Genetic risk factors of agressive periodontitis
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RBBRBBMacchu Picchu. Lost City of the Incas. Cuzco-Perù Song: “My Huancavelica” Interpret: Raùl Garcìa Zàrate
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Asociaciòn Peruana de
Periodoncia y Oseointegraciòn
Programa cientìfico anual 2010
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Factores genèticos
de riesgo en las periodontitis
agresiva
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Pràctica Clìnica de la Asignatura de Periodoncia II. Facultad de Odontologìa de la Universidad de San Marìn de Porres. Prof. Resp. Dr. Ricardo Benza Bedoya
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Pràctica Clìnica de la Asignatura de Periodoncia II. Escuela Acadèmico Profesional de Odontologìa de la Universidad Wiener. Prof. Resp. Dr. Ricardo Benza Bedoya
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Clase teòrica del IV Curso de Post-Grado de Implantologìa Oral Bàsica de la Federaciòn Odontològica del Perù. Prof. Resp. Dr. Ricardo Benza Bedoya
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Pràctica Pre-Clìnica I Curso de Cirugìa Periodontal de la Federaciòn Odontològica del Perù. Prof. Resp. Dr. Ricardo Benza Bedoya RBB
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Diplomado en Implantologìa Oral Bàsica del Colegio Odontològico Regional del Lima Prof. Resp. Dr. Ricardo Benza Bedoya
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Conferencia: “Abscesos Periodontales. Congreso de la Red de Salud de San Juan deLurigancho. Prof. Resp. Dr. Ricardo Benza Bedoya RBB
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OBJETIVOS1. Conocer los principales factores de riesgo genèticos de la periodontitis agresivas
2. Comprender los mecanismos que explican la susceptibilidad genètica en la periodontitis agresivas
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TEMARIO1. Bases teòricas genèticas 2. Caracterìsticas de la Periodontitis Agresivas3. Anàlisis de la evidencia cientìfica
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“El secreto del éxito en la vida de un hombre está en prepararse para aprovechar la ocasión cuando se presente.”Benjamin Disraeli (1766-1848) Estadista ingles.
“Choquequirau. Incas ruins”. Cuzco-Perù
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PARTE I
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Bases teòricas
genèticasRBB
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Genética- Ciencia que
estudia la herencia biológica.
- Examina las características que el ser humano hereda: físicas y mentales, normales y anormales. RBB
www.cs4fn.org/biology/images/mutation.jpg
Cromosomas
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El genoma es la totalidad de la información genética que posee un organismo en particular
GENOMA
Dr. Francis Collins
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GENOTIPODotación genética recibida de los padres ( y demás ancestros)
Conjunto de características evidentes en el ser humano como el color de ojos, tipo de grupo sanguíneo, etc.
FENOTIPO
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CÈLULA HUMANA
Nùcleo celular
46 cromosomas
23 pares
22 pares 1 par
cromosomas no sexuales
cromosomas sexuales
Autosomas
RBBHeterosom
as
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Cromosomas Son estructuras filamentosas contenidas en el núcleo celular, contienen el genoma transportan la información genética dispuesta en una secuencia lineal..
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Telòmeros
Centròmero
Centrómero. Estructura longitudinal con una constricción
Telómeros. Extremos de los cromosomas
Cromàtidas. Unidad longitudinal de un cromosoma duplicado, unida a su cromátida hermana por el centrómero, dos cromàtidas forman un cromosoma
Brazo corto (p)
Brazo largo (q)
Morfologìa de los
Cromosomas
Telòmeros
Brazo corto
(p)
Brazo largo
(q)
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Cromàtida
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Clasificaciòn morfològica de los Cromosomas
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Clasificaciòn por grupos de los Cromosomas
Grupos A
B
C
D
F
E
G
Tamañograndes
grandes
medianosmedianosmedianospequeñospequeños
Cromosomas1,2,3
4,5
6 al 12 + X
13,14,1516,17,18
19,2021,22+Y
Centròmerosmetacèntricosubmetacèntricos
meta o submetacèntrico
acrocèntricometa o
submetacèntricometa o
submetacèntrico
acrocèntrico
Satèlites
NO
NO
NOSI
NONOSI
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Cariotipo
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Cariotipo normalSe describen de la siguiente manera: Sexo masculino:
46, XY Sexo femenino:
46, XXLos cromosomas se presentan en pares
Un cromosoma es de origen paternoOtro cromosoma es de origen materno
No son visibles durante todo el ciclo celular, sólo se hacen evidentes cuando la célula va a dividirse.
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Asas de cromatina comprende las cadenas de ADN en interacción con proteínas (histonas y no histonas) que se pueden encontrar desde estados relajados o poco compactados en estados altamente compactados
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Solenoide: hélice enrollada alrededor de un canal central de ADN, el solenoide está constituido por nucleosomas dispuestos de manera helicoidal. Hay 6 nucleosomas por cada vuelta de solenoide. Los solenoides también siguen un proceso de enrollamiento y forman los bucles de cromatina
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El nucleosoma es una estructura que constituye la unidad fundamental y esencial de cromatina, que es la forma de organización del ADN en las eucariotas. Los nucleosomas están formados por un núcleo proteico constituido por un octámero de histonas
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Las histonas son proteínas básicas, de baja masa molecular, muy conservadas evolutivamente entre los eucariotas y en algunos procariotas. Forman la cromatina junto con el ADN, sobre la base de unas unidades conocidas como nucleosomas.
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El ácido desoxirribonucleico, frecuentemente abreviado como ADN (y también DNA, del inglés DeoxyriboNucleic Acid), es un tipo de ácido nucleico, una macromolécula que forma parte de todas las células. Contiene la información genética usada en el desarrollo y el funcionamiento de los organismos vivos conocidos y de algunos virus, siendo el responsable de su transmisión hereditaria
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GEN: Unidad básica de la herencia, se transmiten de padres a hijos, constituído por ADN, Unidad heredada que ocupa una posición específica (locus), cromosoma, con uno o más efectos específicos sobre el fenotipo
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Alelo.Diferentes
secuencias de DNA que tiene un gen
Un alelo es la “versión” de un gen que está presente en un locus dado.
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Un gen es una secuencia organizada de nucleótidos del ADN que contiene la información para la síntesis de macromoléculas para la función celular El gen es la unidad de almacenamiento de información genética y de la herencia Muchos genes se encuentran constituidos por regiones codificantes (exones) interrumpidas por regiones no codificantes (intrones)
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Los nucleótidos son moléculas orgánicas formadas por la unión covalente de un monosacárido , una base nitrogenada y un grupo fosfato.
Son los monómeros de los ácidos nucleicos (ADN y ARN) en los cuales forman cadenas lineales de miles o millones de nucleótidos, .
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Las bases nitrogenadas son compuestos orgánicos que incluyen dos o más átomos de nitrógeno.
Son parte fundamental de los nucleótidos, Biológicamente existen seis bases nitrogenadas principales (en realidad hay muchas más adenina (A) y la guanina (G) y la timina (T), la citosina (C) Las bases A, T, G y C se encuentran en el ADN,
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Polimorfismo.Región del genoma que varía entre los
distintos miembros de una población y que está presente en un número significativo de individuos.
Un polimorfismo puede consistir en la sustitución de una simple base nitrogenada (por ejemplo, la sustitución de una A (adenina) por una C (citosina)
Son variaciones frecuentes caso contrario se denomina mutaciòn
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Partes del Cromosomas
BandasCromosòmicas:-Subunidades de los cromosomas. Cada una de ellas posee propiedades diferentes de coloración,
N
N
C
C
Q
G
R
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Bandas y sub-bandasUna banda 1q31 se divide en sub-bandas:
Se coloca un punto decimal: 1q31.1 1q31.2 1q31.3
La sub-banda 1q31.2 se subdivide de la misma manera, pero sin punto decimal: 1q31.21 1q31.22 1q31.23
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BandasPara designar una
banda se requiere:El número del
cromosomaEl brazoEl número de la
regiónEl número de la
bandap.e.: 1q31
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Penetrancia
Es la expresión de un genEl efecto del gen puede presentarse en
distinto % en las personas portadoras de ese gen:Penetrancia completa (100%)Penetrancia incompleta
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Synopsis del Genoma Humano
Total de loci: 9098
Chr. Loci
1 864
2 564
3 485
4 345
5 433
6 558
7 417
8 321
Chr. Loci
9 325
10 306
11 574
12 474
13 158
14 276
15 262
16 341
Chr. Loci
17 524
18 136
19 598
20 214
21 119
22 226
X 533
Y 45
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Factores Hormonales
(Embarazo, Menopausia)
Factores Ambientales y del comportamiento
Factores Microbianos
Influyen
Factores Genéticos
Factores Endocrinos
Diabetes Mecanismo de defensa
del huésped
La efectividad de la respuesta inmune de un individuo influirá en el grado de destrucción periodontal.
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FACTORES GENETICOS
Susceptibilidad genética a la Periodontitis
En el sistema Inmunitario
Innato y Adquirido
Anomalías de los tejidos epitelial y conectivo
(defecto de los fibroblastos)
Deficiencia en las fosfatasas alcalinas
Niveles de Ig G Alteraciones de los PMN
Variación de las citocinas
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Síndromes Monogénicos
* Periodontitis pre puberal generalizada
•Clasificada en: - manifestación de defectos en el Nro de neutrofilos. - Patogenia del tejido epitelial o conectivo
* Los PMN son la primera línea de defensa contra la infección.
* Estos efectos tienen influencia en la susceptibilidad del huésped.
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FENOTIPO AMBIENTE
GENOTIPO
BIOLOGICAS INTERACCIONES
= ++
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Pàramo de Frailones. Cajamarca -Perù
RBB
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PARTE II
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RBB
Caracterìsticas de las
Periodontitis Agresivas
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RBB
Ôleo sobre madera: “La estaciòn de Monserrate”Autor: Sèrvulo Gutièrrez
Periodontitis de instalaciòn temprana
Periodontitis del adulto
Periodontitis agresivas
Periodontitis crònica
1999 International Workshop for a Classification of
Periodontal Diseases and Conditions
Ximenez-Fyvie Laurie Ann, Almaguer-Flores Argelia, Lara-Cordoba Mònica, Moreno-Borjas Jazmin-Yunuen, Alcàntara-Maruri Eulalio. Subgingival microbiota of periodontally untreated Mexican subjects with generalizedaggressive periodontitis. J Clin Periodontol 2006; 33: 869-877.
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RBB
Ôleo sobre tela: “Paisaje”Autor: Sèrvulo Gutièrrez
Periodontitis de instalaciòn temprana
Periodontitis agresivas
CUESTIONAMIENTO
EDAD
CRITERIO
CLASIFICACION
a la
como
de
Razones delcambio en la clasificaciòn
Armitage G. Development of a classification system for periodontal diseases and conditions. Annals of Periodontology 1999; 4: 1-6
Periodontitis del adulto
Periodontitis crònica
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RBB
Ôleo sobre tela: “Paisaje de Buenos Aires”Autor: Sèrvulo Gutièrrez
Periodontitis agresivas
Periodontitis crònica
Periodontitis ulcerativa
necrotizante
Periodontitis comomanifestaciòn de
enfermedadessistèmicas
TIPOS DE
PERIODONTITIS
Ximenez-Fyvie Laurie Ann, Almaguer-Flores Argelia, Lara-Cordoba Mònica, Moreno-Borjas Jazmin-Yunuen, Alcàntara-Maruri Eulalio. Subgingival microbiota of periodontally untreated Mexican subjects with generalizedaggressive periodontitis. J Clin Periodontol 2006; 33: 869-877.
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RBB
Crayola sobre papel: “Retrato de JosefinaSalmòn de Cannock”Autor: Sèrvulo Gutièrrez
PERIODONTITSAGRESIVAS
PERIODONTITSCRÒNICA
extensiòn severidad
Clasificaciòn comùn
localizada
generalizada
leve
severa
moderada
Armitage G. Development of a classification system for periodontal diseases and conditions. Annals of Periodontology 1999; 4: 1-6
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RBBSchenkein HA, Van Dyke TE. Early-onset periodontitis: systemic aspects of etiology and pathogenesis. Periodontology 2000 1994; 6: 7-25.
Ôleos sobre lienzo: “Casa del Moral Arequipa”Autor: Ignacio Tomaylla
PERIODONTITIS AGRESIVA
Enfermedad infecciosa
caracterizada
Respuesta anormal
Placa bacteriana
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AGRESIVA
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RBB
Periodontitis agresivas
Enfermedades periodontales
comprende formas
raras severas progresivas
de
Pacientes sistèmicamente sanos
en
“Tapada y escribano”. Autor: Pancho Fierro
Noack B, Gôrgens H, Hoffman T, Schackert HK. Variantes genèticas del CARD 15 en la periodontitis agresiva. J Clin Periodontol 2006; 33: 779-783
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RBB
“El soldado y la rabona”. Autor: Pancho Fierro
Periodontitis agresivas
caracterìsticas
Ràpida destrucciòn periodontal
Antecedentes periodontales
familiares similares
Lang, NP, Bartold PM, Cullinan M, Jeffcoat M, Mombelli A, Murakami S, Page R, Papanou P, Tonetti M, Van Dyke T.Consensus Report: aggressive periodontitis. Annals of Periodontology 1999; 4: 53.
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Tècnica mixta sobre papel: “La Huega”Autor: Sèrvulo Gutièrrez
PERIODONTITSAGRESIVAS
Caracterìsticas primarias
Antecedentes periodontales familiares
Ràpida pèrdida de inserciòn
Destrucción òsea ràpida
Pacientes sistèmicamente sanos
Ximenez-Fyvie Laurie Ann, Almaguer-Flores Argelia, Lara-Cordoba Mònica, Moreno-Borjas Jazmin-Yunuen, Alcàntara-Maruri Eulalio. Subgingival microbiota of periodontally untreated Mexican subjects with generalizedaggressive periodontitis. J Clin Periodontol 2006; 33: 869-877.
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RBB
Paciente de 35 años con Periodontitis agresiva generalizada . Clìnicade Periodoncia e Implantologìa Docente Asistencial Benzahnarzt. Prof. Ricardo Benza Bedoya. 2009
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“Mujer caminante” Autor: Aquiles Ralli
PERIODONTITISAGRESIVAS
Caracterìsticas secundarias
Incoherencia entre destrucciòn periodontal y agente irritante local
Proporciones elevadas de Aa y Pg en algunas poblaciones
Deficienciasfagocìticas Pèrdida òsea y
de inserciòn autolimitante
Hiperrespuesta de macròfagos
Niveles elevados de IL-1B y PG E2
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Paciente de 35 años con Periodontitis agresiva generalizada . Clìnicade Periodoncia e Implantologìa Docente Asistencial Benzahnarzt. Prof. Ricardo Benza Bedoya. 2009
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Periodontitis agresivas
Bases para el diagnòstico
Anamnesis
Hallazgosradiogràficos
Hallazgosclìnicos
Exàmenes delaboratorio
AAP. Parameter on aggressive periodontitis. American Academy of Periodontology. J Periodontol. 2000 May;71(5 Suppl):867-9.
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Periodontitis agresivas
localizadas
Caracterìsticas
1. Comienzo circumpuberal.
2. Localizada en 1M, con pérdida de ins. interprox en al menos dos permanentes, uno de los cuales es un 1M, y que afecta a no más de otros 2 dientes, Puede presentarse patrones atípicos.3. Se asocia frecuentemente con A.a.4. Se asocia frecuentemente con disfunciòn neutrófilica.5. Se asocia frecuentemente con una respuesta elevada de Ab séricos
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Periodontitis agresivas
generalizadas
Caracterìsticas
1. Afecta a sujetos menores de 30 años, pero pueden ser mayores2. Pérdida de ins. Interprx. general, que afecta como mínimo a 3 dientes permanentes además de los 1M e incisivos.3. Se asocia frecuentemente con A.a y P. g4. Se asocia con disfunciòn neutrófilica.5. Se asocia con una baja respuesta de Ab séricos contra los patógenos6. Forma de pérdida de inserción y de hueso de naturaleza episódica.
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Periodontitis agresivas
epidemiologìa
- No hay muchos estudios al respecto de la prevalencia- Puede manifestarse en cualquier tipo de edad y de raza - Mucha variabilidad de resultados, - Prevalencia en jóvenes de 5-11 años varía entre el 0,9 y el 4,5% - prevalencia siempre menor del 1% en sujetos 13 y 20 años- El riesgo de padecer PA no parece ser heterogèno entre distintas razas- 0,2% en Caucasianos y de 2,6% en Afroamericanos entre 18 y 35 años
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RBB
“Escena de carnaval”. Autor: Pancho Fierro
Periodontitis agresivas
Patògenos orales especìficos
Reacciones defensivas del huèsped
es causado por
que inducen
Kinane & Hart 2003, Loos et al. 2005, Shapira et al. 2005
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Periodontitis agresivas
Aspectosmicrobianos
Muchas bacterias se han hallado frecuentemente en sujetos con P.A.L. (A. a. Cp; Ec, Cr.)
Se ha implicado al Aa como patògeno principal de la PA
No todas las investigaciones encuentran asociaciòn entre Aa y PA
La mera presencia de Aa no es tomada en cuenta para diferenciar entre PA y PC
A. a produce gran cantidad de factores de virulencia que pueden contribuir aldesarrollo de la PA
Prevalencia de Aa puede ser similar en PA y PC, 24% y 25%
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Kinane & Hart 2003, Loos et al. 2005, Shapira et al. 2005 RBB
Componente genètico
determina en parte
Autor: Pancho Fierro
Respuesta delhuèsped
Agresiònbacteria
na
Inflamaciòn local
Reacciòn inmune
calidad+cantidad
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RBB
Ôleo sobre lienzo: “Monasterio de Santa Catalina”Autor: Ignacio Tomaylla
Invasiòn bacteriana
Resistenciadel
huèsped1ra. Lìnea de
defensa celular
Neutròfilos
Macròfagos
Nibali, L, Parkar M, Brett P, Knight J, Tonetti MS, Griffiths GS. NADPH oxidase (CYBA) and Fc ץR polymorphisms as risk factors for aggressive periodontitis. A case-control association study. J Clin Periodontol 2006; 33: 529-539
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Acuarela: “Interior monasterio”Autor: Ignacio Tomaylla
Neutròfilos
Respuesta inflamatoria
Rol
Periodontitis de instalaciòn temprana
Investigaciones
Van Dyke TE, Serhan CN. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases,Journal of Dental Research 2003; 82: 82-90
muchas
tratan de explicar el de
los
durante la
en
las
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“Madre de Dios river”. Department of Madre de Dios -Perù
RBB
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PARTE III
RBB
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RBB
Anàlisis de la evidencia
cientìfica
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AP
Single nucleotide polymorphisms
IL
TNF alfa
Fc receptors HLA Vit D receptors
N-formilpèptide receptor
1,4,10 ganma, alfa
RBB
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ESTUDIOS QUE HAN
ENCONTRADO ASOCIACIÒN ENTRE SNP y
PA
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RBB
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El gen de la IL-10 está localizado en el cromosoma 1
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Conclusions: The polymorphisms of IL-1A +4845 and IL-1 B -511 may play an important role in determining GAgP susceptibility in Chinese males. Furthermore, a possible combined effect of the polymorphism of IL-1 B -511 and smoking on GAgP susceptibility was suggested
Association analysis between interleukin-1 family polymorphisms and generalized aggressive periodontitis in a Chinese population Author(s): Li QY, Zhao HS, Meng HX, Zhang L, Xu L, Chen ZB, Shi D, Feng XH, Zhu XL Source: JOURNAL OF PERIODONTOLOGY 75 (12): 1627-1635 DEC 2004
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RBB
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ESTUDIOS QUE NO HAN
ENCONTRADO ASOCIACIÒN ENTRE SNP y
PA
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IL1B and the IL1RN genes are located on chromosome 2. This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.
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IL1B and the IL1RN genes are located on chromosome 2. This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.
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IL1B and the IL1RN genes are located on chromosome 2. This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.
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El interferón gamma participa en la regulación de las respuestas inmune e inflamatoria. En los humanos, sólo hay un tipo de interferón gamma. Se produce en células T activadas. Human immune interferon gene is located on chromosome 12. (IL12B) is located at chromosome 5q31-33
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Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are receptors that recognize structurally conserved molecules derived from microbes. The TLR4 gene is located on chromosome 9q32-q33 .The gene for human IL-18 is located on chromosome 11q22.2-22.3 locus ID 3606
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Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are receptors that recognize structurally conserved molecules derived from microbes. The human TLR2 gene is located on chromosome 4q32
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Caspase recruitment domain family, member 15 (CARD15), which plays an important role in the immune system. It is an intracellular pattern recognition receptor,
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OPG Codificada por un gen situado en el cromosoma 8q23-24
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ESTUDIOS QUE HAN
ENCONTRADO SNP
PROTECTORES ANTE LA PA
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Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are receptors that recognize structurally conserved molecules derived from microbes.
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La ciclooxigenasa 2 (COX-2), una enzima clave en la generación de prostaglandinas proinflamatorias, como PGE2Ique ntervienen en la respuesta inflamatoria:estímulo de las terminaciones nerviosas del dolor...
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CONCLUSIONES
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Se ha demostrado la validez y la utilidad clínica de muy pocos polimorfismos para formas genéticas más complejas de la periodontitis.
Todavìa se està a cierta distancia de determinar la base genética de la PA y PC
Ha aumentado la comprensión de las pautas hereditarias de la periodontitis agresiva,
Se ha observado transmisión autosómica dominante, autosómica recesiva y dominante ligado a X; todavía NO SE ESTABLECE un único patrón.
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- El riesgo de descendientes y hermanos de pacientes afectados con PA se aproxima al 50 %.
- A medida que aumenta de forma exponencial el número de informes que describen los polimorfismos genéticos asociados con la enfermedad periodontal, se hacen más evidentes las limitaciones de dichos estudios.
- Los factores de confusión ambientales a menudo no son considerados adecuadamente
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Para efectuar pruebas de diagnóstico genético para la PC y la PA es necesario planificar cuidadosamente las investigaciones, utilizando hipótesis biológicas verosímiles, evitar el sesgo y la interpretación errónea de las asociaciones genéticas con la enfermedad.
Para comprobar tal perfil de alto riesgo de padecer una enfermedad periodontal se requiere la realización de muchas pruebas en diferentes poblaciones.
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“Choquequirau. Incas ruins”. Cuzco-Perù
Muchasgracias