/dextroza 50% 50 ml la toti intoxicatii cu deprimare SNC + vitamina B1 100 mg (vitamina  neurotropa), Νaltrexona p.o.
  • Antagonizeaza efectele endorfinelor ceea ce impiedica aprofundarea comei.
  1. Terapia de sustinere
  2. Evaluarea psihiatrica

Stabilizarea urmareste abordarea si corectarea functiilor vitale: cai aeriene, respiratie, circulatie, deprimare SNC prin toxice.

Prioritatea I:

  • permeabilitatea cailor aeriene;
  • respiratia prin ventilatie si oxigenare.

Obstructia poate aparea prin:

  • congestia/edematierea mucoasei,  secretii
  • deplasarea posterioara a limbii
  • corpii straini

Insuficienta ventilatorie prin:

  • paralizia mm. respiratori (toxina botulinica, stricnina, veninul de sarpe, tetanus, nicotina, COF)
  • deprimare respiratorie (barbiturice, ADT, opiacee, etanol, metanol, etilenglicol, COF, clonidina)

Simptomele sunt:

  • dispnee, tahipnee, cianoza, disfonie, tiraj
  • alterarea starii mentale, diaforeza

Prioritatea II o reprezinta prevenirea: – starii de soc,

- constienta diminuata

- tensiune arteriala scazuta

- vasoconstrictie periferica

- oligurie

- acidoza metabolica

Statusul hemodinamic poate fi alterat prin urmatoarele mecanisme:

  • hipovolemic (sindrom diareic, sdr. muscarinic – COF/ intoxicatia cu ciuperci, colchicina); hemoragii in intoxicatiile acute cu Fe (leziuni vasculare, hemoragii dig.) si cu compusi cu arsen  – rupturi vasculare pana la gastroenterite hemoragice. (4)
  • modificarea presarcinii (venodilatatie) – care scade in intoxicatiile cu nitriti, nitrati, barbiturice si a postsarcinii (vasoconstrictie) – care creste in intoxicatiile cu droguri de abuz precum : cocaina, amfetamine, adrenergice.
  • modificarea fortei de contractilitate in intoxicatiile cu ADT (antidepresive triciclice), clonidina, barbiturice, neuroleptice.

Prioritatea III reprezinta stabilizarea SNC.

Fata de alte come exista mici diferente in :

- aspectul pupilei :

  • substante ce dau mioza (benzodiazepine, barbiturice, etanol, ciuperci)
  • substante ce dau midriaza (anticolinergice, atropina – midriaza fixa,  antihistaminice, ADT, anticonvulsivante – carbamazepine, cocaine,  amphetamine, glutetimida (midriaza fixa), efedrina, adrenalina, toxina botulinica, cianuri (midriaza fixa), metanol (midriaza fixa), etilenglicol, toluene.

-   prezenta reflexului pupilar fotomotor un element diferential fata de comele endogene (AVC- accident vascular cerebral), in cele exogene e pastrat.

Prioritatea IV este reprezentata de decontaminare, care poate fi:

  1. Decontaminare externa cand:
  • Ø calea de patrundere este:

-         tegumentara se spala cu apa/sol.salina izotona 0,9% din abundenta (ex: insecticide, NH3, caustice)

-         oculara – NH­3, H2S, insecticide se spala cu solutie salina izotona 4 – 6 litri

2.Decontaminare interna :

  • Ø la ingestia de corozive, caustice care  produc leziuni de tip ulcerativ bazele determina necroza de lichefactie si acizii – necroza de coagulare se administreaza lapte, apa pentru a dilua continutul gastric. Singura situatie in care se da lapte 300 ml, in celelalte situatii laptele creste absorbtia substantelor liposolubile.
  • Ø emeza – administrare de substante emetice: sirop de ipeca – se poate repeta doza dupa 30 minute(doza 30 ml), detergent lichid. Aceasta are indicatii la un bolnav constient, respectandu-se intervalul de 6 ore din momentul ingestiei (dupa 6 ore nu mai exista in stomac). Nu se aplica la pacientii epileptici, in coma, cu sdr de HT intracraniana, la  femei gravide, copii < 6 luni, dupa ingestie de corozive si caustice, de toxice cu potential convulsivant :ADT, stricnina, HIN, fenotiazine, COF, opiacee, CO, cianuri ; toxice ce se absorb rapid si produc rapid coma (ADT, cloralhidrat), dupa ioduri, cianuri, nitrat de argint, hidrocarburi slab absorbabile ( gazolina, kerosen) cu risc de aspiratie – exceptie : daca HC e solvent pentru metale/pesticide, daca pacientul prezinta hemoragie, hematemeza.
  • Ø spalatura gastrica (protejarea cailor respiratorii cu sonda oro/nazotraheala). Sonda poate fi nazogastrica sau orogastrica – se introduc 300 ml de ser fiziologic 0,9% cald, timp de 1 minut, apoi lichidul se aspira; se repeta manevra pana ce aspiratul devine limpede.

Contraindicatiile metodei sunt: in intoxicatiile cu substante  corozive, caustice pentru ca se poate patrunde printr-o zona ulcerata si in cazul hemoragiei. In intoxicatia cu Fe se folosesc sol. speciale: NaHCO3 1-4 %

  • Ø formarea de carbune activat : se folosesc pulberi ce se administreaza oral sub forma de suspensie apoasa ¼, aceasta se muleaza la nivelul vilozitatii intestinale avand proprietati de adsorbtie.

 

Pentru extragerea toxicului deja absorbit inapoi in lumen (din capilar), exsorbtie enterocapilara doza utilizata este de 1 g/kgc, aproximativ  60 – 100g (in medie) si se administreaza la majoritatea intoxicatiilor medicamentoase: barbiturice, benzodiazepine, ADT, digitalice, anxiolitice, salicilati, anticonvulsivante (fenitoina), teofilina, nadolol, fenilbutazona. Metoda este  ineficienta in intoxicatiile cu alcool, corozive, caustice, ierbicide, insecticide, electroliti, hidrocarburi, glicoli, acid boric, cianuri, carbonati, metale ( Fe, Li ).

  • Ø cresterea vitezei de eliminare din tubul digestiv prin folosirea purgativelor osmotice:

-         Sulfatul de Mg – cel mai mare timp de latenta

-         Manitol, Sorbitol 70% 240 ml, latenta 1-3 ore

-         Sulfat de Mg solutie 10% 15 – 20 g, latenta 17 ore

-         Citrat de Mg  20 – 30 g, solutie 10 % , latenta 4 ore

-         Sulfat de Na in intoxicatiile cu paracetamol. (5)

  • cresterea eliminarii toxicului: – modificari ale pH – ului plasmatic: se folosesc substante cu caracter de electrolit  slab (alcaline sau acide) care in mediu intern ionizeaza, fenobarbital, salicilati (se corecteaza acidoza metabolica pentru ca favorizeaza trecerea intracelulara a salicilatilor neionizati);

-modificari ale pH – ului urinar: fractia neionizata se reabsoarbe, iar cresterea fractiei ionizate determina scaderea reabsorbtiei. In cazul barbituricelor, salicilatilor se  alcalinizeaza pH – ului urinar 7,5 – 8 cu NaHCO3: 1-2  mEq/kg. Acidifierea Ph – ului urinar 5,5 – 6 cu clorura de amoniu 75 mg/kg/h, p.o, i.v are indicatie in intoxicatiile cu: fenciclidina, amfetamina, stricnina, chinidina.

  • diureza fortata prin administrarea de diuretice: de ansa si osmotice, cand toxicul se elimina urinar nemetabolizat, e hidrosolubil, legat slab de albuminele plasmatice, distribuit preferential extracellular si are indicatie in intoxicatia cu: barbiturice, bromuri, amfetamine, salicilati.
  • hemodializa se utilizeaza la toxicele slab legate de proteinele plasmatice, hidrosolubile, cu greutate moleculara mica <500, cu volum de distributie scazut: alcoolii (metanol> 50mg%, etilenglicol > 50mg%, etanol>0,5g%), cloralhidrat, bromuri, alcool izopropilic, barbiturice cu durata lunga de actiune.
  • hemoperfuzia: toxic adsorbabil pe carbune activat in intoxicatiile cu salicilati, barbiturice cu durata scurta/medie de actiune, sedative hipnotice nebarbiturice ( glutetimida, meprobamat), cloramfenicol, paraquat, COF indirecti, HIN, paracetamol (sdr. hepatorenal)
  • administrarea de carbune activat in doza repetata, care blocheaza circuitul enterohepatic (daca substanta are circuit enterohepatic), ex: cloralhidrat, fenotiazine, fenitoina, digoxina, salicilati, digitoxina, ADT, barbiturice, colchicina, hidrocarburi halogenate (DDT), HIN
  • hiperoxibarism se realizeaza prin administrare de O2 la presiune crescuta de 2,5 atm, fiind  de electie in intoxicatiile cu CO ca scade T1/2 al carboxiHb,  cianuri, H2S unde creste fractia de O2 dizolvat in plasma.
  • exsangvinotransfuzia se practica in intoxicatia cu Fe (capacitatea de chelare e depasita), risc de hemoliza intravasculara la pacientii cu deficit de glucozo-6-fosfatdehidrogenaza la administrare de albastru de metilen pentru antidotismul methemoglobinemiei (albastru de metilen redus la  leucometilen de MetHbreductaza eritrocitara si reduce MetHb la Hb)
  • plasmafereza separa plasma – se indeparteaza 800 ml – 1l (se indeparteaza toxicele ce se leaga bine de proteinele plasmatice), de elementele figurate, care se reintroduc. (5)

 

Terapia de sustinere: necesita monitorizare completa cu sisteme de alarma pentru frecventa cardiaca, tensiunea arteriala, EKG, numarul de respiratii, SatO2 (saturatia de O2), pentru insuficienta respiratorie – intubare orotraheala, ventilatie cu presiune respiratorie pozitiva (impiedica EPA), prevenirea instalarii sindromului de aspiratie cu bronhopneumopatie prin antibioticoterapie si a edemului cerebral ce determina convulsii, letargie, cefalee, delir, coma prin  terapia hiperosmolara (manitol 20% 0,5-1 g/ kgc), corticoizi, furosemid (incarcare cu fluide), pentru convulsii  diazepam: 5-10 mg/iv, restabilirea echilibrului hidroelectrolitic si refacerea deficitului circulator, combaterea hipotensiunii arteriale prin administrarea de solutii cristaloide (glucoza 5%, NaCl 0,9 %), substituenti de plasma, vasopresoare (NA, dopamina, dobutamina, metoxamina), tratarea hipertensiunii arteriale cu nitroprusiat 0,5 – 2μg/kgc/minut si diuretice.

Prevenirea instalarii hipotermiei toxice are gravitate medie, se folosesc solutii preincalzite, iar scaderea potasiului ce determina aritmii cardiace prin administrare de lidocaina.

Hipertermia beneficiaza de racire activa cu comprese reci, ea aparand la substante adrenergice, anticolinergice. In hipertermia maligna, poate aparea hipertonie musculara generalizata, cresterea temperaturii la 42°, constienta fluctuanta, rabdomioliza, diaforeza, paloare, IRA (mioglobinurie).

In hiperpirexie masurile terapeutice impun: rehidratare, reechilibrare acido-bazica, electrolitica, oxigenoterapia, anticonvulsivant.

In sindromul neuroleptic malign se administreaza Dantrolen Na 1 mg/kgc,

Benztropina.

 

Evaluarea psihiatrica reprezinta alaturi de celelalte manevre terapeutice un punct terapeutic principal, deoarece statistic intoxicatiile acute apar datorita suicidului episodic, sindromului depresiv, stress-ului (emotional, economic, fizic), alcoolismului si tratamentului psihiatric.

 

ABREVIERI

ADT- antidepresive triciclice

COF- compusi organo-fosforici

 

BIBLIOGRAFIE

  1. FELICIA LOGHIN : Toxicologie Generala, Ed. Medicala Univ Iuliu Hatieganu, Cluj- Napoca, 2002.
  2. 2. CURS TOXICOLOGIE – UMF CAROL DAVILA 2007
  3. COLLINS J.M.: Inter-species differences in drug properties, Chemico-BiologicalInteractions, 134:237-242, 2001.

3. ANDERSEN H.R., NIELSEN J.B., GRANDJEAN P.: Toxicologic evidence of  developmental neurotoxicity of environmental chemicals, Toxicology, 144:121-127, 2000.

4. BARTHE L., WOODLEY J., HOUIN G.: Gastrointestinal absorption of drugs: methods and studies, Fundam.Clin.Pharmacol., 13:154-168,1999.

5.    D’ARCY P.F., MCELNAY J.C., WELLING P.G.: Mechanisms of Drug Interactions, Springer-Verlag, Berlin,1996.

MOLECULAR PARTICULARITIES OF ORYHOMYXOVIRIDAE VIRUSES FAMILY

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Dr. Emil Ionita

Dr. Ion Cantacuzino Institute

Part one

Rezumat:

Aceasta lucrare este o trecere in revista a datelor din literatura de specialitate asupra biologiei moleculare a virusurilor gripale –ARN negative unicatenare invelite in capsida virala apartinand familiei Orthomyxoviride. Sunt cunoscute 3 tipuri de virusuri gripale: A, B si C conform cu diferenta antigenica dintre nucleoproteinele lor (NP) si proteinele matriceale(M). Sunt discutate particularitatile de structura virala si de ciclu celular ca si  mecanismele de transcriere si replicare virala.

Abstract

This is a review of the literature data on the molecular biology of influenza viruses single stranded,negative –sense,enveloped RNA viruses which belong to Orthomyxoviridae family.There are known three types of influenza viruses namely A,B and C according  to the antigenic difference between their nucleoproteins (NP) and matrix proteins (M).

Are discussed particularities of viral structure and life cycle as well as molecular mechanisms of transcription and replication.

 

Introduction

According to the antigenic difference between  their nucleoproteins(NP) and matrix proteins (M),there are known three types of influenza viruses: A, B and C.

Influenza A and B virus share more structural similarity and both possess 8 RNA genome segments (PB2, PB1, PA, HA, NP, NA, M, NS), while influenza C virus only contains 7 (PB2, PB1, P3, HEF, NP, M, NS). According to the antigenic properties, type A virus can be classified into 16 HA subtypes and 9 NA subtypes, whereas type B and C virus genes have no such subtype classification.

 

From phylogenetic analysis based on HA2/HEF gene , type B and C viruses form the most closely related groups, such that all type A virus HA genes diverged after they separated from type B virus[1].

Within each type of influenza virus, the segmented genome structure, can readly change

genetic information by “reassortment” during co-infection of the same host cell.

The reasortment however, between different subtypes has not been reported, suggesting a form of “speciation” by genetic divergence[2].

Even all three types of influenza viruses can naturally infect human, only type

A virus has a wide range of animal host species, including birds, swine, horses and other

mammals [3];

 

As far as the identification of influenza B and C viruses in animal hosts this is sporadic [4]. Surprisingly, all of the HA and NA subtypes are found in wild aquatic birds (orders Anseriformes and Charadriiformes), indicating they are the nature reservoir of influenza A viruses. Along the migration routes (including northern breeding area, southern wintering area and many stopover sites during migration) of these reservoir species, influenza A viruses can be transmitted to other avian species, creating selfsustaining epidemics, and occasionally to some mammal species like humans, which may result in major pandemics.

Particularities of Viral structure and life cycle of Influenza virusA,B,and C

The main characteristics of Influenza viruses are: a) The prominent projections of

glycoprotein(s) (HA and NA for type A and B viruses, HEF for type C virus) in the lipid membrane envelope, which is derived from the viral-producing cells, and b) A segmented genome comprising the single-stranded negative sense RNA segments that are

encapsidated in a virally encoded nucleoprotein (NP) [5].

 

According to Mellema et al[6]]Influenza A and B viruses share very similar structures that make them virtually indistinguishable by electron microscopy . As a function of the viral strain and passage history, the virions may exhibit a variety of shapes, ranging from spherical particles about 100nm in diameter to elongated filament forms often in excess of 300 nm in length[5]. The viral envelope contains 3 proteins (HA, NA and M2) in type A virus and 4 proteins (HA, NA, BM2 and NB) in type B virus. Beneath the envelope lie the matrix proteins, M1, which bridge the inner core components (RNPs and NEP/NS2) and the membrane proteins, playing a vital role in assembly and budding process.

The RNP (ribonucleoprotein) complex consists of the viral RNA segments,coated by the nucleoprotein (NP) and bound to the polymerase complex, consisting three polymerase proteins (PB1 [polymerase basic 1], PB2 [polymerase basic 2], and PA[polymerase acid]). However, NS1, the nonstructural protein, is not incorporated into the virion. It has multiple functions and plays an important role in evading the host’s innate immune response by acting as the “IFN antagonist”.

 

Concerning  Influenza C virions ,it has been found that they exhibit a structure distinct from type A and B viruses and they can form unusually long (500 μm)cordlike structures on the surface of infected cell. In addition, type C virus has only one glycoprotein, the hemagglutinin-esterase-fusion (HEF) protein, which combines the hemagglutinin, receptor-destroying, and fusion activities [5].

The molecular stages of infecting host

Attachment influenza viruses is initiated by the attachment of viral particle to its target cell through interaction between its hemagglutinin(HA) spikes on the viral envelope and sialic acid receptors on the host cell surface.

Sialic acids are nine-carbon acidic monosaccharides commonly found at the termini of

many glycoconjugates therefore ubiquitous in many cell types and animal species

 

On binding at the cell surface, the virus is internalized by receptor-mediated endocytosis. The low pH in the endosome triggers fusion of the viral and endosomal membranes, releasing the viral RNPs into the cytoplasm. Viral RNPs are imported into the nucleus, where they serve as the template for transcription. New proteins are synthesized from viral mRNA. The viral genome (vRNA) is replicated through a positive-sense intermediate (cRNA). Newly synthesized viral RNPs are exported from the nucleus to the assembly site at the apical plasma membrane, where virus particles bud and are released .

[7]. However, HAs of influenza viruses from different host species often suggest host specificity due to their preference on binding sialic acid through either α2,3 or α2,6 linkage [8]. Specifically, human influenza viruses preferentially bind to sialic acid bearing a α2,6 linkage (SAα2,6Gal), whereas avian influenza viruses mostly bind to sialic acid with a α2,3 linkage [9].

 

This is correspondent to the fact that sialic acid with a α2,6 linkage is predominating in

human tracheal epithelial cells [10], whereas the α2,3 linkage is more common in duck gut epithelium[11] . Crucially, the viral host specificity is not absolute, as both the sialic acids linkages (α2,3 linkage and α2,6 linkage) can be found in human and avian cells, although with differential expression by cell type and location[12]. This may explain the low infectivity of avian influenza virus on human as sialic acids with α2,3 linkage mostly

present in the lower respiratory tract [13].

 

Occasionally, when viruses are passaged in a particular host they can adapt to that host

by accumulating mutations at the receptor-binding sites in HA. Specifically, a single

mutation (D190E) can trigger the change of binding specificity of a 1918 influenza strain

from α2,6 linkage to α2,3 linkage [14]. Therefore, the reverse mutation (E190D) in HA gene might be responsible for the adaptation of 1918 Spanish influenza from avian to human.

 

Membrane Fusion and Uncoating

After the interaction of influenza HA protein and sialic acid, the virus is internalized to a host cell endosome mainly through a clathrin-dependent receptor mediated endocytosis [15].

The low pH in endosome triggers conformational change in the HA thus exposes the ‘fusion peptide’, leading to the merging of virus envelope with the endosomal membrane thus releasing the vRNPs into the host cell cytoplasm (reviewed in [16].

 

The conformation change requires the cleavage of HA0 precursor protein into two

subunits, HA1 and HA2. Consequently, the precursor cleavability is correlated with the

pathogenicity of influenza infection [17]For example, most of HAs can only be cleaved by protease localized in respiratory and intestine organs, resulting in mild localized infections.

However, the cleavage sites of HAs in highly pathogenic avian influenza contain an insertion of multiple basic amino acids (RERRRKKR), which can be cleaved by ubiquitous protease such as furin in a wild range of organs, resulting in lethal

systemic infection [18]. In other cases, absence of acarbohydrate side chain [19] normally located 14 Å membrane distal to the cleavage site can also influence the accessibility of the site to proteases, thus increasing pathogenicity.

 

The successful uncoating of influenza virion also needs the dissociation of viral

matrix and the vRNPs before membrane fusion. The low pH environment of endosome

activates the proton-channel function of M2 proteins located in the viral envelope,

allowing the influx of protons from the endosome into the virus particle[20].

 

The internal acidification thus disrupts the internal protein-protein interactions and

dissociates the matrix protein from viral nucleoprotein, allowing the release of the vRNPs

into the cytoplasm. Blocking the ion channel activity of M2 protein by anti-viral drugs

Amantadine and Rimantadine (the adamantanes) can inhibit the viral replication [21].

Transcription and Replication

Once liberated from the virion, the vRNPs are actively transported to the nucleus

using the cellular nucleus import machinery, mediated by the nuclear localization signal

(NLS) located at the extreme N-terminus of NP[22]. All of the vRNA syntheses including viral transcription, replication and the assembling of vRNPs occur in nucleus. The viral RNA-dependent RNA polymerase uses the negative sense vRNA as template to synthesize both viral mRNAs, which are translated in the cytoplasm, and positive-sense antigenomes, the template for negative-sense RNA segment synthesis.

 

The transcription of viral genome is initiated using primers containing cap-1structure derived from host premature mRNAs by a “cap-snatching” mechanism, in which the cap structure is first recognized by PB2 and the capped oligonucleotide is then cleaved by PB1 [23].

The mRNA chain elongation will then proceeduntil reaching the polyadenalytion signal, consisting of a track of 5 – 7 U residues approximately 17 nucleotides from the 5’ end of vRNA. The stuttering and slipping of polymerase on these poly(U) stretch lead to the non-templated addition of a poly(A) tail that is 150nt long [24]. The primary transcripts of M and NS will then be spliced using cellular machinery to produce M1/M2 and NS1/NS2 mRNAs. These matured viral mRNAs will be exported to the cytoplasm and translated just as the host mRNA.

 

In contrast to transcription, the syntheses of cRNA occur via a primerindependent

mechanism and generate full-length products of vRNAs. The switch from mRNA to cRNA synthesis is proposed depending on the availability of soluble NP proteins, as the newly synthesized cRNAs and vRNAs are both encapsidated. Similarly,the newly synthesized PB2, PB1 and PA will also be imported into nucleus for the assembly of vRNPs, while M1 and NS2 proteins will associate the export of vRNPs to assemble the progeny viral particles [25].

Budding and Release

Followed the synthesis, HA, NA and M2 are processed in the endoplasmic reticulum and Golgi apparatus, and subsequently directed to the assembly site on the apical plasma membrane via their apical signal[26]. The apical budding facilitates the dissemination of progeny virions and thus related to the cell tropism. The HA and NA preferentially concentrate into patches correspondent to lipid raft, which is the key factor for the efficient budding [27]. These regions of plasma membrane form the new virion membrane and they envelop the matrix proteins layer,which interacts with both the cytoplasmic tail of glycoproteins and vRNPs therefore bridging the information between envelope and inner virion. M1 protein is also responsible for recruiting the host factors required for the late stage of budding, making itself a crucial factor in the budding process [28].

 

Due to the binding of sialic acid-containing receptors by HA proteins, the newly formed

progeny virions are initially aggregated at the host cell membrane. The successful

release of the infectious progeny virions requires the enzymatic activity of NA proteins,

which remove the sialic acid on the cell surface (Palese & Compans 1976). NA protein

is also suggested to provide an important role at cell entry by mucus degradation hence

allowing the access of virus to epithelium cells in the respiratory tract [29].

 

REFERENCES

1.  Suzuki Y, Nei M (2002) Origin and evolution of influenza virus hemagglutinin genes.

Mol Biol Evol 19: 501-509

2. Wright PF, Neumann G, Kawaoka Y (2007) Chapter 48: Orthomyxoviruses. In: Knipe

DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott Williams &

Wilkins.1691-1740

3.Webster RG, Yakhno M, Hinshaw VS, Bean WJ, Murti KG (1978) Intestinal influenza:

replication and characterization of influenza viruses in ducks. Virology 84: 268-278

4.Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA (2000)

Influenza B virus in seals. Science 288: 1051-1053

5.Palese P, Shaw ML. (2007) Chapter 47: Orthomyxoviridae: the viruses and their

replication. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott

Williams & Wilkins.1647-1689

6.Mellema JE, Andree PJ, Krygsman PC, Kroon C, Ruigrok RW, et al. (1981) Structural

investigations of influenza B virus. J Mol Biol. 151: 329-336

7.Bouvier NM, Palese P (2008) The biology of influenza viruses. Vaccine. 26 Suppl 4:

D49-53.

8.Skehel JJ, Wiley DC (2000) Receptor binding and membrane fusion in virus entry: the

influenza hemagglutinin. Annu Rev Biochem 69: 531-569

9.Rogers GN, Paulson JC (1983) Receptor determinants of human and animal influenza

virus isolates: differences in receptor specificity of the H3 hemagglutinin based on

species of origin. Virology 127: 361-373

10 Baum LG, Paulson JC (1990) Sialyloligosaccharides of the respiratory epithelium in

the selection of human influenza virus receptor specificity. Acta Histochem Suppl. 40:

35-38.

11. Ito T, Suzuki Y, Suzuki T, Takada A, Horimoto T, et al. (2000) Recognition of Nglycolylneuraminic acid linked to galactose by the alpha2,3 linkage is associated with

intestinal replication of influenza A virus in ducks. J Virol 74: 9300-9305

12.Thompson CI, Barclay WS, Zambon MC, Pickles RJ (2006) Infection of human airway epithelium by human and avian strains of influenza a virus. J Virol 80: 8060-8068

13 Shinya K, Ebina M, Yamada S, Ono M, Kasai N, et al. (2006) Avian flu: influenza virus receptors in the human airway. Nature 440: 435-436.

14. Glaser L, Stevens J, Zamarin D, Wilson IA, García-Sastre A, et al. (2005) A single

amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding

specificity. J Virol 79: 11533-11536.

15.Sidorenko Y, Reichl U (2004) Structured model of influenza virus replication in MDCKcells. Biotechnol Bioeng 88: 1-14.

16. Sieczkarski SB, Whittaker GR (2005) Viral entry. Curr Top Microbiol Immunol 285: 1-23.

17. Chen H, Smith GJ, Li KS, Wang J, Fan XH, et al. (2006) Establishment of multiple

sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proc

Natl Acad Sci USA 103: 2845-2850

18. Baigent SJ, McCauley JW (2003) Influenza type A in humans, mammals and birds:

determinants of virus virulence, host-range and interspecies transmission. BioEssays

25: 657-671.

19. Deshpande KL, Fried VA, Ando M, Webster RG (1987) Glycosylation affects cleavage of an H5N2 influenza virus hemagglutinin and regulates virulence. Proc Natl Acad Sci USA 84: 36-40.

20. Helenius A (1992) Unpacking the incoming influenza virus. Cell 69: 577-578.

21. Pinto LH, Holsinger LJ, Lamb RA (1992) Influenza virus M2 protein has ion channel

activity. Cell 69: 517-528.

22. Cros JF, García-Sastre A, Palese P (2005) An unconventional NLS is critical for the

nuclear import of the influenza A virus nucleoprotein and ribonucleoprotein. Traffic 6:

205-213.

23. Nagata K, Kawaguchi A, Naito T (2008) Host factors for replication and transcription ofthe influenza virus genome. Rev Med Virol 18: 247-260

24.Poon LL, Pritlove DC, Fodor E, Brownlee GG (1999) Direct evidence that the poly(A)tail of influenza A virus mRNA is synthesized by reiterative copying of a U track in thevirion RNA template. J Virol 73: 3473-3476.

25. Palese P, Shaw ML. (2007) Chapter 47: Orthomyxoviridae: the viruses and their

replication. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott

Williams & Wilkins.1647-1689

26.Tatu U, Hammond C, Helenius A (1995) Folding and oligomerization of influenza

hemagglutinin in the ER and the intermediate compartment. EMBO J 14: 1340-1348.

27. Scheiggele P, Rietveld A, Wilk T, Simons K (1999) Influenza viruses select ordered

lipid domains during budding from the plasma membrane. J Biol Chem 174: 2038-

2044.

28.Huang X, Liu T, Muller J, Levandowski RA, Ye Z (2001) Effect of influenza virus matrix protein and viral RNA on ribonucleoprotein formation and nuclear export. Virology 287:405-416.

29.Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD (2004) Human andavian influenza viruses target different cell types in cultures of human airway

epithelium. Proc Natl Acad Sci USA 101: 4620-4624

 

Air GM (1981) Sequence relationships among the hemagglutinin genes of 12 subtypes

of influenza A virus. Proc Natl Acad Sci USA 78: 7639-7643.

2. Air GM, Els MC, Brown LE, Laver WG, Webster RG (1985) Location of antigenic sites

on the three-dimensional structure of the influenza N2 virus neuraminidase. Virology

145: 237-248.

3. Air GM, Gibbs AJ, Laver WG, Webster RG (1990) Evolutionary changes in influenza B

are not primarily governed by antibody selection. Proc Natl Acad Sci USA 87: 3884-

3888

4. Akaike H (1974) A new look at the statistical model identification. IEEE Transactions

on Automatic Control 19: 716-723.

5. Alexander DJ (2000) A review of avian influenza in different bird species. Vet Microbiol

74: 3-13.

6. Alexander DJ (2006) An overview of the epidemiology of avian influenza. Vaccine. 25:

5637-5644.

7. Alexander DJ (2006) Avian influenza viruses and human health. Dev Biol (Basel) 124:

77-84.

8. Alexander DJ, Brown IH (2000) Recent zoonoses caused by influenza A viruses. Rev

Sci Tech 19: 197-225.

9. Anestad G (1987) Surveillance of respiratory viral infections by rapid

immunofluorescence diagnosis, with emphasis on virus interference. Epidemiol Infect

99: 523-531.

10. Baigent SJ, McCauley JW (2003) Influenza type A in humans, mammals and birds:

determinants of virus virulence, host-range and interspecies transmission. BioEssays

25: 657-671.

11. Basler CF, Reid AH, Dybing JK, Janczewski TA, Fanning TG, et al. (2001) Sequence

of the 1918 pandemic influenza virus nonstructural gene (NS) segment and

characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad

Sci USA 98: 2746-2751.

12. Baum LG, Paulson JC (1990) Sialyloligosaccharides of the respiratory epithelium in

the selection of human influenza virus receptor specificity. Acta Histochem Suppl. 40:

35-38.

13. Beard CW, Hitchner SB, Domermuth C, Purchase HG, Williams JE (1980) Avian

Influenza. College Station, Texas: American Association of Avian Pathologists.

14. Behrens G, Stoll M. (2006) Pathogenesis and Immunology. In: Kamps BS, Hoffmann

C, Preiser W, editors. Influenza report. Flying Publisher – Paris, Cagliari, Wuppertal,

Sevilla 92-109.

129

15. Berkhoff EG, Boon AC, Nieuwkoop NJ, Fouchier RA, Sintnicolaas K, et al. (2004) A

mutation in the HLA-B*2705-restricted NP383-391 epitope affects the human influenza

A virus-specific cytotoxic T-lymphocyte response in vitro. J Virol 78: 5216-5622.

16. Berkhoff EG, de Wit E, Geelhoed-Mieras MM, Boon AC, Symons J, et al. (2006)

Fitness costs limit escape from cytotoxic T lymphocytes by influenza A viruses.

Vaccine 24: 6594-6596.

17. Berkhoff EG, de Wit E, Geelhoed-Mieras MM, Boon AC, Symons J, et al. (2005)

Functional constraints of influenza A virus epitopes limit escape from cytotoxic T

lymphocytes. J Virol 79: 11239-11246.

18. Boni MF, Zhou Y, Taubenberger JK, Holmes EC (2008) Homologous recombination is

very rare or absent in human influenza A virus. J Virol 82: 4807-4811.

19. Boon AC, Sandbulte MR, Seiler P, Webby RJ, Songserm T, Guan Y, Webster RG

(2007) Role of terrestrial wild birds in ecology of influenza A virus (H5N1). Emerg

Infect Dis 13: 1720-1724.

20. Bourhy H, Kissi B, Audry L, Smreczak M, Sadkowska-Todys M, Kulonen K, Tordo N,

Zmudzinski JF, Holmes EC (1999) Ecology and evolution of rabies virus in Europe. J

Gen Virol 80: 2545-2558.

21. Bouvier NM, Palese P (2008) The biology of influenza viruses. Vaccine. 26 Suppl 4:

D49-53.

22. Bragstad K, Jorgensen PH, Handberg K, Hammer AS, Kabell S, et al. (2007) First

introduction of highly pathogenic H5N1 avian influenza A viruses in wild and domestic

birds in Denmark, Northern Europe. Virol J 4: 43.

23. Bright RA, Medina MJ, Xu X, Perez-Oronoz G, Wallis TR, et al. (2005) Incidence of

adamantane resistance among influenza A (H3N2) viruses isolated worldwide from

1994 to 2005: a cause for concern. Lancet 366: 1175-1181.

24. Buckley TR, Cunningham CW (2002) The effects of nucleotide substitution model

assumptions on estimates of nonparametric bootstrap support. Mol Biol Evol 19: 394-

405.

25. Campitelli L, Mogavero E, De Marco MA, Delogu M, Puzelli S, et al. (2004)

Interspecies transmission of an H7N3 influenza virus from wild birds to intensively

reared domestic poultry in Italy. Virology 323: 24-36.

26. Centers for Disease Control and Prevention (CDC) (2008) Update: influenza activity–

United States, September 28-November 29, 2008. MMWR Morb Mortal Wkly Rep 57:

1329-32.

27. Chare ER, Gould EA, Holmes EC (2003) Phylogenetic analysis reveals a low rate of

homologous recombination in negative-sense RNA viruses. J Gen Virol 84: 2691-

2703.

28. Chen H, Li Y, Li Z, Shi J, Shinya K, et al. (2006) Properties and dissemination of H5N1

viruses isolated during an influenza outbreak in migratory waterfowl in western China.

J Virol 80: 5976-5983.

130

29. Chen H, Smith GJ, Li KS, Wang J, Fan XH, et al. (2006) Establishment of multiple

sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proc

Natl Acad Sci USA 103: 2845-2850.

30. Chen R, Holmes EC (2006) Avian influenza virus exhibits rapid evolutionary dynamics.

Mol Biol Evol 23: 2336-2341.

31. Chen R, Holmes EC (2009) Frequent inter-species transmission and geographic

subdivision in avian influenza viruses from wild birds. Virology 383: 156-161.

32. Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, Thompson JD

(2003) Multiple sequence alignment with the Clustal series of programs. Nuc Acids

Res 31: 3497-3500.

33. Cheung CL, Rayner JM, Smith GJ, Wang P, Naipospos TS, et al. (2006) Distribution of

amantadine-resistant H5N1 avian influenza variants in Asia. J Infect Dis 193: 1626-

1629.

34. Cheung CL, Vijaykrishna D, Smith GJ, Fan XH, Zhang JX, et al. (2007) Establishment

of influenza A virus (H6N1) in minor poultry species in southern China. J Virol 81:

10402-10412.

35. Chi XS, Bolar TV, Zhao P, Rappaport R, Cheng SM (2003) Cocirculation and evolution

of two lineages of influenza B viruses in Europe and Israel in the 2001-2002 Season. J

Clin Microbiol 41: 5770-5773.

36. Cox NJ, Subbarao K (2000) Global epidemiology of influenza: past and present. Annu

Rev Med 51: 407-421.

37. Cramp, S., Perrins, C.M., (Eds.) 1985-1994. The Birds of the Western Palearctic.

Oxford, UK: Oxford University Press.

38. Cros JF, García-Sastre A, Palese P (2005) An unconventional NLS is critical for the

nuclear import of the influenza A virus nucleoprotein and ribonucleoprotein. Traffic 6:

205-213.

39. Deshpande KL, Fried VA, Ando M, Webster RG (1987) Glycosylation affects cleavage

of an H5N2 influenza virus hemagglutinin and regulates virulence. Proc Natl Acad Sci

USA 84: 36-40.

40. Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, et al. (2007) Surveillance of

resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated

worldwide. J Infect Dis 196: 249-257.

41. Doherty PC, Topham DJ, Tripp RA, Cardin RD, Brooks JW, Stevenson PG (1997)

Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus

infections. Immunol Rev 159: 105-117.

42. Donis RO, Bean WJ, Kawaoka Y, Webster RG (1989) Distinct lineages of influenza

virus H4 hemagglutinin genes in different regions of the world. Virology 169: 408-417.

43. Drummond AJ, Ho SY, Phillips MJ, Rambaut A (2006) Relaxed phylogenetics and

dating with confidence. PLoS Biol 4: e88.

131

44. Drummond AJ, Nicholls GK, Rodrigo AG, Solomon W (2002) Estimating mutation

parameters, population history and genealogy simultaneously from temporally spaced

sequence data. Genetics 161: 1307-1320.

45. Drummond AJ, Pybus OG, Rambaut A, Forsberg R, Rodrigo AG (2003) Measurably

evolving populations. TRENDS in Ecology and Evolution 18: 481-488.

46. Drummond AJ, Rambaut A (2007) BEAST: Bayesian evolutionary analysis by

sampling trees. BMC Evolutionary Biology 7: 214.

47. Dugan VG, Chen R, Spiro DJ, Sengamalay N, Zaborsky J, et al. (2008) The

evolutionary genetics and emergence of avian influenza viruses in wild birds. PLoS

Pathog. 4: e1000076.

48. Easterday BC, Trainer DO, Tumova B, Pereira HG (1968) Evidence of infection with

influenza viruses in migratory waterfowl. Nature 219: 523-524.

49. Edgar RC (2004) MUSCLE: a multiple sequence alignment method with reduced time

and space complexity. BMC Bioinformatics 5: 113.

50. Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high

throughput. Nucleic Acids Res 32: 1792-1797.

51. Escorcia M, Vázquez L, Méndez ST, Rodríguez-Ropón A, Lucio E, et al. (2008) Avian

influenza: genetic evolution under vaccination pressure. Virol J 5:15.

52. Felsenstein J (1981) Evolutionary trees from DNA sequences: a maximum likelihood

approach. J Mol Evol 17: 368-376.

53. Felsenstein, J (1984) Distance methods for inferring phylogenies: a justification.

Evolution 38: 16-24.

54. Ferguson NM, Galvani AP, Bush RM (2003) Ecological and immunological

determinants of influenza evolution. Nature 422: 428-433.

55. Fitch WM, Bush RM, Bender CA, Cox NJ (1997) Long term trends in the evolution of

H(3) HA1 human influenza type A. Proc Natl Acad Sci USA 94: 7712-7718.

56. Fitch WM, Leiter JME, Li X, Palese P (1991) Positive Darwinian evolution in human

influenza A viruses. Proc Natl Acad Sci USA 88: 4270-4274.

57. Flint PL (2007) Applying the scientific method when assessing the influence of

migratory birds on the dispersal of H5N1. Virol J 4: 132.

58. Fouchier RA, Munster V, Wallensten A, Bestebroer TM, Herfst S, et al. (2005)

Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained

from black-headed gulls. J Virol 79: 2814-2822.

59. Fukumi H, Nerome K, Nakayama M, Ishida M (1977) Serological and virological

investigations of orthomyxovirus in birds in South-East Asian area. Dev Biol Stand 39:

475,460.

60. Garamszegi LZ, Moller AP (2007) Prevalence of avian influenza and host ecology.

Proc. R. Soc. B 274: 2003-2012.

132

61. Gerhard W, Yewdell J, Frankel ME, Webster R (1981) Antigenic structure of influenza

virus haemagglutinin defined by hybridoma antibodies. Nature 290: 713-717.

62. Ghedin E, Sengamalay N, Shumway M, Zaborsky J, Feldblyum T, et al. (2005) Largescale

sequencing of human influenza reveals the dynamic nature of viral genome

evolution. Nature 437: 1162-1166.

63. Ghendon (1994) Introduction to pandemic influenza through history. Eur J Epidemiol

10: 451-453.

64. Gibbs MJ, Armstrong JS, Gibbs AJ (2001) Recombination in the hemagglutinin gene of

the 1918 “Spanish flu”. Science 293: 1842-845.

65. Glaser L, Stevens J, Zamarin D, Wilson IA, García-Sastre A, et al. (2005) A single

amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding

specificity. J Virol 79: 11533-11536.

66. Goldman N, Yang Z (1994) A codon-based model of nucleotide substitution for proteincoding

DNA sequences. Mol Biol Evol 11: 725-736.

67. Gorman OT, Bean WJ, Kawaoka Y, Webster RG. (1990a). Evolution of the

nucleoprotein gene of influenza A virus. J Virol 64: 1487-1497.

68. Gorman OT, Donis RO, Kawaoka Y, Webster RG. (1990b). Evolution of influenza A

virus PB2 genes: implications for evolution of the ribonucleoprotein complex and origin

of human influenza A virus. J. Virol. 64: 4893-902.

69. Graur D, Li W-H (2000) Fundamentals of Molecular Evolution. 2nd edn. Sinauer

Associates: Sunderland, MA, USA

70. Guan Y, Peiris JS, Lipatov AS, Ellis TM, Dyrting KC, et al. (2002) Emergence of

multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proc Natl

Acad Sci USA 99: 8950-8955.

71. Guo YJ, Jin FG, Wang P, Wang M, Zhu JM (1983) Isolation of influenza C virus from

pigs and experimental infection of pigs with influenza C virus. J Gen Virol. 64: 177-82.

72. Hahn CS, Hahn YS, Braciale TJ, Rice CM (1992) Infectious Sindbis virus transient

expression vectors for studying antigen processing and presentation. Proc Natl Acad

Sci USA 89: 2679-2683.

73. Hall TA (1999) BioEdit: a user friendly biological sequence alignment editor and

analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 41: 95-98.

74. Han GZ, Liu XP, Li SS (2008) Homologous recombination is unlikely to play a major

role in influenza B virus evolution. Virol J 5:65.

75. Hanada K, Suzuki Y, Gojobori T (2004) A large variation in the rates of synonymous

substitution for RNA viruses and its relationship to a diversity of viral infection and

transmission modes. Mol Biol Evol 21: 1074-1080.

76. Hanson BA, Stallknecht DE, Swayne DE, Lewis LA, Senne DA (2003) Avian influenza

viruses in Minnesota ducks during 1998-2000. Avian Dis 47: 867-871.

133

77. Hatchette TF, Walker D, Johnson C, Baker A, Pryor SP, et al. (2004) Influenza A

viruses in feral Canadian ducks: extensive reassortment in nature. J Gen Virol 85:

2327-2337.

78. Hastings WK (1970) Monte Carlo sampling methods using Markov Chains and their

applications. Biometrika 57: 97-109.

79. Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH (1985) The molecular basis of the

specific anti-influenza action of amantadine. EMBO J 4: 3021-3024.

80. He CQ, Han GZ, Wang D, Liu W, Li GR, et al. (2008) Homologous recombination

evidence in human and swine influenza A viruses. Virology 380: 12-20.

81. He CQ, Xie ZX, Han GZ, Dong JB, Wang D, et al. (2009) Homologous recombination

as an evolutionary force in the avian influenza A virus. Mol Biol Evol 26: 177-187.

82. He G, Qiao J, Dong C, He C, Zhao L, Tian Y (2008) Amantadine-resistance among

H5N1 avian influenza viruses isolated in Northern China. Antiviral Res 77: 72-76.

83. Helenius A (1992) Unpacking the incoming influenza virus. Cell 69: 577-578.

84. Hinshaw VS, Webster RG, Turner B (1978) Novel influenza A viruses isolated from

Canadian feral ducks: Including strains antigenically related to swine influenza

(Hsw1N1) viruses. J Gen Virol 41: 115-127.

85. Hiromoto Y, Saito T, Lindstrom SE, Li Y, Nerome R, et al. (2000) Phylogenetic

analysis of the three polymerase genes (PB1, PB2 and PA) of influenza B virus. J Gen

Virol 81: 929-937.

86. Hoffmann E, Stech J, Guan Y, Webster RG, Perez DR (2001) Universal primer set for

the full-length amplification of all influenza A viruses. Arch Virol 146: 2275-2289.

87. Holder M, Lewis PO (2003) Phylogeny estimation: traditional and Bayesian

approaches. Nat Rev Genet 4: 275-284.

88. Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, et al. (2005) Whole-genome analysis

of human influenza A virus reveals multiple persistent lineage and reassortment

among recent H3N2 viruses. PLoS Biol 3: e300.

89. Holmes EC, Urwin R, Maiden MC (1999) The influence of recombination on the

population structure and evolution of the human pathogen Neisseria meningitidis. Mol

Biol Evol 16: 741-749.

90. Holmes EC, Worobey M, Rambaut A (1999) Phylogenetic evidence for recombination

in dengue virus. Mol Biol Evol 16: 405-409.

91. Horimoto T, Fukuda N, Iwatsuki-Horimoto K, Guan Y, Lim W, et al. (2004) Antigenic

differences between H5N1 human influenza viruses isolated in 1997 and 2003. J Vet

Med Sci 66: 303-305.

92. Horimoto T, Kawaoka Y (2005) Influenza: Lessons from past pandemics, warnings

from current incidents. Nat Rev Microbiol 3: 591-600.

134

93. Huang X, Liu T, Muller J, Levandowski RA, Ye Z (2001) Effect of influenza virus matrix

protein and viral RNA on ribonucleoprotein formation and nuclear export. Virology 287:

405-416.

94. Huelsenbeck JP, Ronquist F, Nielsen R, Bollback JP (2001) Bayesian inference of

phylogeny and its impact on evolutionary biology. Science 294: 2310-2314.

95. Ito T, Gorman OT, Kawaoka Y, Bean WJ, Webster RG (1991) Evolutionary analysis of

the influenza A virus M gene with comparison of the M1 and M2 proteins. J Virol 65:

5491-5498.

96. Ito T, Okazaki K, Kawaoka Y, Takada A, Webster RG, Kida H (1995) Perpetuation of

influenza-A viruses in Alaskan waterfowl reservoirs. Arch. Virol. 140: 1163-1172.

97. Ito T, Suzuki Y, Suzuki T, Takada A, Horimoto T, et al. (2000) Recognition of Nglycolylneuraminic

acid linked to galactose by the alpha2,3 linkage is associated with

intestinal replication of influenza A virus in ducks. J Virol 74: 9300-9305.

98. Jenkins GM, Rambaut A, Pybus OG, Holmes EC (2002) Rates of molecular evolution

in RNA viruses: a quantitative phylogenetic analysis. J Mol Evol 54: 156-165.

99. Johansson BE, Bucher DJ, Kilbourne ED (1989) Purified influenza virus hemagglutinin

and neuraminidase are equivalent in stimulation of antibody response but induce

contrasting types of immunity to infection. J Virol 63: 1239-1246.

100. Jonassen CM, Handeland K (2007) Avian influenza virus screening in wild waterfowl in

Norway, 2005. Avian Dis 51: 425-428.

101. Jukes TH, Cantor CR (1969) Evolution of protein molecules. In Mammalian Protein

Metabolism, ed. HN Munro, pp. 21-132. New York: Academic

102. Kaleta EF, Hergarten G, Yilmaz A (2005) Avian influenza A viruses in birds –an

ecological, ornithological and virological view. Dtsch Tierarztl Wochenschr 112: 448-

456.

103. Kanegae Y, Sugita S, Endo A, Ishida M, Senya S, et al. (1990) Evolutionary pattern of

the hemagglutinin gene of influenza B viruses isolated in Japan: cocirculating lineages

in the same epidemic season. J Virol 64: 2860-2865.

104. Kawaoka Y, Krauss S, Webster RG (1989) Avian-to-human transmission of the PB1

gene of influenza A viruses in the 1957 and 1968 pandemics. J Virol 63: 4603-4608.

105. Kawaoka Y, Webster RG (1985) Evolution of the A/Chicken/Pennsylvania/83 (H5N2)

influenza virus. Virology 146: 130-137.

106. Kawaoka Y, Yamnikova S, Chambers TM, Lvov DK, Webster RG (1990) Molecular

characterization of a new hemagglutinin, subtype H14, of influenza A virus. Virology

179: 759-767.

107. Khatchikian D, Orlich M, Rott R (1989) Increased viral pathogenicity after insertion of a

28S ribosomal RNA sequence into the haemagglutinin gene of an influenza virus.

Nature 340:156-157.

135

108. Kilbourne ED, Cerini CP, Khan MW, Mitchell JW Jr, Ogra PL (1987) Immunologic

response to the influenza virus neuraminidase is influenced by prior experience with

the associated viral hemagglutinin. I. Studies in human vaccinees. J Immunol 138:

3010-3013.

109. Kimura M (1980) A simple method for estimating evolutionary rate of base

substitutions through comparative studies of nucleotide sequences. J Mol Evol 16:

111-120.

110. Kishino H, Thorne JL, Bruno WJ (2001) Performance of a divergence time estimation

method under a probabilistic model of rate evolution. Mol Biol Evol 18: 352-361.

111. Kosakovsky Pond SL, Frost SDW, Muse SV (2005) Datamonkey: rapid detection of

selective pressure on individual sites of codon alignments. Bioinformatics 21: 2531-

2533.

112. Kosakovsky Pond SL, Posada D, Gravenor MB, Woelk CH, Frost SD (2006) GARD: a

genetic algorithm for recombination detection. Bioinformatics 22: 3096-3098.

113. Krauss S, Obert CA, Franks J, Walker D, Jones K, et al. (2007) Influenza in migratory

birds and evidence of limited intercontinental virus exchange. PLoS Pathog 3: e167.

114. Krauss S, Walker D, Pryor SP, Niles L, Chenghong L, et al. (2004) Influenza A viruses

of migrating wild aquatic birds in North America. Vector Borne Zoonotic Dis 4: 177-

189.

115. Krug RM, Yuan W, Noah DL, Latham AG (2003) Intracellular warfare between human

influenza viruses and human cells: the roles of the viral NS1 protein. Virology 309:

181-189.

116. Krumbholz A, Schmidtke M, Bergmann S, Motzke S, Bauer K, et al. (2009) High

prevalence of amantadine resistance among circulating European porcine influenza A

viruses. J Gen Virol 90: 900-908.

117. Latorre-Margalef N, Gunnarsson G, Munster VJ, Fouchier RA, Osterhaus AD, et al.

(2009) Effects of influenza A virus infection on migrating mallard ducks. Proc Biol Sci

276: 1029-1036.

118. Lee CW, Senne DA, Suarez DL (2004) Effect of vaccine use in the evolution of

Mexican lineage H5N2 avian influenza virus. J Virol 78: 8372-8381.

119. Lee CW, Senne DA, Suarez DL (2006) Development and application of reference

antisera against 15 hemagglutinin subtypes of influenza virus by DNA vaccination of

chickens. Clin Vaccine Immunol 13: 395-402.

120. Li C, Yu K, Tian G, Yu D, Liu L, et al. (2005) Evolution of H9N2 influenza viruses from

domestic poultry in Mainland China. Virology 340: 70-83.

121. Li S, Min JY, Krug RM, Sen GC (2006) Binding of the influenza A virus NS1 protein to

PKR mediates the inhibition of its activation by either PACT or double-stranded RNA.

Virology 349: 13-21.

136

122. Lindstrom S, Endo A, Sugita S, Pecoraro M, Hiromoto Y, Kamada M, Takahashi T,

Nerome K (1998) Phylogenetic analyses of the matrix and non-structural genes of

equine influenza viruses. Arch Virol 143: 1585-1598.

123. Lindstrom SE, Cox NJ, Klimov A (2004) Genetic analysis of human H2N2 and early

H3N2 influenza viruses, 1957-1972: evidence for genetic divergence and multiple

reassortment events. Virology 328: 101-119.

124. Lindstrom SE, Hiromoto Y, Nishimura H, Saito T, Nerome R, Nerome K (1999)

Comparative analysis of evolutionary mechanisms of the hemagglutinin and three

internal protein genes of influenza B virus: multiple cocirculating lineages and frequent

reassortment of the NP, M, and NS genes. J Virol 73: 4413-4426.

125. Liu J, Xiao H, Lei F, Zhu Q, Qin K, et al. (2005) Highly pathogenic H5N1 influenza

virus infection in migratory birds. Science 309: 1206.

126. Lopes RJ & Wennerberg L (2006) Geographical segregation in wintering dunlin

Calidris alpina populations along the East Atlantic Flyway: evidence from nitochondrial

DNA anlalysis. In: Boere G, Galbraith CA, Stroud D, Bridge LK, editors. Waterbirds

Around the World. The Stationery Office. 541-544.

127. Ludwig S, Schultz U, Mandler J, Fitch WM, Scholtissek C (1991) Phylogenetic

relationship of the nonstructural (NS) genes of influenza A viruses. Virology 183: 566-

577.

128. Lupiani B, Reddy SM (2008) The history of avian influenza. Comp Immunol Microbiol

Infect Dis 32: 311-323.

129. Macken CA, Webby RJ, Bruno WJ (2006) Genotype turnover by reassortment of

replication complex genes from avian influenza A virus. J Gen Virol 87: 2803-2815.

130. Maddison DR, Maddison WP (2001) MacClade 4: Analysis of phylogeny and character

evolution. Version 4.03 Sinauer Associates, Sunderland, MA

131. Manuguerra JC, Hannoun C (1992) Natural infection of dogs by influenza C virus. Res

Virol 143: 199-204.

132. Martin K, Helenius A (1991) Nuclear transport of influenza virus ribonucleoproteins: the

viral matrix protein (M1) promotes export and inhibits import. Cell 67: 117-130.

133. Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD (2004) Human and

avian influenza viruses target different cell types in cultures of human airway

epithelium. Proc Natl Acad Sci USA 101: 4620-4624

134. Matsuzaki Y, Sugawara K, Takashita E, Muraki Y, Hongo S, et al. (2004) Genetic

diversity of influenza B virus: the frequent reassortment and cocirculation of the

genetically distinct reassortant viruses in a community. J Med Virol 74: 132-140.

135. McCullers JA, Saito T, Iverson AR (2004) Multiple genotypes of influenza B virus

circulated between 1979 and 2003. J Virol 78: 12817-12828.

136. McCullers JA, Wang GC, He S, Webster RG (1999) Reassortment and insertiondeletion

are strategies for the evolution of influenza B viruses in nature. J Virol 73:

7374-7348.

137

137. Meijer A, Lackenby A, Hungnes O, Lina B, van-der-Werf S, et al. (2009) Oseltamivirresistant

influenza virus A (H1N1), Europe, 2007-08 season. Emerg Infect Dis 15: 552-

560.

138. Mellema JE, Andree PJ, Krygsman PC, Kroon C, Ruigrok RW, et al. (1981) Structural

investigations of influenza B virus. J Mol Biol. 151: 329-336.

139. Metropolis N, Rosenbluth AW, Rosenbluth MN, Teller AH, Teller E (1953) Equation of

state calculations by fast computing machines. J Chem Phys 21: 1087-1092.

140. Mikheeva A, Ghendon YZ (1982) Intrinsic interference between influenza A and B

viruses. Arch Virol 73: 287-294.

141. Moscona A (2008) Medical management of influenza infection. Annu Rev Med 59:

397-413.

142. Munster VJ, Baas C, Lexmond P, Waldenstrom J, Wallensten A, et al. (2007) Spatial,

temporal, and species variation in prevalence of influenza A viruses in wild migratory

birds. PLoS Pathog 3: e61.

143. Munster VJ, Veen J, Olsen B, Vogel R, Osterhaus AD, et al. (2006) Towards improved

influenza A virus surveillance in migrating birds. Vaccine 24: 6729-6733.

144. Nagata K, Kawaguchi A, Naito T (2008) Host factors for replication and transcription of

the influenza virus genome. Rev Med Virol 18: 247-260.

145. Nakagawa N, Kubota R, Okuno Y (2005) Variation of the conserved neutralizing

epitope in influenza B virus Victoria group isolates in Japan. J Clin Microbiol 43: 4212-

4214.

146. Nakano T, Lu L, Liu P, Pybus OG (2004) Viral gene sequences reveal the variable

history of hepatitis C virus infection among countries. J Infect Dis 190: 1098-1108.

147. Needham H (2007) H5N1 in wild and domestic birds in Europe – remaining vigilant in

response to an ongoing public health threat. Euro Surveill 12: E071206 071201.

148. Nei M (1986) Phylogenetic analysis in molecular evolutionary genetics. Annu Rev

Genet 30: 371-403.

149. Nei M, Gojobori T (1986) Simple methods for estimating the numbers of synonymous

and nonsynonymous nucleotide substitutions. Mol Biol Evol 3: 418-426.

150. Nelson MI, Simonsen L, Viboud C, Miller MA, Holmes EC (2007) Phylogenetic analysis

reveals the global migration of seasonal influenza A viruses. PLoS Pathog 3: e131.

151. Nelson MI, Simonsen L, Viboud C, Miller MA, Taylor J, et al. (2006). Stochastic

processes are key determinants of short-term evolution in Influenza A virus. PLoS

Pathog 2: e125.

152. Nielsen R, Weinreich DM (1999) The age of nonsynonymous and synonymous

mutations in animal mtDNA and implications for the mildly deleterious theory. Genetics

153: 497-506.

138

153. Nielsen R, Yang Z (1998) Likelihood models for detecting positively selected amino

acid sites and applications to the HIV-1 envelope gene. Genetics 148: 929-936.

154. Nobusawa E, Sato K (2006) Comparison of the mutation rates of human influenza A

and B viruses. J Virol 80: 3675-3678.

155. O’Neill RE, Jaskunas R, Blobel G, Palese P, Moroianu J (1995) Nuclear import of

influenza virus RNA can be mediated by viral nucleoprotein and transport factors

required for protein import. J Biol Chem 270: 22701-22704.

156. Obenauer JC, Denson J, Mehta PK, Su X, Mukatira S, et al. (2006) Large-scale

sequence analysis of avian influenza isolates. Science 311: 1576-1580.

157. Olsen B, Munster VJ, Wallensten A, Waldenstrom J, Osterhaus AD, et al. (2006)

Global patterns of influenza a virus in wild birds. Science 312: 384-388.

158. Orlich M, Gottwald H, Rott R (1994) Nonhomologous recombination between the

hemagglutinin gene and the nucleoprotein gene of an influenza virus. Virology 204:

462-465.

159. Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA (2000)

Influenza B virus in seals. Science 288: 1051-1053.

160. Palese P, Compans RW (1976) Inhibition of influenza virus replication in tissue culture

by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of

action. J Gen Virol 33: 159-163.

161. Palese P, Shaw ML. (2007) Chapter 47: Orthomyxoviridae: the viruses and their

replication. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott

Williams & Wilkins.1647-1689.

162. Parrish CR, Kawaoka Y (2005) The origins of new pandemic viruses: the acquisition of

new host ranges by canine parvovirus and influenza A viruses. Annu Rev Microbiol 59:

553-86.

163. Parvin JD, Moscona A, Pan WT, Leider JM, Palese P (1986) Measurement of the

mutation rates of animal viruses: influenza A virus and poliovirus type 1. J Virol 59:

377-383.

164. Pasick J, Handel K, Robinson J, Copps J, Ridd D, et al. (2005) Intersegmental

recombination between the haemagglutinin and matrix genes was responsible for the

emergence of a highly pathogenic H7N3 avian influenza virus in British Columbia. J

Gen Virol 86: 727-731.

165. Peiris JS, de Jong MD, Guan Y (2007) Avian influenza virus (H5N1): a threat to human

health. Clin Microbiol Rev 20: 243-267.

166. Perroncito E (1878) Epizoozia tifoide nei gallinacei. Annali Accad Agri Torino 21: 87-

126.

167. Pinto LH, Holsinger LJ, Lamb RA (1992) Influenza virus M2 protein has ion channel

activity. Cell 69: 517-528.

139

168. Pond SL, Frost SDW (2005) Datamonkey: rapid detection of selective pressure on

individual sites of codon alignments. Bioinformatics 21: 2531-2533.

169. Poole A, Stettenheim P, Gill F (Eds.) 1993-2003. The Birds of North America.

Philadelphia, PA: The American Ornithologists’ Union and The Academy of Natural

Sciences of Philadelphia.

170. Poon LL, Pritlove DC, Fodor E, Brownlee GG (1999) Direct evidence that the poly(A)

tail of influenza A virus mRNA is synthesized by reiterative copying of a U track in the

virion RNA template. J Virol 73: 3473-3476.

171. Posada D, Crandall KA (1998) MODELTEST: testing the model of DNA substitution.

Bioinformatics 14: 817-818.

172. Pybus OG, Rambaut A, Freckleton RP, Belshaw R, Drummond AJ, et al. (2007)

Phylogenetic evidence for deleterious mutation load in RNA viruses and its

contribution to viral evolution. Mol Biol Evol 24: 845-852.

173. Rambaut A (1996) Se-Al: Sequence Alignment Editor. Available at

http://evolve.zoo.ox.ac.uk/

174. Rambaut A, Grassly NC, Nee S, Harvey PH (1996) Bi-De: an application for simulating

phylogenetic processes. Comput Appl Biosci 12: 469-471.

175. Rambaut A, Pybus OG, Nelson MI, Viboud C, Taubenberger JK, et al. (2008) The

genomic and epidemiological dynamics of human influenza A virus. Nature 453: 615-

619.

176. Rappole JH, Jones P (2002) Evolution of old and new world migration systems. In:

Both C, Piersma T (eds) The Avian Calender: Exploring Biological Hurdles in the

Annual Cycle. Proc. 3rd Conf. European Orn. Union, Groningen, 2001. Ardea 90: 525-

537.

177. Reid AH, Fanning TG, Hultin JV, Taubenberger JK (1999) Origin and evolution of the

1918 “Spanish” influenza virus hemagglutinin gene. Proc Natl Acad Sci USA 96: 1651-

1656.

178. Reid AH, Fanning TG, Janczewski TA, McCall S, Taubenberger JK (2002)

Characterization of the 1918 “Spanish” influenza virus matrix gene segment. J Virol

76: 10717-10723.

179. Reid AH, Fanning TG, Janczewski TA, Taubenberger JK (2000) Characterization of

the 1918 “Spanish” influenza virus neuraminidase gene. Proc Natl Acad Sci USA 97:

6785-6790.

180. Reid AH, Taubenberger JK, Fanning TG (2004) Evidence of an absence: the genetic

origins of the 1918 pandemic influenza virus. Nat Rev Microbiol 2: 909-914.

181. Rogers GN, Paulson JC (1983) Receptor determinants of human and animal influenza

virus isolates: differences in receptor specificity of the H3 hemagglutinin based on

species of origin. Virology 127: 361-373.

140

182. Röhm C, Zhou N, Süss J, Mackenzie J, Webster RG (1996) Characterization of a

novel influenza hemagglutinin, H15: criteria for determination of influenza A subtypes.

Virology 217: 508-516.

183. Romváry J, Mészáros J, Tanyi J, Rózsa J, Fábián L (1976) Influenza infectedness of

captured and shot wild birds on north-eastern and south-eastern parts of Hungary.

Acta Vet Acad Sci Hung 26: 363-368.

184. Rosenberg NA, Nordborg M (2002) Genealogical trees, coalescent theory and the

analysis of genetic polymorphisms. Nat Rev Genet 3: 380-390.

185. Rota PA, Hemhill ML, Whistler T, Regnery HL, Kendal AP (1992) Antigenic and

genetic characterization of the haemagglutinins of recent cocirculating strains of

influenza B virus. J Gen Virol 73: 2737-2742.

186. Rota PA, Wallis TR, Harmon MW, Rota JS, Kendal AP, et al. (1990) Cocirculation of

two distinct evolutionary lineages of influenza type B virus since 1983. Virology 175:

59-68.

187. Runstadler JA, Happ GM, Slemons RD, Sheng ZM, Gundlach N, et al. (2007) Using

RRT-PCR analysis and virus isolation to determine the prevalence of avian influenza

virus infections in ducks at Minto Flats State Game Refuge, Alaska, during August

2005. Arch Virol 152: 1901-1910.

188. Russell CA, Jones TC, Barr IG, Cox NJ, Garten RJ, et al. (2008) The global circulation

of seasonal influenza A (H3N2) viruses. Science 320: 340-346.

189. Salminen MO, Carr JK, Burke DS, McCutchan FE (1995) Identification of breakpoints

in intergenotypic recombinants of HIV type 1 by bootscanning. AIDS Res Hum

Retroviruses 11: 1423-1425.

190. Schäfer JR, Kawaoka Y, Bean WJ, Süss J, Senne D, Webster RG (1993) Origin of the

pandemic 1957 H2 influenza A virus and the persistence of its possible progenitors in

the avian reservoir. Virology 194: 781-788.

191. Schäfer W (1955) Vergleichender sero-immunologische Untersuchungen über die

Viren der Influenza und klassischen Geflügelpest. Z Naturf 10b: 81-91.

192. Scheiggele P, Rietveld A, Wilk T, Simons K (1999) Influenza viruses select ordered

lipid domains during budding from the plasma membrane. J Biol Chem 174: 2038-

2044.

193. Scholtissek C, Ludwig S, Fitch WM (1993) Analysis of influenza A virus nucleoproteins

for the assessment of molecular genetic mechanisms leading to new phylogenetic

virus lineages. Arch 131: 237-250.

194. Scholtissek C, Rohde W, Von Hoyningen V, Rott R (1978) On the origin of the human

influenza virus subtypes H2N2 and H3N2. Virology 87: 13-20.

195. Sharp GB, Kawaoka Y, Jones DJ, Bean WJ, Pryor SP, et al. (1997) Coinfection of wild

ducks by influenza A viruses: distribution patterns and biological significance. J Virol

71: 6128-6135.

141

196. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, et al. (2006) Avian flu: influenza virus

receptors in the human airway. Nature 440: 435-436.

197. Shu LL, Bean WJ, Webster RG. Analysis of the evolution and variation of the human

influenza A virus nucleoprotein gene from 1933 to 1990. J Virol 67: 2723-2729.

198. Sidorenko Y, Reichl U (2004) Structured model of influenza virus replication in MDCK

cells. Biotechnol Bioeng 88: 1-14.

199. Sieczkarski SB, Whittaker GR (2005) Viral entry. Curr Top Microbiol Immunol 285: 1-

23.

200. Simonsen L, Viboud C, Grenfell BT, Dushoff J, Jennings L, Smit M, Macken C, Hata

M, Gog J, Miller MA, Holmes EC (2007) The genesis and spread of reassortment

human influenza A/H3N2 viruses conferring adamantane resistance. Mol Biol Evol 24:

1811-1820.

201. Skehel JJ, Wiley DC (2000) Receptor binding and membrane fusion in virus entry: the

influenza hemagglutinin. Annu Rev Biochem 69: 531-569.

202. Sleigh MJ, Both GW, Underwood PA, Bender VJ (1981) Antigenic drift in the

hemagglutinin of the Hong Kong influenza subtype: correlation of amino acid changes

with alterations in viral antigenicity. J Virol 37: 845-853.

203. Slemons RD, Hansen WR, Converse KA, Senne DA (2003) Type A influenza virus

surveillance in free-flying, nonmigratory ducks residing on the eastern shore of

Maryland. Avian Dis 47: 1107-1110.

204. Slemons RD, Johnson DC, Osborn JS, Hayes F (1974) Type-A influenza viruses

isolated from wild free-flying ducks in California. Avian Dis 18: 119-124.

205. Slepuskin AN, Pysina TV, Gonsovsky FK, Sazonov AA, Isacenko VA, Sokolova NN,

Polivanov VM, Lvov DK, Zakstel’skaja LJ (1972) Haemagglutination-inhibiting activity

to type a influenza viruses in the sera of wild birds from the far east of the USSR. Bull

World Health Organ 47: 527-530.

206. Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, et al. (2004)

Mapping the antigenic and genetic evolution of influenza virus. Science 305: 371-376.

207. Smith GJ, Naipospos TS, Nguyen TD, de Jong MD, Vijaykrishna D, et al. (2006)

Evolution and adaptation of H5N1 influenza virus in avian and human hosts in

Indonesia and Vietnam. Virology 350: 258-268.

208. Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, et al. (2009) Origins and

evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature

Jun 11 [Epub ahead of print]

209. Sorrell EM, Perez DR (2007) Adaptation of influenza A/Mallard/Potsdam/178-4/83

H2N2 virus in Japanese quail leads to infection and transmission in chickens. Avian

Dis 51: 264-268.

210. Spackman E, Stallknecht DE, Slemons RD, Winker K, Suarez DL, et al. (2005)

Phylogenetic analyses of type A influenza genes in natural reservoir species in North

America reveals genetic variation. Virus Res 114: 89-100.

142

211. Stallknecht DE, Shane SM (1988) Host range of avian influenza virus in free-living

birds. Vet Res Commun 12: 125-141.

212. Stallknecht DE, Shane SM, Zwank PJ, Senne DA, Kearney MT (1990) Avian influenza

viruses from migratory and resident ducks of coastal Louisiana. Avian Dis 34: 398-405.

213. Stegmann T (2000) Membrane fusion mechanisms: the influenza hemagglutinin

paradigm and its implications for intracellular fusion. Traffic 1: 598-604.

214. Steinhauer DA, Skehel JJ (2002) Genetics of influenza viruses. Annu Rev Genet 36:

305-332.

215. Suarez DL (2000) Evolution of avian influenza viruses. Vet Micro 74: 15-27.

216. Suarez DL, Perdue ML (1998) Multiple alignment comparison of the non-structural

genes of influenza A viruses. Virus Res 54: 59-69.

217. Suarez DL, Schultz-Cherry S (2000) Immunology of avian influenza virus: a review.

Dev Comp Immunol 24: 269-283.

218. Suarez DL, Senne DA, Banks J, Brown IH, Essen SC, et al. (2004) Recombination

resulting in virulence shift in avian influenza outbreak, Chile. Emerg Infect Dis 10: 693-

699.

219. Subbarao EK, London W, Murphy BR (1993) A single amino acid in the PB2 gene of

influenza A virus is a determinant of host range. J Virol 67: 1761-1764.

220. Suzuki Y (2006) Natural selection on the influenza virus genome. Mol Biol Evol 23:

1902-1911.

221. Suzuki Y, Gojobori T (1999) A method for detecting positive selection at single amino

acid sites. Mol Biol Evol 16: 1315-1328.

222. Suzuki Y, Gojobori T, Nei M (2001) ADAPTSITE: detecting natural selection at single

amino acid sites. Bioinformatics 17: 660-661.

223. Suzuki Y, Nei M (2002) Origin and evolution of influenza virus hemagglutinin genes.

Mol Biol Evol 19: 501-509.

224. Swayne DE (2007) Understanding the complex pathobiology of high pathogenicity

avian influenza viruses in birds. Avian Dis 51: 242-249.

225. Swayne DE, Perdue ML, Beck JR, Garcia M, Suarez DL (2000) Vaccines protect

chickens against H5 highly pathogenic avian influenza in the face of genetic changes

in field viruses over multiple years. Vet Microbiol 74: 165-172.

226. Swayne DE, Suarez DL (2000) Highly pathogenic avian influenza. Rev Sci Tech 19:

463-482.

227. Swofford DL (2003) PAUP*. Phylogenetic Analysis Using Parsimony (*and other

methods). Version 4. ed. Sunderland, MA: Sinauer Associates.

228. Takezaki N, Gojobori T (1999) Correct and incorrect vertebrate phylogenies obtained

by the entire mitochondrial DNA sequences. Mol Biol Evol 16: 590-601.

143

229. Tatu U, Hammond C, Helenius A (1995) Folding and oligomerization of influenza

hemagglutinin in the ER and the intermediate compartment. EMBO J 14: 1340-1348.

230. Taubenberger JK (2006) The origin and virulence of the 1918 “Spanish” influenza

virus.Proc Am Philos Soc 150: 86-112.

231. Taubenberger JK, Morens DM, Fauci AS (2007) The next influenza pandemic: can it

be predicted? JAMA 297: 2025-2027.

232. Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG (1997) Initial genetic

characterization of the 1918 “Spanish” influenza virus. Science 275:1793-1796.

233. Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, et al. (2005)

Characterization of the 1918 influenza virus polymerase genes. Nature 437: 889-893.

234. Thompson CI, Barclay WS, Zambon MC, Pickles RJ (2006) Infection of human airway

epithelium by human and avian strains of influenza a virus. J Virol 80: 8060-8068.

235. Treanor JJ (2004) Influenza virus. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell,

Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 6th ed.

Churchill Livingstone 2060-2085.

236. Treanor JJ, Snyder MH, London WT, Murphy BR (1989) The B allele of the NS gene of

avian influenza viruses, but not the A allele, attenuates a human influenza A virus for

squirrel monkeys. Virology 171: 1-9.

237. van Gils JA, Munster VJ, Radersma R, Liefhebber D, Fouchier RA, et al. (2007)

Hampered foraging and migratory performance in swans infected with low-pathogenic

avian influenza A virus. PLoS ONE 2: e184.

238. van Gils, J.A., Munster. V.J., Radersma. R., Liefhebber. D., Fouchier. R.A. et al.

(2007) Hampered foraging and migratory performance in swans infected with lowpathogenic

avian influenza A virus. PLoS ONE 2: e184.

239. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, et al. (2006) H5N1

Virus Attachment to Lower Respiratory Tract. Science. 2006 312: 399.

240. Viboud C, Alonso WJ, Simonsen L (2006) Influenza in tropical regions. PLOS Medicine

3: 461-471.

241. Viboud C, Bjørnstad ON, Smith DL, Simonsen L, Miller MA, et al. (2006) Synchrony,

waves, and spatial hierarchies in the spread of influenza. Science 312: 447-451.

242. Vijaykrishna D, Bahl J, Riley S, Duan L, Zhang JX, Chen H, Peiris JS, Smith GJ, Guan

Y (2008) Evolutionary dynamics and emergence of panzootic H5N1 influenza viruses.

PLoS Pathog 4: e1000161.

243. Wallensten A, Munster VJ, Latorre-Margalef N, Brytting M, Elmberg J, et al. (2007)

Surveillance of influenza A virus in migratory waterfowl in northern Europe. Emerg

Infect Dis 13: 404-411.

244. Wang C, Takeuchi K, Pinto LH, Lamb RA (1993) Ion channel activity of influenza A

virus M2 protein: characterization of the amantadine block. J Virol 67: 5585-5594.

144

245. Wang R, Soll L, Dugan V, Runstadler JA, Happ GM, et al. (2008) Examining the

hemagglutinin subtype diversity among wild duck-origin influenza A viruses using

ethanol-fixed cloacal swabs and a novel RT-PCR method. Virology 375: 182-189.

246. Webby RJ, Webster RG, Richt JA (2007) Influenza viruses in animal wildlife

populations. Curr Top Microbiol Immunol 315: 67-83.

247. Webster RG, Air GM, Metzger DW, Colman PM, Varghese JN, et al. (1987) Antigenic

structure and variation in an influenza virus N9 neuraminidase. J Virol 61: 2910-2916.

248. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y (1992) Evolution and

ecology of influenza A viruses. Microbiol Rev 56: 152-179.

249. Webster RG, Govorkova EA (2006) H5N1 influenza–continuing evolution and spread.

N Engl J Med 355: 2174-2177.

250. Webster RG, Laver WG (1980) Determination of the number of nonoverlapping

antigenic areas on Hong Kong (H3N2) influenza virus hemagglutinin with monoclonal

antibodies and the selection of variants with potential epidemiological significance.

Virology 104: 139-148.

251. Webster RG, Shortridge KF, Kawaoka Y (1997) Influenza: interspecies transmission

and emergence of new pandemics. FEMS Immunol Med Microbiol 18: 275-279.

252. Webster RG, Yakhno M, Hinshaw VS, Bean WJ, Murti KG (1978) Intestinal influenza:

replication and characterization of influenza viruses in ducks. Virology 84: 268-278.

253. WHO (2008) Cumulative Number of Confirmed Human Cases of Avian Influenza

A/(H5N1) Reported to WHO. Geneva.

254. Widjaja L, Krauss SL, Webby RJ, Xie T, Webster RG (2004) Matrix gene of influenza a

viruses isolated from wild aquatic birds: ecology and emergence of influenza a viruses.

J Virol 78: 8771-8779.

255. Wiley DC, Wilson IA, Skehel JJ (1981) Structural identification of the antibody-binding

sites of Hong Kong influenza haemagglutinin and their involvement in antigenic

variation. Nature 289: 373-378.

256. Winker K, McCracken KG, Gibson DD, Pruett CL, Meier R, et al. (2007) Movements of

birds and avian influenza from Asia into Alaska. Emerg. Infect. Dis. 13: 547-552.

257. Wright PF, Neumann G, Kawaoka Y (2007) Chapter 48: Orthomyxoviruses. In: Knipe

DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott Williams &

Wilkins.1691-1740.

258. Xu KM, Li KS, Smith GJ, Li JW, Tai H, et al. (2007) Evolution and Molecular

Epidemiology of H9N2 Influenza A Viruses from Quail in Southern China, 2000 to

2005. J Virol 81: 2635-2645.

259. Yang Z (1994) Maximum likelihood phylogenetic estimation from DNA sequences with

variable rates over sites: approximate methods. J Mol Evol 39: 306-314.

260. Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum

likelihood. Comput Appl Biosci 13: 555-556.

145

261. Yang Z (2007) PAML 4: Phylogenetic Analysis by Maximum Likelihood. Mol Biol Evol

24: 1586-1591.

262. Yang Z, Nielsen R, Goldman N, Pedersen AM (2000) Codon-substitution models for

heterogeneous selection pressure at amino acid sites. Genetics 155: 431-449.

263. Yellen-Shaw AJ, Wherry EJ, Dubois GC, Eisenlohr LC (1997) Point mutation flanking a

NEW INSIGHTS IN BONE TISSUE ENGINEERING

0
0

Dr.Gabriel Ovidiu Dinu

Floreasca Emmergency Clinical  Hospital

Rezumat:

Acest articol este o trecere in revista a  datelor din literatura de specialitate asupra celor mai recente progrese in dezvoltarea platformelor 2D si 3D pentru facilitarea repararii defectelor osoase de dimendiuni critice,cu referinta in mod special asupra Osului Flexibil,un  comus elastomeric 3D substituent al osului, integrand un hidrogel hidroxilat(pHEMA) cu 50%nHA. Modelul a fost inspirat de rolurile multiple ale nanocristalelor de hidroxiapatita ( nHA) in definirea proprietatilor structurale, mecanice si biochimice ale osului.

Abstract

This article is a review of the literature data on the most recent  progresses in the development of scalable 2-D and 3-D scaffolds for facilitating the repair of critical-size bone defects, focusing on FlexBone, a 3-D elastomeric composite bone substitute integrating hydroxylated biocompatible pHEMA hydrogel with 50 wt% of nHA. The design was inspired by the multifaceted roles of nHA in defining the unique structural,mechanical and biochemical properties of bone.

 

Introduction

The  traditionally synthetic biomaterials(polymers)used in orthopedic surgery including poly(2-hydroxyethyl methacrylate) (pHEMA),terephthalate) (PET) as implant coating, polyetheretherketone (PEEK) as spacers for cervical fusion, maxillofacial defect repair, and hip prostheses[1] (PMMA) as bone cements, ultra high molecular weight polyethylene(UHMWPE) as total joint replacement components, and polysulfone (PSU) as internal fracture fixators[2]were considered bioinert.[3].Because of this feature, they lack the intrinsic ability to promote osteogenesis, thus are unable to structurally or biologically integrate with the host tissue. In an attempt to overcame this  problem,it has been modified the porosity for bending bioinert materials with  bioceramics or biodegradable polymeric components [4]

As bioactive  bone filters clinically  have been used Calcium phosphate–based bioceramics  [5] known for good biocompatibility, osteoconductivity and easy

surgical handling. The main problem  with these  bone substitutes is their poor mechanical properties such as high brittleness and are often unsuitable for weight-bearing

applications.[6].The solution was to integrate them  with the more compliant polymeric matrices,[7]

The most investigated biodegradable synthetic  polymers which have grat potential for resorbable orthopedic implants  were: poly(glycolic acid) [8](PGA), poly(lactic-co-plycolic acid), poly(lactic acid) (PLGA),[9] polyhydroxybutyrate (PHB),[10] polycaprolactone (PCL),[11] and their copolymer  polymers used as  tissue scaffolds. The  porosity in situ generated  of degradable polymers, as a result of hydrolytic degradation, was considered  to be beneficial to tissue penetration / osteointegration.

In order to enhance  further scaffold osteoconductivity have been used biodegradable polyesters with weakly basic osteoconductive minerals such as tri-calcium phosphate (TCP) or hydroxyapatite (HA)  and for neutralizing acidic degradation products and mitigating inflammatory tissue responses.[12].

One of the most significant challenges for the clinical translation of these polymer-mineral nanocomposites for orthopedic care is achieving an  adequate structural integration between the organic matrix and the inorganic minerals represents one of the most significant challenges for the clinical translation of these polymer- mineral nanocomposites for orthopedic care .

Because most polyesters are hydrophobic in nature and exhibit an intrinsically low affinity to bioceramics,it was necessary the development of high affintity HA surface mineralization  strategies to hydrophilic hydrogels such aspoly(2-hydroxyethyl methacrylate) (pHEMA) and pHEMA-based copolymers,[13] and identification of novel HA-binding/nucleating ligands, either small molecule-based[14] or peptide-based,[15] could help address this challenge.

New achivements have been obtained in the past decade  in the design of bioactive

synthetic biomaterials[16],for bone tissue engineering applications, integrin-binding

peptide sequences for promoting cellular adhesion, phosphorylated ligands for promoting

HA-mineralization, heparin-mimicking motifs for drug retention, and degradative

enzyme substrate sequences have all been incorporated into multi-modality synthetic

scaffold designs.,[17]such as the design of self-assembling peptideamphiphile

(PA) gels by Stupp and coworkers for simultaneous presentation of cell adhesion peptide sequences, HA-mineral-nucleating sites, reversible crosslinking sites,

and other therapeutic agents all within a single PA molecule that self-assembles and

dissembles in response to environmental perturbations[18].

The disadvantage of  these unique PA gels include their relatively high manufacturing cost and low mechanical modulus which could limit their use to treatment of small non-weight bearing skeletal lesions.

 

Hubbel and coworkers introduced another innovative concept to induce

scaffold degradation by using peptide substrates of the degradative enzymes matrix

metalloproteinases (MMPs) as the chemical crosslinker of a non-fouling crosslinked

hydrogel system[19] Due to  the elevated expression of some MMPs within both

degenerative bony defects and arthritic knee joints, such a hydrogel system could be

useful for bone and cartilage repair as the in situ increase of scaffold porosity in response

to tissue microenvironment-specific enzymatic degradation could promote cellular

infiltration and matrix deposition. It is not a trivial task the selection of MMP substrates with proper degradation kinetics matching with those of the matrix deposition rate

The problem is that despite the many exciting orthopedic biomaterials emerging in the literature, successful clinical translations are rare because of the difficulty in accomplishing the functional sophistication of viable synthetic bone substitutes  (e.g. physical properties enabling easy surgical handling and stable graft fixation, structural and biomechanical properties facilitating its osteointegration, biocompatibility ensuring long-term safety) within an easy-to-fabricate biomaterial that can be reproducibly manufactured at low cost.

 

The bone tissue composition

Bone ,from a material’s perspective, is an organic-inorganic composite comprising two

major structural components that are hierarchically organized across various length

scales: the calcium apatite crystals (primarily as substituted nanocrystalline

hydroxyapatite, nHA, but also as crystalline precursors in lower quantities) and the type I

collagen matrix[20].

The mechanical properties of bone is influenced by the  quantity and quality of the hard calcium apatite crystals (crystal size, maturity and structural integration with the collagen matrices)[21] For example, the bending and compression strength of bone is known to positively correlate to bone mineral content.[22]In addition, bone minerals also support bone cell attachment, serve as an important reservoir of calcium and phosphate ions, and help retain the secreted factors that are indispensable in regulating the biochemical microenvironment of the bony tissue.

Therefore, HA has long been recognized as an important design element for tissue-engineered bone substitutes.[23] The inspiration to  use of bioceramic scaffold,[24] or polymer-bioceramics composite scaffolds came from intrinsic affinity of the dynamic apatite crystal surface for many acidic non-collagenous proteins widely found in calcified tissues[21]  to retain and deliver recombinant proteins for therapeutic use. Bone tissue engineering have explored opportunity of using HA more as a way to enhance the mechanical strength than as a tool to mediate the biochemical properties of the scaffold.[25]

The  potential of the large surface areas provided by nHA as opposed to micrometer-sized HA for more efficient therapeutics delivery (e.g. higher retention capacity, more sustained release) has not been exploited to the fullest extent in the design of synthetic bone substitutes.

It is well known that type I collagen matrix of bone serves as a compliant template for the structural integration of the calcium apatite crystals, and, along with the mineral component, is responsible for defining the 3-dimensional structure as well as the strong, tough, yet compliant mechanical properties of bone.[26] It also interacts with

many non-collagenous proteins and mediates cellular adhesion and functions.

Also,the Gly-Pro-Hyp (Hyp: hydroxyproline) triplet repeats of type I collagen may also play an important role in template-driven biomineralization. Recent discovery of novel HAbinding oligopeptides using the combinatorial phage display technique reveals a [Pro-

(OH)-X] tripeptide pattern (OH: hydroxylated amino acid residues (Ser, Thr, Tyr); X: any

amino acid) among the dominant HA-binding motifs,resembling  that of the type I collagen, underscoring the importance of hydroxylated residues in directing ligand-mineral interactions on a molecular level. Also,these oligopeptides were shown to template the nucleation and growth of HA in vitro and may be useful in the design of synthetic polymer scaffolds, enabling template-driven mineralization of HA or the preparation of bulk organic-inorganic bone-like composites with improved interfacial binding affinity.The  polymeric hydrogels displaying hydroxylated (e.g. pHEMA) and acidic residues could be used to template the surface mineralization of HA with excellent interfacial adhesion strength, further supporting the favorable interaction between the hydroxyls and the calcium ions.

Also,the strategy of modifying the surface of polymers or metallic substrates with hydroxylated or anionic coatings has also been pursued to facilitate the nucleation and

growth of calcium apatite.[27]

Sinthetic bone scaffolds

There are  a great number  of proteins are known to play roles in the biological healing of bone,including in cellular recruitment and initiating the inflammation / bone remodeling

cascades.[28].  Most scaffold-assisted bone repair would require the supplement of

exogenous therapeutic agents such as osteogenic growth factors to augment the biological

performance of biomaterial scaffolds. The most commonly used clinically  therapeutic agents to enhance bone repair are the Food and Drug Administration (FDA)-approved osteogenic growth factor bone morphogenetic protein -2(BMP-2) and BMP-7.[29]

 

Also, vascular endothelial growth factor (VEGF),[30]receptor activator of nuclear factor kappa-Β ligand (RANKL) and transforming growth factor β (TGFβ)[30] are also used to modulate the graft vascularization, osteoinegration and remodeling. BMP-2/7, is another recombinant factor that has gained quick attention within the bone tissue engineering community which is  a protein heterodimer of BMP-2 and BMP-7 that is more potent in inducing osteogenic differentiation of pluripotent cells in vitro than either homodimer alone.[31] Its higher potency has been attributed to its decreased sensitivity to BMP inhibitors. In particular, BMP-2/7 was found to have decreased sensitivity to Noggin, a

 

BMP antagonist that is secreted from mesenchymal cells in response to BMPs to help control the rate of cellular differentiation. It is known that Noggin binds BMP, inhibiting BMP cell surface receptor binding; however, Noggin’s binding affinity

is lowered in the BMP-2/7 heterodimer. The high potency of BMP-2/7 has important

clinical implications, including more cost-effective low-dose treatment with reduced

systemic side-effects. There a a great  number of laboratories, which  have exploited the

use of BMP-2/7 for augmenting scaffold-assisted repair of bone in vivo.[32]

 

Most recent improvements in biomaterials’ therapeutic delivery characteristics for bone repair were accomplished by incorporating nHA in polymeric hydrogel matrices,  or by combining thin fibrous film-based physical barriers with 3-dimensional hydrogels[33] to enable the retention and release of growth factors in a more localized and sustained manner.Another innovative approach is physical entrapment of therapeutic agents within MMP-degradable poly(ethylene glycol) (PEG)-based hydrogels that has been established for therapeutic delivery by Hubbell and coworkers.[34]

 

The use of electrostatic interactions in hydrogels is another, more established, method for therapeutic delivery,for example, gelatin hydrogels can be basic and positively

charged, or acidic and negatively charged depending on how the gelatin is extracted from

collagen, thus can be designed to interact with a wide range of charged therapeutics.Also an effective method proven was  Hyaluronic acid incorporation

into hydrogels  for not only therapeutic retention of proteins, such as BMP-2, but also for cellular adhesion, migration and proliferation, as well as binding to collagen and fibrin[35]

 

Also,sulfates have  been exploited for therapeutic retention. Hydrogels that incorporate negatively charged heparin sulfate can easily interact with many positively charged proteins, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and BMP-2[36]

In comparison with the latter strategies, the incorporation of nHA has the added advantages of being able to retain and enrich endogenously secreted factors due to its intrinsic affinity to the factors residing in the bony tissue environment and its large surface area available for absorption.

Complimentary synthetic scaffolds:

2-Dimensional vs. 3-Dimensional

Biomaterials for bone repair can be enhanced by the addition of exogenous

therapeutics,but, they can also benefit from exogenous cells (e.g. mesenchymal stem cells,hematopoietic cells, osteoblasts) pre-seeded on the biomaterial scaffolds.100

The cellular attachement  of both endogenous cells and pre-seed exogenous cells has been improved using  collagenous protein mimetics of extracellular matrix components biomaterials with integrin binding peptides such as RGD.[37]

 

For bone repair are attracted all materials possessing the ability to support cellular encapsulation (e.g. 3-D constructs) or surface attachment (e.g. 2-D films or fiber meshes) and that favor specific stem cell differentiation pathways, in addition to the ability to act as a therapeutic delivery vehicle.

 

Towards this goal have ben exploited , both  3-D and 2-D constructs ,104-106 although greater focus has been placed on engineering 3-D scaffolds. A focus has been centred among the 2-D platforms explored, on supporting cellular attachment and differentiation (due to the relative ease of cell attachment on 2-D compared to 3-D scaffolds), as well as

delivery of osteogenic factors in culture.[38]

The unique handling characteristics of 2-D scaffolds could enable versatile in vivo uses, including as a stand-alone graft overlying a fracture, a filler being press-fit into an area of small bony defect, or a synthetic membrane wrapped around a 3-D bone graft .

The combination of 2-D and 3-D constructs has recently been explored by Robert Guldberg and colleagues to achieve spatio-temporal control of growth factor release profiles,[38]  and by others to create hierarchical composites[39]

 

Starting from a biomimetic perspective, 2-D scaffolds that can be wrapped around a 3-D bone scaffold, if engineered properly, can recapitulate some of the important functions of periosteal tissues surrounding long bone in harboring stem cell and directing their differentiation upon injury.

BMP2 and BMP7 are 3-D graft components-  BMP-2 is known to play a critical role in initiating early bone healing while BMP-7 may be more suitably used for stimulating later stages of bone healing[40] One could envision using a 3-D scaffold designed for

slower release of BMP-7 in combination with a 2-D scaffold designed for faster release

of BMP-2.

 

Alternatively, different cell types could be seeded on each construct, such as

seeding bone marrow-derived stem cells on the 2-D construct to more efficiently initiate

graft healing while seeding hematopoietic stem cells on the 3-D construct to promote the

vascularization of the graft for better tissue incorporation. In cases where the 3-D grafts

(i.e. allografts) cannot readily support the seeding of exogenous cells, a cell-laden 2-D

construct could be readily wrapped around the 3-D graft.

 

Electrosppining is a common method for preparing a 2-D fibrous mesh scaffold with controlled fiber dimension, mesh thickness and porosity is by electrospinning. When the polymer fibers are properly chosen, they can be subjected to further chemical modifications to render specific biological properties and/or mechanically strengthened to improve their handling characteristics.[41]

 

Conclusion:

The progress of future research in orthopedics  will bring new strategies to assure a normal bone formation cascade as well as bone disease of different origins to be  treated with novel bone regeneration protocols.

 

REFERENCES

 

1. Eschbach, L. Nonresorbable polymers in bone surgery. Injury 31 Suppl 4, 22,

2000.

2. Wang, M. Developing bioactive composite materials for tissue replacement.

Biomaterials 24, 2133, 2003.

3. Mano, J.F., Sousa, R.A., Boesel, L.F., Neves, N.M., and Reis, R.L. Bloinert,

biodegradable and injectable polymeric matrix composites for hard tissue replacement:

state of the art and recent developments. Composites Science and Technology 64, 789,

2004.

4. Aparecida, A.H., Guastaldi, A.C., and Fook, M.V.L. Development of Ultra High

Molecular Weight Polyethylene (UHMWPE) Porous Supports for Use as Biomaterial in

Osseous Replacement and Regeneration. Polimeros 18, 277, 2008.

5. Nandi, S.K., Roy, S., Mukherjee, P., Kundu, B., De, D.K., and Basu, D.

Orthopaedic applications of bone graft & graft substitutes: a review. Indian Journal of

Medical Research 132, 15, 2010.

6. Tanner, K.E. Bioactive composites for bone tissue engineering. Proceedings of the

Institution of Mechanical Engineers Part H-Journal of Engineering in Medicine 224,

1359, 2010

7. Wang, M., and Bonfield, W. Chemically coupled hydroxyapatite-polyethylene

composites: structure and properties. Biomaterials 22, 1311, 2001

8. Zhang, R.Y., and Ma, P.X. Poly(alpha-hydroxyl acids) hydroxyapatite porous

composites for bone-tissue engineering. I. Preparation and morphology. J Biomed Mater

Res 44, 446, 1999.

9.Ishaug, S.L., Crane, G.M., Miller, M.J., Yasko, A.W., Yaszemski, M.J., and

Mikos, A.G. Bone formation by three-dimensional stromal osteoblast culture in

biodegradable polymer scaffolds. J Biomed Mater Res 36, 17, 1997.

10. Wang, Y.W., Wu, Q.O., and Chen, G.Q. Attachment, proliferation and

differentiation of osteoblasts on random biopolyester poly(3-hydroxybutyrate-co-3-

hydroxyhexanoate) scaffolds. Biomaterials 25, 669, 2004.

11. Yoshimoto, H., Shin, Y.M., Terai, H., and Vacanti, J.P. A biodegradable

nanofiber scaffold by electrospinning and its potential for bone tissue engineering.

Biomaterials 24, 2077, 2003

12.Liao, S., Watari, F., Zhu, Y., Uo, M., Akasaka, T., Wang, W., Xu, G., and Cui, F.

The degradation of the three layered nano-carbonated hydroxyapatite/collagen/PLGA

composite membrane in vitro. Dental Materials 23, 1120, 2007

13. Song, J., Malathong, V., and Bertozzi, C.R. Mineralization of synthetic polymer

scaffolds: A bottom-up approach for the development of artificial bone. Journal of the

American Chemical Society 127, 3366, 2005

14.Licata, A.A. Discovery, clinical development, and therapeutic uses of

bisphosphonates. Ann Pharmacother 39, 668, 2005.

15. Chung, W.J., Kwon, K.Y., Song, J., and Lee, S.W. Evolutionary Screening of

Collagen-like Peptides That Nucleate Hydroxyapatite Crystals. Langmuir,

dx.doi.org/10.1021/la104757g, 2011.

16. Bonzani, I.C., George, J.H., and Stevens, M.M. Novel materials for bone and

cartilage regeneration. Current Opinion in Chemical Biology 10, 568, 2006.

17. Patterson, J., and Hubbell, J.A. Enhanced proteolytic degradation of molecularly

engineered PEG hydrogels in response to MMP-1 and MMP-2. Biomaterials 31, 7836,

2010.

18.Hartgerink, J.D., Beniash, E., and Stupp, S.I. Self-assembly and mineralization of

peptide-amphiphile nanofibers. Science 294, 1684, 2001.

19. Lutolf, M.R., Weber, F.E., Schmoekel, H.G., Schense, J.C., Kohler, T., Muller,

R., and Hubbell, J.A. Repair of bone defects using synthetic mimetics of collagenous

extracellular matrices. Nature Biotechnology 21, 513, 2003.

20.Weiner, S., Traub, W., and Wagner, H.D. Lamellar bone: Structure-function

relations. Journal of Structural Biology 126, 241, 1999.

21Tong, W., Glimcher, M.J., Katz, J.L., Kuhn, L., and Eppell, S.J. Size and shape of

mineralites in young bovine bone measured by atomic force microscopy. Calcified Tissue

International 72, 592, 2003.

22.Follet, H., Boivin, G., Rumelhart, C., and Meunier, P.J. The degree of

mineralization is a determinant of bone strength: a study on human calcanei. Bone 34,

783, 2004.

23.El-Ghannam, A. Bone reconstruction: from bioceramics to tissue engineering.

Expert Review of Medical Devices 2, 87, 2005

24. Le Nihouannen, D., Hacking, S.A., Gbureck, U., Komarova, S.V., and Barralet,

J.E. The use of RANKL-coated brushite cement to stimulate bone remodelling.

Biomaterials 29, 3253, 2008

25. Stevens, M.M. Biomaterials for bone tissue engineering. Materials Today 11, 18,

2008.

26.Scharnweber, D., Born, R., Flade, K., Roessler, S., Stoelzel, M., and Worch, H.

Mineralization behaviour of collagen type I immobilized on different substrates.

Biomaterials 25, 2371, 2004

27.Zhang, H.L., Simpson, D., Kumar, S., and Smart, R.S.C. Interaction of

hydroxylated PACVD silica coatings on titanium with simulated body fluid. Colloids and

Surfaces a-Physicochemical and Engineering Aspects 291, 128, 2006.

28. Einhorn, T.A. The cell and molecular biology of fracture healing. Clin Orthop

Relat Res, S7, 1998.

29.Gautschi, O.P., Frey, S.P., and Zellweger, R. Bone morphogenetic proteins in

clinical applications. ANZ J Surg 77, 626, 2007

30. Patel, Z.S., Young, S., Tabata, Y., Jansen, J.A., Wong, M.E.K., and Mikos, A.G.

Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in

a critical size defect model. Bone 43, 931, 200

31.Zheng, Y.N., Wu, G., Zhao, J., Wang, L.H., Sun, P., and Gu, Z.Y. rhBMP2/7

Heterodimer: An Osteoblastogenesis Inducer of Not Higher Potency but Lower Effective

Concentration Compared with rhBMP2 and rhBMP7 Homodimers. Tissue Eng Part A 16,

879, 2010.

32. Koh, J.T., Zhao, Z., Wang, Z., Lewis, I.S., Krebsbach, P.H., and Franceschi, R.T.

Combinatorial gene therapy with BMP2/7 enhances cranial bone regeneration. Journal of

Dental Research 87, 845, 2008

33.Kolambkar, Y.M., Boerckel, J.D., Dupont, K.M., Bajin, M., Huebsch, N.,

Mooney, D.J., Hutmacher, D.W., and Guldberg, R.E. Spatiotemporal delivery of bone

morphogenetic protein enhances functional repair of segmental bone defects. Bone, 2011.

34.Lutolf, M.P., Weber, F.E., Schmoekel, H.G., Schense, J.C., Kohler, T., Muller, R.,

and Hubbell, J.A. Repair of bone defects using synthetic mimetics of collagenous

extracellular matrices. Nat Biotechnol 21, 513, 2003

35. Kim, J., Kim, I.S., Cho, T.H., Lee, K.B., Hwang, S.J., Tae, G., Noh, I., Lee, S.H.,

Park, Y., and Sun, K. Bone regeneration using hyaluronic acid-based hydrogel with bone

morphogenic protein-2 and human mesenchymal stem cells. Biomaterials 28, 1830, 2007

36. Benoit, D.S.W., and Anseth, K.S. Heparin functionalized PEG gels that modulate

protein adsorption for hMSC adhesion and differentiation. Acta Biomater 1, 461, 2005

37. Holmes, T.C. Novel peptide-based biomaterial scaffolds for tissue engineering.

Trends in Biotechnology 20, 16, 2002.

38. Kolambkar, Y.M., Dupont, K.M., Boerckel, J.D., Huebsch, N., Mooney, D.J.,

Hutmacher, D.W., and Guldberg, R.E. An alginate-based hybrid system for growth factor

delivery in the functional repair of large bone defects. Biomaterials 32, 65, 2011

39. Yeo, M., Lee, H., and Kim, G. Three-Dimensional Hierarchical Composite

Scaffolds Consisting of Polycaprolactone, beta-Tricalcium Phosphate, and Collagen

Nanofibers: Fabrication, Physical Properties, and In Vitro Cell Activity for Bone Tissue

Regeneration. Biomacromolecules 12, 502, 2011.

40.Onishi, T., Ishidou, Y., Nagamine, T., Yone, K., Imamura, T., Kato, M., Sampath,

T.K., ten Dijke, P., and Sakou, T. Distinct and overlapping patterns of localization of

bone morphogenetic protein (BMP) family members and a BMP type II receptor during

fracture healing in rats. Bone 22, 605, 1998.

41.Pham, Q.P., Sharma, U., and Mikos, A.G. Electrospinning of polymeric

nanofibers for tissue engineering applications: A review. Tissue Engineering 12, 1197,

2006.

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